Sunday, May 11, 2025
5/11/2025
CNS Effects of Alcohol: Cellular Neurobiology - Abstract Overall The Scripps Research Institute-Alcohol Research Center (TSRI-ARC) will focus on the cellular and molecular mechanisms that modulate top-down medial prefrontal control of the central amygdala and underlie stress- induced vulnerability to relapse and excessive drinking during protracted abstinence. Our approach consists of coordinated interdisciplinary molecular, neuroproteomic, cellular, neurocircuitry, connectomic, neuropharmacological, and behavioral methods. Specific hypotheses are: (1) Protracted abstinence involves increased vulnerability to stress-induced relapse via changes in modulatory control circuitry from the infralimbic cortex to the central nucleus of the amygdala. (2) Modulatory control changes are a function of altered glutamatergic and γ-aminobutyric acid synaptic transmission, due to actions of stress-related molecules (including hypocretin, corticotropin-releasing factor, dynorphin, and nociceptin) and astrocytic dysfunction. (3) These neurocircuitry changes are associated with altered connectivity and decreased modularity of brain networks, leading to increased vulnerability to stress-induced relapse. (4) Novel translationally relevant ligands of neurobiological targets identified by TSRI-ARC will attenuate the reinstatement of stress-induced alcohol seeking, excessive drinking, and stress-related behaviors in animal models. Our Center-wide aims will be met by 5 Research Components (Functional Connectomics, Neuropharmacology, Molecular, Neurophysiology, and Neurocircuitry), and 4 Cores (Administrative, Dissemination, Animal Models, and Neuroproteomics). The Administrative Core is organized to optimize Center-wide functioning, utilization of Core resources, and research collaborations in the Center-at-Large. TSRI-ARC is structured to promote Diversity, Equity, and Inclusion (DEI), training and career development at all levels of the Center. TSRI-ARC rapidly disseminates its discoveries to scientific, healthcare and lay stakeholders, and engages young people from health disparity backgrounds for internships in TSRI-ARC laboratories to learn about alcohol and careers in alcohol research. Center-wide Specific Aims are: (1) To characterize the cellular and molecular mechanisms that modulate top-down medial prefrontal control of the central amygdala and underlie stress-induced vulnerability to relapse and excessive drinking during protracted abstinence. (2) To understand how reversal of the cellular and molecular stress mechanisms that impair modulatory control systems can prevent stress-induced relapse and excessive drinking during protracted abstinence. (3) To evaluate the efficacy of neuropharmacological targets identified by TSRI- ARC for reversing dysregulated connectivity within and between brain stress systems and modulatory control circuits in protracted abstinence. The ultimate goal of TSRI-ARC is to positively influence public health by generating data relevant to the identification of neurobiological mechanisms mediating alcohol use disorder (AUD), and guide the translation of our basic research findings toward clinical applications to help in prevention, diagnosis, and treatment of individuals with AUD.
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