Hypothalamic oxytocin influence on extended amygdala CRF neurons in alcohol dependence

University Of Tennessee Health Sci Ctr, Memphis TN

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Abstract

PROJECT SUMMARY/ABSTRACT Alcohol Use Disorder (AUD) is a chronic relapsing disorder characterized by compulsive seeking and consumption of alcohol, the result of a transition from recreational use to misuse to AUD. Most AUD sufferers do not receive treatment, and current medications do not work for all patients, highlighting the need for new therapeutics. AUD induces heightened activity of brain stress systems, resulting in the negative affective state associated with withdrawal. The neuropeptide oxytocin (OT) is anti-stress, and systemic administration of OT decreases withdrawal symptom severity and drinking in people with AUD. The central amygdala (CeA) and bed nucleus of the stria terminalis (BNST) are two brain regions considered to be hubs for stress processing, and the role of pro- and anti-stress neuropeptides in these brain regions are critical for the development of AUD. Synaptic activity in the CeA and BNST is sensitive to acute alcohol, and plays a critical role in the behavioral effects of ethanol consumption. The CeA and BNST are rich in neuropeptides and their receptors, including corticotropin releasing factor (CRF) and OT, and ethanol’s effects on synaptic signaling in these regions may be modulated by neuropeptide activity. CRF is involved in the heightened stress and anxiety associated with AUD during withdrawal, and blocking CRF activity in the CeA and BNST can reduce alcohol drinking. Thus, the balance between anti- and pro-stress signaling is likely perturbed during the transition to AUD, characterized by an overactive CRF system. OT producing neurons in the paraventricular and supraoptic nuclei of the hypothalamus project to both the CeA and BNST, to specific subdivisions that contain CRF neurons. Thus, OT may act directly on CRF neurons of the CeA and BNST to decrease withdrawal severity and alcohol drinking. For this Diversity Supplement, Emaya Moss (candidate), will contribute to experiments within all Aims of the parent grant. Initially, Emaya will receive training from the PI in the techniques necessary for this research, including ex vivo slice whole-cell patch clamp electrophysiology, molecular biology techniques, the chronic intermittent ethanol (CIE) vapor dependence model, stereotaxic surgeries, chemogenetics, and alcohol drinking behavior. Once Emaya has learned a technique, she will begin to work on experiments incorporating that technique while training in additional techniques. As such, she will perform research into the connectivity of OT and CRF neurons, intrinsic properties and synaptic function of these neurons, how these circuits are disrupted by CIE vapor dependence, how these circuits contribute to alcohol drinking, and any sex differences within these measures. In addition, throughout the remaining parent grant period, Emaya will finish her graduate coursework, attend weekly journal clubs and lab meetings, and will also have weekly mentorship meetings with the PI focused on publications, grants, awards, conference presentations, workshops, etc. to ensure she is prepared to take on the next steps toward a career as an independent researcher in academia.