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.
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.
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