Dynamic changes of dopamine neuron activity and plasticity at different stages of negative reinforcement learning

Research indicates that midbrain dopaminergic neurons encode reward prediction error (RPE) signals involved in positive reinforcement learning. However, studies on dopamine's role in negative reinforcement learning (NRL) are scarce. Learning to escape aversive stimuli is vital for survival and may differ significantly from positive reinforcement in behavior and neural mechanisms. This study employs footshocks as aversive stimuli to investigate neural activity, synaptic transmission, and intrinsic excitability in a NRL paradigm using fiber photometry and ex vivo electrophysiology. Results show that inescapable footshocks initially increase activity in substantia nigra pars compacta (SNc) dopaminergic neurons, which later shifts to reflect shock termination as exposure increases. Electrophysiological observations reveal increased intrinsic excitability and excitatory synaptic transmission in SNc neurons, with decreased inhibitory transmission. After mice learn to escape the shock by nose-poking, dopaminergic activity shifts from shock termination to shock onset. Furthermore, inhibitory input increases, while excitatory input decreases after learning, with intrinsic excitability returning to baseline levels. This indicates that SNc dopaminergic neurons exhibit RPE-like signals in response to aversive stimuli, with their intrinsic excitability adjusting according to expectations of shock termination. These findings enhance our understanding of RPE encoding in negative reinforcement learning and may inform therapeutic strategies for disorders caused by environmental factors such as aversive stimuli.