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Integrating sensory information to produce appropriate motor outputs is crucial for the survival of living beings. Responses to sensory input are modulated by the state of the animal (e.g. alertness) and ongoing behavior. Previous studies have shown that striatal projection neurons (MSNs) of anesthetized mice integrate sensory inputs from both sides of the body and different sensory modalities. However, it is not clear how these sensory responses are modulated at different brain-states.

To address this question, we obtained in vivo whole-cell recordings in the dorsolateral striatum of awake, head-fixed mice. We used the “optopatcher” to identify direct and indirect pathway MSNs (dMSNs and iMSNs, respectively) in real-time during recordings using focal optogenetic stimulation through the patch pipette.

We found that both dMSNs and iMSNs exhibit sensory responses to whisker deflection from both sides of the body. Similarly to anesthetized mice, MSNs of awake animals encode the laterality of sensory inputs with larger and earlier responses to contralateral than to ipsilateral whisker deflection. During quiet wakefulness, these responses are briefer and smaller in amplitude compared to those of anesthetized mice, and even briefer and smaller during whisking epochs. Laterality coding was lost in dopamine-depleted mice in both MSN types.

Our results show that laterality coding in MSNs is present in both anesthetized and awake animals, but it is impaired in the dopamine-depleted striatum, providing insights into the network mechanisms underlying sensory deficits in Parkinson’s Disease.

The receptive fields of cutaneous input in distinct sensorimotor systems have been found to be organized in accordance with the mechanical loading patterns of the skin that result from the motor activity generated by the corresponding circuit. It is possible that by representing sensory feedback
in this motor frame-of-reference, more efficient information processing and motor adaptations can be achieved. However, establishing the general mapping of sensory feedback to motor networks would require a process of experience-dependent tuning of circuit connectivity. The mechanisms
underlying such functional adaptations during early life have been investigated, but rearrangements of sensory information to different motor circuits could also constitute a key component of sensorimotor learning in the adult nervous system, as part of the gradual acquisition of novel motor
skills.

We have here explored if the temporal and spatial organization of tactile input from the plantar forepaws of the rat to cortical and striatal circuits is affected by a period of extensive sensorimotor training in a skilled reaching and grasping task. In particular, we have focused on cortical and
striatal circuits known to be directly related to forelimb motor control – that is, the forelimb representation of the caudal primary motor cortex (MI) and the dorsolateral (sensorimotor-)part of the striatum, which receives the densest projections from this part of the cerebral cortex.

Our data show that the representation of tactile stimuli in terms of both temporal and spatial response patterns changes as a consequence of the training, and that spatial changes particularly involve the primary motor cortex (fig. 1). Based on the observed reorganization, we propose that the
reshaping of spatiotemporal representation of the tactile afference to motor circuits is an integral component of the learning process that underlies skill-acquisition in reaching and grasping.

Motor skills are the bases of a wide range of common behaviors such as riding a bicycle, driving or playing an instrument. Mastering a motor skill requires extensive practice leading to reproducible and efficient execution, automatization and storage of a motor command. Once learned, the skill is retained for a long time, suggesting that it could be stored as long-lasting changes in neural circuits 1,2. However, how and where these progressive changes allow formation and long-term retention of such skills is still not well understood.
Basal ganglia, and particularly the striatum, as their main input nucleus, are known to be key brain structures for action selection and motor control and learning 2-5. Dorsal striatum is divided into several sub-regions, based on the existence of functional cortico-basal ganglia-thalamo-cortical loops 6,7, the dorsomedial (DMS) and dorsolateral (DLS) striatum, which have a differential global implication of in the motor learning process 8-14.
However, whether and how specific neuronal ensembles in the two circuits could be responsible for the acquisition and consolidation of a motor skill remains unclear. In various brain structures, learning and memory consolidation have been related to the formation of stable functional networks 15. We hypothesized that changes in striatal spatiotemporal dynamics may uncover specific stable neuronal ensembles responsible for the formation and consolidation of a motor skill.
To test this hypothesis, we explore the evolution of neural dynamics of DMS and DLS corticostriatal networks with single-cell resolution, throughout the course of motor learning on an accelerating rotarod. Using ex vivo two-photon calcium imaging, we reveal the formation of specific neuronal ensembles in DMS and DLS. These ensembles are formed by highly active striatal projection neurons (HA SPNs) which arise in the two circuits from distinct spatiotemporal activity patterns. These patterns evolve over the course of training, with transient few sparsely distributed HA SPNs in DMS and progressive formation of spatially restricted HA SPN clusters in DLS. The two types of network reorganization are associated with distinct corticostriatal plasticity at synaptic or anatomical levels. Importantly, selective perturbation of HA ensembles significantly impaired the behavioral performance. Altogether, our results show that motor learning is associated with specific discrete domains of stable HA striatal neuronal ensembles throughout the formation of a new motor skill.

The dorsal striatum receives a major and topographic input from the cortex, and the cortex and striatum are thought to work together to carry out a diverse set of functions. It is unclear how the cortex and striatum influence each other however, and it has been suggested that each carries distinct sensorimotor correlates to serve complementary roles. We sought to record from connected regions of the cortex and striatum in mice during sensory guided behavior to determine the relationship of activity across structures. We found precise spatial correlations in activity following anatomical projections from the cortex to the striatum, and activity in the striatum reflected that in associated cortical regions consistently across behavioral contexts. This match in activity was scaled by learning, as untrained mice exhibited smaller sensory responses selectively in the striatum. These results suggest a simple and scalable mapping of activity between the cortex and striatum.

The proper coordination of movement is known to rely on the balanced action of two antagonistic processing streams through the dorsal striatum: the direct, movement-supporting and the indirect, movement-suppressing pathways. However, the medial part of dorsal striatum (DMS) is afforded context beyond the sensorimotor, receiving inputs from structures considered limbic and associative. This rich context hints at a function more abstract than motor control; a role in the coordination of goal-directed actions, in decision-making.

In this context, a third population of striatal neurons is worthy of consideration: Neurons found within the µ-opiod receptor-enriched striosomal compartment of striatum are embedded in limbic-motivational circuitry and, critically, are poised to regulate the dopaminergic feedback and thus direct-indirect pathway balance in DMS. Due to this connectivity, this population is thought of particular importance with regards to reinforcement and action evaluation.

In mice performing a probabilistic two-alternative choice task, we show that the three populations of DMS spiny projection neurons (SPNs) described above independently signal the (i) trial progress and (ii) choice value. Across pathways, both task aspects, progress and value, were jointly encoded in similar, continuous sequential activity patterns. These results are at odds with the commonly-ascribed distinct and clear-cut roles of the pathways, as well as the concept of discrete decisions emerging from the competition of disjoint ensembles of DMS neurons.

The neurophysiological mechanisms behind the profound perceptual changes induced by psychedelic drugs are not well understood. Both dissociative and classical psychedelics (i.e. NMDA antagonists and 5HT-2A agonists) have been shown to dramatically amplify high-frequency oscillations (HFOs) around 150 Hz in rodents, despite different mechanisms of action. To investigate how these oscillations are generated and spread through the brain, and how they relate to unit activity and spontaneous behavior, we performed simultaneous electrophysiological recordings from several brain structures in cortex, basal ganglia and thalamus with microwire electrodes in freely moving rats. In local field potentials, the prevalence and amplitude of HFOs increased in the prefrontal cortex, olfactory cortex and striatum in a similar way for both drug classes, with ventral striatum being most strongly affected. Behaviorally, 5HT-2A agonists increased the frequency of wet-dog shakes, while NMDA antagonists induced severe hyperlocomotion in all animals. However, we could not link the presence of HFOs to any observable behavior. For unit activity, 5HT-2A agonists had a net inhibitory effect in all neuron populations. NMDA antagonists had a similar inhibitory effect on principal cells, but excited interneurons in most structures. Evidence of spike entrainment was predominantly found in cortical neurons. Similarities in HFO features across brain structures with different cytoarchitecture suggests that important aspects of this phenomenon can only be understood on the systems level.

Parkinson’s disease (PD) is a neurodegenerative disorder caused by progressive loss of nigrostriatal dopaminergic neurons and is characterized by motor and non-motor symptoms, such as bradykinesia, rigidity, tremor, depression, and autonomic dysfunctions. To elucidate the pathophysiological mechanism underlying such symptoms, we examined neuronal activity in the internal (GPi) and external (GPe) segments of the globus pallidus in PD monkeys, the output and relay nuclei of the basal ganglia.
PD monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, dopaminergic neurotoxin, exhibited obvious motor symptoms such as bradykinesia and rigidity. In healthy monkeys, motor cortical stimulation induces a triphasic response composed of early excitation, inhibition and late excitation in both GPi and GPe neurons (see the figure below). However, in PD monkeys, cortically evoked inhibition in the GPi mediated by the cortico-striato-GPi direct pathway was largely diminished, while late excitation in the GPe mediated by the cortico-striato-GPe-subthalamo (STN)-GPe pathway was elongated. L-DOPA treatment normalized cortically evoked responses in both the GPi and GPe and ameliorated PD symptoms, particularly akinesia/bradykinesia. STN blockade by injection of muscimol, GABAA receptor agonist, unmasked cortically evoked inhibition in the GPi and ameliorated the motor deficits. These results suggest that information flow through the direct pathway responsible for the initiation of movements is largely reduced in PD and fails to release movements, resulting in akinesia/bradykinesia, and that restoration of cortically induced inhibition in the GPi may have beneficial effects.

The basal ganglia (BG) are a set of subcortical nuclei known for their implication in motor control, sensorimotor integration and procedural learning. The BG shape the activity pattern in the thalamo-cortical target structures to optimize actions. In particular, plasticity in the BG output induces corrections in behavior to maximize reward and correct motor errors during procedural learning. While BG models typically rely on an action repertoire represented in discrete populations, shaping the right output pattern during reward-driven learning is more difficult than simply choosing from separately encoded actions. We propose that the BG-thalamo-cortical network can shape the motor output based on a dual mechanism involving the rich dynamics of this closed-loop network and the classical RL mechanisms relying on dopamine-dependent cortico-striatal synaptic plasticity.
Based on current anatomical, physiological and behavioral evidence, we have built a model for the generation, learning and adaptation of reaching movement in the BG-thalamo-cortical loop. In this model, we aim at studying the interplay between the rich attractor dynamics of the closed-loop BG-thalamo-cortical network and reward-driven learning enabled by DA-dependent long-term plasticity at the cortico-striatal synapses. In the motor cortex, distributed encoding of actions allows the execution and adaptation of continuous motor patterns. We show that the BG can shape sensorimotor transformation, with the cortical motor output patterns emerging as a function of sensory cortical activity, cortico-striatal synaptic weight patterns and overall gains of the feedback loops. The attractor dynamics of the network confers the system with resistance to noisy input, persistent activity, complex spatiotemporal activity profile in response to transient inputs, and dopamine-dependent cortico-striatal plasticity can drive robust learning in the sensorimotor transformation. Moreover, depleting dopamine in the striatum first leads to a loss of the attractor dynamics and inability of the BG network to shape cortical output and ultimately to the emergence of pathological beta oscillations.

The subthalamic nucleus (STN) is critical for the execution of intended movements. Loss of its normal function is strongly associated with several movement disorders, including Parkinson’s disease for which the STN is an important target area in deep brain stimulation (DBS) therapy. Classical basal ganglia models postulate that two parallel pathways, the direct and indirect pathways, exert opposing control over movement, with the STN acting within the indirect pathway. The STN is regulated by both inhibitory and excitatory input, and is itself excitatory.
While most functional knowledge of this clinically relevant brain structure has been gained from pathological conditions and models, primarily parkinsonian, experimental evidence for its role in normal motor control has remained more sparse. The objective here was to tease out the selective impact of the STN on several motor parameters required to achieve intended movement, including locomotion, balance and motor coordination. Optogenetic excitation and inhibition using both bilateral and unilateral stimulations of the STN were implemented in freely-moving mice. The results demonstrate that selective optogenetic inhibition of the STN enhances locomotion while its excitation reduces locomotion. These findings lend experimental support to basal ganglia models of the STN in terms of locomotion. In addition, optogenetic excitation in freely-exploring mice induced self-grooming, disturbed gait and a jumping/escaping behavior, while causing reduced motor coordination in advanced motor tasks, independent of grooming and jumping.
In addition, we also found that, when given a choice, mice avoided excitation of the STN, as if it was perceived as aversive. This founding suggests that the STN is part of the brain aversion and emotion systems which forms a critical brain hub for motor, cognitive and emotional functions. We hypothesized that the STN activation drives aversion via the lateral habenula (LHb), a major brain center of aversion and we found that optogenetic stimulation of the STN indeed caused firing of LHb neurons.