Early life stress alters transcriptomic patterning across reward circuitry in male and female mice

Catherine Jensen Peña,Milo Smith,Joel Dudley,Li Shen,Austin B Chang,Hannah M Cates,Eric J Nestler,Bhakti Patel,Aarthi Ramakrishnan,Rosemary C Bagot,Hope G Kronman,Hirofumi Morishita,Immanuel Purushothaman

doi:10.1038/s41467-019-13085-6

Abstract

Abuse, neglect, and other forms of early life stress (ELS) significantly increase risk for psychiatric disorders including depression. In this study, we show that ELS in a postnatal sensitive period increases sensitivity to adult stress in female mice, consistent with our earlier findings in male mice. We used RNA-sequencing in the ventral tegmental area, nucleus accumbens, and prefrontal cortex of male and female mice to show that adult stress is distinctly represented in the brain’s transcriptome depending on ELS history. We identify: 1) biological pathways disrupted after ELS and associated with increased behavioral stress sensitivity, 2) putative transcriptional regulators of the effect of ELS on adult stress response, and 3) subsets of primed genes specifically associated with latent behavioral changes. We also provide transcriptomic evidence that ELS increases sensitivity to future stress through enhancement of known programs of cortical plasticity.

Highlights

Abuse, neglect, and other forms of early life stress (ELS) significantly increase risk for psychiatric disorders including depression
Using RNA-sequencing, we asked whether Early life stress (ELS) in male and female mice alters patterns of gene transcription in the brain’s reward circuitry, including ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC), all of which are implicated in stress responses and human depression
There was an interaction between ELS and sub-threshold variable stress (STVS) on latency to eat (Fig. 1b) and on the ratio of latency to eat in a novel vs. home cage environment (Fig. 1c) in the novelty-suppressed feeding test, a test of anxiety-like behavior that is sensitive to chronic but not acute antidepressant treatment similar to responses in human patients[10]

Summary

Introduction

Neglect, and other forms of early life stress (ELS) significantly increase risk for psychiatric disorders including depression. Using RNA-sequencing, we asked whether ELS in male and female mice alters patterns of gene transcription in the brain’s reward circuitry, including ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC), all of which are implicated in stress responses and human depression. We present comprehensive genome-wide analysis of transcriptional changes in both male and female mice, across three brain reward regions, after ELS with or without subsequent adult stress. These transcriptional analyses provide a foundation for future research testing the causal role of molecular pathways implicated in ELS-induced stress sensitivity in both sexes

Methods

Results

Conclusion