STRESS-INDUCED SICKNESS SOCIAL SEPARATION: DEPRESSION

描述（由申请人提供）：在一些灵长类动物和豚鼠中，婴儿在母亲分离期间表现出2阶段的主动/被动反应。从母体依恋中分离的第二阶段（在灵长类动物中称为“绝望”）一直是抑郁症研究的一个长期模型。最近有一种假设认为，豚鼠幼仔在被动阶段表现出的行为代表了“压力诱发的疾病行为”（即，系统性炎症或急性期的组成部分，可以由压力源和免疫刺激引起的反应）。本文提出的研究将进一步验证这一假设（具体目标1），通过确定被动反应和核心温度升高(a。通过测定α -MSH和IL-10的最小有效剂量是否能逆转脂多糖诱导的开诚布公的疾病行为，以及α -MSH和IL-10是否产生内源性IL-10 mRNA的增加，在分离的豚鼠幼鼠中观察到的急性期反应的生理指标，可以通过中央给药α -MSH和白细胞介素-10 （IL- 10）来逆转。具体目标2是开始评估抑郁症研究模型的可行性（特别是作为抑郁症细胞因子假说的动物模型），确定慢性氟西汀和地西帕明暴露是否可以减少假定的应激性疾病反应和分离期间的温度升高，并增加IL-10的活性。建议的工作通过为本科生提供有意义的研究经验来满足AREA机制的目标。此外，本研究解决了2003年NAMHC心理健康基础科学研讨会列出的NIMH研究的几个优先事项，具体而言：确定了三个需要加强强调的领域（情感、发展和社会互动），确定了一种需要的研究工具（动物模型），确定了一个需要重新关注的领域（压力）。这项工作的相关性在于：(1)提供关于大脑、内分泌和免疫系统相互作用产生潜在病理行为变化的新信息；并且，(2)开始重新调整长期存在的抑郁症动物模型与当前的抑郁症观点。

DESCRIPTION (provided by applicant): In some species of primates as well as guinea pigs, infants exhibit a 2 -stage, active /passive response during maternal separation. The second stage (termed "despair" in primates) of separation from the maternal attachment figure has been a long-standing model for the study of depressive illness. It recently has been hypothesized that behaviors that guinea pig pups show during the passive stage represent "stress- induced sickness behaviors" (i.e., components of a systemic inflammatory or acute phase, response that can be elicited by stressors as well as immunological stimuli.) Studies proposed here would further test this hypothesis (Specific Aim 1) by determining if the passive responses and increased core temperature (a . physiological indicator of the acute phase response) that have been observed in separated guinea pig pups can be reversed by central administration of the anti-inflammatory agents alpha -MSH and lnterleukin-10 (IL- 10), by determining if the minimum effective dose of alpha MSH and IL-10 can reverse frank sickness behaviors induced by lipopolysacchride, and by examining whether alpha MSH and IL-10 produce increases in endogenous IL-10 mRNA. Specific Aim 2 is to begin to evaluate the feasibility of the model for the study of depression (specifically as an animal model for the cytokine hypothesis of depression) by determining whether chronic fluoxetine and desipramine exposure can reduce the putative stress-induced sickness responses and temperature elevations during separation, and increase activity of IL-10. The proposed work meets the objectives of the AREA mechanism by providing meaningful research experience to undergraduates. Further, this research addresses several priorities for NIMH research listed by the NAMHC Workshop on the Basic Sciences of Mental Health in 2003, specifically: three areas identified for increased emphasis (emotion, development, and social interactions), one type of identified needed research tool (animal model) and one area identified for refocus (stress). The relevance of the work is that it would: (1) provide new information on the way in which the brain, endocrine, and immune systems can interact to produce potentially pathological behavioral changes; and, (2) begin to realign a long-standing animal model of depression with current views of depressive illness.