Deciphering the complex architecture of neural circuits is a major challenge in Neuroscience. What defines an optimal circuit? Are neuronal networks stable or can they evolve with experience and learning?
These fundamental questions have spawned breakthrough initiatives, such as the Human Brain Project (EU) and the Brain Activity Map (USA), which seek to better understand how the brain generates and transmits information. This seminal work has recently experienced an even greater level of complexity : pre-wired axonal circuits are not rigid. Instead, macrocircuits can dynamically re-structure to define new architecture patterns as the brain learns and evolves. This pioneering work, which contrasts with the traditional microcircuit scale of synaptic plasticity, has led to the emergence of the brain rewiring concept.
In the lab, we strive to understand (i) how neuronal activity regulates brain rewiring, (ii) how circuit remodeling allows optimal learning, and (iii) how it can be targeted to develop novel therapeutic approaches to treat various brain disorders associated with defects in connectivity.
INTRACELLULAR SUBSTRATES OF AXON REMODELING
Formation of axon branches and synaptic contacts during learning highly depends on neuronal activity and requires large amounts of secretory materials. Axonal transport is responsible for addressing these secretory vesicles to remodeling sites. In contrast to dendritic growth that mostly relies on vesicular secretion from the Golgi apparatus, axonal growth appears to be more dynamic and may depend on a local, axonal pool of secretory vesicles. However, mechanisms that control the preferential targeting of axonal vesicles to remodeling branches are unknown.
Using a combination of brain-on-a-chip devices, microelectrode arrays, high-resolution fast videomicroscopy and mathematical models, we identified an activity‐sensitive complex on‐board of vesicles that converts neuronal activity into directional transport toward active branches. Our results highlight the independent nature of the axon vis-a-vis the somatodendritic compartment during network remodeling. This new concept challenges the current vision of the axon shaft as a rigid and static cable by giving it a central role in neuronal plasticity.
We now aim at determining the composition of this on‐board regulatory complex and how we can target this unique mechanism to facilitate or prevent network rewiring in the adult brain.
MANIPULATING BRAIN REWIRING IN HEALTH AND DISEASE
Studies in human and non-human primates revealed adult brain plasticity at a surprising broad scale. When learning new motor skills, long-range axon projections can invade new brain regions or retract from existing circuits. This macroscale axonal rewiring is believed to expand individual capacity and learning performance by restructuring the overall architecture of neural circuits. However, current approaches prevent brain rewiring studies from establishing causality between structural reorganization and individual learning capacities. To overcome this limitation, we directly target axon remodeling programs to reorganize mature neural networks on-demand. This approach, termed Remodeling of Axon Induced by Light (RAIL), uses a photoinducible cytoskeletal remodeling system to connect and disconnect axon projections on-demand.
Using cutting-edge techniques that combine our unique RAIL methodology with state of the art brain-on-a-chip platforms, virus-mediated circuit tracing, electrophysiology, functional network imaging, and behavioral analyses, we manipulate neural networks on-demand to explore how brain rewiring controls individual motor skill capacities.
THERAPEUTIC POTENTIAL OF BDNF MIMETICS
Brain-derived neurotrophic factor (BDNF) is the most abundant growth factor hormone of the adult brain. Binding of BDNF to its cognate receptor, TrkB, activates a number of downstream signaling pathways that promote neurogenesis, cell survival, differentiation or synaptic plasticity. Because of this crucial role in the development and maintenance of the nervous system, BDNF and TrkB are of particular therapeutic interest for numerous disorders, including neurodegenerative and psychiatric disorders, chronic pain and epilepsy. Despite this potential therapeutic significance many clinical trials have met with disappointing results and the development of small TrkB agonists has been a long-sought goal.
Together with the Laboratory of Therapeutics Innovation (D. Rognan, Univ Strasbourg), we use computational modeling and cell-based functional screening to develop positive and negative modulators of TrkB that have functional effects in vivo. We have already developed cyclotraxin (TrkB inhibitor) and ANA12 (BDNF antagonist), available at Sigma, Tocris, R&D Systems, etc.
We are now in the process of releasing LIT-TB molecules, a new family of TrkB positive allosteric modulators (publication in prep, patent pending).
Our projects are supported by :