Changes in dendrite remodeling underlying sex-dependent traumatic stress susceptibility/resilience in the hippocampus

Background: Post-traumatic stress disorder (PTSD) is a multifactorial mental disorder that develops following highly traumatic experiences. Despite clinical studies have highlighted that women are more frequently affected than men by the disease, the neurobiological basis for sex discrepancy in PTSD is still largely unknown. Previous evidence reported functional and morphological alterations in corticolimbic brain areas of patients with PTSD [1]. In particular we consider HPC in which the dorsal part is associated to the spatial memory while ventral part is associated to emotion, mood and stress regulation [2]. 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 pyramidal neurons in the CA1 region and dentate gyrus of the dorsal and ventral hippocampus in an animal model of PTSD. In particular we consider HPCWe selected the hippocampus in which the dorsal part is associated to the spatial memory while the ventral part is associated to emotion, mood, and stress regulation [2]. 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 [32]. After sacrifice, the brain was excisedcollected, and Golgi-Cox staining was performed on brain slices [43]. Images were acquired by light microscopy, the dendritic tree was reconstructed, and dendritic spines were counted using Fiji ImageJ software [54]. Results: Female mice are were found to be more susceptible to acute restraint stress compared to males (40% F vs 25.7% M, pPercentages 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 particular, in the dorsal HPC hippocampus tThe dendritic length of female mice is was shorter compared to males. (2-way ANOVA, Bonferroni post hoc, *p<0.05, **p<0.01). In CA1 from the ventral hippocampusHPC, the In CA1, total dendritic length and spines density are were increased selectively in susceptible males and not in females. In DG from the ventral hippocampus, stress decreaseds 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 ve 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 mices have a greater spine density than male control mices. (One-way ANOVA, Tukey’s post-hoc test; *p<0.05, **p<0.01, ***p<0.001) Conclusion: InOur result suggest that in the dorsal hippocampus, differences in dendritic lengths and number of dendritic spines depended mainly on the sex of the animals. InDifferently, in the ventral hippocampus, differences in dendritic lengths and number of dendritic spines 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.