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

这项建议的首要目标是通过使用一种 孕期饮食和运动模型研究孕鼠认知功能和海马区功能 后代。宫内和早期生活环境为成人疾病的出现奠定了基础。在 在全球肥胖症流行和高脂肪“西方”饮食并行全球化的背景下，理解 相应的胎儿环境的长期后果至关重要。我们的实验室已经建立了一个 孕期和哺乳期母体高脂饮食(MHFD)暴露的成年子代啮齿动物模型 脱机后表现出代谢紊乱和认知障碍的显著特征 变成标准的低脂饮食。我们模型中的后代也显示出海马体胰岛素的变化。已被占用 再加上已知的胰岛素抵抗、代谢失调和认知能力下降之间的联系， 以及新的证据表明胰岛素在正常的海马体发育中的作用，似乎 我们的mHFD模型中胰岛素调节的发育中断可能是观察到的 代谢和认知表型。运动，已被证明可以改善新陈代谢健康，包括 胰岛素失调，以及认知健康，是针对这些表型的一种有前途的干预措施。 关于孕期母亲运动的最新研究表明，孕期运动暴露 持之以恒地改善后代的认知能力和海马区结构。孕期锻炼 也可以改善后代的新陈代谢，在mHFD的环境中，也被证明可以逆转后代 蛋氨酸样表型，包括纠正胰岛素失调。但据我们所知，孕期锻炼 尚未被研究为与mHFD相关的认知障碍的潜在干预措施。我 我建议在怀孕期间使用一个自愿的母亲跑轮练习的范例 与我们已建立的mHFD模型相结合开发和试点以研究海马区介导的 成年后代的认知表现、海马体形态和海马体胰岛素信号。在AIM 1，我试图调查妊娠期运动暴露对mHFD相关损害的影响 子代海马区的结构和功能。在目标2中，我试图阐明胰岛素的机制作用。 MHFD相关海马区损伤的调节及孕期运动对其可能的改善。 我的总体假设是，自愿的母体锻炼将缓解或逆转mHFD的认知影响 在子代中暴露，这种逆转将机械地依赖于海马体的纠正 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问题 未来几代人面临的健康挑战。通过研究母亲锻炼在潜在缓解中的作用 与mHFD相关的子代认知障碍和区分机制因素，这项研究将 理想地促进了行为干预和靶向药物干预的未来发展。

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.