Structured networks support sparse traveling waves in rodent somatosensory cortex.

Neurons responding to different whiskers are spatially intermixed in the superficial layer 2/3 (L2/3) of the rodent barrel cortex, where a single whisker deflection activates a sparse, distributed neuronal population that spans multiple cortical columns. How the superficial layer of the rodent barrel cortex is organized to support such distributed sensory representations is not clear. In a computer model, we tested the hypothesis that sensory representations in L2/3 of the rodent barrel cortex are formed by activity propagation horizontally within L2/3 from a site of initial activation. The model explained the observed properties of L2/3 neurons, including the low average response probability in the majority of responding L2/3 neurons, and the existence of a small subset of reliably responding L2/3 neurons. Sparsely propagating traveling waves similar to those observed in L2/3 of the rodent barrel cortex occurred in the model only when a subnetwork of strongly connected neurons was immersed in a much larger network of weakly connected neurons.

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.

Short Time-Scale Sensory Coding in S1 during Discrimination of Whisker Vibrotactile Sequences.

Rodent whisker input consists of dense microvibration sequences that are often temporally integrated for perceptual discrimination. Whether primary somatosensory cortex (S1) participates in temporal integration is unknown. We trained rats to discriminate whisker impulse sequences that varied in single-impulse kinematics (5-20-ms time scale) and mean speed (150-ms time scale). Rats appeared to use the integrated feature, mean speed, to guide discrimination in this task, consistent with similar prior studies. Despite this, 52% of S1 units, including 73% of units in L4 and L2/3, encoded sequences at fast time scales (≤20 ms, mostly 5-10 ms), accurately reflecting single impulse kinematics. 17% of units, mostly in L5, showed weaker impulse responses and a slow firing rate increase during sequences. However, these units did not effectively integrate whisker impulses, but instead combined weak impulse responses with a distinct, slow signal correlated to behavioral choice. A neural decoder could identify sequences from fast unit spike trains and behavioral choice from slow units. Thus, S1 encoded fast time scale whisker input without substantial temporal integration across whisker impulses.

Synaptic mechanisms for plasticity in neocortex.

Sensory experience and learning alter sensory representations in cerebral cortex. The synaptic mechanisms underlying sensory cortical plasticity have long been sought. Recent work indicates that long-term cortical plasticity is a complex, multicomponent process involving multiple synaptic and cellular mechanisms. Sensory use, disuse, and training drive long-term potentiation and depression (LTP and LTD), homeostatic synaptic plasticity and plasticity of intrinsic excitability, and structural changes including formation, removal, and morphological remodeling of cortical synapses and dendritic spines. Both excitatory and inhibitory circuits are strongly regulated by experience. This review summarizes these findings and proposes that these mechanisms map onto specific functional components of plasticity, which occur in common across the primary somatosensory, visual, and auditory cortices.

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.

Structure of a single whisker representation in layer 2 of mouse somatosensory cortex.

Layer (L)2 is a major output of primary sensory cortex that exhibits very sparse spiking, but the structure of sensory representation in L2 is not well understood. We combined two-photon calcium imaging with deflection of many whiskers to map whisker receptive fields, characterize sparse coding, and quantitatively define the point representation in L2 of mouse somatosensory cortex. Neurons within a column-sized imaging field showed surprisingly heterogeneous, salt-and-pepper tuning to many different whiskers. Single whisker deflection elicited low-probability spikes in highly distributed, shifting neural ensembles spanning multiple cortical columns. Whisker-evoked response probability correlated strongly with spontaneous firing rate, but weakly with tuning properties, indicating a spectrum of inherent responsiveness across pyramidal cells. L2 neurons projecting to motor and secondary somatosensory cortex differed in whisker tuning and responsiveness, and carried different amounts of information about columnar whisker deflection. From these data, we derive a quantitative, fine-scale picture of the distributed point representation in L2.

Cellular mechanisms for response heterogeneity among L2/3 pyramidal cells in whisker somatosensory cortex.

Whisker deflection evokes sparse, low-probability spiking among L2/3 pyramidal cells in rodent somatosensory cortex (S1), with spiking distributed nonuniformly between more and less responsive cells. The cellular and local circuit factors that determine whisker responsiveness across neurons are unclear. To identify these factors, we used two-photon calcium imaging and loose-seal recording to identify more and less responsive L2/3 neurons in S1 slices in vitro, during feedforward recruitment of the L2/3 network by L4 stimulation. We observed a broad gradient of spike recruitment thresholds within local L2/3 populations, with low- and high-threshold cells intermixed. This recruitment gradient was significantly correlated across different L4 stimulation sites, and between L4-evoked and whisker-evoked responses in vivo, indicating that a substantial component of responsiveness is independent of tuning to specific feedforward inputs. Low- and high-threshold L2/3 pyramidal cells differed in L4-evoked excitatory synaptic conductance and intrinsic excitability, including spike threshold and the likelihood of doublet spike bursts. A gradient of intrinsic excitability was observed across neurons. Cells that spiked most readily to L4 stimulation received the most synaptic excitation but had the lowest intrinsic excitability. Low- and high-threshold cells did not differ in dendritic morphology, passive membrane properties, or L4-evoked inhibitory conductance. Thus multiple gradients of physiological properties exist across L2/3 pyramidal cells, with excitatory synaptic input strength best predicting overall spiking responsiveness during network recruitment.

Behavioral detection of passive whisker stimuli requires somatosensory cortex.

Rodent whisker sensation occurs both actively, as whiskers move rhythmically across objects, and in a passive mode in which externally applied deflections are sensed by static, non-moving whiskers. Passive whisker stimuli are robustly encoded in the somatosensory (S1) cortex, and provide a potentially powerful means of studying cortical processing. However, whether S1 contributes to passive sensation is debated. We developed 2 new behavioral tasks to assay passive whisker sensation in freely moving rats: Detection of unilateral whisker deflections and discrimination of right versus left whisker deflections. Stimuli were simple, simultaneous multi-whisker deflections. Local muscimol inactivation of S1 reversibly and robustly abolished sensory performance on these tasks. Thus, S1 is required for the detection and discrimination of simple stimuli by passive whiskers, in addition to its known role in active whisker sensation.

Degraded tactile coding in the Cntnap2 mouse model of autism.

Atypical sensory processing is common in autism, but how neural coding is disrupted in sensory cortex is unclear. We evaluate whisker touch coding in L2/3 of somatosensory cortex (S1) in Cntnap2-/- mice, which have reduced inhibition. This classically predicts excess pyramidal cell spiking, but this remains controversial, and other deficits may dominate. We find that c-fos expression is elevated in S1 of Cntnap2-/- mice under spontaneous activity conditions but is comparable to that of control mice after whisker stimulation, suggesting normal sensory-evoked spike rates. GCaMP8m imaging from L2/3 pyramidal cells shows no excess whisker responsiveness, but it does show multiple signs of degraded somatotopic coding. This includes broadened whisker-tuning curves, a blurred whisker map, and blunted whisker point representations. These disruptions are greater in noisy than in sparse sensory conditions. Tuning instability across days is also substantially elevated in Cntnap2-/-. Thus, Cntnap2-/- mice show no excess sensory-evoked activity, but a degraded and unstable tactile code in S1.

Molecular states underlying neuronal cell type development and plasticity in the whisker cortex.

Mouse whisker somatosensory cortex (wS1) is a major model system to study the experience-dependent plasticity of cortical neuron physiology, morphology, and sensory coding. However, the role of sensory experience in regulating neuronal cell type development and gene expression in wS1 remains poorly understood. We assembled and annotated a transcriptomic atlas of wS1 during postnatal development comprising 45 molecularly distinct neuronal types that can be grouped into eight excitatory and four inhibitory neuron subclasses. Using this atlas, we examined the influence of whisker experience from postnatal day (P) 12, the onset of active whisking, to P22, on the maturation of molecularly distinct cell types. During this developmental period, when whisker experience was normal, ~250 genes were regulated in a neuronal subclass-specific fashion. At the resolution of neuronal types, we found that only the composition of layer (L) 2/3 glutamatergic neuronal types, but not other neuronal types, changed substantially between P12 and P22. These compositional changes resemble those observed previously in the primary visual cortex (V1), and the temporal gene expression changes were also highly conserved between the two regions. In contrast to V1, however, cell type maturation in wS1 is not substantially dependent on sensory experience, as 10-day full-face whisker deprivation did not influence the transcriptomic identity and composition of L2/3 neuronal types. A one-day competitive whisker deprivation protocol also did not affect cell type identity but induced moderate changes in plasticity-related gene expression. Thus, developmental maturation of cell types is similar in V1 and wS1, but sensory deprivation minimally affects cell type development in wS1.

Reward history guides focal attention in whisker somatosensory cortex.

Prior reward is a potent cue for attentional capture, but the underlying neurobiology is largely unknown. In a novel whisker touch detection task, we show that mice flexibly shift attention between specific whiskers on a trial-by-trial timescale, guided by the recent history of stimulus-reward association. Two-photon calcium imaging and spike recordings revealed a robust neurobiological correlate of attention in the somatosensory cortex (S1), boosting sensory responses to the attended whisker in L2/3 and L5, but not L4. Attentional boosting in L2/3 pyramidal cells was topographically precise and whisker-specific, and shifted receptive fields toward the attended whisker. L2/3 VIP interneurons were broadly activated by whisker stimuli, motion, and arousal but did not carry a whisker-specific attentional signal, and thus did not mediate spatially focused tactile attention. Together, these findings establish a new model of focal attention in the mouse whisker tactile system, showing that the history of stimuli and rewards in the recent past can dynamically engage local modulation in cortical sensory maps to guide flexible shifts in ongoing behavior.

A fast and responsive voltage indicator with enhanced sensitivity for unitary synaptic events.

A remaining challenge for genetically encoded voltage indicators (GEVIs) is the reliable detection of excitatory postsynaptic potentials (EPSPs). Here, we developed ASAP5 as a GEVI with enhanced activation kinetics and responsivity near resting membrane potentials for improved detection of both spiking and subthreshold activity. ASAP5 reported action potentials (APs) in vivo with higher signal-to-noise ratios than previous GEVIs and successfully detected graded and subthreshold responses to sensory stimuli in single two-photon trials. In cultured rat or human neurons, somatic ASAP5 reported synaptic events propagating centripetally and could detect ∼1-mV EPSPs. By imaging spontaneous EPSPs throughout dendrites, we found that EPSP amplitudes decay exponentially during propagation and that amplitude at the initiation site generally increases with distance from the soma. These results extend the applications of voltage imaging to the quantal response domain, including in human neurons, opening up the possibility of high-throughput, high-content characterization of neuronal dysfunction in disease.

Degraded tactile coding in the Cntnap2 mouse model of autism.

Atypical sensory processing in autism involves altered neural circuit function and neural coding in sensory cortex, but the nature of coding disruption is poorly understood. We characterized neural coding in L2/3 of whisker somatosensory cortex (S1) of Cntnap2-/- mice, an autism model with pronounced hypofunction of parvalbumin (PV) inhibitory circuits. We tested for both excess spiking, which is often hypothesized in autism models with reduced inhibition, and alterations in somatotopic coding, using c-fos immunostaining and 2-photon calcium imaging in awake mice. In Cntnap2-/- mice, c-fos-(+) neuron density was elevated in L2/3 of S1 under spontaneous activity conditions, but comparable to control mice after whisker stimulation, suggesting that sensory-evoked spiking was relatively normal. 2-photon GCaMP8m imaging in L2/3 pyramidal cells revealed no increase in whisker-evoked response magnitude, but instead showed multiple signs of degraded somatotopic coding. These included broadening of whisker tuning curves, blurring of the whisker map, and blunting of the point representation of each whisker. These altered properties were more pronounced in noisy than sparse sensory conditions. Tuning instability, assessed over 2-3 weeks of longitudinal imaging, was also significantly increased in Cntnap2-/- mice. Thus, Cntnap2-/- mice show no excess spiking, but a degraded and unstable tactile code in S1.

Circuit-level theories for sensory dysfunction in autism: convergence across mouse models.

Individuals with autism spectrum disorder (ASD) exhibit a diverse range of behavioral features and genetic backgrounds, but whether different genetic forms of autism involve convergent pathophysiology of brain function is unknown. Here, we analyze evidence for convergent deficits in neural circuit function across multiple transgenic mouse models of ASD. We focus on sensory areas of neocortex, where circuit differences may underlie atypical sensory processing, a central feature of autism. Many distinct circuit-level theories for ASD have been proposed, including increased excitation-inhibition (E-I) ratio and hyperexcitability, hypofunction of parvalbumin (PV) interneuron circuits, impaired homeostatic plasticity, degraded sensory coding, and others. We review these theories and assess the degree of convergence across ASD mouse models for each. Behaviorally, our analysis reveals that innate sensory detection behavior is heightened and sensory discrimination behavior is impaired across many ASD models. Neurophysiologically, PV hypofunction and increased E-I ratio are prevalent but only rarely generate hyperexcitability and excess spiking. Instead, sensory tuning and other aspects of neural coding are commonly degraded and may explain impaired discrimination behavior. Two distinct phenotypic clusters with opposing neural circuit signatures are evident across mouse models. Such clustering could suggest physiological subtypes of autism, which may facilitate the development of tailored therapeutic approaches.

VIP interneurons in sensory cortex encode sensory and action signals but not direct reward signals.

Vasoactive intestinal peptide (VIP) interneurons in sensory cortex modulate sensory responses based on global exploratory behavior and arousal state, but their function during non-exploratory, goal-directed behavior is not well understood. In particular, whether VIP cells are activated by sensory cues, reward-seeking actions, or directly by reinforcement is unclear. We trained mice on a Go/NoGo whisker touch detection task that included a delay period and other features designed to separate sensory-evoked, action-related, and reward-related neural activity. Mice had to lick in response to a whisker stimulus to receive a variable-sized reward. Using two-photon calcium imaging, we measured ΔF/F responses of L2/3 VIP neurons in whisker somatosensory cortex (S1) during behavior. In both expert and novice mice, VIP cells were strongly activated by whisker stimuli and goal-directed actions (licking), but not by reinforcement. VIP cells showed somatotopic whisker tuning that was spatially organized relative to anatomical columns in S1, unlike lick-related signals which were spatially widespread. In expert mice, lick-related VIP responses were suppressed, not enhanced, when a reward was delivered, and the amount of suppression increased with reward size. This reward-related suppression was not seen in novice mice, where reward delivery was not yoked to licking. These results indicate that besides arousal and global state variables, VIP cells are activated by local sensory features and goal-directed actions, but not directly by reinforcement. Instead, our results are consistent with a role for VIP cells in encoding the expectation of reward associated with motor actions.

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.

Texture coding in the rat whisker system: slip-stick versus differential resonance.

Rats discriminate surface textures using their whiskers (vibrissae), but how whiskers extract texture information, and how this information is encoded by the brain, are not known. In the resonance model, whisker motion across different textures excites mechanical resonance in distinct subsets of whiskers, due to variation across whiskers in resonance frequency, which varies with whisker length. Texture information is therefore encoded by the spatial pattern of activated whiskers. In the competing kinetic signature model, different textures excite resonance equally across whiskers, and instead, texture is encoded by characteristic, nonuniform temporal patterns of whisker motion. We tested these models by measuring whisker motion in awake, behaving rats whisking in air and onto sandpaper surfaces. Resonant motion was prominent during whisking in air, with fundamental frequencies ranging from approximately 35 Hz for the long Delta whisker to approximately 110 Hz for the shorter D3 whisker. Resonant vibrations also occurred while whisking against textures, but the amplitude of resonance within single whiskers was independent of texture, contradicting the resonance model. Rather, whiskers resonated transiently during discrete, high-velocity, and high-acceleration slip-stick events, which occurred prominently during whisking on surfaces. The rate and magnitude of slip-stick events varied systematically with texture. These results suggest that texture is encoded not by differential resonant motion across whiskers, but by the magnitude and temporal pattern of slip-stick motion. These findings predict a temporal code for texture in neural spike trains.

A dynamic spatial gradient of Hebbian learning in dendrites.

Backpropagating action potentials (bAPs) are an important signal for associative synaptic plasticity in many neurons, but they often fail to fully invade distal dendrites. In this issue of Neuron, Sjöström and Häusser show that distal propagation failure leads to a spatial gradient of Hebbian plasticity in neocortical pyramidal cells. This gradient can be overcome by cooperative distal synaptic input, leading to fundamentally distinct Hebbian learning rules for distal versus proximal synapses.

Intrinsic signal imaging of deprivation-induced contraction of whisker representations in rat somatosensory cortex.

In classical sensory cortical map plasticity, the representation of deprived or underused inputs contracts within cortical sensory maps, whereas spared inputs expand. Expansion of spared inputs occurs preferentially into nearby cortical columns representing temporally correlated spared inputs, suggesting that expansion involves correlation-based learning rules at cross-columnar synapses. It is unknown whether deprived representations contract in a similar anisotropic manner, which would implicate similar learning rules and sites of plasticity. We briefly deprived D-row whiskers in 20-day-old rats, so that each deprived whisker had deprived (D-row) and spared (C- and E-row) neighbors. Intrinsic signal optical imaging revealed that D-row deprivation weakened and contracted the functional representation of deprived D-row whiskers in L2/3 of somatosensory (S1) cortex. Spared whisker representations did not strengthen or expand, indicating that D-row deprivation selectively engages the depression component of map plasticity. Contraction of deprived whisker representations was spatially uniform, with equal withdrawal from spared and deprived neighbors. Single-unit electrophysiological recordings confirmed these results, and showed substantial weakening of responses to deprived whiskers in layer 2/3 of S1, and modest weakening in L4. The observed isotropic contraction of deprived whisker representations during D-row deprivation is consistent with plasticity at intracolumnar, rather than cross-columnar, synapses.

Cortical Coding of Whisking Phase during Surface Whisking.

In rodent whisker sensation, whisker position signals, including whisking phase, are integrated with touch signals to enable spatially accurate tactile perception, but other functions of phase coding are unclear. We investigate how phase coding affects the neural coding of surface features during surface whisking. In mice performing rough-smooth discrimination, S1 units exhibit much stronger phase tuning during surface whisking than in prior studies of whisking in air. Among putative pyramidal cells, preferred phase tiles phase space, but protraction phases are strongly over-represented. Fast-spiking units are nearly all protraction tuned. This protraction bias increases the coding of stick-slip whisker events during protraction, suggesting that surface features are preferentially encoded during protraction. Correspondingly, protraction-tuned units encode rough-smooth texture better than retraction-tuned units and encode the precise spatial location of surface ridges with higher acuity. This suggests that protraction is the main information-gathering phase for high-resolution surface features, with phase coding organized to support this function.