Linking functional and epigenetic plasticity at the single-neuron level

Your everyday experiences, such as reading the paper, enjoying a meal or even catching a cold, change your brain to allow learning and adaptation in a constantly-changing world. These changes are collectively known as ‘plasticity’, and occur via a huge array of mechanisms ranging from alterations in the structure of individual molecules through to changes in the strength of connections between entire brain regions. However, while we have some understanding of the way in which experience can alter individual features of the brain, we know much less about how these separate forms of plasticity interact. For example, changes in sensory experience can alter both the electrical properties of brain cells – this is known as ‘functional’ plasticity – and the chemical structure of their DNA – this is known as ‘genomic’ plasticity – but the links, influences and integration between these two forms of plasticity remain almost entirely unexplored. This is the fundamental question I’ll be asking in collaboration with Professor Jon Mill at Exeter University: how does the brain combine functional and genomic plasticity simultaneously in individual cells?

Studying multiple forms of plasticity in single brain cells, neurons, is crucial because of those cells’ sheer diversity. There are not only a multitude of different subclasses of neuron within each region of the nervous system, but just as many variations within each of these subclasses. Such heterogeneity makes it difficult to detect subtle alterations brought about by specific experiences, and most likely obscures a wealth of relationships that exist between different forms of plasticity at the single-cell level. To truly understand the interactions between different types of plasticity – and in so doing, get a clearer idea of how our brains are shaped by the lives we lead – therefore requires us to study multiple forms of plasticity in individual neurons.

Individually-labelled dopaminergic neurons in the mouse olfactory bulb.

Our goal is therefore to simultaneously interrogate two vital but very different forms of plasticity. We think we have the ideal cell population in which to do this: a group of dopaminergic neurons in an area of the mouse brain – the olfactory bulb – that first processes information about the sense of smell. We already know that these cells can be very plastic, and that we can readily manipulate them via simple alterations of olfactory experience. So, we plan to induce plastic alterations in these olfactory bulb dopaminergic cells by either decreasing or increasing their sensory input over a day or so. We will then obtain, one cell at a time, detailed recordings of these neurons’ electrical properties. At the end of each recording we will collect each cell’s nuclear DNA, and will subject it to analyses of epigenetic regulation. Finally, we will employ state-of-the-art statistical approaches to link these two forms of plasticity at the single-cell level. In this way we aim to uncover both predicted and entirely unexpected relationships between gene regulation and electrical function within individual brain cells. In doing so, we hope to understand just a little bit more about how our experiences make us who we are.

Dr Matt Grubb
King’s College London
Research Project Grant