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

项目摘要/摘要： 肠道-脑轴，中枢神经系统(CNS)和肠道之间的双向通讯 神经系统，已经与中枢神经系统的许多病理有关，其中许多导致认知 减损。神经炎症已被确认为认知功能下降和 肠道-脑轴正在成为外周和中枢性炎症的重要调节器。一位酋长 这个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。 中枢神经系统和外围的网络(凯恩)。胃肠(GI)迷走神经传入自胃肠道延伸 已被证明可以激活海马体，海马体是学习和学习的基本整合中心 记忆。因此，本研究的目的是研究迷走神经肠脑回路对海马体的调节。 神经化学、神经炎症和认知仍然知之甚少。这项建议利用了 由我的合作者纪尧姆·德·拉蒂格博士开发的高度创新的技术，选择性地消融 约80%的胃肠道迷走神经传入含有一种用胃肠激素CCK标记的皂苷(SAP)毒素。这就做 然后评估胃肠道迷走神经传入受损对胆碱能神经化学和神经炎症的影响。 用在体微渗析、高效液相色谱和生化分析等方法检测大鼠海马区。我还会评估他们的行为 正如德拉蒂格博士所证明的那样，胃肠道迷走神经消融与新的物体识别任务有关 这项技术损害了海马体依赖的记忆过程。为了进一步阐明这一机制，届时我将 评估α7的阳性变构调节剂能否挽救这些海马区损伤 烟碱型乙酰胆碱受体(NAChRs)作为这些受体存在于巨噬细胞、小胶质细胞和 星形胶质细胞调节该隐。因此，这一提议的首要假设是正变构 α-7nAChRs的调节挽救消融所致的海马胆碱能损伤 胃肠迷走神经传入。这些研究的完成将提供对免疫调节的洞察 肠-脑轴的活动以及这种关系在各种中枢神经系统疾病中所起的整体作用，特别是 那些有神经炎和认知障碍的人。此外，这个项目为我提供了充足的 有机会与一个各自领域的专家导师团队一起使我的技术技能多样化，他们拥有 在合作和联邦资助方面有很强的历史。这支强大的指导团队还提供了广泛的 网络和传播机会，这将把我塑造成一个多产的、独立的研究人员。

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.