The Impact of Normative Aging and Alzheimers Disease on Fear based Disorders and Amygdala Dysfunction

正常衰老和阿尔茨海默病对恐惧障碍和杏仁核功能障碍的影响

基本信息

批准号：
10889548
负责人：
Caesar Miguel Hernandez
金额：
$ 24.9万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10889548
关键词：
Acceleration Address Age Age-associated memory impairment Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Amygdaloid structure Anatomy Anti-Inflammatory Agents Antiepileptic Agents Antiinflammatory Effect Autopsy Award Behavioral Biochemical Cognitive aging Data Dedications Dementia Diet Dietary Intervention Disease Elderly Electrophysiology (science)Elements Esters Extinction Fiber Foundations Fright Functional disorder Hippocampus Human Hyperactivity Impairment In Vitro Individual Inflammation Inflammatory Intervention Ketones Knowledge Learning Lifestyle-related condition Link Longevity Measures Medial Mediator Membrane Modeling Neurodegenerative Disorders Neurons Neurosciences Outcome Pathologic Processes Pathology Phase Photometry Physiological Physiology Post-Traumatic Stress Disorders Prefrontal Cortex Process Property Protocols documentation Quality of life Rattus Research Risk Rodent Role Scientist Sensory Signal Transduction Structure Synapses Techniques Temporal Lobe Testing Therapeutic Intervention Tissues Training Work age related aged aging population career chemokine combat comorbidity conditioned fear cytokine extracellular fear memory functional improvement improved in vivo innovation ketogenic diet ketogentic neural circuit neurobiological mechanism neuroinflammation neuromechanism neurophysiology neuropsychiatric disorder neurotransmission optogenetics patch clamp postsynaptic programs remediation skills success suicide rate translational approach

项目摘要

Not only do fear-based disorders such as posttraumatic stress disorder (PTSD) quintuple the rate of suicide relative to those without these disorders, but they also increase the magnitude of age-related cognitive decline and double the risk for developing Alzheimer’s disease and other dementias in older adults. Fear-based disorders like PTSD are linked to fear memories. Due to the seemingly indelible and hyperactive properties of such fear memories, fear-based disorders can worsen with age. Although normative aging and Alzheimer’s disease have dissociable trajectories, one factor that negatively impacts cognitive aging and Alzheimer’s disease is the comorbidity of PTSD. Perturbations in the functional circuitry supporting fear memory extinction are also key neural mechanisms of PTSD. A critical anatomical structure within the neural circuitry underlying this dysfunctional processing is the basolateral amygdala (BLA), which is considered an integrative hub as it receives sensory and contextual information from the prefrontal cortex and hippocampus. While much of the current scientific focus on cognitive aging and Alzheimer’s disease centers on the prefrontal cortex and hippocampus, little is known about the underlying mechanisms of BLA dysfunction in aging, Alzheimer’s disease (AD), and the impact of co-occurring PTSD. One pathological process common to these disorders is underlying neuroinflammation. Importantly, ketogenic and ketone ester diets are known to ameliorate hyperactivity, inflammation, fear-based disorders, and show promise as treatments for the contributing factors to cognitive aging and AD. To date, no study has investigated how aging and AD act in concert to further impair the BLA’s role in extinguishing hyperactive fear memories (a central component of PTSD). To address the current gap in knowledge, this proposal will leverage the TgF344AD rat model of AD to understand the contribution of BLA inflammation, cellular dysfunction, and synaptic circuit impairment to underlying mechanisms of PTSD. Recent data from the lab suggests, relative to young wild type rats, aging and AD impairs fear extinction and recall, and furthermore, the BLA in aged and AD rats is hyperactive. As such, the overarching hypothesis of this proposal is that hyperactive fear memory, the core element of PTSD, increases with aging and is accelerated in AD due to progressive inflammatory-driven neurophysiological deficits in the BLA. In Specific Aim 1, this proposal will leverage a rodent fear conditioning protocol that models a critical component of PTSD (i.e., the inability to extinguish hyperactive fear memory) and assess how aging and Alzheimer’s disease contribute to BLA cellular dysfunction (both ex vivo and in vivo during fear extinction) and inflammation. Additionally, in Specific Aim 2, this proposal will determine if a ketone ester dietary intervention (known to have anti-epileptic and anti-inflammatory properties) or BLA inactivation can facilitate fear memory extinction and improve BLA hyperactivity and pathology in age and AD. The outcomes of this proposal will be critical to developing translational strategies to combat poor quality of life outcomes in older adults.

不仅基于恐惧的疾病，例如创伤后应激障碍（PTSD），使自杀率占相对于没有这些疾病的人，但它们也增加了与年龄相关的认知下降的幅度并在老年人中患上阿尔茨海默氏病和其他痴呆症的风险增加一倍。基于恐惧像PTSD这样的疾病与恐惧记忆有关。由于看似难以置信的过度活跃的特性这种恐惧记忆，基于恐惧的疾病会随着年龄的增长而担心。虽然正常的衰老和阿尔茨海默氏症疾病的轨迹具有分离的轨迹，这是对认知衰老和阿尔茨海默氏病的负面影响的一个因素是PTSD的合并症。支持恐惧记忆扩展的功能电路中的扰动也是 PTSD的关键神经元机制。在此基础的神经回路内的关键解剖结构功能失调的处理是基础杏仁核（BLA），它被认为是一个集成的集线器来自前额叶皮层和海马的感觉和上下文信息。而大部分电流对认知衰老和阿尔茨海默氏病的科学重点集中于前额叶皮层和海马，关于衰老，阿尔茨海默氏病（AD）的BLA功能障碍的基本机制知之甚少。同时出现的PTSD的影响。这些疾病常见的一个病理过程是基础神经炎症。重要的是，众所周知，酮和酮酯饮食可以改善多动症，炎症，基于恐惧的疾病并显示出对认知因素的疗法的希望衰老和广告。迄今为止，尚无研究调查衰老和广告如何共同行动以进一步损害BLA的在熄灭多动性恐惧记忆（PTSD的核心组成部分）中的作用。解决当前差距知识，该建议将利用AD的TGF344AD大鼠模型来了解BLA的贡献炎症，细胞功能障碍和突触电路对PTSD的基本机制受损。最近的实验室的数据表明，相对于年轻的野生型大鼠，衰老和广告会损害恐惧的扩展和回忆，以及此外，年龄和AD大鼠的BLA是多动的。因此，这是总体假设提案是随着老龄化的过度活跃记忆（PTSD的核心元素），是由于BLA的进行性炎症驱动的神经生理防御，在AD中加速了。在具体目的1，该提案将利用啮齿动物恐惧调节方案，该协议模拟了一个关键组成部分 PTSD（即无法扑灭多动恐惧记忆的无能为力）和评估衰老和阿尔茨海默氏病如何导致BLA细胞功能障碍（在恐惧延伸期间体内和体内）和炎症。此外，在特定的目标2中，该提案将确定酮酯饮食干预是否（已知有抗癫痫和抗炎特性）或BLA失活可以促进恐惧记忆延伸和改善年龄和AD的BLA多动症和病理。该提案的结果对制定翻译策略，以打击老年人的生活质量较差的生活质量。