title: Early life protein restriction alters dopamine circuitry.
abstract: Adverse prenatal environment, such as intrauterine growth retardation (IUGR), increases the risk for negative neurobehavioral outcomes. IUGR, affecting approximately 10% of all US infants, is a known risk factor for attention deficit hyperactivity disorder (ADHD), schizophrenia spectrum disorders and addiction. Mouse dams were fed a protein deficient (8.5% protein) or isocaloric control (18% protein) diet through pregnancy and lactation (a well validated rodent model of IUGR). Dopamine-related gene expression, dopamine content and behavior were examined in adult offspring. IUGR offspring have six to eightfold over-expression of dopamine (DA)-related genes (tyrosine hydroxylase (TH) and dopamine transporter) in brain regions related to reward processing (ventral tegmental area (VTA), nucleus accumbens, prefrontal cortex (PFC)) and homeostatic control (hypothalamus), as well as increased number of TH-ir neurons in the VTA and increased dopamine in the PFC. Cyclin-dependent kinase inhibitor 1C (Cdkn1c) is critical for dopaminergic neuron development. Methylation of the promoter region of Cdkn1c was decreased by half and there was a resultant two to sevenfold increase in Cdkn1c mRNA expression across brain regions. IUGR animals demonstrated alterations in dopamine-dependent behaviors, including altered reward-processing, hyperactivity and exaggerated locomotor response to cocaine. These data describe significant dopamine-related molecular and behavioral abnormalities in a mouse model of IUGR. 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.
authors.affiliation: Department of Pharmacology, Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Vucetic
authors.forename: K
authors.initials: K
authors.lastname: Totoki
authors.forename: H
authors.initials: H
authors.lastname: Schoch
authors.forename: K W
authors.initials: KW
authors.lastname: Whitaker
authors.forename: T
authors.initials: T
authors.lastname: Hill-Smith
authors.forename: I
authors.initials: I
authors.lastname: Lucki
authors.forename: T M
authors.initials: TM
authors.lastname: Reyes
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation; D003042:Cocaine / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D018753:Diet, Protein-Restricted; D004298:Dopamine / Q000502:physiology*; D044127:Epigenesis, Genetic; D005260:Female; D005317:Fetal Growth Retardation / Q000378:metabolism*; D020869:Gene Expression Profiling; D056426:Genetic Loci; D018392:Genomic Imprinting; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D008431:Maternal-Fetal Exchange; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009043:Motor Activity; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; C513121:IGF2 protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D007335:Insulin-Like Growth Factor II; D003042:Cocaine; D004298:Dopamine
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