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: 10370090
• 负责人: Holly Christian Hunsberger
• 金额: $ 13.31万
• 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/10370090
• 关键词: APP-PS1; Address; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Anatomy; Anxiety; Area; Behavior; Behavioral; Brain; Brain imaging; Brain region; Cause of Death; Cells; Clinical; Development; Disease; Disease Progression; Female; Goals; Image; Immediate-Early Genes; Impaired cognition; Impairment; Individual; Label; Lead; Link; Mediating; Memory; Memory Loss; Mental Depression; Mental disorders; Mentorship; Microscopy; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Outcome; Research; Retrieval; Role; Sex Differences; Techniques; Testing; Time; Transgenic Organisms; United States; Woman; anxiety-like behavior; behavioral study; career; comorbidity; experience; in vivo; interest; male; mouse model; neural correlate; neural network; neuropsychiatry; novel; optogenetics; personalized therapeutic; prevent; programs; relating to nervous system; sex; skills; 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.

项目总结/摘要 在K99/R 00中，我将特别讨论焦虑和解剖性别对阿尔茨海默病（AD）的作用。 尤其是记忆力减退AD是一种使人衰弱的神经退行性和精神障碍， 它是美国十大无法预防、减缓或治愈的死亡原因之一。 此外，90%的AD患者还存在抑郁和焦虑等神经精神障碍 患者，并在AD风险人群中频繁发生。虽然大多数AD研究都是使用男性 最近的证据表明，雌性小鼠更容易患抑郁症、焦虑症和AD， 与男性相比。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AD进展后的焦虑和记忆丧失联系起来， 光遗传学、全脑显微镜和雌性和雄性小鼠体内Ca 2+成像。这些研究 代表了AD领域的一些第一：1）第一次测试有争议的假设，即焦虑可以是一个 女性AD的预测因子; 2）第一个研究整个大脑的性别差异作为疾病 3）首次使用体内钙离子成像来标记个体记忆并评估神经元活动 在AD小鼠的行为过程中;以及4）第一个测试靶向AD小鼠的神经相关物的治疗潜力的实验。 记忆力和焦虑。在目标1中，行为差异将与焦虑样行为相关， 随着AD的进展，许多年龄段的记忆丧失。在目标2中，对应于a的单个神经元 将通过利用转基因系，即与AD系（APP/PS1）繁殖的ArcCreERT 2小鼠来研究记忆。 该小鼠系允许对表达立即早期基因（IEG）Arc/Arg3.1的细胞进行不可磨灭的标记。 并允许在体验编码期间激活的细胞之间进行比较， 那些在检索相应记忆时被激活的记忆。我们将使用全脑成像技术 发现在AD期间发生改变的新的大脑区域。目标3：拯救受损的神经网络 在AD x ArcCreERT 2小鼠中使用光遗传学刺激与体内Ca 2+成像的组合。成果 这种有针对性的救援将提供直接证据，表明破坏神经系统会导致认知功能障碍。 在雌性AD小鼠中观察到的下降和焦虑样行为。我的总体职业目标是领导一个 一个独立的研究小组研究神经退行性变的潜在机制， 性别如何影响疾病进展，长期目标是创造个性化治疗方法。这 因此，K99/R 00将为我提供受保护的时间和指导，以获得技术和概念技能， 我成功地实现了我的职业目标，并建立了一个独立的研究计划， 回答神经退行性疾病领域的临床驱动研究问题。