Cross-modality integration of sensory signals leading to initiation of locomotion

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The brain and spinal cord networks controlling and initiating locomotion in adult vertebrates, especially mammals, are remarkably complex. We will exploit a simple system, the hatchling frog tadpole, where we have defined the neurons and networks generating swimming locomotion. In particular, we have identified the "dIN" reticulospinal neurons which drive swimming. In contrast to other model systems like worm, fly and fish we can study detailed neuron and synapse function using in-situ whole-cell recording. We will show: how different modalities of sensory input converge on the key dIN neuron population; how sensory integration determines the "decision" to swim, taking the state of the tadpole into account; and how the tadpole selects and correctly implements the way swimming starts, from different possible directions and strengths. A 'systems biology' approach will operate across 3 labs at 3 levels: (1) Ca imaging and whole-cell recording will trace sensory pathways to dINs neuron-by-neuron, showing how inputs interact (excitation by skin touch or light dimming, inhibition by head pressure) to control dIN firing and so initiation of swimming; optogenetic silencing will test the role of neuron populations; (2) in situ voltage-clamp will show precisely how membrane currents determine dIN responsiveness, single spiking at rest but pacemaking when NMDARs become activated during swim initiation; (3) our detailed model of a small, coupled dIN population will test the contributions of different currents to spike threshold and synaptically induced firing; our axon growth model (lengthened to include the full range of sensory input pathways) will generate a full network connection map (of ~3000 neurons) which we will map onto a functional model to evaluate our understanding of the swim initiation process. We will extend "decision" theory down to the neuronal level where noisy sensory inputs are integrated and compared to a threshold to choose a suitable course of action.

The aim of this project is uncover basic principles about how sensory stimuli lead to the initiation of locomotion in animals. If it is successful, the results will benefit the range of scientific communities around the world studying this problem in a wide range of animals from nematode worms and fruit flies to man. The main academic beneficiaries have already been detailed.

If the fundamental principles about the initiation of locomotion and how nervous systems make decisions are revealed the project should additionally provide insights for:
1) medical profession in relation to movement disorders like Parkinsonism and spinal injury restoration.
2) drug companies and charities interested in such disorders.
3) research policy makers who will see the value of choosing the simplest and most appropriate system to investigate each problem. This also helps to reduce the use of adult mammals in research.

Tadpoles are some of the most familiar of animals to the wider public and attract attention across the whole age spectrum. They therefore provide a valuable, highly accessible entry point to explaining specific issues about brain and behaviour, what nervous systems are and how they work to make animals behave. They also provide a context for broader explanations about how scientific research is carried out, the significance of the 'systems biology' approach, and the importance and relevance of projects like ours which use simple model animals. The research will generate good imagery of tadpole behaviour, the growth processes of model nerve cells as they form circuits in the brain, and the activity patterns of all the neurons in the tadpole's nervous system as it responds to stimulation and swims away. These will be suitable to popularise the study of simple model animals and their brains in websites and museums and science centres like '@ Bristol' (where we have already had some participation).

In terms of training, the physiology RAs will learn specific techniques and broad experimental approaches which will prepare them for research careers in any part of academic, medical or pharmaceutical neuroscience. It is critical that the UK continues to train highly skilled electrophysiologists. These techniques remain essential for providing detailed information on the properties and connectivity of neuronal networks at all levels; however, researchers with suitable skills are becoming scarce. All RAs will gain in experience of working as a group, research organisation, data analysis and presenting their results orally and by writing papers. The computational RA will gain experience working and communicating with biologists, while the physiologists will gain closer insight into the use of computer models and communicating with mathematicians, increasing the effectiveness of the systems biology approach.

Since our research is at a fundamental level we would expect that the true impact of our research outputs on understanding of adult animals will be slow and act cumulatively over a period of many years, as our findings encourage targeted studies into equivalent processes in progressively more complex systems. The impacts of researcher training will be more immediate, contributing to a skill base relevant to all sectors.

Lastly, the tadpole research on which this project is based is recognised internationally but is carried out almost entirely in, and identified with, the UK. The two UK labs with the necessary expertise, Bristol and St Andrews, will collaborate on this project. The contribution that the success of research output from this model system makes to international neuroscience raises the profile of UK research in this area.