Thursday, November 21, 2024
11/21/2024
Project Summary Although the basal ganglia (BG) have long been implicated in action selection, the specific circuit mechanisms remain poorly understood. According to traditional models, the role of the inhibitory BG output is to open a gate to select a specific action via disinhibition. Recent work, however, has questioned this model by demonstrating that BG output is far more complex than originally assumed. By measuring continuous behavioral measures and neural activity simultaneously, recent studies showed that there are multiple functional classes of BG output neurons representing different vector components of actions. In particular, striatal output neurons were shown to encode movement velocity whereas nigral output neurons represent instantaneous position coordinates. These results suggest that BG circuits contain a neural integrator whose output can specify detailed spatial and temporal features of actions precisely and continuously. These results suggest a new model in which direct (striatonigral) and indirect (striatopallidal) pathwayswork together to quantitatively shape action commands. This proposal aims to elucidate how these pathways contribute to motivated behavior in mice. It is hypothesized that direct and indirect pathways implement specific computational functions: whereas direct pathway output determines the rate of change in the neural integrator output, the indirect pathway discharges the integrator. To test this hypothesis, we will use in vivo calcium imaging to measure neural activity in direct and indirect pathway neurons in the sensorimotor striatum with single-neuron resolution in reward-guided behavior. We will also use optogenetic to manipulate activity in these pathways selectively, in order to determine their causal contributions to behavior, and to determine how dopamine may modulate their activity in freely behaving mice. Finally, we will study functional interactions between direct and indirect pathways via recurrent inhibition. Results from proposed experiments will have significant implications for understanding and treating various disorders implicating the BG.
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