Binge alcohol drinking, the most common form of excessive alcohol consumption, contributes to a host of long- term negative health consequences, including the development of alcohol dependence. Repeated episodes of binge drinking drive subsequent alcohol consumption, therefore characterizing the neural circuitry underlying this risky behavior is essential to the development of successful pharmacotherapeutic treatments for alcohol use disorders. The bed nucleus of the stria terminalis (BNST) is critically involved in alcohol drinking and stress-induced relapse of drug seeking. The BNST is enriched with neurons that produce and release corticotropin-releasing factor (CRF), a neuropeptide that has also been shown to regulate these behaviors. However, the specific roles of BNST CRF neurons and their synaptic inputs in binge alcohol drinking have not been examined. I hypothesize that the activity of BNST CRF neurons drives binge alcohol drinking, and that repeated episodes of binge drinking dysregulate their function by enhancing the activity of glutamatergic neurons that directly modulate them. The goals of this proposal are 1) to characterize the roles of BNST CRF neurons and their glutamatergic inputs from the paraventricular nucleus of the thalamus (PVT) in alcohol drinking behavior, and 2) to examine how this neural circuit is altered by repeated cycles of binge drinking. During the K99 phase, I will be trained by Dr. Stuber in the use of in vivo optogenetics, and I will employ in vivo optogenetic and chemogenetic approaches to drive or inhibit the activity of CRF neurons in the BNST and evaluate alcohol drinking behaviors. During the R00 phase, I will use techniques that Dr. Kash has given me extensive training in, including neuronal tracing techniques and slice electrophysiology in combination with ex vivo optogenetics, to characterize and assess the strength of the PVT glutamatergic projection to BNST CRF neurons. Then, I will use in vivo optogenetics to evaluate the causal roles of these pathways in binge alcohol drinking. Finally, I will use ex vivo optogenetics, slice electrophysiology, and immunohistochemistry to examine the effects of repeated binge alcohol drinking on the intrinsic excitability of and synaptic function o BNST CRF neurons and glutamatergic neurons in the PVT that modulate them. Together, these studies will integrate my expertise in slice electrophysiology and immunohistochemistry with training in in vivo optogenetics essential to a making a successful transition to an independent research career. Experiments in this proposal will thoroughly characterize how crucial nodes of circuitry that regulate binge alcohol drinking are altered by repeated binge alcohol drinking, which may reveal pharmacotherapeutic targets for the treatment of alcohol use disorders.
Binge alcohol drinking confers a tremendous burden onto society, as it contributes to many long-term negative health outcomes including alcoholism and mood disorders. The research proposed here will characterize the role of a specific neuronal population and the discrete neural circuits that regulate its function in binge alcohol drinking, and it will examine how this circuit is dysregulated by chronic alcohol drinking. This may lead to the identification of successful therapeutic targets for the treatment of alcohol use disorders.
| Pleil, Kristen E; Skelly, Mary Jane (2018) CRF modulation of central monoaminergic function: Implications for sex differences in alcohol drinking and anxiety. Alcohol 72:33-47 |
| Radke, Anna K; Jury, Nicholas J; Kocharian, Adrina et al. (2017) Chronic EtOH effects on putative measures of compulsive behavior in mice. Addict Biol 22:423-434 |
