Delaying cognitive decline in mouse models of Alzheimer's disease via near-infrared light optogenetics

Information

  • Research Project
  • 10233478
  • ApplicationId
    10233478
  • Core Project Number
    R21AG072803
  • Full Project Number
    1R21AG072803-01
  • Serial Number
    072803
  • FOA Number
    PA-20-195
  • Sub Project Id
  • Project Start Date
    4/15/2021 - 4 years ago
  • Project End Date
    3/31/2023 - 2 years ago
  • Program Officer Name
    WAGSTER, MOLLY V
  • Budget Start Date
    4/15/2021 - 4 years ago
  • Budget End Date
    3/31/2022 - 3 years ago
  • Fiscal Year
    2021
  • Support Year
    01
  • Suffix
  • Award Notice Date
    4/13/2021 - 4 years ago
Organizations

Delaying cognitive decline in mouse models of Alzheimer's disease via near-infrared light optogenetics

ABSTRACT During sleep, the thalamus generates a characteristic brief pattern of 8-15 Hz electroencephalographic (EEG) waves that predominantly occur during light stages of non-rapid eye-movement sleep (NREMS). Reduced spindle may cause impaired learning and Mild Cognitive Impairment (MCI) in AD and is a biomarker for early AD-related changes in brain dynamics. Conversely, promoting sleep oscillations by transcranial stimulation enhances memory consolidation in MCI. By developing a set of novel, noninvasive, bacteriophytochrome-based optogenetic tools to control cAMP synthesis (adenylate cyclase, AC) and breakdown (phosphodiesterase, PDE), we will make spindles accessible for noninvasive manipulations that spare other sleep rhythms. These enzymes are activated by light in the so-called near-infrared optical window (NIRW). The NIRW light-activated modules are suitable for the rapid yet long-lasting and noninvasive manipulation of cAMP in thalamic neurons in intact animals, because NIRW light penetrates through mammalian skulls and brain tissues better than the light of any other spectral region. We will examine a provocative novel hypothesis that cellular pathology and cognitive decline caused by Alzheimer?s disease (AD) related mutations can be restored via enhancing thalamocortical spindles waves during sleep in vivo. We will first develop novel noninvasive optogenetic tools to manipulate AC and spindle oscillations (Aim 1). Then, we will examine whether NIRW-AC and NIRW-PDE bi-directionally modulate the progression of AD?related neuropathology and cognitive decline via their actions re: spindle wave regulations (Aim 2). Upon completion of this project, we will have developed genetically encoded NIRW-light activated tools, allowing noninvasive manipulation in deep brain regions of live animals. Results are expected to provide a sound basis for investigation in disease models that involve spindle wave and cAMP aberrations, such as AD, and suggest novel non- invasive intervention strategies to counteract brain dementias caused by AD.

IC Name
NATIONAL INSTITUTE ON AGING
  • Activity
    R21
  • Administering IC
    AG
  • Application Type
    1
  • Direct Cost Amount
    150000
  • Indirect Cost Amount
    66750
  • Total Cost
    216750
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    866
  • Ed Inst. Type
    SCHOOLS OF ARTS AND SCIENCES
  • Funding ICs
    NIA:216750\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    CDIN
  • Study Section Name
    Cell Death in Neurodegeneration Study Section
  • Organization Name
    UNIVERSITY OF WYOMING
  • Organization Department
    ZOOLOGY
  • Organization DUNS
    069690956
  • Organization City
    LARAMIE
  • Organization State
    WY
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    820712000
  • Organization District
    UNITED STATES