In utero programming of the dopamine system: behavior, neuroanatomy &epigenetics

Summary

Principal Investigator: Teresa M Reyes
Abstract: DESCRIPTION (provided by applicant): Intrauterine growth retardation (IUGR) affects approximately 10% of all US infants. These small-for- gestational age (SGA) babies face increased risk for immediate morbidity and mortality, as well as long-term neurobehavioral disabilities (e.g., attention deficit hyperactivity disorder (ADHD), addiction, schizophrenia). While adverse metabolic and cardiovascular outcomes have been well characterized in these infants, the coincident neurobehavioral disabilities and specific central nervous system (CNS) abnormalities have received significantly less attention. The mechanisms linking IUGR and neurobehavioral disabilities are poorly understood and warrant further investigation, as this knowledge is critical for early diagnosis and intervention. To shed light on these issues, we propose the integration of behavioral, neuroanatomical, and epigenetic approaches to understand the long-term CNS impact of IUGR. Using a well-characterized rodent IUGR model (low protein diet fed to pregnant mice), we have found evidence for behavioral components of ADHD, including altered reward processing and hyperactivity. These behaviors involve dopamine (DA), and in both animal models of and human patients with ADHD, alterations in DA signaling have been documented. Our IUGR offspring have altered expression of genes that control dopamine synthesis and activity, suggesting that dopaminergic function is also altered as a result of the low protein diet and may underlie the observed neurobehavioral changes. We have also identified hypomethylation and increased expression of CDKN1c in IUGR animals, a gene critical for dopaminergic cell differentiation, which may alter the developmental trajectory of dopaminergic neurons. Additionally, we observe altered methylation, both globally and in a gene-specific manner, as well as significant increases in the expression of genes that play an important role in DNA methylation, including DNA methyltransferase 1 (DNMT1) and methyl CpG binding protein 2 (MeCP2). This proposal will test the central hypothesis that maternal low protein diet directly affects DNA methylation in the developing CNS, leading to behavioral changes and dopamine dysfunction, in a manner similar to what is observed in ADHD. In four aims, experiments will (1) test the hypothesis that IUGR animals demonstrate a behavioral profile consistent with ADHD (2) examine dopamine expression and function within the mesolimbic/ mesocortical circuitry (3) determine whether Cdkn1c overexpressing mice replicate the behavioral or gene expression phenotype of the IUGR mice and (4) complete a genome-wide screen of differentially methylated genes in the CNS of IUGR mice. PUBLIC HEALTH RELEVANCE: Intrauterine growth retardation affects up to 10% of all babies born in the US. These babies can have neurobehavioral disabilities, including an increased risk for attention deficit hyperactivity disorder (ADHD). Experiments proposed in this application will use an animal model to explore the underlying mechanisms for these brain and behavior changes and potentially identify possible avenues of intervention.
Funding Period: 2009-12-01 - 2014-11-30
more information: NIH RePORT

Top Publications

  1. pmc Obesity at conception programs the opioid system in the offspring brain
    Nicola M Grissom
    1 Department of Pharmacology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA 2 Institute for Translational Medicine and Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
    Neuropsychopharmacology 39:801-10. 2014
  2. pmc Methyl donor supplementation blocks the adverse effects of maternal high fat diet on offspring physiology
    Jesselea Carlin
    University of Pennsylvania, School of Medicine, Department of Pharmacology, Institute for Translational Medicine and Therapeutics, Philadelphia, Pennsylvania, United States of America
    PLoS ONE 8:e63549. 2013
  3. pmc Reversal of dopamine system dysfunction in response to high-fat diet
    Jesselea Carlin
    Department of Pharmacology, Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, Philadelphia, Pennsylvania, USA
    Obesity (Silver Spring) 21:2513-21. 2013
  4. ncbi Gestational overgrowth and undergrowth affect neurodevelopment: similarities and differences from behavior to epigenetics
    Nicola M Grissom
    Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, United States
    Int J Dev Neurosci 31:406-14. 2013
  5. pmc Epigenetic dysregulation of the dopamine system in diet-induced obesity
    Zivjena Vucetic
    Department of Pharmacology, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
    J Neurochem 120:891-8. 2012
  6. pmc Metabolic adaptations to early life protein restriction differ by offspring sex and post-weaning diet in the mouse
    K W Whitaker
    Department of Pharmacology, Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 5158, USA
    Nutr Metab Cardiovasc Dis 22:1067-74. 2012
  7. pmc Maternal high-fat diet alters methylation and gene expression of dopamine and opioid-related genes
    Zivjena Vucetic
    University of Pennsylvania School of Medicine, Department of Pharmacology, Institute for Translational Medicine and Therapeutics, School of Medicine, 805 Biomedical Research Building II III, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104 6160, USA
    Endocrinology 151:4756-64. 2010
  8. pmc Early life programming and neurodevelopmental disorders
    Tracy L Bale
    Department of Animal Biology, University of Pennsylvania, Philadelphia, Pennsylvania
    Biol Psychiatry 68:314-9. 2010
  9. pmc Early life protein restriction alters dopamine circuitry
    Z Vucetic
    Department of Pharmacology, Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Neuroscience 168:359-70. 2010
  10. ncbi Epigenetic programming of reward function in offspring: a role for maternal diet
    Nicola Grissom
    Department of Pharmacology, Perelman School of Medicine, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, 10 131 Smilow Center for Translational Research, Philadelphia, PA, 19104, USA
    Mamm Genome 25:41-8. 2014

Detail Information

Publications11

  1. pmc Obesity at conception programs the opioid system in the offspring brain
    Nicola M Grissom
    1 Department of Pharmacology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA 2 Institute for Translational Medicine and Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
    Neuropsychopharmacology 39:801-10. 2014
    ..These data are the first to demonstrate that obesity at conception, in addition to during gestation, can program the brain reward system. ..
  2. pmc Methyl donor supplementation blocks the adverse effects of maternal high fat diet on offspring physiology
    Jesselea Carlin
    University of Pennsylvania, School of Medicine, Department of Pharmacology, Institute for Translational Medicine and Therapeutics, Philadelphia, Pennsylvania, United States of America
    PLoS ONE 8:e63549. 2013
    ..Notable sex differences were observed. These findings identify the importance of balanced methylation status during pregnancy, particularly in the context of a maternal high fat diet, for optimal offspring outcome...
  3. pmc Reversal of dopamine system dysfunction in response to high-fat diet
    Jesselea Carlin
    Department of Pharmacology, Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, Philadelphia, Pennsylvania, USA
    Obesity (Silver Spring) 21:2513-21. 2013
    ..To test whether high-fat diet (HFD) decreases dopaminergic tone in reward regions of the brain and evaluate whether these changes reverse after removal of the HFD...
  4. ncbi Gestational overgrowth and undergrowth affect neurodevelopment: similarities and differences from behavior to epigenetics
    Nicola M Grissom
    Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, United States
    Int J Dev Neurosci 31:406-14. 2013
    ....
  5. pmc Epigenetic dysregulation of the dopamine system in diet-induced obesity
    Zivjena Vucetic
    Department of Pharmacology, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
    J Neurochem 120:891-8. 2012
    ..These data identify differential DNA methylation as an epigenetic mechanism linking the chronic intake of HF diet with altered DA-related gene expression, and this response varies by brain region and DNA sequence...
  6. pmc Metabolic adaptations to early life protein restriction differ by offspring sex and post-weaning diet in the mouse
    K W Whitaker
    Department of Pharmacology, Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 5158, USA
    Nutr Metab Cardiovasc Dis 22:1067-74. 2012
    ..However, mice have been relatively understudied in this paradigm and represent a critical resource for investigating the underlying molecular mechanisms that link adverse early life experience and the development of chronic disease...
  7. pmc Maternal high-fat diet alters methylation and gene expression of dopamine and opioid-related genes
    Zivjena Vucetic
    University of Pennsylvania School of Medicine, Department of Pharmacology, Institute for Translational Medicine and Therapeutics, School of Medicine, 805 Biomedical Research Building II III, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104 6160, USA
    Endocrinology 151:4756-64. 2010
    ....
  8. pmc Early life programming and neurodevelopmental disorders
    Tracy L Bale
    Department of Animal Biology, University of Pennsylvania, Philadelphia, Pennsylvania
    Biol Psychiatry 68:314-9. 2010
    ....
  9. pmc Early life protein restriction alters dopamine circuitry
    Z Vucetic
    Department of Pharmacology, Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Neuroscience 168:359-70. 2010
    ..This animal model, with both face validity (behavior) and construct validity (link to IUGR and dopamine dysfunction) may prove useful in identifying underlying mechanisms linking IUGR and adverse neurobehavioral outcomes such as ADHD...
  10. ncbi Epigenetic programming of reward function in offspring: a role for maternal diet
    Nicola Grissom
    Department of Pharmacology, Perelman School of Medicine, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, 10 131 Smilow Center for Translational Research, Philadelphia, PA, 19104, USA
    Mamm Genome 25:41-8. 2014
    ..Epigenetic mechanisms represent a likely link between maternal diet and persistent changes in offspring brain development, and these mechanisms are presented and discussed within the context of perinatal maternal nutrition. ..