Typical and Pathological Cellular Development of the Human Amygdala

摘要 杏仁核与许多神经发育和精神障碍有关，包括 自闭症谱系障碍(ASD)。这很可能是因为它是专注于检测危险的系统的一部分 环境，处理大脑皮层感觉输入，并协调后续反应。如果这个系统 变得不正常，不适当的社交行为或焦虑可能会出现，正如在许多情况下经常观察到的那样 令人衰弱的精神疾病。因此，治疗方法可以通过准确理解 贯穿人类一生的杏仁核细胞组成和发育轨迹。 考虑到社交障碍和焦虑是自闭症的主要特征，难怪 杏仁核广泛参与ASD的病理生理学过程。我们研究的首要目标是 该计划旨在揭示杏仁核结构和功能的细胞和分子机制 典型的人类发育和自闭症的整个寿命。在这个研究项目的第一个资助周期中， 我们通过对大量人类死后杏仁核组织的研究发现了两个现象 样本。首先，在神经典型的人脑发育中，杏仁核经历了一个实质性的、长期的 从年轻到成年，成熟神经元的体积和数量都在增长。我们假设 这是由于基底核和板层旁核内神经元成熟过程延长所致，以及 这种持久的成长对于正常的社会和情感发展至关重要。第二，在ASD中 在大脑发育过程中，杏仁核不会经历与年龄相关的相同生长轨迹。相反， ASD患者的杏仁核经历了一个异常的、终生的发育过程，从早产开始。 儿童期体积增大，成熟神经元和突触棘细胞数量过多。事实上， 成熟神经元的数量在儿童后期达到成人的水平，这表明一个超自然的神经元 成熟过程发生在杏仁核的基底核和板旁核。主要兴奋性树突 ASD儿童杏仁核中的神经元密度也比神经型增加。 儿童，表明神经元突触通讯发生了变化。在这种增长之后，可能会出现 随着ASD患者进入成年期，退行性细胞丢失。我们发现有一个稳定的下降趋势。 成人ASD患者外侧核和基底核中成熟神经元的数量与年龄相关 神经典型的成年人。我们假设杏仁核中的过度活动和兴奋，通过 兴奋性到抑制性(E：I)突触信号，可能导致焦虑、社交障碍和 预期的神经元丢失。我们现在进入该研究计划的下一阶段，以确定具体的 非典型杏仁核细胞的神经元特性和病理生理机制 自闭症患者在整个生命周期中的发育轨迹。

ABSTRACT The amygdala has been implicated in a number of neurodevelopmental and psychiatric disorders, including autism spectrum disorder (ASD). This is likely because it is part of a system focused on detecting danger in the environment, processing cortical sensory input, and orchestrating subsequent responses. If this system becomes dysfunctional, inappropriate social behavior or anxiety may arise, as is observed in many, often debilitating, psychiatric disorders. Thus, treatment approaches may be facilitated by a precise understanding of the amygdala cellular composition and developmental trajectory that occurs across human lifespan. Considering impairments in social interaction and anxiety are key features of ASD, it is not surprising that the amygdala has been extensively implicated in ASD pathophysiology. The overarching objective of our research program is to reveal the cellular and molecular mechanisms underlying amygdala structure and function in typical human development and in ASD across the lifespan. In the first funding cycle of this research program, we discovered two phenomena through our studies of a large collection of human postmortem amygdala tissue samples. First, in neurotypical human brain development, the amygdala undergoes a substantial, protracted growth in both volume and in the number of mature neurons from youth well into adulthood. We hypothesize that this is attributable to a prolonged process of neuronal maturation in the basal and paralaminar nuclei, and that this protracted growth is critically important for normal social and emotional development. Second, in ASD brain development, the amygdala does not undergo the same age-related growth trajectory. Rather, the amygdala in ASD undergoes an aberrant, lifelong developmental time course that begins with premature volumetric enlargement and an excess number of mature neurons and synaptic spines in childhood. In fact, the number of mature neurons reaches adult levels by late childhood, suggesting that a preternatural neuronal maturation process is occurring in the amygdala basal and paralaminar nuclei. Dendrites of principal excitatory neurons in the amygdala of children with ASD also have an increase in spine density relative to neurotypical children, indicating altered neuronal synaptic communication. This increase is followed by a potentially degenerative cell loss as people with ASD age into adulthood. We have found that there is a steady decrease across age in the number of mature neurons in both the lateral and basal nucleus in adults with ASD relative to neurotypical adults. We hypothesize that hyperactivity and excitation in the amygdala, via an imbalance of excitatory to inhibitory (E:I) synaptic signaling, potentially contributes to anxiety, social impairments, and prospective neuron loss. We now move to the next phase of this research program, to identify specific neuronal properties and pathophysiological mechanisms that underlie the atypical amygdala cellular developmental trajectory in ASD that endures throughout the lifespan.