Regulation of behavioral and synaptic plasticity by serotonin release within local modulatory fields in the CNS of Aplysia

In Aplysia, serotonergic neurons are widely activated during sensitization training, but the effects of exogenous serotonin (5-HT) on reflex circuits vary, inducing short- or long-term synaptic facilitation or synaptic inhibition, depending on the site of application. During learning, it is possible that specific spatial patterns of 5-HT release evoked by training may produce different phases of sensitization or behavioral inhibition. To test this hypothesis, we examined the modulation of the tail-induced siphon withdrawal reflex by repeated noxious stimuli applied to one of three sites: the (1) ipsilateral or (2) contralateral sides of the tail or (3) the head. Ipsilateral tail shock produced long-term sensitization, whereas contralateral tail shock induced only short-term sensitization, and head shock produced inhibition. In parallel cellular experiments, tail-nerve shock evoked large 5-HT release localized around the ipsilateral tail sensory neurons (SNs) and motor neurons (MNs) but only modest 5-HT release in the contralateral pleural-pedal ganglia and in the abdominal ganglion, in which the siphon MNs are located. Head-nerve shock, in contrast, produced only modest 5-HT release in the pleural, pedal, and abdominal ganglia. Thus, each training protocol evoked a specific pattern of 5-HT release within the CNS. In addition, we found that 5-HT released in the pleural ganglia was correlated with facilitation of SN-MN synapses; however, in the abdominal ganglion, it was associated with inhibition of the synapses between identified interneurons (L29s) and siphon MNs (LFSs). Because 5-HT differentially modulates synaptic efficacy at different synaptic sites, our data can explain how specific spatial patterns of 5-HT release in local modulatory fields can contribute to the induction of short- or long-term sensitization or to behavioral inhibition.