A lactocrine pathway in programming cognitive behavior

 描述（由申请人提供）：“母体编程”是一个术语，描述了母体因素在发育敏感期的作用，对后代产生持续影响。例如，母体环境中的营养物质供应对胎儿生长和以后的代谢和心理健康有重大影响。此外，母亲的压力环境可以改变后代对压力的反应，母亲护理的质量影响后代的认知和情感发展。我们已经使用小鼠模型确定了一种新的编程范例，其中产后期间母亲自愿活动/锻炼（在带有转轮的大笼子中）与久坐不动的生活（在标准笼子中）相比，改善了后代的许多认知，情感和社会行为。由于自愿轮运行抑制与久坐动物的低度炎症相关的促炎细胞因子的产生，我们通过进一步增加细菌脂多糖（LPS）引起的母体炎症来扩展模型，这使后代行为恶化。因此，在具有运行轮的笼中的母鼠接近具有“正常”产后期的母鼠，而在标准笼中的母鼠和在具有轮的笼中的注射LPS的母鼠代表具有低度炎症（与肥胖和精神疾病相关）和明显炎症（由于围产期感染）的产后并发症的母鼠。虽然运动对个体的长期有益影响是众所周知的，但据我们所知，我们的研究是第一个暗示产后期间母亲运动对行为的代际影响的研究。初步数据表明，这种编程是由牛奶细胞因子和生长因子介导的，因此我们称之为“乳分泌行为编程”。我们的工作模型是，久坐不动的条件和相关的低度炎症在哺乳期，由标准的实验室住房，以及产妇全身炎症条件，导致复杂的变化，细胞因子/生长因子组成的牛奶，这导致后代免疫系统发育的变化。这反过来又改变了我们最近在海马和皮层神经元中发现的环境敏感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，神经元经历结构变化，从而改变其连接和功能，并最终改变其行为。该提案将详细说明牛奶细胞因子/免疫学联系，连接产后母亲与发育中的后代（目标1），母体效应对后代表观基因组的影响（目标2），以及后代行为变化的神经元结构基础（目标3）。

 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).