Role of basal ganglia interactions with brainstem in control of movement

The subthalamic area, comprising the subthalamic and para-subthalamic nucleus, is deeply integrated into basal ganglia circuitry but also exhibits direct input- and output pathways beyond basal ganglia, making it a key integration region combining properties for movement and homeostatic regulation. However, insight into the subthalamic area based on neuronal subpopulations, the recruitment of these neurons during body movement and their roles in movement regulation remain rare. In this dissertation, we investigate the direct connectivity between the subthalamic region and brainstem centers for forelimb execution, most notably the lateral rostral medulla, by elucidating its anatomy and role in the context of a skilled forelimb task in mice. Here we describe a separate neuronal population that projects to forelimb regulating caudal brainstem centers and bypassing the basal ganglia inhibitory output gate, segregated from a population that projects to the major basal ganglia output structure, the substantia nigra reticulata. Using viral tracing and reconstruction approaches, we demonstrate that the lateral rostral medulla projecting population is located medially in the subthalamic region, overlaps anatomically with the parasubthalamic subdivision, and sends synaptic outputs targeted to the forelimb regulatory regions in the caudal brainstem, while anatomically excluding full body regulatory regions with its output. In line with these anatomical findings, and further demonstrating that the subthalamic region is involved in modulating the activity of forelimb motor centers during behavior, we found that lateral rostral medulla neurons involved in different phases of forelimb behavior are modulated by subthalamic region input. Using a combination of optogenetic stimulation of subthalamic neurons and single neuron electrophysiology recordings during a forelimb behavior task, we show that lateral rostral medulla neurons tuned to the handling, but also to the reaching phase of behavior, respond with short latency to subthalamic region activity, consistent with monosynaptic functional connections. Activity of the subthalamic region was also found to be tuned to different aspects of the forelimb task. Single neuron electrophysiology recording of subthalamic regions neurons demonstrated that neurons located in the parasubthalamic division, containing the lateral rostral medulla projecting population, were preferentially tuned to the later phases of the forelimb task, from grasping to handling, while the neurons located in the subthalamic division where preferentially tuned to early phases of the forelimb task containing the reach. Parasubthalamic neurons show a great proportion of tuning to be specific for the grasping movement phase. Applying separation of trials by behavioral performance, we demonstrated that this signal is dependent on the success of the grasp, while being absent when the reaching and grasp movement are performed but the food is not captured. These findings suggest that the subthalamic region transmits this signal to the caudal brainstem centers involved in the ongoing behavior to likely modulate it. Consistent with the “capture success” signal found, we show that the lateral rostral medulla projecting population is integrated into limbic circuitry of the brain. With the use of transsynaptic rabies viruses, we demonstrated that the lateral rostral medulla projecting population receives mainly inputs from regions integrated into limbic basal ganglia circuits and beyond, while the substantia nigra reticulata projecting population receives inputs from the classic motor loop of the basal ganglia. At last, we demonstrate that the activity of parasubthalamic neurons is required for the successful completion of the task. Cell specific optogenetic inhibition of parasubthalamic neurons during the forelimb task resulted in complete abolishment of pellet grasping. Taken together, the results presented in this dissertation reveal that the subthalamic region can communicate both directly and indirectly with the caudal brainstem forelimb regulatory region of the lateral rostral medulla to likely modulate its activity depending on the outcome of the ongoing behavior. Overall, this work advances our knowledge on the understanding of how brainstem motor centers are influenced by higher brain regions to construct behavior including homeostatic signaling