Investigating the Effects of Maternal Separation on Hypothalamic-Pituitary-Adrenal Axis and Glucose Homeostasis under Chronic Social Defeat Stress in Young Adult Male Rat Offspring

Abstract

Introduction: Given the suggested metabolic regulatory effects of stress-responsive genes and based on the impacts of early life stress on HPA axis development, this study aimed to characterize the maternal separation (MS) impact on the communication between glucose metabolism and HPA axis dysregulations under chronic social defeat stress (CSDS). Methods: During the first two weeks of life, male Wistar rats were either exposed to MS or left undisturbed with their mothers (Std). Starting on postnatal day 50, the animals of each group were either left undisturbed in the standard group housing (Con) or underwent CSDS for three weeks. There were four groups (n=10/group): Std-Con, Ms-Con, Std-CSDS, and MS-CSDS. Results: Early-and/or adult life adversity reduced β-cell number, muscular FK506-binding protein 51 (FKBP51) content, and BMI in adulthood. The reduction of β-cell number and BMI in the MS-CSDS rats were more profound than MS-Con group. CSDS either alone or in combination with MS reduced locomotor activity and increased and decreased corticotropin-releasing factor type 1 receptor (CRFR1) content respectively in hypothalamus and pancreas. Although, under CSDS, MS intensified HPA axis overactivity and reduced isolated islets’ insulin secretion, it could promote resilience to depression symptoms. No differences were observed in hypothalamic Fkbp5 gene DNA methylation and glucose tolerance among groups. Conclusion: MS exacerbated HPA axis overactivity and the endocrine pancreas dysfunctions under CSDS. The intensified corticosterone secretion and the diminished content of pancreatic CRFR1 protein could be involved in the reduced β-cell number and islets’ insulin secretion under CSDS. The decreased muscular FKBP51 protein content might be a homeostatic response to slow down insulin resistance development under chronic stress.