ERC FUNDED PROJECTS

Serotonin (5-HT) is a central neuromodulator and a major target of therapeutic psychoactive drugs, but relatively little is known about how it modulates information processing in neural circuits. The theory of predictive coding postulates that the brain combines raw bottom-up sensory information with top-down information from internal models to make perceptual inferences about the world. We hypothesize, based on preliminary data and prior literature, that a role of 5-HT in this process is to report prediction errors and promote the suppression and weakening of erroneous internal models. We propose that it does this by inhibiting top-down relative to bottom-up cortical information flow. To test this hypothesis, we propose a set of experiments in mice performing olfactory perceptual tasks. Our specific aims are: (1) We will test whether 5-HT neurons encode sensory prediction errors. (2) We will test their causal role in using predictive cues to guide perceptual decisions. (3) We will characterize how 5-HT influences the encoding of sensory information by neuronal populations in the olfactory cortex and identify the underlying circuitry. (4) Finally, we will map the effects of 5-HT across the whole brain and use this information to target further causal manipulations to specific 5-HT projections. We accomplish these aims using state-of-the-art optogenetic, electrophysiological and imaging techniques (including 9.4T small-animal functional magnetic resonance imaging) as well as psychophysical tasks amenable to quantitative analysis and computational theory. Together, these experiments will tackle multiple facets of an important general computational question, bringing to bear an array of cutting-edge technologies to address with unprecedented mechanistic detail how 5-HT impacts neural coding and perceptual decision-making.

2 486 074 €

Start date: 2016-01-01, End date: 2020-12-31

The long-term establishment of ancient organisms that have undergone whole genome duplications has been exceedingly rare. On the other hand, tens of thousands of now-living species are polyploid and contain multiple copies of their genome. The paucity of ancient genome duplications and the existence of so many species that are currently polyploid provide an interesting and fascinating enigma. A question that remains is whether these older genome duplications have survived by coincidence or because they did occur at very specific times, for instance during major ecological upheavals and periods of extinction. It has indeed been proposed that chromosome doubling conveys greater stress tolerance by fostering slower development, delayed reproduction and longer life span. Furthermore, polyploids have also been considered to have greater ability to colonize new or disturbed habitats. If polyploidy allowed many plant lineages to survive and adapt during global changes, as suggested, we might wonder whether polyploidy will confer a similar advantage in the current period of global warming and general ecological pressure caused by the human race. Given predictions that species extinction is now occurring at as high rates as during previous mass extinctions, will the presumed extra adaptability of polyploid plants mean they will become the dominant species? In the current proposal, we hope to address these questions at different levels through 1) the analysis of whole plant genome sequence data and 2) the in silico modelling of artificial gene regulatory networks to mimic the genomic consequences of genome doubling and how this may affect network structure and dosage balance. Furthermore, we aim at using simulated robotic models running on artificial gene regulatory networks in complex environments to evaluate how both natural and artificial organism populations can potentially benefit from gene and genome duplications for adaptation, survival, and evolution in general.

2 217 525 €

Start date: 2013-10-01, End date: 2018-09-30

"There has been an immense investment of time, effort and resources in the development of the technologies that enable DNA sequencing in the past 10 years. Despite the significant advances made, all of the current genomic sequencing technologies suffer from two important shortcomings. Firstly, sample preparation is time-consuming and expensive, and requiring a full day for sample preparation for next-generation sequencing experiments. Secondly, sequence information is delivered in short fragments, which are then assembled into a complete genome. Assembly is time-consuming and often results in a highly fragmented genomic sequence and the loss of important information on large-scale structural variation within the genome. We recently developed a super-resolution DNA mapping technology, which allows us to uniquely study genetic-scale features in genomic length DNA molecules. Labelling the DNA with fluorescent molecules at specific sequences and using high-resolution fluorescence microscopy enabled us to produce a map of a genomic DNA sequence with unparalleled resolution, the so called FLUOROCODE. In this project we aim to extend our methodology to map longer DNA molecules and to include a multi-colour version of the FLUOROCODE that will allow us to read genomic DNA molecules like a barcode and probe DNA methylation status. The sample preparation, DNA labelling and deposition for imaging will be integrated to allow rapid mapping of DNA molecules. At the same time nanopores will be explored as a route to high-throughput DNA mapping. FLUOROCODE will develop technology that aims to complement the information derived from current DNA sequencing platforms. The technology developed by FLUOROCODE will enable DNA mapping at unprecedented speed and for a fraction of the cost of a typical DNA sequencing project. We aniticipate that our method will find applications in the rapid identification of pathogens and in producing genomic scaffolds to improve genome sequence assembly."

2 423 160 €

Start date: 2012-09-01, End date: 2017-08-31

Alzheimer's Disease (AD) is a major health problem in aging societies. Remarkable progress in the study of the rare genetic forms of the disease has lead to the identification of several key players like APP and the secretases, but the molecular basis of sporadic AD remains largely unresolved. The convergence of several factors (multicausality) has to be considered. miRNAs are crucially involved in normal brain functioning and integrity. Evidence obtained from analyzing a limited number of brains indicates that miRNA expression is affected in sporadic AD. We propose the hypothesis that such changes can affect normal functioning of neurons increasing their susceptibility to AD. We will document in 3 brain regions in >100 sporadic AD patients and in >100 controls alterations in miRNA expression and explore whether similar alterations can be detected in cerebrospinal fluid. This part of the study will firmly establish which miRNAs are altered in AD. We will then investigate the functional relevance of those miRNAs by gain and loss of function experiments in brains of zebra fish and mice. We will determine the target genes of the miRNA with genetic and proteomic approaches, and establish the functional networks controlled by those miRNA. We anticipate that this will lead to complete novel insights in the role of miRNAs in AD and in maintenance of brain integrity. Our work is likely to have diagnostic relevance for AD and will identify novel drug targets for the disease.

2 500 000 €

Start date: 2011-05-01, End date: 2016-04-30