Aversive And Appetitive Signals Processed By The Lateral Habenula In Freely Behaving Mice

"Making profits and avoiding loss" is the alpha rule for an organism's survival.The brain reward circuit has a central role in reinforcing behaviors that are rewarding and preventing behaviors that lead to punishment.The Lateral Habenula?LHb?is an important part of the reward circuit by providing‘negative reward value'signals to the dopaminergic and serotonergic systems.It remains unknown how LHb neurons encode such signals in a freely moving animal and how learning shapes their responses.Here,we used fiber-photometry recording and optically tagged single-unit recording in VGlut2-cre transgenic mice combined with punishment-and reward-related behavioral assays to track the LHb VGlut2 neurons'activities.Several ecologically relevant aversive stimuli,including footshock,quinine,and social defeat intensively increased Ca²⁺signals from LHb neurons,suggesting strong excitatory responses.In a Pavlovian aversive conditioning task,coupling a sensory cue to either pain or bitterness induced excitatory responses to the punishment-predicting cue in as few as five trials.On the contrary,the LHb VGlut2 neurons were transiently inhibited by unexpected reward or reward predicting cues,and some exhibited inhibition-then-rebound pattern which was unreported in previous studies.In a Pavlovian reward conditioning task,coupling a cue to the reward gradually induced an inhibitory response to the cue following over 100trials of training.Single-unit recordings confirmed the reward-evoked biphasic response pattern in many cells.In reward probabilistic discriminative tasks,the LHb VGlut2neurons were selectively inhibited by conditional stimulus coupled with high probabilistic reward,while uncertain reward had no effects.These results show that LHb neurons can bidirectionally process a diverse array of aversive and reward signals.More importantly,their responses are dynamically shaped by learning,suggesting that the LHb participates in experience-dependent selection of behavioral actions to aversive stimuli.