Alterations in circadian entrainment : translational value in major depression

Adverse conditions of different origin occurring during development can have a negative impact on the nervous system and increase risk for the onset of mental disorders. In mice prenatal exposure to excess glucocorticoids (GC) leads to late onset depression-like behaviour in males which is preceded by alterations in circadian entrainment. The aims of this thesis were to (1) identify sex-related differences in behavioural outcomes with a special focus on circadian activity and mood-related behaviours; (2) investigate the mechanisms behind the behavioural alterations; (3) implement novel computational techniques for characterisation of behaviour in rodents; and (4) explore the translation potential of the analysis of activity in patients suffering from depression. Pregnant C57Bl/6 were exposed to the synthetic GC dexamethasone (Dex) (0.05 mg/Kg/day, i.p.) from gestational day 14 until delivery. We analysed the behaviour of both males and female offspring at the age of 6 months focusing on circadian entrainment of spontaneous activity in the home cage environment. There were sparse differences between Dex and control (Ctrls) males at baseline, which were consistent with decreased social behaviour. In contrast, Dex-females were spontaneously hyperactive, a phenotype resembling ADHD models. Next, we investigated the changes in spontaneous activity following an abrupt advance in dark phase onset (phase shift). Dex-males re-entrained activity faster, while in Dex-females re- entrainment was delayed as compared to Ctrls. We implemented a multivariate approach to analysing the spatial and temporal organisation of behaviour which included affinity propagation (AP) clustering and uniform manifold approximation and projection (UMAP) using a set of 129 features extracted form activity recording. AP-clustering allowed the identification of features with similar patterns of variations following the phase shift, while UMAP supported the visualisation and quantification of changes in organisation of behaviour. The organisation of behaviour changed in both males and females, particularly in the dark phase. Dex-males displayed fewer, but more persistent alterations, while in Dex- females most alterations were transient and returned to baseline values within 5 days after the phase shift. The behaviour alterations in response to the phase shift pointed at alterations in the function of the central clock, the suprachiasmatic nucleus (SCN). In Dex-males the coupling between SCN and peripheral oscillators was disrupted, but was restored by enhancing GC receptor-mediated signalling by the antidepressant DMI. Furthermore, DMI also prevented the onset of depression. In Dex-females instead, the coupling between SCN and peripheral oscillators was preserved, supporting the idea that altered coupling is an early sign specific for depression onset. To investigate the connection between Dex-female behaviour and central clock alterations we performed gene expression analysis by RNA- sequencing followed by SPIA pathway analysis and identified significant alterations in glutamatergic, GABAergic, and dopaminergic signalling. We selected a set of relevant genes to validate the altered expression by cross-referencing differentially expressed genes in the SCN with the international mouse phenotype consortium (IMPC) database for associated phenotypes. Using this approach, we identified several differentially regulated genes supproting a decrease in dopamine signalling and the ADHD-like phenotype in Dex-females. Spontaneous activity can be measured also in human subjects by means of actigraphy. We used actigraphy recordings from patients suffering from major depression to explore possible correlations between patterns of activity and symptom severity or response to internet- delivered cognitive behavioural therapy (iCBT) as antidepressant treatment. We implemented an independent homogenous training of model ensembles using systematic bootstrapping (with replacement) followed by pruning based on goodness-of-fit criteria. The aggregated output outperformed individual models by a factor of 4, indicating that ensemble training increases the accuracy of fitting. We further applied an external validation procedure using an independent dataset to provide proof-of-concept evidence for the possibility to model symptom severity estimated by MADRS-S. Our data suggests that higher symptom severity is associated with less complex patterns of activity, stronger coupling with circadian entrainers and less robust circadian rhythms, while larger improvement following iCBT is associated with less fragmented activity, more robust circadian rhythms, and higher day-to- day variability before treatment. To summarize, these studies suggest a strong connection between circadian activity and neuropsychiatric disorders. Further experimental and clinical investigations are needed to dissect all relevant systems and molecules involved to provide new insight into mental disorders

Initial stages of tundra shrub litter decomposition may be accelerated by deeper winter snow but slowed down by spring warming

The Arctic climate is projected to change during the coming century, with expected higher air temperatures and increased winter snowfall. These climatic changes might alter litter decomposition rates, which in turn could affect carbon (C) and nitrogen (N) cycling rates in tundra ecosystems. However, little is known of seasonal climate change effects on plant litter decomposition rates and N dynamics, hampering predictions of future arctic vegetation composition and the tundra C balance. We tested the effects of snow addition (snow fences), warming (open top chambers), and shrub removal (clipping), using a full-factorial experiment, on mass loss and N dynamics of two shrub tissue types with contrasting quality: deciduous shrub leaf litter (Salix glauca) and evergreen shrub shoots (Cassiope tetragona). We performed a 10.5-month decomposition experiment in a low-arctic shrub tundra heath in West-Greenland. Field incubations started in late fall, with harvests made after 249, 273, and 319 days of field incubation during early spring, summer and fall of the next year, respectively. We observed a positive effect of deeper snow on winter mass loss which is considered a result of observed higher soil winter temperatures and corresponding increased winter microbial litter decomposition in deep-snow plots. In contrast, warming reduced litter mass loss during spring, possibly because the dry spring conditions might have dried out the litter layer and thereby limited microbial litter decomposition. Shrub removal had a small positive effect on litter mass loss for C. tetragona during summer, but not for S. glauca. Nitrogen dynamics in decomposing leaves and shoots were not affected by the treatments but did show differences in temporal patterns between tissue types: there was a net immobilization of N by C. tetragona shoots after the winter incubation, while S. glauca leaf N-pools were unaltered over time. Our results support the widely hypothesized positive linkage between winter snow depth and litter decomposition rates in tundra ecosystems, but our results do not reveal changes in N dynamics during initial decomposition stages. Our study also shows contrasting impacts of spring warming and snow addition on shrub decomposition rates that might have important consequences for plant community composition and vegetation-climate feedbacks in rapidly changing tundra ecosystems

Aluminium release from acidic forest soil following deforestation and maize cultivation in Ghana, West Africa

Acidic tropical soils often have high Al3+ concentrations in soil solutions, which can be toxic to plants and, thereby, reduce agricultural yields. This study focuses on the impact of deforestation and cultivation on the short and long-term Al geochemistry of acidic soils in Ghana, West Africa. Site-specific investigations were made at two sites covered with forest and one site cultivated with maize (Zea mays L.). The capacity of soil to resist acidification was investigated in a leaching experiment and the corresponding release of aluminium quantified. Field results revealed a significant aacidification and Al mobility in the root zone of the cultivated site as compared to the forest sites. The leaching experiment showed that further acidification would significantly enhance Al-release and, consequently, the presence of Al3+ in soil solution. It is concluded that deforestation and cultivation in the study area has resulted in increasing levels of Al3+ and a lowering of the soils capacity to resists further acidification. This may be critical in relation to land-use management and long-term agricultural productions