Studies Of Central Nervous System Functional Anatomy

中枢神经系统功能解剖学研究

• 批准号: 6979916
• 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/6979916
• 关键词: MHC class I antigen; anxiety; autoradiography; brain mapping; cytokine; cytokine receptors; genetically modified animals; immunocytochemistry; immunogenetics; immunoregulation; in situ hybridization; inflammation; laboratory mouse; laboratory rat; lipopolysaccharides; neurochemistry; neuroimmunomodulation; nuclear factor kappa beta; psychoneuroimmunology; stress; toll like receptor

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 have selective gene deletions (transgenic mice) or that are subjected to stress, inflammatory stimuli, or infections. Our approach is to clarify the normal and pathophysiological roles of immune system molecules in the brain, to identify cellular and molecular components 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, enzymes, receptors, transcription factors, and immediate-early genes in studies of adaptive changes to immunological, pharmacological, physiological, behavioral, or surgical manipulations. 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) 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, 2) cataloged immune system mRNA expression level changes in the hippocampus and frontal cortex of rats given a single electroconvulsive shock, 3) mapped activin and brain-derived neurotrophic factor (BDNF) mRNA induction in the kindling model of epilepsy, 4) characterized the role of toll-like receptors (TLR4) in the peripheral hematopoietic versus central (non-hematopoietic) compartments in mediating the CNS response to peripheral lipopolysaccharide (LPS) challenge, and 5) shown for the first time that the p50 subunit of the NF-kB transcription factor is involved in normal expression of emotional behavior in mice. Current work examines the role of other TLRs in detecting pathogen-associated molecules and alerting the brain about peripheral immune challenges. We are also continuing work aimed at defining the role that the NF-kB transcription factor plays in anxiety-like behavior and in response to stressors.

功能神经解剖学部分结合分子和神经解剖学方法来识别与精神健康、传染病和药物滥用问题相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具有选择性基因缺失的动物（转基因小鼠）或遭受压力，炎症刺激或感染的中枢神经系统（CNS）和免疫系统之间的相互作用。我们的方法是澄清免疫系统分子在大脑中的正常和病理生理作用，识别由免疫挑战诱导的细胞和分子成分，并进一步表征分子、解剖和功能水平上的反应。使用组织化学技术绘制了关键的解剖通路和相关的神经递质/受体系统。原位杂交组织化学（ISHH）用于定位和量化神经递质、细胞因子、酶、受体、转录因子和即时早期基因的mRNA表达，用于研究免疫、药理学、生理、行为或手术操作的适应性变化。免疫组织化学和双标记技术用于表征显示诱导免疫信号分子mRNA表达的细胞表型。我们已经1)显示了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I类主要组织相容性复合体（MHC） mRNA的激活，2)编目了单次电休克大鼠海马和额叶皮层免疫系统mRNA表达水平的变化，3)绘制了癫痫点燃模型中激活素和脑源性神经营养因子（BDNF） mRNA的诱导图谱。4)表征了toll样受体（TLR4）在外周造血室和中央（非造血）室中介导CNS对外周脂多糖（LPS）挑战的反应中的作用；5)首次表明NF-kB转录因子的p50亚基参与小鼠正常情绪行为的表达。目前的工作是研究其他tlr在检测病原体相关分子和提醒大脑外周免疫挑战中的作用。我们还在继续研究NF-kB转录因子在类焦虑行为和应激反应中所起的作用。