Neocortical inhibitory imbalance predicts successful sensory detection.

Perceptual success depends on fast-spiking, parvalbumin-positive interneurons (FS/PVs). However, competing theories of optimal rate and correlation in pyramidal (PYR) firing make opposing predictions regarding the underlying FS/PV dynamics. We addressed this with population calcium imaging of FS/PVs and putative PYR neurons during threshold detection. In primary somatosensory and visual neocortex, a distinct PYR subset shows increased rate and spike-count correlations on detected trials ("hits"), while most show no rate change and decreased correlations. A larger fraction of FS/PVs predicts hits with either rate increases or decreases. Using computational modeling, we found that inhibitory imbalance, created by excitatory "feedback" and interactions between FS/PV pools, can account for the data. Rate-decreasing FS/PVs increase rate and correlation in a PYR subset, while rate-increasing FS/PVs reduce correlations and offset enhanced excitation in PYR neurons. These findings indicate that selection of informative PYR ensembles, through transient inhibitory imbalance, is a common motif of optimal neocortical processing.

Firing rate and pattern heterogeneity in the globus pallidus arise from a single neuronal population.

Intrinsic heterogeneity in networks of interconnected cells has profound effects on synchrony and spike-time reliability of network responses. Projection neurons of the globus pallidus (GPe) are interconnected by GABAergic inhibitory synapses and in vivo fire continuously but display significant rate and firing pattern heterogeneity. Despite being deprived of most of their synaptic inputs, GPe neurons in slices also fire continuously and vary greatly in their firing rate (1-70 spikes/s) and in regularity of their firing. We asked if this rate and pattern heterogeneity arises from separate cell types differing in rate, local synaptic interconnections, or variability of intrinsic properties. We recorded the resting discharge of GPe neurons using extracellular methods both in vivo and in vitro. Spike-to-spike variability (jitter) was measured as the standard deviation of interspike intervals. Firing rate and jitter covaried continuously, with slow firing being associated with higher variability than faster firing, as would be expected from heterogeneity arising from a single physiologically distinct cell type. The relationship between rate and jitter was unaffected by blockade of GABA and glutamate receptors. When the firing rate of individual neurons was altered with constant current, jitter changed to maintain the rate-jitter relationship seen across neurons. Long duration (30-60 min) recordings showed slow and spontaneous bidirectional drift in rate similar to the across-cell heterogeneity. Paired recordings in vivo and in vitro showed that individual cells wandered in rate independently of each other. Input conductance and rate wandered together, in a manner suggestive that both were due to fluctuations of an inward current.

An intrinsic neuronal oscillator underlies dopaminergic neuron bursting.

Dopaminergic neurons of the ventral midbrain fire high-frequency bursts when animals are presented with unexpected rewards, or stimuli that predict reward. To identify the afferents that can initiate bursting and establish therapeutic strategies for diseases affected by altered bursting, a mechanistic understanding of bursting is essential. Our results show that bursting is initiated by a specific interaction between the voltage sensitivity of NMDA receptors and voltage-gated ion channels that results in the activation of an intrinsic, action potential-independent, high-frequency membrane potential oscillation. We further show that the NMDA receptor is uniquely suited for this because of the rapid kinetics and voltage dependence imparted to it by Mg(2+) ion block and unblock. This mechanism explains the discrete nature of bursting in dopaminergic cells and demonstrates how synaptic signals may be reshaped by local intrinsic properties of a neuron before influencing action potential generation.

Calcium-activated SK channels influence voltage-gated ion channels to determine the precision of firing in globus pallidus neurons.

Globus pallidus (GP) neurons fire rhythmically in the absence of synaptic input, suggesting that they may encode their inputs as changes in the phase of their rhythmic firing. Action potential afterhyperpolarization (AHP) enhances precision of firing by ensuring that the ion channels recover from inactivation by the same amount on each cycle. Voltage-clamp experiments in slices showed that the longest component of the GP neuron's AHP is blocked by apamin, a selective antagonist of calcium-activated SK channels. Application of 100 nm apamin also disrupted the precision of firing in perforated-patch and cell-attached recordings. SK channel blockade caused a small depolarization in spike threshold and made it more variable, but there was no reduction in the maximal rate of rise during an action potential. Thus, the firing irregularity was not caused solely by a reduction in voltage-gated Na(+) channel availability. Subthreshold voltage ramps triggered a large outward current that was sensitive to the initial holding potential and had properties similar to the A-type K(+) current in GP neurons. In numerical simulations, the availability of both Na(+) and A-type K(+) channels during autonomous firing were reduced when SK channels were removed, and a nearly equal reduction in Na(+) and K(+) subthreshold-activated ion channel availability produced a large decrease in the neuron's slope conductance near threshold. This change made the neuron more sensitive to intrinsically generated noise. In vivo, this change would also enhance the sensitivity of GP neurons to small synaptic inputs.

Layer 6 ensembles can selectively regulate the behavioral impact and layer-specific representation of sensory deviants.

Predictive models can enhance the salience of unanticipated input. Here, we tested a key potential node in neocortical model formation in this process, layer (L) 6, using behavioral, electrophysiological and imaging methods in mouse primary somatosensory neocortex. We found that deviant stimuli enhanced tactile detection and were encoded in L2/3 neural tuning. To test the contribution of L6, we applied weak optogenetic drive that changed which L6 neurons were sensory responsive, without affecting overall firing rates in L6 or L2/3. This stimulation selectively suppressed behavioral sensitivity to deviant stimuli, without impacting baseline performance. This stimulation also eliminated deviance encoding in L2/3 but did not impair basic stimulus responses across layers. In contrast, stronger L6 drive inhibited firing and suppressed overall sensory function. These findings indicate that, despite their sparse activity, specific ensembles of stimulus-driven L6 neurons are required to form neocortical predictions, and to realize their behavioral benefit.

Dysfunction of cortical GABAergic neurons leads to sensory hyper-reactivity in a Shank3 mouse model of ASD.

Hyper-reactivity to sensory input is a common and debilitating symptom in individuals with autism spectrum disorders (ASD), but the neural basis underlying sensory abnormality is not completely understood. Here we examined the neural representations of sensory perception in the neocortex of a Shank3B-/- mouse model of ASD. Male and female Shank3B-/- mice were more sensitive to relatively weak tactile stimulation in a vibrissa motion detection task. In vivo population calcium imaging in vibrissa primary somatosensory cortex (vS1) revealed increased spontaneous and stimulus-evoked firing in pyramidal neurons but reduced activity in interneurons. Preferential deletion of Shank3 in vS1 inhibitory interneurons led to pyramidal neuron hyperactivity and increased stimulus sensitivity in the vibrissa motion detection task. These findings provide evidence that cortical GABAergic interneuron dysfunction plays a key role in sensory hyper-reactivity in a Shank3 mouse model of ASD and identify a potential cellular target for exploring therapeutic interventions.

For things needing your attention: the role of neocortical gamma in sensory perception.

Two general classes of hypotheses for the role for gamma oscillations in sensation are those that predict gamma facilitates signal amplification through local synchronization of a distinct ensemble, and those that predict gamma modulates fine temporal relationships between neurons to represent information. Correlative evidence has been offered for and against these hypotheses. A recent study in which gamma was optogenetically entrained by driving fast-spiking interneurons showed enhanced sensory detection of harder-to-perceive stimuli, those that benefit most from attention, in agreement with the amplification hypotheses. These findings are supported by similar studies employing less specific optogenetic patterns or single neuron stimulation, but contrast with findings based on direct optogenetic stimulation of pyramidal neurons. Key next steps for this topic are described.