Friday, April 26, 2024
4/26/2024
PROJECT SUMMARY Impairments in reward processing and related behavior is a core symptom of addiction, chronic pain, and mood disorders. Dysfunction of the ventral basal ganglia, which is comprised of the ventral pallidum (VP) and nucleus accumbens shell (NAcSh) has been implicated in the etiology of affective symptoms in each of these disorders. Canonical basal ganglia models posit that the VP is exclusively an output of the NAc. However, a subpopulation of VP neurons project to the NAcSh, and reward-related neural activity in the VP precedes reward-related activity in the NAcSh. It is completely unknown whether VP terminals in the NAcSh form functional synapses, or whether this pathway modulates reward-related neural activity in the NAcSh or reward behavior. Moreover, infusion of GABA or endogenous opioid (EOs) receptor agonists in the NAcSh potently increases hedonic reactions to and consumption of reward. While VP neurons synthesize GABA and EOs, it is not known whether the VP is a source of these compounds in the NAcSh. To mechanistically understand how the basal ganglia coordinates reward behavior in health and disease, it is crucial to elucidate the functional role of the VP-NAcSh pathway. The objective of this proposal is to determine whether NAcSh projecting-VP neurons release GABA and EOs to inhibit NAcSh neurons, which increases hedonic responses to rewards. To dissect the contribution of the VP-NAcSh pathway on reward-related behavior, we will first establish the post-synaptic targets and neurochemical identity of VP-NAcSh pathway using viral tracing and optogenetic-assisted circuit mapping (aim 1). We will next use in vivo electrophysiology and optogenetic manipulations to determine the effect of VP-NAcSh pathway activation on reward-related behavior and reward-related NAcSh activity in vivo (aim 2). We will determine whether the VP-NAcSh pathway releases EOs in the NAcSh using a novel opto-dialysis approach to detect evoked peptide release in vivo. Finally, we will elucidate whether EOs modulate function of the VP-NAcSh pathway using fISH and patch clamp electrophysiology (aim 3). This proposal will re-examine the classical model of the basal ganglia, which posits that the VP is exclusively an output structure of the NAc, and will determine the role of this pathway on NAcSh activity reward-related behavior. Our long-term goal is to elucidate the circuit basis of impaired reward processing in disease states, and to leverage this understanding to develop circuit-based therapies (such as deep brain stimulation) to treat deficits in reward processing and related behavior in addiction, chronic pain and substance use disorders.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
