Investigation of an Optogenetic Vagus Nerve Stimulation Device in an Animal Model of Post-traumatic Stress Disorder

光遗传学迷走神经刺激装置在创伤后应激障碍动物模型中的研究

• 批准号: 10614408
• 负责人: Arjun K Fontaine
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614408
• 关键词: 3D Print; Adverse effects; Amygdaloid structure; Animal Model; Anti-Inflammatory Agents; Anxiety; Attenuated; Autonomic nervous system; Behavior; Behavioral; Brain; Brain region; Cardiac; Cells; Cervical; Cholinergic Fibers; Chronic; Clinical; Clinical Data; Clinical Trials; Conditioned Stimulus; Control Animal; Crohn' s disease; Cues; Custom; Data; Development; Devices; Diabetes Mellitus; Disease; Effectiveness; Electric Stimulation; Epilepsy; Exposure to; Extinction; Fiber; Fiber Optics; Freezing; Fright; Future; Genetic; Glutamates; Head; Heart Diseases; Heart Rate; Hippocampus; Implant; Individual; Inflammation; Inflammation Mediators; Inflammatory; Intervention; Investigation; Light; Lighting; Longevity; Measurement; Measures; Mechanics; Mental Depression; Mental disorders; Methodology; Methods; Modeling; Moods; Mus; Nature; Nerve; Nerve Tissue; Operative Surgical Procedures; Opsin; Optic Nerve; Optics; Organ; Outcome; Pathology; Pathway interactions; Patients; Peripheral Nerves; Polyethylene Glycols; Post-Traumatic Stress Disorders; Property; Protocols documentation; Reaction; Research; Rheumatoid Arthritis; Risk Factors; Rodent; Rodent Model; Shock; Signal Transduction; Specificity; Spleen; Stimulus; Stress; Surgical sutures; System; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Time; Tissues; Trauma; Vagus nerve structure; Validation; Veterans; Viral; Visceral; Work; anxiety reduction; awake; biomaterial compatibility; cell type; cholinergic; cohort; comorbidity; conditioned fear; cytokine; field study; implantable device; improved; improved outcome; in vivo; interest; light emission; military veteran; mouse model; neural; neural circuit; neuroregulation; novel; novel strategies; optical fiber; optogenetics; pre-clinical; response; selective expression; subcutaneous; tool; vagus nerve stimulation

The proposed research will develop a novel system for optogenetic vagus nerve stimulation and investigate the impact of vagal stimulation in a rodent model of post-traumatic stress disorder (PTSD). Therapeutic interventions using peripheral nerves of the autonomic nervous system are increasingly being considered and applied to modulate organ function for disease treatments. Vagus nerve stimulation (VNS) has been clinically approved for over two decades for its treatment of epileptic seizures and depression. It has also demonstrated positive clinical outcomes in the treatment of inflammatory disorders such as rheumatoid arthritis and Crohn’s disease, while clinical and pre-clinical data suggest therapeutic benefit in heart disease and diabetes. Cholinergic (parasympathetic) pathways of the vagus nerve are an important factor in the therapeutic effects that are observed. The ‘cholinergic anti-inflammatory pathway’ is an established signaling mechanism by which the expression and release of pro-inflammatory cytokines are reduced in the spleen and in other visceral tissues. Because inflammation is a driver of numerous diseases, the ability to regulate inflammatory mediators is of major interest. In state-of-the-art electrical vagus nerve stimulation (VNS), however, current is applied broadly to the nerve and the non-specific nature of this stimulation activates off- target pathways causing adverse effects to the patient, and furthermore, does not provide adequate precision to study and understand therapeutically relevant nerve pathways. The proposed research will develop and apply an optogenetic system for vagus nerve stimulation that can eliminate these off-target complications. With optogenetic tools, light-sensitive actuators can be targeted to cell-types of interest via genetic targeting and tissue-specific viral delivery, thus enabling highly specific activation and investigation of neural circuits. This neuromodulation methodology will be applied to PTSD, a highly prevalent burden among the U.S. Veteran population. PTSD is highly correlated with elevated inflammation and often co-morbid with many of the diseases mentioned above. In addition to the anti-inflammatory pathways of the vagus nerve, beneficial impacts observed in psychiatric and inflammatory disorders suggest that vagal stimulation may be effective in treating PTSD, and indeed, VNS in rodent models enhances fear extinction and reduces anxiety. The current study will develop a 3D-printed vagus nerve cuff system for optogenetic studies (Aim 1). This biocompatible, single-component, optical stimulation nerve implant will enable an easy-to-fabricate and easy-to-implant device for chronic stimulation. The effectiveness and longevity of the system will be validated by assessing cardiac responsivity longitudinally in surgically implanted mice (Aim 2), before testing the system in a PTSD mouse model (Aim 3). A previously described single electric footshock protocol will be used to condition associative fear to a conditioned stimulus – the shock chamber. Vagal stimulation of optogenetically targeted efferent (cholinergic) and/or afferent (glutamatergic) fiber subtypes will be applied concurrently with exposure to the conditioned stimulus over a period of 5 days. Extinction of fear, and anxiety level measured with the ‘elevated plus maze’ test will be assessed in stimulated and non-stimulated control animals.

拟议的研究将开发一种用于光遗传迷走神经刺激的新系统，并研究其在神经系统中的作用。 迷走神经刺激对创伤后应激障碍（PTSD）啮齿动物模型的影响。 使用自主神经系统的外周神经的治疗性干预越来越多地被应用于神经系统。 考虑并应用于调节器官功能以用于疾病治疗。迷走神经刺激（VNS） 二十多年来，它被临床批准用于治疗癫痫发作和抑郁症。它还 在治疗炎性疾病如类风湿性关节炎中显示出积极的临床结果 和克罗恩病，而临床和临床前数据表明，在心脏病和 糖尿病迷走神经的胆碱能（副交感神经）通路是在迷走神经传导中的重要因素。 观察到的治疗效果。“胆碱能抗炎通路”是一种已建立的信号传导途径， 脾中促炎细胞因子的表达和释放减少的机制， 在其他内脏组织中。因为炎症是许多疾病的驱动因素， 炎性介质是主要关注的。在最先进的迷走神经电刺激（VNS）中， 然而，电流被广泛地施加到神经，并且这种刺激的非特异性性质激活关闭， 对患者造成不良影响的靶向途径，此外，未提供足够的精确度 来研究和理解治疗相关的神经通路。该研究计划将开发和 将光遗传学系统应用于迷走神经刺激，可以消除这些脱靶并发症。 利用光遗传学工具，光敏致动器可以通过遗传靶向靶向感兴趣的细胞类型 和组织特异性病毒递送，从而能够高度特异性地激活和研究神经回路。 这种神经调节方法将应用于创伤后应激障碍，这是美国退伍军人中非常普遍的负担。 人口PTSD与炎症升高高度相关，并且通常与许多 上述疾病。除了迷走神经的抗炎通路， 在精神疾病和炎症性疾病中观察到的影响表明，迷走神经刺激可能有效， 在啮齿类动物模型中治疗PTSD和VNS可以增强恐惧消退并减少焦虑。当前 研究将开发用于光遗传学研究的3D打印迷走神经袖带系统（目标1）。这种生物相容性， 单部件、光学刺激神经植入物将实现易于制造和易于植入装置 慢性刺激。系统的有效性和寿命将通过评估心脏 在PTSD小鼠中测试该系统之前，在手术植入小鼠中纵向响应性（目标2） 模型（目标3）。将使用先前描述的单次电脚电击方案来调节关联性 恐惧的条件刺激-休克室。迷走神经刺激光遗传学靶向传出神经 （胆碱能）和/或传入（多巴胺能）纤维亚型将与暴露于 条件刺激超过5天的时间。恐惧和焦虑水平的消退与"升高“ 在受刺激和未受刺激的对照动物中评估十字迷宫试验。