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

老龄化人口继续增长，阿尔茨海默病(AD)的流行也在继续增长， 导致疾病改变治疗方法。虽然阿尔茨海默病的特点通常是工作记忆下降，但它是 同时还伴有抑郁、冷漠和其他非认知障碍。由于突出的 AD患者存在记忆障碍，该领域的大部分研究都集中在大脑皮层和海马区 病理生理学。然而，阿尔茨海默病的病理发展遍及整个大脑，并与其相关的条件 涉及皮质下结构，特别是中脑多巴胺能系统。最近，两家公司都有报道称 动物模型和人类表明腹侧被盖区(VTA)到海马区的回路可能是 在AD中中断。有趣的是，老鼠模型中的一份报告表明，投射到内侧VTA的细胞 以皮质边缘结构为主，优先受影响，提示不同的亚群 VTA多巴胺能神经元受AD病理的影响。该领域目前受到信息匮乏的限制。 异质性如何影响腹侧中脑的病理生理易感性。这项建议旨在 阐明阿尔茨海默病及其相关痴呆认知和非认知缺陷的潜在机制。 该方案中的实验将使用已建立的表达突变的淀粉样蛋白和tau的小鼠模型。 来调查集体知识中的这一差距。一般的策略是使用3、6和12岁的动物 几个月龄，在海马区病理中代表明确的病理时间点。我们将隔离 通过免疫组织化学、单细胞测序和逆行示踪检测VTA细胞亚群。 牺牲后，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。目标 1将构建皮质和皮质下淀粉样蛋白和tau积聚的时空时间线。 结构。目标2将研究固有的多巴胺能特性，包括轴突长度、动作电位 产生，控制激发的离子通道电导，和单细胞转录图谱。 了解发生在皮质区域之外的细胞和电路的减少是发展的关键 有效的治疗方法。这些研究旨在建立AD病理生理学中的多巴胺能过程，以 了解单细胞异质性如何导致细胞功能衰退，并确定新的靶点 用于AD的干预。

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.