Waggoner Center for Alcohol and Addiction Research and the College of Pharmacy, University of Texas, 1 University Station, Austin, TX, USA.
Neuropsychopharmacology. 2010 May;35(6):1402-11. doi: 10.1038/npp.2010.10. Epub 2010 Feb 10.
Severe stress or trauma can cause permanent changes in brain circuitry, leading to dysregulation of fear responses and the development of posttraumatic stress disorder (PTSD). To date, little is known about the molecular mechanisms underlying stress-induced long-term plasticity in fear circuits. We addressed this question by using global gene expression profiling in an animal model of PTSD, stress-enhanced fear learning (SEFL). A total of 15 footshocks were used to induce SEFL and the volatile anesthetic isoflurane was used to suppress the behavioral effects of stress. Gene expression in lateral/basolateral amygdala was measured using microarrays at 3 weeks after the exposure to different combinations of shock and isoflurane. Shock produced robust effects on amygdalar transcriptome and isoflurane blocked or reversed many of the stress-induced changes. We used a modular approach to molecular profiles of shock and isoflurane and built a network of regulated genes, functional categories, and cell types that represent a mechanistic foundation of perturbation-induced plasticity in the amygdala. This analysis partitioned perturbation-induced changes in gene expression into neuron- and astrocyte-specific changes, highlighting a previously underappreciated role of astroglia in amygdalar plasticity. Many neuron-enriched genes were highly correlated with astrocyte-enriched genes, suggesting coordinated transcriptional responses to environmental challenges in these cell types. Several individual genes were validated using RT-PCR and behavioral pharmacology. This study is the first to propose specific cellular and molecular mechanisms underlying SEFL, an animal model of PTSD, and to nominate novel molecular and cellular targets with potential for therapeutic intervention in PTSD, including glycine and neuropeptide systems, chromatin remodeling, and gliotransmission.
严重的压力或创伤会导致大脑回路发生永久性变化，从而导致恐惧反应失调和创伤后应激障碍（PTSD）的发展。迄今为止，人们对压力引起的恐惧回路长期可塑性的分子机制知之甚少。我们通过在 PTSD 的动物模型（增强恐惧学习，SEFL）中使用全局基因表达谱来解决这个问题。总共使用 15 次电击来诱导 SEFL，并使用挥发性麻醉剂异氟烷来抑制应激的行为效应。在暴露于不同的电击和异氟烷组合 3 周后，使用微阵列测量外侧/基底外侧杏仁核中的基因表达。电击对杏仁核转录组产生了强大的影响，而异氟烷阻止或逆转了许多应激引起的变化。我们使用了一种模块化的方法来对电击和异氟烷的分子谱进行分析，并构建了一个由受调控的基因、功能类别和细胞类型组成的网络，这些代表了杏仁核中扰动诱导可塑性的机制基础。该分析将扰动诱导的基因表达变化分为神经元和星形胶质细胞特异性变化，突出了星形胶质细胞在杏仁核可塑性中的先前未被充分认识的作用。许多神经元富集的基因与星形胶质细胞富集的基因高度相关，这表明这两种细胞类型对环境挑战具有协调的转录反应。使用 RT-PCR 和行为药理学验证了几个单独的基因。这项研究首次提出了 SEFL 的具体细胞和分子机制，SEFL 是 PTSD 的动物模型，并提名了新的分子和细胞靶点，这些靶点可能成为 PTSD 的治疗干预靶点，包括甘氨酸和神经肽系统、染色质重塑和神经胶质传递。
