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: 10537306
• 负责人: Harris Blankenship
• 金额: $ 3.56万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10537306
• 关键词: 3xTg-AD mouse; Action Potentials; Affect; Age; Age-Months; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amygdaloid structure; Amyloid; Anhedonia; Animal Model; Animals; Area; Aspirate substance; Atlases; Award; Bioinformatics; Brain; Brain region; Cells; Cognition; Cognitive; Confocal Microscopy; Coupled; Data; Dementia; Deposition; Development; Disease; Dopaminergic Cell; Electrophysiology (science); Fluorescence; Functional disorder; Future; Gene Expression Profile; Generations; Goals; Heterogeneity; Hippocampus (Brain); Human; Image; Immunoassay; Immunohistochemistry; Impaired cognition; Individual; Intervention; Ion Channel; Knowledge; Label; Length; Link; Measures; Medial; Memory impairment; Mental Depression; Midbrain structure; Molecular; Molecular Biology; Mood Disorders; Morphology; Mus; Neurites; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Nucleus Accumbens; Operative Surgical Procedures; Pathologic; Pathology; Pathway interactions; Physiological; Potassium Channel; Predisposition; Prevalence; Process; Property; Proteins; Public Health; Publishing; Reporting; Research; Role; Scheme; Senile Plaques; Short-Term Memory; Signal Transduction; Slice; Specificity; Structure; Synapses; System; Time; TimeLine; Tissue-Specific Gene Expression; Training; Transgenic Organisms; Ventral Tegmental Area; aged; aging population; base; biocytin; career; comorbid depression; comorbidity; dopamine replacement therapy; dopaminergic neuron; efficacious treatment; experimental study; functional decline; functional disability; improved; insight; memory encoding; molecular phenotype; mouse model; multimodality; mutant; neuronal cell body; new therapeutic target; novel; patch clamp; patch sequencing; prevent; protein aggregation; reconstruction; reward processing; sex; single cell sequencing; skills; spatiotemporal; tau Proteins; tau aggregation; transcriptome; transcriptome sequencing; transcriptomics

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。