Impact of Prenatal Alcohol Exposure on CRF1R Mediated Neural Mechanisms and Social Behavior

项目摘要/摘要 胎儿酒精谱障碍是由产前酒精暴露(PAE)引起的一组不同的情况 会导致各种各样的身体、行为和智力缺陷，在一生中持续存在。 重要的是，PAE还与情绪调节缺陷有关，包括增加的非社会性和 社交焦虑症。然而，PAE诱导的神经生物学变化是这种高度脆弱性的基础 导致社交焦虑增加的原因还没有得到很好的理解。这种知识上的差距是有问题的，因为 准确了解PAE导致的神经适应对于开发有针对性的治疗方法是必要的 经历与PAE相关的社会障碍的个人。促肾上腺皮质激素释放因子的活性及其意义 杏仁中央内侧亚核(CEM)的受体(CRF1R)长期以来一直被认为是调节 焦虑样行为和CEM CRF系统功能的中断可能导致 暴露于PAE的个体的社交焦虑样行为。我们的实验室最近证明了适度的 在妊娠12天，大约在大鼠杏仁核神经发生的时候，PAE增加了社交焦虑。 与成年雄性大鼠的行为相似。此外，G12 PAE干扰CRF1R调节的抑制作用 雄性大鼠的神经传递和非社交焦虑样行为，提示适度的G12 PAE 损伤CEM CRF1R调节的成年雄性大鼠的突触和行为功能。这些赤字可能 随后改变CEM下游投射靶点的功能，如导水管周围灰质，其 是一个已知的大脑区域，负责调节防御行为，以应对威胁，包括社会威胁。这导致了 我们的中心假设的发展，适度的G12 PAE会增加社交焦虑样行为 雄性大鼠CRF1R阳性CEM-PAG投射功能下降。为了测试这一点，我们将使用 全细胞膜片钳电生理学评估神经元兴奋性和神经传递的差异 在PAG阳性的CRF1R+细胞中。此外，我们还将从化学上刺激CRF1R+CEM-PAG 在修改的社交互动测试中测试之前的投影，以产生类似社交焦虑的测量 行为。最后，我们将进一步探讨PAG是PAE引起的社会损伤的基础的可能性 通过评估在社会互动测试后男性和女性PAG中细胞激活的差异 老鼠。拟议的实验将扩大我们对PAE诱导的神经改变的理解。 机制，这些变化如何与类似社交焦虑的行为相关，并为未来提供证据 旨在调查中度PAE导致的神经适应的研究。此外，成功 完成这项提案中概述的目标将为我提供尖端技术方面的培训， 科学交流和指导，这将为我作为一名独立科学家的职业生涯做好准备。

PROJECT SUMMARY/ABSTRACT Fetal Alcohol Spectrum Disorder is a set of diverse conditions caused by prenatal alcohol exposure (PAE) that can produce a wide variety of physical, behavioral, and intellectual deficits persisting throughout the lifespan. Importantly, PAE is also associated with deficits in emotional regulation, including increased non-social and social anxiety. However, the PAE-induced neurobiological changes that underlie this heightened vulnerability to develop increased social anxiety are not well understood. This gap in knowledge is problematic because a precise understanding of neuroadaptations resulting from PAE is necessary to develop targeted treatments for individuals experiencing PAE-related social impairments. Activity of corticotropin-releasing factor (CRF) and its receptor (CRF1R) in the medial subnucleus of the central amygdala (CeM), has long been known to regulate anxiety-like behavior, and disruption of the function of the CeM CRF system could contribute to increased social anxiety-like behavior in individuals exposed to PAE. Our lab has recently demonstrated that moderate PAE on gestational day (G)12, around the time of neurogenesis in the rat amygdala, increased social anxiety- like behavior in adult male rats. Additionally, G12 PAE disrupted CRF1R modulated inhibitory neurotransmission and non-social anxiety-like behavior in male rats, suggesting that moderate G12 PAE impairs CeM CRF1R regulated synaptic and behavioral function in adult male rats. These deficits could subsequently alter the function of CeM downstream projection targets, such as the periaqueductal gray, which is a brain region known to regulate defensive behaviors in response to threats, including social threats. This led us to the development of our central hypothesis, that moderate G12 PAE increases social anxiety-like behavior due to decreased function of the CRF1R positive (+) CeM-PAG projection in male rats. To test this, we will use whole-cell patch clamp electrophysiology to assess differences in neuronal excitability and neurotransmission in PAG-projecting CRF1R+ cells. Additionally, we will chemogenetically stimulate the CRF1R+ CeM-PAG projection prior to testing in a modified social interaction test to generate a measure of social anxiety-like behavior. Finally, we will further explore the possibility that the PAG underlies PAE-induced social impairments by assessing differences in cellular activation in the PAG following social interaction testing in male and female rats. The proposed experiments will expand our understanding of PAE-induced alterations in neural mechanisms, how these alterations relate to social anxiety-like behavior, and provide evidence to inform future studies designed to investigate the neuroadaptations resulting from moderate PAE. Additionally, successful completion of the goals outlined in this proposal will provide me with training in cutting-edge techniques, science communication, and mentoring that will prepare me for a career as an independent scientist.