The Interactions of Temporal and Sensory Representations in the Basal Ganglia.

In rodents and primates, interval estimation has been associated with a complex network of cortical and subcortical structures where the dorsal striatum plays a paramount role. Diverse evidence ranging from individual neurons to population activity has demonstrated that this area hosts temporal-related neural representations that may be instrumental for the perception and production of time intervals. However, little is known about how temporal representations interact with other well-known striatal representations, such as kinematic parameters of movements or somatosensory representations. An attractive hypothesis suggests that somatosensory representations may serve as the scaffold for complex representations such as elapsed time. Alternatively, these representations may coexist as independent streams of information that could be integrated into downstream nuclei, such as the substantia nigra or the globus pallidus. In this review, we will revise the available information suggesting an instrumental role of sensory representations in the construction of temporal representations at population and single-neuron levels throughout the basal ganglia.

Unbalanced Inhibitory/Excitatory Responses in the Substantia Nigra Pars Reticulata Underlie Cannabinoid-Related Slowness of Movements.

The substantia nigra pars reticulata (SNr), where the basal ganglia (BG) direct and indirect pathways converge, contains among the highest expression of cannabinoid receptor type 1 (CB1r) in the brain. Hence, SNr is an ideal locus to study pathway interactions and cannabinergic modulations. The objective of this study was to characterize the effects of systemic injections of the CB1r agonist (CP55940) on the balanced activity of the direct/indirect pathways in the SNr and its associated behaviors. To this aim, we recorded somatosensory and pathway-specific representations in the spiking activity of the SNr of male rats under CP55940. CB1r activation mainly decreased the inhibitory, potentially direct pathway component while sparing the excitatory, potentially indirect pathway component of somatosensory responses. As a result, cutaneous stimulation produced unbalanced responses favoring increased SNr firing rates, suggesting a potential locus for cannabinergic motor-related effects. To test this hypothesis, we implemented an ad hoc behavioral protocol for rats in which systemic administration of CP55940 produced kinematic impairments that were completely reverted by nigral injections of the CB1r antagonist (AM251). Our data suggest that cannabinoid-related motor effects are associated with unbalanced direct/indirect pathway activations that may be reverted by CB1r manipulation at the SNr.SIGNIFICANCE STATEMENT The cannabinergic system has been the target of multiple studies to master its potential use as a therapeutic agent. However, significant advances have been precluded by the lack of mechanistic explanations for the variety of its desirable/undesirable effects. Here, we have combined electrophysiological recordings, pharmacological and optogenetic manipulations, and an ad hoc behavioral protocol to understand how basal ganglia (BG) is affected by cannabinoids. We found that cannabinoids principally affect inhibitory inputs, potentially from the direct pathway, resulting in unbalanced responses in the substantia nigra pars reticulata (SNr) and suggesting a mechanism for the cannabinoid-related slowness of movements. This possibility was confirmed by behavioral experiments in which cannabinoid-related slowness of purposeful movements was reverted by cannabinoid receptor type 1 (CB1r) manipulations directly into the SNr.

Cannabinoid CB1 receptors activation and coactivation with D2 receptors modulate GABAergic neurotransmission in the globus pallidus and increase motor asymmetry.

The cannabinoid CB1 (CB1R) and dopaminergic D2 (D2R) receptors modify GABAergic transmission in the globus pallidus. Although dopaminergic denervation produces changes in the expression and supersensitization of these receptors, the consequences of these changes on GABAergic neurotransmission are unknown. The aim of this study was to show the effects of CB1R and D2R activation and coactivation on the uptake and release of [(3) H]GABA in the globus pallidus of hemiparkinsonian rats as well as their effects on motor behavior. The activation of CB1R blocked GABA uptake and decreased GABA release in the globus pallidus in the dopamine denervated side, whereas the co-activation of CB1R-D2R increased GABA release and had no effect on GABA uptake. A microinjection of the CB1R agonist ACEA into the globus pallidus ipsilaterally to a 6-OHDA lesion potentiated turning behavior that was induced by methamphetamine. However, a microinjection of the D2R agonist quinpirole did not modify this behavior, and a microinjection of a mixture of CB1R and D2R agonists significantly potentiated turning behavior. The behavioral effects produced after the activation of the CB1R and the co-activation of CB1R and D2R can be explained by increased GABAergic neurotransmission produced by a block of GABA uptake and an increase in the release of GABA in the globus pallidus, respectively.

Cortico-striatal circuits for bilaterally coordinated movements.

Movement initiation and control require the orchestrated activity of sensorimotor cortical and subcortical regions. However, the exact contribution of specific pathways and interactions to the final behavioral outcome are still under debate. Here, by combining structural lesions, pathway-specific optogenetic manipulations and freely moving electrophysiological recordings in rats, we studied cortico-striatal interactions in the context of forelimb bilaterally coordinated movements. We provide evidence indicating that bilateral actions are initiated by motor cortical regions where intratelencephalic bilateral cortico-striatal (bcs-IT) projections recruit the sensorimotor striatum to provide stability and duration to already commanded bilateral movements. Furthermore, striatal spiking activity was correlated with movement duration and kinematic parameters of the execution. bcs-IT stimulation affected only the representation of movement duration but spared that of kinematics. Our findings confirm the modular organization of information processing in the striatum and its involvement in moment-to-moment movement control but not initiation or selection.

The Central Medial Thalamic Nucleus Facilitates Bilateral Movement Execution in Rats.

Intralaminar thalamic nuclei, including the central medial nucleus (CMT), have been classically implicated in the control of attentional functional states such as sleep-wake transitions. In rodents, the CMT innervates large cortical and subcortical areas bilaterally, including sensorimotor regions of the cortex and striatum, but its contribution to motor function, which regularly develops in faster temporal scales than attentional states, is still far from being completely understood. Here, by using a novel behavioral protocol to evaluate bilateral coordination in rats, combined with electrophysiological recordings and optogenetic manipulations, we studied the contribution of the CMT to motor control and coordination. We found that optogenetic stimulation of the central region of the CMT produced bilateral recruitment of neural activity in the sensorimotor cortex and striatum. The same type of stimulations produced a significant increase in bilateral movement coordination of the forelimbs accompanied by a decrease in movement trajectory variability. Optogenetic inactivation of the CMT did not affect motor execution but significantly increased execution times, suggesting less interest in the task. Altogether, our results indicate that brief CMT activations create windows of synchronized bilateral cortico-striatal activity, suitable to facilitate motor coordination in temporal scales relevant for motor execution.

Altered Sensory Representations in Parkinsonian Cortical and Basal Ganglia Networks.

In parkinsonian conditions, network dynamics in the cortical and basal ganglia circuits present abnormal oscillations and periods of high synchrony, affecting the functionality of multiple striatal regions including the sensorimotor striatum. However, it is still unclear how these altered dynamics impact on sensory processing, a key feature for motor control that is severely impaired in parkinsonian patients. A major confound is that pathological dynamics in sensorimotor networks may elicit unspecific motor responses that may alter sensory representations through sensory feedback, making it difficult to disentangle motor and sensory components. To address this issue, we studied sensory processing using an anesthetized model with robust sensory representations throughout cortical and basal ganglia sensory regions and limited motor confounds in control and hemiparkinsonian rats. A general screening of sensory-evoked activity in large populations of neurons recorded in the primary sensory cortex (S1), dorsolateral striatum (DLS) and substantia nigra pars reticulata (SNr) revealed increased excitability and altered sensory representations in the three regions. Further analysis revealed uncoordinated population dynamics between DLS and S1/SNr. Finally, DLS lesions in hemiparkinsonian animals partially recovered population dynamics and execution in the rotarod.