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），引起重叠的行为症状，其特征为过度觉醒、社交回避、焦虑、惊吓反应增加和情感麻木或对愉悦刺激的兴趣降低（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，所有这些信号汇聚到激活转录因子核因子？B（NF？B），其被认为在人类的情绪和焦虑障碍的病因学中起作用。使用慢性社会失败的压力，小鼠模型的压力相关的情绪和焦虑症，我们已经观察到增加NF？B在脑桥核（NAc）的活动，一个关键的大脑奖励结构。此外，我们发现慢性社交失败会改变NAc神经元的形态，而这些神经元是行为长期变化的基础。使用单纯疱疹病毒（HSV）表达组成型活性I κ激酶（IKKca）激活NF？B或显性阴性I κ激酶（IKKdn）抑制NF？B，我们发现IKKca在未处理小鼠NAc中的表达模拟了慢性社交失败产生的焦虑表型。此外，与失败小鼠中的发现一致，IKKca增加树突棘数量，IKKdn减少NAc中棘神经元上的树突棘数量。虽然NF的生化机制？B介导的棘改变是未知的，将HSV-IKK突变体颅内注射到NAc中导致Rac 1-PAK 1信号传导的总体变化，Rac 1-PAK 1信号传导是已知介导肌动蛋白细胞骨架重组和新棘发育的RhoGT 3途径。抑制NF？B与IKKdn一起降低Rac 1-PAK 1通路内的活性，而IKKca大大增加其活性。有趣的是，社交失败也降低了NAc中Rac 1和PAK 1的活性，显性负突变体抑制Rac 1信号传导，增加了对压力的易感性，进一步突出了这些生化变化在产生社交失败诱导的回避中的重要性。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某些方面的基础。我们还在进一步研究这些压力诱导的树突棘和行为的增加是否是通过NF？B调节RhoGT β信号传导。 公共卫生相关性：开发有效的化合物来治疗精神障碍一直很困难，并且对于完全缓解诸如重度抑郁症和创伤后应激障碍之类的障碍的治疗选择有限。来自这些基础神经生物学研究的数据将为开发针对大脑中核因子κ B的新型和更具选择性的药理学药物奠定基础，以治疗或预防焦虑和情绪障碍。

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.