Neurovascular signaling and associated forebrain circuits in PTSD

PTSD 中的神经血管信号传导和相关前脑回路

• 批准号: 10005544
• 负责人: RENU SAH
• 金额: --
• 依托单位: CINCINNATI VA MEDICAL CENTER RESEARCH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005544
• 关键词: Acidosis; Air; Angiotensin-Converting Enzyme Inhibitors; Area; Attenuated; Behavior; Behavior Disorders; Blood - brain barrier anatomy; Brain; Brain region; Captopril; Carbon Dioxide; Cell Communication; Cells; Data; Development; Electrophysiology (science); Endothelial Cells; Endothelium; Extinction (Psychology); Female; Fright; Functional disorder; Genetic Polymorphism; Goals; IL1R1 gene; Impairment; Individual; Individual Differences; Inhalation; Interleukin-1; Interleukin-1 Receptors; Interleukin-1 beta; Intervention; Link; Losartan; Measures; Modeling; Molecular; Mus; Neurobiology; Neuroimmune; Neurons; Outcome; Patient Care; Peptidyl-Dipeptidase A; Pharmacology; Post-Traumatic Stress Disorders; Predisposition; Prosencephalon; Reaction; Receptor Signaling; Receptor, Angiotensin, Type 1; Regulation; Renin-Angiotensin System; Reporter; Reporting; Research; Risk; Risk Factors; Role; Saline; Sensory; Shapes; Signal Transduction; Slice; Structure of terminal stria nuclei of preoptic region; Subfornical Organ; Symptoms; Testing; Therapeutic; Transgenic Organisms; Trauma; Veterans; Work; anakinra; attenuation; base; combat veteran; conditioned fear; disorder risk; emotion regulation; male; military veteran; mouse model; neurovascular; novel; patch clamp; pre-clinical; predictive marker; resilience; response; therapeutic target; trauma exposure

Posttraumatic Stress Disorder (PTSD) is a disabling psychiatric condition that is highly prevalent in combat veterans. Only a fraction of trauma-exposed individuals develop PTSD, suggesting that pre-existing neurobiological factors contribute to susceptibility/ risk. Currently, specific molecular/ circuit-level mechanisms that contribute to PTSD risk are not well-defined. Substantial information supports that pre-existing dysfunction in fear circuits may promote vulnerability to PTSD, however mechanisms contributing to pre-trauma individual differences in fear regulation are unclear. To date, most of our current understanding of fear is based on defensive reactions to external threats. While the importance of “body-to-brain” signaling in emotional regulation has long been recognized, the role of homeostatic threats in shaping individual differences in fear and PTSD risk has not been investigated. Previous studies reported increased sensitivity in veterans with PTSD to carbon dioxide (CO2), a homeostatic threat producing intense fear. Importantly, pre-deployment CO2 sensitivity associates with later development of PTSD symptoms, suggesting that CO2 sensitivity and associated mechanisms can provide valuable information on PTSD risk. Previous work from the PI’s lab reported a unique role of interleukin 1 receptor (IL-1R1) signaling within blood-brain-barrier (BBB) compromised sensory circumventricular area, subfornical organ (SFO) in CO2-evoked fear responses. In a mouse model of CO2 sensitivity-PTSD, we observed delayed fear extinction deficits and enhanced startle in CO2-sensitive mice, a response attenuated by IL-1R1 antagonism in SFO. Our molecular studies reveal IL-1R1 localization on SFO endothelial cells and interaction with renin angiotensin system (RAS) targets, and forebrain regions infralimbic cortex and bed nucleus of stria terminalis (BNST), also implicated in PTSD. Collectively, our data support a unique neurovascular signaling mechanism in an interoceptive brain region (SFO) that may regulate forebrain fear circuits contributing to increased PTSD risk. Proposed studies will investigate how neurovascular mechanisms within the SFO regulate fear circuits and contribute to PTSD- relevant behaviors. We will use cell-circuit based transgenic, electrophysiological and chemogenetic approaches in male and female mice. Our hypothesis that, SFO neurovascular IL-1R1-RAS interactions with forebrain circuits promote CO2-sensitivity and PTSD relevant behaviors will be tested under three aims. Aim 1 will test the hypothesis that CO2-associated PTSD relevant behaviors are dependent on SFO endothelial IL-1R1 and RAS Delayed fear conditioning, extinction, and startle (PTSD-relevant behaviors) will be measured in air/CO2 exposed wild type or endothelial-specific deletion of IL-1R1 (Tie-2Cre:IL1R1fl/fl) mice treated with SFO-targeted RAS modulators. Aim 2 will test the hypothesis that CO2-evoked activation of SFO projection neurons is dependent on endothelial IL-1R1 and AT1R signaling Functional IL-1R1-RAS associations will be assessed using patch clamp electrophysiology and pharmacology in SFO slices from wild type, Tie-2Cre:IL1R1fl/fl or AT1R-tdtomato reporter mice. Aim 3 will test the hypothesis that SFO►IL and SFO►BNST projections regulate PTSD relevant behaviors. Using a retroCre-dependent chemogenetic strategy we will modulate SFO ►IL and SFO►BNST projections during the CO2 challenge and measure delayed PTSD-relevant fear and startle behaviors Relevance: Our data will reveal a unique neurovascular core mechanism and novel circuit underlying PTSD risk. Beyond CO2, this mechanism is relevant to underlying neuroimmune, RAS and neurovascular abnormalities reported in veterans with PTSD The long-term goal is to identify predictive risk factors and therapeutic targets for management of PTSD in the veteran population.

创伤后应激障碍（PTSD）是一种致残性精神疾病， 退伍军人只有一小部分创伤暴露的个体会发展为PTSD，这表明先前存在的创伤可能会导致PTSD。 神经生物学因素有助于易感性/风险。目前，特定的分子/电路水平机制 导致创伤后应激障碍风险的因素还没有很好的定义。大量的信息表明，预先存在的功能障碍 在恐惧回路中，可能会促进创伤后应激障碍的脆弱性，然而， 恐惧调节的差异尚不清楚。到目前为止，我们对恐惧的理解大多基于 对外部威胁的防御性反应。虽然“身体到大脑”信号在情绪调节中的重要性 长期以来，人们已经认识到，稳态威胁在形成恐惧和PTSD风险的个体差异中的作用 尚未被调查。先前的研究报告说，患有PTSD的退伍军人对碳的敏感性增加 二氧化碳（CO2），一种产生强烈恐惧的稳态威胁。重要的是，部署前的二氧化碳敏感性 与PTSD症状的后期发展有关，这表明CO2敏感性和相关的 机制可以提供有关PTSD风险的有价值的信息。 PI实验室以前的工作报告了白细胞介素1受体（IL-1 R1）信号在细胞内的独特作用。 血脑屏障（BBB）损害感觉室周区，穹窿下器官（SFO）在CO2诱发的 恐惧反应。在CO2敏感性-PTSD小鼠模型中，我们观察到延迟性恐惧消退缺陷， 增强CO2敏感小鼠的惊吓，SFO中IL-1 R1拮抗作用减弱的反应。我们的分子 研究揭示了IL-1 R1在SFO内皮细胞上的定位以及与肾素血管紧张素系统（RAS）的相互作用 靶点以及前脑区域边缘下皮质和终纹床核（BNST）也参与其中 创伤后应激障碍总的来说，我们的数据支持内感受性大脑中独特的神经血管信号传导机制 区域（SFO）可能调节前脑恐惧回路，导致PTSD风险增加。拟议的研究将 研究SFO内的神经血管机制如何调节恐惧回路并导致PTSD- 相关行为。我们将使用基于细胞电路的转基因、电生理和化学遗传学方法 在雄性和雌性小鼠中。我们的假设是，SFO神经血管IL-1 R1-RAS与前脑回路的相互作用 促进CO2敏感性和PTSD相关行为将在三个目标下进行测试。目标1将测试 CO2相关PTSD相关行为依赖于SFO内皮细胞IL-1 R1和RAS的假设 将在空气/CO2暴露条件下测量延迟恐惧条件反射、消退和惊吓（PTSD相关行为） 用SFO靶向RAS处理的野生型或内皮特异性IL-1 R1缺失（Tie-2Cre：IL 1 R1 fl/fl）小鼠 调制器。目的2将检验CO2诱发的SFO投射神经元激活依赖于 对内皮细胞IL-1 R1和AT 1 R信号传导的影响 来自野生型、Tie-2Cre：IL 1 R1 fl/fl或AT 1 R-td番茄的SFO切片中的钳位电生理学和药理学 报告小鼠。目的3将检验SFO BNST和SFO BNIL投射调节PTSD相关的假设， 行为。使用一种依赖于逆转录Cre的化学发生策略，我们将调节SFO β IL和SFO β BNST。 预测在CO2挑战和测量延迟PTSD相关的恐惧和惊吓行为 相关性：我们的数据将揭示一个独特的神经血管核心机制和新的电路潜在的创伤后应激障碍 风险除CO2外，该机制与潜在的神经免疫、RAS和神经血管异常相关 长期目标是确定预测性风险因素和治疗靶点 治疗退伍军人的创伤后应激障碍