Melanin-concentrating hormone signaling regulates persistence and updating of reward-guided actions

Abstract

Flexible behavior requires persistence when a strategy remains effective and rapid updating when its consequences change. Melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus regulate feeding, reward and memory, but their contribution to reward guided flexibility is unknown. Here, mice learned an action-outcome contingency in a T-maze and then adapted when the reward location switched. MCHR1 antagonism throughout learning did not measurably alter Initial Learning but reduced perseverative choices and accelerated behavioral adaptation after the contingency switched. Endogenous LH-MCH activity was strongest while contingencies were being established or revised, declined as performance stabilized, distinguished rewarded from unrewarded outcomes, and reflected current outcomes in the context of recent and accumulated experience. MCHR1 blockade altered prelimbic responses to successful outcomes in both phases and opposed their progressive weakening during Rule Switch. Together, these findings identify MCH signaling as a regulator of how strongly past reward continues to guide behavior when contingencies change and reveal accompanying changes in prefrontal processing of successful outcomes.