Environmental factors contribute to the risk for autism spectrum disorders (ASD), and a greater understanding of these factors is needed. An adverse in utero environment significantly impacts the developing central nervous system (CNS) and can result in serious neurobehavioral outcomes, such as ASD and anxiety. Abnormal birthweight is a biomarker of adverse in utero environment, and can be affected by maternal diet or hypertension, uterine or placental dysfunction, and maternal smoking and/or drug use. In total, small-for-gestational age (SGA) or large-for-gestational age (LGA) may affect over half a million American infants every year. Importantly, epidemiological evidence indicates that both SGA and LGA infants are at an increased risk for ASD. Thus, common intrauterine environmental conditions may predispose infants to ASD and anxiety. We have developed two mouse models based on an adverse in utero environment that result in SGA or LGA offspring by feeding pregnant dams a low protein diet or high fat diet, respectively. These SGA and LGA offspring have significant behavioral and CNS gene expression differences pointing to dysfunction in the dopaminergic, serotonergic and opioid systems, which are known to be altered in ASD and anxiety. Importantly, expression levels of MeCP2 are significantly different in both SGA and LGA offspring, identifying MeCP2 expression as a potential important epigenetic mechanism responsive to adverse in utero conditions. Accumulating evidence suggests that MeCP2 is critical for synaptic plasticity, and deficits in synaptic function may underlie some components of ASD. Further, MeCP2 deletion results in Rett Syndrome in humans and a hypothalamic specific MeCP2 deletion resulted in altered social behavior in mice. In two aims, this proposal will (1) examine the development of social and anxiety-related behaviors in SGA and LGA offspring and compare the critical periods of pregnancy or lactation and (2) analyze genome-wide gene expression changes in SGA and LGA mice and MeCP2 promoter residency using genome wide chromatin immunoprecipitation-sequencing (ChIP-Seq) and profiling technology in medial prefrontal cortex and amygdala. We hypothesize that both SGA and LGA animals are at increased risk for altered social and anxiety-related behaviors, and that alterations in expression of MeCP2 contribute to differential gene expression and adverse neurobehavioral outcomes. The development of these models will allow for future studies of neurobiological mechanisms that link adverse in utero environment and altered social and emotional behaviors with an eventual goal of the development of targeted therapeutics and interventions.

Public Health Relevance

Adverse prenatal conditions can affect the development of the infant brain, increasing the risk for neurobehavioral disabilities, such as autism spectrum disorders (ASD) or anxiety. Experiments proposed in this application will use animal models to examine brain and behavior changes in response to adverse in utero conditions and potentially identify possible avenues of intervention.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZMH1-ERB-L (02))
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Beckel-Mitchener, Andrea C
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University of Pennsylvania
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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
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
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; Kimmel, Jessica; Reyes, Teresa M (2011) Chronic high-fat diet drives postnatal epigenetic regulation of ?-opioid receptor in the brain. Neuropsychopharmacology 36:1199-206