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OlfSwitch: Neural circuit switches from molecules to behaviour

Periodic Reporting for period 3 - OlfSwitch (OlfSwitch: Neural circuit switches from molecules to behaviour)

Reporting period: 2018-07-01 to 2019-12-31

Our group is interested in the general problem of how the brain processes information in order to make behavioural decisions. Individual brains cells (neurons) are connected together in a complex network. It is believed that the set of connections in this network are a key determinant of brain function – an analogy is often drawn to the layout of electronic circuit diagrams. Our major goal is to understand what we call elementary circuit motifs, small networks of neurons that serve a very specific function and whose logic may be widely conserved across different kinds of brain. Such basic research into brain function is a crucial complement to applied research in areas such as neurodegeneration and mental health, which are huge issues for our society – especially in the ageing population in Europe.

Our work principally uses the fruit fly (Drosophila melanogaster). This has a tiny brain with just 100,000 neurons (one thousand times fewer than a mouse, one million times fewer than a human) but is nevertheless capable of many sophisticated behaviours. Furthermore we can identify and manipulate the same neurons from one fly to the next using genetic tools. This allows us to study how they encode information about the outside world, how this contributes to behaviour and how particular circuit motifs are specified during brain development by the action of control genes. This grant will focus on the processing of smells, because they require little brain processing before contributing to decision processes. We will focus on sexually dimorphic circuits and on pathways mediating unlearned responses to different kinds of odours. This will enable us to understand how genes can sculpt circuits to specify different behaviours and how signals with opposite or similar behavioural significance are integrated in the brain. We can address these issues with great precision in the fly brain, but we feel that are results are very likely to reveal principles conserved across species.
In this first project period, we have assembled an excellent team, developed much of the technical infrastructure to enable our project and made useful scientific advances in several areas. On the technical side we have published an important neuron analysis tool that will help with multiple areas of the project (see NBLAST image) as well as developing new molecular genetic tools for labelling neurons in the brain.

We have developed approaches to measure gene expression in identified neurons down to the level of single cells. We are now using this to identify the genes expressed in our neurons of interest and determine how gene expression differs between males and females.

We have made substantial progress in setting up sophisticated behavioural apparatus so that we can carry out highly quantitative studies of behaviour in wild type and experimentally manipulated animals.

We have also made significant progress in integrating light and electron microscopy data. This now enables us to carry out EM tracing in collaboration with the newly established connectomics group in the University of Cambridge Zoology Department and colleagues at HHMI Janelia Research Campus in the USA. This has already revealed new and unexpected connectivity in both sexually dimorphic and general odour circuits. We are now planning functional investigation of these results.
The ability to map circuits with synaptic resolution through whole brain electron microscopy data (often referred to as EM connectomics) will be transformative for our area of neuroscience. The toolset that we have built up that enables us to link connectivity and morphology data derived from EM with many different experimental approaches in a particularly effective model system leaves us very well-placed to produce a major impact through this grant. We believe that our studies in the fly will have a major impact on how the field understands brain circuits and also on how researchers using other model systems will study the brain in future. Fundamental research into brain circuits will provide the context for applied studies of brain dysfunction.
NBLAST clustering reveals anatomical subtypes of male P1 neurons