The role of suboptimal mitochondrial function in stress adaptation and depression pathogenesis
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2017-02-01
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en
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The brain requires massive amounts of energy to operate optimally. These demands are almost exclusively covered by the powerhouses of neurons, the mitochondria. Recently, a considerable body of evidence implicates impaired mitochondrial bioenergetics in psychopathology, although the mechanism behind this link remains elusive. Here we test the hypothesis that interaction of suboptimal mitochondrial function with chronic stress confers vulnerability to depression, using the novel Ndufs4 deficient transgenic mouse model. To this end, we subjected wild type and transgenic adult male mice to the well-established chronic variable stress (CVS) paradigm and assessed its effects on physiological parameters and affective behavior. We found that chronically stressed Ndufs4 deficient mice showed reduced exploration behavior and a markedly higher preference for the outer zone in the open field arena that is not decreased with time, a greater propensity to passive coping and earlier signs of behavioral despair in the forced swim test, but no significant loss of interest in self-care in the splash test and no weight change alterations. Moreover, cFos imaging analysis revealed that impaired mitochondrial function was linked with higher activity in the dorsomedial hypothalamic nucleus (DMH) in response to acute stress and aberrant spontaneous activity in significant stress-related areas, i.e DMH and the ventral portions of hippocampal CA1 and dentate gyrus, under conditions of chronic stress. Taken together, these results provide evidence that compromised mitochondrial function mediates effects of chronic stress on mood and may be a vulnerability factor to maladaptive stress-coping. Our research could be the basis for the development of novel antidepressant pharmaceuticals that target brain metabolic processes and could benefit at least a portion of currently treatment-resistant patients.
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Faculteit der Sociale Wetenschappen