Advancing animal models of depression : a behavioural, cellular and molecular approach

• Main Author: Musaelyan, Ksenia
• Other Authors: Thuret, Sandrine ; Fernandes, Catherine ; Pariante, Carmine Maria
• Published: King's College London (University of London) 2017
• Subjects: 616.85
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.721682

Animal models of depression have provided invaluable insight into the disease neurobiology, yet when it comes to novel antidepressant targets, the research progress in this area struggled to keep up with the growing prevalence of the disease. Thus this thesis is dedicated to improvement and optimisation of two frequently used models in mice, the unpredictable chronic mild stress (UCMS) with its good construct and predictive validity, and lipopolysaccharide (LPS) exposure relevant for the inflammatory theory of depression. The experiments described in this thesis show that following optimisation, UCMS can be a reliable model to induce some of the depression-like behaviours, as well as alterations in adult hippocampal neurogenesis (AHN) in mice. However, it appeared that the prefrontal cortex (PFC) but not the hippocampus responds to UCMS with profound gene expression changes and microglial activation. Importantly, UCMS was not associated with a strong profile of systemic inflammatory changes seen in depressed patients. Therefore, the need for an intervention specifically targeting the immune system became apparent. For this, LPS exposure, which induces a depression-like phenotype by activating the immune system, was employed. Results suggested that repeated LPS injections rather than frequently used single LPS exposure might be a suitable model to induce chronic immune changes relevant for depression, as well as some alteration of AHN. However, measures such as dose increment and sufficient recovery time between injections should be taken to avoid development of tolerance towards LPS, although they were not successful in sustaining the long-term behavioural depressive-like phenotype. In conclusion, this research showed that both UCMS and LPS-based interventions induce some endophenotypes relevant for depression, yet neither is sufficient to fully model behavioural changes and neurobiology of the disease in mice. It is suggested that future work combining the two treatments might be more suitable for uncovering and testing novel antidepressant targets.