TMP 922 B

1
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Matthew T. K. Kirkcaldie, School of Medicine, University of Tasmania
Contents
ko|e of the neocortex ............................................................................................. 3
Structure of neocortex ........................................................................................... 4
Layers ........................................................................................................................................ 4
Layer 1 (exLernal plexlform, molecular or superflclal) .......................................................... 3
Layer 2/3 (supragranular pyramldal) .................................................................................... 6
Layer 4 (granular) .................................................................................................................. 6
Layer 3 (deep pyramldal) ...................................................................................................... 6
Layer 6 (polymorphlc) ........................................................................................................... 7
Layer 7 (subgrlseal) ............................................................................................................... 7
Ce||u|ar const|tuents .............................................................................................. 8
neurons ..................................................................................................................................... 8
Morphologlcal classlflcaLlon ...................................................................................................... 9
Ca[al-8eLzlus neurons ......................................................................................................... 10
rlnclpal neurons ................................................................................................................ 10
yramldal cells .............................................................................................................................. 11
Splny sLellaLe cells ......................................................................................................................... 12
CLher prlnclpal neurons ................................................................................................................ 12
lnLerneurons ....................................................................................................................... 13
8askeL cells ................................................................................................................................... 14
Chandeller cells ............................................................................................................................. 14
MarLlnoLLl cells .............................................................................................................................. 13
neurogllaform ............................................................................................................................... 13
8lpolar cells ................................................................................................................................... 16
8lLufLed cells ................................................................................................................................. 16
CLher lnLerneurons ....................................................................................................................... 17
lmmunohlsLochemlcal classlflcaLlon ....................................................................................... 17
lnLerneurons ....................................................................................................................... 19
arvalbumln .................................................................................................................................. 19
CalreLlnln ....................................................................................................................................... 20
Calblndln ....................................................................................................................................... 20
SomaLosLaLln ................................................................................................................................. 21
vasoacLlve lnLesLlnal polypepLlde ................................................................................................. 21
neuropepLlde ? ............................................................................................................................. 22
Chollne aceLylLransferase ............................................................................................................. 22
CholecysLoklnln ............................................................................................................................. 22
8eelln ............................................................................................................................................ 23
Mlscellaneous proLelns ................................................................................................................. 23
Llneage classlflcaLlon ............................................................................................................... 23
lnLerneurons ....................................................................................................................... 24
MCL lnLerneurons ........................................................................................................................ 24
2
CCL lnLerneurons .......................................................................................................................... 23
LCL lnLerneurons .......................................................................................................................... 23
CA lnLerneurons ......................................................................................................................... 26
LlecLrophyslologlcal classlflcaLlon ........................................................................................... 26
luLure classlflcaLlon ................................................................................................................ 27
ChemoarchlLecLonlcs .............................................................................................................. 28
AceLylchollnesLerase ........................................................................................................... 28
nAuP dlaphorase / nlLrlc oxlde ........................................................................................ 29
Zlnc ...................................................................................................................................... 30
LxLracellular maLrlx ............................................................................................................. 31
CyLochrome oxldase and succlnaLe dehydrogenase ........................................................... 31
Clla .......................................................................................................................................... 31
8adlal glla ............................................................................................................................ 32
AsLrocyLes ........................................................................................................................... 32
CllgodendrocyLes ................................................................................................................ 33
erlneuronal saLelllLe cells .................................................................................................. 34
erlcyLes ............................................................................................................................. 34
olydendrocyLes / ollgodendrocyLe precursor cells ........................................................... 34
Mlcroglla ............................................................................................................................. 33
Iunct|on of the neocortex .................................................................................... 3S
ConnecLlvlLy ............................................................................................................................ 36
CorLlcocorLlcal ..................................................................................................................... 37
Corpus callosum ............................................................................................................................ 37
AnLerlor commlssure .................................................................................................................... 38
Clngulum and arcuaLe fasclculus .................................................................................................. 38
1halamus ............................................................................................................................. 38
1halamocorLlcal ............................................................................................................................ 38
CorLlcoLhalamlc ............................................................................................................................. 39
SLrlaLum .............................................................................................................................. 40
Amygdalar nuclel ................................................................................................................ 40
Plppocampus ...................................................................................................................... 40
ClausLrum ............................................................................................................................ 40
Mldbraln ............................................................................................................................. 41
Plndbraln ............................................................................................................................ 41
Splnal cord .......................................................................................................................... 42
Columns and modularlLy ......................................................................................................... 42
ClrculLs and processlng ........................................................................................................... 43
AfferenL processlng ............................................................................................................. 44
1halamocorLlcal ............................................................................................................................ 44
CorLlcocorLlcal ............................................................................................................................... 43
LfferenL processlng ............................................................................................................. 43
CorLlcoLhalamlc ............................................................................................................................. 46
CorLlcosLrlaLal ............................................................................................................................... 46
lnLracorLlcal processlng ...................................................................................................... 47
ModulaLory sysLems ................................................................................................................ 48
Aplcal dendrlLes .................................................................................................................. 49
neuromodulaLors ............................................................................................................... 49
AceLylchollne ................................................................................................................................ 30
noradrenallne ............................................................................................................................... 31
uopamlne ..................................................................................................................................... 31
SeroLonln ...................................................................................................................................... 32
PlsLamlne ...................................................................................................................................... 32
3
keg|ons of the neocortex ..................................................................................... S3
LsLabllshmenL of corLlcal reglons ............................................................................................ 33
CorLlcal parcellaLlon schemes ................................................................................................. 33
Speclflc corLlcal areas .............................................................................................................. 36
Stra|n var|at|on .................................................................................................... S7
Mouse-human homo|ogy ..................................................................................... S7
Acknow|edgements .............................................................................................. 60
keferences ........................................................................................................... 60

Note: Many reviews of the cerebral cortex use information derived from primates,
carnivores, rodents and other species, focusing on common traits to synthesise a
general description of the mammalian cortex. Where possible, this chapter
concentrates on studies that refer specifically to the neocortex of the mouse. Strain
differences, and the comparability of the mouse and human cortex, are also discussed.
This review is not intended as an analysis; rather, it should be used as an
introduction to the fundamentals of the neocortex and as a guide for further reading.
ko|e of the neocortex
The mouse cerebral cortex, bordered by the medial pallium (archicortex) on the
medial side, and the lateral pallium (allocortex) laterally, is dominated by a large
expanse of neocortex (~ 120 to 130 mm
2
in area, on average 112mm
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in volume;
Schz & Palm, 1989; Schz et al., 2006; Gagliani et al., 2009) derived from the dorsal
pallium of the telencephalon. The telencephalon originates as an outgrowth of the
most rostral segments of the developing nervous system (prosomeres 5 and 6; Redies
& Puelles, 2001; Monuki, Porter, & Walsh, 2001) and is the largest region to develop
independently of the segmental template that patterns most of the central nervous
system (CNS). This supplemental origin reflects the role of the cortex in the CNS as
an associative and analytical region, directing simpler systems in the rest of the
nervous system. Behaviourally, the role of the cortex is to provide sophisticated
control and integration, on the basis of an analytical overview of the interoceptive and
exteroceptive environment. A flat-map illustrating its relationship with the remaining
CNS (Fig 1) makes this role clear. The cortex does not deal directly with sensory
afferents or motor neurons, but receives pre-processed sensory information via
thalamic relays, and controls behaviour by modulating the activity of other CNS
structures. In fact, mice whose nervous systems form without functional cortical
connections are able to survive postnatally and perform basic behaviours and co-
ordinated movements (Zhou et al., 2010). Whereas the majority of the CNS is
concerned with the efficient routing and processing of sensory and motor activity, the
cortex is far more abstract. Its key function is to elaborate, integrate and analyse
sensory information in the light of past experience, as well as to plan and oversee
appropriate responses (e.g. Ferezou et al., 2007). In essence, the cerebral cortex is
characterised by its handling of high-level information.
Fig 1 Neocortex and CNS
This abstraction process is facilitated by the essentially uniform structure of the
neocortexhence its alternative name isocortex. Typically, the subcortical relay and
Figure 1: Flat map of the central nervous system.
Cerebral cortex connects to the sensory / effector trunk only through a small and defned conduit,
the cerebral peduncles and thalamocortical tracts. Adapted from Swanson (2000j.
Placement: near section Role of the neocortex.
The Mouse Nervous System: Neocortex
Figures - Matthew Kirkcaldie 2011 except as credited
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Figure 2: Layers of the mouse cerebral cortex.
Somatosensory barrel feld region (S1BF, at leftj transitioning to S1 dysgranular (S1DZ, rightj.
Coronal section, oriented so the layers run horizontally. The section is stained for Nissl substance
(cresyl violet stainj. Note the diversity of nuclear sizes and the high packing density of neurons.
lmage courtesy Dr Erika Gyengesi, NeuRA.
Placement: near section Layers.
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processing nuclei for the special senses are structurally varied, reflecting the layout
and properties of sense organs, the cortical regions for those senses are structurally
similar to each other (Douglas & Martin, 2007). The cortical sheet offers a lattice of
general-purpose processing architecture, which is adapted and modified during
development to suit particular types of analysis, an association-oriented role famously
posited by Hebb (1949). The assignment of cortical regions to particular abilities is
closely regulated by genes as well as by the developmental interactions that determine
inputs and outputs, but the system as a whole is remarkably labile and adaptable
(Kaas, 2009; Krubitzer & Hunt, 2009; OLeary & Nakagawa, 2002). In the mouse,
genetic manipulations that introduce an additional class of visual cone receptors
induce a smooth, behaviourally useful reconfiguration of the visual cortex (Jacobs et
al., 2007).
Structure of neocortex
For reviews of the basic structure of the cortex the reader is referred to Nieuwenhuys
(1994), and the definitive Cerebral Cortex series (1984 et seq.).
The neocortex consists of glia and radially extending neurons in tangential strata,
defined by their cellular composition and characteristic connectivity. In mice, layers
1, 2/3, 4, 5, and 6 are named by homology with other mammals (Ramn y Cajal,
translated in DeFelipe & Jones, 1988 ch. 23), and a thin, deep layer 7 is also present,
(Reep, 2000). These layers sit on top of a dense plexus of axons and glia referred to as
white matter (deep cortical white matter, contiguous with the corpus callosum
between the hemispheres, and the internal and external capsules converging on the
cerebral peduncles near the midbrain). Cellular morphology, layer thickness, gene
expression and the distribution of characteristic cellular markers vary between cortical
regions, often defining functional boundaries (see section below). Underlying these
variations are common qualities exhibited by all neocortical regions.
Layers
Above all, the neocortex is a layered structure (Fig 2). This organising principle
provides a scaffold that constrains the way in which neurons can connect (Douglas
& Martin, 2004, p421), maximising the connective potential of cortical circuits and
scaling efficiently with increasing size. In turn, this seems to underpin the
extraordinary adaptability and usefulness of the mammalian cerebral cortex (Kaas,
2009).
The layered structure is fundamental to the anatomy and function of the neocortex.
The neurons of each layer are born concurrently (see later section), and as a result
their gene expression and subsequent growth share key similarities (Molyneaux et al.,
2007; Watakabe et al., 2007). Recent studies utilising in situ hybridisation (ISH) and
insights from the genetic regulation of development have yielded dozens of genes
whose expression is specific to individual cortical layers or subsets of layers (for
comprehensive reviews see Molyneaux et al., 2007; Lein et al., 2007). Although the
concept of layers has proven remarkably durable since its 1868 proposal by Meynert
(Seitelberger, 1997), there are no absolute laminar boundaries within the neocortex.
Recent studies have identified gene expression patterns which subdivide or disregard
the classical layers (Molyneaux et al., 2007, 2009), and may correspond to many
reported superficial or deep sublayer characterisations.
5
The subsequent formation of connections and circuits depends on experience and
activity, but the resultant cortex retains its ingrained laminar organisation. The famous
cortical mutant reeler, in which a fundamental organising cue is disrupted and the
layers become inverted and intermixed, demonstrates that although neurons can still
connect without a coherent laminar structure, the resulting functionality is severely
compromised and not much better than lacking a cortex altogether (DArcangelo &
Curran, 1998; Zhou et al., 2010).
Figure 2 - layers
Little published data characterises glial populations by lamina (but see Takata &
Hirase, 2008; Garcia et al., 2010; Takasaki et al., 2010), and therefore the following
descriptions focus on the types and characteristics of neurons found in each layer.
When neurons are described as being located in a particular layer, this refers only to
their soma and proximal dendrites; their distal dendrites and axons often extend
across several layers and for considerable lateral distances, depending on the type of
neuron.
The neuron types mentioned in the layer descriptions are characterised in a later
section. Briefly, the neocortex is dominated by principal neurons, which are
excitatory cells with dendrites covered in spines to receive excitatory inputs, and
giving rise to axons spreading laterally and radially in the cortex. In addition to these
excitatory neurons, a diverse array of inhibitory interneurons shape and coordinate
cortical activity into complex patterns.
Layer 1 (externa| p|ex|form, mo|ecu|ar or superf|c|a|)
Layer 1, a thin plexus on the outermost rim of the cortex, lies directly below the pia
mater and the glia limitans (see below), and is almost devoid of neurons (Lorente de
N, 1922; Meller, Breipohl, & Glees, 1968a,1968b; Peters & Jones, 1984). It consists
largely of axons running across the cortical surface, sparsely distributed inhibitory
and Cajal-Retzius neurons, glia, and the apical dendrites of pyramidal neurons whose
somata lie in deeper layers (Douglas & Martin, 2004; Xu & Callaway, 2009;
Chowdhury et al., 2010; in rat: Winer & Larue, 1989; Chu, Galarreta, & Hestrin,
2003). Uniquely among cortical layers, layer 1 inhibitory interneurons outnumber
excitatory neurons (9:1 in rat: Winer & Larue, 1989) and inhibitory receptor density is
also high (in rat: de Blas, Vitorica, & Friedrich, 1989).
Layer 1 is principally a meeting ground for modulatory influences on the neurons of
deeper layers (Shlosberg et al., 2003). Many layer 2/3, 5 and 7 neurons, often
inhibitory, send axons to layer 1 to synapse on the neurons there or on apical
dendrites (Shlosberg et al., 2003; Douglas & Martin, 2007; in rat: Clancy & Cauller,
1999; Mitchell & Cauller, 2001; Rubio-Garrido et al., 2009). Extensive, diffuse
thalamic projections also pervade layer 1, modulating the arousal and attention of
large parts of the cortex (Herkenham, 1986; Llins, Leznik, & Urbano, 2002;
Monconduit & Villanueva, 2005; Theyel, Lee, & Sherman, 2010). Large-scale
midbrain catecholamine projections extend across layer 1, descending to ramify in the
infragranular layers (Lidov, Rice, & Molliver, 1978), whereas forebrain cholinergic
projections ascend through the cortex to synapse in layer 1 (Kristt et al., 1985; in rat:
Christophe et al., 2002). Dynamics in layer 1 are thought to influence fundamental
processes such as attention and plasticity (in rat: Zhu & Zhu, 2004).
6
Layer 2]3 (supragranu|ar pyram|da|)
Layer 2/3 has a varied population of neurons, predominantly small pyramidal cells,
and is chiefly involved with local and corticocortical connectivity. Compared to
primate layers 2 and 3, the mouse cortex has thinner and less differentiated
supragranular layers (Hutsler, Lee, & Porter, 2005; DeFelipe, Alonso-Nanclares, &
Arellano, 2002). Accordingly, layer 2/3 is treated as a single layer in the mouse
cortex, although there are signs of functional segregation within the layer (e.g.
Bureau, von Saint Paul, & Svoboda, 2006).
Layer 2/3 pyramidal cells project to adjacent and nearby parts of the cortex, as well as
across the corpus callosum (Wang et al., 2007; Ramos, Tam, & Brumberg, 2008;
Fame, Macdonald, & Macklis, 2011). In the motor cortex, they also drive the sub-
cortical projection neurons of layer 5 (Weiler et al., 2008; Yu et al., 2008). Among the
interneurons of layer 2/3 are the chandelier cells, which regulate pyramidal axon
firing (Woodruff et al., 2009), and basket cells, which modulate the excitability of
pyramidal cells via synapses on the soma (Czeiger & White, 1997). Both of these
interneuron types form extended networks coupled by gap junctions, enhancing
synchrony and co-ordination across large areas of layer 2/3 (Galarreta & Hestrin,
2001). Also numerous in supragranular layers are neurogliaform, bipolar, and bitufted
interneurons (Lorente de N, 1922; Xu, Roby, & Callaway, 2010; Miyoshi et al.,
2010).
Neurons of layer 2/3 are notable for the expression of Cux2 (Nieto et al., 2004;
Ferrere et al., 2006; Molyneux et al., 2007), a transcription factor which controls
dendritic branching and synapse formation (Cubelos et al., 2010), regulated by Pax6
(Georgala, Manuel, & Price, 2011).
Layer 4 (granu|ar)
In sensory regions, layer 4 is prominent, and is the principal destination for
thalamocortical fibres (Frost & Caviness, 1980). In these regions, spiny stellate cells
crowd into layer 4 (Lefort et al., 2009), forming a tightly packed band of nuclei for
which granular cortex or koniocortex is named
1
. Thalamic afferents are the most
potent extra-cortical input to layer 4 (Gil, Connors, & Amitai, 1999) and may be so
numerous as to distort the structure of layer 4. This is evident in the barrel field of
the somatosensory cortex, where dense tufts of thalamic fibres reporting individual
whisker activity push the neurons into ring-like arrangements (Lorente de N, 1922;
Woolsey & van der Loos, 1970; Frost & Caviness, 1980; Sehara et al., 2010).
In the rat somatosensory cortex, callosally projecting pyramidal cells are interleaved
with spiny stellate cells receiving thalamic projections, in contrast to the arrangement
of other projection neurons (DeFelipe & Farias, 1992; in rat: Staiger et al., 2004).
Layer 4 also contains the apical dendrites of layer 6 pyramidal neurons, enabling
rapid feedback to the thalamus (Escobar et al., 1986; Ledergerber & Larkum, 2010).
Layer S (deep pyram|da|)
Layer 5 contains the largest pyramidal neurons of the cortex (Lorente de N, 1922),
which project their axons to a variety of cortical and sub-cortical targets (Larsen,

1
Ramn y Cajal at one stage called this the layer of the medium pyramids and stated that mice lack a
granular layer (tr. DeFelipe, & Jones, 1988, p. 438), but later described granule layers in various rodent
sensory regions (ibid, ch. 23). His pupil Lorente de N (1922) identified stellate cells in murine layer 4.
7
Wickersham, & Callaway, 2009). A smaller population of corticocortical callosal
projection neurons (see below) is distributed across the entire layer (Ramos, Tam, &
Brumberg, 2008). Axons from layer 5 target various subcortical structures, including
the striatum, midbrain and pontine nuclei, the brainstem and the spinal cord (see
section below). On the basis of these projections, the layer is often subdivided into
layers 5A (corticostriatal) and 5B (corticospinal; Hersch & White, 1982; Anderson et
al., 2010). In motor and frontal regions, layer 5B can be further divided into
superficial and deep populations (Caviness, 1975; Yu et al., 2008).
Layer 6 (po|ymorph|c)
Layer 6 is also primarily an output layer, where the bulk of corticothalamic fibres
originate and receives a strong thalamic projection in return (White & Hersch, 1982;
Thomson, 2010). Specific thalamic projections from layer 6 are directed to the nuclei
sending afferents to that region, unlike layer 5, which sends non-reciprocal thalamic
projections. By influencing thalamic drive to other regions, these projections may be a
major corticocortical communication pathway in rodents (Lam & Sherman, 2010).
Layer 6 has also been found to project to adjacent and distant ipsilateral cortical
regions, as well as to local cells in other layers (Thomson, 2010) which may modulate
incoming thalamic activity (Lee & Sherman, 2009). Developmental and
morphological distinctions exist between thalamocortical projection neurons and local
corticocortical neurons (Arimatsu & Ishida, 2002; Brumberg, Hamzei-Sichani, &
Yuste, 2003; Briggs, 2010; in rat: Zhang & Deschnes, 1997). Interneurons,
principally basket cells, form an inhibitory network for layer 6 principal neurons (in
rat: Zhang & Deschnes, 1997).
Layer 6 is typically thick and often occupies a large fraction of the cortical depth in
mice. Ramn y Cajal named it the layer of the polymorphic cells (tr. DeFelipe &
Jones, 1988) for its wide range of neuron morphologies, which include inverted,
horizontal and fusiform (Lorente de N, 1922; Meller, Breipohl, & Glees, 1969;
Ferrer, Fabregues, & Condom, 1986; DeFelipe & Farias, 1992; Chen et al., 2009;
Andjelic et al., 2010; in rat: Zhang & Deschnes, 1997; Mendizabal-Zubiaga, Reblet,
& Bueno-Lopez, 2007). Although diverse, these neurons can be categorised on the
basis of projections to primary and secondary thalamic nuclei, local cortical neurons
or transcallosally (Thomson, 2010; Briggs, 2010).
Layer 7 (subgr|sea|)
Below layer 6, separated from it by a cell-poor stratum, a thin layer of subplate cells
persists in many cortical regions. In rodents, these cells have been identified as a
distinct layer 7, with specific projection targets including layer 1 and across the
corpus callosum (Reep & Goodwin, 1988; Mitchell & Macklis, 2005; in rat: Mitchell
& Cauller, 2001), properties which are quite distinct from layer 6 (Staiger, 2010).
This layer is less known because it is named inconsistently in the literature: upper
subplate neurons, border neurons, the deep cortical band, deep/lower layer 6, layer 6b
and subgriseal neurons (Ferrer, Fabregues and Condom, 1986; Clancy & Cauller,
1999; Chen et al., 2009).
In mice, the rostral lateral edge of layer 7 merges with the claustrum, although in
other species these structures are distinct (Reep, 2000). In mice, connective tissue
growth factor is selectively expressed by a subset of neurons of layer 7 and the dorsal
endopiriform nucleus, but not in the claustrum (Heuer et al., 2003).
8
Ce||u|ar const|tuents
The mature mouse cortex consists of approximately 14 million neurons and 12
million glia (Herculano-Houzel et al., 2006)
2
. Beyond sheer numbers, the diversity of
neuronal phenotypes in the mammalian cerebral cortex is unmatched in any other
region of the nervous system, or has at least been better characterised and described.
Santiago Ramn y Cajals student Rafael Lorente de N made a point of
demonstrating that the mouse cortex exhibits a highly complex texture
comparable to that of the higher mammals and even to the human (1992, p35;
Woolsey, 2001) as well as a wide array of neuron morphology (Lorente de N, 1922,
1992). However, Ramn y Cajal felt otherwise, and opined that anatomical
degradation or simplification begins especially in the rodents (tr. DeFelipe & Jones,
1988, p437). While the human cortex is undoubtedly more complex in overall
structure and neuron diversity (Jones, 2009; Fame, MacDonald, & Macklis, 2011), the
cells of the mouse neocortex have merited a century of intensive study and
characterisation, not least by Ramn y Cajal himself.
Neurons
In the mammalian cerebral cortex, neurons assume a dazzling variety of shapes and
spatial arrangements. This extreme diversity has generated more than a centurys
worth of observation and inference. A principal goal has been neuron classification, to
make cortical complexity more manageable, and to allow generalisation from studies
of single neurons to entire populations (DeFelipe, 2002). These efforts have
succeeded to varying degrees, although the conclusions drawn are often strongly
influenced by the techniques chosen. Classically, neurons of the neocortex were
characterised using Golgi impregnation and morphology (Lorente de N, 1922; Peters
& Jones, 1984; DeFelipe & Jones, 1988; White, 1989). In more recent decades,
immunohistochemical studies of the cortex have showed that interneurons, in
particular, express a range of proteins which correlate with morphology and
electrophysiology. These combine with connectivity and gene expression to permit
multidimensional characterisation of neuron phenotypes (DeFelipe, 1993; Cauli et al.,
1997; Hill, Kalloniatis, & Tan, 2001; Markram et al., 2004; Gonchar, Wang, &
Burkhalter, 2007; Miyoshi et al., 2010).
In recent years, new classification tools have been provided by genetic techniques
including developmental fate mapping, gene expression repertoires and transcriptional
regulation (Lein et al., 2007; Sugino et al., 2006). They have yielded startling insights
into the array of cortical interneurons (Xu, de la Cruz, & Anderson, 2003; Fishell,
2007; Butt et al., 2005; Miyoshi et al., 2010) and subgroups of principal neurons,
which are the most numerous and least heterogeneous of the recognised types (but see
Molnr & Cheung, 2006; Molyneaux et al., 2007; Fishell & Hanashima, 2008).
The relationship between morphological, immunohistochemical and lineage-based
neuron typologies is elusive, and they correlate only partially with functional and
physiological data (Markram et al., 2004). All are in current use, and therefore are
presented side by side instead of attempting an unsatisfactory reconciliation. Since
these phenotypes appear to be at least partially influenced by local cues (Fishell,
2007), it seems likely that no definitive typology exists, and that within broad lineage

2
These direct counts contradict the historical dogma of glia greatly outnumbering neurons (e.g.
Nishiyama, Yang, & Butt, 2005), but they are much easier to reconcile with observations of single
astrocytes that occupy cortical domains encompassing dozens of neurons (Halassa et al., 2007).
9
classes, interneurons should be clustered on the basis of multiple features (Petilla
group, 2008); whether such clusters correspond to fundamental types, or represent
typical developmental outcomes, is perhaps a moot point.
All of these typologies respect three fundamental groupings, the first being the
developmentally early Cajal-Retzius neurons. Then there are the excitatory or
principal neurons, which send axons and collaterals locally, across the cortex and to
other parts of the CNS. Finally, the inhibitory interneurons generally participate in
local circuits, rarely projecting their axons for long distances. This distinction
between excitation and inhibition usually refers to two specific neurotransmitter
typesglutamate / aspartate for excitation, and !-aminobutyric acid (GABA) for
inhibition. Combined, they account for the bulk of synaptic transmission in the cortex
(Peters & Jones, 1984; White, 1989; Nieuwenhuys, 1994). A subset of cortical
neurons use other neurotransmitters instead of, or in conjunction with, these major
transmitters.
The cortex needs a balance between excitation and inhibition, however there are far
more principal neurons than interneurons in all layers apart from layer 1, where 90%
of neurons are inhibitory (in rat: Winer & Larue, 1989). There is evidence that
regulatory mechanisms adjust the growth and innervation density of interneurons to
match the principal neurons (Alpr et al, 2004).
Morpho|og|ca| c|ass|f|cat|on
For a comprehensive overview of morphological neuron types, the reader is referred
to volume 1 of Peters and Jones Cerebral Cortex (1984).
The modern era of attempts to understand the workings of the cerebral cortex began
in the late nineteenth century, with Ramn y Cajals refinement of Golgi
impregnation techniques and his subsequent peerless descriptions (tr. DeFelipe &
Jones, 1988). His careful delineations of the forms and arrangements of cortical cells
were later compounded and expanded by Lorente de N among a series of superb
anatomists and histologists (reviewed in Peters & Jones, 1984; White, 1989;
Nieuwenhuys, 1994). The extraordinary and detailed morphologies revealed by Golgi
impregnation are powerfully suggestive of specialised function, and it has long been
hoped that careful and comprehensive descriptions of these forms will enable cortical
functions to be characterised (e.g. Markram, 2006). In particular, identifying neurons
with characteristic dendrite shapes and specific axon terminations suggests which
inputs they utilise, and how they distribute their responses. Much of the detail of these
interrelationships was painstakingly pieced together by studies using electron
microscopy (Peters & Jones, 1984; White, 1989) and many of the following
descriptions refer to such studies. Ultrastructurally, excitatory and inhibitory synapses
are distinguished by the shape of presynaptic vesicles and the thickness of the density
on the pre- and postsynaptic membranes. Inhibitory synapses have flattened vesicles
and symmetric densities, whereas excitatory synapses have round vesicles and an
asymmetric appearance due to their thick postsynaptic density (White, 1989; Knott et
al., 2002).
The frustration experienced in dealing with cortical neurons on the basis of
morphology alone is expressed in the remark by Fairn, DeFelipe and Regidor that
even after more than a century of possessing suitable methods to reveal the forms of
neurons, morphological criteria to define neuronal groups are not established (1984,
p243). As Nieuwenhuys (1994) observes, the task is ultimately impossible, since the
10
tailored modification of neuron structure is an essential underpinning of cortical
maturation and function. Despite this limitation, the major forms identified by
morphology remain in current use providing a useful basis and comparison for other
typologies.
Ca[a|-ketz|us neurons
Cajal-Retzius (C-R) neurons are restricted to layer 1, where their axons descend
toward the boundary with layer 2 and make extensive tangential ramifications with
numerous ascending processes (DeFelipe & Jones, 1988; Soriano & Del Ro, 2005).
These neurons are principally involved in developmental processes, secreting reelin to
structure the growing cortex (Mienville, 1999; Nishikawa et al., 2002; Soriano & Del
Ro, 2005). Around 97% die in later development (Chowdhury et al., 2010). Their
adult distribution is irregular, tending to concentrate in the primary motor and sensory
regions (Bielle et al., 2005). C-R neurons receive axodendritic and axosomatic
synapses from Martinotti neurons, ascending fibres which terminate in layer 1,
inhibitory interneurons of layer 1, and from the widespread thalamocortical and
monoaminergic fibre plexuses on the pial surface of the cortex. C-R neurons also
make excitatory synapses with pyramidal neuron apical dendrites (DeFelipe & Jones,
1988; Ina et al., 2007; Kirmse et al., 2007; in rat: Chu, Galarreta, & Hestrin, 2003),
and may organise the latters structure during development (Nishikawa et al., 2002).
r|nc|pa| neurons
For a comprehensive review of classical and ultrastructural studies of pyramidal
neurons the reader is referred to DeFelipe and Farias (1992).
Principal neurons constitute 62 to 85% of all neocortical neurons, and are abundant
throughout all regions and layers except layer 1 (DeFelipe & Farias, 1992), although
Cajal-Retzius neurons may be considered principal cells because of their excitatory
nature (Kirmse et al., 2007). In addition to their local connectivity, principal neurons
are the dominant projection cells of the cortex. They send axons down through
inferior layers to the deep cortical white matter, which continue to other parts of the
cortex or the CNS. These axons supply excitatory synapses, using either glutamate,
aspartate or quite often both (rat: Giuffrida & Rustioni, 1989; DeFelipe & Farias,
1992). A small proportion of projections come from GABAergic neurons (Tomioka et
al., 2005), but their non-spinous dendrites and lack of excitatory transmission
disqualify them as principal neurons.
The dendritic field, 90 to 95% of the receptive surface of principal neurons, receives
inputs from a wide variety of sources that are local, corticocortical and subcortical in
origin. Most synapses onto the dendrites are excitatory (75 to 95%; DeFelipe &
Farias, 1992) and are concentrated on spines, which are short cytoplasmic structures
extending 1 to 2 "m from dendrites (White, 1989; DeFelipe & Farias, 1992; Knott et
al., 2002; Benavides-Piccione et al., 2002; Ballesteros-Yez et al., 2006; Spruston,
2008). Spines develop in response to repeated synaptic stimulation and represent
established synaptic pathways (Trachtenberg et al., 2002; in rodents: Mller &
Connor, 1991; Maletic-Savatic, Malinow, & Svoboda, 1999). These pathways may be
altered by experience but can persist for long periods (Xu et al., 2009). Dendritic
shafts receive fewer, mostly inhibitory, synapses from local interneurons (Feldman,
1984; White, 1989; Knott et al., 2002).
Figure 3: Pyramidal cells of mouse neocortex.
Note apical dendrites with terminal tuft near layer 1,
basal dendrites projecting laterally from cell bodies,
and axons descending radially. Spines can be seen
on many of the dendrites. The image has been level
inverted to show detail, and shows region S1Tr
from layer 1 to layer 6; most of the cell bodies are
in superfcial layer 5. A subset of layer 5 pyramidal
neurons are labelled in this thy1-GFP-M transgenic
mouse (Feng et al., 2000j. Section courtesy Stan
Mitew, Menzies Research lnstitute.
Placement: near section Morphological classifcation / Principal
neurons / Pyramidal cells.
1
2/3
4
5
6
Martinotti
neurogliaform
bipolar
bitufted
multipolar
bipolar
basket
(largej
100 m
chandelier
basket
(nestj
Figure 4: Interneurons.
Representative morphologies of mouse interneu-
ron types. Note that the axon (redj and dendrite
(bluej arbors are typically less elaborate than in
primate cortex. Two variants of bipolar cells and
basket cells (large and nestj are shown. lndividual
cell types adapted from original fgures: chande-
lier cell (Woodruff et al., 2009j; bipolar and basket
cells (Miyoshi et al., 2007j; bitufted, multipolar, and
neurogliaform cells (Miyoshi et al., 2010j; Martinotti
cell (Goldberg, Lacefeld, & Yuste, 2004j.
Placement: near section Morphological classifcation / lnterneurons.
11
Unlike dendritic inputs, virtually all synapses on the soma and the axon initial
segment of principal neurons are formed by terminals containing GABA as well as a
variety of peptides (White, 1989; DeFelipe & Farias, 1992; Spruston, 2008).
However, due to variations in the transmembrane chloride gradient, these synapses
may not always be inhibitory (Woodruff et al., 2009; in rat: Szabadics et al., 2006).
Basket cells and other interneurons provide many of the somatic synapses. Chandelier
cells make chains of GABAergic boutons along the axon initial segments of principal
neurons in layers 2/3 and 5 (Peters, 1984; Tams et al., 2000; in rat: Szabadics et al.,
2006). In addition to input from other sources, some principal neurons also
spontaneously generate activity (MacLean et al., 2005; Le Bon-Jego & Yuste, 2007).
Principal neurons have a continuum of forms, from the fully developed pyramidal cell
through intermediates and variations such as the star pyramid and the polymorphic
cells of layer 6, to the small spiny stellate cells of layer 4 (DeFelipe & Jones, 1988;
DeFelipe & Farias, 1992). These morphological characteristics vary systematically
with cortical regions (Benavides-Piccione et al., 2006) as well as with the physiology
and projection targets of the neurons (Akemann et al., 2004; Christophe et al., 2005;
Larsen, Wickersham, & Callaway, 2007). The net result is a diverse population of
excitatory neurons, which receive specific mixes of the available inputs (in rat:
Dantzker & Callaway, 2000) and project qualitatively distinct derivatives of that
activity to specific targets.
!"#$%&'$( *+((,
Fig 3 Pyramidal cells
The form and size of pyramidal cells varies widely throughout cortical regions and
layers (Feldman, 1984; Hevner et al., 2003; Benavides-Piccione et al., 2006;
Spruston, 2008), but they are morphologically consistent. Cells of this type are
usually identified by a pyramidal or ovoid soma in layers 2/3 to upper 6, as well as a
prominent ascending apical dendrite and several basal dendrites (Fig 3). They
typically have an axon arising from the base of the soma or a basal dendrite,
descending through and extending out of the cortex, and spines on all but the
proximal parts of dendrites (DeFelipe & Farias, 1992; Spruston, 2008). However,
none of these qualities are ubiquitous (Nieuwenhuys, 1994).
The apical dendrite often reaches layer 1, although in the mouse cortex they
frequently do not, terminating instead in layer 2/3 or layer 4 for the deepest pyramidal
neurons (Lorente de N, 1922; DeFelipe & Farias, 1992; Tsiola et al., 2003; Ramos,
Tam, & Brumberg, 2008; Ledergerber & Larkum, 2010). At its tip, the apical dendrite
may ramify into a dense tuft of collaterals, depending on the projection type made by
the neuron (Spruston, 2008; see Molnr & Cheung, 2006). These general
characteristics do not always apply, as layer 5 pyramidal cells exhibit a variety of
forms (Tsiola et al., 2003; Akemann et al., 2004) and layer 6 apical dendrites may not
always ascend (DeFelipe & Farias, 1992; Chen et al., 2009).
The axons of pyramidal cells are principally descending (projecting away from the
pial surface), and many leave the cortex for targets in other cortical or subcortical
regions, although some travel long distances within the grey matter (Feldman, 1984).
Accordingly, pyramidal neurons may be classified by their projection targets. These
targets may be commissural in nature, i.e. across the corpus callosum, with or without
striatal or ipsilateral frontal projection. Subcortical projections are called corticofugal,
and target either the thalamus or structures further down the neuraxis (corticotectal,
corticopontine, or corticospinal; Molyneux et al., 2007). However, nearly all
12
pyramidal neurons also give rise to collateral branches that make synapses with
nearby cortical neurons (DeFelipe & Farias, 1992; Schz et al., 2006). Proximal
collaterals ascend, forming a plexus of processes and terminals around their origin
and in more superficial layers, extending tangentially for long distances within the
cortex (Feldman, 1984; Schz et al., 2006). Their primary cortical targets are
dendritic spines, though non-spiny cells are also innervated (White, 1989).
Among mouse pyramidal neurons, morphological varieties have been recognised
since Ramn y Cajal (tr. DeFelipe & Jones, 1988, ch. 23) and Lorente de N (1922).
More recently, subtypes have been identified using dendrite and axon analysis
(Larsen & Callaway, 2006), cluster analysis of dendrite trees (Tsiola et al., 2003) and
by correlation with projection targets (Larsen, Wickersham, & Callaway, 2007).
-.&/" ,0+(($0+ *+((,
Spiny stellate cells resemble pyramidal cells, although they lose their apical dendrites
as they mature (Peinado & Katz, 1990; DeFelipe & Farias, 1992; Nieuwenhuys,
1994). Their electrophysiological qualities also overlap with layer 2/3 pyramidal cells
(Andjelic et al., 2009).
Spiny stellate cell distribution is limited to layer 4 of primary sensory regions (visual,
auditory and somatosensory), and some associated secondary regions. Their nuclei
pack together to form a granular layer seen in Nissl stains (White, 1989), and form
the characteristic barrel shapes observed in the primary somatosensory barrel field
(S1BF) (Lorente de N, 1922, 1992; White, 1989). Granular layers often contain few
neurons of other types, although not all granular layers are spiny stellate cells (Lund,
1984; Lefort et al., 2009). In areas where these cells are numerous, thalamocortical
axons terminate predominantly in layer 4 to preferentially innervate them (White,
1989) and other spiny neurons there (in rat: Staiger et al., 2004). However, for
individual spiny stellate cells, the actual proportion of thalamocortical inputs is only
around 10 to 20%, which is less than inputs from layer 6 pyramidal cells and other
spiny stellate neurons (Benshalom & White, 1986; in cat: Ahmed et al., 1997); in fact,
interneurons are far more reliably activated by thalamocortical activity (Porter,
Johnson, & Agmon, 2001). The observed pattern of synaptic distribution resembles
that for pyramidal cells, except that excitatory synapses are rarely seen on dendritic
shafts (Benshalom & White, 1986; Knott et al., 2002). Spiny stellate dendritic fields
vary, some stratifying tangentially, and others ascending or descending radially for
one layer, under the strong developmental influence of thalamic innervation
(Guellmar, Rudolph, & Bolz, 2009). Their axons nearly always emerge from the
descending side of the soma, but often recurve and ascend with arc-like collaterals,
first noticed by Ramn y Cajal (tr. DeFelipe & Jones, 1988; in rat: Staiger et al.,
2004) to target more superficial layers (e.g. Lefort et al., 2009). The axon initial
segment is generally free of synapses (Lund, 1984). These axons are primarily local
(limited to layers 2/3, 4 and 5; Lund, 1984) and form excitatory synapses (DeFelipe,
1997) with dendrite spines and shafts of principal neurons and interneurons (White,
1989).
102+# .#&/*&.$( /+3#4/,
Other spiny, non-pyramidal forms of these cells have been described in the neocortex
of mice. Staiger and colleagues (2004) describe a range of spiny layer 4 cells
including star pyramids, an intermediate form between pyramidal and spiny stellate
cells. In the general class of pyramidal cells, DeFelipe and Farias (1992) include
layer 5 cells with multiple apical dendrites, layer 2/3 cells without apical dendrites,
13
layer 5 and 6 cells with horizontal or inverted apical dendrites, as well as layer 5 and
6 horizontal and vertical fusiform spiny neurons. These are apparent in deeper layers
of mouse cortex (Ferrer, Fabregues, & Condom, 1986). Layers 6 and 7, in particular,
have a large proportion of excitatory spinous neurons whose morphology is unlike the
normal pyramidal form (Andjelic et al., 2009; Chen et al., 2009; in rat: Zhang &
Deschnes, 1997; Mendizabal-Zubiaga, Reblet, & Bueno-Lopez, 2007), but which
make corticocortical projections (Brumberg, Hamzei-Sichani, & Yuste, 2003).
Interneurons
Complementing the excitatory activity of principal neurons, interneurons are
distributed across all layers of the mouse neocortex, giving rise to axon terminals that
densely innervate both principal neurons and interneurons (Solberg, White, & Keller,
1988). Since spiny stellate neurons have been discussed as a subtype of pyramidal
neurons, the term interneuron is used here to refer to interneurons lacking spines.
Most of these aspinous interneurons, termed neurons with short axons by Ramn y
Cajal, have axons that ramify locally rather than projecting away from their cortical
region. Most also use GABA as a neurotransmitter, although this should not be
considered a purely inhibitory role since GABA can sometimes depolarise (Huang, Di
Cristo, & Ango, 2007; Woodruff et al., 2009). Many of these interneurons also make
dendrite-to-dendrite connections between neurons of the same type, mediated by gap
junctions rather than chemical synapses. These form spatially extended networks,
which tend to synchronise and interact with afferent activity (Deans et al., 2001;
Galarreta & Hestrin, 2001; in rat: Gibson, Beierlein, & Connors, 2005; Sun, 2009).
Most of the variety in cortical neuron types is seen among interneurons, although they
are numerically a minority (DeFelipe & Jones, 1988). The range of morphologies,
physiological properties and innervation targets of these interneurons powerfully
shapes the response properties of the cortex, allowing incoming activity to evoke
diverse responses for use in cortical processing (White, Benshalom, & Hersch, 1984;
Gupta, Wang, & Markram, 2000; Blatow, Caputi, & Monyer, 2005; Huang, Di Cristo,
& Ango, 2007).
In functional terms, interneurons are activated and inhibited by many of the same
types of innervation received by pyramidal cells, although subtypes receive distinct
mixes of inputs (Xu & Callaway, 2009). On the postsynaptic side, there are
systematic differences in interneuron receptor properties. For example, interneuron
AMPA receptors have a characteristic subunit makeup (in rat: Kondo et al., 2000) and
are typically less calcium-permeant than those of pyramidal neurons (reviewed by
Blatow, Caputi, & Monyer, 2005).
Since dendrite arbours can vary widely, and only suggest the influences on a given
cell, most classifications distinguish interneurons on the basis of axon distribution
(Markram et al., 2004). Exuberant connectivity in cortical grey matter ensures that
interneurons will be included in the activity of their local region. Each interneuron
transforms this activity into a characteristic derivative firing pattern, and delivers that
pattern to carefully selected targets. The axons of interneurons are far more
convoluted and torturous than the relatively straight branches of pyramidal axons,
making direct, targeted contacts rather than spine-mediated plug in connections
typical of excitatory communication (Huang, Di Cristo, & Ango, 2007). Axon-based
classification therefore groups interneurons by the types of targets they select and by
implication, which is the type of modulation they exert on neurons in their vicinity (in
rat: Karube, Kubota, & Kawaguchi, 2004).
14
Fig 4 - Interneurons
5$,6+0 *+((,
Basket cells are the most common interneuron (Markram et al., 2004; Fishell, 2007).
They are usually large-bodied cells, although nest and small subtypes have been
identified (in rat: Wang et al., 2002; Fig 4). They are found in layers 2/3 to 6, and the
proportion of subtypes varies (White, 1989; Markram et al., 2004). Basket cells have
four to ten sparsely-spinous dendrites that spread radially and tangentially for
millimetres, extending through all cortical layers in some cases (Jones & Hendry,
1984; Markram et al., 2004). Some evidence suggests that basket cell axons are at
least partially myelinated in adults (Keller & White, 1987; in rat: Peters & Proskauer,
1980). From the pial side of the soma these axons ascend or descend, to give off long
horizontal collaterals, which in turn sprout small branches ending in dense tufts of
terminals (Nieuwenhuys, 1994). They may also form plexuses in superficial layers
(Ichinohe et al., 2003). These axons may terminate on dendrites and spines, but
specifically target the somata of excitatory neurons, where, along with other cells,
they envelop pyramidal cell bodies in dense complexes resembling baskets (Jones &
Hendry, 1984; Czeiger & White, 1997). In rodents, the terminals of individual basket
cells are not basket-like, since many cells contribute to each basket, and only a
minority of axosomatic synapses come from basket cells (White, 1989; Czeiger &
White, 1997).
Basket cell function is well characterised, due to their readily recognisable chemical
phenotype (see below) and synaptic targets. Pericellular axon terminals and fast-
spiking behaviour (Blatow et al., 2003) are a powerful inhibitory influence on
pyramidal neurons (White, 1989), particularly in depressing the excitation from
axospinous synapses (Galarreta & Hestrin, 1998). Basket cell dendrites receive many
asymmetric and symmetric synapses, both thalamocortical and corticocortical (Jones
& Hendry, 1984). In addition, large networks of basket cells are mutually
interconnected via gap junctions and GABAergic synapses, leading to frequency-
specific spreading activity through large networks of these neurons in layer 2/3 and
layer 5 (Deans et al., 2001; Meyer et al., 2002; in rat: Tams et al., 2000; Szabadics,
Lorincz, & Tams, 2001; see Peinado, Yuste, & Katz, 1993; Galarreta & Hestrin,
2001). The strong innervation of basket cells from extrinsic afferents suggests they
are coactivated with the pyramidal cells receiving these inputs (White & Keller,
1987). Basket cell responses then interact with the evoked activity, providing
synchronised modulation of incoming excitation (Beierlein et al., 2002).
72$/'+(&+# *+((,
Chandelier cells were the only major short-axon type not observed by Ramn y Cajal
(tr. DeFelipe & Jones, 1988). They are rare but widespread in the rodent cortex,
usually being found in layer 2/3 (Woodruff et al., 2009; White, 1989; in rat: Zhu,
Stornetta, & Zhu, 2004). Their cell bodies are generally small and round, and their
dendritic arbours vary considerably between multipolar and bitufted morphology.
These dendrites have few spines and can extend to encompass layers 1 to 4. They
appear not to receive the initial excitation accompanying sensory events, but are
activated by other local activity (in rat: Zhu, Stornetta, & Zhu, 2004). Chandelier cell
axons originate on the lower side of the cell body, and may ascend or descend; their
collaterals form a profuse plexus of varying shape, typically confined to layer 2/3
(Peters, 1984; Woodruff et al., 2009; Fig 4).
15
Chandelier cells make highly specialised synapses with the axon initial segments of
pyramidal neurons in layer 2/3, wrapping them with candle-shaped synaptic
cartridges that give the cell its name (Peters, 1984; in rat: Kawaguchi, 1995). These
terminals are GABAergic (White, 1989; Woodruff et al., 2009) but chloride gradients
vary at the axon initial segment, meaning that GABA release may either inhibit or
depolarise these axons, yielding complex dynamics (Szabadics et al., 2006; Woodruff
et al., 2009; in rat: Zhu, Stornetta, & Zhu, 2004). Most chandelier cells fire fast bursts
of action potentials when active (in rat: Kawaguchi, 1995).
8$#0&/400& *+((,
Early Golgi studies of the mouse cortex identified large, nonspiny neurons, called
Martinotti cells by Ramn y Cajal (DeFelipe & Jones, 1988), in deep cortical layers.
They are found across layers 2/3 to 6 (Ferrer, Fabregues, & Condom, 1986; Markram
et al., 2004; Xu & Callaway, 2009) and send long axons up to layer 1 (Lorente de N,
1922). Their dendrites radiate in a multipolar or bitufted pattern, often favouring the
descending side (McGarry et al., 2010), and receive much stronger inputs from
neurons in layers 2/3 and 4 than from deeper layers (Xu & Callaway, 2009).
Martinotti cells are both rapidly responsive to incoming activity (Fanselow,
Richardson, & Connors, 2008) and spontaneously active (Le Bon-Jego & Yuste,
2007); they are also linked together in a gap-junction coupled network like the basket
and chandelier cells (Fanselow, Richardson, & Connors, 2008). Their axons ascend
directly from the superficial side of the soma, travel upward without branching and
form a fan-like plexus or horizontal ramification in layer 1, which may extend 1000
"m (Ferrer, Fabregues, & Condom, 1986). These ramifications contact spines, which
are most likely the axon tufts of pyramidal cells and Cajal-Retzius neurons, not the
numerous inhibitory neurons of this layer (Shlosberg et al., 2003).
Many studies of Martinotti cells have identified their expression of somatostatin
(SOM; Markram et al., 2004) as a characteristic marker, however significant non-
Martinotti populations have been described in the brains of mice expressing green
fluorescent protein (GFP) in SOM interneurons (Ma et al., 2006; McGarry et al.,
2010). One of these mouse lines was used to identify Martinotti neurons which also
express calretinin (Xu, Roby, & Callaway, 2006; Xu & Callaway, 2009) with
differences in axon structure and proportions of supragranular inputs.
9+3#4:(&$;4#%
Neurogliaform (or spiderweb) cells were identified among the short-axon cells by
Ramn y Cajal (tr. DeFelipe & Jones, 1988) and Lorente de N (1922). They occur
across all layers but concentrate superficially (Miyoshi et al., 2010) and predominate
in layer 1 (in rat: Hestrin & Armstrong, 1996). Their dendrite and axon fields overlap
to some extent: the dendrites receive excitation from layers 2/3 to 5 and local
inhibition; their axons are finely branched, thin fibres that inhibit nearby dendrites
(Markram et al., 2004; Xu & Callaway, 2009). In the neocortex and hippocampus,
neurogliaform interneurons are identifiable by their expression of the actin binding
protein #-actinin-2 (in rat: Uematsu et al., 2008). Neurogliaform cells exhibit
characteristic late-spiking activity (Miyoshi et al., 2010), and have been identified as a
specific source of slow inhibition, innervating synapses rich in GABA
B
receptors
(Tams et al., 2003).
16
5&.4($# *+((,
Aside from the forms already described, many of the remaining interneurons are
named on the basis of radially oriented dendrite fields growing above and below the
cell body. They have been classed as bitufted, bipolar and double-bouquet in
descriptions of the neocortex of various species. Unfortunately, these terms can be
quite loosely defined, leading to confusion and contradictionfor example,
Kawaguchi and Kubota (1997) disagree with Ballesteros-Yez and colleagues
(2005) on whether double bouquet cells exist in rodents. Many authors define criteria
for bitufted and bipolar cells, but the most common distinction is that bipolar cells
have a principal dendrite ascending and one descending from the cell body, which
begin to branch some distance from the soma.
Bipolar cells are particularly common in rodent brains (DeFelipe, 2002), and appear
to be evenly distributed in the cortex, so that no regions larger than 100"m across lack
them, and each has its own columnar domain 30"m across on average (in rat:
Morrison et al., 1984). Their cell bodies are found in layers 2/3 to 6 but the specific
distribution varies between regions (Peters, 1984b; Xu, Roby, & Callaway, 2010).
Bipolar cells have two principal dendrites extending radially from the upper and
lower poles of the small, ovoid soma. These dendrites have few spines, and branching
in narrow fields that span up to five layers. Bipolar cells are distinguished from
bitufted cells by the long, unbranched, proximal portions of their principal dendrites
and the simplicity of the axonal plexus (Markram et al., 2004). The somata, but
particularly the dendrites receive symmetric and asymmetric synapses, including
thalamocortical synapses (White, 1989) and synapses from basket cells (in rat: Peters,
1984b). Bipolar cell axons synapse on the spines of principal neurons (DeFelipe &
Farias, 1992), as well as interneuron dendrites and bodies. Axonal branches may run
parallel to the apical dendrite of a pyramidal cell, forming a chain of boutons (Peters,
1984b).
Although morphologically distinctive, the bipolar cell population encompasses
subgroups with fundamentally different physiology. Bipolar cells are heterogeneous
in transmitter use: although they often express vasoactive intestinal polypeptide
(VIP), some of them use it as an excitatory transmitter, whereas others use GABA (cf.
Peters, 1990; DeFelipe, 1993; Markram et al., 2004); some may also use acetylcholine
(ACh; in rat: Bayraktar et al., 1997).
5&03;0+' *+((,
Bitufted interneurons are widespread in the cortex, having their small, ovoid cell
bodies in layer 2/3 or 4 (Lorente de N, 1922,1992; review by Somogyi & Cowey,
1984). They are characterised by having tufts of dendrites extending from two
opposite poles of the soma, which receive corticocortical and thalamocortical
synapses (Keller & White, 1987). Bitufted cell axons form a plexus which spreads
widely (Markram et al., 2004), usually descending, and more diffuse in mice than in
primates (Somogyi & Cowey, 1984; Fig 4). They may also be myelinated in some
cases (Keller & White, 1987; in rat: Peters & Proskauer, 1980).
Mouse data on bitufted cells are scarce, but in other mammals the axons of these cells
make relatively infrequent symmetric synapses mostly on dendritic shafts, with a
small proportion on spines and on the somata of nonpyramidal cells (Somogyi &
Cowey, 1984; DeFelipe, 1997; Markram et al., 2004).
17
102+# &/0+#/+3#4/,
Although the literature focuses on more recognised interneuron phenotypes, a
substantial proportion remain unclassified or incompletely characterised (see for
example Fig 7). Interneurons in layer 1 have varied morphologies, form a gap-
junction-coupled network across the layer, and provide inhibitory inputs to the apical
dendrites of pyramidal neurons (in rat: Christophe et al., 2002; Chu, Galarreta, &
Hestrin, 2003; Wozny & Williams, 2011). Transgenic animals expressing GFP under
interneuron-specific promoters have allowed targeted recording and cell filling in
cortical slices, yielding previously unknown physiological and morphological
variations, such as non-Martinotti somatostatin-expressing neurons (Ma et al., 2006;
McGarry et al., 2010), parvalbumin-expressing multipolar bursting cells (Blatow et
al., 2003) and multipolar calretinin neurons with wide tangential dendrite and axon
fields (Caputi et al., 2009).
Many other aspinous or sparsely spinous neurons are found in all cortical layers, Most
have small, local axon plexuses which overlap with their dendritic fields. They can be
named in accordance with the form of the dendritic field (e.g. horizontal) or of the
axon plexus (e.g. arcade cells, superficial plexus cells; overview by DeFelipe, 2002).
At a less specific level of description, a range of general terms (such as multipolar)
are used by authors reporting data from incompletely characterised cells. These
neurons form GABAergic synapses with a variety of elements, including somata and
dendrite shafts of pyramidal and nonpyramidal cells, and axon initial segments
(White, 1989; DeFelipe, 1997).
In parallel to the standard Golgi-based morphological classifications presented here,
Cobas and colleagues (1987) made a comprehensive survey of neurons
immunolabelled for glutamic acid decarboxylase (GAD, the enzyme which
synthesises GABA) in the mouse barrel cortex. Due to the staining pattern of the
GAD antibody, their classification was based on the soma and proximal dendrites,
and yielded eight archetypes with an uncertain relationship to the axon-based or
ontological classifications (Cobas & Fairn, 1988), but which resemble the somatic
descriptions used by the Petilla terminology (Petilla Interneuron Nomenclature
Group, 2008).
Immunoh|stochem|ca| c|ass|f|cat|on
For thorough overviews of immunohistochemically defined interneuron types the
reader is referred to DeFelipe (1993, 1997), Huang, Di Cristo and Ango (2007) and
Markram and colleagues (2004).
Since the 1980s, immunohistochemical (IHC) labelling has demonstrated a diverse
and heterogeneous array of cellular protein expression in the neocortex. Studies
attempting to classify subpopulations of cortical neurons have focused on several
calcium binding proteinsparvalbumin (PV), calbindin D28k (CB) and calretinin
(CR)and the peptides somatostatin (SOM), vasointestinal polypeptide (VIP),
neuropeptide Y (NPY), and cholecystokinin (CCK; Xu, Roby, & Callaway, 2010;
DeFelipe, 1997). In addition to their utility as type-specific markers, these protein
markers give functional clues to the activity of the neurons which express them; most
notably, the calcium binding proteins are thought to manage calcium levels during
bursts of intense activity (e.g. Aponte, Bischofberger, & Jonas, 2008) and correlate
with physiological parameters (in rat: Kawaguchi & Kubota, 1997). Single-cell RT-
PCR from electrically characterised rat interneurons has yielded co-expression
18
analyses which link PV, CB and CR with distinct sets of ion channels, suggesting a
biophysical underpinning for this correlation (in rat: Toledo-Rodriguez et al., 2004).
More recently, genetic manipulation techniques have enabled reporter constructs to be
added to the sequences that make up these proteins, or, more commonly, to be driven
by the same promoters and hence expressed in tandem with them (e.g. Meyer et al.,
2002). The fact that the correlations between interneuron morphology and the
expression of various proteins are only partial has complicated and frustrated
classification attempts in the last few decades (Markram et al., 2004; Fishell, 2007;
Petilla group, 2008).
The lack of clear-cut relationships between IHC markers, physiology, and
morphology has led an increasing proportion of researchers to consider multi-marker
clustering as a way to define neuronal subtypes. Some studies have used wider-
ranging arrays of markers and regulatory gene products in a bid to extract new
categories (Hill, Kalloniatis, & Tan, 2000, 2001; Molnr & Cheung, 2006; in rat:
Kubota et al., 2011). A recent lineage study of the mouse cortex found that 95% of
mouse neocortical interneurons fall into four non-overlapping IHC groups: PV-IR,
SOM-IR, non-SOM-IR/Reelin-IR, and VIP-IR (Miyoshi et al., 2010).
Among the early Cajal-Retzius neurons, CR immunoreactivity (IR) identifies cells
originating in the ventral pallium, whereas those born in the septum are not CR-IR
(Bielle et al., 2005).
r|nc|pa| neurons
As Molnr and Cheung (2006) note, few IHC markers of principal neuron
subpopulations have been identified. The excitatory function of principal neurons
correlates with a widespread presence of aspartate, glutamate and its synthetic
enzyme glutaminase (Hornung & de Tribolet, 1995). In rats, corticocortical neurons
label with antibodies to glutamate, aspartate, or both (Giuffrida & Rustioni, 1989b). A
partial distinction between principal neurons and interneurons can be made on the
basis of glutamate receptor subunit expression (in rat: Kondo, Sumino, & Okado,
1997; Kondo et al., 2000).
In rodents, around 10% of pyramidal neurons are immunoreactive for neurofilament
triplet proteins (van der Gucht et al., 2007; Watson & Paxinos, 2010; Paulussen et al.,
2011; in rat: Hiscock, Mackenzie, & Willoughby, 1996; Kirkcaldie et al., 2002;
Paxinos et al., 2009), and the presence of neurofilament often correlates with
subcortical projection targets (van der Gucht et al., 2007; in rat: Voelker et al., 2004).
CBPs have been infrequently detected in the pyramidal cells of various species
(DeFelipe, 1997), and PV is expressed by a few corticostriatal glutamatergic neurons
(Jinno & Kosaka, 2004). Molnr and Cheung (2006) describe CR in transcallosal
projection neurons in the rat, and somatostatin and related peptides have been
observed in pyramidal neurons (Morrison et al., 1983; Hendry, Jones, & Emson,
1984). The protein inhibitor latexin is expressed by corticocortical (but not
thalamocortical) neurons in layers 5 and 6 in rats (Arimatsu & Ishida, 2002).
Combinations of well-established protein markers and the transcription products of
several key genes suggest a principal neuron taxonomy (Molnr & Cheung, 2006),
that could provide new insights into cortical architecture using well-established IHC
methods.
19
Interneurons
To date, the most helpful IHC classifications have been made among the interneurons
(DeFelipe, 1997). Pioneering work by Kawaguchi and Kubota in the rat frontal cortex
showed that a small set of markers can subdivide the interneuron population with little
overlap, and these subdivisions closely correlate with classifications based on
morphology and connectivity, as well as with distinct electrophysiological
characteristics (in rat: Kawaguchi, 1995; Kawaguchi & Kubota, 1997). More recently,
detailed studies of these markers have been undertaken in mouse neocortex (Gonchar,
Wang, & Burkhalter, 2007; Xu, Roby, & Callaway, 2010).
In rats, PV, SOM, and CR can be used to divide the majority of interneurons into
functionally distinct groups with minimal overlap of markers (Kawaguchi & Kubota,
1997); however these distinct markers are not intrinsic to functional differences
between these neurons, since in the mouse cortex there is around 30% overlap
between SOM and CR (Xu, Roby, & Callaway, 2006). The proportion of neurons
labelled by these markers is fairly consistent (Fig 5), but regional variation is
observed (Xu, Roby, & Callaway, 2010).
The CBPs and peptides used for interneuron classification are highly soluble and
disperse throughout the soma, axons and dendrites of the neurons expressing them. As
a result, antibodies label both the locations of the cell bodies, and the full extent of
their processes. When the neurons are numerous this gives labelling whose intensity
varies with the density of axons and dendrites; axon terminals can often be
distinguished by their punctate appearance.
Fig 5 - laminar interneuron proportions
!$#<$(=3%&/
Parvalbumin, a low molecular weight soluble protein, binds calcium with high affinity
(Schwaller, Meyer, & Schiffmann, 2002) and is strongly implicated in intracellular
calcium regulation and trafficking (Arif, 2009). During nervous system development,
its expression accompanies the maturation of functional circuits (del Ro et al., 1994;
Collin et al., 2005).
In mouse neocortex, parvalbumin IHC labels a dense network of processes pervading
layers 2/3 to 7, with a sharply defined, reticulated boundary between layer 1 and 2/3
(Ichinohe et al., 2003; Shlosberg et al., 2003) and fading out in the deep part of layer
6, aside from a narrow band of density in layer 7. Where present, layer 4 is densely
innervated, and in all regions layer 5 has a superficial layer of lesser labelling, but
deep to that is strongly labelled with clusters of puncta forming clear outlines
(baskets) around unlabelled pyramidal cell bodies (del Ro et al., 1994; Czeiger &
White, 1997). The labelling extends across the dorsal neocortex with small regional
variations in intensity, but cuts off sharply at a ventrolateral boundary (rostrally,
between dysgranular insular and agranular insular; caudally, between ectorhinal and
perirhinal cortical areas). In agranular insular and perirhinal cortex, only layers 2/3
and 5 are labelled (Watson & Paxinos, 2010).
PV is expressed by the largest subgroup of cortical interneurons, whose cell bodies
are distributed across layers 2/3 to superficial 6 (del Ro et al., 1994; Tamamaki et al.,
2003; Fishell, 2007; Xu, Roby, & Callaway, 2010). The label is quite specific,
showing essentially no overlap with IHC for CR, SOM, VIP or NPY (Xu, Roby, &
Callaway, 2010). Most parvalbumin-expressing neurons are basket cells (Meyer et al.,
2002; in rat: Kawaguchi & Kubota, 1993; Gabbott et al., 1997) and chandelier cells
1 all
by layer
p
r
o
p
o
r
t
i
o
n

o
f

a
l
l

i
n
t
e
r
n
e
u
r
o
n
s

(
%
j
2/3 4
50
40
30
20
10
0
5 6
parvalbumin
somatostatin
calretinin
neuropeptide Y
vasoactive intestinal
polypeptide
Figure 5: Interneuron markers by layer.
Counts of interneuron cell bodies, labelled
for fve major immunohistochemical mark-
ers, across the layers of anterior medial
frontal cortex. Note that the proportions
are of the total counts in each layer, so
that the increased proportions of non-Pv
interneurons in layer 6 is the result of a
relative lack of other interneurons, rather
than increased Pv interneuron numbers.
Adapted from fgure 6 in Xu, Roby, and
Callaway (2010j.
Placement: near section lmmunohistochemical classif-
cation / lnterneurons.
Figure 6: Calbindin chemoarchitectonics.
lmmunohistochemistry for calbindin-D28k
reveals cell bodies (punctate labellingj and
processes (diffuse labellingj of CB-lR inter-
neurons. Note intense labelling in supragranu-
lar layers and superfcial 5, and mid layer 4
restricted to S1BF. Detail, fg 54 of Watson
and Paxinos (2010j.
Placement: near section lmmunohistochemical classifcation /
lnterneurons / Calbindin.
Figure 7: Interneuron lineages.
Physiologically and morphologically distinct interneuron types deriving from progenitors in the
medial ganglionic eminence (green soma and dendritesj and caudal ganglionic eminence (blue
soma and dendritesj. Adapted from Miyoshi and colleagues (2007, 2010j who classifed these
subtypes by their electrophysiological responses to current injection.
Abbreviations: (f/rjAD, (f/rapidlyj adapting; (djFS, (delayedj fast spiking; (d/r/sjlB, (delayed/rebound/sigmoidj intrinsic bursting; lS,
irregular spiking; LS(1/2j, late-spiking subtypes; bNA(1/2j, burst nonadapting subtypes; (djNFS(1/2/3j, (delayedj non-fast spiking
subtypes. See original papers for details. Placement: near section Lineage classifcation / lnterneurons.
100 m
1
2/3
4
5
6
FS
LS
LS1
LS2
dFS
rAD
fAD
dNFS2
dNFS3
NFS1
FS
Medial ganglionic eminence derived interneurons
Caudal ganglionic eminence derived interneurons
lS
ilB
rlB
dlB
bNA1
bNA2
slB
20
(Inda, DeFelipe, & Muoz, 2009; in rat: Kawaguchi & Kubota, 1997; Gabbott et al.,
1997; Zhu, Stornetta, & Zhu, 2004), although a physiologically distinct class of
interneurons expressing PV and CB has also been identified in mouse cortex (Blatow
et al., 2003). PV labelling is also observed in a few fibres of the subcortical white
matter and corpus callosum (del Ro et al., 1994); this labelling may derive from the
PV-IR subset of corticostriatal projection neurons, which are mostly glutamatergic,
unlike most PV-IR neurons (Jinno & Kosaka, 2004).
Transgenic mice expressing enhanced green fluorescent protein (EGFP) under the
parvalbumin promoter (PV-EGFP; Meyer et al., 2002) have permitted studies of these
interneurons in vivo and in living slices, building on rat-based observations of fast-
spiking physiology and gap junction coupling between PV interneurons (in rat:
Fukuda & Kosaka, 2000,2003). Conversely, knockouts affecting PV expression have
been used to study its function; the knockouts exhibited increased gamma-band
excitability and susceptibility to seizures (Schwaller at al., 2004; Lucas et al., 2010).
The PV gene tends to co-express with ion channels associated with high frequency
discharge (in rat: Toledo-Rodriguez et al., 2004).
7$(#+0&/&/
Calretinin, a calcium binding protein first identified in the retina, has not been
functionally characterised beyond its ability to modulate neuron excitability by rapid
calcium buffering (Camp & Wijesinghe, 2009). In adult mouse neocortex CR IHC
reveals sparse labelled processes in layers 1 to superficial 6, supplied by cell bodies
mostly in layer 2/3 (Park et al., 2002; Shlosberg et al., 2003). A strong transient CR
expression occurs in S1BF deep layer 4 / superficial layer 5 a few days after birth, but
reduces dramatically to the adult pattern by postnatal day 20 (Melvin & Dyck, 2003).
CR-expressing neurons have fusiform cell bodies with bipolar dendrite fields running
radially, although horizontal and multipolar cells are also observed (Park et al., 2002;
Caputi et al., 2009; in rat: Gabbott et al., 1997). The CR-IR subpopulation of SOM-IR
cells found by Xu, Roby and Callaway (2006) resembles the latter group.
A CR-EGFP transgenic mouse has permitted physiological investigations in cortical
slices, revealing two principal supragranular GABAergic populations with distinct
physiology, both of which tend to target interneurons rather than principal neurons
(Caputi et al., 2009). In addition to these populations, 92% of cholinergic bipolar
interneurons are CR-IR (von Engelhardt et al., 2007). The CR gene is part of an
expression cluster with ion channels associated with accommodating firing patterns
(see below; in rat: Toledo-Rodriguez et al., 2004).
7$(=&/'&/
Calbindin D28k, a CBP of intermediate affinity between PV and CR, is capable of
rapid intracellular calcium buffering (Schwaller, Meyer, & Schiffmann, 2002). CB
IHC in mouse cortex shows dense labelling in layers 1 and 2/3, and lighter labelling
in superficial layer 5 (Park et al., 2002; Watson & Paxinos, 2010; Fig 6). Despite this
pattern, CB-IR cell bodies are most numerous in layer 5 of visual cortex (Park et al.,
2002). Uniquely, in S1BF (barrel cortex) an additional mid-layer-4 band is apparent
which is absent in rat S1BF (Torres-Fernndez et al., 2005; Paxinos et al., 2009;
Watson & Paxinos, 2010; Fig 6).
Fig 6 Calbindin in neocortex
A labelling study in mouse visual cortex found cells with a range of shapes including
fusiform, bipolar, horizontal and stellate (Park et al., 2002), whereas in rat cortex CB-
21
IR neurons have a multipolar or BT morphology (in rat: Kawaguchi & Kubota, 1993;
Gabbott et al., 1997). Some cells are both CB-IR and CR-IR (Park et al., 2002).
Interneuron expression of CB often correlates with ion channels associated with burst
firing activity (in rat: Toledo-Rodriguez et al., 2004).
-4%$04,0$0&/
Somatostatin, a peptide, is employed in inhibitory signalling throughout the body
(Kumar & Grant, 2010). In mouse neocortex, SOM IHC shows dense labelling in
layer 1 and sparse labelling in other layers, with labelled cell bodies predominantly in
layers 5 and 6 (Naus & Bloom, 1988; Forloni, Hohmann, & Coyle, 1990; Shlosberg et
al., 2003; Xu, Roby, & Callaway, 2010). Labelled cell bodies are usually identified as
Martinotti cells, although studies of GAD67-GFP and SOM-GFP mice have identified
two previously unknown phenotypes in addition to Martinotti cells (Ma et al., 2006;
Halabisky et al., 2006; McGarry et al., 2010). Although Martinotti cells are usually
characterized by local projections to layer 1, Tomioka and colleagues (2005) describe
a GABAergic corticocortical projection network in the mouse cerebral cortex, greater
than 90% of which are SOM-IR. In addition to neuronal processing, SOM neurons
also couple activity to blood vessel dynamics (in rat: Cauli et al., 2004).
Co-labelling and transgenic studies have identified a CB-IR SOM subpopulation (Ma
et al., 2006) as well as a significant overlap between SOM-IR and CR-IR interneurons
(Xu, Roby, & Callaway, 2010).
>$,4$*0&<+ &/0+,0&/$( .4(".+.0&'+
Vasoactive intestinal polypeptide (VIP) is a peptide used for signalling in the gut and
the CNS (Magistretti, 1990). Like somatostatin, it is employed as a neurotransmitter
by the cells which express it (Csillag et al., 1993) and the two are never co-expressed
(Xu, Roby, & Callaway, 2010). VIP-IR neurons are less numerous compared to CBP
and SOM expressing neurons (Markram et al., 2004; Xu, Roby, & Callaway, 2010),
but receptors for VIP are widespread among cortical neurons (Csillag et al., 1993). In
rodent cortex VIP IHC labels bipolar interneurons, mostly in layer 2/3, which are
spaced such that each occupies a similar volume of cortex (Magistretti, 1990; Xu,
Roby, & Callaway, 2010; in rat: Morrison et al., 1984). As previously described, this
phenotype includes groups with different physiological characteristics, but the data
are somewhat conflicting: between 30100% are GABAergic, and 3080% are
probably cholinergic, in addition to their VIP neurotransmission; in rats, some
neurons appear to use all three transmitters (Magistretti, 1990; von Engelhardt et al.,
2007; in rat: Peters & Harriman, 1988; Bayraktar et al., 1997; Cauli et al., 2004).
However, rat-based data are not useful in this instance since the two species differ in
the expression of cholinergic markers (see section on choline acetyltransferase
below).
Secreted VIP activates receptors located on blood vessels, astrocytes, and neurons
(Martin et al., 1992; Csillag et al., 1993; in rat: Cauli et al., 2004), and application of
VIP to cortical slices causes glycogenolysis (Magistretti et al., 1981, 1984).
Considering the uniform distribution of VIP-IR interneurons and their strong
innervation from fast-spiking interneurons and ascending cholinergic and serotonergic
fibres (Staiger et al., 2002; in rat: Cauli et al., 2004), it appears that VIP-IR cells
regulate both neuronal excitability and metabolic activity (Magistretti et al., 1981;
Csillag et al., 1993; Zilles et al., 1993; Staiger et al., 2002; in rat: Peters & Harriman,
1988).
22
9+3#4.+.0&'+ ?
The expression of NPY in the neocortex is quite labile, and can be induced by
cytokines and seizures, for example (Kharlamov, Kharlamov, & Kelly, 2007; in rat:
Wahle et al., 2000). In normal mouse cortex NPY-IR neurons are sparse, around 10%
of GABAergic interneurons, and are predominantly located in layer 1 (except region
S1), layer 2/3, and smaller numbers in layers 46 (Fogarty et al., 2007; b et al., 2010;
Xu, Roby, & Callaway, 2010). Many NPY-IR neurons couple to blood vessels and are
influenced by both local activity and subcortical cholinergic and serotonergic
afferents (in rat: Aoki & Pickel, 1990; Cauli et al., 2004). A subgroup of NPY-IR
neurons also utilise nitric oxide signalling (see later section). NPY co-localises with a
subset of SOM-IR neurons, and was present in 82% of the GABAergic projection
neurons reported by Tomioka and colleagues (2005).
724(&/+ $*+0"(0#$/,;+#$,+
Choline acetyltransferase (ChAT), the enzyme used to synthesise acetylcholine
(ACh), is expressed by a small population of mouse cortical neurons. A transient
ChAT-IR population is observed in the embryonic cortex, originating at the dorsal
ventricular surface and hence derived from principal neuron rather than interneuron
progenitors (see below; Schambra et al., 1989). After birth, ChAT enzymatic activity
and IR increases in cortical neurons during the second postnatal week, reaching adult
levels by 7 weeks (Hhmann & Ebner, 1985; Consonni et al., 2009). In adult mouse
cortex, Kitt and colleagues (1994) suggested there was a near-complete overlap of
ChAT-IR and AChE histochemistry, but their antibody failed to show ChAT-IR cell
bodies. More recent studies have established the existence of a small ChAT-IR
interneuron population mostly in superficial layers, bipolar in form, and extensively
co-labelled with VIP, CR and NPY (see VIP section above; von Engelhardt et al.,
2007; Gonchar, Wang, & Burkhalter, 2007; Consonni et al., 2009). In addition a
weakly immunoreactive population with multipolar morphology, located in deeper
cortical layers, accounts for 11% of the ChAT-IR population (von Engelhardt et al.,
2007; Consonni et al., 2009).
In rats, a significant proportion of ChAT-IR interneurons are also GABAergic
(Bayraktar et al., 1997), but in mouse cortex this relationship is unclear. Gonchar,
Wang and Burkhalter (2007) reported a 99% colocalization, whereas von Engelhardt
and colleagues (2007) found that no ChAT-EGFP bipolar cortical neurons, but 96.3%
of labelled multipolar neurons, expressed GABA markers. Finally, Consonni and
colleagues (2009) found that very few ChAT-IR neurons expressed GABA, GAD65
or GAD67. Either there are strain differences between FVB (Consonni et al., 2009),
C57Bl/6J (Gonchar, Wang, & Burkhalter, 2007) and ChAT-EGFP transgenic C57Bl/6
(von Engelhardt et al., 2007) mice, or there are significant technical differences in
antibody use between these studies. Whether this represents a non-GABAergic
interneuron population remains an open question.
724(+*",046&/&/
Disagreement exists about the expression of CCK in mouse cortical neurons, although
it has been widely used to classify rat interneurons (in rat: Kawaguchi & Kubota,
1997; Uematsu et al., 2008). CCK receptors are present throughout the mouse cortex
(Saito, Goldfine, & Williams, 1981), and CCK mRNA is strongly transcribed in
mouse cortex (Vitale et al., 1990; Meziane et al., 1997; Marsicano & Lutz, 1999;
Petersson et al., 2000; Beinfeld et al., 2009). Several studies have described CCK-IR
neurons in mouse cortex, but the data are not consistent; one study found weakly
23
staining supragranular pyramidal neurons, particularly in Cg1 / Cg2 (Meziane et al.,
1997), but another reported a major class of interneurons, some co-expressing NPY
and/or VIP (Gonchar, Wang, & Burkhalter, 2007; Lee et al., 2010a). Against this, Xu,
Roby and Callaway (2010) describe CCK-IR cells as quite scarce in mouse cortex
(p392) and did not go on to describe them. They failed to comment on this
discrepancy, but separately queried Gonchar, Wang, and Burkhalters antibody
characterisation.
Multiple molecular forms of CCK are found in brain and peripheral tissue, and the
forms can be modified post-translation (Meziane et al., 1997; Beinfeld et al., 2009),
which may complicate the choice of suitable antibodies.
@++(&/
During neural development the secreted protein reelin has a key role in the formation
of the cortex (Soriano & del Ro, 2005; review by Frster et al., 2010). During
development, reelin is initially secreted by Cajal-Retzius cells, but postnatally some
GABAergic interneurons begin to secrete it. By postnatal day 21 (P21) reelin is only
expressed by interneurons (Alcntara et al., 1998; Yoshida et al., 2006; Miyoshi et al.,
2010). Co-localisation of gene expression and IHC for common markers suggests that
most reelin-expressing interneurons are labelled for NPY (Alcntara et al., 1998;
Gelman & Marn, 2010), with a substantial SOM-IR overlap as well (Miyoshi et al.,
2010).
8&,*+(($/+43, .#40+&/,
Peptides such as corticotropin-releasing factor are occasionally considered alongside
the more established interneuron markers in describing interneurons (in rat: Kubota et
al., 2011). Similarly, Uematsu and colleagues (in rat: 2008) found that IHC for the
actin binding protein #-actinin-2 identified neurogliaform cells and 66% of layer 1
interneurons. Although the neurotransmitter substance P appears to be expressed by a
subpopulation of layer 4 and 5 PV-IR interneurons in rat cortex (in rat: Vruwink et al.,
2001), expression in the mouse is limited to a transient layer 6 population during the
first postnatal week (del Ro, Soriano, & Ferrer, 1991). A transgenic mouse line
reported by Basu and colleagues (2008) suggests that expression of CaM-kinase-II#
distinguishes interneurons from principal neurons.
L|neage c|ass|f|cat|on
Principal neurons and interneurons arise separately, assuming distinct sets of mature
phenotypes (Anderson et al., 1997; Rubenstein, 2000; Parnavelas, 2000; in rat: Mione
et al., 1994). Principal neurons derive from pallial precursors lining the ventricles,
whereas interneurons are subpallial in origin, invading the pallial territory by
tangential migration. The two progenitor pools are differentiated by mutually
repressive regionalising factors SOX5 and SOX6 (Fogarty et al., 2007; Azim et al.,
2009). Although this ontogenetic distinction results in different transcriptional
repertoires, many of the fundamental properties of neurons depend on their eventual
place in the cortex; that is, lineage defines an envelope of potential, but neurons adapt
their properties according to local cues (Fishell, 2007).
Cajal-Retzius neurons originate before any other neurons of the cortex are generated,
arising principally from the cortical hem as well as the septum and ventral pallium
(Bielle et al., 2005; Yoshida et al., 2006; Molyneaux et al., 2007; Molnr, Tavare, &
24
Cheung, 2009). During development they transiently express the cortex-specific
homoeodomain protein EMX1 (Gorski et al., 2002) and the secreted factor reelin
(Soriano & del Ro, 2005), and may play an active role in regulating the laminar
structure of the cortex, although this has been questioned (Yoshida et al., 2006). Most
of them undergo apoptosis in the second postnatal week, although the surviving
population can be identified by their expression of early B-cell factor 2 (Ebf2;
Chowdhury et al., 2010).
r|nc|pa| neurons
For a review of principal neuron transcription factors see Molyneaux and colleagues
(2007).
Principal neurons derive from stem cells on the ventricular margin of the dorsal
pallium, and migrate radially into the developing cortical plate as it accumulates
below the Cajal-Retzius cells (Chan et al., 2001; Gorski et al., 2002). As a group, they
express a number of characteristic molecular markers (Hevner et al., 2003).
Historically, they have been difficult to subdivide, but recent genetic manipulation
and in situ hybridisation studies have revealed a wealth of diverse gene expression,
often specific to cortical layers and projection targets (Lein et al., 2007; reviews by
Molnr & Cheung, 2006; Molyneaux et al., 2007). Among the dozens of lineages
studied, specific markers have been identified for cortical layer location (Hevner et
al., 2003; Inoue et al., 2004), corticospinal and corticotectal projection (Arlotta et al.,
2005; Christophe et al., 2005), and callosal projection (Arlotta et al., 2005;
Molyneaux et al., 2009).
Interneurons
For reviews of interneuron lineages see Wonders and Anderson (2006) and Gelman
and Marn (2010).
Interneurons arise from the ganglionic eminences, clusters of cells bulging into the
ventricular space at the ventrolateral margin of the ventral pallium, which also give
rise to the striatum (Anderson et al., 1997, 2001; Wichterle et al., 1999; Nery, Fishell,
& Corbin, 2002). The medial and caudal ganglionic eminences (MGE and CGE), and
the preoptic area (POA) ventral to the MGE give rise to distinct populations of
neocortical interneurons, with only minor overlap in phenotypes (Fig 7). This
diversity is driven by the ventral pallium transcription factor SOX6 (Fishell, 2007;
Gelman et al., 2009; Azim et al., 2009). The MGE / LGE / CGE / POA domains may
be analogous to the neural progenitor domains identified in the developing spinal cord
(Butt et al. 2005). A rapidly advancing literature has described the relative
contributions of these regions to cortical interneuron populations, and the first steps
have been taken toward thorough genetic analysis of interneuron lineages (Cobos et
al. 2006).
Fig 7 interneuron lineages
8AB &/0+#/+3#4/,
Although early labelling studies implicated the lateral ganglionic eminence (LGE;
Anderson et al., 1997, 2001; Jimnez et al., 2002), later studies used explant cultures
and embryonic transplants to conclude that the MGE is the primary source of
neocortical interneurons (Wichterle et al. 1999; Butt et al. 2005). Neurons from the
MGE also contribute to piriform cortex, striatum, lateral globus pallidus,
hippocampus, amygdala, and the bed nucleus of the stria terminalis (Wichterle et al.,
25
2001). MGE derivatives are specified by the regionalising gene Nkx2-1, and can be
identified by the expression of Nkx6-2, Olig2 or Lhx6 (Lim homeobox 6; Fogarty et
al., 2007; Miyoshi et al., 2007; Butt et al., 2008).
MGE interneurons comprise 70% of neocortical interneurons (Miyoshi et al., 2010),
including essentially all PV-IR, CB-IR and SOM-IR neurons and a quarter of the CR-
IR and NPY-IR populations (Xu et al. 2004; Fogarty et al., 2007). These neurons
assume well-described phenotypes on maturation: over half are fast-spiking basket
and chandelier cells (Butt et al., 2005; Woodruff et al., 2009), with the remainder
comprising Martinotti, multipolar and bitufted cells, and additional physiologically
distinct subtypes (Wichterle et al., 2001; Miyoshi et al., 2007; Fig 7, green dendrites).
The SOM-IR, regular spiking population includes non-CR-IR neurons, and CR-IR
Nkx6-2-specified neurons which differ slightly in spiking patterns (Xu et al., 2004;
Butt et al., 2005; Sousa et al. 2009). The various phenotypes of MGE interneurons are
correlated with their date of birth, due to their precursor cells undergoing
transcriptional changes during neurogenesis (Miyoshi et al., 2007; Sousa et al. 2009),
as well as progenitor location within the MGE (Wonders et al. 2008).
7AB &/0+#/+3#4/,
The CGE is the caudal part of the ganglionic eminences in which the MGE and LGE
fuse, and contains discrete domains with molecular similarities to those structures
(Butt et al., 2005; Wonders & Anderson, 2006); CGE precursors specifically express
Gsh2 (genomic screened homeobox 2; Fogarty et al., 2007).
The CGE gives rise to interneuron populations which tend to localise in the
supragranular layers (Fig 7, blue dendrites), including VIP-IR / CR-IR / NPY-IR,
non-SOM-IR / Reelin-IR, bipolar and bitufted cells, neurogliaform cells, and adapting
firing cells, some of which overlap with MGE interneurons (Nery, Fishell, & Corbin,
2002; Butt et al., 2005; Fogarty et al., 2007; Miyoshi et al., 2010). This overlap
reflects an underlying similarity, since MGE derivatives shift to CGE phenotypes if
Nkx2-1 or Sox6 expression is suppressed (Butt et al., 2008; Azim et al., 2009). Some
physiological types, as well as neurogliaform neurons of superficial and deep layers,
are unique to CGE derivatives (Butt et al., 2005; Miyoshi et al., 2010). CGE
interneurons also differ in their cortical roles. They innervate interneurons
preferentially (Xu, de la Cruz, & Anderson, 2003) and although MGE interneurons
migrate to occupy the same cortical layers as principal neurons born
contemporaneously (Miyoshi & Fishell, 2010), CGE interneurons migrate to
supragranular layers regardless of birthdate (Miyoshi et al., 2010).
CGE interneurons were originally thought to comprise 20% of the interneuron
population (Fishell, 2007), but more recent estimates suggest it is around 30%
(Miyoshi et al., 2010).
CAB &/0+#/+3#4/,
Initial reports identified the LGE as a source of cortical interneurons, but it was
subsequently realised that MGE interneuron precursors had been labelled while
migrating through the LGE (Anderson et al. 1997; Wichterle et al. 1999, 2001;
Wonders & Anderson, 2006). Some evidence suggests a minor LGE contribution to
neocortex, with LGE interneurons following a distinct route via the subventricular
area (Anderson et al., 2001). However, virtually all neurons originating in the LGE
end up in the striatum, nucleus accumbens, olfactory tubercule and olfactory bulb
(Wichterle et al. 2001).
26
!1D &/0+#/+3#4/,
A small population of Nkx5-1-expressing interneuron progenitors in the preoptic area
(POA; ventral to the MGE) produce at most 5% of neocortical interneurons (Gelman
et al., 2009; Miyoshi et al., 2010). These neurons are found across the neocortex,
principally in supragranular layers; at least 30% express neuropeptide Y and/or reelin,
but none express the other major markers such as PV or SOM, and physiologically
they are in the adapting class (Gelman et al., 2009; Gelman & Marn, 2010).
L|ectrophys|o|og|ca| c|ass|f|cat|on
Interneurons may also be classified by their responses to depolarising stimuli and
their characteristic firing patterns. As with morphology and immunohistochemistry,
deciding which attributes represent fundamental groupings and which are variations
within groups is difficult, and authors vary in their choice of categories. Agmon and
Connors (1992) classified thalamically stimulated cortical neurons (including
principal neurons) as fast-spiking (FS), regular spiking (RS) and intrinsically bursting
(IB) based on the speed and timing of elicited action potentials. Pyramidal neurons in
auditory cortex can be grouped into several RS and IB subtypes, in proportions which
vary systematically across layers (Huggenberger, Vater, & Deisz, 2008). In rat cortex,
Kawaguchi (1995) identified RS and FS cells, adding late-spiking (LS) and low-
threshold spiking (LTS) categories. When the cells were visualised, their
physiological types corresponded to multipolar, bipolar, and bitufted (RS), basket and
chandelier (FS), neurogliaform (LS), and Martinotti
3
(LTS) morphologies
respectively. A later categorisation reclassified LTS as burst spiking (BS) (in rat:
Kawaguchi & Kubota, 1997) and suggested that three of these physiological types
were associated with markers: FS with PV, RS with SOM and CB, and BS with VIP.
Blatow and colleagues (2003) identified another physiological type, multipolar
bursting, among PV-labelled interneurons of superficial layer 2/3.
The recent overview by the Petilla group (2008) presents an overarching descriptive
nomenclature for interneuron physiology, and provides an insight to the features they
consider necessary for characterisation. It is a long list, organised into passive
parameters, action potential measurements, and the response to a sustained
depolarising step. For the latter, the onset response may be continuous, burst, delayed,
single AP with pause, or other. While the depolarisation is maintained, the response
may be accommodating (amplitude or after-hyperpolarisation), spike frequency
adapting, saturated (sustained maximum rate), sustained at a lower rate, slow after
hyperpolarisation, irregular spiking / stuttering, repetitive bursts, silent, or other. A
range of characterisations of the after-hyperpolarisation and the relationship of the
neurons spiking behaviour to nearby activity complete the exhaustive description.
This vast parameter space is essentially opposite to the reductionist categorisations in
current use, since it tries to retain as much information specific to the individual
neuron as possible. It is intended that by using the broadest parameter space
(including morphology and molecular markers) and the use of unbiased cluster
analysis will uncover groupings which were not obvious in conventional descriptions,
as has been demonstrated in recent studies (Tsiola et al., 2003; Burkhalter, 2008;
McGarry et al., 2010).

3
Kawaguchi described these as cells with an axon projecting to layer 1however in the 1997
classification they place Martinotti cells, which express somatostatin, in the RS category instead.
27
Iuture c|ass|f|cat|on
After this brief survey of overlapping and partly reconcilable classification systems
for cortical neurons, it is clear that the established types described are labile
descriptions of co-occurring properties with varying degrees of linkage. For example,
PV expression and FS physiology occur in MGE-derived basket and chandelier cells,
but regional heterogeneity for co-labelling with the HNK-1 antibody and the
multipolar bursting subtype suggests further specialisation among PV-IR
interneurons, and there is a wide range of morphology, connectivity and physiology
among these neurons (Ren, Heizmann, & Kosaka, 1994; Blatow et al., 2003;
Markram et al., 2004). Outside of a few recognised types, most of the remainder
remain stubbornly difficult to classify.
A natural reaction to this intractability is to choose a particular interneuron
typologythose of Kawaguchi and Kubota (1997) and Gonchar and Burkhalter
(1997) are well likedand to treat those summary relationships as fundamental,
while acknowledging a range of minor variation. Although capable and authoritative,
these classifications are attempts to regularise a complex and partly contradictory
literature into a consensus of types, and must themselves disregard a range of
variation to focus on better-characterised feature groupings. Some authors simplify
their observations by fitting them to one of these schemes, which minimises the
apparent variation reported, and forces data from other species to conform to rat-
derived typologies, which are demonstrably specific to rat neocortex. Multi-marker
studies in mouse neocortex (Gonchar, Wang, & Burkhalter, 2007; Xu, Roby, &
Callaway, 2010) have revealed significant differences in expression patterns, both
undermining the fundamental status of the rat typologies and highlighting their
inapplicability to the cortex of another species, even closely related species. Markram
and colleagues (2004) acknowledge this difficulty more directly, producing a less neat
but more inclusive summary of feature relationships.
Partial correlations between morphology, distribution, function, and histochemistry
are intrinsic to cortical neurons, rather than indicative of a failure to identify hidden
regularities. The only fundamental distinction is between the major lineages: Cajal-
Retzius neurons from the pallial margins, interneurons from the subpallial ganglionic
eminences, and principal neurons from pallial radial glia. Within these key
populations, a range of gene expression repertoires and connectional preferences is
possible (Blatow, Caputi, & Monyer, 2005; Cobos et al. 2006; Fishell, 2007), and
certain features tend to cluster together, perhaps under the influence of shared
promoters (Cobos et al. 2006; e.g. in rat: Toledo-Rodriguez et al., 2004). To this end,
promoter-based labelling (e.g. Oliva et al., 2000; Xu & Callaway, 2009) and
unsupervised cluster analysis may offer fresh insights to principal neuron and
interneuron populations (Tsiola et al., 2003; Burkhalter, 2008; McGarry et al., 2010).
Also pertinent is DeFelipes (2002) observation (after Preuss) that fundamental
mammalian interneuron types are based on observations in few species, often selected
for their similarity to humans. If consistent groupings have failed to emerge within the
primates and rodents (the euarchontoglires) it is highly unlikely that fundamental
mammal interneuron types exist. Rather than imposing regularity on interneuron
descriptions, it may be more useful to systematise the characterisation of cellular
variation instead. The Petilla terminology (Petilla Interneuron Nomenclature Group,
2008) seeks to do exactly this by offering a descriptive framework for morphological,
molecular and physiological characterisation, to regularise the description of
interneuron features. Despite this broader perspective, it is still motivated by hopes of
28
a true classification. Yuste (2005) characterises the groups conviction that
interneurons different anatomical, molecular, and physiological features are but
reflections of one unique reality (p525).
The hope of lineage classification is that it offers insight to the fundamental genetic
predispositions of neurons, and therefore will help identify which features are
variation, induced by the specific cortical environment in which the cell finds itself.
Against this is the contention that the individual features of each neuron define its
function just as much as its lineage. Ontogeny may be the key determinant of location
and transcriptional repertoire, but these are probably most significant during early
development and migration. The staggering diversity of cortical neurons shows that
they have a vast and flexible repertoire of growth, protein expression and physiology
(e.g. Costa et al. 2010). The genes regulating the growth and connectivity of
interneurons must be selected for flexibility, since the specific mix of neurons, glia,
and afferents in which each cell finds itself is unique. Although there are clearly large
scale regularities, individual interneurons may be extensively tailored and modified
for ad-hoc cortical circuits based on the local mix of neurons and afferent activity.
Chemoarch|tecton|cs
Although many functional descriptions of cerebral cortex focus on individual cellular
elements, a range of histochemical techniques provide a complementary perspective.
Utilising biochemical reactions to deposit visible reaction products at the site of
enzymatic activity or biologically significant molecules and ions, histochemical
techniques provide information at the tissue level, so that the distribution of
neurotransmitters or other significant molecules can be visualised across large areas.
At the tissue level, IHC for many of the soluble CBPs has been used to distinguish
interneurons. This creates large scale patterns corresponding to the density of these
neurons fine processes (Fig 6), and standard histological stains such as those for
Nissl substance also label cellular nuclei and processes to varying degrees of intensity
(Fig 2). Examining these patterns and density changes can provide important clues to
the significant cytoarchitectonic divisions of the neocortex, a technique called
chemoarchitectonics (Jacobowitz & Abbott, 1997; Van De Werd et al., 2010; Watson
& Paxinos, 2010; in rat: Zilles, 1985; Palomero-Gallagher & Zilles, 2004; Paxinos et
al., 2009).
Acety|cho||nesterase
AChE, the breakdown enzyme for ACh, is the general term for a family of related
enzymes expressed throughout the body, including the brain (Rakonczay, 1988;
Pezzementi & Chatonnet, 2010). AChE histochemistry produces a differentially
distributed intensity pattern across the forebrain (Franklin & Paxinos, 2007; Fig 12).
In the neocortex, AChE is primarily located in axons from the basal forebrain
cholinergic innervation (Kitt et al., 1994) and in a small population of layer 7 cells
(Garrett, Geneser, & Slomianka, 1991; in rat: Kristt, 1979). Compared to the dense
deposits in the striatum, the cortex is only lightly stained, but it does show a general
pattern of fibrous, diffuse labelling which varies between layers: somewhat labelled in
1; sparse in 2/3; a band at the junction between 2/3 and 4; greater intensity in 4 where
present; very sparse in superficial 5; more intense in deep 5 and superficial 6
(particularly in motor related regions); sparse in deep 6, with a thin band of greater
intensity and labelled somata in 7 (Garrett, Geneser, & Slomianka, 1991; Kitt et al.,
1994; Franklin & Paxinos, 2007; Anderson, Christianson, & Linden, 2009; in rat:
Kristt, 1979).
29
Specific regions show variation: in S1BF layer 4 there may be a sub-band of greater
intensity resembling the calbindin band described earlier (Kristt & Waldman, 1982;
Torres-Fernndez et al., 2005) and a more diffuse band with greater intensity in the
interbarrel septa (Kristt & Waldman, 1982; Bennett-Clarke, Chiaia, & Rhoades,
1999). V1 shows greater layer 4 intensity than adjoining regions, whereas A1 shows
less intensity variation between layers (Garrett, Geneser, & Slomianka, 1991;
Anderson, Christianson, & Linden, 2009). An abrupt band of greater intensity across
all layers indicates the agranular insular cortices (AID, AIV, AIP) and the prelimbic
cortex is more intense in layer 2/3 (Franklin & Paxinos, 2007).
NADn d|aphorase ] n|tr|c ox|de
Another common histochemical marker, reduced nicotinamide adenine dinucleotide
phosphate diaphorase (NADPH-d), is a synthetic enzyme for nitric oxide (NO) (Hope
et al., 1991). In addition to the well-known role of NO signalling in vasodilatation
(Meng et al., 1996; Kitaura et al., 2007), it is an essential retrograde signal for
presynaptic plasticity (Esplugues, 2002), and plays a role in cortical development
(Oermann et al., 1999; Imura et al., 2005). Nitric oxide signalling is difficult to
characterise because it is a lipid soluble gas and does not require discrete synaptic
structures for signalling, and nor can it be stored by cells (Esplugues, 2002); in fact,
the major proposed source of neuronal NO is an intracellular neuronal NO synthase
(nNOS) coupled to N-methyl-D-aspartate (NMDA) receptors by the synapse scaffold
protein PSD95 (Sattler et al., 1999; Vincent, 2010). Neuronal NO synthesis is
regulated by calcium influx to cells, and NO is reciprocally involved in calcium
regulation (Esplugues, 2002; Lee et al., 2010b; Vincent, 2010).
NADPH-d histochemistry and nNOS IHC identify labeled neurons across the entire
mouse neocortex, more in dorsolateral and lateral than dorsomedial regions, with
most cell bodies in infragranular layers and weakly reactive neurons in layer 2/3 (Yan
& Garey, 1997; Matsushita et al., 2001; Gotti et al., 2005; Lee & Jeon, 2005;
Gonchar, Wang, & Burkhalter, 2007). Matsushita and colleagues (2001) described
labelled processes as lightly stained and evenly permeating the entire cortex, a pattern
like that observed in rat (in rat: Gonchar & Burkhalter, 1997; Paxinos et al., 2009).
However, other studies have demonstrated NADPH-d labelling with marked
intensities in layers 4 and 5 of primary somatosensory and visual regions, and suggest
that differences in fixation and histochemical method profoundly alter labelling
(Oermann et al., 1999; Pereira Jr et al., 2000; Freire et al., 2005). Barrels of
thalamocortical terminals in region S1BF are densely labelled with NADPH-d,
perhaps because of the great need for plasticity in this system (Pereira Jr et al., 2000;
Freire et al., 2005). Others have reported densely nNOS-IR processes in superficial
layer 2/3 (Eliasson et al., 1997; Gotti et al., 2005).
In mouse cortex, nitrergic neurons are described as medium sized multipolar neurons,
with some smaller bipolar and monopolar cells in layer 6 (Matsushita et al., 2001;
Freire et al., 2005; Lee & Jeon, 2005). In rat cortex, nitrergic neurons have been
described as Martinotti cells (in rat: visual: Lth et al., 1995), although a range of
different morphologies have been described (in rat: prefrontal: Gabbott et al., 1997).
Nitrergic neurons also display other IHC markers. Gonchar, Wang and Burkhalter
(2007) characterised 95% of nNOS-IR neurons as GABAergic
4
. Of 130 nNOS-IR

4
Stated in text, p3; data is missing from table 1
30
neurons reported, 52% were SOM-IR, 48% were CR-IR (4% with all three markers),
and 22% were nNOS-IR + CR-IR + NPY-IR. They saw absolutely no overlap with
PV, whereas Lee and Jeon (2005) surprisingly reported 25% co-localisation for PV,
along with 52% CR-IR and 17% CB-IR; both studies were in visual cortex of
C57/Bl6 mice. Nearly all of the NPY-IR GABAergic projection neurons observed by
Tomioka and colleagues (2005) were also nNOS-IR. Among all the cortical SOM-IR
interneurons they observed, 6.6% were also nNOS-IR, far more than the 0.9%
observed by Gonchar, Wang and Burkhalter (2007, table 3), although the latter
stressed that their counts were not statistically representative of the smallest
subgroups.
In addition to a possible role in manipulating cortical plasticity (Vincent, 2010),
specific activation of cortical nNOS-IR/NPY-IR neurons has been observed during
sleep states, with a subgroup of nitrergic neurons activating during spontaneous sleep,
and the great majority activating during recovery sleep after deprivation
(Geraschenko et al., 2008; Pasumarthi, Gerashchenko, & Kilduff, 2010). Like its role
in development, this nitrergic activity may be related to cortical circuit plasticity
during sleep (Imura et al., 2005; Diekelmann & Born, 2010).
2|nc
In addition to its roles in normal physiology, neuronal zinc metabolism has become a
focus of interest in neurodegenerative disorders, and therefore in mouse models of
those disorders (e.g. Lee, Mook-Jung, & Koh, 1999; Adlard et al., 2010). Zinc is
usually labelled using sulphide or selenide precipitation and silver amplification
(Danscher, 1981, 1982; Christensen et al., 1992; Danscher et al., 2004) or fluorescent
zinc binding dyes (Frederickson et al., 1987). In the neocortex after P11, layers 1, 2/3,
5 and superficial 6 are typically strongly labelled, whereas layer 4 (where present) is
devoid of zinc; the latter can distinguish primary sensory areas (Frederickson et al.,
1987; Garrett & Slomianka, 1992; in rat: Danscher 1981, 1982; in grey squirrel:
Wong & Kaas, 2008). Layers 1 and 5 are particularly intense across the neocortex
(Frederickson et al., 1987; Garrett & Slomianka, 1992; Danscher et al., 2004; in rat:
Danscher 1981; Fig 8). Although zinc is observed in some layer 2/3 cell bodies, most
of the labelling is confined to fine processes, thought to be axon terminals (Garrett &
Slomianka, 1992) from ipsilateral and transcallosal corticocortical principal neurons
in layers 2/3, deep 6 and 7 (Garrett, Srensen, & Slomianka, 1992; Brown & Dyck,
2005a).
Zinc is very labile due to its release from axon terminals; it is rapidly modulated by
sensory events, and is thought to be involved in gain control and plasticity at
glutamatergic synapses (Quaye, Shamalla-Hannah, & Land, 1999; Brown & Dyck,
2002, 2003, 2005b; Nakashima & Dyck, 2008). The zinc content and lability of
neocortical boutons increases as the cortex matures (Czupryn & Skangiel-Kramska,
1997, 2001, 2003) and zinc lability decreases with senescence (Brown & Dyck,
2003). Experience-related alterations in zinc reflect changes in the proportion of
synapses containing vesicular zinc, indicating that at least some neurons can
selectively utilise zincergic transmission (Nakashima & Dyck, 2010).
Fig 8 zinc in the neocortex
Figure 8: Zinc in the neocortex.
The sulphide-based Timm-Danscher silver stain
labels metals with insoluble sulphide salts,
principally zinc in synaptic terminals. This image
shows somatosensory cortex, mostly S1ULp,
rostral to S1BF, with a thick zinc-free stripe in
layers 4 and superfcial 5. Medial to S1, somatic
motor regions show greater labelling; the very
dark labelling at lower left is dysgranular and
agranular insular cortex (Gl, AlD, Alvj. lmage
courtesy Professor Gorm Danscher, Aarhus
University.
Placement: near section Chemoarchitectonics / Zinc.
Figure 9: Glia limitans.
Astrocytes labelled for glial fbrillary acidic protein
(GFAPj meet in a continuous sheet at the pial sur-
face of a neocortical slice. Note that astrocyte pro-
cesses extend far beyond the GFAP cytoskeleton
seen here, and permeate the neuropil. lmage cour-
tesy Dr Jerome Staal, Menzies Research lnstitute.
Placement: near section Glia / Astrocytes.
!"
!#$
%"&
$&!
$&!
!#"
"%!"
"#$'
!#"
#($
#($
#(
"#"'
#)"
$%
*%
*%
$%
!$
!$
!"
$%
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co|o0s ca||os0m
Figure 10: Thalamic primary projections
to the neocortex.
Studies of fber degeneration after tha-
lamic lesions reveal the specifc projection
territories of individual nuclei. ln this rep-
resentation the curved sheet of neocortex
has been fattened, and is oriented with
rostral to the left and medial to the bot-
tom. Colours approximate those in fgure
13 of this chapter, but the regions are not
entirely congruent. Adapted from Cavi-
ness and Frost (1980j.
Abbreviations of thalamic nuclei (nomenclature con-
formed to Franklin & Paxinos, 2007j: AD, anterodorsal
nucleus; DLG, dorsal lateral geniculate nucleus; LDvL,
laterodorsal nucleus, ventrolateral part; LPLR, lateral
posterior nucleus, laterorostral part; LPMR, lateral
posterior nucleus, mediorostral part; MD, mediodorsal
nucleus; MGv, medial geniculate nucleus, ventral part;
PlL, posterior intralaminar nucleus; Po, posterior nuclear
group; PoM, posteromedian nucleus; vL, ventrolateral
nucleus; vM, ventromedial nucleus; vPL, ventral pos-
terolateral nucleus; vPM, ventral posteromedial nucleus.
Placement: near section Connectivity / Thalamus.
31
Lxtrace||u|ar matr|x
The extracellular texture of the cortical neuropil is characterised by adhesion and
structural molecules: glycosaminoglycans, hyaluronan, and glycoproteins including
tenascins and the chondroitin sulphate proteoglycans (CSPGs; Rhodes & Fawcett,
2004; Zimmermann & Dours-Zimmermann, 2008). These molecules, which stabilize
the structure of some dendrites and axons by inhibiting growth, can be labelled by
antibodies, by lectins which selectively adhere to the carbohydrates in these
molecules, or by various histochemical methods (Steindler et al., 1989; Murakami et
al., 1999). These assemblies of extracellular matrix molecules are often found in tight
spatial association with neuron cell bodies, from which they derive the name
perineuronal nets (Rhodes & Fawcett, 2004).
IHC or labelling based on reporter-linked lectins can reveal variations in the
extracellular matrix around individual neurons, or between cortical regions, with
implications for local regulation of plasticity and neurite outgrowth (Brckner et al.,
2006; in rat: Brckner et al., 1994; Pizzorusso et al., 2002). Lectins and glycoprotein
antibodies label discrete intrabarrel, barrel perimeter, and septal domains in the
developing S1BF, which becomes less distinct in the mature cortex (Cooper &
Steindler, 1986; Steindler et al., 1989; Oermann et al., 1999; Nakamura et al., 2009).
Cytochrome ox|dase and succ|nate dehydrogenase
Variations in laminar and regional metabolic demands correspond to the density of
mitochondria within the tissue. To visualise mitochondria at the tissue scale,
histochemical methods have been devised which utilise mitochondrial enzymes to
label tissue (Hevner & Wong-Riley, 1989). The best-known of these is cytochrome
oxidase (CO; Wong-Riley, 1979; Silverman & Tootell, 1987), an enzyme which is
prevalent across the entire neocortex, but which labels layer 4 of the primary visual
and auditory regions, S1 and the barrel hollows of S1BF with particular intensity
(Wong-Riley & Welt, 1980; Wallace, 1987; Anderson, Christianson, & Linden,
2009). CO labelling reflects changes in energy demands, such as those observed when
previously active afferents become inactive (Wong-Riley & Welt, 1980), or when
plasticity is modulated (Nishimura et al., 2002). Succinate dehydrogenase, another
mitochondrial enzyme, labels with a similar pattern to CO (Wallace, 1987; in rat:
Koralek, Olavarria, & Killackey, 1990).
G||a
Glia have historically been classified on the basis of a combination of morphology,
interactions with neurons, and cell-specific markers, but in recent years the
boundaries between glial types, and the roles of glia and neurons, have come under
scrutiny. Their common progenitors, and the ability of radial glia and polydendrocytes
to divide and differentiate into both glia and neurons, blurs these distinctions. Within
the class of glia, the most significant distinction is between microglia, whose
functions are immune-related, and macroglia (astrocytes, oligodendrocytes,
polydendrocytes, perineuronal cells) which act as functional partners to neurons (Kim
& de Vellis, 2005). During development, macroglia derive from the same radial glial
cells as principal neurons, a lineage which is specific to the neocortex and
hippocampus (Gorski et al., 2002). This raises the important possibility that there may
be undiscovered differences between the macroglia of the neocortex and those of the
spinal cord and other CNS regions. Some glial properties are specific to the cortex (Le
32
Roux & Reh, 1995) and evidence of regional and laminar variation in astrocyte
phenotypes is beginning to emerge (Garcia et al., 2010).
Neuron-glia ratios vary throughout the nervous system (Herculano-Houzel et al.,
2006), implying a variety of reciprocal relationships. Recent studies have clearly
indicated that neuronal-glial interactions are of great significance in cortical dynamics
(Giaume et al., 2010; in ferret: Schummers, Yu, & Sur, 2008).
kad|a| g||a
Before their true nature was realised, these cells were thought to act as a temporary
scaffold for the developing cortex, and were named glia because of this supporting
role. Some authors consider them to be a form of astrocyte, since they eventually
transform into that cell type (Meller, Breipohl, & Glees, 1968a; Takahashi, Mission,
& Caviness, 1990; Fields & Stevens-Graham, 2002; in monkey: Schmechel & Rakic,
1979). Functionally they have little in common with other glia, although in late
development they generate the differentiated macroglia (astrocytes and
oligodendrocytes) of the cortex (Merkle et al., 2004). They are the pallial stem cells,
giving rise to all the principal neurons, astrocytes and oligodendrocytes of the
neocortex (Gorski et al. 2002). Near the midline, groups of radial glia go through their
generative cycle more quickly and generate the indusium griseum, a strip of neural
tissue which sits on top of the corpus callosum (Smith et al., 2006). In the adult brain,
a population of radial glia persist as astrocyte-like neural stem cells resident in the
subventricular zone (Merkle et al., 2004).
Astrocytes
Astrocytes pervade the CNS grey matter with delicate processes, enveloping neuronal
surfaces and blood vessel basement membranes. Throughout the cortex, individual
astrocytes occupy non-overlapping volumes, each spanning tens of microns, within
which they envelop several hundred dendrites and tens of thousands of synapses
(Wilhelmsson et al., 2006; Halassa et al., 2007; Agulhon et al., 2008). These volumes
average 43 000 "m
3
, of which the astrocyte occupies more than half (average
25 000 "m
3
; Wilhelmsson et al., 2006). This allows astrocytes to closely regulate
tissue volume by means of osmotic shifts and permeability changes in response to
local conditions (Benesova et al., 2009), essential in a tissue where neuronal elements
are constantly adding and removing synapses.
The name astrocyte derives from these cells starlike appearance when labelled for
glial fibrillary acidic protein (GFAP). However, GFAP shows only the internal
cytoskeleton and not their complex surfaces, which extend considerably beyond the
GFAP core into fine, feathery processes (Wilhelmsson et al., 2006; in rat: Bushong et
al., 2002). These processes permeate the cortical parenchyma and unite into the glia
limitans, a continuous sheet forming the margin of cortical tissue below the pia,
around cortical blood vessels and along the interstitial clefts through which solutes
penetrate the tissue (Meller, Breipohl, & Glees, 1968a; Choi, 1994; Brightman &
Kaya, 2000; Brightman, 2002; Fig 9).
Astrocytes regulate neuronal metabolism (Magistretti et al., 1999; Kasischke et al.,
2004; Lovatt et al., 2007), excitability (Fields & Stevens-Graham, 2002), and synapse
dynamics (Volterra & Meldolesi, 2005; Reichenbach, Derouiche, & Kirchhoff, 2010).
They actively regulate neuronal signalling by clearing neurotransmitters from
synaptic clefts (e.g. Genoud et al., 2006), and have been shown to regulate the
33
formation and maintenance of dendrites and spines (Le Roux & Reh, 1994; Murai et
al., 2003). The tight reciprocal coupling between neuron and astrocyte activity has
only recently begun to be appreciated, with some studies going so far as to explore
stimulus-related properties of astrocyte dynamics (in ferret: Schummers, Yu, & Sur,
2008). The ability of astrocytes to transduce metabolic demands into changes in
capillary diameter (Takano et al., 2006) is of particular importance in the cerebral
cortex, where neuronal activity is accompanied by significant haemodynamics, the
basis of intrinsic imaging (e.g. Erinjeri & Woolsey, 2002; Kalatsky & Stryker, 2008)
and functional magnetic resonance imaging (Nair & Duong, 2004; Lovatt et al., 2007;
Adamczak et al., 2010).
Fig 9 Glia limitans
Astrocytes are extensively interconnected via gap junctions, which play an important
role in astrocyte physiology. This network is highly dynamic, and is modulated by
neurotransmission, metabolic demand, membrane potential, and calcium levels
(Kettenmann, Orkand, & Schachner, 1983; review by Giaume et al., 2010). Gap
junctions between astrocytes that contribute to the glia limitans and those in the
parenchyma may also provide an important transport network for solutes entering the
brain (Brightman & Kaya, 2000); glutamate- and potassium-related changes in the
permeability of this network may modulate the blood-brain barrier in an activity-
dependent manner (in rat: Enkvist & McCarthy, 1994).
Although they lack action potentials, astrocytes exhibit dynamic activity with surges
of intracellular calcium, which may occur in individual cells or propagate across the
gap junction networks (reviewed by Agulhon et al., 2008; Giaume et al., 2010).
Calcium surges can occur in response to neuronal activity, or can be driven
independently by the astrocytes themselves (Perea & Araque, 2002; in rat: Takata &
Hirase, 2008). Astrocytes and neurons are in continuous functional interaction;
spillover glutamate from neuronal signalling can activate NMDA receptors on
astrocytes, raising calcium levels and modulating reuptake transporters (Lalo et al.,
2006; Genoud et al., 2006). Conversely, astrocyte activity may prompt the release of
gliotransmitters such as glutamate, D-serine and adenosine triphosphate (ATP) to
reciprocally influence neurons (Fields & Burnstock, 2006; Halassa & Haydon, 2010;
Verderio & Matteoli, 2011). These tight mutual relationships are referred to as
tripartite synapses due to the association of pre- and postsynaptic neuronal elements
with an astrocyte process.
Evidence is accumulating that astrocyte subtypes may be usefully distinguished.
Cortical astrocytes derive from pallial precursors, unlike other populations (Gorski et
al., 2002), and differ from other CNS astrocytes in trophic interactions with neurons
(Le Roux & Reh, 1994, 1995). Among cortical astrocytes, heterogeneity in connexin
expression (Houades et al., 2008; Koulakoff, Ezan, & Giaume, 2008), lineage (Garcia
et al., 2010), and responses to ischaemia (Benesova et al., 2009) indicate regional and
individual specialisations. There is also some indication that interaction with neurons
helps to determine astrocyte phenotype (Garcia et al., 2010). Greater understanding of
astrocyte physiology will doubtless reveal many such distinctions.
C||godendrocytes
Oligodendrocytes establish and maintain myelination in the cortex and underlying
white matter (e.g. Fancy et al., 2010), arising from the same progenitors as cortical
neurons, and also differentiating when required from Olig2 expressing precursor cells
34
in the adult cortex (Ivanova et al., 2003; Dimou et al., 2008; Girolamo et al., 2010).
The process of myelination is an essential component of cortical maturation, and
requires multiple layers of cell membrane to be synthesised by the oligodendrocyte.
This process is regulated by complex axon-oligodendrocyte interactions, mediated by
ATP, cell surface molecules, astrocytes and physical interactions (Fields & Stevens,
2000; Ishibashi et al., 2006; Fields & Burnstock, 2006; Kippert et al., 2009; Bauer &
ffrench-Constant, 2009; Mitew et al., 2010; Verderio & Matteoli, 2011).
Demyelination and remyelination processes maintain a dynamic balance, with
oligodendrocytes extending and retracting processes, and (de-)differentiating to and
from precursor forms; this typically results in the myelination of around 10% of
cortical axons (Piaton, Gould, & Lubetzki, 2010; Girolamo et al., 2010). Unlike
Schwann cells in the periphery, each oligodendrocytes myelinates many different
axons, resulting in branched and elaborate morphology. Compared to white matter
tracts, cortical oligodendrocytes are smaller and myelinate shorter axon segments
(Murtie, Macklin, & Corfas, 2007).
Oligodendrocytes are far more than passive insulators of cell membranes; they
communicate extensively with neurons, and couple to each other in a gap junction
network which is largely separate to that of astrocytes (Kettenmann, Orkand, &
Schachner, 1983; Maglione et al., 2010). They also provide trophic support essential
to axonal growth and survival (Sturrock, 1980; Lappe-Siefke et al., 2003; Vincze et
al., 2008).
er|neurona| sate|||te ce||s
Oligodendrocytes, astrocytes and microglia are all occasionally found in close
association with neuron cell bodies; in this context they are referred to as perineuronal
satellite cells (Takasaki et al., 2010). Such cells were described by Ramn y Cajal as
sitting close to the base of pyramidal cells near the origin of the axon (tr. DeFelipe &
Jones, ch. 21). Perineuronal oligodendrocytes are a non-myelinating phenotype found
in deeper cortical layers which may specialise in trophic support and neuronal
protection (Ludwin, 1984; LeVine & Torres, 1993; Taniike et al., 2002; Takasaki et
al., 2010).
er|cytes
These pluripotent cells surround capillaries outside the glia limitans, but appear to be
an important mediator coupling cortical metabolic demand to changes in capillary
diameter (Peppiatt et al., 2006), further mediating flow-dependent functional imaging.
o|ydendrocytes ] o||godendrocyte precursor ce||s
Oligodendrocyte precursor cells, also known as NG2+ (nerve/glial antigen 2) glia, and
polydendrocytes (Nishiyama, 2007), act as glial stem cells in the mature CNS, giving
rise to oligodendrocytes in white matter and persisting in the cortical grey matter in a
variety of functional roles (Dimou et al., 2008). A continuum of progenitor cells
including glial-restricted progenitors, oligodendrocyte precursors and pre-myelinating
oligodendrocytes are persistently present throughout layers 1-6 of the adult mouse
neocortex (Dimou et al., 2008; Girolamo et al., 2010). In CNS regions outside the
neocortex, evidence suggests that these cells can also differentiate into neurons
(Rivers et al., 2008; Zhu, Bergles, & Nishiyama, 2008; Guo et al., 2009, 2010),
astrocytes (Zhu, Bergles, & Nishiyama, 2008; Guo et al., 2009), and can even
generate Schwann cells in the CNS (Zawadzka et al., 2010). Conversely, a recent
35
study suggests that expression of NG2 commits these cells to the oligodendrocyte
lineage, and they do not generate neurons or astrocytes under normal or traumatic
conditions (Kang et al., 2010).
Polydendrocytes are not the only glial progenitors to persist in the adult cortex: glial-
restricted precursors capable of generating astrocytes and polydendrocytes can also be
detected by their expression of the ganglioside marker A2B5 (Rao & Mayer-Proschel,
1997; Girolamo et al., 2010).
M|crog||a
Microglia derived from embryonic macrophages (Ginhoux et al., 2010) enter the CNS
and assume a sentry role to sample the extracellular space in the cerebral cortex.
Microglia respond to pathogens and disruption of CNS activity with an array of
cytokines and other secreted molecules, and by transforming state between resting,
activated and phagocytic forms (for review, see Kim & de Vellis, 2005).
Iunct|on of the neocortex
The neocortex is concerned with the most abstract level of nervous system analysis
and behaviour guidance. Among CNS structures, it has the widest access to sensory
information from diverse (but not all) receptor systems, allowing it to couple
behaviour to sensory events (e.g. Matyas et al., 2010; Zhou et al., 2010; in rat: Krupa
et al., 2001). The striking cytoarchitectonic regularity of the neocortex is suggestive
of a corresponding functional regularity; the implication is that the neocortex extracts
characteristic stimulus qualities regardless of modality. The overwhelming
interconnection of the neocortex combines and correlates these derived properties,
allowing multimodal integration suitable for shaping response patterns.
Pyramidal neuron axons project locally and into the subcortical white matter, where
they disseminate these responses to other cortical regions or other parts of the nervous
system (White, 1989). Around 80% of cortical neurons are excitatory, and 20% are
inhibitory (Nieuwenhuys, 1994). Although these influences must closely match to
prevent seizure or coma, in numeric terms excitatory synapses outnumber inhibitory
connections in mouse neocortex by around 5:1 (DeFelipe, Alonso-Nanclares, &
Arellano, 2002; White, 1989). This ratio is even higher in rats (8:1) and humans (8:1;
DeFelipe, Alonso-Nanclares, & Arellano, 2002).
The actual processing of the cortex includes responses to afferents (principally from
thalamocortical afferents), interactions between the excitatory and inhibitory neurons
of the cortex itself, corticocortical interactions, and corticofugal outputs which
communicate influence to effector systems and other parts of the CNS (Nieuwenhuys,
1994). Intrinsic activity of single and networked cortical neurons also drives cortical
excitation (MacLean et al., 2005; Le Bon-Jego & Yuste, 2007), as do loops between
cortex and thalamus, in which cortical outputs drive thalamic nuclei to excite further
cortical activity (Theyel, Llano, & Sherman, 2010). These activities are shaped and
potentiated by modulatory systems, in which subcortical nuclei influence cortical
processing using a variety of neurotransmitters (McCormick, Wang, & Huguenard,
1993; Saper, Scammell, & Lu, 2005).
36
Connect|v|ty
For detailed treatments of cortical connectivity the reader is referred to Braitenburg
and Schz, Cortex: Statistics and Geometry of Neuronal Connectivity (1998) and
Peters and Jones, Cerebral Cortex, Volume 5: Sensory-Motor Areas and Aspects of
Cortical Connectivity (1986).
The mouse neocortex is crammed with connections, which occupy 84% of cortical
volume: it is estimated that there are 3.3 to 4 km of axon and nearly a billion synapses
in every cubic millimetre of grey matter. Cortical neurons average 3.6 mm of
dendrites, and the average length of pyramidal cell axons is 20 to 40 mm in total
(Schz & Palm, 1989; Braitenburg & Schz, 1998).
The relatively uniform structure of neocortex implies that each areas function is
determined by its connectivity with other cortical regions and subcortical structures.
This in turn means that connectivity is established, maintained and altered with great
care by regulatory mechanisms. Collectively, these processes are referred to as
plasticity. Early developmental exuberance of connectivity is winnowed down to
specific relationships, which are then used as the basis for selective addition, removal
and modification of synapses. For example, corticotectal projection neurons of the
visual cortex initially send axons down the corticospinal tract as well (OLeary &
Koester, 1993) which are pruned in a subsequent phase of development (Low et al.,
2008), although some neurons maintain dual projections (Mitchell & Macklis, 2005).
Most of the connectivity of the mouse neocortex is local: axo-dendritic and axo-
axonic synapses, and dendrite-to-dendrite connections via gap junctions. The
dendrites of pyramidal cells and interneurons ramify locally on a typical scale of tens
of microns, whereas the axons of some interneurons can extend for millimetres across
layers or tangentially. The axons of pyramidal cells (and some inhibitory neurons) can
project tens of millimetres, joining regions of the cortex and connecting directly to
other forebrain, hindbrain and even spinal cord targets. These longer projections are
achieved by axons travelling radially straight down to the subcortical white matter,
within which they travel to other cortical areas and re-emerge to make synapses with
neurons, or from which they join descending tracts to travel to subcortical
destinations, most notably the thalamus. However, in the mouse these two types of
connectivity are not distinct categories, and even quite long-range corticocortical
projections may travel within the grey matter (Schz et al., 2006).
Incoming activity derives largely from the thalamus, conveying all the special senses
apart from olfaction (whose primary cortex is piriform, although the olfactory bulb
projects directly to insular neocortex; Shipley & Adamek, 1984), as well as excitatory
drive from motor and non-specific thalamic nuclei (Herkenham, 1986). Fibres from
the thalamus enter the cortex from the subcortical white matter or by travelling in the
superficial plexus of layer 1, where they are joined by other subcortical projection
fibres influencing cortical activity. This activity triggers corticofugal projections to
the thalamus, striatum, midbrain, brainstem and spinal cord, mediated by distinct
layer 5 populations, each with characteristic physiology, connectivity and dynamics
(Hattox & Nelson, 2007; Brown & Hestrin, 2009).
The consistent arrangement of cortical tracts and layers ensures efficient and diverse
connectivity for all cortical regionsinstead of ad hoc linkages, the grouping and
routing of cortical fibres allows for efficient distribution of activity and for large areas
of neocortex to be involved in processing (Douglas & Martin, 2004). The famous
reeler mouse mutation, in which a disruption of developmental contact guidance leads
37
to disordered cortical layering, illustrates that even a minor disruption to these
relationships can have a significant impact on cortical efficiency (DArcangelo &
Curran, 1998).
Cort|cocort|ca|
Cortical neurons in close proximity connect profusely, and each region of mouse
neocortex is connected on average to six other regions (Schz & Prei$l, 1996), in
accord with size-related scaling observed across many mammal species (Changizi &
Shimojo, 2005). A quantitative survey using anterograde tracer injections in the
mouse cortex found that local connectivity dominated, although most locations
revealed additional projection fields covering an area hundreds of times the size of the
injection site (Schz et al., 2006).
The great majority of these projections originate with excitatory pyramidal cells of
layers 2/3, 5 and 6 (White, 1989), although some GABAergic projection neurons have
also been described (Tomioka et al., 2005). Thomson and Lamy (2007) emphasize the
reciprocity of most corticocortical projections; in sensory regions, forward
projections originate in layer 2/3 and terminating in layers 2/3 and 4, and feedback
projections arise in layers 2/3, 5 and 6 and terminate primarily in layers 1, 2/3 and 5
(Carvell & Simons, 1987; Welker, Hoogland, & van der Loos, 1988; White, 1989).
Among the excitatory projection neurons, the corticocortical and transcallosal
populations can be identified on the basis of glutamate receptor subunit and
transcription factor expression (Hisaoka et al., 2010; in rat: Kondo, Sumino, &
Okado, 1997).
74#.3, *$((4,3%
The largest commissural connection system is the corpus callosum, a band of axonal
fibres linking a subset of homotopic regions on the two cerebral hemispheres (Yorke
& Caviness, 1975; White & Czeiger, 1991; Olavarria & Van Sluyters, 1995). The
corpus callosum also contains a small number of heterotopic connections (Schz et
al., 2006). Using light microscopy, Tomasch and MacMillan (1957) estimated that the
corpus callosum of the mouse contains somewhat more than 300 000 fibres. Since
their methods were inadequate to clearly distinguish unmyelinated fibers (Innocenti,
1986), this figure appears to be a gross underestimate. Ultrastructural surveys indicate
that 30% of mature callosal axons are myelinated (Sturrock, 1980; Vincze et al.,
2008), so Tomasch and MacMillans count of 300 000 myelinated fibres implies a
true total of around a million axons in the corpus callosum. However the extent of the
corpus callosum is highly variable between strainssee the section Strain Variation
below.
Although callosal connectivity is extensive, it is far from ubiquitous, and many
cortical areas are sparsely connected to the opposite hemisphere (Yorke & Caviness,
1975; the primary auditory cortex has a strong transcallosal innervation, but V1 and
S1 have very little (Wang, Gao, & Burkhalter, 2007). Although projections are not
strictly reciprocal (Hartenstein & Innocenti, 1981), areas receiving few transcallosal
fibres also send very few fibres to the opposite hemisphere (Yorke & Caviness, 1975),
and callosally projecting neurons are targets for return callosal projection (Porter &
White, 1984). Eighty per cent of callosally projecting neurons reside in layer 2/3, and,
20% in layer 5, with a few in layer 6 (White, 1989; Czeiger & White, 1993; Ramos,
Tam, & Brumberg, 2008; Molyneaux et al., 2009; Fame, MacDonald, & Macklis,
2011); likewise, callosal axons preferentially terminate in layer 2/3, and almost
38
invariably on spiny dendrites (Hartenstein & Innocenti, 1981; White & Czeiger,
1991). Callosal projection neurons of layer 5 closely resemble those of layer 2/3 in
terms of morphology and physiology, suggesting that they fulfil a similar role for
supragranular and infragranular networks (Ramos, Tam, & Brumberg, 2008).
D/0+#&4# *4%%&,,3#+
Further interhemispheric connectivity is provided by the anterior commissure, a
smaller fibre tract located rostral and ventral to the corpus callosum. It contains
500 000 to 600 000 axons in the mouse, 20% of which are myelinated (Sturrock,
1987; Livy et al., 1997). Although the bulk of anterior commissure fibres link the two
olfactory bulbs and associated piriform cortex, parts of the ventral agranular insular
neocortex send interhemispheric projections via this pathway (in rat: Horel &
Stelzner, 1981; Jouandet & Hartenstein, 1983; Livy et al., 1997). In mice that lack a
corpus callosum, the anterior commissure has been reported to contain 17% more
fibres than usual, although these seem not to be rerouted callosal axons (Livy et al.,
1997).
7&/:3(3% $/' $#*3$0+ ;$,*&*3(3,
Within each hemisphere a bundle of axons runs longitudinally, deep to the
retrosplenial and cingulate cortex and running dorsal to the corpus callosum inside the
medial surface of each hemisphere. Ramn y Cajal termed the medial part of this
bundle the cingulum, with a broader arcuate fasciculus lateral to it (tr. DeFelipe &
Jones, 1988, ch. 18; Iwahori & Mizuno, 1981; Vincze et al, 2008).
1ha|amus
Fig 10 Primary thalamic projections
The thalamus is the most significant subcortical input to the neocortex, and in turn
receives an even larger corticothalamic projection (Sherman & Guillery, 1996; Jones,
1998). The functional regions of the cortex are defined by the spread of projecting
axons from specific thalamic nuclei (Caviness & Frost, 1980; Guldin, Pritzel, &
Markowitsch, 1981), and the interaction between cortex and thalamus is fundamental
to cortical operation (e.g. Jafari, Zhang, & Yan, 2007; in rat: Hirata & Castro-
Alamancos, 2010). Genetic ablation of the thalamus results in a non-functional cortex
and is lethal at birth (Miyashita-Lin et al., 1999).
Connections between cortex and thalamus are usually ipsilateral (White & DeAmicis,
1977), but a small proportion of crossed fibres has been observed (Carretta et al.,
1996). Thalamocortical afferents cluster together as the internal capsule on the surface
of the thalamus, which splits into fibre bundles traversing the striatum and then
merges into the subcortical white matter (Bernardo & Woolsey, 1987).
Corticothalamic projections follow the same route in reverse.
E2$($%4*4#0&*$(
Several types of projections are made by nuclei of the thalamus to the neocortex. The
principal distinction is between specific projections, which target a single area or
cluster of areas, and non-specific projections which connect across wide regions
(Caviness & Frost, 1980; Fig 10).
Specific afferents terminate in all layers, but concentrate in layers 4 and 6, whereas
projections from cortex back to thalamus tend to originate with layer 5 and 6 neurons
(Frost & Caviness, 1980; Bernardo & Woolsey, 1987; White, 1989; Lam & Sherman,
39
2010). The layers in which they terminate differ between nuclei and cortical regions
(Frost & Caviness, 1980), targeting principal neurons (White, 1989) and interneurons
(White, Benshalom, & Hersch, 1984), and preserving strong topographic organisation
in sensory projections (Hoogland, Welker, & van der Loos, 1987).
Specific projections to sensory cortex have two components (Sherman & Guillery,
1996), termed primary and secondary, or lemniscal and non-lemniscal (Poggio &
Mountcastle, 1963, describing somatosensory pathways). For mouse somatosensation,
the ventral posteromedial (VPM) and posterior medial (PoM) nuclei convey the
lemniscal and non-lemniscal projections to cortical S1. These projections terminate
quite differently in the cortex, VPM targeting layers 4, deep 5 and superficial 6, and
PoM superficial 5; the intracortical pathways diverge from there (Bureau, von Saint
Paul, & Svoboda, 2006; Aronoff et al., 2010; Frost & Caviness, 1980). In the auditory
system the medial geniculate and posterior intralaminar nuclei (MG and PIL) supply
the primary and secondary projections, conveying precise tonotopic and polymodal
integrative information respectively (Hofstetter and Ehret, 1992; Cruikshank,
Killackey, & Metherate, 2001; Hu, 2003). For the visual system, the dorsal lateral
geniculate and the lateral posterior nuclei (DLG and LP) originate the primary and
secondary thalamic projections (Caviness & Frost, 1980; Simmons, Lemmon, &
Pearlman, 1982).
Motor-related cortical regions also receive direct thalamic projections, although no
distinction is made between primary and secondary. Primary motor cortex is
innervated by the ventrolateral (VL), ventral posterolateral (VPL, sometimes called
lateral ventrobasal) and lateral dorsal ventrolateral (LDVL) nuclei, conveying
cerebellar feedback and basal ganglia influences (Caviness & Frost, 1980; Terashima
et al., 1987; Tlamsa & Brumberg, 2010). Frontal regions receive thalamocortical
fibres from the medial dorsal (MD) and anteromedial (AM) nuclei (Guldin, Pritzel, &
Markowitsch, 1981).
Non-specific thalamic nuclei send excitatory projections across the surface of the
neocortex in layer 1, contacting the apical dendrites of layer 2/35 pyramidal cells in
a cortical-area-dependent fashion (Frost & Caviness, 1980; in rat: Mitchell & Cauller,
2001; Zhu & Zhu, 2004; Rubio-Garrido et al., 2009). Other nuclei such as the
centromedial make widespread projections to deep cortical layers (Scheibel &
Scheibel, 1967; in rat: Herkenham, 1986). These non-specific projections originate
with a subset of thalamic nuclei which also includes the centrolateral (Llins, Leznik,
& Urbano, 2002; Theyel, Lee, & Sherman, 2010), (lateral) ventromedial (Caviness &
Frost, 1980; in rat: Mitchell & Cauller, 2001; Monconduit & Villanueva, 2005;
Herkenham, 1986), posterior and lateral posterior (White & DeAmicis, 1977;
Caviness & Frost, 1980; in rat: Herkenham, 1986). Nonspecific (or superficial: Jones,
1998) projections are thought to modulate attention and arousal levels of cortex
(Scheibel & Scheibel, 1967; Herkenham, 1986; Sherman & Guillery, 1996), for
example as the result of nociceptive stimuli (in rat: Monconduit & Villanueva, 2005).
They may also interact with specific, stimulus-related thalamic projections to bind
and cohere cortical activity (Llins, Leznik, & Urbano, 2002). Return cortical
projections to specific and non-specific nuclei are made by distinct populations of
layer 5 and 6 neurons (White & Hersch, 1982; in rat: Zhang & Deschnes, 1998).
74#0&*402$($%&*
Corticothalamic projections greatly influence thalamic activity, but exactly how
remains an active topic for research (Castro-Alamancos, 2004; Lam & Sherman,
40
2010). Cortical activity can also drive thalamic nuclei to excite other areas of cortex,
in ways which differ qualitatively from direct corticocortical projection, and which
may even be more significant than direct activation (Reichova & Sherman, 2004;
Llano & Sherman, 2008; Theyel, Llano, & Sherman, 2010). In addition to their
thalamic targets, corticothalamic projection neurons activate local inhibitory neurons
in cortex (White & Keller, 1987).
Str|atum
A prominent subcortical influence on cortical motor control, attention and salience is
the interplay between the striatum, globus pallidus, substantia nigra and the
subthalamic nucleus. This network is frequently called the basal ganglia, although the
term has long been criticised for grouping unrelated structures. The principal input to
this network is via the striatum (Tepper, Abercrombie, & Bolam, 2007), to which the
motor, somatosensory, cingulate, and retrosplenial cortical areas make direct
projections (White & DeAmicis, 1977; Jinno & Kosaka, 2004; Aronoff et al., 2010;
Matyas et al., 2010). This projection is predominantly ipsilateral, but is also
contralateral, and originates with upper layer 5 neurons slightly superficial to those
projecting to the spinal cord and brainstem (Hersch & White, 1982; Pan, Mao, &
Dudman, 2010; Anderson et al., 2010). Parietal and temporal cortical layer 5 neurons
(areas PtPR and AuD/AuV; Jinno & Kosaka, 2004; Pan, Mao, & Dudman, 2010), and
frontal layer 2/3 neurons also project significantly to the striatum (Pan, Mao, &
Dudman, 2010; in rat: Akintunde & Buxton, 1992). The striatum does not project
back to cortex (White & DeAmicis, 1977). Instead, its predominantly GABAergic
efferent neurons project to the substantia nigra and globus pallidus (Ding, Peterson, &
Surmeier, 2008; Ding et al., 2010).
Amygda|ar nuc|e|
The neocortex is extensively and reciprocally connected with the amygdalar nuclei
see chapter 7 for details.
n|ppocampus
The neocortex is extensively and reciprocally connected with the hippocampal
formationsee chapter 5 for details.
C|austrum
The claustrum, a small nucleus interposed between rostral insular cortex and the
underlying white matter (Guirado et al., 2003; Real, Dvila, & Guirado, 2003) may
integrate activity across the cortex. Studies of cortico-claustral connections in the
mouse are scarce, but rats and mice both have extensive excitatory projections to the
claustrum from frontal and cingulate, but not motor, cortex (Sherk, 1986; Sadowski et
al., 1997; Kowia!ski, Timmermans, & Mory", 2001). The rat claustrum receives
projections from secondary visual cortex, but hamsters lack this projection (Sherk,
1986), indicating that rodents differ in their claustral connectivity.
There is evidence for extensive return projections from claustrum to cortex. In rats,
the dorsal claustrum sends projections back to frontal, motor and somatosensory
cortex, and the ventral claustrum sends projections to auditory and visual cortex
(Sadowski et al., 1997); in mice, claustral zincergic neurons project ipsilaterally to V1
and S1BF (Garrett, Srensen, & Slomianka, 1992; Brown & Dyck, 2005).
41
M|dbra|n
Sensory neocortical regions send projections to midbrain regions via collaterals from
the corticospinal tract (see below), notably from visual and somatosensory cortex to
the superior colliculus (Lemmon & Pearlman, 1981; Welker, Hoogland, & van der
Loos, 1988; Aronoff et al., 2010; Yoshihara et al., 2010), and from ipsilateral and
contralateral auditory cortex layer 5 to the inferior colliculus (Huffman & Henson,
1990; Yoshihara et al., 2010). Motor neocortical regions send ipsilateral projections to
the red nucleus (Iwahori & Nakamura, 1991; in rat: Brown, 1974; Akintunde &
Buxton, 1992) and the midbrain tegmental nucleus (in rat: Wise & Donoghue, 1986).
The medial prefrontal and insular regions project to the periaqueductal grey, a pain
modulatory centre (in rat: Christie, James, & Beart, 1986; Legg, Mercier, &
Glickstein, 1989 fig 9).
Other midbrain projections from cortex include the midbrain raphe (in rat: Wise &
Donoghue, 1986) and a small bilateral projection from frontal, cingulate and
retrosplenial cortex to the ventral tegmental area (Irle et al., 1984).
n|ndbra|n
Projections from the neocortex to the hindbrain are one of the major effector
pathways for the cortical regulation of behaviour and physiology. Neuron assemblies
which generate specific behaviours such as feeding and breathing are located in the
hindbrain, as well as the motor nuclei for cranial nerves; face-related motor and
somatosensory cortex projects to hindbrain effector nuclei (Hattox & Nelson, 2007; in
rat: Li, Florence, & Kaas, 1990) and primary motor cortex projects to the parvicellular
reticular formation to drive patterned movements (Alstermark & Ogawa, 2004;
Matyas et al., 2010).
The pontine nuclei of the hindbrain relay activity to the cerebellum, and ipsilateral
corticopontine connections have been described originating in layer 5 of most, but
especially motor, somatosensory and visual regions, of the neocortex (White &
DeAmicis, 1977; Welker, Hoogland, & van der Loos, 1988; Aronoff et al., 2010; in
rat: Legg, Mercier, & Glickstein, 1989; Akintunde & Buxton, 1992; Leergaard &
Bjaalie, 2007). Another nucleus which provides input to the cerebellum, the inferior
olive, is innervated by fibres from the motor cortex (in rat: Wise & Donoghue, 1986).
The cerebellum projects back to the motor cortex chiefly by means of the
ventrolateral nucleus of the thalamus (in rat: Wise & Donoghue, 1986).
Various cortical sensory regions project to afferent relay nuclei in the hindbrain. The
parabrachial nucleus, which coordinates visceral efferent activity and processes taste,
receives projections from layer 5 of ipsilateral cortex, predominantly the insular
regions (Tokita, Inoue, & Boughter, 2009). The auditory cortex projects to the
cochlear nuclei (Yan & Ehret, 2002; Meltzer & Ryugo, 2006; Luo et al., 2008; Liu et
al., 2010), and somatosensory cortex projects to the spinal trigeminal nucleus
(Welker, Hoogland, & van der Loos, 1988; Aronoff et al., 2010), although this
projection may also be movement related (Matyas et al., 2010).
Several hindbrain nuclei project to the cortex as transmitter-specific modulatory
systems, described in a later section.
42
Sp|na| cord
Excitatory pyramidal cells (Wise & Donoghue, 1986; Giuffrida & Rustioni, 1989a) in
layer 5 of the motor cortex and adjoining somatosensory cortex (Steward et al., 2004)
give rise to axons of the corticospinal tract (Liang, Paxinos, & Watson, 2010). These
fibres pass through the same striatal bundles of the internal capsule, from which they
converge on the cerebral peduncles and course along the underside of the hindbrain, a
pathway confusingly known as the pyramidal tract despite its lack of a raised shape in
mice (Terashima, 1995). In the caudal hindbrain most of these fibres turn dorsally and
cross the midline, continuing in the innermost dorsal columns of the spinal cord
(Canty & Murphy, 2008) or the dorsolateral column (14%; Steward et al., 2004).
There is also a small uncrossed projection which travels in the ventral white matter
(Wise & Donoghue, 1986; Terashima, 1995).
The corticospinal tract is often considered to be a major component of motor control,
but this not significantly true for rodents (Wise & Donoghue, 1986; Lemon, 2008;
Watson & Harvey, 2009); in fact mice manipulated to disconnect the cortex during
development are able to walk and swim quite normally (Zhou et al., 2010). Although
primates have some direct corticospinal connections with # motor neurons, and other
rodents have a significant corticospinal input to spinal circuits generating movement,
neither of these are present in the mouse (Alstermark & Ogawa, 2004; Asante et al.,
2010); instead the murine corticospinal tract is probably more involved in modulating
sensory relays, particularly for nociception (Lemon, 2008).
Co|umns and modu|ar|ty
From the earliest connectional descriptions of the mammalian cortex (Ramn y Cajal,
tr. DeFelipe & Jones, 1988), it has been apparent that most dendrites and axons
extend radially. The obvious implication is that activity spreads radially within the
cortex: activating a neuron is most likely to influence other neurons superficial and
deep to it, creating a column of activity. Whether these are fundamental groupings
which remain constant, regardless of processing demands (termed modules), or are
temporary associations, has been a topic of considerable interest to cortical
physiologists.
DeFelipe (2002) traces the idea of cortical modularity to an original proposal of an
elementary cortical unit of operation by Lorente de N in 1938, based on what is
now known to be barrel cortex (Lorente de N, 1922;1992). This attempt to
characterise the quasi-regularity of cortical neurons and layering had a profound
effect on subsequent studies, most notably those of Mountcastle and Hubel and
Wiesel (see Mountcastle, 1997), working in cat sensory cortex. The extraordinary
regularity and organisation of the cortical representations observed by these
researchers offered hope that cortical complexity may be reducible to interactions
between simpler modules. In the mouse cortex the most striking example of repeated
units is the barrel cortex, which may arise as a consequence of devoting a large
cortical region to a small number of discrete afferent sources, although this fails to
occur in other species (Purves, Riddle, & LaMantia, 1992) and may be interpreted
more simply as very obvious somatotopy (Horton & Adams, 2005).
Aside from the regularities of barrel cortex (Lorente de N, 1922; Woolsey & van der
Loos, 1970; White & Peters, 1993), other candidates for modularity in the mouse
cortex have been proposed, notably the bundling of pyramidal neuron apical dendrites
(Escobar et al., 1986; White & Peters, 1993; Lev & White, 1997). These studies found
43
that the apical dendrites from neurons in layer 6, and layers 2/35, cluster together as
they ascend toward their tufts in layers 4 and 1 respectively, suggesting to the authors
that the neurons involved were organised into modules. The functional significance of
these proposed modules remained unclear: in the 1986 and 1993 studies the bundles
related to sensory barrels, whereas Lev and White (1997) observed selective grouping
of callosally projecting neurons. More recently, Krieger, Kuner, and Sakmann (2007)
examined whether these clusters implied commonality of connections for the neurons
comprising them. Although their dendritic fields overlapped substantially, there was
no particular correlation of connections between members of the same bundle,
suggesting that clusters are not modules in a functional sense. The fact that the
dendrites of callosally projecting neurons preferentially cluster together (Lev &
White, 1997) implies that common dendritic guidance cues may be responsible.
Clustering and grouping of thalamocortical and interneuron terminals on a 100 "m
scale have been observed in rat layers 1 and 2 (Ichinohe et al., 2003), and in fact there
is evidence for a range of scales for observed regularities, none of which is
fundamental (Rockland & Ichinohe, 2004). Over the years, comprehensive reviews
have concluded that the evidence for cortical modularity is patchy, contradictory, and
highly species- and function-specific, varying even between individuals of the same
species (Purves, Riddle, & LaMantia, 1992; Swindale, 2000; Horton & Adams, 2005;
Douglas & Martin, 2007). Even where functional columns can be identified
physiologically, anatomical regularities observed in the neocortex simply do not
correlate with them. This is not to deny that there are fundamental regularities in the
connectional arrangements of cortical neurons, but instead suggests that the neocortex
is not preordained to use fixed processing clusters. Instead afferents to the neocortex
evoke spreading patterns of influence and interaction, dynamically grouping neurons
as they process shared information.
The debate over cortical modularity has diminished with time. A conservative view to
take is that the cellular and laminar patterning of the neocortex produces an ordered
array of cells, that can behave as if modular when given a highly structured input.
Although the cortex is not intrinsically modular, inputs which are strongly patterned
during key developmental phases can impose module-like regularity on the physical
structure of the cortex, evident in barrel cortex, ocular dominance columns, and other
famous anomalies.
C|rcu|ts and process|ng
In small mammals, the cerebral cortex is an integrated processing environment in
which sensory analysis is firmly predicated on the behaviour it enables, and the act of
understanding a stimulus is inextricably woven into the process of framing responses
to that stimulus (cf. Ferezou et al., 2007; Niell & Stryker, 2010; Matyas et al., 2010).
The cortex attends to precisely as much sensory information as it can behaviourally
use, characterised by Douglas and Martin as just-enough and just-in-time analysis
(Douglas & Martin, 2007).
Cortical activity is recurrent and self-sustaining, with corticopetal afferents
contributing less influence than the highly interconnected local neurons (Douglas &
Martin, 2007; Burkhalter, 2008). Afferents and efferents offer starting points for the
analysis of cortical activity, and are linked by a range of sophisticated and diverse
pathways. Inputs and outputs may be linked quite directly, as well as by larger scale
activity spanning local neurons and interacting cortical regionsa relationship
originally recognised by Ramn y Cajal (Jones, 2011). The relative contribution of
44
these influences varies in a state- and situation-dependent manner, regulated by
cortical activity, plasticity, and modulatory neurotransmitters biasing the mix of
competing pathways.
Afferent process|ng
The diversity of neuron forms and physiology allows incoming activity to elicit a
diversity of responses, from which it is possible to derive a range of useful
interactions between afferent patterns (Huang, Di Cristo, & Ango, 2007; in rat: Gupta,
Wang, & Markram, 2000). Combining this property with the prodigious connectivity
of the cortex (described as a mixing machine by Schz et al., 2006) suggests that
cortex is a combinatorial analysis engine, where incoming stimuli interact with
current activity in a pattern-dependent manner, so that certain stimulus aspects are
enhanced and others disregarded.
Thalamocortical and corticocortical afferents influence both principal neurons and
interneurons in their terminal fields, usually exciting them, although a small minority
of inhibitory corticocortical projections exist (Tomioka et al., 2005). Early
assumptions of indiscriminate innervation in the terminal field are being displaced by
data on the specificity and heterogeneity of connection targets, although the added
complexity is daunting (White, 1989, 2002; Nieuwenhuys, 1994; Thomson & Morris,
2002). As for connectivity, the focus of most rodent thalamocortical research is the
barrel field, and so most of the following data derives from studies on this region.
E2$($%4*4#0&*$(
The thalamus is anything but a passive relay: it extensively transforms the activity it
receives. Its processing is strongly influenced by return corticothalamic projections
and neuromodulators from the midbrain and ventral forebrain, allowing information
processing to change with behavioural and conscious states (Steriade, 2000; Castro-
Alamancos, 2004; Sato et al., 2007; in rat: Hirata & Castro-Alamancos, 2010).
Activity triggered by thalamocortical afferents is closely similar to intrinsic activity,
even in primary sensory cortex (Gil & Amitai, 1996; MacLean et al., 2005), which
reflects the fact that even in layer 4, thalamic afferents supply only a small proportion
of excitatory synapses on principal neurons (Benshalom & White, 1986; Beierlein et
al., 2002), albeit with greater synaptic efficiency (Gil, Connors, & Amitai, 1999).
Incoming activity must interact with intrinsic activity, which imposes frequency and
timing constraints on effective thalamocortical activation (in rat: Pinto et al., 2003).
Presynaptic GABA
B
receptors (Porter & Nieves, 2004), regular synchronous
fluctuations between up and down states of networked cortical neurons (Petersen
et al., 2003; Mohajerani et al., 2010), and influences from other cortical layers (Lee &
Sherman, 2009) alter the activity evoked by thalamocortical fibres.
In cortex, thalamic afferents excite both principal neurons and interneurons (White &
Hersch, 1981; White, Benshalom, & Hersch, 1984; Agmon & Connors, 1992; Rose &
Metherate, 2005). This incoming activity triggers some excitation, and, more
significantly, variably timed inhibitory responses. The latter come from different
interneuron populations which interact with ongoing network activity, including at
least two gap junction-coupled, mutually inhibitory interneuron networks spanning
layer 4 (Porter, Johnson, & Agmon, 2001; Beierlein et al., 2002; in rat: Amitai et al.,
2002; Beierlein et al., 2003). The fast spiking network (which in layer 4 is
predominantly basket cells) is reliably activated by intrinsic and extrinsic innervation
and tends to specifically inhibit thalamocortical spine synapses (in rat: Kubota et al.,
45
2007; Staiger et al., 2009). The regular spiking interneuron network is highly
frequency-dependent and interacts with the fast spiking network to amplify and
propagate high-frequency activity to other layers, and suppress low frequencies
(Beierlein et al., 2002).
In fact, thalamocortical afferents activate interneurons far more than they activate
principal neurons, triggering a rapidly damped cascade of feed-forward inhibition to
layers 4 and 2/3, which is not evoked by intracortical excitation (Gil & Amitai, 1996;
Porter, Johnson, & Agmon, 2001; Agmon & Connors, 1992; Cruikshank, Lewis, &
Connors, 2007; Ma et al., 2010). Thalamocortical inputs also prime interneurons
across all layers, subtly shaping cortical receptive fields and inhibitory dynamics
(Verbny et al., 2006). The mix of delayed responses is, unsurprisingly, complex: fast-
spiking basket cells are directly activated but rapidly damped (Agmon & Connors,
1992; Tan et al., 2008) and supragranular Martinotti cells activate immediately, albeit
weakly (Fanselow, Richardson, & Connors, 2008; Cruikshank et al., 2010; Ma et al.,
2010). Chandelier cells make delayed responses after other neurons have fired (in rat:
Zhu, Stornetta, & Zhu, 2004), as do layer 5 SOM interneurons, so that cortical
responses change in quality during sustained activation (Tan et al., 2008; Ma et al.,
2010).
In barrel cortex, the net result of these complex interactions is a fine selectivity for
particular stimulus qualities and the timing of thalamic activity, enabling the barrel to
act as a temporal contrast detector (in rat: Pinto et al., 2003). In the auditory cortex,
thalamic inputs shape cortical receptive fields to attend to the responses of the most
active medial geniculate neurons (Jafari, Zhang, & Yan, 2007).
74#0&*4*4#0&*$(
The laminar specifics of direct connections between cortical regions are thought to
vary depending on the processing relationship between the areas: feedforward activity
from primary to secondary sensory areas targets layers 2/3 and 4, as thalamic input
does in the primary areas; in fact corticocortical and thalamocortical synapses are
very similar in layer 4 (Gil, Connors, & Amitai, 1999). Feedback projection, which
modulates rather than evokes activity, is primarily targeted at the modulatory layer 1,
along with some influence in layers 2/3 and 6 (Thomson & Bannister, 2003).
Lfferent process|ng
Layers 5 and 6 are the principal corticofugal projection layers, relaying the sensory
modulations and behavioural responses the cortex requires. Layer 5 pyramidal
neurons project to the tectum, thalamus and cortex (Larsen, Wickersham, &
Callaway, 2007), and in somatomotor areas, excitation from layer 2/3 stimulates the
large pyramidal neurons in layer 5 to activate striatal, hindbrain and spinal cord
targets (Weiler et al., 2008). These layer 5 projections give off collaterals to the
nonspecific thalamic nuclei, whereas superficial layer 6 pyramids project directly to
the specific nuclei innervating that region (White & Hersch, 1982; Castro-Alamancos,
2004). Layer 6 neurons project to a variety of targets, including specific and
nonspecific thalamic nuclei, local layers 4 and 1, and to cortical regions across the
corpus callosum (Thomson, 2010). These diverse projection classes are
morphologically distinct, and draw their inputs from thalamocortical afferents and
distinct local neuronal populations (Frost & Caviness, 1980; Bernardo & Woolsey,
1987; in rat: Zarrinpar & M Callaway, 2006).
46
Corticofugal efferents from primary sensory regions often target the afferent
pathways leading to the thalamic nuclei that provide them with input. The exquisite
time dependence of barrel cortex afferent processing is closely coupled to the direct
control it exerts over the movements of the whiskers via projections to the spinal
trigeminal nucleus, adjusting the timing with which vibrissae strike objects of interest
for optimum analysis (Matyas et al., 2010; Aronoff et al., 2010). Auditory cortex also
influences its afferents at a pre-thalamic level, projecting to the cochlear nucleus
(Meltzer & Ryugo, 2006; Liu et al., 2010) and the inferior colliculus (Hofstetter and
Ehret, 1992) to close the loop of a self-tuning system which dynamically optimises
receptive fields and tuning curves (Yan & Ehret, 2002; Luo et al., 2008). For visual
cortex, intracortical interactions appear to be the principal determinant of dynamic
receptive field optimisation (e.g. Niell & Stryker, 2010). However evidence exists for
cortical modulation of retinal ganglion cells (in rat: Molotchnikoff & Tremblay, 1983,
1986), analogous to the modulatory projections from auditory and somatosensory
cortex.
74#0&*402$($%&*
Corticothalamic fibres are the most abundant inputs to the thalamus (Sherman &
Guillery, 1996). This system has been simplistically likened to a relay, with thalamic
nuclei passing information to the cortex when enabled to do so by hindbrain and
midbrain modulatory systems and corticothalamic activity. In reality, the subtle
interplay of these influences remains difficult to characterise (Castro-Alamancos,
2004). Layer 6 corticothalamic activity is excitatory to the specific and non-specific
nuclei, but it also activates neurons of the prethalamic reticular nucleus, which inhibit
thalamic neurons; the net result is a complex pattern of facilitation and inhibition
(Jones, 1998; Zhang & Jones, 2004; Castro-Alamancos, 2004; Cruikshank et al.,
2010; Lam & Sherman, 2010), which may be related to maintaining the waking state
of thalamic activity (Coulon et al., 2010).
The number of corticothalamic fibres is an order-of-magnitude greater than the
number of thalamocortical fibers (Sherman & Guillery, 1996), which implies that they
convey specific influences dependent on the details of cortical processing, rather than
generalised regulation (e.g. in rat: Krupa et al., 2001). Corticothalamic synapses are
plastic, whereas subcortical thalamic afferent synapses are not, which implies that
cortical influences are also subject to modification (Castro-Alamancos, 2004).
Corticothalamic fibres from auditory and somatosensory regions can also drive
thalamic nuclei to excite other cortical areas (Llano & Sherman, 2008; Theyel, Llano,
& Sherman, 2010), which may couple rhythmic activity across wide areas of cortex
(Steriade, 2000). This latter projection is made by layer 5 neurons rather than layer 6,
with different cortical inputs, suggesting that corticothalamic feedback and
corticothalamocortical pathways are functionally distinct (Llano & Sherman, 2009;
Theyel, Llano, & Sherman, 2010). Corticothalamic fibres also make local excitatory
connections via axon collaterals (White & Keller, 1987).
74#0&*4,0#&$0$(
As described earlier, the somatomotor regions of cortex project extensively to the
striatum (Aronoff et al., 2010; Pan, Mao, & Dudman, 2010). In motor cortex, striatal
outputs parallel corticospinal outputs, employing similar but distinct intracortical
pathways from layer 2/3 to different sublayers within 5 (Anderson et al., 2010). Most
corticostriatal projecting neurons are pyramidal cells and hence excitatory (Hersch &
White, 1982), but a few from somatosensory and retrosplenial cortex are GABAergic
47
(Jinno & Kosaka, 2004). Thalamic and cortical inputs interact in the striatum as part
of a complex feedback loop influencing cortical processing, attention, stimulus
salience, and motor control (Ding et al., 2010; Doig, Moss, & Bolam, 2010; Pan,
Mao, & Dudman, 2010).
Intracort|ca| process|ng
In between the divergent activity evoked by afferents, and the influences converging
on corticofugal projection cells, the cortex combines and analyses information. The
sheer scale and subtlety of cortical interactions, even in mice, has prompted a range of
metaphors and analogies to explain cortical circuits about whose mode of
organization and operation we are still greatly ignorant, (Douglas & Martin, 2007,
p226). There is no prima facie reason why cortex should function in a way we can
understand, but we can observe regularities in its activity and describe it in useful
ways. As functional and anatomical techniques are refined, the sheer volume of data
becomes daunting, but several useful analyses distil the complexity into manageable
sets of characteristic relationships (White, 1989; Nieuwenhuys, 1994; Douglas &
Martin, 2004, 2007; Bannister, 2005; Thomson & Lamy, 2007; Fig 11). Like other
sources cited here, these references are based on literature from multiple species,
although mouse-specific findings are used to illustrate general statements where
possible.
Fig 11 Nieuwenhuys diagram of cortical connectivity
Although the thalamus is not necessarily the primary driver of cortical activity,
analyses of cortical processing often start with thalamocortical activity arriving in
layer 4 (e.g. Bernardo et al., 1990). Connectivity and electrophysiological studies
indicate that the typical inter-laminar spread of excitation runs from layer 4 to 3 to 5,
joining input to output, whereas connection in the opposite direction largely targets
inhibitory interneurons (Bannister, 2005; Thomson & Lamy, 2007). Although this
resembles a simple reflex circuit, each step involves significant divergence, each
neuron innervating multiple neurons in the next layer, along with complex local
dynamics resulting from the activation of interneurons alongside principal neurons.
The layer 4 to 3 to 5 sequence only applies to primary thalamic projections such as
the lemniscal projection of VPM to S1, whereas the paralemniscal pathway from
POm excites corticocortical neurons in superficial 5 then superficial 2/3 across wider
areas of cortex (Bureau, von Saint Paul, & Svoboda, 2006; Huggenberger, Vater, &
Deisz, 2009).
The processing of multiple simultaneous inputs also produces crosstalk between
adjacent cortical activations, resulting in a rich intermeshing which allows analysis of
higher-order properties combining multiple afferents (e.g. Aroniadou-Anderjaska &
Keller, 1996). The degree of lateral connectivity varies: for example, in barrel cortex
there is strong within-barrel connectivity in layer 4, whereas layer 2/3 neurons make
inter-barrel connections (Lefort et al., 2009; in rat: Petersen & Sakmann, 2000;
Holmgren et al., 2003). The latter are strongly excited by thalamic recipient layer 4
neurons (Thomson & Lamy, 2007) and hippocampal afferents (e.g. in rat: Burke et
al., 2005), whereas layer 2/3 interneurons receive different inputs depending on type
(in rat: Dantzker & Callaway, 2000). This mix of influences suggests that principal
neurons of layer 2/3 might be characterised as recruiting resources on the basis of
received activity, driving layer 5 and 6 outputs and communicating with other cortical
regions as required (Bannister, 2005; Anderson et al., 2010). Layer 6 neurons which
1
2/3
4
5
6
l
l
l
l
tc tc tc ct ct ct cc cc cc cc cf cf
N
SS
SS
SS
BP
H
B B B
B B
M
C
C
Figure 11: Connectional relationships in the neocortex.
Common connection patterns between cortical neurons organised by morphological classifca-
tion. Principal neurons are depicted in orange (pyramidalj and pink (spiny stellatej, and excitatory
connections are shown in in red and orange. lnterneurons and inhibitory connections are depict-
ed in green; green shading behind basket cells indicates that they are coupled by gap junctions
into an inhibitory network. Adapted from Nieuwenhuys (1994j and based on data from rodents,
cats and primates.
Abbreviations: B, basket cell; BP, bipolar cell; C, chandelier cell; cc, corticocortical (afferent or efferentj; cf, corticofugal (to
midbrain, hindbrain, spinal cordj; ct, corticothalamic; H, horizontal inhibitory cell; l, interneuron; N, neurogliaform cell; SS, spiny
stellate cell.
Placement: near section Connectivity / Thalamus.
Figure 12: Acetylcholinesterase in the neocortex.
Histochemical demonstration of the localisation of acetylcholine breakdown enzymes, indicating
locations innervated by cholinergic terminals. Note densely stained striatum below lightly stained
cortex. Cortical regions shown are, from rostral to caudal (left to rightj: motor cortex above the
striatum, somatosensory cortex above the ventricular space and visual cortex above the hippo-
campus. Fibres radiating through the striatum converge on the internal capsule at left. Sagittal
section, 1.44 mm from midline. Detail of Plate 113 from Franklin and Paxinos (2008j.
48
project to primary thalamic nuclei also excite layer 4, forming complex loops between
thalamus, layer 4 and layer 6 (White & Keller, 1987; Briggs, 2010).
The highly re-entrant connectivity of cortex requires that inhibition is scaled
proportionally to activity levels, to avoid runaway excitation (Burkhalter, 2008; Okun
& Lampl, 2009; Chen et al., 2010; in rat: Zhu, Stornetta, & Zhu, 2004). The drivers
and targets of inhibition are as diverse as the interneuron populations (Xu &
Callaway, 2009), and different interneuron types interact with each other as well as
with principal neurons (e.g. Gentet et al., 2010; Ktzel et al., 2010). Basket and
chandelier cells form functional assemblies in layers 3 and 5, coupled by gap
junctions and inhibitory synapses (Deans et al., 2001; Meyer et al., 2002). This
facilitiates synchronised oscillations of their membrane potentials, thought to be a
major source of coherence in cortical dynamics (Peinado, Yuste, & Katz, 1993; in rat:
Szabadics, Lorincz, & Tams, 2001; Gibson, Beierlein, & Connors, 2005). Other gap
junction and synaptic networks have been observed in supragranular layers, where
subtypes of CR-EGFP interneurons couple to each other or with PV-IR multipolar
cells (Caputi et al., 2009).
Implicit in any discussion of cortical processing is a consideration of the behavioural
state of the animal: as Steriade (2000, p243) put it, the brain scrutinizes the external
world with different degrees of attentiveness during various states of wakefulness
and sleep. In particular, afferent thalamocortical activity is handled very differently by
vigilant and quiescent animals: during high arousal, thalamocortically evoked activity
is locally focused and the cortex adapts rapidly to incoming stimuli, whereas the
anaesthetised or quiescent brain favours spreading activation (Petersen et al., 2003;
Ferezou, Bolea & Petersen, 2006; Ferezou et al., 2007; in rat: Castro-Alamancos,
2002). Network coherence is contingent on behavioural state: during quiet behaviour
membrane potential is synchronous across large neuron populations, which shifts to
desynchrony during active exploration, accompanied by population changes in
interneuron activity (Poulet & Petersen, 2008; Gentet et al., 2010). Frequency gating,
receptive fields and cortical representations are all dynamically altered by arousal and
attention (Castro-Alamancos, 2004; Crochet & Petersen, 2006; Niell & Stryker,
2010). In addition to these global modulations, low frequency shifts in membrane
potential impose a bistable pattern of excitability thresholds on some principal
neurons, referred to as up and down states (Steriade, 2000; Crochet & Petersen, 2006;
Wilson, 2008). These may be triggered by thalamic afferents, and in turn influence
cortical responses to thalamic activity (MacLean et al., 2005).
Although rigorous demonstrations of neuronal connectivity have previously required
laborious cell filling and electron microscopy (Nieuwenhuys, 1994; White, 2002),
recent techniques labelling all the presynaptic neurons connecting to a single
transfected neuron (Wickersham et al., 2007), and targeted optical stimulation (Xu &
Callaway, 2009; O'Connor, Huber, & Svoboda, 2009; Ktzel et al., 2010) offer fresh
opportunities for unravelling the tangle of the cortex.
Modu|atory systems
Choosing an appropriate behaviour depends on context and the current goals of the
animal, meaning that cortical processing needs to adjust for changing circumstances.
Although mice lack the behavioural sophistication of primates, they are able to adjust
behavioural responses by means of modulatory systems that enhance some qualities
of cortical activity while suppressing others.
49
The extent and quality of cortical processing in sensory analysis and response
formulation is modulated to suit behavioural goals, circadian patterns, and energy
conservation. Differing behavioural states and drives require different levels and
qualities of cortical activity. In general, the cortex is activated and driven by intrinsic
and thalamic activity, whereas bias systems alter the quality of cortical processing.
Because thalamocortical interaction is a major influence on cortical activity, many of
the modulatory systems which affect the cortex also achieve their effects by altering
thalamic processing, selecting among a range of thalamic modes with distinct effects
on the type of afferent activity reaching the neocortex (Castro-Alamancos, 2004). By
affecting this fundamental cortical interaction, the behavioural alertness of the animal
(e.g. wakefulness, vigilance, sleep) may also be effectively regulated (Steriade, 2000).
Such ascending arousal projections are themselves the subject of complex patterns of
excitation and inhibition across the circadian cycles of sleep, wakefulness, and
vigilance (see Saper, Scammell, & Lu, 2005).
Ap|ca| dendr|tes
A prominent feature of cortical pyramidal cells is the ascending apical dendrite, which
is usually covered in spines and richly innervated, branching near its distal end into a
characteristic tuft of processes (DeFelipe & Farias, 1992; Spruston, 2008). Although
the length of apical dendrites suggests that their distal synapses would have little
effect on firing, complex integrative dynamics and non-linear propagation of dendritic
potentials make them significant as timing-dependent modulators of pyramidal neuron
activity (Spruston, 2008; in rat: Williams & Stuart, 2002). In mouse cortex, most
apical dendrites reach almost to the cortical surface, with their apical tufts in or near
layer 1, although those from layer 6 cells terminate in layer 4 (Ledergerber &
Larkum, 2010; in rat: Cauller & Connors, 1994). This concentration of processes
allows neurons and axon terminals in layer 1 to make contact with a majority of the
principal neurons of the cortex, allowing large-scale modulatory effects.
The influences which converge on these apical dendrites are diverse. Layer 1 neurons,
excitatory and inhibitory neurons from deeper layers, and projections from thalamus
and other subcortical structures combine to exert a predominantly inhibitory influence
(Herkenham, 1986; Shlosberg et al., 2003; in rat: Mitchell & Cauller, 2001). Among
cortical neurons, significant layer 1 projections come from layers 5 and 7 (Reep &
Goodwin, 1988; in rat: Clancy & Cauller, 1999; Mitchell & Cauller, 2001). Inhibitory
influences include layer 1 interneurons (Shlosberg et al., 2003; in rat: Winer & Larue,
1989) and Martinotti cells of deeper layers (in rat: Silberberg & Markram, 2007). In
addition to a general modulatory effect on cortical processing, converging layer 1
influences are a significant factor in cortical processing and attention (in rat: Zhu &
Zhu, 2004; Shlosberg, Amitai, & Azouz, 2006). Thalamic nuclei furnish profuse layer
1 projections to influence large areas, relaying information including nociception to
the entire dorsolateral neocortex, and perhaps biasing neurons in deeper layers to
respond to different subsets of their inputs (in rat: Monconduit & Villanueva, 2005;
Rubio-Garrido et al., 2009).
Neuromodu|ators
Discrete nuclei in the hindbrain, midbrain, and hypothalamus send widespread axonal
projections to the thalamus and cortex, delivering neurotransmitters whose effect is to
shift cortical and thalamic activity patterns, as well as shaping synaptic plasticity.
These systems allow other CNS regions to bias cortical activity to integrate with
50
physiological states and behavioural needs, and inputs to the modulatory systems are
diverse. Chief among these neuromodulators are acetylcholine (ACh), noradrenaline
(NA), dopamine (DA), serotonin (5-hydroxytryptamine, 5-HT), and histamine (HA).
To a lesser extent, glutamate and GABA can also have longer-duration biasing effects
by means of metabotropic receptors (Foote & Morrison, 1987; McCormick, Wang, &
Huguenard, 1993; Gu, 2002). In addition to direct effects, these neuromodulators
often interact with each other, and also with glutamatergic and GABAergic
transmission (e.g. Schlicker et al., 1992; Marek et al., 2000; Cangioli et al., 2002;
Zhang et al., 2010; Coulon et al., 2010).
D*+0"(*24(&/+
External cholinergic innervation is supplied to the cortex by cells of the basal nucleus
of Meynert and related nuclei, whose axons travel in the external capsule, subcortical
white matter and layer 6 before ascending to innervate the cortex in anterior, median
and lateral groupings (in rat: Kristt et al., 1985; see also Chapter 28). There is also a
small intrinsic population of cholinergic interneurons, discussed in the section
Choline acetyltransferase above. Cholinergic axons permeate the cortex (see
Acetylcholinesterase above) and terminate with a strong preference for layers 4, 5
and 1 (Hhmann & Ebner, 1985; Lysakowski et al., 1986; in rat: Kristt et al., 1985;
Fig 12). They release ACh, often non-synaptically (Vizi, Kiss, & Lendvai, 2004;
Yamasaki, Matsui, & Watanabe, 2010), to activate nicotinic (ionotropic, rapidly
depolarising) and muscarinic (metabotropic, slower acting) receptors on the dendrites
and somata of a range of cortical neurons. Nicotinic receptors are found in cholinergic
synapses on two interneuron populations: layer 1 interneurons, mediating an
apparently disinhibitory effect on layer 2/3 (in rat: Christophe et al., 2002), and on
VIP/NPY-IR bipolar interneurons innervating vessels (in rat: Porter et al., 1999; Cauli
et al., 2004) which may mediate observed ACh effects on cortical blood flow (Meng
et al., 1996).
Fig 12 AChE in neocortex
Muscarinic receptors are numerous throughout layers 2/3 to 7 (Hhmann, Pert, &
Ebner, 1985; Schwab et al., 1992; Yamasaki, Matsui, & Watanabe, 2010) and their
actions on cortical neurons are mixedincreasing spontaneous activity, and altering
responses to stimuli by directly facilitating or indirectly suppressing via interneurons
(Gu, 2002; Kuczewski et al., 2005; Spruston, 2008; in rat: Kawaguchi, 1997). As
might be expected, this has complex effects on cortical dynamics. Carbachol, a
muscarinic agonist, can trigger theta band oscillation in coupled interneurons of layer
2/3, imposing coherent inhibition on local activity across a wide area of cortex
(Blatow et al., 2003).
Muscarinic activation can also prevent cortical inhibition of thalamic nuclei (Lam &
Sherman, 2010), altering sensory processing and attention by modulating the relative
contributions of thalamic afferents and internal cortical networks. When attention is
required, ACh may cause cortex to suppress existing associations and focus on
afferent processing in order to maximise awareness of sensory stimuli (see Sarter et
al., 2005; in rat: Oldford & Castro-Alamancos 2003). This attentional focus may be
driven by return projections from prefrontal cortex to the forebrain cholinergic nuclei
(in rat: Golmayo, Nuez, & Zaborszky, 2003; Rasmusson, Smith, & Semba, 2007), or
orienting stimuli received by subcortical structures (e.g. Dringenberg et al., 2006).
Attentional effects are one facet of complex shifts corresponding to a range of
behavioural states. ACh alters thalamic excitability, thalamocortical interactions and
51
cortical synchrony in waking and sleep states, adapting sensory processing by altering
cortical dynamics (Gil, Connors, & Amitai, 1997; Steriade, 2000; Van Dort,
Baghdoyan, & Lydic, 2009; in rat: Buzski et al., 1988; Eggermann & Feldmeyer,
2009; Goard & Dan, 2009). It also alters transmission from thalamus to cortex,
preserving high frequency activity and suppressing low frequency firing (Castro-
Alamancos & Calcagnotto, 2001). In the cortex itself, muscarinic receptors modulate
plasticity during development and in the adult, both in waking behavioural contexts
and during sleep (Yan & Zhang, 2005; Origlia et al., 2006; see Gu, 2002; Spruston,
2008; Diekelmann & Born, 2010, for reviews).
94#$'#+/$(&/+
Noradrenergic innervation of the neocortex comes from the locus coeruleus (LC),
which projects through the ventral forebrain and forward to the frontal pole. From
there they travel rostrocaudally within layers 5 and 6, diverging and branching
radially to innervate the entire cortex; deep layer 1 also has fibres travelling
mediolaterally (Foote & Morrison, 1987; in rat: Morrison et al., 1981; Miner et al.,
2003). These fibres often release NA at varicosities rather than synapses, activating a
range of alpha and beta adrenergic receptor subtypes which vary in laminar
distribution (Mundorf et al., 2001; Vizi, Kiss, & Lendvai, 2004; in rat: Schliebs &
Gdicke, 1988). Adrenergic receptors are located on neurons and polydendrocytes as
well as astrocytes, in which NA induces glycogenolysis (Magistretti et al., 1981;
Papay et al., 2004; in rat: Aoki, 1992).
Although the role of NA has long been characterised as mediating wakefulness,
activity, vigilance, and response to stress (for reviews see Berridge & Waterhouse,
2003; Berridge, 2008; Itoi & Sugimoto, 2010), adrenergic activity has a generally
suppressive effect on neocortical neurons. This is more pronounced for spontaneous
activity than evoked activity (traditionally interpreted as improving the signal to noise
ratio of stimulus detection; Foote & Morrison, 1987), and is driven by converging
influences. NA alters thalamocortical interaction, suppressing noise, focusing
receptive fields, and high-pass filtering transmission from thalamus to cortex
(Berridge & Waterhouse, 2003; in rat: Hirata, Aguilar, & Castro-Alamancos, 2006;
Castro-Alamancos & Calcagnotto, 2001). Layer 1 adrenergic activity shifts inhibitory
patterns in layer 2/3 below, primarily via by presynaptic modulation of GABAergic
terminals (Salgado et al., 2011). NA also promotes synchrony in the activity of
neuronal populations of cortex, thalamus and striatum (Dzirasa et al., 2010).
Consistent with its role in vigilance and salience, NA also has a significant effect on
cortical plasticity, both during development and in dynamically tuning receptive fields
in the adult cortex (Osterheld-Haas, van der Loos, & Hornung, 1994; Gu, 2002;
Berridge & Waterhouse, 2003; in rat: Manunta & Edeline, 2004).
F4.$%&/+
Dopamine in the forebrain is supplied by the substantia nigra (A9) and ventral
tegmental area (A10) (SN/VTA) (in rat: Oades & Halliday, 1987; Foote & Morrison,
1987). The SN/VTA is not purely mesencephalic, but instead spans the diencephalon,
midbrain and isthmus. Dopaminergic fibres, labelled by antibodies to tyrosine
hydroxylase (in rat: Miner et al., 2003), lightly permeate some neocortical regions
from layer 2/3 to 6; frontal and insular regions are particularly innervated, and the
frontal cortex projects back to the VTA (Irle et al., 1984; in rat: Descarries et al.,
1987; Viggiano, Ruocco, & Sadile, 2003; Paxinos et al., 2009; van de Werd et al.,
2010; Zhang et al., 2010). Like ACh and NA, DA is also released outside synapses
52
and diffuses in the extracellular space (Mundorf et al., 2001; Vizi, Kiss, & Lendvai,
2004). The expression of dopamine receptor types varies considerably during
proliferation and development, but in mature cortex, the D1 (or D1A) receptor is most
abundant, followed by D2, D4, and D5 (D1B); D3 is primarily expressed in
subcortical structures (Viggiano, Ruocco, & Sadile, 2003; Araki, Sims, & Bhide,
2007). These receptors are located on pyramidal neuron dendrites and somata of
layers 2/3 to 6, localising in region-specific and receptor-specific patterns (e.g. Lidow,
Koh, & Arnsten, 2003; Noan et al., 2006).
The cortical dopaminergic system is a potent behavioural modulator, involved in
learning, attention, motivation, reward, and addiction. The rich experimental literature
in these domains is beyond the scope of this review (see Chapter 33, and reviews by
Wise, 2004; Montague et al., 2004; Leknes & Tracey, 2008).
-+#404/&/
Serotonin in the neocortex is supplied by the dorsal and median raphe nuclei of the
hindbrain, projecting fine and coarse fibres respectively via the medial forebrain
bundle to a dorsomedial distribution of convoluted processes innervating layers 1-6
(Fujimiya, Kimura, & Maeda, 1986; in rat: Azmitia & Segal, 1978; Lidov, Grzanna,
& Molliver, 1980; Kosofsky & Molliver, 1987).
Serotonergic fibres stimulate a broad array of mostly metabotropic receptors on
principal neurons and interneurons, with laminar distributions varying by region and
receptor type (e.g. Touri, Welker, & Riederer, 2004; Weber & Andrade, 2010; in rat:
Willins, Deutch & Roth, 1997; Neumaier et al., 2001; Aznar et al., 2003; Santana et
al., 2004). The ionotropic 5-HT
3A
receptor colocalises with nicotinic receptors on the
VIP and NPY interneuron populations which modulate excitability and bloodflow, as
well as some neurogliaform cells (Vucurovic et al., 2010; Lee et al., 2010a; in rat:
Cauli et al., 2004).
It has also been suggested that 5-HT and NA have complementary actions on sensory
processing, with 5-HT acting to reduce cortical responsiveness to stimuli (Berridge &
Waterhouse, 2003). 5-HT actions on cortical neurons are once again complex,
modulating principal neuron and interneuron activity and cortical synchrony without
disturbing the overall balance of excitation and inhibition (in rat: Puig et al., 2010;
Moreau et al., 2010). Behaviourally, 5-HT is a key mediator in aggression and
responses to uncontrollable stressors (in rat: Barratta et al., 2009; Neumann,
Veenema, & Beiderbeck, 2010), as well as its longstanding association with sleep,
which elevates cortical 5-HT (Morgan, Yndo, & McFadin, 1974). Currently,there is a
major research focus on the role of 5-HT in mood and anxiety (Toth, 2007; Akimova,
Lanzenberger, & Kasper, 2009; Homberg & Contet, 2009; Graeff & Zangrossi, 2010).
G&,0$%&/+
The source of forebrain histaminergic innervation is the tuberomammillary nucleus of
the hypothalamus, which projects via the medial forebrain bundle to innervate layers
2/3 to 6 with sparse histamine-IR axons (Watanabe et al., 1984; Airaksinen et al.,
1992; Brown, Stevens, & Haas, 2001). The four histaminergic receptors (H1-H4) are
present throughout cortex, with differential laminar distribution (Haas & Panula,
2003; Connelly et al., 2009). Another significant histaminergic action in cortex is
modulation of NMDA receptors (Brown, Stevens, & Haas, 2001). Histamine has a
generally excitatory action on cortical activity, corresponding to its role in
53
maintaining wakefulness (Saper, Scammell, & Lu, 2005), but more specific cognitive
actions are becoming apparent (e.g. Zlomuzica et al., 2008).
keg|ons of the neocortex
Despite its reasonably uniform structure, the neocortex exhibits large-scale
organisation, particularly in the arrangement and relative size of the functional
regions. The organization of these regions varies greatly between different groups of
mammals, but the pattern is consistent between individuals of the same species. The
processes regulating neocortical organisation have become clearer with increasing
knowledge of developmental processes, which are key determinants of the adult
cortical arrangement.
The value of subdividing a cerebral cortex as small as that of the mouse has not
always been obvious: some atlases as recent as the 1970s considered it adequate to
refer to cerebral cortex as a whole, or made a simple division into frontal, temporal,
parietal and occipital regions (Slotnick & Leonard, 1975; Sidman, Angevine, &
Pierce, 1971). It also seems that far fewer discrete regions are necessary for the
efficient function of small rodent brains (Changizi & Shimojo, 2005). However,
across the last hundred years, evidence from anatomy, electrophysiology, ontology,
hodology and genetics has converged to produce a broadly agreed regional division of
functional areas, although specifics are contested and regularly revised. Some areas
such as barrel cortex are easily identified, whereas useful parcellation of other regions
requires evidence from multiple fields.
Lstab||shment of cort|ca| reg|ons
Cortical regions are principally defined by their relationship with specific thalamic
nuclei (Caviness & Frost, 1980), but the causal question of how these relationships
arise is key in this classification. The isotropic anatomy of neocortex suggests that all
areas might be equipotential, and at first glance several prominent studies are
consistent with this idea. Schlaggar and OLeary (in rat: 1991) transplanted late
embryonic occipital cortex to a parietal location, where it developed distinctive
hallmarks of the barrel cortex it had replaced. The Sur laboratory redirected retinal
axons to auditory thalamus in ferrets, and found behaviourally useful receptive fields
and connectional structures typical of visual cortex in the resultant hybrid A1 region
(in ferret: Sharma, Angelucci, & Sur, 2000; von Melchner, Pallas, & Sur, 2000). Such
drastic shifts in sensory specialisation might imply that the developing cortex is a
blank sheet on which thalamic innervation is free to write a functional arrangement.
Certainly it has been demonstrated that thalamocortical activity exerts a powerful
developmental influence on the physical structure of the cortex, triggering anatomical
differentiation (Hannan et al., 2001; Ince-Dunn et al., 2006).
However it is important to realise that these functional reassignments were enabled by
successful establishment of thalamocortical connectivity: the transplanted occipital
cortex was placed on a bed of somatosensory afferents, and the ferret retinal activity
was relayed to A1 by an intact medial geniculate projection. In addition, neither
cortex developed quite normally: for example, visual A1 provided poor, low-acuity
vision (von Melchner, Pallas, & Sur, 2000).
The current view is that optimal function requires coherent, well-routed thalamic
projections targeted to cortex that is genetically equipped to make full use of the
54
innervation it receives. Neocortex that develops in the near-absence of a thalamus
(Miyashita-Lin et al., 1999) or while disconnected from the rest of the CNS (Zhou et
al., 2010) still generates the characteristic gradients that determine regionalisation, but
fails to mature correctly in the absence of suitable inputs. In fact both thalamus and
cortex are independently genetically patterned, and after successful interconnection,
interact to determine the functional arrangement of both structures (Nakagawa,
Johnson, & OLeary, 1999; Grove & Fukuchi-Shimogori, 2003).
Recent understanding of the roles of major regulatory genes in the developing
nervous system suggests a relatively parsimonious mechanism for generating cortical
regions. Expression of the patterning gene fgf8 at the commissural plate of the rostral
pole of the protocortex appears to organise the expression of regionalising genes
(Grove & Fukuchi-Shimogori, 2003; OLeary, Chou, & Sahara, 2007), and studies
and models of such factors demonstrate the possibility that the complete neocortical
pattern may derive from simple interactions between a small set of genes, driven by
fgf8 (Fukuchi-Shimogori & Grove, 2001; Grove & Fukuchi-Shimogori, 2003;
OLeary, Chou, & Sahara, 2007; Giacomantonio & Goodhill, 2010). Also important
are the mediolateral expression gradients established by the cortical hem, at the
medial border of the dorsal pallium, and the antihem, which separates the dorsal
pallium from the ganglionic eminences (Grove & Fukuchi-Shimogori, 2003; OLeary,
Chou, & Sahara, 2007; Subramanian & Tole, 2009). Together these influences define
a heterogeneous field of multiple gradients, known as the protomap, with a unique
mix of influences at each locus on the cortical sheet.
The regional protomap is established early in cortical development, before
neurogenesis, and imbues developing principal neurons with connectional preferences
and other regional properties; timed waves of differentiation for principal neuron
subtypes also ensure the orderly establishment of relationships between the cortex and
subcortical structures (see Caviness, Nowakowski, & Bhide, 2009, for review; Ferrere
et al., 2006). This ensures that neurons generated by the same pallial progenitor cell
express the same mix of transcriptional regulators and downstream genes, and attract
compatible inputs. Thalamocortical afferents must negotiate with neurons in this zone
as well, relying on them for cues to encounter and follow axons coming from neurons
of corresponding cortical areas (Deng & Elberger, 2003).
Areal patterning drives downstream genes for recognition and guidance that establish
thalamocortical relationships (Nakagawa, Johnson, & OLeary, 1999; Leamey et al.,
2008; Bedogni et al., 2010). Further downstream, hierarchical regulation may confine
expression of a gene to individual regions, or even a single layer in a single sub-field,
still preceding the arrival of thalamocortical afferents (Cohen-Tannoudji, Babinet, &
Wassef, 1994; Joshi et al., 2008).
During postnatal development, the cortex is substantially altered by afferent activity,
and afferents compete for cortical representation in an activity-dependent manner
(Hunt, Yamoah, & Krubitzer, 2006). As might be expected, cortical and thalamic
patterning does not need to match precisely for successful connection and
differentiation. For example, cortical patterning is fairly robust and can accommodate
the loss of even a major driver like Pax6 without serious disruption of thalamocortical
connectivity (Pion et al., 2008). Manipulation of the size of S1 cortex results in
complete somatosensory representations with expanded or reduced thalamic
connectivity, adjusted to maintain cellular and synaptic density in layer 4 (Gutirrez-
Ospina et al., 2004). Quite large strain variations in the size and shape of cortical
55
areas can be accommodated (Airey et al., 2005, 2006), and adding a new class of
visual receptors results in additional stimulus dimensions being processed in the same
visual areas (Jacobs et al., 2007). Such flexibility must have been selected for among
mammals whose cortical regions vary greatly between species, far more than other
parts of the nervous system (Krubitzer & Hunt, 2009).
The process of guiding and terminating axons during development produces fields
following single or multiple gradients, which coalesce into functional arrangements
under the influence of early activity (e.g. Ince-Dunn et al., 2006). The basic
topography generated by region-specific axon guidance and ligand-receptor
interactions in areas of axon termination produces a cortex with an orderly
connectional structure, a foundation for coherent functional arrangements (Grove &
Fukuchi-Shimogori, 2003; Wang & Burkhalter, 2007). The outstanding example of
topographic coherence in the mouse cortex is barrel cortex, and it may be that the
extreme topographic order of S1BF imposes on other cortical regions to some extent.
Other primary sensory and motor regions of the rodent cortex are less obviously
structured, but have topographic arrangements (e.g. A1, Bandyopadhyay, Shamma, &
Kanold, 2010; Hackett et al., 2011; M1, Tennant et al., 2010; V1, Wagor, Mangini, &
Pearlman, 1980; Smith & Husser, 2010), and retain precise topographic order in their
projections to downstream, higher-order regions (Wang & Burkhalter, 2007). Since
neocortex is highly interconnected between regions, it may be that a strong functional
pattern imposed early in development by the dominant sensory system tends to
impinge on the functional arrangements of other regions. In mice, cortical regions
need to deal usefully with their own sensory inputs or motor patterning, but must
coherently interact with the large cortical regions processing whisker inputs, so that
the functional architecture may end up as a compromise between these constraints.
Cort|ca| parce||at|on schemes
Deciding what constitutes a distinct cortical area, and how it should be delineated, is a
complex interpretation of diverse evidence. Nomenclature, subdivisions and criteria
are all to some extent a matter of individual preference, but the measure of the utility
of a cortical parcellation is the degree to which it is used by the research community.
That in turn depends on its accuracy, utility, and the ability to incorporate new
techniques and findings for refinement.
Historically cortical maps were based on cytoarchitectonicsthe spatial arrangement
of nuclei, labelled by stains for Nissl substance, and myelinated axons revealed by a
range of staining techniques. In the 1960s and 70s histochemical techniques
(acetylcholinesterase, cytochrome oxidase) and hodological methods based on axon
degeneration, anterograde and retrograde transport added immensely to the
identification of functional relationships and areas. The advent of
immunohistochemistry in the 1980s created the field of chemoarchitectonics, in which
the expression of cell-type-specific proteins could be visualised across large areas of
cortex (see section Immunohistochemical classification above), with a
corresponding wealth of data suggesting new relationships in the cortex. The 1990s
and 2000s saw the introduction of techniques of gene expression, including the
visualisation of arealising regulators and fate marker genes. Also significant was the
use of digital techniques for the presentation and organisation of vast amounts of
primary data on gene expression, of which the Allen Institutes atlas is the most
visible representative (e.g. Ng et al, 2009, Hawrylycz et al, 2010). Advances in high
resolution magnetic resonance imaging and three-dimensional manipulation are
Figure 13: Regions of the mouse neocortex
(aj oblique view showing anterior dorsolateral surface; (bj overhead view perpendicular to the
horizontal plane defned by lambda and bregma; (cj side view perpendicular to the sagittal plane.
These views are redrawn and modifed from Brain Navigator three-dimensional representations of
structures delineated in Franklin and Paxinos (2007j. lnsular" refers to combined insular regions
too foreshortened to delineate.
Abbreviations: AlD, agranular insular - dorsal part; AlP, agranular insular - posterior part; Alv, agranular insular - ventral part; Au1,
primary auditory; AuD, secondary auditory - dorsal area; Auv, secondary auditory - ventral area; Cg1/Cg2, cingulate - area 1/2;
Dl, dysgranular insular; DLO, dorsolateral orbital; DP, dorsal peduncular; DTr, dorsal transition zone; Fr3, frontal - area 3; FrA,
frontal association; Gl, granular insular; lL, infralimbic; LO, lateral orbital; LPtA, lateral parietal association; M1, primary motor; M2,
secondary motor; MO, medial orbital; MPtA, medial parietal association; PRh, perirhinal; PrL, prelimbic; PtPD, parietal - posterior
area - dorsal part; PtPR, parietal - posterior area - rostral part; RSD, retrosplenial dysgranular; RSGa/b/c, retrosplenial granular
- a/b/c region; S1, primary somatosensory; S1BF, primary somatosensory - barrel feld; S1DZ, primary somatosensory - dys-
granular zone; S1FL, primary somatosensory - forelimb region; S1HL, primary somatosensory - hindlimb region; S1J, primary
somatosensory - jaw region; S1Sh, primary somatosensory - shoulder region; S1Tr, primary somatosensory - trunk region;
S1ULp, primary somatosensory - upper lip region; S2, secondary somatosensory; TeA, temporal association; v1, primary visual;
v1B, primary visual - binocular area; v1M, primary visual - monocular area; v2L, secondary visual - lateral area; v2ML, secondary
visual - mediolateral area; v2MM, secondary visual - mediomedial area; vO, ventral orbital
Placement: near section Regions of the neocortex / Cortical parcellation.
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56
poised to update the field again, introducing structural accuracy unaffected by fixation
and dissection, and the opportunity to link structural maps to the research literature in
unprecedented ways (e.g. Bohland et al, 2009).
Parallel to these anatomical techniques, functional studies based on electrophysiology,
induced gene expression, calcium imaging and intrinsic imaging show the cortex at
work, linking anatomy to external stimuli and measurable responses (e.g. Kalatsky &
Stryker, 2008; Ayling et al., 2009; Llano et al., 2009; Bandyopadhyay, Shamma, &
Kanold, 2010; Tennant et al., 2010).
Although rodent cortex was described by Brodmann (in rat: 1909; Brodmann, 1994),
the first cytoarchitectonic subdivision specific to the mouse cortex was made by
Dllken in 1907. Within five years, six other maps had been proposed, most notably
by Rose (1926; reviewed by Wree, Zilles, & Schleicher, 1983). Brodmanns and
Roses maps were used as the basis for an albino rat cortical map by Krieg (in rat:
1946a,b). Three decades later Caviness (1975) used Kriegs studies and Woolsey and
van der Loos (1970) description of the barrel field for another complete
cytoarchitectonic parcellation of the mouse, later revised on the basis of
thalamocortical projections (Caviness & Frost, 1980; Krettek & Price, 1977). All of
these studies used Brodmann area numbering, but Wree, Zilles and Schleicher (1983)
produced an alternative map with anatomically descriptive region names, excepting
somatosensory regions, which were named functionally. Their parcellation, based on
grey-level quantitation of Nissl and myelin staining, resembled the Caviness maps
aside from disparities in the temporal regions.
More recent maps (Paxinos & Franklin, 1997, 2001; Franklin & Paxinos, 2007; Hof et
al., 2001; Watson & Paxinos, 2010) have promoted a more functional nomenclature,
particularly for identifiable sensory and motor regions. These maps have also been
informed by maps of the rat neocortex (in rat: Zilles, 1985; Palomero-Gallagher &
Zilles, 2004; Paxinos & Watson, 1982, 1986, 1997, 1998, 2004, 2007; Swanson,
1992, 1998, 2004; Paxinos et al., 1998, 1999, 2009).
Fig 13surface of cortical areas
Figure 13 consists of geometrically accurate renderings (after that of Krieg, 1946a)
showing cortical region boundaries as determined by Franklin and Paxinos (2007),
rendered in three dimensions for Elseviers Brain Navigator online service. Since
fixation, sectioning, and mounting inevitably introduce distortions, registering the two
dimensional sections into a three dimensional model is technically challenging,
resulting in irregular region borders which have been elided for the purpose of this
illustration. It indicates the possibility for dimensionally accurate renderings based on
histological data, easing translation between cross-sectional anatomy and surface-
based or tangential data (e.g. Wang & Burkhalter, 2007).
Spec|f|c cort|ca| areas
The organization of individual cortical regions is discussed elsewhere in this book, in
the context of the systems of which they are part. Refer to table 1 for the relevant
chapters.
Areas System(s) Chapter(s)
M1, M2 somatic motor 19
S1 and subregions, S2 somatosensory 21
57
Au1, AuD, AuV, TeA auditory 24
V1 and subregions, V2 and subregions visual 25
GI, DI, AID, AIV, AIP gustatory, visceral 17, 22
Fr1, Fr2, Fr3, MO, VO, LO orbital / frontal 30
Stra|n var|at|on
Even within a single species, considerable variation exists in neocortical anatomy and
physiology. The recognized laboratory strains of mice reduce variability by
inbreeding, but differences can be observed between strains. Genetic manipulations
used to provide disease models and visualise gene expression necessarily alter the
CNS genome, and the possibility of unintended effects on cortical anatomy and
function should always be considered. Although the subject deserves a full and
systematic review, the following notes give some indication of anatomical strain
variation in the neocortex.
One of the most common sources of variation is the shape and extent of cortical
regions, although they retain their relative layout. For example, the size and shape of
somatosensory and visual cortex differs significantly between strains C57BL/6J and
DBA/2J (Airey et al., 2005, 2006) and substantial inter-strain variations in the size of
the barrel field have been attributed to just a handful of genes (Li et al., 2005; Jan et
al., 2008). Hof et al. (2000) systematically document the cortical areas of C57BL/6
and 129/Sv strains, revealing differences most noticeable in the extent of motor,
visceral and visual regions.
Overall cortical volume varies about 30% between DBA/2 and C57BL/6J mice, and
even more widely between other strains (Rosen et al., 1990; Gaglani et al., 2009). The
corpus callosum is also highly variable between strains, exhibiting far greater
thickness in SEC/1ReJ mice than C57BL/6J (Gozzo, Renzi, & DUdine, 1979),
varying significantly in cross section between NZB/BINJ, BXSB/MpJ, and DBA/2J
strains (Rosen et al., 1990) and entirely absent from about 20% of crossbred C129F
2
,
BALB/cWahl, and 129/J mice, and from all B6D2F
2
offspring (Livy & Wahlsten,
1997).
Although it is impractical to re-derive all the relevant data from every strain and
genetic manipulation, it should never be assumed that strain-based data is
interchangeable. The choice of appropriate controls is usually a good safeguard, but
critical interpretations should be referenced to the original criteria used to delineate
areas and neuronal types (e.g. Wang & Burkhalter, 2007; Franklin & Paxinos, 2007;
Paxinos et al., 2009; van de Werd et al., 2010; Watson & Paxinos, 2010). The most
cited stereotaxic atlas, by Franklin and Paxinos (2007), is based on the C57BL/6J
strain.
Mouse-human homo|ogy
The relative ease of genetic manipulation in mice has made them the preferred species
for studying the nervous system, often in an attempt to understand human disease.
Greater understanding of the pathology and genetic underpinnings of diseases such as
Alzheimers, Parkinsons, Huntingtons, multiple sclerosis, and amyotrophic lateral
58
sclerosis has led to a range of experimental manipulations and genetically modified
animals in which hypotheses can be evaluated. The degree to which these findings
can be extrapolated to human brains is a question of critical importance. It is often
assumed that the structure of mouse and human neocortex is equivalent, but this
assertion should be examined with care.
In functional terms, the principal difference between mouse and human neocortex is
their importance to behaviour (see Crawley, 2007, ch 10). In humans the cortex is far
more involved in most purposeful behaviour; mice may use cortical analysis for
guidance, but there is far less direct cortical control of movement (Alstermark &
Ogawa, 2004; Asante et al., 2010; Zhou et al., 2010). Drugs and treatments intended
for human psychiatric disorders are screened using mouse models of specific
symptoms and features of these diseases (see Chapters 31-33 for examples).
Historically, the high rate of false positives has arisen from assumptions about
behavioural motivation, and a strong demand for novel treatments (Markou et al.,
2009; Fernando & Robbins, 2011). Of course, when the basis for the human disorder
is poorly understood, the criteria used to identify suitable mouse models may be
inferential and somewhat arbitrary. Although such approaches are potentially
problematic, they must be tolerated if the alternative is not to screen potentially useful
treatments.
At the cellular level, homology between human and mouse cerebral cortex has been
debated in neuroscience since the earliest structural studies (Lorente de N, 1922,
1992; DeFelipe & Jones, 1988). Ramn y Cajals final advice to Lorente de N was
that the mouse is not a good choice for the study of cortical circuits because of its
paucity of short-axon cells (1934, quoted in Woodruff & Yuste, 2008). Clearly the
human brain is quantitatively and qualitatively different from that of mice,
particularly in the case of the neocortex (Nieuwenhuys, 1994; Jones, 2009). The
neocortex of primate and rodent species scale differently with brain weight and body
weight, indicating fundamental differences between the two orders in the regulation
of brain growth and development (Herculano-Houzel, 2009). However, the numerical
relationships between the numbers of cortical and cerebellar neurons are strikingly
consistent across four mammal orders including primates and rodents (Herculano-
Houzel, 2010). There are core similarities between mouse and human neocortex: they
both have comparable layered structures, populated by neurons with similar properties
(Woodruff & Yuste, 2008), although von Economo or spindle neurons and double-
bouquet neurons are both found in humans but not in mice (Kaas, 2009; Nimchinsky
et al., 1999; Ballesteros-Yez et al., 2005; Jones, 2009), and bipolar interneurons are
much more common in mice than humans (DeFelipe, 2002). Debate lingers as to
whether key developmental features differ between rodents and primates. Although
tangential interneuron migration is convincingly established for mice, primate studies
appear to show interneurons arising from dorsal pallium instead of ganglionic
eminences (Letinic, Zoncu, & Rakic, 2002; Rakic, 2009; Jones, 2009), although this
is difficult to reconcile with the rodent data (e.g. Hernndez-Miranda, Parnavelas, &
Chiara, 2009).
An influential study by Rockel, Hiorns and Powell (1980) found strikingly similar
numbers of neurons in equal-width cortical strips from pia to white matter from
multiple areas in rodents, cats and humans, suggesting that the differences between
species were attributable to neurite elaboration and connections rather than cellular
composition (Nieuwenhuys, 1994). Recently, however, automated counts of
equivalent volumes found almost three-fold differences even between primate
59
species, suggesting that the earlier finding may be misleading (Herculano-Houzel et
al., 2008). In fact, mouse cortical neurons are packed with extraordinary density:
estimates include ~92 000/mm
3
(Schz & Palm, 1989), ~120 000/mm
3
(DeFelipe,
Alonso-Nanclares, & Arellano, 2002) and ~117 000/mm
3
(Tsai et al., 2009),
compared to human (24 000/mm
3
) and even rat (55 000/mm
3
; DeFelipe, Alonso-
Nanclares, & Arellano, 2002).
This high density suggests either fewer processes per neuron (e.g. DeFelipe & Jones,
1988, p86) or reduced glial volume. Glial configurations not found in mice have
indeed been described in primate supragranular cortex (e.g. Reisin & Colombo,
2002). Mice do have less elaborate dendritic fields (e.g. Benavides-Piccione et al.,
2002), and the reduction in supragranular layers implies that corticocortical and
locally projecting neurons are less numerous. Since these cells have the vast bulk of
their dendrite and axon volume within the cortex, lesser numbers would reduce the
average neuropil volume per nucleus in grey matter. Additionally, since the small
physical size and dense packing of the mouse brain means that cells are close
together, thinner axons and dendrites could be used to achieve similar latencies in
cortical circuitry (Chklovskii, Schikorski, & Stevens, 2002). Inter-region connectivity
is also much less in the mouse brain (Changizi & Shimojo, 2005), which may further
reduce the bulk of axons in the neuropil.
It has been suggested that the quality of mouse corticocortical connectivity is also
different to that of primates; mouse cortex appears isotropically connected at the time
of birth whereas primate cortex is relatively specialised, hypothesised to result from
delayed cortical maturation in primates (Kennedy & Dehay, 1993). Notions of the
early cortex as a pluripotent, plastic sheet of cells have been strongly influenced by
mouse-based experiments (e.g. Schlaggar & OLeary, 1991), although it has been
realised that even in the mouse, a great deal of underlying organisation prefigures
anatomical specialisation (OLeary & Nakagawa, 2002; Grove & Fukuchi-Shimogori,
2003; O'Leary, Chou, & Sahara, 2007).
Other measures imply differences in cortical dynamics: in mice, the supragranular
layers are much smaller (Jones, 2009; Hutsler, Lee, & Porter, 2005) and the subplate
remnant layer 7 persists into adulthood (Reep, 2000). Mouse principal neuron spines
are smaller than in humans (Benavides-Piccione et al., 2002) and spine density on
dendrites does not appear to vary between regions as it does in primates (Ballesteros-
Yez et al., 2006). The excitatory to inhibitory synapse ratio is slightly lower in mice
than in humans (DeFelipe, Alonso-Nanclares, & Arellano, 2002; White, 1989),
perhaps reflecting a difference in synaptic regulation, or the lack of some kinds of
inhibitory cells such as double-bouquet (Ballesteros-Yez et al., 2005). Total
synapse numbers in mice may also be proportionally lower: DeFelipe, Alonso-
Nanclares, and Arellano (2002) estimated 21 000 and 30 000 synapses per neuron for
mice and humans respectively, but Schz and Palm (1989) found between 6 700 and
10 600 per neuron in their surveys.
Interactions between cortex and subcortical structures offer other distinctions. Rodent
thalamic nuclei lack the embedded inhibitory interneurons present in primates (Jones,
1998; Steriade, 2000), so in mice, thalamic inhibition is achieved by the prethalamic
reticular nucleus alone (Castro-Alamancos, 2004). A strong layer 6 thalamocortical
termination is specific to mice (Staiger, 2010), suggesting that infragranular circuitry
is altered when supragranular elements are missing. The mouse corticospinal tract
Figure 14: Mouse and human neocortex.
A: Although the layers of the mouse, macaque and human neocortex are homologous in terms of
cellular constituents and projection targets, their thickness and the relative thickness of the indi-
vidual layers are very different. Note that by convention, supragranular layers 2 and 3 are referred
to as a single layer, 2/3, in the mouse. Adapted from Fame, MacDonald, and Macklis (2010j. B:
Basal dendrites of human (leftj and mouse (rightj supragranular pyramidal neurons in temporal
cortex, flled with Lucifer Yellow and labelled with DAB. Note that the size of the soma is compa-
rable but human dendrite felds are far greater in extent, i.e. the total length of dendrites per cell
is much less in mouse cortex. Dendritic spines are also considerably smaller in the mouse. Scale
varies: bar represents 425 m (i, iij; 45 m (iii, ivj; 10 m (v, vij. Adapted from Benavides-Piccione
and colleagues (2002j.
Placement: near section Mouse-human homology.
1
2/3
4
5
6
wm
mouse
1
2
3
4
5
6
wm
human
mouse human
Pyramidal cell,
corticocortical
or callosal
projection
Pyramidal cell,
corticothalamic
projection
Pyramidal cell,
sub-cortical
projection
Spiny stellate
neuron
Axon layers

i ii
iii iv
v vi
60
makes no direct connection with spinal motor neurons, and has little influence on
forelimb movement (Alstermark & Ogawa, 2004).
Fig 14 mouse and human comparisons
Although the mouse cortex is a fascinating subject in its own right, it is important to
realise that many of its similarities with human cortex are quite superficialprotein
sequences, patterns of growth, similarities between neuron and glial phenotypes, and
a common organising structure inherited from shared lineage. In recent years the
wealth of mouse-based findings and the relative paucity of equivalent human data has
encouraged wider assumptions of homology, particularly for research whose funding
is predicated on its relevance to human disease. The historical tendency for reviews
combining cortical data from studies of mice, rats, hamsters, rabbits, ferrets, cats,
dogs, marmosets, macaques, cetaceans, chimpanzees, and humans in descriptions of
mammal cortex is both a cause and a product of this assumption. Although data
from one species may usefully parallel the properties of another, the substantial
differences between mouse and human cortex should be appreciated and respected by
all who work in this field.
Acknow|edgements
I am grateful to Dr Alison Canty for her insights on a draft of this chapter.
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