Tognini, P. | Search bioRxiv

bioRxiv2021

The gut microbiota of environmentally enriched mice regulates visual cortical plasticity

Exposing animals to an enriched environment (EE) has dramatic effects on brain structure, function and plasticity. The poorly known "EE derived signals" mediating the EE effects are thought to be generated within the central nervous system. Here, we shift the focus to the body periphery, revealing that gut microbiota signals are crucial for EE-driven plasticity. Developmental analysis of intestinal bacteria composition in EE mice revealed striking differences from standard condition (ST) animals and enhanced levels of short-chain fatty acids (SCFA). Depleting the EE mice gut microbiota with an antibiotic cocktail decreased SCFA and prevented EE induction of adult ocular dominance (OD) plasticity, spine dynamics and microglia rearrangement. SCFA treatment in ST mice mimicked the EE induction of adult OD plasticity and morphological microglial rearrangement. Remarkably, transferring the microbiota of EE mice to ST recipients activated adult OD plasticity. Thus, taken together our data suggest that experience-dependent changes in gut microbiota regulate brain plasticity.

neuroscience↗

bioRxiv2021

Brain histone beta-hydroxy-butyrylation couples metabolism with gene expression

Little is known about the impact of metabolic stimuli on brain tissue at a molecular level. The ketone body beta-hydroxybutyrate (BHB) can be a signaling molecule regulating gene transcription. Thus, we assessed lysine beta-hydroxybutyrylation (K-bhb) levels in proteins extracted from the cerebral cortex of mice undergoing a ketogenic metabolic challenge (48 hrs fasting). We found that fasting enhanced K-bhb in a variety of proteins including histone H3. ChIP-seq experiments showed that K9 beta-hydroxybutyrylation of H3 (H3K9-bhb) was significantly enriched by fasting on more than 8000 DNA loci. Transcriptomic analysis showed that H3K9-bhb on enhancers and promoters correlated with active gene expression. One of the most enriched functional annotations both at the epigenetic and transcriptional level was "circadian rhythms. Indeed, we found that the diurnal oscillation of specific transcripts was modulated by fasting at distinct zeitgebers both in the cortex and suprachiasmatic nucleus. Moreover, specific changes in locomotor activity daily features were observed during re-feeding after 48-hour fasting. Thus, our results suggest that fasting dramatically impinges on the cerebral cortex transcriptional and epigenetic landscape, and BHB acts as a powerful epigenetic molecule in the brain through direct and specific histone marks remodeling in neural tissue cells.

neuroscience↗