Perinatal Malnutrition Leads to Sexually Dimorphic Behavioral Responses with Associated Epigenetic Changes in the Mouse Brain

Daniel Nätt,Eric J Nestler,Jian Feng,Josef Murad,Annika Thorsell,Frances A Champagne,Riccardo Barchiesi

doi:10.1038/s41598-017-10803-2

Abstract

Childhood malnutrition is a risk factor for mental disorders, such as major depression and anxiety. Evidence shows that similar early life adversities induce sex-dependent epigenetic reprogramming. However, little is known about how genes are specifically affected by early malnutrition and the implications for males and females respectively. One relevant target is neuropeptide Y (NPY), which regulates both stress and food-intake. We studied maternal low protein diet (LPD) during pregnancy/lactation in mice. Male, but not female, offspring of LPD mothers consistently displayed anxiety- and depression-like behaviors under acute stress. Transcriptome-wide analysis of the effects of acute stress in the amygdala, revealed a list of transcription factors affected by either sex or perinatal LPD. Among these immediate early genes (IEG), members of the Early growth response family (Egr1/2/4) were consistently upregulated by perinatal LPD in both sexes. EGR1 also bound the NPY receptor Y1 gene (Npy1r), which co-occurred with sex-specific effects of perinatal LPD on both Npy1r DNA-methylation and gene transcription. Our proposed pathway connecting early malnutrition, sex-independent regulatory changes in Egr1, and sex-specific epigenetic reprogramming of its effector gene, Npy1r, represents the first molecular evidence of how early life risk factors may generate sex-specific epigenetic effects relevant for mental disorders.

Highlights

Y1 and presynaptic Y2 receptors in specific sub-nuclei is believed to control the anxiolytic effects of NPY25
This finding was mirrored in the open-field, where activity in the center was significantly reduced in male offspring from low protein diet (LPD) dams compared to control offspring, while there was no effect in females exposed to perinatal LPD (Fig. 1D)
We present a novel link between epigenetic reprogramming by early life adversity, in the form of perinatal low protein diet (LPD), and neuropeptide Y (NPY)-dependent stress-regulation in the rodent brain

Summary

Introduction

Y1 and presynaptic Y2 receptors in specific sub-nuclei is believed to control the anxiolytic effects of NPY25. Expression of NPY and its receptors are regulated via several stress-related transcription factors, such as the glucocorticoid receptor[28, 29] and immediate early genes (IEGs)[30]. Several IEGs are known to regulate networks of effector genes involved in neural activation and plasticity[37] Among these are the Fos-family transcription factors (e.g. cFos, Fosb), as well as the early growth response elements (Egr[1, 2, 3, 4]). Studying the epigenetic landscapes at relevant IEG effector genes, in brain regions known to control anxiety (e.g. amygdala and hypothalamus), may be an effective strategy for disentangling the molecular events involved in the neurodevelopmental effects following perinatal malnutrition. To account for sex-dependent effects, we included both male and female offspring in the study

Methods

Results

Conclusion