THE NEUROANATOMICAL BASIS OF SOCIAL-AFFECTIVE DEFICITS IN AUTISM

自闭症社交情感缺陷的神经解剖学基础

• 批准号: 7560756
• 负责人: GENE J BLATT
• 金额: $ 17.63万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7560756
• 关键词: GABA aminotransferase; GABA receptor; amygdala; autism; autoradiography; behavioral /social science research tag; cellular pathology; cingulate gyrus; communication behavior; cooperative study; frontal lobe /cortex; hippocampus; human tissue; immunocytochemistry; interneurons; ligands; limbic system; membrane transport proteins; mental disorders; microglia; neuropathology; postmortem; psychopathology; receptor binding; serotonin; social behavior

Neuropathological findings in autism have consistently implicated the hippocampus and amygdala, two key limbic system structures with specific but wide-ranging connections throughout many cortical regions. While the hippocampus has important functions in declarative and short term memory processes, the amygdala in contrast has been implicated in emotions, fear, anxiety and is critically important for social interaction with 3eers and the environment, in autism, individuals have difficulties with declarative memory and with socioemotional and affective behavior. Although the hippocampus and amygdala are the subject of many ongoing research studies, the direct and indirect cortical connectivity of these two key brain areas have not been well studied in autism. Thus, the present study will investigate six key cortical areas including two in the frontal lobe (medial and orbital frontal cortex), three areas in the cingulate gyrus (anterior and posterior cingulate and retrosplenial cortex) and the temporal lobe fusiform face area in the fusiform gyrus, each of which have important connections with either the hippocarnpus, amygdala or both. The hypothesis is that the circuitry within these limbic cortices is altered contributing to the social affective behavioral deficits in autism. The cellular structure and cortical cytoarchitecture will be studied via standard Nissl stains for cellular pathology in the six cortices. Since it now appears that abnormalities in benzodiazepine binding sites and GABA-A receptors have been identified in the hippocampus, the GABAergic will be investigated in the six cortical areas using a variety of methods. Immunocytochemistry will quantify subpopulations of cortical GABAergic intemeurons and assess the functional activity utilizing antibodies dierected against three types of GABAergic transporters (uptake sites). In addition, in vitro multiple concentration ligand binding will quantify the density of binding and affinity to bind benzodiazepine and GABA-A sites as well as three types of serotonergic receptors, another transmitter system implicated in autistic spectrum. Finally, the dynamic state within the brain of autistic individuals will be assessed utilizing antibodies toward two types of neuroglia: microglia and astrocytes. Microglial aggregations at sites of neuropathological changes wilt be a focus of the study with the hypothesis that autism is an ongoing process and not a static disorder.

自闭症的神经病理学发现始终与海马体和杏仁核有关，这两个关键的边缘系统结构在许多皮质区域具有特定但广泛的联系。虽然海马体在陈述性记忆和短期记忆过程中具有重要功能，但相比之下，杏仁核与情绪、恐惧、焦虑有关，并且对于与 3e 人和环境的社交互动至关重要。在自闭症患者中，个体在陈述性记忆和记忆方面存在困难。具有社会情感的 和情感行为。尽管海马体和杏仁核是许多研究的主题 正在进行的研究表明，这两个关键大脑区域的直接和间接皮质连接在自闭症中尚未得到很好的研究。因此，本研究将研究六个关键皮质区域，包括额叶中的两个区域（内侧和眶额皮质）、扣带回中的三个区域（前扣带回、后扣带回和压后皮质）以及梭形颞叶梭状面区域每个脑回都与海马、杏仁核或两者都有重要的联系。假设是这些边缘皮质内的回路发生改变，导致自闭症的社会情感行为缺陷。将通过标准尼氏染色来研究六个皮质中细胞病理学的细胞结构和皮质细胞结构。由于现在看来，苯二氮卓结合异常 海马体中的位点和 GABA-A 受体已被确定，将使用多种方法在六个皮质区域中研究 GABA 能。免疫细胞化学将量化皮质 GABA 能中间神经元的亚群，并利用针对三种类型的 GABA 能转运蛋白（摄取位点）的抗体评估其功能活性。此外，体外多浓度配体结合将量化结合苯二氮卓和 GABA-A 位点以及三种类型的血清素受体（与自闭症谱系有关的另一种递质系统）的结合密度和亲和力。最后是动态 将利用针对两种神经胶质细胞的抗体来评估自闭症患者的大脑状态：小胶质细胞和星形胶质细胞。神经病理变化部位的小胶质细胞聚集将成为研究的焦点，假设自闭症是一个持续的过程，而不是一种静态的疾病。