Influence of diet on the development of homeostatic neurocircuits

饮食对稳态神经回路发育的影响

基本信息

批准号：
10065504
负责人：
Kirsteen Nairn Browning
金额：
$ 38.98万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10065504
关键词：
Affect Area Back Behavior Brain Brain Stem Cell Nucleus Clinical Development Diet Eating Efferent Neurons Elderly Electrophysiology (science)Environment Epigenetic Process Exposure to Food Energy Food Intake Regulation Gastrointestinal tract structure Genetic Glucose Glycine Receptors Heart Diseases High Fat Diet Homeostasis Human Hyperlipidemia Hypertension Laboratory Animals Lactation Late pregnancy Leptin Mediating Motor Motor Neurons Motor output Nerve Neurons Non-Insulin-Dependent Diabetes Mellitus Obesity Organ Overnutrition PF4 Gene Pacemakers Pathway interactions Perinatal Perinatal Exposure Peripheral Pharmacology Phenotype Physiological Play Pregnancy Prevalence Public Health Rattus Reflex action Role Satiation Sensory Signal Transduction Stomach Synapses Testing Time Vagus nerve structure Viscera Visceral autonomic reflex cell motility comorbidity designer receptors exclusively activated by designer drugs dietary control dorsal motor nucleus energy balance fetal gastrointestinal function in vivo neural circuit neurodevelopment neuromechanism neurophysiology neuroregulation novel nutrient absorption nutrition obesity development offspring perinatal period postnatal transmission process

项目摘要

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.

项目摘要/摘要肥胖的患病率在全球范围内以巨大的速度伴随合并症的不祥之图，包括2型糖尿病，心脏病，高血压和高脂血症。尽管越来越接受肥胖是由环境，遗传和表观遗传因素的结合，几条证据已有建议围产期环境在神经的发展中至关重要负责能量稳态的电路和调节自主反射的整合饱腹感。模糊介导的反射被认为在神经中起着至关重要的作用能量稳态的机制。我们之前已经证明了暴露于高的围产期（i。中央迷走运动神经元的兴奋性和反应性；在本提案中，我们将使用多种电生理，神经生理和生理学方法调查新的总体假设，即围产期暴露于高脂饮食会阻碍脑干内抑制性神经电路的发育成熟。 AIM 1将调查HFD暴露在围产期期间的假设脑干神经通路的永久变化，通过捕捉糖连突触输入到迷走神经（DMV）神经元背运动核的输入。 AIM 2意志研究内源性产后瘦素激增对正常至关重要的假设抑制性迷走神经神经环路的发展成熟，AIM 3将调查葡萄糖调节围产期HFD的DMV神经元的兴奋性的假设，但由于甘氨酸受体的阳性变构调节，大鼠无法控制。检查饮食引起的脑干神经记录的永久变化的潜力 - 在围产期诱导的瘦素神经营养信号传导带来的破坏带来发现新颖的脑肠神经信号途径的机会，脆弱的时间点脑干神经循环的发育以及模糊的神经调节和可塑性可能在自主神经稳态途径中广泛适用的依赖反射。