Shaping of axonal complexity by a dynamic regulation of local metabolic pathways in the developing cortex

Informations projet

NEUROMET

N° de convention de subvention: 678302

DOI

10.3030/678302

Projet clôturé

Date de signature de la CE 11 Juillet 2016

Date de début 1 Août 2016

Date de fin 31 Juillet 2022

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 1 300 000,00

Contribution de l’UE

€ 1 300 000,00

Coordonné par

UNIVERSITE LYON 1 CLAUDE BERNARD
France

Periodic Reporting for period 4 - NEUROMET (Shaping of axonal complexity by a dynamic regulation of local metabolic pathways in the developing cortex)

Période du rapport: 2021-02-01 au 2022-07-31

Résumé du contexte et des objectifs généraux du projet

The proper function of neuronal circuits in the adult brain relies heavily on glucose metabolism to ensure energy-demanding neuronal functions such as synaptic activity or long distance axonal transport. Deregulation of the energy metabolism is strongly associated to many neurodegenerative diseases and has been linked to some neuropsychiatric diseases such as schizophrenia. However our current understanding of metabolic regulation in the developing brain and in particular in rapidly growing neurons is still fragmental.
The project NEUROMET aimed at better understanding how a local regulation of metabolic pathways underlie neuron development and circuit formation in the mouse neocortex. Our research combined cutting-edge microscopy methods, functional metabolomic analyses and models to identify and characterize the relationship between glucose metabolism and axon development. This project has provide new insights into the molecular mechanisms underlying the development of the neocortex as well as point out some of the consequences of metabolic imbalance on the development of the brain, a question that has many important implications for public health.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

The implementation of the project has included the purchase of all equipment required to perform the experiments including a live-imaging setup suitable for real-time imaging of the metabolic activity in developing axons. We gathered a team of researchers and clinicians to work on this project and could implement three parallel aims. The main achievements are as follow :
We have validated methods to measure and manipulate metabolic activity in cultured neurons. With this set of techniques, we contributed to demonstrate the central role of mitochondria in the regulation of cortical circuits complexity, and identified some of the molecular mechanisms involved, which constitute putative druggable targets (work in progress).
We uncovered how extracellular signals tied to the local regulation of axonal morphogenesis converge on the regulation of neuronal signaling pathways that are important for metabolic regulation in the developing brain.
We tested the relevance of polymorphisms identified in cohorts of patients suffering from neurodevelopmental disorders and demonstrated that the NUAK1 gene is haploinsufficient in regards to cortical circuits development and demonstrated the potential pathogenicity of mutations in this gene and associated to neurodevelopmental disorders.
Overall, this project led to 9 publications, and several other articles are in preparation. Two PhD students defended and earned a PhD with two more students still in progress.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

The project NEUROMET has two technological goals, which were to develop methods to measure, but also to manipulate the metabolic activity in cortical neurons. The latter is especially a promising development of the project and an important perspective of our work with translational potential at term. We furthermore investigate how distinct extracellular factors converge to signaling pathways to induce the remodeling of axonal projections in callosal axons and especially how the balance between ipsilateral and contralateral projections is affected by metabolic imbalance. Overall the completion of our project enriched our understanding of the molecular and cellular mechanisms tying the remodeling of metabolic pathways and the development of cortical connectivity. Hence project NEUROMET had a fundamental value for basic science, pushing the knowledge beyond the state of art, but will also be continued with fundamental and applied research projects.

Visualization of population of cortical neurons in the mouse somatosensory cortex