Increased depression-like behaviors with altered brain dopamine metabolisms in male mice housed in large cages are alleviated by bupropion.

Psycho-environmental stress-based animal models of anxiety and depression are useful for investigating pathological mechanisms and drug development. Although several rodent-based studies have reported the beneficial effects of environmental enrichment (EE) on brain plasticity and anxiety- and depression-like behaviors, other studies have reported inverse effects. Here, we found that housing male mice in EE involving large cages and other EE materials increased anxiety- and depression-like behaviors in open field and tail suspension tests (TST). We further confirmed that housing in large cages was sufficient to induce increased depression-like behaviors in the TST and reduce the saccharine preference percentage, a sign of anhedonia, in male mice. In these experiments, the number of animals per cage was equivalent to that in standard cage housing, suggesting that low density in large cages may be a determining factor for behavioral alteration. In mice housed in large cages, sex-specific dysregulation of brain monoamine systems was observed; dopamine turnover to homovanillic acid or norepinephrine in the prefrontal cortex was elevated in males, while serotonin turnover to 5-hydroxyindoleacetic acid in the amygdala was increased in females. Finally, we demonstrated that daily intraperitoneal injections of bupropion, a dopamine and norepinephrine reuptake inhibitor, counteracted large-cage housing-induced changes in depression- and anhedonia-like behaviors in male mice. Our results suggest that housing in large cages with a low density of mice is a novel paradigm to clarify the mechanisms of environmental stress-induced emotional dysregulation and to identify drugs or food factors to alleviate the dysregulation.

Unstable mutant lysozymes are degraded through the interaction with calnexin homolog Cne1p in Saccharomyces cerevisiae.

Cne1p is a yeast homolog of calnexin, which is a constituent of endoplasmic reticulum (ER)-associated protein quality control system in mammals. Cne1p may be involved in the degradation of misfolded lysozymes in Saccharomyces cerevisiae. To test this, c-Myc-tagged lysozymes were expressed in CNE1-deficient S. cerevisiae. The expression and secretion of an unstable lysozyme mutant G49N/D66H were enhanced and its intracellular localization was changed in the CNE1-deficient strain. Furthermore, when Cne1p was co-expressed with unstable lysozyme mutants (G49N/D66H, G49N/C76A, and K13D/G49N), its affinity to the misfolded mutant proteins was revealed by co-immunoprecipitation. The interaction with Cne1p was abrogated by the addition of tunicamycin, an inhibitor of N-glycosylation, indicating that N-linked carbohydrates might be necessary for protein binding to Cne1p. These results suggest that in yeasts, Cne1p interacts with misfolded lysozyme proteins possibly causing their retention in the ER and subsequent elimination via ER-associated degradation.