Novel Developmental Pathways Underlying Psychiatric Disorders

精神疾病背后的新发育途径

• 批准号: 9341394
• 负责人: Anju Vasudevan
• 金额: $ 41.63万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9341394
• 关键词: Adopted; Adult; Affect; Autistic Disorder; Autocrine Communication; Axon; Behavior; Blood Vessels; Blood flow; Brain; Cell Proliferation; Cells; Cerebral cortex; Complex; Cues; Darkness; Development; Disease; Embryo; Embryonic Development; Endothelial Cells; Event; Feedback; GABA Receptor; Genes; Glutamates; Impairment; In Vitro; Interneurons; LOX gene; Light; Link; Mediating; Mental Health; Mental disorders; Molecular; Morphology; Nature; Neuroglia; Neurons; Neurophysiology - biologic function; Pathway interactions; Pattern; Pattern Formation; Population; Positioning Attribute; Process; Prosencephalon; Public Health; Radial; Receptor Signaling; Reporting; Research; Route; Schizophrenia; Signal Pathway; Signal Transduction; Technology; Telencephalon; Testing; Vascular System; Ventricular; Work; angiogenesis; design; gamma-Aminobutyric Acid; in vivo; information processing; insight; knockout gene; migration; nerve stem cell; neurogenesis; neurovascular; novel; postnatal; prenatal; receptor

Abstract The cerebral cortex is essential for integration and processing of information that is required for most behaviors. Correct functioning of the cerebral cortex necessitates the concerted assembly of circuits involving glutamatergic projection neurons and GABAergic interneurons. The exquisitely precise laminar arrangement of neurons, axon collaterals and dendritic processes arises during embryonic development when neurons migrate successively from proliferative ventricular zones to coalesce into specific cortical layers. While radial glia was identified as substrates or guide rails for migration of projection neuron precursors to the cortical plate in the early seventies, the substrate for GABAergic interneuron migration was a missing link. Our recent work has shown that pre-formed vascular networks in the embryonic forebrain are strategically positioned to fulfill the formidable task of providing support and guidance cues to GABA neurons as they migrate from the subpallium to the developing cerebral cortex. This application will examine this novel paradigm of endothelial cell-neuron interactions at detailed cellular and molecular levels. It will elucidate the importance of new signaling mechanisms via forebrain endothelial cells that were hitherto believed to be exclusively neuronal. It will examine how alterations in these novel developmental pathways disturb hierarchical vascular patterns; perturb neuronal migration and cortical organization. Results will illustrate a powerful impact on cerebral cortex circuitry, blood flow and postnatal behavior with new significance for psychiatric disorders.

摘要 大脑皮层对于整合和处理信息是必不可少的，这些信息是 大多数行为。大脑皮层的正确功能需要协调一致的组装 涉及谷氨酸能投射神经元和GABA能中间神经元的回路。这个 神经元、轴突侧支和树突的精细层状排列 在胚胎发育期间，当神经元从增殖的神经元连续迁移时出现 脑室带结合成特定的皮质层。而放射状胶质细胞被鉴定为 用于将投射神经元前体迁移到皮质板的底物或导轨 七十年代初，GABA能神经元间迁移的底物是缺失的一环。我们的 最近的研究表明，胚胎前脑中预先形成的血管网络是 处于战略地位，能够完成为以下方面提供支持和指导线索的艰巨任务 GABA神经元从大脑皮层下迁移到发育中的大脑皮层。这 应用程序将详细检查这一内皮细胞-神经元相互作用的新范例 细胞和分子水平。它将阐明新的信号机制的重要性，通过 到目前为止被认为完全是神经元的前脑内皮细胞。它将检查 这些新的发育途径的改变如何扰乱分级血管模式； 扰乱神经元迁移和皮质组织。结果将说明对 大脑皮质回路、血流和出生后行为对精神病学的新意义 精神错乱。