Novel circUnc79 regulates morphine-induced reward memory via the miR-149-3p/EAAT2 axis and glutamatergic plasticity

Opioid addiction is driven by maladaptive reward memory, yet its molecular underpinnings remain poorly understood. Circular RNAs (circRNAs) have emerged as key regulators of neuroplasticity, but their roles in addiction-related memory remain unclear. Here, we identify circUnc79, a neuron-enriched and synaptically localized circRNA, as a critical modulator of morphine reward memory in the medial prefrontal cortex (mPFC). In the morphine-induced conditioned place preference (CPP) model, circUnc79 expression is dynamically downregulated during cue-induced memory retrieval. Gain- and loss-of-function experiments demonstrate that circUnc79 bidirectionally regulates the acquisition and persistence of morphine reward memory, without affecting locomotion, anxiety-like behavior, social interaction, or sucrose reward. Mechanistically, circUnc79 acts as a competing endogenous RNA for miR-149-3p, thereby relieving its repression of excitatory amino acid transporter 2 (EAAT2, encoded by Slc1a2). Elevated neuronal EAAT2 enhances presynaptic glutamate reuptake and recycling, supporting reward memory encoding. Manipulation of miR-149-3p produces opposite behavioral and synaptic effects, supporting the functional relevance of this regulatory axis. These findings reveal a circUnc79/miR-149-3p/EAAT2 pathway that regulates synaptic plasticity underlying opioid reward memory and highlight circUnc79 as a potential therapeutic target for opioid use disorders.