Periodic Reporting for period 1 - ENSEMBLE (Structure and functions of the brain extracellular space)
Période du rapport: 2021-05-01 au 2022-10-31
Brain research has made tremendous progress over the last few decades in nearly all areas of investigation with the exception of one: the extracellular space (ECS). It is however a key compartment defined as the web-like space between brain cells, filled with a myriad of molecules that enable brain functions and homeostasis. How molecules navigate in the ECS is a very important, yet unsolved, challenge that precludes conceptual advance in brain science and innovation in therapeutics (e.g. immunotherapy). The lack of knowledge is mainly due to the absence of dedicated investigation strategies for such a complex and finely structured biological entity. Our ground-breaking project (ENSEMBLE) will shed light on the conceptual and methodological roadblocks that have prevented us from understanding the fine architecture of the ECS and how molecules navigate within it throughout the brain. We posit that molecular diffusion in the ECS is locally regulated by the properties of the ECS, which is essential for brain functions. Four world-class scientists, L. Groc (molecular neuroscience), E. Bezard (systems neuroscience), L. Cognet (optics & nanoscience), and U.V. Nägerl (neurophotonics), team up to develop and apply unconventional investigation approaches, based on original nano-imaging strategies (super-resolution microscopy and carbon nanotube/nanoparticle tracking), to the in vivo brain. Yet, to consider and achieve such an experimental and multidisciplinary tour de force a side-by-side and daily interactive effort is necessary. Thanks to our complementary expertise and geographical proximity, ENSEMBLE will provide a unique opportunity to unveil in vivo the structure and functions of this crucial brain compartment and will offer a new theoretical and experimental framework to manipulate molecule navigation. The ENSEMBLE project will also cross-fertilize the fields of nanoscience, optical imaging, organ pathophysiology and immunotherapy.
The ENSEMBLE project started in May 2021, i.e. right in the middle of the COVID outbreak. Even though we faced (like everyone else) enormous difficulties, we are proud to claim massive progress in line with the planned objectives. Two issues are worth mentioning: a recurrent problem in hiring high-profile students and post-doctoral researchers and a slowness in purchasing equipment due to the ill-adapted size of the University of Bordeaux public procurement unit. The hiring difficulties are shared by many of our colleagues worldwide. This is not unique to Bordeaux.
Despite these hurdles, we are comparably less affected, although we did not hire as many high profiles as we would have liked. The purchase of most types of equipment has eventually been completed (CNRS, INSERM), enabling it to set up the so-called Woodstock single particle tracking system entirely. To complete the second SUSHI system, some final pieces must be purchased (University of Bordeaux).
The two systems, proprietary of the ENSEMBLE project, are established within the dedicated 150 m2 open lab (refurbishment completed as per plan, most hired staff working into that project-dedicated environment) and are due to merge at some point to enable the dual mode of operation for the in vivo imaging of both SUSHI and SWCNT tracking. We have launched web-based working and information-sharing tools and established weekly topic-oriented meetings (small groups discussing operational details) with an additional monthly general meeting (project-wide meetings to share science and orientations).
Despite these hurdles, we are comparably less affected, although we did not hire as many high profiles as we would have liked. The purchase of most types of equipment has eventually been completed (CNRS, INSERM), enabling it to set up the so-called Woodstock single particle tracking system entirely. To complete the second SUSHI system, some final pieces must be purchased (University of Bordeaux).
The two systems, proprietary of the ENSEMBLE project, are established within the dedicated 150 m2 open lab (refurbishment completed as per plan, most hired staff working into that project-dedicated environment) and are due to merge at some point to enable the dual mode of operation for the in vivo imaging of both SUSHI and SWCNT tracking. We have launched web-based working and information-sharing tools and established weekly topic-oriented meetings (small groups discussing operational details) with an additional monthly general meeting (project-wide meetings to share science and orientations).
As detailed in the above section, the project has moved forward on several frontlines. The progresses are described above in details.
The expected results until the end of the project are the following:
i) Defining the ECS characteristics in brain slices (hippocampus, cortex, striatum...) from organotypic and acute preparations.
ii) Defining the ECS in vivo in the cortex of mice using both SPT and SUSHI-based methods
iii) Defining the movement of extracellular proteins, such as autoantibodies, in the ECS of brain areas
iv) Defining the ECS in models of neurodegenerative diseases.
The expected results until the end of the project are the following:
i) Defining the ECS characteristics in brain slices (hippocampus, cortex, striatum...) from organotypic and acute preparations.
ii) Defining the ECS in vivo in the cortex of mice using both SPT and SUSHI-based methods
iii) Defining the movement of extracellular proteins, such as autoantibodies, in the ECS of brain areas
iv) Defining the ECS in models of neurodegenerative diseases.