Cardiovascular disease, depression, and oxytocin

描述（由申请人提供）：抑郁症是CVD的一个重要危险因素，无论是在医学健康的个人和那些有心脏病史。这两种疾病都有几种稳态变化，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还没有得到很好的理解。催产素（OT）被认为参与了这种关联，因为它在情绪/情绪和心血管稳态中发挥作用。OT具有抗应激特性，并调节人类和非人类动物中抗抑郁和抗焦虑样行为的表达。此外，OT已被证明可以降低脉搏率和血压，这表明OT可能具有心脏保护作用。目前的建议的主要目的是调查的假设，涉及OT神经机制介导抑郁症和CVD之间的联系。这项研究计划提出利用一个独特的啮齿动物系统，一夫一妻制的草原田鼠（Microtus ochrogaster），调查行为，神经内分泌和心血管反应的物种相关和翻译的压力，社会隔离。像人类一样，草原田鼠在长期孤立时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类似于抑郁人类的心脏功能障碍，包括心率加快，HRV降低，以及对应激源的心脏反应改变。OT水平升高孤立的田鼠和OT治疗减弱抑郁样影响和心血管功能障碍孤立的个人。为了检验上述假设，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会隔离的有害影响的易感性。具体来说，这项研究将1）使用有效的负面影响行为测定（例如，强迫游泳试验）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，和3）研究分离和OTA对OT受体结合的影响（通过受体放射自显影）和基因表达（通过RT-PCR）在大脑区域与情绪和自主功能以及心脏组织。总的来说，这些实验将提供有关CVD和抑郁症之间联系的潜在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一步。 公共卫生相关性：心血管疾病（CVD）是美国的主要死亡原因。抑郁症是心血管疾病的一个重要危险因素，无论其他基线医学变量（如吸烟和肥胖）如何，抑郁症的症状都预示着医学良好个体的致命性和非致命性心脏病的增加。本文提出的研究将探索这些疾病之间的联系，为心脏病的治疗和预防提供进一步的见解。

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.