Sex differences in hypothalamic–pituitary–adrenal axis regulation after chronic unpredictable stress

Abstract

Introduction: Exposure to stress, mediated through the hypothalamic-pituitary-adrenal (HPA) axis, elicits sex differences in endocrine, neurological, and behavioral responses. However, the sex-specific factors that confer resilience or vulnerability to stress and stress-associated psychiatric disorders remain largely unknown. The evident sex differences in stress-related disease prevalence suggest the underlying differences in the neurobiological underpinnings of HPA axis regulation. Method:Here, we used a chronic unpredictable stress (CUS) model to investigate the behavioral and biochemical responses of the HPA axis in C57BL/6 mice. Animals were tested in the open field and forced swim test to examine anxiety-like and depressivelike behaviors. Plasma corticosterone levels were measured after behavior and CUS, and glucocorticoid receptor (GR) expression and cytosolic and nuclear fractions of binding protein FKBP51 expression were taken to measure function and regulation of the stress response. Results:Our results indicate increased depressive-like behavior in males and females which correlated with increased corticosterone levels following CUS. However, females displayed more anxiety-like behaviors with and without CUS. Interestingly, we found trends toward dysregulation of GR protein expression in CUS females, and an increase in the GR inhibitory protein, FKBP51, in the cytosol of CUS males but not females. Conclusion:These results suggest biochemical alterations to the HPA axis regulation which may elicit a glucocorticoid resistance in females after chronic stress and may contribute to the sex-biased vulnerability to stress-related psychiatric disorders. K E Y W O R D Schronic stress, FKBP51, glucocorticoid receptor, HPA axis, sex differences

From Obesity to Hippocampal Neurodegeneration: Pathogenesis and Non-Pharmacological Interventions

“…Obese and diabetic animals show depression-like behaviors [ 90 , 91 , 92 ], which could be partly contributed by impaired hippocampal adult neurogenesis [ 93 , 94 , 95 ]. Both rodent models of depression [ 96 , 97 , 98 , 99 ] and diabetes [ 100 , 101 , 102 ] have shown a hyper-activated hypothalamic-pituitary-adrenal (HPA) axis, resulting in elevated glucocorticoid levels in response to stressors. The hippocampus exerts inhibitory feedback control to the activation of the HPA axis through GABAergic innervation to the paraventricular nucleus (PVN) of the hypothalamus [ 103 , 104 , 105 ].…”

Small intestinal flora graft alters fecal flora, stool, cytokines and mood status in healthy mice

“…Both singly housing and repeated intragastric administration procedure caused slight stress. Female C57Bl/6 mice are more susceptive to stress-induced neurobehavioral alterations, such as dysregulation of the HPA axis, whereas male C57Bl/6 mice were reported to be of more resilience ( Hodes et al, 2015 ; Marchette et al, 2018 ; Palumbo et al, 2020 ). Given that the current study aimed at comparing the effects of SIMT and LIMT in healthy host or under physiological condition, only male C57Bl/6 mice thus were used in our study.…”

Sex Differences in Anxiety and Depression: What Can (and Cannot) Preclinical Studies Tell Us?

“…Normal-cycling C57BL/6J female mice exhibited greater exploratory behavior but less time in the center of the OFT than male mice; however, when subjected to a chronic unpredictable stress paradigm, both male and female mice presented greater immobility time in the FST and an increase in basal corticosterone levels. However, only stressed female mice had reduced levels of hippocampal and hypothalamic glucocorticoid receptor, and only stressed male mice had higher cytoplasmatic levels of the co-chaperone protein, FKBP51, in the cortex, indicating a sex difference in HPA axis regulation [46]. Dong et al (2020) [67] have shown a different regulation of the HPA axis and vulnerability to developing a depressive and anxiety-like phenotype between male and normalcycling female mice after chronic isolation and restraint stress.…”

“…There are some conflicting results with respect to behavioral outcomes in the OFT that seem to depend on the species, strain, or the pre-evaluation treatment of the animals used. Some studies found males rearing Sexes 2022, 3 146 more than females [43], but equivalent time in the center or exploratory behavior [37,44,45], while others found that females expressed less anxiety-like behavior than males, more exploration [32,[46][47][48], or spent more time in the center [32,39]. The reverse was also found, with males spending more time at the center [46,47].…”

“…Regarding the effect of estrous cycle on depressive-like behavior, Kokras et al ( 2015) [46] found that adult female Wistar rats exhibited higher levels of immobility in the FST than males, and that the phase of the estrous cycle did not affect the sex difference observed. Remarkably, they showed no association of gonadal hormones and FST behavioral performance, suggesting an organizational gonadal hormone effect [57].…”