Mechanisms of neuronal network remodeling in the adult mammalian brain

Project Information

NeuroRemod

Grant agreement ID: 758817

DOI

10.3030/758817

Project closed

EC signature date 29 March 2018

Start date 1 April 2018

End date 31 December 2023

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 493 750,00

EU contribution

€ 1 493 750,00

Coordinated by

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 4 - NeuroRemod (Mechanisms of neuronal network remodeling in the adult mammalian brain)

Reporting period: 2022-10-01 to 2023-12-31

Summary of the context and overall objectives of the project

Over the course of our life, experiences shape the way our brain process information. As we learn or adapt to changes, be they intrinsic or extrinsic, new connections are formed between neurons as others are pruned, while existing connections can be strengthened or weakened. The constant remodeling through diverse means of the flow of neural information is known as plasticity. The purpose of the NeuroRemod project is to study the phenomena of structural brain plasticity in adults of axonal and vascular networks in the whole brain. The structural support of cerebral plasticity, be it axonal or vascular, is not well characterized in the adult brain. Understanding this is a prerequisite to tailor strategies for cognitive rehabilitation in pathological contexts (stroke, brain injuries...).
We used different model systems of plasticity: 2 models to probe activity-dependant plasticity, using circuits for processing sensory information from the whiskers and the auditory system in mice. We also implemented a model to study plasticity driven by changes in internal states, using pregnancy as a model. The study of this phenomenon was divided into three research objectives:
1. Characterize the anatomical and connectivity changes induced by the loss of sensory information in adults at the whole brain level
2. Establish molecular mechanisms to control axonal plasticity in adults
3. Explore the role of cerebral vasculature in the control of adult plasticity

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

To enabled the exploration of adult structural plasticity, we have developed during this project key technologies that were necessary for the precise measurement of network plasticity in the adult brain. We implemented quantification strategies for the 3D mapping of axons, enabling us to measure precisely this phenomenon with an unprecedented resolution. For this, we used both viral tracings and structural axonal markers. The use of structural markers enabled us to clearly define the timeframe and locations of adult structural plasticity in the whole brain. We documented molecular modifications to thalamocortical axons following sensory deprivation. The manuscript for these findings is under preparation.
We also developed a novel mapping tool for the vascular system, which produced one of the first complete map of the brain vascular system at the capillary level. Using this technology, we mapped the changes imposed on the vascular structure of the brain after a sensory loss (Kirst et al. Cell 2020). Following up on the possibilities offered by this tool, we generated a brain atlas of vascular development, and studied how it is altered by sensory loss (manuscript submitted, data available at https://lambada.icm-institute.org).
In another manuscript, we used these mapping tools to document how sensory deprivation induce long-term vascular loss in the whole brain, revealing life-long interactions between neuronal activity levels and vascular topology. These results may be important in the context of neurodegenerative diseases, where minute alterations to network activity may influence in the long-term the stability of the vascular network. These results are now being assembled in a manuscript to be submitted soon.
Lastly, we also studied neuronal adult plasticity in the context of changes to internal states, by using pregnancy as a model. In this work, we documented the role of progesterone on the plasticity of a small population of neurons, in the Edinger Westphal nucleus, which we had identified via an unbiased screen. We found that plasticity in the activity patterns of this group of neurons was essential for the onset of maternal behavior, such as nesting, during pregnancy (Topilko et al. Neuron 2022).
Overall, the project enabled us to create advanced tools for the brain-wide study of post-natal plasticity. It helped us find clear instances of structural and functional plasticity, both on neuronal and vascular networks, revealing unsuspected interactions between neuronal activity and vascular topology in the adult brain. This level of description will facilitate the description of molecular pathways involved in branch pruning.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The NeuroRemod project has driven significant progress by developing cutting-edge tools that surpass current methodologies for studying adult structural brain plasticity. A key breakthrough is the creation of an advanced vascular mapping tool, capable of producing comprehensive 3D visualizations of the entire brain vasculature down to the capillary level. This innovation allows for unprecedented precision in mapping axonal and vascular networks across the adult brain, providing a robust platform for future studies of neuronal and vascular remodeling.
These tools have already enabled the identification of previously unknown structural plasticity events in both neuronal and vascular networks. For instance, we have documented long-term vascular modifications following sensory deprivation, revealing intricate interactions between neuronal activity and vascular topology. Our work on cortical axonal plasticity has further clarified how specific neuronal populations and axonal branches undergo remodeling, shedding light on molecular mechanisms governing axonal pruning and regeneration. Additionally, by investigating plasticity driven by internal physiological states—such as pregnancy-induced remodeling—we have expanded the understanding of how systemic factors shape neural circuits and behaviors.
To facilitate broader access to these findings, we are generating a web portal that will host comprehensive datasets derived from our vascular and axonal mapping efforts. This portal will serve as an open-access resource for the research community, providing high-resolution maps of structural and functional plasticity across the brain.
Furthermore, the project is producing extensive atlas resources detailing gene expression patterns and vascular organization in both the adult brain and during developmental stages. These atlases will offer a foundational reference for studies exploring the molecular and structural dynamics of neurovascular plasticity, supporting future investigations into cognitive rehabilitation and neurodegenerative disease mechanisms.

Project summary: mapping technologies developed during the first half of the project