Abstract

Drug-associated reward memory underlies both the development and relapse of addiction, yet its molecular basis remains poorly understood. Here, transcriptomic profiling and functional validation identified a novel long non-coding RNA (lncRNA), Gm44763, as a critical regulator of morphine-induced reward memory specifically in neurons of the medial prefrontal cortex (mPFC). Behavioral and molecular analyses demonstrated that Gm44763 functions as a sponge for miR-298-5p, thereby relieving the repression of the downstream target gene, eukaryotic translation initiation factor 4E (eIF4E), and modulating both the acquisition and retrieval of reward memory. Golgi staining and fiber photometry further revealed that Gm44763 normalized morphine-induced alterations in synaptic structure and neuronal excitability. miR-298-5p bidirectionally regulated morphine-induced reward memory and reversed both behavioral and neuronal effects mediated by Gm44763. Mechanistically, the downstream effector eIF4E modulates translation via its interaction with eIF4G, thereby contributing to morphine-induced memory regulation. This process can be effectively modulated by 4EGI-1, a selective inhibitor of the eIF4E/eIF4G interaction. In summary, this study characterized lncRNA expression profiles in the mPFC of mice with morphine-induced conditioned place preference. We identified and validated Gm44763 as a novel lncRNA regulator of morphine-induced reward memory and synaptic plasticity. We further delineate a previously uncharacterized Gm44763/miR-298-5p/eIF4E axis that may represent a novel regulatory pathway linking transcriptional and translational control to drug-associated memory formation.