Activation of CREB in the nucleus accumbens shell produces anhedonia and resistance to extinction of fear in rats.
Activation of CREB in the nucleus accumbens shell produces anhedonia and resistance to extinction of fear in rats.
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DOI：
10.1523/jneurosci.5973-10.2011
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发表时间：
2011-02-23
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影响因子：
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通讯作者：
Carlezon WA Jr
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作者：
Muschamp JW;Van't Veer A;Parsegian A;Gallo MS;Chen M;Neve RL;Meloni EG;Carlezon WA Jr
压力会引发精神疾病，包括抑郁症和焦虑症。压力导致行为持续变化的机制还没有完全被理解。在这里，我们在大鼠身上展示了应激(足部电击)激活了伏隔核外壳(NAS)内的转录因子CREB(cAMP反应元件结合蛋白)，NAS是大脑中参与编码奖励和厌恶的区域。为了检测NAS中CREB功能改变的行为学意义，我们使用病毒载体来上调或干扰该区域的CREB。CREB升高导致颅内自我刺激(ICSS)阈值升高，这是一种反映快感缺乏(对奖励敏感性降低)的抑郁样征象，而显性负CREB表达导致CREB功能障碍则相反。为了确定随后产生快感缺失的神经适应是否会影响对应激诱导的行为适应的易感性，我们让NAS中CREB功能改变的大鼠接受恐惧条件反射。虽然CREB功能的升高或中断都不会改变条件性恐惧的发展，但CREB的升高会削弱条件性恐惧的消退。为了模拟CREB激活对阿片肽强啡肽表达的下游影响，我们将kappa-阿片受体(KOR)激动剂U50,488直接注射到NAS。KOR刺激产生快感缺失，但对条件性恐惧的表达或消退没有影响。这些发现表明，在NAS中激活CREB会产生多种行为迹象(快感缺乏、消退障碍)，这些症状是创伤后应激障碍(PTSD)等经验依赖型精神疾病的特征。虽然CREB激活是一个常见的触发因素，但这些信号的表达似乎涉及不同的下游机制。
Stress triggers psychiatric conditions including depressive and anxiety disorders. The mechanisms by which stress produces persistent changes in behavior are not fully understood. Here we show in rats that stress (footshock) activates the transcription factor CREB (cAMP response element binding protein) within the nucleus accumbens shell (NAS), a brain area involved in encoding reward and aversion. To examine the behavioral significance of altered CREB function in the NAS, we used viral vectors to elevate or disrupt CREB in this region. Elevated CREB produced increases in intracranial self-stimulation (ICSS) thresholds, a depressive-like sign reflecting anhedonia (decreased sensitivity to reward), whereas disruption of CREB function by expression of a dominant negative CREB had the opposite effect. To determine if neuroadaptations that produce anhedonia subsequently affect vulnerability to stress-induced behavioral adaptations, we subjected rats with altered CREB function in the NAS to fear conditioning. While neither elevation nor disruption of CREB function altered the development of conditioned fear, elevation of CREB impaired extinction of conditioned fear. To mimic downstream effects of CREB activation on expression of the opioid peptide dynorphin, we microinjected the kappa-opioid receptor (KOR) agonist U50,488 directly into the NAS. KOR stimulation produced anhedonia but had no effect on expression or extinction of conditioned fear. These findings demonstrate that activation of CREB in the NAS produces multiple behavioral signs (anhedonia, impaired extinction) characteristic of experience-dependent psychiatric conditions such as post-traumatic stress disorder (PTSD). Although CREB activation is a common trigger, expression of these individual signs appears to involve divergent downstream mechanisms.