# Molecular, Cellular and Circuit Effects of Sleep Deprivation on Hippocampal Function

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2022 · $309,000

## Abstract

PROJECT SUMMARY
There are currently no therapeutic options to slow or stop the progression of Alzheimer’s Disease and
Alzheimer’s Disease-related Dementias (AD/ADRD) and this partly due to the complexity of these diseases
and the inability to identify high-risk individuals and implement early interventions. AD/ADRD are typically
associated with memory deficits, but additional symptoms include cognitive impairments, motor deficits
and changes in mood are also commonly seen. In particular, motor deficits seen in individuals with
AD/ADRD can have a dramatic impact on quality of life with severe cases resulting in accidental injury or
individuals becoming bed bound. Importantly, sleep disruption is also prevalent in individuals with
AD/ADRD and it has been shown to contribute to AD/ADRD symptoms. As the population continues to live
longer, and as sleep deprivation levels continue to rise in nearly all age groups, it is critical that we
understand the molecular mechanisms impacted by sleep deprivation in AD/ADRD. One potential avenue
of research that connects sleep deprivation and AD/ADRD at the molecular level is Protein Kinase A. PKA
activity is important in sleep/wake states and is also dysregulated in AD/ADRD, and recent results obtained
using mice with a mutation in a PKA subunit, Prkar1b, revealed that mice aged 15 months or older exhibited
motor deficits. What remains unknown is how sleep deprivation may impact already disrupted PKA activity
at different ages representing the pre-clinical and clinical phases. The overall objective in this
supplement proposal is to identify the impact of a gene-environment interaction between a Prkar1b
mutation and sleep deprivation on behavior and the phosphorylome at different ages of an already
generated mouse model relevant to AD/ADRD. The central hypothesis is that sleep deprivation, in the
presence of the Prkar1b mutation, exacerbates aberrant PKA activity at earlier ages, which promotes
neurodegeneration, and results in behavioral deficits. The rationale for the proposed research is that a
mechanistic determination of how PKA activation becomes dysregulated prior to the emergence of
neurodegenerative symptoms may provide the basis for the identification of PKA-specific therapeutic
targets. We will use already generated Prkar1b mice at three ages (2-4 months old, 10-12 months old, and
16-18 months old) to study behavioral changes and phosphoproteomics in the hippocampus, a region
particularly susceptible to sleep deprivation. The proposed research is potentially innovative because it
utilizes the Prkar1b-L50R mutation, with known links to AD/ADRD symptoms in both humans and mice.
The proposed project is significant because detection and treatment of the role of sleep in AD/ADRD may
increase treatment effectiveness and efficacy, thereby improving the outcome of individuals with
AD/ADRD.

## Key facts

- **NIH application ID:** 10499845
- **Project number:** 3R01MH117964-04S1
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** EDWIN TED G. ABEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $309,000
- **Award type:** 3
- **Project period:** 2018-09-10 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10499845

## Citation

> US National Institutes of Health, RePORTER application 10499845, Molecular, Cellular and Circuit Effects of Sleep Deprivation on Hippocampal Function (3R01MH117964-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10499845. Licensed CC0.

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