Many neuroscience studies have shown that specific cell types within a brain network have unique contributions to behavioral output and that even a single neuron makes connections to large portions of the brain. Therefore, in order to truly get at the problem of uncovering brain function we need measurements with cellular specificity across the whole brain during behavior. As such, due to technological limitations, our current understanding of global brain circuit mechanisms is extremely limited. My recent development of optogenetic functional magnetic resonance imaging (ofMRI) technology provides a partial solution. However, challenges still remain: how do you non-invasively deliver cell type specific neuromodulation? How do you image the whole brain function in freely moving subjects? In this Pioneer Award proposal, I propose a novel approach that enables non-invasive, cell type specific, whole mammalian brain imaging in freely moving subjects. In particular, we propose to develop a non-invasive cell type specific stimulation in mammalian brain termed ?Mechanogenetics? and a functional ultrasound (fUS) imaging technology that can image whole brain function in awake-behaving animals. Mechanogenetics will utilize mechanosensitive ion channels expressed in selective cell types enabling neuromodulation using mechanical deflection from ultrasound probes delivered non-invasively instead of using optical probes that need to be surgically implanted. For imaging, miniaturized functional ultrasound technologies with high-resolution, 3D real-time imaging capability that can be mountable on the subject's head will be developed. The resulting ?Mechanogenetic functional ultrasound (MfUS)? technology will enable non-invasive flexible modulation of neuronal populations while the impact of such modulation can be monitored in freely moving animals across the whole brain with high spatiotemporal resolution. Instead of measuring large-scale neuronal activity associated with binary behavioral readout or complex behaviors related to single neuronal populations, my goal is to establish a new paradigm for understanding brain function, where cell type specific whole brain function during behavior can be monitored continuously. With such data, combined with computational modeling, whole brain algorithms of behavioral control can be constructed. Furthermore, the Mechanogenetics technology can bring cell type specific neuromodulation closer to human translation. Functional ultrasound technology development will also enable human brain function monitoring in non-laboratory settings. This will ultimately enable brain circuits to be engineered the way electrical engineers engineer electronic circuits allowing direct treatment of neurological disease including Alzheimer's disease and related dementias or directly manage pain addressing the opioid crisis.
Due to the extreme complexity of the brain, we still have a very limited understanding of how different cells in our brains work together to give rise to our behaviors. Through development of novel technologies that enable non-invasive, precise, selective excitation and/or inhibition of brain cells while measuring high-resolution videos of the associated whole brain interactions during behavior, we aim to reverse-engineer the brain function algorithms underlying behavior. Upon success, these measurements will enable quantitative description of normal brain function and how it changes during brain disorders including Alzheimer's disease and related dementias or pain leading to opioid crisis, which in turn will enable us to systematically design therapies that can restore normal brain circuit function.
