Frenois François, Moreau Maïté, O'Connor Jason, Lawson Marc, Micon Charlotte, Lestage Jacques, Kelley Keith W, Dantzer Robert, Castanon Nathalie
Integrative Immunology and Behavior Program, University of Illinois at Urbana-Champaign, 212 Edward R. Madigan Laboratory, 1201 West Gregory Drive, Urbana, IL 61801, USA.
Psychoneuroendocrinology. 2007 Jun;32(5):516-31. doi: 10.1016/j.psyneuen.2007.03.005. Epub 2007 May 4.
Proinflammatory cytokines induce both sickness behavior and depression, but their respective neurobiological correlates are still poorly understood. The aim of the present study was therefore to identify in mice the neural substrates of sickness and depressive-like behavior induced by lipopolysaccharide (LPS, 830 microg/kg, intraperitoneal). LPS-induced depressive-like behavior was dissociated from LPS-induced sickness by testing mice either at 6 h (at which time sickness was expected to be maximal) or at 24 h post-LPS (at which time sickness was expected to be minimal and not to bias the measurement of depressive-like behavior). Concurrently, the expression of acute and chronic cellular reactivity markers (c-Fos and FosB/DeltaFosB, respectively) was mapped by immunohistochemistry at these two time points. In comparison to saline, LPS decreased motor activity in a new cage at 6 h but not at 24 h. In contrast, the duration of immobility in the tail suspension test was increased at both 6 and 24 h. This dissociation between decreased motor activity and depressive-like behavior was confirmed at 24 h post-LPS in the forced swim test. LPS also decreased sucrose consumption at 24 and 48 h, despite normal food and water consumption by that time. At 24 h post-LPS, LPS-induced depressive-like behavior was associated with a delayed cellular activity (as assessed by FosB/DeltaFosB immunostaining) in specific brain structures, particularly within the extended amygdala, hippocampus and hypothalamus, whereas c-Fos labeling was markedly decreased by that time in all the brain areas at 6 h post-LPS. These results provide the first evidence in favor of a functional dissociation between the brain structures that underlie cytokine-induced sickness behavior and cytokine-induced depressive-like behavior, and provide important cues about the neuroanatomical brain circuits through which cytokines could have an impact on affect.
促炎细胞因子可引发疾病行为和抑郁，但它们各自的神经生物学关联仍知之甚少。因此，本研究的目的是在小鼠中确定脂多糖（LPS，830微克/千克，腹腔注射）诱导的疾病行为和抑郁样行为的神经基质。通过在LPS注射后6小时（此时预计疾病症状最为严重）或24小时（此时预计疾病症状最轻且不会影响抑郁样行为的测量）对小鼠进行测试，将LPS诱导的抑郁样行为与LPS诱导的疾病行为区分开来。同时，在这两个时间点通过免疫组织化学绘制急性和慢性细胞反应性标志物（分别为c-Fos和FosB/ΔFosB）的表达情况。与生理盐水相比，LPS在6小时时降低了小鼠在新笼子中的运动活性，但在24小时时没有。相反，在6小时和24小时时，悬尾试验中的不动时间均增加。在强迫游泳试验中，LPS注射后24小时证实了运动活性降低与抑郁样行为之间的这种分离。尽管此时食物和水消耗正常，但LPS在24小时和48小时时也降低了蔗糖消耗。在LPS注射后24小时，LPS诱导的抑郁样行为与特定脑结构中延迟的细胞活性（通过FosB/ΔFosB免疫染色评估）相关，特别是在扩展杏仁核、海马体和下丘脑内，而在LPS注射后6小时时，所有脑区的c-Fos标记均明显降低。这些结果首次证明了细胞因子诱导的疾病行为和细胞因子诱导的抑郁样行为背后的脑结构之间存在功能分离，并提供了有关细胞因子可能影响情感的神经解剖学脑回路的重要线索。
