Whisker Map Research Articles

Tuning instability of non-columnar neurons in the salt-and-pepper whisker map in somatosensory cortex

Rodent sensory cortex contains salt-and-pepper maps of sensory features, whose structure is not fully known. Here we investigated the structure of the salt-and-pepper whisker somatotopic map among L2/3 pyramidal neurons in somatosensory cortex, in awake mice performing one-vs-all whisker discrimination. Neurons tuned for columnar (CW) and non-columnar (non-CW) whiskers were spatially intermixed, with co-tuned neurons forming local (20 µm) clusters. Whisker tuning was markedly unstable in expert mice, with 35-46% of pyramidal cells significantly shifting tuning over 5-18 days. Tuning instability was highly concentrated in non-CW tuned neurons, and thus was structured in the map. Instability of non-CW neurons was unchanged during chronic whisker paralysis and when mice discriminated individual whiskers, suggesting it is an inherent feature. Thus, L2/3 combines two distinct components: a stable columnar framework of CW-tuned cells that may promote spatial perceptual stability, plus an intermixed, non-columnar surround with highly unstable tuning.

Layers 3 and 4 Neurons of the Bilateral Whisker-Barrel Cortex

In Robo3R3-5cKO mouse brain, rhombomere 3-derived trigeminal principal nucleus (PrV) neurons project bilaterally to the somatosensory thalamus. As a consequence, whisker-specific neural modules (barreloids and barrels) representing whiskers on both sides of the face develop in the sensory thalamus and the primary somatosensory cortex. We examined the morphological complexity of layer 4 barrel cells, their postsynaptic partners in layer 3, and functional specificity of layer 3 pyramidal cells.Layer 4 spiny stellate cells form much smaller barrels and their dendritic fields are more focalized and less complex compared to controls, while layer 3 pyramidal cells did not show notable differences. Using in vivo 2-photon imaging of a genetically encoded fluorescent [Ca2+] sensor, we visualized neural activity in the normal and Robo3R3-5cKO barrel cortex in response to ipsi- and contralateral single whisker stimulation. Layer 3 neurons in control animals responded only to their contralateral whiskers, while in the mutant cortex layer 3 pyramidal neurons showed both ipsi- and contralateral whisker responses. These results indicate that bilateral whisker map inputs stimulate different but neighboring groups of layer 3 neurons which normally relay contralateral whisker-specific information to other cortical areas.

Brainstem local microglia induce whisker map plasticity in the thalamus after peripheral nerve injury

Whisker deafferentation in mice disrupts topographic connectivity from the brainstem to the thalamic ventral posteromedial nucleus (VPM), which represents whisker map, by recruiting "ectopic" axons carrying non-whisker information in VPM. However, mechanisms inducing this plasticity remain largely unknown. Here, we show the role of region-specific microglia in the brainstem principal trigeminal nucleus (Pr5), a whisker sensory-recipient region, in VPM whisker map plasticity. Systemic or local manipulation of microglial activity reveals that microglia in Pr5, but not in VPM, are necessary and sufficient for recruiting ectopic axons in VPM. Deafferentation causes membrane hyperexcitability of Pr5 neurons dependent on microglia. Inactivation of Pr5 neurons abolishes this somatotopic reorganization in VPM. Additionally, microglial depletion prevents deafferentation-induced ectopic mechanical hypersensitivity. Our results indicate that local microglia in the brainstem induce peripheral nerve injury-induced plasticity of map organization in the thalamus and suggest that microglia are potential therapeutic targets for peripheral nerve injury-induced mechanical hypersensitivity.

An increase in dendritic plateau potentials is associated with experience-dependent cortical map reorganization

The organization of sensory maps in the cerebral cortex depends on experience, which drives homeostatic and long-term synaptic plasticity of cortico-cortical circuits. In the mouse primary somatosensory cortex (S1) afferents from the higher-order, posterior medial thalamic nucleus (POm) gate synaptic plasticity in layer (L) 2/3 pyramidal neurons via disinhibition and the production of dendritic plateau potentials. Here we address whether these thalamocortically mediated responses play a role in whisker map plasticity in S1. We find that trimming all but two whiskers causes a partial fusion of the representations of the two spared whiskers, concomitantly with an increase in the occurrence of POm-driven N-methyl-D-aspartate receptor-dependent plateau potentials. Blocking the plateau potentials restores the archetypical organization of the sensory map. Our results reveal a mechanism for experience-dependent cortical map plasticity in which higher-order thalamocortically mediated plateau potentials facilitate the fusion of normally segregated cortical representations.

Brainstem Local Microglia Induce Whisker Map Plasticity in the Thalamus after Peripheral Nerve Injury

Whisker deafferentation in mice disrupts topographic connectivity from the brainstem to the thalamic ventral posteromedial nucleus (VPM), which represent whisker map, by recruiting ‘ectopic’ axons carrying non-whisker information in VPM. However, mechanisms inducing this plasticity remain largely unknown. Here, we show the role of pathway- and region-specific microglial activation in the brainstem principal trigeminal nucleus (Pr5), a whisker sensory-recipient region, in VPM whisker map plasticity. Systemic or local manipulation of microglial activity reveals that activated microglia in Pr5, but not in VPM, is necessary and sufficient for recruiting ectopic axons in VPM. Deafferentation causes Pr5 neuronal hyperexcitability dependent on microglial activity. Inactivating Pr5 neurons abolishes this somatotopic reorganization in VPM. Additionally, microglial activity prevents deafferentation-induced ectopic mechanical hypersensitivity. Our results indicate that local microglial activity in the brainstem induces nerve injury-induced plasticity of map organization in the thalamus, and suggest that microglia are potential therapeutic targets for nerve injury-induced hypersensitivity.

Spatiotemporal properties of whisker-evoked tactile responses in the mouse secondary somatosensory cortex

The representation of rodents’ mystacial vibrissae within the primary somatosensory (S1) cortex has become a major model for studying the cortical processing of tactile sensory information. However, upon vibrissal stimulation, tactile information first reaches S1 but also, almost simultaneously, the secondary somatosensory cortex (S2). To further understand the role of S2 in the processing of whisker inputs, it is essential to characterize the spatio-temporal properties of whisker-evoked response dynamics in this area. Here we describe the topography of the whiskers representation in the mouse S2 with voltage sensitive dye imaging. Analysis of the spatial properties of the early S2 responses induced by stimulating individually 22 to 24 whiskers revealed that they are spatially ordered in a mirror symmetric map with respect to S1 responses. Evoked signals in S2 and S1 are of similar amplitude and closely correlated at the single trial level. They confirm a short delay (~3 ms) between S1 and S2 early activation. In both S1 and S2 caudo-dorsal whiskers induce stronger responses than rostro-ventral ones. Finally, analysis of early C2-evoked responses indicates a faster activation of neighboring whisker representations in S2 relative to S1, probably due to the reduced size of the whisker map in S2.

Enrichment drives emergence of functional columns and improves sensory coding in the whisker map in L2/3 of mouse S1.

Sensory maps in layer (L) 2/3 of rodent cortex lack precise functional column boundaries, and instead exhibit locally heterogeneous (salt-and-pepper) tuning superimposed on smooth global topography. Could this organization be a byproduct of impoverished experience in laboratory housing? We compared whisker map somatotopy in L2/3 and L4 excitatory cells of somatosensory (S1) cortex in normally housed vs. tactile-enriched mice, using GCaMP6s imaging. Normally housed mice had a dispersed, salt-and-pepper whisker map in L2/3, but L4 was more topographically precise. Enrichment (P21 to P46-71) sharpened whisker tuning and decreased, but did not abolish, local tuning heterogeneity. In L2/3, enrichment strengthened and sharpened whisker point representations, and created functional boundaries of tuning similarity and noise correlations at column edges. Thus, enrichment drives emergence of functional columnar topography in S1, and reduces local tuning heterogeneity. These changes predict better touch detection by neural populations within each column.

Elementary motion sequence detectors in whisker somatosensory cortex.

How somatosensory cortex (S1) encodes complex patterns of touch, as occur during tactile exploration, is poorly understood. In mouse whisker S1, temporally dense stimulation of local whisker pairs revealed that most neurons are not classical single-whisker feature detectors, but instead are strongly tuned to 2-whisker sequences involving the columnar whisker (CW) and one, specific surround whisker (SW), usually in SW-leading-CW order. Tuning was spatiotemporally precise and diverse across cells, generating a rate code for local motion vectors defined by SW-CW combinations. Spatially asymmetric, sublinear suppression for suboptimal combinations and near-linearity for preferred combinations sharpened combination tuning relative to linearly predicted tuning. This resembles computation of motion direction selectivity in vision. SW-tuned neurons, misplaced in the classical whisker map, had the strongest combination tuning. Thus, each S1 column contains a rate code for local motion sequences involving the CW, providing a basis for higher-order feature extraction.

Rapid Disinhibition by Adjustment of PV Intrinsic Excitability during Whisker Map Plasticity in Mouse S1.

Rapid plasticity of layer (L) 2/3 inhibitory circuits is an early step in sensory cortical map plasticity, but its cellular basis is unclear. We show that, in mice of either sex, 1 d whisker deprivation drives the rapid loss of L4-evoked feedforward inhibition and more modest loss of feedforward excitation in L2/3 pyramidal (PYR) cells, increasing the excitation-inhibition conductance ratio. Rapid disinhibition was due to reduced L4-evoked spiking by L2/3 parvalbumin (PV) interneurons, caused by reduced PV intrinsic excitability. This included elevated PV spike threshold, which is associated with an increase in low-threshold, voltage-activated delayed rectifier (presumed Kv1) and A-type potassium currents. Excitatory synaptic input and unitary inhibitory output of PV cells were unaffected. Functionally, the loss of feedforward inhibition and excitation was precisely coordinated in L2/3 PYR cells, so that peak feedforward synaptic depolarization remained stable. Thus, the rapid plasticity of PV intrinsic excitability offsets early weakening of excitatory circuits to homeostatically stabilize synaptic potentials in PYR cells of sensory cortex.SIGNIFICANCE STATEMENT Inhibitory circuits in cerebral cortex are highly plastic, but the cellular mechanisms and functional importance of this plasticity are incompletely understood. We show that brief (1 d) sensory deprivation rapidly weakens parvalbumin (PV) inhibitory circuits by reducing the intrinsic excitability of PV neurons. This involved a rapid increase in voltage-gated potassium conductances that control near-threshold spiking excitability. Functionally, the loss of PV-mediated feedforward inhibition in L2/3 pyramidal cells was precisely balanced with the separate loss of feedforward excitation, resulting in a net homeostatic stabilization of synaptic potentials. Thus, rapid plasticity of PV intrinsic excitability implements network-level homeostasis to stabilize synaptic potentials in sensory cortex.

Chapter 4 - Somatosensory maps

Somatosensory areas containing topographic maps of the body surface are a major feature of parietal cortex. In primates, parietal cortex contains four somatosensory areas, each with its own map, with the primary cutaneous map in area 3b. Rodents have at least three parietal somatosensory areas. Maps are not isomorphic to the body surface, but magnify behaviorally important skin regions, which include the hands and face in primates, and the whiskers in rodents. Within each map, intracortical circuits process tactile information, mediate spatial integration, and support active sensation. Maps may also contain fine-scale representations of touch submodalities, or direction of tactile motion. Functional representations are more overlapping than suggested by textbook depictions of map topography. The whisker map in rodent somatosensory cortex is a canonic system for studying cortical microcircuits, sensory coding, and map plasticity. Somatosensory maps are plastic throughout life in response to altered use or injury. This chapter reviews basic principles and recent findings in primate, human, and rodent somatosensory maps.

Interspersed Distribution of Selectivity to Kinematic Stimulus Features in Supragranular Layers of Mouse Barrel Cortex.

Neurons in the primary sensory regions of neocortex have heterogeneous response properties. The spatial arrangement of neurons with particular response properties is a key aspect of population representations and can shed light on how local circuits are wired. Here, we investigated how neurons with sensitivity to different kinematic features of whisker stimuli are distributed across local circuits in supragranular layers of the barrel cortex. Using 2-photon calcium population imaging in anesthetized mice, we found that nearby neurons represent diverse kinematic features, providing a rich population representation at the local scale. Neurons interspersed in space therefore responded differently to a common stimulus kinematic feature. Conversely, neurons with similar feature selectivity were located no closer to each other than predicted by a random distribution null hypothesis. This finding relied on defining a null hypothesis that was specific for testing the spatial distribution of tuning across neurons. We also measured how neurons sensitive to specific features were distributed relative to barrel boundaries, and found no systematic organization. Our results are compatible with randomly distributed selectivity to kinematic features, with no systematic ordering superimposed upon the whisker map.

Imprecise Whisker Map in the Neonatal Rat Barrel Cortex.

The somatosensory barrel cortex in rodents contains a topographic map of the facial whiskers where each cortical barrel is tuned to a corresponding whisker. However, exactly when this correspondence is established during development and how precise the functional topography of the whisker protomap is at birth, before the anatomical formation of barrels, are questions that remain unresolved. Here, using extracellular and whole-cell recordings from the barrel cortex of 0- to 7-day-old (P0-7; P0 = day of birth) rat pups in vivo, we report a low level of tuning to the principal whisker at P0-1, with multiple adjacent whiskers evoking large multi- and single-unit responses and excitatory postsynaptic currents in cortical neurons. Additionally, we found broad and largely overlapping projection fields (PFs) for neighboring whiskers in the barrel cortex at P0-1. Starting from P2-3, a segregated whisker map emerged, characterized by preferential single whisker tuning and segregated whisker PFs. These results indicate that the functional whisker protomap in the somatosensory cortex is imprecise at birth, that for 2-3 days after birth, whiskers compete for the cortical target territories, and that formation of a segregated functional whisker map coincides with emergence of the anatomical barrel map.

Rapid homeostasis by disinhibition during whisker map plasticity

How homeostatic processes contribute to map plasticity and stability in sensory cortex is not well-understood. Classically, sensory deprivation first drives rapid Hebbian weakening of spiking responses to deprived inputs, which is followed days later by a slow homeostatic increase in spiking responses mediated by excitatory synaptic scaling. Recently, more rapid homeostasis by inhibitory circuit plasticity has been discovered in visual cortex, but whether this process occurs in other brain areas is not known. We tested for rapid homeostasis in layer 2/3 (L2/3) of rodent somatosensory cortex, where D-row whisker deprivation drives Hebbian weakening of whisker-evoked spiking responses after an unexplained initial delay, but no homeostasis of deprived whisker responses is known. We hypothesized that the delay reflects rapid homeostasis through disinhibition, which masks the onset of Hebbian weakening of L2/3 excitatory input. We found that deprivation (3 d) transiently increased whisker-evoked spiking responses in L2/3 single units before classical Hebbian weakening (≥5 d), whereas whisker-evoked synaptic input was reduced during both periods. This finding suggests a transient homeostatic increase in L2/3 excitability. In whole-cell recordings from L2/3 neurons in vivo, brief deprivation decreased whisker-evoked inhibition more than excitation and increased the excitation-inhibition ratio. In contrast, synaptic scaling and increased intrinsic excitability were absent. Thus, disinhibition is a rapid homeostatic plasticity mechanism in rodent somatosensory cortex that transiently maintains whisker-evoked spiking in L2/3, despite the onset of Hebbian weakening of excitatory input.

Chirikov and Nekhoroshev diffusion estimates: Bridging the two sides of the river

We present theoretical and numerical results pointing towards a strong connection between the estimates for the diffusion rate along simple resonances in multidimensional nonlinear Hamiltonian systems that can be obtained using the heuristic theory of Chirikov and a more formal one due to Nekhoroshev. We show that, despite a wide-spread impression, the two theories are complementary rather than antagonist. Indeed, although Chirikov’s 1979 review has thousands of citations, almost all of them refer to topics such as the resonance overlap criterion, fast diffusion, the Standard or Whisker Map, and not to the constructive theory providing a formula to measure diffusion along a single resonance. However, as will be demonstrated explicitly below, Chirikov’s formula provides values of the diffusion coefficient which are quite well comparable to the numerically computed ones, provided that it is implemented on the so-called optimal normal form derived as in the analytic part of Nekhoroshev’s theorem. On the other hand, Chirikov’s formula yields unrealistic values of the diffusion coefficient, in particular for very small values of the perturbation, when used in the original Hamiltonian instead of the optimal normal form. In the present paper, we take advantage of this complementarity in order to obtain accurate theoretical predictions for the local value of the diffusion coefficient along a resonance in a specific 3DoF nearly integrable Hamiltonian system. Besides, we compute numerically the diffusion coefficient and a full comparison of all estimates is made for ten values of the perturbation parameter, showing a very satisfactory agreement.

Plasticity of Recurrent L2/3 Inhibition and Gamma Oscillations by Whisker Experience

Local recurrent networks in neocortex are critical nodes for sensory processing, but their regulation by experience is much less understood than for long-distance (translaminar or cross-columnar) projections. We studied local L2/3 recurrent networks in rat somatosensory cortex during deprivation-induced whisker map plasticity, by expressing channelrhodopsin-2 (ChR2) in L2/3 pyramidal cells and measuring light-evoked synaptic currents in exvivo S1 slices. In columns with intact whiskers, brief light impulses evoked recurrent excitation and supralinear inhibition. Deprived columns showed modestly reduced excitation and profoundly reduced inhibition, providing a circuit locus for disinhibition of whisker-evoked responses observed in L2/3 invivo. Slower light ramps elicited sustained gamma frequency oscillations, which were nearly abolished in deprived columns. Reduction in gamma power was also observed in spontaneous LFP oscillations in L2/3 of deprived columns invivo. Thus, L2/3 recurrent networks are a powerful site for homeostatic modulation of excitation-inhibition balance and regulation of gamma oscillations.

Sensory Map Transfer to the Neocortex Relies on Pretarget Ordering of Thalamic Axons

Sensory maps, such as the representation of mouse facial whiskers, are conveyed throughout the nervous system by topographic axonal projections that preserve neighboring relationships between adjacent neurons. In particular, the map transfer to the neocortex is ensured by thalamocortical axons (TCAs), whose terminals are topographically organized in response to intrinsic cortical signals. However, TCAs already show a topographic order early in development, as they navigate toward their target. Here, we show that this preordering of TCAs is required for the transfer of the whisker map to the neocortex. Using Ebf1 conditional inactivation that specifically perturbs the development of an intermediate target, the basal ganglia, we scrambled TCA topography en route to the neocortex without affecting the thalamus or neocortex. Notably, embryonic somatosensory TCAs were shifted toward the visual cortex and showed a substantial intermixing along their trajectory. Somatosensory TCAs rewired postnatally to reach the somatosensory cortex but failed to form a topographic anatomical or functional map. Our study reveals that sensory map transfer relies not only on positional information in the projecting and target structures but also on preordering of axons along their trajectory, thereby opening novel perspectives on brain wiring.

Spike-Timing-Dependent Potentiation of Sensory Surround in the Somatosensory Cortex Is Facilitated by Deprivation-Mediated Disinhibition

Functional maps in the cerebral cortex reorganize in response to changes in experience, but the synaptic underpinnings remain uncertain. Here, we demonstrate that layer (L) 2/3 pyramidal cell synapses in mouse barrel cortex can be potentiated upon pairing of whisker-evoked postsynaptic potentials (PSPs) with action potentials (APs). This spike-timing-dependent long-term potentiation (STD-LTP) was only effective for PSPs evoked by deflections of a whisker in the neuron's receptive field center, and not its surround. Trimming of all except two whiskers rapidly opened the possibility to drive STD-LTP by the spared surround whisker. This facilitated STD-LTP was associated with a strong decrease in the surrounding whisker-evoked inhibitory conductance and partially occluded picrotoxin-mediated LTP facilitation. Taken together, our data demonstrate that sensory deprivation-mediated disinhibition facilitates STD-LTP from the sensory surround, which may promote correlation- and experience-dependent expansion of receptive fields.

Neurotransmitter Release at the Thalamocortical Synapse Instructs Barrel Formation But Not Axon Patterning in the Somatosensory Cortex

To assess the impact of synaptic neurotransmitter release on neural circuit development, we analyzed barrel cortex formation after thalamic or cortical ablation of RIM1 and RIM2 proteins, which control synaptic vesicle fusion. Thalamus-specific deletion of RIMs reduced neurotransmission efficacy by 67%. A barrelless phenotype was found with a dissociation of effects on the presynaptic and postsynaptic cellular elements of the barrel. Presynaptically, thalamocortical axons formed a normal whisker map, whereas postsynaptically the cytoarchitecture of layer IV neurons was altered as spiny stellate neurons were evenly distributed and their dendritic trees were symmetric. Strikingly, cortex-specific deletion of the RIM genes did not modify barrel development. Adult mice with thalamic-specific RIM deletion showed a lack of activity-triggered immediate early gene expression and altered sensory-related behaviors. Thus, efficient synaptic release is required at thalamocortical but not at corticocortical synapses for building the whisker to barrel map and for efficient sensory function.

Parallel Regulation of Feedforward Inhibition and Excitation during Whisker Map Plasticity

Sensory experience drives robust plasticity of sensory maps in cerebral cortex, but the role of inhibitory circuits in this process is not fully understood. We show that classical deprivation-induced whisker map plasticity in layer 2/3 (L2/3) of rat somatosensory (S1) cortex involves robust weakening of L4-L2/3 feedforward inhibition. This weakening was caused by reduced L4 excitation onto L2/3 fast-spiking (FS) interneurons, which mediate sensitive feedforward inhibition and was partially offset by strengthening of unitary FS to L2/3 pyramidal cell synapses. Weakening of feedforward inhibition paralleled the known weakening of feedforward excitation. As a result, mean excitation-inhibition balance and timing onto L2/3 pyramidal cells were preserved. Thus, reduced feedforward inhibition is a covert compensatory process that can maintain excitatory-inhibitory balance during classical deprivation-induced Hebbian map plasticity.

What can we get from ‘barrels’: the rodent barrel cortex as a model for studying the establishment of neural circuits

Sensory inputs triggered by external stimuli are projected into discrete arrays of neuronal modules in the primary sensory cortex. This whisker-to-barrel pathway has gained in popularity as a model system for studying the development of cortical circuits and sensory processing because its clear patterns facilitate the identification of genetically modified mice with whisker map deficits and make possible coordinated in vitro and in vivo electrophysiological studies. Numerous whisker map determinants have been identified in the past two decades. In this review, we summarize what have we learned from the detailed studies conducted in various mutant mice with cortical whisker map deficits. We will specifically focus on the anatomical and functional establishment of the somatosensory thalamocortical circuits.