The basal ganglia (BG) are a collection of subcortical nuclei critical for voluntary behavior. Dysfunctions in the BG circuit are found in many disorders, such as Parkinson's disease Huntington's disease, obsessive-compulsive disorder, and addiction. A better understanding of the mechanisms is critical for therapeutic developments for these disorders. Despite significant progress in our understanding of the anatomy and physiology of the BG, their contributions to voluntary behavior remain poorly understood. This proposal aims to determine how BG outputs initiate actions. Preliminary results showed a critical role of the BG circuits in controlling movement kinematics: striatal output reflects movement velocity, which is integrated by the substantia nigra pars reticulata to generate instantaneous position commands to downstream structures in the midbrain and diencephalon, nigrostriatal dopaminergic signaling, on the other hand, modulates the rate of transitions between body configurations, i.e., movement velocity. Thus single unit activity in the BG can be used to quantitatively predict the actual trajectory of any voluntary movement. This proposal aims to elucidate the computational functions of specific components of the BG circuit, and how this circuit can be recruited in motivated behavior directed towards rewards. An integrative approach will be employed, combining 1) a novel motion tracking program that provides unprecedented quantitative data on movement parameters in freely moving mice; 2) wireless in vivo recording from many single neurons in the BG during behavior; 3) optogenetic manipulation of defined BG neuronal populations. These tools will be used to determine the neural code used by the BG circuits in controlling voluntary behavior, and shed light on how rewards and motivational states can modulate behavioral vigor.
By elucidating the neural mechanisms in the basal ganglia circuits quantitatively determine motivated behavior, results collected from the proposed studies can shed light on the major clinical symptoms of disorders implicating the BG and lead to novel treatment strategies.