Hyperactivity of the thalamo-hippocampal-prefrontal circuit as a mechanism for anxiety in Alzheimer disease - Resubmission - 1

PROJECT SUMMARY/ABSTRACT Anxiety is a highly prevalent symptom in the early stages of Alzheimer disease (AD), with correlation to AD biomarkers and association with faster decline. As such, understanding the mechanism of anxiety in AD is critical to understanding its impact on outcomes and to developing better therapies for this distressing

symptom that may also have disease-modifying effects. Yet, the pathophysiology of anxiety in AD is unclear. The CA1 region of ventral hippocampus (vCA1) may play a critical role, given that it is vulnerable to AD and that the activity of its pyramidal neurons (PNs) increases during anxious behavior in non-AD contexts.

Moreover, it receives direct input from nucleus reuniens of thalamus (nRT), and provides input to medial prefrontal cortex (mPFC), both of which have also been implicated in anxiety as well. Here, we propose experiments in AD models known to display anxiety in order to support a central hypothesis that AD-related

anxiety is driven by increased engagement of the nRT→vCA1→mPFC circuit. This hypothesis is supported by the above, as well as additional literature and preliminary data suggesting a role for nRT, vCA1, and mPFC in AD-related anxiety and their vulnerability to intrinsic hyperexcitability and excitatory-inhibitory imbalance. Using

the 3xTg-AD and 5xFAD mouse models, we test our central hypothesis with the following aims. In Aim 1, we use ex vivo opto-electrophysiology and retrograde labeling to elucidate AD-related alterations in the functional synaptic architecture of the nRT→vCA1→mPFC circuit. In Aim 2, we use implantable microendoscope imaging

of GCaMP calcium signals, immediate early gene c-fos readouts, and retrograde labeling to determine the in vivo activity of vCA1-projecting nRT neurons, mPFC-projecting vCA1 PNs, and mPFC PNs during anxious behavior in AD mice. In Aim 3, we use optogenetic strategies to suppress or increase the activity of nRT input

to vCA1 PNs and vCA1 inputs to mPFC to determine the effect on anxious behavior in AD mice. We also test if these manipulations also improve memory. This work will provide three major results that will in sum causally test our central hypothesis and significantly add to the understanding of anxiety in AD, at the level of circuit

architecture (Aim 1), population activity (Aim 2), and population activity manipulation (Aim 3). This knowledge will push forward a line of experimentation to develop treatments for anxiety in AD that may have disease- modifying impact. More broadly, the knowledge uncovered related to this important but understudied circuit will

inform on other functions on this network in social and motivational behaviors, and cognitive performance.