Melanin-concentrating hormone signaling regulates prefrontal updating of learned avoidance

Adaptive avoidance depends on a delicate balance: animals must act rapidly when a cue predicts danger, but suppress the same action when the cue no longer has consequence. How MCH neuromodulatory signaling shapes this prefrontal updating process remains poorly understood. Here, we identify melanin-concentrating hormone receptor 1 (MCHR1) signaling as a regulator of active avoidance extinction. Pharmacological MCHR1 antagonism with SNAP-94847 left acquisition of two-way active avoidance intact, but promoted extinction once the tone was no longer followed by shock. This effect was reproduced by prelimbic mPFC-targeted SNAP infusion, indicating that prefrontal MCHR1 signaling contributes to the persistence of learned avoidance. Fiber photometry from CaMKII-positive mPFC neurons revealed that MCHR1 antagonism enhanced excitatory prefrontal activity during successful avoidance and altered trial-history-dependent mPFC activity during extinction, most prominently on avoidance trials that followed previous avoidance. These findings identify MCHR1 signaling as a regulator of adaptive avoidance updating and suggest that MCHR1 antagonism facilitates extinction by altering prefrontal processing of recent action history when a formerly protective response loses behavioral value. Significance StatementIn anxiety- and trauma-related disorders, avoidance can persist long after danger is gone, interfering with daily life. While avoidance is essential for survival, it can become harmful when it is no longer needed. We found that blocking brain receptors for melanin-concentrating hormone helps mice stop responding to outdated warning signals while preserving their ability to learn from danger. We identify the medial prefrontal cortex as a key brain region where this intervention changes activity during fear-guided behavior. This study highlights a potential therapeutic strategy for reducing excessive avoidance without compromising normal protective responses.