Bidirectional modulation of accumbens dopamine by MCH neurons during learning and consummatory behavior

The formation of sensory cue-reward associations is essential for survival, but in the modern calorie-rich and advertising-intensive environment, such associations may become maladaptive - leading to negative health consequences such as obesity or diabetes. Recent research has demonstrated the importance of hypothalamic melanin-concentrating hormone (MCH)-expressing neurons in driving hedonically-motivated feeding and in forming these associations. The MCH system interacts with mesolimbic dopamine (DA) transmission, offering a potential mechanism for the effects of MCH neurons on hedonic feeding and associative conditioning. However, this interaction has not been fully characterized in vivo with modern approaches that offer high temporal and spatial resolution. We characterized MCH-DA interactions during feeding and food- motivated Pavlovian conditioning using in vivo fiber photometry in the lateral hypothalamus/zona incerta (LH/ZI) and nucleus accumbens (NAc). We found that MCH neuron activity and DA release in the medial-shell of the NAc (mNAcSh) were co-activated during consumption and in response to reward-predicting cues. During consumption, DA release preceded MCH activity, while responses to reward-predicting cues emerged in MCH neurons earlier than in the DA system. Lastly, gain and loss-of function of the MCH system bidirectionally modulates DA release in the mNAcSh. These results indicate that physiological co-activation of the MCH and DA systems occurs during food-motivated learning, and demonstrate a capacity for bidirectional modulation of DA release in the mNAcSh by the MCH system.