Stress induces equivalent remodeling of hippocampal spine synapses in a simulated postpartum environment and in a female rat model of major depression

Abstract

Stress and withdrawal of female reproductive hormones are known risk factors of postpartum depression. Although both of these factors are capable of powerfully modulating neuronal plasticity, there is no direct electron microscopic evidence of hippocampal spine synapse remodeling in postpartum depression. To address this issue, hormonal conditions of pregnancy and postpartum period were simulated in ovariectomized adult female Sprague-Dawley rats (n=76). The number of hippocampal spine synapses and the depressive behavior of rats in an active escape task were investigated in untreated control, hormone-withdrawn ‘postpa rtum’, simulated proestrus, and hormone-treated ‘postpartum’ animals. After ‘postpartum’ withdrawal of gonadal steroids, inescapable stress caused a loss of hippocampal spine synapses, which was related to poor escape performance in hormone-withdrawn ‘postpartum’ females. These responses were equivalent with the changes observed in untreated controls that is an established animal model of major depression. Maintaining proestrus levels of ovarian hormones during ‘postpartum’ stress exposure did not affect synaptic and behavioral responses to inescapable stress in simulated proestrus animals. By contrast, maintaining pregnancy levels of estradiol and progesterone during ‘postpartum’ stress exposure completely prevented the stress-induced loss of hippocampal spine synapses, which was associated with improved escape performance in hormone-treated ‘postpartum’ females. This protective effect appears to be mediated by a muted stress response as measured by serum corticosterone concentrations. In line with our emerging ‘synaptogenic hypothesis’ of depression, the loss of hippocampal spine synapses may be a novel perspective both in the pathomechanism and in the clinical management of postpartum affective illness.

Reduced Synapse and Axon Numbers in the Prefrontal Cortex of Rats Subjected to a Chronic Stress Model for Depression

“…Results of the sucrose consumption behavioral test were analyzed with a two-way ANOVA (stress × time) followed by Bonferroni’s post hoc test. We used parametric tests for our data analysis because of the following reasons: (1) Other studies quantifying stress-induced synaptic changes also use parametric tests (e.g., Hajszan et al, 2009 ; Nava et al, 2014 ; Baka et al, 2017 ); (2) We had only four animals/group, but in each animal we did 400–500 measurements and the results of these measurements showed normal distribution; (3) Non-parametric tests have very low statistical power when the number of individuals is low.…”

The maternal reward system in postpartum depression

“…These include alterations in the ovarian hormones, estrogen and progesterone, as well as dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis (Glynn et al 2013;Schiller et al 2014). As such, there are models of PPD which employ peripartum-related hormonal manipulations involving either withdrawal from ovarian steroids (Galea et al 2001;Green and Galea 2008;Suda et al 2008;Navarre et al 2010;Schiller et al 2013;Baka et al 2017) or administration of high dose corticosterone postpartum (Brummelte and Galea 2010) as well as other strategies to interfere with HPA axis function (Melón et al 2018).…”

Gestational Folic Acid Administration Alleviated Maternal Postpartum Emotional and Cognitive Dysfunction in Mice

“…Unlike general major depression disorder and cognitive impairment, with pathogenic mechanisms associated with psychosocial stress or neurological injury, postpartum symptoms are often speculated to be caused by hormonal fluctuations (Becker et al, 2016;Brown and Schaffir, 2019). A growing number of studies have shown that hippocampus-related mechanisms are implicated in the pathogenesis of postpartum emotional and cognitive dysfunction (Pawluski and Galea, 2007;Baka et al, 2017). Anatomical hippocampal neurogenesis and synaptic plasticity functional dysregulation have been shown to mediate the presentation of certain types of cognitive or affective dysfunction behaviors (Brummelte and Galea, 2016;Workman et al, 2012).…”