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

创伤后应激障碍(PTSD)等基于恐惧的障碍不仅会使自杀率增加五倍 相对于那些没有这些障碍的人，但他们也增加了与年龄相关的认知下降的幅度 老年人罹患阿尔茨海默病和其他痴呆症的风险增加一倍。基于恐惧的 像创伤后应激障碍这样的疾病与恐惧记忆有关。由于看似不可磨灭的和过度活跃的特性 这种恐惧记忆，即以恐惧为基础的障碍，可能会随着年龄的增长而恶化。尽管标准衰老和阿尔茨海默氏症 疾病具有不可关联的轨迹，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共病。支持恐惧记忆消退的功能电路中的扰动也 创伤后应激障碍的关键神经机制。神经回路中的一个关键的解剖学结构 功能障碍的处理是基底外侧杏仁核(BLA)，它被认为是一个整合的中枢，因为它接受 来自前额叶皮质和海马体的感觉和背景信息。虽然目前的大部分时间 对认知老化和阿尔茨海默病的科学关注集中在前额叶皮质和海马体上， 关于BLA功能障碍在衰老、阿尔茨海默病(AD)和 共同发生的创伤后应激障碍的影响。这些疾病的一个共同的病理过程是潜在的 神经炎。重要的是，生酮和酮酯饮食已知可以改善多动症， 炎症、基于恐惧的障碍，以及显示出希望作为认知促进因素的治疗方法 衰老和AD。到目前为止，还没有研究调查衰老和阿尔茨海默病是如何协同作用进一步损害血乳酸的 在消除过度活跃的恐惧记忆中的作用(创伤后应激障碍的中心组成部分)。要解决当前的差距 知识，这项建议将利用AD的TgF344AD大鼠模型来了解血乳酸的贡献 炎症、细胞功能障碍和突触回路损伤是创伤后应激障碍的潜在机制。近期 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会削弱对灭绝和记忆的恐惧，而且 此外，老年组和AD组大鼠的BLA也处于高活性状态。因此，这一最重要的假设 建议是过度活跃的恐惧记忆，创伤后应激障碍的核心元素，随着年龄的增长而增加，并且 在阿尔茨海默病中由于进行性炎症驱动的血乳酸神经生理学缺陷而加速。在……里面 具体目标1，该提案将利用啮齿动物恐惧条件调节协议，该协议模拟了 创伤后应激障碍(即无法消除过度活跃的恐惧记忆)和评估衰老和阿尔茨海默病 导致BLA细胞功能障碍(包括体内和体外的恐惧消退)和炎症。 此外，在具体目标2中，这项建议将确定酮酯饮食干预(已知有 抗癫痫和抗炎特性)或血乳酸灭活可促进恐惧记忆的消退和 改善老年性和阿尔茨海默病患者的BLA多动和病理改变。这项提案的结果将对 制定翻译策略，以应对老年人不良的生活质量结果。

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.