Altered neural connectivity in adult female rats exposed to early life social stress

doi:10.1016/j.bbr.2016.08.051

Behavioural Brain Research

Volume 316, 1 January 2017, Pages 225-233

https://doi.org/10.1016/j.bbr.2016.08.051 Get rights and content

Highlights

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Early life social stress induces changes in resting state functional connectivity.
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The prefrontal cortex and hippocampus exhibited particularly robust changes.
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Stress affects connectivity in social and depression relevant brain regions.

Abstract

The use of a variety of neuroanatomical techniques has led to a greater understanding of the adverse effects of stress on psychiatric health. One recent advance that has been particularly valuable is the development of resting state functional connectivity (RSFC) in clinical studies. The current study investigates changes in RSFC in F1 adult female rats exposed to the early life chronic social stress (ECSS) of the daily introduction of a novel male intruder to the cage of their F0 mothers while the F1 pups are in the cage. This ECSS for the F1 animals consists of depressed maternal care from their F0 mothers and exposure to conflict between their F0 mothers and intruder males. Analyses of the functional connectivity data in ECSS exposed adult females versus control females reveal broad changes in the limbic and reward systems, the salience and introspective socioaffective networks, and several additional stress and social behavior associated nuclei. Substantial changes in connectivity were found in the prefrontal cortex, nucleus accumbens, hippocampus, and somatosensory cortex. The current rodent RSFC data support the hypothesis that the exposure to early life social stress has long term effects on neural connectivity in numerous social behavior, stress, and depression relevant brain nuclei. Future conscious rodent RSFC studies can build on the wealth of data generated from previous neuroanatomical studies of early life stress and enhance translational connectivity between animal and human fMRI studies in the development of novel preventative measures and treatments.

Introduction

The use of a variety of neuroanatomical techniques has led to a greater understanding of the adverse effects of stress on psychiatric health. One recent advance that has been particularly valuable is the development of resting state functional connectivity (RSFC) in clinical studies. This technique measures intrinsic neural connectivity through the measurement of spontaneous fluctuations in BOLD activity in different brain regions [1], [2]. RSFC analysis allows for the simultaneous assessment of long term changes in multiple neural circuits involved in psychiatric etiology. This method has recently been adapted to imaging in conscious rodents [3], [4], and is a valuable tool to enhance the translational value of behavioral neuroscience studies of rodent models of psychiatric illness. Comparisons of clinical and animal model RSFC data will enhance our understanding of susceptibility and resilience, pathological etiology, and treatment response. When compared to other methods of assessing neural activity and connectivity (immunohistochemistry, various tract tracing techniques, pcr for neural activity), a single RFSC study can add a temporal dimension, even allowing the longitudinal collection of several months or years’ worth of data, a scale typically not possible with other time course approaches such as electrophysiological methods. Given similar financial resources, collecting similar amounts of data using other techniques may be impossible. In addition, RSFC in conscious rodents presents tremendous potential for enhanced etiological relevance through the longitudinal assessment of the effects of stress on multiple neural networks at several life history stages.

We have developed an ethologically relevant transgenerational model of the effects of chronic social stress (CSS) in postpartum depression and anxiety [5], [6], [7], [8], [9] (Fig. 1). Exposure of F0 dams to the chronic social stress of a daily exposure to a novel male intruder depresses maternal care, impairs lactation in both the F0 dams as well as their female F1 offspring, where CSS is an early life CSS (ECSS) Neuroendocrine studies of the F1 offspring of stressed F0 dams have revealed several behaviorally relevant changes in gene expression in a select set of nuclei involved in both the control of social behavior and the stress response that parallel similar findings in human studies of depression, anxiety and autism [5]. However, given that tissues were sampled at the end of lactation, it is unclear when the neural changes in gene expression occurred; for example, if they were present prior to gestation.

Recent study of the effects of a single traumatic stress exposure in rats indicated that it can cause long-term changes in the RSFC between the amygdala and mPFC, providing additional, clinically relevant support for the face and construct validity of this animal model of PTSD [10]. The development of RSFC in related animal models of psychiatric illness is postulated to enhance the identification of susceptibility indicators and the identification of effective preventative measures and treatments. The current study sought to build on this finding and apply RSFC to the study of the long term effects of early life stress, a mechanism relevant to a vast array of psychiatric disorders. It was hypothesized that animals exposed to ECSS would exhibit substantial changes in connectivity between several nuclei implicated in the early life stress associated disorders in both humans and animal models, including components of the Default Mode Network (DMN) and limbic network.

Section snippets

Animals

Sprague Dawley rats (Charles River, Wilmington, MA) in this study were maintained in accordance with the guidelines of the Committee of the Care and Use of Laboratory Animals Resources, National Research Council, and the research protocol was approved by the Tufts University and University of Massachusetts Institutional Animal Care and Use Committees. For an overview of the CSS paradigm, see Fig. 1. “CSS dams” refers to the adult females exposed to CSS during lactation (F0), and “ECSS females”

Results

Table 1 lists the brain regions discussed in the current study. Table 2 summarizes all the significant differences in RSFC between the F1 controls and the ECSS adult females for the 13 seed regions. Fig. 2A–D display the difference maps for four specific ROIs where there were significant differences (or multiple trends) in RSFC: PFC, NAc, HP and SSp. Fig. 3A–D are graphs of the differences in these nuclei, with asterisks denoting significance at p < 0.05.

Using the PFC as a seed, there are several

Discussion

Previous behavioral and neuroendocrine gene expression analyses of ECSS exposed animals have described depressed maternal care, decreased aggression, increased anxiety, and numerous behaviorally relevant changes in gene expression in stress and depression associated nuclei [5], [6], [15]. The present approach identified functional connectivity in the range of our previous rat studies [10], [11], [16] and those of other groups [17], [18], and was sensitive to group differences even at modest

Conclusions

The simultaneous evaluation of numerous brain regions in conscious rodent fMRI studies facilitates the integration of findings from many previous neuroanatomical studies to generate robust, broad conclusions which may span several neural networks and enhance translational connectivity between clinical and animal investigations. While data on stress induced changes in RSFC in rodents has recently been published [68], comparisons with this study are difficult given the major differences in awake

Acknowledgements

The authors would like to thank Dr. Jessica Babb for assistance with the CSS protocol at the Cummings School and Kelly Tam for experimental logistics at the CCNI. The laboratory animal medicine service staff at the Cummings School provided exceptional care of our rodents. This work was supported by a National Institutes of Health award (NICHD R00 HD056643) and a Brain and Behavior Research Foundation NARSAD Young Investigator Award to BCN and NIH S10 OD018132-01 to the UMass CCNI.

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Research reportAltered neural connectivity in adult female rats exposed to early life social stress

Highlights

Abstract

Introduction

Section snippets

Animals

Results

Discussion

Conclusions

Acknowledgements

Neuroimage

J. Neurosci. Methods.

Psychoneuroendocrinology

Hormones Behav.

Neuroimage

Neuropharmacology

Neuropeptides

Neuroimage

Magn. Reson. Imaging

Data Brief

Behav. Brain Res.

Neuron

Biol. Psychiatry

Biol. Psychiatry

J. Psychiatric Res.

Brain Res.

Neuropharmacology

J. Chem. Neuroanat.

J. Chem. Neuroanat.

Biol. Psychiatry

Neuroscience

Physiol. Behav.

Neuroscience

Brain Res.

Behav. Brain Res.

Neurobiol. Learn. Mem.

Neurosci. Lett.

Brain Res. Bull.

Neuroscience

Neuroimage

Functional connectivity in the motor cortex of resting human brain using echo-planar mri

Magn. Reson. Med.

Uncovering intrinsic connectional architecture of functional networks in awake rat brain

J. Neurosci.

Using chronic social stress to model postpartum depression in lactating rodents

J. Visualized Exp.

Effects of chronic central arginine vasopressin (AVP) on maternal behavior in chronically stressed rat dams

Brain Sci.

Effects of chronic social stress during lactation on maternal behavior and growth in rats

Stress

Nicotine and resting state functional connectivity: effects of intermittent doses

Nicotine Tobacco Res.

Research report
Altered neural connectivity in adult female rats exposed to early life social stress