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Abstract
Macrophage inhibitory cytokine-1 (MIC-1), also known as growth differentiation factor 15 (GDF15), is a stress response cytokine. MIC-1/GDF15 is secreted into the cerebrospinal fluid and increased levels of MIC-1/GDF15 are associated with a variety of diseases including cognitive decline. Furthermore, Mic-1/Gdf15 knockout mice (Mic-1 KO) weigh more, have increased adiposity, associated with increased spontaneous food intake, and exhibit reduced basal energy expenditure and physical activity. The current study was designed to comprehensively determine the role of MIC-1/GDF15 on behavioural domains of male and female knockout mice including locomotion, exploration, anxiety, cognition, social behaviours, and sensorimotor gating. Mic-1 KO mice exhibited a task-dependent increase in locomotion and exploration and reduced anxiety-related behaviours across tests. Spatial working memory and social behaviours were not affected by Mic-1/Gdf15 deficiency. Interestingly, knockout mice formed an increased association with the conditioned stimulus in fear conditioning testing and also displayed significantly improved prepulse inhibition. Overall sex effects were evident for social behaviours, fear conditioning, and sensorimotor gating. This is the first study defining the role of Mic-1/Gdf15 in a number of behavioural domains. Whether the observed impact is based on direct actions of Mic-1/Gdf15 deficiency on the CNS or whether the behavioural effects are mediated by indirect actions on e.g. other neurotransmitter systems must be clarified in future studies.
Highlights
Macrophage inhibitory cytokine-1 (MIC-1), known as growth differentiation factor 15 (GDF15), is a stress response cytokine that is a divergent member of the transforming growthPLOS ONE | DOI:10.1371/journal.pone.0168416 January 12, 2017Behaviour of Mic-1/Gdf15 Knockout Mice factor (TGF)-β superfamily
2way analysis of variance (ANOVA) revealed that Mic-1 KO mice exhibit a subtle, task-specific increase in locomotor activity compared to control mice, but only in the Elevated plus maze (EPM) for number of arm entries [F(1,48) = 7.4, p = .009] but not the distance travelled in all arms [F(1,48) = .5, p = .5] or the total distance travelled in the Open field (OF) test [F(1,48) = 1.2, p = .3] (Table 1)
The Mic-1 genotype impacted significantly on the habituation of the locomotive response to a novel environment in the latter test with Mic-1 KO mice displaying a stronger reduction of the locomotor response over time compared to control animals [repeated measures (RM) ANOVA ‘5 min block’ x ‘genotype’: F(5,240) = 4.3, p < .0009] (Fig 1)
Summary
Macrophage inhibitory cytokine-1 (MIC-1), known as growth differentiation factor 15 (GDF15), is a stress response cytokine that is a divergent member of the transforming growthPLOS ONE | DOI:10.1371/journal.pone.0168416 January 12, 2017Behaviour of Mic-1/Gdf Knockout Mice factor (TGF)-β superfamily. The placenta is the only tissue that expresses large amounts of MIC-1/ GDF15 [2]. It is expressed in low amounts in the liver, lung and kidney as well as adipocytes and a variety of epithelial cells, including the choroid plexus [2,3,4]. MIC-1/GDF15 is present in the serum of all individuals with a normal range of 150–1150 pg/ml, but these serum levels increase further with injury, inflammation and malignancy. MIC-1/GDF15 blood levels are a powerful predictor of all-cause mortality, suggesting a fundamental role in biological processes associated with ageing [5]. In some disease states such as chronic renal and cardiac failure and advanced cancer, MIC-1/GDF15 expression is dramatically increased by up to 10–100 fold [3, 6,7,8]
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