Typical and Pathological Cellular Development of the Human Amygdala

描述（由申请人提供）：杏仁核结构和功能在大量神经发育和精神疾病中异常。然而，人类杏仁核的正常细胞发育仍然几乎完全没有研究。因此，没有基线信息可用于识别与这些疾病相关的细胞改变。自闭症是最常见的神经发育障碍之一，其特征是在生命的最初几年杏仁核的生长发生了深刻的变化。然而，目前还没有定量的，尸检研究的细胞功能的基础上，这些早期结构变化的幼儿自闭症。在迄今为止发表的唯一一项关于杏仁核的定量死后研究中，我们发现患有自闭症的成年人神经元数量减少。有趣的是，这些变化在杏仁核的外侧（感觉输入）核中最为强烈。然而，产生这种减少的神经元群体的细胞过程仍然未知。因此，该提案的总体目标是定义人类杏仁核从童年到成年的典型发育中的细胞成熟，并将该细胞概况与自闭症个体杏仁核的发育轨迹进行对比。我们还将探讨什么样的神经缺陷和疾病状态可能会导致自闭症细胞群的病理变化。我们的研究计划将检查80个死后大脑（40个自闭症患者，40个对照组）的杏仁核，平均分布在2-40岁的年龄范围内。我们将采用一种新的方法进行人脑组织的研究，通过进行多个实验，包括定量体视学估计神经元和神经胶质细胞的数量，高尔基体浸渍评估树突的成熟，和免疫组织化学评估神经炎症和神经变性在同一主题。这种方法不仅使我们能够最大限度地从每一个大脑捐赠中获得知识，而且还可以检查多个细胞特征之间的关系。这项研究计划将是第一个全面描述人类杏仁核从童年到成年的细胞成熟的研究，代表了我们对人类大脑典型发育细胞特性的理解的重大进展，并完成了检查许多神经发育和精神疾病起源的关键第一步。该计划也将是第一个定量研究自闭症儿童大脑细胞变化的项目，增强了我们对这种疾病的发育神经病理学的理解，并为有效的生物疗法指明了方向。 公共卫生相关性：对典型发育中杏仁核的细胞组成和结构发育的精确理解将作为比较几种常见神经发育和精神疾病中杏仁核神经病理学的基线。此外，这项研究将提供一个全面的地图杏仁核细胞发育的自闭症。这些信息将有助于我们了解这些疾病的原因和治疗方案的发展。

DESCRIPTION (provided by applicant): Amygdala structure and function are abnormal in a remarkable number of neurodevelopmental and psychiatric disorders. However, the normal cellular development of the human amygdala remains almost entirely unstudied. As a result, there is no baseline information that can be used to identify the cellular alterations that are associated with these disorders. Autism is one of the most common neurodevelopmental disorders and is marked by profound changes in the growth of the amygdala in the first years of life. However, there have been no quantitative, postmortem studies of the cellular features underlying these early structural changes in young children with autism. In the only quantitative postmortem study of the amygdala published to date, we found that in adults with autism, neuron number is reduced. Interestingly, these alterations are most robust in the lateral (sensory input) nucleus of the amygdala. However, the cellular processes that create this diminished neuronal population remain unknown. Thus, the overarching goal of this proposal is to define the cellular maturation of the human amygdala from childhood to adulthood in typical development and contrast this cellular profile with developmental trajectory of the amygdala in individuals with autism. We will also explore what neural defects and disease states might produce pathological changes in cell populations in autism. Our research program will examine the amygdala from 80 postmortem brains (40 autism, 40 control) equally distributed across the age range of 2-40 years. We will employ a novel approach to conducting studies of human brain tissue by carrying out multiple experiments, including quantitative stereology to estimate neuron and glia numbers, Golgi impregnation to assess dendritic maturation, and immunohistochemistry to assess neuroinflammation and neurodegeneration within the same subject. This approach not only allows us to maximize the amount of knowledge we can gain from every brain donation, but also to examine the relationships between multiple cellular features. This research program will be the first to comprehensively describe the cellular maturation of the human amygdala from childhood to adulthood, representing a major advance in our understanding of the cellular properties of the typically developing human brain and completing a critical first step in examining the origins of many neurodevelopmental and psychiatric disorders. The program will also be the first to quantitatively examine cellular alterations in the brain in children with autism, enhancing our understanding of the developmental neuropathology of this disorder and pointing the way towards targets for effective biological therapeutics. PUBLIC HEALTH RELEVANCE: A precise understanding of the cellular composition and structural development of the amygdala in typical development would serve as a baseline for which to compare amygdala neuropathology found in several common neurodevelopmental and psychiatric disorders. In addition, this research will provide a comprehensive map of amygdala cellular development in autism. This information will facilitate our understanding of the causes of these disorders and the development of treatments options.