The effects of alcohol on synaptic plasticity in the visual system

描述（由申请人提供）：酗酒是我们社会的一个长期问题。饮酒会导致饮酒者和饮酒母亲未出生的后代的大脑回路发生改变。这些变化可能会持续很长时间，并严重影响大脑功能。事实上，1%的儿童出生时患有胎儿酒精谱系障碍，这是由于产前酒精暴露导致的神经衰弱症状。虽然我们认识到突触功能障碍通常与认知障碍有关，并且在酒精滥用期间也观察到突触功能障碍，但我们对完整大脑中突触变化的动态进展及其机制知之甚少。我们假设发育性酒精暴露会导致小胶质细胞对突触动力学的异常调节，从而导致突触可塑性的缺陷。利用能够实时观察体内细胞形态的成像技术，我们第一次可以在单个突触的水平上观察大脑皮层网络在发育过程中暴露于酒精后的重新布线，并直接检查这种重新布线的全新机制。在我们的实验室里，这些强大的技术已经提供了大量关于体内突触功能的信息，但还没有应用于酒精对大脑影响的研究。为了确定酒精治疗期间突触功能障碍如何影响正常的可塑性，我们将以视觉系统为模型，并将我们目前对小鼠眼优势可塑性的研究作为这些实验的参考点。使用这些方法，我们将测试以下情景：早期酒精暴露会影响小胶质细胞-突触的相互作用，破坏突触结构的稳定，并导致对视觉刺激的反应可塑性降低。我们将在胎儿酒精综合征的孕晚期暴露小鼠模型（目的1）中量化酒精诱导的结构突触可塑性的关键方面，并在该系统中测定视觉可塑性（目的2）。我们将使用体内功能的结合

DESCRIPTION (provided by applicant): Alcohol abuse is a chronic problem in our society. Alcohol consumption can lead to alterations of brain circuitry both in drinkers and in the unborn offspring of drinking mothers. These changes can be long lasting and severely affect brain function. In fact, 1% of children are born with fetal alcohol spectrum disorder due to prenatal alcohol exposure with debilitating neurological symptoms. While it is appreciated that synaptic dysfunction is often associated with cognitive disorders and is observed during alcohol abuse, very little is known about the dynamic progression of synaptic changes and their mechanisms in the intact brain. We hypothesize that developmental alcohol exposure leads to abnormal regulation of synaptic dynamics by microglia leading to deficits in synaptic plasticity. Using imaging techniques which allow real time visualization of cellular morphology in vivo, we can, for the first time, visualize the rewiring of cortical networks in brains upon exposure to alcohol during development at the level of a single synapse and directly examine entirely novel mechanisms of this rewiring. These powerful techniques have already provided a wealth of information on the function of synapses in vivo in our laboratory, but have not been applied to the study of alcohol's effects on the brain. In order to determine how synaptic dysfunction during alcohol treatment impacts normal plasticity, we will use the visual system as a model and our current studies on ocular dominance plasticity in the mouse as the reference point for these experiments. Using these methods, we will test the following scenario: early alcohol exposure affects microglia-synapse interactions, destabilizes synaptic structure and leads to reduced plasticity in response to visual stimuli. We will quantify key aspects of alcohol- induced structurl synaptic plasticity in a third trimester exposure mouse model of fetal alcohol syndrome (Aim 1), and assay visual plasticity in this system (Aim 2). We will use a combination of in vivo functional and structural 4D imaging with histological, molecular and genetic tools which will provide unique insights into the synaptic changes that occur following early alcohol exposure. PUBLIC HEALTH RELEVANCE: Project narrative The structure of synapses is crucial to the proper functioning of the nervous system and changes in this structure are observed during brain development, learning, and in many neurological disorders. In this study we will explore how synapse structure and microglial behavior is altered in a mouse model of fetal alcohol syndrome, a devastating disorder which is accompanied by severe mental retardation. We will also determine whether dendritic spines and microglia can be therapeutic targets in the treatment of fetal alcohol syndrome.