Role of Microglia in Prenatal ethanol exposure-induced Impairment of Endocannabinoid Signaling

小胶质细胞在产前乙醇暴露引起的内源性大麻素信号传导损伤中的作用

• 批准号: 10708739
• 负责人: ROH-YU SHEN
• 金额: $ 36.65万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708739
• 关键词: Adult; Animals; Area; Attention; Behavior; Behavioral; Biological Models; Brain; Chronic; Cognitive; Cognitive deficits; Data; Development; Dose; Endocannabinoids; Excitatory Synapse; Executive Dysfunction; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Functional disorder; Goals; High Prevalence; Homeostasis; Impairment; Inhibitory Synapse; Intervention; Knowledge; Lead; Learning Disabilities; Literature; Maintenance; Mediating; Methods; Microglia; Minocycline; Mood Disorders; Morphology; Neurodevelopmental Disorder; Neurons; Physiological; Play; Population; Prevalence; Rattus; Regulation; Reporting; Research; Risk; Role; Study models; Synapses; Testing; Translating; Ventral Tegmental Area; addiction; dopaminergic neuron; effective intervention; endocannabinoid signaling; experimental study; glial activation; interdisciplinary approach; male; neuroinflammation; neurotransmission; neurotransmitter release; perinatal alcohol exposure; receptor; sex; synaptic function

Prenatal ethanol exposure (PE) leads to fetal alcohol spectrum disorders (FASD), which consist of many cognitive/behavioral deficits including learning disabilities, attention and executive function deficits, increased addiction risk, and mood disorders. FASD is the most preventable neurodevelopmental disorder, yet the prevalence is still high which is at least 2-5% in the US and the world. Therefore, developing effective interventions is an important goal for FASD research. Persistent synaptic dysfunctions including immature synapses are critical cellular mechanisms mediating cognitive/behavioral deficits in FASD. Currently, the underlying mechanisms for these effects are not clear. We have shown PE leads to microglial activation and aberrant endocannabinoid (eCB) signaling during adulthood. Both microglia and eCB signaling play a critical role in the maturation, maintenance, and regulation of synaptic functions in the brain. Furthermore, increased eCB release from activated microglia has been reported to counter neuroinflammation. We have also observed that reducing microglial activation is associated with normalized eCB signaling, synaptic functions, and behaviors in PE animals. These observations lead to our central hypothesis that PE-induced persistent microglial activation leads to aberrant tonic eCB signaling, which contributes to long-lasting impairments in synaptic maturation/dysfunctions and behavioral deficits. This hypothesis will be verified using the ventral tegmental area dopaminergic (VTA DA) neurons as a model system because these neurons represent an excellent approach for studying eCB signaling and synaptic functions. Furthermore, persistent microglial activation, aberrant tonic eCB signaling, and impaired synaptic maturation/dysfunctions have been observed in the VTA. The PE-induced synaptic dysfunctions of VTA DA neurons are also associated with a clearly defined behavioral deficit - increased addiction risk. There are three Specific Aims utilizing multidisciplinary approaches to systematically verify the central hypothesis. Aim 1 will thoroughly characterize the dose and sex effects of PE-induced impairments in tonic eCB signaling, synaptic maturation/homeostasis, and microglial activation. Aim 2 will test the hypothesis that PE- induced aberrant tonic eCB signaling is caused by increased eCB synthesis/release from activated microglia. Aim 3 will test the hypothesis that reducing microglial activation in PE animals can restore synaptic dysfunctions and behavioral deficits. The results of the proposed studies will lead to important understanding in the cellular mechanisms mediating the persistent cellular and cognitive/behavioral deficits of PE. The results also fill a knowledge gap regarding how PE impacts the neuron/microglia interaction, a new exciting area of research. Lastly, the approach employs various methods aiming at reducing microglial activation to rescue cellular and behavioral deficits induced by PE. Therefore, the results can be readily translated to intervention strategies for FASD.

产前乙醇暴露（PE）导致胎儿酒精谱系（FASD），其中许多 认知/行为缺陷，包括学习障碍，注意力和执行功能缺陷， 增加成瘾风险和情绪障碍。 FASD是最可预防的神经发育障碍， 然而，流行率仍然很高，在美国和世界上至少占2-5％。因此，发展有效 干预是FASD研究的重要目标。 持续的突触功能障碍，包括未成熟突触是介导的关键细胞机制 FASD中的认知/行为缺陷。当前，这些影响的基本机制尚不清楚。我们 已显示PE导致成年期间的小胶质细胞激活和异常内源性大麻素（ECB）信号传导。 小胶质细胞和欧洲央行信号在突触的成熟，维持和调节中都起着至关重要的作用 大脑的功能。此外，据报道，从活化小胶质细胞中释放的欧洲央行释放增加了 反神经炎症。我们还观察到，减少小胶质激活与 PE动物中的欧洲央行信号传导，突触功能和行为。这些观察导致了我们 中心假设，即PE诱导的持续的小胶质细胞激活导致异常欧洲央行信号传导，这 有助于突触成熟/功能障碍和行为缺陷的长期障碍。这 假设将使用腹侧对段区域多巴胺能（VTA DA）神经元作为模型进行验证 系统，因为这些神经元代表了研究欧洲央行信号和突触的极好方法 功能。此外，持续的小胶质细胞激活，异常的欧洲央行信号传导和突触受损 在VTA中观察到成熟/功能障碍。 VTA DA的PE诱导的突触功能障碍 神经元还与明确定义的行为不足 - 增加成瘾风险有关。有三个 具体的目的是利用多学科方法系统地验证中心假设。 AIM 1将彻底表征PE诱导的损害在补品ECB中的剂量和性别影响 信号传导，突触成熟/稳态和小胶质激活。 AIM 2将检验以下假设。 诱导的异常欧洲央行信号传导是由活化小胶质细胞的欧洲央行合成/释放增加引起的。 AIM 3将检验以下假设：减少PE动物中的小胶质细胞激活可以恢复突触 功能障碍和行为缺陷。 拟议的研究结果将导致在细胞机制中的重要理解 介导PE的持续性细胞和认知/行为缺陷。结果还填补了知识差距 关于PE如何影响神经元/小胶质细胞相互作用，这是一个新的令人兴奋的研究领域。最后， 方法采用各种旨在减少小胶质激活来挽救细胞和行为的方法 PE引起的缺陷。因此，结果可以很容易地转化为FASD的干预策略。