Mechanisms of structural plasticity in stress-related disorders

描述(申请人提供)：情绪和焦虑症，如严重抑郁障碍(MDD)和创伤后应激障碍(PTSD)，会导致重叠的行为症状，表现为高度唤醒、社交回避、焦虑、惊吓反应增加和情绪麻木或对快乐刺激的兴趣减弱(快感缺乏)。对介导这些症状的神经底物和分子机制的详细了解将为我们提供新的、更具选择性的药物开发靶点，并最终提高治疗效果。最近的研究提供了强有力的证据表明，细胞外信号分子，如神经营养因子，谷氨酸和促炎细胞因子在MDD和PTSD患者中升高。有趣的是，所有这些信号汇聚在一起激活了转录因子核因子B(NFB)，它被认为在人类情绪和焦虑症的病因中发挥了作用。利用慢性社会失败应激，一种与压力相关的情绪和焦虑障碍的小鼠模型，我们观察到伏隔核(NAC)中的核因子？B活性增加，这是大脑的一个关键奖励结构。此外，我们发现，慢性社交失败改变了NAC神经元的形态，而NAC神经元是行为长期变化的基础。我们用单纯疱疹病毒(HSV)表达固有活性的I-KappaKinase(IKKca)来激活核因子？B，或用显性阴性的I-Kappa-Kinase(IKKdn)来抑制核因子？B。结果表明，在NA小鼠的NAc中，IKKca的表达与慢性社会失败所产生的焦虑表型相似。此外，与失败小鼠的研究结果一致，IKKca增加了NAC介质刺神经元上的树突棘数量，而IKKdn减少了树突棘数量。尽管核因子B介导的脊柱改变的生化机制尚不清楚，但脑内注射HSV-IKK突变体到NAC导致了rac1-PAK1信号的显著变化，这是一条RhoGTP酶途径，介导了肌动蛋白细胞骨架的重组和新脊柱的发育。用IKKdn抑制核因子？B降低了rac1-PAK1通路的活性，而IKKca则大大增加了它的活性。有趣的是，社交失败也降低了NAC中的rac1和PAK1的活性，并且用显性负突变抑制rac1信号，增加了对应激的敏感性，进一步强调了这些生化变化在产生社交失败诱导的回避中的重要性。根据到目前为止的研究结果，我们认为，慢性生理和心理压力导致的脊柱密度变化是社交失败行为综合征的某些方面的基础。我们还在进一步研究这些应激诱导的树突棘和行为的增加是否是通过RhoGTPase信号的核因子B调节。

DESCRIPTION (provided by applicant): Mood and anxiety disorders such as major depressive disorder (MDD) and post traumatic stress disorder (PTSD) cause overlapping behavioral symptoms marked by hyperarousal, social avoidance, anxiety, increased startle responses and emotional numbing or diminished interest in pleasurable stimuli (anhedonia). A detailed understanding of the neural substrates and molecular mechanisms that mediate these symptoms will provide us with novel and more selective targets for drug development and ultimately increase the efficacy of treatment. Recent studies have provided strong evidence that extracellular signaling molecules, such as neurotrophic factors, glutamate and pro-inflammatory cytokines are elevated in patients with MDD and PTSD. Interestingly, all of these signals converge to activate the transcription factor nuclear factor ?B (NF?B), which has been suggested to play a role in the etiology of mood and anxiety disorders in humans. Using chronic social defeat stress, a mouse model of stress-related mood and anxiety disorders, we have observed an increase in NF?B activity in the nucleus accumbens (NAc), a key brain reward structure. Additionally, we found that chronic social defeat changes the morphology of NAc neurons that underlie the very long-lasting changes in behavior. Using a herpes simplex virus (HSV) expressing a constitutively active I Kappa Kinase (IKKca) to activate NF?B or a dominant negative I Kappa Kinase (IKKdn) to inhibit NF?B, we show that expression of IKKca in the NAc of na¿ve mice mimics the anxiety phenotype produced by chronic social defeat. In addition, and consistent with findings in defeated mice, IKKca increases dendritic spine number and IKKdn decreases dendritic spine number on NAc medium spiny neurons. Although the biochemical mechanisms of NF?B mediated spine alterations are unknown, intracranial injections of the HSV-IKK mutants into the NAc resulted in gross changes in Rac1-PAK1 signaling, a RhoGTPase pathway known to mediate actin cytoskeletal reorganization and the development of new spines. Inhibition of NF?B with IKKdn decreases activity within the Rac1-PAK1 pathway, whereas, IKKca greatly increases its activity. Interestingly, social defeat also reduces activity of Rac1 and PAK1 in the NAc, and inhibition of Rac1 signaling with a dominant negative mutant, increases susceptibility to stress, further highlighting the importance of these biochemical changes in producing social defeat-induced avoidance. Based on the results thus far, we believe that chronic physical and psychological stress-induced changes in spine density underlie certain aspects of the social defeat behavioral syndrome. We are also further examining whether these stress-induced increases in dendritic spines and behavior are via NF?B regulation of RhoGTPase signaling.