Synaptic plasticity and microglial-synapse interactions after developmental alcohol exposure

 描述(由申请人提供)：胎儿酒精谱系障碍(FASD)是导致非遗传性精神残疾的主要原因。全球发病率从活产儿的1%到7%不等，没有可用的治疗方法。在妊娠期接触乙醇(Etoh)后，FASD患者一生都在与许多认知功能作斗争，包括学习、记忆、视觉处理、注意力、规划、语言和运动技能。这种广泛的缺陷表明，乙醇可能通过一种共同的机制扰乱了整个大脑的神经网络。乙醇对发育中的神经元的急性毒性作用一直是FASD研究的主要焦点。关于对胶质细胞的影响，特别是在早期接触乙醇后，胶质细胞与幸存神经元的相互作用可能长期处于扰动状态，人们了解较少。小胶质细胞是大脑中常见的常驻免疫细胞，是对环境侮辱、感染或损伤的第一反应细胞，因此可能对乙醇非常敏感。除了病理之外，小胶质细胞还具有生理作用，对于神经元网络在整个生命过程中的维持和可塑性至关重要。在健康的大脑中，高运动性的小胶质突起经常与突触上的神经元相互作用，影响被称为树突的兴奋性突触后位置的物理重构和周转。我将测试这一假设，即发育中的乙醇暴露对小胶质细胞的生理功能有长期影响，损害小胶质细胞与神经元的相互作用，从而导致神经网络可塑性缺陷。我将在人类妊娠晚期高剂量乙醇暴露的小鼠模型中检验这一假设，目标是大脑生长激增(BGS)。BGS是强烈突触发生和神经元网络初步形成的时期，在此期间，发育中的大脑可能特别容易受到乙醇的影响。使用青春期的单眼剥夺(MD)来诱导眼优势可塑性(ODP)，我将测量剥夺眼向非剥夺眼的神经元反应的变化(目标1)。初步数据显示，在BGS Etoh后，ODP值的诱导受到损害，这表明早期接触Etoh会导致活性依赖的突触可塑性的长期缺陷。为了探索这种缺陷的机制，我将研究BGS乙醇对树突棘结构动力学的影响(目标2)以及小胶质细胞的生理和免疫行为(目标3)。这些互补但独立的目标旨在评估青春期持续的可塑性损害是否源于1)特定树突棘亚群周转的变化2)小胶质细胞突起运动性的变化3) 小胶质细胞对局灶性组织损伤的迁移反应4)小胶质细胞-突触相互作用异常。拟议的研究将提高我们对FASD认知功能障碍的理解，并有可能为新的治疗策略提供信息。

 DESCRIPTION (provided by applicant): Fetal Alcohol Spectrum Disorder (FASD) is the leading cause of non-heritable mental disability. Global prevalence ranges from 1% to 7% of live births, with no available treatment. After gestational exposure to ethanol (EtOH), FASD patients struggle throughout life with many cognitive functions, including learning, memory, visual processing, attention, planning, language, and motor skills. This broad range of deficits suggests that EtOH may disrupt neural networks throughout the brain via a common mechanism. The acutely toxic effects of EtOH on developing neurons have been a primary focus of FASD research. Less is understood about effects on glia, particularly how glial interactions with surviving neurons may remain perturbed long-term after early-life EtOH exposure. Microglia, resident immune cells found throughout the brain, are the first responders to environmental insult, infection, or injury, and thus may be exquisitely sensitive to EtOH. Outside of pathology, microglia also have physiological roles that are critical for the maintenance and plasticity of neuronal networks throughout life. In the healthy brain, highly motile microglial processes frequently interact with neurons at synapses, influencing the physical remodeling and turnover of excitatory postsynaptic sites called dendritic spines. I will test the hypothesis that developmental EtOH exposure has long-term effects on the physiological functions of microglia, impairing microglial interactions with neurons, thus leading to deficits in neural network plasticity. I will examine this hypothesis in a mouse model of human third trimester high binge EtOH exposure, targeting the brain growth spurt (BGS). The BGS is period of intense synaptogenesis and initial formation of neuronal networks during which the developing brain may be particularly vulnerable to EtOH. Using monocular deprivation (MD) in adolescence to induce ocular dominance plasticity (ODP), I will measure shifts in neuronal responses from the deprived eye toward the non-deprived eye (Aim 1). Preliminary data show that the induction of ODP is impaired after BGS EtOH, indicating that early-life EtOH exposure causes a long-term deficit in activity-dependent synaptic plasticity. To explore mechanisms that underlie this deficit, I will investigate the effects of BGS EtOH on the structural dynamics of dendritic spines (Aim 2) as well as the physiological and immune behaviors of microglia (Aim 3). These complementary yet independent aims are designed to assess whether enduring impairments in plasticity during adolescence could stem from 1) alterations in the turnover of specific dendritic spine subpopulations 2) changes in microglial process motility 3) differences in the migratory response of microglia toward focal tissue injury 4) abnormal microglia-synapse interactions. The proposed research will improve our understanding of cognitive dysfunction in FASD, with the potential to inform novel treatment strategies.