Ovarian steroid regulation of the midbrain corticotropin releasing factor and urocortin systems in macaques

Abstract

A significant number of postmenopausal women report increased anxiety and vulnerablity to stress, which has been linked to decreased secretion of ovarian steroids. Communication between the serotonin system and the CRF system determines stress sensitivity or resilience. This study examines the effects of the ovarian steroids, estradiol (E) and progesterone (P) on the CRF system components that impact serotonin neurons in the midbrain of nonhuman primates. Ovariectomized rhesus macaques were treated with placebo, E alone for one month, or E supplemented with P for the last 2 weeks. Quantitative (q)RT-PCR and immunocytochemistry were employed. E±P treatment decreased CRF-R1 and increased CRF-R2 gene expression in hemi-midbrain blocks and in laser captured serotonin neurons. Also in hemi-midbrains, E treatment increased UCN1 and CRFBP gene expression, but supplemental P treatment reversed these effects. E±P suppressed the already very low UCN3 mRNA, but had no effect on UCN2 mRNA. E±P decreased CRF fiber density in the dorsal, interfascicular and median raphe nuclei and decreased CRF-R1 immunostaining in the dorsal raphe. E increased CRF-R2 immunostaining in the dorsal and median raphe. E±P increased UCN1 immunostaining in the cell bodies and increased UCN1 fiber density in the caudal linear nucleus. ERβ, but not ERα was detected in the nucleus of UCN1-positive neurons. While the mechanism of ovarian hormone regulation of the midbrain CRF system requires further investigation, these studies clearly demonstrate another pathway by which ovarian hormones may have positive effects on anxiety and mood regulation.

Effects of citalopram on serotonin and CRF systems in the midbrain of primates with differences in stress sensitivity

“…Thus, it has been generalized that activation of CRF-R1 by CRF increases anxiety-like behavior whereas activation of CRF-R2 by UCN1 decreases anxiety-like behavior. CRF-R1 and R2 receptors are present in the dorsal raphe of macaques (Sanchez et al, 2010). Therefore, we hypothesized that UCN1 fiber density would be lower in SS animals and that CIT would increase UCN1 fiber density.…”

“…CRF receptors have been detected in the raphe of rodents (Chalmers et al, 1995, Van Pett et al, 2000) and primates (Sanchez et al, 2010). The opposing effects of CRF and UCN on serotonin were established in rodents.…”

The role of CRF family peptides in the regulation of food intake and anxiety-like behavior

“…By contrast, steroids increase serotonin effects in the brain by acting through the CRF system, which include decreased CRF transport to serotonin neurons and decreased CRFR1 expression, in conjunction with an increase in UCN1 transported caudally and an increase in CRFR2 and CRF-binding protein expression. As a result, the increase in serotonin action elevates mood, increases stress resistance, and decreases anxiety (32). Nevertheless, CRF-deficient mice display normal behavioral responses to stressors (33).…”

The effect of long-term ovariectomy on midbrain stress systems in free ranging macaques

“…All of these actions could translate to improved mood and stress resilience in women. In addition, we found that administration of E or E+P to ovariectomized macaques decreased CRF gene and protein expression in the PVN of macaques (Bethea and Centeno, 2008), decreased CRF innervation of the dorsal and median raphe, decreased CRF-R1 receptors and increased CRF-R2 receptors in the dorsal raphe, increased detectable midbrain urocortin (UCN1) cell number and increased UCN1 fiber densitiy (Sanchez et al, 2010). Together these data suggest that ovarian hormone administration may improve stress resilience through the serotonin, CRF and UCN systems.…”