Synaptic plasticity and microglial-synapse interactions after developmental alcohol exposure

发育酒精暴露后的突触可塑性和小胶质细胞突触相互作用

• 批准号: 9271806
• 负责人: Elissa Wong
• 金额: $ 3.61万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9271806
• 关键词: Acute; Adolescence; Adolescent; Affect; Alcohols; Attention; Behavior; Biological Neural Networks; Brain; Cells; Chronic; Cognition; Data; Dendritic Spines; Development; Excitatory Synapse; Exhibits; Exposure to; Eye; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Growth; Human; Image; Immune; Immunoelectron Microscopy; Impaired cognition; Impairment; Infection; Injury; Language; Lead; Learning; Life; Literature; Live Birth; Long-Term Effects; Maintenance; Measures; Mediating; Memory; Microglia; Microscopy; Modeling; Morphology; Motor Skills; Mus; Neuroglia; Neuroimmune; Neuronal Plasticity; Neurons; Ocular Dominance; Optics; Pathology; Patients; Phagocytosis; Phase; Physiological; Physiological Processes; Pregnancy; Prevalence; Process; Psyche structure; Research; Role; Signal Transduction; Site; Somatosensory Cortex; Structure; Synapses; Synaptic plasticity; Testing; Third Pregnancy Trimester; Tissues; Toxic effect; Vertebral column; Visual; Visual Cortex; alcohol consumption during pregnancy; alcohol effect; alcohol exposure; alcohol measurement; cell motility; cognitive disability; cognitive function; critical period; density; design; disability; early life exposure; effective therapy; emergency service responder; experience; immune function; improved; in vivo; insight; migration; monocular deprivation; mouse model; novel; postnatal; postsynaptic; public health relevance; response; stem; synaptogenesis; therapy development; treatment strategy; two-photon; visual processing

 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.

 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。全球活产患病率为 1% 至 7%，且尚无可用的治疗方法。妊娠期接触乙醇 (EtOH) 后，胎儿酒精谱系障碍 (FASD) 患者一生中许多认知功能都会受到影响，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乙醇可能通过一种常见的机制破坏整个大脑的神经网络。乙醇对神经元发育的急性毒性作用一直是 FASD 研究的主要焦点。人们对神经胶质细胞的影响知之甚少，特别是在生命早期接触乙醇后，神经胶质细胞与存活神经元的相互作用如何可能长期受到干扰。小胶质细胞是遍布大脑的常驻免疫细胞，是对环境侵害、感染或损伤的第一反应者，因此可能对乙醇极其敏感。除了病理学之外，小胶质细胞还具有对于整个生命过程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，高度活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部位的物理重塑和周转。我将验证以下假设：发育过程中接触乙醇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大量暴饮乙醇暴露的小鼠模型中检验这一假设，目标是大脑生长突增 (BGS)。 BGS 是突触发生和神经元网络初始形成的时期，在此期间发育中的大脑可能特别容易受到乙醇的影响。在青春期使用单眼剥夺 (MD) 来诱导眼优势可塑性 (ODP)，我将测量从被剥夺的眼睛到非被剥夺的眼睛的神经元反应的变化（目标 1）。初步数据表明，BGS EtOH 后 ODP 的诱导受到损害，这表明生命早期的 EtOH 暴露会导致活动依赖性突触可塑性的长期缺陷。为了探索这种缺陷背后的机制，我将研究 BGS EtOH 对树突棘结构动力学（目标 2）以及小胶质细胞的生理和免疫行为（目标 3）的影响。这些互补但独立的目标旨在评估青春期可塑性的持久损伤是否可能源于 1) 特定树突棘亚群周转的改变 2) 小胶质细胞过程运动的变化 3) 小胶质细胞对局灶性组织损伤的迁移反应4）异常的小胶质细胞-突触相互作用。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。