# Neurophysiology Component - Roberto

> **NIH NIH P60** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $208,981

## Abstract

Abstract  
 
Our TSRI-ARC has focused on preclinical work on the cellular, neurochemical, and molecular mechanisms of
alcohol dependence, with a major interest in the role of the central nucleus of the amygdala (CeA) in excessive
alcohol drinking. However, there  is  a  great  need  to  understand  the  mechanisms  that  mediate  dependence-­
induced  drinking  motivated  directly  by  withdrawal/abstinence  symptoms.  The  Neurophysiology  Project  will 
continue  to  study  the  neuroadaptations  induced  by  alcohol  dependence  in  the  CeA,  and  will  now  investigate 
upstream neuronal circuits that are responsible for dysregulation of the CeA during alcohol abstinence.
Corticotropin-­releasing factor (CRF) and CRF1 receptors are involved in the ethanol-­induced increase in GABA 
release in the CeA and the CRF system is upregulated after ethanol dependence. Chronic CRF1 antagonism 
blocked  alcohol  dependence-­induced  increases  in  ethanol  consumption.  Notably,  the  transition  to  alcohol 
dependence also dysregulates executive function, and the infralimbic (IL) subdivision of the mPFC exerts “top-­
down” control over the amygdala to regulate emotional aspects of goal-­directed behaviors. Thus, this renewal 
application  focuses  on  the  overall  hypothesis  that  ethanol  dependence  and  withdrawal  are  driven  by  the 
recruitment of CRF and serotonin (5-­HT) signaling in cortical-­amygdala circuits. We will study neural function 
during  ethanol  abstinence  and  characterize  how  long  those  neuroadaptive  changes  persist.  In  particular,  our 
goal  is  to  characterize  neuroadaptations  in  the  CRF  and  5-­HT  systems  and  their  effects  in  the  CeA  and  IL 
through  common  cellular  systems  to  induce  a  maladaptation  in  neural  function  that  promotes  ethanol 
withdrawal-­induced anxiety-­like behavior. Our project is designed to test the hypothesis that dependence and 
withdrawal (early withdrawal = 2-­8 h;; late withdrawal = 2 weeks) differentially alter responses to 5-­HT and CRF 
in CeA neurons (Specific Aim 1) and will affect the excitability of IL pyramidal neurons in layer V that project to 
the  CeA  (Specific  Aim  2).  Finally,  Specific  Aim  3  will  electrophysiologically  assess  the  ethanol-­induced 
synaptic  and  molecular  mechanisms  of  candidate  drugs  that  are  identified  and  tested  in  preclinical  animal 
models  (Contet  and  Animal  Models  Core)  and  subsequently  tested  in  the  clinical  component  (Mason).  The 
project  will  use  IL  and  CeA  brain  slices  and  standard  whole-­cell  patch-­clamp  and  cell-­attached 
electrophysiological methods, as well as measures of protein levels and chemogenetic and behavioral testing 
that  will  involve  continued  collaboration  with  the  George/Zorrilla,  Contet,  Martin-­Fardon,  and  Mason  projects 
and Animal Models Core. It is imperative to provide data that elucidate the cellular basis of the susceptibility of 
a...

## Key facts

- **NIH application ID:** 9836779
- **Project number:** 5P60AA006420-37
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** MARISA ROBERTO
- **Activity code:** P60 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $208,981
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9836779

## Citation

> US National Institutes of Health, RePORTER application 9836779, Neurophysiology Component - Roberto (5P60AA006420-37). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9836779. Licensed CC0.

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