Department of Experimental Psychology, University of Oxford, Oxford, UK.
Danish Research Institute of Translational Neuroscience (DANDRITE), Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
Transl Psychiatry. 2019 Apr 17;9(1):139. doi: 10.1038/s41398-019-0476-8.
Genetic variation in the human serotonin transporter (5-HTT) has been linked to altered fear learning but the data are inconsistent and the mechanism is unclear. The present study investigated conditioned aversive learning in 5-HTT knockout (KO) mice while simultaneously recording neural network activity (theta oscillations) and hemodynamic responses (tissue oxygen delivery) from the amygdala, a brain region necessary for forming fearful memories. Conditioned aversive learning was measured using a discrimination learning task in which one auditory cue was paired with foot-shock, whereas a second auditory cue was not. Compared with wild-type mice, 5-HTTKO mice exhibited faster discrimination learning. This effect was associated with stronger theta frequency oscillations and greater hemodynamic changes in the amygdala in response to both the emotionally relevant cues and the unconditioned foot-shock stimulus. Furthermore, hemodynamic responses to the unconditioned stimulus predicted behavioral discrimination performance the following day. Acute pharmacological 5-HTT blockade in wild-type mice produced a similar effect, to the extent that administration of citalopram during the fear conditioning sessions enhanced fear memory recall. Collectively, our data argue that loss of 5-HTT function enhances amygdala responsivity to aversive events and facilitates learning for emotionally relevant cues.
人类 5-羟色胺转运体（5-HTT）的遗传变异与恐惧学习的改变有关，但数据不一致，其机制尚不清楚。本研究通过同时记录杏仁核的神经网络活动（θ振荡）和血液动力学反应（组织氧输送），在 5-HTT 敲除（KO）小鼠中研究了条件性厌恶学习，杏仁核是形成恐惧记忆所必需的脑区。通过使用辨别学习任务来测量条件性厌恶学习，其中一个听觉线索与足部电击配对，而第二个听觉线索则不配对。与野生型小鼠相比，5-HTTKO 小鼠表现出更快的辨别学习。这种效应与更强的θ频率振荡以及杏仁核对情绪相关线索和非条件足部电击刺激的更大血液动力学变化有关。此外，对非条件刺激的血液动力学反应预测了第二天的行为辨别表现。在野生型小鼠中进行急性 5-HTT 药理学阻断产生了类似的效果，以至于在恐惧条件反射期间给予西酞普兰增强了恐惧记忆的回忆。总的来说，我们的数据表明，5-HTT 功能的丧失增强了杏仁核对厌恶事件的反应性，并促进了与情绪相关线索的学习。
