Novel Developmental Pathways Underlying Psychiatric Disorders

精神疾病背后的新发育途径

• 批准号: 10584586
• 负责人: Anju Vasudevan
• 金额: $ 53.28万
• 依托单位: HUNTINGTON MEDICAL RESEARCH INSTITUTES
• 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 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584586
• 关键词: Adult; Affect; Anxiety; Behavior; Behavioral; Birth; Blood Vessels; Blood flow; Brain; Cells; Central Nervous System; Cerebral cortex; Cerebrovascular system; Communication; Complex; Cues; Defect; Development; Disease; Electrophysiology (science); Embryo; Endothelial Cells; Endothelium; Epilepsy; Etiology; Event; GABA Receptor; GAD65 enzyme; GAD67 enzyme; GAT3 transporter; Gene Expression; Gene Expression Profile; Genes; Goals; Impairment; Individual; Mediating; Mental Depression; Mental disorders; Microcirculation; Midbrain structure; Molds; Molecular; Moods; Mus; Neocortex; Neurons; Obsessive-Compulsive Disorder; Pathogenesis; Pathway interactions; Phase; Population; Positioning Attribute; Process; Prosencephalon; Public Health; Regulation; Research; Role; Schizophrenia; Shapes; Signal Pathway; Signal Transduction; Time; Variant; Vascularization; Ventricular; Work; angiogenesis; anxiety-related disorders; autism spectrum disorder; conditional knockout; design; early embryonic stage; gamma-Aminobutyric Acid; hindbrain; in vivo; insight; loss of function; migration; neocortical; neuropsychiatric disorder; neuropsychiatry; neurotransmission; neurovascular; novel; postnatal; postnatal development; postnatal period; prenatal; programs; receptor; repaired; vascular factor; vesicular GABA transporter; vessel regression

Abstract The central nervous system (CNS) acquires its vasculature by angiogenesis, a process that is critical for its development and repair. Our findings have offered new perspectives on intrinsic regulation of angiogenesis and highlighted the importance of vascular diversity during brain development. Pre-formed vascular networks act as a template for the formation of the neocortex. They are strategically positioned, spatially and temporally to provide support and critical guidance cues to instruct key events of brain development. Recently, our studies uncovered a novel GABA signaling pathway in embryonic forebrain endothelial cells that works independently from neuronal GABA signaling. It revealed that disruptions in endothelial GABA signaling from early embryonic stages can directly contribute to the origin of psychiatric disorders including autism, epilepsy, schizophrenia, anxiety and depression. This vascular GABA signaling pathway extends into the postnatal phase with added complexities. Therefore, our renewal application will examine the key fundamental mechanisms of action of endothelial GABAA receptor-GABA signaling components during the postnatal period with new significance for neocortical development and disease. It aims at highlighting hitherto unknown mechanisms of endothelial GABA’s role in vascular regression and stabilization. It explores the novel concept that endothelial GABA components are indispensable for postnatal brain development and can differentially shape blood flow. Results will uncover fundamental mechanisms governing postnatal angiogenesis, offer new perspectives on the cellular and molecular landscape of the developing neocortex and will lead to discoveries with unprecedented implications for understanding and treatment of several neuropsychiatric illnesses.

摘要 中枢神经系统（CNS）通过血管生成获得其血管，血管生成是其发育和修复的关键过程。我们的研究结果为血管生成的内在调控提供了新的视角，并强调了血管多样性在脑发育过程中的重要性。预先形成的血管网络充当新皮层形成的模板。它们在空间和时间上都处于战略性的位置，以提供支持和关键的指导线索，指导大脑发育的关键事件。最近，我们的研究发现了一种新的GABA信号通路在胚胎前脑内皮细胞，独立于神经元GABA信号。它揭示了胚胎早期内皮GABA信号的中断可以直接导致精神疾病的起源，包括自闭症，癫痫，精神分裂症，焦虑和抑郁症。这种血管GABA信号通路延伸到出生后阶段，增加了复杂性。因此，我们的更新申请将检查关键的基本机制的行动内皮GABAA受体GABA信号成分在出生后的时期与新的意义，新皮层的发展和疾病。它的目的是强调迄今未知的机制，内皮GABA的作用，血管退化和稳定。它探讨了新的概念，即内皮GABA成分是必不可少的出生后的大脑发育，可以差异化地塑造血流。研究结果将揭示控制出生后血管生成的基本机制，为发育中的新皮层的细胞和分子景观提供新的视角，并将导致对理解和治疗几种神经精神疾病具有前所未有的影响的发现。