Integration of functional and structural knowledge across scales to decipher information processing in the mammalian brain

The mammalian brain is one of the most complex structures known to mankind. A lot of this complexity stems from the fact that brains operate on a plethora of time and length scales: neurons stretch for millimetres, yet the connections between neurons are of nanometre scale. Understanding how information is processed in this complex structure is a critical prerequisite for understanding dysfunction such as psychiatric disease as well as for building advanced "artificial intelligences". This, however, can only be achieved if the activity of neurons can be linked to the structure of the network of neurons that provides the substrate for neuronal computation. The last decades have seen astonishing progress in using electron microscopy to decipher the logic of neural circuits. Electron microscopy, however, is time-consuming and as electrons do not permeate into tissue for more than a few nanometres, brain tissue has to be cut into thin sections before or during electron imaging. This has so far limited electron microscopy to relatively small tissue volumes, cubes with up to few 100 um length. X-rays, on the other hand, can penetrate tissue for long distances (millimetres or even centimetres). Synchrotrons produce the most powerful X-rays and there is an ongoing revolution in synchrotron technology to further increase the power - the number of photons as well as the quality (coherence) of the X-ray beams - by many orders of magnitude. The ESRF synchrotron (where the UK is a member country) is the first high-energy synchrotron to have received such upgrade. In this project we propose to fully make use of this new X-ray technology and further develop X-ray tomography, the ability to obtain 3-dimensional images without cutting, to allow us to resolve fine neuronal structures from large (several cubic millimetre) pieces of brain tissue. We will combine this new X-ray tomography with prior functional imaging in living mice in order to link the neural activity to the neural structure. We will subsequently perform high resolution electron microscopy on parts of the tissue to combine detailed identification of synaptic contacts between neurons with large-scale information about neuron identity and neuronal processes from X-ray imaging. We will initially apply this new approach to understand how information is transformed in a most prominent brain region, the mouse olfactory bulb, that processes information from the nose for the rest of the brain. Due to the high throughput of synchrotron X-ray imaging we will be able to directly compare the same, genetically labelled, circuits between different individuals. This will allow us to answer the long-standing question how different or alike two mammalian brains are. Finally, combining all of the above - functional imaging, synchrotron X-ray imaging and electron microscopy - enables us to describe the logic of how information is processed by the network of neurons in the olfactory bulb. Altogether, we will develop a new tool to understand how neural circuits process information. Establishing synchrotron X-ray imaging together with functional imaging and electron microscopy in biological tissue will, however, have even wider potential to become a versatile tool to understand the properties of cells and subcellular structure (viruses, cancer microenvironments, immune niches) in the context of entire tissues (lung, liver, thymus). Thus, by developing this joint approach we will not only solve immediate neuroscience questions but also develop a new physical science approach to life science and grow a group of researchers equally at home in both specialties.