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Identifier 000427354
Title Identification of novel genes implicated in habituation of D. melanogaster, using Minos transposable element.
Alternative Title Ανίχνευση νέων γονιδίων που σχετίζονται με την εξοικείωση στη D. melanogaster, με την βοήθεια του Minos μεταθέσιμου γενετικού στοιχείου.
Author Ρούσσου, Ηλιάννα Γεωργία
Thesis advisor Σαββάκης, Χαράλαμπος
Reviewer Σκουλάκης, Ευθύμιος
Δελιδάκης, Χρήστος
Κόνσουλας, Χρήστος
Καραγωγέως, Δόμνα
Σιδηροπούλου, Κυριακή
Ταβερναράκης, Νεκτάριος
Abstract This doctoral thesis was performed at the B.S.R.C. “Alexander Fleming” in Vari, Athens under the supervision of Professor Charalambos Savakis together with Researcher A’, Efthimios M.C. Skoulakis. The research study involves a genetic screen employing MiMIC transposable element. The aim was to identify new genes implicated in habituation of Drosophila melanogaster. Habituation is a highly conserved, yet little understood form of behavioral plasticity that enables salience filtering, by precipitating perceptual changes that attenuate the value of environmental stimuli. Normal habituation allows animals to ignore/devalue repetitive or prolonged non-reinforced stimuli and does not involve sensory adaptation or fatigue. It likely underlies selective attention. Defective habituation is the retention of the value of an inconsequential stimulus beyond the time typical for the onset of the attenuated response and is thought to underlie Schizophrenia (SD) as SD patients present characteristic deficits in devaluing and attenuating responses to repeated stimulation. Here, we used MiMIC insertions within different genetic loci of Drosophila melanogaster, to identify genes involved in habituation. Drosophila, as an experimental animal model, exhibits multiple assets such as its ease of handling, low cost of breeding and availability of scientific tools that allow molecular and genetic analysis. MiMIC mutants were tested using the shock habituation experimental paradigm. Several insertion lines that exhibited abnormal responses were identified. Among them, insertions within the genes Btk, Tau and rut were further analyzed. The Btk gene encodes a non-receptor tyrosine kinase. This study showed that footshock habituation consists of two distinct phases, which both depend on different mushroom body neurons and Btk is necessary for both of them. Btk is expressed in the mushroom bodies of Drosophila melanogaster and has distinct roles in different neurons. In the α/β neurons, it protects from premature habituation, while in the α’/β’ neurons promotes habituation after repetitive electric footshocks. Thus, elimination of Btk protein in the α/β neurons results in premature habituation whereas in the α’/β’ neurons it results in defective habituation. Defective habituation can be restored after administration of the antipsychotic drugs clozapine and risperidone. Hence, we propose a link between defective habituation and schizophrenia. A second identified gene, Tau, encodes a protein involved in microtubule stabilization and is found mainly in axons. It is implicated in human neurodegenerative diseases. According to our study, elimination of drosophila Tau protein from the α’/ β’ mushroom body neurons results in defective habituation while its overexpression leads to premature habituation. The third identified gene examined in this thesis is rut, which codes for an adenylate cyclase. Experiments showed that rut is required within the mushroom bodies for the fly to ignore the repetitive stimuli during the footshock habituation assay. As for Btk, defective habituation of rut mutants can be restored after administration of risperidone. Further experiments are required to clarify rut function. In conclusion, this study contributed to the identification of new genes implicated in habituation and shed light on yet poorly known mechanisms. These genes and their mechanisms of action will certainly lead to a better understanding of the habituation related diseases of great complexity, such as schizophrenia. Thus the study demonstrated that Drosophila melanogaster can be a potent model not only for studying habituation as an endophenotype of schizophrenia and the identification of new implicated genes, but also for the verification and further study of already known genes related to human diseases.
Language English
Subject Drosophila
Issue date 2020-03-24
Collection   Faculty/Department--School of Medicine--Department of Medicine--Doctoral theses
  Type of Work--Doctoral theses
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