Engagement of novel noradrenergic and CRF circuit interactions by chronic alcohol

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DESCRIPTION (provided by applicant): Alcoholism is a vexing health problem accounting for 2.5 million deaths per year around the world, representing the third largest risk factor for global disease. Alcoholism is the number one leading risk factor for disease in the United States, as an estimated 43% of men and 28% of women can be classified as binge drinkers and about 7% of Americans are considered alcoholics. One of the major issues facing the treatment of alcoholism is the high rate (50-90%) of relapse. Finding new strategies for the treatment of alcoholism is my major long-term career goal. Long-term stress vulnerability and reduced capacity to control drinking are hallmarks of alcoholism and determining the causes of these symptoms may lead to better treatments strategies. These enduring dysfunctions likely result from equally enduring changes in key neuronal pathways involved in stress and reward signaling, such as the bed nucleus of the stria terminalis (BNST). Corticotropin releasing factor (CRF) signaling within the BNST plays a key role in negative reinforcement-based enhancement of alcohol drinking induced by chronic alcohol exposure. This system may also play an important role in the inability of alcoholics to limit drinking and in their propensity for relapse However, the mechanism by which chronic alcohol recruits this important pathway at the intersection of stress and reward signaling remains unclear. Determining the mechanisms by which chronic alcohol exposure alters BNST signaling in my current short-term goal. In this proposal we will use a combination of cutting edge neuroscience techniques to determine how BNST-CRF neurocircuitry is integrated with alcohol sensitive brain regions in the naive state and examine how chronic alcohol exposures disrupts this connectivity. Accumulating evidence suggests that increased norepinephrine transmission in the BNST may play a critical role in the enhancement of BNST-CRF signaling during alcohol withdrawal. Our previous findings indicate that alpha- adrenergic receptors activation generally decreases BNST excitability while beta-adrenergic receptors activation can depolarize BNST-CRF neurons and promote increased BNST excitability. Therefore, alpha- and beta-adrenergic receptors may balance the overall effect of norepinephrine on BNST activity. In a related brain region, the basolateral amygdala, alpha/beta-adrenergic receptors also balance norepinephrine modulation of neuronal activity and stress can shift this balance towards increased beta-adrenergic receptor excitation. Since chronic alcohol exposure is a stress, chronic alcohol may shift the alpha/beta -adrenergic balance to promote norepinephrine mediated excitation of BNST-CRF neurons during withdrawal. We will explore this hypothesis in Aim 1 of this proposal in a novel transgenic CRF reporter mouse using a combination of optogenetic, electrophysiological, and pharmacologic approaches. Dendritic spines play a key role in the regulation of afferent-specific plasticity and chronic drug exposure can alter dendritic spine morphology. However little is known about how chronic alcohol may alter BNST-CRF neuron dendritic spines. We propose that chronic alcohol may induce long-term adaptations in the dendritic architecture of BNST-CRF neurons that may "lock in" enduring BNST-CRF neuron excitability. This hypothesis will be examined in Aim 2 using a novel combination of electrophysiological and neuroanatomical approaches. These two aims will involve the development of new scientific skills "marrying" the selective examination of regulatory influences onto BNST-CRF neurons with studies examining the form and function of this neuronal population critical to the development of alcoholism. This work will be mentored by leaders in the fields of alcoholism (Dr. Danny Winder) and neuroanatomy (Dr. Ariel Deutch) at Vanderbilt University School of Medicine, a world-renowned biomedical research institution. While these two aims will allow for a better understanding of how norepinephrine transmission may recruit BNST-CRF circuitry during chronic alcohol, little is known about how chronic alcohol modulates the source of this norepinephrine signaling. Recent evidence suggests that neurons in the nucleus of the tractus solitarius (NTS) are the main source of norepinephrine transmission in the BNST, but these neurons have yet to be directly examined in the context of alcoholism. The independent phase of this proposal will determine if norepinephrine neurons in the NTS, particularly those neurons that project to the BNST, are modulated by acute and chronic alcohol. This work will set the stage for independent research program aimed at determining how BNST-projecting NTS- norepinephrine neurons regulate alcohol seeking during the development of alcoholism. This integrative approach is a novel way to examine mechanisms of neuropathology in alcoholism and may lead to the development of better treatment strategies to alleviate this debilitating disease.