Project Summary – Project 2 Striatal dopamine loss in Parkinson’s disease triggers abnormal neuronal activity in the extrastriatal basal ganglia and thalamus. Such changes undoubtedly influence the processing of information in cortical motor fields, con- tributing to clinical features of parkinsonism such as akinesia or bradykinesia. However, cortical activity changes remain poorly understood, in part because of the complexity of the organization of the cortical areas that partic- ipate in the basal ganglia thalamocortical ‘motor’ circuit. Neurons in the motor portion of the basal ganglia output nuclei project to neurons in the ventral motor thalamus which, in turn, send their projections mostly to the sup- plementary motor area (SMA), with additional projections to the primary motor cortex (M1). Previous studies of cortical activity in MPTP-treated parkinsonian monkeys showed that corticospinal neurons in M1 change their spontaneous and task-related activity in the parkinsonian state. However, much remains to be known about activity changes of corticospinal projection neurons in the SMA and the effects of antiparkinsonian therapies on cortical activity. Under aim 1, we will study the parkinsonism-associated changes in spontaneous and task-re- lated activities of neurons in SMA and M1 that give rise to projections to the cervical spinal cord. To identify these specific neurons, we will inject retrogradely transported viruses (AAV2-retro) into the cervical spinal cord, to express opsins in corticospinal neurons, which will then enable identification of these neurons by opto-tagging during cortical optrode recordings. For aim 2, we will investigate whether antiparkinsonian treatments (systemic levodopa injections, or deep brain stimulation of the subthalamic nucleus) influence the altered cortical activities in the parkinsonian state. We hypothesize that the antiparkinsonian interventions will normalize some of the changes identified in aim 1, but that their primary actions may differ. For example, stimulation of the subthalamic nucleus may induce prominent activity changes in corticospinal projection neurons due to antidromic activation (by stimulation of corticosubthalamic collaterals of the corticospinal pathway), an effect that is obviously not expected to occur with levodopa treatment. The proposed studies will significantly contribute to our understand- ing of the pathophysiology of parkinsonism and of the effects of antiparkinsonian therapies, and may pave the way for new antiparkinsonian treatments, such as chemogenetic approaches or new deep brain stimulation ap- proaches, to normalize activity patterns of the studied corticospinal neurons. The planned studies are closely aligned with those in project 1 (studies with similar questions, examined with wide-field imaging and brain slice recordings in rodents, as well as computational modeling), project 3 (studies of ultrastructural synaptic plasticity affecting specific projection neuron fami...