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Functional connectomics of a simple brain centre for discrimination and memory

Reference	BB/N007948/1
Principal Investigator / Supervisor	Professor Cahir O'Kane
Co-Investigators / Co-Supervisors	Dr Liria Nakagawa
Institution	University of Cambridge
Department	Genetics
Funding type	Research
Value (£)	461,360
Status	Completed
Type	Research Grant
Start date	01/05/2016
End date	31/10/2019
Duration	42 months

Abstract

Animal brains can selectively encode an enormous range of sensory information, and this sets the limits of memory. This universal challenge for animals has elicited common solutions across phyla for coding and discriminating among sensory cues - typically using sparse and distributed ensembles of central neurons that fire selectively to specific input. Our goal is to understand the circuit and synaptic mechanisms that govern this - for example the mechanisms that regulate sparseness, and adapt coding mechanisms to need. We use one of the simplest discrimination centres known, the mushroom body of the Drosophila larva; this comprises hundreds of neurons, rather than billions as in human cortex, but still supports complex discrimination and learning. A complete description of the circuitry of such a centre can be a community resource, and an engine for generating and testing models of the neural and synaptic mechanisms of cognition and behaviour. This resource, a connectome, is now feasible in the Drosophila larval brain; by contributing to a global larval brain connectome project, we will identify all the major pathways that provide sensory information in the mushroom body, monitor it, and regulate it. We will achieve this by serial electron microscopy reconstruction of neurons that synapse with the major neuronal classes that innervate the input region, the calyx, of the first instar larval mushroom body, thus generating a comprehensive neuronal and synaptic map of calyx input and output pathways. We will identify transgenic expression tools, to verify the wider generality of this map, and allow the identified neurons to be monitored and manipulated. Finally, we will test selected hypotheses for the circuit mechanisms that mediate global regulation of selective sensory coding in this centre. From our work, we expect a comprehensive framework for circuit models for the regulation of sensory discrimination, that will also be applicable to more complex systems.

Summary

Complex behaviours in animals, including humans, are made possible by the ability of brains to distinguish among an enormous range of sensory cues, and to selectively form and recall memories associated with specific cues. Brains have evolved ways to recognise and remember enormous numbers of sensory cues. It is estimated that humans can distinguish a trillion odors; we can remember very many faces or inanimate objects; and the 2014 Nobel Prize in Physiology and Medicine recognised O'Keefe, Moser and Moser for showing how mammalian brains encode sensory information for specific places. We want to understand the principles of the brain circuitry that recognises and discriminates such a range of cues, and that underlies behaviours that depend on this. Animals as diverse as humans and fruitflies have found common solutions to this challenge - distinct sensory cues, like faces, sounds or smells, cause sparse activity in few scattered neurons in higher brain; and different cues are distinguished by activating different scattered neurons. Since humans have millions of times more neurons than flies, they can distinguish and remember enormously more sensory objects- but the principle of sparse coding is shared between them. How are representations of sensory objects formed and regulated, to maximise the ability of the brain to discriminate among them, and tune representations to the needs of the animal? They must be regulated optimally: if too few neurons respond to a given sensory stimulus, the brain may not take notice of it; but too many, and the neurons that respond to different sensory cues will overlap too much, and the different cues will not be distinguished. Also, many routine sensory cues simply do not have to be remembered - the impact of a sensory experience depends on circumstances like wakefulness, where our attention is directed, or how aroused we are. To answer this question, we need to know the exact organisation of the underlying circuitry: all the neurons involved, the contacts they make, the stimuli they respond to, and their effects on each other. This is easiest in a brain that has few neurons, but still high sensory discrimination, used to form and retrieve memories. Therefore, we will describe the complete circuitry for sensory discrimination in the fruitfly larva (maggot); the main brain structure for this, the mushroom body (MB), has only hundreds of neurons in fruitfly larvae, compared to many billions in humans. A comprehensive map of the neurons and their connections will tell us which other brain regions, or sensory organs, provide information to the mushroom body, or use information provided from it. We, and other scientists who access it, can then formulate and test theories for how the circuitry encodes and regulates specific sensory representations. This will be the first such brain map for any animal. We will do this by tracing each neuron individually through many consecutive thin sections of a larval brain. We will analyse sections at very high magnification, to reveal each neuron's contacts with other neurons. We will then try to identify genetic fly stocks that can target expression of other genes to those neurons, allowing them to be labelled fluorescently, used to monitor neuronal activity, and activated or blocked specifically in living preps. We will prioritise neurons whose anatomy suggests belonging to the circuits that regulate the whole of the MB input region. Finally we will test specific models of how regulation of the MB affects its ability to process sensory information: we will block or activate specific neurons using genetic means, and test the effects of this on activity of other identified neurons, or on the abilities of behaving larvae to discriminate odors. Our work will generate a comprehensive resource for the wider scientific community, to make predictions and assess them experimentally. We expect predictions also to be applicable to more complex brains.

Impact Summary

The work proposed here is basic underpinning research, to reveal the logic of how the brain recognizes, discriminates and remembers complex sensory objects. The principal beneficiaries will be academic, but the insights are likely to interest a wider field. First, work on the calyx can provide circuit models for similar centers in the mammalian brain, e.g. sensory cortex or amygdala. The latter is where memory of fear-associated events or stimuli is formed, and is important for socio-emotional behaviour, and implicated in diseases of sensory processing, including autism, schizophrenia, and posttraumatic disorders. It receives sensory information from different modalities, and its main output is the hypothalamus, which controls our physiological responses, but it is not clear how sensory information is integrated to form fear memories. Regulation of the responsiveness of higher brain regions to sensory stimuli may play a role in disease conditions: autistic individuals have deficits in controlling the levels of brain activity in sensory cortex and amygdala in response to sensory stimuli (J Am Acad Child Adoles Psychiat 52:1158-72, 2013). Research in this field is largely at the behavioural level, and understanding of sensory regulation at the cellular and synaptic level is still rudimentary; insights from processes that control the responsiveness and integration of sensory stimuli in the calyx may therefore provide circuit models of predictive value for neuropsychiatric disorders. Finally, understanding the influence of nutrient sensing on behaviour and brain function may also provide models for human metabolic diseases. Second, there are applications of the science of odor discrimination in insects. Chemical attractants (e.g. pheromones) and repellents (e.g. DEET) have long been in use against insect pests and disease vectors. The former in particular have a less deleterious environmental impact than insecticides, since they can be adapted to specific insects.More recently there has been tentative but increasing interest (and investment) in insects as chemodetectors for substances such as explosives, e.g. www.inscentinel.com/ (based at BBSRC Rothamsted), or landmine detection (www.defense.gov/specials/bees/natures.html). While peripheral olfaction mechanisms are most directly applicable to these problems, understanding higher brain mechanisms can provide valuable background understanding such as the potential discriminatory power of the system. Third, understanding the nature and function of brains is of wide public interest, largely because of questions such as what makes us human, and our understanding of animals and their welfare requirements. Indeed, the more sophisticated we are at interrogating insect behavior, the more sophisticated we realize it is. Public interest is shown by regular media articles on Drosophila behaviour e.g. role of olfactory learning in courtship (http://www.bbc.co.uk/news/science-environment-19299068), interpretation of complex visual scenarios (http://www.telegraph.co.uk/science/science-news/10758291/Fruit-flies-outdo-Tom-Cruises-Top-Gun.html), and by the fascinated response of school groups to regular outreach talks that we give. Interaction between nutrient sensing and brain function is also likely to be of public interest, given awareness of metabolic diseases. Fourth, insect behavior, particularly locomotion and vision, continues to provide blueprints for robotics (e.g. Floreano et al., Miniature curved artificial compound eyes, PNAS 110:9267-72; and 245 papers in PubMed on insects and robots/robotics). So far there is less robotic work based on insect sensory discrimination and associative learning, but since computers are yet nowhere near as good as animals at object recognition, there is both need and potential. This depends entirely on a better understanding of the circuitry, which is the major goal of our work.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Neuroscience and Behaviour
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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