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新型的用于光遗传迷走神经刺激的系统，并研究 迷走神经刺激在创伤后应激障碍（PTSD）的啮齿动物模型中的影响。 使用自主神经系统外周神经系统的治疗干预措施越来越多 考虑并应用于调节器官功能以进行疾病治疗。迷走神经刺激（VNS）具有 它还在临床上批准了二十年来，用于治疗癫痫发作和抑郁症。 在治疗诸如类风湿关节炎等炎症性疾病时表现出阳性临床结果 和克罗恩病，虽然临床和临床前数据表明心脏病和 糖尿病。迷走神经的胆碱能（副交感神经）途径是重要因素 观察到的治疗作用。 “胆碱能抗炎途径”是已建立的信号传导 脾脏中促炎细胞因子的表达和释放的机理 在其他内脏组织中。因为炎症是许多疾病的驱动力，所以调节的能力 炎症介体具有重大关注。在最先进的电动迷走神经刺激（VNS）中 但是，电流广泛应用于该刺激的神经和非特异性的性质 目标途径会对患者造成不利影响，此外，无法提供足够的精度 研究和理解与治疗相关的神经途径。拟议的研究将发展和 将光遗传系统应用于迷走神经刺激，可以消除这些脱靶并发症。 借助光遗传学工具，光敏的致动器可以通过遗传靶向靶向有趣的细胞类型 和组织特异性的病毒递送，从而实现了高度特异性的激活和神经回路的投资。 这种神经调节方法将应用于PTSD，这是美国退伍军人的高度普遍燃烧 人口。 PTSD与注射升高高度相关，通常与许多 上面提到的疾病。除了迷走神经的抗炎途径外，有益 在精神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 治疗PTSD，甚至在啮齿动物模型中的VNS可以增强恐惧扩展并减少动画。电流 研究将开发3D打印的迷走神经袖口系统用于光遗传学研究（AIM 1）。这个生物相容性， 单组分，光刺激神经植入物将启用易于制作和易于植入的设备 用于慢性刺激。系统的有效性和寿命将通过评估心脏来验证 在测试系统中的PTSD小鼠之前，在手术植入小鼠中纵向响应性（AIM 2） 模型（AIM 3）。先前描述的单个电动脚印协议将用于调节关联 害怕有条件的刺激 - 冲击室。迷走神经刺激光源靶向有效的 （胆碱能）和/或传入（谷氨酸能）纤维亚型将同时应用，并暴露于 有条件的刺激时间为5天。恐惧的灭绝和动画水平以‘升高 加上迷宫的测试将在受刺激和未刺激的对照动物中进行评估。