The sex specific impact of anxiety on Alzheimer's disease progression

焦虑对阿尔茨海默病进展的性别特异性影响

• 批准号: 9905477
• 负责人: Holly Christian Hunsberger
• 金额: $ 12.94万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9905477
• 关键词: 4-Hydroxy-Tamoxifen; APP-PS1; Address; Affect; Age; Age-Months; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Amygdaloid structure; Anatomy; Anesthetics; Anxiety; Area; Asses; Atrophic; Award; Behavior; Behavioral; Biological Assay; Brain; Brain imaging; Brain region; Cause of Death; Cells; Clinical; Clinical Research; Cognitive deficits; Development; Diagnosis; Disease; Disease Progression; Exhibits; Exposure to; Female; Fostering; Genetic; Goals; Hippocampus (Brain); Image; Immediate-Early Genes; Impaired cognition; Impairment; Individual; Label; Lead; Learning; Link; Mediating; Memory; Memory Loss; Memory impairment; Mental Depression; Mental disorders; Mentorship; Microscope; Microscopy; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Outcome; Population; Reporting; Research; Retrieval; Role; Sex Differences; Short-Term Memory; Symptoms; System; Techniques; Testing; Time; Training; Transgenic Organisms; United States; Woman; anxiety symptoms; anxiety-like behavior; behavior test; behavioral study; career; cognitive task; comorbid depression; comorbidity; conditioned fear; dentate gyrus; depressive symptoms; design; epidemiology study; experience; in vivo; interest; long term memory; male; memory encoding; memory retrieval; mouse model; neural correlate; neural network; neuropsychiatry; novel; optogenetics; personalized therapeutic; prevent; processing speed; programs; relating to nervous system; sex; skills; spatial memory; therapeutic evaluation; therapeutic target

PROJECT SUMMARY / ABSTRACT For this K99/R00, I will specifically address the role of anxiety and anatomical sex on Alzheimer’s disease (AD) progression, specifically memory loss. AD, a debilitating neurodegenerative and mental disorder, stands alone as one of the ten leading causes of death in the United States that cannot be prevented, slowed, or cured. Furthermore, neuropsychiatric disturbances, such as depression and anxiety, are observed in 90% of AD patients and are frequent in those at risk for AD. Although most AD studies have been performed using male mice, recent evidence suggests that females are more susceptible to depression, anxiety, and AD when compared to males. In fact, two-thirds of AD patients are women. Here, we aim to identify the neural ensembles linking anxiety and memory loss following AD progression by utilizing behavioral studies, optogenetics, whole-brain microscopy, and in vivo Ca2+ imaging in female and male mice. These studies represent a number of firsts in the AD field: 1) the first to test the controversial hypothesis that anxiety can be a predictor of AD in females; 2) the first to investigate sex differences across the whole brain as the disease progresses; 3) the first to use in vivo Ca2+ imaging to tag an individual memory and asses neuronal activity during behavior in AD mice; and 4) the first to test the therapeutic potential of targeting neural correlates of memory and anxiety in AD mice. In Aim 1, behavioral differences will be correlate anxiety-like behavior with memory loss across numerous ages as AD progresses. In Aim 2, the individual neurons corresponding to a memory will be investigated by utilizing a transgenic line, the ArcCreERT2 mice bred with an AD line (APP/PS1). This mouse line allows for the indelible labeling of cells expressing the immediate early gene (IEG) Arc/Arg3.1 and allows for a comparison between the cells that are activated during the encoding of an experience and those that are activated during the retrieval of the corresponding memory. We will use whole brain imaging to find novel brain regions of interest that are altered during AD. In Aim 3, I will rescue impaired neural networks in AD x ArcCreERT2 mice using optogenetic stimulation in combination with in vivo Ca2+ imaging. The outcome of this targeted rescue will provide direct evidence that disrupted neural ensembles results in the cognitive decline and anxiety-like behavior observed in female AD mice. My overall career goal is to lead an independent research group examining the underlying mechanisms of neurodegeneration and to determine how sex impacts disease progression with the long-term goal of creating personalized therapeutics. This K99/R00 will thus provide me protected time and mentorship to acquire the technical and conceptual skills to successfully achieve my career goals and establish an independent research program geared towards answering clinically driven research questions in the area of neurodegenerative diseases.

项目摘要/摘要 在这篇K99/R00中，我将专门讨论焦虑和解剖性行为在阿尔茨海默病(AD)中的作用 进展，特别是记忆力丧失。AD是一种衰弱的神经退行性和精神障碍，独立存在 作为美国十大无法预防、减缓或治愈的死亡原因之一。 此外，90%的阿尔茨海默病患者会出现神经精神障碍，如抑郁和焦虑 常见于AD高危人群中。尽管大多数AD研究都是使用男性 老鼠，最近的证据表明，女性更容易患抑郁症、焦虑症和AD 与雄性相比。事实上，三分之二的AD患者是女性。在这里，我们的目标是识别神经 通过利用行为研究，将阿尔茨海默病进展后的焦虑和记忆丧失联系在一起， 雌性和雄性小鼠的光遗传学、全脑显微镜和体内钙成像。这些研究 代表了AD领域的许多第一：1)第一次测试了有争议的假设，即焦虑可能是一种 女性阿尔茨海默病的预测因子；2)第一次调查了整个大脑的性别差异作为疾病 进展；3)第一次使用活体钙成像来标记个人记忆和评估神经元活动 在AD小鼠的行为过程中；以及4)首次测试靶向神经的治疗潜力与 阿尔茨海默病小鼠的记忆和焦虑。在目标1中，行为差异将与焦虑样行为相关 随着阿尔茨海默病的进展，记忆力会随着年龄的增长而丧失。在目标2中，对应于 将利用一种转基因品系--用AD品系(APP/PS1)培育的ArcCreERT2小鼠来研究记忆。 该小鼠系允许对表达即刻早期基因(IEG)Arc/Arg3.1的细胞进行不可磨灭的标记 并且允许在编码体验期间被激活的细胞和 在检索相应记忆的过程中被激活的那些。我们将使用全脑成像技术 寻找在AD期间改变的新的大脑感兴趣区域。在《目标3》中，我将拯救受损的神经网络 在AD x ArcCreERT2小鼠中，使用光遗传刺激结合体内钙成像。结果是 这一有针对性的救援将提供直接证据，表明扰乱神经集合会导致认知 在雌性阿尔茨海默病小鼠中观察到衰退和焦虑样行为。我的总体职业目标是领导一个 独立研究小组研究神经退行性变的潜在机制并确定 性行为如何影响疾病的进展，并以创造个性化治疗为长期目标。这 因此，K99/R00将为我提供受保护的时间和指导，以获得以下技术和概念技能 成功实现了我的职业目标，并建立了一个独立的研究计划，旨在 回答神经退行性疾病领域的临床研究问题。