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？

基本信息

批准号：
10661728
负责人：
Iris Haleakala Garcia-Pak
金额：
$ 5.27万
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：
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/10661728
关键词：
Acute Address Adult Affect Aging All-Trans-Retinol Alzheimer&apos s Disease Area Basal Ganglia Behavior Biological Blood - brain barrier anatomy Blood Vessels Blood brain barrier dysfunction Brain Brain region Cell Differentiation process Cell Survival Central Nervous System Cerebellum Cochlear nucleus Corpus striatum structure Development Developmental Process Diet Disease Disease Progression Dopamine Dopamine D2 Receptor Dopamine Receptor Drug Addiction Endothelial Cells Endothelium Environment Equilibrium Exhibits Gene Expression Gene Expression Profile Genes Goals Health system Heterogeneity Hippocampus Homeostasis Hypothalamic structure Immune system Individual Knock-out Knockout Mice Knowledge Learning Membrane Metabolism Molecular Mus Nervous System Physiology Neurons Nucleus Accumbens Organ Pathway interactions Peripheral 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 neural circuit neuropsychiatric disorder receptor single-cell RNA sequencing therapeutic target

项目摘要

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.

项目概要/摘要血脑屏障（BBB）是描述中枢神经系统（CNS）独特性质的术语血管使它们能够严格调节周围神经的细胞外环境众所周知，不同的大脑区域由不同的细胞类型组成并执行不同的任务。功能，尚不清楚 BBB 是否在功能不同的区域表现出不同的特征来调节特定的由于对 BBB 的异质性知之甚少，该项目将解决这一差距。知识并探究血脑屏障的区域专业化是否可以调节的问题这将确定 BBB 是否可以针对调节特定行为，包括奖励和成瘾。单细胞 RNA 测序揭示 BBB 存在显着的区域间异质性内皮细胞 (EC) 中的差异基因表达，而有助于形成典型 BBB 基因。限制性屏障特性在所有大脑区域的 EC 中表达，许多基因涉及运输，研究发现，特定大脑区域的 EC 中富含信号传导和代谢功能，例如 Stra6。视黄醇转运调节剂，在伏隔核壳 (sNAc) 和腹侧极其丰富与大脑的其他区域相比，耳蜗核（VCN）尤其令人感兴趣，因为它的作用。由于药物成瘾的普遍性和强化学习的功能，该区域与药物成瘾有关。鉴于成瘾的严重性，迫切需要找到新的目标来治疗这一重大公共卫生问题通过 Stra6 询问 BBB 是否在调节成瘾方面发挥作用。拟议的研究将通过确定 (1) Stra6 的区域特殊性是否满足这一关键需求 BBB 对于 sNAc 的发育或成年功能是必需的，(2) Stra6 通过什么分子机制调节 sNAc 功能，以及（3）Stra6 是否是学习成瘾行为所必需的。该提案将测试 sNAc 功能。假设 Stra6 将类视黄醇浓缩在 sNAc 内，从而动态调节多巴胺受体 Stra6 在空间学习和成瘾中的重要性。 BBB 将使用有条件的 EC 特异性 Stra6out 敲除小鼠在发育过程中切除 Stra6 进行测试这些目标还将测试提高膳食维生素A（类维生素A的来源）是否可以。在没有 Stra6 的情况下增加类视黄醇水平并挽救 sNAc 功能该提案的中心目标是。更深入地了解 BBB 对大脑功能的贡献，明确成瘾机制，以及评估哪些因素可能会增加个体对毒瘾的易感性。