How can snails help us understand memory formation

The human brain has ~86 billion neurons, and each one forms over 10,000 connections with other neurons. It is the most complicated object in the universe, and we are only scratching the surface in understanding how it works.

Within the brain's neural network, the connections known as synapses harbour a high density of proteins. These proteins assemble into precise 3D arrays that govern the transmission of information. The resolution of optical microscopy, however, is limited to ~200 nanometres due to the wave nature of light.

Consequently, the application of fluorescence microscopy to visualise these protein structures is restricted. Fortunately, the emergence of super-resolution microscopy has provided us with the means to directly observe synaptic proteins in brain slices, leading to the ground-breaking discovery that proteins are organised into "nanoclusters".

Moreover, these structures exhibit significant heterogeneity across the brain, challenging the previous assumption of their homogeneity.

In this project, the student will have the opportunity to develop a super-resolution probe specifically designed to target a class of neuroreceptors critical for memory formation and learning. These probes are based on neurotoxic peptides derived from the venom of marine cone snails. Notably, these probes are much smaller than conventional antibodies, enabling them to navigate the dense protein network and bind directly to the receptors.

This breakthrough will not only allow us to generate high-resolution maps of synaptic proteins, but also track their movements in real-time, offering invaluable insights into the dynamic nature of the brain and cognitive processes such as memory formation at the molecular level.

The project offers a comprehensive learning experience encompassing multiple experimental techniques and analytical approaches, combining molecular biology, microscopy, coding, and electrophysiology. The student will have a valuable hands-on experience in various areas, including molecular biology, immunohistochemistry, and super-resolution microscopy techniques such as PAINT, dSTORM, and PALM.

Super-resolution microscopes produce extensive datasets, presenting an excellent opportunity for the student to acquire coding skills, particularly in Python, to handle complex data analysis effectively. Additionally, the biological activity of the developed probes will be evaluated using patch-clamp electrophysiology. This technique allows for the assessment of the probes' impact on the neuroreceptor activity, providing valuable insights into their functionality and suitability for further studies.