Multimodal ventral tegmental area decrements in a mouse Alzheimer's model

人口老龄化持续增长，阿尔茨海默病（AD）的患病率也在不断上升， 从而需要改变疾病的疗法。虽然AD通常以工作记忆下降为特征，但它 也与抑郁、冷漠和其他非认知障碍高度共病。由于突出的 AD患者的记忆缺陷，该领域的大部分研究集中在皮层和海马 病理生理学然而，AD病理学在整个大脑中发展，其相关病症 牵涉到皮层下结构特别是中脑多巴胺能系统最近，两份报告 动物模型和人类表明，腹侧被盖区（VTA）到海马回路可能是 在AD中中断。有趣的是，小鼠模型的一份报告表明，腹侧被盖内侧的细胞投射出 主要是皮质边缘结构，优先受到影响，这表明不同的亚群 腹侧被盖区多巴胺能神经元受到AD病理学的影响。该领域目前因缺乏信息而受到限制 异质性如何影响腹侧中脑的病理生理倾向。这项建议旨在 阐明AD及其相关痴呆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蛋白的已建立的小鼠模型 来调查集体知识中的这个缺口。一般策略是使用3、6和12岁的动物 月龄，代表海马病理学中明确定义的病理学时间点。我们将隔离 通过免疫组织化学、单细胞测序和逆行追踪来检测VTA细胞亚群。 处死后，我们将记录电生理学参数，进行RNA测序， 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蛋白在皮质和皮质下积聚的时空时间轴 结构.目的2将研究多巴胺能神经元的内在特性，包括轴突长度，动作电位 产生，控制放电的离子通道电导和单细胞转录组学概况。 理解发生在皮层区域之外的细胞和回路减少是发展神经系统的关键。 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使细胞功能下降，并确定新的靶点 干预AD。

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.