Brain neural networks regulating inflammation

项目总结/摘要 炎症是对损伤和感染的主要生物学反应，对于生存和精确控制是必不可少的。 神经元控制感觉神经元，密集地支配所有身体组织， 炎症对大脑的影响，因为细胞因子和其他炎症介质刺激动作电位。的 传入的感觉信号的到达刺激大脑神经元发送返回到身体的调节信号 调节细胞因子的产生。迷走神经是体脑信号的主要通道， 关节炎、结肠炎、局部缺血、器官移植、焦虑-抑郁 糖尿病和其他疾病。在初步研究中，我们（1）使用光遗传学和功能定位来揭示 脑干中的胆碱能神经元显著增加脾神经活动，并通过 一个显著特异性的神经通路;（2）组装了一个独特的生物电子迷走神经记录工具包， 伤害感受器转基因小鼠集落，以揭示由IL-1和TNF激活的感觉迷走神经通路;和 (3)适应的基于Cre的小鼠系和病毒构建体， 激活的大脑网络和随后使用药物遗传学靶向重新激活这些网络。我们 确定了对IL-1和TNF有特异性反应的脑神经网络，但这些网络的功能在 炎症的发展和进展仍不明确。我们的长期目标是揭示大脑神经 调节炎症的发生和进展的网络，特别是在炎性 感觉神经元激活在其中起关键病因作用的关节炎。该补助金的目的是描述 脑神经网络活动在关节炎发病和进展中的作用。核心假设是大脑 神经网络活动在调节炎症性关节炎中起着关键作用，这些神经元的激活 调节炎症。尽管临床相关性和直接重要性，以了解基本 炎症的功能性神经机制，控制发病的脑网络的作用， 炎症性关节炎的进展完全没有得到充分研究。我们的理由是， 在炎症性关节炎的背景下调节脑神经元的机制将揭示新的治疗方法， 机会在这里，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，以揭示大脑网络是如何被激活的， 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，我们已经用来“陷阱”神经元的子集 在由暴露于细胞因子诱导的活动条件下，以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 调节迷走神经信号传导，并因此调节炎性关节炎的发作和进展。的 提出的研究是创新的，因为我们研究了大脑神经网络活动对 炎症性关节炎，一个以前未研究的机制。 1

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