A lactocrine pathway in programming cognitive behavior

认知行为编程中的乳分泌途径

• 批准号: 9104820
• 负责人: Miklos Toth
• 金额: $ 64.16万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9104820
• 关键词: Adrenal Cortex Hormones; Adult; Animals; Behavior; Behavioral; Birth; Brain; Brain region; Caring; Cognitive; Complex; Data; Dendritic Spines; Development; Elderly; Emotional; Environment; Epigenetic Process; Exercise; Fetal Growth; Fright; Genes; Genetic; Growth; Hippocampus (Brain); Housing; Human Development; Immune system; Individual; Infection; Inflammation; Inflammatory; Laboratories; Lactation; Lead; Learning; Life; Link; Lipopolysaccharides; Mediating; Mediator of activation protein; Memory; Mental Health; Mental disorders; Metabolic; Milk; Modeling; Morphology; Mothers; Neuronal Differentiation; Neurons; Nutrient; Obesity; Pathway interactions; Postpartum Period; Postpartum Programs; Prefrontal Cortex; Pregnancy; Production; Psyche structure; Reporting; Running; Social Behavior; Source; Specific qualifier value; Stress; Synapses; Systems Development; TNF gene; Testing; Weaning; Work; base; cognitive function; cytokine; density; emotional behavior; epigenetic memory; epigenome; fetal; improved; intergenerational; maternal stress; mouse model; novel; offspring; postnatal; programs; public health relevance; sedentary; transmission process

 DESCRIPTION (provided by applicant): "Maternal programming" is a term that describes the action of maternal factors during sensitive periods of development that produces persistent effects in the offspring. For example, nutrient availability in the maternal environment has a major impact on fetal growth and later later-life metabolic and mental health. Also, a stressful maternal environment can alter offspring responsiveness to stress, and the quality of maternal care influences the cognitive and emotional development of the offspring. We have identified a novel programming paradigm using a mouse model in which maternal voluntary activity/exercise (in large cages with running wheels) vs. sedentary life (in standard cages) during the postpartum period improves a number of cognitive, emotional and social behaviors of the offspring. Since voluntary wheel running suppresses the production of proinflammatory cytokines associated with the low grade inflammation of sedentary animals, we extended the model by further increasing maternal inflammation by bacterial lipopolysaccharide (LPS), which worsened offspring behaviors. Therefore, dams in cages with running wheels approximate mothers with "normal" postpartum period, while dams in standard cages and LPS-injected dams in cages with wheels represent mothers with postpartum complications of low grade inflammation (associated with obesity and psychiatric disease) and frank inflammation (as a result of peripartum infection). Although the long-term beneficial effect of exercise in individual is well known, to the best of our knowledge, our study is the first that implicates an intergenerational effect of maternal exercise during the postpartum period on behavior. Preliminary data suggest that this programming is mediated by milk cytokines and growth factors and therefore we refer to it as "lactocrine behavioral programming". Our working model is that sedentary conditions and the associated low grade inflammation during lactation, imposed by standard laboratory housing, as well as maternal systemic inflammatory conditions, result in complex changes in the cytokine/growth factor composition of the milk, which lead to changes in offspring immune system development. This in turn alters the offspring epigenome at environmentally sensitive domains we recently identified in hippocampal and cortical neurons. Because of the association of epigenetic domains with synaptic genes, neurons undergo structural changes that alter their connectivity and function and ultimately behavior. This proposal will specify the milk cytokine/immunological link, connecting the postpartum mother with the developing offspring (Aim 1), the impact of the maternal effect on the offspring epigenome (Aim 2), and the neuron structural basis of the behavioral changes in the offspring (Aim 3).

 描述（由适用提供）：“孕产妇编程”是一个术语，描述了在敏感的开发期间产生因素的作用，从而在后代产生持久影响。例如，孕产妇环境中的营养可用性对胎儿生长以及后来的新陈代谢和心理健康有重大影响。此外，压力性的孕产妇环境可以改变对压力的后代反应，而产妇护理的质量会影响后代的认知和情感发展。我们使用小鼠模型确定了一种新颖的编程范式，其中在产后期间（在标准笼中）与久坐的寿命（在标准笼中）进行了主要的自愿活动/运动（在带轮的大笼子中），改善了后代的许多认知，情感和社交行为。由于运行自愿的车轮会抑制与久坐动物的低年级炎症相关的促炎细胞因子的产生，因此我们通过进一步增加了脂多糖（LPS）的孕产妇感染来扩展模型，而脂多糖（LPS）被遗忘的后代行为。因此，笼子里的笼子中的大坝具有“正常”产后的近似母亲，而标准笼子里的大坝和LPS注入LPS的大坝代表了笼子中的笼子中的大坝代表具有低年级感染的产后并发症的母亲（与肥胖和精神疾病有关）和坦率的感染（尽管是一个知识的长期益处，但它是众所周知的，这是一个最众所周知的，这是一个最众所周知的，这是一个最富有的研究，是我们的最佳研究，是我们的最佳研究，是我们的最佳研究。在产后行为期间的孕产妇运动。在后代免疫系统开发中。这反过来又改变了我们最近在海马和皮质神经元中确定的环境敏感领域的后代表观基因组。由于表观遗传结构域与突触基因的关联，在结构变化下神经元改变了其连通性和功能并最终行为。该提案将指定牛奶细胞因子/免疫联系，将产后母亲与发展后代（AIM 1），孕产妇对后代表观基因组的影响（AIM 2）以及行为变化的神经元结构基础（AIM 3）（AIM 3）。