Neural Circuits Underlying Post-operative Delirium in Early Stage Alzheimer's Disease

早期阿尔茨海默病术后谵妄的神经回路

• 批准号: 10590280
• 负责人: Kathleen Frances Vincent
• 金额: $ 13.52万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10590280
• 关键词: Acute; Address; Adult; Advisory Committees; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid; Anesthesia procedures; Anesthetics; Animals; Attention; Attentional deficit; Attenuated; Automobile Driving; Award; Basic Science; Behavioral; Brain; Brain Pathology; Chronic; Clinical; Clinical Research; Cognitive deficits; Communication; Communities; Complication; Confusion; Curiosities; Dementia; Development; Development Plans; Elderly; Environment; Functional disorder; General Anesthesia; General Hospitals; General anesthetic drugs; Genetic; Genetic Techniques; Goals; Grant; Healthcare; Histopathology; Hospitalization; Hour; Human; Impairment; Intervention; Lead; Linear Models; Massachusetts; Mediating; Mentors; Mentorship; Neurocognitive; Neurons; Operant Conditioning; Outcome; Pathologic; Pathology; Phase; Positioning Attribute; Postoperative Complications; Pre-Clinical Model; Rattus; Reaction Time; Research; Research Personnel; Risk; Rodent Model; Role; Severities; Symptoms; Techniques; Testing; Therapeutic Intervention; Time; Training; Transgenic Organisms; Translational Research; Unconscious State; Variant; Ventral Tegmental Area; Viral; Work; Writing; behavior test; brain tissue; career; career development; career networking; clinically relevant; cognitive function; cognitive recovery; cognitive testing; cost; dopaminergic neuron; inattention; insight; locus ceruleus structure; medical schools; mortality risk; neural circuit; neuropathology; noninvasive brain stimulation; noradrenergic; novel; novel therapeutics; postoperative delirium; pre-clinical; prevent; prodromal Alzheimer' s disease; programs; skills; statistics; sustained attention; tau Proteins; tau aggregation; therapeutic target; tool; touchscreen; transgenic model of alzheimer disease

Postoperative delirium (POD) is a common and serious postoperative complication among the elderly, especially those with Alzheimer’s disease (AD), and has no available treatments. Interestingly, the risk for POD begins at preclinical AD stages when mild sustained attention deficits emerge. For this K99/R00, I will investigate the role of the locus coeruleus and ventral tegmental area – two regions affected by AD pathology and inhibited by general anesthetics – on the development of sustained attention deficits and POD using the rodent model of AD, TgF344-AD. I have developed a variant of the 5-choice serial reaction time task, a touchscreen sustained attention task, in which real-time cognitive recovery is assessed in rats following general anesthesia to capture the severity and duration of POD symptoms. In Aim 1 (K99), I will characterize the progression of sustained attention deficits in TgF344-AD and aging rats and its association with POD and AD histopathology. In Aim 2.1 (K99), I will use a novel dual-viral mediated chemogenetic targeting technique to establish the role of ventral tegmental area dopaminergic neurons in AD-related attentional impairments. With these skills, I will be well- equipped to independently pursue Aim 2.2 (R00), which applies the same techniques to investigate noradrenergic locus coeruleus neurons in AD-related attention impairments, and Aim 3 (R00), where chronic and acute activation of the ventral tegmental area and locus coeruleus will be used to mitigate AD-associated POD. My overall career goal is to lead an independent research group examining the underlying neural circuits impacting POD in AD with the long-term goal of creating interventional therapeutic strategies against dementia- associated POD. To accomplish this goal, I will need additional training in chemogenetic techniques, transgenic rodent models of AD, and AD neuropathology. For the K99 phase, I will have the guidance of my mentor, Dr. Ken Solt, who will train me in chemogenetics, and co-mentor, Dr. Zhongcong Xie, an expert in AD and POD research. My Advisory Committee, Drs. Christiane Wrann (AD transgenic model expertise) and Timothy Houle (statistics expertise), will provide research and professional guidance as I near independence. My career development plan integrates didactics in AD pathology and neuroengineering; training in communication, lab management, and grant writing; and professional networking opportunities. Massachusetts General Hospital and Harvard Medical School provide the ideal environment to conduct the proposed research, providing all the facilities necessary within a supportive, collaborative team of researchers and clinicians. The protected time and mentorship provided by this K99/R00 will allow me to acquire the technical and conceptual skills required to lead a focused research program on POD and AD research as an independent investigator. The outcome of this work will yield important insight into the role of neural circuits implicated in prodromal AD and aging and how they may be targeted to prevent and treat POD.

术后谵妄（POD）是老年人术后常见而严重的并发症， 那些患有阿尔茨海默病（AD）的人，并且没有可用的治疗方法。有趣的是，POD的风险始于 出现轻度持续注意力缺陷的临床前AD阶段。对于此K99/R 00，我将研究 蓝斑和腹侧被盖区--这两个区域受到AD病理学的影响并被抑制 全身麻醉药-使用AD啮齿动物模型对持续注意力缺陷和POD的发展， TgF344-AD。我开发了一个5选择系列反应时间任务的变体，一个触摸屏持续 注意力任务，其中在全身麻醉后评估大鼠的实时认知恢复以捕获 POD症状的严重程度和持续时间。在目标1（K99）中，我将描述持续性 TgF 344-AD和衰老大鼠的注意缺陷及其与POD和AD组织病理学的关系。在目标2.1 (K99)，我将使用一种新的双病毒介导的化学遗传靶向技术来建立腹侧的作用， 被盖区多巴胺能神经元与AD相关注意力障碍有了这些技能，我会很好- 配备独立追求目标2.2（R 00），它应用相同的技术来调查 去甲肾上腺素能蓝斑神经元在AD相关的注意力障碍，和Aim 3（R 00），其中慢性 腹侧被盖区和蓝斑的急性激活将用于减轻AD相关的 POD。我的总体职业目标是领导一个独立的研究小组， 影响AD中的POD，长期目标是创建针对痴呆症的干预性治疗策略- 相关POD为了实现这个目标，我需要在化学遗传学技术，转基因， AD的啮齿动物模型和AD神经病理学。对于K99阶段，我将有我的导师，博士的指导。 肯·索尔特，他将在化学遗传学方面训练我，以及共同导师，谢忠聪博士，AD和POD专家 research.我的顾问委员会，Christiane Wrann博士（AD转基因模型专家）和Timothy Houle博士 （统计专业知识），将提供研究和专业指导，因为我接近独立。我的职业生涯 发展计划整合了AD病理学和神经工程学的教学法;交流，实验室 管理，并授予写作;和专业网络的机会。马萨诸塞州总医院和 哈佛医学院为开展拟议的研究提供了理想的环境， 在研究人员和临床医生的支持性协作团队中提供必要的设施。受保护的时间和 K99/R 00提供的指导将使我获得领导所需的技术和概念技能 作为一名独立的研究者，专注于POD和AD研究的研究计划。这项工作的成果 将产生重要的洞察神经回路的作用牵连在前驱AD和老化，以及他们如何可能 有针对性地防治POD。