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Download Draft Proposal to the Keck Foundation KECK CENTER FOR
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Draft Proposal to the Keck Foundation KECK CENTER FOR INTEGRATIVE IMAGING OF DYNAMIC NEURAL PROCESSES Principal Investigators: Enrico Gratton, William Greenough, Martha Gillette, and Andrew Webb A major challenge facing biology is understanding the working of the brain. Brain function emerges from the interaction of subcellular, cellular, and network levels. Each must be understood at its own level and in terms of interactions with the other levels. Among the most useful tools developed in recent years to attack this problem are the methods of functional dynamic imaging that can be applied from the level of the functioning human brain to that of cellular and molecular biology and biophysics. We propose the KECK CENTER FOR INTEGRATIVE IMAGING OF DYNAMIC NEURAL PROCESSES that spans this breadth of brain function and that uses three principal technologies, magnetic resonance, near-infrared (near-ir), and multiphoton fluorescence microscopy, to complement each other in analyzing dynamic brain functions and to conjointly understand the biological sources of the signals utilized by each technique. The fMRI BOLD contrast technique, which measures deoxyhemoglobin, can be validated because near-ir techniques can quantify both oxyhemoglobin and deoxyhemoglobin. Time resolved near-ir techniques can detect light scattering which reflects actual neurophysiological activity, providing much higher temporal resolution than fMRI. New developments in multiphoton fluorescence techniques are capable of determining proximity of fluorescent probes in the 10 nm to 300 nm range. Below 10 nm fluorescence energy transfer techniques are highly accurate; above 300 nm, conventional optical and multiphoton techniques can be used. The availability at the Keck Center of the new technologies for imaging at the macro and micro level brings together more than 25 researchers from physics, biology, neuroscience, psychology, chemistry, and engineering to form a unique alliance that can put us in the forefront of these innovative functional dynamic imaging technologies applied to the neurosciences. BRAIN The organization of the Keck Center, shown in the diaKECK gram, reflects the continuum CENTER across which biological signals can (Gratton, be fruitfully processed. The PIs Greenough, Webb, Gillette) are unique in that they have FUNCTIONAL NEAR worked across the spectrum, MRI Common Resources INFRARED ranging from brain functional Image/Signal Analysis Display imaging (near-ir and fMRI) to a Technical Development wide range of microscopic CELLULAR SUBCELLULAR/ techniques at the cellular and NETWORKS MULTIPHOTON MOLECULAR subcellular levels. MICROSCOPY A key component of the proposed Keck Center is the emphasis on technical development at points across this spectrum. At the micro level, techniques, such as single molecule detection, fluctuation correlation spectroscopy, multiphoton microscopy, and lifetime resolved microscopy, are combined with genetic or exogenous optical markers to provide new ways to study processes such as cellular trafficking, vesicle membrane fusion, locally regulated dendritic ionic flows and protein synthesis, and rhythmic activities of individual neurons and neural networks. New engineering breakthroughs in our group also allow magnetic resonance imaging and spectroscopy to be performed on single neurons. In the Keck Center, we will study functioning biological systems at all levels from the molecular to that of the cellular network. At the macro level, a principal goal is understanding the relationship of signal fluctuations to biological phenomena in brain imaging. We have developed near-ir methods to explore the cerebral cortex non-invasively and in real time. Combining fMRI and near-ir provides unique detailed quantitative measures of the hemodynamic and neuronal processes that reflect regional brain activation. Recently, we have demonstrated that near-ir measurements can be performed simultaneously with fMRI and we have learned that some assumptions used to interpret fMRI signals provide an incomplete picture of the hemodynamic changes. The combination of high temporal resolution of near-ir and high spatial resolution of fMRI can provide entirely new information regarding dynamic brain function. This kind of interdisciplinary approach will enable similar breakthroughs at other levels as well. By housing the Keck Center in the Physics Department, we will integrate biologists and physicists to foster rapid and profound developments in neural imaging. The bi-directional technology transfer between physicists and biologists will equip each with the basic skills of the other discipline and produce a new breed of multidisciplinary scientists. The proposed Keck Center is a high risk, large potential return enterprise. The risk is in the novelty of the approach, which is at present not in the mainstream of research, but rather at the forefront of imaging research in neuroscience. Total requested: $5,000,000.