Neuroendocrine-immune (NEI) system programming of zebrafish embryos and larva: Implications for stress resilience, disease resistance, and longevity

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Livestock and aquaculture species are routinely subjected to a variety of stressors such as microbial infections. The neuroendocrine-immune (NEI) system plays a central role in initiating and regulating the host response to stress and helps restore physiological homeostasis after a stress event. The NEI system is sensitive to prenatal and perinatal stressors, and when they are experienced during certain windows of development, NEI system programming can be permanently affected; researchers have historically focused on maternal and neonatal stress, although paternal stress may be equally important. It has been proposed that NEI plasticity during early development is an adaptive mechanism that helps newborn animals prepare for their postnatal environment; however, when developmental programming is mismatched to the environment that offspring ultimately reside in, it may negatively impact stress resilience, disease resistance and longevity, all of which are important health, economic and welfare concerns for Canadian livestock and aquaculture producers. Human studies have shown stress-induced programming of the developing NEI system, by stressors such as nutrient restriction, traumatic experiences and microbial infection, can manifest across generations, and sex differences are common; the impact of stress-induced programming on the NEI systems of livestock and aquaculture species is largely unknown. The mechanisms of action (MOA) by which stress-induced programming occurs are just beginning to be understood and appear to involve permanent changes in gene regulation.   A major limitation of domestic animal studies is that they are extremely costly and time consuming to perform, especially when generational, parental and sex effects, and MOA are investigated. We believe the zebrafish (Zf), which is an emerging vertebrate model, has the potential to greatly advance our understanding of how stress impacts NEI programming in livestock and aquaculture species. In this proposal, we plan to develop larval and adult Zf immune stress models using innate immune stressors (microbial-associated molecular patterns; MAMPs) to study stress-induced programming of the NEI system, investigate protection provided by phytochemicals, and explore MOA. Since fish lack an important mammalian pattern-recognition receptor (PRR) orthologue, Toll-like receptor 4 (TLR4), it will be important to identify other PRR that facilitate recognition of MAMPs that are TLR4 ligands; these may serve as alternate targets for nutrition-based or vaccine-directed immune stimulation, and they may be polymorphic across species, which will be important for genetic selection to enhance disese resistance. This research will help us to better understand the long-term impact of stress-induced NEI system programming in developing animals and will allow us to investigate regulatory processes that may be modulated by phytochemicals to promote offspring health without relying on antimicrobials.