Brain-immune crosstalk in myocardial infarction

心肌梗死患者的脑免疫串扰 项目摘要 心肌梗死（MI）仍然是全世界死亡的主要原因，甚至幸存者也遭受减少的心肌梗死。 生活质量、住院率增加、医疗保健费用高和预期寿命降低。几十年的 研究已经改善了初级预防以及干预和药物治疗，但临床 对于MI患者来说，这仍然是一个巨大的问题，特别是关于MI后愈合方面。虽然一些患者 形成稳定的疤痕，存活心肌适应性重塑， 功能多年，其他患者的初始损害程度相当，迅速发展缺血性心脏 失败，预后极差。此外，MI触发恶性炎症循环， 动脉粥样硬化加速，增加后续缺血事件的风险。各种研究表明 免疫系统在这些过程中起着关键作用。心肌梗塞会激活多种感觉系统， 大脑，包括疼痛，压力和自主神经中心，以及下丘脑和脑干的传感器， 炎症和血流动力学。最近有人描述说，不同的大脑区域控制着大规模的 在急性应激发作期间白细胞移动和功能改变（Poller等人，Nature 2022）。如何 不同的大脑中心协调对MI的免疫反应，以及这些神经免疫轴是否可以 通过靶向非侵入性脑组织，在治疗上用于优化MI后炎症和愈合 干预措施是未知的。该项目结合了神经科学、心脏病学和 全面探索MI如何改变局部大脑活动以及不同的大脑如何 中心反过来又形成MI愈合的过程。AIM 1结合了不同感觉输入分支的中断 使用iDISCO cFos ClearMap组织学、纤维光度测定和逆行追踪来绘制MI诱导的改变 神经元回路活动。初步数据显示心肌梗死后神经元放电发生强烈改变。目标2阐明 MI激活的脑中枢对MI后外周免疫反应的影响。初步数据显示 消融大脑中的应激中心会增加心肌梗死后骨髓和心脏中的白细胞增多，而 MI后下丘脑CRH神经元的化学发生刺激强烈地减少心肌炎症， 这与更好的功能结果相关。目标2将不同的MI模型与 建立了一套获得和丧失功能的干预措施，包括化学遗传学，光遗传学，病毒追踪， 脑区域特异性KO小鼠和细胞类型特异性应激激素受体KO小鼠，以研究如何 不同的脑区域有助于MI后炎症和愈合。最后，Aim 3整合了获得的见解 并专注于阻断有害的同时增强神经免疫信号传导的有益方面，例如通过 在MI后的限定阶段期间动态操纵CRH神经元活动，以治疗性地定制脑- 更好的MI愈合的免疫串扰。目标3将为翻译方法提供科学依据 例如对特定大脑区域进行经颅磁刺激以改善MI患者的预后。

Brain-immune crosstalk in myocardial infarction Project Summary Myocardial infarction (MI) remains a leading cause of death worldwide and even survivors suffer from reduced quality of life, increased hospitalization rates, high health care costs, and lower life expectancy. Decades of research have improved primary prevention as well as interventional and drug therapies, but the clinical problem for MI patients remains huge, particularly regarding aspects of post-MI healing. While some patients develop a stable scar with adaptive remodeling of the surviving myocardium and a compensated cardiac function for many years, other patients with comparable extent of initial damage rapidly develop ischemic heart failure with extremely poor prognosis. Furthermore, an MI triggers a vicious inflammatory cycle of further atherosclerosis acceleration, increasing the risk for subsequent ischemic events. Various studies have shown that the immune system plays a critical role in these processes. An MI activates multiple sensory systems of the brain, including pain, stress, and autonomic centers, as well as hypothalamic and brainstem sensors of inflammation and hemodynamics. It was recently described that distinct brain regions control large scale leukocyte shifts and functional alterations during episodes of acute stress (Poller et al., Nature 2022). How different brain centers orchestrate the immune response to an MI and whether such neuro-immune axes can be therapeutically harnessed to optimize post-MI inflammation and healing via targeted non-invasive brain interventions is unknown. This project combines state-of-the-art tools of neuroscience, cardiology, and immunology to comprehensively explore how an MI alters regional brain activity and how different brain centers in turn shape the course of MI healing. Aim 1 combines interruption of different sensory input branches with iDISCO cFos ClearMap histology, fiber photometry, and retrograde tracing to map MI-induced alterations in neuronal circuit activity. Preliminary data show strongly altered neuronal firing after an MI. Aim 2 elucidates the effects of MI-activated brain centers on the peripheral immune response after an MI. Preliminary data show that ablation of stress centers in the brain increases post-MI leukocytosis in bone marrow and heart, whereas chemogenetic stimulation of hypothalamic CRH neurons after an MI strongly reduces myocardial inflammation, which is known to correlate with better functional outcomes. Aim 2 combines different MI models with an established set of gain and loss-of-function interventions, including chemogenetics, optogenetics, viral tracing, brain-region specific KO mice, and cell-type specific stress hormone receptor KO mice to investigate how different brain regions contribute to post MI inflammation and healing. Finally, Aim 3 integrates gained insights and focuses on blocking detrimental while enhancing beneficial aspects of neuro-immune signaling, e.g. by dynamically manipulating CRH neuron activity during defined phases after an MI, to therapeutically tailor brain- immune crosstalk toward better MI healing. Aim 3 will provide the scientific basis for translational approaches such as transcranial magnetic stimulation of specific brain regions to improve MI patients’ outcomes.