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.

抽象的血脑屏障是一个术语，用于描述血管化的血管的独特特性中枢神经系统。这些血管严格调节离子、分子和细胞的运动血液和大脑之间，从而控制神经组织的细胞外环境。尽管血脑屏障的重要性，但人们对血脑屏障如何调节神经系统知之甚少环境来调节复杂的行为。我们已经确定，产生的代谢酶并分解内皮细胞中富含的单胺神经递质多巴胺和血清素中枢神经系统血管的变化，表明血脑屏障代谢可能调节这些单胺神经递质的水平对于许多复杂的行为至关重要。在初步我们的研究发现，内皮细胞中这些酶的缺失会导致社交能力缺陷相互作用，并进一步发现证据表明这些血管酶充当代谢缓冲剂单胺前体的运输。有趣的是，编码这些基因的多态性酶与自闭症风险和/或严重程度有关，但是作用部位和机制它们调节自闭症相关行为的方式尚不清楚。在这里我们将检验血脑的假设屏障代谢调节自闭症相关行为，包括社交互动。我们将进一步审查血脑屏障代谢调节单胺类神经递质水平的机制中枢神经系统的内部结构，以及它如何影响行为。我们的最终目标是确定是否血脑屏障是调节行为的治疗靶点。