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

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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.