Ventral CA1 perineuronal nets modulate morphine-associated contextual memory via vCA1–NAcC synaptic remodeling in male mice

Repeated opioid exposure forms reward-context associations that can drive persistent drug seeking. Perineuronal nets (PNNs), reticular extracellular matrices surrounding parvalbumin interneurons (PV-INs), regulate hippocampal plasticity and memory, but their role in morphine-associated contextual memory remains unclear. Here, we show that in male mice, repeated morphine conditioning increased PNN abundance in the ventral CA1 (vCA1), accompanied by attenuated PV-IN-mediated inhibition of vCA1 pyramidal neurons and enhanced hippocampal output to D1-type medium spiny neurons (D1-MSNs) in the nucleus accumbens core (NAcC).

ChABC-mediated degradation of vCA1 PNNs diminished morphine conditioning-induced pyramidal neuronal plasticity, reduced glutamatergic transmission to NAcC D1-MSNs, and impaired morphine-conditioned place preference (CPP) memory acquisition. Importantly, chemogenetic inhibition of vCA1 PV-INs attenuated the circuit dysfunction and CPP memory deficits induced by ChABC treatment. These findings support a modulatory role for vCA1 PNNs in regulating local, PV-IN-mediated inhibitory circuit function and downstream hippocampal output during morphine CPP acquisition.

We thank Professor Zhe Zhang of Xuzhou Medical University for providing the PV-Cre mice used in this study. Fuxing Dong from the Public Experimental Research Center for technical assistance with laser-scanning confocal microscopy using the Leica STELLARIS 5 system (Leica Microsystems, Mannheim, Germany), and Yongxia Tan of Meca Scientific for technical support with panoramic image acquisition using the PanoBrain panoramic scanner system (Meca Scientific, China). C.G., X.Y., N.S. and K.T. disclose support for the research and publication of this work from the National Natural Science Foundation of China (82671567 and 82371215 to C.G.; 82602336 to X.Y.; 82201696 to N.S.; 82401422 to K.T.); the China Postdoctoral Science Foundation (2025M782214 to X.Y.); Suzhou Talents (GSWS2023023 to X.Y.); and the Basic Research Pilot Project of Suzhou (SSD2024051 to X.Y.).

These authors contributed equally: Shi-Jie Wang, Hang Yang, Zhong-Hao Gan. School of Anesthesiology, Xuzhou Medical University, Xuzhou, China Shi-Jie Wang, Hang Yang, Zhong-Hao Gan, Le Liu, Yue You, Kun Tong, Jing-Ru Hao, Nan Sun & Can Gao Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China Jiangsu Province Key Laboratory of Anesthesiology and Brain Science, Xuzhou Medical University, Xuzhou, China Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, China The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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