These transmitters use a large number of G protein-coupled receptors, which share signal transduction systems in cells. In addition to regulating key physiological functions, many of these systems are involved in important human neurodegenerative diseases. Our research focuses on identification and functional roles of new modulatory systems, and their role in brain diseases.
Aminergic (e.g. dopaminergic) and peptidergic systems regulate e.g. sleep, diurnal rhythms, feeding and addiction, together with the fast-acting transmitters. The modulatory systems show significant plasticity in human disease conditions. For example, in Parkinson’s disease degeneration of the midbrain dopaminergic neurons is associated with increased brain histamine, and in narcolepsy degeneration of the hypocretin neurons is accompanied by an increase in adjacent histamine neurons. New methods were developed to use zebrafish in combined studies of complex neuronal systems. Confocal, two-photon and light-sheet imaging systems allow three-dimensional imaging of whole neurotransmitter systems in the zebrafish brain at a time when the fish display complex behaviors. Quantitative behavioral analysis systems were developed to simultaneously analyze the behaviour of up to 100 fish. Identification and cloning of fish orthologs of important human disease genes with poorly known functions, followed by translation inhibition and phenotypic analysis of novel mutant zebrafish are used to answer crucial questions of neurobiological basis of diseases.
The methods created in the project also allow use of zebrafish in the development of new drugs for CNS disorders, including those related to motor functions, anxiety-related behaviour, and memory. The zebrafish studies are accompanied by molecular, structural and behavioral analyses of mouse models.