Substantia nigra circuits in instrumental action

Project Summary / Abstract Degeneration of dopamine neurons in the substantia nigra pars compacta (SNc) and resulting pathophysiology in basal ganglia circuits are central to the core motor impairments in Parkinson's Disease (PD). A variety of non-motor symptoms also are highly prevalent in PD, including motivation-related deficits

manifesting as apathy, fatigue, and depression, which have significant negative impacts on quality of life for patients and caregivers. However, we still have limited understanding of how nigrostriatal dopamine contributes to specific aspects of motivated behavior spanning action selection and invigoration, particularly in

the context of cost-benefit decisions entailing effortful reward seeking. Recent work has increasingly highlighted a remarkable diversity of midbrain dopamine neurons, and indeed some subpopulations of SNc dopamine neurons are preferentially vulnerable in PD. Defining the circuits regulating distinct nigrostriatal

dopamine projections and determining their subtype-specific roles in motivated behavior will address critical knowledge gaps and represents important first steps toward developing more effective and specific treatments for disorders such as PD. Our preliminary data suggest that manipulating afferent inputs can drive highly

divergent responses in different nigrostriatal dopamine projections. In particular, stimulating subthalamic nucleus glutamatergic neurons drives diametrically opposed responses in nigrostriatal dopamine projections to distinct striatal subregions. Additionally, stimulating different populations of descending striatonigral projections

evokes opposing patterns of dopamine release within the same region of the striatum. However, the circuit interactions underlying these divergent effects remain unknown. Beyond its recognized role as a major basal ganglia output nucleus, the substantia nigra pars reticulata (SNr) provides critical inhibitory regulation of SNc

dopamine neurons, and we propose that this may differ between dopamine neuron subtypes and mediate their divergent responses to other basal ganglia afferent inputs. Given the anatomically segregated projections of SNc dopamine neuron subtypes to different striatal subregions, we will test the hypothesis that these dopamine

subpopulations differentially contribute to dissociable aspects of effortful reward-seeking behavior. The major goals of this proposal are therefore 1) to characterize how SNr GABA neurons regulate divergent nigrostriatal dopamine pathways and potentially mediate pathway-specific responses to distinct afferent inputs, and 2) to

determine the roles of these SNc dopamine neuron subpopulations in effort-based decisions and instrumental action invigoration. Collectively this research program will yield important advances in understanding basal ganglia circuit regulation of diverse dopamine neuron subtypes and their contributions to motivated behaviors

often impacted in PD.