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

项目总结/摘要 老年抑郁症很普遍，影响了近五分之一的老年人，并给他们带来了巨大的负担。 公共卫生晚年抑郁症的一个标志是失去体验快乐的能力， 寻求有益经验的动机。快乐和动力的丧失限制了对活动的参与， 可以改善身心健康，导致社会孤立，并增加自杀和过早死亡的风险。 mortality.这些奖励功能的破坏性损伤也是众所周知的难以发现和治疗， 部分原因是对导致奖励功能受损的机制的理解有限。升高 与抑郁症密切相关的炎症被认为是一种生物学上的奖赏机制 临床前模型中的失调。翻译工作表明，促炎性挑战，如 内毒素给药也改变健康成人的奖赏行为和奖赏神经回路。我们 实验室已经将这一调查延伸到老年人，初步数据显示， 给药可以减少焦虑程度升高但不低的非抑郁老年人的动机行为。 焦虑在老年人中很普遍，是抑郁症的一个危险因素，并增加了炎症的脆弱性- 诱发的消极情绪;此外，衰老增加了对炎症的暴露（例如，更易受 感染、慢性疾病、炎症）。因此，焦虑和炎症是风险因素，可能包括 “两次打击”损害老年人的奖励行为。然而，还没有研究测试这种行为影响是否 是由奖赏神经回路的改变驱动的，以帮助澄清机制途径并确定干预措施。 目标的本研究的目的是使用奖励函数的多水平分析和实验 测试实验诱导的炎症对奖励行为（目标1）和奖励的影响的设计 神经回路（目标2）作为老年人焦虑的函数。一项双盲、安慰剂对照、炎症性 在有（n=40）和无（n = 40）焦虑症状的老年人（60-80岁）中用内毒素激发， 评估焦虑的老年人是否特别容易受到炎症诱导的奖励缺陷的影响 应优先进行监测和干预。奖励的多层次分析 可用于为患者提供基于精确度和个性化医疗策略的开发信息， 预防和治疗老年抑郁症。在K 01奖的支持下，我将利用这项研究， 启动一项独立的研究计划，使用实验方法来确定晚年的机制， 抑郁症，以改善老年人的健康和福祉。为此，我正在寻求高级培训， 使用内毒素模型的实验性临床试验方法，以加速我作为 独立调查员; 2）获得神经成像技术和数据分析技能，以评估 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，以扩大我的研究计划和测试新的概念模型的奖励赤字。

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.