VGF in the nucleus accumbens: roles in synaptic and opioid-evoked plasticity

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.

Grant Number: 5F30DA060027-02
NIH Institute/Center: NIH
Principal Investigator: Anisha Adke