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

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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.