Skip to main content

Douglas O. Frost, PhD

Academic Title:

Professor

Primary Appointment:

Pharmacology

Secondary Appointment(s):

Anesthesiology, Psychiatry

Location:

Howard Hall, 407

Phone (Primary):

(410) 706-0413

Education and Training

            Ph.D. Brain and Cognitive Science, Massachusetts Institute of Technology (M.I.T.)

            M.S. Electrical Engineering, M.I.T.

            B.S. Electrical Engineering, M.I.T.

Biosketch

November 14, 2011

            I am a developmental neurobiologist. The overall goal of my research is to investigate how brain development and function are affected in psychiatric disorders, and by psychotherapeutic drugs, experiential factors, and their interactions. In this project, using a rat maternal immune activation (MIA) model (the “poly I:C” model) that expresses behavioral/ cognitive phenotypes of schizophrenia (SZ):  1) We will identify sex differences in resting state functional connectivity in poly I:C- and control rats, pre-pubertally, during adolescence and in young adulthood. We hypothesize that sex interacts with gestational maternal poly I:C treatment and age to impact the RSF connectivity of seed ROIs previously shown to be disrupted pre- and post- conversion in SZ patients.  2) We test the hypotheses that a) in the two sexes, the timing and severity of specific abnormalities in RSF connectivity predict a) the relative severity of behavioral/ cognitive phenotypes of SZ in young, adult poly I:C rats; b) sex differences in the timing and severity of RSF connectivity anomalies predict sexual dimorphism in relative phenotypic severity in young adulthood.

            These studies will be the first in patients or animals to assess early life sex differences in the ontogeny of RSF connectivity phenotypes of SZ, and their utility as predictors of the timing and severity of behavioral/ cognitive phenotypes at maturity. ii) It would argue for the use of improved neuropsychological metrics for linking RSF connectivity data to behavioral/ cognitive outcomes in patients. iii) Our results will inform future studies of the mechanisms underlying behavioral/ cognitive phenotypes, and sex differences among them, in animal models and SZ patients. iv) Our approach provides a template for similar studies in animal models of other mental illnesses.

      My prior experience has provided me with expertise in a broad range of neuroscience research skills used to study brain development and plasticity in health and disease. These include behavioral testing of humans and experimental animals, and quantitative neuroanatomical, neurophysiological, molecular and cellular techniques.  Drs. Gullapalli and Xu are experts in using a broad range of MR imaging approaches, including resting state fMRI and MRS, which are used in this project and our prior collaboration.  The complementarity of their skills and mine form an excellent basis for our continued collaboration. I am experienced in statistics, by virtue of having previously served as director of our graduate course in biostatistics and >40 years of neurobiological research exprience.

      Supplemental references:

            Poppel, E., Held, R. and Frost, D.O., Residual visual function after brain wounds involving the central pathways in man.  Nature, 1973, 243, 295-296. PMID: 4774871.

            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. PMID: 15476682.       

           Can, A., Zanos, P., Moaddel, R., Kang, H.J., Dossou, K.S.S., Wainer, I.W., Cheer, J.F., Frost, D.O. , Huang, X.-P., Gould, T.D. Effects of ketamine and ketamine metabolites on evoked striatal dopamine release, dopamine receptors, and monoamine transporters.  In press, J. Pharm. Expt. Ther., 2016.

 

B.   Positions and Honors

Positions and Employment

9/75 - 12/78            Premier Assistant, Institute of Anatomy, Faculty of Medicine, University of Lausanne, Lausanne, Switzerland

1/79 - 9/80              Maitre Assistant, Institute of Anatomy, Faculty of Medicine, University of Lausanne, Lausanne, Switzerland

9/80 - 6/86              Assistant Professor, Section of Neuroanatomy, Yale University School of Medicine, New Haven, CT

7/86 - 9/88              Associate Professor, Section of Neuroanatomy, Yale University School of Medicine, New Haven, CT

10/88 - 6/93            Associate Neuroscientist, Dept. of Neurology, Massachusetts General Hospital, Boston, MA

10/88 - 6/93            Associate Director, Developmental Neurobiology Laboratory, Dept. of Neurology, Massachusetts General Hospital, Boston, MA

10/88 - 6/93            Associate Professor, Neuroscience Program, Harvard Medical School, Boston, MA

7/93 - present         Professor (Tenured), Dept. of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD

1/06-8/06                Visiting Professor, Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI

 

Other Experience and Professional Memberships

1973 - Present            Member, Society for Neuroscience

1973 – Present            Member, International Brain Research Organization

1995 - 1998                President elect, President, Past president, Baltimore Chapter, Society for Neuroscience

1996 - 1999                Program Committee, Society for Neuroscience (National Organization)

1998 – 2001                National Science Foundation, Developmental Neuroscience Panel, 1998-2001

1999                    NIH/NIMH Special Emphasis Panel, "Research Career Development in Mental Disorders of                                                                                      Children" (ZMH1 CRB-H(01)

2001 – 2004                NIH Study Section, “Brain Disorders and Clinical Neuroscience”, ZRG1 BDCN-5

2006-2007              NIH Special Emphasis Panel, “Brain Disorders and Clinical Neuroscience”, ZRG1 F01-N                                                                                          (20) (S)

2009                           NIH Study Section, “Developmental Brain Disorders” (DBD)

2009 – Present            Full Member, Collegium Internationale Neuro-Psychopharmacologicum

 

Honors

1966                           New York State Regents Scholar

1969 - present             Eta-Kappa Nu (Electronics Engineering Honorary)

1969 – present            Society of Sigma Xi (Research Honorary)

1969 – 1970                Woodrow Wilson Fellow

1975 – 1976                Fellow - American-Swiss Foundation for Scientific Exchange, Inc.

2002                           Siemens Foundation Lecturer

2003                           Raines Foundation Visiting Professor, University of Western Australia, Perth, Australia

2004                    National Association for Research in Schizophrenia and Depression, Distinguished                                                                                               Investigator Award

2005                            Grass Foundation Traveling Lecturer, Southern Ontario Neuroscience Society

2009 – present             Collegium Internationale Neuro-Psychopharmacologicum, Full  Member

C. CONTRIBUTIONS TO SCIENCE

            I am a developmental neurobiologist who is particularly interested in how genetic and environmental factors interact with fundamental ontogenetic mechanisms to regulate the brain’s developmental trajectory and mature function. The results of these pre-clinical studies contribute to understanding the mechanisms of a variety of neurologic and psychiatric disorders with developmental origins.

            1. We demonstrated the long-term effects on behavior and brain function of early life treatment with antipsychotic drugs. Most relevant to the proposed experiments, my group has shown that treatment of adolescent rats with atypical antipsychotic drugs (AAPDs), under dosing conditions that approximate those employed therapeutically in humans, causes long-term behavioral dysfunction and alters the developmental trajectory and of brain regions that belong to neural networks that mediate the disrupted behaviors. Previous work had shown that environmental stimuli (including drug treatment) that act on the brain prior to maturity (approximately the middle of the 3rd decade) can, potentially, alter the brain’s ontogenetic trajectory, and thus, its function and future responsiveness to environmental stimuli. AAPDs are widely used in pediatric populations to treat several common, serious disorders (and disruptive behavior) despite minimal data concerning their long-term effects. My group found that adolescent AAPD treatment in rats causes i) abnormalities in 3 different types of learning. We also showed, in brain regions that contribute to those behaviors, ii) neuroanatomical and neurophysiological abnormalities of the ontogenetic trajectory and adult function of neural circuits; iii) defects of mature dopaminergic, glutamatergic and GABAergic neurotransmission. These data are significant because: i) They demonstrate previously unknown, long term functional abnormalities that result from adolescent AAPD treatment. Confirmation of these effects in humans would provide objective data for evaluating the risks and benefits of adolescent AAPD treatment in individual cases. ii) For >3 decades no new antipsychotic drugs with fundamentally different mechanisms of action have been approved for clinical use. Thus, have begun study the cellular mechanisms of these changes with the goal of developing new therapeutic approaches to inhibit the adverse effects of AAPDs, while maintaining their therapeutic efficacy. iii) They demonstrate that the long term effects of AAPD treatment are age-dependent and underscore the importance of testing of new psycho-tropic medications for their long-term developmental impact. I was the principal investigator for all these studies.

                        Vinish, M., Elnabawi, A., Milstein, J.A., Burke, J.S., Kallevang, J.K., Turek, K.C., Lansink, C.S., Merchenthaler, I., Bailey, A., Kolb, B., Cheer, J.F. and Frost, D.O., Olanzapine treatment of adolescent rats alters adult reward behavior and nucleus accumbens function, Int J Neuropsychopharmacol. 2013, 16 (7),1599-609. PMID: 23351612.

                        Milstein, J.A., Elnabawi, A., Vinish, M., Swanson, T., Enos, J.K., Bailey, A.M., Kolb, B. and Frost, D.O., Olanzapine treatment of adolescent rats causes enduring specific memory impairments and alters cortical development and function, PLoS ONE 8(2): e57308. doi:10.1371/journal.pone.0057308 PMID: 23437365.

                        Xu, S., Gullapali, R., Frost, D.O., Olanzapine antipsychotic treatment of adolescent rats causes long-term changes in glutamate and GABA levels in the nucleus accumbens, Schizophrenia Research, 1(2-3), 452-457, 2015, PMID: 25487700

                        Brooks, J., O’ Donnell, P. and Frost, D.O. Olanzapine treatment of adolescent rats alters adult D2 modulation of cortical inputs to the ventral striatum, Int. J. Neuropsychopharmacol. 2016 May 12. pii: pyw034. doi: 10.1093/ijnp/pyw034. [Epub ahead of print]  PMID: 27207908.

 

            2. We demonstrated that developing retinal afferents that are "redirected" into non-visual, primary sensory systems can reproduce features of normal visual system organization in those systems, and take over the function of damaged visual pathways. Previous studies had shown that neonatal lesions of some cerebral targets of the rodent retina could result in the formation of permanent, abnormal retinal projections to the principle thalamic nucleus of the auditory system. I demonstrated that developing retinal axons could be made to form permanent connections with the primary thalamic nucleus of the somatosensory system. We then used these two sets of “cross-modal projections”, and additional data obtained from normal infant animals, to elucidate some fundamental developmental mechanisms that regulate i) axonal growth, initial target selection, and the stabilization or elimination of immature projections; ii) the formation of receptotopically organized connections in sensory systems; iii) the organization of synaptic glomeruli – specialized complexes in which multiple neuronal elements synapse upon one and other and, in combination with other mechanisms, regulate patterns of neuronal firing in response to the activity of afferent axons. We then used neurophysiological and behavioral assays to demonstrate that i) in “re-wired” (but not normal) animals, neurons in the somatosensory cortex respond to visual stimuli and that their receptive field properties did not differ significantly from those of neurons in the primary visual cortex of normal animals; ii) in “re-wired” animals, the auditory cortex could mediate the discrimination of visual patterns when the visual cortex, the normal mediator of this function, is ablated. Together, our results are significant in multiple ways: i) they furthered understanding of several key principles of neural development that were confirmed in other neural systems; ii) they spurred investigations of “cross-modal plasticity” in humans who were blind or deaf, either congenitally or from an early age. Those studies showed that sensory cortical regions deprived of inputs in their normal sensory modality received functional inputs from intact modalities and contributed to enhanced function in those modalities; iii) they suggest that functions normally mediated by damaged sensory cortices might be remediated by rewiring of sensory afferents to intact cortical regions or by sensory prostheses that stimulate the intact regions.

                        Frost, D.O. and Métin, C., Induction of functional retinal projections to the somatosensory system.  Nature, 1985, 317, 162-164. PMID: 4033796

                        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. PMID: 2911580

                        Bhide, P.G. & Frost, D.O., Axon substitution in the reorganization of developing neural connections.  Proc. Nat. Acad. Sci., 1992, 89, 11847-11851. PMID: 1465409

                        Frost, D.O., Boire, D., Gingras, G. and Ptito, M., Surgically-created neural pathways mediate visual pattern discrimination.  Proc. Nat. Acad. Sci., 2000, 97, 11068-11073. PMID: 10995465

 

            3. We demonstrated that various forms of abnormal visual experience early in life can alter the distribution of neurons in the primary visual cortex that maintain their immature projections through the corpus callosum to the contralateral cortex. In normal adult mammals, cortical neurons that send an axon to the contralateral hemisphere (“callosal neurons” have characteristic distributions, both through the depth of the cortex and parallel to the cortical surface. In the visual cortex, callosal neurons are restricted to the region of the boundary between the primary (V1) and secondary (V2) visual areas and are concentrated in layers III and VI. This distribution arises from a more diffuse distribution: Postnatally, callosal neurons disappear (by dying, or eliminating their callosal connections) from most of areas V1 and V2 and decreasing in number in layer VI. Giorgio Innocenti and I were the first to show that post-natal visual experience is one regulator of the selection of immature callosal neurons for stabilization or elimination. (This process is distinct from the experience-dependent “pruning” of immature axonal arbors and synapses). Although kittens deprived of pattern vision by binocular lid suture still develop an apparently normal distribution of callosal neurons, monocularly deprived or enucleated, bilaterally squinted and bilaterally enucleated kittens retain to adulthood callosal neurons in parts of V1 where such neurons are not normally found. The total number of callosal neurons does not necessarily change in parallel with the distribution of neurons. We subsequently found that i) some of these effects are layer specific; ii) vision is actively responsible for both the maintenance and the elimination of fractions of the juvenile callosal connections; (iii) the elimination that normally takes place during the second postnatal month requires normal binocular vision. My group also showed, using neonatal splitting of the optic chiasm, and rearing with alternating monocular occlusion, that coordinated, binocular pattern vision is the critical factor for selectively stabilizing the normal complement of callosal neurons.  Together, these results provide the neural basis for understanding the long-term visual deficits caused by early life, peripheral impediments to pattern vision and abnormalities of ocular alignment.

                        Innocenti, G.M. and Frost, D.O., Effects of visual experience on the maturation of the efferent system to the corpus callosum.  Nature, 1979, 280, 231-234. PMID: 450139

                        Innocenti, G.M. and Frost, D.O. and Illes, J., Maturation of visual callosal connections in visually deprived kittens:  A challenging critical period.  J. Neurosci., 1985, 5, 255-267. PMID: 3973665

                        Frost, D.O., Moy, Y.P. and Smith, D.C., Effects of alternating monocular occlusion on the development of visual callosal connections.  Exp. Br. Res., 1990, 83, 200-209. PMID: 2073939

 

            4. My group has made significant contributions to understanding how BDNF synthesis, trafficking and signaling through the trkB receptor are modulated by sensory experience and mediate both experience-dependent and experience-independent effects on cerebral development. Using pharmacologic agents and constitutive heterozygous and homozygous knock-outs of BDNF, NT4 and trkB, we demonstrated that target-derived BDNF, signaling through trkB, determines the rate of developmental retinal ganglion cell death (all of which takes place prior to the onset of vision) but not the number of retinal ganglion cells that survive to maturity. We also showed that BDNF mRNA expression and BDNF protein levels are not always modulated in parallel by early life sensory experience. We correctly hypothesized that altered BDNF release (and, possibly, BDNF trafficking or processing) account for the impaired maturation of GABAergic circuitry in the dark-reared visual cortex, despite our apparently paradoxical finding that dark rearing reduced BDNF mRNA expression but increased the tissue concentration of BDNF protein. We also demonstrated that BDNF protein levels undergo circadian regulation in brain regions that mediate sensory, motor and cognitive function. Finally, we used trkB knockout mice to demonstrate the diversity and regional specificity of functionally significant features of the organization of retinal projections whose development is regulated, in part, by trkB signaling.  Together, these results provided crucial insights into how BDNF acts to mediate the activity-dependent sculpting of neural circuitry during ontogeny.

                        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. PMID: 9482796.

                        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. PMID: 11356880

                        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. PMID: 14602830

                        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

 

            5. I was a co-investigator of several early studies of how a spontaneous mutation of the reelin gene affects the trajectories and sites of termination of thalamocortical axons and retinal ganglion cell axons. In normal mice, after exiting the internal capsule, thalamacortical axons reach their target fields by passing parallel to the cortical surface (“tangentially”) among “polymorphic” neurons in the deepest cortical layer (layer VI). Upon reaching their target fields the axons turn upwards into the cortex, where morphologically distinct sub-types of thalamocortical axons terminate selectively in different layers, each of which contains a characteristic mix of distinct populations of neuronal somata and dendrites. In “reeler” mutant mice, the “radial” distribution (ie., distribution perpendicular to the cortical surface) of different neuron types is inverted and less precise than normal, and there are numerous pyramidal neurons whose apical dendrites are oriented towards the depths of the cortex, rather than to the cortical surface, as in normal animals. Thus, in reeler mice, poly-morphic neurons are found at the cortical surface. We found that upon exiting the internal capsule, reeler thala-mocortical axons ascend to the cortical surface where they pass tangentially to their target fields, then turn radially into the cortex, where each sub-type of axon terminates among its normal neuronal targets, although they lie at an abnormal depth. Furthermore, the topographic mapping of axons from each thalamic nucleus across its target fields is normal. Retinal projections to the superior colliculus, also a laminated structure, show similar effects. Thus, in both systems of the reeler mouse brain, afferent axons pass among and terminate upon the same types of neurons and have a normal topographic organization, even though they take abnormal trajectories to do so. These studies were among the first to use genetic mutations in mice to investigate potential molecular mechanisms of the development of neural connections.  They show that although the reelin gene product is a key regulator of the radial positioning of neurons in laminated brain regions, it is not part of the cellular mechanisms that guide axons from their cells of origin to their target regions, identify appropriate neuronal sub-types on which to form connections, or organize the topography of those projections.

                        Caviness, V.S., Frost, D.O. and Hayes, N.L., Barrels in somatosensory cortex of normal and reeler mutant mice, Neurosci. Letters, 1976, 3, 7-14. PMID: 19604860

                        Caviness, V.S. and Frost, D.O., Architecture of thalamocortical projections in reeler mutant mice.  J. Comp. Neurol., 1983, 219, 182-202. PMID: 6194186

                    Frost, D.O., Edwards, M.A., Sachs, G. and Caviness, V.S., Retinotectal projections in the reeler mutant mouse:  Relationships among axon trajectories, arborization patterns, and cytoarchitecture.  Developmental Brain Research, 1986, 28, 109-120. PMID: 3730887

D.         Research Support

Ongoing Research Support

None.

Pending Research Support

None.

Completed Research Support

R01-MH07083-5 - Douglas O. Frost, PI, 9/1/06-8/31/11 (No-cost extension 9/1/11-8/31/12).

Antipsychotic drugs and cortical development

The major goal of this project is to study the effects of early exposure to antipsychotic drugs on behavioral, endocrine and other functional and morphological measures of cortical development in male rats.  No overlap with proposed project.

Role:  PI

 

Research/Clinical Keywords

Schizophrenia Depression and Anxiety Anti-Depressant Drugs Anti-Psychotic Drugs Biological Psychiatry Brain Cellular Neuroscience Developmental Neurobiology Magnetic Resonance Imaging (Resting State Functional MRI; Magnetic Resonance Spectroscopy) Molecular Neuroscience Neuroanatomy Neuroinflammation Neuropsychology Neurophysiology Neuroscience Stress

Highlighted Publications

            Can, A., Zanos, P., Moaddel, R., Kang, H.J., Dossou, K.S.S., Wainer, I.W., Cheer, J.F., Frost, D.O., Huang, X.-P., Gould, T.D. Effects of ketamine and ketamine metabolites on evoked striatal dopamine release, dopamine receptors, and monoamine transporters.  J Pharmacol Exp Ther. 2016 Oct;359(1):159-70. doi: 10.1124/jpet.116.235838 PMID: 27469513.

            Can, A., Frost, D.O., Cachope, R., Cheer, J.F., Gould, T.D. Chronic Lithium Treatment Rectifies Maladaptive Dopamine Release in the Nucleus Accumbens.  J. Neurochem 2016 Aug 11. doi: 10.1111/jnc.13769. [Epub ahead of print]. PMID 27513916.

            Brooks, J., O’ Donnell, P. and Frost, D.O. Olanzapine treatment of adolescent rats alters adult D2 modulation of cortical inputs to the ventral striatum, Int. J. Neuropsychopharmacol. 2016 May 12. pii: pyw034. doi: 10.1093/ijnp/pyw034. [Epub ahead of print]  PMID: 27207908.

             Xu, S., Gullapali, R., Frost, D.O., Olanzapine antipsychotic treatment of adolescent rats causes long-term changes in glutamate and GABA levels in the nucleus accumbens, Schizophr Res. 2015 Feb;161(2-3):452-7. doi: 10.1016/j.schres.2014.10.034. Epub 2014 Dec 5. PMID: 25487700.

             Milstein, J.A., Elnabawi, A., Vinish, M., Swanson, T., Enos, J.K., Bailey, A.M., Kolb, B. and Frost, D.O., Olanzapine treatment of adolescent rats causes enduring specific memory impairments and alters cortical development and function, PLoS ONE 2013 8(2): e57308. doi:10.1371/journal.pone.0057308. Epub 2013 Feb 20 PMID: 23437365.

             Vinish, M., Elnabawi, A., Milstein, J.A., Burke, J.S., Kallevang, J.K., Turek, K.C., Lansink, C.S., Merchenthaler, I., Bailey, A., Kolb, B., Cheer, J.F. and Frost, D.O., Olanzapine treatment of adolescent rats alters adult reward behavior and nucleus accumbens function, Int J Neuropsychopharmacol. 2013 Aug; 16(7):1599-609. doi: 10.1017/S1461145712001642. Epub 2013 Jan 25.  PMID: 23351612.

            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. PMID: 14602830

            Frost, D.O., Boire, D., Gingras, G. and Ptito, M., Surgically-created neural pathways mediate visual pattern discrimination.  Proc. Nat. Acad. Sci., 2000, 97, 11068-11073. PMID: 10995465