Amygdala hyper-connectivity in a mouse model of unpredictable early life stress

Frances K Johnson,Peter Herman,Jean-Christophe Delpech,Garth J Thompson,Lan Wei,Jin Hao,Fahmeed Hyder,Arie Kaffman

doi:10.1038/s41398-018-0092-z

Abstract

Childhood maltreatment is associated with a wide range of psychopathologies including anxiety that emerge in childhood and in many cases persist in adulthood. Increased amygdala activation in response to threat and abnormal amygdala connectivity with frontolimbic brain regions, such as the hippocampus and the prefrontal cortex, are some of the most consistent findings seen in individuals exposed to childhood maltreatment. The underlying mechanisms responsible for these changes are difficult to study in humans but can be elucidated using animal models of early-life stress. Such studies are especially powerful in the mouse where precise control of the genetic background and the stress paradigm can be coupled with resting-state fMRI (rsfMRI) to map abnormal connectivity in circuits that regulate anxiety. To address this issue we first compared the effects of two models of early-life stress, limited bedding (LB) and unpredictable postnatal stress (UPS), on anxiety-like behavior in juvenile and adult mice. We found that UPS, but not LB, causes a robust increase in anxiety in juvenile and adult male mice. Next, we used rsfMRI to compare frontolimbic connectivity in control and UPS adult male mice. We found increased amygdala–prefrontal cortex and amygdala–hippocampus connectivity in UPS. The strength of the amygdala–hippocampal and amygdala–prefrontal cortex connectivity was highly correlated with anxiety-like behavior in the open-field test and elevated plus maze. These findings are the first to link hyperconnectivity in frontolimbic circuits and increased anxiety in a mouse model of early-life stress, allowing for more mechanistic understanding of parallel findings in humans.

Highlights

Childhood maltreatment in the form of abuse, neglect, or adulthood including anxiety, depression, psychosis, somatization disorders, and substance abuse6
The volume of the hippocampus (t[8] = 9.18, p < 0.0005, Fig. 1c) and the total amount of proteins extracted from the hippocampus (t[12] = 2.58, p = 0.024, Fig. 1d) were both significantly reduced in P14 limited bedding (LB) pups, but these results were no longer significant when normalized to body weight (t[12] = 0.34, p = 0.730)
Together with our work in juvenile mice, these findings suggest that exposure to LB is associated with increased anxiety in the open field in juvenile but not adult male mice whereas unpredictable postnatal stress (UPS) leads to increased anxiety in both juvenile and adult male mice

Summary

Introduction

Childhood maltreatment in the form of abuse, neglect, or adulthood including anxiety, depression, psychosis, somatization disorders, and substance abuse. Childhood maltreatment in the form of abuse, neglect, or adulthood including anxiety, depression, psychosis, somatization disorders, and substance abuse6 It is currently erratic parenting is responsible for almost half of all child- unclear how multiple adverse events early in life synergize hood psychiatric disorders in the USA including anxiety, depression, and behavioral dysregulation. In the absence to affect such a broad clinical presentation and whether different types of childhood maltreatment Johnson and Jean-Christophe Delpech contributed to this work

Methods

Results

Discussion

Conclusion