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.
Highlights
The spatial learning abilities of developing mice benefit from extrinsic cues, such as an enriched environment, with concomitant enhancement in cognitive functions
There was a significant increase for the Bacillus Calmette-Guérin (BCG) Enr mice toward displaying higher levels of exploration activity relative to the PBSEnr mice (Fig. 1a, b)
We previously reported that neonatal BCG vaccination elevated neurogenesis, synaptic plasticity, cognitive function, and the levels of neurotrophic factors in mice housed in a standard environment by affecting the neuroimmune cross talk between the periphery and the brain, which may be associated with a systemic Th1 bias [8,9,10]
Summary
The spatial learning abilities of developing mice benefit from extrinsic cues, such as an enriched environment, with concomitant enhancement in cognitive functions Such enhancements can be further increased through intrinsic Bacillus Calmette-Guérin (BCG) vaccination. Bilbo et al [2] reported that neonatal immune activation caused by Escherichia coli protected against rather than aggravated stressorinduced depressive-like symptoms Another feasible scenario is that preconditioning with a low dose of lipopolysaccharide (LPS) can attenuate the pathological effects of a subsequent stimulus, such as a larger LPS challenge [3], brain trauma [4], or stress [5, 6]. Mice trained in a spatial learning and memory test, the Morris water maze (MWM), led to recruitment of IL-4-producing T lymphocytes into the meninges, and depletion of T lymphocytes from the meningeal spaces skewed meningeal macrophages toward a proinflammatory phenotype [14]
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