Download Draft Proposal to the Keck Foundation KECK CENTER FOR

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.