Research Interests:Our group's principal research interest is in studying the cellular and molecular mechanisms underlying normal neural development and the perturbation of these mechanisms in disease states or by therapeutic, psychotropic drugs. We also study how these mechanisms can be harnessed for brain repair. Current research in the laboratory is focused in several areas:
Effects of drugs on the developing nervous system: Therapeutic and illicit drugs are taken by pregnant women, children and adolescents. We investigate the consequences of early life treatment with these drugs on the development of neural circuitry in rodent models, as well as sex differences and temporal windows of vulnerability for different effects. The endpoints studied include gene expression profiling (real time PCR and in situ hybridization), endocrine assays (HPA stress axis activation), behavior (measures of activity, motor skill, affect, cognition, learning and memory, social interactions), functional MRI, neurophysiology (fast scanning voltammetric measures of dopamine secretion, whole cell patch clamp) and neuroanatomical and receptor binding measures. We also study how the effects of early life drug exposure interact with those of psychiatric disease and the environment. Our work in this little-studied area promotes understanding of the behavioral effects of fetal drug exposure in humans and the development of new therapeutic strategies. We are beginning collaborative studies of antidepressant drug metabolism during pregnancy in humans.
Human disease states: We use human post-mortem tissue to study alterations of neurotrophin expression and signaling in schizophrenia.
Neurotrophins: We also study the role of neurotrophins in regulating the structural and functional development of neural circuitry. In other experiments, we manipulate neurotrophin signaling in vivo, then assay the effects on the survival of immature neurons, neuronal connectivity patterns, synaptic physiology and network function.
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.
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.
• Prof. Bryan Kolb (University of Lethbridge, Alberta, Canada) – long-term effects on brain development of fetal exposure to antidepressant and antipsychotic drugs
• Prof. Susan Andersen (McClean Hospital & Harvard Medical School, Boston, MA) – long-term effects on brain development of fetal exposure to antidepressant and antipsychotic drugs
• Prof. Todd Gould (University of Maryland School of Medicine) – effects of fetal antidepressant exposure on brain development
• Prof Margaret Fahnestock (McMaster Universtiy, Hamilton, Ontario, Canada - Altered neurotrophin signaling in schizophrenia. Neurotrophin signaling in visual system development
• Prof. Jean-Francois Bouchard (Université de Montréal, Montreal, Quebec, Canada) - Netrin signaling in CNS development
• Prof. Patricio O'Donnell (University of Maryland School of Medicine) - whole cell patch physiology
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.
Milstein, J.A.*, Vinish, M.*, Adle, T., Robson, S., Enos, J.K., Fomum Mugri, M., Kolb, B. and Frost, D.O., Peripubertal olanzapine treatment induces deficits in social interaction and working memory in rats. Submitted for publication. (*indicates equal contribution to the research).
Vinish*, M., Milstein, J.A.*, Swanson, T., Carroll, C., Enos, J.K., Elnabawi, A. Kolb, B. and Frost, D.O., Peripubertal olanzapine treatment alters the development of cortical circuitry and dopamine receptor binding. Submitted for publication. (*indicates equal contribution to the research).
Vinish, M., Milstein, J.A., Bailey, A., Kolb, B., Cheer, J.F. and Frost, D.O., Peripubertal olanzapine treatment alters conditioned increases in response salience and alters dopaminergic function in the nucleus accumbens. Manuscript in preparation.
Marchese, M., Garzon, D., Roberts, R., Fahnestock, M. and Frost, D.O., Transcript-specific alteration of hippocampal BDNF mRNA expression in schizophrenia, Manuscript in preparation.
Ghose, S., Gao, X.-M., Roberts, R.C., Tamminga, C.A., Frost, D.O., Schizophrenia-associated increases in BDNF mRNA in specific populations of hippocampal dendrites, Manuscript in preparation.
Frost, D.O., Gibb, R. and Kolb, B., Trick or Treat? Neurodevelopmental Consequences of Pharmacotherapy for Affective Disorders, Neuropsychopharmacology, 35(1), 344-345, 2010. PMID: 20010711
Frost, D.O., Cercio Page, S. Carroll, C. and Kolb, B., Early Exposure to Haloperidol or Olanzapine Induces Long-Term Alterations of Dendritic Form, Synapse, 64, 191-199, 2010. PMID: 19862684
Halliwell, C., Comeau, W., Gibb, R., Frost, D.O. and Kolb, B., Factors influencing frontal cortex development and recovery from early frontal injury, Developmental Neurorehabilitation, 12, 269-278, 2009. PMID: 20477557
Rodger, J. and Frost, D.O., Effects of trkB knockout on topography and segregation of uncrossed retinal projections, Exp. Neurol., 2009, 195, 35-44. PMID: 19283373
Turner, C.A., Calvo, N., Frost, D.O., Akil, H. and Watson, S.J., The fibroblast growth factor system is downregulated following social defeat, Neurosci. Lett., 2008, 430, 147-150. PMID: 18061349
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., 2004, 56, 540-543.
Pollock, G.S., Robichon, R., Boyd, K., Kerkel, K.A., Kramer, M., Lyles, J., Ambalavanar, R., Khan, A., Kaplan, D.R., Williams, R.W. and Frost, D.O. TrkB receptor signaling regulates developmental death dynamics, but not final number, of retinal ganglion cells, J. Neurosci., 2003, 23, 10137-10145.
Pollock, G.S. and Frost, D.O., Complexity in the modulation of neurotrophic factor mRNAs by early visual experience, Dev. Br. Res., 2003, 143, 225-232.
Tamminga, C.A. and Frost, D.O., Changing concepts in the neurochemistry of schizophrenia, Am. J. Psychiatr., 2001, 158, 1365-1366.
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., 2001, 49, 173-187.
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., 2001, 21, 3923-3931.
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. and Frost, D.O., Intrinsic heterogeneity of retinal ganglion cells in their potential to form thalamic connections. J Comp Neurol. 1999, 411, 119-129.
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., 1998, 18, 2097-2107.
Bhide, P.G. and Frost, D.O., Axon substitution in the reorganization of developing neural connections. Proc. Nat. Acad. Sci., 1992, 89, 11847-11851.
Bhide, P.G. Frost, D.O. Stages of growth of hamster retinofugal axons: Implications for developing axonal pathways with multiple targets. J. Neurosci., 1991, 11, 485-504.
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., 1989, 86, 357-361.
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