# Circadian dysfunction and neurodegenerative disease

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $593,432

## Abstract

Cognitive function varies greatly throughout the day and night due to an intrinsic molecular clock localized
hippocampal cells. In our last project period, we demonstrated that day-night differences in neuronal
excitability, long-term potentiation, and memory are regulated by the circadian clock-controlled mechanisms
such as kinase activation and ion channel regulation, and that excitability of central clock neurons in the
suprachiasmatic nucleus is dysregulated in a mouse model of Alzheimer's disease. However, little is known
about the underlying regulation of neuronal excitability by the molecular clock in hippocampus during both
physiological and pathological states. Further investigation of the circadian regulation of passive and active
membrane properties in excitatory pyramidal cells as well as inhibitory, parvalbumin-expressing interneurons is
required to discover novel chronotherapeutic strategies for early intervention of hyper-excitability, cognitive
dysfunction, and pathogenesis in Alzheimer's disease. In this competitive renewal request, we will test the
novel hypotheses that the cell-autonomous molecular clock drives day-night differences in active and passive
membrane properties of pyramidal neurons and PV+ interneurons at opposite times of the day. We predict that
these anti-phase relationships promote day-night differences in excitatory-inhibitory balance, synaptic
plasticity, and memory, and that disruption of circadian regulation of hippocampal membrane properties could
contribute to hyper-excitability of the network and hasten cognitive impairment and pathogenesis. Using
conditional transgenic mice, slice electrophysiology, bioluminescence imaging, chemogenetics, and behavioral
assays, we will test whether rhythmic transcription and excitability of CA1 pyramidal neurons (Aim 1) and
parvalbumin-expressing interneurons (Aim 2) are driven by the molecular clock and necessary for day-night
differences in memory and plasticity. Aim 3 will use chemogenetics to determine whether restoration of day-
night differences in the depolarization state and intrinsic excitability of CA1 pyramidal neurons is protective
against Alzheimer's disease pathology and memory impairment. Altogether, these experiments have the
potential to reveal an entirely novel mechanism by which the hippocampal clock regulates day-night
differences in plasticity and cognition and could give critical insight into Alzheimer's disease hyperexcitability,
memory impairment, and pathogenesis.

## Key facts

- **NIH application ID:** 10127710
- **Project number:** 5R01NS082413-09
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Karen L Gamble
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $593,432
- **Award type:** 5
- **Project period:** 2013-03-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10127710

## Citation

> US National Institutes of Health, RePORTER application 10127710, Circadian dysfunction and neurodegenerative disease (5R01NS082413-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10127710. Licensed CC0.

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