IκB kinase regulates social defeat stress-induced synaptic and behavioral plasticity.
IκB kinase regulates social defeat stress-induced synaptic and behavioral plasticity.
复制标题
DOI：
10.1523/jneurosci.4763-10.2011
复制
发表时间：
2011-01-05
期刊：
影响因子：
--
通讯作者：
Russo SJ
中科院分区：
文献类型：
--
作者：
Christoffel DJ;Golden SA;Dumitriu D;Robison AJ;Janssen WG;Ahn HF;Krishnan V;Reyes CM;Han MH;Ables JL;Eisch AJ;Dietz DM;Ferguson D;Neve RL;Greengard P;Kim Y;Morrison JH;Russo SJ
情绪和焦虑症的神经生物学基础与伏隔核（NAc）有关，伏隔核是处理刺激的奖励和情感显着性的重要区域。使用慢性社交失败压力（一种情绪和焦虑障碍的动物模型），我们研究了突触可塑性的改变是否是由这种压力引起的长期行为症状的原因。我们假设，慢性社交失败压力会改变 NAc 中中棘神经元 (MSN) 的突触强度或连接性，从而诱发社交回避。为了测试这一点，我们通过荧光素黄色填充细胞的共聚焦成像、突触后密度的超微结构分析以及社交失败后小鼠微型 EPSC (mEPSC) 的电生理记录来分析 MSN 的突触特征。我们发现 NAc MSN 具有更粗短的脊柱结构，突触后密度更小，并且在社交失败后 mEPSC 的频率增加。与这些结构变化并行的是，我们观察到社交失败后 NAc 中 IκB 激酶 (IKK) 显着增加，这是一种已被证明可以调节神经元形态的分子途径。事实上，我们发现，使用病毒介导的显性失活和组成型活性 IKK 突变体的基因转移，在社会失败期间激活 IKK 信号通路对于诱导突触改变和压力的行为影响是必要且充分的。这些研究确立了 IKK 在调节应激诱导的适应性可塑性中的因果作用，并可能为治疗人类情绪和焦虑症的药物开发提供新的靶点。
The neurobiological underpinnings of mood and anxiety disorders have been linked to the nucleus accumbens (NAc), a region important in processing the rewarding and emotional salience of stimuli. Using chronic social defeat stress, an animal model of mood and anxiety disorders, we investigated whether alterations in synaptic plasticity are responsible for the long-lasting behavioral symptoms induced by this form of stress. We hypothesized that chronic social defeat stress alters synaptic strength or connectivity of medium spiny neurons (MSNs) in the NAc to induce social avoidance. To test this, we analyzed the synaptic profile of MSNs via confocal imaging of Lucifer-yellow-filled cells, ultrastructural analysis of the postsynaptic density, and electrophysiological recordings of miniature EPSCs (mEPSCs) in mice after social defeat. We found that NAc MSNs have more stubby spine structures with smaller postsynaptic densities and an increase in the frequency of mEPSCs after social defeat. In parallel to these structural changes, we observed significant increases in IκB kinase (IKK) in the NAc after social defeat, a molecular pathway that has been shown to regulate neuronal morphology. Indeed, we find using viral-mediated gene transfer of dominant-negative and constitutively active IKK mutants that activation of IKK signaling pathways during social defeat is both necessary and sufficient to induce synaptic alterations and behavioral effects of the stress. These studies establish a causal role for IKK in regulating stress-induced adaptive plasticity and may present a novel target for drug development in the treatment of mood and anxiety disorders in humans.