Investigating the vagal gut-brain circuit regulating hippocampal neurochemistry and neuroinflammation

研究调节海马神经化学和神经炎症的迷走神经肠脑回路

• 批准号: 10534301
• 负责人: HANNAH Burzynski
• 金额: $ 3.76万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-31 至 2024-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10534301
• 关键词: Ablation; Acetylcholine; Address; Affect; Anti-Cholinergics; Anti-Inflammatory Agents; Astrocytes; Attention; Attenuated; Behavioral; Binding; Biochemical; Biological Assay; Brain; Cell Nucleus; Central Nervous System Diseases; Cholecystokinin; Cognition; Cognitive deficits; Collaborations; Communication; Deafferentation procedure; Disease; Enteric Nervous System; Functional disorder; Funding; Gastrointestinal Hormones; Gastrointestinal tract structure; Goals; High Pressure Liquid Chromatography; Hippocampus (Brain); Immune; Immune response; Impaired cognition; Impairment; Inflammation; Inflammatory; Inflammatory Response; Injections; Learning; Link; Literature; Measures; Mediating; Mediator of activation protein; Memory; Mentors; Mentorship; Microdialysis; Microglia; Neuraxis; Nodose Ganglion; Pathology; Peripheral; Pharmacology; Play; Property; Receptor Signaling; Recording of previous events; Reflex action; Research Personnel; Role; Shapes; Speed; Surface; Synapses; Synaptic plasticity; System; Technical Expertise; Techniques; Testing; Therapeutic; Toxin; Vagus nerve structure; Work; alpha-bungarotoxin receptor; basal forebrain; cholinergic; cytokine; gastrointestinal; gut-brain axis; immunoregulation; in vivo; innovation; insight; interest; macrophage; memory process; neural circuit; neurochemistry; neuroinflammation; neurotransmission; novel; object recognition; positive allosteric modulator; preclinical study; prevent; receptor; relating to nervous system; response; therapeutic target; training opportunity; vagus nerve stimulation

Project Summary/Abstract: The gut-brain axis, the bidirectional communication between the central nervous system (CNS) and enteric nervous system, has become implicated in numerous pathologies in the CNS, many of which result in cognitive impairments. Neuroinflammation has been identified as a critical mechanistic mediator of cognitive decline and the gut-brain axis is emerging as an important regulator of peripheral and central inflammation. A chief component of this immunomodulatory axis is the vagus nerve, as it mediates the cholinergic anti-inflammatory network (CAIN) in both the CNS and periphery. Gastrointestinal (GI) vagal afferents extending from the GI tract to the brain have been shown to activate the hippocampus, an essential integration center for learning and memory. Accordingly, the goal of this study is to investigate the vagal gut-brain circuit regulating hippocampal neurochemistry, neuroinflammation and cognition which remains poorly understood. This proposal utilizes a highly innovative technique developed by my collaborator Dr. Guillaume de Lartigue that selectively ablates ~80% of GI vagal afferents with a saporin (SAP) toxin tagged with the GI hormone cholecystokinin (CCK). I will then assess how impairing GI vagal afferents affects cholinergic neurochemistry and neuroinflammation in the hippocampus with in vivo microdialysis, HPLC and biochemical assays. I will also assess the behavioral consequences of GI vagal ablation with the novel object recognition task as Dr. de Lartigue has shown this technique impairs hippocampal-dependent memory processes. To further elucidate this mechanism, I will then assess if these hippocampal impairments can be rescued by a positive allosteric modulator (PAM) of α7 nicotinic acetylcholine receptors (nAChRs) as these receptors on the surface of macrophages, microglia and astrocytes mediate the CAIN. Thus, the overarching hypothesis of this proposal is that positive allosteric modulation of α7 nAChRs rescues hippocampal cholinergic deficits induced by the ablation of gastrointestinal vagal afferents. Completion of these studies will provide insight into the immunoregulatory actions of the gut-brain axis and the integral role this relationship plays in various CNS disorders, especially those with neuroinflammation and cognitive impairments. In addition, this project provides me ample opportunities to diversify my technical skills with a team of mentors who are experts in their fields and have a strong history of collaboration and federal funding. This strong mentorship team also provides extensive networking and dissemination opportunities that will shape me into a productive, independent researcher.

项目摘要/摘要： 肠脑轴，中枢神经系统 (CNS) 和肠道之间的双向通讯 神经系统，与中枢神经系统的许多病理有关，其中许多会导致认知障碍 神经炎症已被确定为认知能力下降的关键机制介质。 肠-脑轴正在成为外周和中枢炎症的重要调节因子。 该免疫调节轴的组成部分是迷走神经，因为它介导胆碱能抗炎作用 中枢神经系统和外周胃肠道（GI）迷走神经传入神经网络（CAIN）从胃肠道延伸。 已被证明可以激活海马体，这是学习和学习的重要整合中心 因此，本研究的目的是研究迷走神经肠脑回路调节海马体。 神经化学、神经炎症和认知仍然知之甚少。 我的合作者 Guillaume de Lartigue 博士开发的高度创新技术，可选择性消融 大约 80% 的胃肠道迷走神经传入带有皂草素 (SAP) 毒素，标记有胃肠道激素胆囊收缩素 (CCK)。 然后评估胃肠道迷走神经传入受损如何影响胆碱能神经化学和神经炎症 我还将通过体内微透析、HPLC 和生化分析对海马进行评估。 胃肠道迷走神经消融与新颖的物体识别任务的后果，正如 de Lartigue 博士所展示的那样 技术会损害海马依赖性记忆过程。为了进一步阐明这种机制，我将随后进行阐述。 评估这些海马损伤是否可以通过α7的正变构调节剂（PAM）来挽救 烟碱乙酰胆碱受体 (nAChR) 是巨噬细胞、小胶质细胞和 因此，该提议的总体假设是正变构。 α7 nAChR 的调节可挽救因消融而引起的海马胆碱能缺陷 完成这些研究将有助于深入了解胃肠道迷走神经传入。 肠脑轴的作用以及这种关系在各种中枢神经系统疾病中发挥的不可或缺的作用，特别是 此外，这个项目还为我提供了充足的帮助。 与导师团队一起使我的技术技能多样化的机会，他们是各自领域的专家，并且拥有 这个强大的指导团队还提供了广泛的合作历史和联邦资助。 网络和传播机会将使我成为一名富有成效的独立研究人员。