Exposure of Hyperandrogen During Pregnancy Causes Depression- and Anxiety-Like Behaviors, and Reduced Hippocampal Neurogenesis in Rat Offspring

Abstract

The hippocampus is a region in which neurogenesis persists and retains substantial plasticity throughout lifespan. Accumulating evidences indicate an important role of androgens and androgenic signaling in the regulation of offspring hippocampal neurogenesis and the survival of mature or immature neurons and gliocyte. Hyperandrogenic disorders have been associated with depression and anxiety. Previous studies have found that pregnant hyperandrogenism may increase the susceptibility of the offspring to depression or anxiety and lead to abnormal hippocampal neurogenesis in rats. In this study, pregnant rats were given subcutaneous injection of aromatase inhibitor letrozole in order to establish a maternal hyperandrogenic environment for the fetal rats. The lithium chloride (LICl) was used as an intervention agent since a previous study has shown that lithium chloride could promote neurogenesis in the hippocampus. The results revealed that pregnant administration of letrozole resulted in depressive- and anxious-like behaviors in the adolescent period. A remarkable decrease in immature nerve cells marked by doublecortin and mature neurons co-expressed by Brdu and NeuN in adult years were detected in the hippocampal dentate gyrus of adolescent rats. Lithium chloride alleviated the effects on neurobehavioral and promoted the differentiation and proliferation of neural progenitor cells, while a hyperandrogenic intrauterine environment had no effects on astrocytes marked by GFAP in the dentate gyrus. Furthermore, the Wnt/β-catenin signaling pathway related to normal development of hippocampus was examined but there was no significant changes in Wnt signaling pathway members. Our study provides evidence that exposure of androgen during pregnancy leads to alterations in depressive, anxious and stereotypical behaviors and these phenotypes are possibly associated with changes in neurogenesis in the dentate gyrus.

Chronic d-ribose and d-mannose overload induce depressive/anxiety-like behavior and spatial memory impairment in mice

“…The multi-functional enrichment analysis indicated that the effects of RIB were implicated in the Wnt signaling pathway and TCF7L2. It has been reported that the TCF7L2 is a key transcriptional effector of the Wnt signaling pathway 50 , which is linked to psychiatric diseases and AD 51 , 52 . Based on the metabolite–gene network analysis, RIB induced depressive- and anxiety-like behavior and spatial memory impairment might be mediated by the insulin-POMC-MEK-TCF7L2 pathway.…”

Maternal aromatase inhibition via letrozole altered RFamide-related peptide-3 and gonadotropin releasing hormone expression in pubertal female rat

“…Decreased Gnrh gene expression as a result of prenatal letrozole treatment in female rats was proved in this study for the rst time. In a similar study, pregnant treatment of letrozole in rats caused depression and anxiety-like behaviors due to decreased neurogenesis in hippocampus (17). Letrozole induced mouse model of PCOS showed increased expression of gonadotropin releasing hormone receptor (Gnrhr) in the pituitary, that was not reversible by utamide treatment (18).…”

“…Taken together, given that intrauterine hyperandrogenic environment is a critical etiological agent in neurodevelopmental diseases and also hyperandrogenism status in PCOS women, such studies are very important for evaluating PCOS neuroendocrine and neuro-behavior abnormalities (17). Although in our study addressing to main purpose of assessing neuroendocrine changes speci c to PCOS was not straightforward, but this study is a background for future assessments.…”

Neurobehavioral alternations of the female offspring born to polycystic ovary syndrome model rats administered by Chinese herbal medicine

“…In addition, this study explored the effect of BSTJF on the neurological alteration of female offspring born to PCOS model rats. As the dentate gyrus in the hippocampus has an essential role in spatial behavior [ 72 ] and the depression, anxiety and stereotypical behavior of offspring caused by androgen exposure during pregnancy may also be related to changes in the dentate gyrus [ 73 ], our morphological observation focused only on the dentate gyrus. BSTJF affects the behavior of offspring at 5 weeks of age and these effects disappeared at 13 weeks of age; however, the effects on the expression of hippocampal dendritic spines and related receptor proteins were still present.…”