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的关键危险因素。在灵长类动物中，AT在生命早期就很明显，很稳定，并与威胁反应性的增加有关。众所周知，早期的逆境会增加患极端AT的风险。虽然逆境很常见，但将其与AT联系起来的神经机制尚不清楚。这一理解将使识别新的治疗靶点具有开发神经科学知情干预措施的潜力。这项建议 建立在验证AT表型和识别AT背后的神经回路的工作基础上。最近的微阵列和RNA测序(RNA-seq)工作表明，假设极端AT反映了杏仁中央核外侧分裂的神经可塑性缺陷 杏仁核(CEL)是杏仁核流出到引起焦虑迹象的区域的关键调节因子，也是我们成像工作中对AT最具预测性的区域。这项建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的AT，这在人类研究中是不可能的。灵长类动物的使用增加了发现转化为高危儿童的可能性。将对PR和母养(MR)动物进行纵向评估，测试逆境对AT发展的影响。重复的多模式成像将评估逆境对杏仁核反应性和前额叶-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的有害影响是否通过细胞神经可塑性途径的改变来调节。免疫组织化学和rna-seq分析将在细胞显微解剖的神经元上进行。这一新的工具合成有望提供新的见解，以了解逆境诱导的分子变化如何在大脑功能、连通性和结构中表现出来，以及这些宏观变化如何有助于实现分子水平的啮齿动物或系统水平的人类研究所不具备的极端AT洞察力。此外，还将建立CEL GABA能神经元的干细胞模型，并将其与CEL的神经元进行比较。一个有效的干细胞模型将加强对AT分子基础的了解，并加快新疗法的筛选。

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.