- 2013 - Present: Chancellor’s Fellow at the University of Edinburgh.
- 2010 - 2013: Investigator Scientist, MRC Laboratory of Molecular Biology, Cambridge.
- 2008 - 2010: Swiss National Science Foundation Advanced Researcher at MRC Laboratory of Molecular Biology, Cambridge.
- 2007 - 2008: EMBO long-term Fellow at MRC Laboratory of Molecular Biology, Cambridge.
- 2006 - 2010: Research Fellow of Darwin College, Cambridge.
- 2005 - 2007: Marie Curie Fellow at the MRC Laboratory of Molecular Biology, Cambridge.
- 2004 - 2004: PhD, European Molecular Biology Laboratory, Heidelberg and University of Basel.
- 2001 - 2004: Roche Research Foundation Predoctoral Fellow at EMBL Heidelberg.
Synapses, Circuits and Behaviour
To survive, animals dynamically adapt their behaviour to ever changing conditions. This is why, unlike the static circuits of microprocessors, neurons and neural circuits in the brain are highly plastic in their structure and function.
Yet neural circuits have to produce reliable behavioural output to specific sensory input, and sustain these responses throughout the lifetime of an individual. Facing diverse variables affecting their function (previous experience; genotype; environmental conditions; metabolic state etc.) how do sensory circuits deal with these challenges?
The question is particularly relevant for the maintenance of homeostasis of the body, where nervous systems must continuously monitor and respond to sensory information that is key to survival, such as oxygen levels. Tonic sensory receptors can perceive such constant information: they report a stimulus for as long as it is presented.
However, their physiology is not well understood. How are responses to sustained sensory signals generated, and how do they reconfigure neural circuits to change animal behaviour?
Tonic signalling from O2 sensors sets neural circuit activity and behavioural state
The nematode Caenorhabditis elegans provides a unique opportunity to tease apart the complexity of signalling in neural circuits of the living organism. We focus on the neural circuit regulating oxygen homeostasis. C. elegans mounts sophisticated behavioural responses to ambient [O2], avoiding both too high (atmospheric) and too low (hypoxic) levels.
Avoidance of high O2 is mediated by three head neurons and one tail neuron which continuously respond to [O2]. Tonic signalling in these neurons is sustained by a calcium relay that consists of cGMP-gated channels, voltage-gated calcium channels, as well as the ryanodine and IP3 receptor channels, which release calcium from intracellular stores (Busch et al., 2012).
Tonic activity of these sensors is necessary and sufficient to set the behavioural state according to ambient [O2] for many minutes and even hours. Tonic signalling propagates to downstream neural circuits, including the hub interneuron RMG, which is required to mediate oxygen responses.
C. elegans oxygen responses show plasticity depending on experience, context, genetic background, food availability, and are integrated with other sensory input, setting the stage for the in-depth study of the molecular mechanisms underpinning the complexity of circuit function in vivo.
Long-lasting neural signalling in C. elegans
We aim to create a complete understanding of tonic signalling in the O2 neural circuit in vivo at the gene, cell, circuit and behavioural level, and systematically dissect the neuronal machinery that sustains neural and behavioural responses to homeostatic signals such as O2 for hours, even days.
For this we will identify and characterize genes and signalling pathways required to generate sustained responses, and for tuning them to specific oxygen levels.
We will also take advantage of being able to control Ca2+ levels in these sensory neurons for long periods of time simply by keeping the animals at different oxygen levels, and compare the consequences of sustained high or low calcium on the physiology of these neurons, on synaptic transmission, and on downstream neural circuits.
The function of electrical coupling in neural circuits in vivo
We are also interested in how tonic signals propagate in neural circuits downstream from the sensory neurons to set long-lasting behavioural states. We aim to focus on the role of electrical synapses in these circuits.
Electrical synapses are formed by gap junctions, which can directly connect the cytoplasm of two adjacent neurons. Gap junction channels are widely expressed in nervous systems and have been implicated in neural disorders such as ischemic strokes, epilepsy, or inflammation; yet even basic questions about their functions in vivo have not yet been answered, such as how they are regulated.
The neural circuit which mediates O2 responses, and integrates them with other sensory input, contains numerous electrical synapses. We aim to dissect how gap junctions contribute to information processing in this and other circuits, and examine how gap junction coupling is regulated.
To investigate these questions we will use quantitative behavioural assays, genetics and whole-genome sequencing, in vivo imaging of neural activity, optogenetic control of neuronal activity and other state-of-the-art techniques.
For our studies, C. elegans offers unique advantages. Its relatively simple and exceptionally well-characterised nervous system consists of 302 neurons with defined structure: their entire synaptic connectivity (“connectome”) has been mapped.
The animals are transparent and thus accessible to fluorescence microscopy, such as calcium imaging. High-throughput genetic screens offer a powerful tool to identify the players underpinning neural function.
Ambient oxygen dramatically affects the behavioural state of C. elegans: high O2 causes a sustained increase in locomotion (roaming); likewise, decreased locomotion (dwelling) lasts for as long as oxygen is kept low. Movies of npr-1 animals are 50x accelerated.
Watch video of oxygen affecting the behavioural state
Activation with blue light causes speeding in animals expressing the optogenetic activator Channelrhodopsin in the O2-sensing neurons (AQR, PQR URX) kept at low O2. Movie is speeded up 18x. (From Busch et al., 2012)
Watch video of blue light activation
- Medical Research Council, New Investigator Grant
- The Wellcome Trust, Seed Award in Science
EU COST networking grant
Qiaochu Li (PhD student) Nathalie Vladis (PhD student) Peta Greer (Research Assistant) Daniel Cosmin-Marcu (Research Assistant) Marios Diamantopoulos (MSc student)
Sebastian Greiss (University of Edinburgh) Maria Doitsidou (University of Edinburgh) Mike Shipston (University of Edinburgh) Iain Rowe (Robert Gordon University) Mario de Bono (MRC Laboratory of Molecular Biology) Kotaro Kimura (Osaka University) Johanna Höög (Gothenburg University) Michael Witting (Helmholtz Centre München) Oliver Hardt (McGill University)
Y. Tanimoto, A.Yamazoe-Umemoto, K.Fujita, Y. Kawazoe, Y. Miyanishi, S. J Yamazaki, X. Fei, K.E.Busch, K.Gengyo-Ando, J.Nakai, Y.Iino, Y.Iwasaki, K.Hashimoto, K.D Kimura (2017) Calcium dynamics regulating the timing of decision-making in C. elegans.
K. D. Kimura and K. E. Busch: From connectome to function: Using optogenetics to shed light on the C. elegans nervous system, in: Optogenetics. Ed. By K. Appasani, Cambridge Univ. Press (2016) doi.org/10.1017/9781107281875.005
G. A. Linneweber, J. Jacobson, K. E. Busch, B. Hudry, C. P. Christov, D. Dormann, M. Yuan, T. Otani, E. Knust, M. de Bono and I. Miguel-Aliaga: Nutrient-responsive neurons regulate metabolism through organ-specific modulation of tracheal branching. Cell. Jan 16, 2014; 156(1-2): 69-83.
E. Kodama-Namba, A. J. Bretscher, L. A. Fenk, E. Gross, K. E. Busch and M. de Bono: Cross-modulation of homeostatic responses in C. elegans. PLoS Genet. Dec 2013; 9(12).
K.E. Busch*, P. Laurent*, Z. Soltesz, R. Murphy, O. Faivre, B. Hedwig, M. Thomas, H. Smith and M. de Bono: Tonic signaling from O2 sensors sets neural circuit activity and behavioral state. Nature Neuroscience 15(2012), 581-591. doi: 10.1038/nn.3061 Comment in: R. Benton, Nature Neuroscience 15(2012), 501-503.
K. Milward, K. E. Busch, R. Murphy, M. de Bono and B. Olofsson: Neuronal and molecular substrates for optimal foraging in Caenorhabditis elegans. Proc Nat Acad Sci USA 108(2011), 20672-20677. doi: 10.1073/pnas.1106134109
A. J. Bretscher, E. Kodama-Namba, K. E. Busch, R. Murphy, Z. Soltesz, P. Laurent and M. de Bono: Temperature, oxygen and salt sensing neurons in C. elegans are carbon dioxide sensors that control avoidance behaviour. Neuron 69(2011), 1099-1113. doi: 10.1016/j.neuron.2011.02.023
A. Persson*, E. Gross*, P. Laurent, K. E. Busch, H. Bretes and M. de Bono: Natural variation in a neural globin tunes oxygen sensing in wild Caenorhabditis elegans. Nature 458(2009), 1030-1033. doi: 10.1038/nature07820