Typical and Pathological Cellular Development of the Human Amygdala

描述(申请人提供)：杏仁核的结构和功能在许多神经发育和精神障碍中都是异常的。然而，人类杏仁核的正常细胞发育几乎完全没有研究。因此，没有基线信息可以用来识别与这些疾病相关的细胞变化。自闭症是最常见的神经发育障碍之一，其特点是出生后头几年杏仁核的生长发生了深刻的变化。然而，目前还没有关于自闭症儿童早期结构变化背后的细胞特征的死后定量研究。在迄今为止发表的唯一一项杏仁核定量尸检研究中，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)最为强烈。然而，造成神经元数量减少的细胞过程仍然未知。因此，这项建议的首要目标是定义人类杏仁核从儿童到成年在典型发育过程中的细胞成熟，并将这一细胞轮廓与自闭症患者杏仁核的发育轨迹进行对比。我们还将探索哪些神经缺陷和疾病状态可能会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(40个自闭症患者和40个对照组)的杏仁核，这些大脑平均分布在2-40岁的年龄范围内。我们将使用一种新的方法来进行人脑组织的研究，通过执行多个实验，包括定量体视学来估计神经元和神经胶质细胞的数量，高尔基体染色来评估树突状细胞的成熟，以及免疫组织化学来评估同一对象中的神经炎症和神经变性。这种方法不仅可以让我们从每一次脑捐赠中获得最大限度的知识，还可以检查多个细胞功能之间的关系。这项研究计划将首次全面描述人类杏仁核从童年到成年的细胞成熟过程，代表着我们在理解典型发育的人脑的细胞特性方面取得的重大进展，并完成了研究许多神经发育和精神疾病的起源的关键的第一步。该项目还将首次定量检查自闭症儿童脑细胞的变化，增强我们对这种疾病的发育神经病理学的理解，并为有效的生物疗法的目标指明方向。 公共卫生相关性：准确了解杏仁核在典型发育过程中的细胞组成和结构发育，将作为比较几种常见神经发育和精神障碍中杏仁核神经病理的基线。此外，这项研究将提供自闭症患者杏仁核细胞发育的全面图谱。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.