John Henry Wittig Jr.
Audition: Cochlear Nucleus

Personal Background

Audition: Cochlear Nucleus
A Southern Californian at heart, I was born in Los Angeles and attended college in San Diego at UCSD. Although starting out as a bioengineer, my undergraduate degrees eventually shifted to computer engineering and biochemistry. La Jolla is a hot spot for biotechnology and basic biological research. As such, I had the good fortune to work at several outstanding organizations during my time there. As a sophmore I worked at The Scripps Research Institute for Dr. Peter Ghazal, who studies the adenovirus.

John Henry Whiting Jr.

In this lab I preformed bacterial cloning and di-deoxy sequencing primarily. It was at Scripps that my love for biology was cultivated, as well as my realization that better approaches to studying biological systems need to be found in order expedite progress. Near the end of my year and a half long stint at Scripps, I shifted my majors and began intensive computer science courses. For the next year and a half I worked for an educational software development company called ScienceMedia. For the first time I was able to apply my engineering knowledge to the advancement of science by designing animations/web pages conveying scientific information. Eventually I shifted towards more research-oriented uses of my programming skill by designing biological data quantification tools (image processors) for Prof. John Newport and Prof. Bill Schafer in the UCSD biology department. Additionally, during my junior and senior years, I started working with Prof. Peter Asbeck from the Electrical Engineering department, who became my primary masters thesis advisor.

My masters thesis, entitled "Microfabricated Cell Cultures Plates for Studying Spiral Ganglion Growth", was carried out both in the UCSD microfabrication facility and the animal research facilities at the top of the UCSD VA hospital. This work was done under the tutelage of Prof. Asbeck and Prof. Allen Ryan of the medical school. It was during this time that my interest and knowledge in the auditory system expanded as I was performing modified cell culture experiments with the neurons that convey information from the cochlea in towards the brain (the spiral ganglion neurons). My coursework was primarily signal /speech processing related, gearing up for future research in the auditory system. Prof. Robert Hecht-Nielsen, my mentor/instructor, introduced me to the beautiful complexity of neural computation while I was taking his year long course entitled NeuroComputing. Through many inspirational courses and discussions, I realized my experience and training had led perfectly to a life of researching the central nervous system, addressing the two BIG questions of how information is represented and processed in the brain. In 2001, I decided to matriculate to the University of Pennsylvania Bioengineering Department to be advised by Prof. Kwabena Boahen and Prof. James C. Saunders.

Research Goals

I propose to examine how anatomical and physiological specializations enable the mammalian nervous system to encode and enhance acoustic information. In particular I am interested in the first levels of acoustic processing: encoding sound at the inner hair cell afferent synapse and enhancing sound features a single synapse later at the cochlear nucleus. In the inner hair cells, large numbers of synaptic vesicles are tethered close to each presynaptic active zone by synaptic ribbons, which likely contribute to the extended duration and temporal precision of exocytosis in these cells. I propose to computationally examine how presynaptic calcium buffering affects this synapse's ability to encode timing information. In the cochlear nucleus, various cell types enhance acoustic information, such as waveform phase, spectrum, and pitch, despite variability in neuronal components such as conductance activation threshold, maximal conductance levels, and synaptic convergence. Using a physical model with inherent component variability, I propose to theoretically explore how the cellular and network architecture of the cochlear nucleus functions to consistently enhance acoustic information. Together, my proposed aims address how specializations in the first stages of the auditory system enable the remarkable perception of sound, by overcoming the temporal limitations of conventional synapses when encoding acoustic information, and by overcoming neural component variability when enhancing it.

Project Status

In the Spring of 2003 I began developing a detailed model of the hair cell synapse to address the first part of my proposed goals. Under the guidance of Dr. Tom D. Parsons, I have constructed a computational model of the bullfrog saccular hair cell synapse. Our model is derived from experimental data, and describes the processes of calcium influx, buffered diffusion of calcium, and exocytosis. Specific attention is paid to such details as channel gating properties, spatial location of vesicles in the active zone, and probabilistic binding of calcium to the exocytitic machinery of individual vesicles. We have presented our modeling technique as a poster at ARO 2004. We are currently drafting a manuscript detailing the model's features as well as the magnitude of exocytic response under differing stimulus and buffer conditions. Future work with the model includes detailed examination of the time course of the simulated exocytic response, and response to acoustic stimuli.

Calcium buffering at the hair cell ribbon synapse. A 2-D representation of the bullfrog sacculus hair cell synapse. Labeled dimensions are in nanometers along the cell membrane (x-axis) and into the cytoplasm (y-axis). Calcium channels are found between x= +/- 150nm. The observed calcium profiles (gradients) are produces by a 25 msec depolarization to the stated test potential with 0.1 mM EGTA as the mobile buffer in the cell. The scale at the upper right indicates minimum [Ca] in uM. The large circle (center) represents the dense body a synaptic specialization in the amphibian hair cell. Small circles represent vesicles docked to the membrane or dense body (black), and found in the cytoplasm (green). Vesicles that have exocytosed during the 25 msec depolarization are filled with red and white.

The second of my proposed goals involves creating a large-scale model of the cochlear nucleus in silicon. Paramount to creating a good model is thoughtful implementation of the electrophysiological properties of individual cells, including both ionic and synaptic currents. In order to hone my understanding of cochlear nucleus electrophysiology I spent three months recording from cochlear nucleus neurons at Prof. Donata Oertel's Laboratory at the University of Madison, Wisconsin during Summer 2003. Using a brain slice technique, I patch clamped several distinct cell types to characterize their membrane properties. While in Madison, I learned a great deal about the cochlear nucleus though discussions with Dr. Oertel and other members of the auditory research community in Madison.

Recording from a cochlear nucleus slice. I patched this cell on September 20th, 2003 while visiting Prof. Oertel's laboratory. The inset shows the biocytin labeled t-stellate cell from the ventral cochlear nucleus. Current traces were elicited by both hyperpolarizing and depolarizing voltage steps from a holding potential of -50 mV. The hyperpolarizing steps activated the mixed-cation, hyperpolarization activated current Ih. Depolarizing steps activated one or more large potassium conductances, which seem to have both fast and slow innactivating components.

Currently I am collecting data from the silicon cochlear nucleus chip that I designed and submitted for fabrication during spring 2005. With 544,692 transistors in 11.33 mm2, it was fabricated in TSMC's 0.25 um CMOS process. The chip models 4410 conductance-based neurons (approximately 15% of the cat's population) composed of five distinct cell types. I have included circuitry that allows me to stimulate the neurons with voltage-clamp, current-clamp, and synaptic input from a virtual auditory nerve. All auditory nerve (input) and cochlear nucleus (output) spikes are communicated digitally using the Address Event Representation (AER), and can be routed to and from a desktop computer via an AER-USB2.0 link. Ultimately, I designed the silicon cochlear nucleus chip to be driven directly by Bo Wen's silicon cochlea and auditory nerve.

Experimental setup for the silicon cochlear nucleus. A custom PCB board (bottom) combines an AER-USB2.0 interface and a testing platform for the cochlear nucleus chip. On the computer screen (upper left) the physical mapping of input and output spikes are shown on the upper left, while spike-rasters and period histograms from several different cell types are show on the right. The oscilloscope (upper right) displays the membrane voltage and conductances from a user-selected neuron anywhere on the chip.

Refereed Conference and Journal Publications

ID Article Full Text
C32
J H Wittig Jr. and K Boahen, Silicon Neurons that Phase-Lock, IEEE International Symposium on Circuits and Systems, 2006. In press.

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M9
Merolla P, Arthur J, and Wittig J Jr. The USB Revolution. The Neuromorphic Engineer, 2(2):10-11, 2005.
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Wittig Jr., J., Parsons, T.D. Hybrid deterministic-stochastic model of synaptic vesicle exocytosis. In Preparation
 
Wittig Jr., J., Hecht-Nielsen, R. Behavioral Manifolds for Quantitative Analysis of Animal Behavior. In Preparation
 
 
Ryan AF, Wittig J, Evans A, Dazert S, Mullen L. Environmental micro-patterning for the study of spiral ganglion neurite guidance. Audiololgy and Neurootology, 11(2):134-43, 2006

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Wittig Jr., J., Ryan, A., Asbeck P.M. A reusable microfluidic plate with alternate-choice architecture for assessing growth preference in tissue culture. Journal of Neuroscience Methods, 144(1), pp 79-89, 2005.
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Feng Z, Cronin CJ, Wittig JH Jr, Sternberg PW, Schafer WR. An imaging system for standardized quantitative analysis of C.elegans behavior. BMC Bioinformatics, 5(1):115. 2004

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Wittig Jr. Encoding and Enhancing Acoustic Information at the First Stages of the Auditory System. PhD Proposal from the UPenn Bioengineering Department. Accepted April 2004
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Wittig Jr., J., Parsons, T.D. Modeling exocytosis using a hybrid deterministic-stochastic implementation. Association for Research in Otolaryngology Winter Meeting, 2003

Poster
 
Wittig Jr., J. Development of a Large Scale Model of the Mammalian Cochlear Nucleus PhD Qualifying Exam from the UPenn Bioengineering Department. May 2002
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P.G. Musial, J.H. Wittig Jr, S.K. Talwar, G.L. Gerstein. Inactivation of rat auditory cortex: effect on unit activity in ventral medial geniculate Program No. 354.6. 2002 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, 2002.

Abstract
 
Wittig Jr., J. Controlled Guidance of Spiral Ganglion Neurite Growth. Masters Thesis from the UCSD Electrical Engineering Department. June 2001
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