Typical and Pathological Cellular Development of the Human Amygdala

描述（由申请人提供）：杏仁核的结构和功能在许多神经发育和精神疾病中都是异常的。然而，人类杏仁核的正常细胞发育几乎完全没有被研究过。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，其特点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，目前还没有对自闭症儿童早期结构变化背后的细胞特征进行定量的、死后的研究。在迄今为止发表的唯一一项对杏仁核的定量死后研究中，我们发现，在成年自闭症患者中，神经元数量减少。有趣的是，这些改变在杏仁核的外侧核（感觉输入）中最为明显。然而，造成这种神经元数量减少的细胞过程仍然未知。因此，本研究的首要目标是定义人类杏仁核从童年到成年的典型发育过程，并将这种细胞图谱与自闭症患者杏仁核的发育轨迹进行对比。我们还将探讨哪些神经缺陷和疾病状态可能在自闭症患者的细胞群中产生病理变化。我们的研究项目将检查80个死后大脑的杏仁核（40个自闭症患者，40个对照组），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，通过开展多种实验来进行人类脑组织的研究，包括定量立体学来估计神经元和胶质细胞的数量，高尔基浸染来评估树突成熟，免疫组织化学来评估同一受试者的神经炎症和神经退行性变。这种方法不仅使我们能够最大限度地从每次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。这个研究项目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过程的项目，代表着我们对典型发育的人类大脑的细胞特性的理解取得了重大进展，并在研究许多神经发育和精神疾病的起源方面完成了关键的第一步。该项目也将是第一个定量检查自闭症儿童大脑细胞变化的项目，增强我们对这种疾病的发育神经病理学的理解，并为有效的生物治疗指明方向。

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.