Controlling the timing of human cortical neuron development: from upstream mechanisms to impact on circuit plasticity.

Informacje na temat projektu

NEUROTEMPO

Identyfikator umowy o grant: 101020617

DOI

10.3030/101020617

Data podpisania przez KE 24 Listopada 2021

Data rozpoczęcia 1 Grudnia 2021

Data zakończenia 30 Listopada 2026

Finansowanie w ramach

• EXCELLENT SCIENCE - European Research Council (ERC)

Koszt całkowity

€ 2 499 496,88

Wkład UE

€ 2 499 496,88

Koordynowany przez

VIB VZW
Belgium

Periodic Reporting for period 2 - NEUROTEMPO (Controlling the timing of human cortical neuron development: from upstream mechanisms to impact on circuit plasticity.)

Okres sprawozdawczy: 2023-06-01 do 2024-11-30

Podsumowanie kontekstu i ogólnych celów projektu

The human cerebral cortex takes a long time to develop its neurons compared to other species. It takes years to reach full maturity, instead of weeks in the mouse. This slow growth is also thought to be crucial for the enhanced functions of the human brain. Previous studies from the Vanderhaeghen Lab showed that this timing is controlled by cells themselves and not external factors, but it was unknown how.
Mitochondria are responsible for energy production in cell, but also to regulate transitions during development.
In NEUROTEMPO we aim to determine whether and how mitochondria also determine the development rate of human cortical neurons. This knowledge can have a significant impact on the study of neurological diseases, including mitochondria and metabolic diseases, as well as diseases that may be linked to disrupted developmental timing.
Speciifcally, we focus on the following aims:
Are mitochondria and metabolism similar during development of mouse and human neurons, or can we detect differences?
If so, what could be the impact of mitochondria and metabolism on the speed of human neuronal maturation, and how to they do so?
Finally, what could be the impact of accelerating experimentally human neuronal development on their function?

Prace wykonane od początku projektu do końca okresu sprawozdawczego oraz najważniejsze dotychczasowe rezultaty

We first found that mitochondria in young human neurons behave differently from those of mouse neurons at the same age: the human mitochondria grow much more slowly, and their energy metabolism is much less active.
Could this be related to the slow speed of human neuron maturation? To test this, we pharmacologically and genetically manipulated the neurons to enhance mitochondrial function. We saw that this accelerated the pace of neuron development, so neurons became more mature months ahead. Conversely, decreasing mitochondrial function led to slower growth in the mouse neurons. This confirmed the hypothesis that mitochondria set the tempo of neuronal maturation.

Innowacyjność oraz oczekiwany potencjalny wpływ (w tym dotychczasowe znaczenie społeczno-gospodarcze i szersze implikacje społeczne projektu)

When studying neuronal diseases in vitro, the slow development of neurons often hampers research. Mimicking the slow pace of maturation observed in vivo, growing human neurons in the lab takes several months to years to reach maturity. This makes them particularly difficult to study experimentally. Now, scientists will be able to accelerate neuronal maturation, allowing them to better study the brain’s function and models of neural diseases.
This work also has potentially important implications for some brain diseases. Some diseases strike mitochondria, and the affected patients often show early brain symptoms, which could be related to the discovery reported here. Conversely, some disorders that affect human brain development, leading to intellectual deficiency or autism spectrum disorders, could be linked to mitochondria. The Vanderhaeghen team will follow up on these critical questions in the future.
We are now following up by determining the mechanisms by which mitochondria influence developmental tempo, and what couod be the consequences of changing this tempo on neuronal function and plasticity.

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