Abstract
Some individuals are resilient, whereas others succumb to despair in repeated stressful situations. The neurobiological mechanisms underlying such divergent behavioral responses remain unclear. Here, we employed an automated method for mapping neuronal activity in search of signatures of stress responses in the entire mouse brain. We used serial two-photon tomography to detect expression of c-FosGFP – a marker of neuronal activation – in c-fosGFP transgenic mice subjected to the learned helplessness (LH) procedure, a widely used model of stress-induced depression-like phenotype in laboratory animals. We found that mice showing “helpless” behavior had an overall brain-wide reduction in the level of neuronal activation compared with mice showing “resilient” behavior, with the exception of a few brain areas, including the locus coeruleus, that were more activated in the helpless mice. In addition, the helpless mice showed a strong trend of having higher similarity in whole-brain activity profile among individuals, suggesting that helplessness is represented by a more stereotypic brain-wide activation pattern. This latter effect was confirmed in rats subjected to the LH procedure, using 2-deoxy-2[18F]fluoro-D-glucose positron emission tomography to assess neural activity. Our findings reveal distinct brain activity markings that correlate with adaptive and maladaptive behavioral responses to stress, and provide a framework for further studies investigating the contribution of specific brain regions to maladaptive stress responses.
Highlights
Coping with various kinds of environmental stress is a fundamental brain function
To mimic environmental stressors associated with mood disorders, we used the learned helplessness (LH) procedure in which animals were subjected to periods of inescapable and unpredictable foot shocks (Figures 1A–C; and see Materials and Methods; Chourbaji et al, 2005; Li et al, 2011; Perova et al, 2015)
To achieve a subsequent detection of neuronal activity related to distinct behavioral responses, we used the c-fosGFP transgenic mice expressing c-FosGFP under the control of a c-fos promoter (Barth, 2004; Reijmers et al, 2007; Wang et al, 2014; Kim et al, 2015; Perova et al, 2015)
Summary
Coping with various kinds of environmental stress is a fundamental brain function. persistent stress can often lead to mental disorders, including depression (Franklin et al, 2012). Previous studies based on this model have explored brain activity measurements related to distinct behavioral phenotypes, which led to the discovery of several behaviorally relevant circuit changes (Mirrione et al, 2014; Wang et al, 2014; Perova et al, 2015). Most of these studies have focused on selected brain regions and might have missed additional brain regions or functional features critical for the expression of the stress-induced depression-like behavior
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