Uncharted Territory: Mapping and Manipulating Cholinergic Basal Forebrain Activity in a Mouse Model of Alzheimer's Disease

项目摘要 阿尔茨海默氏病（AD）是最常见的痴呆症，在美国约有580万人受到影响。 美国的AD最有效的干预措施是含有乙酰胆碱酯酶的药物 抑制剂，防止乙酰胆碱的降解。虽然这些治疗方法能够暂时 虽然它们改善了疾病的症状，但它们不会阻止或逆转AD的进展。几种组织病理学 特征与AD相关，包括细胞外Aβ斑块的形成，神经元缠结， 以及基底前脑神经元（大脑中乙酰胆碱的主要来源）的加速变性。这 在人类AD MRI研究中已经观察到基底前脑的显著变性， 早期疾病的出现。事实上，乙酰胆碱投射或胆碱能神经元的变性， 这一区域被认为是认知缺陷的重要潜在原因，这些认知缺陷表现为疾病 进步。然而，人类的研究是有限的，因为我们不能用细胞来检查大脑的退化。 类型特异性使用目前可用的成像模式。这突出了我们在这方面的一个重要差距。 对AD的理解：尚不清楚基底前脑胆碱能神经元（BFCN）变性是否发生在 一种有组织的方式，也不知道这种退化的程度如何与认知缺陷相关。因此进一步 需要在AD的背景下研究BFCN。这就引出了我们的核心假设：BFCN 信号以一致的时间和空间模式被不利地改变，并且刺激BFCN 活动会减轻认知症状。该项目的总体目标是更好地描述BFCN 在AD的病理背景下的信号传导。这将通过两个主要目标进行审查，这两个目标都利用 AD的5xFAD模型，一种已知快速表现AD表型的转基因小鼠模型， 已被证明表现出BFCN变性。目标1中提出的实验将研究纵向 通过利用无数的靶向细胞操作来进行BFCN电路的体内fMRI， 清醒小鼠中的BFCN功能连接，并使用 TRAP-seq.目的2将探讨人工刺激和沉默BFCN如何影响认知功能， AD的背景。总之，这些数据将进一步加深我们对AD中BFCN变性的理解， 定义BFCN在认知中的作用。

PROJECT SUMMARY Alzheimer’s Disease (AD) is the most common form of dementia, affecting roughly 5.8 million people in the United States. The most effective interventions for AD are pharmaceuticals that include acetylcholinesterase inhibitors, which prevent the degradation of acetylcholine. While these treatments are capable of temporarily improving the symptoms of disease, they do not halt or reverse AD progression. Several histopathological hallmarks have been associated with AD, including formation of extracellular Aβ plaques, neurofibrillary tangles, and accelerated degeneration of basal forebrain neurons (the primary source of acetylcholine in the brain). This marked degeneration of the basal forebrain has been observed in human AD MRI studies and typically indicates the advent of early disease. In fact, the degeneration of acetylcholine projecting, or cholinergic neurons in this region that is believed to be an important underlying cause of the cognitive deficits that emerge as disease progresses. However, human studies are limited, as we are not able to examine brain degeneration with cell type specificity using currently available imaging modalities. This highlights an important gap in our understanding of AD: it is unknown whether basal forebrain cholinergic neuron (BFCN) degeneration occurs in an organized manner, nor how the extent of this degeneration correlates to cognitive deficits. Therefore, further investigation of BFCNs in the context of AD is needed. This leads to our central hypothesis: that BFCN signaling is adversely altered in a consistent temporal and spatial pattern, and that stimulating BFCN activity will mitigate cognitive symptoms. The overarching goal of this project is to better characterize BFCN signaling in the pathological context of AD. This will be examined through two primary aims, both of which utilize the 5xFAD model of AD, a transgenic mouse model known for rapid manifestation of the AD phenotype and has been shown to exhibit BFCN degeneration. Experiments proposed in Aim 1 will investigate longitudinal alterations in BFCN circuitry by leveraging myriad targeted cellular manipulations to perform in vivo fMRI of BFCN functional connectivity in awake mice, and to generate a timeline of molecular profiles for BFCNs using TRAP-seq. Aim 2 will explore how artificially stimulating and silencing BFCNs influences cognitive function in the context of AD. Together, these data will further our understanding of BFCN degeneration in AD and better define the roles of BFCNs in cognition.