Abstract：
The high rate of relapse to compulsive methamphetamine (MA)-taking and seeking behaviors after abstinence constitutes a major obstacle to the treatment of MA addiction. Perineuronal nets (PNNs), essential components of the extracellular matrix, play a critical role in synaptic function, learning, and memory. Abnormalities in PNNs have been closely linked to a series of neurological diseases, such as addiction. However, the exact role of PNNs in MA-induced related behaviors remains elusive. Here, we established a MA-induced conditioned place preference (CPP) paradigm in female mice and found that the number and average optical density of PNNs increased significantly in the medial prefrontal cortex (mPFC) of mice during the acquisition, extinction, and reinstatement stages of CPP. Notably, the removal of PNNs in the mPFC via chondroitinase ABC (ChABC) before extinction training not only facilitated the extinction of MA-induced CPP and attenuated the relapse of extinguished MA preference but also significantly reduced the activation of c-Fos in the mPFC. Similarly, the ablation of PNNs in the mPFC before reinstatement markedly lessened the reinstatement of MA-induced CPP, which was accompanied by the decreased expression of c-Fos in the mPFC. Collectively, our results provide more evidence for the implication of degradation of PNNs in facilitating extinction and preventing relapse of MA-induced CPP, which indicate that targeting PNNs may be an effective therapeutic option for MA-induced CPP memories.
摘要：
禁欲后强迫性甲基苯丙胺（MA）的高复发率和寻求行为构成了治疗MA成瘾的主要障碍。神经周网（PNN），细胞外基质的基本成分，在突触功能中起关键作用，学习,和记忆。PNN的异常与一系列神经系统疾病密切相关，比如上瘾。然而,PNN在MA诱导的相关行为中的确切作用仍然难以捉摸。这里,我们在雌性小鼠中建立了MA诱导的条件性位置偏爱（CPP）范式，发现在采集过程中，小鼠内侧前额叶皮层（mPFC）中PNN的数量和平均光密度显着增加，灭绝,和CPP的恢复阶段。值得注意的是,在灭绝训练之前通过软骨素酶ABC（ChABC）去除mPFC中的PNN，不仅促进了MA诱导的CPP的灭绝，减轻了熄灭的MA偏好的复发，而且显着降低了mPFC中c-Fos的激活。同样，恢复前mPFC中PNN的消融显著降低了MA诱导的CPP的恢复，伴随着c-Fos在mPFC中的表达降低。总的来说，我们的结果为PNNs降解在促进灭绝和预防MA诱导的CPP复发中的意义提供了更多的证据，这表明靶向PNN可能是MA诱导的CPP记忆的有效治疗选择。
