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.

项目总结