Winkler Zsuzsanna, Kuti Dániel, Ferenczi Szilamér, Gulyás Krisztina, Polyák Ágnes, Kovács Krisztina J
Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary; János Szentágothai Doctoral School of Neurosciences, Semmelweis University, Budapest, Hungary.
Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary.
Behav Brain Res. 2017 Sep 15;334:119-128. doi: 10.1016/j.bbr.2017.07.023. Epub 2017 Jul 20.
Microglia, resident immune cells of the CNS are sensitive to various perturbations of the environment, such as stress exposure, and may be involved in translating these changes to behavior. Among the pathways mediating stress-related neuronal cues to microglia, the fractalkine-fractalkine receptor (CXCR1) signaling plays a crucial role. Using mice, in which the CXCR1 gene was deleted, we explored hormonal and behavioral responses to acute and chronic stress along with changes in hypothalamic microglia. CXCR1 animals display active escape in forced swim- and tail suspension tests, exaggerated neuronal activation in the hypothalamic paraventricular nucleus and increased corticosterone release in response to restraint. Analysis of Iba1 immunostaining of hypothalamic sections revealed stress-related reduction of microglia in CXCR1 mice. Because microglia also contribute to energy balance regulation, we characterized metabolic phenotype of CXCR1 mice. Comparison of respiratory exchange ratio did not show genotype effect on fuel preference, however, the energy expenditure was increased in CXCR1 mice, which may be related to their active coping behavior. Microglia and fractalkine signaling has been repeatedly shown to be involved chronic stress-induced depressive state. CXCR1 mice did not become anhedonic in the "two hit" chronic stress paradigm, confirming resistance of these animals to chronic stress-induced mood alterations. However, there was no difference in stress hormone levels, open field performance and hypothalamic microglia distribution between the genotypes. These results highlight differential involvement of microglia fractalkine signaling in controlling/integrating hormonal-, metabolic and behavioral responses to acute and chronic stress challenges.
小胶质细胞是中枢神经系统中的常驻免疫细胞，对环境中的各种干扰（如应激暴露）敏感，并可能参与将这些变化转化为行为。在介导应激相关神经元信号传递给小胶质细胞的途径中，趋化因子-趋化因子受体（CXCR1）信号传导起着关键作用。我们使用CXCR1基因缺失的小鼠，探索了对急性和慢性应激的激素和行为反应以及下丘脑小胶质细胞的变化。CXCR1基因缺失的小鼠在强迫游泳和悬尾试验中表现出积极逃避，下丘脑室旁核中的神经元激活增强，并且对束缚应激的反应中皮质酮释放增加。对下丘脑切片进行Iba1免疫染色分析显示，CXCR1基因缺失小鼠中与应激相关的小胶质细胞减少。由于小胶质细胞也参与能量平衡调节，我们对CXCR1基因缺失小鼠的代谢表型进行了表征。呼吸交换率的比较未显示基因型对燃料偏好的影响，然而，CXCR1基因缺失小鼠的能量消耗增加，这可能与其积极的应对行为有关。小胶质细胞和趋化因子信号传导已被反复证明与慢性应激诱导的抑郁状态有关。CXCR1基因缺失小鼠在“两次打击”慢性应激范式中未出现快感缺失，证实这些动物对慢性应激诱导的情绪改变具有抵抗力。然而，不同基因型之间在应激激素水平、旷场试验表现和下丘脑小胶质细胞分布方面没有差异。这些结果突出了小胶质细胞趋化因子信号传导在控制/整合对急性和慢性应激挑战的激素、代谢和行为反应中的不同作用。
