Interdisciplinary Research Projects

Interdisciplinary Analysis of Epileptic Activity in Neural Tissue

PI: David Pinto, Asst. Prof., Neurobiol. &Anatomy and Biomed. Engineering

Co-Investigators:

• James Burchfiel, Prof., Neurology
• Maiken Nedergaard, Prof., Center for Aging &Develop. Biol.
• G. Bard Ermentrout, Prof. Mathematics, Univ. of Pittsburgh
• William Troy, Prof. Mathematics, Univ. of Pittsburgh

More than ever before, research into the causes, treatment, and prevention of epilepsy requires an interdisciplinary approach, marshalling the full resources of modern mathematical, experimental, and clinical strategies to understand this complex disorder. In this project, we capitalize on the shared expertise of our group to explore the mechanisms of epilepsy using both experiments and computer modeling and to cultivate the translation of our results into clinical practice.

Our explorations will encompass three central questions:
1. How do epileptic events in the brain begin? Can we interrupt the transition from normal to explosive activity?
2. How does epileptic activity spread into adjacent brain regions? Can the spread be predicted and contained?
3. What controls the return to normal activity? How is brain tissue altered once the event has passed?

Our hope is that our unique multidisciplinary venture will foster both new ways of conceptualizing this mysterious disorder and new strategies for controlling or curtailing epilepsy in a clinical setting.

Adult Neurogenesis and Adaptive Vocal Plasticity

PI: Kathy Nordeen, Prof., Brain &Cognitive Sciences

Co-Investigators:

• Co-PI: Steve Goldman, Prof., Neurology
• Eliot Brenowitz, Prof., Psychology, Univ. of Washington
• Ernie Nordeen, Prof. Brain &Cognitive Sciences

The transplantation of embryonic stem cells into the brain is certain to become a therapeutic tool in neurology. Yet, despite progress made in understanding the regulation of neural stem cell production and differentiation, very little work has focused on how the behavioral output of existing neural circuits will be affected by the insertion of new, and functionally “naïve” neurons. The goal of this research is to investigate how naturally occurring neuronal replacement contributes to changes in adult behavior. Specifically, we will use several different methods to reduce the extent to which new neurons are incorporated into the motor pathway that controls avian song behavior, and test whether these manipulations reduce the rate at which song behavior changes after adult deafening. Also, we will assess whether deafening affects motor driven gene expression in neurons that are added in adulthood. The work has implications for understanding the biological nature of “error signals”, and the neural substrates upon which they act to recalibrate sensory and motor circuitry. Additionally, the studies provide a unique opportunity to assess whether new neurons added into circuits controlling established, learned behaviors require training in order to be behaviorally adaptive.

Peripheral Inflammation Contributes to the Development of AD

PI: Stephanos Kyrkanides, Assoc. Prof., Dentistry

Co-PI: M. Kerry O’Banion, Assoc. Prof., Neurobio. & Anatomy

The purpose of our investigation is to study the effects of arthritis on the brain using mice. As the aging population increases and arthritis presents in 80% of humans over the age of 65, it becomes very important to understand the effects of arthritis outside the joints. Studies like the present one will allow us to better understand the connection of arthritis with the brain and evaluate whether arthritis plays a role in the development of diseases such as Alzheimers.

Development of transgenic models to modulate neuronal CGRP/AM receptor function

PI:Ian Dickerson, Assoc. Prof., Neurobio. &Anatomy, Pharm/Physiol.

Co-PIs:

• Anne Luebke, Assoc. Prof., Neurobio. &Anatomy, Biomed. Engr.
• Maiken Nedergaard, Prof., Surgery, CADB
• Carl Pinkert, Prof., Pathology &Lab Med., CADB

Calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) are neuropeptides that are important for control of vasculature in hypertension and migraine. Despite their broad distribution in the brain, elucidation of the role of CGRP and AM has been hampered by lack of animal models to enable physiologic studies. The proposed studies will generate new animal models for CGRP and AM receptor function in the CNS, and will use these transgenic animals to study the role of CGRP and AM in hearing and in control of cerebral vasculature.

Post-Doctoral Awards

Xiaorong Xu

Mentors:

• Peter Schrager
• Roman Giger

I  currently study neuronal development, particularly the formation of the initial segment in spinal motor neurons, in Dr. Peter Shrager’s laboratory, using cell biology, molecular biology and electrophysiology techniques. I have become interested in research in Dr. Roman Giger’s laboratory, which is focused on axon regeneration after spinal cord injury. This fellowship will provide me an opportunity to gain new knowledge and acquire techniques in a related area. I intend to find an independent research position in an area related to spinal cord injury in the future.

Seth Perry

Mentors:

• Harris Gelbard
• Lukas Novotny

This proposed research will establish a uniquely interdisciplinary collaboration between a biomedical neuroscience laboratory, and a nano-physics/nano-optics laboratory, for development of high-resolution optical microscopy techniques for biomedical research, and ultimately high-throughput disease detection technologies. In doing so, this research will also provide valuable cross-disciplinary training for the candidate, and help seed further independent funding and career advancement. The ability to image biological materials at the single-molecule level is becoming increasingly important for advancing biomedical research. Traditional diffraction limited optical microscopy achieves lateral resolution limited to about 200nM with the best high numerical aperture (NA) objectives currently available, which is not sufficient to directly observe single molecule interactions. A technique recently developed by Dr. Novotny, Tip-Enhanced Near-field Optical Microscopy (TENOM), has thus far achieved spatial (lateral) resolutions as low as 10-20nM and topographic (vertical) resolutions of 5-10nM, approaching the size of individual proteins. This technique has significant potential to advance our understanding of biological and disease mechanisms, but further development is required to render it suitable for biomedical research.

Three specific aims are proposed, representing a step-wise progression of achievements necessary to advance TENOM technology for utility in biomedical research:

1. Standardized fabrication of finite-sized optical antennas to serve as near-field probes for biologic imaging;
2. Refinement of procedures for aqueous environments and variable topography, to allow study of synaptic structures and biologic events, and
3. “Proof of concept” functional imaging of individual protein interactions occurring at single synaptic vesicles, to elicit the role of glycogen synthase kinase-3 beta (GSK-3beta) in synaptic transmission and neurologic disease.

GSK-3beta is a validated therapeutic target for multiple neurologic diseases, and a known mediator of synaptic transmission and function, but has not been shown to interact directly with synaptic vesicles to affect their uptake or release. Such evidence would have significant therapeutic potential for neurologic disease. We believe TENOM will enable insights into synaptic function that substantially advance both basic neuroscience research, and our understanding of neurodegenerative diseases including Alzheimer’s, Parkinson’s, and NeuroAIDS. Once developed for bioresearch, TENOM would be widely applicable to other basic biologic questions requiring molecular-scale resolution, including protein interactions, nucleic acid functions, membrane dynamics, and receptor binding and signal transduction. Ultimately this technology may be adaptable to single-molecule detection in high-throughput environments, e.g. biomarkers of disease.