Neurocircuitry of Illness Induced Behavioral Depression

疾病引起的行为抑郁的神经回路

• 批准号: 6867495
• 负责人: LISA E GOEHLER
• 金额: $ 30.06万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6867495
• 关键词: arousal; behavior test; behavioral /social science research tag; brain stem; catecholamines; cognition; depression; emotions; epinephrine; ethology; fos protein; gene expression; immune response; immunocytochemistry; laboratory rat; lipopolysaccharides; microdialysis; neuroanatomy; neurochemistry; neuroimmunomodulation; neuropathology; neurotransmitters; norepinephrine; prosencephalon; psychoneuroimmunology

DESCRIPTION (provided by applicant): The recent recognition that symptoms of behavioral depression form an integral component of the sickness response to many infectious and inflammatory conditions expanded views on the powerful influence of the immune system on the brain. It is now clear that immune activation not only contributes to classic host defense responses, such as fever, but also modulates cognitive and affective states. Whereas studies using the neuronal activation marker c-Fos have identified a constellation of brain nuclei that respond to immune activation, the roles that any of these regions play in the induction of sickness-induced behavioral depression remains undetermined. Our preliminary studies have shown that treatment with an immune stimulant suppresses behavior-related activation of forebrain nuclei associated with arousal, attention and memory, which may underlie the behavioral effects of immune activation. We have also shown that inactivation of the dorsal vagal complex in the brainstem blocks symptoms of behavioral depression and rescues behaviorally associated forebrain activation, i.e. it prevents illness-induced suppression of forebrain nuclei. These findings suggest that incoming neural signals regarding immune activation drive an active inhibition of forebrain regions that is initiated or mediated by the dorsal vagal complex. We intend to tease apart neurocircuitry that drives symptoms of behavioral depression by combining neuroanatomical tract tracers with immunohistochemical detection of neurotransmitter substances and c-Fos expression to identify the connections and neurochemical phenotypes of neurons driven by immune activation. We will then inactivate the neurons associated with the dorsal vagal complex to determine whether they contribute to the symptoms of illness-induced behavioral depression. The experiments designed for this proposal are directed toward developing a clearer picture of the structural and functional organization of brain regions driven by immune activation, and the neurochemical signals involved, that contribute to symptoms of behavioral depression. Findings from these experiments can provide a framework for the understanding and management of cognitive and affective sequelae to illness and chronic inflammatory disorders. An ultimate goal is to be able to predict which type or component of an immune or inflammatory stimulus may trigger anhedonic/depressive symptoms, and be able to predict effective treatments, based on the neurochemistry of the activated immunosensory pathways in the brain.

描述（由申请人提供）：最近认识到，行为抑郁的症状构成了对许多感染性和炎症状况的疾病反应的组成部分，扩大了对免疫系统对大脑的强大影响的看法。现在很明显，免疫激活不仅有助于经典的宿主防御反应，例如发烧，还可以调节认知和情感状态。 使用神经元激活标记C-FOS的研究已经确定了对免疫激活反应的脑核的星座，但这些区域中任何一个地区在诱导疾病引起的行为抑郁症中的作用仍未确定。我们的初步研究表明，使用免疫刺激剂的治疗抑制了与唤醒，注意力和记忆相关的前脑核的行为相关的激活，这可能是免疫激活的行为影响的基础。我们还表明，在脑干中对背部迷走神经复合物的失活会阻止行为抑郁症的症状并挽救行为相关的前脑激活，即，它可以防止疾病引起的前脑核的抑制。这些发现表明，有关免疫激活的传入神经信号驱动了对背部迷走神经复合物引发或介导的前脑区域的主动抑制。我们打算通过将神经解剖学示踪剂与神经递质物质的免疫组织化学检测和C-FOS表达相结合，从而确定由免疫激活驱动的神经化学表型，从而分解神经通路，从而通过将神经解剖学示踪剂与免疫组织化学检测和C-FOS表达相结合来驱动行为抑郁症状。然后，我们将使与背部迷走神经络合物相关的神经元失活，以确定它们是否有助于疾病引起的行为抑郁症的症状。 为该提案设计的实验旨在开发出由免疫激活驱动的大脑区域的结构和功能组织以及所涉及的神经化学信号的更清晰图像，这些信号导致了行为抑郁症的症状。这些实验的发现可以为理解和管理认知和情感后遗症对疾病和慢性炎症性疾病提供一个框架。最终目标是能够预测免疫或炎症刺激的哪种类型或成分可能会触发厌食症/抑郁症状，并基于大脑中激活的免疫感觉途径的神经化学，能够预测有效的治疗方法。