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.

项目摘要/摘要 胎儿酒精谱系障碍是由产前酒精暴露（PAE）引起的一组不同的疾病 可以在整个生命周期中产生各种各样的身体，行为和智力缺陷。 重要的是，PAE还与情绪调节的缺陷有关，包括增加非社会和 社交焦虑。但是，PAE引起的神经生物学变化是这种增加的脆弱性的基础 为了发展增加社交焦虑尚未得到充分理解。知识差距是有问题的，因为 必须精确理解对由PAE产生的神经照顾的理解，以开发针对性的治疗方法 遇到与PAE相关的社会障碍的个人。皮质激素释放因子（CRF）及其活性 中央杏仁核（CEM）的内侧亚核中的受体（CRF1R）长期以来一直在调节 类似焦虑的行为以及CEM CRF系统功能的破坏可能有助于增加 暴露于PAE的个体中的社交焦虑行为。我们的实验室最近证明了中等 在大鼠杏仁核神经发生的时候，妊娠日（g）12的pae增加了社交焦虑 - 像成年男性大鼠的行为一样。另外，G12 PAE破坏了CRF1R调制的抑制作用 雄性大鼠的神经传递和非社会焦虑行为，表明中等G12 PAE 破坏成年​​雄性大鼠的CEM CRF1R调节的突触和行为功能。这些赤字可能 随后改变CEM下游投影靶标的功能，例如周围的灰色，该灰色 是一个大脑区域，该地区旨在根据威胁（包括社会威胁）来调节防御行为。这引发了 我们为中心假设的发展发展，中等的G12 PAE增加了社交焦虑般的行为 由于雄性大鼠的CRF1R阳性（+）CEM-PAG投影的功能降低。为了测试这一点，我们将使用 全细胞贴片夹电生理学评估神经元兴奋性和神经传递的差异 在PAG投射CRF1R+细胞中。此外，我们将在化学上刺激CRF1R+ CEM-PAG 在经过修改的社交互动测试中进行测试之前投影，以产生类似社交焦虑的度量 行为。最后，我们将进一步探讨PAG是PAE引起的社会障碍的可能性 通过评估男性和女性社交相互作用测试后PAG中细胞激活的差异 老鼠。提出的实验将扩大我们对PAE诱导的神经变化的理解 机制，这些变化与社交焦虑般的行为有何关系，并提供证据以告知未来 旨在研究中等PAE引起的神经适应的研究。另外，成功 该提案中概述的目标的完成将为我提供尖端技术的培训， 科学沟通和指导，这将使我成为独立科学家的职业。