Hoonkyo Suh, Ph. D. - US grants

DESCRIPTION (provided by applicant): The long-term goal of this project is to map neural circuits in order to understand how adult neurogenesis accounts for cognition and mental stability, as well as how dysfunctions of neural circuits of new neurons underlie neurological, affective, addictive, and psychiatric diseases. The persistent production and incorporation of new neurons into hippocampal circuits (neurogenesis) plays a key role in learning and memory, but almost nothing is understood about how adult neurogenesis can impact and contribute to normal and pathological brains. In this application, we propose to understand the role of new neurons in cognition and emotion at the circuitry level. To understand neural circuits formed by neurogenesis in normal and pathological brains, we will determine the precise connectivity of new neurons in normal and alcoholic brains. Alcohol use disorder (AUD) is one of the most prevalent and devastating neurological and addictive disorders causing cognitive impairments. We hypothesize that chronic alcohol abuse negatively regulates proliferation and neuronal production of neural stem cells (NSCs), and that aberrant neural circuit formation of hippocampal newborn neurons may underlie cognitive and addictive behaviors of alcoholic mice. In order to understand how chronic alcohol abuse contributes to aberrant neural circuits of new neurons, we will apply a novel rabies virus-mediated retrograde transsynaptic system to determine altered brain inputs into newborn neurons. In Aim 1, we will test the hypothesis that chronic alcohol abuse disrupts proliferation and neuronal differentiation of NSCs. In Aim 2, we will test the hypothesis that chronic alcohol interferes with synapse formation of input neurons and physiological maturation of new neurons. In Aim 3, we will determine aberrant neural circuits caused by hippocampal newborn neurons in order to test the hypothesis that chronic alcohol induces abnormal circuit formation of hippocampal newborn neurons. We will particularly investigate whether chronic alcohol disrupts and reinforces circuits for cognition and addiction, respectively. In Aim 4, we will test impaired cognitive behaviors of alcoholic mice in order to understand the consequence of abnormal neural circuit formation induced by chronic alcohol exposure. These studies will provide mechanistic insights into the role of new GCs and the abnormal circuits involved in alcohol-induced behavior deficits, which will likely suggest potential therapeutic targets for AUD. Furthermore, this knowledge has direct implications for the potential therapeutic modulation of neurogenesis in a variety of brain diseases.

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.