Stress Enables Reinforcement-Elicited Serotonergic Consolidation of Fear Memory.
Stress Enables Reinforcement-Elicited Serotonergic Consolidation of Fear Memory.
复制标题
DOI：
10.1016/j.biopsych.2015.06.025
复制
发表时间：
2016-05-15
影响因子：
10.6
通讯作者：
Goosens KA
中科院分区：
文献类型：
--
作者：
Baratta MV;Kodandaramaiah SB;Monahan PE;Yao J;Weber MD;Lin PA;Gisabella B;Petrossian N;Amat J;Kim K;Yang A;Forest CR;Boyden ES;Goosens KA
先前的压力暴露是发生创伤后应激障碍（PTSD）的一个风险因素，但其发生的机制尚不清楚。利用应激易感性啮齿动物模型，我们研究了血清素在这一现象中的作用。成年小鼠暴露于反复的固定应激或处理中，并使用药理学操作和血清素受体的western blot检测、血清素测量、高速光遗传沉默和行为来评估血清素在随后的恐惧学习中的作用。应激增强恐惧记忆的过程中，背中叶5-羟色胺活性和记忆巩固过程中杏仁核5-羟色胺2c受体（5-HT2CR）活性都是必需的，但这两个过程都不影响非应激小鼠的恐惧记忆。此外，先前的应激通过促进5-HT2CR的表面表达而不影响杏仁核中血清素的组织水平，从而增加杏仁核对血清素的敏感性。我们还表明，驱动联想线索恐惧记忆的压力增强的血清素可能来自成对或不成对的脚震，这是联想学习的理论模型无法预测的效果。压力增强了厌恶强化的结果，不是通过简单地增强用于在无压力的动物中编码恐惧的神经生物学信号，而是通过参与不同的机械途径。这些结果表明，经典联想学习模型的预测并不总是适用于应激动物，并表明5-HT2CR阻断可能代表了以过度恐惧反应为特征的精神疾病的有希望的治疗靶点，例如在PTSD中观察到的。
Prior exposure to stress is a risk factor for developing post-traumatic stress disorder (PTSD) in response to trauma, yet the mechanisms by which this occurs are unclear. Using a rodent model of stress-based susceptibility to PTSD, we investigated the role of serotonin in this phenomenon. Adult mice were exposed to repeated immobilization stress or handling, and the role of serotonin in subsequent fear learning was assessed using pharmacological manipulation and western blot detection of serotonin receptors, measurements of serotonin, high-speed optogenetic silencing, and behavior. Both dorsal raphe serotonergic activity during aversive reinforcement and amygdala serotonin 2c receptor (5-HT2CR) activity during memory consolidation are necessary for stress enhancement of fear memory, but neither process affects fear memory in unstressed mice. Additionally, prior stress increases amygdala sensitivity to serotonin by promoting surface expression of 5-HT2CR without affecting tissue levels of serotonin in the amygdala. We also show that the serotonin that drives stress enhancement of associative cued fear memory can arise from paired or unpaired footshock, an effect not predicted by theoretical models of associative learning. Stress bolsters the consequences of aversive reinforcement, not by simply enhancing the neurobiological signals used to encode fear in unstressed animals, but rather by engaging distinct mechanistic pathways. These results reveal that predictions from classical associative learning models do not always hold for stressed animals, and suggest that 5-HT2CR blockade may represent a promising therapeutic target for psychiatric disorders characterized by excessive fear responses such as that observed in PTSD.