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Studies Of Central Nervous System Functional Anatomy

中枢神经系统功能解剖学研究

基本信息

批准号：
7735101
负责人：
MILES A. HERKENHAM
金额：
$ 104.81万
依托单位：
NATIONAL INSTITUTE OF MENTAL HEALTH
依托单位国家：
美国
项目类别：
财政年份：
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/7735101
关键词：
Alternative Therapies Alzheimer&apos s Disease Anatomy Anhedonia Animal Model Animals Antibodies Anxiety Disorders Attenuated Autistic Disorder Autoimmune Diseases Behavior Behavioral Binding Biochemical Biological Brain Cell Death Cell Nucleus Cell Proliferation Cell Survival Cell physiology Cells Central Nervous System Diseases Cessation of life Child Chromatin Chronic Chronic stress Clinical Research Cognition Commit Complex Condition Cultured Cells Cytoplasm Data Desire for food Development Disease Dose Elements Endotoxins Enzymes Epigenetic Process Etiology Exposure to Functional disorder Gene Expression Genes Glutamates Goals High Prevalence Histocytochemistry Immediate-Early Genes Immune Immune System Diseases Immune System and Related Disorders Immune system Immunity Immunohistochemistry Impaired cognition In Situ Hybridization Infection Inflammation Inflammatory Inflammatory Response Injury Intervention Lead Lipopolysaccharides Localized Measures Mediating Mental Depression Mental disorders Modeling Molecular Mood Disorders Moods Mothers Multiple Sclerosis Mus NF-Kappa B p65 NF-kappa B Nerve Degeneration Nervous System Physiology Neuraxis Neuroanatomy Neurodegenerative Disorders Neurodevelopmental Disorder Neuroglia Neuronal Plasticity Neurons Neurotransmitters Operative Surgical Procedures Pathogenesis Pathologic Pathway interactions Patient currently pregnant Phosphorylation Physiological Play Population Post-Traumatic Stress Disorders Pregnancy Production Psychosocial Stress RNA RNA Probes Rattus Reporting Role Schizophrenia Seizures Signaling Molecule Stimulus Stress System TNFRSF5 gene Techniques Thinking Transgenic Mice Virus Diseases Work chemokine cognitive function cytokine day depressive symptoms design excitotoxicity experience hypothalamic-pituitary-adrenal axis immune function in vivo insight intracellular protein transport mRNA Expression mature animal neurochemistry neuroprotection novel therapeutics prenatal prevent promoter protein transport receptor research study resilience response social social stress stressor therapeutic target tool transcription factor

项目摘要

Our approaches to understanding the relationship between the immune system and the CNS are manifold. On a molecular level, we are working to identify the cellular and molecular pathways in the brain that are engaged in immune challenges, seizures, and behavior manipulations. We are working to further characterize these responses at molecular, anatomical, and functional levels. On a systems and behavioral level, we are working with animal models of chronic stress and prenatal immune challenge to understand the mechanism by which the brain effects the immune system and by which the immune system effects the brain. Our molecular studies focus on the immune molecule NF-kB and the role it plays in neuronal function. NF-kB is found in all cells, but it is normally associated with regulating inflammatory cascades in immune cells. However, its presence in neurons suggests other roles, possibly related to cell survival or neuronal plasticity. We are designing tools to measure NF-kB exclusively in neurons in vivo and to identify the genes it regulates in models of neuronal excitation and excitotoxicity (both of which occur in seizure). We use the technique of in situ hybridization histochemistry (the binding of RNA probes to transcribed RNA targets) 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. We are also using the technique of immunohistochemistry (the binding of antibodies to target moieties) to try and localize and characterize NF-kB activation in neurons. Additionally, we are working with several strains of transgenic mice that either report NF-kB activity or have selectively altered NF-kB function. These mice allow us to analyze the NF-kB response at a neuron-specific cellular level. Some of our findings with these tools include: 1) that the p50 subunit of the NF-kB transcription factor is involved in resilience to stressors in mice, 2) that one function of p50 in controlling gene expression is to modify the epigenetic (chromatin) state of cytokine and chemokine gene promoters, 3) that neuronal NF-kB may be involved in neuroprotection in seizures and in the ability to recall a fearful experience, and 4) that phosphorylation of the p65 subunit of NF-kB occurs in the nuclei of neurons in cell culture and that phosphorylation levels are increased by glutamate stimulation. Also in mice, we are studying the effects of chronic psychosocial stress and environmental enrichment on depressive behavior and immune function. Chronic stress has been implicated in the cause and progression of various psychiatric disorders, including depression and post-traumatic stress disorder (PTSD). Furthermore, chronic stress has been shown to activate the stress axis (hypothalamic-pituitary-adrenal (HPA) axis) and to dysregulate the inflammatory response to infectious elements. Working with a naturalistic model of unavoidable chronic social stress, using a dominant-subordinate animal pairing design, we have shown that exposure to chronic stress dysregulates the immune system. We are continuing to work to identify the mechanisms by which stress has this deleterious effect. Additionally, our lab has shown that environmental enrichment can actually prevent and attenuate this immune dysfunction as well as depressive-like behaviors in subordinate mice exposed to social stress. Moreover, animals exposed to environmental enrichment are generally healthier, have better cognitive function, and are less susceptible to neurodegenerative diseases than animals not exposed to environmental enrichment. This work offers insight into the ways in which the CNS and the immune system interact, and it suggests that environmental enrichment can counter the damaging effects of chronic stress and should be considered as an alternative therapy in depressive diseases. Sickness behavior, like that which follows bacterial or viral infection, has CNS-mediated components that mimic depression in that loss of appetite, sleepiness, anhedonia, and lethargy accompany both. There have been arguments that infections and immune system disorders contribute to depression and other mental disorders. Low-to-high doses of pathogenic stimuli such as the bacterial endotoxin lipopolysaccharide (LPS) have been used to mimic infections in animal models of inflammation-induced neurochemical and behavioral alterations. The changes are usually transient in adult animals. However, there are some data showing that high-dose LPS administration can cause long-lasting and even permanent CNS inflammatory and neurodegenerative changes. Moreover, exposure to immune challenge during development appears to have profound, permanent effects on the offspring of the infected mother (effects that mimic depressive, autistic, and psychotic behavior). In clinical studies, correlations have been reported between maternal infections and higher prevalence of mental illness in their children. We are using the maternal immune activation (MIA) model to study disorders with early neurodevelopmental etiology, such as schizophrenia, autism, and anxiety disorder. In a set of experiments performed in rats, we have developed a MIA model in which pregnant dams are subjected to an immune challenge (LPS administration) at day 15 of gestation, and the offspring are studied for behavioral alterations (like social deficits that mirror autism and cognitive dysfunctions that mirror schizophrenia) and their underlying biochemical causes. By studying the biological changes underlying these behavioral changes, we hope to better understand the etiology and pathogenesis of these and other diseases.

我们理解免疫系统和中枢神经系统之间关系的方法是多种多样的。在分子水平上，我们正在努力识别大脑中参与免疫挑战，癫痫发作和行为操纵的细胞和分子途径。我们正在努力在分子、解剖和功能水平上进一步表征这些反应。在系统和行为水平上，我们正在研究慢性应激和产前免疫挑战的动物模型，以了解大脑影响免疫系统的机制以及免疫系统影响大脑的机制。我们的分子研究集中在免疫分子NF-kB及其在神经元功能中的作用。 NF-kB存在于所有细胞中，但它通常与调节免疫细胞中的炎症级联反应有关。然而，它在神经元中的存在表明了其他作用，可能与细胞存活或神经元可塑性有关。我们正在设计工具来测量NF-kB专门在体内神经元和确定它调节的基因在模型中的神经元兴奋和兴奋性毒性（这两者都发生在癫痫发作）。我们使用原位杂交组织化学技术（RNA探针与转录的RNA靶点结合）来定位和定量神经递质、细胞因子、酶、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、行为学或手术操作的适应性变化。我们还使用免疫组织化学技术（抗体与靶分子的结合）来尝试定位和表征神经元中的NF-kB激活。此外，我们正在研究几种转基因小鼠，这些小鼠要么报告NF-kB活性，要么选择性改变NF-kB功能。这些小鼠使我们能够在神经元特异性细胞水平上分析NF-kB反应。我们使用这些工具的一些发现包括：1）NF-κ B转录因子的p50亚基参与小鼠对应激源的恢复，2）p50在控制基因表达中的一个功能是修饰表观遗传学上的细胞因子和趋化因子基因启动子的（染色质）状态，3）神经元NF-kB可能参与癫痫发作的神经保护和回忆恐惧经历的能力，和4）NF-κ B的p65亚基的磷酸化发生在细胞培养物中的神经元的核中，并且磷酸化水平通过谷氨酸刺激而增加。同样在小鼠中，我们正在研究慢性心理社会压力和环境丰富对抑郁行为和免疫功能的影响。慢性压力与各种精神疾病的原因和进展有关，包括抑郁症和创伤后应激障碍（PTSD）。此外，慢性应激已被证明激活应激轴（下丘脑-垂体-肾上腺（HPA）轴）和失调的炎症反应感染元素。通过一个不可避免的慢性社会压力的自然主义模型，使用一个支配-从属动物配对设计，我们已经证明了暴露于慢性压力会使免疫系统失调。我们正在继续努力确定压力产生这种有害影响的机制。此外，我们的实验室已经表明，环境丰富实际上可以预防和减轻这种免疫功能障碍以及暴露于社会压力的从属小鼠的抑郁样行为。此外，暴露于环境富集的动物通常更健康，具有更好的认知功能，并且比未暴露于环境富集的动物更不易患神经退行性疾病。这项工作提供了对中枢神经系统和免疫系统相互作用的方式的深入了解，它表明环境丰富可以对抗慢性压力的破坏性影响，应该被认为是抑郁症的替代疗法。疾病行为，如细菌或病毒感染后的行为，具有CNS介导的类似抑郁的成分，即食欲不振、嗜睡、快感缺乏和嗜睡。有人认为感染和免疫系统紊乱会导致抑郁症和其他精神疾病。低到高剂量的致病性刺激物，如细菌内毒素脂多糖（LPS）已被用于模拟炎症诱导的神经化学和行为改变的动物模型中的感染。这些变化在成年动物中通常是短暂的。然而，有一些数据表明，高剂量LPS给药可引起持久的甚至永久性的CNS炎症和神经退行性变化。此外，在发育过程中暴露于免疫攻击似乎对受感染母亲的后代产生了深远的永久影响（模仿抑郁症，自闭症和精神病行为的影响）。在临床研究中，据报道，母亲感染与其子女精神疾病的发病率较高之间存在相关性。我们正在使用母体免疫激活（MIA）模型来研究早期神经发育病因学疾病，如精神分裂症，自闭症和焦虑症。在大鼠中进行的一组实验中，我们开发了一种MIA模型，其中妊娠母鼠在妊娠第15天接受免疫挑战（LPS给药），并研究后代的行为改变（如反映自闭症的社会缺陷和反映精神分裂症的认知功能障碍）及其潜在的生化原因。通过研究这些行为变化背后的生物学变化，我们希望更好地了解这些和其他疾病的病因和发病机制。