Using proxy measures of a depressive-like state to assess the impact of pre-clinical models of chronic diseases on the welfare of mice

Assessing chronic discomfort and distress in laboratory animals is a difficult task. Here we propose a novel proxy measure for a chronic negative subjective experience in animals: the reduction of adult hippocampal neurogenesis (AHN) in the dentate gyrus. Many different chronic distress treatments which lead to depression-like symptoms in laboratory animals (e.g. social stress, restraint stress, chronic mild stress) lead to reduction in AHN. This reduction is recovered by anti-depressants on the same time-scale as the reduction of the depression-like symptoms. Similar evidence is also emerging in human depressed patients. Reduction in AHN may therefore serve as a proxy for a chronic state of distress.

We will investigate the sensitivity and time-course of the reduction in AHN to different durations of a known chronic stressor, as a background to the rest of the study. We will then quantify the reduction of AHN in different mouse models of chronic disease (cancer, liver disease), and compare them to chronic mild stress to put the distress experienced by the animals in context. Quantification of AHN is normally a very time-consuming process of counting cell in tissue prepared for microscopy, but recently, faster molecular techniques have emerged, which we are also developing in our research group. This will make this a viable method for (post-mortem) assessment of the severity of chronic distress in these models.

Having assessed the severity of chronic distress, we will then also assess to what extent the experimental treatments to treat the diseases alleviate this distress, and to what extent other refinement methods can be used to alleviate the chronic distress in the animals. These refinement methods will be developed in consultation with the researchers using the models, to make sure the validity of the disease model is not compromised.