Experimental model of depression in aging: anxiety, inflammation, and reward mechanisms

项目摘要/摘要 老年抑郁症很普遍，影响了近五分之一的老年人，并给老年人带来了巨大的负担 公共卫生。老年抑郁症的一个特征是丧失体验快乐的能力，并减少 寻求有益经历的动力。快感和动力的丧失限制了人们对 可能会改善身心健康，导致社会孤立，并增加自杀和过早自杀的风险 死亡率。这些奖赏功能的破坏性损害也是出了名的难以发现和治疗， 部分原因是对导致奖赏功能受损的机制了解有限。高架 与抑郁症密切相关的炎症被认为是一种生物奖赏机制。 临床前模型中的失调。翻译工作表明，促炎挑战，如 给予内毒素，也会改变健康成人的奖赏行为和奖赏神经回路。我们的 实验室已经将这一调查范围扩展到老年人，初步数据显示，内毒素 在焦虑升高但不低的非抑郁老年人中，管理减少了动机行为。 焦虑在老年人中很普遍，是抑郁症的风险因素，并增加了对炎症的易感性。 诱发的负面情绪；此外，衰老增加了对炎症的暴露(例如，更容易患上 感染、慢性病、炎症)。因此，焦虑和炎症是危险因素，可能包括 “两次点击”，以削弱老年人的奖励行为。然而，还没有研究测试这种行为的影响 是由奖赏神经回路的变化驱动的，以帮助澄清机械路径和识别干预 目标。本研究的目的是使用多水平分析的奖励函数和一个实验 实验诱导炎症对奖赏行为(目标1)和奖赏影响的试验设计 神经回路(目标2)作为老年人焦虑的一种功能。一种双盲、安慰剂对照、炎症性的 有焦虑症状和无焦虑症状的老年人(60-80岁)使用内毒素挑战将 评估焦虑的老年人是否特别容易受到炎症引起的奖赏缺失的影响 应优先进行监测和干预。报酬多层次分析的启示 可用于为基于精确和个性化的医疗战略的发展提供信息 预防和治疗老年抑郁症。在K01奖的支持下，我将利用这项研究 启动一项独立研究计划，利用实验方法来确定晚年生活的机制 抑郁症以改善老年人的健康和幸福感。为此，我正在寻求进修 实验性临床试验方法学使用内毒素模型加速我作为一名 独立调查员；2)掌握神经成像技术和数据分析方面的技能 可能对炎症敏感并驱动异常行为的神经机制；以及3)晚期- 生活焦虑拓宽了我的研究计划，并测试了奖励赤字的新概念模型。

PROJECT SUMMARY/ABSTRACT Depression in late life is prevalent, affects nearly one fifth of older adults, and exacts an enormous burden on public health. One hallmark of late-life depression is a loss in the ability to experience pleasure and reduced motivation to seek rewarding experiences. Loss of pleasure and motivation limits engagement in activities that could improve physical and mental health, leads to social isolation, and increases risk of suicide and early mortality. These devastating impairments in reward function are also notoriously difficult to detect and treat, due in part to a limited understanding of the mechanisms that contribute to impaired reward function. Elevated inflammation, which is closely linked to depression, has been implicated as a biological mechanism of reward dysregulation in preclinical models. Translational work has shown that pro-inflammatory challenges, such as endotoxin administration, also alter reward behavior and reward neurocircuitry in healthy human adults. Our laboratory has extended this line of inquiry to older adults, and preliminary data show that endotoxin administration reduces motivational behavior in non-depressed older adults with elevated, but not low, anxiety. Anxiety is prevalent in older adults, a risk factor for depression, and increases vulnerability to inflammation- induced negative mood; moreover, aging increases exposure to inflammation (e.g., higher susceptibility to infection, chronic disease, inflammaging). As such, anxiety and inflammation are risk factors that may comprise “two hits” to impair reward behavior in older adults. Yet, no studies have tested whether such behavioral effects are driven by alterations in reward neurocircuitry to help clarify mechanistic pathways and identify intervention targets. The objective of the current study is to use multilevel analysis of reward function and an experimental design to test effects of experimentally induced inflammation on reward behavior (Aim 1) and reward neurocircuitry (Aim 2) as a function of anxiety in older adults. A double-blind, placebo-controlled, inflammatory challenge with endotoxin in older adults (60-80 y) with (n=40) and without (n=40) anxiety symptoms will evaluate whether anxious older adults are especially vulnerable to inflammation-induced deficits in reward function and should be prioritized for monitoring and intervention. Insights from multilevel analysis of reward can be used to inform the development of precision-based and personalized medicine strategies for the prevention and treatment of late-life depression. With the support of the K01 Award, I will use this study to launch an independent research program that uses experimental methods to identify mechanisms of late-life depression to improve health and well-being in older adults. To this end, I am seeking 1) advanced training in experimental clinical trial methodology using the endotoxin model to accelerate my development as an independent investigator; 2) acquisition of skills in neuroimaging techniques and data analysis to evaluate neural mechanisms that may be sensitive to inflammation and drive aberrant behavior; and 3) expertise in late- life anxiety to broaden my research program and test new conceptual models of reward deficits.