Serotonin is produced in neurons of the raphe nuclei. Ascending serotonergic neurons of the brain are restricted to the dorsal raphe nucleus (DRN) and median raphe nucleus (MRN). Neurons in the DRN and MRN project widely throughout the brain, where they regulate diverse physiological and behavioral processes. Several electrophysiological studies have demonstrated that serotonergic neurons alter their firing rates in response to reward-predictive cues and consumption of food and liquid rewards; however, the causal role of these neurons in controlling reward learning remains unknown. To characterize the role of serotonin in these processes, we have undertaken a multifaceted behavioral approach. First, we explored whether mice would self-stimulate serotonergic neurons using the light-activated ion channel Channelrhodopsin-2 (ChR2) delivered virally into serotonergic neurons of the DRN or MRN. In both cases, mice failed to self-stimulate these brain regions, suggesting that serotonin from these neurons does not convey a reinforcement signal. We next performed loss-of-function experiments knocking out the enzyme tryptophan hydroxylase-2 (tph2), the rate-limiting enzyme in serotonin synthesis. Knockout was induced by virally injecting virus expressing cre recombinase into either the DRN or MRN of adult mice. Although knockout did not alter general measures of locomotion, it produced opposing effects in a Pavlovian conditioned approach experiment, with knockout in the DRN enhancing measures of reward learning and knockout in the MRN reducing such measures. Interestingly, the opposite pattern of results were observed in a conditioned reinforcement paradigm: DRN knockouts performed normally, whereas MRN knockouts showed greatly enhanced responding. Experiments are currently underway targeting efferent projections of DRN and MRN serotonergic neurons, to test what brain region(s) mediate these effects.

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Budget End
Support Year
7
Fiscal Year
2017
Total Cost
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Name
National Institute on Drug Abuse
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