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Final Report Summary - FLIACT (Systems neuroscience of Drosophila: from genes to circuits to behaviour)

Understanding how the brain works represents one of the greatest challenges in modern science. The mission of the FLiACT network has been to train a group of talented early stage researchers in the concepts and state-of-the art techniques to study integrated brain functions. By working on collaborative projects, the FLiACT fellows have learned to apply interdisciplinary approaches to tackle ambitious questions in neuroscience. They also discovered that multi-lab collaborations represent an effective way to achieve goals intractable by single labs that work in isolation. The FLiACT network focuses on one model organism, the fruit fly Drosophila melanogaster, which represents a premier model system to study the molecular and cellular logic of perception and cognition.

Drosophila offers a unique opportunity to model neural functions from the integration of data pertaining to different scales at which information processing takes place, from the molecules behind the formation and the function of synapses, to the neurons and the neural circuits that underlie particular behaviours. The main goal of the FLiACT network has been to dissect the molecular and cellular mechanisms directing sensory navigation, social behaviours and the modulation of innate responses by internal state. The main scientific results obtained during the lifetime of the FLiACT network cover six major areas:
1) Tool building and paradigm development: The FLiACT network has highlighted the use Drosophila as a model to study the genetic basis of behavioural control and evolutionary adaption. Weinberger´s work at VIB has revealed how changes in the coding sequence of the transcription factor atonal can result in the modification of cell fate specification during the development of sensory organs. At a computational level, Tastekin at CRG has developed mathematical models that predict how sensory neurons encode complex time-varying stimuli and how this information directs navigational decisions. To measure Drosophila social behaviour, Nath at DCI and Liu at Peira have built multiple-animal tracking software capable of quantifying the structure of social interactions in groups of flies. We anticipate that this tracking system will be of general interest to the Drosophila community.
2) Olfactory processing: Due to the turbulent nature of the environment, odorant stimuli are intrinsically stochastic. Smells travel as discontinuous packets of odorant molecules or plumes. FLiACT has attempted to understand how the fly olfactory system controls odour-tracking behaviour based on the detection of naturalistic stimuli. Sayin at MPIN has developed an assay where adult flies are tethered to a spherical treadmill and stimulated by controlled patterns of odour stimuli. With this assay, he has started analysing the orientation response induced by intermittent odour stimulation. In a separate line of research, Mohamed at MPI-CE has studied how flies decide whether an odour is attractive or not. Combining a new behavioural approach (FlyWalk assay) and neurophysiological experiments (2-photon imaging), he is investigating the mechanisms underpinning the integration of attractive and aversive stimuli at the level of the interneuron circuitry of the antennal lobe.
3) Neural computations directing navigational behaviours: Fruit fly larvae have been used as a model to understand how navigational decisions emerge from the integration of sensory signals. Within FLiACT, we focused on two sensory modalities: vision and olfaction. Using fly molecular genetics, Larderet at UNIFR deconstructed the function of the visual circuit of the larva into its components. He tested the role of different types of photoreceptors (PR) in the control of behavioural responses elicited by light of different wavelengths. Results by electron microscopy, show that each PR subtype has its distinct neuronal pathway and that visual interneurons form a functional hierarchy in the circuit.
Second, Deogade at the CRG has investigated the neural basis of innate chemotactic behaviour in the larva. Larval chemotaxis involves two types of decisions: when to interrupt and where to direct a turn. In collaboration with Janelia Research Campus (associate partner), he has devised a closed-loop tracker in which the sensorimotor integration of olfactory inputs can be studied by means of optogenetics. In this paradigm light to artificially control the activity of the peripheral olfactory system was used. By remote-controlling olfactory behaviour, we built and tested mathematical models describing the conversion of olfactory inputs into navigational decisions. As for the visual system, we are now using EM tracing to map the circuitry involved in the processing of olfactory inputs.
Unlike larvae, adult flies mostly rely on vision to navigate their environment. Visual navigation necessitates maintaining a balance between wide-field stabilisation and object fixation. Soselisa at IMP has studied how this balance is achieved by the visual system. This work is building on the functional characterization of a group of dorsal neurons previously discovered. Using GFP Reconstitution Across Synaptic Partners (GRASP), she has initiated the mapping of the synaptic partners of the dorsal cluster neurons. This work contributes to massive efforts to comprehensive reconstruct the fly visual system.
4) Behavioural modulation by internal states: We have uncovered that the reproductive state profoundly changes the nutritional requirements of female flies in a way consistent with the increase in sodium appetite observed during the pregnancy of mammals. Walker at CI has investigated how internal states modify neuronal information processing to ensure homeostasis. He found that mating modulates gustatory processing to increase the probability of initiating feeding on salt. This result indicates that the postmating circuit can modify the palatability of specific nutrients.
5) Cross-species comparisons: Within the Drosophila genus, we have observed that species have evolved strong preferences for specific host substrates while others exploit a variety of substrates. These results suggest that host specialisation is associated with the existence of species-specific shifts in olfactory behaviours. What are the sensory mechanisms underlying olfactory adaptation? Fink at CRG has addressed this question in the Drosophila larva by screening for species-specific differences in the sensitivity towards a fixed panel of odorants. She is now trying to explain the origin of behavioural shifts at the level of the peripheral olfactory system (loss or recruitment of specific odorant receptors). In adult flies, Karageorgi at IBDML studied the strong preference of Drosophila suzukii to lay eggs on fresh (ripening) fruits, as opposed to the preference of Drosophila species for rotting fruits. Results indicate that this preference shift is mainly driven by changes in its chemosensory system. As for larvae, the olfactory system of the adult fly seems to be an evolutionary target of this behavioural shift.
6) Drosophila as a model for human diseases: Drosophila has recently emerged as a powerful system to study human diseases and, in particular, neurodegenerative diseases. Published examples comprise the study of human colorectal cancer in flies as well as for Alzheimer’s disease. Ferlito at Brainwave has used different mutants of Amyloid-β expressed in the olfactory system of Drosophila flies. These mutants display orientation defects that are reminiscent of those observed during early stages of neurodegenerative diseases. After studying the expression of different Amyloid-β mutants in the peripheral olfactory system of the larva, we propose that these pan-neuronally larvae mutants can be used for developing faster drugs screen for neurodegenerative diseases.
Science outreach: Besides their contribution to collaborative research projects, the FLiACT fellows have been involved in numerous science-outreach activities. In September 2015, they organized an international summer school in the Champalimaud Foundation in Lisbon. During this school, the fellows ran the practicals and acted as research assistants. In December 2015, the FLiACT fellows took the lead in the organization and the management of the first workshop for Drosophila neurobiology in Ghana (see flier attached) http://fliact.org/welcomeghana. During this workshop, the fellows transferred the knowledge and skills they acquired during their thesis to a new generation of students. FLiACT has also developed an application for cell phones and tables. This App consists in a puzzle game using the scientific images obtained by the fellows during their PhD work (see app snapshots in annex). Through this App, we hope to encourage the general public to learn about research fly neuroscience and its impact on our society. This App will be made available at the end of March 2016 (see snapshots of the app in annex attached). For more information about the science and the dissemination activities of FLiACT, please check: http://fliact.org/home.

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FUNDACIO PRIVADA CENTRE DE REGULACIO GENOMICA
Spain
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