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

产前酒精暴露对 CRF1R 介导的神经机制和社会行为的影响

• 批准号: 10751645
• 负责人: Kelcie Schatz
• 金额: $ 6.91万
• 依托单位: STATE UNIVERSITY OF NY,BINGHAMTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751645
• 关键词: Address; Adult; Adult Children; Affect; Air; Alcohol consumption; Amygdaloid structure; Anxiety; Anxiety Disorders; Behavior; Behavioral; Brain region; Cells; Central Medial Thalamic Nucleus; Communication; Corticotropin-Releasing Hormone; Development; Electrophysiology (science); Enterobacteria phage P1 Cre recombinase; Experimental Designs; FOS gene; Female; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal Development; Fetal alcohol effects; Future; Genetic; Glutamates; Goals; Impairment; Individual; Investigation; Knowledge; Learning; Longevity; Measures; Medial; Mediating; Mentors; Mus; Neurobiology; Neurons; Pattern; Persons; Physiology; Pre-Clinical Model; Prefrontal Cortex; Pregnancy; Rattus; Regulation; Reporting; Research Design; Research Personnel; Role; Science; Scientist; Social Behavior; Social Functioning; Social Interaction; Stains; Synapses; System; Techniques; Testing; Time; Training; United States; alcohol exposure; antagonist; anxiety-like behavior; anxiety-related behavior; career; cell type; design; emotion regulation; experimental study; gamma-Aminobutyric Acid; in utero; in vivo; male; midbrain central gray substance; neural circuit; neuroadaptation; neurobiological mechanism; neurogenesis; neuromechanism; neuronal excitability; neurotransmission; novel; offspring; patch clamp; prenatal experience; receptor; response; skills; social; social anxiety; social defeat; social influence; synaptic function; therapy development; transmission process

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.

项目概要/摘要 胎儿酒精谱系障碍是由产前酒精暴露 (PAE) 引起的一系列不同病症， 可能会造成终生持续的各种身体、行为和智力缺陷。 重要的是，PAE 还与情绪调节缺陷有关，包括非社交和情绪调节的增加。 社交焦虑。然而，PAE 引起的神经生物学变化是这种脆弱性加剧的基础 社交焦虑增加的原因尚不清楚。这种知识差距是有问题的，因为 准确了解 PAE 引起的神经适应对于开发针对 PAE 的针对性治疗方法是必要的 患有 PAE 相关社交障碍的个人。促肾上腺皮质激素释放因子（CRF）的活性及其 中央杏仁核 (CeM) 内侧亚核中的受体 (CRF1R) 长期以来一直被认为可以调节 焦虑样行为以及 CeM CRF 系统功能的破坏可能会导致 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，适度 妊娠日 (G)12 的 PAE，大约在大鼠杏仁核神经发生的时间，社交焦虑增加 - 类似成年雄性大鼠的行为。此外，G12 PAE 破坏了 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，表明中度 G12 PAE 损害成年雄性大鼠 CeM CRF1R 调节的突触和行为功能。这些赤字可能 随后改变 CeM 下游投影目标的功能，例如导水管周围灰质， 是一个众所周知的调节防御行为以应对威胁（包括社会威胁）的大脑区域。这导致 我们的中心假设的发展，即适度的 G12 PAE 会增加社交焦虑样行为 由于雄性大鼠中 CRF1R 阳性 (+) CeM-PAG 投射的功能下降。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 投射的 CRF1R+ 细胞中。此外，我们将以化学遗传学方式刺激 CRF1R+ CeM-PAG 在修改后的社交互动测试中进行测试之前进行预测，以生成类似社交焦虑的测量值 行为。最后，我们将进一步探讨 PAG 是 PAE 引起的社交障碍的可能性 通过评估男性和女性社交互动测试后 PAG 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，这些改变如何与社交焦虑样行为相关，并为未来提供证据 旨在调查中度 PAE 引起的神经适应的研究。此外，成功 完成本提案中概述的目标将为我提供尖端技术的培训， 科学传播和指导将使我为独立科学家的职业生涯做好准备。