探讨双环己酮草酰二腙(CPZ)诱导小鼠模型行为学检测及脑代谢物变化的意义。

20只8周龄雄性C57BL/6小鼠，分成CPZ处理组(n＝10)、空白对照组(n＝10)，饲养于温度(22±1)℃明暗各12 h环境中。CPZ处理组给予0.2%(质量分数)CPZ混合鼠饲料连续4周，饮用纯净水；空白对照组给予正常鼠饲料，同样饮用纯净水。两组动物均行旷场实验和Y迷宫行为学检测实验、氢质子磁共振波谱(¹HMRS)和T2WI检查。所有数据均用SPSS 15.0统计软件包处理，T2强度与脑脊液的比值及脑代谢物水平用独立样本t检验。

CPZ处理组小鼠在中央区活动的路程较空白对照组长[(295.430±83.250)cm，(257.440±75.430)cm，t＝0.031，P<0.05]；两组T2WI侧脑室体积视觉定量分析中，CPZ组侧脑室体积[(0.980±0.050)mm²]大于空白对照组[(0.890±0.470)mm²]，差异有统计学意义(t＝5.670，P<0.05)。T2强度与脑脊液比值：CPZ组均高于空白对照组，大脑皮层(0.787±0.015，0.628±0.027，t＝0.880，P<0.05)、尾状核区(0.732±0.012，0.628±0.021，t＝0.003，P<0.05)和海马区(0.745±0.021，0.620±0.022，t＝0.027，P<0.05)差异有统计学意义；丘脑区CPZ组增高，但差异无统计学意义(0.602±0.016，0.562±0.019，t＝0.378，P>0.05)。频谱结果显示，CPZ组CPU区神经元标志物N-乙酰天冬氨酸(4.217±0.488)和其化合物天冬氨酸和乙酰天冬氨酰谷氨酸化合物(4.236±0.389)、谷氨酸类化合物(5.147±0.477)及短TE序列兴奋性神经递质谷氨酸绝对水平比空白对照组明显下降，差异有统计学意义(t＝9.014，10.990，7.307；P<0.05)。丘脑区主要位于3.05 ppm的与能量代谢有关的肌酸和磷酸肌酸化合物浓度(4.415±0.527)和与胶质细胞增生有关的肌醇绝对水平(3.737±0.428)在CPZ组明显下降且差异有统计学意义(t＝9.120，5.911；P<0.05)；其余测到的脑代谢物水平差异无统计学意义(P>0.05)。

CPZ处理组小鼠显示焦虑样行为异常改变及脑白质损伤，并且CPZ处理过程中出现能量代谢及神经递质的异常改变。提示CPZ处理小鼠模型可以充当潜在的精神分裂症动物模型。

To investigate the behavioral and neurochemical alterations in mice exposed to cuprizone.

C57BL/6 mice were given 0.2% CPZ-containing diet for 4 weeks while controls ate the same diet without CPZ.The animals were subjected to behavioral tests, T2WI and ¹HMRS scan.An ultra short echo stimulated echo acquisition (STEAM) localization sequence (TR/TM/TE=5 000/10/2.2 ms) was used to measure in vivo proton spectra from the left striatum (voxel volume: 8 μL) and thalamus (27 μL) of C57BL/6 mice at 7.0T and acquired proton spectra post-processed offline with LCModel.The difference of the T2WI signal intensity was compared with independent sample t-test, and the difference of neurochemical alterations was compared with one-way analysis of variance.

CPZ-fed mice showed significant decrease of spontaneous alternation in the Y-maze test[295.430±83.250)cm, (257.440±75.430)cm, t=0.031, P<0.05]. In quantitative analysis of visual, lateral ventricle volume in CPZ-fed mice was larger than that in control mice, and the difference was statistically significant[(0.980±0.050)mm², (0.890±0.470)mm², t=5.670, P<0.05]. The signal of intensity in the CTX(0.787±0.015, 0.628±0.027), CPU (0.732±0.012, 0.628±0.021) and Hip (0.745±0.021, 0.620±0.022) were significantly high in CPZ-fed mice(t=0.880, 0.003, 0.027; P<0.05). The concentrations of N-acetyl aspartate (NAA, 4.217±0.488), N-acetyl aspartate + N-acety laspartyl glutamate (NAA+ NAAG, 4.236±0.389) in the left striatum and thalamus were significantly reduced in CPZ-fed mice(t=9.014, 10.990; P<0.05). In addition, the concentration of Glu+ Gln (5.147±0.477, t=7.307, P<0.05) in the left thalamus of CPZ-fed mice was significantly lower than that in control mice.The concentrations of Cr+ PCr (4.415±0.527) and MI (3.737±0.428) in thalamus were significantly reduced in CPZ-fed mice(t=9.120, 5.911; P<0.05). There were no satitistically significant difference in levels of rest metabolites.

CPZ-fed mice show deficit in working memory as indicated by Y-maze test and have a higher Glx level in their thalamus.Higher signal intensity of T2WI and lower NAA and NAA+ NAAG levels may reflect an overall reduction of cellular processes in the brain of CPZ-fed mice, which may be related to demyelination and oligodendrocyte loss.The results prompt that the CPZ processing model can be served as potential animal model of schizophrenia in mice.