Endocrine Abstracts

The hypothalamic-pituitary-adrenal (HPA) axis is the main stress-responsive neuroendocrine system in humans. Glucocorticoids (GC) constitute the principal systemic mediators of HPA axis function by governingmetabolic and behavioural responses to stress. Those include the modulation of transcriptional processes through the coordinated action of glucocorticoid (GR) and mineralocorticoid (MR) receptors. To study the effects of systemic malfunctioning of the HPA axis on the developing and adult brain, we are using zebrafish as the in vivo model of choice due to their highly conserved neuroendocrine systems. We are employing bioinformatic approaches (RNAseq analysis) to characterise transcriptomes of zebrafish mutants with disrupted functioning of the GC receptors, generated with CRISPR/cas9 gene-editing technology. Additionally, we are performing whole-mount in situ hybridisation, RT-qPCR and behavioural tests. We hypothesise that we will identify a novel set of differentially expressed genes in the brains of our mutants (MR and GR), establish how these are developmentally regulated by these receptors, as well as provide insights into which subset of genes might be co-regulated by MR/GR. Ultimately, we wish to identify the GC-inducible mediators that play roles in neuronal plasticity and thus may contribute to the pathophysiology of human stress-induced disorders. Our recent in silico analysis confirms altered GC signalling in zebrafish with mutations in MR and/or GR. We reveal novel stress-induced mediators and we highlight the neuroendocrine pathways that may contribute to stress-induced alterations in the brain. Going forward, we will perform whole-mount in situ hybridisation to spatially map expression patterns in both adulthood and during different stages of development. These experiments will be complemented by quantification of behavioural phenotypes using different stress paradigms and pharmacological treatments. A combination of the approaches discussed above is likely to bring new insights into these processes, which will be necessary in order to find more effective treatments of stress-related disorders.