A lactocrine pathway in programming cognitive behavior

 描述(申请人提供)：“母体规划”是一个术语，描述了母体因素在敏感的发育时期对后代产生持续影响的行为。例如，母体环境中的营养可获得性对胎儿生长以及以后的新陈代谢和心理健康有重大影响。此外，充满压力的母体环境会改变后代对压力的反应，母体护理的质量会影响后代的认知和情感发展。我们使用一个小鼠模型确定了一种新的编程范式，在该模型中，母亲在产后期间的自愿活动/锻炼(在带滚轮的大笼子里)与久坐不动的生活(在标准笼子里)相比，改善了后代的一些认知、情感和社会行为。由于随意的车轮运动抑制了与久坐动物低度炎症相关的促炎细胞因子的产生，我们扩展了该模型，进一步增加了细菌脂多糖(LPS)导致的母体炎症，这会恶化子代的行为。因此，放在有滚轮的笼子里的母鸡与母亲的产后“正常”时期接近，而放在标准笼子里的母坝和放在有轮子的笼子里的注射了内毒素的母坝代表着母亲有产后轻度炎症(与肥胖和精神疾病有关)和明显的炎症(由于围产期感染)的情况。尽管运动对个人的长期益处是众所周知的，但据我们所知，我们的研究是第一次发现产后母亲运动对行为的代际影响。初步数据表明，这种编程是由乳汁细胞因子和生长因子介导的，因此我们将其称为“乳分泌行为编程”。我们的工作模型是，在哺乳期间，标准实验室房间施加的久坐条件和相关的低级别炎症，以及母亲的全身炎症条件，会导致乳汁中细胞因子/生长因子组成的复杂变化，从而导致后代免疫系统发育的变化。这反过来改变了我们最近在海马神经元和大脑皮层神经元中发现的环境敏感区域的后代表观基因组。由于表观遗传域与突触基因的关联，神经元经历了结构变化，改变了它们的连通性和功能，并最终改变了行为。该提案将明确乳汁细胞因子/免疫学联系，将产后母亲与发育中的后代联系起来(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).