# Activation of the parasubthalamic nucleus in alcohol dependence

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $435,375

## Abstract

SUMMARY
Alcohol use disorders are in part characterized by the loss of control over alcohol drinking and the emergence
of negative emotionality during abstinence from alcohol. While the brain regions and neurotransmitter systems
affected by chronic alcohol exposure are well characterized, our understanding of the specific neural circuits
driving drinking escalation and negative affect during withdrawal remains limited. We have generated data
indicating that neurons located in the parasubthalamic nucleus (PSTN), a small region of the posterior lateral
hypothalamus whose function in addiction is currently unknown, may be a critical component of this circuitry.
Specifically, we show that chemogenetic stimulation of PSTN neurons expressing the neuropeptide corticotropin-
releasing factor (CRF) replicates the behavioral symptomatology of withdrawal and that PSTN neurons become
activated in ethanol-dependent mice experiencing withdrawal. A first aim of this proposal is to explore the
mechanisms underlying the phenotypes resulting from the chemogenetic activation of PSTN CRF neurons. We
will evaluate the contribution of PSTN neurons projecting to the central nucleus of the amygdala (as opposed to
other targets of the PSTN) and the role of CRF signaling (as opposed to other neurotransmitters co-released by
PSTN CRF neurons). Another goal is to test the hypothesis that the PSTN is a critical node of the neuronal
network driving the behavioral symptomatology of ethanol withdrawal. We will determine whether the activation
of PSTN neurons is necessary to the expression of withdrawal symptoms in dependent mice, whether it drives
the activation of downstream central amygdala neurons, and which neurotransmitter is implicated. Finally, we
aim to understand how PSTN neurons become activated during ethanol withdrawal. We will use retrograde
tracing combined with c-Fos mapping as well as electrophysiological recordings to investigate the mechanisms
controlling the activity of PSTN neurons in the context of ethanol withdrawal. Throughout the project, we will
leverage state-of-the-art genetic tools for the functional manipulation of specific neural pathways, local silencing
of gene expression and neuronal mapping, along with whole-brain imaging. In addition, we will use a well-
validated mouse model of ethanol dependence that we have refined with novel measures of affective
perturbation. Altogether, the proposed experiments are designed to enhance our understanding of the neural
circuitry that contributes to motivational and emotional dysfunction in alcohol use disorders and may provide
novel avenues for the development of more efficacious treatments.

## Key facts

- **NIH application ID:** 9899906
- **Project number:** 5R01AA026685-03
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Candice Contet
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $435,375
- **Award type:** 5
- **Project period:** 2018-05-10 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899906

## Citation

> US National Institutes of Health, RePORTER application 9899906, Activation of the parasubthalamic nucleus in alcohol dependence (5R01AA026685-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9899906. Licensed CC0.

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