Phosphorylation of calcium/calmodulin-dependent protein kinase II in the rat dorsal medial prefrontal cortex is associated with alcohol-induced cognitive inflexibility.
Phosphorylation of calcium/calmodulin-dependent protein kinase II in the rat dorsal medial prefrontal cortex is associated with alcohol-induced cognitive inflexibility.
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DOI：
10.1111/adb.12568
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发表时间：
2018-09
影响因子：
3.4
通讯作者：
Parsons LH
中科院分区：
文献类型：
--
作者：
Natividad LA;Steinman MQ;Laredo SA;Irimia C;Polis IY;Lintz R;Buczynski MW;Martin-Fardon R;Roberto M;Parsons LH
酒精（乙醇；乙醇）中毒和戒断的反复循环使大脑中的兴奋性谷氨酸能系统失调，并诱导内侧前额叶皮层（mPFC）的神经适应，从而导致认知功能障碍。mPFC由功能不同的细分组成，背侧区域促进药物线索关联，腹侧区域在没有药物的情况下调节新学习。谷氨酸能活性的一个关键调节剂是全酶钙/钙调素依赖性蛋白激酶II (CaMKII)，它使嗜离子性谷氨酸受体磷酸化。在这里，我们检验了一种假设，即慢性间歇性EtOH （CIE）暴露的戒断会使mPFC中的CaMKII活性失调，从而损害认知灵活性。我们使用了一个策略转移的操作模型，在雄性Long-Evans大鼠中显示，在视觉线索引导任务中，与白化品系相比，对试验遗漏的易感性降低。相对于naïve对照组，经历了大约10天CIE蒸汽暴露禁欲的大鼠在从视觉线索到空间位置识别的程序转变过程中表现出受损的表现。暴露于cie的大鼠的背侧mPFC中CaMKII亚型α的磷酸化上调，而腹侧mPFC中CaMKII亚型α的磷酸化上调，并且在set-shift期间与持久性反应呈正相关。研究结果表明，对CIE暴露的戒断诱导了激酶活性的暗流（例如CaMKII），这可能会促进mPFC特定区域的异常谷氨酸反应。考虑到mPFC在调节行为执行控制中的作用，我们提出CaMKIIα活性的增加反映了一个失调的“自上而下”回路，该回路干扰了在不断变化的环境需求下的适应性行为表现。
Repeated cycles of alcohol (ethanol; EtOH) intoxication and withdrawal dysregulate excitatory glutamatergic systems in the brain, and induce neuroadaptations in the medial prefrontal cortex (mPFC) that contribute to cognitive dysfunction. The mPFC is comprised of subdivisions that are functionally distinct, with dorsal regions facilitating drug-cue associations, and ventral regions modulating new learning in the absence of drug. A key modulator of glutamatergic activity is the holoenzyme calcium/calmodulin-dependent protein kinase II (CaMKII) that phosphorylates ionotropic glutamate receptors. Here, we examined the hypothesis that abstinence from chronic intermittent EtOH (CIE) exposure dysregulates CaMKII activity in the mPFC to impair cognitive flexibility. We used an operant model of strategy set-shifting in male Long-Evans rats demonstrating reduced susceptibility to trial omissions during performance in a visual cue-guided task versus albino strains. Relative to naïve controls, rats experiencing approximately 10 days of abstinence from CIE vapor exposure demonstrated impaired performance during a procedural shift from visual cue to spatial location discrimination. Phosphorylation of CaMKII subtype α was upregulated in the dorsal, but not ventral mPFC of CIE-exposed rats, and was positively correlated with perseverative-like responding during the set-shift. The findings suggest that abstinence from CIE exposure induces an undercurrent of kinase activity (e.g., CaMKII) which may promote aberrant glutamatergic responses in select regions of the mPFC. Given the role of the mPFC in modulating executive control of behavior, we propose that increased CaMKIIα activity reflects a dysregulated “top-down” circuit that interferes with adaptive behavioral performance under changing environmental demands.
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DOI：
10.1523/jneurosci.2933-15.2016
发表时间：
2016-05-04
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Benn A;Barker GR;Stuart SA;Roloff EV;Teschemacher AG;Warburton EC;Robinson ES
通讯作者：
Robinson ES
影响因子：
10.6
作者：
Cools, Roshan;D'Esposito, Mark
通讯作者：
D'Esposito, Mark
影响因子：
3.4
作者：
Beas BS;Setlow B;Bizon JL
通讯作者：
Bizon JL
影响因子：
2.7
作者：
Chudasama, Y;Passetti, F;Robbins, TW
通讯作者：
Robbins, TW
影响因子：
16.2
作者：
De Rosa, E;Desmond, JE;Sullivan, EV
通讯作者：
Sullivan, EV