Learning and Stress Shape the Reward Response Patterns of Serotonin Neurons

Abstract

The ability to predict reward promotes animal survival. Both dopamine neurons in the ventral tegmental area and serotonin neurons in the dorsal raphe nucleus (DRN) participate in reward processing. Although the learning effects on dopamine neurons have been extensively characterized, it remains largely unknown how the response of serotonin neurons evolves during learning. Moreover, although stress is known to strongly influence reward-related behavior, we know very little about how stress modulates neuronal reward responses. By monitoring Ca signals during the entire process of Pavlovian conditioning, we here show that learning differentially shapes the response patterns of serotonin neurons and dopamine neurons in mice of either sex. Serotonin neurons gradually develop a slow ramp-up response to the reward-predicting cue, and ultimately remain responsive to the reward, whereas dopamine neurons increase their response to the cue but reduce their response to the reward. For both neuron types, the responses to the cue and the reward depend on reward value, are reversible when the reward is omitted, and are rapidly reinstated by restoring the reward. We also found that stressors including head restraint and fearful context substantially reduce the response strength of both neuron types, to both the cue and the reward. These results reveal the dynamic nature of the reward responses, support the hypothesis that DRN serotonin neurons signal the current likelihood of receiving a net benefit, and suggest that the inhibitory effect of stress on the reward responses of serotonin neurons and dopamine neurons may contribute to stress-induced anhedonia. Both serotonin neurons in the dorsal raphe and dopamine neurons in the ventral tegmental area are intimately involved in reward processing. Using long-term fiber photometry of Ca signals from freely behaving mice, we here show that learning produces a ramp-up activation pattern in serotonin neurons that differs from that in dopamine neurons, indicating complementary roles for these two neuron types in reward processing. Moreover, stress treatment substantially reduces the reward responses of both serotonin neurons and dopamine neurons, suggesting a possible physiological basis for stress-induced anhedonia.

Modulation of depression-related behaviors by adiponectin AdipoR1 receptors in 5-HT neurons

“…The common behavioral phenotype observed in both male and female mice lacking AdipoR1 in 5-HT neurons is anhedonia. Previous studies have suggested that 5-HT neurons in the DRN encode reward signals [50,51,84,85]. Rewards activate 5-HT neurons [51], and stimulation of 5-HT neurons induces self-administration [50] and resembles the natural reward of sucrose [84].…”

Reward Inhibits Paraventricular CRH Neurons to Relieve Stress

“…Our analyses provide a foundation for further functional dissection of the circuitry of the PVN CRH system. In summary, by combining physiological and behavioral techniques, we provide evidence that reward inhibits PVN CRH neurons to relieve stress, which might aid the development of new clinical strategies for neuropsychiatric disorders, such as depression and anxiety [48,49].…”

“…We implanted intraoral cheek fistulae to deliver sucrose or other solution in order to precisely control the duration of volume of each delivery (5 s delivery at 10 mL s -1 ). The surgery followed a previously described procedure [49]. This type of surgery is a delicate cheek implantation technique that is less invasive and has very little pain.…”

The Pursuit of Pleasure

“…9,10 Motivational and memory components of reward are crucially mediated by DA transmission in limbic regions including the nucleus accumbens (NAcc) and hippocampus. 21,22 In contrast, 5HT influx to the hypothalamus and cortical regions modulates mood, stress, and emotional valence, 11,23,24 and 5HT transmission to striatal regions moderates DA-driven actions on reward function. 25 Early evidence from experimental animals suggested that DA is critically involved in reward processing.…”

“…For example, 5HT and DA neurotransmission interact to influence striatal reward responses and their conditioned cues depending on the predicted reward value. 24,39 Downstream signal transduction substrates associated with 5HT receptor activation have also been linked to the actions of these neurochemicals on reward processing, particularly in MDD. 40 For example, successful treatment responses in patients undergoing pharmacotherapy for MDD are marked by increased expression of hippocampal brain-derived neurotrophic factor (BDNF).…”