Cellular Structure of the Amygdala in Autism

描述(申请人提供)：杏仁核是一种皮质下的颞叶结构，在调节社会行为以及识别和产生情绪方面发挥着关键作用。由于这些功能在自闭症中受损最严重，杏仁核长期以来一直被认为是潜在的病理部位。通过结构磁共振成像观察到自闭症杏仁核在出生后异常增大，但在成人中没有观察到大体结构体积的一致差异。这些体积变化背后的细胞异常在很大程度上仍未得到描述，但据报道，患有自闭症的成年人神经元数量减少。可能存在什么细胞变化，使得神经元数量的减少不会导致杏仁核体积的明显减少？一种很大的可能性是小胶质细胞的激活，这会导致胶质细胞密度和胞体体积的增加；这些变化可能存在于自闭症发育宏观结构和功能异常的其他高峰期。我们将进行小胶质细胞数量的体视学计数，应用各向同性核素计算小胶质细胞胞体平均横截面积，并对小胶质细胞-神经元聚集程度以及神经元-神经元聚集程度进行空间格局分析。这些评估将在已经观察到神经元丢失的情况下进行，使我们能够将神经胶质和神经元的变化联系起来。另一种可能的解释是树枝和轴突占据的空间增加，即神经纤维。然而，杏仁核树突状分枝的正常发育过程尚未建立。因此，我们将在恒河猴模型中研究杏仁核神经元树突的出生后发育，并将这种发育与神经元-神经元聚集的程度联系起来。以前在同一灵长类动物中进行的评估包括对侧杏仁核神经元数量和体积的体视学分析，以及通过结构磁共振对大结构体积的评估。在我们的人类受试者中，发现小胶质细胞激活与神经元丢失在同一大脑中，可能会为发生这种激活的个人带来直接的治疗益处。我们对细胞异常的描述将进一步促进该领域对这种疾病背后的神经病理学的理解，为改进动物模型和开发更好的生物标记物指明方向。我们的灵长类研究将作为未来人类在多种神经精神障碍中杏仁核神经元和神经束发育异常的研究的参考点。

DESCRIPTION (provided by applicant): The amygdala is a subcortical temporal lobe structure that plays a critical role in the modulation of social behavior and the recognition and production of emotion. Because these functions are among the most impaired in autism, the amygdala has long been considered a potential locus of pathology. Abnormal postnatal enlargement has been observed in the autistic amygdala via structural magnetic resonance imaging, but no consistent difference in macrostructural volume has been observed in adults. The cellular abnormalities underlying these volumetric changes have remained largely undescribed, but a decreased number of neurons has been reported in adults with autism. What cellular alterations might be present such that a reduction in neuron number does not result in a detectable decrease in amygdala volume? One strong possibility is microglial activation, which would cause increases in glial density and somal volume; these alterations may be present in other regions of peak developmental macrostructural and functional abnormality in autism. We will conduct a stereological count of microglial number, apply isotropic nucleator to calculate average microglial somal cross-sectional area, and carry out a spatial pattern analysis of the degree of microglia-neuron clustering as well as neuron-neuron clustering. These assessments will be conducted in cases in which neuron loss has already been observed, allowing us to relate glial and neuronal alterations. Another possible explanation is an increase in the space occupied by dendritic arbors and axons i.e. neuropil. However, the normal developmental course of dendritic arborization in the amygdala has not been established. Thus, we will examine the postnatal development of the dendritic arbors of amygdala neurons in a rhesus monkey model, and relate this development to the degree of neuron-neuron clustering. Previous assessments performed in the same primates include stereological analysis of neuron number and volume in the contralateral amygdala and macrostructural volume assessment via structural MRI. In our human subjects, a finding of microglial activation in the same brains as neuron loss might lead to direct therapeutic benefit for individuals in whom this activation is taking place. Our description of cellular abnormalities will further advance the field's understanding of the neuropathology underlying this disorder, pointing the way toward improved animal models and the development of better biomarkers. Our primate study will serve as a reference point for all future human studies of abnormal neuronal and neuropil development in the amygdala in multiple neuropsychiatric disorders.