Finding the pathology of major depression through effects on gene interaction networks

The disease signature of major depressive disorder is distributed across multiple physical scales and investigative specialties, including genes, cells and brain regions. No single mechanism or pathway currently implicated in depression can reproduce its diverse clinical presentation, which compounds the difficulty in finding consistently disrupted molecular functions. We confront these key roadblocks to depression research - multi-scale and multi-factor pathology - by conducting parallel investigations at the levels of genes, neurons and brain regions, using transcriptome networks to identify collective patterns of dysfunction. Our findings highlight how the collusion of multi-system deficits can form a broad-based, yet variable pathology behind the depressed phenotype. For instance, in a variant of the classic lethality-centrality relationship, we show that in neuropsychiatric disorders including major depression, differentially expressed genes are pushed out to the periphery of gene networks. At the level of cellular function, we develop a molecular signature of depression based on cross-species analysis of human and mouse microarrays from depression-affected areas, and show that these genes form a tight module related to oligodendrocyte function and neuronal growth/structure. At the level of brain-region communication, we find a set of genes and hormones associated with the loss of feedback between the amygdala and anterior cingulate cortex, based on a novel assay of interregional expression synchronization termed "gene coordination". These results indicate that in the absence of a single pathology, depression may be created by dysynergistic effects among genes, cell-types and brain regions, in what we term the "floodgate" model of depression. Beyond our specific biological findings, these studies indicate that gene interaction networks are a coherent framework in which to understand the faint expression changes found in depression and complex neuropsychiatric disorders

29th Annual Computational Neuroscience Meeting: CNS*2020

Meeting abstracts This publication was funded by OCNS. The Supplement Editors declare that they have no competing interests. Virtual | 18-22 July 202

Solving some problems in teaching by using combinatorial optimization methods

U ovom radu se istražuju neki aktuelni problemi kombinatorne optimizacije...In this work some actual combinatorial optimization problem are investigated..

Phylotranscriptomic investigation into the evolution of endothermy in fish

Regional endothermy, where metabolically-derived heat is used to maintain elevated temperatures in parts of the body, has independently evolved in several lineages of pelagic, predatory fish, including billfish, tuna, lamnid sharks and the opah. The lamnid sharks and tunas demonstrate a striking phenotypic convergence, despite 450 million years of independent evolution. This is characterised by a distinctive muscle morphology, which has enabled them to utilise a unique stiff-bodied swimming style and maintain elevated muscular temperatures and metabolic capacities. This has facilitated expansions in thermal niche and increases in swimming speed and exercise recovery rate. We find selection has acted on one gene independently in both groups, glycogenin-1, which is associated with post-exercise glycogen replenishment. Different metabolic pathways have been targeted by selection in either group. Amongst the endothermic fish, there is considerable variability between species in endothermic capacity and cold-tolerance. By investigating diversification among the eight Thunnus tuna species, we find that the three highly cold-tolerant and endothermic bluefin tuna species are paraphyletic. We infer that parallel selection on ancestral genetic variation is likely to have enabled their evolution. This includes selection for variants in genes associated with metabolism and thermogenesis in other animals. Adaptations in the cardiac system of bluefin tuna are crucial to their ability to tolerate cold-water, as their heart operates at ambient temperature yet must supply oxygen for metabolically demanding warm muscle. We show that this elevated cardiac capacity is associated with increased expression of a key sarcoplasmic reticulum calcium-cycling gene, SERCA2b, in the atrium. Tuna muscle has a thermal gradient, with temperatures highest in the centre of the body. We found no upregulation of metabolic or thermogenesis genes in regions of warm muscle, indicating that intrinsic muscular contraction is sufficient for heat production. Our results provide insight into the genomic basis of endothermy in fish.Open Acces