Metaplasticity & Bioinformatics

PRINCIPAL INVESTIGATOR

MISSION STATEMENT

Understand and harness CNS plasticity to promote recovery of function after brain and spinal injury through bench-science and translational computational approaches.

GENERAL OVERVIEW

Our research focuses on mechanisms of recovery after neurological trauma. Injuries to the brain and spinal cord invoke numerous, interacting biological changes that work in concert to determine recovery success. Some of these biological changes have contradictory effects at different phases of recovery. For example, mechanisms of synaptic regulation can contribute to cell death in the early phases of recovery but may promote plasticity and restoration of function at later stages. Understanding the mechanisms of neurological recovery in the complex microenvironment of the injured central nervous system (CNS) requires large-scale integration of biological information and functional outcomes (i.e., Bioinformatics). Our work uses a combination of laboratory studies and statistical modeling approaches to provide an information-rich picture of the syndrome produced by trauma in translational in vivo models. The long term goal of this research is to provide system-level therapeutic targets for enhancing recovery of function after brain and spinal injury.

AREAS OF FOCUS

Computational Syndromic Discovery: Development of an aggregate database of basic spinal cord injury research data from multiple research centers to enable sophisticated knowledge-discovery, data-sharing, and multivariate quantification of the complete constellation of changes produced by spinal cord injury.

Bench science: Modulation of glutamate receptor metaplasticity and its role in spinal cord learning and recovery of function after spinal cord injury. Techniques: biochemistry (quantitative western, qRT-PCR, ELISA), histology (immunohistochemistry, in situ hybridization), quantitative image analysis (robotic microscopy, confocal, deconvolution, image math) and behavioral analysis (locomotor scaling, fine-motor control, learning and memory).

FUNDING AND CONTRIBUTORS

NIH , VA, DoD

CURRENT LAB MEMBERS

Ellen J Dahl, B.S., Staff Research Associate

Cristian Guandique, B.A., Staff Research Assistant

J Russell Huie, PhD, Postdoctoral Scholar

Aiwen Liu, B.S., Staff Research Assistant

Jessica L Nielson, PhD, Postdoctoral Scholar

Xiaokui Ma, MD, Core Histopathology Specialist

Vladimir Muraru, MS, Core Database Developer

COLLABORATORS

UCSF: Michael S. Beattie, PhD; Jacqueline C. Bresnahan, PhD; Geoffery T. Manley, MD/PhD; Susanna Rosi, PhD; Mark Segal, PhD; Shirley I. Stiver, MD/PhD; Hua Su, MD; Esther L. Yuh, MD/PhD

UCSD: Mark H. Tuszynski, MD/PhD; Ephron S. Rosenzweig, PhD

UCLA: V. Reggie Edgerton, PhD

University of Louisville: Scott R. Whittemore, PhD; David S.K. Magnuson, PhD; Darlene Burke, MS

Texas A&M University: James W. Grau, PhD; Michelle A. Hook, PhD

The Ohio State University: Phillip G. Popovich, PhD; Dana M. McTigue, PhD; D. Michele Basso, EdD

Stanford University: Karen-Amanda Irvine, PhD

SELECTED PUBLICATIONS (selected from 83 papers and abstracts)

Sieve, A. N., King, T. E., Ferguson, A. R., Grau, J. W., Meagher, M. W. (2001). Pain and negative affect: Evidence the inverse benzodiazepine agonist DMCM inhibits pain and learning. Psychopharmacology, 153, 180-190.

Ferguson, A. R., Hook, M.A., Garcia, G., Bresnahan, J. C., Beattie, M. S., & Grau, J. W. (2004). A simple post-hoc transformation that improves the metric properties of the BBB scale for rats with moderate to severe spinal cord injury. Journal of Neurotrauma, 21, 1601-1613.

Ferguson, A. R., Patton, B. C., Bopp, A. C., Meagher, M. W., & Grau, J. W. (2004). Brief exposure to a mild stressor enhances morphine conditioned place preference in male rats. Psychopharmacology, 75, 47-52.

Ferguson, A. R., Crown, E. D., & Grau, J. W. (2006). Nociceptive plasticity inhibits adaptive learning in the spinal cord. Neuroscience, 141, 421-431.

Hook, M.A., Liu, G.T., Washburn, S.N., Ferguson, A.R., Bopp, A.C., Huie, J.R., & Grau, J.W. (2007). Impact of morphine after a spinal cord injury. Behavioural Brain Research, 179, 281-293.

Gómez-Pinilla, F., Huie, J. R., Ying, Z., Ferguson, A.R., Crown, E.D., Baumbauer, K.M., Edgerton, V.R., & Grau, J.W. (2007). BDNF and learning: Evidence that instrumental training promotes learning within the spinal cord by up-regulating BDNF expression. Neuroscience, 148, 893-906.

Miller, B.A., Crum, J.M., Tovar, C.A., Ferguson, A.R., Bresnahan, J.C., & Beattie, M.S. (2007). Developmental stage of oligodendrocytes determines their response to activated microglia in vitro. Journal of Neuroinflammation.

Ferguson, A.R., Christensen, R.N., Gensel, J.C., Miller, B.A., Sun, F., Beattie, E.C., Bresnahan, J.C., & Beattie, M.S. (2008). Cell death after spinal cord injury is exacerbated by rapid TNFα-induced trafficking of GluR2-lacking AMPARs to the plasma membrane. Journal of Neuroscience, 28, 11391-11400.

Ferguson, A. R., Bolding, K.A., Huie, J. R., Hook, M. A., Santillano, D.R., Miranda, R.C. & Grau, J. W. (2008). Group I Metabotropic Glutamate Receptors Control Metaplasticity of Spinal Cord Learning through a PKC-Dependent Mechanism. Journal of Neuroscience, 28, 11939-11949.

Rosenzweig, E.S., Courtine, G.C., Jindrich, D.L., Brock, J.H., Strand, S.S., Ferguson, A.R., Nout, Y.S., Roy, R.R., Miller, D., Beattie, M.S., Havton, L.A., Bresnahan, J.C., Edgerton, V.R., Tuszynski, M.H. (2010). Extensive spontaneous plasticity of corticospinal projections after primate spinal cord injury. Nature Neuroscience, 13, 1505-1510.

Irvine, K-A., Ferguson, A.R., Mitchell, K.D., Beattie, S.B., Beattie, M.S., and Bresnahan, J.C. (2010). A novel method for assessing proximal and distal forelimb function in the rat: The Irvine, Beatties and Bresnahan (IBB) Forelimb Scale. Journal of Visualized Experiments.46, http://www.jove.com/Details.stp?ID=2246.