Michael Williams

Michael T Williams

Associate Professor - Aff

Childrens Hospital Bldg R

5009

COM Pediatrics Neurology - 0054

Cincinnati Children's Hospital Medical Center
3333 Burnet Avenue
Cincinnati, Ohio 45229

Professional Summary

One are that we are investigating are the effects of manganese (Mn) alone and in combination with stress when these occur during early development. This is an important area of investigation in children’s health since Mn exposure occurs in young children from soy-based infant formulas, ferromanganese industrial plants, and well water in areas with naturally occurring ground water Mn. In addition, Mn exposure is seen more often in low social economic status (SES) families.
Low SES conditions have been associated with stress, and children in these situations tend to have higher levels of circulating cortisol.
We are investigating the effects of Mn and stressors as models of low SES on the development of monoamine neurotransmitters in the brain, hormonal responses to stress, and behavior, especially learning and memory.
We find that early exposure to Mn leads to long-term changes in neurotransmitters, especially dopamine, and to spatial and egocentric learning and memory deficits. Chronic stress has similar effects. We are currently investigating the mechanisms of these effects and how these factors interact.
In addition, we have recently shown that early Mn exposure places the organism at increased risk for later development of Parkinson-like effects. After we exposed laboratory rats to Mn early in life and later give them 6-hydroxydopamine, a drug that induces Parkinson-like effects, but given at a threshold dose that does not elicit symptoms by itself, all groups show learning impairments but the combination group shows severe effects. We have a pilot grant to further understand how Mn exposure imparts increased risk for Parkinsonism.

As of 2006, 25 percent of pregnant women entering drug treatment reported methamphetamine as their primary drug of abuse. This is compared with 8 percent in 1994. This upward trend has continued.
These data underestimate the prevalence of this problem since the majority of drug users do not enter treatment, and methamphetamine has become more widely available since 2006. Yet little is known about how methamphetamine affects brain development.
We investigate how methamphetamine affects brain development. We have found that it results in enduring learning and memory impairments. We are also interested in treatments that may ameliorate such deficits.
In our experiments, laboratory rats are exposed to methamphetamine during selected stages of brain development. We have found that early exposure to methamphetamine causes ACTH release from the anterior pituitary and corticosterone release from the adrenals, and transient reductions in brain serotonin (5-HT). After exposure ends, methamphetamine-exposed rats show long-term dopamine reductions, and altered dopamine D1 receptor function and utilization.
Developmental methamphetamine exposure also causes changes to dopamine D1, D2, and NMDA receptors. We are testing several hypotheses about the mechanisms of methamphetamine’s effects on brain development, including whether the drug induces reactive oxygen species (ROS) that may damage neurons or cause overstimulation of dopamine receptors. We are measuring markers of ROS and using microPET imaging to assess the functional integrity of dopamine-rich areas of the brain.
In adults, chronic methamphetamine users exhibit evidence of neurotoxicity by brain imaging, changes that can be replicated in laboratory rats. People who exhibit evidence of reduced brain dopamine uptake have impairments in learning and memory. How the drug causes cognitive effects is unknown. We are testing whether cognitive deficits can be prevented by injecting dopamine D1 and D2 receptor inhibitors into brain areas we hypothesize are critical to the cognitive deficits before exposing them to methamphetamine in order to test if these drugs are protective. These are proof of principle experiments that could lead to treatments to prevent

Education

Ph.D., Wright State University Dayton, OH, 1997 (Biomedical Science, Neuroscience tract)

Publications

Peer Reviewed Publications

Braun, Amanda A; Amos-Kroohs, Robyn M; Gutierrez, Arnold; Lundgren, Kerstin H; Seroogy, Kim B; Skelton, Matthew R; Vorhees, Charles V; Williams, Michael T (2015. )Dopamine depletion in either the dorsomedial or dorsolateral striatum impairs egocentric Cincinnati water maze performance while sparing allocentric Morris water maze learning.Neurobiology of learning and memory, ,118 ,55-63

Vorhees, Charles V; Graham, Devon L; Braun, Amanda A; Schaefer, Tori L; Skelton, Matthew R; Richtand, Neil M; Williams, Michael T Prenatal immune challenge in rats: effects of polyinosinic-polycytidylic acid on spatial learning, prepulse inhibition, conditioned fear, and responses to MK-801 and amphetamine.Neurotoxicology and teratology, ,47 ,54-65

Amos-Kroohs, Robyn M; Bloor, Colin P; Qureshi, Momina A; Vorhees, Charles V; Williams, Michael T Effects of developmental exposure to manganese and/or low iron diet: Changes to metal transporters, sucrose preference, elevated zero-maze, open-field, and locomotion in response to fenfluramine, amphetamine, and MK-801.Toxicology reports, ,2 ,1046-1056

Hautman, Emily R; Kokenge, Amanda N; Udobi, Kenea C; Williams, Michael T; Vorhees, Charles V; Skelton, Matthew R (2014. )Female mice heterozygous for creatine transporter deficiency show moderate cognitive deficits.Journal of inherited metabolic disease, ,37 (1 ),63-8

Williams, Michael T; Skelton, Matthew R; Longacre, Ian D; Huggins, Kimberly N; Maple, Amanda M; Vorhees, Charles V; Brown, Russell W (2014. )Neuronal reorganization in adult rats neonatally exposed to (±)-3,4-methylenedioxymethamphetamine.Toxicology reports, ,1 ,699-706

Graham, Devon L; Amos-Kroohs, Robyn M; Braun, Amanda A; Grace, Curtis E; Schaefer, Tori L; Skelton, Matthew R; Williams, Michael T; Vorhees, Charles V (2013. )Neonatal +-methamphetamine exposure in rats alters adult locomotor responses to dopamine D1 and D2 agonists and to a glutamate NMDA receptor antagonist, but not to serotonin agonists.The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), ,16 (2 ),377-91

Vorhees, Charles V; Graham, Devon L; Braun, Amanda A; Schaefer, Tori L; Skelton, Matthew R; Richtand, Neil M; Williams, Michael T (2012. )Prenatal immune challenge in rats: altered responses to dopaminergic and glutamatergic agents, prepulse inhibition of acoustic startle, and reduced route-based learning as a function of maternal body weight gain after prenatal exposure to poly IC.Synapse (New York, N.Y.), ,66 (8 ),725-37

Chen, Ying; Curran, Christine P; Nebert, Daniel W; Patel, Krishna V; Williams, Michael T; Vorhees, Charles V (2012. )Effect of chronic glutathione deficiency on the behavioral phenotype of Gclm-/- knockout mice.Neurotoxicology and teratology, ,34 (4 ),450-7

Braun, Amanda A; Graham, Devon L; Schaefer, Tori L; Vorhees, Charles V; Williams, Michael T (2012. )Dorsal striatal dopamine depletion impairs both allocentric and egocentric navigation in rats.Neurobiology of learning and memory, ,97 (4 ),402-8

Chen, Y; Curran, C P; Nebert, D W; Patel, K V; Williams, M T; Vorhees, C V (2012. )Effect of vitamin C deficiency during postnatal development on adult behavior: functional phenotype of Gulo-/- knockout mice.Genes, brain, and behavior, ,11 (3 ),269-77

Grace, Curtis E; Schaefer, Tori L; Herring, Nicole R; Williams, Michael T; Vorhees, Charles V Effects of neonatal methamphetamine treatment on adult stress-induced corticosterone release in rats.Neurotoxicology and teratology, ,34 (1 ),136-42

Vorhees, Charles V; Morford, LaRonda R; Graham, Devon L; Skelton, Matthew R; Williams, Michael T (2011. )Effects of periadolescent fluoxetine and paroxetine on elevated plus-maze, acoustic startle, and swimming immobility in rats while on and off-drug.Behavioral and brain functions : BBF, ,7 ,41

Braun, Amanda A; Skelton, Matthew R; Vorhees, Charles V; Williams, Michael T (2011. )Comparison of the elevated plus and elevated zero mazes in treated and untreated male Sprague-Dawley rats: effects of anxiolytic and anxiogenic agents.Pharmacology, biochemistry, and behavior, ,97 (3 ),406-15

Curran, Christine P; Vorhees, Charles V; Williams, Michael T; Genter, Mary Beth; Miller, Marian L; Nebert, Daniel W (2011. )In utero and lactational exposure to a complex mixture of polychlorinated biphenyls: toxicity in pups dependent on the Cyp1a2 and Ahr genotypes.Toxicological sciences : an official journal of the Society of Toxicology, ,119 (1 ),189-208

Schaefer, T L; Grace, C E; Gudelsky, G A; Vorhees, C V; Williams, M T (2010. )Effects on plasma corticosterone levels and brain serotonin from interference with methamphetamine-induced corticosterone release in neonatal rats.Stress (Amsterdam, Netherlands), ,13 (6 ),469-80

Grace, Curtis E; Schaefer, Tori L; Graham, Devon L; Skelton, Matthew R; Williams, Michael T; Vorhees, Charles V (2010. )Effects of inhibiting neonatal methamphetamine-induced corticosterone release in rats by adrenal autotransplantation on later learning, memory, and plasma corticosterone levels.International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience, ,28 (4 ),331-42

Vorhees, Charles V; Skelton, Matthew R; Grace, Curtis E; Schaefer, Tori L; Graham, Devon L; Braun, Amanda A; Williams, Michael T (2009. )Effects of (+)-methamphetamine on path integration and spatial learning, but not locomotor activity or acoustic startle, align with the stress hyporesponsive period in rats.International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience, ,27 (3 ),289-98

Vorhees, Charles V; Schaefer, Tori L; Skelton, Matthew R; Grace, Curtis E; Herring, Nicole R; Williams, Michael T (2009. )(+/-)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 twenty.Developmental neuroscience, ,31 (1-2 ),107-20

Skelton, Matthew R; Able, Jessica A; Grace, Curtis E; Herring, Nicole R; Schaefer, Tori L; Gudelsky, Gary A; Vorhees, Charles V; Williams, Michael T (2008. )(+/-)-3,4-Methylenedioxymethamphetamine treatment in adult rats impairs path integration learning: a comparison of single vs once per week treatment for 5 weeks.Neuropharmacology, ,55 (7 ),1121-30

Sun, Ying; Jia, Li; Williams, Michael T; Zamzow, Matt; Ran, Huimin; Quinn, Brian; Aronow, Bruce J; Vorhees, Charles V; Witte, David P; Grabowski, Gregory A (2008. )Temporal gene expression profiling reveals CEBPD as a candidate regulator of brain disease in prosaposin deficient mice.BMC neuroscience, ,9 ,76

Sun, Ying; Witte, David P; Ran, Huimin; Zamzow, Matt; Barnes, Sonya; Cheng, Hua; Han, Xianlin; Williams, Michael T; Skelton, Matthew R; Vorhees, Charles V; Grabowski, Gregory A (2008. )Neurological deficits and glycosphingolipid accumulation in saposin B deficient mice.Human molecular genetics, ,17 (15 ),2345-56

Herring, Nicole R; Schaefer, Tori L; Tang, Peter H; Skelton, Matthew R; Lucot, James P; Gudelsky, Gary A; Vorhees, Charles V; Williams, Michael 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

Pan, Dao; Sciascia, Anthony; Vorhees, Charles V; Williams, Michael T (2008. )Progression of multiple behavioral deficits with various ages of onset in a murine model of Hurler syndrome.Brain research, ,1188 ,241-53

Lingrel, Jerry B; Williams, Michael T; Vorhees, Charles V; Moseley, Amy E (2007. )Na,K-ATPase and the role of alpha isoforms in behavior.Journal of bioenergetics and biomembranes, ,39 (5-6 ),385-9

Vorhees, Charles V; Schaefer, Tori L; Williams, Michael T (2007. )Developmental effects of +/-3,4-methylenedioxymethamphetamine on spatial versus path integration learning: effects of dose distribution.Synapse (New York, N.Y.), ,61 (7 ),488-99

Williams, Michael T; Herring, Nicole R; Schaefer, Tori L; Skelton, Matthew R; Campbell, Nicholas G; Lipton, Jack W; McCrea, Anne E; Vorhees, Charles V (2007. )Alterations in body temperature, corticosterone, and behavior following the administration of 5-methoxy-diisopropyltryptamine ('foxy') to adult rats: a new drug of abuse.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, ,32 (6 ),1404-20

Moseley, Amy E; Williams, Michael T; Schaefer, Tori L; Bohanan, Cynthia S; Neumann, Jon C; Behbehani, Michael M; Vorhees, Charles V; Lingrel, Jerry B (2007. )Deficiency in Na,K-ATPase alpha isoform genes alters spatial learning, motor activity, and anxiety in mice.The Journal of neuroscience : the official journal of the Society for Neuroscience, ,27 (3 ),616-26

Schaefer, Tori L; Ehrman, Lisa A; Gudelsky, Gary A; Vorhees, Charles V; Williams, Michael T (2006. )Comparison of monoamine and corticosterone levels 24 h following (+)methamphetamine, (+/-)3,4-methylenedioxymethamphetamine, cocaine, (+)fenfluramine or (+/-)methylphenidate administration in the neonatal rat.Journal of neurochemistry, ,98 (5 ),1369-78

Able, Jessica A; Gudelsky, Gary A; Vorhees, Charles V; Williams, Michael T (2006. )3,4-Methylenedioxymethamphetamine in adult rats produces deficits in path integration and spatial reference memory.Biological psychiatry, ,59 (12 ),1219-26

Brown, Russell W; Perna, Marla K; Schaefer, Tori L; Williams, Michael T (2006. )The effects of adulthood nicotine treatment on D2-mediated behavior and neurotrophins of rats neonatally treated with quinpirole.Synapse (New York, N.Y.), ,59 (5 ),253-9

Vorhees, Charles V; Williams, Michael T (2006. )Morris water maze: procedures for assessing spatial and related forms of learning and memory.Nature protocols, ,1 (2 ),848-58

Becker, Lora A; Kunkel, Aaron J; Brown, Michelle R; Ball, Erin E; Williams, Michael T Effects of dietary phytoestrogen exposure during perinatal period.Neurotoxicology and teratology, ,27 (6 ),825-34

Williams, Michael T; Schaefer, Tori L; Ehrman, Lisa A; Able, Jessica A; Gudelsky, Gary A; Sah, Renu; Vorhees, Charles V (2005. )3,4-Methylenedioxymethamphetamine administration on postnatal day 11 in rats increases pituitary-adrenal output and reduces striatal and hippocampal serotonin without altering SERT activity.Brain research, ,1039 (1-2 ),97-107

Vorhees, Charles V; Reed, Tracy M; Morford, LaRonda L; Fukumura, Masao; Wood, Sandra L; Brown, Carrie A; Skelton, Matthew R; McCrea, Anne E; Rock, Stephanie L; Williams, Michael T 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 ),117-34

Skelton, Matthew R; Blankenmeyer, Tracy L; Gudelsky, Gary A; Brown-Strittholt, Carrie A; Vorhees, Charles V; Williams, Michael T (2004. )Metyrapone attenuates the sequential learning deficits but not monoamine depletions following d,l-fenfluramine administration to adult rats.Synapse (New York, N.Y.), ,54 (4 ),214-22

Williams, Michael T; Moran, Mary S; Vorhees, Charles V Behavioral and growth effects induced by low dose methamphetamine administration during the neonatal period in rats.International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience, ,22 (5-6 ),273-83

Williams, Michael T; Brown, Russell W; Vorhees, Charles V (2004. )Neonatal methamphetamine administration induces region-specific long-term neuronal morphological changes in the rat hippocampus, nucleus accumbens and parietal cortex.The European journal of neuroscience, ,19 (12 ),3165-70

Williams, Michael T; Moran, Mary S; Vorhees, Charles V (2003. )Refining the critical period for methamphetamine-induced spatial deficits in the Morris water maze.Psychopharmacology, ,168 (3 ),329-38

Williams, Michael T; Morford, LaRonda L; Wood, Sandra L; Wallace, Tanya L; Fukumura, Masao; Broening, Harry W; Vorhees, Charles V (2003. )Developmental D-methamphetamine treatment selectively induces spatial navigation impairments in reference memory in the Morris water maze while sparing working memory.Synapse (New York, N.Y.), ,48 (3 ),138-48

Williams, Michael T; Morford, LaRonda L; Wood, Sandra L; Rock, Stephanie L; McCrea, Anne E; Fukumura, Masao; Wallace, Tanya L; Broening, Harry W; Moran, Mary S; Vorhees, Charles V (2003. )Developmental 3,4-methylenedioxymethamphetamine (MDMA) impairs sequential and spatial but not cued learning independent of growth, litter effects or injection stress. Brain research, ,968 (1 ),89-101

Williams, Michael T; Vorhees, Charles V; Boon, Francis; Saber, Andrea J; Cain, Donald P (2002. )Methamphetamine exposure from postnatal day 11 to 20 causes impairments in both behavioral strategies and spatial learning in adult rats. Brain research, ,958 (2 ),312-21

Williams, M T; Davis, H N; McCrea, A E; Hennessy, M B Stress during pregnancy alters the offspring hypothalamic, pituitary, adrenal, and testicular response to isolation on the day of weaning. Neurotoxicology and teratology, ,21 (6 ),653-9

Williams, M T; Davis, H N; McCrea, A E; Hennessy, M B The distribution of radiolabeled corticotropin-releasing factor in pregnant rats: an investigation of placental transfer to the fetuses. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience, ,16 (3-4 ),229-34

Williams, M T; Hennessy, M B; Davis, H N (1995. )CRF administered to pregnant rats alters offspring behavior and morphology. Pharmacology, biochemistry, and behavior, ,52 (1 ),161-7

Post Graduate Training and Education

10-01-1997-07-01-2000 Research Fellow, Cincinnati Children's Research Foundation, ,Cincinnati, OH

Contact Information

Academic - Cincinnati Children's Hospital Medical Center
3333 Burnet Avenue
Cincinnati  Ohio, 45229
Phone: 513-636-4222
michael.williams@cchmc.org