Corticotropin-Releasing Hormone and Pro-Opiomelanocortin Gene Expression in Female Monkeys with Differences in Sensitivity to Stress

Abstract

Background/Aims: The expressions of corticotropin-releasing hormone (CRH) and pro-opiomelanocortin (POMC) were assessed in brain tissue collected from nonstressed female cynomolgus monkeys previously categorized as highly stress resilient (HSR), medium stress resilient (MSR), or stress sensitive (SS) with respect to stress-induced anovulation. Methods: In situ hybridization and quantitative image analysis was used to measure mRNAs coding for CRH in the hypothalamic paraventricular nucleus (PVN) and thalamic center median-subfascicular complex (CM-Sf). Then, CRH neurons in the PVN were immunostained and the area of immunostaining was measured. Also, CRH fibers were immunostained in the central nucleus of the amygdala and the area of immunostaining was obtained. Finally, POMC mRNA expression was characterized in the hypothalamic infundibular nucleus. The groups were compared with ANOVA and Student-Newman-Keul’s (SNK) post hoc comparison. Results: CRH mRNA was significantly elevated in the caudal PVN in the MSR and SS animals compared to HSR animals (p < 0.05, SNK). There was a significant increase in average and total CRH-positive area in the MSR and SS groups compared to the HSR group (p < 0.05, SNK). There was also a significant increase in CRH volume in the MSR and SS groups compared to the HSR group (p < 0.05, SNK). In the CM-Sf, the average CRH optical density was significantly higher in the MSR and SS groups than in the HSR group (p < 0.05, SNK). In the central nucleus of the amygdala, the area of CRH fiber staining was significantly higher in the SS group than in the MSR or HSR groups (p < 0.05, SNK). There was no difference between the groups in POMC mRNA expression in the mediobasal hypothalamus. Conclusion: Macaques that exhibit immediate suppression of reproductive function upon stress are considered stress sensitive. These animals have elevated CRH in the hypothalamus and limbic structures, which may play a role in suppressing the hypothalamic-gonadal axis upon stress initiation.

Interactions of Corticotropin-Releasing Factor, Urocortin and Citalopram in a Primate Model of Stress-Induced Amenorrhea

“…The CRF innervation of the dorsal raphe is believed to originate in the caudal portion of the PVN and in the amygdala, where we had previously observed an increase in CRF in SS individuals relative to SR individuals [13]. This difference was reflected in the CRF fiber density in the dorsal raphe of the Pb-treated animals.…”

“…More recently, gynecologists have recognized that individual differences in stress sensitivity play a role in the pathology of infertility [4,40]. We have previously shown that monkeys who are sensitive to stress-induced amenorrhea exhibit significantly more CRF mRNA and CRF protein in the caudal region of the PVN, significantly more CRF mRNA in the thalamus and a significantly higher CRF fiber density in the central nucleus of the amygdala relative to stress-resilient animals under nonstressed basal conditions [13]. In contrast, rodent strains with different sensitivities to stress exhibit no difference in hypothalamic CRF expression [41].…”

“…We also found a significant increase in corticotropin-releasing factor (CRF) gene and protein expression in the hypothalamic paraventricular nucleus (PVN) of SS individuals compared to HSR individuals [13]. In many stressful situations, the hypothalamic-pituitary-adrenal axis becomes activated with increases in CRF, adrenocorticotropic hormone and cortisol, and CRF may inhibit GnRH release [14,15,16].…”

Sensitivity to stress-induced reproductive dysfunction is associated with a selective but not a generalized increase in activity of the adrenal axis

“…This finding does not support the hypothesis that SS monkeys have elevated chronic basal activity of the HPA axis. We had explored this hypothesis in part because we had reported previously that both MSR and SS monkeys have increased CRH gene expression in the caudal paraventricular nucleus (PVN), amygdala, and thalamus compared with HSR monkeys (18). Both glucocorticoids and CRH itself have been shown to be capable of suppressing reproductive axis activity in some circumstances.…”

Social Subordination and Polymorphisms in the Gene Encoding the Serotonin Transporter Enhance Estradiol Inhibition of Luteinizing Hormone Secretion in Female Rhesus Monkeys1

“…Previous studies show that female rhesus monkeys that are most reactive to stress are characterized by diminished serotonergic (5HT) activity, evidenced by reduced response to the 5HT transporter (5HTT) inhibitor-5HT releaser fenfluramine [13], reduced expression for the genes encoding the 5HTT (SLC6A4) and monoamine oxidase A (MAOA) in the dorsal raphe [14], and reduced 5HT receptor expression in the paraventricular nucleus of hypothalamus and infundibulum [15], and greater corticotropin-releasing hormone (CRH) expression in limbic-hypothalamic regions [16]. Diminished 5HT function is associated with traitlike disinhibition of behavior in response to social adversity, including increased impulsivity and aggression as well as poor regulation of affect [17,18].…”