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.

产前酒精暴露（PE）导致胎儿酒精谱系障碍（FASD），其中包括许多 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，在美国和全世界，其患病率仍然很高，至少为2-5%。因此，开发有效 干预是FASD研究的一个重要目标。 持续性突触功能障碍，包括未成熟的突触是介导 FASD的认知/行为缺陷目前，这些影响的潜在机制尚不清楚。我们 已经表明PE导致成年期小胶质细胞活化和异常的内源性大麻素（eCB）信号传导。 小胶质细胞和eCB信号传导在突触的成熟、维持和调节中起关键作用。 在大脑中的功能。此外，据报道，从活化的小胶质细胞释放的eCB增加， 对抗神经炎症我们还观察到，减少小胶质细胞活化与 正常化的eCB信号传导、突触功能和PE动物中的行为。这些观察导致我们 PE诱导的持续性小胶质细胞活化导致异常紧张性eCB信号传导的中心假设， 导致突触成熟/功能障碍和行为缺陷的长期损害。这 将使用腹侧被盖区多巴胺能（VTA DA）神经元作为模型来验证假设 系统，因为这些神经元代表了研究eCB信号传导和突触的极好方法。 功能协调发展的此外，持续的小胶质细胞激活，异常的紧张性eCB信号传导，以及受损的突触 在VTA中观察到成熟/功能障碍。PE诱发的腹侧被盖区DA突触功能障碍 神经元也与明确定义的行为缺陷有关-增加成瘾风险。有三 具体目标利用多学科方法系统地验证中心假设。 目的1将彻底描述PE诱导的强直性eCB损伤的剂量和性别效应 信号传导、突触成熟/稳态和小胶质细胞活化。目标2将检验PE- 诱导的异常紧张性eCB信号传导是由激活的小胶质细胞的eCB合成/释放增加引起的。 目的3将检验减少PE动物中的小胶质细胞活化可以恢复突触的假设。 功能障碍和行为缺陷。 这些研究的结果将有助于对细胞机制的理解 介导PE的持续细胞和认知/行为缺陷。这一结果也填补了一个知识空白 关于PE如何影响神经元/小胶质细胞的相互作用，这是一个令人兴奋的新研究领域。最后 该方法采用各种旨在减少小胶质细胞活化以拯救细胞和行为的方法， 由PE引起的缺陷。因此，这些结果可以很容易地转化为FASD的干预策略。