Research Interests

My group's principal interest is in studying the cellular and molecular mechanisms underlying the development of neural connections. We also study how these mechanisms are altered in disease states and how they can be harnessed for brain repair. Current research in the laboratory is focused in several areas:

Neurotrophins: We study the role of neurotrophins in regulating the structural and functional development of neural circuitry. We manipulate in vivo neurotrophin signaling pharmacologically or using transgenic- and null mutant mice, then assay the effects of these treatments on the survival of immature neurons, neuronal connectivity patterns, synaptic physiology and network function. We also investigate the molecular mechanisms of trk receptor signaling in vitro by transfection of trk receptors and functional mutations of downstream signaling molecules into secondary cell lines and primary cells.

Disesase states: We are investigating alterations of neurotrophin signaling in Huntington's disease using a transgenic mouse model and culture of secondary cell lines. We study neurotrophin signaling in schizophrenia using human post-mortem tissue. We are also investigating treatments for hypoxic brain damage due to premature birth.
 
Axon growth: Our previous research has demonstrated that developing axons pass through distinct growth states during which their behavior is different. We are investigating the role of neurotrophin signaling in this process using time-lapse video imaging of growing axons in vitro under various experimental conditions.

Brain repair: We have developed a technique that allows us to "rewire" the eye to abnormal brain targets. The resulting neural circuits can take over the neurophysiologic and behavioral function of natural visual circuits that are damaged. We are now studying how rewiring alters patterns of cerebral gene expression and downstream connectivity.
 
Effects of drugs on the developing nervous system: Therapeutic and illicit drugs are taken by pregnant women. We are investigating the effects of these drugs on neural circuit development in mouse models. Our work in this little-studied area promotes understanding of the behavioral effects of fetal drug exposure and the development of new therapetic strategies.

Lab Techniques and Equipment

Techniques used in the lab: Neuroanatomical pathway tracing (cholera toxin, HRP, Di-I, diamidino yellow, etc.), tissue and cell culture, viral transfection, polymerase chain reaction, RNase protection assay, protein measurement (by electrochemiluminescence immunoassay, ELISA, immunoprecipitation/immunoblotting), immunohistochemistry, confocal microscopy, computerized neuronal reconstruction and morphometry, time lapse video imaging, in vivo single unit neurophysiology, in vitro whole cell patch clamp recording and behavioral testing.

Collaborators:

• Prof. Louis Reichardt (University of California, San Francisco): Neurotrophin signaling and cell death.
• Prof. John Rubenstein (University of California, San Francisco): Sensory control of transcription factor expression.
• Prof. Blair Leavitt (University of British Columbia, Vancouver): Neurotrophin signaling in Huntington's disease.
• Profs. Paul Fishman and George Oyler (University of Maryland School of Medicine): mechanisms of trk receptor signaling and neurotrophin signaling in Huntington's disease.
• Prof. Carol Tamminga (University of Texas Southwestern Medical Center): Altered neurotrophin signaling in schizophrenia.
• Dr. Bai Lu (National Institutes of Health): Neurotrophin signaling in visual system development.
• Prof. Birgit Roerig (University of Maryland School of Medicine): Neurotrophin signaling in visual system development.
• Prof. Tim Kennedy (Montreal Neurological Institute): Netrin signaling in CNS development.
• Prof. Maurice Ptito (Université de Montréal): Behavioral testing neurophysiological recording and pathway tracing in animals with rewired neural connections.

Training History:

BS and MS in electrical engineering, PhD in Neuroscience, all from the Massachusetts Institute of Technology. Faculty member at the Faculty of Medicine, University of Lausanne (Switzerland); Yale Medical School and Harvard Medical School before joining the University of Maryland Medical School in 1993.

Publications

• Pollock, G.S., Robichon, R., Boyd, K., Kerkel, K.A., Lyles, J., Kaplan, D.R., Ambalavanar, R., Williams, R.W. and Frost, D.O. TrkB receptor signaling regulates rate of developmental retinal ganglion cell death but not final number, Neuron, submitted.
• Pollock, G.S. and Frost, D.O., Modulation of neurotrophic factor mRNAs by early visual experience. Dev. Br. Res., in press.
• Frost, D.O., Tamminga, C.A., Medoff, D.R., Caviness, V.S., Jr., Innocenti, G.M. and Carpenter, W.T., Jr., Neuroplasticity and schizophrenia. Biol. Psychiatr., in press.
• Tamminga,C.A. and Frost, D.O., Changing concepts in the neurochemistry of schizophrenia. Am. J. Psychiatr., 158, 1365-1366, (2001).
• Frost, D.O., Ma, Y.-T., Hsieh, T., Forbes, M.E. and Johnson, J.E., Developmental changes in BDNF protein levels in the hamster retina and superior colliculus. J. Neurobiol., 49, 173-187, (2001).
• Pollock, G.S., Vernon, E., Forbes, M.E., Yan, Q., Ma, Y.-T., Hsieh, T., Robichon, R., Frost, D.O., Johnson, J.E., Modulation of BDNF mRNA and protein levels by early visual experience and diurnal rhythms. J. Neurosci., 21, 3923-3931, (2001).
• Frost, D.O. BDNF/trkB signaling in the developmental sculpting of visual connections, Prog. Br. Res., 134, 35-49, (2001).
• Ptito, M., Giguère, J-F, Boire, D., Frost, D.O. and Casanova, C. When the auditory cortex turns visual, Prog. Br. Res., 134, 447-458, (2001).
• Frost, D.O., Boire, D., Gingras, G. and Ptito, M., Surgically-created neural pathways mediate visual pattern discrimination. Proc. Natl Acad. Sci., 97, 11068-11073, (2000).
• Frost, D.O. and Cadet, J.L. Effects of drug-induced neurotoxicity on development of neural circuitry: A hypothesis. Br. Res. Rev., 34 (3), 103-118, (2000).
• Bhide, P.G. & Frost, D.O., Intrinsic heterogeneity of retinal ganglion cells in their potential to form thalamic connections. J Comp Neurol. 411, 119-129 (1999).
• Ma, Y.-T., Hsieh, T., Forbes, M.E., Johnson, J.E. and Frost, D.O., BDNF injected into the superior colliculus reduces developmental retinal ganglion cell death. J. Neurosci., 18, 2097-2107 (1988)
• Boire, D., Morris, R., Ptito, M., LePore, F., and Frost, D.O. Effects of neonatal splitting of the optic chiasm on the development of feline visual callosal connections. Exp. Br. Res., 104, 275-286 (1995).
• Bhide, P.G. & Frost, D.O., Axon substitution in the reorganization of developing neural connections. Proc. Nat. Acad. Sci., 89, 11847-11851 (1992).
• Bhide, P.G. & Frost, D.O., Stages of growth of hamster retinofugal axons: Implications for developing axonal pathways with multiple targets. J. Neurosci.,11, 485-504 (1991).
• Frost, D.O. Visual processing by novel, surgically created neural circuits. In: D. M.-K. Lam and G.M. Bray (Eds.), Regeneration and plasticity in the mammalian visual system, 1992, MIT Press, Cambridge, MA, pp. 197-219.
• Métin, C. and Frost, D.O., Visual responses of neurons in somatosensory cortex of hamsters with experimentally induced retinal projections to somatosensory thalamus. Proc. Nat. Acad. Sci., 86, 357-361 (1989).