Michael Williams Lab
| Contact Dr. Williams |
|---|
Michael T. Williams, PhD
Research Associate Professor of Pediatrics
Children's Hospital Research Foundation
Child Neurology, MLC 7044
3333 Burnet Ave.
Cincinnati, OH 45229-3039
Phone 513-636-8624
Fax 513-636-3912
Related Links:
• Dr. Williams' Faculty Bio
• Animal Behavioral Core site
|
 |
Current research in the Williams Lab has several different focuses. Our lab works seamlessly with Dr. Charles Vorhees’ lab and the primary focus is on the effects of developmental exposure to various exogenous agents and in particular, drugs of abuse, environmental agents, and stress as well as the stress response of the animal following drug administration or environmental agents. In particular, we currently have a grant to examine the effects of lead (Pb2+) in combination with stress and manganese. This topic is an important issue in children’s health since lead exposure still occurs in the population, mostly in very young children in low social economic status (SES) families, and these exposures lead to long-term cognitive and behavioral changes. Co-factors thought to be important for the effects of lead on development include but are not limited to stressors and manganese. We are currently developing a model of human exposure and are investigating the effects of lead and stressors on the development of the monoamine system in the brain and of the hormonal response to stressors. To date we have investigated the combination of lead and environmental deprivation and are currently working on the combination of lead and isolation. Once a combination is identified as having an interaction we will investigate if manganese influences this interaction. We are also investigating the effects of PCBs during development in collaboration with Dan Nebert’s lab at the University of Cincinnati.
Williams Lab Members
The
Williams and Vorhees lab at the International Behavioral Neuroscience
Society Conference in St. Thomas, Virgin Islands 2008. From left to
right, Amanda Braun (Neuroscience graduate student), Devon Graham,
Ph.D. (Post-doctoral fellow), Curtis Grace (Molecular and Developmental
Biology graduate student), Michael Williams, Ph.D., Matthew Skelton,
Ph.D. (Research Associate), Charles Vorhees, Ph.D., and Tori Schaefer
(Molecular and Developmental Biology graduate student).
The second area of research is on the effects of methamphetamine (MA) and methylenedioxymethamphetamine (MDMA) during development, two compounds that are widely abused but there is little understanding about the consequences of fetal exposure. We use the neonatal rat as a model of human third trimester exposure and have found that MA and MDMA produce long-term spatial learning deficits as well as deficits in path integration. Spatial learning is assessed using the Morris water maze and path integration using the Cincinnati water maze. The differences and commonalities in the learning deficits produced by these two drugs are of interest, especially since it may clarify the neurochemical, neuroendocrine, and/or molecular changes that underlie the different learning effects produced by the drugs. In pursuit of these issues, we have shown that neonatal rats exposed to MA or MDMA do not show an adult-like response to either drug, that is, no long-lasting depletions to neurotransmitters or any indication of neurotoxicity occur. We have also demonstrated that both MA and MDMA administration cause elevated corticosterone (CORT) and ACTH levels, and MA produces an extremely protracted increase (i.e., over 36 h after administration). Therefore, we are trying to understand how this protracted change in CORT may be altering the developing central nervous system and consequently impair learning and memory following MA exposure. We are also investigating the short-term decreases in serotonin following neonatal MDMA exposure and the impact this has on learning and memory. We have also investigated a drug that is similar to MDMA in its psychological effects, but with a much different mode of action called 5-methoxy-diisopropyltryptamine (or ‘Foxy’). This drug is fairly new in relation to MDMA and MA, however it has become such a problem that the DEA has classified the drug as Schedule I and it seems to be growing in popularity in places like Canada and Japan.
A third area of research is on the adult effects of the various aforementioned drugs of abuse. While human populations show altered cognitive function following drug use, very few cognitive effects have been noted after adult exposure in animals, although some of these drugs produce neurotoxicity. We are therefore investigating the exposure of animals to various dosing regimens and examining the learning potential of the animals following these administrations. We have found some exaggerated deficits in animals exposed to MA in their path integration ability. In looking for a mechanism, we found that these animals have a protracted increase in corticosterone, and therefore investigated if adrenalectomy would alleviate the learning deficits. However, deficits were still observed even in those animals with adrenalectomy. Animals that had been adrenalectomized did not show the normal hyperthermic response to MA, but still showed neurotoxicity. In conjunction with the learning studies, we are also investigating the changes in neurotrophins and neuropeptides in collaboration with Kim Seroogy’s lab and the EEG response of these animals in collaboration with Katie Holland’s lab. In the near future we plan to conduct magnetic resonance spectroscopy on the animals using the new 7T magnet in the Cincinnati Children’s Research Foundation’s Imaging Research Center.
The lab has several other collaborators with whom we phenotyped or are currently phenotyping various mutant mice. Some of the gene targeted knock-out mice assessed or currently being examined include mice with altered genes for: creatine transporter, PDE1B, NPAS3, PET-1, MPS1, prosaposin, saposin B and C, and the alpha isoforms of the Na+/K+ ATPase. The creatine transporter knock-out is an important gene deletion since in humans it leads to mental retardation and was discovered by Ton Degrauw’s lab. Future studies may include investigation of antiepileptic drugs administered during the neonatal period. We also are currently working on collaborations to investigate models of autism and ADHD as well as epilepsy.
Recent Publications
Skelton, M. R., Williams, M. T., McInturf, S.A., Rossi III, J., Aronow, B. J., Vorhees, C. V. (in preparation). Neonatal exposure to ±3,4-methelynedioxymethamphetamine alters NMDA receptor subunit 1, nNOS and PSD95 expression and LTP in adult rats.
Herring, N. R., Gudelsky, G. A., Vorhees, C. V., Williams, M. T. (submitted 5-28-2008). Dissociation of dopaminergic neurotoxicity and path integration learning deficits from hyperthermia after (+)-methamphetamine treatment in adrenalectomized rats.
Vorhees, C. V., Schaefer, T. L., Skelton, M. R., Grace, C. E., Herring, N. R., Williams, M. T. (accepted with minor revision). ±3,4-Methylenedioxymethamphetamine (MDMA) dose-dependently impairs spatial learning in the Morris water maze after exposure of rats to different five-day intervals from birth to postnatal day 20. Developmental Neuroscience
Vorhees, C. V., Johnson, H. L., Burns, L. N., Williams, M. T. (major revision, resubmitted 6-26-2008). Effects of developmental quinpirole treatment on adult behavior. Neurotoxicology and Teratology
Loepke, A.W., Istaphanous, G.K., Miles, L., Hughes, E.A., McCann, J.C., Kurth, C.D., Williams, M.T., Vorhees, C.V., Danzer, S.C. (in press). Effects of neonatal isoflurane anesthesia on neuronal structure and adult neurocognitive function in mice. Anesthesia & Analgesia
Skelton, M. R., Able, J. A., Grace, C. E., Herring, N.R., Schaefer, T. L., Gudelsky, G. A., Vorhees, C. V., Williams, M. T. (in press). (±)-3,4-methylenedioxymethamphetamine treatment in adult rats impairs path integration learning: A comparison of single versus once per week treatment for five weeks. Neuropharmacology
Sun, Y., Jia, L., Williams M. T., Zamzow, M., Ran, H., Quinn, B., Aronow, B.J., Vorhees, C. V., Witte, D. P., Grabowski, G. A. (in press). Gene expression profiling and neurobehavioral assessments in prosaposin deficient mice: Molecular alterations precede neuronal deficits. BMC Neuroscience
Herring, N.R., Schaefer, T. L., Gudelsky, G. A., Vorhees, C. V., Williams, M. T. (in press). Effect of (+)-methamphetamine on path integration learning, novel object recognition, and neurotoxicity in rats. Psychopharmacology
Vorhees, C. V., Herring, N.R., Schaefer, T. L., Grace, C. E., Skelton, M. R., Johnson, H. L., Williams, M. T. (2008). Effects of (+)-methamphetamine on path integration and spatial learning in rats: Effects of dose and rearing conditions. International Journal of Developmental Neuroscience 26(6):599-610.
Sun, Y., Witte, D.P., Ran, H., Zamzow, M., Barnes, S., Cheng, H., Han, X., Williams, M.T., Skelton, M.R., Vorhees, C.V., Grabowski, G.A. (2008). Neurological deficits and glycosphingolipid accumulation in Saposin B deficient mice. Human Molecular Genetics 17:2345-2356.
Herring, N.R., Schaefer, T.L., Tang, P.H., Skelton, M.R., Lucot, J.P., Gudelsky, G.A., Vorhees, C.V., Williams, M.T. (2008). Comparison of time-dependent effects of (+)-methamphetamine or forced swim on monoamines, corticosterone, glucose, creatine, and creatinine in rats. BMC Neuroscience 9:49.
Skelton, M. R., Williams, M. T., Vorhees, C. V. (2008). Developmental effects of 3,4-methylenedioxymethamphetamine: A review. Behavioural Pharmacology 19(2):91-111.
Schaefer, T. L., Skelton, M. R., Herring, N.R., Gudelsky, G. A., Vorhees, C. V., Williams, M. T. (2008). Short- and long-term effects of (+)-methamphetamine and (±)-3,4-methylenedioxymethamphetamine on monoamine and corticosterone levels in the neonatal rat following multiple days of treatment. Journal of Neurochemistry 104:1674-1685.
Pan, D., Sciascia, A., Vorhees, C. V., Williams, M. T. (2008). Progression of multiple behavioral deficits during development in a murine model of Hurler Syndrome: Age of onset during development. Brain Research, 1188:241-253.
Grace, C. E., Schaefer, T. L., Herring, N.R., Skelton, M. R., McCrea, A. E., Vorhees, C. V., Williams, M. T. (2008). (+)-Methamphetamine increases corticosterone in plasma and BDNF in brain more than forced swim or isolation in neonatal rats. Synapse, 62(2):110-121.
Lingrel, J. B., Williams, M. T., Vorhees, C. V., Moseley A. E. (2007). Na,K-ATPase and the role of α isoforms. J Bioenergetics and Biomembranes 39(5-6):385-9. (Review)
Vorhees, C. V., Skelton, M. R., Williams, M. T. (2007). Age-dependent effects of neonatal methamphetamine exposure on spatial learning. Behavioural Pharmacology, 18(5-6):549-562.
Skelton, M. R., Williams, M. T., Schaefer, T. L., Vorhees, C. V. (2007). Neonatal methamphetamine increases brain derived neurotrophic factor, but not nerve growth factor, during treatment and results in long-term spatial learning deficits. Psychoneuroendocrinology, 32(6): 734-745.
Williams, M. T.*, Herring, N.R.*, Schaefer, T. L., Skelton, M. R., Campbell N. G., Lipton, J. W., McCrea, A. E., Vorhees, C. V. (2007). Alterations in corticosterone and behavior following the administration of 5-methoxy-diisopropyltryptamine (‘Foxy’) to adult rats: A new drug of abuse. *denotes equal authorship. Neuropsychopharmacology 32: 1404-1420.
Vorhees, C. V., Schaefer, T. L., Williams, M. T. (2007). Developmental exposure to 3,4-methylenedioxymethamphetamine results in differential long-term deficits in spatial vs. path integration learning as a function of dose distribution. Synapse 61(7): 488-499.
Moseley A. E.*, Williams, M. T.*, Schaefer, T. L., Bohanan, C. S., Behbehani, M. M., Vorhees, C. V., Lingrel, J. B. (2007). Deficiency in Na,K-ATPase alpha isoform genes alters spatial learning, motor activity and anxiety in mice. *denotes equal authorship. Journal of Neuroscience 27(3):616-626.
Skelton, M. R., Williams, M. T., Vorhees, C. V. (2006). Treatment with MDMA from P11-20 disrupts spatial learning and path integration learning in adolescent rats but only spatial learning in older rats. Psychopharmacology 189(3):307-318.
Thacker, S. K., Perna, M. K., Ward, J. J., Schaefer, T. L., Williams, M. T., Kostrzewa, R. M., Brown, R. W. (2006). The effects of adulthood olanzapine treatment on cognitive performance and neurotrophic factor content in male and female rats neonatally treated with quinpirole. European Journal of Neuroscience. 24:2075-2083.
Williams, M. T., Furay, A. F., Ehrman, L. A., Schaefer, T. L., Vorhees, C. V. (2006). Ontogeny of the adrenal response to (+)-methamphetamine in neonatal rats: the effect of prior drug exposure. Stress 9(3): 153-163.
Vorhees, C. V., Williams, M. T. (2006). Morris water maze: Procedures for assessing spatial and related forms of learning and memory. Nature Protocols, 1(2): 848-858.
Schaefer, T. L., Ehrman, L. A., Gudelsky, G. A., Vorhees, C. V., Williams, M. T. (2006). A comparison of monoamine and corticosterone levels 24 hours following d-methamphetamine, ±3,4-methylenedioxymethamphetamine, cocaine, d-fenfluramine, or methylphenidate administration in the neonatal rat. Journal of Neurochemistry 98(5): 1369-1378.
Ehrman, L. A., Williams, M. T., Schaefer, T. L., Gudelsky, G. A., Reed, T. M., Fienberg, A. A., Greengard, P., Vorhees, C. V. (2006). Phosphodiesterase 1B modulates the effects of methamphetamine on locomotor activity and spatial learning through a DARPP32-dependent pathway: evidence from PDE1B-DARPP32 double knockout mice. Genes, Brain, and Behavior, 5: 540-551.
Able, J. A., Gudelsky, G. A., Vorhees, C. V., Williams, M. T. (2006). ±3, 4-Methylenedioxymethamphetamine in adult rats produces deficits in path integration and spatial reference memory. Biological Psychiatry, 59(12): 1219-1226.
Crawford, C. A., Williams, M. T., Kohutek, J. L., Choi, F. A., Yoshida, S. T., McDougall, S. A., Vorhees, C. V. (2006). Neonatal 3,4-methylenedioxymethamphetamine (MDMA) exposure alters neuronal protein kinase A activity, serotonin and dopamine content, and [35S]GTPγS binding in adult rats. Brain Research, 1077: 178-186.
Brown, R. W., Perna, M. K., Schaefer, T. L., Williams, M. T. (2006). The effects of nicotine on D2-mediated behaviors and neurotrophins of rats neonatally treated with quinpirole. Synapse 59(5): 253-259.
Becker, L. A., Kunkel, A. J., Brown, M. R., Ball, E. E., Williams, M. T. (2005). Effects of dietary phytoestrogen exposure during perinatal period. Neurotoxicology and Teratology 27(6):825-834.
Brunskill, E. W., Erhman, L. A., Williams, M. T., Klanke, J., Hammer, D., Schaefer, T. L., Sah, R., Dorn, G. W., Potter, S. S., Vorhees, C. V. (2005). Abnormal neurodevelopmental, behavioral, and neurotransmitter signaling in NPAS-3 deficient mice. European Journal of Neuroscience 22(6): 1265-1276.
Cohen, M. A., Skelton, M. R., Schaefer, T. L., Gudelsky, G. A., Vorhees, C. V., Williams, M. T. (2005). Learning and memory after neonatal exposure to 3,4-methylenedioxymethamphetamine (ecstasy) in rats: Interaction with exposure in adulthood. Synapse 57(3): 148-159.
Williams, M. T., Schaefer, T. L., Ehrman, L. A., Able, J. A., Gudelsky, G. A., Sah, R., Vorhees, C. V. (2005). 3,4-Methylenedioxymethamphetamine administration on postnatal day 11 in rat increases pituitary-adrenal output and reduces striatal and hippocampal serotonin without altering SERT activity. Brain Research 1039(1/2):95-105.
Vorhees, C. V., Reed, T. M., Morford, L. L., Fukumura, M., Wood, S. L., Brown, C. A., Skelton, M. R., McCrea, A. E., Rock, S. L., and Williams, M. T. (2005). Periadolescent rats (P41-50) exhibit increased susceptibility to d-methamphetamine-induced long-term spatial and sequential learning deficits compared to juvenile (P21-30 or P31-40) or adult rats (P51-60). Neurotoxicology and Teratology 27(1): 117-134.
Kuan, C.-Y., Schloemer, A. J., Lu, A., Burns, K. A., Weng, W.-L., Williams, M. T., Strauss, K. I., Vorhees, C. V., Flavell, R. A., Davis, R. J., Sharp, F. R., Rakic, P. (2004). Hypoxia-ischemia induces DNA synthesis without cell proliferation in dying neurons in adult rodent brain. Journal of Neuroscience 24(47):10763-10772.
Skelton, M. R., Blankemeyer, T. L., Gudelsky, G. A., Brown-Strittholt, C. A., Vorhees, C. V., Williams, M. T. (2004). Metyrapone attenuates the sequential learning deficits, but not monoamine depletions following d,l-fenfluramine administration to adult rats. Synapse 54(4): 214-222.
Williams, M. T., Brown, C. A., Skelton, M. R., Vinks, A. A., and Vorhees, C. V. (2004). Absorption and clearance of ±3,4-methylenedioxymethamphetamine from the plasma of neonatal rats. Neurotoxicology and Teratology 26(6): 849-856.
Vorhees, C. V., Reed, T. M., Skelton, M. R., and Williams, M. T. (2004). Exposure to 3,4-methylenedioxymethamphetamine (MDMA) on postnatal days 11-20 induces reference but not working memory deficits in the Morris water maze in rats: implications of prior learning. International Journal of Developmental Neuroscience. 22(5/6): 247-259.
Williams, M. T., Moran, M. S., & Vorhees , C. V. (2004). Behavioral and growth effects induced by low dose methamphetamine administration during the neonatal period in rats. International Journal of Developmental Neuroscience. 22(5/6): 273-283.
Brown, R. W., Flanigan, T. J., Thompson, K. N., Thacker, S. K., Schaefer, T. L., Williams, M. T. (2004). Neonatal quinpirole treatment impairs Morris water task performance in early postweanling rats: Relationship to increases in corticosterone and decreases in neurotrophic factors. Biological Psychiatry 56(3):161-168.
Williams, M. T.*, Brown, R. W.*, Vorhees, C. V. (2004). Neonatal methamphetamine administration induces region-specific long-term neuronal morphological changes in the rat hippocampus, nucleus accumbens, and parietal cortex. European Journal of Neuroscience 19(12): 3165-3170. *denotes equal authorship.
Brown, R. W., Thompson, K. D., Thompson, K. N., Ward, J. J., Thacker, S. K., Williams, M. T., and Kostrzewa, R. M. (2004). Adulthood nicotine treatment alleviates behavioral impairments in rats neonatally treated with quinpirole: Possible roles of acetylcholine function and neurotrophic factor expression. European Journal of Neuroscience 19(6): 1634-1642.
Williams, M. T., Blankemeyer, T. L., Schaefer, T. L., Brown, C. A., Gudelsky, G. A., Vorhees, C. V. (2003). Long-term effects of neonatal methamphetamine exposure in rats on spatial learning in the Barnes maze and on cliff avoidance, corticosterone release, and neurotoxicity in adulthood. Dev Brain Res 147(1-2): 163-175.
Williams, M. T., Moran, M. S., & Vorhees , C. V. (2003) Refining the critical period for methamphetamine-induced spatial deficits in the Morris water maze. Psychopharmacology 168, 329-338.
Williams, M. T., Morford, L. L., Wood, S. L., Wallace, T. L., Fukumura, M., Broening, H. W., and Vorhees, C. V. (2003). Developmental d-methamphetamine treatment selectively induces spatial navigation impairments in reference memory in the Morris water maze while sparing working memory. Synapse 48, 138-148.
Crawford, C. A., Williams, M. T., Newman, E. R., McDougall S. A., & Vorhees, C. V. (2003) Methamphetamine exposure during the preweanling period causes prolonged changes in dorsal striatal protein kinase A activity, dopamine D2-like binding sites, and dopamine content. Synapse 48, 131-137.
Williams, M. T., Morford, L. L., Wood, S. L., Rock, S. L., McCrea, A. E., Fukumura, M., Wallace, T. L., Broening, H. W., Moran, M. S., & Vorhees, C. V. (2003). Developmental 3,4-methylenedioxymethamphetamine (MDMA)-induced learning deficits are not related to undernutrition or litter effects: novel use of litter size to control for MDMA-induced growth decrements. Brain Research 968 (1), 89-101.
