The role of aldosterone in mediating depressive-like behavior in a rat model of heart failure

项目摘要 充血性心力衰竭(CHF)和情绪障碍以令人震惊的高比率并存。 据报道，存活于心肌梗死(MI)的患者抑郁的发生率为 高达45%，而在普通人群中的发病率为2%-9%。发展为心肌梗塞后的患者 抑郁症在一年内经历不良心血管事件的风险要大得多，因为 与非抑郁症患者相比。尽管有深刻的临床相关性，但促进 充血性心力衰竭患者是否存在抑郁尚不清楚。一个令人信服的假设是关于 心血管疾病和抑郁症是两种疾病的致病机制相似。其中 常见的生理适应障碍，高循环肾上腺皮质激素水平 激素醛固酮(aldosterone，Aldo)在动物模型和人类临床病例中已有报道。 抑郁症和充血性心力衰竭。目前的提案将探讨Aldo在促进情感和 慢性心力衰竭大鼠模型中的认知损害，概括了在... 人类病人。心力衰竭是由冠状动脉结扎诱发心肌梗死引起的，心梗是心力衰竭最常见的原因。 人类。然后用行为学和电生理学方法研究CHF对神经的影响。 具体地说，我们将测量快感缺失，这是人类严重抑郁障碍的核心症状，以及 充血性心力衰竭患者和重度抑郁症患者的认知功能经常受损 无序。使用盐皮质激素受体拮抗剂的中枢治疗预防抑郁的能力- 类似的行为以及学习和记忆缺陷将被确定。海马区的突触功能，a 心力衰竭动物的大脑区域与情绪障碍和认知功能有关，使用 电生理技术。最后，我们将研究神经营养因子脑源性神经营养因子 (BDNF)作为CHF中高循环Aldo行为效应的潜在下游介体。脑源性神经营养因子 海马区的表达与情绪、认知和神经反应有关 生理和心理压力源。脑源性神经营养因子直接注入大鼠海马区的疗效 将测试CHF患者异常行为表型的预防，以及运动的有效性，a 众所周知，行为手法对情绪、认知和心脏功能有积极影响，而且效果显著 增强脑源性神经营养因子的表达。这项建议所产生的结果将加深我们对 心脏疾病状态对大脑的影响以及建议潜在的治疗途径来减少 充血性心力衰竭对生活质量的有害影响。

Project Summary Congestive heart failure (CHF) and mood disorders occur as comorbid conditions at an alarmingly high rate. The incidence of depression in patients that have survived a myocardial infarction (MI) has been reported to be as high as 45%, while occurring at a rate of 2-9% in the general population. Post-MI patients that develop depression are at a much greater risk of experiencing an adverse cardiovascular event within one year as compared to non-depressed patients. In spite of the profound clinical relevance, the mechanisms that promote depression in CHF patients are not known. A compelling hypothesis regarding the coincidence of cardiovascular disease and depression is that the etiological mechanisms in both disorders are similar. Among the commonly observed physiological maladaptations, high circulating levels of the adrenal mineralocorticoid hormone aldosterone (ALDO) have been reported in animal models and human clinical cases of major depressive disorder and CHF. The current proposal will explore the role of ALDO in promoting affective and cognitive impairments in a rat model of CHF that recapitulates many of the physiological outcomes observed in human patients. CHF is induced by coronary artery ligation to induce MI, the most frequent cause of CHF in humans. The neurological impact of CHF is then studied using behavioral and electrophysiological methods. Specifically, we will measure anhedonia, a core symptom of major depressive disorder in humans, as well as cognitive function which is frequently impaired in CHF patients and in individuals with major depressive disorder. The ability of central treatments with mineralocorticoid receptor antagonists to prevent depressive- like behavior and learning and memory deficits will be determined. Synaptic function in the hippocampus, a brain region implicated in mood disorders and cognitive function, is assessed in animals with CHF using electrophysiological techniques. Finally, we will investigate the neurotrophin brain-derived neurotrophic factor (BDNF) as a potential downstream mediator of the behavioral effects of high circulating ALDO in CHF. BDNF expression in the hippocampus has been implicated in mood and cognition and neurological responses to physiological and psychological stressors. The efficacy of direct infusion of BDNF into the hippocampus in preventing aberrant behavioral phenotypes in CHF will be tested, as well as the efficacy of exercise, a behavioral manipulation known to have positive effects on mood, cognition, and cardiac function, and robustly enhance BDNF expression. Results generated from this proposal will enhance our understanding of the impact of cardiac disease states on the brain as well as suggest potential therapeutic avenues for reducing the deleterious impact of CHF on quality of life.