Ovarian hormones modify anxiety behavior and glucocorticoid receptors after chronic social isolation stress

Abstract

Chronic social isolation could lead to a disruption in the Hypothalamic-Pituitary-Adrenal (HPA) axis, resulting in anxiety and depressive-like behaviors but cycling estrogens could modify these behaviors. The aim of this study was to determine if changes in ovarian hormones during the normal cycle could interact with social isolation to alter anxiety and depressive-like behaviors. In parallel, we examined the expression of glucocorticoid receptor (GR) and synaptic vesicle protein synaptophysin in the hippocampus and hypothalamus of Sprague Dawley normal cycling female rats. We assigned rats to either isolated or paired housing for 8 weeks. To assess anxiety and depressive-like behaviors, we used the open field test and forced swim test, respectively. Female rats were tested at either diestrus, estrus, or proestrus stage of the estrous cycle. After behaviors, rats were perfused and brains collected. Brain sections containing hippocampus and hypothalamus were analyzed using immunohistochemistry for synaptophysin and glucocorticoid receptor (GR) levels. We found an increase in depressive-like behaviors for isolated animals compared to paired housed rats, regardless of the estrous cycle stage. Interestingly, we found a decrease in anxiety behaviors in females in the estrus stage accompanied by a decrease in GR expression in hippocampal DG and CA3. However, no changes in synaptophysin were observed in any of the areas of studied. Our results support the beneficial effects of circulating ovarian hormones in anxiety, possibly by decreasing GR expression.

Maternal Deprivation Increases Anxiety- and Depressive-Like Behaviors in an Age-Dependent Fashion and Reduces Neuropeptide Y Expression in the Amygdala and Hippocampus of Male and Female Young Adult Rats

“…All behavioral assessments in females were carried out during the estrous phase, which, together with proestrous, is characterized by lesser anxiety-like profile among the phases of the cycle. For instance, female rats in estrous behave similarly to males in the elevated T maze ( Gouveia et al, 2004 ) and EPM ( Marcondes et al, 2001 ), whereas in the open field, they are less anxious than in the other phases of the cycle ( Ramos-Ortolaza et al, 2017 ). Interestingly, females tested in the EPM and in the punished conflict test are less anxious and more responsive to NPY anxiolytic effect in late proestrous than in metestrous ( Molina-Hernández et al, 2006 ).…”

“…Comparing all estrous phases in the punished conflict test, it has been observed that during late proestrous and estrous, females are less anxious and more responsive to diazepam than in metestrous and diestrous ( Molina-Hernández et al, 2001 ). Data regarding depressive-like behavior, on the other hand, seem to be controversial; on the one hand, neither the FST ( Ramos-Ortolaza et al, 2017 ) nor the saccharin preference test ( Borrow and Cameron, 2017 ) is influenced by the estrous cycle. On the other hand, findings show that female hormones protect ovariectomized animals in tests of depressive-like behavior ( Bredemann and McMahon, 2014 ; Ibrahim et al, 2016 ).…”

“…This age range was chosen because in humans, this period seems to mark the onset of manifestations of emotional problems ( Patten et al, 2006 ) and females were tested during the estrous phase; from PND 52 on, vaginal smears were collected and the female was tested once estrous phase was detected. This phase of the cycle was chosen because, together with proestrous, females display less anxiety-like behavior in classical tests ( Marcondes et al, 2001 ; Ramos-Ortolaza et al, 2017 ) and in diestrous, females show more depressive-like behavior ( Walf and Frye, 2010 ). Moreover, during diestrous and metestrous, when estradiol levels are low, females behave more similarly to males ( ter Horst et al, 2012 ), hindering possible sex differences.…”

Stress as a potential moderator of ovarian hormone influences on binge eating in women

“…Specifically, ovarian hormones regulate HPA-axis functioning via antagonistic effects on glucocorticoids 87 . At high levels of estradiol, as in ovarian hormone regulation of eating behavior, glucocorticoid receptor levels are decreased 88 , HPA-axis responsivity is enhanced 18 , and animals exhibit fewer stress-like (for example, anxiety) behaviors 88, 89 . Conversely, when either progesterone alone or both ovarian hormones are elevated, glucocorticoid levels increase 90– 92 , HPA-axis activity decreases 18 , and animals exhibit more stress-like behaviors 88 .…”

d-Serine administration affects nitric oxide synthase 1 adaptor protein and DISC1 expression in sex-specific manner

“…The estrous cycle time points during which drug administration occurs may interact with the main effects of these drugs on the expression of these proteins. Estrogen fluctuations throughout the estrous cycle influence expression of various synaptic proteins in vivo (Ramos-Ortolaza et al, 2017; Sarkar and Kabbaj, 2016; Tada et al, 2015). Hormones, such as estrogen, may be involved in the regulation of treatment response and thus subsequently affect treatment-mediated expression of NOS1AP, DISC1, and D2 receptor in female rats.…”