Identification and manipulation of the neural ensembles mediating sundowning in an Alzheimer's disease mouse model

阿尔茨海默病小鼠模型中介导日落的神经群的识别和操作

基本信息

项目摘要

PROJECT SUMMARY / ABSTRACT Circadian rhythms are everywhere in living matter from protozoans to human beings. Every cell, organ, and biological system works on an endogenous 24-hour rhythm. However, in patients with Alzheimer's disease (AD), a neurodegenerative disorder affecting memory, this rhythm is dampened. In addition to cognitive decline, many AD patients (~50%) also exhibit agitation and increased anxiety in the evening or nocturnal hours, often referred to as sundowning. Here, we aim to dissect the neural circuitry underlying sleep disturbances, circadian rhythm abnormalities, and increased anxiety-like behavior representing sundowning and how it relates to cognitive decline and AD pathology. We will utilize behavioral assays, optogenetics, whole-brainmicroscopy, and in vivo Ca 2+ imaging. Our preliminary evidence suggests that AD mice exhibit increased anxiety-like (e.g., sundowning) behavior compared to control (Ctrl) mice immediately before their sleep cycle but not before their wake cycle. Therefore, in Aim 1A, we will use the PiezoSleep mouse behavioral tracking system to monitor sleep/wake cycles and circadian homecage locomotor activity in Ctrl and AD mice at different ages in order to better characterize AD mice throughout their wake/sleep cycle. We will also measure anxiety-like behavior at various points throughout their sleep/wake cycles. Using an activity- dependent tagging mouse, the ArcCreERT2 x enhanced yellow fluorescent protein (EYFP) mice crossed with the APP/PS1 (AD) model, we will then identify whole-brain neural ensembles and therefore, neural networks that contribute to sundowning in Aim 1B. This mouse line allows for the indelible labeling of cells expressing the immediate early gene (IEG) Arc/Arg3.1 and allows for a comparison between the cells that are activated during one experience and those that are activated during a second experience. Here, we will compare and contrast the neural ensembles within subjects that are active during anxiety-like behaviors prior to the sleep and wake cycles. In Aim 2A, after identifying which neuronal ensembles are altered during sundowning, we will use nVoke minimicroscopes from Inscopix, to image Ca2+ transients in freely moving AD x ArcCreERT2 mice, injected with a GCaMP6f virus, during the dark versus light cycle. Here, we will be able increase resolution and the time points at which we can correlate neural activity with increased anxiety-like (e.g., sundowning) behavior. In Aim 2B, we will then test the hypothesis that optogenetic modulation of these neural ensembles drives/inhibits sundowning behavior. The neural circuitry underlying sundowning has not yet been elucidated, but this project will inform us of novel brain regions and the neural circuitry affected by sundowning and how we can manipulate these systems to rescue this phenotype in AD.
项目摘要/摘要

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Christine Ann Denny其他文献

(R,S)-Ketamine is Antidepressant and Prophylactic Against Stress in Adolescent but Not Aged Mice
  • DOI:
    10.1016/j.biopsych.2022.02.050
  • 发表时间:
    2022-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Alessia Mastrodonato;Ina Pavlova;Noelle Kee;Josephine C. McGowan;Christine Ann Denny
  • 通讯作者:
    Christine Ann Denny

Christine Ann Denny的其他文献

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{{ truncateString('Christine Ann Denny', 18)}}的其他基金

Identifying the neural ensembles mediating fear generalization during adolescence
识别青春期介导恐惧泛化的神经系统
  • 批准号:
    10648352
  • 财政年份:
    2023
  • 资助金额:
    $ 20.25万
  • 项目类别:
Single-cell and target-specific resolution of multiple memories across the brain
大脑中多个记忆的单细胞和目标特异性分辨率
  • 批准号:
    10018072
  • 财政年份:
    2019
  • 资助金额:
    $ 20.25万
  • 项目类别:
Single-cell and target-specific resolution of multiple memories across the brain
大脑中多个记忆的单细胞和目标特异性分辨率
  • 批准号:
    9790044
  • 财政年份:
    2019
  • 资助金额:
    $ 20.25万
  • 项目类别:
Single-cell and target-specific resolution of multiple memories across the brain
大脑中多个记忆的单细胞和目标特异性分辨率
  • 批准号:
    10689742
  • 财政年份:
    2019
  • 资助金额:
    $ 20.25万
  • 项目类别:
Single-cell and target-specific resolution of multiple memories across the brain
大脑中多个记忆的单细胞和目标特异性分辨率
  • 批准号:
    10254286
  • 财政年份:
    2019
  • 资助金额:
    $ 20.25万
  • 项目类别:
Single-cell and target-specific resolution of multiple memories across the brain
大脑中多个记忆的单细胞和目标特异性分辨率
  • 批准号:
    10475683
  • 财政年份:
    2019
  • 资助金额:
    $ 20.25万
  • 项目类别:
Optogenetic dissection of hippocampal circuitry underlying Alzheimers disease
阿尔茨海默病海马回路的光遗传学解剖
  • 批准号:
    9135544
  • 财政年份:
    2014
  • 资助金额:
    $ 20.25万
  • 项目类别:
Optogenetic dissection of hippocampal circuitry underlying Alzheimers disease
阿尔茨海默病海马回路的光遗传学解剖
  • 批准号:
    8921853
  • 财政年份:
    2014
  • 资助金额:
    $ 20.25万
  • 项目类别:
Optogenetic dissection of hippocampal circuitry underlying Alzheimers disease
阿尔茨海默病海马回路的光遗传学解剖
  • 批准号:
    8917731
  • 财政年份:
    2014
  • 资助金额:
    $ 20.25万
  • 项目类别:
Optogenetic dissection of hippocampal circuitry underlying Alzheimers disease
阿尔茨海默病海马回路的光遗传学解剖
  • 批准号:
    9354198
  • 财政年份:
    2014
  • 资助金额:
    $ 20.25万
  • 项目类别:

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  • 批准号:
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  • 批准号:
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    2013
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Selective over expression of TDP-43 in APP/PS1 mice alters APP processing
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  • 批准号:
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    $ 20.25万
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The role of ABCA1 in mediating the beneficial effects of GW3965 on biochemical and cognitive outcomes in the APP/PS1 mouse model of Alzheimer's Disease
ABCA1 在介导 GW3965 对阿尔茨海默病 APP/PS1 小鼠模型生化和认知结果的有益影响中的作用
  • 批准号:
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Early diagnosis of alzheimer's disease in app/ps1 transgenic mice
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  • 批准号:
    347789-2008
  • 财政年份:
    2008
  • 资助金额:
    $ 20.25万
  • 项目类别:
    Postgraduate Scholarships - Master's
Early diagnosis of alzheimer's disease in app/ps1 transgenic mice
app/ps1 转基因小鼠阿尔茨海默病的早期诊断
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    2007
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