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

• 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
• 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' s Disease; Alzheimer' 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

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.

创伤后应激障碍（PTSD）等基于恐惧的疾病不仅使自杀率增加了五倍， 但它们也增加了与年龄相关的认知能力下降的程度 老年人患阿尔茨海默病和其他痴呆症的风险增加一倍。基于恐惧 创伤后应激障碍与恐惧记忆有关由于表面上不可磨灭的和过度活跃的性质， 这种恐惧记忆，恐惧导致的紊乱会随着年龄的增长而恶化。虽然正常老化和老年痴呆症 疾病具有可分离的轨迹，这是对认知老化和阿尔茨海默病产生负面影响的一个因素 是创伤后应激障碍的并发症支持恐惧记忆消退的功能回路的扰动也是 创伤后应激障碍的关键神经机制神经回路中的一个关键解剖结构 基底外侧杏仁核（BLA）被认为是一个整合枢纽，因为它接收 前额叶皮层和海马体的感觉和上下文信息。虽然目前的大部分 认知老化和阿尔茨海默病的科学研究集中在前额叶皮层和海马体， 关于BLA功能障碍在衰老、阿尔茨海默病（AD）和阿尔茨海默病（AD）中的潜在机制知之甚少。 创伤后应激障碍的影响。这些疾病的一个共同病理过程是潜在的 神经炎症重要的是，生酮和酮酯饮食已知可改善多动， 炎症，基于恐惧的疾病，并显示出作为认知障碍的贡献因素的治疗方法的希望。 老化和AD。到目前为止，还没有研究调查衰老和AD如何协同作用以进一步损害BLA 在消除过度活跃的恐惧记忆（PTSD的核心组成部分）中的作用。为了解决目前的差距， 知识，该提案将利用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回路损伤与PTSD的潜在机制有关。最近 来自实验室的数据表明，相对于年轻的野生型大鼠，衰老和AD损害了恐惧消失和回忆， 此外，老年和AD大鼠的BLA是过度活跃的。因此，这一假设的总体假设 过度活跃的恐惧记忆是PTSD的核心因素，随着年龄的增长而增加， 由于BLA中进行性炎症驱动的神经生理学缺陷，AD中的这种加速。在 具体目标1，该提案将利用啮齿动物恐惧条件反射协议，该协议模拟 PTSD（即，无法消除过度活跃的恐惧记忆），并评估衰老和阿尔茨海默病 导致BLA细胞功能障碍（在恐惧消退期间的离体和体内）和炎症。 此外，在具体目标2中，该提案将确定酮酯饮食干预（已知具有 抗癫痫和抗炎特性）或BLA失活可以促进恐惧记忆消退， 改善老年和AD中BLA活性亢进和病理学。该提案的结果将对以下方面至关重要： 制定转化战略，以应对老年人生活质量差的结果。