The overarching goal of this proposal is to examine early environmental contributors to cognition by using a model of maternal diet and exercise during pregnancy to investigate cognitive and hippocampal function in offspring. The intrauterine and early life environments set the path for the emergence of adult disease. In the midst of a worldwide obesity epidemic and parallel globalization of the high-fat ?Western? diet, understanding the long-term consequences of a corresponding fetal environment is crucial. Our laboratory has established a rodent model of maternal high-fat diet (mHFD) exposure during pregnancy and lactation, with adult offspring displaying hallmark characteristics of both metabolic dysregulation and cognitive impairment despite weaning onto a standard low-fat diet. The offspring in our model show hippocampal insulin alterations as well. Taken together with the known association between insulin resistance, metabolic dysregulation, and cognitive decline, and emerging evidence for the role of insulin in normal hippocampal development, it appears that developmental disruption of insulin regulation in our mHFD model may be a major mechanism for the observed metabolic and cognitive phenotypes. Exercise, which has been shown to improve metabolic health, including insulin dysregulation, as well as cognitive health, is a promising intervention in targeting these phenotypes. Emerging studies on maternal exercise during pregnancy suggest that gestational exercise exposure persistently improves cognitive performance and hippocampal architecture of offspring. Gestational exercise also improves offspring metabolism, and in the setting of mHFD has also been shown to reverse the offspring MetS-like phenotype, including a correction of insulin dysregulation. Yet to our knowledge, gestational exercise has not been studied as a potential intervention for the cognitive dysregulation associated with mHFD. I propose to use a paradigm of voluntary maternal running wheel exercise during gestation that I have developed and piloted in combination with our established mHFD model to study hippocampally-mediated cognitive performance, hippocampal morphology, and hippocampal insulin signaling in adult offspring.
In Aim 1, I seek to investigate the effects of gestational exercise exposure on mHFD-associated impairment in offspring hippocampal structure and function.
In Aim 2, I seek to elucidate the mechanistic role of insulin regulation in mHFD-associated hippocampal impairment and its potential amelioration by gestational exercise. My overall hypothesis is that voluntary maternal exercise will mitigate or reverse the cognitive effects of mHFD exposure in offspring, and that this reversal will be mechanistically dependent on correction of hippocampal insulin regulation. The increasing prevalence of maternal overnutrition creates significant clinical and public health challenges for future generations. By examining the role of maternal exercise in potentially mitigating mHFD-associated cognitive impairment in offspring and distinguishing mechanistic contributors, this study will ideally facilitate the future development of both behavioral and targeted pharmaceutical interventions.

Public Health Relevance

Exposure to an adverse nutritional environment during pregnancy and lactation through maternal high fat diet consumption significantly impairs hippocampally-mediated cognition in offspring. Using behavioral, morphological, and molecular measures, I will investigate maternal exercise during pregnancy as a potential intervention for this cognitive impairment and elucidate the mechanistic role of hippocampal insulin therein.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Raiten, Daniel J
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Johns Hopkins University
Schools of Medicine
United States
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