Presynaptic structure and function in ethanol tolerance development

乙醇耐受发展中的突触前结构和功能

• 批准号: 10194238
• 负责人: FREDERICK W WOLF
• 金额: $ 20.93万
• 依托单位: UNIVERSITY OF CALIFORNIA, MERCED
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10194238
• 关键词: Acute; Affect; Alcohols; Animal Model; Applications Grants; Architecture; Behavior; Behavioral; Brain; Code; Complex; Desire for food; Development; Dopamine; Dose; Drosophila genus; Electrophysiology (science); Ethanol; Foundations; Future; Genes; Goals; Hour; Human; Individual; Interneurons; Learning; Link; Maintenance; Mammals; Measures; Memory; Microscopy; Modeling; Molecular; Molecular Genetics; Mushroom Bodies; Neuromodulator; Neurons; Neurotransmitters; Outcome Study; Output; Pathway interactions; Physiological; Property; Proteins; Recurrence; Regulation; Relapse; Research; Resistance; Resolution; Rewards; Role; Signal Transduction; Site; Structure; Synapses; Synaptic Vesicles; Synaptic plasticity; Testing; Transgenic Organisms; Withdrawal; addiction; alcohol effect; alcohol exposure; alcohol reward; alcohol risk; alcohol use disorder; behavioral plasticity; drinking; experience; experimental study; fly; nanoarchitecture; neural circuit; novel strategies; preference; presynaptic; reinforcer; response; targeted treatment; tool; vesicular release

Project Summary / Abstract A single acute ethanol exposure causes lasting changes in behavior and brain function. Acute changes may form a foundation for progressive changes with subsequent ethanol exposures, incrementally increasing the risk of alcohol use disorder. We found evidence of structural changes in presynaptic active zones in neurons that promote behavioral plasticity (tolerance, preference, and reward), in response to acute ethanol in Drosophila. In mammals there is much evidence for electrophysiological and circuit driven changes in presynaptic activity in models of AUD. However, molecular changes at presynapses remain difficult to measure, making assessment of the mechanistic coding of plasticity incomplete. Advances in Drosophila transgenics and microscopy resolution let us determine the effects of ethanol on evolutionarily conserved presynaptic architecture. We hypothesize that presynaptic changes contribute to the coding of ethanol-induced behavioral plasticity, to bias the behavioral and circuit effects of subsequent ethanol exposures. The goal of this exploratory grant proposal is to gain a mechanistic handle on ethanol-induced presynaptic change in Drosophila. The long-term goal is to develop a new approach towards understanding how alcohol changes the structure and function of the brain, that can be applied across a variety of model organisms for addiction research, and combined with rigorous physiological and circuit-level understanding. To accomplish our goal, we will perform three independent experiments. First, We will ask how widespread presynaptic plasticity is found in the seats of Drosophila learning and memory. Second, we will ask about the role of presynaptic plasticity genes in ethanol-induced presynaptic change. Third, we will ask if presynaptic change is due to a property of the circuitry upstream and downstream of the sites of change. We predict that the study outcome will define specific presynaptic sites that show ethanol-induced plasticity. This information will allow us to explore the functional role of synapse assembly and maintenance pathways, and homeostatic versus Hebbian mechanisms, taking into account the neurotransmitter and neuromodulator synaptic profiles.

项目总结/摘要 单次急性乙醇暴露会导致行为和大脑功能的持久变化。急性变化可能 形成一个基础，为渐进的变化与随后的乙醇暴露，逐步增加 酒精使用障碍的风险。我们发现神经元突触前活动区的结构变化的证据 促进行为可塑性（耐受性，偏好和奖励），以响应急性乙醇， 果蝇在哺乳动物中，有许多证据表明，电生理和电路驱动的变化， AUD模型中的突触前活动。然而，突触前的分子变化仍然很难解释。 措施，使评估的机械编码的可塑性不完整。果蝇研究进展 转基因和显微镜分辨率让我们确定乙醇对进化保守的影响 突触前结构我们假设突触前的变化有助于乙醇诱导的神经元的编码。 行为可塑性，偏向随后的乙醇暴露的行为和电路的影响。的目标 这项探索性的拨款提案是为了获得乙醇诱导的突触前变化的机械处理， 果蝇长期目标是开发一种新的方法来了解酒精如何改变 大脑的结构和功能，可以应用于各种成瘾模型生物 研究，并结合严格的生理和电路水平的理解。为了实现我们的目标， 我们将进行三个独立的实验。首先，我们将探讨突触前可塑性有多普遍 在果蝇学习和记忆的座位上发现的。第二，我们将探讨突触前神经元的作用， 可塑性基因在乙醇诱导的突触前变化中的作用。第三，我们会问突触前的变化是否是由于 改变位点的上游和下游电路的性质。我们预测研究结果 将定义特定的突触前位点，显示乙醇诱导的可塑性。这些信息将使我们能够 探索突触组装和维持途径的功能作用，以及稳态与赫布 机制，考虑到神经递质和神经调质突触概况。