CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli
CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli
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DOI：
10.1073/pnas.172091899
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发表时间：
2002-08-20
影响因子：
11.1
通讯作者：
Nestler, EJ
中科院分区：
文献类型：
--
作者：
Barrot, M;Olivier, JDA;Nestler, EJ
转录因子cAMP反应元件（CRE）结合蛋白（CREB）已被证明调节神经可塑性。滥用药物会激活脑桥核中的CREB，这是大脑奖励途径的重要组成部分，并且CREB活性的局部操纵已被证明会影响可卡因奖励，这表明CREB在暴露于滥用药物后的适应性过程中发挥积极作用。使用CRE-LacZ报告小鼠，我们表明，不仅奖励刺激，如吗啡，但也厌恶刺激，如压力，激活CRE-mediated转录的核壳。使用病毒介导的基因转移局部改变CREB的活性，我们表明，这种操作影响吗啡的奖励，以及对蔗糖的偏好，一个更自然的奖励。然后，我们表明，CREB活性的局部变化诱导一个更普遍的综合征，通过改变反应的焦虑，厌恶，以及伤害性刺激。增加的CREB活性在核壳减少动物的反应，这些刺激，而减少CREB活性诱导相反的表型。这些结果表明，环境刺激调节CREB介导的转录核壳内，CREB活性的变化在这个大脑区域内随后改变情绪刺激和他们的行为反应之间的门控。这种控制似乎与刺激的内在欲望或厌恶价值无关。这些数据成瘾和情绪障碍的潜在相关性进行了讨论。
The transcription factor cAMP response element (CRE)-binding protein (CREB) has been shown to regulate neural plasticity. Drugs of abuse activate CREB in the nucleus accumbens, an important part of the brain's reward pathways, and local manipulations of CREB activity have been shown to affect cocaine reward, suggesting an active role of CREB in adaptive processes that follow exposure to drugs of abuse. Using CRE-LacZ reporter mice, we show that not only rewarding stimuli such as morphine, but also aversive stimuli such as stress, activate CRE-mediated transcription in the nucleus accumbens shell. Using viral-mediated gene transfer to locally alter the activity of CREB, we show that this manipulation affects morphine reward, as well as the preference for sucrose, a more natural reward. We then show that local changes in CREB activity induce a more general syndrome, by altering reactions to anxiogenic, aversive, and nociceptive stimuli as well. Increased CREB activity in the nucleus accumbens shell decreases an animal's responses to each of these stimuli, whereas decreased CREB activity induces an opposite phenotype. These results show that environmental stimuli regulate CRE-mediated transcription within the nucleus accumbens shell, and that changes in CREB activity within this brain area subsequently alter gating between emotional stimuli and their behavioral responses. This control appears to be independent of the intrinsic appetitive or aversive value of the stimulus. The potential relevance of these data to addiction and mood disorders is discussed.