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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH087978-04
Application #
8390497
Study Section
Special Emphasis Panel (ZRG1-PMDA-A (01))
Program Officer
Beckel-Mitchener, Andrea C
Project Start
2009-12-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
4
Fiscal Year
2013
Total Cost
$380,160
Indirect Cost
$142,560
Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Thanos, Panayotis K; Zhuo, Jianmin; Robison, Lisa et al. (2016) Suboptimal maternal diets alter mu opioid receptor and dopamine type 1 receptor binding but exert no effect on dopamine transporters in the offspring brain. Int J Dev Neurosci :
Grissom, Nicola M; Herdt, Christopher T; Desilets, Jeffery et al. (2015) Dissociable deficits of executive function caused by gestational adversity are linked to specific transcriptional changes in the prefrontal cortex. Neuropsychopharmacology 40:1353-63
Grissom, Nicola; Bowman, Nicole; Reyes, Teresa M (2014) Epigenetic programming of reward function in offspring: a role for maternal diet. Mamm Genome 25:41-8
Reyes, Teresa M (2014) Diet, inflammation and the brain: commentary on the 2014 named series. Brain Behav Immun 42:6-9
Grissom, Nicola M; Lyde, Randolph; Christ, Lori et al. (2014) Obesity at conception programs the opioid system in the offspring brain. Neuropsychopharmacology 39:801-10
Carlin, Jesselea; Hill-Smith, Tiffany E; Lucki, Irwin et al. (2013) Reversal of dopamine system dysfunction in response to high-fat diet. Obesity (Silver Spring) 21:2513-21
Carlin, Jesselea; George, Robert; Reyes, Teresa M (2013) Methyl donor supplementation blocks the adverse effects of maternal high fat diet on offspring physiology. PLoS One 8:e63549
Whitaker, K W; Totoki, K; Reyes, T M (2012) Metabolic adaptations to early life protein restriction differ by offspring sex and post-weaning diet in the mouse. Nutr Metab Cardiovasc Dis 22:1067-74
Grissom, Nicola M; Reyes, Teresa M (2012) Gestational overgrowth and undergrowth affect neurodevelopment: similarities and differences from behavior to epigenetics. Int J Dev Neurosci :
Vucetic, Zivjena; Carlin, Jesse Lea; Totoki, Kathy et al. (2012) Epigenetic dysregulation of the dopamine system in diet-induced obesity. J Neurochem 120:891-8

Showing the most recent 10 out of 14 publications