Zhong Weixin, Li Yi, Feng Qiru, Luo Minmin
Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.
National Institute of Biological Sciences, Beijing 102206, China, and.
J Neurosci. 2017 Sep 13;37(37):8863-8875. doi: 10.1523/JNEUROSCI.1181-17.2017. Epub 2017 Aug 8.
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.
预测奖励的能力有助于动物生存。腹侧被盖区的多巴胺神经元和中缝背核（DRN）的5-羟色胺神经元都参与奖励处理。尽管对多巴胺神经元的学习效应已有广泛研究，但5-羟色胺神经元在学习过程中的反应如何演变仍 largely 未知。此外，虽然已知压力会强烈影响与奖励相关的行为，但我们对压力如何调节神经元奖励反应知之甚少。通过在巴甫洛夫条件反射的整个过程中监测钙信号，我们在此表明，学习以不同方式塑造了雌雄小鼠中5-羟色胺神经元和多巴胺神经元的反应模式。5-羟色胺神经元逐渐对奖励预测线索产生缓慢的上升反应，并最终对奖励保持反应，而多巴胺神经元对线索的反应增加，但对奖励的反应减少。对于这两种神经元类型，对线索和奖励的反应都取决于奖励价值，当奖励被省略时是可逆的，并且通过恢复奖励可迅速恢复。我们还发现，包括头部束缚和恐惧环境在内的应激源会大幅降低这两种神经元类型对线索和奖励的反应强度。这些结果揭示了奖励反应的动态性质，支持了DRN 5-羟色胺神经元信号表示当前获得净收益可能性的假设，并表明压力对5-羟色胺神经元和多巴胺神经元奖励反应的抑制作用可能导致压力诱导的快感缺失。中缝背核的5-羟色胺神经元和腹侧被盖区的多巴胺神经元都密切参与奖励处理。通过对自由行为小鼠的钙信号进行长期纤维光度测定，我们在此表明，学习在5-羟色胺神经元中产生了一种与多巴胺神经元不同的上升激活模式，表明这两种神经元类型在奖励处理中具有互补作用。此外，应激处理会大幅降低5-羟色胺神经元和多巴胺神经元的奖励反应，提示压力诱导的快感缺失可能存在的生理基础。
