Biophysical and Architectural Mechanisms of Subthalamic Theta under Response Conflict

The cortico-basal ganglia circuit is needed to suppress prepotent actions and to facilitate controlled behavior. Under conditions of response conflict, the frontal cortex and subthalamic nucleus [STN] exhibit increased spiking and theta band power, which are linked to adaptive regulation of behavioral output. The electrophysiological mechanisms underlying these neural signatures of impulse control remain poorly understood. To address this lacuna, we constructed a novel large-scale, biophysically principled model of the subthalamopallidal [STN-Globus Pallidus externus (GPe)] network, and examined the mechanisms that modulate theta power and spiking in response to cortical input. Simulations confirmed that theta power does not emerge from intrinsic network dynamics but is robustly elicited in response to cortical input as burst events representing action selection dynamics. Rhythmic burst events of multiple cortical populations, representing a state of conflict where cortical motor plans vacillate in the theta range, led to prolonged STN theta and increased spiking, consistent with empirical literature. Notably, theta band signaling required NMDA, but not AMPA, currents, which were in turn related to a triphasic STN response characterized by spiking, silence and bursting periods. Finally, theta band resonance was also strongly modulated by architectural connectivity, with maximal theta arising when multiple cortical populations project to individual STN "conflict detector" units, due to an NMDA-dependent supralinear response. Our results provide insights into the biophysical principles and architectural constraints that give rise to STN dynamics during response conflict, and how their disruption can lead to impulsivity and compulsivity.

Astrocytic Regulation of Basal Ganglia Dopamine/D2-Dependent Behaviors

Astrocytic involvement in dopamine dynamics related to motivational and sensorimotor gating abilities is unknown. We found that dysbindin-1 (Dys1) hypofunction increases the activity of as-trocytes, which express only the isoform Dys1A that is reduced in the caudate of patients with schizophrenia. Astrocytic Dys1A disruption resulted in avolition and sensorimotor gating deficits, increased astrocytic dopamine D2 receptors and decreased dopaminergic tone within basal gan-glia. Notably, astrocytic Dys1A hypofunction disrupted dopamine dynamics linked to reward ex-pectancy and interconnected with astrocytes Ca2+ responses mainly in the globus pallidus externus (GPe). Finally, we proved these phenotypes were mediated by D2 receptors in astrocytes as their selective deletion in astrocytes either in GPe or SNc/VTA enhanced motivation and sensorimotor gating abilities as well as dopaminergic release in the GPe. Therefore, astrocytes control motivational and sensorimotor gating processes through Dys1A/D2-dependent mechanisms within the basal ganglia.

Indirect pathway from caudate tail mediates rejection of bad objects in periphery

The essential everyday task of making appropriate choices is a process controlled mainly by the basal ganglia. To this end, subjects need not only to find “good” objects in their environment but also to reject “bad” objects. To reveal this rejection mechanism, we created a sequential saccade choice task for monkeys and studied the role of the indirect pathway from the CDt (tail of the caudate nucleus) mediated by cvGPe (caudal-ventral globus pallidus externus). Neurons in cvGPe were typically inhibited by the appearance of bad objects; however, this inhibition was reduced on trials when the monkeys made undesired saccades to the bad objects. Moreover, disrupting the inhibitory influence of CDt on cvGPe by local injection of bicuculline (GABAA receptor antagonist) impaired the monkeys’ ability to suppress saccades to bad objects. Thus, the indirect pathway mediates the rejection of bad choices, a crucial component of goal-directed behavior.

Indirect pathway of caudate tail for choosing good objects in periphery

Choosing good objects is essential for real life, which is controlled mainly by the basal ganglia. For that, a subject need to not only find good objects, but ‘reject’ bad objects. To reveal this ‘rejection’ mechanism, we created a sequential saccade choice task for monkeys and studied the indirect pathway of caudate tail mediated by cvGPe (caudal-ventral globus pallidus externus). The inhibitory responses of cvGPe neurons to bad objects were smaller when the monkey made saccades to them by mistake. Moreover, experimental reduction of the inhibitory response by local injection of bicuculline (GABAA antagonist) disabled the monkey to reject bad objects. In conclusion, rejecting bad objects is crucial for goal-directed behavior, which is controlled by the indirect pathway in the basal ganglia.

A Single-Cell Atlas of Cell Types, States, and Other Transcriptional Patterns from Nine Regions of the Adult Mouse Brain

The mammalian brain is composed of diverse, specialized cell populations, few of which we fully understand. To more systematically ascertain and learn from cellular specializations in the brain, we used Drop-seq to perform single-cell RNA sequencing of 690,000 cells sampled from nine regions of the adult mouse brain: frontal and posterior cortex (156,000 and 99,000 cells, respectively), hippocampus (113,000), thalamus (89,000), cerebellum (26,000), and all of the basal ganglia – the striatum (77,000), globus pallidus externus/nucleus basalis (66,000), entopeduncular/subthalamic nuclei (19,000), and the substantia nigra/ventral tegmental area (44,000). We developed computational approaches to distinguish biological from technical signals in single-cell data, then identified 565 transcriptionally distinct groups of cells, which we annotate and present through interactive online software we developed for visualizing and re-analyzing these data (DropViz). Comparison of cell classes and types across regions revealed features of brain organization. These included a neuronal gene-expression module for synthesizing axonal and presynaptic components; widely shared patterns in the combinatorial co-deployment of voltage-gated ion channels by diverse neuronal populations; functional distinctions among cells of the brain vasculature; and specialization of glutamatergic neurons across cortical regions to a degree not observed in other neuronal or non-neuronal populations. We describe systematic neuronal classifications for two complex, understudied regions of the basal ganglia, the globus pallidus externus and substantia nigra reticulata. In the striatum, where neuron types have been intensely researched, our data reveal a previously undescribed population of striatal spiny projection neurons (SPNs) comprising 4% of SPNs. The adult mouse brain cell atlas can serve as a reference for analyses of development, disease, and evolution.