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Neurophysiology

At The Scripps Research Institute Alcohol Research Center, we're dedicated to understanding the complex ways our brains contribute to alcohol addiction. One of our key projects focuses on a specific part of the brain called the infralimbic cortex. We believe changes in this area may make individuals more likely to drink excessively, especially under stress or during withdrawal from alcohol. Our research is exploring how stress and the body's response to stress can affect this part of the brain and lead to a strong urge to consume alcohol. By studying the brain's wiring and how it changes with alcohol use, we aim to find new ways to help people combat addiction. This advanced work involves a wide range of techniques, from examining the electrical activity of brain cells to analyzing proteins, to better understand how the brain functions during addiction and recovery. Through collaboration within our center and utilizing our state-of-the-art resources, we're working to unveil the mysteries of addiction and pave the way for new treatments.

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Neurophysiology
Aims

The Neurophysiology Project will test the hypothesis that dysfunction of the infralimbic (IL) subdivision of the mPFC contributes to the negative affect that drives withdrawal-induced drinking. We predict that IL pyramidal neurons that project to CeA (IL->CeA) 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. Mechanistically, we anticipate that ethanol dependence and abstinence produce an imbalance between brain stress (e.g., CRF) and anti-stress [e.g., nociceptin/orphanin FQ (N/OFQ)] systems within the IL->CeA circuitry.

Our preliminary data support that the IL->CeA neurons represent a subset of neurons with unique electrophysiological properties and responsiveness to chronic ethanol. Thus, we will investigate 1) the mechanisms mediating N/OFQ and CRF modulation of IL function and 2) the unique electrophysiological properties of the IL->CeA neurons and their role in the behavioral symptomatology of ethanol withdrawal.

We will use ex vivo electrophysiology and proteomics of circuit-defined IL->CeA neurons, in situ hybridization, protein assays, neuronal tracing, chemogenetics, and behavioral testing.

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Integration with Center: We will elucidate the role of IL->CeA projections in the negative-affect symptoms associated with ethanol withdrawal (with Zorrilla); provide mechanistic insight for CRF/KOR and hypocretin studies (with Martin-Fardon) and the mechanism of actions of candidate translational drugs tested by the Contet and George Components. We will utilize extensively the Animal Core (Roberts) and Neuroproteomics Core (Yates) will conduct proteomic analyses.

Marisa Roberto

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Michal Bajo

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