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Lawless, J. A.

Publications and source records attributed to Lawless, J. A..

2 recordsLinked to original sources

Gut Microbial Signals Influence Motivational Responses in the Male Mouse

Mammalian motivation to obtain natural rewards is regulated by internal biological and external environmental factors. Increasing evidence suggests the gut microbiota may represent one such factor. Here, we observed that antibiotic (ABX)-induced disruption of the gut microbiota increased the motivation to obtain palatable rewards, elevated inflammatory cytokine levels and elicited significant alterations in synaptic plasticity-related gene pathways in the mouse nucleus accumbens (NAc). We also observed that the dynamic state of the gut microbiota partially impacts motivational responses and identified several gut microbial metabolites that could be driving this phenotype. Finally, surgical ablation of vagal signalling via subdiaphragmatic vagotomy partially rescued transcriptomic signatures in the NAc and elevations in inflammatory markers but was not enough to prevent the increase in motivational responses. Overall, our results highlight an important new role for the gut microbiota in regulating the cascade of metabolic, neurochemical and immunological events necessary for reward processing and motivation.

neuroscience↗

Microbiota-sensitive glial and metabolic programs define a critical window in early postnatal brainstem development

Paediatric brain tumours are increasingly recognised as diseases of disrupted development, arising when lineage progression programs, that normally govern neural and glial maturation, become stalled or dysregulated. Diffuse midline glioma (DMG), a highly aggressive paediatric brainstem tumour, emerges during early childhood in the pons, a region undergoing rapid postnatal growth characterized by oligodendrocyte precursor cell (OPC) proliferation and differentiation. However, the environmental factors that shape these developmental trajectories remain poorly defined. Here, using germ-free and conventionally colonized mice, we investigated whether early-life microbiota influences transcriptional and metabolic programs in the developing brainstem during this critical developmental window. Bulk RNA sequencing revealed pronounced microbiota-associated transcriptional differences at postnatal day 2 (P2), but not at P8, identifying a temporally restricted period during which microbial colonization is associated with pathways linked to oligodendrocyte lineage progression, myelination, and neuroimmune signalling. Transcriptional analyses further identified altered expression of genes associated with CD11c microglia, a developmental microglial subtype implicated in regulating oligodendrocyte maturation. Untargeted metabolomic profiling revealed parallel microbiota-associated differences in pathways related to mitochondrial function, redox balance, and methyl-donor metabolism. Integrated multi-omics analyses identified coordinated networks linking glial lineage programs with metabolites involved in cellular metabolism and epigenetic regulation. Notably, several of these transcriptional and metabolic programs overlap with gene signatures reported in diffuse midline glioma, suggesting that microbiota-sensitive developmental pathways intersect with cellular states relevant to paediatric brainstem tumour biology.

neuroscience↗