Dorsal Raphe Dopamine Neurons Control The Expression Of Morphine-related Reward And Aversion Memory

Memories of rewarding and aversive stimuli guide future behavioral choices.Drugs of abuse often engage the neural pathways for learning and memory,through which stimuli,including environmental contexts and animals' internal states,are conditioned with both the rewarding effects of drug intake and the withdrawal-induced aversive states to form addiction memories.These pathological memories drive continuous drug seeking and render patients vulnerable to relapse.Dopamine(DA)fundamentally contribute to both memory formation and memory expression.In mammals,DA neurons in the canonical ventral tegmental area(VTA)of the midbrain are important for appetitive associative learning and the formation of reward memories.In particular,addictive drugs—for example,opioids—hijack VTA DA neurons to mediate the initial behavioral reinforcement and the formation of opioid addiction memories.Multiple brain structures,including the central amygdala(CeA),the nucleus accumbens,and the periventricular thalamus,participate in the expression of normal and opioid addiction memories.Although these areas receive substantial dopaminergic inputs,the exact roles and detailed circuit mechanisms of the DA system in memory expression remain elusive.Here we find an unique DA population in the dorsal raphe nucleus(DRN).Using fiber photometry and an AAV-mediated calcium indicator which can be specifically expressed in the target neurons,we find DRN DA neurons are activated by multiple rewarding stimuli,such as sucrose solution,high fat food pellets and social interaction after social isolation.Their activity depends on the size of sucrose solution and changes according to their homeostatic states when facing the same high fat food pellets.And they response to the auditory cues which followed by sucrose solution in a learning-dependent manner.Besides rewarding stimuli,DRN DA neurons are also activated by foot shock and can learn to reponse to the auditory cues which predict foot shock.Using optogenetics and the conditioned place preference(CPP)test,we find that in the test phase,not the conditioning phase,inhibition of DRN DA neurons blocks high fat food-induced CPP.Using auditory cued fear conditioning test,we find inhibition of DRN DA neurons reduces freezing in both conditioning and test phase.Taking together,our data show the important role of DRN DA neurons in regulating reward and fear memory expression.Then,we wonder whether DRN DA neurons have the same role in controlling morphine addiction memory.By c-Fos immunostaining and fiber photometry,we show that these neurons are activated in the morphine-related chamber during the test phase of morphine-induced CPP test.Inhibiting these neurons in the test phase,but not the conditioning phase impairs morphine-induced CPP.Using the same technology,we find DRN DA neurons are activated in the fourth day of conditioning phase and the test phase of spontaneous morphine withdrawal-induced conditioned place aversion(CPA)test.Their inhibition in both phases leads to the reduction of CPA score,without affecting the physical symptoms of morphine withdrawal.These data show that DRN DA neurons are impotant to the expression of reward and aversion memory in both normal and addiction condition.Moreover,we identify one input,the lateral parabrachial nucleus,to DRN DA neurons which changes after morphine administration via rabies virus retrograde tracing.Using electrophysiology and the CPP test,we demonstrate that the glutamatergic pathway from the lateral parabrachial nucleus to DRN DA neurons selectively regulates the expression of reward memories associated with opioids or foods.Therefore,DRN DA neurons critically regulate memory expression,suggesting new targets for intervention of drug addiction.