Cellular Structure of the Amygdala in Autism

描述（由申请人提供）：杏仁核是皮质下颞叶结构，在社会行为的调节以及情感的识别和产生中起关键作用。由于这些功能在自闭症中受损最严重，杏仁核一直被认为是一个潜在的病理部位。通过结构磁共振成像，在自闭症患者的杏仁核中观察到了出生后的异常增大，但在成年人中没有观察到宏观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被描述，但在自闭症成人中已报告神经元数量减少。什么样的细胞改变可能会导致神经元数量的减少不会导致杏仁核体积的可检测到的减少？一个很大的可能性是小胶质细胞活化，这将导致胶质细胞密度和体体积的增加;这些改变可能存在于自闭症的峰值发育宏观结构和功能异常的其他区域。我们将进行小胶质细胞数量的体视学计数，应用各向同性成核剂计算平均小胶质细胞体横截面积，并进行小胶质细胞-神经元聚类以及神经元-神经元聚类程度的空间模式分析。这些评估将在已经观察到神经元损失的情况下进行，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突状乔木和轴突（即神经轴突）占据的空间增加。然而，杏仁核树突分支的正常发育过程尚未建立。因此，我们将研究出生后的发展杏仁核神经元的树突状乔木在恒河猴模型，并将这种发展的神经元-神经元集群的程度。先前在相同灵长类动物中进行的评估包括对侧杏仁核中神经元数量和体积的体视学分析以及通过结构MRI进行的宏观结构体积评估。在我们的人类受试者中，在与神经元损失相同的大脑中发现小胶质细胞激活可能会为发生这种激活的个体带来直接的治疗益处。我们对细胞异常的描述将进一步推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志物指明了方向。我们的灵长类动物研究将作为未来人类研究多种神经精神疾病中杏仁核异常神经元和神经元发育的参考点。

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.