Minocycline attenuates interferon-α-induced impairments in rat fear extinction.
Minocycline attenuates interferon-α-induced impairments in rat fear extinction.
复制标题
米诺环素减轻干扰素α诱导的大鼠恐惧消退损伤
DOI：
10.1186/s12974-016-0638-z
复制
发表时间：
2016-06-30
影响因子：
9.3
通讯作者：
Qin L
中科院分区：
文献类型：
--
作者：
Bi Q;Shi L;Yang P;Wang J;Qin L
背景条件恐惧消退是动物适应新环境的重要脑功能。越来越多的证据表明先天免疫细胞因子参与了精神障碍的病理过程。然而，参与恐惧失调的细胞因子仍然很少调查。在本研究中，我们研究了干扰素（IFN）-α如何干扰条件性恐惧的消退，并提出了一种方法来拯救IFN-α诱导的神经功能缺损。方法我们使用大鼠听觉恐惧条件化模型来研究IFN-α对恐惧记忆过程的影响。将IFN-α直接注入大鼠杏仁核，观察大鼠对恐惧条件刺激的行为反应（冻结）。免疫组织化学染色观察杏仁核内胶质细胞的活性状态。采用酶联免疫吸附法检测杏仁核中促炎细胞因子白细胞介素（IL）-1β和肿瘤坏死因子（TNF）-α的含量。我们还给予米诺环素，小胶质细胞活化抑制剂，前IFN-α输液，以证明可能性，以扭转IFN-α诱导的effects.ResultsInfusing杏仁核IFN-α削弱了大鼠条件性恐惧的消退和激活杏仁核中的小胶质细胞和星形胶质细胞。二甲胺四环素可阻止IFN-α损害恐惧消退。免疫组化和生化结果表明，米诺环素抑制IFN-α诱导的小胶质细胞活化，减少IL-1β和TNF-α的产生。ConclusionsOur研究结果表明，IFN-α通过激活杏仁核中的胶质细胞破坏听觉恐惧的消退，为调节精神障碍患者先天免疫系统的新治疗方法的临床研究提供了方向。
BackgroundExtinction of conditioned fear is an important brain function for animals to adapt to a new environment. Accumulating evidence suggests that innate immune cytokines are involved in the pathology of psychotic disorders. However, the involvement of cytokines in fear dysregulation remains less investigated. In the present study, we investigated how interferon (IFN)-α disrupts the extinction of conditioned fear and propose an approach to rescue IFN-α-induced neurologic impairment.MethodsWe used a rat model of auditory fear conditioning to study the effect of IFN-α on the fear memory process. IFN-α was infused directly into the amygdala of rats and examined the rats’ behavioral response (freezing) to fear-conditioned stimuli. Immunohistochemical staining was used to examine the glia activity status of glia in the amygdala. The levels of the proinflammatory cytokines interleukin (IL)-1β and tumor necrosis factor (TNF)-α in the amygdala were measured by enzyme-linked immunosorbent assay. We also administrated minocycline, a microglial activation inhibitor, before the IFN-α infusion to testify the possibility to reverse the IFN-α-induced effects.ResultsInfusing the amygdala with IFN-α impaired the extinction of conditioned fear in rats and activated microglia and astrocytes in the amygdala. Administering minocycline prevented IFN-α from impairing fear extinction. The immunohistochemical and biochemical results show that minocycline inhibited IFN-α-induced microglial activation and reduced IL-1β and TNF-α production.ConclusionsOur findings suggest that IFN-α disrupts the extinction of auditory fear by activating glia in the amygdala and provides direction for clinical studies of novel treatments to modulate the innate immune system in patients with psychotic disorders.