Stress-induced alterations in large-scale functional networks of the rodent brain
Introduction
Stress has a major impact on brain functioning. Whereas the stress response first and foremost constitutes a highly adaptive mechanism that enables an organism to respond optimally to potential threats, dysregulation or prolonged exposure to stress can cumulate in psychopathology, such as post-traumatic stress disorder or depression (de Kloet et al., 2005).
Implementing a top–down approach, neuroimaging studies in humans have investigated the functional and structural abnormalities observed in the mentally diseased brain. Patient studies revealed functional impairments and volumetric reductions of the hippocampus and prefrontal cortex, and a hyperactive amygdala (Drevets et al., 2008, Pitman et al., 2012). However, recent advances in the field have elicited a shift away from such region-of-interest-based approaches towards network based approaches, in which the brain is regarded as a set of functional networks, each representing a unique brain function. Importantly, these analyses revealed that stress-related psychopathology is also characterized by alterations in structural integrity and functional connectivity patterns throughout the brain, which might in fact distinguish the healthy from the diseased individual (Whitfield-Gabrieli and Ford, 2012, Admon et al., 2013, Patel et al., 2012).
To elucidate the potential neural underpinnings of stress-related illnesses, animal research has investigated the effects of prolonged (i.e., chronic) stress exposure on neuronal function and structure, using a bottom–up approach. Chronic stress was shown to affect both brain function and structure in a region-specific manner. Higher-order cognitive function, involving the hippocampus and medial prefrontal cortex, was shown to be deteriorated following chronic stress (McEwen, 2001, Pavlides et al., 2002, Liston et al., 2006, Cerqueira et al., 2007), which was accompanied by a reduction in hippocampal volume (Lee et al., 2009), and dendritic hypotrophy (reduced dendritic length and number of branch points) in hippocampal and medial prefrontal neurons (Woolley et al., 1990, Watanabe et al., 1992, Cook and Wellman, 2004, Radley et al., 2004). Conversely, amygdala neurons were shown to display dendritic hypertrophy, and an increased anxiety phenotype (Vyas et al., 2002). Remarkably, similar to the amygdala, chronic stress was shown to enhance plasticity of the most ventral part of the hippocampus, contrary to its dorsal part (Suvrathan et al., 2013, Maggio and Segal, 2007).
Despite the detailed knowledge about regional effects of chronic stress, it is currently entirely unknown whether these microscopic effects observed in animals translate to altered large-scale connectivity as observed in the diseased human brain. We here set out to investigate the effects of chronic stress exposure on the large-scale functional connectivity patterns and structural integrity of the rodent brain. Implementing a controlled design, we exposed male rats to 10 days of chronic immobilization stress, and tested its effects on functional connectivity networks as identified by independent component analysis (ICA) of resting-state functional MRI (rs-fMRI). Additionally, we performed post-mortem high-resolution structural MRI and diffusion kurtosis imaging (DKI) to assess structural changes resulting from stress exposure. To confirm the presence of the expected chronic stress-induced changes in dendritic morphology in the hippocampus, amygdala, and prefrontal cortex, a subset of rats was used for Golgi staining.
Section snippets
Stress manipulation
Thirty-six male Wistar rats (RccHan™, Harlan) were housed in groups of three animals per cage with ad libitum access to food and water. Animals were kept in a temperature-controlled room (22–24 °C), with a light/dark cycle of 12 h (lights on at 7:00 A.M.). At the beginning of the experiments, animals were approximately 3 months old and weighed 325–400 g. The rats were randomly assigned to one of two experimental groups, entering either a chronic immobilization stress (CIS) or control protocol for
Physiology and neuronal morphology
At the start of the experiment (day 1), the control and stress groups did not differ on average weight (p > 0.2). However, over the course of the experiment the groups' weight developed differentially as indicated by a time × group interaction in weight gain (F(10,25) = 25.2, p < 0.001). Whereas the control animals significantly gained weight over the course of the experiment (F(10,8) = 51.0, p < 0.001), the stressed animals did not (F(10,8) = 1.6, p > 0.2), which resulted in a significantly lower body weight
Discussion
Here we show that chronic stress alters large-scale functional connectivity in the rodent brain. Functional connectivity was significantly increased in the somatosensory, visual, and default mode network (DMN) following stress. Moreover, chronic stress induced higher mean diffusivity in the lateral ventricles, which was related to an increase in their volume, while no differences were found in hippocampal volume or shape, nor in the volume of any other brain regions. Thus, this study shows that
Acknowledgments
This work was supported by grants of the Netherlands Organization for Scientific Research (NWO) (021.002.053), and the Utrecht University High Potential Program. We thank C. Beckmann and E. Hermans for the useful discussions on the data analyses, and W. Mol, B. Jongbloets, H. Karst, T. Bezemer, K. van den Hoven, M. Terpstra, S. Versteeg and A. van der Sar for their practical assistance.
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Both authors contributed equally to the manuscript.