ERC FUNDED PROJECTS

Sensory perception involves the discrimination and binding of multiple modalities of sensory input. This is especially evident in the somatosensory system where different modalities of sensory input, including thermal and mechanosensory, are combined to generate a unified percept. The neural mechanisms of multisensory binding are unknown, in part because sensory perception is typically studied within a single modality in a single brain region. I propose a multi-level approach to investigate thermo-tactile processing in the mouse forepaw system from the primary sensory afferent neurons to thalamo-cortical circuits and behaviour. The mouse forepaw system is the ideal system to investigate multisensory binding as the sensory afferent neurons are well investigated, cell type-specific lines are available, in vivo optogenetic manipulation is possible both in sensory afferent neurons and central circuits and we have developed high-resolution somatosensory perception behaviours. We have previously shown that mouse primary somatosensory forepaw cortical neurons respond to both tactile and thermal stimuli and are required for non-noxious cooling perception. With multimodal neurons how, then, is it possible to both discriminate and bind thermal and tactile stimuli? I propose 3 objectives to address this question. We will first, perform functional mapping of the thermal and tactile pathways to cortex; second, investigate the neural mechanisms of thermo-tactile discrimination in behaving mice; and third, compare neural processing during two thermo-tactile binding tasks, the first using passively applied stimuli, and the second, active manipulation of thermal objects. At each stage we will perform cell type-specific neural recordings and causal optogenetic manipulations in awake and behaving mice. Our multi-level approach will provide a comprehensive investigation into how the brain performs multisensory perceptual binding: a fundamental yet unsolved problem in neuroscience.

1 999 877 €

Start date: 2016-09-01, End date: 2021-08-31

The frequency of Alzheimer's disease (AD) will dramatically increase in the ageing western society during the next decades. Currently, about 18 million people suffer worldwide from AD. Since no cure is available, this devastating disorder represents one of the most challenging socio-economical problems of our future. As onset and progression of AD is triggered by the amyloid cascade, I will put particular attention on amyloid ß-peptide (Aß). The reason for this approach is, that even though 20 years ago the Aß generating processing pathway was identified (Haass et al., Nature 1992a & b), the identity of the Aß species, which initiate the deadly cascade is still unknown. I will first tackle this challenge by investigating if a novel and so far completely overlooked proteolytic processing pathway is involved in the generation of Aß species capable to initiate spreading of pathology and neurotoxicity. I will then search for modulating proteins, which could affect generation of pathological Aß species. This includes a genome-wide screen for modifiers of gamma-secretase, one of the proteases involved in Aß generation as well as a targeted search for RNA binding proteins capable to posttranscriptionally regulate beta- and alpha-secretase. In a disease-crossing approach, RNA binding proteins, which were recently found not only to be deposited in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis but also in many AD cases, will be investigated for their potential to modulate Aß aggregation and AD pathology. Modifiers and novel antibodies specifically recognizing neurotoxic Aß assemblies will be validated for their potential not only to prevent amyloid plaque formation, but also spreading of pathology as well as neurotoxicity. In vivo validations include studies in innovative zebrafish models, which allow life imaging of neuronal cell death, as well as the establishment of microPET amyloid imaging for longitudinal studies in individual animals.

2 497 020 €

Start date: 2013-03-01, End date: 2018-02-28

At every moment in time, the brain receives a vast amount of sensory information about the environment. This makes attention, the process by which we select currently relevant stimuli for processing and ignore irrelevant input, a fundamentally important brain function. Studies in primates have yielded a detailed description of how attention to a stimulus modifies the responses of neuronal ensembles in visual cortex, but how this modulation is produced mechanistically in the circuit is not well understood. Neuronal circuits comprise a large variety of neuron types, and to gain mechanistic insights, and to treat specific diseases of the nervous system, it is crucial to characterize the contribution of different identified cell types to information processing. Inhibition supplied by a small yet highly diverse set of interneurons controls all aspects of cortical function, and the central hypothesis of this proposal is that differential modulation of genetically-defined interneuron types is a key mechanism of attention in visual cortex. To identify the interneuron types underlying attentional modulation and to investigate how this, in turn, affects computations in the circuit we will use an innovative multidisciplinary approach combining genetic targeting in mice with cutting-edge in vivo 2-photon microscopy-based recordings and selective optogenetic manipulation of activity. Importantly, a key set of experiments will test whether the observed neuronal mechanisms are causally involved in attention at the level of behavior, the ultimate readout of the computations we are interested in. The expected results will provide a detailed, mechanistic dissection of the neuronal basis of attention. Beyond attention, selection of different functional states of the same hard-wired circuit by modulatory input is a fundamental, but poorly understood, phenomenon in the brain, and we predict that our insights will elucidate similar mechanisms in other brain areas and functional contexts.

1 466 505 €

Start date: 2014-02-01, End date: 2019-01-31

Background. We have detailed maps of brain structure and function, yet are lacking understanding of how the highly connected units interact and give rise to mental processes. The Virtual Brain (TVB), a whole brain simulation framework, aims to bridge that gap. Yet it is still developing. We are proposing here breakthrough advances that reveal mechanisms of brain function and foster collaboration between research groups. Vision. Clinical applications that simulate individual patient brains and predict trajectories of recovery or decline or test therapies to select the best one for that person. Goal. Using biologically realistic brain models and multimodal functional and structural imaging data to elucidate control mechanisms of the human brain in aging. A database collects key data and allows identifying most generic models and mechanisms below the spatial and temporal resolution of non-invasive imaging techniques taking into account the complex interaction in the brain that without a model would be impossible to keep track of. Objectives. 1) Parameter optimization for large parameter space search and a library of dynamical regimes linking dynamical regimes and underlying mechanisms to biological (cognitive) age. 2) Identifying the role of intrinsic plasticity for network reconfigurations in the resting state and its age dependency. 3) Model based identification of task related plasticity mechanisms and their functional consequences for network reconfigurations in coordination learning in aging. 4) An interactive tool that provides access to the dynamical regimes library and makes pre-computed simulations easily accessible allowing researchers to benefit and learn from existing work. Impact. Understanding development, aging and brain disorders from the perspective of disruption of information processing architectures provides an opportunity for new interventions that re-establish control in brain pathology hence posing a breakthrough in the health and biotech sector.

1 870 588 €

Start date: 2016-08-01, End date: 2021-07-31