Szente Laszlo, Balla Gyula Y, Varga Zoltan K, Toth Blanka, Biro Laszlo, Balogh Zoltan, Hill Matthew N, Toth Mate, Mikics Eva, Aliczki Mano
Translational Behavioural Neuroscience Research Group, Institute of Experimental Medicine, Hungarian Research Network, Budapest, Hungary.
János Szentágothai Doctoral School of Neurosciences, Semmelweis University, Budapest, Hungary.
Neurobiol Stress. 2024 Jul 25;32:100662. doi: 10.1016/j.ynstr.2024.100662. eCollection 2024 Sep.
Traumatic experiences result in the development of posttraumatic stress disorder (PTSD) in 10-25% of exposed individuals. While human clinical studies suggest that susceptibility is potentially linked to endocannabinoid (eCB) signaling, neurobiological PTSD susceptibility factors are poorly understood. Employing a rat model of contextual conditioned fear, we characterized distinct resilient and susceptible subpopulations based on lasting generalized fear, a core symptom of PTSD. In these groups, we assessed i.) eCB levels by mass spectrometry and ii.) expression variations of eCB system- and iii.) neuroplasticity-related genes by real-time quantitative PCR in the circuitry relevant in trauma-induced changes. Furthermore, employing unsupervised and semi-supervised machine learning based statistical analytical models, we assessed iv.) gene expression patterns with the most robust predictive power regarding PTSD susceptibility. According to our findings, in our model, generalized fear responses occurred with sufficient variability to characterize distinct resilient and susceptible subpopulations. Resilient subjects showed elevated prelimbic and lower ventral hippocampal levels of eCB 2-arachidonoyl-glycerol (2-AG) compared to resilient and non-shocked control subjects. Ventral hippocampal 2-AG content positively correlated with the strength of fear generalization. Furthermore, susceptibility was associated with i.) prefrontal, hippocampal and amygdalar neuronal hypoactivity, ii.) marked decrease in the expression of genes of transcription factors modulating neuroplasticity and iii.) an altered expression pattern of eCB-related genes, including enzymes involved in eCB metabolism. Unsupervised and semi-supervised statistical approaches highlighted that hippocampal gene expression patterns possess strong predictive power regarding susceptibility. Taken together, the marked eCB and neuroplasticity changes in susceptible individuals associated with abnormal activity patterns in the fear circuitry possibly contribute to context coding deficits, resulting in generalized fear.
创伤经历会导致10%-25%的受影响个体患上创伤后应激障碍（PTSD）。虽然人类临床研究表明，易感性可能与内源性大麻素（eCB）信号传导有关，但对PTSD易感性的神经生物学因素却知之甚少。我们利用情境性条件恐惧的大鼠模型，根据PTSD的核心症状——持续的广泛性恐惧，对不同的韧性和易感亚群进行了表征。在这些组中，我们通过质谱法评估了i）eCB水平，ii）通过实时定量PCR评估了eCB系统相关基因以及iii）与创伤诱导变化相关的神经可塑性相关基因的表达变化。此外，我们采用基于无监督和半监督机器学习的统计分析模型，评估了iv）对PTSD易感性具有最强预测能力的基因表达模式。根据我们的研究结果，在我们的模型中，广泛性恐惧反应具有足够的变异性，可用于表征不同的韧性和易感亚群。与韧性和未受电击的对照受试者相比，韧性受试者的前边缘皮质中eCB 2-花生四烯酸甘油酯（2-AG）水平升高，腹侧海马中的水平降低。腹侧海马中的2-AG含量与恐惧泛化的强度呈正相关。此外，易感性与以下因素有关：i）前额叶、海马和杏仁核神经元活动减退，ii）调节神经可塑性的转录因子基因表达显著降低，iii）eCB相关基因的表达模式改变，包括参与eCB代谢的酶。无监督和半监督统计方法强调，海马基因表达模式对易感性具有很强的预测能力。综上所述，易感个体中明显的eCB和神经可塑性变化与恐惧回路中异常的活动模式相关，可能导致情境编码缺陷，从而产生广泛性恐惧。
