A history of corticosterone exposure regulates fear extinction and cortical NR2B, GluR2/3, and BDNF.
A history of corticosterone exposure regulates fear extinction and cortical NR2B, GluR2/3, and BDNF.
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DOI：
10.1038/npp.2008.123
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发表时间：
2009-02
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接触压力源的历史可能是创伤后发生创伤后应激障碍（PTSD）的诱发因素。 PTSD 中条件性恐惧的消退似乎受到损害，但先前的压力或过量糖皮质激素暴露对消退学习的影响尚不清楚。我们报告说，先前长期暴露于应激激素皮质酮（CORT），会在环境再暴露时减少内源性 CORT 分泌，并在大鼠环境恐惧调节后损害消退，同时保持恐惧记忆的获取和表达完好无损。训练后给予糖皮质激素受体 (GR) 拮抗剂 RU38486，部分模仿了之前在恐惧消退训练期间接触 CORT 对冻结的影响。条件性恐惧的消除是一个主动学习过程，被认为涉及腹内侧前额叶皮层 (vmPFC) 中的谷氨酸靶标（包括特定的 NMDA 和 AMPA 受体亚基），其中包括前边缘、下边缘和内侧眶额皮质。 CORT 暴露后，在皮质区域检测到 NMDA 受体 NR2B 亚基和 AMPA 受体亚基、GluR2/3 以及脑源性神经营养因子的减少，但在背侧海马 (CA1) 中未检测到。 vmPFC 中的受体亚基表达水平与训练期间的冻结相关。此外，先前的 CORT 选择性降低了对蔗糖的偏好，这与已建立的快感缺失模型一致，并且对 PTSD 的影响减弱。总之，这些数据表明了一种细胞机制，通过这种机制，长期升高的糖皮质激素暴露（如反复暴露于压力源时可能会经历的那样）会干扰调节行为灵活性的神经系统，从而可能导致精神病理学恐惧状态。
A history of exposure to stressors may be a predisposing factor for developing posttraumatic stress disorder (PTSD) after trauma. Extinction of conditioned fear appears to be impaired in PTSD, but the consequences of prior stress or excess glucocorticoid exposure for extinction learning are not known. We report that prior chronic exposure to the stress hormone, corticosterone (CORT), decreases endogenous CORT secretion upon context reexposure and impairs extinction after contextual fear conditioning in rats, while leaving fear memory acquisition and expression intact. Posttraining administration of the glucocorticoid receptor (GR) antagonist, RU38486, partially mimicked prior CORT exposure effects on freezing during fear extinction training. Extinction of conditioned fear is an active learning process thought to involve glutamatergic targets—including specific NMDA and AMPA receptor subunits—in the ventromedial prefrontal cortex (vmPFC), which includes the prelimbic, infralimbic, and medial orbitofrontal cortices. After CORT exposure, decreases in the NMDA receptor NR2B subunit and AMPA receptor subunits, GluR2/3, as well as brain-derived neurotrophic factor, were detected in cortical regions, but not dorsal hippocampus (CA1). Receptor subunit expression levels in the vmPFC correlated with freezing during training. In addition, prior CORT selectively decreased sucrose preference, consistent with established models of anhedonia and with blunted affect in PTSD. Together, these data suggest a cellular mechanism by which chronically elevated glucocorticoid exposure—as may be experienced during repeated exposure to stressors—interferes with the neural systems that modulate behavioral flexibility and may thereby contribute to psychopathological fear states.
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DOI：
10.1523/jneurosci.2021-06.2006
发表时间：
2006-09-13
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
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作者：
Kalisch R;Korenfeld E;Stephan KE;Weiskopf N;Seymour B;Dolan RJ
通讯作者：
Dolan RJ
影响因子：
17.7
作者：
Kendler, KS;Karkowski, LM;Prescott, CA
通讯作者：
Prescott, CA
影响因子：
6.9
作者：
Bremner, JD;Vermetten, E;Charney, DS
通讯作者：
Charney, DS
影响因子：
2.5
作者：
Moldow, RL;Beck, KD;Servatius, RJ
通讯作者：
Servatius, RJ
影响因子：
64.8
作者：
Milad, MR;Quirk, GJ
通讯作者：
Quirk, GJ