R01AG061785

Circadian Changes in Network Excitability and Alzheimer's Disease Pathogenesis - Project Summary

Converging evidence indicates that neuronal and network hyperexcitability is an important early event in Alzheimer's disease (AD) patients. The cellular and molecular basis of this hyperexcitability is a critical area of investigation, and the presence of similar hyperexcitability in animal models enables studies to dissect underlying mechanisms.

A key insight is that hyperexcitability in both AD patients and mouse models has a strong diurnal rhythm. Emerging data also indicate that neural excitability in the forebrain is normally under control of the circadian clock, which regulates seizure thresholds and susceptibility to epileptiform activity. Circadian variation in cellular function is driven by transcriptional molecular clocks expressed in most cells, and molecular clock ablation increases AD pathology.

We have compelling preliminary evidence for rhythmic variation in neuronal excitability that is at least partly due to circadian regulation of the membrane properties of inhibitory interneurons, especially fast-spiking cells expressing parvalbumin (PV). Given that PV+ interneurons in the cortex and dentate gyrus are strongly implicated in AD, and that circadian rhythms are disrupted in AD patients and AD mouse models, we propose rigorous experiments to test the hypothesis that dysregulation of the molecular clock and resulting changes in PV+ interneuron gene expression and activity contribute to AD-related neuronal hyperexcitability.

Specifically, we will evaluate the differences in circadian clock and clock-controlled gene expression in PV+ interneurons vs. excitatory neurons in the mouse models of AD, using a combination of RNA sequencing, state-of-the-art bioinformatics, and recently developed tools to evaluate molecular clock rhythmicity and transcription in a cell-specific manner (Aim 1). We will record from inhibitory and excitatory neurons in the dentate gyrus and cortex to determine if clock-driven changes in PV+ inhibitory neuron activity are disrupted in AD models and contribute to overall hyperexcitability (Aim 2). Finally, we will utilize an innovative chemogenetic chronotherapeutic approach to manipulate PV+ interneuron physiology to determine whether reinstating the normal circadian patterns of PV+ interneuron activity in AD mice protects against hyperexcitability, cognitive impairment, and pathology (Aim 3).

The proposed studies, led by a strong interdisciplinary team, use powerful approaches to determine how disruption of circadian rhythms facilitates neuronal hyperexcitability that contributes to early stages of AD. Understanding these mechanisms may catalyze the development of behavioral or pharmacologic interventions.

University Of Alabama At Birmingham

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Birmingham, Alabama 352940004 United States

Single Zip Code

Sleep disorders and circadian clock disruption in Alzheimers disease and other dementias of aging (R01 Clinical Trial Not Allowed) (PAR-18-497)

Amendment Since initial award the total obligations have increased 417% from $760,861 to $3,932,477.