# Reverse engineering context-dependent recall of audiomotor memories in mouse models of AD

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2022 · $409,375

## Abstract

PROJECT SUMMARY
An astonishing, but underappreciated, aspect of AD and related dementias (ADRD) is the moment-to-moment
fluctuation in cognitive health. Moments of higher cognitive and sensorimotor performance, including ‘episodes
of lucidity’ or ‘lucid intervals’ occur, though are rare, unpredictable and yet undeniably precious. Sensory cues
and contexts may play a critical role in triggering periods of improved cognition. For example, a nostalgic smell
or a wedding song can elicit periods of lucidity even for patients in advanced stages of disease. One study
concludes that “environmental context” is key to such episodes. Memories and other cognitive capacities may
thus exist in the AD brain, but for the most part remain inaccessible. Can these “hidden memories” be
unlocked? The underlying neural basis of cognitive fluctuations in AD in general, and lucid intervals in particular,
remains completely unknown. Severe dementia is generally considered irreversible, yet even patients with
advanced AD appear to be able to tap into intrinsic mechanisms that transiently improve cognition.
To identify these intrinsic mechanisms, we propose to focus on the auditory cortex (AC). The AC serves as
integrative hub for feedforward sensory information, top-down signals, and ascending neuromodulation. The
pathological hallmarks of AD, including amyloid-beta (Aβ) plaques and neurofibrillary tangles, accumulate in the
AC. Neurons in the cholinergic basal forebrain (CBF), which degenerate early in AD, strongly innervate the AC.
A large body of literature, including our own previous work, demonstrates that optimal CBF neuromodulation of
inhibitory networks in the AC is critical for audiomotor task performance. Our overarching hypothesis is that
the accumulation of Aβ disrupts the integration of state-dependent neuromodulation into cortical networks. In a
default ‘pathological’ state due to Aβ accumulation, sub-optimal CBF tone interferes with inhibitory gating of
auditory cues and impairs behavior. We propose that transient improvements in performance (‘lucid-like states’)
(Aim 1) arise when inhibitory networks are engaged (Aim 2) by endogenous CBF tone that is spontaneously
tuned to an optimal level (Aim 3) thereby enabling task-relevant processing of auditory cues. In this supplement,
we propose to perform foundational experiments achievable within the 1-year period of the award and that build
on the behavioral and neural approaches from the active award (R01).

## Key facts

- **NIH application ID:** 10498479
- **Project number:** 3R01DC018650-02S1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Kishore V Kuchibhotla
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $409,375
- **Award type:** 3
- **Project period:** 2020-11-15 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10498479

## Citation

> US National Institutes of Health, RePORTER application 10498479, Reverse engineering context-dependent recall of audiomotor memories in mouse models of AD (3R01DC018650-02S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10498479. Licensed CC0.

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