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 大脑皮层对于信息的整合和处理至关重要， 大多数行为。大脑皮层的正确运作需要协调一致的组装 的回路，包括谷氨酸能投射神经元和γ-氨基丁酸能中间神经元。的 神经元、轴突侧支和树突状突起的精细层状排列 在胚胎发育过程中，当神经元从增殖的 心室区合并成特定的皮质层。而放射状胶质细胞被鉴定为 用于投射神经元前体迁移到皮层板的基底或导轨 70年代早期，GABA能中间神经元迁移的底物是缺失的一环。我们 最近的研究表明，胚胎前脑中预先形成的血管网络， 战略定位，以履行提供支持和指导线索， GABA神经元从软腭下迁移到发育中的大脑皮层。这 应用程序将详细研究这种内皮细胞-神经元相互作用的新范式， 细胞和分子水平。它将阐明新的信号机制的重要性， 前脑内皮细胞，迄今为止被认为是专门的神经元。它将审查 这些新的发育途径的改变如何干扰分级血管模式; 扰乱神经元迁移和皮质组织。结果将说明一个强大的影响 大脑皮层回路、血流和产后行为对精神病的新意义 紊乱