Influence of diet on the development of homeostatic neurocircuits

项目总结/摘要 肥胖症的患病率在世界范围内以惊人的速度增加， 合并症的不祥增加，包括2型糖尿病，心脏病， 高血压和高脂血症。虽然越来越多的人认为肥胖是由于 结合环境、遗传和表观遗传因素，有几条证据表明， 表明，围产期环境是至关重要的发展，神经 负责能量稳态和自主反射调节整合的回路 饱腹感迷走神经介导的反射被认为在神经系统中起着关键作用。 能量平衡的机制我们以前已经证明， 围产期的脂肪饮食（HFD）（即，e..，妊娠晚期和哺乳期） 中枢迷走神经运动神经元的兴奋性和反应性;在本建议中，我们将 使用各种电生理学、神经生理学和生理学方法， 调查新的总体假设，即围产期暴露于高脂肪饮食逮捕 脑干内抑制性神经回路的发育成熟。 目的1：探讨围产期高脂饮食暴露是否会导致 脑干神经回路的永久性变化， 对迷走神经背侧运动核（DMV）神经元的甘氨酸能突触输入。目标2将 研究内源性出生后瘦素激增对正常的 抑制性迷走神经脑干神经回路的发育成熟，Aim 3将研究 假设葡萄糖调节围产期HFD DMV神经元的兴奋性，但 由于甘氨酸受体的正向变构调节，大鼠中没有对照。 检查由饮食引起的脑干神经回路永久性改变的可能性- 在围产期，瘦素神经营养信号的诱导破坏带来了 有机会发现新的脑肠道神经信号通路，脆弱的时间点， 脑干神经回路的发展，以及迷走神经内的神经调节和可塑性， 依赖性反射，其可以广泛地应用于自主稳态通路。

Project Summary/Abstract The prevalence of obesity is increasing worldwide at a dramatic rate accompanied with an ominous increase in comorbid conditions including Type 2 Diabetes, heart disease, hypertension and hyperlipidemia. While it is increasingly accepted that obesity arises from a combination of environmental, genetic and epigenetic factors, several lines of evidence have suggested that the perinatal environment is critically important in the development of neural circuits responsible for energy homeostasis and the integration of autonomic reflexes regulating satiety. Vagally-mediated reflexes are recognized as playing a critical role in the neural mechanisms of energy homeostasis. We have demonstrated previously that exposure to a high fat diet (HFD) during the perinatal period (i.,e.., late pregnancy and lactation) decreases the excitability and responsiveness of central vagal motoneurons; in the present proposal, we will use a variety of electrophysiological, neurophysiological and physiological approaches to investigate the novel overarching hypothesis that perinatal exposure to a high fat diet arrests the developmental maturation of inhibitory neurocircuits within the brainstem. Aim 1 will investigate the hypothesis that HFD exposure in the perinatal period induces permanent changes in brainstem neurocircuits by arresting the developmental decline in glycinergic synaptic inputs to dorsal motor nucleus of the vagus (DMV) neurons. Aim 2 will investigate the hypothesis that the endogenous postnatal leptin surge is critical for the normal developmental maturation of inhibitory vagal brainstem neurocircuits, and Aim 3 will investigate the hypothesis that glucose regulates the excitability of DMV neurons from perinatal HFD, but not control, rats due to positive allosteric modulation of glycine receptors. The potential to examine permanent alterations in brainstem neurocircuitry resulting from diet- induced disruption of leptin neurotrophic signaling in the perinatal period brings with it the opportunity to uncover novel brain-gut neurosignaling pathways, the vulnerable time-points in brainstem neurocircuit development, and neuromodulation and plasticity within vagally- dependent reflexes which may be broadly applicable across autonomic homeostatic pathways.