# Neural circuit mechanisms underlying AD-related memory impairments

> **NIH NIH RF1** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $1,921,280

## Abstract

Project Summary / Abstract
 Dementia and age-related cognitive decline is an escalating major health concern in the United States.
Approximately 20% of the US population will be 65 or older by year 2030, and roughly 8 million of these
individuals are expected to suffer from Alzheimer’s disease (AD). We propose to examine detailed AD-related
neural circuit mechanisms that will be critical for developing new AD treatment strategies by use of two
complementary AD mouse models, which share many features of human AD. Our guiding hypothesis is that
AD-related neurodegeneration causes maladaptive changes of memory circuit connections and neural ensemble
activities in the hippocampus. We discovered recently in the mouse that non-canonical subicular back-
projections to hippocampal CA1 underlie object-place learning, a prominent impairment in AD. This circuit has
been recently identified in human brain. We will test our hypothesis that significant impairments in bidirectional
information processing between hippocampal CA1 and the subiculum (SUB) develop over time during AD
progression. In Aim 1, we will determine the effect of AD-like neurodegeneration on local and global circuit
connections to hippocampal CA1 and SUB excitatory neurons. We will map and compare circuit input
connections and output projections of excitatory CA1 and SUB neurons in adult control, and AD-like mice using
retrograde monosynaptic rabies tracing and anterograde monosynaptic herpes simplex virus (HSV) tracing.
Further, we will perform experiments in postmortem human hippocampus of aged-matched control and AD
patients to map the SUB-CA1 pathway in human brains and understand detailed changes of this brain circuit in
AD patients. In Aim 2, we will test the hypothesis that neurodegeneration in AD-like mice degrades object-
location memory encoded by hippocampal CA1 and SUB excitatory neurons. To map neuronal activity to
behavioral performance, we will use in vivo miniature microscopic imaging to examine and compare spatial
representations of CA1 excitatory neurons and SUB excitatory neurons during open-field exploration, track-
based route-running and object-location memory tasks. Thus, we can longitudinally track progressive AD-like
functional defects. In Aim 3, we will determine whether spatial memory can be rescued by patterned stimulation
of the non-canonical SUB-CA1 back-projection in the AD model mice. Human literature and our preliminary data
show high relevance of our proposed research for Alzheimer’s disease. Together, the proposed research will
advance our understanding of specific neural mechanisms underlying AD etiology and help to identify new
therapeutic targets in humans.

## Key facts

- **NIH application ID:** 10121076
- **Project number:** 1RF1AG065675-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** XIANGMIN XU
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,921,280
- **Award type:** 1
- **Project period:** 2020-09-11 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10121076

## Citation

> US National Institutes of Health, RePORTER application 10121076, Neural circuit mechanisms underlying AD-related memory impairments (1RF1AG065675-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10121076. Licensed CC0.

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