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: 10593105
• 负责人: Holly Christian Hunsberger
• 金额: $ 24.9万
• 依托单位: ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593105
• 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; Atrophic; Award; Behavior; Behavioral; Biological Assay; Brain; Brain imaging; Brain region; Breeding; Cause of Death; Cells; Clinical; Clinical Research; Cognitive deficits; Development; Diagnosis; Disease Progression; Exhibits; Exposure to; Female; Fostering; Genetic; Goals; Hippocampus; 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; Predisposition; 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; neural correlate; neural network; neuropsychiatry; novel; optogenetics; personalized therapeutic; prevent; processing speed; programs; 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.

项目概要/摘要 对于本 K99/R00，我将专门讨论焦虑和解剖性别对阿尔茨海默病 (AD) 的作用 AD，一种使人衰弱的神经退行性疾病和精神障碍，是一种独立的疾病进展。 作为美国十大死因之一，无法预防、减缓或治愈。 此外，90% 的 AD 患者都存在神经精神障碍，例如抑郁和焦虑 尽管大多数 AD 研究都是针对男性进行的，但这种情况在有 AD 风险的患者中很常见。 老鼠，最近的证据表明，女性在以下情况下更容易患抑郁症、焦虑症和 AD 事实上，三分之二的 AD 患者是女性。 通过行为研究将 AD 进展后的焦虑和记忆丧失联系起来， 这些研究包括雌性和雄性小鼠的光遗传学、全脑显微镜检查和体内 Ca2+ 成像。 代表了 AD 领域的多项第一：1）第一个测试了有争议的假设，即焦虑可能是一种 女性 AD 的预测因子；2) 第一个将整个大脑的性别差异作为疾病进行研究的人 取得进展；3) 第一个使用体内 Ca2+ 成像来标记个体记忆并评估神经活动 在 AD 小鼠的行为过程中；4) 第一个测试针对神经相关因素的治疗潜力 AD 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 AD 的进展，各个年龄段的记忆丧失。在目标 2 中，单个神经元对应于一个神经元。 将通过利用转基因品系（与 AD 品系 (APP/PS1) 繁殖的 ArcCreERT2 小鼠）来研究记忆能力。 该小鼠系可以对表达即早基因 (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与 那些在检索相应记忆的过程中被激活的神经元，我们将使用全脑成像来进行。 找到 AD 期间发生改变的新的大脑区域。在目标 3 中，我将拯救受损的神经网络。 在 AD x ArcCreERT2 小鼠中使用光遗传学刺激与体内 Ca2+ 成像相结合的结果。 这种有针对性的救援将提供直接证据，证明神经系统紊乱会导致认知能力下降 在雌性 AD 小鼠中观察到的衰退和焦虑样行为。 独立研究小组检查神经退行性变的潜在机制并确定 性别如何影响疾病进展，以实现个性化治疗的长期目标。 因此，K99/R00 将为我提供受保护的时间和指导，以获取技术和概念技能 成功实现我的职业目标并建立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。