Sex-dependent hippocampal dendrite remodeling in a model of traumatic stress susceptibility/resilience

Background: Post-traumatic stress disorder (PTSD) is a multifactorial mental disorder that develops following highly traumatic experiences. The neurobiological basis for sex discrepancy differences in PTSD is still largely unknown despite clinical studies have highlighted that women are more frequently affected. Previous evidence reported functional and morphological alterations in corticolimbic brain areas of PTSD patients with PTSD [1]. Aim: The aim of this work was to evaluate sex-dependent morphological differences, in terms of dendritic lengths and number of dendritic spines, at the level of CA1 pyramidal neurons in the CA1 region and dentate gyrus neurons of in the dorsal and ventral hippocampus in of an animal model of PTSD. Methods: The model was obtained by exposing mice to prolonged acute isolation stress (AIS, 24 h), and subsequent classification of the animals into susceptible and resilient, based on their behavioral phenotype [2]. After sacrifice, the brain was collected, and Golgi-Cox staining was performed on brain slices [3]. Images were acquired by light microscopy, the dendritic tree was reconstructed, and dendritic spines were counted using Fiji ImageJ software [4]. Results: Female mice were found to be more susceptible to acute restraint stress compared to males (40% F vs 25.7% M, percentages of segregation using AIS model [2]). Variations in terms of dendritic length and number of dendritic spines were obtained at the level of the different hippocampal areas studied in male and female controls, as well as in resilient and susceptible mice. In the dorsal hippocampus, which is associated to spatial memory [5], the dendritic length of female mice was shorter compared to males (2-way ANOVA, Bonferroni post hoc, *p<0.05, **p<0.01). In CA1, from the ventral hippocampus which is associated to emotion, mood, and stress regulation [5], the total dendritic length and spines density were increased selectively in susceptible males and not in females. In DG from the ventral hippocampus, stress decreased the total dendritic length in resilient females but not in resilient males (Two-way ANOVA, Bonferroni’s post-hoc test. *p<0.05, **p<0.01). As regards the count of dendritic spines, in the basal CA1 and DG, stress-susceptible male animals had a higher spine density than controls and resilient animals (One-way ANOVA, Tukey’s post-hoc test; *p<0.05, **p<0.01, ***p<0.001). In the DG, female control mice hadve a greater spine density than male control mice. (One-way ANOVA, Tukey’s post-hoc test; *p<0.05, **p<0.01, ***p<0.001) Conclusion: Our results suggests that in the dorsal hippocampus, differences in dendritic lengths and number of dendritic spines depend mainly on the sex of the animals. Differently, in the ventral hippocampus they mainly depended on the behavioral phenotype after stress exposure. The attribution of a biological and clinically relevant meaning to the morphological-structural alterations identified requires the interdependent consideration of several factors: sex differences, the classification of animals as resilient/vulnerable to stress, and the specific hippocampal subregion, in turn correlated with function of different dendritic bundles within specific neuronal circuits involved in the stress response.Overall, our study shows that dendrite remodeling induced by traumatic stress is dependent on the biological sex of the animals, thus supporting the idea that PTSD might be associated with sex-dependent changes, which should be taken in account for the development of innovative personalized therapies