Studying Axonal Remodeling in Adult Brains: Application to Neurological Disorders – SARABANDe

SARABANDe is based on the emergence of a new concept in connectomics: the adult brain constantly rewires with experience.
The goal of the present study is to understand how brain rewiring is regulated, how it is relevant for learning and cognition, and how it can be targeted to treat brain disorders.

The adult brain is often seen as a rigid and ageing organ. However, growing body of evidence including our work have recently highlighted the remarkable plasticity of adult neural networks, which keep restructuring in response to neuronal activity. This emerging concept postulates that structural plasticity contributes to the global remodeling of brain circuits that dynamically form and retract with experience and learning. A dynamic connection/disconnection process implies efficient communication between the neuronal cell body (the computing center where electrical activity is generated) and its long-range connections (the effective remodeling sites that contact relevant targets). But what regulates the flow of information circulating within the axon to dictate active remodeling? How is neuronal activity translated into a go/no go message for axonal vesicles to reach the proper targets?

Interestingly, we and others have shown that structural remodeling remains very selective in the adult brain since only specific projections have the capacity to refine, leaving other networks hard-wired. These observations suggest the existence of specific "remodeling codes" in plastic but not rigid networks. What are these codes? Could we reactivate them in rigid networks?

Alterations in brain connectivity exist in psychiatric disorders but also in neurodegenerative diseases, both of which showing specific hyper- or hypo-connected networks. The success of structure-targeted therapies such as deep brain stimulation suggest that reactivating specific dysfunctional networks can restore global brain functions and rescue symptoms in treated patients. Could we thus develop similar strategies to restore the architecture of dysfunctional networks on-demand? Conversely, could we use reverse engineering to generate (and thus better understand) brain disorders by artificially manipulating the connectivity status between structures?

In the present project I propose to Study Axonal Remodeling in the Adult Brain with Applications to Neurological Disorders (SARABANDe project). This project will evolve around three main axes in which I propose to decipher the molecular and cellular codes that regulate the active remodeling of long-range connections in the adult brain; to investigate the heterogeneity and functional specificity of this structural remodeling in vivo; and to develop innovative strategies to manipulate the architecture of defective circuits on-demand in the diseased brain.