ERC FUNDED PROJECTS

The brain evolves, develops, and operates in the context of animal movements. As a consequence, fundamental brain functions such as spatial perception and motor control critically depend on the precise knowledge of the ongoing body motion. An accurate internal estimate of self-movement is thought to emerge from sensorimotor integration; nonetheless, which circuits perform this internal estimation, and exactly how motor-sensory coordination is implemented within these circuits are basic questions that remain to be poorly understood. There is growing evidence suggesting that, during locomotion, motor-related and visual signals interact at early stages of visual processing. In mammals, however, it is not clear what the function of this interaction is. Recently, we have shown that a population of Drosophila optic-flow processing neurons —neurons that are sensitive to self-generated visual flow, receives convergent visual and walking-related signals to form a faithful representation of the fly’s walking movements. Leveraging from these results, and combining quantitative analysis of behavior with physiology, optogenetics, and modelling, we propose to investigate circuit mechanisms of self-movement estimation during walking. We will:1) use cell specific manipulations to identify what cells are necessary to generate the motor-related activity in the population of visual neurons, 2) record from the identified neurons and correlate their activity with specific locomotor parameters, and 3) perturb the activity of different cell-types within the identified circuits to test their role in the dynamics of the visual neurons, and on the fly’s walking behavior. These experiments will establish unprecedented causal relationships among neural activity, the formation of an internal representation, and locomotor control. The identified sensorimotor principles will establish a framework that can be tested in other scenarios or animal systems with implications both in health and disease.

1 500 000 €

Start date: 2017-11-01, End date: 2022-10-31

The formation of a functional patterned vascular network is essential for development, tissue growth and organ physiology. Several human vascular disorders arise from the mis-patterning of blood vessels, such as arteriovenous malformations, aneurysms and diabetic retinopathy. Although blood flow is recognised as a stimulus for vascular patterning, very little is known about the molecular mechanisms that regulate endothelial cell behaviour in response to flow and promote vascular patterning. Recently, we uncovered that endothelial cells migrate extensively in the immature vascular network, and that endothelial cells polarise against the blood flow direction. Here, we put forward the hypothesis that vascular patterning is dependent on the polarisation and migration of endothelial cells against the flow direction, in a continuous flux of cells going from low-shear stress to high-shear stress regions. We will establish new reporter mouse lines to observe and manipulate endothelial polarity in vivo in order to investigate how polarisation and coordination of endothelial cells movements are orchestrated to generate vascular patterning. We will manipulate cell polarity using mouse models to understand the importance of cell polarisation in vascular patterning. Also, using a unique zebrafish line allowing analysis of endothelial cell polarity, we will perform a screen to identify novel regulators of vascular patterning. Finally, we will explore the hypothesis that defective flow-dependent endothelial polarisation underlies arteriovenous malformations using two genetic models. This integrative approach, based on high-resolution imaging and unique experimental models, will provide a unifying model defining the cellular and molecular principles involved in vascular patterning. Given the physiological relevance of vascular patterning in health and disease, this research plan will set the basis for the development of novel clinical therapies targeting vascular disorders.

1 618 750 €

Start date: 2016-09-01, End date: 2022-02-28

A great deal is known about the neural basis of associative fear learning. However, many animal species are able to use social cues to recognize threats, a defence mechanism that may be less costly than learning from self-experience. We have previously shown that rats perceive the cessation of movement-evoked sound as a signal of danger and its resumption as a signal of safety. To study transmission of fear between rats we assessed the behavior of an observer while witnessing a demonstrator rat display fear responses. With this paradigm we will take advantage of the accumulated knowledge on learned fear to investigate the neural mechanisms by which the social environment regulates defense behaviors. We will unravel the neural circuits involved in detecting the transition from movement-evoked sound to silence. Moreover, since observer rats previously exposed to shock display observational freezing, but naive observer rats do not, we will determine the mechanism by which prior experience contribute to observational freezing. To this end, we will focus on the amygdala, crucial for fear learning and expression, and its auditory inputs, combining immunohistochemistry, pharmacology and optogenetics. Finally, as the detection of and responses to threat are often inherently social, we will study these behaviors in the context of large groups of individuals. To circumvent the serious limitations in using large populations of rats, we will resort to a different model system. The fruit fly is the ideal model system, as it is both amenable to the search for the neural mechanism of behavior, while at the same time allowing the study of the behavior of large groups of individuals. We will develop behavioral tasks, where conditioned demonstrator flies signal danger to other naïve ones. These experiments unravel how the brain uses defense behaviors as signals of danger and how it contributes to defense mechanisms at the population level.

1 412 376 €

Start date: 2013-12-01, End date: 2018-11-30

Centrioles are essential for the formation of several microtubule organizing structures including cilia, flagella and centrosomes. These structures are involved in a variety of functions, from cell motility to division. Centrosome defects are seen in many cancers, while abnormalities in cilia and flagella can lead to a variety of human diseases, such as polycystic kidney disease. The molecular mechanisms regulating centriole biogenesis have only recently started to be unravelled, opening new ways to answer a wide range of questions that have fascinated biologists for more than a century. In this grant we are asking two fundamental questions that are central to human disease: how is centriole structure and number established and regulated in the eukaryotic cell? To address these questions we propose to identify new molecular players, and to test the role of these and known players in the context of specific mechanistic hypothesis, using in vitro and in vivo models. We propose to develop novel assays for centriole structure and regulation in order to address mechanistic problems not accessible with today s assays. In our search for novel components we will use a multidisciplinary approach combining bioinformatics with high throughput screening. The use of in vitro systems will permit the quantitative dissection of molecular mechanisms, while the study of those mechanisms in Drosophila will allow us to understand them at the whole organism level. Furthermore, this analysis, together with studies in human tissue culture cells, will allow us to understand the consequences of misregulation of these fundamental centriole properties for human disease, such as ciliopathies and cancer. My group is already collaborating with medical doctors in the study of centriole aberrations in human disease (cancer and ciliopathies), which will be invaluable to bringing the results of this study to the translational level.

1 500 000 €

Start date: 2011-01-01, End date: 2016-12-31