Duration of Environmental Enrichment Determines Astrocyte Number and Cervical Lymph Node T Lymphocyte Proportions but Not the Microglial Number in Middle-Aged C57BL/6 Mice

Abstract

Environmental enrichment (EE) has been shown to modulate behavior and immunity. We recently reported that both short and long-term EE enhance baseline locomotion and alleviate depressive-like behavior, but only long-term EE affects locomotion adversely in a threatening environment and enhances anxiety-like behavior in middle-age mice. We have now investigated whether the observed changes in behavior after short-and long-term EE were associated with underlying immune changes. Hence, at the end of behavioral testing, mice were sacrificed, and brains and cervical lymph nodes were collected to investigate the differential effects of the duration of EE (short-and long-term) on the number of immunopositive glial cells in the dentate gyrus, CA1, CA2, and CA3 regions of the hippocampus and proportions of T cell subsets in the cervical lymph nodes using immunohistochemistry and flow cytometry, respectively. EE, regardless of duration, caused an increase in microglia number within the dentate gyrus, CA1 and CA3 hippocampal regions, but only long-term EE increased astrocytes number within the dentate gyrus and CA3 hippocampal regions. A significantly higher proportion of CD8 + naive T cells was observed after long-term EE vs. short-term EE. No significant differences were observed in the proportion of central memory and effector memory T cells or early activated CD25 + cells between any of the test groups. Our results suggest that EE, irrespective of duration, enhances the numbers of microglia, but long-term EE is required to modify astrocyte number and peripheral T cell proportions in middle-aged mice. Our findings provide new insights into the therapeutic effects of EE on various brain disorders, which may be at least partly mediated by glial and neuroimmune modulation.

Astrogenesis in the murine dentate gyrus is a life‐long and dynamic process

“…Intriguingly, we observed a significant increase in adult astrogenesis upon running wheel stimulus, which was driven by increased proliferation of local astrocytes. Together with evidence that enriched environment, another pro‐neurogenic stimulus, evokes a similar increase in astrogenesis (Williamson et al , 2012; Singhal et al , 2020), our data suggest that adult astrogenesis is a dynamic process able to adapt to environmental stimuli (Fig 7B). However, even though total numbers increased, the percentage of neurons and astrocytes among all newly generated cells did not differ between standard housing conditions and running wheel.…”

Long‐term environmental enrichment reduces microglia morphological diversity of the molecular layer of dentate gyrus

“…Many studies have shown that environmental enrichment including voluntary exercise and somatomotor and visuospatial stimulation is capable of promoting the modulation of cytokines (Pedersen, 2009) and chemokines (Trøseid et al, 2004), natural killer cells (Benaroya‐Milshtein et al, 2004), and T lymphocytes mobilization (Marashi, Barnekow, Ossendorf, & Sachser, 2003; de Sousa et al, 2011; Singhal et al, 2020), microglia (Gomes et al., 2019; de Sousa et al., 2015) and astrocytes numerical and morphological changes (Diniz et al, 2010; Diniz, Silva, et al, 2016; Leardini‐Tristão et al, 2020; Singhal et al, 2020) and neurogenesis (Valero, Paris, & Sierra, 2016; Wasinski, Batista, Bader, Araujo, & Klempin, 2018). Bi‐directional cross talk between microglia, astrocytes and neurons (Singhal et al, 2020; Kofuji & Araque, 2020) are key elements to achieve homeostatic conditions, and chemokine signaling seems to be essential to orchestrate communication among them, preserving brain function (Trettel, Di Castro, & Limatola, 2019). The morphometric studies of the present work compared the microglial morphology of elderly mice kept in impoverished cages with that of the same age animals kept in enriched cages.…”

Microglial Morphology Across Distantly Related Species: Phylogenetic, Environmental and Age Influences on Microglia Reactivity and Surveillance States

“…It has been also shown that short duration moderate exercise can improve survival in mice infected with a lethal dose of influenza virus (177). It has been shown that environmental enrichment and physical exercise, when combined, reduce brain cytokine expression (178), which may contribute to this outcome. Consistent with these findings, 6-month old mice under environmental enrichment, subjected to the neurotropic Piry arbovirus infection, increase T-cell infiltration and show less CNS cell infection by the virus and/or faster virus clearance, less microgliosis, and less damage to the extracellular matrix, than infected mice maintained in standard laboratory cages (27).…”

“…differentiated effector memory T-cells, weak proliferative responses to mitogenic agents, and a ratio of CD4 to CD8 lymphocytes of less than 1.0 (179). Physical exercise and environmental enrichment can modulate immunity in aged humans (180,181) and in experimental models (15,27,178,182,183). Indeed, it has been suggested that exercise might exert an anti-immunosenescence effect, delaying the onset of immunological ageing and rejuvenating aged immune profiles (179).…”