Bruce Wheeler - US grants

It is now possible to make microelectrode arrays capable of stimulating and recording from many neurons at intervals approaching the dimensions of the neurons themselves. The arrays proposed offer an order of magnitude increase in observational power over conventional techniques, with the promise of hundredfold improvement in the future. The technology is basic to the study of neural populations just as the microelectrode is basic to the study of single cells, and will provide neurobiological systems. Similarly, these tools are critical to the development of human neural protheses which must have multidimensional interaction with various neural subsystems. The primary goal of this research is to develop the planar electrode array as a stimulation and recording tool for research with the brain slice preparation. Dr. Bruce Wheeler has successfully applied a planar microelectrode array to the hippocampal brain slice preparation demonstrating that the array makes it possible to record from and stimulate a significant fraction of the slice at 200 micro meter intervals simultaneously or in an arbitrary pattern in time and space. Many experiments currently done with one or two electrodes can be repeated with much greater observational power to survey the possible the state of the different slice subregions. The number of channels is vastly greater than that possible with microdrives or manipulators. The efficiency of the experiment is multiplied b the increase in recorded data and the increase in the number of stimulus points, while the experimenter's efficiency is aided by the fact that all electrodes ate positioned merely by placing the slice on top of the array. A technical advantage of the array does not occupy any of the restricted space above the slice, this leaving room for additional electrodes and probes to stimulate, record, measure ion concentrations, and administer drugs. Still, the power of the array lies in its ability to give the experimenter a two dimensional image of slice activity and the ability to control or stimulate it as a system.

In order to optimize interdisciplinary approaches that capitalize upon new technical and theoretical developments, a Center for the Neurobiology of Learning and Memory is being established at the Beckman Institute (currently under construction) of the University of Illinois at Urbana-Champaign . This center will serve as 1) a Resource Center, providing advanced facilities for the study of the learning and memory process, including optical imaging (for histological studies), multi-electrode array recording (to allow functional patterns of interactions among neurons to be examined), and rapid tissue freezing (for assessment of sub-cellular dynamics); 2) a Research Center that fosters communication and collaboration among scientists pursuing common and related problems of memory and neural plasticity; 3) a Training Center which prepares graduate and postdoctoral investigators for research careers in learning and memory, and 4) a Recruiting Center that to attract outstanding young people to scientific careers. This program of scientific development and interaction is taking advantage of the unusual resources of the Beckman Institute and the University of Illinois Urbana-Champaign campus in neurobiology, interdisciplinary collaboration and cooperation, and strengths of the component disciplines of neural and behavioral sciences. Technical foci of the Center include large array neurophysiological recording facilities, with which the interactions among brain regions during learning are studied; rapid freezing facilities for examining brain slices in vitro, (with which the nature of plasticity at the level of the synapse is studied), and neuroanatomical imaging and analysis facilities (where memory processes are studied at levels ranging from the molecular to the morphological). Several types of learning are being studied, including discriminative conditioning, acquisition of motor skill, acquisition of acoustic discriminative ability, and the traditional psychological animal learning tasks such as mazes. In addition, current "models" of memory (such as long-term potentiation and kindling) are being examined. The function of the Center for the Neurobiology of Learning and Memory is to advance our knowledge of brain substrates of learning and memory from the cellular and molecular to the integrative brain system levels.

9816376
Wheeler

This award provides funds to permit Dr. Bruce C. Wheeler, Department of Electrical and Computer Engineering, University of Illinois at Urbana-Chamoaign, to pursue with Dr. Sung June Kim, School of Electrical Engineering, Seoul National University, for 24 months, a program of cooperative research on micropatterned neural networks and microelectrode arrays. In this project, the neuronal cell patterning expertise at the University of Illinois is coupled with the microelectronics fabrication expertise at Seoul National University. The research team at the University of Illinois has shown that novel surface treatment can be used to grow micropatterned neural networks in culture. Essential elements of the technology are the ability to retard cell attachment and growth from background areas, to confine somata to desired positions, and to control axonal extension so as to create an oriented network. Microlithographic techniques, primarily microcontact printing, will be used to create patterns of biomolecules on planar culture surfaces in order to effect control of position of attachment and extension of neurons and glia. The Korean team will greatly enhance the Illinois efforts by making passive electrode arrays available on a routine basis and pursuing novel fabrication technologies for electrode design. In addition the Korean team will design and fabricate arrays incorporating active electronics for stimulation, amplification, and multiplexing. Their instrumentation goal is to obtain better signal to noise ratio by placing first stage amplifiers nearly in contact with the low level signal source. The Korean team has substantial capabilities for microelectronic fabrication and already has made devices for neural signal amplification. Collaboration on this project will provide a biological context in which to improve their designs, for the benefit of both teams.

The complementary expertise of the two research teams will be mutually beneficial and will advance knowledge in this important field of research. The collaborators are highly regarded scientists in their respective fields of research. Korean and American graduate students will be included in the teams of collaborators. This project is relevant to the objectives of the U.S.-Korea Cooperative Science Program which seeks to increase the level of cooperation between U.S. and Korean scientists and engineers through the exchange of scientific information, ideas, skills, and techniques and through collaboration on problems of mutual benefit. Korean participation is supported by the Korea Science and Engineering Foundation (KOSEF).
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EIA-0130828 -Bruce C. Wheeler-University of Illinois-BITS: Information processing in Designed Neuronal Circuits

BITS: Information processing in Designed Neuronal Circuits

The aim of this project is to enhance our understanding of information processing by small numbers of neurons arranged in designed circuits. This is an ideal time for this initiative because:

We can intentionally design neuronal microcircuits due to progress in serum free media to support relatively pure neuronal populations, in microlithgraphy as applied to the deposition of proteins and other biomolecules to surfaces, and in understanding of the conditions under which sparse pattern populations of neurons become functionally active in culture.

We can study the information processing capabilities of these neuronal circuits due to advances microelectrode array technology, permitting both stimulation and recording of electrical activity, as well as the supporting real-time data acquisition technology.

We can analyze the data utilizing theories of neural coding derived as applications of rich theoretical foundations in signal processing and communications theory.

We have three specific goals, creation of reliable, repeatable, robust neuronal circuits of cultured hippocampal neurons. Stable circuit behavior is essential to further investigation of information processing.

The first aim emphasizes geometric properties, including guiding axonal extension, the second aim emphasizes functional properties, and the third aim is neuronal information processing. Models to be evaluated include rate codes, precise timing codes and phase synchronization codes.

DESCRIPTION (provided by applicant): The goal of this research is to facilitate efforts to understand brain function. The immediate goal is the construction of a neural cell culture system that recapitulates with one of the brain's principal memory circuits - the trisynaptic pathway of hippocampus: entorhinal cortex (EC), dentate gyrus (DG), CA3 and CA1 regions. The brain on a chip technology employed combines precisely controlled cell culture, state-of-the-art cell culture media, large scale microelectrode arrays, newly developed directional microtunnels for guiding neural growth with near patch-clamp quality recording of axon potentials, and advanced algorithms for detecting patterns of activity distributed across many neurons and electrodes. Specific hypotheses will be tested as to the computations performed by the different tissues, how they their responses change with stimulation, and how network level feedback influences how information is represented. The research is highly innovative and highly risky. The potential payoff is substantial, as the paradigm being created and investigated provides a basis for others to investigate many hypotheses as to normal and abnormal brain circuit function in a distributed fashion, whereas current practice is for single neuron or average activity. The potential exists for the creation of a new and more powerful technology for the routine screening of new drugs for their effects on memory. The specific aims are: Aim #1: Develop the technology for culturing dissociated neural networks of two distinct anatomical regions with connections comprising axons extending unidirectionally through guiding microtunnels. Develop protocols for stimulation, recording and analysis. Test that dissociated tissues maintain their salient in vivo properties. At the end of Aim 1, we will have established functional capability (stimulation, characterization), and also will understand differences in the representation of information in each hippocampal subregion Aim #2: Test the principal computational and learning properties of two components: DG and CA3. At the end of Aim 2, we will have established circuit responses distinct and appropriate to the two tissue types and exploited their likely very different connectivity and response patterns to induce plastic change. Aim #3: Evaluate CA1 as a correlator and novelty discriminator in the completed EC-DG-CA3-CA1 circuit, including feedback to the entorhinal cortex. Learn how feedback reinforces circuit responses. Aim #4: Test the hypothesis that a very effective means of inducing repeatable patterns of activity is through stimulation at theta frequencies (4-10Hz) with phasic encoding. Completion of these aims will provide a novel engineered platform for basic and applied science. It will increase our understanding of the advantages of staged signal processing in information analysis.