Antoine G. Almonte, PhD - US grants

Summary Although considerable progress has been made in identifying brain regions and neural substrates that contribute to the etiology of alcohol use disorder (AUD), translating these discoveries into effective treatments has proven difficult. Recent methodological advances in the field of neuroscience have revealed that many of the brain regions that contribute to AUD are not comprised of homogenous neuronal populations but, instead, contain distinct subpopulations of neurons with unique afferent and efferent connections. The overarching scientific premise of this application is that a better understanding of the specific neural pathways that are dysregulated in AUD may lead to the identification of better targets for the development of more effective treatments for this disorder. The basolateral amygdala (BLA) is a brain region that is known to play an integral role in AUD. Although considerable evidence suggests that chronic ethanol leads to BLA hyperexcitability and that this increased excitability contributes to elements of the negative affective state that develops in withdrawal (e.g. anxiogenesis), the specific BLA circuits responsible for these maladaptive behaviors are not fully understood. Preliminary rodent data from our lab demonstrate that chemogenetic silencing of an excitatory projection from the BLA to the ventral hippocampus (vHC) reduces anxiety-like behaviors and ethanol drinking and that withdrawal following a well-established rodent model of ethanol dependence (chronic intermittent ethanol vapor, CIE) promotes increases in synaptic excitability in the vHC. Based on these recent findings, the experiments in this application will integrate chemogenetic, optogenetic, electrophysiological and behavioral approaches to test the hypothesis that CIE promotes increases in BLA-vHC excitability and that this adaptation contributes to the negative affective state that manifests in withdrawal. A secondary hypothesis, based on emerging literature, will determine if females are less sensitive to the behavioral and neurobiological consequences of CIE. Collectively, these pilot studies will provide a critical foundation for a comprehensive study that will more fully characterize the role of the BLA-vHC in the negative affective state that develops following CIE, identify neurobiological mechanisms through which CIE promotes increases in BLA-vHC excitability, and seek to develop novel pharmacotherapies that can reverse these maladaptive CIE-associated alterations.