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
- 批准号:10016163
- 负责人:
- 金额:$ 20.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-01 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:4-Hydroxy-TamoxifenAPP-PS1AffectAgeAge-MonthsAgitationAlzheimer&aposs DiseaseAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAnxietyBehaviorBehavioralBehavioral AssayBiological AssayBrainBrain imagingBrain regionCaregiversCellsCharacteristicsCircadian DysregulationCircadian RhythmsDataDevelopmentExhibitsExposure toFOS ProteinFOS geneGoalsHourHumanHypothalamic structureImageImmediate-Early GenesImpaired cognitionImpairmentLabelLateralLightMeasuresMediatingMemoryMethodsMicroscopeModelingMolecularMotor ActivityMouse ProteinMusNeurodegenerative DisordersNeurofibrillary TanglesNeuronsPatientsPhenotypePlayPolysomnographyPropertyProteinsResearchResolutionRoleSignal TransductionSleepSleep Wake CycleSleep disturbancesSynapsesSystemTestingTimeVirusVisualizationWorkanxiety-like behavioranxiousawakebiological systemsbody systemcircadiandiscrete timeexperienceimprovedin vivoin vivo imaginglong term hospitalizationmouse modelnetwork dysfunctionneural circuitneural correlateneural networknoveloptogeneticsrelating to nervous systemsuprachiasmatic nucleus
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)
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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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