Effects of Developmental Exposure to Maternal Diet and Exercise on Offspring Cognition

这项提案的首要目标是通过使用一个 模型的母亲饮食和运动在怀孕期间调查认知和海马功能， 后代子宫内和早期生活环境为成人疾病的出现奠定了基础。在 在世界范围内的肥胖流行和高脂肪“西方”饮食的平行全球化中，理解 相应的胎儿环境的长期后果是至关重要的。我们的实验室建立了一个 妊娠期和哺乳期母体高脂饮食（mHFD）暴露的啮齿类动物模型（含成年后代） 显示出代谢失调和认知障碍的标志性特征， 标准的低脂饮食我们模型中的后代也显示出海马胰岛素的改变。采取 连同已知的胰岛素抵抗、代谢失调和认知衰退之间的关联， 以及胰岛素在正常海马发育中作用的新证据，似乎 在我们的mHFD模型中，胰岛素调节的发育中断可能是所观察到的 代谢和认知表型。运动，已被证明可以改善代谢健康，包括 胰岛素失调以及认知健康是针对这些表型的有希望的干预措施。 关于母亲在怀孕期间锻炼的新研究表明， 持续改善后代的认知能力和海马结构。体操 也改善了后代的新陈代谢，在mHFD的情况下，也被证明可以逆转后代的新陈代谢。 MetS样表型，包括胰岛素失调的纠正。但据我们所知，孕期锻炼 尚未研究作为与mHFD相关的认知失调的潜在干预。我 我建议在怀孕期间使用一种自愿的母亲转轮运动的范例， 与我们建立的mHFD模型相结合，开发并试验研究了乳腺癌介导的 成年后代的认知能力、海马形态和海马胰岛素信号传导。在Aim中 1，我试图调查妊娠期运动暴露对mHFD相关损伤的影响， 后代海马结构和功能。在目标2中，我试图阐明胰岛素的机制作用 mHFD相关海马损伤的调节及其通过妊娠期运动的潜在改善。 我的总体假设是，自愿的母亲运动将减轻或逆转mHFD的认知影响 暴露在后代中，并且这种逆转将在机械上依赖于海马神经元的校正。 胰岛素调节产妇营养过剩的日益普遍造成了重大的临床和公共卫生问题。 未来几代人的健康挑战。通过研究产妇锻炼在潜在减轻 mHFD相关的认知障碍的后代和区分机械贡献者，这项研究将 理想地促进行为和靶向药物干预两者的未来发展。

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.