Dependence-Induced Excessive Ethanol Consumption: Role of Corticostriatal Kv7 Channels

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ABSTRACT This is an application for a Mentored Research Scientist Development Award (K01) to support the career development and intensive training of Dr. Jennifer Rinker to facilitate her transition to an independent academic investigator in the alcohol research field. The candidate is an early-stage investigator transitioning from Postdoctoral Fellow to Assistant Professor. Dr. Rinker has extensive experience with in vivo pharmacology and chemogenetic manipulations to study the neural circuitry involved in alcohol use disorder, but has limited experience with slice electrophysiology and advanced molecular techniques to examine plasticity-related events. An intense and comprehensive training, mentoring and research plan has been developed that will provide training in advanced techniques to assess Kv7 channel involvement in alcohol dependence-induced changes in functional plasticity. Dr. Rinker's training will be supported by a firm institutional commitment to her career development and a strong mentoring team of leaders in the alcohol research field, each providing strategic guidance in both the development of this proposal and mentoring as her career progresses. The proposed research plan is a natural extension of the recent studies Dr. Rinker has been conducting in the mentor's laboratory, but is distinguished by its examination of Kv7 channels in discrete corticostriatal circuits in modulating the effects of dependence-induced ethanol consumption. The medial prefrontal cortex (mPFC) is a critical structure involved in imposing inhibitory control over reward-motivated behaviors and projects to the nucleus accumbens (NAc), an essential component of the mesolimbic reward pathway. Ethanol dependence is associated with elevated and uncontrolled drinking and is known to alter the plasticity and physiology of mPFC pyramidal neurons. Specifically, ethanol withdrawal results in the hyperexcitability of NAc-projecting mPFC neurons, the underlying mechanism of which remains unknown. Kv7 channels generate the M-current that critical regulates neuronal excitability by maintaining the membrane potential and dampening neuronal firing. These channels have been implicated in regulating ethanol consumption in the NAc, but their role in the corticostriatal circuits in dependent rodents remains unexplored. Thus, the overarching hypothesis of this proposal is that dependence-induced neuroadaptations in Kv7 channels in the corticostriatal circuitry (i.e., mPFC to NAc) drive the escalated and uncontrolled ethanol consumption in dependence. This proposal will test this hypothesis using a multifaceted approach incorporating subcellular analysis of protein expression and analysis of structural and functional plasticity using diolistic labeling and slice electrophysiology, respectively. Our results demonstrating involvement of Kv7 channels in heavy drinking and dependent mice suggests that continuing these studies will significantly advance our understanding of the cellular mechanisms underlying ethanol dependence. This opportunity will provide the candidate with comprehensive training and a solid foundation on which to build a successful and independent research program in the alcohol neuroscience field.