Behavior is affected by genetics, the environment, and a complex interplay between the two. Exposure to nutritional deficiencies at critical time points during development, particularly while in utero and during the postpartum period, increases the risk of psychiatric disease in humans, and alters behavioral outcomes in animal models of human psychiatric disease. Some of these effects have been linked to changes in methylation and gene expression, implying that epigenetic factors may contribute to the underlying disease process. Identifying specific genes that respond both to environmental variation and that influence behavior in animal models can reveal not only genetic pathways involved in brain development and function, but also how such pathways are sensitive to external factors in the environment. Such studies can thereby shed light on the etiology of human psychiatric disease, and provide new clues to prevention and treatment. The goal of this proposal is to identify genes whose actions are modulated by maternal nutrition and that influence behavior in adult offspring. The experimental design contains several innovative components, and makes use of a powerful new genetic resource for mouse studies, the Collaborative Cross (CC). The CC is a panel of recombinant inbred mouse lines, each of whose genomes comprises a balanced but randomized mosaic of genetic material from eight diverse founder strains. The proposed study uses the known haplotypic composition of the CC lines to generate sparse diallel cross of reciprocal matings between CC strains (CC recombinant inbred mice, or CC-RIX) that allows a genomewide survey of genetic effects that vary by parent of origin and maternal diet. Specifically, mating CC females will be exposed to nutritional deficiencies during gestation and in the postpartum period. CC-RIX offspring will then be subject to behavioral testing and assayed for gene expression by microarray. Novel statistical methodology developed during the project will be applied in order to identify and characterize strain- and diet-specific effects, as well as parent of origin effects due to allelic imbalance. Candidate genes will be assessed by direct behavioral examination of knockout mice and also by knockout complementation testing to validate the role of both diet and strain. The proposed research represents a novel application of a powerful new genetic platform in order to elucidate how genetics, in utero exposures, maternal diet and parent-of-origin combine to affect behavior.

Public Health Relevance

The goal of the project is to identify genes whose expression is altered by nutritional deficiency in utero and during the postpartum period and that affect behaviors that model human psychiatric disease. Successful completion of the project could lead to the identification of genetic pathways that are sensitive to a known environment risk factor and that predispose individuals to develop psychiatric disease later in life.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Beckel-Mitchener, Andrea C
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Schoenrock, S A; Oreper, D; Farrington, J et al. (2018) Perinatal nutrition interacts with genetic background to alter behavior in a parent-of-origin-dependent manner in adult Collaborative Cross mice. Genes Brain Behav 17:e12438
Oreper, Daniel; Schoenrock, Sarah A; McMullan, Rachel et al. (2018) Reciprocal F1 Hybrids of Two Inbred Mouse Strains Reveal Parent-of-Origin and Perinatal Diet Effects on Behavior and Expression. G3 (Bethesda) 8:3447-3468
Xue, Jing; Gharaibeh, Raad Z; Pietryk, Edward W et al. (2018) Impact of vitamin D depletion during development on mouse sperm DNA methylation. Epigenetics 13:959-974
Oreper, Daniel; Cai, Yanwei; Tarantino, Lisa M et al. (2017) Inbred Strain Variant Database (ISVdb): A Repository for Probabilistically Informed Sequence Differences Among the Collaborative Cross Strains and Their Founders. G3 (Bethesda) 7:1623-1630
Schoenrock, Sarah Adams; Oreper, Daniel; Young, Nancy et al. (2016) Ovariectomy results in inbred strain-specific increases in anxiety-like behavior in mice. Physiol Behav 167:404-412
Schoenrock, S A; Tarantino, L M (2016) Developmental vitamin D deficiency and schizophrenia: the role of animal models. Genes Brain Behav 15:45-61
Xue, Jing; Schoenrock, Sarah A; Valdar, William et al. (2016) Maternal vitamin D depletion alters DNA methylation at imprinted loci in multiple generations. Clin Epigenetics 8:107