Sex differences in associations between maternal deprivation and alterations in hippocampal calcium-binding proteins and cognitive functions in rats

Hongyu Xu,Zhou Fei,Zhiqiang Yan,Yelu Hao,Guohao Yuan,Fei Shi,Yuqin Ye,Xiaosheng He,Yuefan Yang

doi:10.1186/s12993-018-0142-y

Abstract

Background and objectiveAdverse early-life experiences have been suggested as one of the key contributors to neurodevelopmental disorders, such that these experiences influence brain development, cognitive ability and mental health. Previous studies indicated that hippocampal levels of the calcium-binding proteins calretinin (CALR) and calbindin-D28k (CALB) changed in response to maternal deprivation (MD), a model for adverse early-life experiences. We investigated the effects of MD on hippocampal CALR and CALB protein levels and cognitive behaviors, and explored whether these effects were sex-related.MethodsFrom postnatal day 2 (PND-2) to PND-14, rat pups in the MD group were separated from their mothers for 3 h/day for comparison with pups raised normally (control). To determine hippocampal CALR and CALB levels, fluorescent immunostaining of hippocampal sections and Western blot analysis of hippocampal tissues were employed at various timepoints (PND-21, -25, -30, -35 and -40). Behavioral and cognitive changes were determined by open field test (PND-21) and Morris water maze (PND-25).ResultsWestern blot analysis showed changes in the hippocampal CALR and CALB levels in both male and female MD groups, compared with controls. The open field test showed reduced exploration only in male MD groups but not female MD groups. The Morris water maze tests indicated that MD caused spatial memory impairment both in male and female rats, but there was a sex difference in CALR and CALB levels.ConclusionsMale rats are relatively more vulnerable to MD stress than female rats, but both male and female rats demonstrate spatial learning impairment after exposure to MD stress. Sex difference in CALR and CALB levels may reveal the different mechanisms behind the behavioral observations.

Highlights

Background and objectiveAdverse early-life experiences have been suggested as one of the key contributors to neurodevelopmental disorders, such that these experiences influence brain development, cognitive ability and mental health
Hippocampal CALR from postnatal day (PND)‐21 to PND‐35 On PND-21, abundant CALR protein was observed in the dentate gyrus of the hippocampus in both the maternal deprivation (MD) and control groups (Fig. 1)
In the male rats of the MD and control groups, the hippocampal CALR levels were at maximum on PND-25 and PND-30, respectively

Summary

Introduction

Adverse early-life experiences have been suggested as one of the key contributors to neurodevelopmental disorders, such that these experiences influence brain development, cognitive ability and mental health. Previous studies indicated that hippocampal levels of the calcium-binding proteins calretinin (CALR) and calbindin-D28k (CALB) changed in response to maternal deprivation (MD), a model for adverse early-life experiences. Life experiences have a profound influence on the development of the central nervous system (CNS) and endocrine system, and have been suggested as a key contributor to neurodevelopmental disorders [11, 12]. Adverse life events during early life have been shown to lead to changes in the hypothalamic–pituitary–adrenal (HPA) axis and cause high-anxiety-like behavior and memory impairment [12,13,14,15]. The effects can even persist throughout life [16, 17]

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