# Neurophysiology Component - Roberto

> **NIH NIH P60** · SCRIPPS RESEARCH INSTITUTE, THE · 2024 · $219,627

## Abstract

Abstract
Protracted withdrawal is characterized by negative emotional symptoms and their alleviation is a driving force
for continued alcohol consumption. Our TSRI-ARC focuses on identifying the enduring neuroadaptations in the
brain stress systems that drive relapse. In rats with ethanol dependence, an overactivation of the central nucleus
of the amygdala (CeA) is driven by recruitment of the corticotropin-releasing factor (CRF) and CRF1 receptors
(CRF1). Nociceptin/orphanin FQ (N/OFQ) peptide and its receptor (NOP) exert anti-stress effects by
counteracting the function of endogenous CRF in CeA. The infralimbic (IL) subdivision of the mPFC exerts “top-
down” control over the amygdala to regulate emotional aspects of goal-directed behaviors. Our main hypothesis
is that dysfunction of mPFC contributes to the negative affect that drives withdrawal-induced drinking. We predict
that IL pyramidal neurons that project to CeA (ILàCeA) may normally inhibit ethanol seeking and drinking under
stress, a function that is compromised (decreased) in AUD, rendering subjects vulnerable to stress-induced
negative urgency for ethanol. Preliminary chemogenetic data from Zorrilla’s component point to a causal role of
rat ILàCeA inhibition in negative affect. Moreover, Martin-Fardon’s component showed that intra-IL CRF1 or
hypocretin/orexin (Hcrt) antagonist infusion reduced stress-induced reinstatement of ethanol seeking in rats.
These peptides are highly expressed in IL, but their interplay is understudied. The Neurophysiology Project
(Lead: Roberto; Co-Lead: Bajo) will elucidate the mechanisms and neurotransmitters that disrupt IL functions
and identify the ILàCeA role in these behavioral phenotypes. We will test the hypothesis that ethanol
dependence [induced by chronic intermittent ethanol (CIE)] and abstinence produce an imbalance between brain
stress (e.g., CRF) and anti-stress (e.g., N/OFQ) systems within the ILàCeA circuitry. Here we show that 1) CRF
decreases spontaneous GABA release but increases glutamate release onto layer V IL pyramidal neurons of
naïve male rats, 2) the CRF-associated reduction of GABA release onto ILàCeA neurons is stronger than onto
other IL neurons. Our preliminary data support that the ILàCeA neurons represent a subset of neurons with
unique electrophysiological properties and responsiveness to dependence/withdrawal that account for a
decrease in ILàCeA connectivity. Moreover, CRF-induced facilitation of glutamate release and firing are
opposed by N/OFQ in the IL. Thus, this proposal will a) investigate the mechanisms mediating N/OFQ and CRF
modulation of overall IL function (Specific Aim 1) and b) will unveil the unique electrophysiological properties of
IL pyramidal neurons that project to CeA and their role in negative behavioral symptomatology of ethanol
withdrawal (Specific Aim 2). This project will use ex vivo electrophysiology and proteomics of circuit-defined
neurons, protein assays, in situ hybridization, neuronal tracing...

## Key facts

- **NIH application ID:** 10757673
- **Project number:** 5P60AA006420-41
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** MARISA ROBERTO
- **Activity code:** P60 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $219,627
- **Award type:** 5
- **Project period:** 1983-12-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10757673

## Citation

> US National Institutes of Health, RePORTER application 10757673, Neurophysiology Component - Roberto (5P60AA006420-41). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10757673. Licensed CC0.

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