Chronic uncontrollable stress can precipitate or exacerbate many highly prevalent and debilitating neuropsychiatric disorders such as major depression and schizophrenia. Such stress-related disorders often share common motivational symptoms that result in reduced engagement in activities in pursuit of once- desired outcomes. Dopamine plays critical roles in voluntary movement, motivation, and reward-based learning, but its precise contribution to self-initiated goal-directed behavior remains poorly understood. The dorsomedial striatum (DMS) is well established in supporting goal-directed behavior and receives prominent dopaminergic input from the substantia nigra pars compacta (SNc). Anatomical inputs to these nigrostriatal dopamine neurons have been identified, but little is known about how this circuitry regulates nigrostriatal dopamine dynamics during goal-directed action. Furthermore, chronic stress manipulations in rodent models have revealed complex effects of stress on the adjacent mesolimbic dopamine projections to the ventral striatum, as well as structural and physiological alterations of corticostriatal inputs to the DMS. However, the effects of stress on nigrostriatal dopamine and the circuitry regulating it during goal-directed behavior has not been well characterized. The proposed experiments therefore will address these critical gaps by examining nigrostriatal dopamine transmission (Aim 1) and the striatonigral circuitry regulating these dopamine dynamics (Aim 2) in mice performing goal-directed behavior. These K99 mentored phase experiments will entail the integration of modern optogenetic techniques with the candidate's expertise in recording dopamine using fast-scan cyclic voltammetry, and they will provide opportunities for acquiring advanced technical training with in vivo electrophysiology and cutting-edge viral circuit-manipulation techniques under the guidance of Dr. Xin Jin (mentor) and Dr. Ed Callaway (co-mentor). Training in this suite of systems neuroscience tools will permit subsequent R00 independent phase investigations of how chronic stress alters the functional circuitry regulating nigrostriatal dopamine during goal-directed actions and more complex cost-benefit decision making (Aim 3). These experiments will entail distinct stress manipulations implemented following further guidance from Dr. Byungkook Lim (consultant) and a novel decision-making task adapted from the candidate's doctoral work examining decisions involving tradeoffs between reward and effort. Collectively, the research proposed in this Pathway to Independence award will yield unprecedented insight into how chronic stress affects the circuitry regulating an under-examined dopamine pathway in goal-directed behavior and action selection; it will provide the technical training and career development to launch the candidate's independent research program; and it will reveal important additional questions for future investigations of mechanisms supporting motivated behavior and mental health.
Chronic uncontrollable stress can cause or worsen many debilitating psychiatric disorders such as major depression, which often is characterized by motivational deficits and reduced engagement in activities directed toward the pursuit of goals. Dopamine plays critical roles in voluntary movement, motivation, and reward-based learning, but its precise contribution to self-initiated goal-directed behavior remains poorly understood. The proposed experiments will address this critical gap by examining the circuitry regulating dopamine during such goal-directed behavior and investigating how these circuits are altered by chronic stress.
