PDF(Pubmed)
Abstract：
Fear-related disorders, including post-traumatic stress disorder (PTSD), and anxiety disorders are pervasive psychiatric conditions marked by persistent fear, stemming from its dysregulated acquisition and extinction. The primary treatment for these disorders, exposure therapy (ET), relies heavily on fear extinction (FE) principles. Adolescence, a vulnerable period for developing psychiatric disorders, is characterized by neurobiological changes in the fear circuitry, leading to impaired FE and increased susceptibility to relapse following ET. Ketamine, known for relieving anxiety and reducing PTSD symptoms, influences fear-related learning processes and synaptic plasticity across the fear circuitry. Our study aimed to investigate the effects of ketamine (10 mg/kg) on FE in adolescent male C57 BL/6 mice at the behavioral and molecular levels. We analyzed the protein and gene expression of synaptic plasticity markers in the hippocampus (HPC) and prefrontal cortex (PFC) and sought to identify neural correlates associated with ketamine\'s effects on adolescent extinction learning. Ketamine ameliorated FE in the adolescent males, likely affecting the consolidation and/or recall of extinction memory. Ketamine also increased the Akt and mTOR activity and the GluA1 and GluN2A levels in the HPC and upregulated BDNF exon IV mRNA expression in the HPC and PFC of the fear-extinguished mice. Furthermore, ketamine increased the c-Fos expression in specific brain regions, including the ventral HPC (vHPC) and the left infralimbic ventromedial PFC (IL vmPFC). Providing a comprehensive exploration of ketamine\'s mechanisms in adolescent FE, our study suggests that ketamine\'s effects on FE in adolescent males are associated with the activation of hippocampal Akt-mTOR-GluA1 signaling, with the vHPC and the left IL vmPFC as the proposed neural correlates.
摘要：
与恐惧有关的疾病，包括创伤后应激障碍(PTSD),焦虑症是普遍存在的精神疾病，以持续的恐惧为特征，源于其失调的获取和灭绝。这些疾病的主要治疗方法，暴露疗法（ET），严重依赖恐惧灭绝(FE)原则。青春期,发展为精神疾病的脆弱时期，其特征是恐惧回路的神经生物学变化，导致FE受损和ET后复发的易感性增加。氯胺酮,以缓解焦虑和减轻创伤后应激障碍症状而闻名，影响恐惧相关的学习过程和整个恐惧电路的突触可塑性。我们的研究旨在从行为和分子水平研究氯胺酮（10mg/kg）对青春期雄性C57BL/6小鼠FE的影响。我们分析了海马（HPC）和前额叶皮质（PFC）中突触可塑性标记的蛋白质和基因表达，并试图确定与氯胺酮对青少年灭绝学习的影响相关的神经相关性。氯胺酮改善了青春期男性的FE，可能影响灭绝记忆的巩固和/或回忆。氯胺酮还增加了恐惧熄灭小鼠HPC中Akt和mTOR活性以及GluA1和GluN2A的水平，并上调了HPC和PFC中BDNF外显子IVmRNA的表达。此外，氯胺酮增加了特定大脑区域的c-Fos表达，包括腹侧HPC（vHPC）和左下侧腹内侧PFC（ILvmPFC）。全面探索氯胺酮在青少年FE中的作用机制，我们的研究表明氯胺酮对青少年男性FE的影响与海马Akt-mTOR-GluA1信号的激活有关，用vHPC和左ILvmPFC作为所提出的神经相关性。
