Nick Garber Hollon - US grants

DESCRIPTION (provided by applicant): The orbitofrontal cortex (OFC) and mesolimbic dopamine represent two neural substrates that are critical for adaptive motivated behavior, and their dysfunction has been implicated in the neuropathological mechanisms underlying substance use disorders. Neurons in both the OFC and the dopaminergic midbrain signal information related to learned values associated with reward-predicting stimuli, and both substrates are thereby thought to contribute to value-based decision making. Although each substrate may influence how the other stores and updates this value information, recent research has provided evidence of their distinct contributions to reward learning. Thus, investigations of the relative independence versus interactions of the OFC and mesolimbic dopamine function represent an open area of research that will enhance our understanding of the neurobiology underlying motivated behavior. The proposed studies aim to probe these circuit-level interactions by examining how perturbations of OFC activity affect mesolimbic dopamine transmission and value-based decision making. Toward this end, these experiments will employ a behavioral design adapted from a well-established tradition of animal learning theory and informed by recent advances in computational models of reinforcement learning. Additionally, this approach combines our lab's expertise in electrochemical detection techniques and my co-sponsor's novel viral tools for manipulating specific neuronal activity. After selectivel devaluing a previously reinforcing outcome and inactivating the OFC, I will record mesolimbic dopamine transmission using fast-scan cyclic voltammetry while rats perform a dual-reinforcer decision-making task. I will test the effects of OFC inactivation on the gradual updating of dopaminergic value signals and examine whether such dopamine release could contribute to the rats' decisions when the OFC is unavailable to flexibly guide behavioral choices. This inherently integrative and innovative approach will advance our understanding of valuation processes subserved by decision-making circuits whose normal function is disrupted in addiction.

Project Summary / Abstract 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.