The role of hippocampal neurogenesis in alcohol withdrawal seizure and cognition

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Abstract Alcohol withdrawal (AW) after chronic alcohol exposure produces a series of symptoms. Among them, generalized tonic-clonic seizures and impairments in cognition and emotion are the most severe and dangerous symptoms. Despite alcohol’s aversive effects, alcohol’s positive- reinforcing effects of euphoria, anxiolysis, and reduction in pain and seizures dramatically increase the vulnerability to relapse and alcohol abuse. The severity and susceptibility to relapse and perpetuation of alcohol abuse underscore the urgent need to understand mechanisms underlying alcohol dependence and withdrawal in order to develop new therapeutic strategies to intervene and treat AW-associated syndromes. In this application, we will test the novel hypothesis that structural and functional changes in hippocampal newborn dentate granule cells (DGCs) underlie the development and maintenance of AW-associated physiological and psychological dysfunctions. DGCs are continuously produced and integrate into hippocampal neural circuits, and this process has been implicated in seizures, as well as cognitive and emotional function. The central goal of this proposal is to use novel, genetic methods for mapping and understanding hippocampal neural circuits that are responsible for maladaptation during alcohol exposure and withdrawal. In Aim 1, we will determine whether AW alters synaptic, neuronal, and functional connectivity of DGCs by using structural, electrophysiological, and rabies virus-mediated mapping methods. In Aim 2, to test the essential role of newborn DGCs in AW- induced seizure expression, we will use a DREADD (Designer Receptors Exclusively Activated by Designer Drugs) method and produce models with gain-of-function and loss-of-function in newborn DGCs. Using this method, we will assess whether specific activation and inhibition of newborn DGCs will enhance and decrease AW seizures, respectively. In Aim 3, we will determine whether altered activity of newborn DGCs is responsible for deficits in cognition and emotion during abstinence. Our studies will unveil the essential function of hippocampal newborn DGCs in AW syndromes at the level of neural circuits and provide a critical foundation for understanding and treating AW-induced physiological and psychological dysfunctions.