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Blood-brain barrier monoamine metabolism regulation of social behavior

血脑屏障单胺代谢对社会行为的调节

基本信息

批准号：
10053133
负责人：
Richard Daneman
金额：
$ 47.25万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10053133
关键词：
3,4-Dihydroxyphenylacetic Acid Adolescent Adult Affect Age Behavior Blood Blood - brain barrier anatomy Blood Vessels Brain Buffers Cell Line Cells Chemicals Complex DOPA decarboxylase Data Data Set Development Dopamine Dopamine Antagonists Embryonic Development Endothelial Cells Endothelium Environment Enzymes Functional disorder Gene Expression Genes Genetic Polymorphism Goals Haloperidol In Vitro Ions Knockout Mice Lead Link Maintenance Metabolic Metabolism Modeling Molecular Monoamine Oxidase Movement Mus Nature Neuraxis Neuromodulator Neurophysiology - biologic function Neurotransmitters Peripheral Phenotype Physiology Property RNA Regulation Risk Role Series Serotonin Severities Signal Transduction Site Social Behavior Social Interaction Testing Tight Junctions Tissues autism spectrum disorder behavior test conditional knockout developmental disease experimental study extracellular genetic variant in vivo monoamine mouse model novel relating to nervous system repetitive behavior therapeutic target transcriptome sequencing transcytosis vocalization

项目摘要

Abstract The blood-brain barrier is a term used to describe the unique properties of the blood vessels that vascularize the central nervous system. These blood vessels tightly regulate the movement of ions, molecules and cells between the blood and the brain, thus controlling the extracellular environment of the neural tissue. Despite the importance of the blood-brain barrier, very little is known about how this barrier regulates the neural environment to modulate complex behaviors. We have identified that the metabolic enzymes that generate and breakdown the monoamine neurotransmitters dopamine and serotonin are enriched in the endothelial cells of central nervous system blood vessels, suggesting that blood-brain barrier metabolism may regulate the levels of these monoamine neurotransmitters which are critical for many complex behaviors. In preliminary studies we have identified that deletion of these enzymes in endothelial cells leads to deficits in social interaction, and have further found evidence that these vascular enzymes act as a metabolic buffer to the transport of monoamine precursors. Interestingly, polymorphisms in the genes encoding each of these enzymes have been linked with autism risk and/or severity, however the site of action and mechanism by which they regulate autism-related behaviors is not known. Here we will test the hypothesis that blood-brain barrier metabolism regulates autism-related behaviors including social interaction. We will further examine the mechanism by which blood-brain barrier metabolism may regulate the levels of monoamine neurotransmitters within the central nervous system, and how this affects behavior. Our ultimate goal is to determine whether the blood-brain barrier is a therapeutic target to modulate behavior.

摘要血脑屏障是一个用来描述血管形成的独特性质的术语中枢神经系统这些血管紧密地调节着离子、分子和细胞的运动在血液和大脑之间，从而控制神经组织的细胞外环境。尽管血脑屏障的重要性，很少有人知道这个屏障是如何调节神经系统的。环境来调节复杂的行为。我们已经发现，单胺类神经递质多巴胺和血清素在内皮细胞中富集提示血脑屏障代谢可能调节中枢神经系统血管的这些单胺神经递质的水平，这是许多复杂行为的关键。初步我们的研究已经确定，内皮细胞中这些酶的缺失会导致社交功能的缺陷，相互作用，并进一步发现证据表明，这些维管酶作为代谢缓冲液，单胺前体的运输。有趣的是，编码这些基因的基因多态性酶与自闭症风险和/或严重程度有关，然而，它们对自闭症相关行为的调节作用尚不清楚。在这里，我们将测试假设，血脑屏障代谢调节自闭症相关的行为，包括社会互动。我们将进一步研究血脑屏障代谢可能调节单胺神经递质水平的机制在中枢神经系统中，以及它如何影响行为。我们的最终目标是确定血脑屏障是调节行为的治疗靶点。