Neuroscience research on animal models plays a fundamental role in improving the diagnosis and treatment of human neurological disorders, because of the capacity for genetic and pharmacological manipulations. Among the most widely used methods to investigate brain function, electrophysiological recordings benefit from a high temporal resolution, but are invasive and have a limited spatial coverage. Conversely, blood oxygenation level-dependent functional MRI is noninvasive and provides full brain coverage, but cannot quantitatively and accurately localize neural activity in space and time because of the complex neurovascular coupling. A novel MRI technique, termed Lorentz effect imaging (LEI), which detects the ionic currents and surrounding water molecules induced by neural activity, was proposed to address these limitations. This technique has been applied to image ionic currents in solution with current densities similar to those induced by neural activity as well as sensory nerve action potentials in the human median nerve in vivo with a millisecond temporal specificity. Given these promising results, it is hypothesized that LEI can be further developed to image neural activity in the brain with a high spatial and temporal specificity across functional networks. The goal of this project is to develop such a noninvasive and specific functional neuroimaging technique for animal research, which would have a significant impact in neuroscience. Because of potential confounding factors such as physiological noise, the application of LEI to the brain requires a further increase in sensitivity. In addition, its validation requires a robust stimulation paradigm that can be accurately controlled in space and time. These two requirements can be met by using a 7 T animal MRI scanner with a significantly higher field strength and gradient amplitude as compared to the human scanner used previously, as well as a novel transgenic mouse model expressing the light-activated ion channel Channelrhodopsin-2 (ChR2) in selected neurons throughout the brain, which can be activated in vivo by photostimulation with visible light.
Three specific aims are proposed.
Aim 1 is to demonstrate the feasibility of LEI to image neural activity in the brain in vivo by photostimulating the cortical surface of anesthetized ChR2 transgenic mice and by using a careful experimental design to remove any confounding hemodynamic modulations.
Aim 2 is to demonstrate the ability of LEI to accurately localize neural activity in space and time by varying the spatial extent or timing of the photostimulation.
Aim 3 is to demonstrate the ability of LEI to track and map neural activity across functional networks by photostimulating the olfactory bulb and by using different activation paradigms designed to selectively track neural activity in different regions of the olfactory neural circuit or to simultaneously map all functionally connected areas.
The goal of this project is to develop a novel MRI technique for animal functional neuroimaging combining the high temporal specificity of electrophysiological recordings with the noninvasiveness and high spatial coverage inherent in MRI. Such a technique has the potential to noninvasively track and map neural activity in vivo with a high spatial and temporal specificity across the whole brain, which would significantly enhance our ability to investigate the function of the nervous system and hence improve the understanding, prevention, diagnosis, and treatment of many neurological and psychiatric disorders.
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