Burgstaller, J. | bioRxiv Science

bioRxiv2020

Differences in mitochondrial activity trigger cell competition during early mouse development.

Cell competition is emerging as a quality control mechanism that eliminates unfit cells in a wide range of settings from development to the adult. However, the nature of the cells normally eliminated by cell competition and what triggers their elimination remains poorly understood. In mouse, prior to gastrulation 35% of epiblast cells are eliminated. Here we have performed single cell transcriptional profiling of these cells and find that they show the hallmarks of cell competition and have mitochondrial defects. We demonstrate that mitochondrial defects are common to a range of different loser cell types and that manipulating mitochondrial function is sufficient to trigger competition. Importantly, we show that in the embryo cell competition eliminates cells with mitochondrial DNA mutations and that even non-pathological changes in mitochondrial DNA sequence can induce cell competition. Our results therefore suggest that cell competition is a purifying selection that optimises mitochondrial performance prior to gastrulation.

developmental biology↗

bioRxiv2019

Light-sheet imaging and graph-theoretical analysis of antidepressant action in the larval zebrafish brain network

The zebrafish is increasingly being employed as an experimental platform to model neuropsychiatric diseases and to screen for novel neuro-active compounds. While the superb genetic and optical access that this system offers has long been recognized, these features have not been fully exploited to investigate disease mechanisms and possible therapeutic interventions. Here we introduce a light-sheet imaging and graph-theoretical analysis pipeline to determine the effects of the known or suspected antidepressant compounds fluoxetine, ketamine and cycloserine on brain-wide neural activity patterns. We imaged the brains of both wildtype fish and grs357 mutants, which harbor a missense mutation that abolishes glucocorticoid receptor transcriptional activity. The grs357 mutation results in a chronically elevated stress axis together with behavioral endophenotypes of depression. Consistent with broad expression of the glucocorticoid receptor throughout the brain, we show that the mutant fish exhibit an altered correlational structure of resting-state brain activity. Intriguingly, in grs357 mutant fish, an increased modularity, which represents the degree of segregation of the network into highly clustered modules, was restored by acute fluoxetine administration to wildtype levels. Ketamine and cycloserine also normalized specific parameters of the graph. Fluoxetine altered network function in the same direction in mutant and wildtype, while ketamine and cycloserine had effects that were opposite for the two genotypes. We propose that light-sheet imaging, followed by graph analysis, is a content-rich and scalable first-pass approach for studying the neural consequences of drug effects and drug x genotype interactions in zebrafish models of psychiatric disorders.

neuroscience↗