Cardiovascular disease, depression, and oxytocin

描述（由申请人提供）：抑郁是心血管疾病的重要危险因素，无论是在医学上健康的个体还是那些有心脏病史的人。这两种疾病都有一些共同的内稳态变化，包括心率增加和心率变异性（HRV）降低。然而，这种关系背后的机制尚不清楚。催产素（OT）被认为与这种关联有关，因为它在情绪/情绪和心血管稳态中都起着作用。OT具有抗应激特性，并调节人类和非人类动物的抗抑郁和焦虑样行为的表达。此外，OT已被证明可以降低脉搏率和血压，这表明OT可能对心脏有保护作用。当前建议的主要目的是调查涉及OT的神经机制介导抑郁和CVD之间联系的假设。本研究计划拟利用一种独特的啮齿动物系统，即一夫一妻制草原田鼠（Microtus ochrogaster），来研究行为、神经内分泌和心血管对物种相关和转化应激源——社会隔离的反应。像人类一样，草原田鼠在长期孤立的情况下会产生消极的情感行为（与抑郁和焦虑有关）。孤立的草原田鼠也表现出与抑郁的人类相似的心功能障碍，包括心率加快、HRV降低和心脏对压力源的反应改变。在孤立的田鼠中，OT水平升高，OT治疗减轻了孤立个体的抑郁样影响和心血管功能障碍。为了验证上述假设，将对OT受体进行拮抗，以确定缺乏OT受体刺激是否会增加对长期社会隔离有害影响的易感性。具体而言，本研究将1)使用经过验证的负面影响行为分析（例如，强迫游泳测试）来确定对社会隔离和OT拮抗剂（OTA）的行为反应；2)使用心脏监测技术来记录社会隔离和OTA对心血管功能的影响。3)研究分离和OTA对与情绪和自主神经功能相关的大脑区域以及心脏组织中OT受体结合（通过受体放射自显影）和基因表达（通过RT-PCR）的影响。总的来说，这些实验将为CVD和抑郁症之间联系的潜在机制提供有价值的信息。拟议研究的完成将为申请人（Melissa-Ann Scotti）开发和使用转化动物模型以进一步了解和改善人类身心健康的长期目标迈出重要的一步。

DESCRIPTION (provided by applicant): Depression is an important risk factor for CVD both in medically healthy individuals and those with a history of heart disease. Several homeostatic changes are common to both these disorders, including increased heart rate and decreased heart rate variability (HRV). However, the mechanisms underlying this relationship are not well understood. Oxytocin (OT) is thought to be involved in this association as it plays a role in both emotion/mood and cardiovascular homeostasis. OT has anti-stress properties and modulates the expression of antidepressant- and anxiolytic-like behaviors in both humans and non-human animals. Additionally, OT has been shown to reduce pulse rate and blood pressure suggesting that OT may be cardiac protective. The primary aim of the current proposal is to investigate the hypothesis that neural mechanisms involving OT mediate the link between depression and CVD. This research plan proposes to take advantage of a unique rodent system, the monogamous prairie vole (Microtus ochrogaster), to investigate behavioral, neuroendocrine, and cardiovascular responses to a species-relevant and translational stressor, social isolation. Like humans, prairie voles develop negative affective behaviors (relevant to depression and anxiety) when exposed to chronic isolation. Isolated prairie voles also display cardiac dysfunction similar to that of depressed humans, including increased heart rate, decreased HRV, and altered cardiac responses to stressors. OT levels are elevated in isolated voles and OT treatment attenuates depressive-like affect and cardiovascular dysfunction in isolated individuals. To test the above hypothesis, OT receptors will be antagonized to determine if the lack of OT receptor stimulation will increase susceptibility to the deleterious effects of prolonge social isolation. Specifically, this research will 1) use validated behavioral assays of negative affect (e.g., forced swim test) to determine the behavioral response to social isolation and an OT antagonist (OTA), 2) use cardiac monitoring technology to record the effects of social isolation and OTA on cardiovascular function, and 3) investigate the effect of isolation and OTA on OT receptor binding (via receptor autoradiography) and gene expression (via RT-PCR) in brain regions associated with mood and autonomic function as well heart tissue. Collectively, these experiments will provide valuable information about mechanisms underlying the link between CVD and depression. The completion of the proposed research will provide an important step in the applicant's (Melissa-Ann Scotti's) long-term goal of developing and using translational animal models to provide further understanding of and improve human physical and mental health. PUBLIC HEALTH RELEVANCE: Cardiovascular disease (CVD) is the dominant cause of death in the United States. Depression is an important risk factor for CVD and symptoms of depression predict an increase in fatal and non-fatal heart disease in medically well individuals regardless of other baseline medical variables such as smoking, and obesity. The research proposed here will explore the link between these disorders, providing further insight into the treatment and prevention of heart disease.