S1 laminar specialization

• Prof. Ehud Ahissar, Department of Neurobiology, The Weizmann Institute, Rehovot

• Prof. Jochen Staiger, Anatomy, University of Freiburg, Germany

The neocortex is classically considered to be organized into 6 different but “equally well-developed” layers. However, unlike this basic Bauplan of the neocortex, primary somatosensory cortex (S1) possesses a very well-developed layer IV and thus qualifies itself as a typical koniocortical area, as all primary sensory cortical areas. This laminar organization can be easily visualized with many different types of cell stains (e.g., Nissl-staining). It is based on the differential number, size and packing density of neurons in different layers, which show a characteristic pattern when compared with each other, both qualitatively and quantitatively. It will be argued in the main text, however, that when considering more fine-grained morphological properties of the neurons and especially their connections, more than 6 layers should be distinguished. Based on the hypothesis that cortical lamination promotes economic and efficient wiring (Kaas, 1997), the focus will be on the cellular composition of excitatory projection neurons and how their assembly into cortical layers organizes intra- but also extracortical connectivity. Here, the 6 layers, from the pial surface to the white matter, will be shortly introduced.

Layer I is a cell-sparse layer that houses a dense connectivity matrix between the apical dendrites of pyramidal cells of virtually all other layers with pathways of many types of origin (e.g. intracortical, thalamic, transmitter-specified from brain stem). Layer II, which is often pooled with layer III because of the lack of a clear cytoarchitectonic border into layer(s) II/III, is mainly composed of medium-sized pyramidal cells which have the potential to receive and issue cortico-cortical projections with the same (associational) and contralateral (callosal) hemisphere but do not project to subcortical sites. Layer IV is characterized by a very cell-dense appearance, mainly consisting of spiny stellate and star pyramidal cells which on the one hand serve as targets of lemniscal thalamic projections and on the other hand efficiently distribute this sensory information to the other layers. Layer V houses the largest pyramidal cells and is (together with layer I) the prime target layer for paralemniscal thalamic projections and, in rodents, can issue virtually any of the known local and distant cortical projections. Layer VI is composed of a morphologically highly variable population of excitatory neurons, which seem to subserve two basic functions: (i) to provide specific feedback to the lemniscal thalamus and (ii) to orchestrate local intracolumnar with longer-distance intra-areal activity. In all layers, a complimentary set of GABAergic inhibitory interneurons can be found, that are too diverse in form and function to shortly integrate them into this summary.

Figure 1: This schematic diagram shows the three parallel pathways transmitting different aspects of the tactile information acquired by the receptors (trigeminal ganglion cells, TG) associated with the large mystacial whiskers to the primary (S1) and secondary somatosensory cortex (S2) (from Diamond et al., 2008; reprinted with permission). The pathways possess subcortical processing stations, some of which are shown for the brainstem (trigeminal nuclei, TN) and the diencephalon (posterior thalamic nucleus, POm; dorsomedial part of the ventroposterior medial thalamic nucleus, VPMdm; ventrolateral part of the ventroposterior medial thalamic nucleus, VPMvl). In red, the “classic” lemniscal pathway, in green, the paralemniscal pathway and in blue, the newly discovered extralemniscal pathway.

What is S1?

S1 represents a certain nomenclature of cortical areas and stands for primary somatosensory cortex. Somatosensory tells us that here the information coming from exteroceptors (nociceptors, thermoreceptors and, within the scope of this chapter, mainly mechanoreceptors) gains access to the cortex for its conscious perception and fine-grained analysis (Diamond et al., 2008). Primary in this case means that a hierarchy of cortical areas is assumed in which the initial processing of tactile information is continued in secondary (S2) and so forth “higher” somatosensory areas. In rodents as well as in other species, the lemniscal pathway is the classic route by which somatosensory information reaches the cortex (S1) after processing in the thalamus (dorsomedial part of ventroposteromedial nucleus; VPMdm; Figure 1). However, the recently discovered extralemniscal thalamic somatosensory nucleus (ventrolateral part of ventroposteromedial nucleus; VPMvl) and the paralemniscal nucleus (medial portion of the posterior nucleus; POm) directly issue parallel projections to S1 and S2 (Carvell and Simons, 1987; Pierret et al., 2000; Diamond et al., 2008). Within the scope of this chapter it should be added that the lemniscal pathway mainly terminates, in a barrel-aligned manner, in layer IV and (still ill-defined) in the rat on the layer V/VI border region whereas in the mouse a layer VI terminal field can be observed. The extralemniscal pathway shows no distinct termination tiers (and seemingly avoids layer I) and it should be noted that it is mainly septum-aligned (see below for explanation of barrel versus septum compartments). Finally, the paralemniscal pathway has two nearly exclusive layers of termination, i.e. layer I and layer V(a), which do, however, distribute freely across barrel and septum compartments (see also Figure 3).

One has to concur that at present it is completely unclear how much sequential (hierarchical) or simultaneous (parallel/”democratic”) processing takes place in all parts of the somatosensory system, especially when looking at the layers forming a cortical column or the columns communicating with each other across different areas (Hendry and Hsiao, 2003).

Rodent S1 is a peculiar kind of cortical area. On the one hand it houses the entire representation of the body (as a “ratunculus” or “musculus”, in analogy to the famous “homunculus”) and it does so in the form of a typical primary sensory cortex, i.e. a “koniocortex” showing a very well developed granular cell layer (IV) which leads to the highest gray level index of the entire rat cortex (Palomero-Gallagher and Zilles, 2004).

As seen in Figure 2, some parts of the body are mapped in a one-to-one fashion (e.g. each whisker to a corresponding barrel in the posteromedial barrel subfield; S1BF, (Paxinos and Watson, 1998), whereas other parts are mapped to barrels in a non-one-to-one fashion (e.g. the forepaw digits and palm to the forelimb area barrels; S1FL) and still further body parts are represented in subdivisions of S1 not being modularly organized at all (trunk in S1TR) (Welker and Woolsey, 1974; Chapin and Lin, 1984). On the other hand, the modules (here: barrels) which represent the granular cortex are embedded in a matrix of dysgranular cortex (to which also the septal compartments belong) with very different connectional and functional properties. Here, a tight relationship to ipsilateral primary motor and contralateral primary somatosensory cortex can be observed (Alloway, 2008). The situation is further complicated by the fact that rodent S1 contributes heavily to the subcortical projections reaching the brainstem and the spinal cord, which is reflected by a prominent layer Vb housing large pyramidal neurons so that some researchers have described at least part of the primary somatosensory cortex as a sensory-motor amalgam (Donoghue et al., 1979).

Figure 2: Flattened left hemisphere of GAP-43 wildtype mouse cortex immunostained with serotonin transporter (see Barrels web: http://simonslab.neurobio.pitt.edu/barrels/figure3.html ); rostral is to the left, caudal to the right, medial to the top and lateral to the bottom. The primary somatosensory cortex is represented by a disproportionately large portion of the cortex and consists of the large whisker representation (isomorphic to the five rows on the snout, named A-E), the small whisker representation (SW), the lower lip (LL), forelimb (FL), hindlimb (HL) and trunk (T) representation. The secondary somatosensory cortex (S2) is located laterally adjacent to S1. Also the primary auditory (A1) and the primary visual (V1) cortex get demarcated by the brown reaction product.

Species similarities and differences

It is well known that the complexity of the primary visual cortex (V1) shows huge differences according to the importance and functional specialization of the sense of vision for a given species (Van Hooser, 2007). It should also be stated that V1-circuitry in monkey and cat is well established (Callaway, 1998; Binzegger et al., 2004) and would lend itself to direct comparison of rodent S1-circuitry as described below. When one looks for species differences in S1, it becomes clear that they are less striking (Welker and Woolsey, 1974; Leclerc et al., 1994; Geyer et al., 1999). This might be explained by the fact that this is a basic sensory modality of similar importance for all mammals (Glassman, 1994). An obvious difference is the existence of barrels is some species and the lack of such cellular agglomerations in others. However, no systematic relationship between the appearance of barrels and phylogenetic or functional aspects could be found with certainty (Woolsey et al., 1975). Another obvious difference is that in rodent S1 the infragranular layers take up half of the cortical thickness whereas in feline or primate S1 the supragranular layers (especially layer III) are developed prominently. Layer III in the latter, furthermore, shows very large pyramidal cells whereas they are rare in layer V when compared to the rodent. This is very likely to possess a correlate in the functional connectivity of S1 with different cortical and subcortical areas, which might have a stronger “motor component” in rodents and a more prominent “associative component” in primates (Diamond, 1979).

What are cortical layers?

In an earlier review on cortical lamination, Jones (1981) stated at the beginning of p. 201: “The first scheme of cortical lamination was proposed by Meynert in 1867. Despite many years of subsequent work, the significance of lamination is still little understood. To a large extent, this is because the cortex changes its laminar pattern from area to area […]. Any analysis is further complicated by the fact that pyramidal cell somata situated in one lamina have dendrites that extend through several supra- and subjacent laminae. Finally, there is no agreement regarding the classes and distribution of interneurons […].” In the present chapter on S1 laminar organization it will become clear that although much has been learned since then on cortical cell types and their physiology, neurochemistry and morphology, the big picture of the functional meaning of cortical lamination has remained obscure.

The 6 (or so, see below) cortical layers are established in an inside-out sequence. They probably are “by-products” of the developmental dynamics of the ventricular and subventricular zones, the germinal neuroepithelium which gives rise to the neuroblasts which differentiate into the different excitatory cells of the neocortex (Mountcastle, 1997; Molyneaux et al., 2007).

Box 1: Nomenclature of cortical layers (L)*

Layer number	Standard name	Synonym
I	Molecular layer	None
II	External granular layer	Corpuscular layer
III	External pyramidal layer	Pyramidal layer
IV	Internal granular layer	Granular layer
V	Internal pyramidal layer	Ganglionic layer
VI	Multiform layer	Polymorph layer

• Please note the right column which makes the widely used terms supragranular (L I-III) and infragranular (L V-VI) layers understandable.

When all 6 cortical layers have been formed after the first postnatal week (Rice, 1995), they can be described as tiers of neurons that share a similar appearance or packing density (classically observed in Nissl staining), which differs qualitatively and/or quantitatively from the neighboring tiers (Figure 3A).

Figure 3: Different views on cortical layers. (A) “Six layers” (Roman numerals) shown by “fluorescent Nissl-staining” (Neurotrace) staining (scale bar: 250 µm). (B) Layer-specific markers suggest a much richer stratification (Molyneaux et al., 2007).

However, with more refined methods massive differences in gross morphology or neurochemistry of the individual neurons forming one cytoarchitectonically coherent layer can be observed (for details see following paragraphs). Let us testify here that delineating 6 layers is a convention, which from the beginning did not remain without alternatives (Jones, 1984a). Especially recent molecular studies offer a glimpse into a much richer stratification (Figure 3B; (Lein et al., 2007) which is very likely to reflect also functional differences, as has been shown, for example, when layer Va was compared with Vb (Schubert et al., 2007; Groh et al., 2010).

Thus, below, each layer will shortly be characterized in terms of its classical appearance in Nissl staining. Furthermore, a necessarily eclectic (due to space and time constraints) description of the finer morphological details of the individual cells, their associated functional properties, their neurochemistry and their connectivity will be added. Especially GABAergic interneurons are not featured extensively here, due to their rich diversity of basically all features, except clear-cut laminar specificities (i.e. I would consider them under a conceptual framework different from layers and in a separate chapter). The interested reader is advised to consider seminal original work or some of the recent extensive reviews (as a very incomplete suggestion: (Kawaguchi, 1995; Cauli et al., 1997; Markram et al., 2004; Ascoli et al., 2008; Helmstaedter et al., 2009a). Most emphasis will be placed on laminar connectivity differences.

Laminar specificity of long-range input-output connectivity

In order to understand the functional capacity of a certain brain area, it is a prerequisite to know its inputs, the local circuitries and the outputs. Here, no written overview will be given on intracortical and thalamo-cortical layer-specific input of rodent S1, which is either badly studied (intracortical) or subject to a different chapter of Scholarpedia. A summary diagram of pattern of cortical inputs can be found in Figure 4. The local circuitry is presented in a very simplified manner as the "canonical microcircuit", a concept which highlights only a selected series of excitatory feedforward projections that can also be found embedded in Figure 6. The remaining of this paragraph is focused on the layer-specific outputs that have been determined for rodent S1 in the recent years. Considering only the excitatory principal cells of the neocortex (i.e. the glutamatergic pyramidal, star pyramidal and spiny stellate neurons), a striking feature of cortical laminar organization is an extensive similarity of projection targets for each individual layer (Figure 5), although this organizing principle is much less clear in the rodent than in the primate (Jones, 1984b; White and Keller, 1989).

Figure 4: Cortical layer-specific inputs. Cortical layers are targeted in a specific manner by intracortical and thalamic projections but much less so (if at all) by major ascending (transmitter-specified modulatory) pathways (not shown). Due to our sparse knowledge on the cellular origin and the precise laminar termination of these connections in rodent S1, a very schematic and thus oversimplifying (to the extent of a putative faultiness) diagram has been generated. Here, the pattern of cortico-cortical connections is adopted from the concept by Felleman and van Essen (Felleman and van Essen, 1991). For thalamo-cortical projections, the concept worked out by Herkenham (Herkenham, 1980; Herkenham, 1986) is used.

The long-range projections of layer II pyramidal cells, Jones (1984b) are issued over shorter-distance (than layer III, see directly below) for both, associational as well as commissural projections. According to the classical scheme L III pyramidal cells are responsible for the majority of long-range associational and a portion of the callosal projections (Jones, 1984b). In S1 this seems, at least partially, to fulfill a sensory-motor integration function since a major associative route of supragranular pyramidal neurons is to the primary motor cortex whereas a major homotypical callosal projection is targeted to septa of the contralateral S1 (Alloway, 2008).

The circuitry of L IV neurons has now been thoroughly studied. In terms of outputs, in contrast to cat and monkey, in the rodent it is usually stated that layer IV-spiny neurons are “excitatory interneurons” without associational, commissural or corticofugal projections. However, upon closer look, a number of studies show retrogradely-labeled neurons in layer IV (mainly septal compartment) after tracer injections in ipsilateral S2 (Chakrabarti and Alloway, 2006) or contralateral S1 (Hayama and Ogawa, 1997).

In terms of their long-range connections, the bilateral projections of L Va pyramidal cells to primary motor cortex and striatum are especially well characterized (Wright et al., 2001; Alloway, 2008). This strongly suggests a participation in the control of motor and sensory aspects of whisking behavior (Derdikman et al., 2006), a notion which is further supported by the organization of the local intracortical circuits into which L Va pyramidal cells are integrated.

The long-range projections of L Vb pyramidal cells in rodent S1 are very diverse. They form part of the neurons-of-origin of associational and callosal projections, just like virtually all other layers except I and IV. However, they represent the only neurons which are able to project to target areas downstream of the thalamus, such as the superior colliculus, pontine and trigeminal nuclei or spinal cord (Jones, 1984b; Welker et al., 1988; White and Keller, 1989). Thus they are in a position to directly influence circuits mediating behavior as well as controlling the ascending flow of sensory information at various hierarchical levels. Due to their firing rate being the highest of all neurons in a barrel-related column, the large-tufted (IB) pyramidal cells are supposed to be the major contributors to driving subcortical circuits (de Kock et al., 2007; de Kock and Sakmann, 2008). In general, however, only little is known about cell type-specific subcortical projection patterns, but promising work is underway to understand this type of specificity by looking at developmental genetic programs (Molyneaux et al., 2007).

The subcortical projections of L VIa are very restricted, as are the intracortical. The projections to the thalamus end exclusively in (i) the lemniscal ventrobasal nucleus and (ii) the reticular nucleus which themselves are reciprocally connected (Bourassa et al., 1995).

Figure 5: Cortical layers organize long-range (but also short-range; see following paragraphs) projections. Please note that although this scheme has been derived from literature specific for rodent S1, it does not consider the differential origin of some of the projections in terms of their relationship to barrel-related vs. septum-related columns (see references below). It also does not reflect all known morphological details of the neurons of origin, for the sake of simplicity. Stippled layer IV-neurons represent (star-)pyramidal cells which are not considered to be projection neurons in the rodent but can be seen in (Chakrabarti and Alloway, 2006) for associative and were described in (Jones, 1984b) for callosal projections. Pyramidal cells with an asymmetric apical dendritic tuft either form no tuft at all, or, a very small one. For layer Vb-callosal cells, this was reported e.g. by (Le Be et al., 2007). For the subcortical projections originating in layer Vb a uniform symbol was used because there are only very few reports on the detailed somatodendritic morphology of projection-identified neurons. Such papers suggest that regular-spiking and intrinsically burst-spiking cells do, at least partially, project to different targets (Larsen et al., 2007; Hattox and Nelson, 2007). A separate neuron is shown for each of the different subcortical targets since there is no agreement in the field to what extent collateralization of the axon to different targets does exist. Major additional papers consulted: (Wise and Jones, 1977; Killackey et al., 1989; Koralek et al., 1990; Mercier et al., 1990; Bourassa et al., 1995; Veinante et al., 2000; Wright et al., 2001; Alloway et al., 2004).

Figure 6: Recent update on canonical microcircuits with a more differentiated view on different intracortical and thalamo-cortico-thalamic interactions (Reproduced with permission from (Lübke and Feldmeyer, 2007). These circuits are shown in 3 panels for didactic reasons. In vivo they are all implemented into one module.

Layers and their short-range connectivity re-visited

Taking the “canonical microcircuit” in its updated form as a guideline (cf. (Silberberg et al., 2005; Lübke and Feldmeyer, 2007; Douglas and Martin, 2007; Thomson and Lamy, 2007), we will start with the input layer IV, continue with layers III and II to proceed to the major output layers Va, Vb and VIa (Figure 6). This scheme has recently gained important extensions by additional experimental data (Schubert et al., 2007; Lefort et al., 2009). In short, the "canonical microcircuit" is regarded as a series of excitatory feedforward projections, in which the lemniscal thalamus innervates layer IV that projects to layers II/III that innervate layer V, which on the way to their subcortical target sites give off a collateral projection to layer VI that closes the loop with the lemniscal thalamus. We will end with a characterization of layers I and VIb which are by now not reasonably well integrated into this scheme.

Layer IV (Lamina granularis interna)

for nomenclature see Box 1.

Cellular composition: This layer shows a high packing density of relatively small-sized neuronal somata providing it in Nissl-stainings with a grain-like appearance. With the advent of Golgi labeling or biocytin filling it has become clear that medium-sized neurons with symmetrical (spherical) or asymmetrical small dendritic trees populate this layer, dendrites which show either (i) high numbers of spines (spiny neurons) or (ii) zero to medium numbers of spines (smooth/aspiny or sparsely spiny stellate cells) (Simons and Woolsey, 1984; Lorente de Nó et al., 1992). The spiny stellate neurons are considered to represent excitatory pyramidal neurons which have lost their apical dendrite during development (Vercelli et al., 1992). Indeed, in addition to classical spiny stellate cells pyramidal-like cell types can also be found in this layer, namely symmetrical and asymmetrical star pyramidal neurons as well as classical pyramids (Staiger et al., 2004). These are, however, often not well differentiated in terms of their basal dendritic configuration and the terminal tuft of the apical dendrite which is mostly missing completely. The actual proportion of these cells in L IV is highly area and species specific (Jones, 1975; Martin and Whitteridge, 1984; Lund, 1984; Smith and Populin, 2001; Saez and Friedlander, 2009). However, precise quantifications of their absolute or proportional numbers are still missing due to the lack of appropriate markers at the population level. In terms of neurochemistry little more than the fact that they express low levels of calbindin d-28K, like their “relatives” in the supragranular layers, is known (Celio, 1990; van Brederode et al., 1991; Alcantara et al., 1993). The spine-poor or spine-free neurons are considered to be GABAergic interneurons which are especially numerous in L IV (Ren et al., 1992).

Connectivity: Until recently it was believed that L IV-neurons possess only two substantial input sources: (i) the lemniscal thalamic projection (Gibson et al., 1999; Bureau et al., 2006) and (ii) local collaterals of neurons residing within the same column (Feldmeyer et al., 1999; Petersen and Sakmann, 2000). Although these inputs can still be considered as the two quantitatively most imported ones, evidence has accumulated that, in a cell type-specific manner, intracolumnar feedback projections originating from supra- and infragranular layers as well as transcolumnar projections directly originating in L IV of neighboring columns can also be consistently found (Martin and Whitteridge, 1984; Staiger et al., 2000; Schubert et al., 2003; Egger et al., 2008). These horizontal L IV-connections are functional and contribute to the receptive fields of these neurons (Fox et al., 2003) which can be fairly large at the subthreshold level (Moore and Nelson, 1998; Brecht and Sakmann, 2002). Nevertheless, it can be stated that L IV is likely to process sensory information with the lowest level of context-dependent integration of what is going on in the neighboring sensory periphery as well as in hierarchically higher cortical areas.

Layer III (Lamina pyramidalis externa)

In certain species and areas (e.g. rodent S1), there are no cytoarchitectural differences between layers II and III. Thus, these two layers are often pooled into a "layer II/III". However, several recent papers have clearly demonstrated that the input-output function (see respective chapters below) of pyramidal cells located close to the pia is different from those located close to the barrels. Therefore, it was chosen to present the two layers here as distinguishable entities, the exact border location of which may become visible with future molecular markers.

Cellular composition: This layer shows, in Nissl-stained sections, a high density of pyramidal-shaped cell bodies which is due to the presence of a morphologically homogeneous population of typical medium-sized pyramidal cells. In Golgi studies they were revealed in more detail, with little variation of their somatodendritic morphological features. In fact, together with the L V (a and b) pyramidal cells they represent the “purest” representatives of this cell type in the brain (Peters and Kara, 1985). The apical dendrite always reaches layer I where it forms a well-defined tuft, whereas the basal dendrites mainly originate from the opposite pole of the soma ramifying in layers III and IV. This was later confirmed by biocytin fillings in S1 (Schröder and Luhmann, 1997; Lübke et al., 2003) as earlier studies already had shown in cat primary visual cortex (Gilbert and Wiesel, 1979; Martin and Whitteridge, 1984). The molecular or neurochemical characterization of these neurons is not very well advanced at the identified single-cell level (Andjelic et al., 2009; Karagiannis et al., 2009), although numerous layer-specific traits can be expected (Arion et al., 2007). The other major group of neurons are the non-pyramidal cells: These are very frequent in the supragranular layers III and II (Peters et al., 1985) and probably cover all possible types of inhibitory interneurons which occur in the neocortex (Markram et al., 2004; Helmstaedter et al., 2009a; Helmstaedter et al., 2009b). It is obvious, however, that bipolar and bitufted cells expressing many different neuropeptides are especially numerous here (Cauli et al., 2000).

Connectivity: The intracolumnar circuitry of layer III pyramidal neurons is dominated by two sources: (i) local intralaminar connections (Feldmeyer et al., 2006), which are, however, often outweighed by (ii) L IV translaminar input (Yoshimura et al., 2005; Shepherd and Svoboda, 2005; Schubert et al., 2007; Lefort et al., 2009). Recent evidence suggests that this is also true for at least a subpopulation of L III inhibitory cells, i.e. the fast-spiking basket cells (Xu and Callaway, 2009). The transcolumnar circuitry of L III pyramidal cells has been more difficult to study in the slice. Although structurally and functionally supragranular transcolumnar pathways have been described (Fox, 2002; Brecht et al., 2003; Broser et al., 2008), they are much less numerous in L III than in L II (Larsen and Callaway, 2006; Bruno et al., 2009)( own still unpublished results). This may be one reason for the so far lacking paired recordings of L III pyramidal neurons located in neighboring columns, in vitro and in vivo. Since the connection probability decreases monotonically with distance (Holmgren et al., 2003), new methods to pre-identify connected neurons (Wickersham et al., 2007) have to be further refined (Boldogkoi et al., 2009), in order to study the precise functional and morphological determinants of transcolumnar L III circuits (which is true for all other layers as well). Concerning the output of L III, consistently, L V(b) has been found to be the major intracolumnar target structure which represents one of the backbone feedforward projections of the “canonical microcircuitry” (Martin and Whitteridge, 1984; Thomson and Bannister, 2003; Kampa et al., 2006; Lefort et al., 2009). However, evidence has accumulated that also a functionally weak but anatomically consistent feedback projection to L IV excitatory neurons is formed (Martin and Whitteridge, 1984; Schubert et al., 2003; Larsen and Callaway, 2006; Lefort et al., 2009).

Concerning their function, the circuits described above can be interpreted to link ongoing tactile information processing in S1 with (i) the related activity of a multitude of afferent and efferent columns and (ii) different functional cortical areas outside S1. Furthermore, reliable experience-dependent plasticity can be found in these cells (Diamond et al., 1994; Huang et al., 1998; Fox, 2002; Feldman and Brecht, 2005), and also a memory storage capacity was repeatedly proposed (Goldman-Rakic, 1996; Harris et al., 2002) which should be enabled by the strong context- or learning task-related modulation of the above described circuits.

Layer II (Lamina granularis externa)

Cellular composition: Due to the close proximity to the pial surface, most pyramidal neurons of this layer do not form a typical apical dendrite, the origin of which must not strictly be located at the somal pole pointing toward the pia. Thus, these cells have a less triangular and more ovoid to round appearance which led to the classification as a granular layer despite the presence of mainly modified (obliquely oriented or tilted) pyramidal cells (Peters and Kara, 1985; van Brederode et al., 2000). Concerning the molecular and neurochemical features of L II neurons, they have not been shown to differ significantly from their L III counterparts. This holds true by and large for excitatory as well as inhibitory neurons (see L III-paragraph). It is, however, conceivable, that fine scale molecular differences between layer II and III (Lein et al., 2007; Molyneaux et al., 2007) do translate to neurochemical differences, yet to be identified at the single cell level. So a significant difference, when layer II neurons are compared to layer III, should be found in their connectivity (see below), in order to justify a separate account of these layers instead of just merging them into a “single layer II/III” as is usually done in rodents.

Connectivity: Their local circuitry is not simply dominated by the same afferent pathways as described for layer III. In addition to local and layer IV inputs, a reproducible finding was a prominent layer Va input, not only for septum-related (Shepherd and Svoboda, 2005) but also for barrel-related neurons (Lefort et al., 2009)(own still unpublished results). In the rodent, a synopsis of recent data suggests that in terms of intracolumnar-translaminar and transcolumnar projections the pyramidal cells in layers II and III differ significantly (Shepherd and Svoboda, 2005; Larsen and Callaway, 2006; Lefort et al., 2009)(own still unpublished results). L II pyramidal cells possess denser and more extensive transcolumnar axonal arbors that preferentially target layers II and Va within the home and neighboring columns whereas L III pyramidal cells issue a much sparser intralaminar transcolumnar projection and mainly target L Vb. Furthermore, L III pyramidal cells also have a substantial number of recurrent axonal collaterals in L IV.

In terms of function, it is presently unclear whether L II really differs from L III because no studies have rigorously addressed this issue. This also holds true for other cortical areas (than S1) or species (than rodents) where these layers have been found to be distinguishable on a reliable basis. However, evidence has recently been presented that some key neuronal properties are actually different between pyramidal cells in these two layers which allows to assume a functional segregation as well (Gur and Snodderly, 2008).

Layer Va (Lamina pyramidalis interna “a”)

Cellular composition: This layer shows a low packing density of medium-sized pyramidal cell bodies and serves as a prominent feature to delineate S1 from the neighboring areas (Palomero-Gallagher and Zilles, 2004). The pyramidal cells usually form a slender dendritic tree with a little elaborated terminal tuft in layer I (Schubert et al., 2006; Frick et al., 2007). Since we and others have recently shown that their morphology and its correlation with intrinsic and extrinsic physiological parameters differs dramatically from those of layer Vb, we have suggested that these neurons form a genuine layer Va which should not be regarded as a mere “sublayer” of layer V (Ahissar et al., 2001; Manns et al., 2004; Schubert et al., 2006). In other cortical areas different types of specialization of layer Va may occur (Molnar and Cheung, 2006). These authors also presented some data on molecular and neurochemical features of layer Va-pyramidal neurons, which might, however, be mainly of developmental importance. The GABAergic interneurons, on the other hand, so far received little attention in layer Va, although they occur rather frequently at the layer IV/Va-border (Ren et al., 1992; Porter et al., 2001). Of course, Martinotti cells have to be mentioned in this context (Fairen et al., 1984), which in their classic form have a soma located in the infragranular layer and an axon that targets layer I (but also often strongly ramifies in layer IV; (Wang et al., 2004). This has recently been associated with “linearization”-effect on the different tactile stimulation strengths (Murayama et al., 2009).

Connectivity: Local circuits are dominated by two sources: (i) intra- and transcolumnar inputs from L Va itself have been found to be especially numerous and strong (Schubert et al., 2006; Frick et al., 2008; Lefort et al., 2009) and (ii) apart from L II (Lefort et al., 2009) translaminar input derives mainly from L IV (Feldmeyer et al., 2005; Schubert et al., 2006) making L Va a putative early cortical interface for lemniscal and paralemniscal sensory information. The latter two publications further suggest that the axonal output of L Va-pyramidal cells is targeted to the same layers from which they receive their major inputs.

Layer Vb (Lamina pyramidalis interna “b”)

Cellular composition: This layer was usually equated with layer V as such and consists of a mixture of differently sized pyramidal cells. In rodent S1 L Vb can be easily distinguished from L Va due a much higher cell density and occurrence of very large pyramidal cells in L Vb. The ratio of medium-sized to large pyramidal neurons has been estimated to be 2,5 : 1 in rat visual cortex (Peters and Kara, 1985). Interestingly, here the somato-dendritic morphology of the pyramidal cells correlates well with many connectional, physiological and pharmacological features (cf.(White et al., 1994; Kasper et al., 1994; Schubert et al., 2001; Bodor et al., 2005; Christophe et al., 2005; de Kock et al., 2007; Larsen et al., 2007). Upon somatic current injection and dye filling in vitro (see below) but also in vivo (Zhu and Connors, 1999), a basic distinction can be made between (i) neurons with medium-sized somata and a sparse to mediocre dendritic tree which display a so-called regular spiking pattern (RS; consisting of single action potentials with various adaptation rates) and (ii) neurons with large somata and a very well elaborated dendritic tree which display a so-called intrinsically burst-spiking firing pattern (IB; consisting an initial burst of usually two or three but up to five action potential with interspike intervals of less than 10 ms which ride on a depolarizing envelop) (Connors et al., 1982; McCormick et al., 1985; Chagnac-Amitai et al., 1990; Mason and Larkman, 1990; Hefti and Smith, 2000; Schubert et al., 2001). Other groups, mostly those which used parasagittal slices, did not find this characteristic bursting behavior and usually call their labeled cells “slender” versus “thick-tufted” neurons but it is very likely that both terminologies represent the same types of neurons (e.g.(Markram, 1997; Angulo et al., 2003). Recently, a third population of pyramidal cells was characterized in L V(b): cortico-callosal pyramidal cells whose dendrites did not reach L I and did not form a terminal tuft (Le Be et al., 2007). GABAergic interneurons, on the other hand, did not receive the same attention in this layer as the principal cells. It is very likely that all types of GABAergic interneurons are present in L Vb in order to function according to their “standard mode” of operation (Thomson et al., 1996; Markram et al., 2004; Silberberg and Markram, 2007).

Connectivity: In terms of the local columnar and transcolumnar connectivity, much has been learned in recent years. It appears that a selective pattern of local connections exists between cells differing in their long-distance targets which is not dependent on the firing pattern or the specific minicolumnar identity of the respective neurons (Deuchars et al., 1994; Markram et al., 1997; Kozloski et al., 2001; Morishima and Kawaguchi, 2006; Krieger et al., 2007; Brown and Hestrin, 2009). Generally it can be stated that RS pyramidal cells have a more home column-focused connectivity whereas IBs are much more transcolumnarly connected. In addition, RS cells have a patchy input pattern with some focal hot-spots, in contrast to IB cells which possess spatially more uniform and dense input with on average lower strength (Schubert et al., 2001). In the latter study we also showed a strong feedback projection from layer VI which was recently corroborated by paired recordings and shown to originate from the subpopulation of cortico-cortical cells (Mercer et al., 2005).

Functionally, this makes IB-pyramidal neurons the prime candidates for multiwhisker integration (Simons, 1978; Ito, 1992; de Kock et al., 2007) and cortical pacemaker function which has indeed been shown experimentally (Chagnac-Amitai and Connors, 1989).

Layer VIa (Lamina multiformis “a”)

Cellular composition: In no other layer than (the entire) L VI such a high shape variability for spiny neurons ranging from classical over oblique to inverted pyramidal cells to all variations of spiny stellate-like neurons has been found (Tömböl, 1984; Kaneko and Mizuno, 1996; Zarrinpar and Callaway, 2006; Chen et al., 2009; Andjelic et al., 2009). However, the less multiform “sublayer” VIa (of L VI) shows a high packing density of more uniform small somata often possessing a pyramidal to ovoid shape.

Connectivity: Intracolumnarly, cortico-thalamic projection neurons rarely connect to each other but seem to prefer GABAergic interneurons as their targets (West et al., 2006). On the other hand, they are sparsely afferented by local cortico-cortical excitatory, L V and IV neurons (Figure 7) (Mercer et al., 2005; Zarrinpar and Callaway, 2006; Lefort et al., 2009).

Their efferents are not only directed to the thalamus but they also possess terminal axons in L IV (Zhang and Deschenes, 1997; Kumar and Ohana, 2008). It is debated how specific this feedback projection is in terms of targeting GABAergic interneurons but it is very likely that both, excitatory and inhibitory L IV neurons receive synapses (White and Keller, 1987; Staiger et al., 1996). In contrast to the thalamic “driver” input to L IV, these recurrent collaterals have been considered as “modulators” (Stratford et al., 1996; Lee and Sherman, 2008).

Figure 7: This figure 4 from (Zarrinpar and Callaway, 2006) shows the excitatory (color-coded strength) intracortical translaminar connectivity of three types of cells in L VI of rat visual cortex. It is obvious that only putative cortico-thalamic pyramidal cells (A) but not putative cortico-cortical pyramidal cells (C) or putative inhibitory interneurons (E) receive a multiple “extra-L VI-input”. Reproduced with permission.

From a functional point of view we are left with a fascinating circuit construction. Layer VIa forms an important input structure for the very same thalamic nucleus to which it directly projects back. At the same time it issues a second feedback projection to the other (primary) input layer of the thalamus: L IV. The above-mentioned input from L Vb can be considered to close the intracortical loop (IV→III/II→Vb→VI). As such L VI holds a “raw” representation of a tactile stimulus and is capable of comparing this to the same but cortically processed information. The cortical feedback has a facilitatory effect on the thalamus (Yuan et al., 1986) which is considered, together with the reticular nucleus’ effects, to focus attention to salient sensory stimuli (Sillito et al., 1994; Temereanca and Simons, 2004).

The following two layers have been studied only infrequently and are not well understood concerning their contribution to cortical circuitry and thus tactile information processing. They will only be briefly touched upon here for the sake of completeness. Interestingly, during cortical development both layers together formed the primordium of the cortex, the so-called preplate, before they were split by the growing cortical plate (Molyneaux et al., 2007).

Layer VIb (Lamina multiformis “b”)

Cellular composition: This layer shows less densely packed neurons than L VIa, already tightly intermingled with many horizontally oriented myelinated fiber pathways. The spiny excitatory neurons in L VIb, which some also call L VII (Reep, 2000), are considered to represent the remnants of the subplate but also contain cortical plate-derived neurons, with pyramidal cells being found only very rarely (Friauf et al., 1990; Chen et al., 2009; Andjelic et al., 2009).

Connectivity: The connections of these cells beyond the initial developmental circuits they are involved in (Hanganu et al., 2002) are ill-defined. There seems to be a population of associationally projecting neurons (Zhang and Deschenes, 1997) with a strong layer I component (Clancy and Cauller, 1999) as well as one projecting to various nuclei of the thalamus, a connection which is likely to be organized reciprocally (Zhang and Deschenes, 1998).

Layer I (Lamina molecularis)

Cellular composition: This layer shows the lowest cell density of all, the rat being cell poorer than the mouse. It is generally accepted that, at the adult stage, virtually all cells located there are GABAergic interneurons (Ren et al., 1992; Beaulieu, 1993; Hestrin and Armstrong, 1996). A very low number of Cajal-Retzius cells which are now considered as glutamatergic interneurons (Hevner et al., 2003; Ina et al., 2007) were reported in some studies to survive the first two postnatal weeks of development (Derer and Derer, 1990; Zhou and Hablitz, 1996). However, from this age on, after the completion of the cortical layers, they are of unknown function. It could be hypothesized that in areas in which adult neurogenesis takes place they could still serve the function to guide the migration of these neurons to their final target layer; alternatively, neuronal plasticity may be influenced via interaction of reelin with NMDA receptors (Herz and Chen, 2006).

Connectivity: As for the subplate neurons, some of the transient connectivity of the Cajal-Retzius cells has been also inferred by electrical or pharmacological stimulation, the cellular or laminar origin of these connections, however, has remained largely obscure. Altogether, these transient circuits have been proposed to play a role in the formation of an early columnar circuitry (Dupont et al., 2006). For L I-GABAergic interneurons, a plausible hypothesis is that they directly regulate (i) feedforward information-transfer from thalamus (Galazo et al., 2008) and (ii) feedback from “higher” cortical areas which could co-innervate these neurons as well as the terminal tufts of pyramidal cell arborizing in layer I (Vogt, 1995; Zhu and Zhu, 2004).

Summary and Conclusions

This chapter offers but a S1-biased glimpse on the very rich cortical circuit architecture which is strongly dependent on the individual layers but certainly possesses some cell type-, area- and species-specific traits as well. This circuit analysis is very advanced in the primary somatosensory (barrel) cortex which leads to the expectation that by modeling the basic circuitry contained within one barrel-related column we will begin to understand the basic modes of operation in input, local and output circuits of the cerebral cortex (Markram, 2006; Sarid et al., 2007). Based on this in-depth knowledge of cell types and their connections, a reasonable study of experience-dependent plasticity should finally become feasible (Feldman and Brecht, 2005; Fox and Wong, 2005; Staiger, 2006; Clem et al., 2008; Bruno et al., 2009). However, one has to realize that a clear-cut unraveling of the functions of these layer-dependent circuits has still not been achieved. Although recently concepts like decision making by layer Vb-pyramidal neurons (Helmstaedter et al., 2007) have been advanced, most researchers agree that such more complex functions have to be carried out by larger ensembles of neurons distributed over several layers and spatially distant areas in cortical as well as subcortical structures (Krupa et al., 2004; Burke et al., 2005; Diamond et al., 2008).

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Sponsored by: Prof. Ehud Ahissar, Department of Neurobiology, The Weizmann Institute, Rehovot

Sponsored by: Prof. Tony J. Prescott, Dept Psychology, Univ of Sheffield, UK

Reviewed by: Anonymous

Accepted on: 2010-07-18 19:12:36 GMT