The influence of the gut metabolite δ-valerobetaine on the medial prefrontal cortex at molecular and functional levels

• Applicant: Privatdozent Dr. Thomas Blank
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 565656520

The proposal aims to comprehensively investigate the influence of the gut metabolite δ-valerobetaine (dVB) on the medial prefrontal cortex (mPFC). Four main objectives will be pursued: First, the effects of dVB on mPFC-connected neuronal networks will be explored using resting-state functional magnetic resonance imaging (rs-fMRI) and graph theoretical network analysis to understand changes in functional connectivity. Second, metabolome shifts in the mPFC following dVB application will be characterized to elucidate metabolic impacts. Third, the influence of dVB on mitochondrial bioenergetics in the main cell types of the mPFC will be examined to capture cellular energetic changes. Fourth, dVB-induced transcriptional changes in the mPFC will be analyzed using single-cell RNA sequencing (scRNA-seq) to identify specific cellular and molecular responses. This multidimensional investigation aims to provide a comprehensive understanding of dVB's effects on the mPFC, from the network level to cellular and molecular changes, and could offer important insights into the role of the gut-brain axis in cognitive functions and age-dependent processes, potentially revealing new targets for therapeutic interventions. This research is particularly relevant given recent findings that dVB levels increase with age in both mice and humans, accumulating in the blood and brain. Studies have shown that dVB alters neuronal function in the mPFC, modulating inhibitory synaptic transmission and population synchronization. When injected into young mice, dVB was found to impair learning and memory performance, similar to that seen in old mice. The proposal's focus on the mPFC is significant, as this brain region plays a key role in numerous behaviors and cognitive functions, including action control, emotional regulation, attention, memory, and decision-making.

• DFG Programme: Research Grants