神经炎症是许多精神疾病的共同特征以及神经退行性疾病的共同潜在机制。性别已被证明强烈影响这些病理的发育和临床表达。然而,在啮齿动物实验中仍然忽略了对性别影响的考虑,在研究中女性的代表性严重不足。这项工作旨在扩大我们对雌性小鼠神经炎症机制的认识,在行为和分子水平上。
■这项研究使用GFAP-IL6小鼠,慢性神经炎症的模型,其中白细胞介素-6(IL6)在神经胶质原纤维酸性蛋白(GFAP)启动子的控制下在中枢神经系统中过表达。我们在评估焦虑的行为测试中评估了年龄(11-15个月大)野生型(WT)和GFAP-IL6雌性小鼠(升高的迷宫,EPM,亮/暗箱),和空间学习和记忆(Y-迷宫,YM和巴恩斯迷宫,BM)和联想学习(恐惧条件,FC)。我们还检查了与神经炎症相关的标志物的基因表达,通过RT-qPCR在参与运动控制的大脑区域中的神经变性和神经传递,焦虑,学习和记忆。
■雌性GFAP-IL6小鼠在EPM中表现出减少的焦虑样行为,在明暗测试和EPM中运动不足。短期记忆障碍在YM中很明显,但在GFAP-IL6小鼠中,FC中的联想学习是完整的,提示雌性GFAP-IL6小鼠的领域特异性认知缺陷。在BM中,所有小鼠都表现出完整的学习和记忆,但是GFAP-IL6小鼠比WT小鼠表现出更高的进入逃脱孔的潜伏期。我们分析了搜索策略,发现与WT相比,GFAP-IL6小鼠搜索逃逸孔的方式存在差异。RT-qPCR显示小脑中参与促炎途径的分子的mRNA水平增加,运动皮层,海马体,GFAP-IL6小鼠的杏仁核。在检查的地区中,与WTs相比,GFAP-IL6小鼠的小脑和海马显示神经炎症因子上调,谷氨酸能和GABA能神经传递基因表达失调.
■总而言之,我们表明,在老年雌性小鼠中,通过IL6过表达的慢性神经炎症导致了较少的焦虑样表型,YM中的运动障碍和中期空间学习和记忆受损。
UNASSIGNED: Neuroinflammation is a common feature of many psychiatric disorders as well as a common underlying mechanism of neurodegenerative diseases. Sex has been shown to strongly influence the development as well as the clinical expression of these pathologies. However, there is still a neglect regarding the consideration of sex effects in rodent experiments, and a substantial underrepresentation of females in studies. This work set out to expand our knowledge of neuroinflammatory mechanisms in female mice, at both a behavioral and molecular level.
UNASSIGNED: This study used GFAP-IL6 mice, a model of chronic neuroinflammation, in which interleukin-6 (IL6) is overexpressed in the central nervous system under the control of the glial fibrillary acidic protein (GFAP) promoter. We evaluated aged (11-15-month-old) wild type-like (WT) and GFAP-IL6 female mice in behavioral tests assessing anxiety (elevated plus-maze, EPM, Light/dark box), and spatial learning and memory (Y-maze, YM and Barnes Maze, BM) and associative learning (fear conditioning, FC). We also examined gene expression of markers linked to neuroinflammation, neurodegeneration and neurotransmission via RT-qPCR in brain regions involved in motor control, anxiety, learning and memory.
UNASSIGNED: Female GFAP-IL6 mice exhibited reduced anxiety-like behavior in the EPM, and hypolocomotion in the light-dark test and EPM. Short-term memory impairment was evident in the YM but associative learning in FC was intact in GFAP-IL6 mice, suggesting domain-specific cognitive deficits in female GFAP-IL6 mice. In the BM, all mice showed intact learning and memory, but GFAP-IL6 mice exhibited higher latencies to enter the escape hole than WT mice. We analyzed the search strategy and found differences in the way GFAP-IL6 mice searched for the escape hole compared to WTs. RT-qPCR showed increased mRNA levels for molecules involved in pro-inflammatory pathways in the cerebellum, motor cortex, hippocampus, and amygdala in GFAP-IL6 mice. Of the regions examined, the cerebellum and the hippocampus showed upregulation of neuroinflammatory makers as well as dysregulation of glutamatergic and GABAergic neurotransmission gene expression in GFAP-IL6 mice compared to WTs.
UNASSIGNED: In conclusion, we showed that chronic neuroinflammation via IL6 overexpression in aged female mice led to a less anxious-like phenotype, hypolocomotion and impaired intermediate-term spatial learning and memory in the YM.