Health & Medicine ︱ Prof Simon Schultz and Dr Konstantin Nikolic Computational meets : Unlocking the ’s secrets

Working at the interface omposed of billions of specialised responsible for perception, action Simplified models allow researchers to study how the geometry of a ’s “dendritic tree” affects its ability to process information. between engineering and nerve cells (called ) wired and . But this is changing. neuroscience, Professor Simon C together in complex, intricate Schultz and Dr Konstantin webs, the brain is inherently challenging LET THERE BE LIGHT Nikolic at Imperial College to study. Neurons communicate with A powerful new tool (invented by Boyden of and Director of SHEDDING LIGHT ON THE BRAIN AN INSIGHT INTO NEURONAL GAIN London are developing tools each other by transmitting electrical and and Deisseroth just a little over a decade the Imperial Centre of Excellence in Their innovative approach uses Using two biophysical models of to help us understand the chemical signals along neural circuits: ago) allows researchers to map the brain’s Neurotechnology, Dr Konstantin Nikolic, sophisticated two-photon microscopy, neurons, genetically-modified to include intricate workings of the brain. signals that vary both in space and time. connections, giving unprecedented Associate Professor in the Department optogenetics and two distinct light-sensitive proteins Combining a revolutionary Until now, technical limitations in the access to the workings of the brain. Its of Electrical and Electronic Engineering, to measure (and disturb) patterns of (called ): -2 technology – optogenetics available research methods to study the impressive resolution enables precise and Dr Sarah Jarvis are taking a unique neuronal activity in vivo (in living tissue). (ChR2) or (NpHP), Prof – with computational approach: combining optogenetics with Combining these experiments with Schultz and team could either induce neuroscience, the team are computational modelling. Although theoretical work allows the team to or inhibit the connections between developing powerful tools to A powerful new tool allows researchers optogenetics has been applied to the tease apart and understand the data neurons (their synaptic activity). Using study the real-time physiology field of neuroscience, computational that they generate. On the theoretical light to probe the cells, the researchers of individual neurons and their to map the brain’s connections, giving modelling of the brain has not taken side, the team develops algorithms explored the extent to which a neuron’s function. Their work is unlocking this new tool onboard. With this for analysing the data and models shape (its morphology) affects the level the complex secrets of the unprecedented access to the workings truly multidisciplinary approach, the to help interpret it. to which its gain can be controlled. circuitry of the brain and has Imperial researchers have developed a significance for debilitating of the brain. sophisticated computational optogenetic In a recently published study, the team Most nerve cells have branched neural disorders such as Alzheimer’s disease. brain has meant that we are a long way measurement of neural circuitry of living tool. Prof Schultz is widely known for his explored one of the basic principles extensions called (rather from understanding how information is brain circuits in real-time. The technology, work on , which explores the of information processing in neural like branches of a tree) that propagate represented and processed named optogenetics, makes use of light core principles that underlie information (or cortical) circuits, called ‘neural the electrochemical messages from by neural circuits () together with (neurons processing in other cells to the that have been genetically sensitised to biological nervous cell body (). light). By shining a light on the genetically systems. The key This ground-breaking research In their study, by modified cells that are light-sensitive, aspect to their measuring the effect researchers can switch them on or off. For current study is that is helping refine our understanding that different ratios the first time, the messages that neurons for the first time of the excitatory and send to each other can be manipulated in computational of the modulation of individual nerve inhibitory opsins have with a sophistication that mimics naturally neuroscience, cells and how this may relate to when experimentally occurring neural activity. By disturbing the models of opsins placed in different activity of individual neurons, their effect are incorporated different aspects of neural circuits. parts of the neuron, on the system can be studied – something with detailed the team were able that could not have been envisaged multi-compartment models of neurons: gain control.’ Specifically, they were to directly investigate the effect that several decades ago. This revolutionary in essence, ‘reverse engineering’ the interested in ways that the gain (slope) the cell’s shape has on gain. The team methodology enables researchers to information processing architecture of of a neuron’s input-output function investigated four common types of establish causal relationships between the brain. Using optogenetic tools, the can be modulated. Neural gain can dendritic shape and demonstrated that nerve-circuit activity and function, rather team can test the predictions made be thought of as an amplifier of neural the arrangement of the dendrites is than merely observing correlations by their models directly, rather than communication. When gain is increased, an important factor in controlling gain between the two. indirectly. They are particularly interested excited neurons become even more (either naturally, by , in changes in cortical circuit properties active; conversely, when gain is inhibited or artificially, using optogenetics). OPTOGENETICS MEETS during dementias such as Alzheimer’s neurons become less active. As Prof The symmetry of the dendrites relative COMPUTATIONAL NEUROSCIENCE disease. Prof Schultz explains: ‘I believe Schultz explains: ‘an important property to the soma (cell body) was also Charting new territories in neuroscience, that understanding the functional of a neuron is, using engineering found to be important. The Imperial researchers at Imperial College London principles of cortical circuits is crucial to terminology, its ‘gain’. That is, the slope researchers thus showed that the are taking this revolutionary technology understanding, and treating, the effects of its input/output function, or the structure of an individual neuron is key a step further. Simon Schultz, Professor of brain disorders’. extent to which it amplifies its inputs’. to its functional role within the network.

www.researchfeatures.com www.researchfeatures.com Behind the Research

Professor Dr Konstantin Simon Schultz Nikolic

E: [email protected] W: www.schultzlab.org E: [email protected] W: www.imperial.ac.uk/bio-modelling/ Research Objectives References

Prof Schultz and Dr Nikolic combine the relatively new Jarvis S, Nikolic K, Schultz S. (2018) Neuronal gain modulability field of optogenetics with computational neuroscience is determined by dendritic morphology: A computational to understand how the ‘gain’ of a neuron’s input/output optogenetic study. PLoS Comput Biol 14(3): e1006027. system is modulated. https://doi.org/10.1371/journal.pcbi.1006027

Grossman N, Simiaki V, Martinet C, et al., (2013) The spatial pattern of light determines the kinetics and modulates Detail backpropagation of optogenetic action potentials, Journal of Computational Neuroscience, Vol:34, ISSN:0929-5313, Prof Simon Schultz Pages:477-488. Dept of Bioengineering Imperial College London Nikolic K, Grossman N, Grubb M, Burrone J, Toumazou C, South Kensington Campus Degenaar P. (2009) Photocycles of Channelrhodopsin-2. London SW7 2AZ Photochemistry and Photobiology, 85: 400–411. The shape of the cell’s arms or ‘dendrites’ affects the neuronal gain. UK Evans B D, Jarvis S, Schultz S R, Nikolic K. (2016) “PyRhO: Dr Konstantin Nikolic A Multiscale Optogenetics Simulation Platform”, Frontiers The researchers showed that one Institute of in , 10 (8). doi:10.3389/fninf.2016.00008 common cell type in particular – the For the first time in computational Imperial College London – is highly modulable. South Kensington Campus Their finding reinforces our current neuroscience, models of opsins are London SW7 2AZ Personal Response understanding that the role of pyramidal UK cells within neural circuits is to act not only incorporated with detailed multi- as the primary excitatory neuron but also compartment models of neurons. Bio Your research holds promise for unravelling as a key element for setting the gain of Simon Schultz is Professor of Neurotechnology and Director the complexities behind disorders of the brain and to develop new treatments. How far are the circuit. Other cell types investigated of the Centre for Neurotechnology at Imperial College we from achieving this? by Prof Schultz and his team were found of – devices that connect rather than over-writing neural activity with London. to be less modulable. This suggests that to brain cells to deliver information that new information. Progress on understanding and treating brain although these other cell types have a diseased cell can no longer receive Dr Konstantin Nikolic is Associate Professor – Research disorders is at the moment being limited, in my view, by our relatively poor understanding of how brain circuits important roles within the , on its own, for example. As Prof Schultz ILLUMINATING RESEARCH (Senior Research Fellow ) at Centre for Bio-Inspired process information, how that leads to behaviour, and the gain of their input-output functions explains: ‘the potential for a new type Using powerful new technology Technology, Institute of Biomedical Engineering. of course how these circuits are perturbed in disease states. is unlikely to be modulated in vivo. They of optical neuroprosthesis – one where, to manipulate individual neuronal It is that “circuit-level” understanding that is crucial for put forward the idea that it is likely that rather than just optically stimulating cells circuits with sophisticated spatial and Funding further progress on problems such as neurodegenerative these cells experience shifts in overall and making them fire (in effect over- temporal accuracy, the team’s ground- European Union, BBSRC, Wellcome Trust and neurodevelopmental disorders. In one sense, the excitability through changes in the writing what they otherwise might have breaking research is helping refine our brain is extremely complex, and we are still a long way off amount of excitation or inhibition. said), the gain of the cell’s input/output understanding of the modulation of Collaborators any kind of complete understanding. However, there have function is instead changed.’ In essence, individual nerve cells and how this may • Sarah Jarvis been tremendous advances in neurotechnology in the last UNDERSTANDING THE BRAIN – the tool enables researchers to adjust relate to different aspects of neural circuits. decade – from new ways to image brain activity at cellular level, to new ways to alter activity in neural circuits with A WORK IN PROGRESS the sensitivity of a cell’s response to its A better understanding of this, our most The potential for computational inputs, while at the same time preserving complex and most precious organ, may potential therapeutic applications, to ways to deliver drugs across the blood-brain barrier into targeted brain areas. optogenetic modelling is vast. It is likely its ability to process information coming help us understand the dysfunction behind I am thus optimistic that in the next decade we will see to impact on many areas of study, helping in. It is conceivable that this could neurodegenerative disorders such as substantial progress in the development of new to bridge the gap between computational allow development of an ‘attentional Alzheimer’s disease, and has the potential treatments for brain disorders. and experimental studies. Excitingly, it ’. That is, make a specific set to lead to effective treatments for many could be harnessed to extend the ability of neurons more sensitive to their inputs, neurological conditions.

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