ERC FUNDED PROJECTS

Parkinson’s disease (PD) is the second most common neurodegenerative disorder primarily caused by the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN). Despite the advances in gene discovery associated with PD, the knowledge of the PD pathogenesis is largely limited to the involvement of these genes in the generic cell death pathways, and why degeneration is specific to DA neurons and why the degeneration is progressive remain enigmatic. Broad goal of our work is therefore to elucidate the mechanisms underlying specific and progressive DA neuron degeneration in PD. Our new Drosophila model of PD ⎯Fer2 gene loss-of-function mutation⎯ is unusually well suited to address these questions. Fer2 mutants exhibit specific and progressive death of brain DA neurons as well as severe locomotor defects and short life span. Strikingly, the death of DA neuron is initiated in a small cluster of Fer2-expressing DA neurons and subsequently propagates to Fer2-negative DA neurons. We therefore propose a novel two-step model of the neurodegeneration in PD: primary cell death occurs in a specific subset of dopamindegic neurons that are genetically defined, and subsequently the failure of the neuronal connectivity triggers and propagates secondary cell death to remaining DA neurons. In this research, we will test this hypothesis and investigate the underlying molecular mechanisms. This will be the first study to examine circuit-dependency in DA neuron degeneration. Our approach will use a combination of non-biased genomic techniques and candidate-based screening, in addition to the powerful Drosophila genetic toolbox. Furthermore, to test this hypothesis beyond the Drosophila model, we will establish new mouse models of PD that exhibit progressive DA neuron degeneration. Outcome of this research will likely revolutionize the understanding of PD pathogenesis and open an avenue toward the discovery of effective therapy strategies against PD.

1 518 960 €

Start date: 2013-06-01, End date: 2018-05-31

This project presents a new concept for the detection, diagnosis and monitoring of cancer biomarker patterns in point-of-care. The device under development will make use of the selectivity of the plastic antibodies as sensing materials and the interference they will play on the normal operation of a photovoltaic cell. Plastic antibodies will be designed by surface imprinting procedures. Self-assembled monolayer and molecular imprinting techniques will be merged in this process because they allow the self-assembly of nanostructured materials on a “bottom-up” nanofabrication approach. A dye-sensitized solar cell will be used as photovoltaic cell. It includes a liquid interface in the cell circuit, which allows the introduction of the sample (also in liquid phase) without disturbing the normal cell operation. Furthermore, it works well with rather low cost materials and requires mild and easy processing conditions. The cell will be equipped with plasmonic structures to enhance light absorption and cell efficiency. The device under development will be easily operated by any clinician or patient. It will require ambient light and a regular multimeter. Eye detection will be also tried out.

998 584 €

Start date: 2013-02-01, End date: 2018-01-31

Serotonin (5-HT) is implicated in a wide spectrum of brain functions and disorders. However, its functions remain controversial and enigmatic. We suggest that past work on the 5-HT system have been significantly hampered by technical limitations in the selectivity and temporal resolution of the conventional pharmacological and electrophysiological methods that have been applied. We therefore propose to apply novel optogenetic methods that will allow us to overcome these limitations and thereby gain new insight into the biological functions of this important molecule. In preliminary studies, we have demonstrated that we can deliver exogenous proteins specifically to 5-HT neurons using viral vectors. Our objectives are to (1) record, (2) stimulate and (3) silence the activity of 5-HT neurons with high molecular selectivity and temporal precision by using genetically-encoded sensors, activators and inhibitors of neural function. These tools will allow us to monitor and control the 5-HT system in real-time in freely-behaving animals and thereby to establish causal links between information processing in 5-HT neurons and specific behaviors. In combination with quantitative behavioral assays, we will use this approach to define the role of 5-HT in sensory, motor and cognitive functions. The significance of the work is three-fold. First, we will establish a new arsenal of tools for probing the physiological and behavioral functions of 5-HT neurons. Second, we will make definitive tests of major hypotheses of 5-HT function. Third, we will have possible therapeutic applications. In this way, the proposed work has the potential for a major impact in research on the role of 5-HT in brain function and dysfunction.

2 318 636 €

Start date: 2010-07-01, End date: 2015-12-31

When faced with a threat, an animal must decide whether to freeze, reducing its chances of being noticed, or to flee to the safety of a refuge. Animals from fish to primates choose between these two alternatives when confronted by an attacking predator, a choice that largely depends on the context in which the threat occurs. Recent work has made strides identifying the pre-motor circuits, and their inputs, which control freezing behavior in rodents, but how contextual information is integrated to guide this choice is still far from understood. We recently found that fruit flies in response to visual looming stimuli, simulating a large object on collision course, make rapid freeze/flee choices that depend on the social and spatial environment, and the fly’s internal state. Further, identification of looming detector neurons was recently reported and we identified the descending command neurons, DNp09, responsible for freezing in the fly. Knowing the sensory input and descending output for looming-evoked freezing, two environmental factors that modulate its expression, and using a genetically tractable system affording the use of large sample sizes, places us in an unique position to understand how a information about a threat is integrated with cues from the environment to guide the choice of whether to freeze (our goal). To assess how social information impinges on the circuit for freezing, we will examine the sensory inputs and neuromodulators that mediate this process, mapping their connections to DNp09 neurons (Aim 1). We ask whether learning is required for the spatial modulation of freezing, which cues flies are using to discriminate different places and which brain circuits mediate this process (Aim 2). Finally, we will study how activity of DNp09 neurons drives freezing (Aim 3). This project will provide a comprehensive understanding of the mechanism of freezing and its modulation by the environment, from single neurons to behaviour.

1 969 750 €

Start date: 2019-02-01, End date: 2024-01-31