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）是非遗传性精神残疾的主要原因。全球流行率为活产婴儿的1%至7%，没有可用的治疗方法。在妊娠期暴露于乙醇（EtOH）后，FASD患者一生都在许多认知功能方面挣扎，包括学习，记忆，视觉处理，注意力，计划，语言和运动技能。这种广泛的缺陷表明EtOH可能通过一种共同的机制破坏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。对神经胶质的影响了解较少，特别是神经胶质与存活神经元的相互作用如何在早期生活EtOH暴露后长期保持扰动。小胶质细胞，在整个大脑中发现的常驻免疫细胞，是对环境损伤，感染或损伤的第一反应者，因此可能对EtOH非常敏感。在病理学之外，小胶质细胞还具有对整个生命中神经元网络的维持和可塑性至关重要的生理作用。在健康的大脑中，高度能动的小胶质细胞过程经常与突触处的神经元相互作用，影响称为树突棘的兴奋性突触后位点的物理重塑和周转。我将测试这一假设，即发育EtOH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的缺陷。我将在人类妊娠晚期高酒精暴露的小鼠模型中研究这一假设，目标是大脑生长突增（BGS）。BGS是强烈的突触发生和神经元网络的初始形成的时期，在此期间，发育中的大脑可能特别容易受到EtOH的影响。使用单眼剥夺（MD）在青春期诱导眼优势可塑性（ODP），我将测量神经元反应的变化，从剥夺的眼睛向非剥夺的眼睛（目的1）。初步数据显示，ODP的诱导受损后BGS乙醇，表明早期生活乙醇暴露导致活动依赖性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 EtOH对树突棘的结构动力学（目的2）以及小胶质细胞的生理和免疫行为（目的3）的影响。这些互补但独立的目的旨在评估青春期可塑性的持久损伤是否源于1）特定树突棘亚群的转换改变2）小胶质细胞过程运动性的变化3） 小胶质细胞向局部组织损伤的迁移反应4）异常的小胶质细胞-突触相互作用。这项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.