The mapping of pathways connecting neurons in the developing brain has been completed

Over a century after the neuroanatomist Santiago Ramón y Cajal discovered the neuron, scientists continue to increase their knowledge of the brain and how it develops. This is the case despite the fact that the discovery of the neuron occurred over a century ago. On April 5, a team from the Institut Pasteur and the CNRS, in collaboration with Harvard University, revealed new insights into the ways in which cells in the outer layers of the brain interact immediately after birth during the formation of the cerebellum, which is a brain region towards the back of the skull. These findings were published in Science Advances. Even before the establishment of synapses, which are the usual junctions between neurons, the scientists established a novel type of connection that can occur between neural precursor cells through the use of nanotubes.

In 2009, the group led by Chiara Zurzolo at the Institut Pasteur’s Membrane Traffic and Pathogenesis Unit discovered a novel way for direct communication between brain cells in culture through the use of nanoscopic tunnels called tunnelling nanotubes. These play a role in the dissemination of a variety of harmful proteins, which are known to build up in the brain in the course of neurodegenerative illnesses. As a result, nanotubes might be an appropriate target for the therapy of various diseases or tumours, particularly in cases where they are also present.

In this recent study, the researchers found nanoscopic tunnels that connect precursor cells in the brain, more especially in the cerebellum – an area that develops after birth and is essential for making postural changes to preserve balance. These nanoscopic tunnels were discovered when the precursor cells were maturing into neurons. Although they are around the same size, the shapes of these tunnels are somewhat distinct from one another. Some of them have branching, while others do not; some are encased by the cells that they connect, while others are open to the environment in their immediate vicinity. As the brain develops, the authors believe that these intercellular connections (ICs) may permit the interchange of substances that assist pre-neuronal cells in physically migrating through several layers and arriving at their ultimate destination.

Curiously, ICs and the bridges that are created after cells complete their divisions have certain physical characteristics in common. This study has the potential to give information on the processes that allow for coordination between cell division and migration, which are both involved in brain development. Since ICs could originate from cellular division but continue to exist during cell migration, this study has the potential to shed light on those systems. On the other hand, intracellular connections that are generated between cells after mitosis could enable direct interchange between cells that goes beyond the typical synaptic connections. This would be a revolutionary step forward in our comprehension of how the brain connects. According to Dr. Zurzolo, who is the senior author of the study and the head of the Membrane Traffic and Pathogenesis Unit at the Institut Pasteur/CNRS, “We show that there are not only synapses allowing communication between cells in the brain, but there are also nanotubes.”

Take a look at the 3D animation.

The researchers were able to make these discoveries by employing a technique known as three-dimensional (3D) electron microscopy together with brain cells derived from mouse models in order to investigate the manner in which the various regions of the brain communicate with one another. It would therefore be possible to rebuild neural network maps at a very high resolution. More than 2,000 cells may be found in the 3D volume of the cerebellum that was created and used for the research. “If you really want to understand how cells behave in a three-dimensional environment, and map the location and distribution of these tunnels, you have to reconstruct an entire ecosystem of the brain,” said Diego Cordero, the first author of the article. “This requires extraordinary effort with approximately twenty or so people involved over the course of four years.”

The authors made use of an AI tool that automatically differentiated between the different cortical layers in order to tackle the obstacles that come with working with the diverse array of cell types that the brain possesses. In addition to this, in order to characterise the morphological properties of 3D segments, they developed an open-source programme that they termed CellWalker. After analysing photos of brain sections, the tissue block was rebuilt. Scientists will be able to swiftly and simply analyse the complicated anatomical information that is embedded in these types of microscope images as a result of the programme that is being made freely available.

The subsequent step will be to determine the biological function of these cellular tunnels in order to gain an understanding of their part in the formation of the central nervous system and in other regions of the brain, as well as their part in the communication between brain cells in conditions such as neurodegenerative illnesses and malignancies. The computational tools that have been built are going to be made available to other study teams all around the world.