Activation of dorsal raphe serotonergic neurons promotes persistent waiting independently of reinforcing effects

Abstract

The central neuromodulator serotonin (5-HT) has been implicated in a wide range of behaviors and affective disorders, but the principles underlying its function remain elusive. One influential line of research has implicated 5-HT in response inhibition and impulse control. Another has suggested a role in affective processing. However, whether and how these effects relate to each other is still unclear. Here, we report that optogenetic activation of 5-HT neurons in the dorsal raphe nucleus (DRN) produces a dose-dependent increase in mice's ability to withhold premature responding in a task that requires them to wait several seconds for a randomly delayed tone. The 5-HT effect had a rapid onset and was maintained throughout the stimulation period. In addition, movement speed was slowed but stimulation did not affect reaction time or time spent at the reward port. Using similar stimulation protocols in place preference and value-based choice tests, we found no evidence of either appetitive or aversive effects of DRN 5-HT neuron activation. These results provide strong evidence that the efficacy of DRN 5-HT neurons in promoting waiting for delayed rewards is independent of appetitive or aversive effects and support the importance of 5-HT in behavioral persistence and impulse control. 3 !

The Long and the Short of Serotonergic Stimulation: Optogenetic activation of dorsal raphe serotonergic neurons changes the learning rate for rewards

“…On a subset of trials, when mice entered 77 a side port, one second of photo-stimulation was provided to DRN 5-HT neurons via 78 an implanted optical fiber (Figure 1b). ChR2-YFP expression was histologically con-79 firmed to be localized to the DRN in SERT-Cre mice (Figure 1c) [22]. 80 Following previous experiments in macaque monkeys [54,10,39], the probability 81 that a reward is associated with a side port per trial was fixed in a given block of needed to track the history of rewards in order to maximize rewards.…”

“…Despite theoret- 37 ical suggestions for an association with aversive learning [19,53,13,6,15], direct 38 experimental tests into serotonin's role in RL tasks have led to a complex pattern of 39 results [12,52,42,45,22,11]. For instance, recent optogenetic studies reporting that 40 stimulating 5-HT neurons could lead to positive reinforcement [42] do not appear to 41 be consistent with other optogenetic findings, which instead suggest an involvement 42 with patience [22,45] and even locomotion [11]. 43 Here, we study a different aspect of the involvement of 5-HT in RL.…”

“…It could also be associated with some, but 53 not other, of the many decision-making systems [14,25,9,40] that are known to be 54 involved in RL. 55 We therefore reanalyzed experiments in which mice performed a partially self- 56 paced, dynamic foraging task for water rewards [22]. In this task, 5-HT neurons in 57 the dorsal raphe nucleus (DRN) were optogenetically-activated during reward delivery 58 in a trial-selective manner.…”

“…(ITIs) 69 We reanalyzed data from a dynamic foraging or probabilistic choice task in which 70 subjects faced a two-armed bandit [22]. Full experimental methods are given in that 71 publication.…”

“…Full experimental methods are given in that 71 publication. Briefly, the subjects were four adult transgenic mice expressing CRE re-72 combinase under the serotonin transporter promoter (SERT-Cre) and four wild-type 73 littermates (WT) [22]. In this task (Figure 1a), mice were required to poke the cen- 74 ter port to initiate a trial.…”