Multimodal ventral tegmental area decrements in a mouse Alzheimer's model
小鼠阿尔茨海默病模型中多模式腹侧被盖面积减少
基本信息
- 批准号:10537306
- 负责人:
- 金额:$ 3.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:3xTg-AD mouseAction PotentialsAffectAgeAge-MonthsAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAmygdaloid structureAmyloidAnhedoniaAnimal ModelAnimalsAreaAspirate substanceAtlasesAwardBioinformaticsBrainBrain regionCellsCognitionCognitiveConfocal MicroscopyCoupledDataDementiaDepositionDevelopmentDiseaseDopaminergic CellElectrophysiology (science)FluorescenceFunctional disorderFutureGene Expression ProfileGenerationsGoalsHeterogeneityHippocampus (Brain)HumanImageImmunoassayImmunohistochemistryImpaired cognitionIndividualInterventionIon ChannelKnowledgeLabelLengthLinkMeasuresMedialMemory impairmentMental DepressionMidbrain structureMolecularMolecular BiologyMood DisordersMorphologyMusNeuritesNeurodegenerative DisordersNeurofibrillary TanglesNeuronsNucleus AccumbensOperative Surgical ProceduresPathologicPathologyPathway interactionsPhysiologicalPotassium ChannelPredispositionPrevalenceProcessPropertyProteinsPublic HealthPublishingReportingResearchRoleSchemeSenile PlaquesShort-Term MemorySignal TransductionSliceSpecificityStructureSynapsesSystemTimeTimeLineTissue-Specific Gene ExpressionTrainingTransgenic OrganismsVentral Tegmental Areaagedaging populationbasebiocytincareercomorbid depressioncomorbiditydopamine replacement therapydopaminergic neuronefficacious treatmentexperimental studyfunctional declinefunctional disabilityimprovedinsightmemory encodingmolecular phenotypemouse modelmultimodalitymutantneuronal cell bodynew therapeutic targetnovelpatch clamppatch sequencingpreventprotein aggregationreconstructionreward processingsexsingle cell sequencingskillsspatiotemporaltau Proteinstau aggregationtranscriptometranscriptome sequencingtranscriptomics
项目摘要
The aging population continues to grow, as does the prevalence of Alzheimer’s disease (AD),
necessitating disease altering therapies. While AD is often characterized by a decline in working memory, it is
also highly comorbid with depression, apathy, and other non-cognitive impairments. Due to the prominent
memory deficits seen in AD patients, the bulk of research in the field has focused on cortical and hippocampal
pathophysiology. However, AD pathology develops throughout the brain, and its associated conditions
implicate subcortical structures, specifically the midbrain dopaminergic system. Recently, reports in both
animal models and humans indicate that the ventral tegmental area (VTA) to hippocampus circuit may be
disrupted in AD. Interestingly, a report in a mouse model indicates that cells in the medial VTA, which project
predominantly to corticolimbic structures, are preferentially affected, suggesting differential subpopulations of
VTA dopaminergic neurons are affected by AD pathology. The field is currently limited by a lack of information
on how heterogeneity affects pathophysiological predisposition in the ventral midbrain. This proposal aims to
elucidate the underlying mechanisms of cognitive and non-cognitive deficits in AD and its related dementias.
The experiments in this proposal will use an established mouse model that expresses mutant amyloid and tau
to investigate this gap in the collective knowledge. The general strategy will be to use animals of 3, 6, and 12
months of age, representing well defined pathological timepoints in hippocampal pathology. We will isolate
subpopulations of VTA cells through immunohistochemistry, single cell sequencing, and retrograde tracing.
Following sacrifice, we will record electrophysiological parameters, perform RNA-sequencing, and
morphological reconstruction of single VTA dopaminergic neurons of transgenic and non-transgenic mice. Aim
1 will construct a spatiotemporal timeline of amyloid and tau accumulation across cortical and subcortical
structures. Aim 2 will investigate intrinsic dopaminergic properties including neurite length, action potential
generation, the ion channel conductances that govern firing, and single cell transcriptomic profile.
Understanding cellular and circuit decrements occurring outside of cortical regions is key to development of
efficacious treatments. These studies aim to establish dopaminergic processes in AD pathophysiology, to
understand how single cell heterogeneity predisposes cells to functional decline, and to identify novel targets
for intervention in AD.
人口老龄化持续增长,阿尔茨海默病(AD)的患病率也在持续增长,
需要改变疾病的疗法。虽然 AD 通常以工作记忆下降为特征,但
还与抑郁、冷漠和其他非认知障碍高度共存。由于突出的
AD 患者的记忆缺陷,该领域的大部分研究都集中在皮质和海马体上
病理生理学。然而,AD 病理学在整个大脑及其相关病症中发展
涉及皮质下结构,特别是中脑多巴胺能系统。近日,两地报道
动物模型和人类表明,腹侧被盖区(VTA)到海马体的回路可能是
在公元中断。有趣的是,小鼠模型的一份报告表明,内侧 VTA 中的细胞负责投射
主要针对皮质边缘结构,优先受到影响,表明不同的亚群
VTA 多巴胺能神经元受到 AD 病理的影响。该领域目前因缺乏信息而受到限制
关于异质性如何影响腹侧中脑的病理生理倾向。该提案旨在
阐明 AD 及其相关痴呆症认知和非认知缺陷的潜在机制。
本提案中的实验将使用表达突变淀粉样蛋白和 tau 蛋白的已建立小鼠模型
调查集体知识中的这一差距。一般策略是使用 3、6 和 12 只动物
月龄,代表海马病理学中明确定义的病理时间点。我们将隔离
通过免疫组织化学、单细胞测序和逆行追踪分析 VTA 细胞亚群。
处死后,我们将记录电生理参数,进行 RNA 测序,并
转基因和非转基因小鼠单个 VTA 多巴胺能神经元的形态重建。目的
1 将构建跨皮质和皮质下淀粉样蛋白和 tau 蛋白积累的时空时间线
结构。目标 2 将研究内在的多巴胺能特性,包括神经突长度、动作电位
生成、控制放电的离子通道电导以及单细胞转录组谱。
了解发生在皮质区域之外的细胞和电路衰减是发展的关键
有效的治疗。这些研究旨在建立 AD 病理生理学中的多巴胺能过程,
了解单细胞异质性如何导致细胞功能衰退,并识别新靶标
用于 AD 干预。
项目成果
期刊论文数量(0)
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{{ truncateString('Harris Blankenship', 18)}}的其他基金
Multimodal ventral tegmental area decrements in a mouse Alzheimer's model
小鼠阿尔茨海默病模型中多模式腹侧被盖面积减少
- 批准号:
10709503 - 财政年份:2022
- 资助金额:
$ 3.56万 - 项目类别:
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