PROJECT SUMMARY Parkinson’s disease (PD) is the second most common neurodegenerative disease of aging and as such it associates with a rapidly growing socioeconomic burden. A hallmark of PD is the loss of dopaminergic (DA) neurons in the substantia nigra, which is causally linked to the debilitating motor symptoms that characterize this disease. However, motor function is not confined to the substantia nigra –other brain structures, like the primary motor cortex (M1) that controls specific sets of motor skills, are affected in PD. Until recently, the abnormal activity of M1 neurons observed in PD was thought to be a direct consequence of an increased basal ganglia inhibition due to the loss of nigral DA neurons. There is now strong evidence indicating that M1 circuitry exhibits adaptive changes in response to loss of DA neurons. Our preliminary data show numerous intrinsic and synaptic adaptations in M1 circuitry. Yet, we lack fundamental understanding of M1 circuitry dysfunction in PD in the context of its neuronal heterogeneity and synaptic complexity. Moreover, compelling evidence shows M1 dysfunction occurs early in PD, but it remains unclear whether it is adaptative or maladaptive as the disease progresses. In the proposed research, we will systematically study how the loss of nigral DA neurons induces adaptative changes in the intrinsic properties of pyramidal neuron subtypes in the layer 5 of M1. We will also determine molecular and ionic mechanisms that associate with these changes (Aim 1). A combination of ex vivo patch-clamp recording with pharmacological and biophysical approaches will be used to address these two questions. Moreover, by combining ex vivo patch-clamp recording with optogenetics, chemogenetics, and connectomics, how the loss of nigral DA neurons alters the connection strength and plasticity of thalamocortical synapses will be determined (Aim 2). Last, the time course of M1 circuitry dysfunction as neurodegeneration occurs will be studied using a mouse model that shows progressive loss of nigral DA neurons and levodopa- responsive motor deficits. In these studies, M1 circuitry dysfunction will be related to the development of motor deficits to determine its role in the onset and progression of motor dysfunction (Aim 3). The information arising from the proposed research will fill the gap in knowledge regarding M1 circuitry dysfunction associated with the loss of nigral DA neurons. This knowledge will aid the identification of novel physiological biomarkers for PD progression and the design of noninvasive approaches targeting M1 for treatment of motor dysfunction in PD.