Mechanisms of structural plasticity in stress-related disorders

描述（由申请人提供）：情绪和焦虑障碍，如重度抑郁症（MDD）和创伤后应激障碍（PTSD），会导致重叠的行为症状，其特征是过度兴奋、社交回避、焦虑、惊吓反应增加、情绪麻木或对愉悦刺激（快感缺乏）的兴趣减少。对介导这些症状的神经基质和分子机制的详细了解将为我们提供新的和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，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，所有这些信号汇聚起来激活转录因子核因子？B (NF吗?B)，它被认为在人类情绪和焦虑障碍的病因学中起作用。使用慢性社会失败压力（应激相关情绪和焦虑障碍的小鼠模型），我们观察到NF？伏隔核（NAc）中B的活动，这是一个关键的大脑奖励结构。此外，我们发现长期的社会失败改变了NAc神经元的形态，这是行为长期变化的基础。使用单纯疱疹病毒（HSV）表达组成活性I κ激酶（IKKca）来激活NF？B或显性负I Kappa激酶（IKKdn）抑制NF？B，我们发现IKKca在na - ve小鼠NAc中的表达模仿了慢性社交失败产生的焦虑表型。此外，与战败小鼠的研究结果一致，IKKca增加NAc中棘神经元的树突棘数，IKKdn减少树突棘数。尽管NF的生化机制？B介导的脊柱改变尚不清楚，将HSV-IKK突变体颅内注射到NAc中导致Rac1-PAK1信号的明显变化，这是一种RhoGTPase途径，已知可介导肌动蛋白细胞骨架重组和新脊柱的发育。抑制NF？含有IKKdn的B降低了Rac1-PAK1通路内的活性，而IKKca则大大增加了其活性。有趣的是，社交失败也降低了NAc中Rac1和PAK1的活性，并且抑制了显性负突变的Rac1信号，增加了对应激的易感性，进一步强调了这些生化变化在产生社交失败诱导的逃避中的重要性。基于迄今为止的结果，我们认为慢性生理和心理压力引起的脊柱密度变化是社会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力诱导的树突棘和行为的增加是否通过NF？RhoGTPase信号的调控。

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. PUBLIC HEALTH RELEVANCE: Developing effective compounds to treat psychiatric disorders has been difficult and there are limited treatment options for full remission of disorders such as major depressive disorder and post-traumatic stress disorder. The data from these basic neurobiological studies will lay the groundwork for the development of novel and more selective pharmacological agents targeting nuclear factor kappa B in the brain to treat or prevent anxiety and mood disorders.