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. 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). The parent proposal is testing 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. Our preliminary data support the existence of sex differences, and the current proposal will extend our funded analyses to include female IUGR offspring. Preliminary data with female IUGR mice demonstrate resilience to the behavioral effects and drastically different DA and methylation-associated gene expression. Detailed analyses of these sex differences may identify novel mechanisms important in conferring both risk and resilience to the neurobehavioral effects of IUGR.
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. Gender differences in ADHD are observed, and the proposed experiments will use both males and females, in an effort to understand this difference.
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