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：
10709503
负责人：
Harris Blankenship
金额：
$ 3.65万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
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：
https://reporter.nih.gov/project-details/10709503
关键词：
3xTg-AD mouse Action Potentials Affect Age Age Months Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Amygdaloid structure Amyloid Anhedonia Animal Model Animals Area Atlases Award Bioinformatics Brain Brain region Cells Classification Cognition Cognitive Confocal Microscopy Coupled Data Dementia Deposition Development Disease Dopaminergic Cell Electrophysiology (science)Fluorescence Functional disorder Future Gene Expression Profile Generations Genes Goals Heterogeneity Hippocampus Human Image Immunoassay Immunohistochemistry Impaired cognition Impairment 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 Tissue-Specific Gene Expression Training Transgenic Organisms Ventral Tegmental Area aged aging population aspirate 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 timeline transcriptome transcriptome sequencing transcriptomics

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.

老龄化人口继续增长，阿尔茨海默氏病（AD）的患病率也在必要的疾病改变疗法。虽然广告通常以工作记忆下降为特征，但它是还与抑郁症，冷漠和其他非认知障碍一起高度合并。由于突出记忆定义在AD患者中，该领域的大部分研究集中在皮质和海马上病理生理学。但是，AD病理在整个大脑及其相关条件中发展暗示皮质结构，特别是中脑多巴胺能系统。最近，两者的报告动物模型和人类表明，腹侧换盖区域（VTA）可能是海马电路在广告中被破坏。有趣的是，鼠标模型中的报告表明内侧VTA中的细胞（该细胞）最好受到皮质脂质结构的主要影响，优选受到影响，表明 VTA多巴胺能神经元受AD病理学的影响。该领域目前受到缺乏信息的限制关于异质性如何影响腹中脑中的病理生理易感性。该建议旨在阐明AD及其相关痴呆症中认知和非认知缺陷的潜在机制。该提案中的实验将使用表达突变淀粉样蛋白和tau的既定小鼠模型在集体知识中调查这一差距。一般策略将是使用3、6和12的动物几个月大，代表海马病理中定义明确的病理时间点。我们将孤立通过免疫组织化学，单细胞测序和逆行跟踪对VTA细胞的亚群。在牺牲之后，我们将记录电生理参数，执行RNA测序，然后转基因和非转基因小鼠的单个VTA多巴胺能神经元的形态重建。目的 1将构建淀粉样蛋白和tau的时空时间轴结构。 AIM 2将研究固有的多巴胺能特性，包括神经落长度，动作电位生成，控制放电的离子通道电导和单细胞转录组轮廓。了解在皮质区域之外发生的细胞和电路减少是发展的关键这些研究旨在在AD病理生理学中建立多巴胺能过程了解单细胞异质性如何使细胞易于功能下降，并确定新靶标用于干预广告。