Alcohol-induced neurogenesis

酒精诱导的神经发生

• 批准号: 8921110
• 负责人: Hoonkyo Suh
• 金额: $ 34.59万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-05 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8921110
• 关键词: Accounting; Addictive Behavior; Affect; Affective; Alcohol abuse; Alcoholic Intoxication; Alcohols; Animals; Behavior; Behavioral; Brain; Brain Diseases; Cells; Chronic; Cognition; Cognitive; Dendritic Spines; Development; Disease; Dorsal; Emotions; Functional disorder; Glutamates; Goals; Health; Hippocampal Formation; Hippocampus (Brain); Impaired cognition; Impairment; Kinetics; Knowledge; Lead; Learning; Maps; Mediating; Memory; Mental disorders; Mus; Neurodegenerative Disorders; Neurologic; Neuronal Differentiation; Neurons; Parahippocampal Gyrus; Pattern; Physiological; Play; Process; Production; Proliferating; Property; Psyche structure; Rabies virus; Resolution; Role; Specific qualifier value; Specificity; Synapses; Synaptic Transmission; System; Testing; Therapeutic; addiction; adult neurogenesis; alcohol behavior; alcohol effect; alcohol exposure; alcohol use disorder; base; cognitive function; conditioned fear; dentate gyrus; functional disability; granule cell; insight; mouse model; nerve stem cell; nervous system disorder; neural circuit; neurogenesis; newborn neuron; novel; problem drinker; stem cell fate; synaptogenesis; therapeutic target; tool; virus genetics

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.

描述(申请人提供)：这个项目的长期目标是绘制神经回路图，以了解成人神经发生是如何解释认知和精神稳定性的，以及新神经元的神经回路功能障碍如何导致神经、情感、成瘾和精神疾病。新神经元的持续产生和整合到海马神经元回路(神经发生)在学习和记忆中发挥着关键作用，但几乎没有人了解成人神经发生如何影响和促进正常和病理的大脑。在这一应用中，我们建议在电路水平上理解新神经元在认知和情绪中的作用。为了了解正常和病理大脑中神经发生形成的神经回路，我们将确定正常和酒精中毒大脑中新神经元的精确连接。酒精使用障碍(AUD)是最普遍和最具破坏性的神经和成瘾疾病之一，会导致认知障碍。我们假设，慢性酒精滥用对神经干细胞(NSCs)的增殖和神经元产生具有负面调节作用，而海马区新生神经元神经回路的异常形成可能是酒精中毒小鼠认知和成瘾行为的基础。为了了解慢性酒精滥用如何影响新神经元的异常神经回路，我们将应用一种新的狂犬病病毒介导的逆行突触系统来确定新生神经元的大脑输入的变化。在目标1中，我们将检验长期酗酒破坏神经干细胞增殖和神经元分化的假说。在目标2中，我们将检验长期酒精干扰输入神经元的突触形成和新神经元的生理成熟的假设。在目标3中，我们将确定由海马新生神经元引起的异常神经回路，以验证慢性酒精诱导海马新生神经元异常回路形成的假说。我们将特别调查长期饮酒是否会扰乱和加强认知回路和 分别是上瘾。在目的4中，我们将测试酒精中毒小鼠的认知行为，以了解慢性酒精暴露导致的神经回路形成异常的后果。这些研究将提供对新的GC的作用和涉及酒精诱导的行为缺陷的异常回路的机械性见解，这可能会为AUD的潜在治疗靶点提供建议。此外，这一知识对多种脑部疾病中神经发生的潜在治疗调节有直接影响。