Endocannabinoid and neuroplasticity-related changes as susceptibility factors in a rat model of posttraumatic stress disorder

IF 4.3 2区 医学 Q1 NEUROSCIENCES
Laszlo Szente , Gyula Y. Balla , Zoltan K. Varga , Blanka Toth , Laszlo Biro , Zoltan Balogh , Matthew N. Hill , Mate Toth , Eva Mikics , Mano Aliczki
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引用次数: 0

Abstract

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.

作为创伤后应激障碍大鼠模型易感因素的内源性大麻素和神经可塑性相关变化
10%-25%的受创伤者会因创伤经历而患上创伤后应激障碍(PTSD)。人类临床研究表明,创伤后应激障碍的易感性可能与内源性大麻素(eCB)信号传导有关,但人们对创伤后应激障碍的神经生物学易感因素却知之甚少。我们利用大鼠情境条件性恐惧模型,根据创伤后应激障碍的核心症状--持久的广泛性恐惧,确定了不同的抗逆性亚群和易感性亚群。在这些亚群中,我们通过质谱分析评估了 i.) eCB 水平,以及 ii.) eCB 系统和 iii.) 神经可塑性相关基因的表达变化。此外,我们还利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) 对创伤后应激障碍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,泛化的恐惧反应具有足够的变异性,可以描述出不同的抗逆性亚群和易感性亚群。与恢复能力强的对照组和未受惊吓的对照组相比,恢复能力强的受试者表现出边缘前区 eCB 2-arachidonoyl-glycerol (2-AG) 水平升高,而海马腹侧 eCB 2-AG 水平降低。腹侧海马 2-AG 含量与恐惧泛化的强度呈正相关。此外,易感性还与以下因素有关:i.)前额叶、海马和杏仁核神经元活性低下;ii.)调节神经可塑性的转录因子基因表达明显减少;iii.)eCB 相关基因(包括参与 eCB 代谢的酶)的表达模式改变。无监督和半监督统计方法突出表明,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,易感人群中明显的 eCB 和神经可塑性变化与恐惧回路中的异常活动模式有关,可能会导致情境编码缺陷,从而导致广泛性恐惧。
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来源期刊
Neurobiology of Stress
Neurobiology of Stress Biochemistry, Genetics and Molecular Biology-Biochemistry
CiteScore
9.40
自引率
4.00%
发文量
74
审稿时长
48 days
期刊介绍: Neurobiology of Stress is a multidisciplinary journal for the publication of original research and review articles on basic, translational and clinical research into stress and related disorders. It will focus on the impact of stress on the brain from cellular to behavioral functions and stress-related neuropsychiatric disorders (such as depression, trauma and anxiety). The translation of basic research findings into real-world applications will be a key aim of the journal. Basic, translational and clinical research on the following topics as they relate to stress will be covered: Molecular substrates and cell signaling, Genetics and epigenetics, Stress circuitry, Structural and physiological plasticity, Developmental Aspects, Laboratory models of stress, Neuroinflammation and pathology, Memory and Cognition, Motivational Processes, Fear and Anxiety, Stress-related neuropsychiatric disorders (including depression, PTSD, substance abuse), Neuropsychopharmacology.
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