The role of the immune system in mediating the effect of chronic stress on adult hippocampal neurogenesis

鸡蛋消费者越来越关注动物福利，导致鸡蛋生产商倾向于散养或开放式蛋鸡舍系统。然而，无笼系统中母鸡的流动性增加可能会导致福利问题，如受伤和感染，这可能会导致产蛋效率降低。因此，重要的是要了解环境因素，可能会导致慢性应激在蛋鸡和所涉及的生理mechanism.Our实验室目前正在研究使用成年海马神经发生（AHN）作为一种工具，以监测慢性应激在家禽。我们已经证明，当母鸡经历了一段时间的实验诱导的慢性应激时，海马脑区产生的新神经元较少。然而，向大脑发出慢性应激信号的生理机制还没有很好地理解。肾上腺糖皮质激素的分泌在鸟类和哺乳动物中被广泛研究，作为对急性和慢性环境应激的保护性反应。然而，在哺乳动物中，增加的糖皮质激素分泌可分别与响应于负性和正性刺激的神经发生减少和增加两者相关。因此，有必要研究其他信号作为慢性应激对大脑影响的可能介质。生物医学研究表明，慢性炎症是应激相关疾病的常见因素，炎症细胞因子可能是神经发生的重要介质。然而，这还没有在鸟类，包括家禽中进行过研究。因此，本研究将探讨免疫反应在介导慢性应激对蛋鸡AHN影响中的作用。作为第一步，我们将测量各种促炎和抗炎细胞因子分子及其受体在脑和脾组织中的免疫系统中的基因表达，这些细胞因子分子及其受体是在我们以前对蛋鸡慢性应激的一些研究中收集的。这些包括不可预测的慢性轻度应激（UCMS）的实验诱导，商业笼舍和自由放养的住房系统的比较，以及调查商业鸡群中自然发生的严重脚垫皮炎，可能会导致慢性疼痛。我们将免疫系统基因表达的定量与我们的措施，在个别鸟类的神经发生的目的是确定免疫系统标记物，与减少neurogenes.Once我们已经确定了与慢性应激相关的尼古丁相关的标记基因，我们将调查实验免疫系统和慢性应激之间的联系与我们的利物浦合作伙伴。我们计划了一个2x2实验设计，包括两组接受UCMS或促炎或抗炎治疗的母鸡，以及两个相应的对照组。我们预测，实验性治疗将改变AHN和促炎标记基因的表达。实验中还将评估肠道微生物群的变化。这将建立特定肠道微生物类群产生的炎症信号与神经发生减少之间的可能联系。这为进一步研究改变肠道植物群组成（例如通过粪便移植）在通过减少炎症信号的产生来促进对慢性应激的恢复力方面的作用提供了机会。总的来说，该项目将有助于对鸟类慢性压力和免疫系统之间联系的基本了解。更具体地说，它将允许在产蛋鸡中鉴定慢性应激的分子标志物，这些分子标志物可以在工业环境中进行监测，以评估对住房和其他生产条件的福利的影响。建立肠道微生物群和大脑免疫信号之间的联系可能允许开发可以在工业中实施的操纵肠道植物群的方法。

Egg consumers are becoming increasingly concerned with animal welfare, leading to an incentive for egg producers to favour free-range or open-barn housing systems for laying hens. However, the increased mobility of hens in cage-free systems may cause welfare problems such as injury and infection that may additionally lead to reduced egg production efficiency. It is therefore important to understand the environmental factors that may induce chronic stress in laying hens and the physiological mechanisms involved.Our lab is currently investigating the use of adult hippocampal neurogenesis (AHN) as a tool to monitor chronic stress in poultry. We have demonstrated that fewer new neurons are produced in the hippocampus brain region when hens experience chronic stress induced experimentally over a period of weeks. However, the physiological mechanisms signalling chronic stress to the brain are not well understood. The secretion of adrenal glucocorticoid hormones is widely studied in birds and mammals as a protective response to acute and chronic environmental stressors. However, in mammals, increased glucocorticoid secretion can be associated both with decreased and increased neurogenesis in response to negative and positive stimuli, respectively. Therefore, there is a need to investigate other signals as possible mediators of the effects of chronic stress on the brain. It is known from biomedical research that chronic inflammation is a common factor in stress-related disease and that inflammatory cytokines may be important mediators of neurogenesis. However this has not been investigated in birds, including poultry. This project will therefore investigate the role of the immune response in mediating the effect of chronic stress on AHN in laying hens. As a first step, we will measure the gene expression in the immune system of a variety of pro- and anti-inflammatory cytokine molecules and their receptors in brain and spleen tissue collected during some of our previous studies of chronic stress in laying hens. These include experimental induction of unpredictable chronic mild stress (UCMS), comparison of commercial caged and free-range housing systems, and investigation of birds in commercial flocks with naturally-occurring severe footpad dermatitis that may cause chronic pain. We will relate the quantification of immune system gene expression to our measures of neurogenesis in individual birds with the aim of identifying immune system markers that are linked to decreased neurogenesis.Once we have identified cytokine-related marker genes associated with chronic stress we will investigate experimentally the link between the immune system and chronic stress in collaboration with our Liverpool partner. We plan a 2x2 experimental design comprising two groups of hens subjected to UCMS or a pro- or anti-inflammatory treatment, with two respective control groups. We predict that the experimental treatments will alter AHN and the expression of pro-inflammatory marker genes. Changes in gut microbiota will also be assessed in the experiment. This will establish a possible link between inflammatory signals produced by specific gut microbe taxa and reduced neurogenesis. This provides an opportunity for a further study to investigate the effects of changing the gut flora composition (for example by faecal transplantation) in promoting resilience to chronic stress by reduced production of inflammatory signals. Overall, the project will contribute to basic understanding in birds of the link between chronic stress and the immune system. More specifically it will allow the identification of molecular markers of chronic stress in laying hens that can be monitored in industrial settings to evaluate the effect on welfare of housing and other production conditions. Establishing a link between gut microbiota and immune signalling to the brain may allow the development of methods to manipulate the gut flora that could be implemented in industry.