The role of hippocampal neurogenesis in alcohol withdrawal seizure and cognition

海马神经发生在酒精戒断癫痫和认知中的作用

• 批准号: 10380860
• 负责人: Hoonkyo Suh
• 金额: $ 49.42万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-10 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10380860
• 关键词: 3-Dimensional; Abstinence; Alcohol Withdrawal Seizures; Alcohol abuse; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; American; Anxiety; Axon; Behavior; Behavioral; Brain; Chronic; Cognition; Dangerousness; Data; Dendritic Spines; Dependovirus; Development; Electron Microscopy; Electrophysiology (science); Emotions; Epilepsy; Euphoria; Foundations; Functional disorder; Genetic; Genetic study; Goals; Hippocampus (Brain); Hour; Human; Impaired cognition; Impairment; Label; Maintenance; Maps; Mediating; Memory impairment; Methods; Modeling; Nature; Neurons; Newborn Infant; Outcome; Pain; Pathogenesis; Pharmacology; Physical Function; Physiological; Predisposition; Process; Psyche structure; Rabies virus; Relapse; Retroviridae; Role; Seizures; Series; Severities; Structure; Symptoms; Synapses; Syndrome; Testing; Tonic - clonic seizures; Vertebral column; alcohol abstinence; alcohol effect; alcohol exposure; alcohol relapse; associated symptom; cognitive function; density; designer receptors exclusively activated by designer drugs; emotional functioning; excitatory neuron; experience; experimental study; gain of function; granule cell; inhibitory neuron; loss of function; mental function; mouse model; neural circuit; neural network; neuroadaptation; neurogenesis; newborn neuron; novel; novel therapeutic intervention; presynaptic; presynaptic neurons; psychologic

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.

抽象的 慢性酒精暴露后，酒精戒断（AW）产生一系列符号。之中 他们是认知和情感中广义的强直性癫痫发作和障碍是最大的 尽管酒精的厌恶作用，但酒精还是阳性的 - 欣快症，抗焦虑分析以及疼痛和癫痫发作的减轻的增强作用 增加对救济和酗酒的脆弱性。救济的严重性和敏感性 酗酒的永久性强调了迫切需要了解机制 为了制定新的治疗策略的基本酒精依赖和提取 干预并治疗与AW相关的综合征。在此应用程序中，我们将测试小说 假设海马新生儿牙齿颗粒细胞的结构和功能变化 （DGC）基于AW相关生理学的发展和维护 心理功能障碍。 DGC连续生产并整合到海马 神经回路，并且在癫痫发作以及认知和认知和 情绪功能。该提案的核心目标是使用新颖的遗传方法进行映射 并了解负责在 酒精暴露和戒断。在AIM 1中，我们将确定AW是否改变了突触， 通过使用结构，电生理和狂犬病，DGC的神经元和功能连通性 病毒介导的映射方法。在AIM 2中，测试新生儿DGC在AW中的重要作用 诱导的癫痫发作表达，我们将使用dreadd（设计器受体专门激活 设计师药物）方法和生产模型，具有功能获得和功能丧失 新生儿DGC。使用这种方法，我们将评估特定的激活和抑制 新生儿DGC将分别增强和减少癫痫发作。在AIM 3中，我们将确定 新生儿DGC的活动改变是否导致认知和情感缺陷 戒酒期间。我们的研究将揭示海马新生儿DGC的基本功能 在神经回路级别的AW综合症中，为理解提供了关键的基础 并治疗AW引起的生理和心理功能障碍。