Finding cures for the future in the brains of the past

Brain mapping: Uniting multi-scale brain data to reveal disease mechanisms

This collaborative project combines cellular resolution data with whole-brain information to provide genuinely new insights into the pathological mechanisms underlying human brain disorders.

The challenge
In the past it has been difficult to reconcile advances made at a cellular level with a whole-brain approach

Pioneering 3D maps of the entire human brain

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Could cellular level maps of the entire human brain lead to early interventions in disorders like Alzheimer’s disease? The team, from the Wyss Center, the University of Geneva and Geneva University Hospital, describes the innovative approach in which they compare healthy and diseased brains to detect cellular-level changes early.

For decades the microscopic study of brain tissue has helped pathologists understand disease, describe the cellular diversity of the nervous system and define specific features of brain disorders. In parallel, neuroimaging methods have revealed the function and dysfunctions of whole brain neural circuits. However, technical limitations of traditional microscopy have made it difficult to relate cellular level advances to whole brain observations.

Our approach unifies neuroscience across scales, from genes to the whole brain, with the goal of revealing the mechanisms of brain disease, establishing diagnostic biomarkers and identifying new therapeutic targets. 

The collaboration

This collaborative project with the University of Geneva (UNIGE) and Hôpitaux Universitaires de Genève (HUG) works closely with the Geneva Brain Collection (GBC) and also uses healthy and diseased human brain tissue from other sources. 

Advances in imaging techniques, particularly lightsheet microscopy present at the Advanced Lightsheet Imaging Center (ALICe), enable the imaging of much larger samples while retaining their structure. 

The team will develop a next-generation histopathology approach taking advantage of novel molecular labelling techniques coupled with advanced microscopy and data analysis tools, to explore the relationship between cellular and whole brain mechanisms in both healthy and diseased tissue. It will initially focus on neurodegenerative dementia and eventually explore the broad range of conditions contained in the GBC.

A section of human cerebellum from the Lamylab at the University of Geneva imaged with the Wyss Center’s mesoSPIM lightsheet microscope. The image shows blood vessels labelled with the marker lectin. Blood supplies energy to the brain and is known to be disregulated in some diseases. Imaging brain vasculature with advanced microscopes helps drive research into neurodegenerative diseases and stroke. Credit: Tomàs Jordà – Lamylab, University of Geneva

Five times larger than life: This new image of an expanded section of human cortex shows individual neurons (pink) and cell nuclei (pale blue). The team is using expansion microscopy – a technique that physically expands the tissue using polymers that swell in a similar way to a diaper when wet – so that more detail can be seen under a microscope. Chemical anchors fix the expanding polymer gel to the biological molecules in the sample increasing its 3D size. Here, the nuclei were 6 microns before expansion and around 30 microns after, making them five times larger. The team plans to use the technique to study synapses, the physical junctions that allow communication between neurons. By comparing synapses in healthy and diseased brains, the team hopes to discover precursors to neurodegenerative disorders and ultimately find ways to treat them. Data acquired for the human brain mapping project using a confocal microscope. Labelling: Propidium iodide in pale blue (nuclei), MAP2 in pink (neurons). Credit: Samira Osterop, Laura Batti, Tomas Jorda.

From thin brain slices…

To thicker slices like this which are clarified and imaged in order to reconstruct an entire human brain in 3D.


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