2016 — 2017 |
Kirson, Dean |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Oxytocin Effects On Gabaergic Signaling in the Alcohol Dependent Cea. @ Scripps Research Institute
PROJECT SUMMARY/ABSTRACT Alcoholism is a chronic disorder described by compulsive seeking and consumption of alcohol, the result of a transition from recreational alcohol use to abuse and dependence. Alcohol dependence and withdrawal are characterized by negative emotional states resulting from recruited brain stress systems. The amygdalar nuclei, in particular the central amygdala (CeA), are considered a hub for negative emotional circuitry, and the role of pro- and anti-stress neuropeptides in this brain structure is critical for the development of alcohol dependence. The CeA contains primarily GABAergic neurons, and the inhibitory synapses are very sensitive to acute ethanol and play a critical role in the behavioral effects of acute and chronic ethanol consumption. Pro- stress neuropeptides like corticotropin releasing factor (CRF) have been found to enhance GABAergic transmission in the CeA, while anti-stress neuropeptides like nociceptin/orphanin FQ (N/OFQ) and neuropeptide Y (NPY) decrease GABAergic transmission. The balance between anti- and pro-stress signaling is perturbed during the transition to alcohol dependence, characterized by an overactive CRF system. Importantly, one anti-stress neuropeptide, oxytocin (OT), has been shown to decrease drinking and block withdrawal symptoms when administered to human alcoholics. However, no studies have investigated the effects of OT and its interactions with ethanol on the GABAergic system in the CeA. Therefore, the goal of this proposal is to characterize the effects of OT on CeA GABAergic signaling, its interactions with acute ethanol and the potential neuroadaptations induced by ethanol dependence in the OT system, using electrophysiological techniques. The data generated by this project will elucidate the mechanisms of action of OT in the CeA and provide important information to the neuronal changes that contribute to the transition from recreational alcohol consumption to alcohol dependence, and could lead to the development of better therapeutics in the treatment of alcoholism.
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0.904 |
2019 — 2020 |
Kirson, Dean |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. |
Hypothalamic Oxytocin Influence On Extended Amygdala Crf Neurons in Alcohol Dependence @ Scripps Research Institute
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.
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0.904 |