Brain neural networks regulating inflammation

调节炎症的脑神经网络

基本信息

批准号：
10718412
负责人：
Sangeeta S. Chavan
金额：
$ 64.1万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-18 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10718412
关键词：
Action Potentials Afferent Neurons Anxiety Arthritis Biological Brain Brain Stem Colitis Communication Creativeness Cytokine Signaling Data Deep Brain Stimulation Development Diabetes Mellitus Diagnostic Etiology Exposure to Fostering Genetic Genetic Techniques Goals Grant Health Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Arthritis Inflammatory Response Interleukin-1 Ischemia Maps Mental Depression Mission Mus Nerve Nervous System Neuroimmunomodulation Neurologic Neurons Nociceptors Organ Transplantation Output Pathogenesis Pathway interactions Peripheral Pharmacogenetics Physiological Play Process Production Public Health Reporting Research Role Sensory Signal Transduction TNF gene Techniques Tissues Transcranial magnetic stimulation Transgenic Mice United States National Institutes of Health Vagus nerve structure Virus Work bioelectronics cholinergic neuron clinically relevant cytokine innovation neural neural circuit neural network neurotransmission novel novel therapeutics optogenetics response response to injury

项目摘要

Project Summary/Abstract Inflammation, the primary biological response to injury and infection, is essential for survival and under precise neuronal control. Sensory neurons, which densely innervate all bodily tissues, report the occurrence of inflammation to the brain, because cytokines and other inflammatory mediators stimulate action potentials. The arrival of incoming sensory signals stimulates brain neurons to send regulatory signals that return to the body and regulate cytokine production. The vagus nerve, a major conduit for body-brain signaling, inhibits inflammation and cytokine production in arthritis, colitis, ischemia, organ transplantation, anxiety-depression, diabetes, and other conditions. In preliminary studies, we (1) used optogenetics and functional mapping to reveal cholinergic neurons in the brain stem significantly increase splenic nerve activity and inhibit TNF production via a significantly specific neuronal pathway; (2) assembled a unique bioelectronic vagus nerve recording toolkit and nociceptor transgenic mouse colonies to reveal sensory vagus nerve pathways activated by IL-1 and TNF; and (3) adapted Cre-based mouse lines and virus constructs enabling the functional combination of mapping activated brain networks and subsequent targeted reactivation of these networks using pharmacogenetics. We identified brain neural networks that respond specifically to IL-1 and TNF, but the function of these networks on the development and progression of inflammation remain undefined. Our long-term goal is to reveal brain neural networks regulating the onset and progression of inflammation, particularly within the setting of inflammatory arthritis in which sensory neuron activation plays a key etiologic role. The objective of this grant is to characterize the role for brain neural network activity in arthritis onset and progression. The central hypothesis is that brain neural network activity plays a critical role in regulating inflammatory arthritis, and the activation of these neurons regulates inflammation. Despite the clinical relevance and the direct importance to understanding basic functional neurological mechanisms of inflammation, the role of brain networks controlling the onset and progression of inflammatory arthritis is completely understudied. Our rationale is that identification of the mechanism(s) to modulate brain neurons in the setting of inflammatory arthritis will reveal new therapeutic opportunities. Here, we will leverage powerful genetic, pharmacogenetic, optogenetic, and bioelectronic approaches for functional mapping and neural circuit analysis to unravel how brain networks are activated by peripheral signals and how they relay outputs to the vagus nerve to impact inflammatory physiological responses. We Aim to use (1) our recently developed genetic techniques which we have used to “trap” subsets of neurons during conditions of activity induced by exposure to cytokines to define brain neural network activity during the onset and progression of inflammatory arthritis and (2) our recently developed pharmacogenetic techniques to selectively “reactivate” these same brain network neurons to assess the mechanisms by which these networks modulate vagus nerve signaling, and therefore, the onset and progression of inflammatory arthritis. The proposed research is innovative because we investigate the effect of brain neural network activity on inflammatory arthritis, a previously unstudied mechanism. 1

项目概要/摘要炎症是对损伤和感染的主要生物反应，对于生存至关重要，并且在精确的控制下神经元控制感觉神经元密集地支配所有身体组织，报告发生的情况。大脑炎症，因为细胞因子和其他炎症介质会刺激动作电位。传入感觉信号的到来刺激大脑神经元发送返回身体的调节信号并调节细胞因子的产生，迷走神经是体脑信号传导的主要管道，可抑制细胞因子的产生。关节炎、结肠炎、缺血、器官移植、焦虑抑郁症中的炎症和细胞因子产生，在初步研究中，我们 (1) 使用光遗传学和功能图谱来揭示。脑干中的胆碱能神经元通过显着增加脾神经活动并抑制 TNF 产生 (2)组装了独特的生物电子迷走神经记录工具包并伤害感受器转基因小鼠群体揭示了 IL-1 和 TNF 激活的感觉迷走神经通路； (3) 适应的基于 Cre 的小鼠品系和病毒构建体能够实现图谱的功能组合激活大脑网络并随后使用药物遗传学有针对性地重新激活这些网络。确定了对 IL-1 和 TNF 做出特异性反应的大脑神经网络，但这些网络的功能炎症的发生和进展仍不清楚，我们的长期目标是揭示大脑神经。调节炎症发生和进展的网络，特别是在炎症环境中感觉神经元激活在关节炎中起关键的病因作用这项资助的目的是确定其特征。大脑神经网络活动在关节炎发作和进展中的作用的中心假设是大脑。神经网络活动在调节炎症性关节炎中起着至关重要的作用，这些神经元的激活尽管具有临床相关性并且对理解基础知识具有直接重要性。炎症的功能性神经机制，大脑网络控制炎症发生和发作的作用我们对炎症性关节炎的进展进行了完全充分的研究。在炎症性关节炎中调节脑神经元的机制将揭示新的治疗方法在这里，我们将利用强大的遗传学、药物遗传学、光遗传学和生物电子学。功能映射和神经回路分析的方法，以揭示大脑网络如何被激活外周信号以及它们如何将输出传递到迷走神经以影响炎症生理反应。我们的目标是使用（1）我们最近开发的遗传技术，我们用它来“捕获”神经元子集在暴露于细胞因子诱导的活动条件下定义脑神经网络活动炎症性关节炎的发病和进展以及（2）我们最近开发的药物遗传学技术选择性地“重新激活”这些相同的大脑网络神经元，以评估这些网络的机制调节迷走神经信号传导，从而调节炎症性关节炎的发生和进展。拟议的研究具有创新性，因为我们研究了大脑神经网络活动对炎症性关节炎，一种以前未经研究的机制。 1