Institute of Neuroscience, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario, Canada K1S5B6.
Brain Behav Immun. 2010 Mar;24(3):462-73. doi: 10.1016/j.bbi.2009.12.001. Epub 2009 Dec 18.
Pro-inflammatory cytokines promote behavioral and neurochemical variations similar to those evident following stressor exposure, and have been implicated in promoting depressive illness. Indeed, immunotherapeutic application of the cytokine, interferon-alpha, promoted depressive illness in cancer and hepatitis C patients. We assessed the possibility that another interferon cytokine family member, interferon-gamma (IFN-gamma), might contribute to the behavioral and biochemical alterations provoked by a chronic stressor regimen that has been used to model neuropsychiatric pathology in rodents. As predicted, IFN-gamma-deficient mice displayed basal differences in behavior (e.g., reduced open field exploration) and altered neurochemical activity (e.g., increased noradrenergic and serotonergic activity within the central amygdala), relative to their wild-type counterparts. Moreover, stressor-induced elevations of corticosterone and the pro-inflammatory cytokine, tumor necrosis factor-alpha, were attenuated in IFN-gamma-deficient mice. Similarly, the IFN-gamma null mice were refractory to the chronic stressor-induced alterations of dopamine metabolism (within the prefrontal cortex, paraventricular nucleus of the hypothalamus and central amygdala) evident in wild-type mice. Yet, the chronic stressor provoked signs of anxiety (e.g., reduced open field exploration) and depression-like behavior (e.g., increased forced swim immobility, reduced consumption of a palatable solution) among both wild-type and IFN-gamma knockout mice alike, suggesting a dissociation of behavioral functioning from the stressor-induced alterations of immunological, hormonal and dopaminergic activity. Together, these data suggest a complex neurobehavioral phenotype, wherein IFN-gamma deletion engenders a state of heightened basal emotionality coupled with increased monoaminergic activity in the amygdala. At the same time, however, IFN-gamma deficiency appears to blunt some of the neurochemical, corticoid and cytokine alterations ordinarily associated with chronic stressor exposure.
促炎细胞因子可促进类似于应激暴露后出现的行为和神经化学变化，并与抑郁疾病的发生有关。事实上，细胞因子干扰素-α的免疫治疗应用在癌症和丙型肝炎患者中促进了抑郁疾病的发生。我们评估了另一种干扰素细胞因子家族成员干扰素-γ（IFN-γ）是否可能导致慢性应激方案引起的行为和生化改变，该方案已被用于模拟啮齿动物的神经精神病理学。正如预测的那样，与野生型相比，IFN-γ 缺陷型小鼠在行为（例如，减少开阔场探索）和神经化学活性（例如，增加中央杏仁核中的去甲肾上腺素和 5-羟色胺活性）方面显示出基础差异。此外，IFN-γ 缺陷型小鼠中的应激诱导的皮质酮和促炎细胞因子肿瘤坏死因子-α升高被减弱。同样，IFN-γ 缺失型小鼠对野生型小鼠中明显的慢性应激诱导的多巴胺代谢改变（在前额叶皮层、下丘脑室旁核和中央杏仁核内）具有抗性。然而，慢性应激在野生型和 IFN-γ 敲除小鼠中都引起了焦虑（例如，减少开阔场探索）和类似的抑郁样行为（例如，增加强迫游泳不动、减少美味溶液的消耗）的迹象，表明行为功能与应激诱导的免疫、激素和多巴胺活性改变分离。总之，这些数据表明存在复杂的神经行为表型，其中 IFN-γ 缺失导致基础情绪性增强，并伴有杏仁核中单胺能活性增加。然而，与此同时，IFN-γ 缺乏似乎削弱了一些通常与慢性应激暴露相关的神经化学、皮质酮和细胞因子改变。
