Abstract
Aging is associated with increased central nervous system inflammation, in large part due to dysfunctional microglia. Environmental enrichment (EE) provides a model for studying the dynamics of lifestyle factors in the development of age-related neuroinflammation and microglial dysfunction. EE results in improvements in learning and memory, metabolism, and mental health in a variety of animal models. We recently reported that implementing EE in middle age promotes healthy aging. In the present study, we investigated whether EE influences microglial morphology, and whether EE is associated with changes in expression of microglial and neuroinflammatory markers. Inflammatory cytokines and MHC-II were reduced following 12-month EE in 10-month-old mice. Long-term EE for 7.5 months resulted in broad increases in Iba1 expression in hippocampus, hypothalamus, and amygdala detected by immunohistochemistry. Quantification of microglial morphology reveal both hypertrophy and ramification in these three brain regions, without increases in microglial cell density. These data indicate that long-term EE implemented in middle age results in a microglial state distinct from that of normal aging in standard laboratory housing, in specific brain regions, associated with reduced neuroinflammatory markers and improvement of systemic metabolism.
Highlights
Normal aging is associated with broad, systemic physiological decline
We recently reported that implementing EE in middle age promotes healthy aging
We investigated whether EE influences microglial morphology, and whether EE is associated with changes in expression of microglial and neuroinflammatory markers
Summary
Normal aging is associated with broad, systemic physiological decline. Age-related deterioration of the central nervous system (CNS) coincides with peripheral organ dysfunction, and communication between the CNS and the periphery is essential for overall homeostasis [1, 2]. Sensing of immunogenic stimuli or tissue injury activate microglia to produce proinflammatory mediators to propagate an immune signal, phagocytose cellular debris, and present antigens to the immune system [19] These “reactive” cells acquire a bushy morphology with short, retracted processes and cellular hypertrophy, with reduced surveilling process motility [20]. Similar hypothalamic gene expression profiles were found in mice overexpressing BDNF in the hypothalamus [14] These findings led us to ask whether EE could be affecting microglial cells in old age, in brain regions which are involved with the response of old mice to EE. We characterized the morphological changes in the hypothalamus, amygdala, and hippocampus in middle age mice after long-term EE of 7.5 months
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