Department of Psychology and Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK.
Rodent Behavioral Core, Department of Neuroscience and Physiology, Neuroscience Institute, New York University Medical Center, New York, NY, 10016, USA.
Psychopharmacology (Berl). 2018 Jul;235(7):2101-2111. doi: 10.1007/s00213-018-4907-7. Epub 2018 Apr 22.
Dysregulation of the serotonin (5-HT) system is a pathophysiological component in major depressive disorder (MDD), a condition closely associated with abnormal emotional responsivity to positive and negative feedback. However, the precise mechanism through which 5-HT tone biases feedback responsivity remains unclear. 5-HT2C receptors (5-HT2CRs) are closely linked with aspects of depressive symptomatology, including abnormalities in reinforcement processes and response to stress. Thus, we aimed to determine the impact of 5-HT2CR function on response to feedback in biased reinforcement learning.
We used two touchscreen assays designed to assess the impact of positive and negative feedback on probabilistic reinforcement in mice, including a novel valence-probe visual discrimination (VPVD) and a probabilistic reversal learning procedure (PRL). Systemic administration of a 5-HT2CR agonist and antagonist resulted in selective changes in the balance of feedback sensitivity bias on these tasks.
Specifically, on VPVD, SB 242084, the 5-HT2CR antagonist, impaired acquisition of a discrimination dependent on appropriate integration of positive and negative feedback. On PRL, SB 242084 at 1 mg/kg resulted in changes in behaviour consistent with reduced sensitivity to positive feedback. In contrast, WAY 163909, the 5-HT2CR agonist, resulted in changes associated with increased sensitivity to positive feedback and decreased sensitivity to negative feedback.
These results suggest that 5-HT2CRs tightly regulate feedback sensitivity bias in mice with consequent effects on learning and cognitive flexibility and specify a framework for the influence of 5-HT2CRs on sensitivity to reinforcement.
血清素（5-HT）系统的失调是重度抑郁症（MDD）的一种病理生理成分，这种病症与对正性和负性反馈的异常情绪反应密切相关。然而，5-HT 张力如何影响反馈反应的精确机制尚不清楚。5-HT2C 受体（5-HT2CRs）与抑郁症状的多个方面密切相关，包括强化过程中的异常和对压力的反应。因此，我们旨在确定 5-HT2CR 功能对偏向性强化学习中反馈反应的影响。
我们使用了两种触摸屏检测，旨在评估正性和负性反馈对概率强化在小鼠中的影响，包括新颖的效价探测视觉辨别（VPVD）和概率反转学习程序（PRL）。5-HT2CR 激动剂和拮抗剂的系统给药导致这些任务上反馈敏感性偏差的平衡发生选择性变化。
具体而言，在 VPVD 上，5-HT2CR 拮抗剂 SB 242084 损害了对适当整合正性和负性反馈的辨别能力的获取。在 PRL 上，SB 242084 在 1mg/kg 时导致与对正性反馈敏感性降低一致的行为变化。相比之下，5-HT2CR 激动剂 WAY 163909 导致与增加对正性反馈的敏感性和降低对负性反馈的敏感性相关的变化。
这些结果表明，5-HT2CR 紧密调节小鼠的反馈敏感性偏差，从而对学习和认知灵活性产生影响，并为 5-HT2CR 对强化敏感性的影响提供了框架。
