Macrostructural, microstructural, and cellular effects of neuroinflammation on the mouse brain

Neuroinflammation is increasingly implicated in post-infectious brain atrophy and cognitive impairment, as well as the etiology of neurodegenerative and psychiatric disorders. Here, we employed an established mouse model of neuroinflammation (systemic lipopolysaccharide [LPS]) and studied its macrostructural, microstructural, and cellular effects on the mouse brain. We combined whole-brain two-photon microscopy, multiparametric magnetic resonance imaging, and in silico transcriptomics. We demonstrate that LPS increases microglial soma size, a marker of microglial proinflammatory transformation, throughout the brain. LPS also induces in vivo volumetric increases of multiple brain regions, but not the cerebral cortex. These in vivo increases are no longer observed ex vivo (post-fixation), suggesting they may be due to brain edema. Moreover, LPS induces microstructural alterations, as indicated by ex vivo reductions in fractional anisotropy and magnetization transfer ratio, which were most pronounced in the cerebral cortex. These reductions had the largest effect size in regions with higher expression of genes specific to parvalbumin inhibitory neurons and excitatory layer 4/5 intratelencephalic neurons, which were enriched in genes encoding synapse components. Thus, these results suggest that LPS-induced neuroinflammation may lead to brain edema, which spares the cerebral cortex, and microstructural alterations, which impact the cerebral cortex and may involve specific subtypes of inhibitory and excitatory neurons and their synapses.