PROJECT SUMMARY Reward neurocircuitry relies in part on endogenous neuropeptide signaling to integrate complex, multivalent information and influence behavior. Opioid addiction can result in neuropeptide imbalances in the nucleus accumbens (NAc), a brain region critical for processing reward. Signaling by neuropeptides derived from VGF (non-acronymic) may be dysregulated by exogenous opioid exposure with repeated withdrawal. The neuropeptide precursor VGF and its derived peptide TLQP-62 serve important functions in experience- dependent plasticity in the nervous system, and VGF transcripts are upregulated in the nucleus accumbens (NAc) after drug exposure and withdrawal. My preliminary data demonstrate that knocking out VGF in the NAc eliminates the behavioral changes typically evoked by opioid exposure and withdrawal in mice. Because these behavioral adaptations are proxies for neuroplasticity in reward circuitry, we hypothesize that VGF is necessary for synaptic plasticity in the NAc. The objective of this work is to interrogate the function of VGF and its derived peptide TLQP-62 in facilitating synaptic plasticity in the NAc, and to understand its contribution to withdrawal- evoked behaviors. First, I will measure the effect of exogenous TLQP-62 on synaptic transmission in the NAc using whole-cell patch-clamp electrophysiology in acute mouse brain slices. Past work in other regions of the central nervous system have shown that TLQP-62 potentiates excitatory transmission. We therefore hypothesize that TLQP-62 will augment excitatory glutamatergic transmission into the NAc. I will then use RNA in situ hybridization to map endogenous VGF transcripts in the NAc and identify in which neuronal subpopulations it is expressed. Finally, I will evaluate the effect of endogenous VGF on withdrawal-evoked behavior adaptations. I will combine transgenic mice and viral vectors to conditionally knock out VGF expression from the NAc and use a model of spontaneous oxycodone withdrawal before performing a battery of behavioral assays to determine the locomotor, social, and sensory impact of VGF in the NAc. With these methods, spanning physiology, neuroanatomical mapping, and behavior, we will build an understanding of the function of VGF and TLQP-62 in the NAc and the role they play in opioid exposure and withdrawal. Beyond identifying a novel target for treating opioid use and withdrawal, the interdisciplinary techniques used in this proposal will examine the basic science mechanisms of clinically urgent questions, laying the groundwork for a career planted at the intersection of clinical need and basic research.

PROJECT NARRATIVE This proposal aims to address significant gaps in our understanding of how neuropeptides derived from a specific gene (vgf) modulate synaptic plasticity in the nucleus accumbens, and how they modulate neurobehavioral plasticity caused by oxycodone exposure and withdrawal. Elucidating specific mechanisms of plasticity will contribute to the development of novel therapeutics that harness neuropeptides and counteract the impact of opioids on the brain.