What is the role of blood-brain-barrier regional specificity in the nucleus accumbens?

伏隔核中血脑屏障区域特异性的作用是什么？

• 批准号: 10314954
• 负责人: Iris Haleakala Garcia-Pak
• 金额: $ 3.89万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10314954
• 关键词: Acute; Address; Adult; Affect; Aging; All-Trans-Retinol; Alzheimer' s Disease; Area; Basal Ganglia; Behavior; Biological; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain region; Cell Differentiation process; Cell Survival; Cerebellum; Cochlear nucleus; Corpus striatum structure; Development; Developmental Process; Diet; Disease; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Drug Addiction; Endothelial Cells; Endothelium; Environment; Equilibrium; Exhibits; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Goals; Health system; Heterogeneity; Hippocampus (Brain); Homeostasis; Hypothalamic structure; Immune system; Individual; Knock-out; Knockout Mice; Knowledge; Lead; Learning; Metabolism; Molecular; Mus; Nervous System Physiology; Neuraxis; Neurons; Nucleus Accumbens; Organ; Pathway interactions; Peripheral; Play; Predisposition; Prevalence; Prevention; Property; Psychological reinforcement; Public Health; RXR; Retinoids; Rewards; Role; Self Administration; Sensory; Severities; Signal Transduction; Source; Specific qualifier value; Specificity; Spinal Cord; Stimulus; Tamoxifen; Testing; Thalamic structure; Time; Tissue-Specific Gene Expression; Tissues; Toxin; Traumatic Brain Injury; Tretinoin; Variant; Ventral Striatum; Vitamin A; Work; addiction; brain endothelial cell; cell type; conditional knockout; dietary; extracellular; interest; learned behavior; nervous system disorder; neural circuit; neuropsychiatric disorder; pleasure; receptor; relating to nervous system; single-cell RNA sequencing; therapeutic target

PROJECT SUMMARY/ABSTRACT The blood-brain barrier (BBB) is a term that describes the unique properties of central nervous system (CNS) blood vessels which allow them to stringently regulate the extracellular environment of the surrounding neural tissue. While it is known that different brain regions are made up of diverse cell types and execute distinct functions, it is unknown if the BBB exhibits varied features in functionally distinct regions to regulate specific neural circuits. Since little is known about heterogeneity of the BBB, this project will address this gap in knowledge and pursue the question of whether regional specializations of the blood-brain barrier may regulate local circuit function and behavior. This will identify if the BBB could be targeted to modulate specific behaviors, including reward and addiction. Single cell RNA sequencing revealed that there is significant inter-regional heterogeneity of the BBB via differential gene expression in endothelial cells (ECs). While the canonical BBB genes that contribute to restrictive barrier properties were expressed in ECs across all brain regions, many genes involved in transport, signaling, and metabolism were found to be enriched in ECs of specific brain regions. For instance, Stra6, a transport regulator of retinoids, is remarkably enriched in the nucleus accumbens shell (sNAc) and the ventral cochlear nucleus (VCN) compared to other areas of the brain. The sNAc is particularly of interest because its function in reward and reinforcement learning implicates the region in drug addiction. Due to the prevalence and severity of addiction, it is urgently important to find new targets for treating this major public health issue by asking if the BBB, via Stra6, plays a role in regulating addiction. The proposed study will address this critical need by determining (1) if the regional specificity of Stra6 at the BBB is necessary for the development or adult function of the sNAc, (2) by what molecular mechanisms Stra6 regulates sNAc function, and (3) if Stra6 is required for learning addiction behavior. This proposal will test the hypothesis that Stra6 concentrates retinoids within the sNAc, thereby dynamically regulating dopamine receptor levels and thus the adult function of the sNAc in both spatial learning and addiction. The importance of Stra6 at the BBB will be tested using conditional, EC-specific Stra6 knockout mice to excise Stra6 during development or in adulthood. These aims will also test whether elevating dietary Vitamin A, the source of retinoids, can increase retinoid levels in the absence of Stra6 and rescue sNAc function. The central goals of this proposal are to gain deeper understanding of the BBB’s contribution to brain function, specify mechanisms of addiction, and assess what factors might increase individual susceptibility to drug addiction.

项目摘要/摘要 血脑屏障（BBB）是一个描述中枢神经系统（CNS）独特特性的术语 血管使他们能够严格调节周围中性的细胞外环境 组织。众所周知，不同的大脑区域是由各种细胞类型组成的，并且执行不同 功能，未知BBB是否在功能不同的区域中表现出各种特征来调节特定 神经回路。由于对BBB的异质性知之甚少，因此该项目将解决此差距 知识并追求一个问题，即血脑屏障的区域专业化是否可能调节 本地电路功能和行为。这将确定是否可以将BBB定位为调节特定行为， 包括奖励和成瘾。 单细胞RNA测序表明，BBB通过 内皮细胞（EC）中的差异基因表达。而有助于的规范BBB基因 限制性障碍特性在所有大脑区域的EC中表达，许多与运输有关的基因， 发现信号传导和代谢富集在特定大脑区域的EC中。例如，stra6，一个 类维生素类似的转运调节剂在伏隔核（SNAC）和腹侧非常富集 与大脑的其他区域相比，耳蜗核（VCN）。 SNAC特别感兴趣，因为它 在奖励和加强学习中发挥作用，使该地区在药物成瘾中实现。由于流行和 成瘾的严重程度，迫切重要的是要找到一个新的目标来治疗这一重大公共卫生问题 询问BBB是否通过Stra6在调节成瘾中起作用。 拟议的研究将通过确定（1）在Stra6的区域特异性来解决这一关键需求 BBB对于SNAC的发展或成人功能是必需的，（2）通过哪种分子机制stra6 调节SNAC功能，（3）如果需要Stra6来学习成瘾行为。该建议将测试 假设Stra6在SNAC中浓缩了类视黄素，从而动态调节多巴胺受体 水平以及SNAC在空间学习和成瘾中的成年功能。 Stra6的重要性 BBB将使用有条件的EC特异性Stra6敲除小鼠进行测试，以在开发过程中体验Stra6 或成年。这些目的还将测试升高性维生素A（类视黄素的来源）是否可以 在缺乏Stra6和Rescue SNAC功能的情况下增加退休水平。该提议的核心目标是 为了更深入地了解BBB对大脑功能的贡献，指定成瘾机制，并 评估哪些因素可能会增加个人对吸毒成瘾的敏感性。