Sex-dependent effects of maternal corticosterone and SSRI treatment on hippocampal neurogenesis across development

Abstract

BackgroundPostpartum depression affects approximately 15% of mothers and represents a form of early life adversity for developing offspring. Postpartum depression can be treated with prescription antidepressants like fluoxetine (FLX). However, FLX can remain active in breast milk, raising concerns about the consequences of neonatal FLX exposure. The hippocampus is highly sensitive to developmental stress, and males and females respond differently to stress at many endpoints, including hippocampal plasticity. However, it is unclear how developmental exposure to FLX alters the trajectory of hippocampal development. The goal of this study was to examine the long-term effects of maternal postpartum corticosterone (CORT, a model of postpartum depression) and concurrent FLX on hippocampal neurogenesis in male and female offspring.MethodsFemale Sprague-Dawley rat dams were treated daily with either CORT or oil and FLX or saline from postpartum days 2–23. Offspring were perfused on postnatal day 31 (pre-adolescent), postnatal day 42 (adolescent), and postnatal day 69 (adult). Tissue was processed for doublecortin (DCX), an endogenous marker of immature neurons, in the dorsal and ventral hippocampus.ResultsMaternal postpartum CORT reduced density of DCX-expressing cells in the dorsal hippocampus of pre-adolescent males and increased it in adolescent males, suggesting that postpartum CORT exposure disrupted the typical progression of the density of DCX-expressing cells. Further, among offspring of oil-treated dams, pre-adolescent males had greater density of DCX-expressing cells than pre-adolescent females, and maternal postpartum CORT prevented this sex difference. In pre-adolescent females, maternal postpartum FLX decreased the density of DCX-expressing cells in the dorsal hippocampus compared to saline. As expected, maternal CORT reduced the density of DCX-expressing cells in adult female, but not male, offspring. The combination of maternal postpartum CORT/FLX diminished density of DCX-expressing cells in dorsal hippocampus regardless of sex or age.ConclusionsThese findings reveal how modeling treatment of postpartum depression with FLX alters hippocampal neurogenesis in developing offspring differently depending on sex, predominantly in the dorsal dentate gyrus and earlier in life.

Maternal Folic Acid Supplementation During Pregnancy Promotes Neurogenesis and Synaptogenesis in Neonatal Rat Offspring

“…In rats, the layers of the cerebral cortex start to form around embryonic day (E) 15, and the newly generated neurons migrate from the ventricular surface to cortical layers during this period and subsequently continue dendritic maturation and synaptogenesis throughout gestation (Fletcher et al 2017). However, the hippocampus undergoes continued neurogenesis after birth to generate the majority of dentate gyrus granule neurons (Gobinath et al 2017;Sourial and Doering 2017), and the fully Figure 1. Flow chart for the experimental design with maternal diet.…”

“…and (4) folate-supplemented diet long-period (FD-L) group fed the folate-supplemented diet from 1 week before mating until the end of pregnancy. matured form of hippocampus was not developed until weaning (Gobinath et al 2017). Thus, the hippocampus and cerebral cortex were used to detect neurogenesis and synaptogenesis in neonatal offspring, respectively.…”

Antidepressant-like effects of Dipyrone researched with forced swim test

“…Depresyon tedavisinde kullanılan selektif serotonin reuptake inhibitörü fluoksetinin, serotonin düze-yinde artmaya neden olmasının yanı sıra yükselen sitokin düzeylerini azalttığı ve beyinde neurorejenerasyonu sağladığı böylece antidepresan etkinliğinin olduğu bildirilmektedir 31,32 . Selekoksib, asetil salisilik asit, parasetamol gibi çeşitli analjezik ilaçların da serotonin seviyesini artırdığı, IL6 ve TNFα gibi sitokinlerin düzeyinin azalttığı yapılan çalışmalarla gösterilmiştir 30,31,33 .…”

Folic acid, but not folate, regulates different stages of neurogenesis in the ventral hippocampus of adult female rats

“…Here, we provide the number of DCX‐expressing cells and the morphology of those cells to determine whether morphological phenotype differs with dietary condition. Immunohistochemistry for DCX was conducted as described previously . Briefly, sections were rinsed 5 × 10 minutes in 0.1 mol L ‐1 phosphate‐buffered saline (PBS), treated with 0.3% hydrogen peroxide in dH 2 O for 30 minutes and incubated at 4°C in primary antibody solution: goat anti‐DCX (sc‐8066; dilution 1:1000; Santa Cruz Biotechnology, Santa Cruz, CA, USA) with 0.04% Triton‐X in PBS and 3% normal rabbit serum for 24 hours.…”

“…Immunohistochemistry for DCX was conducted as described previously. 43,44 Briefly, sections were rinsed 5 × 10 min- Finally, sections were developed using diaminobenzidine in the presence of nickel (DAB Peroxidase Substrate Kit; Vector Laboratories), mounted on slides and dried. Sections were then counterstained with cresyl violet, dehydrated, and cover-slipped with Permount (Fisher Scientific Co., Pittsburgh, PA, USA).…”