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）是一种残疾的精神病病，在 战斗退伍军人。只有一小部分暴露于创伤的人会发展为PTSD，这表明已经存在 神经生物学因素有助于敏感/风险。目前，特定的分子/电路级机制 这有助于PTSD风险的定义不明确。大量信息支持预先存在的功能障碍 在恐惧电路中可能会促进PTSD的脆弱性，但是有助于创伤前个体的机制 恐惧调节的差异尚不清楚。迄今为止，我们当前对恐惧的大多数理解是基于 对外部威胁的防御反应。而情绪调节中“身体对脑”信号的重要性 长期以来一直被认可，稳态威胁在塑造恐惧和PTSD风险中的个体差异中的作用 尚未进行调查。先前的研究报告说，PTSD对碳的退伍军人的敏感性提高 二氧化碳（CO2），一种稳态威胁，产生了强烈的恐惧。重要的是，预部部二氧化碳敏感性 与后来发展PTSD症状的伴侣，表明CO2敏感性和相关性 机制可以提供有关PTSD风险的宝贵信息。 PI实验室的先前工作报道了白介素1受体（IL-1R1）信号的独特作用 血脑屏障（BBB）折衷的感觉环周围区域，副骨架器官（SFO）二氧化碳诱发 恐惧回应。在CO2敏感性-PTSD的小鼠模型中，我们观察到延迟的恐惧扩展定义了，并且 二氧化碳敏感小鼠的惊吓增强，这是SFO中IL-1R1拮抗作用减弱的反应。我们的分子 研究揭示了IL-1R1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 靶标和前脑区域的肌层皮质和质子末端的床核（BNST）也在 PTSD。总的来说，我们的数据支持互感大脑中独特的神经血管信号传导机制 可能调节前脑恐惧电路的区域（SFO）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有助于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，即SFO神经血管IL-1R1-RAS与前脑电路的相互作用 促进CO2敏感性和PTSD相关行为将在三个目标下进行测试。 AIM 1将测试 CO2相关的PTSD相关行为取决于SFO内皮IL-1R1和RAS的假设 将在暴露的空气/二氧化碳中测量延迟的恐惧调节，扩展和惊吓（PTSD相关的行为） IL-1R1的野生型或内皮特异性缺失（TIE-2CRE：IL1R1FL/FL）小鼠用SFO靶向RAS处理的小鼠 调节器。 AIM 2将检验以下假设：二氧化碳诱发的SFO投影神经元的激活取决于 在内皮内皮IL-1R1和AT1R信号传导功能IL-1R1-RAS关联将使用斑块进行评估 野生型SFO切片中的夹具电生理学和药理学，TIE-2CRE：IL1R1FL/FL或AT1R-TDTOMATO 记者小鼠。 AIM 3将检验SFO►IL和SFO►BNST项目规范PTSD相关的假设 行为。使用逆转录依赖性的化学遗传策略，我们将调整SFO►IL和SFO►BNST 二氧化碳挑战和测量与PTSD相关的恐惧和惊吓行为期间的预测 相关性：我们的数据将揭示独特的神经血管核心机制和新型电路PTSD 风险。除了CO2之外，该机制与潜在的神经免疫性，RA和神经血管异常有关 在具有PTSD的退伍军人中报告的长期目标是确定预测危险因素和治疗目标 用于资深人口中PTSD的管理。