How to generate new neurons in the brain

Summary: After discovering the importance of cellular metabolism in neurogenesis, the researchers were able to increase the number of neurons in the brains of adult and aged mice.

Source: University of Geneva

Certain areas of the adult brain contain quiescent or dormant neural stem cells that can potentially be reactivated to form new neurons. However, the transition from quiescence to proliferation is still poorly understood.

A team led by scientists from the Universities of Geneva (UNIGE) and Lausanne (UNIL) has discovered the importance of cellular metabolism in this process and identified how to awaken these neural stem cells and reactivate them.

Biologists have succeeded in increasing the number of new neurons in the brains of adult and even old mice.

These results, promising for the treatment of neurodegenerative diseases, are to be discovered in the journal Scientists progress.

Stem cells have the unique ability to continuously produce copies of themselves and give rise to differentiated cells with more specialized functions. Neural stem cells (NSCs) are responsible for building the brain during embryonic development, generating all cells of the central nervous system, including neurons.

The capacity for neurogenesis decreases with age

Surprisingly, NSCs persist in certain brain regions even after complete brain formation and can make new neurons throughout life. This biological phenomenon, called adult neurogenesis, is important for specific functions such as learning and memory processes. However, in the adult brain, these stem cells become more silent or “dormant” and reduce their capacity for renewal and differentiation.

As a result, neurogenesis decreases dramatically with age.

The laboratories of Jean-Claude Martinou, Professor Emeritus in the Department of Molecular and Cellular Biology of the Faculty of Sciences of UNIGE, and of Marlen Knobloch, Associate Professor in the Department of Biomedical Sciences of the Faculty of Biology and Medicine of UNIL, revealed a mechanism by which adult NSCs can emerge from their dormant state and become active.

“We have discovered that mitochondria, the energy-producing organelles within cells, are involved in regulating the level of activation of adult NSCs”, explains Francesco Petrelli, researcher at UNIL and co-first author of the study. study with Valentina Scandella.

This shows the newly produced neurons in the dentate gyrus
Newly produced neurons (red) in the dentate gyrus with cell nuclei (blue) and a marker for immature neurons (green). Credit: Knobloch Lab – UNIL

The mitochondrial pyruvate transporter (MPC), a protein complex discovered eleven years ago in Professor Martinou’s group, plays a particular role in this regulation. Its activity influences the metabolic options a cell can use.

By knowing the metabolic pathways that distinguish active cells from dormant cells, scientists can wake up dormant cells by altering their mitochondrial metabolism.

New perspectives

Biologists have blocked the activity of MPC by using chemical inhibitors or by generating mutant mice for the Mpc1embarrassed. Thanks to these pharmacological and genetic approaches, scientists were able to activate dormant NSCs and thus generate new neurons in the brains of adult and even old mice.

”With this work, we show that the redirection of metabolic pathways can directly influence the activity state of adult CNSs and consequently the number of new neurons generated”, summarizes Professor Knobloch, co-lead author of the study.

”These results shed new light on the role of cellular metabolism in the regulation of neurogenesis. In the long term, these results could lead to potential treatments for conditions such as depression or neurodegenerative diseases,” concludes Jean-Claude Martinou, co-lead author of the study.

See also

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About this neurogenesis research news

Author: Antoine Guénot
Source: University of Geneva
Contact: Antoine Guenot – University of Geneva
Picture: The image is credited to Knobloch Lab – UNIL

Original research: Free access.
“Mitochondrial pyruvate metabolism regulates the activation of quiescent adult neural stem cells” by Jean-Claude Martinou et al. Scientists progress


Mitochondrial pyruvate metabolism regulates activation of quiescent adult neural stem cells

Cellular metabolism is important for the behavior of adult neural stem/progenitor cells (NSPC). However, its role in the transition from quiescence to proliferation is not fully understood.

Here we show that the mitochondrial pyruvate transporter (MPC) plays a crucial and unexpected role in this process. MPC transports pyruvate into the mitochondria, linking cytosolic glycolysis to the mitochondrial tricarboxylic acid cycle and oxidative phosphorylation. Despite its key metabolic function, the role of MPC in NSPCs has not been addressed.

We show that resting NSPCs have an active mitochondrial metabolism and express high levels of MPC. Pharmacological inhibition of MPCs increases aspartate and triggers NSPC activation.

Additionally, genetics Mpc1 in vitro and in vivo ablation also activates NSPCs, which differentiate into mature neurons, leading to an overall increase in hippocampal neurogenesis in adult and aged mice.

These results highlight the importance of metabolism for NSPC regulation and identify an important pathway by which mitochondrial pyruvate import controls NSPC quiescence and activation.

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