DL: DigiBrain - From genes to brain function in health and disease

Brain related disorders and disease are among the largest health challenges in the world today and will only increase with an aging population. Our current understanding of underlying mechanisms of brain disorders is limited, and this often leads to inefficient treatment with negative side effects. Through large-scale Genome Wide Association Studies (GWAS), mapping gene variants from large groups of patients with matched controls, core members in DigiBrain together with international partners showed some few hundred gene variants occur more often in patients with schizophrenia compared to controls. Many of these genes are involved in how neurons communicate with each other. In the DigiBrain project, we aim to reveal the relationships between the risk gene variants and neuron function in order to explain some of the basic underlying mechanisms of clinical findings of schizophrenia and bipolar disorders. Using a multidisciplinary approach, we have a platform integrating mathematical modeling, experimental neuroscience and clinical measurements to reveal basic mechanisms which may in turn lead to the discovery of novel drug targets and improved treatment. Combinations of gene variants, all known to be specific to the central nervous system, have been explored in mathematical models of single neurons and neural network models. The findings from these models are comparable to an increased excitability of neurons also observed in our measurements from human patients and in experiments with the zebra fish. In the network models, we have reproduced some of the characteristic patterns in EEG measurements from human patients with increased delta-frequency activity. We have collected DNA samples and recorded brain activity from several hundred patients and healthy volunteers, and are now exploring these data in light of the genetic risk profiles of these individuals. We are also investigating neurons rederived from the skin samples from patients and healthy volunteers to allow us to explore the impact of these donors' particular genetic make-up (their collection of variations across all genes) on the activity of the cells. This will be compared to the brain activity recordings we obtain from the patients. The effects of selected risk genes are also being explored experimentally in animal models. In the zebra fish, we have found that loss-of-function mutations of a schizphrenia risk gene, CACNA1c, leads to increased excitability of neurons and impaired prepulse inhibition. Finally, we have established gene editing tools in both mouse, fish and human stem cells to directly manipulate target gene variants within cells and explore the resulting impacts of these manipulations on the cells' activity. Together, the various components and methods in this project will facilitate a better understanding of brain function, both in health and disease, as they explore the effects of genetic variations in target genes from the molecular, to cellular, to organism levels.

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Despite enormous research efforts, there are still no cures available for major brain diseases such as Alzheimer's dementia or major psychiatric afflictions like schizophrenia or bipolar disorder. Moreover, due to recent costly failures, several major pharmaceutical companies have reduced their research on brain disorders. Future development of new drugs will benefit hugely from a better understanding of disease mechanisms, in turn requiring a better understanding of the brain, and in particular the link between the microscopic (genetic/molecular) and macroscopic (whole brain) scales. Building on the strong Norwegian traditions in neuroscience and computational physics, DigiBrain is tailored to face these challenges: By means of a transdisciplinary approach using tools from computer science, physics and engineering and targeted biology and psychiatry, multiscales model linking genes to brain function will be developed by a consortium of theoretical and experimental scientists at University of Oslo, Norwegian University of Life Sciences, SIMULA Research Center, University of Bergen, University of Tromsø and Norwegian University of Science and Technology. In tight interaction with industrial partners in Norway (Pharmasum Therapeutics, Holberg EEG) and abroad, these multiscale models will in turn be used in the search for new candidate drugs for psychiatric disorders. In the development, implementation and execution of the multiscale model, full advantage will be taken from our participation in the EU Human Brain Project and our links to Project MindScope at the Allen Institute of Brain Science.