Biomimetic quantum-dot nanodonuts for membrane voltage imaging

Our brains are incredible organs. There are around 80 billion neurons that make up our brain, and they need to talk with each other to make our brains work. Interestingly, they do this by using electricity - incredibly, the membrane that gives a neuron its shape can create an electric field that has the same magnitude as a lightning bolt! However, despite the incredibly large signal, it can be extremely difficult to visualise how signals are generated within a single neuron, how these signals propagate to other neurons and spread around large networks. This is because this big lightning bolt-sized signal is confined to the thickness of just a handful of atoms, and positioning a sensor just in the right space is incredibly tricky.

In this project, we will take inspiration from natural proteins that sit in the membranes of neurons to develop a method to seamlessly integrate a sensor right where it needs to go to 'see' the electrical signals, and send out a message about it that we can see visually. By harnessing techniques from the computer industry, we will adapt methods that are used to make computer chips, TVs, and other advanced electrical devices to create our bioinspired voltage sensors.

These sensors will unlock the ability to visualise how neurons communicate with each other in diverse organisms, complex networks and more. For instance, other cells, such as sperm, are electrically active, and these bioinspired sensors will enable us to see why, and how, these electrical signals impact areas such as fertility.

In the end, by taking inspiration from nature and combining it with the power of nanofabrication, this project will unlock a revolutionary new strategy for seeing how our cells use electricity to communicate, and how these communications may get scrambled in the case of injury, disease, or simply old age.

Measuring rapid spatiotemporal changes of the electric fields in individual neurons and neural networks is critically important for understanding the normal and pathophysiology of the brain. Although a neuronal membrane supports electric fields on the order of 10 MV/m - greater than the estimated field generated during initiation of a lightning bolt - we still lack the technology required to measure these fields with the sensitivity and spatiotemporal resolution necessary to monitor neural activity. While voltage-sensitive organic dyes and genetically encoded fluorescent proteins have been developed to address this challenge, they all have problems: they are either too slow, weakly sensitive, unstable, difficult to deliver to cells, phototoxic, or (typically) a combination of these.

Quantum dots (QDs), in contrast, are bright, stable, non-phototoxic, and voltage-sensitive. If one could position them in the membrane to experience the full trans-membrane electric potential, they would make exquisite voltage sensors. This feat is challenging, however, because it requires a QD to face both the extracellular and intracellular solutions at the same time. By mimicking the topology of natural voltage-sensitive transmembrane proteins, we propose to fabricate membrane-partitioning nanoparticles filled with voltage-sensitive QDs and use them as novel optical voltage sensors.

This highly integrative project aims to create a transformational nanotechnology-based platform that will provide insights into neuronal integration and the complex network of mammalian neural circuits, including in the auditory cortex. By developing a sensitive method to sense voltage in neurons optically at the small and large scales (neuronal compartments and large networks), this project can revolutionize the future of neuroscience in a way similar to how the invention of optogenetics did.