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

项目概要/摘要： 肠-脑轴是中枢神经系统（CNS）和肠道之间的双向通讯， 中枢神经系统的神经系统疾病，已经涉及CNS中的许多病理，其中许多导致认知障碍。 损伤神经炎症已被确定为认知衰退的关键机制介导剂， 肠-脑轴正在成为外周和中枢炎症的重要调节器。一名首席 这种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神经系统中的CAIN。胃肠道（GI）迷走神经传入从胃肠道延伸 已经证明，对大脑的刺激可以激活海马体，海马体是学习和 记忆因此，本研究的目的是探讨迷走神经的肠-脑回路对海马神经元的调节作用， 神经化学，神经炎症和认知，仍然知之甚少。该提案利用了 由我的合作者Guillaume de Lartigue博士开发的高度创新的技术， ~80%的胃肠道迷走神经传入神经带有标记有胃肠道激素胆囊收缩素（CCK）的皂草素（SAP）毒素。我会 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， 海马与在体微透析，HPLC和生化测定。我也会评估 GI迷走神经消融与新的物体识别任务的后果，如de Lartigue博士所示， 这种技术损害了依赖于大脑的记忆过程。为了进一步阐明这一机制，我将 评估是否可以通过α7的正变构调节剂（PAM）来挽救这些海马损伤 烟碱乙酰胆碱受体（nAChR）作为巨噬细胞、小胶质细胞和巨噬细胞表面上的这些受体， 星形胶质细胞介导CAIN。因此，该提议的总体假设是，正变构 α7 nAChRs的调节挽救了由消融海马引起的海马胆碱能缺陷 胃肠迷走神经传入这些研究的完成将提供对免疫调节的深入了解。 肠-脑轴的作用以及这种关系在各种中枢神经系统疾病中的整体作用， 那些患有神经炎症和认知障碍的人。此外，该项目为我提供了充足的 有机会与一个导师团队一起使我的技术技能多样化，他们是各自领域的专家， 有着悠久的合作历史和联邦资助。这个强大的导师团队还提供广泛的 网络和传播的机会，这将塑造我成为一个富有成效的，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.