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 mecha...