Distributed and specific encoding of sensory, motor, and decision information in the mouse neocortex during goal-directed behavior.

Goal-directed behaviors involve coordinated activity in many cortical areas, but whether the encoding of task variables is distributed across areas or is more specifically represented in distinct areas remains unclear. Here, we compared representations of sensory, motor, and decision information in the whisker primary somatosensory cortex, medial prefrontal cortex, and tongue-jaw primary motor cortex in mice trained to lick in response to a whisker stimulus with mice that were not taught this association. Irrespective of learning, properties of the sensory stimulus were best encoded in the sensory cortex, whereas fine movement kinematics were best represented in the motor cortex. However, movement initiation and the decision to lick in response to the whisker stimulus were represented in all three areas, with decision neurons in the medial prefrontal cortex being more selective, showing minimal sensory responses in miss trials and motor responses during spontaneous licks. Our results reconcile previous studies indicating highly specific vs. highly distributed sensorimotor processing.

Striatal Dopamine Signals and Reward Learning.

We are constantly bombarded by sensory information and constantly making decisions on how to act. In order to optimally adapt behavior, we must judge which sequences of sensory inputs and actions lead to successful outcomes in specific circumstances. Neuronal circuits of the basal ganglia have been strongly implicated in action selection, as well as the learning and execution of goal-directed behaviors, with accumulating evidence supporting the hypothesis that midbrain dopamine neurons might encode a reward signal useful for learning. Here, we review evidence suggesting that midbrain dopaminergic neurons signal reward prediction error, driving synaptic plasticity in the striatum underlying learning. We focus on phasic increases in action potential firing of midbrain dopamine neurons in response to unexpected rewards. These dopamine neurons prominently innervate the dorsal and ventral striatum. In the striatum, the released dopamine binds to dopamine receptors, where it regulates the plasticity of glutamatergic synapses. The increase of striatal dopamine accompanying an unexpected reward activates dopamine type 1 receptors (D1Rs) initiating a signaling cascade that promotes long-term potentiation of recently active glutamatergic input onto striatonigral neurons. Sensorimotor-evoked glutamatergic input, which is active immediately before reward delivery will thus be strengthened onto neurons in the striatum expressing D1Rs. In turn, these neurons cause disinhibition of brainstem motor centers and disinhibition of the motor thalamus, thus promoting motor output to reinforce rewarded stimulus-action outcomes. Although many details of the hypothesis need further investigation, altogether, it seems likely that dopamine signals in the striatum might underlie important aspects of goal-directed reward-based learning.

Membrane potential dynamics of excitatory and inhibitory neurons in mouse barrel cortex during active whisker sensing.

Neocortical neurons can increasingly be divided into well-defined classes, but their activity patterns during quantified behavior remain to be fully determined. Here, we obtained membrane potential recordings from various classes of excitatory and inhibitory neurons located across different cortical depths in the primary whisker somatosensory barrel cortex of awake head-restrained mice during quiet wakefulness, free whisking and active touch. Excitatory neurons, especially those located superficially, were hyperpolarized with low action potential firing rates relative to inhibitory neurons. Parvalbumin-expressing inhibitory neurons on average fired at the highest rates, responding strongly and rapidly to whisker touch. Vasoactive intestinal peptide-expressing inhibitory neurons were excited during whisking, but responded to active touch only after a delay. Somatostatin-expressing inhibitory neurons had the smallest membrane potential fluctuations and exhibited hyperpolarising responses at whisking onset for superficial, but not deep, neurons. Interestingly, rapid repetitive whisker touch evoked excitatory responses in somatostatin-expressing inhibitory neurons, but not when the intercontact interval was long. Our analyses suggest that distinct genetically-defined classes of neurons at different subpial depths have differential activity patterns depending upon behavioral state providing a basis for constraining future computational models of neocortical function.

Learning-related congruent and incongruent changes of excitation and inhibition in distinct cortical areas.

Excitatory and inhibitory neurons in diverse cortical regions are likely to contribute differentially to the transformation of sensory information into goal-directed motor plans. Here, we investigate the relative changes across mouse sensorimotor cortex in the activity of putative excitatory and inhibitory neurons-categorized as regular spiking (RS) or fast spiking (FS) according to their action potential (AP) waveform-comparing before and after learning of a whisker detection task with delayed licking as perceptual report. Surprisingly, we found that the whisker-evoked activity of RS versus FS neurons changed in opposite directions after learning in primary and secondary whisker motor cortices, while it changed similarly in primary and secondary orofacial motor cortices. Our results suggest that changes in the balance of excitation and inhibition in local circuits concurrent with changes in the long-range synaptic inputs in distinct cortical regions might contribute to performance of delayed sensory-to-motor transformation.

Rapid suppression and sustained activation of distinct cortical regions for a delayed sensory-triggered motor response.

The neuronal mechanisms generating a delayed motor response initiated by a sensory cue remain elusive. Here, we tracked the precise sequence of cortical activity in mice transforming a brief whisker stimulus into delayed licking using wide-field calcium imaging, multiregion high-density electrophysiology, and time-resolved optogenetic manipulation. Rapid activity evoked by whisker deflection acquired two prominent features for task performance: (1) an enhanced excitation of secondary whisker motor cortex, suggesting its important role connecting whisker sensory processing to lick motor planning; and (2) a transient reduction of activity in orofacial sensorimotor cortex, which contributed to suppressing premature licking. Subsequent widespread cortical activity during the delay period largely correlated with anticipatory movements, but when these were accounted for, a focal sustained activity remained in frontal cortex, which was causally essential for licking in the response period. Our results demonstrate key cortical nodes for motor plan generation and timely execution in delayed goal-directed licking.

Cell-type-specific nicotinic input disinhibits mouse barrel cortex during active sensing.

Fast synaptic transmission relies upon the activation of ionotropic receptors by neurotransmitter release to evoke postsynaptic potentials. Glutamate and GABA play dominant roles in driving highly dynamic activity in synaptically connected neuronal circuits, but ionotropic receptors for other neurotransmitters are also expressed in the neocortex, including nicotinic receptors, which are non-selective cation channels gated by acetylcholine. To study the function of non-glutamatergic excitation in neocortex, we used two-photon microscopy to target whole-cell membrane potential recordings to different types of genetically defined neurons in layer 2/3 of primary somatosensory barrel cortex in awake head-restrained mice combined with pharmacological and optogenetic manipulations. Here, we report a prominent nicotinic input, which selectively depolarizes a subtype of GABAergic neuron expressing vasoactive intestinal peptide leading to disinhibition during active sensorimotor processing. Nicotinic disinhibition of somatosensory cortex during active sensing might contribute importantly to integration of top-down and motor-related signals necessary for tactile perception and learning.

Cell Type-Specific Membrane Potential Changes in Dorsolateral Striatum Accompanying Reward-Based Sensorimotor Learning.

The striatum integrates sensorimotor and motivational signals, likely playing a key role in reward-based learning of goal-directed behavior. However, cell type-specific mechanisms underlying reinforcement learning remain to be precisely determined. Here, we investigated changes in membrane potential dynamics of dorsolateral striatal neurons comparing naïve mice and expert mice trained to lick a reward spout in response to whisker deflection. We recorded from three distinct cell types: (i) direct pathway striatonigral neurons, which express type 1 dopamine receptors; (ii) indirect pathway striatopallidal neurons, which express type 2 dopamine receptors; and (iii) tonically active, putative cholinergic, striatal neurons. Task learning was accompanied by cell type-specific changes in the membrane potential dynamics evoked by the whisker deflection and licking in successfully-performed trials. Both striatonigral and striatopallidal types of striatal projection neurons showed enhanced task-related depolarization across learning. Striatonigral neurons showed a prominent increase in a short latency sensory-evoked depolarization in expert compared to naïve mice. In contrast, the putative cholinergic striatal neurons developed a hyperpolarizing response across learning, driving a pause in their firing. Our results reveal cell type-specific changes in striatal membrane potential dynamics across the learning of a simple goal-directed sensorimotor transformation, helpful for furthering the understanding of the various potential roles of different basal ganglia circuits.

Axonal and Dendritic Morphology of Excitatory Neurons in Layer 2/3 Mouse Barrel Cortex Imaged Through Whole-Brain Two-Photon Tomography and Registered to a Digital Brain Atlas.

Communication between cortical areas contributes importantly to sensory perception and cognition. On the millisecond time scale, information is signaled from one brain area to another by action potentials propagating across long-range axonal arborizations. Here, we develop and test methodology for imaging and annotating the brain-wide axonal arborizations of individual excitatory layer 2/3 neurons in mouse barrel cortex through single-cell electroporation and two-photon serial section tomography followed by registration to a digital brain atlas. Each neuron had an extensive local axon within the barrel cortex. In addition, individual neurons innervated subsets of secondary somatosensory cortex; primary somatosensory cortex for upper limb, trunk, and lower limb; primary and secondary motor cortex; visual and auditory cortical regions; dorsolateral striatum; and various fiber bundles. In the future, it will be important to assess if the diversity of axonal projections across individual layer 2/3 mouse barrel cortex neurons is accompanied by functional differences in their activity patterns.

Cortical circuits for transforming whisker sensation into goal-directed licking.

Animals can learn to use sensory stimuli to generate motor actions in order to obtain rewards. However, the precise neuronal circuits driving learning and execution of a specific goal-directed sensory-to-motor transformation remain to be elucidated. Here, we review progress in understanding the contribution of cortical neuronal circuits to a task in which head-restrained water-restricted mice learn to lick a reward spout in response to whisker deflection. We first examine 'innate' pathways for whisker sensory processing and licking motor control, and then discuss how these might become linked through reward-based learning, perhaps enabled by cholinergic-gated and dopaminergic-gated plasticity. The aim is to uncover the synaptically connected neuronal pathways that mediate reward-based learning and execution of a well-defined sensory-to-motor transformation.

Match Making in Sensory Cortex.

Cortical sensory areas are supposed to encode immediate sensory inputs. In this issue of Neuron, Condylis et al. (2020) show that they can also recall information about a past event when in need of comparing two temporally segregated sensory inputs.

Projection-specific Activity of Layer 2/3 Neurons Imaged in Mouse Primary Somatosensory Barrel Cortex During a Whisker Detection Task.

The brain processes sensory information in a context- and learning-dependent manner for adaptive behavior. Through reward-based learning, relevant sensory stimuli can become linked to execution of specific actions associated with positive outcomes. The neuronal circuits involved in such goal-directed sensory-to-motor transformations remain to be precisely determined. Studying simple learned sensorimotor transformations in head-restrained mice offers the opportunity for detailed measurements of cellular activity during task performance. Here, we trained mice to lick a reward spout in response to a whisker deflection and an auditory tone. Through two-photon calcium imaging of retrogradely labeled neurons, we found that neurons located in primary whisker somatosensory barrel cortex projecting to secondary whisker somatosensory cortex had larger calcium signals than neighboring neurons projecting to primary whisker motor cortex in response to whisker deflection and auditory stimulation, as well as before spontaneous licking. Longitudinal imaging of the same neurons revealed that these projection-specific responses were relatively stable across 3 days. In addition, the activity of neurons projecting to secondary whisker somatosensory cortex was more highly correlated than for neurons projecting to primary whisker motor cortex. The large and correlated activity of neurons projecting to secondary whisker somatosensory cortex might enhance the pathway-specific signaling of important sensory information contributing to task execution. Our data support the hypothesis that communication between primary and secondary somatosensory cortex might be an early critical step in whisker sensory perception. More generally, our data suggest the importance of investigating projection-specific neuronal activity in distinct populations of intermingled excitatory neocortical neurons during task performance.

Neural Circuits for Goal-Directed Sensorimotor Transformations.

Precisely wired neuronal circuits process sensory information in a learning- and context-dependent manner in order to govern behavior. Simple sensory decision-making tasks in rodents are now beginning to reveal the contributions of distinct cell types and brain regions participating in the conversion of sensory information into learned goal-directed motor output. Task learning is accompanied by target-specific routing of sensory information to specific downstream cortical regions, with higher-order cortical regions such as the posterior parietal cortex, medial prefrontal cortex, and hippocampus appearing to play important roles in learning- and context-dependent processing of sensory input. An important challenge for future research is to connect cell-type-specific activity in these brain regions with motor neurons responsible for action initiation.

Diverse Long-Range Axonal Projections of Excitatory Layer 2/3 Neurons in Mouse Barrel Cortex.

Excitatory projection neurons of the neocortex are thought to play important roles in perceptual and cognitive functions of the brain by directly connecting diverse cortical and subcortical areas. However, many aspects of the anatomical organization of these inter-areal connections are unknown. Here, we studied long-range axonal projections of excitatory layer 2/3 neurons with cell bodies located in mouse primary somatosensory barrel cortex (wS1). As a population, these neurons densely projected to secondary whisker somatosensory cortex (wS2) and primary/secondary whisker motor cortex (wM1/2), with additional axon in the dysgranular zone surrounding the barrel field, perirhinal temporal association cortex and striatum. In three-dimensional reconstructions of 6 individual wS2-projecting neurons and 9 individual wM1/2-projecting neurons, we found that both classes of neurons had extensive local axon in layers 2/3 and 5 of wS1. Neurons projecting to wS2 did not send axon to wM1/2, whereas a small subset of wM1/2-projecting neurons had relatively weak projections to wS2. A small fraction of projection neurons solely targeted wS2 or wM1/2. However, axon collaterals from wS2-projecting and wM1/2-projecting neurons were typically also found in subsets of various additional areas, including the dysgranular zone, perirhinal temporal association cortex and striatum. Our data suggest extensive diversity in the axonal targets selected by individual nearby cortical long-range projection neurons with somata located in layer 2/3 of wS1.

The Cortical States of Wakefulness.

Cortical neurons process information on a background of spontaneous, ongoing activity with distinct spatiotemporal profiles defining different cortical states. During wakefulness, cortical states alter constantly in relation to behavioral context, attentional level or general motor activity. In this review article, we will discuss our current understanding of cortical states in awake rodents, how they are controlled, their impact on sensory processing, and highlight areas for future research. A common observation in awake rodents is the rapid change in spontaneous cortical activity from high-amplitude, low-frequency (LF) fluctuations, when animals are quiet, to faster and smaller fluctuations when animals are active. This transition is typically thought of as a change in global brain state but recent work has shown variation in cortical states across regions, indicating the presence of a fine spatial scale control system. In sensory areas, the cortical state change is mediated by at least two convergent inputs, one from the thalamus and the other from cholinergic inputs in the basal forebrain. Cortical states have a major impact on the balance of activity between specific subtypes of neurons, on the synchronization between nearby neurons, as well as the functional coupling between distant cortical areas. This reorganization of the activity of cortical networks strongly affects sensory processing. Thus cortical states provide a dynamic control system for the moment-by-moment regulation of cortical processing.

Reward-Based Learning Drives Rapid Sensory Signals in Medial Prefrontal Cortex and Dorsal Hippocampus Necessary for Goal-Directed Behavior.

The neural circuits underlying learning and execution of goal-directed behaviors remain to be determined. Here, through electrophysiological recordings, we investigated fast sensory processing across multiple cortical areas as mice learned to lick a reward spout in response to a brief deflection of a single whisker. Sensory-evoked signals were absent from medial prefrontal cortex and dorsal hippocampus in naive mice, but developed with task learning and correlated with behavioral performance in mice trained in the detection task. The sensory responses in medial prefrontal cortex and dorsal hippocampus occurred with short latencies of less than 50 ms after whisker deflection. Pharmacological and optogenetic inactivation of medial prefrontal cortex or dorsal hippocampus impaired behavioral performance. Neuronal activity in medial prefrontal cortex and dorsal hippocampus thus appears to contribute directly to task performance, perhaps providing top-down control of learned, context-dependent transformation of sensory input into goal-directed motor output.

Highly Dynamic Spatiotemporal Organization of Low-Frequency Activities During Behavioral States in the Mouse Cerebral Cortex.

Although low-frequency (LF < 10 Hz) activities have been considered as a hallmark of nonrapid eye movement (NREM) sleep, several studies have recently reported LF activities in the membrane potential of cortical neurons from different areas in awake mice. However, little is known about the spatiotemporal organization of LF activities across cortical areas during wakefulness and to what extent it differs during NREM sleep. We have thus investigated the dynamics of LF activities across cortical areas in awake and sleeping mice using chronic simultaneous local field potential recordings. We found that LF activities had higher amplitude in somatosensory and motor areas during quiet wakefulness and decreased in most areas during active wakefulness, resulting in a global state change that was overall correlated with motor activity. However, we also observed transient desynchronization of cortical states between areas, indicating a more local state regulation. During NREM sleep, LF activities had higher amplitude in all areas but slow-wave activity was only poorly correlated across cortical areas. Despite a maximal amplitude during NREM sleep, the coherence of LF activities between areas that are not directly connected dropped from wakefulness to NREM sleep, potentially reflecting a breakdown of long-range cortical integration associated with loss of consciousness.

Movement Initiation Signals in Mouse Whisker Motor Cortex.

Frontal cortex plays a central role in the control of voluntary movements, which are typically guided by sensory input. Here, we investigate the function of mouse whisker primary motor cortex (wM1), a frontal region defined by dense innervation from whisker primary somatosensory cortex (wS1). Optogenetic stimulation of wM1 evokes rhythmic whisker protraction (whisking), whereas optogenetic inactivation of wM1 suppresses initiation of whisking. Whole-cell membrane potential recordings and silicon probe recordings of action potentials reveal layer-specific neuronal activity in wM1 at movement initiation, and encoding of fast and slow parameters of movements during whisking. Interestingly, optogenetic inactivation of wS1 caused hyperpolarization and reduced firing in wM1, together with reduced whisking. Optogenetic stimulation of wS1 drove activity in wM1 with complex dynamics, as well as evoking long-latency, wM1-dependent whisking. Our results advance understanding of a well-defined frontal region and point to an important role for sensory input in controlling motor cortex.

Cell-Type-Specific Sensorimotor Processing in Striatal Projection Neurons during Goal-Directed Behavior.

Goal-directed sensorimotor transformation drives important aspects of mammalian behavior. The striatum is thought to play a key role in reward-based learning and action selection, receiving glutamatergic sensorimotor signals and dopaminergic reward signals. Here, we obtain whole-cell membrane potential recordings from the dorsolateral striatum of mice trained to lick a reward spout after a whisker deflection. Striatal projection neurons showed strong task-related modulation, with more depolarization and action potential firing on hit trials compared to misses. Direct pathway striatonigral neurons, but not indirect pathway striatopallidal neurons, exhibited a prominent early sensory response. Optogenetic stimulation of direct pathway striatonigral neurons, but not indirect pathway striatopallidal neurons, readily substituted for whisker stimulation evoking a licking response. Our data are consistent with direct pathway striatonigral neurons contributing a "go" signal for goal-directed sensorimotor transformation leading to action initiation. VIDEO ABSTRACT.

Cortical Sensorimotor Reverberations.

In this issue of Neuron, Manita et al. (2015) report that reciprocal excitatory interactions between higher-order frontal motor cortex and primary sensorimotor cortex might play a key role in hindlimb sensory perception in mice.

Cholinergic signals in mouse barrel cortex during active whisker sensing.

Internal brain states affect sensory perception, cognition, and learning. Many neocortical areas exhibit changes in the pattern and synchrony of neuronal activity during quiet versus active behaviors. Active behaviors are typically associated with desynchronized cortical dynamics. Increased thalamic firing contributes importantly to desynchronize mouse barrel cortex during active whisker sensing. However, a whisking-related cortical state change persists after thalamic inactivation, which is mediated at least in part by acetylcholine, as we show here by using whole-cell recordings, local pharmacology, axonal calcium imaging, and optogenetic stimulation. During whisking, we find prominent cholinergic signals in the barrel cortex, which suppress spontaneous cortical activity. The desynchronized state of barrel cortex during whisking is therefore driven by at least two distinct signals with opposing functions: increased thalamic activity driving glutamatergic excitation of the cortex and increased cholinergic input suppressing spontaneous cortical activity.