Dissecting Glutamatergic Pathway-Specific Ensembles Guiding Motivated Behavior

About This Grant

Project Summary/Abstract Opioid use disorder (OUD) is a devastating public health crisis, characterized by a lack of inhibitory control over drug seeking. Opioid use causes persistent adaptations in the excitatory circuitry governing motivated behavior, enabling drug-paired cues to trigger seeking despite negative consequences. Therefore, understanding how opioids engage and adapt unique glutamatergic circuit elements to promote maladaptive, reward-driven behavior would provide significant insight into habitual heroin use and identify treatment strategies to prevent relapse. This K99/R00 proposal seeks to determine the projection-specific glutamatergic neurons that functionally guide motivated behavior and reveal the pathway-specific circuit adaptations that emerge during heroin use to drive reward seeking. As I begin my independent career, I aim to develop a research program that investigates the spatiotemporal dynamics of drug-naive and drug-experienced glutamatergic networks and causally implicate pathway-specific ensembles in guiding reward-driven behavior and relapse. The Otis laboratory identified that the glutamatergic pathway from the paraventricular thalamus to the nucleus accumbens shell (PVT→NAc) pervasively governs naturalistic reward-seeking behavior, and stimulation of this pathway is sufficient to profoundly inhibit motivated action. Recently, I established that heroin use dampens PVT→NAc projection activity and weakens downstream synaptic efficacy, functionally disinhibiting reward seeking. Using two-photon (2P) calcium imaging in head-fixed, self-administering mice, we found three unique ensembles emerge in the PVT→NAc pathway during taking, with inhibitory neuronal dynamics reliably predicting goal-directed behavior in sucrose- and heroin-seeking tasks. However, it is currently unknown whether this inhibitory ensemble functionally encodes motivated behavior and actively guides reward seeking. During the K99, I will receive world-class training in 2P single-cell optogenetics to selectively photostimulate the inhibitory PVT→NAc ensemble that encodes goal-directed behavior in sucrose-seeking mice, both before and after heroin exposure. I will learn advanced computational analysis to determine the outcome of ensemble photostimulation on the within- projection dynamics guiding inhibitory control and heroin-induced disinhibition of seeking (Aim 1). I will expand my investigations into other key glutamatergic inputs to the NAc and determine the heroin-induced adaptations in hippocampal circuit- and cell-type-specific connectivity that facilitates relapse (Aim 2) and hippocampus-to- NAc-specific projection neurons that guide heroin-motivated behavior (Aim 3). Collectively, this proposal tests the hypothesis that heroin induces functional adaptations in pathway-specific glutamatergic circuit elements to drive maladaptive reward seeking. Results will reveal the network computations that guide motivated behavior in naïve and drug-exposed systems. This K99/R00 will grant me the unparalleled opportunity to receive training in state-of-the-art approaches as I develop my own independent research program in OUD.