# Regulation of central circadian rhythms by dopamine

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2020 · $290,807

## Abstract

Project Summary/Abstract: Alzheimer’s disease (AD) causes dementia due to progressive neurodegeneration.
This becomes detrimental to a person's ability to function independently. Fragmented sleep–wake patterns, daily
cycles of confusion and agitation, and disorganized physiological rhythms are commonly observed in AD. These
are also hallmarks of impaired circadian rhythms. In healthy individuals, synchronization of biological rhythms to
the day/night cycle ensures optimal physiological and behavioral responses at appropriate times. A process,
termed entrainment, aligns the molecular clock machinery in the suprachiasmatic nucleus (SCN), the central
master circadian clock, using predictable daily environmental cues (zeitgebers). For mammals, the most
dominant zeitgeber is light. However, other cues such as availability of food, social interactions or physical
exercise also influence the phase of the SCN. Two of the most robust non-photic entrainment cues are regular
daily availability of food (time restricted feeding or TRF) or exercise (time restricted exercise or TRE). In
conjunction with light cycle, these types of time restricted schedules strengthen the periodicity of circadian clocks.
 Do impaired circadian rhythms hasten AD progression? Indeed, circadian rhythm defects often precede
the onset of memory problems in AD, leading to our hypothesis that strengthening circadian clock output will
ameliorate or slow the onset and progression of AD symptoms. In this application, we will use TRE, TRF or both
of these restriction schedules simultaneously (TRE/F) to generate high amplitude behavioral and physiological
circadian rhythms to revert the deleterious effects of AD-like pathology in 3xTg-AD mice. To this end, we will
generate separate cohorts of 2-, 6- and 15-month old 3xTg-AD mice and place them on one of the three time
restricted schedules and assess the impact of these treatments on their metabolism and physiology (Aim 1),
learning and memory (Aim 2), and AD-like pathology (Aim 3). In Aim 1, we will assess whether any of these
schedules improve general activity pattern, energy utilization, glucose intolerance, insulin insensitivity and
impaired gluconeogenesis in this AD model. In Aim 2, we will determine if these circadian clock strengthening
treatments diminish age-dependent cognitive decline in novel-object recognition or Morris water maze assays.
In Aim 3, we will monitor the extent of AD-like pathology to ascertain whether the improved metabolism and
cognitive abilities are paralleled by decreased levels of neuroinflamation, amyloid-β (Aβ) deposition or
intracellular hyperphosphorylated tau aggregation. If proven impactful, synchronization of biological rhythms to
the proper phase of the day using time restricted eating and exercise is readily implementable for AD patients
and people with high-risk of developing the disease.

## Key facts

- **NIH application ID:** 10123239
- **Project number:** 3R01GM121937-05S1
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Ali Guler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $290,807
- **Award type:** 3
- **Project period:** 2016-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123239

## Citation

> US National Institutes of Health, RePORTER application 10123239, Regulation of central circadian rhythms by dopamine (3R01GM121937-05S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10123239. Licensed CC0.

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