Figure 4 - uploaded by Joachim H. R. Lübke
Content may be subject to copyright.
Camera lucida reconstruc- tion of the pair of spiny stellate cells shown in Figure 3 A. For clarity, the presynaptic and postsynaptic neurons were separated. The dendritic configu- ration of the neurons is drawn in red and black for presynaptic and postsyn- aptic neurons, respectively. The axonal arborization is drawn in blue (presynap- tic neuron) and green (postsynaptic neu- ron). The gray shading delineates the barrel structure. Note the dense projec- tion of axon collaterals in layer 2/3. Scale bar, 100 m.
Source publication
Cortical columns are the functional units of the neocortex that are particularly prominent in the "barrel" field of the somatosensory cortex. Here we describe the morphology of two classes of synaptically coupled excitatory neurons in layer 4 of the barrel cortex, spiny stellate, and star pyramidal cells, respectively. Within a single barrel, their...
Contexts in source publication
Context 1
... stellate cell dendrites in the barrel cortex have a character- istic asymmetric orientation (Figs. 2 B, 3A, 4, 5), in contrast to spiny stellate cells in layer 4 of the visual cortex that generally display a multipolar, almost radially symmetric dendritic field (LeVay, 1973;Lund, 1984;Martin and Whitteridge, 1984;1988;but see Katz et al., 1989;Kossel et al., 1995). Three to six thick primary dendrites emerged from the spherical to ovoid somata that gave rise to several secondary, tertiary, and higher-order dendrites. ...
Context 2
... to six thick primary dendrites emerged from the spherical to ovoid somata that gave rise to several secondary, tertiary, and higher-order dendrites. These den- drites formed an asymmetric dendritic field of various size ( Table 1) that was confined to a single barrel and always oriented toward its center (Figs. 2 B, 3A, 4). Higher-order dendrites were densely covered with spines (Fig. 5). ...
Context 3
... axonal collaterals of spiny stellate cells project throughout all cortical laminae from layer 1 to the white matter (Figs. 3A, 4) and remain largely confined to a single cortical column. The main axon emerges from the soma and descends toward the white mat- ter, giving rise to numerous collaterals. Most of these collaterals branch off in layer 4 and ascend toward layer 2/3. In layers 5 and 6, a few long horizontal collaterals (length 500 -800 m) were ob- served ...
Context 4
... 2/3. In layers 5 and 6, a few long horizontal collaterals (length 500 -800 m) were ob- served that may project to adjacent cortical columns. The densest axonal projection was found in layers 4 and 2/3 where the axons show a high degree of collateralization. In these layers most of the axonal collaterals were confined to a single cortical column (Fig. 4). Their orientation is predominantly vertical in layers 2/3 and 4, whereas in layers 5 and 6 they follow a slightly descending hori- zontal course (Figs. 3A, ...
Context 5
... axonal projection was found in layers 4 and 2/3 where the axons show a high degree of collateralization. In these layers most of the axonal collaterals were confined to a single cortical column (Fig. 4). Their orientation is predominantly vertical in layers 2/3 and 4, whereas in layers 5 and 6 they follow a slightly descending hori- zontal course (Figs. 3A, ...
Context 6
... result suggests that the main target cells of spiny stellate cell axons are spiny neurons in layer 4 and pyramidal neurons in 2/3, implying that the flow of excitation is preferentially directed from layer 4 to layer 2/3. This Figure 5. Camera lucida reconstruction of the same pair of spiny stellate cells as shown in Figures 3A and 4. A, The projecting neuron (cell 1) with its dendritic arbor in red and the axon in blue. ...
Context 7
... a few but long collaterals (up to 700 m) were observed to descend to layers 5 and 6 (Figs. 3B, 6). Again, the most dense axonal projection was established in layers 4 and 2/3, but the density of collaterals and the degree in branching of the axonal collaterals were lower when compared with the axonal arborization of spiny stellate cells (compare Figs. 4 and 6). In layer 4, axonal collaterals are largely confined to a single barrel, whereas in upper layer 2/3 they fan out so that a few appear to project to adjacent cortical columns (Figs. 3B, 6). In upper layer 2/3 axonal collaterals were often organized in clusters, as described for pyramidal cells of cortical laminae 2/3 and 5 (Fig. 3B) ...
Similar publications
Unlabelled:
It is generally thought that neurons in the thalamic reticular nucleus (TRN) form GABAergic synapses with other TRN neurons and that these interconnections are important for the function of the TRN. However, the existence of such intrinsic connections is controversial. We combine two complementary approaches to examine intrinsic GABAer...
Cortical columns are the functional units of the neocortex that are particularly prominent in the “barrel” field of the somatosensory cortex. Here we describe the morphology of two classes of synaptically coupled excitatory neurons in layer 4 of the barrel cortex, spiny stellate, and star pyramidal cells, respectively. Within a single barrel, their...
Citations
... Indeed, the parcellation of the mammalian cerebral cortex into vertically oriented units of about 10 4 neurons, called cortical columns, was demonstrated for macaque primary somatosensory cortex (Mountcastle 1957), cat visual cortex (Hubel and Wiesel 1962), rodent somatosensory cortex (Woolsey and Van der Loos 1970), and postulated for higher cortical areas, as well (Felleman andVan Essen 1991, Harris, Mihalas et al. 2019). Based on decades of anatomical and functional experiments, a number of main connectivity streams into and within cortical columns have been identified (Gilbert and Wiesel 1979, Gilbert and Wiesel 1983, Jones 1986, Johnson and Burkhalter 1996, Feldmeyer, Egger et al. 1999, Svoboda, Helmchen et al. 1999, Lubke, Egger et al. 2000, Schubert, Staiger et al. 2001, Callaway 2002, Feldmeyer, Lubke et al. 2002, Staiger, Masanneck et al. 2002, Brecht, Roth et al. 2003, Lubke, Roth et al. 2003, Schubert, Kotter et al. 2003, Silver, Lubke et al. 2003, Brecht, Krauss et al. 2004, Brecht, Schneider et al. 2004, Bureau, Shepherd et al. 2004, Feldmeyer, Roth et al. 2005, Shepherd, Stepanyants et al. 2005, Bureau, von Saint Paul et al. 2006, Feldmeyer, Lubke et al. 2006, Schubert, Kotter et al. 2006, Helmstaedter, de Kock et al. 2007, Lübke and Feldmeyer 2007, Sarid, Bruno et al. 2007, Frick, Feldmeyer et al. 2008, Luo, Callaway et al. 2008, Helmstaedter, Sakmann et al. 2009, Holtmaat and Svoboda 2009, Petreanu, Mao et al. 2009, Sato and Svoboda 2010, Mao, Kusefoglu et al. 2011, Marx and Feldmeyer 2013, Rah, Bas et al. 2013, Koelbl, Helmstaedter et al. 2015, Sarid, Feldmeyer et al. 2015, Yu, Gutnisky et al. 2016, Leinweber, Ward et al. 2017, Feldmeyer, Qi et al. 2018, Winnubst, Bas et al. 2019, Wu, Sevier et al. 2023, Huang, Wu et al. 2024. In particular, the sensory input via thalamocortical afferents , Oberlaender, de Kock et al. 2012)into cortical granular layer 4, transmitted to supragranular layers 2/3, from there to infragranular layer 5, and then to distal targets, was described as the canonical circuit (Douglas, Martin et al. 1989) with substantial supporting evidence Martin 1991, Lubke, Roth et al. 2003, Binzegger, (which was not certified by peer review) is the author/funder. ...
... Inset, high-density VPM at L5B-L6 border shown without subsampling. (F) Analysis of dendritic morphologies of excitatory neurons (ExNs) in layer 4 (L4), which have been reported to exhibit strong dendritic asymmetry towards the home column (Feldmeyer, Egger et al. 1999, Lubke, Egger et al. 2000. Two example neurons, left, with mean dendritic directionality vector in the tangential plane, and quiver plot of all dendritic directionality vectors for n=2,002 neurons in L4 showing similar columnar pattern as from VPM synapse distribution (compare F, right with E, (which was not certified by peer review) is the author/funder. ...
The cerebral cortex of mammals has long been proposed to comprise unit-modules, so-called cortical columns. The detailed synaptic-level circuitry of such a neuronal network of about 104 neurons is still unknown. Here, using 3-dimensional electron microscopy, AI-based image processing and automated proofreading, we report the connectomic reconstruction of a defined cortical column in mouse barrel cortex. The cortical column appears as a structural feature in the connectome, without need for geometrical or morphological landmarks. We then used the connectome for definition of neuronal cell types in the column, to determine intracolumnar circuit modules, analyze the logic of inhibitory circuits, investigate the circuits for combination of bottom-up and top-down signals in the column and the specificity of bottom-up and top-down cortical input, search for higher-order circuit structure within homogeneous neuronal populations, and estimate the degree and symmetry of Hebbian learning in the various connection types. With this, we provide a first column-level connectomic description of the cerebral cortex, the likely substrate for a synaptic-level mechanistic understanding of sensory-conceptual integration and learning.
... A recent study has proposed that glutamatergic pathways between the cortex and thalamus transmit information to L4 through transthalamic circuits, and from L4 to other laminas via internal intercellular communication 102 . In the rat barrel cortex, L4 has averaged 62% more GABA contacts per unit volume than any other cortical layer 103 , and the axonal projection of spiny L4 neurons highly associates with the structure of a cortical column 104 . These findings highlight that the cortical differentiation microstructure underpins the developmental of the WM connectome and predict that the association may be dominated by genes that tend to regulate neuronal cell proliferation, differentiation, and migration. ...
From childhood to adolescence, the spatiotemporal development pattern of the human brain white matter connectome and its underlying transcriptomic and cellular mechanisms remain largely unknown. With a longitudinal diffusion MRI cohort of 604 participants, we map the developmental trajectory of the white matter connectome from global to regional levels and identify that most brain network properties followed a linear developmental trajectory. Importantly, connectome-transcriptomic analysis reveals that the spatial development pattern of white matter connectome is potentially regulated by the transcriptomic architecture, with positively correlated genes involve in ion transport- and development-related pathways expressed in excitatory and inhibitory neurons, and negatively correlated genes enriches in synapse- and development-related pathways expressed in astrocytes, inhibitory neurons and microglia. Additionally, the macroscale developmental pattern is also associated with myelin content and thicknesses of specific laminas. These findings offer insights into the underlying genetics and neural mechanisms of macroscale white matter connectome development from childhood to adolescence.
... Overall, our findings highlight roles for spiny stellate neurons as sensitive coincidence detectors of sensory input to the cortex, helping to amplify and conduct the initial flow of information to within functional cortical units 6,50,77 . Here, their critical position within barrel circuits is determined by specific TCA-derived cues (molecular and/or activity), that appear to drive a transcriptional program leading to spiny stellate specification from an immature cortical landscape. ...
Excitatory spiny stellate neurons are prominently featured in the cortical circuits of sensory modalities that provide high salience and high acuity representations of the environment. These specialized neurons are considered developmentally linked to bottom-up inputs from the thalamus, however, the molecular mechanisms underlying their diversification and function are unknown. Here, we investigated this in mouse somatosensory cortex, where spiny stellate neurons and pyramidal neurons have distinct roles in processing whisker-evoked signals. Utilizing spatial transcriptomics, we identified reciprocal patterns of gene expression which correlated with these cell-types and were linked to innervation by specific thalamic inputs during development. Genetic manipulation that prevents the acquisition of spiny stellate fate highlighted an important role for these neurons in processing distinct whisker signals within functional cortical columns, and as a key driver in the formation of specific whisker-related circuits in the cortex.
... The logic of signal transformation in the main thalamocortical recipient layer of the mammalian brain, layer 4 (L4) of the sensory cortices, has been a major focus of functional (Brecht and Sakmann, 2002;de Kock et al., 2007;Gutnisky et al., 2017;Hubel and Wiesel, 1962;Kanold et al., 2003;Kara et al., 2002;Martinez et al., 2005;Stratford et al., 1996;Yu et al., 2016;Yu et al., 2019) and structural (Ahmed et al., 1994;Ahmed et al., 1997;Egger et al., 2008;Elston et al., 1997;Lübke et al., 2000;Lübke et al., 2003;Motta et al., 2019;Schubert et al., 2003;Staiger et al., 2004;Woolsey and Van der Loos, 1970) investigations. While functional studies have shown the relevance of feedforward inhibition (Bruno and Simons, 2002;Cruikshank et al., 2007;Gabernet et al., 2005;House et al., 2011;Pouille and Scanziani, 2001;Staiger et al., 2009), and recent recordings have demonstrated differential activation of subtypes of interneurons (Yu et al., 2016;Yu et al., 2019), a detailed circuit-level picture of the transformation of the thalamocortical (TC) signal onto excitatory neurons in the cortex is still lacking. ...
... We then used our online annotation tool webKnossos to reconstruct the upward pointing (apical) dendrites of n=1,976 neurons in a fraction of the dataset with optimal staining and image alignment (corresponding to about 1/4 th of a barrel). The two primary cell types within L4, spiny stellates (SpS) and star pyramidals (StP) (Feldmeyer et al., 1999;LeVay, 1973;Lorente De No, 1938;Lübke et al., 2000;McCormick et al., 1985;Simons and Woolsey, 1984b;White, 1978;Woolsey et al., 1975) were distinguishable based on the existence or lack of an apical dendrite (Fig. 1E) StP, but which could also be L5A pyramidal neurons. We also found evidence that StP neurons had a higher number of somatic input synapses than SpS, yielding a slightly higher fraction of inhibitory synaptic inputs (Suppl. ...
In mammals, sensory signals are transmitted via the thalamus primarily to layer 4 of the primary sensory cortices. While information about average neuronal connectivity in this layer is available, the detailed and higher-order circuit structure is not known. Here, we used 3-dimensional electron microscopy for a connectomic analysis of the thalamus-driven inhibitory network in a layer 4 barrel. We find that thalamic input drives a subset of interneurons with high specificity. These interneurons in turn target spiny stellate and star pyramidal excitatory neurons with subtype specificity. In addition, they create a directed disinhibitory network directly driven by the thalamic input. Together, this circuit can create differential windows of opportunity for activation of the types of excitatory neurons in dependence of strength and timing of thalamic input. With this, we have identified a so-far unknown degree of specialization of the microcircuitry in the main thalamocortical recipient layer of the primary sensory cortex.
... For example, focal caged glutamate photolysis reveals that substantial inputs to RS cells from neighboring barrels exist (Schubert et al., 2003), along with several investigations indicating either anatomical or functional connectivity among neighboring barrels (Brecht & Sakmann, 2002a;Petersen & Sakmann, 2001). It should be noted that lateral barrel-to-barrel connections may not involve direct layer IV to layer IV synapses, as arborization of layer IV cells may be largely confined to the barrel of origin (Harris & Woolsey, 1983;Lubke et al., 2000;Petersen & Sakmann, 2000); rather, nongranular layers may provide the medium for interbarrel information transfer (Gottlieb & Keller, 1997), with AW information relayed to layer IV via intrabarrel connections from nongranular layers (Thomson et al., 2002). ...
... It is important to note that while there is empirical evidence that lateral barrel-to-barrel connections exist (Schubert et al., 2003;Brecht & Sakmann, 2002a;Petersen & Sakmann, 2001), such lateral connections are as of yet poorly characterized in the experimental literature, and it is possible that they do not involve direct layer IV to layer IV connections, but rather multisynaptic connections traversing through intermediary nongranular layers (Harris & Woolsey, 1983;Lubke et al., 2000;Petersen & Sakmann, 2000;Gottlieb & Keller, 1997;Thomson et al., 2002). Thus, our model of lateral connectivity is by necessity a simplification, intended only to provide a general framework within which to assess the effects of interbarrel communication. ...
... Intrabarrel connectivity Since FS cells have been shown to lack direction selectivity and respond strongly to all deflection directions (Lee & Simons, 2004;Simons & Carvell, 1989;Bruno & Simons, 2002), it is likely that TC input to FS cells is not direction selective (Swadlow & Gusev, 2002); hence, within a barreloid/barrel system we set a TC→ FS connection probability of 0.65 for all TC PW direction groups (Bruno & Simons, 2002). The model has an intrabarrel FS→ FS connection probability of 0.5 (FS→ FS synapses in the model serve only to curtail the stimulusinduced FS population response) and an intrabarrel FS→ RS connection probability of 1. Experiments show that an RS PW direction domain within a barrel has a horizontal span of ∼100 m (Bruno et al., 2003;Bruno & Simons, 2002;Keller & Carlson, 1999) (with individual RS cell dendritic arbors spanning ∼200 m (Lubke et al., 2000;Simons & Woolsey, 1984)), while a TC cell axon arborizes widely throughout the horizontal span of the full barrel (Jensen & Killackey, 1987), with the highest density of axon terminals within a ∼200 m horizontal range (Jensen & Killackey, 1987;Arnold et al., 2001); the extensive overlap of TC cell axon terminals with RS cell dendritic arbors suggests that a TC cell makes widespread synaptic connections to RS cells throughout its corresponding barrel, though synaptic densities vary with RS PW direction domain. Experimentally, the TC→ RS connection probability has been estimated to be ∼ 0.37 on average (with each RS cell receiving input from ∼ 80-90 TC cells) (Timofeeva et al., 2003;Bruno & Simons, 2002;Bruno & Sakmann, 2006), and while RS cells are known to receive input from TC cells varying in PW direction preference (Timofeeva et al., 2003), experiments indicate that the likelihood of a TC→ RS synapse varies considerably in a direction-dependent manner, with higher connection probabilities associated with greater alignment between TC and RS PW direction preferences (Bruno & Simons, 2002;Bruno et al., 2003;Furuta et al., 2011). ...
While cells within barrel cortex respond primarily to deflections of their principal whisker (PW), they also exhibit responses to non-principal, or adjacent, whiskers (AWs), albeit responses with diminished amplitudes and longer latencies. The origin of multiwhisker receptive fields of barrel cells remains a point of controversy within the experimental literature, with three contending possibilities: (i) barrel cells inherit their AW responses from the AW responses of thalamocortical (TC) cells within their aligned barreloid; (ii) the axons of TC cells within a barreloid ramify to innervate multiple barrels, rather than only terminating within their aligned barrel; (iii) lateral intracortical transmission between barrels conveys AW responsivity to barrel cells. In this work, we develop a detailed, biologically plausible model of multiple barrels in order to examine possibility (iii); in order to isolate the dynamics that possibility (iii) entails, we incorporate lateral connections between barrels while assuming that TC cells respond only to their PW and that TC cell axons are confined to their home barrel. We show that our model is capable of capturing a broad swath of experimental observations on multiwhisker receptive field dynamics within barrels, and we compare and contrast the dynamics of this model with model dynamics from prior work in which employ a similar general modeling strategy to examine possibility (i).
... In sensory cortices, layer 4 neurons receive direct thalamocortical input and distribute intracortical excitation and inhibition to other cortical layers. While the neuronal composition and synaptic connectivity of layer 4 have been studied extensively (Feldmeyer et al. 1999;Gibson et al. 1999;Lubke et al. 2000;Beierlein et al. 2003;Xu et al. 2013;Koelbl et al. 2015;Emmenegger et al. 2018;Scala et al. 2019) a comprehensive study on their modulation by ACh or other neuromodulators is still lacking. Here, we investigated how low concentrations of ACh affect the intrinsic properties of different L4 neuron types and subtypes in acute brain slices using patch-clamp recordings and bathapplication of cholinergic agonists and antagonists. ...
... In addition to their electrophysiological diversity, L4 neurons show highly distinct dendritic and in particular axonal morphologies (Fig. 1D). L4 excitatory neurons fall into two main groups, spiny stellate neurons (SSNs) without an obvious apical dendrite and star pyramidal cells (SPCs) (Feldmeyer et al. 1999;Lubke et al. 2000); but see (Staiger et al. 2004). Their axons originate from the soma or the initial part of one basal dendrite and project locally in layer 4 and to supra-and infragranular layers. ...
... With the development and sophistication of single-cell mRNA sequencing techniques, the molecular features of neurons add an additional layer of complexity to neuronal classification (Zeng and Sanes 2017;Yuste et al. 2020). We have performed a series of studies to dissect the neuronal diversity in layer 4 of rat barrel cortex (Feldmeyer et al. 1999;Lubke et al. 2000;Koelbl et al. 2015;Emmenegger et al. 2018). In general, layer 4 comprises three neuronal cell classes showing distinct repetitive firing properties: regular spiking, fast spiking and non-fast spiking (adapting, irregular, late etc). ...
The neuromodulator acetylcholine (ACh) plays an important role in arousal, attention, vigilance, learning and memory. ACh is released during different behavioural states and affects the brain microcircuit by regulating neuronal and synaptic properties. Here, we investigated how a low concentration of ACh (30 μM) affects the intrinsic properties of electrophysiologically and morphologically identified excitatory and inhibitory neurons in layer 4 (L4) of rat barrel cortex. ACh altered the membrane potential of L4 neurons in a heterogeneous manner. Nearly all L4 regular spiking (RS) neurons responded to bath-application of ACh with a M4 muscarinic ACh receptor-mediated hyperpolarisation. In contrast, in the majority of L4 fast spiking (FS) and non-fast spiking (nFS) interneurons 30 μM ACh induced a depolarisation while the remainder showed a hyperpolarisation or no response. The ACh-induced depolarisation of L4 FS interneurons was much weaker than that in L4 nFS interneurons. There was no clear difference in the response to ACh for three morphological subtypes of L4 FS interneurons. However, in four morpho-electrophysiological subtypes of L4 nFS interneurons, VIP+-like interneurons showed the strongest ACh-induced depolarisation; occasionally, even action potential (AP) firing was elicited. The ACh-induced depolarisation in L4 FS interneurons was exclusively mediated by M1 muscarinic ACh receptors; in L4 nFS interneurons it was mainly mediated by M1 and/or M3/5 muscarinic ACh receptors. In a subset of L4 nFS interneurons, a co-operative activation of nicotinic ACh receptors was also observed. The present study demonstrates that low-concentrations of ACh affect the different L4 neurons types in a cell-type specific way. These effects result from a specific expression of different muscarinic and/or nicotinic ACh receptors on the somatodendritic compartments of L4 neurons. This suggests that even at low concentrations ACh may tune the excitability of L4 excitatory and inhibitory neurons and their synaptic microcircuits differentially depending on the behavioural state during which ACh is released.
... (Adaptation de (Tremblay et al., 2016))Les neurones excitateurs, majoritairement pyramidaux, présentent une large dendrite apicale, plus ou moins longue, pouvant traverser plusieurs couches corticales. La couche VI contient les neurones cortico-thalamiques(Kandel et al., 2012; Purves et al., 2019)(Lefort et al., 2009), la V, des neurones cortico-striataux, neurones à projection calleuse et neurones à projection subcorticale qui comprennent les neurones corticospinaux(Kandel et al., 2012; Purves et al., 2019)(Rivara et al., 2003;Mitchell and Macklis, 2005;Lefort et al., 2009), la IV les interneurones excitateurs de forme stellaire(Lübke et al., 2000;Swadlow, 2003;Cowan and Stricker, 2004;Staiger et al., 2004;Zhuang et al., 2013) et les couches II/III contiennent des neurones cortico-corticaux dont des neurones à projection calleuse. La couche I, elle, est pauvre en cellules et contient principalement les dendrites apicales des neurones pyramidaux des couches II/III, V et VI (Lefort et al., 2009). ...
La sclérose latérale amyotrophique (SLA) est une maladie neurodégénérative caractérisée par la perte des neurones corticospinaux, localisés dans le cortex cérébral, et des motoneurones bulbaires et spinaux, localisés dans le tronc cérébral et la moelle épinière. Les patients atteints de SLA présentent une hyperexcitabilité corticale précoce, voire pré-symptomatique, et négativement corrélée à leur survie. Une étude du laboratoire a permis de mettre en évidence la présence d’une hyperexcitabilité corticale dans des modèles murins de la maladie : les souris Sod1G86R et Fus+/ΔNLS. Les travaux présentés dans cette thèse ont eu pour but de déterminer des mécanismes pouvant sous-tendre l’altération de cette balance entre excitation et inhibition corticale dans ces mêmes modèles. Nous avons mis en évidence une déplétion des niveaux de noradrénaline, une diminution des projections noradrénergiques et de l’expression de récepteurs adrénergiques inhibiteurs dans le cortex cérébral de ces modèles associées, chez les souris Sod1G86R, à une réduction du nombre de neurones noradrénergiques. Chez des souris sauvages, la déplétion noradrénergique suffit à induire un déséquilibre de la balance excitation-inhibition corticale, tandis qu’une supplémentation en noradrénaline dans le modèle Sod1G86R permet un rétablissement de cette dernière. Ainsi, la déplétion des niveaux corticaux de noradrénaline contribuerait à l’hyperexcitabilité corticale et la régulation de ces derniers pourrait permettre un rééquilibrage de la balance excitation-inhibition corticale.
... In S1bf, the information about the angular direction of whisker deflection is inherited from the ventral posteromedial nucleus (VPM) of the thalamus at the level of L4, the principal target of VPM thalamocortical projections (Chmielowska et al. 1989;Staiger et al. 1996;Feldmeyer 2012). Axonal projections of L4 principal cells contact neighboring L4 cells (Feldmeyer et al. 1999;Lübke et al. 2000) and superficial L2/3 neurons (Lübke et al. 2000;Feldmeyer et al. 2002;Lubke et al. 2003), providing strong feedforward excitation, which, according to the canonical model, drives these superficial layers (Douglas and Martin 2004). Despite the inputs from L4 excitatory cells, the strength of the directional tuning in suprathreshold response of L2/3 excitatory cells is debated Bruno and Simons 2002;Minnery et al. 2003;Lee 2004;Andermann and Moore 2006;Kerr et al. 2007;Kremer et al. 2011;Bale and Maravall 2018;Kwon et al. 2018). ...
... In S1bf, the information about the angular direction of whisker deflection is inherited from the ventral posteromedial nucleus (VPM) of the thalamus at the level of L4, the principal target of VPM thalamocortical projections (Chmielowska et al. 1989;Staiger et al. 1996;Feldmeyer 2012). Axonal projections of L4 principal cells contact neighboring L4 cells (Feldmeyer et al. 1999;Lübke et al. 2000) and superficial L2/3 neurons (Lübke et al. 2000;Feldmeyer et al. 2002;Lubke et al. 2003), providing strong feedforward excitation, which, according to the canonical model, drives these superficial layers (Douglas and Martin 2004). Despite the inputs from L4 excitatory cells, the strength of the directional tuning in suprathreshold response of L2/3 excitatory cells is debated Bruno and Simons 2002;Minnery et al. 2003;Lee 2004;Andermann and Moore 2006;Kerr et al. 2007;Kremer et al. 2011;Bale and Maravall 2018;Kwon et al. 2018). ...
In the barrel field of the rodent primary somatosensory cortex (S1bf), excitatory cells in layer 2/3 (L2/3) display sparse firing but reliable subthreshold response during whisker stimulation. Subthreshold responses encode specific features of the sensory stimulus, for example, the direction of whisker deflection. According to the canonical model for the flow of sensory information across cortical layers, activity in L2/3 is driven by layer 4 (L4). However, L2/3 cells receive excitatory inputs from other regions, raising the possibility that L4 partially drives L2/3 during whisker stimulation. To test this hypothesis, we combined patch-clamp recordings from L2/3 pyramidal neurons in S1bf with selective optogenetic inhibition of L4 during passive whisker stimulation in both anesthetized and awake head-restrained mice. We found that L4 optogenetic inhibition did not abolish the subthreshold whisker-evoked response nor it affected spontaneous membrane potential fluctuations of L2/3 neurons. However, L4 optogenetic inhibition decreased L2/3 subthreshold responses to whisker deflections in the preferred direction, and it increased L2/3 responses to stimuli in the nonpreferred direction, leading to a change in the direction tuning. Our results contribute to reveal the circuit mechanisms underlying the processing of sensory information in the rodent S1bf.
... d Sketch of mouse primary somatosensory cortex with presumed circuit modules ("barrels") in cortical input layer 4 (L4). Currently known constraints of pairwise connectivity and cell prevalence of excitatory (ExN) and inhibitory (IN) neurons (p ee : pairwise excitatory-excitatory connectivity [30][31][32][33]36 , p ei : pairwise excitatory-inhibitory connectivity 31,33 , p ii : pairwise inhibitory-inhibitory connectivity 31,34 , p ie : pairwise inhibitory-excitatory connectivity 31,33,35 , r ee : pairwise excitatory-excitatory reciprocity 30,31,33 ). ...
... Of these about 90% are excitatory, and about 10% inhibitory 28,29 (Fig. 1d), which establish a total of about 3 million chemical synapses within L4. The ensuing average pairwise synaptic connectivity within a barrel has been estimated based on data from paired whole-cell recordings [30][31][32][33][34][35] : excitatory neurons connect to about 15-25% of the other intra-barrel neurons; inhibitory neurons connect to about 50-60% of the other intrabarrel neurons (Fig. 1d). Moreover, the probability of a connection to be reciprocated ranges between 15% and 35% [29][30][31]33,36 . ...
... How critical were the particular circuit constraints which we considered for initial model validation (Fig. 1d)? What if, for example, pairwise excitatory connectivity was lower than concluded from pairwise recordings in slice (Fig. 1d [28][29][30][31][32][33][34][35][36] ), and instead for example rather 10%, not 15-25% in L4? The results on discriminability of trained RNNs (Fig. 7), which was higher for sparser networks, may indicate that model identification would even improve for lower overall connectivity regimes. ...
With the availability of cellular-resolution connectivity maps, connectomes, from the mammalian nervous system, it is in question how informative such massive connectomic data can be for the distinction of local circuit models in the mammalian cerebral cortex. Here, we investigated whether cellular-resolution connectomic data can in principle allow model discrimination for local circuit modules in layer 4 of mouse primary somatosensory cortex. We used approximate Bayesian model selection based on a set of simple connectome statistics to compute the posterior probability over proposed models given a to-be-measured connectome. We find that the distinction of the investigated local cortical models is faithfully possible based on purely structural connectomic data with an accuracy of more than 90%, and that such distinction is stable against substantial errors in the connectome measurement. Furthermore, mapping a fraction of only 10% of the local connectome is sufficient for connectome-based model distinction under realistic experimental constraints. Together, these results show for a concrete local circuit example that connectomic data allows model selection in the cerebral cortex and define the experimental strategy for obtaining such connectomic data.
... The experience-dependent plasticity of barrel cortex layer IV neurons is largest when the experience is manipulated early (before P7), but the plasticity of layer II/III responses persists beyond the first week of life (Fox, 1992). During the second postnatal week, the layer IV map serves as a template for the growth and Hebbian refinement of the cortical circuitry underlying the layer II/III map, and layer IV to layer II/III feedforward excitatory projections are confined almost exclusively to one barrel column (Lübke et al., 2000). Therefore, we investigated whether IGF-I modulates the efficacy of these synapses. ...
Insulin-like growth factor-I (IGF-I) signaling plays a key role in learning and memory processes. While the effects of IGF-I on neurons have been studied extensively, the involvement of astrocytes in IGF-I signaling and the consequences on synaptic plasticity and animal behavior remain unknown. We have found that IGF-I induces long-term potentiation (LTP IGFI ) of the postsynaptic potentials that is caused by a long-term depression of inhibitory synaptic transmission in mice. We have demonstrated that this long-lasting decrease in the inhibitory synaptic transmission is evoked by astrocytic activation through its IGF-I receptors (IGF-IRs). We show that LTP IGFI not only increases the output of pyramidal neurons, but also favors the NMDAR-dependent LTP, resulting in the crucial information processing at the barrel cortex since specific deletion of IGF-IR in cortical astrocytes impairs the whisker discrimination task. Our work reveals a novel mechanism and functional consequences of IGF-I signaling on cortical inhibitory synaptic plasticity and animal behavior, revealing that astrocytes are key elements in these processes.
SIGNIFICANCE STATEMENT Insulin-like growth factor-I (IGF-I) signaling plays key regulatory roles in multiple processes of brain physiology, such as learning and memory. Yet, the underlying mechanisms remain largely undefined. Here we demonstrate that astrocytes respond to IGF-I signaling, elevating their intracellular Ca ²⁺ and stimulating the release of ATP/adenosine, which triggers the LTD of cortical inhibitory synapses, thus regulating the behavioral task performance related to cortical sensory information processing. Therefore, the present work represents a major conceptual advance in our knowledge of the cellular basis of IGF-I signaling in brain function, by including for the first time astrocytes as key mediators of IGF-I actions on synaptic plasticity, cortical sensory information discrimination and animal behavior.
