Functional Genomic and Proteomic Analysis Reveals Disruption of Myelin-Related Genes and Translation in a Mouse Model of Early Life Neglect

Becky C Carlyle,Arthur A Simen,Angus C Nairn,Thomas B Abbott,Robert R Kitchen,Tukiet T Lam,Shrikant M Mane,Alvaro Duque,Christopher M Colangelo,Kathryn L Stone,Elizabeth D George,Kelly A Bordner

doi:10.3389/fpsyt.2011.00018

Abstract

Early life neglect is an important public health problem which can lead to lasting psychological dysfunction. Good animal models are necessary to understand the mechanisms responsible for the behavioral and anatomical pathology that results. We recently described a novel model of early life neglect, maternal separation with early weaning (MSEW), that produces behavioral changes in the mouse that persist into adulthood. To begin to understand the mechanism by which MSEW leads to these changes we applied cDNA microarray, next-generation RNA-sequencing (RNA-seq), label-free proteomics, multiple reaction monitoring (MRM) proteomics, and methylation analysis to tissue samples obtained from medial prefrontal cortex to determine the molecular changes induced by MSEW that persist into adulthood. The results show that MSEW leads to dysregulation of markers of mature oligodendrocytes and genes involved in protein translation and other categories, an apparent downward biasing of translation, and methylation changes in the promoter regions of selected dysregulated genes. These findings are likely to prove useful in understanding the mechanism by which early life neglect affects brain structure, cognition, and behavior.

Highlights

Child neglect is currently the most prevalent form of child maltreatment in the United States, accounting for close to half of all childhood maltreatment fatalities (Us-Government-Report, 2008)
We recently described a novel model of early life neglect, maternal separation with early weaning (MSEW), that produces behavioral changes in the mouse that persist into adulthood
The results show that MSEW leads to dysregulation of markers of mature oligodendrocytes and genes involved in protein translation and other categories, an apparent downward biasing of translation, and methylation changes in the promoter regions of selected dysregulated genes

Summary

Introduction

Child neglect is currently the most prevalent form of child maltreatment in the United States, accounting for close to half of all childhood maltreatment fatalities (Us-Government-Report, 2008). A fully comprehensive evaluation of the molecular changes that occur following early life neglect has not yet been performed. This task, which would significantly enhance the understanding of the consequences of early life neglect, requires the use of an adequate animal model. Mice subjected to MSEW exhibit consistent, long lasting behavioral hyperactivity, and altered emotionality that persists well into adulthood (George et al, 2010)

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