Optogenetic Dissection of Pathway-Specific Processing in the Basal Ganglia

The role of the basal ganglia in motor control has been the subject of intense interest over the past several decades. It is well known that many movement disorders including Parkinson's disease and Huntington's disease are associated with basal ganglia pathology. However, the normal functions of the basal ganglia, and their disruption in pathological states, are still poorly understood. Two parallel anatomical pathways in the basal ganglia have been proposed to oppositely regulate the propensity for movement. According to this so-called "classical model" of basal ganglia function, activation of the direct pathway facilitates movement, while activation of the indirect pathway suppresses movement. We have now utilized in vivo optogenetic activation of medium spiny neurons (MSNs) that form the origin of the direct and indirect pathways to address the question of how activation of these circuits affects motor behavior. We have found that we can selectively target ChR2 to either direct or indirect pathway MSNs via Cre-dependent expression in either D1-Cre or D2-Cre BAC transgenic mice. In vivo recordings performed under anesthesia demonstrate activation of ChR2-expressing MSNs in the striatum, and both direct pathway-mediated inhibition, and indirect pathway-mediated excitation of SNr neurons. Direct pathway activation in behaving mice elicits robust locomotor activation, while indirect pathway activation strongly suppresses movement. We have also utilized pathway-specific activation of the striatum to investigate the modulation of SNr activity by direct and indirect pathways in awake behaving mice. We found that both direct and indirect pathway stimulation produce some of the effects predicted by the classical model, namely that direct pathway activation robustly inhibits some SNr cells, while indirect pathway excites some SNr cells, concurrent with changes in locomotion. However, we also observe that pathway stimulation produces responses in some SNr cells opposite to classical model predictions, possibly as a consequence of strong lateral inhibition in this nucleus. Furthermore, we find that focal inhibition of SNr drives locomotor initiation, while global excitation elicits motor suppression. These results are consistent with predictions that the direct pathway provides focused inhibition for action selection, while indirect pathway globally suppresses action.