# Vagus nerve stimulation modulates synaptic plasticity in the rat prefrontal cortex during the extinction of drug-seeking

> **NIH NIH R01** · UNIVERSITY OF TEXAS DALLAS · 2024 · $409,327

## Abstract

Drug use causes the formation of strong cue/reward associations which persist long after cessation of drug-taking and
contribute to the long-term risk of relapse. Breaking these associations is an important goal in the treatment of substance
use disorders. Extinction is a form of learning that inhibits behavioral responses to a learned stimulus. Modulating
extinction processes and consolidating the newly-formed memories has clinical potential to reshape maladaptive behavior
and to prevent relapse. We have recently shown that vagus nerve stimulation (VNS) facilitates extinction learning and
reduces cue-induced reinstatement of drug-seeking in cocaine self-administering rats. These changes correlate with
altered activity in a network that centers on the infralimbic (IL) cortex. Our preliminary data also show that drug-taking
and reinstatement reduce AMPA-receptor currents at layer 5 IL pyramidal neurons, and that VNS reverses these changes.
Systemic blockade of TrkB receptors for the brain-derived neurotrophic factor (BDNF) during extinction abolishes VNS’
effects on cue-induced reinstatement and on glutamatergic transmission in the IL. We hypothesize that extinction training
reverses drug-induced changes in synaptic AMPARs in the IL. Pairing extinction with VNS leads to (additional) BDNF release
which consolidates these changes and reduces reinstatement. In this application we will use a combination of behavioral,
electrophysiological, and celltype-specific morphological analyses to 1) further investigate the time- and circuit-specific
dysfunctional neuroadaptations in the IL that contribute to drug-seeking and relapse, and 2) to determine the mechanisms
through which VNS consolidates extinction memory to reduce relapse. Experiments in Aim 1 will use patch-clamp
electrophysiology and optogenetic stimulation of afferents from the basolateral amygdala (BLA) to the IL to determine
how these inputs are altered by drug-seeking, extinction, and VNS. We will perform voltage-clamp recordings from 2 types
of IL projection neurons (to the BLA and Nucleus accumbens shell) and determine VNS-induced changes in postsynaptic
glutamate receptor function and presynaptic release during extinction and reinstatement. These experiments will be
supported with morphological analyses in the same type of IL projection neurons to determine VNS-induced changes
specifically in cells that were activated by reinstatement (labeled by the activity marker pCREB) to test our hypothesis that
VNS preferentially modulates networks relevant in behaviors paired with VNS. In Aim 2 we will determine whether the
VNS-induced consolidation of extinction depends on endogenous BDNF levels in the IL or its inputs. To this end we will
use CRISPR/Cas9 to knock down BDNF produced either from cells within the IL or from cells in the hippocampus that
project to the IL, respectively, in order to determine how VNS-evoked BDNF modulates extinction and reinstatement.
Experiments in Aim 3 will determine...

## Key facts

- **NIH application ID:** 10764820
- **Project number:** 5R01DA055008-03
- **Recipient organization:** UNIVERSITY OF TEXAS DALLAS
- **Principal Investigator:** SVEN KROENER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $409,327
- **Award type:** 5
- **Project period:** 2022-04-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10764820

## Citation

> US National Institutes of Health, RePORTER application 10764820, Vagus nerve stimulation modulates synaptic plasticity in the rat prefrontal cortex during the extinction of drug-seeking (5R01DA055008-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10764820. Licensed CC0.

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