Coping with various kinds of environmental stress is a fundamental brain function. However, persistent stress can often lead to mental disorders, including depression (Franklin et al., 2012). A number of animal models have been developed for studying the mechanisms of depression (Krishnan and Nestler, 2008). The learned helplessness (LH) procedure has been extensively used to produce stress-induced depression-like behavior in rodents (Abramson et al., 1978; Vollmayr and Henn, 2003), and has proved useful in preclinical studies (Vollmayr and Henn, 2003) as well as in studies investigating the neurobiological processes that may be involved in the pathogenesis of stress-induced depression (Li et al., 2011; Wang et al., 2014; Perova et al., 2015). 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). However, most of these studies have focused on selected brain regions and thus might have missed additional brain regions or functional features critical for the expression of the stress-induced depression-like behavior.
In this study we examined whole-brain activity patterns using automated unbiased mapping at single-cell resolution (Kim et al., 2015) in mice subjected to the LH procedure. Specifically, we used the expression of green fluorescent protein-tagged immediate early gene product c-Fos (c-FosGFP) in the c-fosGFP transgenic mice (Barth, 2004; Reijmers et al., 2007) as an indicator of neuronal activation, which was imaged across the entire brain with serial two-photon tomography (STPT; Ragan et al., 2012). As an alternative approach, we also used 2-deoxy-2[18F]fluoro-D-glucose positron emission tomography (18FDG-PET; Mirrione et al., 2014) to assess neural activity in rats subjected to the LH procedure. We identified a list of brain regions that show differential activity in helpless versus resilient animals. In addition, we uncovered abnormally stereotypic brain activity in helpless animals. Our study demonstrates the utility of inspecting brain-wide activity patterns for revealing circuits participating in specific behaviors, and supports the view that defining neuronal circuits underlying stress-induced depression-like behavior in animal models can help identify new targets for the treatment of depression.
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