Early neurodevelopment origins of anxiety

描述（由申请人提供）：儿童焦虑气质（AT）是发展焦虑和共病抑郁症的关键危险因素。在灵长类动物中，AT在生命早期是明显的，稳定的，并且与增加的威胁反应性相关。众所周知，早期的逆境会增加患极端AT的风险。虽然逆境是常见的，但将其与AT联系起来的神经机制尚不清楚。这种理解将允许识别新的治疗靶点，具有开发神经科学干预的潜力。这项建议 建立在验证AT表型和识别AT背后的神经回路的基础上。最近的微阵列和RNA测序（RNA-seq）工作表明，极端AT反映杏仁核中央核外侧分裂的神经可塑性缺陷的假设 (CeL)这是杏仁核流出到引起焦虑症状的区域的关键调节器，也是我们成像工作中最能预测AT的区域。这项提议旨在了解同伴养育（PR），一种受控的早期逆境操纵，如何在灵长类动物中导致极端AT，这在人类研究中是不可能的。使用灵长类动物增加了将发现转化为风险儿童的可能性。将对PR和母系饲养的动物进行纵向评估，测试逆境对AT发展的影响。重复的多模态成像将评估逆境对杏仁核反应性和前额杏仁核焦虑调节回路发展的影响。重要的是，灵长类动物模型提供了一个机会来测试逆境对AT的有害影响是否是由细胞神经可塑性通路的改变介导的。将对CeL显微切割的神经元进行免疫组织化学和RNA-seq分析。这种新的工具合成有望对逆境诱导的分子改变如何在大脑功能，连接和结构中表现出新的见解，以及这些宏观变化如何促成极端AT-分子水平的啮齿动物或系统水平的人类研究中不容易获得的见解。此外，将创建CeL GABA能神经元的干细胞模型并与来自CeL的神经元进行比较。有效的干细胞模型将增强对AT分子基础的理解，并加速新疗法的筛选。

DESCRIPTION (provided by applicant): Childhood anxious temperament (AT) is a key risk factor for developing anxiety and co- morbid depression. In primates, AT is evident early in life, stable, and associated with increased threat reactivity. Early adversity is known to increase the risk of developing extreme AT. While adversity is common, the neural mechanisms linking it to AT are not understood. This understanding would permit identification of novel therapeutic targets with the potential for developing neuroscientifically-informed interventions. This proposal builds on work validating the AT phenotype and identifying the neural circuit underlying AT. Recent microarray and RNA sequencing (RNA-seq) work suggests the hypothesis that extreme AT reflects neuroplasticity deficits in the lateral division of the central nucleus of the amygdala (CeL), a key regulator of amygdalar outflow to regions that give rise to signs of anxiety, and the region most predictive of AT in our imaging work. This proposal aims to understand how peer rearing (PR), a controlled early adversity manipulation, causes extreme AT in primates, something not possible in human studies. The use of primates increases the likelihood that discoveries will translate to at-risk children. PR and maternally- reared (MR) animals will be longitudinally assessed, testing adversity's impact on the development of AT. Repeated multimodal imaging will assess adversity's impact on the development of amygdala reactivity and prefrontal-amygdala anxiety regulation circuits. Importantly, the primate model affords an opportunity to test whether adversity's harmful effects on AT are mediated by alterations in CeL neuroplasticity pathways. Immunohistochemical and RNA-seq analyses will be performed on CeL microdissected neurons. This novel synthesis of tools promises new insights into how adversity-induced molecular alterations manifest in brain function, connectivity, and structure, and how these macroscopic changes contribute to extreme AT- insights not readily available from molecular-level rodent or systems-level human studies. Further, a stem cell model of CeL GABAergic neurons will be created and compared to neurons from CeL. A valid stem cell model would enhance understanding of AT's molecular bases and accelerate the screening of new therapeutics.