The Dynamic Neuromodulome in Alzheimer's Disease and Aging
阿尔茨海默病和衰老中的动态神经模块
基本信息
- 批准号:10901011
- 负责人:
- 金额:$ 63.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-15 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AD transgenic miceAcetylcholineAgeAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease diagnosisAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAnatomyAnimalsAreaArousalAtlasesAttentionAxonBehaviorBehavioralBehavioral AssayBenchmarkingBiological AssayBrainCell DeathCell NucleusCognitionCompetenceControl AnimalCritical PathwaysDataData SetDevelopmentDiagnosticDiseaseDisease MarkerDisease ProgressionDisease modelDopamineExhibitsFunctional disorderFutureGoalsHistologicHumanImpaired cognitionIndividualLongevityMeasurementMeasuresMemoryMemory LossMental DepressionModelingMotivationMultiplexed Analysis of Projections by SequencingMusMydriasisNeuromodulatorNeuronsNorepinephrinePathologicPathologyPatientsPatternPerceptionPhenotypePhysiologicalPhysiologyPlayPredispositionPupilResolutionRoleSensorySerotoninShapesStructureSubstantia nigra structureSystemTechniquesTestingTherapeuticTimeTranslationsWorkawakebasal forebraincellular pathologycohortdiagnostic tooldisorder riskhuman datain vivojuvenile animallocus ceruleus structureluminancemodel buildingmouse modelmultimodalitynerve supplyneuropsychiatric symptomnonhuman primatenoninvasive diagnosisnormal agingnoveloptogeneticspostsynapticpredictive modelingpresynapticraphe nucleiresponsesensory stimulusstemtemporal measurementtranscriptomics
项目摘要
PROJECT SUMMARY
Neuromodulators such as dopamine, serotonin, acetylcholine, and norepinephrine play important
roles in shaping perception, cognition, and behavior. Evidence suggests that these systems may
be particularly susceptible to dysfunction in Alzheimer’s disease (AD). This dysfunction can lead
to neuropsychiatric symptoms that can appear early in disease progression, before the profound
decline in cellular integrity and associated deficits in memory and cognition that are hallmarks of
AD. These neuromodulators vary quickly from moment to moment, but it’s not clear how these
dynamics vary across aging, and when they diverge from normal aging over the progression of
AD. Understanding when these changes occur relative to well-described anatomical and
behavioral benchmarks of AD disease progression would reveal the “critical path” of
neuromodulator pathology in AD that distinguishes it from normal aging, and could suggest
potential targets for treatment or diagnosis of AD prior to the onset of memory loss and cognitive
decline. The overall goals of this project are to understand how fast activity these ascending
systems change during the progression of AD, and to enable the development of diagnostic tools
for non-invasive assessment of disease risk. We will perform systematic measurements of
neuromodulator release at multiple ages in two different Alzheimer’s disease mouse lines and
control animals using a novel combination of techniques developed by our team. We will combine
these in vivo functional measurements with anatomical data in the same mice that includes
markers of cellular pathology, axonal integrity, and transcriptomics, as well as behavioral assays,
in order to produce a multimodal atlas of disease progression bridging structure and function in
the brain’s major modulatory systems. Finally, building on our previous finding that spontaneous
fluctuations in pupil size are correlated with specific patterns of neuromodulator release in the
brain, we will attempt to build models that allow us to infer neuromodulator levels from
pupillometric measurements, and we will validate the translation relevance of these models in a
unique human data set. In summary, this project will provide the clearest view to date of
pathological changes in neuromodulator dynamics with AD, where they diverge from normal
changes during aging, and their relationship to underlying anatomical changes throughout the
brain.
项目总结
神经调节剂如多巴胺、5-羟色胺、乙酰胆碱和去甲肾上腺素起着重要作用。
在塑造感知、认知和行为方面的作用。有证据表明,这些系统可能
特别容易受到阿尔茨海默病(AD)功能障碍的影响。这种功能障碍会导致
到神经精神症状,可以在疾病进展的早期出现,在严重的
细胞完整性下降以及与之相关的记忆和认知缺陷,这是
广告。这些神经调节剂每时每刻变化很快,但还不清楚它们是如何变化的
随着年龄的增长,动态会有所不同,当它们偏离正常衰老的过程时,
广告。了解这些变化发生的时间与描述良好的解剖学和
AD疾病进展的行为基准将揭示出
阿尔茨海默病的神经调节剂病理,将其与正常衰老区分开来,并可能提示
在记忆丧失和认知障碍发作之前治疗或诊断AD的潜在靶点
拒绝。这个项目的总体目标是了解这些活动上升的速度
系统在AD发展过程中发生变化,并使诊断工具的开发成为可能
用于疾病风险的非侵入性评估。我们将进行系统的测量
在两个不同的阿尔茨海默病小鼠系和
使用我们团队开发的一种新技术组合来控制动物。我们将联合起来
这些体内功能测量使用的是同一组小鼠的解剖学数据,包括
细胞病理,轴突完整性,转录组,以及行为分析的标记物,
为了制作疾病进展的多模式图谱,桥接结构和功能在
大脑的主要调节系统。最后,基于我们之前的发现,自发的
瞳孔大小的波动与特定的神经调节剂释放模式相关
大脑,我们将尝试建立模型,允许我们从
测量,我们将验证这些模型的平移相关性
唯一的人类数据集。总而言之,这个项目将提供迄今为止最清晰的观点
阿尔茨海默病患者神经调节器动力学的病理变化
衰老过程中的变化,以及它们与整个年龄段潜在解剖变化的关系
大脑。
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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{{ truncateString('JEANNIE CHIN', 18)}}的其他基金
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10189710 - 财政年份:2014
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Role of deltaFosB in hippocampal gene expression and function in neurological disease
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10394933 - 财政年份:2014
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9222062 - 财政年份:2014
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Role of deltaFosB in epigenetic regulation of gene expression and cognition
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- 批准号:
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Role of deltaFosB in epigenetic regulation of gene expression and cognition
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Accelerated depletion of hippocampal neural stem cells in neurological disease
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8822339 - 财政年份:2014
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Accelerated depletion of hippocampal neural stem cells in neurological disease
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Role of deltaFosB in epigenetic regulation of gene expression and cognition
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8867311 - 财政年份:2014
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