The differential effects of short-term physical exercise, environmental enrichment and their combination, and short- and long-term environmental enrichment on behavior and associated molecular changes in the brain of C57BL/6 mice

Abstract

Background: Animal studies have shown that with increasing age, there is impaired cognition, enhanced anxiety- and depressive-like behaviors, and reduced locomotor activity, accompanied by neurobiological changes, such as enhanced inflammation, decreased neurotrophins, and altered neurotransmitter levels. Evidence suggests that external environmental conditions can modify the effects of aging. Environmental enrichment (EE), where the immediate environment of experimental animals is modified, has been reported to reverse the adverse effects of brain aging. Past studies on EE have, however, also utilized physical exercise (PE) as a part of EE. Additionally, the duration of EE and the age of rodents varies greatly across studies. Hence, the current literature fails to explain the effects that PE has in EE studies across age, as well as the differential effects of the duration of EE, if any, on behavior and underlying molecular biology. Methods: We analyzed the differential effects of short-term PE, EE, and PE+EE, and the effects of short- vs. long-term EE on cognition-, anxiety- and depressive-like behaviors in 4-, 9- and 14-month-old C57BL/6 mice using an established behavioral battery. Changes in the expression of hippocampal genes, microglial and astrocyte numbers in the dentate gyrus, and T cell subsets in the cervical lymph nodes were also analyzed. Results: We found that short-term EE reversed the adverse effects of age on cognitive- and anxiety-like behaviors at 14 months. Conversely, short-term PE was found to impair cognition and enhance depressive-like behavior at 4 months. Furthermore, PE and PE+EE, but not EE alone, were observed to modify the expression of several hippocampal genes at 9 months compared to control mice. EE also enhanced the number of microglia in the dentate gyrus at 4 and 9 months while PE and PE+EE increased it only at 9 months. Significant differences were also noted between the treatment- and age-matched cohorts for the proportion of CD4+ and CD8+ T cell subsets in the cervical lymph nodes. At 9 months, both short-term and long-term EE significantly enhanced locomotion in the home cage and reduced depressive-like behavior in the forced swim test. Conversely, long-term EE reduced locomotion in the open-field test. Additionally, short-term EE showed anxiolytic effects in the elevated zero maze, while these effects were lost after long-term EE. EE, irrespective of duration, increased microglia number within the dentate gyrus and had no significant effects on the expression of 43 hippocampal genes of interest. Long-term EE, however, increased astrocytic numbers in the dentate gyrus, as well as total CD8+ and proportions of CD8+ TNaive cells in the cervical lymph nodes. Conclusion: The above results suggest that short-term EE is effective in alleviating the age-related impaired cognition and enhanced anxiety-like behavior in the absence of altered hippocampal gene expression. Conversely, short-term PE adversely affects cognition and affective behaviors at an early age, with modification of hippocampal genes only occurring at middle age. Finally, the longer duration of EE affects locomotion adversely in a threatening environment, reverses the beneficial effects of short-term EE on anxiety-like behavior, and may alter the neuroinflammatory response during middle age.