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Typical and Pathological Cellular Development of the Human Amygdala

人类杏仁核的典型和病理性细胞发育

基本信息

批准号：
10332736
负责人：
Cynthia Schumann
金额：
$ 39.25万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10332736
关键词：
Abnormal Cell Adult Age Age-Years Amygdaloid structure Anxiety Autopsy BCL2 gene Basal Ganglia Brain Brain Diseases Brain region Cell Nucleus Cells Child Childhood Clinical Collection Communication Data Dendrites Dendritic Spines Development Electron Microscopy Emotional Environment Epilepsy Equilibrium Functional disorder Funding Glutamates Growth Human Human Development Hyperactivity Image Impairment Inhibitory Synapse Label Lateral Life Longevity Measures Mental disorders Methods Molecular Neurodevelopmental Disorder Neurons Outcome Paint Parvalbumins Pathologic Phase Process Property Research Resolution Sampling Signal Transduction Social Behavior Social Interaction Statistical Data Interpretation Structure Synapses System Therapeutic Intervention Time Tissue Sample Vertebral column Youth adult with autism spectrum disorder age related autism spectrum disorder autistic children base cellular development cohort density excitatory neuron excitotoxicity gephyrin individuals with autism spectrum disorder inhibitory neuron neuron loss neurotransmission premature programs prospective response sensory input sex social social anxiety targeted treatment

项目摘要

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.

摘要杏仁核与许多神经发育和精神疾病有关，包括自闭症谱系障碍（ASD）。这可能是因为它是一个系统的一部分，该系统专注于检测危险，环境，处理皮层感觉输入，并协调随后的反应。如果这个系统如果出现功能失调，可能会出现不适当的社会行为或焦虑，正如在许多人中观察到的那样，使人衰弱的精神疾病因此，通过准确理解以下因素，杏仁核的细胞组成和人类一生中的发育轨迹。考虑到社交互动和焦虑障碍是ASD的主要特征，杏仁核与ASD的病理生理学有着广泛的联系。我们研究的首要目标该项目旨在揭示杏仁核结构和功能的细胞和分子机制，典型的人类发展和ASD的整个生命周期。在这项研究计划的第一个资助周期中，通过对大量人类死后杏仁核组织的研究，我们发现了两个现象样品首先，在典型的人类大脑神经发育中，杏仁核经历了大量的，从青年到成年，成熟神经元的体积和数量都在增长。我们假设这可归因于基底核和间板核中神经元成熟的延长过程，这种持久的生长对正常的社会和情感发展至关重要。第二，在ASD 大脑发育，杏仁核不经历相同的年龄相关的增长轨迹。而是 ASD患者的杏仁核经历了一个异常的、终身的发育时间过程，体积增大，成熟神经元和突触棘数量过多。实际上成熟神经元的数量在儿童后期达到成人水平，这表明一个超自然的神经元成熟过程发生在杏仁核基底核和杏仁核。主兴奋性树突 ASD儿童杏仁核中的神经元也具有相对于神经典型的棘密度增加，儿童，表明改变神经元突触通信。这一增长之后，随着ASD患者进入成年期，细胞会退化。我们发现， ASD成年人外侧核和基底核中成熟神经元数量的年龄变化与典型的成年人。我们假设，杏仁核的过度活跃和兴奋，通过一个不平衡的，兴奋性到抑制性（E：I）突触信号传导，潜在地导致焦虑、社交障碍和预期神经元丢失。我们现在进入这项研究计划的下一阶段，非典型杏仁核细胞的神经元特性和病理生理机制 ASD的发展轨迹贯穿整个生命周期。