View source for Talk:S1 microcircuits


Scholarpedia article: ‘S1 microcircuits’
http://www.scholarpedia.org/article/S1_microcircuits


Dirk Feldmeyer
1Research Centre Jülich, Institute of Neuroscience and Medicine, INM-2 Medicine, D–52425 Jülich, Germany, 2Department of Psychiatry, Psychotherapy and Psychosomatics, Medical School, RWTH Aachen University, D-52074 Aachen, Germany, 3JARA-Translational Brain Medicine


Word count: 359 
==Introduction==

The whisker-related portion of the primary somatosensory (S1) area (the ‘barrel cortex’) in rodents exhibits a topological arrangement that mirrors the peripheral (contralateral) tactile receptors called the vibrissae on the rodent’s snout. In cortical layer 4, barrel-like cytoarchitectonic units are discernible each of which represents a single whisker hair. The extension of the barrel borders in layer 4 barrel, throughout all cortical layers has been taken to define a vertical barrel ‘column’ which is the anatomical correlate of a cortical column (Szentágothai, 1975). Because of this well-defined organisation the barrel cortex has become a model system for investigating synaptic microcircuits and even long-range synaptic connectivity related to the structural representation of sensory receptors (for recent reviews see e.g. Fox, 2008; Bosman et al., 2011; Feldmeyer et al., 2013). This chapter will concentrate on the excitatory microcircuit in the barrel cortex, where a comprehensive structure and function relationship is gradually emerging. 

==Thalamocortical input to the barrel cortex==

Excitation arrives in the neocortex at least via two different pathways, the so-called lemniscal  pathway that relays through the the ventroposterior medial (VPM) nucleus of the whisker-related thalamus and the paralemniscal pathway that involves the posterior medial (POm) nucleus. All layers of the barrel cortex receive excitatory synaptic input from at least one of these thalamic nuclei (Meyer et al., 2010a; Oberlaender et al., 2012; Constantinople and Bruno, 2013; see also Alloway, 2008; Deschênes, 2009 for an overview of thalamic projection pathways). 
The major thalamorecipient layer in the somatosensory barrel cortex is layer 4 shown by the highest density of thalamocortical (TC) axons per given dendritic length (Jensen and Killackey, 1987; Chmielowska et al., 1989; Oberlaender et al., 2012). These TC afferents emanate from VPM and target both excitatory and inhibitory neurons in a L4 barrel. In addition, VPM axons innervate pyramidal cells and GABAergic interneurons in layers 3, 5B and 6A. The majority of their boutons establish synapses onto excitatory neurons, solely because they vastly outnumber L4 interneurons (inhibitory/excitatory neuron ratio in layer 4 ~ 8% vs. 92%; Lefort et al., 2009; Meyer et al., 2011). However, synaptic contacts formed by TC axons comprise only about 10-20% of the total number of synaptic contacts in layer 4 (White and Rock, 1979; Benshalom and White, 1986) and are therefore considerably outnumbered by intracortical synaptic connections. Under in vivo conditions, the average amplitude of unitary VPM-L4 spiny neuron EPSPs is ~1 mV suggesting that this synapse has a very low efficacy. However, after whisker stimulation, VPM synaptic input to L4 spiny neurons is highly coincident and synchronous resulting in an efficient TC signal transfer (Jia et al., 2014; Schoonover et al., 2014). It does not require intralaminar amplification (Brumberg et al., 1999; Miller et al., 2001; Bruno and Sakmann, 2006). 
The major target regions of POm (paralemniscal) TC input are layers 5A, 1 and 2. In addition, POm axons innervate also the septa between layer 4 barrels (Alloway, 2008; Meyer et al., 2010b; Meyer et al., 2010a; Wimmer et al., 2010; Oberlaender et al., 2012) and layer 3 where they overlap with VPM axon. VPM and POm inputs are proposed to be cconstituents of distinct intacortical columnar pathways, the ‘barrel column’ and the ‘septal column’ (Alloway, 2008). 
In layer 5A, POm afferents probably establish synaptic contacts with basal dendrites of L5A pyramidal neurons while in layer 1 and upper layer 2 they may target apical dendritic tufts of L2, L3 and L5 pyramidal neurons as well as L1 and L2 interneurons. '''Reference needed?'''--[[User:Shruti Muralidhar|Shruti Muralidhar]] ([[User talk:Shruti Muralidhar|talk]]) 21:19, 1 April 2015 (UTC)

==Excitatory S1 microcircuits==

Excitation by the whisker-related thalamus is distributed within the barrel cortex via many distinct microcircuits. These microcircuits can be grouped into different subnetworks or microcircuits; however, these subnetworks are not separate and independent entities but interact at many different levels. 
The first prototypical neuronal microcircuit described synaptic signaling from the sensory thalamus, to and within the primary visual cortex. This was termed 'canonical  microcircuit' by Rodney Douglas and Kevan Martin (Douglas and Martin, 1991, 2004; Figure 1)

===The ‘canonical’ S1 microcircuit===

In this microcircuit, afferents from the primary sensory thalamic nucleus target excitatory neurons in the granular and supragranular cortical layers. In addition, ‘smooth’ inhibitory interneurons also receive thalamic input, along with infragranular pyramidal cells to a significantly lesser extent. Thus, the signal flow in this microcircuit is from granular and supragranular layers to infragranular layers and subsequently to other cortical areas and subcortical brain regions. However, there is a substantial degree of intralaminar feedback excitation. 
In the S1 barrel cortex, a similar ‘canonical’ microcircuit exists which - in approximation - can be considered as the intracortical part of the lemniscal pathway. The main intracortical element of this subnetwork are L4 excitatory neurons (spiny stellates, star pyramids and pyramidal cells; Staiger et al., 2004; Oberlaender et al., 2012), L2 and L3 pyramidal cells and L5B pyramidal cells (Figure 2). Synaptic signalling in this microcircuit is largely feed-forward and vertical within the ‘barrel column’. In simplified terms, excitation arriving from the VPM results in strong recruitment of L4 excitatory neurons (L3 and L5B pyramidal cells are also recruited, but to a lesser degree). Within an L4 barrel these neurons are recurrently interconnected with a high connectivity ratio of ~0.3 (see Table 1). Their translaminar targets are mainly pyramidal cells in supragranular layers (i.e. layers 2 and 3; but see below). In particular, spiny stellate cells which are the most numerous L4 cell type, show a largely ‘barrel column’-confined, vertical axonal projection and innervate pyramidal cells in both layer 2 and 3 (Lübke et al., 2000). L2 and L3 pyramidal cells innervate other pyramidal cells in their ‘home’ layer but provide also substantial synaptic input to thick-tufted pyramidal neurons in infragranular layer 5B. These L5B pyramidal cells provide in turn output to subcortical target structures such as the thalamus, caudate-putamen, inferior colliculi and cerebellum (e.g. Zingg et al., 2014). The individual intracortical excitatory synaptic connections in this ‘canonical’ microcircuit in the S1 barrel cortex have been characterised in detail. These microcircuits comprise the synaptic connections between between L4 excitatory neurons and L2/3 pyramidal cells, between L2/3 pyramidal cells and thick-tufted L5B pyramidal cells as well as the reciprocal, recurrent connections between these the L4, L2/3 and L5B neurons (Markram et al., 1997; Feldmeyer et al., 1999; Feldmeyer et al., 2002; Holmgren et al., 2003; Silver et al., 2003; Feldmeyer et al., 2006; Lefort et al., 2009). Figure 2 shows a schematic wiring diagram (Figure 2A) and morphological reconstruction of these synaptic connections (Figure 2B). The majority shows a high release probability, as evidenced by a low EPSP failure rate in response to a presynaptic action potential (AP), a low variation in the EPSP amplitude (low coefficient of EPSP variation, c.v.) and a low paired pulse ratio (see also Table 1). This has been tested directly in the L4-L2/3 synapse, in the presence of 2 mM extracellular Ca2+, the release probability was 0.8 (Silver et al., 2003). The number of synaptic contacts for these individual connections varied between 2 and 8; the majority of these synaptic contacts was proximally located on the basal dendrites. 
Taken together, this data shows that synaptic connections in the ‘canonical’ microcircuit are reliable, thereby ensuring an efficient sensory signal transfer in the barrel column. However, it is also clear from the morphology of L2/3 and L5 pyramidal cells that there is a strong and prominent horizontal projections both in layers 2, 3 and/or 5. These horizontal collaterals project across the entire barrel field (Bruno et al., 2009; Oberlaender et al., 2011) thereby integrating whisker-touch induced synaptic excitation from different barrel columns. In addition, there are long-range axon collaterals projecting to cortical areas outside the S1 barrel cortex that facilitate interactions between the S1 cortex and other cortices (e.g. the sensorimotor loop; see also Petreanu et al., 2007; Aronoff et al., 2010; Mao et al., 2011; Petreanu et al., 2012; Zingg et al., 2014).

===Non-canonical, intracortical neuronal networks===

Apart from the excitatory neurons in the ‘canonical’ microcircuit described above, there are several other synaptic connection types that do not fit this scheme. In general, these synaptic connections are part of the paralemniscal thalamic pathway from the POm to the neocortex. However, the ‘paralemniscal’ intracortical microcircuit described here is not a segregated, independent pathway but highly interdigitated with the ‘canonical’, largely lemniscal pathway (Figure 4A).
Constituent elements of the intracortical paralemniscal pathway are L5A pyramidal cells as well as the L2, L3 pyramidal cells and the apical tufts of L5B pyramidal cells since these neurons are located in the major target regions of POm afferents (Fig. 3A; Bureau et al., 2006 see also Oberlaender et al., 2012). L4 septal neurons are also part of this microcircuit (see above; Wimmer et al., 2010). The major target neuron of POm afferents are the slender-tufted L5A pyramidal cells that have an extensive axonal projection in layers 1 and 2 (Fig. 3B). Feed-forward synaptic signalling from these neurons will establish synaptic contacts, not only with other L5A pyramidal cells (Fig. 3C) and L2 pyramidal cells - to a very significant degree -  but also the apical tufts of pyramidal cells in layer 3, 5A and 5B. This is functionally significant because the tuft region of pyramidal cells has a high density of Ca2+ channels and can be considered as a initiation zone for dendritic Ca2+ spikes (Figure 3A; Larkum et al., 1999; Larkum and Zhu, 2002; for reviews see Spruston, 2008; Larkum, 2013) which is involved in coincidence detection mechanisms. Although the connectivity of L5A pyramidal cells with supragranular pyramidal cell should be high, Lefort and coworkers (Lefort et al., 2009) report low connectivity ratios for supragranular projections (L3: 0.02, L2: 0.04) while synaptic input ''from'' these layers is relatively strong (L2: 0.1; L3: 0.06). Furthermore, the connectivity in layer 5 is relatively high (L5A: 0.19, L5B: 0.08). These results are most likely due to slice artifacts (i.e. the truncation of axonal collaterals) but also due to the difficulty in detecting EPSPs from synaptic contacts on distal dendritic structures.
The only synaptic connection in the ‘paralemniscal’ microcircuit that has been studied in significant detail is the L5A-L5A connection (Fig. 3C; Frick et al., 2008). It exhibits a low EPSP failure rate (2%) and CV (0.3), indicating that it has similar reliability as other excitatory synaptic connections in the barrel cortex. Synaptic contacts are found on both basal dendrites and the apical dendritic tufts. To date, the properties of translaminar connections in this ‘paralemniscal’ microcircuit are not known. 
The axonal projection fields of slender-tufted L5A pyramidal cells show a surprising overlap with that of the POm afferents. Thus L5A pyramidal cells may therefore serve to maintain the initial excitation induced of the apical dendritic tufts. 

==Early convergence of VPM and POm pathways in the S1 barrel cortex==

As mentioned above the lemniscal ‘canonical’ microcircuit and the paralemniscal microcircuit interact at several different stages. First of all, both thick-tufted L5B and L3 pyramidal cells receive monosynaptic and prominent TC input from both VPM (to their basal dendrites) and POm (to their apical tufts, s. Figure 4A); this input is near-simultaneous. Further interaction occurs at the level of layer 4 and 5A, the dominant target regions of VPM and POm TC afferents, respectively, where L4 excitatory neurons are monosynaptically connected to L5A pyramidal cell with a connectivity ratio of 0.1. The connection shows a high reliability (similar to other excitatory connections in the S1 barrel cortex, see table 1); synaptic contacts are established on both basal and apical dendrites. This connection provides another short-latency link between the lemniscal and the paralemniscal pathways in the barrel cortex (Figure 4B; Feldmeyer et al., 2005; Bureau et al., 2006; Schubert et al., 2006; Lefort et al., 2009). 
The lemniscal and paralemniscal pathways converge also at several other stages of the neuronal network of the barrel column as shown in Fig. 3A and 4A, albeit disynaptically via slender-tufted L5A pyramidal cells and/or L4 excitatory neurons. For example, L5A pyramidal cells innervate apical tufts of L2, L3 and thick-tufted L5B pyramidal cells all of which receive monosynaptic and/or disynaptic (via L4 excitatory neurons; Lefort et al., 2009; Feldmeyer et al., 2002; Staiger et al., 2014; Qi and Feldmeyer, unpublished) VPM input to their basal dendrites (Fig. 4A). The near-coincident activation of basal dendrites and the apical dendritic tufts of these pyramidal cells through VPM and POm synaptic input has been suggested to play a role during sensory-motor behavioural paradigms, such as object location during active whisking (Oberlaender et al., 2011).


Thalamocortical pathways
In addition two the lemniscal and paralemniscal TC pathways an additional intracortical subnetwork exists that serves TC-CT feed-back. The central elements of this feedback circuit are the L6 corticothalamic (CT) pyramidal cells that receive strong and depressing synaptic input from VPM (Fig. 5A; Beierlein and Connors, 2002; Cruikshank et al., 2010). L6A CT axon project back mainly to the same thalamic nucleus; however, projections to POm as well as to both of these thalamic nuclei have been described (Figure 5A; s. Zhang and Deschênes, 1997; Deschênes et al., 1998). In contrast to pyramidal cells from other cortical layers, the majority of L6A pyramidal cells have short apical dendrites with sparse or even no apical tufts terminating predominantly in layers 3 to 5A. L6A pyramidal cells that provide only CT to VPM are predominantly located in the upper half of layer 6. Most L6A CT pyramidal cells have a rather short axons - even when in vivo dye fillings are used - with a narrow axonal domain that is almost confined to a ‘barrel column’. In marked contrast to L6A CT pyramidal cells corticocally (CC) projecting pyramidal cells in layer 6A have extensive, profusely branching axons and send collaterals to other cortical areas such as the secondary somatosensory (S2) cortex or motor cortex but have no obvious subcortical target (Zhang and Deschênes, 1997; Kumar and Ohana, 2008; Chen et al., 2009; Tanaka et al., 2011; Pichon et al., 2012). 
In general, L6 pyramidal cells have been reported to receive only synaptic input from layers 4, 5 and 6; the synaptic connectivity was apparently low, ranging from 0.03 to 0.06 (Lefort et al., 2009). Thus, apart from direct, monosynaptic TC VPM input, L4 excitatory neurons and thick-tufted L5B pyramidal cells provide disynaptic VPM input and thus serve as introcortical elements of a TC-CT feedback loop (Figure 5B). Translaminar synaptic input showed paired pulse EPSP depression indicative of a high release probability (Qi and Feldmeyer, 2015; see also Mercer et al., 2005; Thomson, 2010). L6A CC and CT pyramidal project also back to layers 5 and 6 (Mercer et al., 2005; Thomson, 2010); in addition, L6 projection to L4 excitatory neurons have been identified in the barrel cortex (Qi et al., 2015, cf. Stratford et al., 1996 for visual cortex); these connections were exceptional because the showed paired-pulse EPSP  facilitation in contrast to the paired pulse depression observed for other TC and CC connections (Qi et al., 2015). Thus, L4 excitatory neurons and L6 pyramidal cells provide also a secondary, intracortical feed-back control with the L4-L6 connection showing a delayed recruitment because of the paired pulse depression.
It has been suggested, that the L4 input to L6 CT pyramidal cells is strong and focussed to their home ‘barrel column’, indicating that neurons in this layer are involved in shaping the cortical modulation of activity in the somatosensory thalamus (Tanaka et al., 2011; Qi and Feldmeyer, 2015). Notably, most synaptic contacts established by L4 excitatory neurons are on apical tufts of L6A pyramidal cells (Qi and Feldmeyer, 2015; under this condition dendritic filtering is substantial which may explain the low L4-L6 connectivity ratio found in in vitro experiments (Lefort et al., 2009). In addition to the L4 input a strong synaptic input from L6 itself is likely to exist because corticocortically (CC) projecting L6 pyramidal cells have extensive, profusely branching axons that project to other cortical areas such as the secondary somatosensory (S2) cortex or motor cortex but have no obvious subcortical target. The connection probability is comparable to other intracortical excitatory connection (Mercer et al., 2005; Qi and Feldmeyer, unpublished; but see Lefort et al., 2009 for lower connectivity ratios). This is another example of a distinct, apical tuft targting and basal dendrite targeting synaptic arrangement (as found e.g. for VPM and POm innervation or L4 and L5A input to basal and apical dendritic tufts, respectively, of L5B pyramidal cells) and may serve in the detection of coincident synaptic stimuli.
Another neuron population involved in CT signalling is a subset of thick-tufted L5B pyramidal cells that receive VPM afferents but project back to POm, i.e. a connection that does not project back directly back to the thalamic nucleus from which it receives TC input. This connection may serve as a feedback control of the VPM over the POm in a VPM-L5B-POm loop. Thick-tufted L5B pyramidal cell axons receive VPM input (see above) and  generate one or two clusters of large diameter (2-8 µm) presynaptic boutons in POm (Hoogland et al., 1991; Bourassa et al., 1995; Groh et al., 2008; Groh et al., 2013). L5B-POm synapses show a high release probability of 0.8 are a very efficacious: Single unitary EPSPs can elicit several APs in the thalamic relay neurons thereby acting as ‘drivers’ of the POm (Groh et al., 2008). However, spontaneous activity of the L5B pyramidal cells significantly reduces this ‘driving’ action through a strong short-term synaptic depression. Because of this it has been suggested that the L5B-PoM synapse works in two functional modes. When the spontaneous activity of this synapse is high only synchronous activity of several L5B inputs will induce spiking of the thalamic neurons: the synapse will therfore act as a coincidence detector. On the other hand, when the spontaneous activity is low (which is the case during active whisking or cortical silence) a single L5B input will ‘fire’ of the postsynaptic POm neuron. Thus, the degree of spontaneous activity determines whether the CT L5B-PoM synapse acts as a detector of synchronous neuronal activity or of cortical silence (Groh et al., 2008).
According to another hypothesis the L5B-POm connection is part of a feed-forward, trans-thalamic signalling pathway from VPM via L5B pyramidal cells of barrel cortex to POm and from where it ‘drives’ higher order cortical areas such as the S2 cortex (see e.g. Killackey and Sherman, 2003; Theyel et al., 2010; Sherman and Guillery, 2011; for a review see Guillery and Sherman, 2011). However, it is likely that the L5B CT pyramidal cells are elements in both the feedforward and the feed-back pathways described above. 

Conclusion
It should be noted that this review provides a simplified concept of the neuronal microcircuits in the S1 barrel cortex. The S1 mircocircuits laid out here are certainly not separate subnetworks but synaptically interact at several distinct stages; this will make an understanding of their functional properties still difficult. It is likely that with our increasing knowledge of the morphological, electrophysiological and synaptic data from both in vivo and in vitro experiments, we will understand more about the structure-function relationship of barrel cortex synaptic microcircuit, within a ‘barrel column’ and beyond. An important step in this will certainly be a more detailed description of interneuron connections in S1 barrel cortex, a field that is now in the process of intense study.

 
References
Alloway KD (2008) Information processing streams in rodent barrel cortex: the differential functions of barrel and septal circuits. Cereb Cortex 18:979-989.
Aronoff R, Matyas F, Mateo C, Ciron C, Schneider B, Petersen CC (2010) Long-range connectivity of mouse primary somatosensory barrel cortex. Eur J Neurosci 31:2221-2233.
Beierlein M, Connors BW (2002) Short-term dynamics of thalamocortical and intracortical synapses onto layer 6 neurons in neocortex. J Neurophysiol 88:1924-1932.
Benshalom G, White EL (1986) Quantification of thalamocortical synapses with spiny stellate neurons in layer IV of mouse somatosensory cortex. J Comp Neurol 253:303-314.
Bosman LW, Houweling AR, Owens CB, Tanke N, Shevchouk OT, Rahmati N, Teunissen WH, Ju C, Gong W, Koekkoek SK, De Zeeuw CI (2011) Anatomical pathways involved in generating and sensing rhythmic whisker movements. Front Integr Neurosci 5:53.
Bourassa J, Pinault D, Deschênes M (1995) Corticothalamic projections from the cortical barrel field to the somatosensory thalamus in rats: a single-fibre study using biocytin as an anterograde tracer. Eur J Neurosci 7:19-30.
Brumberg JC, Pinto DJ, Simons DJ (1999) Cortical columnar processing in the rat whisker-to-barrel system. J Neurophysiol 82:1808-1817.
Bruno RM, Sakmann B (2006) Cortex is driven by weak but synchronously active thalamocortical synapses. Science 312:1622-1627.
Bruno RM, Hahn TT, Wallace DJ, de Kock CP, Sakmann B (2009) Sensory experience alters specific branches of individual corticocortical axons during development. J Neurosci 29:3172-3181.
Bureau I, von Saint Paul F, Svoboda K (2006) Interdigitated paralemniscal and lemniscal pathways in the mouse barrel cortex. PLoS Biol 4:e382.
Chen CC, Abrams S, Pinhas A, Brumberg JC (2009) Morphological heterogeneity of layer VI neurons in mouse barrel cortex. J Comp Neurol 512:726-746.
Chmielowska J, Carvell GE, Simons DJ (1989) Spatial organization of thalamocortical and corticothalamic projection systems in the rat SmI barrel cortex. J Comp Neurol 285:325-338.
Constantinople CM, Bruno RM (2013) Deep cortical layers are activated directly by thalamus. Science 340:1591-1594.
Cruikshank SJ, Urabe H, Nurmikko AV, Connors BW (2010) Pathway-specific feedforward circuits between thalamus and neocortex revealed by selective optical stimulation of axons. Neuron 65:230-245.
Deschênes M (2009) Vibrissal afferents from trigeminus to cortices. In: Scholarpedia, 8 May 2009 Edition, p 7454.
Deschênes M, Veinante P, Zhang ZW (1998) The organization of corticothalamic projections: reciprocity versus parity. Brain Res Brain Res Rev 28:286-308.
Douglas RJ, Martin KA (1991) A functional microcircuit for cat visual cortex. J Physiol 440:735-769.
Douglas RJ, Martin KA (2004) Neuronal circuits of the neocortex. Annu Rev Neurosci 27:419-451.
Feldmeyer D, Roth A, Sakmann B (2005) Monosynaptic connections between pairs of spiny stellate cells in layer 4 and pyramidal cells in layer 5A indicate that lemniscal and paralemniscal afferent pathways converge in the infragranular somatosensory cortex. The Journal of Neuroscience 25:3423-3431.
Feldmeyer D, Lübke J, Sakmann B (2006) Efficacy and connectivity of intracolumnar pairs of layer 2/3 pyramidal cells in the barrel cortex of juvenile rats. J Physiol 575:583-602.
Feldmeyer D, Egger V, Lübke J, Sakmann B (1999) Reliable synaptic connections between pairs of excitatory layer 4 neurones within a single 'barrel' of developing rat somatosensory cortex. J Physiol 521 Pt 1:169-190.
Feldmeyer D, Lübke J, Silver RA, Sakmann B (2002) Synaptic connections between layer 4 spiny neurone-layer 2/3 pyramidal cell pairs in juvenile rat barrel cortex: physiology and anatomy of interlaminar signalling within a cortical column. The Journal of Physiology 538:803-822.
Feldmeyer D, Brecht M, Helmchen F, Petersen CC, Poulet JF, Staiger JF, Luhmann HJ, Schwarz C (2013) Barrel cortex function. Prog Neurobiol 103:3-27.
Fox KD (2008) Barrel Cortex, 1st edition Edition. Cambridge, UK: Cambridge University Press.
Frick A, Feldmeyer D, Helmstaedter M, Sakmann B (2008) Monosynaptic connections between pairs of L5A pyramidal neurons in columns of juvenile rat somatosensory cortex. Cereb Cortex 18:397-406.
Groh A, de Kock CP, Wimmer VC, Sakmann B, Kuner T (2008) Driver or coincidence detector: modal switch of a corticothalamic giant synapse controlled by spontaneous activity and short-term depression. J Neurosci 28:9652-9663.
Groh A, Bokor H, Mease RA, Plattner V, Hangya B, Stroh A, Dêschenes M, Acsády L (2013) Convergence of cortical and sensory driver inputs on single thalamocortical cells. Cereb Cortex.
Guillery RW, Sherman SM (2011) Branched thalamic afferents: what are the messages that they relay to the cortex? Brain Res Rev 66:205-219.
Holmgren C, Harkany T, Svennenfors B, Zilberter Y (2003) Pyramidal cell communication within local networks in layer 2/3 of rat neocortex. J Physiol 551:139-153.
Hoogland PV, Wouterlood FG, Welker E, van der Loos H (1991) Ultrastructure of giant and small thalamic terminals of cortical origin: a study of the projections from the barrel cortex in mice using Phaseolus vulgaris leuco-agglutinin (PHA-L). Exp Brain Res 87:159-172.
Jensen KF, Killackey HP (1987) Terminal arbors of axons projecting to the somatosensory cortex of the adult rat. I. The normal morphology of specific thalamocortical afferents. J Neurosci 7:3529-3543.
Jia H, Varga Z, Sakmann B, Konnerth A (2014) Linear integration of spine Ca2+ signals in layer 4 cortical neurons in vivo. Proc Natl Acad Sci U S A 111:9277-9282.
Killackey HP, Sherman SM (2003) Corticothalamic projections from the rat primary somatosensory cortex. J Neurosci 23:7381-7384.
Kumar P, Ohana O (2008) Inter- and intralaminar subcircuits of excitatory and inhibitory neurons in layer 6a of the rat barrel cortex. J Neurophysiol 100:1909-1922.
Larkum M (2013) A cellular mechanism for cortical associations: an organizing principle for the cerebral cortex. Trends Neurosci 36:141-151.
Larkum ME, Zhu JJ (2002) Signaling of layer 1 and whisker-evoked Ca2+ and Na+ action potentials in distal and terminal dendrites of rat neocortical pyramidal neurons in vitro and in vivo. J Neurosci 22:6991-7005.
Larkum ME, Zhu JJ, Sakmann B (1999) A new cellular mechanism for coupling inputs arriving at different cortical layers. Nature 398:338-341.
Lefort S, Tomm C, Floyd Sarria JC, Petersen CC (2009) The excitatory neuronal network of the C2 barrel column in mouse primary somatosensory cortex. Neuron 61:301-316.
Lübke J, Egger V, Sakmann B, Feldmeyer D (2000) Columnar organization of dendrites and axons of single and synaptically coupled excitatory spiny neurons in layer 4 of the rat barrel cortex. The Journal of Neuroscience 20:5300-5311.
Mao T, Kusefoglu D, Hooks BM, Huber D, Petreanu L, Svoboda K (2011) Long-range neuronal circuits underlying the interaction between sensory and motor cortex. Neuron 72:111-123.
Markram H, Lübke J, Frotscher M, Roth A, Sakmann B (1997) Physiology and anatomy of synaptic connections between thick tufted pyramidal neurones in the developing rat neocortex. J Physiol 500 ( Pt 2):409-440.
Mercer A, West DC, Morris OT, Kirchhecker S, Kerkhoff JE, Thomson AM (2005) Excitatory connections made by presynaptic cortico-cortical pyramidal cells in layer 6 of the neocortex. Cereb Cortex 15:1485-1496.
Meyer HS, Wimmer VC, Oberlaender M, de Kock CP, Sakmann B, Helmstaedter M (2010a) Number and laminar distribution of neurons in a thalamocortical projection column of rat vibrissal cortex. Cereb Cortex 20:2277-2286.
Meyer HS, Schwarz D, Wimmer VC, Schmitt AC, Kerr JN, Sakmann B, Helmstaedter M (2011) Inhibitory interneurons in a cortical column form hot zones of inhibition in layers 2 and 5A. Proc Natl Acad Sci U S A 108:16807-16812.
Meyer HS, Wimmer VC, Hemberger M, Bruno RM, de Kock CP, Frick A, Sakmann B, Helmstaedter M (2010b) Cell type-specific thalamic innervation in a column of rat vibrissal cortex. Cereb Cortex 20:2287-2303.
Miller KD, Pinto DJ, Simons DJ (2001) Processing in layer 4 of the neocortical circuit: new insights from visual and somatosensory cortex. Curr Opin Neurobiol 11:488-497.
Oberlaender M, Boudewijns ZS, Kleele T, Mansvelder HD, Sakmann B, de Kock CP (2011) Three-dimensional axon morphologies of individual layer 5 neurons indicate cell type-specific intracortical pathways for whisker motion and touch. Proc Natl Acad Sci U S A 108:4188-4193.
Oberlaender M, de Kock CP, Bruno RM, Ramirez A, Meyer HS, Dercksen VJ, Helmstaedter M, Sakmann B (2012) Cell type-specific three-dimensional structure of thalamocortical circuits in a column of rat vibrissal cortex. Cereb Cortex 22:2375-2391.
Petreanu L, Huber D, Sobczyk A, Svoboda K (2007) Channelrhodopsin-2-assisted circuit mapping of long-range callosal projections. Nat Neurosci 10:663-668.
Petreanu L, Gutnisky DA, Huber D, Xu NL, O'Connor DH, Tian L, Looger L, Svoboda K (2012) Activity in motor-sensory projections reveals distributed coding in somatosensation. Nature 489:299-303.
Pichon F, Nikonenko I, Kraftsik R, Welker E (2012) Intracortical connectivity of layer VI pyramidal neurons in the somatosensory cortex of normal and barrelless mice. Eur J Neurosci 35:855-869.
Qi G, Feldmeyer D (2015) Dendritic target region-specific formation of synapses between excitatory layer 4 neurons and layer 6 pyramidal cells. Cereb Cortex.
Qi G, Radnikow G, Feldmeyer D (2015) Electrophysiological and morphological characterization of neuronal microcircuits in acute brain slices using paired patch-clamp recordings. J Vis Exp:e52358.
Schoonover CE, Tapia JC, Schilling VC, Wimmer V, Blazeski R, Zhang W, Mason CA, Bruno RM (2014) Comparative strength and dendritic organization of thalamocortical and corticocortical synapses onto excitatory layer 4 neurons. J Neurosci 34:6746-6758.
Schubert D, Kötter R, Luhmann HJ, Staiger JF (2006) Morphology, electrophysiology and functional input connectivity of pyramidal neurons characterizes a genuine layer Va in the primary somatosensory cortex. Cereb Cortex 16:223-236.
Sherman SM, Guillery RW (2011) Distinct functions for direct and transthalamic corticocortical connections. J Neurophysiol 106:1068-1077.
Silver RA, Lübke J, Sakmann B, Feldmeyer D (2003) High-probability uniquantal transmission at excitatory synapses in barrel cortex. Science 302:1981-1984.
Spruston N (2008) Pyramidal neurons: dendritic structure and synaptic integration. Nat Rev Neurosci 9:206-221.
Staiger JF, Bojak I, Miceli S, Schubert D (2014) A gradual depth-dependent change in connectivity features of supragranular pyramidal cells in rat barrel cortex. Brain Struct Funct.
Staiger JF, Flagmeyer I, Schubert D, Zilles K, Kötter R, Luhmann HJ (2004) Functional diversity of layer IV spiny neurons in rat somatosensory cortex: quantitative morphology of electrophysiologically characterized and biocytin labeled cells. Cereb Cortex 14:690-701.
Stratford KJ, Tarczy-Hornoch K, Martin KA, Bannister NJ, Jack JJ (1996) Excitatory synaptic inputs to spiny stellate cells in cat visual cortex. Nature 382:258-261.
Szentágothai J (1975) The 'module-concept' in cerebral cortex architecture. Brain Res 95:475-496.
Tanaka YR, Tanaka YH, Konno M, Fujiyama F, Sonomura T, Okamoto-Furuta K, Kameda H, Hioki H, Furuta T, Nakamura KC, Kaneko T (2011) Local connections of excitatory neurons to corticothalamic neurons in the rat barrel cortex. J Neurosci 31:18223-18236.
Theyel BB, Llano DA, Sherman SM (2010) The corticothalamocortical circuit drives higher-order cortex in the mouse. Nat Neurosci 13:84-88.
Thomson AM (2010) Neocortical layer 6, a review. Front Neuroanat 4:13.
White EL, Rock MP (1979) Distribution of thalamic input to different dendrites of a spiny stellate cell in mouse sensorimotor cortex. Neurosci Lett 15:115-119.
Wimmer VC, Bruno RM, de Kock CP, Kuner T, Sakmann B (2010) Dimensions of a projection column and architecture of VPM and POm axons in rat vibrissal cortex. Cereb Cortex 20:2265-2276.
Zhang ZW, Deschênes M (1997) Intracortical axonal projections of lamina VI cells of the primary somatosensory cortex in the rat: a single-cell labeling study. J Neurosci 17:6365-6379.
Zingg B, Hintiryan H, Gou L, Song MY, Bay M, Bienkowski MS, Foster NN, Yamashita S, Bowman I, Toga AW, Dong HW (2014) Neural networks of the mouse neocortex. Cell 156:1096-1111.