Sex-specific roles of hippocampal microRNAs in stress vulnerability and resilience

Abstract

Contrary to intuition, most individuals are resilient to psychological trauma and only a minority is vulnerable. Men and women are known to respond differently to trauma exposure, however, mechanisms underlying the relationship between sex differences and trauma resilience and vulnerability are not yet fully understood. Taking advantage of the Behavioral Profiling approach, which enables differentiating between ‘affected’ and ‘unaffected’ individuals, we examined sex-associated differences in stress exposure effects on hippocampal expression of selected stress-related GABA-A receptor targeting miRNAs. Levels of the miRNA-144 and miRNA-33 were measured in male and female affected (vulnerable, e.g., higher freezing time) and unaffected (resilient) rats. In male rats, increased levels of miRNA-144 and miRNA-33 were observed in the dorsal dentate gyrus (dDG) and ventral dentate gyrus (vDG) respectively, of stress-exposed but unaffected animals. In females, we observed an increased expression of miRNA-144 and miRNA-33 in the ventral cornu ammonis 1 (vCA1) of affected animals. Accordingly, we inhibited miRNAs expression selectively in hippocampal subregions using oligonucleotides containing locked nucleic acid bases, to examine the miRNAs’ causal contribution to either vulnerability or resilience to stress in each sex. Inhibition of miRNA-144 in dDG and miRNA-33 in vDG in males resulted in an increased prevalence of vulnerable animals, while inhibition of miRNA-144 and miRNA-33 in vCA1 in females increased the proportion of resilient animals. The current findings reveal a critical sex-associated difference in the role of miRNAs in stress vulnerability and resilience. This novel understanding of sex-associated epigenetic involvement in the mechanism of stress-related psychopathologies may help improve gender-specific diagnosis and effective treatment.

Profiling Small RNA From Brain Extracellular Vesicles in Individuals With Depression

“…Our study is one of the first to examine not only potential alterations of miRNAs in both males and females but also brain EVs in the context of depression. Although little is known about sex-specific factors relating to the role of miRNAs in depression ( Hodes et al, 2017 ), sex differences in miRNA regulation in other conditions, such as stress ( Krispil-Alon et al, 2022 ), Tau pathology ( Kodama et al, 2020 ), ASD ( Schumann et al, 2017 ), and schizophrenia ( Ragan et al, 2017 ), have been documented in the brain. Sex-specific transcriptomic dysregulation in the depressed brain has also been reported ( Labonte et al, 2017 ).…”

Recent advances in the role of miRNAs in post-traumatic stress disorder and traumatic brain injury

“…Meanwhile, both symptoms of PTSD and TBI can vary upon time. PTSD symptoms gradually fade away but can be evoked given exposure to certain events and depend on the resilience of the patient, which is a dynamic process that has recently been found to be associated with the expression of specific miRNAs in certain brain hippocampal regions [ 143 ]. Emerging evidence has suggested that miRNAs could be highly involved in the resilience process [ 144 , 145 ].…”