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： 肠道轴，中枢神经系统（CNS）之间的双向通信，然后进入 神经系统已在中枢神经系统中的许多病理中被隐含，其中许多导致认知 障碍。神经炎症已被确定为认知下降和 肠脑轴正在成为周围和中央注射的重要调节剂。酋长 该免疫调节轴的成分是迷走神经，因为它介导胆碱能抗炎 中枢神经系统和外围的网络（该隐）。胃肠道（GI）迷走神经传入从胃肠道延伸 已经证明大脑可以激活海马，这是一个学习和 记忆。根据这项研究的目的是研究调节海马的迷走神经肠脑电路 神经化学，神经炎症和认知仍然知之甚少。该建议利用 由我的合作者Guillaume de Lartigue博士开发的高度创新技术，有选择地消融 〜80％的胃肠道传入含有糖蛋白（SAP）毒素，上标有Gi Horsene胆囊动蛋白（CCK）。我会 然后评估胃肠道迷走神经传入如何影响胆碱能神经化学和神经炎症 海马带有体内微透析，HPLC和生化测定法。我还将评估行为 Gi迷走融化与新的对象识别任务的后果，因为De Lartigue博士已经证明了这一点 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 评估这些海马损伤是否可以通过α7的阳性变构调节剂（PAM）挽救 烟碱乙酰胆碱受体（NACHRS）作为巨噬细胞，小胶质细胞和 星形胶质细胞介导该隐。这就是该提议的总体假设是积极的变构 α7NACHRS的调节营救了由消融诱导的海马胆碱能缺乏症 胃肠道迷走神经传入。这些研究的完成将提供有关免疫调节的洞察力 肠道轴的作用和这种关系在各种中枢神经系统疾病中起着不可或缺的作用，尤其是 患有神经炎症和认知障碍的人。此外，这个项目为我提供了足够的 与一组专家的导师团队，有机会多样化我的技术技能，并拥有 合作和联邦资金的悠久历史。这个强大的心态团队还提供了广泛的 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。