STRESS-INDUCED SICKNESS SOCIAL SEPARATION: DEPRESSION

描述（由申请方提供）：在某些灵长类动物和豚鼠中，婴儿在母体分离期间表现出2阶段主动/被动反应。第二阶段（在灵长类动物中称为“绝望”）是从母亲依恋形象中分离出来的，这是抑郁症研究的一个长期模型。最近已经假设豚鼠幼崽在被动阶段表现出的行为代表“应激诱导的疾病行为”（即，全身炎症或急性期的组分，可以由应激源以及免疫刺激引起的反应。这里提出的研究将进一步测试这一假设（具体目标1），确定是否被动反应和增加核心温度（a。急性期反应的生理指标）可以通过中枢给予抗炎剂α-MSH和白细胞介素-10（IL- 10）来逆转，通过确定最小有效剂量的α-MSH和IL-10是否可以逆转由脂多糖诱导的明显病态行为，并通过检查α MSH和IL-10是否产生内源性IL-10 mRNA的增加。具体目标2是通过确定慢性氟西汀和地昔帕明暴露是否可以减少分离期间假定的应激诱导的疾病反应和温度升高，并增加IL-10的活性，来开始评估用于抑郁症研究的模型的可行性（特别是作为抑郁症的细胞因子假说的动物模型）。拟议的工作符合区域机制的目标，提供有意义的研究经验，本科生。此外，这项研究解决了几个优先事项NIMH的研究所列出的NAMHC研讨会在2003年心理健康的基础科学，特别是：三个领域确定为增加强调（情绪，发展和社会互动），一种类型的确定所需的研究工具（动物模型）和一个领域确定为重新聚焦（压力）。这项工作的相关性在于：（1）提供新的信息，说明大脑、内分泌和免疫系统如何相互作用，产生潜在的病理行为变化;（2）开始将长期存在的抑郁症动物模型与当前的抑郁症观点重新结合起来。

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.