Functional connectomics of a simple brain centre for discrimination and memory

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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.