Our Research and Focus
How does changes in the lifestyle or nutritional challenges impact brain function and plasticity? The key concept of Tognini Lab research is that metabolic influence on neuronal function could be mediated by the interaction between distinct and intertwined players: the diet, the gut microbiota, and the circadian clock converging at the level of the brain epigenome. Thus, we are embracing a novel approach to address this outstanding issue, merging knowledge and methodologies coming from different but interconnected fields: metabolism, gut microbiota, neurophysiology of sensory systems and epigenetics.
Project 1: Gut Microbiota and Brain Plasticity
We have recently demonstrated how signals coming from the gut microbiota are involved in the regulation of experience-dependent plasticity. We discovered that environmental enrichment was able to remodel the gut microbiota composition in mice and that treatment with an antibiotic cocktail prevented the enriched-driven plasticity enhancement, as well as dendritic spine dynamics and microglia morphology changes. Strikingly, it was possible to transfer the plastic phenotype from an enriched mouse to a standard animal (which is not plastic) through fecal transplantation. Finally, we identified short chain fatty acids as the possible bacterial metabolites which convey plasticity signals from the gut to the brain. Our findings introduce a paramount concept: experience-dependent changes in the gut microbiota composition can modulate brain circuit function and plasticity. I propose the idea of an “experience-gut microbiota-brain” link: experience does not only impact the brain directly, but also through a pathway involving signals coming from the body periphery (Lupori, Cornuti et al., Cell Reports 2022).
We are now investigating the involvement of the gut microbiota in critical period plasticity. The data are promising! Stay tuned!!!
Project 2: Molecular and behavioral effects of fasting
The metabolic status has a well-documented influence on peripheral organs’ physiology and pathology, however mounting evidence suggests that it can also affect brain function. For example, brain resilience to aging is enhanced by caloric restriction, and ketogenic diets have been used to treat neurological diseases. Despite this information, 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 in peripheral tissue, such as the liver. My team 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. Overall, this study suggests 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 (Cornuti et al., Cellular and Molecular Life Sciences 2023). We are now applying intermittent fasting to counteract behavioral and metabolic disruption in obese mice. Through integrating sequencing and metabolomics data from brain, liver and plasma, we are exploring specific mechanisms and metabolic cascades.
Project 3: Brain-body communication mechanisms in neurodevelopmental disorders
Over the past few years, our lab has focused on translational research, with a particular interest in neurodevelopmental disorders, specifically CDKL5 deficiency disorders (CDD). Through a seed grant from the Telethon Foundation and the Family Association CDKL5 insieme verso la cura, we have been exploring the role of gut microbiota in CDD patients and animal models.
Since sleep disturbances are frequent in CDD and represent a tremendous emotional burden for caregivers, we am exploring circadian rhythms in CDKL5 mice. My team is performing molecular and functional/behavioral analyses to dissect potential alterations in the endogenous clock which could contribute to neurological symptoms and sleep problems in patients. We express our gratitude to The Jerome Lejeune Foundation for their belief in and funding of this exciting project!
Project 4: Role of the Circadian clock in the heart-brain axis
We are thrilled to announce a new project financed by The Italian Ministry of University and Research (PRIN PNRR 2022) in collaboration with Dr. Carolina Greco (Humanitas University, Italy) and Prof. Marina Bellet (University of Perugia).
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