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

未知领域：绘制和操纵阿尔茨海默病小鼠模型中的胆碱能基础前脑活动

• 批准号: 10537906
• 负责人: Benjamin Belfort
• 金额: $ 4.71万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537906
• 关键词: Acetylcholine; Acetylcholinesterase Inhibitors; Affect; Age-Months; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Attention; Behavioral; Behavioral Assay; Biological Assay; Brain; Cell physiology; Cells; Cholinesterase Inhibitors; Cognition; Cognitive deficits; Control Groups; Data; Decision Making; Dementia; Disease; Disease Progression; Exhibits; Functional Magnetic Resonance Imaging; Goals; Human; Image; Impaired cognition; Investigation; Magnetic Resonance Imaging; Maps; Measures; Mediating; Memory; Molecular; Molecular Analysis; Molecular Profiling; Mus; Mutation; Nerve Degeneration; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Pathogenesis; Pathologic; Pathology; Pattern; Persons; Pharmacologic Substance; Pharmacotherapy; Physiological; Research; Role; Senile Plaques; Signal Transduction; Source; Specificity; Symptoms; Therapeutic; TimeLine; Tissues; Transgenic Mice; United States; awake; basal forebrain; basal forebrain cholinergic neurons; base; behavioral outcome; brain cell; cell type; cellular targeting; cholinergic; cholinergic neuron; cognitive function; data modeling; disease phenotype; effective intervention; experimental study; extracellular; genetic manipulation; healthy aging; hyperphosphorylated tau; imaging modality; improved; in vivo; insight; mouse model; neural circuit; optogenetics; prevent; symptomatic improvement; symptomatology; therapeutic target; transcriptome; transcriptomics

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.

项目摘要 阿尔茨海默氏病（AD）是痴呆症的最常见形式，影响了大约580万人 美国。 AD的最有效干预措施是包括乙酰胆碱酯酶的药物 抑制剂，可防止乙酰胆碱的降解。尽管这些治疗能够暂时 改善疾病的症状，它们不会停止或反向AD进展。几种组织病理学 标志与AD有关，包括形成细胞外Aβ斑块，神经原纤维缠结， 以及基本前脑神经元的加速变性（大脑中乙酰胆碱的主要来源）。这 在人类AD MRI研究中已经观察到了基本前脑的明显变性，通常表明 早期疾病的发展。实际上，乙酰胆碱投射的变性或胆碱能神经元在其中 被认为是认知的重要根本原因，将其定义为疾病 进展。但是，人类研究是有限的，因为我们无法检查细胞的脑变性 使用当前可用的成像方式键入特异性。这突出了我们的重要差距 对AD的理解：尚不清楚基本前脑胆碱能神经元（BFCN）变性是否发生在 有组织的方式，也不是这种退化的程度与认知缺陷有关。因此，进一步 需要在AD的背景下对BFCN进行调查。这导致了我们的中心假设：BFCN 信号在一致的临时和空间模式中不利地改变，并刺激BFCN 活动将减轻认知症状。该项目的总体目标是更好地描述BFCN 在AD的病理环境中发出信号。这将通过两个主要目标来检查，这两者都利用 AD的5xFAD模型，一种以AD表型快速表现而闻名的转基因小鼠模型，并且 我们被证明表现出BFCN变性。 AIM 1中提出的实验将研究纵向 通过利用无数靶向细胞操作来进行体内fMRI，通过利用无数的细胞操作来改变 BFCN在清醒小鼠中的功能连通性，并使用BFCN生成分子剖面的时间表 陷阱序列。 AIM 2将探讨人为刺激和沉默BFCN如何影响认知功能 广告的上下文。这些数据一起将进一步理解AD中的BFCN变性 定义BFCN在认知中的作用。