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

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 PTSD, we characterized distinct resilient and susceptible subpopulations based on generalized fear, a core symptom of PTSD. In these groups, we assessed i.) eCB levels by mass spectrometry and 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 supervised 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. Susceptible subjects showed lower prelimbic and higher ventral hippocampal levels of eCB 2-arachidonoyl-glycerol (2-AG) compared to resilient subjects. Ventral hippocampal 2-AG content positively correlated with the strength of fear generalization. Furthermore, susceptibility was associated with i.) neuronal prefrontal, hippocampal and amygdalar 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. Highlights ### Competing Interest Statement The authors have declared no competing interest. * 2-AG : 2-arachidonoylglycerol AEA : N-arachidonoylethanolamine, anandamide AMY : amygdala BLA : basolateral amygdala CB1R : cannabinoid receptor type-1 DAGLα : diacylglycerol lipase alpha DAGLβ : diacylglycerol lipase beta eCB : endocannabinoid HC : hippocampus IL : infralimbic cortex mPFC : medial prefrontal cortex Npas4 : neuronal PAS domain protein 4 PrL : prelimbic cortex PTSD : posttraumatic stress disorder vHC : ventral hippocampus