Alcohol-induced neurogenesis

描述（由申请人提供）：该项目的长期目标是绘制神经回路图，以了解成人神经发生如何解释认知和精神稳定性，以及新神经元的神经回路功能障碍如何成为神经、情感、成瘾和精神疾病的基础。新神经元的持续产生和整合到海马回路中（神经发生）在学习和记忆中起着关键作用，但关于成人神经发生如何影响和促进正常和病理大脑，我们几乎一无所知。在这个应用中，我们建议在电路水平上理解新神经元在认知和情感中的作用。为了了解正常和病理大脑中神经发生形成的神经回路，我们将确定正常和酗酒大脑中新神经元的精确连接。酒精使用障碍（AUD）是导致认知障碍的最普遍和最具破坏性的神经和成瘾性疾病之一。我们假设慢性酒精滥用对神经干细胞（NSCs）的增殖和神经元生成产生负性调节，并且海马新生神经元的异常神经回路形成可能是酒精小鼠认知和成瘾行为的基础。为了了解慢性酒精滥用如何导致新生神经元的神经回路异常，我们将应用一种新的狂犬病毒介导的逆行跨突触系统来确定新生神经元的大脑输入改变。在目的1中，我们将检验慢性酒精滥用破坏NSCs增殖和神经元分化的假设。在Aim 2中，我们将检验慢性酒精干扰输入神经元突触形成和新神经元生理成熟的假设。在Aim 3中，我们将确定由海马新生神经元引起的异常神经回路，以检验慢性酒精诱导海马新生神经元异常回路形成的假设。我们将特别研究慢性酒精是否会破坏和加强认知和神经回路

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.