Hypothalamic oxytocin influence on extended amygdala CRF neurons in alcohol dependence

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PROJECT SUMMARY/ABSTRACT Alcoholism is a chronic relapsing disorder characterized by compulsive seeking and consumption of alcohol, the result of a transition from recreational use to abuse and dependence. Most alcoholics do not receive treatment, and current medications do not work for all sufferers, highlighting the need for new therapeutics. Alcohol dependence 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 alcoholics. 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 alcohol dependence. 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 alcohol dependence and 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 alcohol dependence, 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. This project will characterize hypothalamic OT neuronal input to CRF neurons of the CeA and BNST, whether these circuits are disrupted by alcohol dependence, and involvement of these circuits in alcohol dependence induced drinking. Viral vector mediated expression of fluorescent markers and Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) will allow for electrophysiological and molecular characterization of OT circuits in the CeA and BNST, and behavioral testing of OT circuit involvement in alcohol dependence induced alcohol drinking. Experimental studies will begin during the K99 phase, and will be completed during the R00 phase at a new institution in the principal investigator’s (PI) independent laboratory. Towards this career goal, during the K99 phase, the PI will train under the mentorship team in new techniques including the use of viral vector based protein expression and synaptic tracing, immunohistochemistry, in situ hybridization, and behavioral pharmacology to complement the PI’s experience with electrophysiology. During the R00 phase, the mentorship team will help establish these techniques in the PI’s independent laboratory to ensure continuity and reproducibility of the research plan. Collectively, this work will provide insight into the role of OT as a potential therapeutic in treating alcohol and stress/anxiety disorders.