Cellular Density and Morphology in the Autistic Temporal Human Cerebral Cortex

自闭症人类大脑皮层颞叶的细胞密度和形态

• 批准号: 8164110
• 负责人: Veronica Martinez-Cerdeno
• 金额: $ 34.59万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-02 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8164110
• 关键词: Age; Astrocytes; Autistic Disorder; Autopsy; Behavior; Brain; Categories; Cells; Cellular Morphology; Cerebral cortex; Child; Classification; Clinical; Communication; Data; Dendrites; Dendritic Spines; Diagnosis; Electroencephalography; Exhibits; Future; Golgi method; Human; Interneurons; Length; Mental Retardation; Methods; Morphology; Neurodevelopmental Disorder; Neuroglia; Neurons; Oligodendroglia; Pathogenesis; Patients; Pattern; Principal Investigator; Publishing; Reciprocal Social Interaction; Recording of previous events; Relative (related person); Seizures; Staining method; Stains; Structure; Temporal Lobe; Testing; Therapeutic Intervention; Tissues; United States; Vertebral column; autism spectrum disorder; base; case-based; cell type; cognitive function; density; hippocampal pyramidal neuron; interest; mind control; neuropathology; neurotransmission; novel therapeutic intervention; programs; research study; social

DESCRIPTION (provided by applicant): Patients with autism exhibit altered cognitive function that is revealed in EEG recordings as an imbalance of excitation to inhibition in the cerebral cortex. Imbalanced excitation / inhibition could be the product of multiple alterations of brain structure and function, such as an altered ratio of pyramidal neurons to interneurons in the autistic cerebral cortex. Imbalanced excitation / inhibition could also be produced by an alteration in the number of non-neuronal cell types (such as oligodendrocytes or astrocytes) that participate in neurotransmission; and / or by altered morphology or density of neuronal dendrites and dendritic spines in the cerebral cortex. Existing data on the relative number of specific cell types in the cerebral cortex of human autistic brains is at this point insufficient, as is data on the morphology of neurons in the human autistic cerebral cortex. The number of published studies is scarce, the number of cases included in the published studies is small, and the cases used for analysis is heterogeneous. A full understanding of the cellular basis of autism in human brain is essential for establishing the basic underlying mechanisms that, in turn, will result in therapeutic interventions. This project will analyze the temporal lobe of 21 autistic postmortem human brains (diagnosed as autistic, not as other autism spectrum disorders) and the temporal lobe of 18 control postmortem human brains, and investigate: 1) Density of total neurons, pyramidal neurons, and interneuronal subtypes in the autistic versus control temporal cortex using unbiased stereological methods for cell quantification. 2) Density of total glial cells, astrocytes, and oligodendrocytes in the autistic versus control temporal cortex using unbiased stereological methods. Cellular classification will be based on cellular morphology in Nissl stained sections, and on cellular marker expression in immunohistochemical experiments. 3) Dendrite length, dendritic branching, and spine density in the temporal lobe of autistic and control brains. We will stain neurons using the Golgi method, Neurolucida and the Scholl method to determine total dendritic length, total number of dendritic branches and spine density in pyramidal neurons and interneurons. We will classify our cases based on the subject's clinical history, including age, the presence of seizures or mental retardation, and the levels of social, communicative, and repetitive behaviors. We will statistically compare densities in the autistic versus control temporal cortex within clinical categories. A full understanding of the cellular basis of autism in the human brain is essential for establishing underlying mechanisms that in turn could yield new therapeutic interventions. The data obtained from this project will also serve as the basis for future studies focusing on the neuropathology and the imbalance excitation / inhibition of the autistic brain. PUBLIC HEALTH RELEVANCE: Autism is a neurodevelopmental disorder defined by a pattern of qualitative abnormalities in reciprocal social interaction, communication, and repetitive interest and behavior. It is estimated that 1 in 110 children in the United States have autism spectrum disorders. The proposed project investigates the contribution of the density and morphology of distinct cortical cell types in the temporal lobe, to the pathogenesis of autism. A full understanding of the cellular basis of autism in the human brain is essential for establishing underlying mechanisms that in turn could yield new therapeutic interventions.

描述（由申请人提供）：自闭症患者表现出认知功能改变，在EEG记录中显示为大脑皮层中兴奋与抑制的不平衡。不平衡的兴奋/抑制可能是大脑结构和功能的多重改变的产物，例如自闭症大脑皮层中锥体神经元与中间神经元的比例改变。参与神经传递的非神经元细胞类型（如少突胶质细胞或星形胶质细胞）的数量改变;和/或大脑皮层中神经元树突和树突棘的形态或密度改变也可能产生不平衡的兴奋/抑制。关于人类自闭症患者大脑皮层中特定细胞类型的相对数量的现有数据在这一点上是不够的，关于人类自闭症患者大脑皮层中神经元形态的数据也是如此。已发表的研究数量很少，已发表研究中纳入的病例数量较少，用于分析的病例具有异质性。全面了解人类大脑中自闭症的细胞基础对于建立基本的潜在机制至关重要，而这反过来又会导致治疗干预。本项目将分析21例自闭症患者死后大脑（诊断为自闭症，而不是其他自闭症谱系障碍）的颞叶和18例对照死后大脑的颞叶，并研究：1）使用无偏体视学方法进行细胞定量，研究自闭症患者与对照颞叶皮层中总神经元、锥体神经元和神经元间亚型的密度。2)使用无偏体视学方法比较孤独症患者与对照颞叶皮质中总胶质细胞、星形胶质细胞和少突胶质细胞的密度。细胞分类将基于尼氏染色切片中的细胞形态和免疫组织化学实验中的细胞标志物表达。3)自闭症患者和对照组颞叶的树突长度、树突分支和棘密度。我们将使用Golgi方法、Neurolucida和Scholl方法对神经元进行染色，以确定锥体神经元和中间神经元中的总树突长度、树突分支总数和棘密度。我们将根据受试者的临床病史对病例进行分类，包括年龄、癫痫发作或精神发育迟滞的存在以及社交、沟通和重复行为的水平。我们将在统计学上比较自闭症患者与对照组颞叶皮层在临床类别中的密度。全面了解人类大脑中自闭症的细胞基础对于建立潜在机制至关重要，而这些机制反过来又可能产生新的治疗干预措施。从这个项目中获得的数据也将作为未来研究的基础，重点是自闭症大脑的神经病理学和不平衡的兴奋/抑制。 公共卫生关系：自闭症是一种神经发育障碍，其定义为在相互的社会互动、交流和重复的兴趣和行为方面的定性异常。据估计，美国每110名儿童中就有1名患有自闭症谱系障碍。拟议的项目调查颞叶不同皮质细胞类型的密度和形态对自闭症发病机制的贡献。全面了解人类大脑中自闭症的细胞基础对于建立潜在机制至关重要，而这些机制反过来又可能产生新的治疗干预措施。