Beyond super-resolution: ultra-resolution imaging provides solutions for synapse physiology and brain pathology (ULTRARESOLUTION)

Neurons contain hundreds of specialized proteins, whose topology reflects activity, plasticity and disease.

Present imaging techniques are unable to present this topology accurately, since even the best super-resolution tools are limited to at least 20-30 nm, many times the size of individual proteins (~3-7 nm).

To solve this problem, our ground-breaking objective is to develop reliable ultra-resolution imaging, with true molecular resolution of 1-5 nm.

We will combine optics-based super-resolution with a recent innovation, pioneered by our team – physical expansion of the samples.

Our efforts will be aided by several imaging tools we have generated, from super-resolution modalities to nano-affinity probes, which, thanks to their power and ease-of-use, are already employed by hundreds of research groups.

We will apply ultra-resolution to reveal the functional organization of key components of the synapse, in health and disease. We will also develop protocols for brain pathology samples, for future use in medical diagnostics.

Finally, we will establish simple protocols that will enable the application of ultra-resolution in every biomedical laboratory.

Our multidisciplinary group, composed of a synapse physiologist (Rizzoli), a single-molecule imaging chemist (Sauer), and a physics and bio-engineering specialist (Boyden), is optimally placed to address this challenge.

All PIs are also super-resolution specialists, with extensive expertise in stimulated emission depletion (STED), direct stochastic optical reconstruction microscopy (dSTORM) and expansion microscopy (ExM), respectively.

The vast expertise required by this project implies that none of our groups could pursue it alone, and that no other groups, world-wide, could attempt it.

Its successful implementation will provide: 1) imaging technology far beyond the state-of-the-art, which will prove transformative in many branches of biology; 2) solutions to multiple questions on synaptic and brain function.