Cardiovascular disease, depression, and oxytocin

描述(申请人提供)：抑郁症是心血管疾病的一个重要风险因素，无论是在医学上健康的个人还是有心脏病病史的人。这两种疾病都有几种常见的动态平衡变化，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还没有被很好地理解。催产素(OT)被认为参与了这种联系，因为它在情绪/情绪和心血管内稳态方面都发挥着作用。OT具有抗应激特性，在人类和非人类动物中调节抗抑郁和抗焦虑行为的表达。此外，OT已被证明可以降低脉搏和血压，这表明OT可能具有心脏保护作用。目前这项建议的主要目的是调查这一假说，即涉及OT的神经机制在抑郁和CVD之间起中介作用。这项研究计划建议利用一种独特的啮齿动物系统，一夫一妻制的草原田鼠(Microtus Ochrogaster)，来研究行为、神经内分泌和心血管对一种与物种相关的和翻译的应激源--社会隔离--的反应。像人类一样，草原田鼠在长期与世隔绝的情况下会产生负面的情感行为(与抑郁和焦虑有关)。孤立的草原田鼠也表现出类似于抑郁人类的心脏功能障碍，包括心率加快，心率变异性降低，以及对应激源的心脏反应改变。OT水平在隔离的田鼠中升高，OT治疗减轻孤立个体的抑郁样情绪和心血管功能障碍。为了验证上述假设，将拮抗OT受体，以确定缺乏OT受体刺激是否会增加对长期社交隔离有害影响的敏感性。具体地说，这项研究将1)使用有效的负面影响行为分析方法(如强迫游泳试验)来确定社会隔离和OT拮抗剂(OTA)的行为反应，2)使用心脏监测技术记录社会隔离和OTA对心血管功能的影响，以及3)研究隔离和OTA对与情绪、自主神经功能和心脏组织相关的脑区OT受体结合(通过受体放射自显影术)和基因表达(通过RT-PCR)的影响。总而言之，这些实验将提供关于心血管疾病和抑郁症之间潜在联系的机制的有价值的信息。拟议研究的完成将为申请人(Melissa-Ann Scotti)开发和使用翻译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.