Alterations in Ventral Hippocampal CA1 Processing as a Mechanism for Anxiety in Alzheimer’s Disease

项目摘要/摘要 焦虑是阿尔茨海默病(AD)的一种高度普遍和负担沉重的症状，尤其是在早期， 并与更快的衰退有关。进一步的机械论理解将改进目前的治疗方法，这些治疗方法 效果不佳和/或有明显的副作用。然而，阿尔茨海默病焦虑的病理生理机制尚不清楚。CA1 腹侧海马区(VCA1)，特别是其深锥体神经元(DPN)，可能在 在阿尔茨海默病焦虑发生中的重要作用。众所周知，vCA1 DPN在焦虑时会增加它们的活动 行为和投射到广泛的焦虑症网络的其他区域，包括杏仁核、前额叶皮质和 下丘脑。此外，与背侧CA1相比，vCA1具有更强的内源性和突触兴奋性 基线，似乎更容易受到早期阿尔茨海默病的影响。在这里，我们的目标是获得特定于细胞类型的 了解AD如何影响腹侧CA1，以便更好地了解AD的焦虑发生。具体来说，我们 验证阿尔茨海默病患者焦虑与vCA1DPN过度兴奋有关的假设。这一假设是 得到上述支持，并发表了初步工作，表明AD相关的vCA1存在漏洞 焦虑，在AD中，DPN容易出现内在的过度兴奋和兴奋-抑制失衡。vbl.使用 在3xTg-AD小鼠模型中，我们以以下目的验证我们的中心假设。在目标1中，我们使用体外 电生理学和逆行标记阐明突触和固有的AD相关改变 VCA1DPN的兴奋性由其投射面积定义。在目标2中，我们使用植入式显微内窥镜 GCaMP钙信号成像、c-fos免疫组织化学和逆行标记检测In 阿尔茨海默病小鼠焦虑行为期间vCA1DPN和投射定义的DPN亚群的活体活性。 这项工作将提供两个主要结果，将显著增加对AD焦虑的理解，在 电路体系结构和总体编码的级别。我们的战略在概念和技术上都是创新的， 利用特定细胞类型的电路知识和最先进的方法来应对疾病 细胞水平的病理生理学。为了支持我们的假设，这些实验将确定哪个vCA1 DPN亚群及其兴奋机制将是未来工作的重点。更广泛地说， 这些结果将促进对腹侧海马区AD变化的特定细胞类型的理解 这在机械学研究中受到的关注较少，非常容易受到AD的影响，而且不仅对 焦虑，但也包括社交和激励行为。

PROJECT SUMMARY/ABSTRACT Anxiety is a highly prevalent and burdensome symptom of Alzheimer disease (AD), especially at early stages, and is linked to faster decline. Further mechanistic understanding would improve current treatments, which are suboptimal and/or carry significant side effects. Yet, the pathophysiology of anxiety in AD is unclear. The CA1 region of ventral hippocampus (vCA1), and specifically its deep pyramidal neurons (dPNs), may play a significant role in anxiogenesis in AD. The vCA1 dPNs are known to increase their activity during anxious behavior and project to other areas of the broad anxiogenic network, including amygdala, prefrontal cortex, and hypothalamus. In addition, compared to dorsal CA1, vCA1 features more intrinsic and synaptic excitability at baseline and appears to be more vulnerable to early AD. Here, our objective is to obtain a cell type-specific understanding of how AD affects ventral CA1 in order to better understand anxiogenesis in AD. Specifically, we test the hypothesis that anxiety in AD relates to hyperexcitability of the vCA1 dPNs. This hypothesis is bolstered by the above, and published and preliminary work suggesting vulnerability of vCA1 in AD-related anxiety and that, in AD, dPNs are prone to intrinsic hyperexcitability and excitatory-inhibitory imbalance. Using the 3xTg-AD mouse model, we test our central hypothesis with the following aims. In Aim 1, we use in vitro electrophysiology and retrograde labeling to elucidate AD-related alterations in synaptic and intrinsic excitability in vCA1 dPNs defined by their projection area. In Aim 2, we use implantable microendoscope imaging of GCaMP calcium signals, c-fos immunohistochemistry, and retrograde labeling to determine the in vivo activity of vCA1 dPNs and projection-defined dPN subpopulations during anxious behavior in AD mice. This work will provide two major results that will significantly add to the understanding of anxiety in AD, at the level of circuit architecture and population coding. Our strategy is conceptually and technically innovative by leveraging cell type-specific circuit knowledge and state-of-the-art approaches to address disease pathophysiology at a cellular level. In supporting our hypothesis, these experiments will determine which vCA1 dPN subpopulations and what excitability mechanisms would be the focus of future work. More generally, these results will further a cell type-specific understanding of AD changes in ventral hippocampus, a structure that has received less attention in mechanistic studies, is highly vulnerable to AD, and is important for not only anxiety but also social and motivational behaviors.