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.
Kandasamey, P., Bracey, E., Odermatt, L., Burdakov, D., Peleg-Raibstein, D.
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