Stress-altered synaptic plasticity and DAMP signaling in the hippocampus-PFC axis; elucidating the significance of IGF-1/IGF-1R/CaMKIIα expression in neural changes associated with a prolonged exposure therapy.
Stress-altered synaptic plasticity and DAMP signaling in the hippocampus-PFC axis; elucidating the significance of IGF-1/IGF-1R/CaMKIIα expression in neural changes associated with a prolonged exposure therapy.
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DOI：
10.1016/j.neuroscience.2017.04.008
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发表时间：
2017-06-14
期刊：
影响因子：
3.3
通讯作者：
Francis J
中科院分区：
文献类型：
--
作者：
Ogundele OM;Ebenezer PJ;Lee CC;Francis J
创伤应激患者在长时间暴露于无关刺激后表现出显著的行为改善。这种治疗方法试图促进与最初创伤经历相关的恐惧记忆的消失。然而，随后长时间暴露于这种刺激会产生额外的神经压力。虽然机制尚不清楚，但长时间暴露疗法（PET）可能涉及突触可塑性，神经递质功能和炎症的变化;特别是在与恐惧记忆的形成和恢复有关的大脑部分（海马和前额叶皮层：PFC）。由于某些突触蛋白也参与危险相关分子模式信号传导（DAMP），我们确定了IGF-1/IGF-1 R/CaMKIIα表达的重要性，作为应激中突触和炎症变化同时进展之间的潜在联系。因此，比较应激和PET中IGF-1/IGF-1 R/CaMKIIα、突触和DAMP蛋白可能突出PET对突触形态和神经元炎症反应的意义。在行为特征的Sprague道利大鼠中，神经IGF-1（p<0.001）、海马（p<0.001）和皮质（p<0.05）IGF-1 R表达显著下降。这些动物表现出突触前标记物（突触体蛋白; p<0.001）的显著损失和神经递质（VGLUT 2、酪氨酸羟化酶、GABA、ChAT）的变化。此外，未处理应激大鼠记录到突触后标记物（PSD-95; p<0.01）和突触调节物（CaMK II α; p<0.001）的显著降低。作为对脑CaMK Ⅱ α减少的突触反应的一部分，在未处理应激大鼠脑中小离子电导通道（KCa 2.2）上调（p<0.01）。在PET之后，在应激-PET组中记录到IGF-1（p<0.05）和IGF-1 R（p<0.001）的增加。因此，海马（p<0.001）而非皮质（ns）突触体蛋白表达在应激-PET中增加。虽然PSD-95在海马和PFC中相对不变，但在应激PET中CaMK II α（p<0.001）和KCa 2.2（p<0.01）上调，并且可能参与恐惧记忆相关突触电位的消退。这些变化也与正常的神经递质功能，并在开放空间回避显着减少，当动物在高架十字迷宫（ESTA）进行评估。除了IGF-1/IGF-1 R的减少，在应激（p<0.05）和PET后（应激-PET; p<0.001）观察到激活的海马和皮质小胶质细胞的增加。此外，这与神经元中HMGB 1（海马：p<0.001，PFC：p<0.05）和TLR 4表达（海马：p<0.01; PFC：ns）的显著增加有关。总之，这项研究表明，创伤应激和随后的PET涉及IGF 1/IGF-1 R/CaMKIIα的事件依赖性改变。首先，我们发现了IGF-1/IGF-1 R表达，突触前功能（突触素）和神经递质活性在应激和PET之间的直接关系。其次，我们确定了CaMK Ⅱ α在突触后功能和小离子传导通道调节中的可能作用。最后，我们强调了IGF 1/IGF-1 R/CaMKIIα，DAMP蛋白表达，小胶质细胞活化之间的一些可能联系，以及其在应激和PET过程中对突触可塑性的影响。
Traumatic stress patients showed significant improvement in behavior after a prolonged exposure to an unrelated stimulus. This treatment method attempts to promote extinction of the fear memory associated with the initial traumatic experience. However, the subsequent prolonged exposure to such stimulus creates an additional layer of neural stress. Although the mechanism remains unclear, prolonged exposure therapy (PET) likely involve changes in synaptic plasticity, neurotransmitter function and inflammation; especially in parts of the brain concerned with the formation and retrieval of fear memory (Hippocampus and Prefrontal Cortex: PFC). Since certain synaptic proteins are also involved in danger associated molecular pattern signaling (DAMP), we identified the significance of IGF-1/IGF-1R/CaMKIIα expression as a potential link between the concurrent progression of synaptic and inflammatory changes in stress. Thus, a comparison between IGF-1/IGF-1R/CaMKIIα, synaptic and DAMP proteins in stress and PET may highlight the significance of PET on synaptic morphology and neuronal inflammatory response. In behaviorally characterized Sprague Dawley rats, there was a significant decline in neural IGF-1 (p<0.001), hippocampal (p<0.001) and cortical (p<0.05) IGF-1R expression. These animals showed a significant loss of presynaptic markers (synaptophysin; p<0.001), and changes in neurotransmitters (VGLUT2, Tyrosine hydroxylase, GABA, ChAT). Furthermore, naïve stressed rats recorded a significant decrease in post-synaptic marker (PSD-95; p<0.01) and synaptic regulator (CaMKIIα; p<0.001). As part of the synaptic response to a decrease in brain CaMKIIα, small ion conductance channel (KCa2.2) was upregulated in the brain of naïve stressed rats (p<0.01). After a PET, an increase in IGF-1 (p<0.05) and IGF-1R was recorded in the Stress-PET group (p<0.001). As such, hippocampal (p<0.001), but not cortical (ns) synaptophysin expression increased in Stress-PET. Although PSD-95 was relatively unchanged in the hippocampus and PFC, CaMKIIα (p<0.001) and KCa2.2 (p<0.01) were upregulated in Stress-PET, and may be involved in extinction of fear memory-related synaptic potentials. These changes were also associated with a normalized neurotransmitter function, and a significant reduction in open space avoidance; when the animals were assessed in elevated plus maze (EPM). In addition to a decrease in IGF-1/IGF-1R, an increase in activated hippocampal and cortical microglia was seen in stress (p<0.05) and after a PET (Stress-PET; p<0.001). Furthermore, this was linked with a significant increase in HMGB1 (Hippocampus: p<0.001, PFC: p<0.05) and TLR4 expression (Hippocampus: p<0.01; PFC: ns) in the neurons. Taken together, this study showed that traumatic stress and subsequent PET involves an event dependent alteration of IGF1/IGF-1R/CaMKIIα. Firstly, we showed a direct relationship between IGF-1/IGF-1R expression, presynaptic function (synaptophysin) and neurotransmitter activity in stress and PET. Secondly, we identified the possible role of CaMKIIα in post-synaptic function and regulation of small ion conductance channels. Lastly, we highlighted some of the possible links between IGF1/IGF-1R/CaMKIIα, the expression of DAMP proteins, Microglia activation, and its implication on synaptic plasticity during stress and PET.
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影响因子：
64.8
作者：
Benke, TA;Lüthi, A;Collingridge, GL
通讯作者：
Collingridge, GL
影响因子：
16.2
作者：
Gazit N;Vertkin I;Shapira I;Helm M;Slomowitz E;Sheiba M;Mor Y;Rizzoli S;Slutsky I
通讯作者：
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影响因子：
3.6
作者：
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通讯作者：
Nielsen, Heber C.
IGF-1R 是 let-7b 的靶标，介导 IRS-2/Akt 和 MAPK 通路之间的串扰，促进口腔鳞状细胞癌的增殖
影响因子：
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作者：
Gao L;Wang X;Wang X;Zhang L;Qiang C;Chang S;Ren W;Li S;Yang Y;Tong D;Chen C;Li Z;Song T;Zhi K;Huang C
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Huang C
DOI：
10.1016/j.ijdevneu.2013.06.002
发表时间：
2013-11-01
影响因子：
1.8
作者：
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通讯作者：
Quincozes-Santos, Andre