The role of hippocampal neurogenesis in alcohol withdrawal seizure and cognition

摘要 酒精戒断（AW）在慢性酒精暴露后会产生一系列症状。之间 其中，全身性强直阵挛发作和认知情感障碍最多 严重和危险的症状。尽管酒精有负面影响，但它是积极的- 增强欣快、抗焦虑、减轻疼痛和癫痫发作的效果， 增加复发和酗酒的可能性。复发的严重程度和易感性 和酗酒的长期存在强调迫切需要了解机制， 潜在的酒精依赖和戒断，以开发新的治疗策略， 干预和治疗AW相关综合征。在这个应用程序中，我们将测试小说 新生海马齿状回细胞结构和功能变化假说 （DGC）是AW相关生理和 心理障碍DGC持续产生并整合到海马 神经回路，这一过程与癫痫发作有关，以及认知和 情感功能这项建议的中心目标是使用新的遗传方法来绘制地图 并了解海马神经回路，负责适应不良， 酒精暴露和戒断。在目标1中，我们将确定AW是否改变突触， 通过使用结构，电生理和狂犬病的DGC神经元和功能连接 病毒介导的作图方法。在目的2中，为了测试新生DGC在AW中的重要作用， 诱导癫痫发作的表达，我们将使用DREADD（设计师受体独家激活 通过Designer Drugs）方法，并产生功能获得和功能丧失的模型， 新生儿DGC使用这种方法，我们将评估是否特异性激活和抑制 新生儿DGC将分别增强和减少AW发作。在目标3中，我们将确定 新生儿DGC活性的改变是否是认知和情感缺陷的原因 在禁欲期间我们的研究将揭示海马新生DGC的基本功能 在AW综合征的神经回路水平，并提供了一个重要的基础，了解 以及治疗AW引起的生理和心理功能障碍。

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.