Combined effect of BCG vaccination and enriched environment promote neurogenesis and spatial cognition via a shift in meningeal macrophage M2 polarization

Abstract

BackgroundThe spatial learning abilities of developing mice benefit from extrinsic cues, such as an enriched environment, with concomitant enhancement in cognitive functions. Interestingly, such enhancements can be further increased through intrinsic Bacillus Calmette-Guérin (BCG) vaccination.ResultsHere, we first report that combined neonatal BCG vaccination and exposure to an enriched environment (Enr) induced combined neurobeneficial effects, including hippocampal long-term potentiation, and increased neurogenesis and spatial learning and memory, in mice exposed to the Enr and vaccinated with BCG relative to those in the Enr that did not receive BCG vaccination. Neonatal BCG vaccination markedly induced anti-inflammatory meningeal macrophage polarization both in regular and Enr breeding mice. The meninges are composed of the pia mater, dura mater, and choroid plexus. Alternatively, this anti-inflammatory activity of the meninges occurred simultaneously with increased expression of the neurotrophic factors BDNF/IGF-1 and the M2 microglial phenotype in the hippocampus. Our results reveal a critical role for BCG vaccination in the regulation of neurogenesis and spatial cognition through meningeal macrophage M2 polarization and neurotrophic factor expression; these effects were completely or partially prevented by minocycline or anti-IL-10 antibody treatment, respectively.ConclusionsTogether, we first claim that immunological factor and environmental factor induce a combined effect on neurogenesis and cognition via a common pathway-meningeal macrophage M2 polarization. We also present a novel functional association between peripheral T lymphocytes and meningeal macrophages after evoking adaptive immune responses in the periphery whereby T lymphocytes are recruited to the meninges in response to systemic IFN-γ signaling. This leads to meningeal macrophage M2 polarization, subsequent to microglial M2 activation and neurotrophic factor expression, and eventually promotes a positive behavior.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0808-7) contains supplementary material, which is available to authorized users.

CD8+ T cells are essential for the effects of enriched environment on hippocampus-dependent behavior, hippocampal neurogenesis and synaptic plasticity

“…The mechanisms by which CD8 + T cells are affecting plasticity are also unknown. Since there is no direct physical contact between T cells and neurons in the brain parenchyma, the intercellular dialogue mediated by soluble molecules may involve cellular intermediates, which could be perivascular or meningeal macrophages, microglia, and/or astrocytes (Qi et al, 2017). We have obtained interesting data suggesting that in EE mice, astrocytes may serve as intermediates in the cascade linking EE-CD8 + T cells to neuronal plasticity in hippocampus (Suppl Fig 11).…”

“…Various cytokines have been shown to participate in the recruitment of T cells from the periphery (Qi et al, 2017). One can hypothesize that the changes observed in CD8 + T cells from the choroid plexus of EE vs.…”

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