# The impact of aging and amyloidosis on interval timing in corticostriatal circuits and its rescue by controlled cholinergic fiber activation

> **NIH NIH RF1** · JOHNS HOPKINS UNIVERSITY · 2020 · $2,166,616

## Abstract

Project Summary
 Alzheimer's disease (AD) degrades the ability to learn and make appropriate decisions. As the basal
forebrain cholinergic system is highly susceptible to amyloidosis, one neuromodulator that is especially
implicated in cognitive decline caused by AD is acetylcholine, which is essential in many forms of learning and
memory. While higher-order brain areas associated with decision-making have been intensively investigated as
they relate to AD, recently there has been a call for greater focus on the consequences of AD in sensory- and
motor-related areas. As we have previously characterized a cholinergic-dependent form of learning and memory
in the visual cortex, one sensory- and motor-related system that is particularly attractive in this regard is the
visual corticostriatal pathway. A rudimentary, yet fundamental, form of decision-making that epitomizes a
sensorimotor transformation carried out by the corticostriatal pathway is when to time reward-seeking actions
in response to reward-predicting stimuli. Observation of neural activity from the visual cortex and the dorsal
striatum reveal visually-cued timing activity to expected reward, providing a window into the process of
transforming visual cues into reward-seeking motor action. By combining a mouse model of AD that develops
amyloidosis with a line that affords a means to control and functionally image cholinergic axons, the effects of
amyloidosis on cholinergic-dependent interval timing activity can be assessed, neurally and behaviorally,
compared to that caused by the normal course of aging, and rescued by augmenting cholinergic signaling of
reward using a novel optogenetic intervention.
 We hypothesize that aging and amyloidosis disrupts the ability of the visual corticostriatal system to learn
and produce visually-cued interval timing activity (Aim1-Impairment), which degrades the ability to produce
appropriately timed reward-seeking behaviors, and that the proximal cause is a functional impairment of
cholinergic signaling of reward (Aim2-Proximal Cause). We further hypothesize that optogenetic
augmentation of intact cholinergic fibers' report of reward will rescue visually-cued interval timing activity in the
corticostriatal system, thereby re-establishing appropriately timed reward-seeking behavior (Aim3-
Intervention). These aims will 1) reveal new neurophysiological and behavioral biomarkers foretelling future
onset of the disease (Aim1), 2) lead to a greater understanding of the causative processes underlying cognitive
decline (Aim2), and 3) point to new interventions for mitigating dysfunction caused by AD pathology (Aim3).

## Key facts

- **NIH application ID:** 10052419
- **Project number:** 1RF1AG063783-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Marshall Gilmer Shuler
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,166,616
- **Award type:** 1
- **Project period:** 2020-09-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10052419

## Citation

> US National Institutes of Health, RePORTER application 10052419, The impact of aging and amyloidosis on interval timing in corticostriatal circuits and its rescue by controlled cholinergic fiber activation (1RF1AG063783-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10052419. Licensed CC0.

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