Early life protein restriction alters dopamine circuitry.
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.
Vucetic
Z
Z
Department of Pharmacology, Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Totoki
K
K
Schoch
H
H
Whitaker
K W
KW
Hill-Smith
T
T
Lucki
I
I
Reyes
T M
TM
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
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
Hum Mol Genet. 2006 Mar 1;15(5):705-16
16421170
Dev Neurobiol. 2009 Jan;69(1):1-21
18814313
Behav Pharmacol. 2006 Feb;17(1):19-29
16377960
Biochem Biophys Res Commun. 2007 Jan 19;352(3):823-9
17150178
Int J Obes (Lond). 2008 Dec;32 Suppl 7:S62-71
19136993
Reprod Sci. 2010 Mar;17(3):227-38
19923380
JAMA. 2009 Sep 9;302(10):1084-91
19738093
Placenta. 1996 Mar-Apr;17(2-3):169-72
8730887
Brain Res. 2009 Apr 10;1265:196-204
19236855
J Biol Chem. 2007 Jan 5;282(1):390-6
17092932
BMC Dev Biol. 2007 May 21;7:53
17517131
Biol Psychiatry. 2005 Jun 1;57(11):1397-409
15950014
Nat Neurosci. 2009 Dec;12(12):1559-66
19898468
Am J Physiol Regul Integr Comp Physiol. 2009 Aug;297(2):R291-9
19458276
Pediatr Res. 2007 May;61(5 Pt 2):43R-47R
17413842
Brain Res. 2008 Oct 27;1237:62-74
18703024
Nat Genet. 2005 Aug;37(8):853-62
16007088
PLoS One. 2008 Jan 09;3(1):e1422
18183302
Neuroscience. 2004;124(3):629-35
14980733
J Child Adolesc Psychopharmacol. 2001 Spring;11(1):15-24
11322741
JAMA. 1999 Aug 4;282(5):455-62
10442661
J Am Acad Child Adolesc Psychiatry. 2007 Mar;46(3):370-377
17314723
Nutrition. 2010 Apr;26(4):411-22
19811894
Neuroscience. 2008 Apr 9;152(4):859-66
18329816
Am J Psychiatry. 2007 Apr;164(4):622-9
17403976
PLoS One. 2009;4(3):e4950
19308256
Neurosci Biobehav Rev. 2005 May;29(3):421-30
15820547
Br J Psychiatry. 1995 May;166(5):601-6
7620744
Synapse. 1991 Oct;9(2):121-8
1821483
J Pharmacol Exp Ther. 2001 Sep;298(3):1101-7
11504807
Neurosci Biobehav Rev. 2007;31(4):597-618
17316796
Trends Neurosci. 2009 Jan;32(1):2-8
18986716
Behav Pharmacol. 1999 Jul;10(4):379-87
10780806
Am J Clin Nutr. 2007 Oct;86(4):1219-24
17921405
PLoS One. 2008;3(11):e3745
19015723
Nat Rev Genet. 2007 Apr;8(4):253-62
17363974
Am J Physiol Regul Integr Comp Physiol. 2010 Feb;298(2):R275-82
19889862
PLoS One. 2009 Aug 12;4(8):e6606
19672298
Neuropharmacology. 2005 Mar;48(4):538-46
15755481
J Neurosci. 2007 Jan 3;27(1):152-7
17202482
Behav Brain Res. 2005 Jun 3;161(1):45-59
15904709
J Psychiatry Neurosci. 2003 Jan;28(1):27-38
12587848
Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15619-24
14671317
Nucleic Acids Res. 2001 May 1;29(9):e45
11328886
Am J Physiol Endocrinol Metab. 2008 Feb;294(2):E251-60
18029443
Nat Neurosci. 2004 Aug;7(8):847-54
15220929
Am J Clin Nutr. 2009 May;89(5):1488S-1493S
19261726
Addiction. 2008 Mar;103(3):433-8
18190668
Ann N Y Acad Sci. 2008;1136:185-92
18579882
Neurosci Biobehav Rev. 2000 Jan;24(1):51-7
10654661
J Neurosci. 2003 Nov 26;23(34):10827-31
14645475
J Neurosci. 2003 Jul 2;23(13):5607-16
12843263
JAMA. 2005 Aug 3;294(5):557-62
16077049
Neuroscience. 2007 Dec 5;150(2):449-58
17935891
Biochim Biophys Acta. 2009 Sep;1790(9):878-85
19364482
Neuroscience. 2009 Mar 3;159(1):161-71
19162132
J Nutr. 1979 Jun;109(6):1045-50
36448
Neurosci Lett. 2006 Jul 31;403(1-2):119-24
16682119
Neuroscience. 2006;137(1):221-9
16226384
J Dev Behav Pediatr. 2002 Feb;23(1):16-22
11889347
Neuropsychopharmacology. 2007 Jul;32(7):1462-76
17164817
Dev Psychobiol. 1974 Nov;7(6):551-61
4217288
Am J Psychiatry. 2000 Feb;157(2):190-5
10671386
Genomics. 2004 Dec;84(6):961-70
15533713
Psychopharmacology (Berl). 2000 Jan;148(1):52-8
10663417
Endocrinology. 2006 Jun;147(6):2909-15
16513834
Int J Dev Neurosci. 1997 Apr;15(2):257-63
9178043
Neuroscience. 2009 Mar 3;159(1):47-58
19135135
Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12253-8
14519846
J Am Acad Child Adolesc Psychiatry. 1987 May;26(3):356-62
3597291
Brain Res. 2008 Jul 30;1222:95-105
18589406
Annu Rev Psychol. 2008;59:29-53
18154498
Reproduction. 2006 Aug;132(2):265-77
16885535
J Child Psychol Psychiatry. 2006 Nov;47(11):1167-74
17076756
J Neurosci. 1995 Jan;15(1 Pt 2):821-9
7823183
Neurotoxicol Teratol. 2003 Jul-Aug;25(4):447-58
12798962
Sci STKE. 2005 Nov 08;2005(309):re14
16278489
Neuroinformatics. 2007 Spring;5(1):79-94
17426354