Document text
Principal Investigator: Arjun Vijay Masurkar
Organization: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
Fiscal Year: 2024
Award: $2,044,038
Funding agency: National Institute on Aging
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.
Terms: <3xTg><3xTg-AD mice><3xTg-AD mouse><AAV vector><AAV-based vector><AD dementia><AD model><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's biomarker><Alzheimer's disease biological marker><Alzheimer's disease model><Alzheimer's disease patient><Alzheimer's patient><Alzheimers Dementia><Alzheimer’s biological marker><Alzheimer’s disease biomarker><Ammon Horn><Anti-Anxiety Agents><Anti-Anxiety Drugs><Anxiety><Anxiolytic Agents><Anxiolytics><Architecture><Behavior><Behavioral Assay><Benefits and Risks><Biological Markers><Calcium Ion Signaling><Calcium Signaling><Cerebrovascular Circulation><Clinical><Cornu Ammonis><Data><Dependence><Disease><Disease Progression><Disorder><Distress><Dorsal><Dysfunction><Electrophysiology><Electrophysiology (science)><Engineering / Architecture><FOS gene><Functional disorder><G0S7><Goals><Head><Hippocampus><Human><Hyperactivity><Image><Immediate-Early Genes><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Implant><Knowledge><Label><Link><Literature><Measures><Medial><Memory><Mice><Mice Mammals><Minor Tranquilizing Agents><Modern Man><Molecular><Motivation><Murine><Mus><NIH><National Institutes of Health><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Neurophysiology / Electrophysiology><Nucleus Reuniens Thalami><Opsin><Outcome><Pathology><Patients><Perfusion><Physiopathology><Play><Population><Prefrontal Cortex><Primary Senile Degenerative Dementia><Process><Protooncogene FOS><Pyramidal neuron><Reuniens Nucleus><Reuniens Thalamic Nucleus><Risk><Risk Factors><Rod-Opsin><Role><Site><Subgroup><Subthalamic structure><Subthalamus><Symptom Burden><Symptoms><Synapses><Synaptic><Testing><Thalamic structure><Thalamus><Therapeutic><United States National Institutes of Health><Work><adeno-associated viral vector><adeno-associated virus vector><alzheimer model><anxiety reduction><anxiety treatment><anxiety-like behavior><anxiety-related behavior><anxious behavior><bio-markers><biologic marker><biomarker><blood flow in brain><brain blood circulation><brain blood flow><c fos><c-fos Gene><c-fos Proto-Oncogenes><cell type><cerebral blood flow><cerebral circulation><cerebrocirculation><cerebrovascular blood flow><cognitive performance><electrophysiological><endomicrosope><executive control><executive function><experiment><experimental research><experimental study><experiments><hippocampal><hippocampal pyramidal neuron><human data><imaging><improved><in vivo><microendoscope><mouse model><murine model><neural circuit><neural circuitry><neurobiological mechanism><neurocircuitry><neuronal><neuropsychiatric symptom><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><optogenetics><patch clamp><pathophysiology><patient living with Alzheimer's disease><patient profile><patient suffering from Alzheimer's disease><patient with Alzheimer's><patient with Alzheimer's disease><primary degenerative dementia><profiles in patients><senile dementia of the Alzheimer type><social><social role><synapse><synaptic circuit><synaptic circuitry><thalamic><v-FOS FBJ Murine Osteosarcoma Viral Oncogene Homolog><ventral thalamus>