Stress-Induced Sickness Behavior during Social Separation

描述(由申请人提供)：目前抑郁症研究的一个主要焦点是儿童时期的依恋中断和其他形式的早期逆境增加了在以后的生活中发展为严重抑郁障碍的易感性。这种效应的机制仍然不清楚，但被认为涉及到与压力相关的过程的敏化。最近抑郁症研究的第二个重点是促炎因子在调节抑郁症状中的作用。这里提出的研究使用一只豚鼠模型来检验由母体分离的应激源引起的促炎活动是否可能介导抑郁样行为的长期敏感化。豚鼠表现出特定的依恋过程，对母体分离表现出由促炎活动介导的抑郁样行为反应，并在反复分离时表现出抑郁样行为的敏化，伴随着敏化的核心温度反应。这里提议的工作将首先确定在上一个供资期间确定的长期(9天)敏化是否由促炎活动的敏化(增强的促炎反应或对促炎反应的敏感性增加(目标1))所调节。这将通过尝试用抗炎剂(白介素10和吲哚美辛)阻断抑郁样行为的敏感化和核心体温升高，以及通过确定预先分离是否增加了中枢细胞因子和/或对后来免疫挑战的行为反应来实现。接下来，我们将评估敏化的行为反应是否反映了由促炎活动介导的更广泛的潜在抑郁样状态的敏化(目标2)。这将通过确定早期分离是否提高了对抑郁样行为(强迫游泳)的有效行为测试的反应性，该测试独立于初始诱导剂(分离)，以及强迫游泳效应是否可以被抗炎化合物逆转。

DESCRIPTION (provided by applicant): A primary current focus in the study of depression is the means by which attachment disruption in childhood and other forms of early adversity increase vulnerability for developing major depressive disorder in later life. The mechanism for this effect remains obscure but is thought to involve sensitization of stress-related processes. A second recent emphasis in depression research has been the role of proinflammatory factors in mediating depressive symptoms. Research proposed here uses a guinea pig model to examine the possibility that proinflammatory activity induced by the stressor of maternal separation mediates a prolonged sensitization of depressive-like behavior. Guinea pigs exhibit a specific attachment process, display a depressive-like behavioral response to maternal separation that is mediated by proinflammatory activity, and show a sensitization of depressive-like behavior upon repeated separation that is accompanied by a sensitized core temperature response. Work proposed here will first determine if a prolonged (9 day) sensitization identified during the last funding period is mediated by a sensitization of proinflammatory activity (either enhanced proinflammatory response or increased sensitivity to a proinflammatory response (Aim 1). This will be done by attempting to block sensitization of depressive-like behavior and core temperature increase with anti-inflammatory agents (Interleukin-10 and indomethacin) and by determining whether prior separation increases the central cytokine and/or behavioral response to later immune challenge. Next, we will assess whether the sensitized behavioral response reflects sensitization of a broader underlying depressive-like state mediated by proinflammatory activity (Aim 2). This will be accomplished by determining if early separation enhances responsiveness in a validated behavioral test of depressive-like behavior (forced swim) that is independent of the initial inducing agent (separation), and whether the forced swim effect can be reversed by an anti-inflammatory compound.