Studies Of Central Nervous System Functional Anatomy

中枢神经系统功能解剖学研究

• 批准号: 6501252
• 负责人: MILES A. HERKENHAM
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6501252
• 关键词: biological signal transduction; blood brain barrier; brain mapping; cannabinoids; corticotropin releasing factor; cytokine; cytokine receptors; drug receptors; growth factor receptors; hypothalamic pituitary axis; immunocytochemistry; in situ hybridization; interleukin 1; lipopolysaccharides; long term potentiation; neuroanatomy; neurochemistry; neuroendocrine system; neuropeptides; neuropharmacologic agent; neurotransmitter metabolism; neurotransmitter receptor; neurotrophic factors; nuclear factor kappa beta; psychoneuroimmunology; tumor necrosis factor alpha

The Section on Functional Neuroanatomy combines molecular and neuroanatomical methods to identify dynamic aspects of nervous system function that relate to issues of mental health, infectious disease, and drug abuse. The current objective of our laboratory is to explore the interaction between the central nervous system (CNS) and the immune system in animals that are subjected to stress, inflammatory stimuli, or infections. Our approach is to identify cellular and molecular components in the brain induced by immunological challenges and to further characterize the responses at molecular, anatomical, and functional levels. Key anatomical pathways and relevant neurotransmitter/receptor systems are mapped using histochemical techniques. In situ hybridization histochemistry (ISHH) is used to localize and quantify mRNA expression of neurotransmitters, cytokines, receptors, transcription factors, and immediate-early genes in studies of adaptive changes to immunological, pharmacological, physiological, or surgical interventions. Immunohistochemistry and double-label techniques are used to characterize the phenotypes of the cells that show induced mRNA expression of immune signaling molecules. We have 1) mapped in the brain the immune response to acute administration of lipopolysaccharide, a bacterial endotoxin, 2) mapped the cerebrospinal and interstitial fluid flow pathways that may be involved in conveying immune signals throughout the brain, 3) shown how an immune stimulus (lipopolysaccharide) behaves once inside the blood-brain barrier, 4) developed a model of chronic immune system activation (trypanosome parasite infection), 5) shown activation of class I major histocompatibility complex (MHC) mRNA in both neuronal and non-neuronal cells under conditions of immune and non-immune physiological challenges, and 6) mapped the cascade of events leading to brain-wide glial activation following central administration of interleukin-1 (IL-1). Gene transcripts shown to be induced in acute and chronic challenges include IL-1, IL-6, IL-12, tumor necrosis factor-alpha (TNF-alpha), IL-1 receptor antagonist (IL-1ra), IL-1 converting enzyme (ICE), transforming growth factor beta (TGF-beta), and other immune signaling molecules such as inhibitory factor kappa B (IkappaB), inducible cyclooxygenase (COX-2), and inducible nitric oxide synthase (iNOS). The mRNAs are shown to be induced in specific cell types (endothelia, microglia, astrocytes, and meninges) and in specific patterns (high levels of expression in the blood vessels, choroid plexus and circumventricular organs). We propose that an important functional component of the innate immune response involves centrally produced cytokines. New projects underway explore interactions between the brain and the immune system during adaptive immune responses. Experimental models include the development of an antineuronal autoimmune response in Lewis rats and the initiation of work in mice using transplanted bone marrow stem cells, which are the progenitor cells of the immune system, including brain microglia.

功能神经解剖学部分结合分子和神经解剖学方法，以确定与心理健康，传染病和药物滥用问题有关的神经系统功能的动态方面。我们实验室目前的目标是探索中枢神经系统（CNS）和免疫系统之间的相互作用，在动物受到压力，炎症刺激，或感染。我们的方法是识别由免疫挑战诱导的大脑中的细胞和分子成分，并进一步表征分子，解剖和功能水平的反应。关键的解剖通路和相关的神经递质/受体系统映射使用组织化学技术。原位杂交组织化学（ISHH）用于定位和定量神经递质，细胞因子，受体，转录因子和即刻早期基因的mRNA表达，以研究免疫学，药理学，生理学或手术干预的适应性变化。免疫组织化学和双标记技术用于表征显示免疫信号分子的诱导mRNA表达的细胞的表型。我们已经1）绘制了大脑中对脂多糖（一种细菌内毒素）急性给药的免疫反应，2）绘制了可能参与整个大脑传递免疫信号的脑脊髓和间质液流动途径，3）显示了免疫刺激如何（脂多糖）一旦进入血脑屏障，4）建立了慢性免疫系统激活模型（锥虫寄生虫感染），5）在免疫和非免疫生理挑战条件下，神经元和非神经元细胞中的I类主要组织相容性复合体（MHC）mRNA均被激活，和6）绘制了在中枢施用白细胞介素-1（IL-1）后导致全脑神经胶质细胞活化的级联事件。显示在急性和慢性激发中诱导的基因转录物包括IL-1、IL-6、IL-12、肿瘤坏死因子-α、IL-12、TNF-α、TNF-α、TNF-α和TNF-α。（TNF-α）、IL-1受体拮抗剂（IL-1 ra）、IL-1转化酶（ICE）、转化生长因子β（TGF-β）和其它免疫信号分子，如抑制因子κ B（IkappaB）、诱导型环氧合酶（考克斯-2）、和诱导型一氧化氮合酶（iNOS）。显示mRNA在特定细胞类型（内皮细胞、小胶质细胞、星形胶质细胞和脑膜）和特定模式（在血管、脉络丛和室周器官中高水平表达）中被诱导。我们提出，先天免疫反应的一个重要功能组成部分涉及集中产生的细胞因子。正在进行的新项目探索在适应性免疫反应期间大脑和免疫系统之间的相互作用。实验模型包括在刘易斯大鼠中产生抗神经元自身免疫反应和使用移植的骨髓干细胞在小鼠中开始工作，骨髓干细胞是免疫系统的祖细胞，包括脑小胶质细胞。