ERC FUNDED PROJECTS

One’s ability to remember visual material such as objects, faces, and spatial locations over a short period of time declines with age. The proposed research will examine whether these deficits are explained by a reduction in visual working memory (VWM) capacity, or an impairment in one’s ability to maintain, or ‘bind’ appropriate associations among pieces of related information. In this project successful binding is operationally defined as the proper recall or recognition of objects that are defined by the conjunction of multiple visual features. While tests of long-term memory have demonstrated that, despite preserved memory for isolated features, older adults have more difficulty remembering conjunctions of features, no research has yet investigated analogous age related binding deficits in VWM. This is a critical oversight because, given the current state of the science, it is unknown whether these deficits are specific to the long-term memory system, or if they originate in VWM. The project interweaves three strands of research that each investigate whether older adults have more difficulty creating, maintaining, and updating bound multi-feature object representations than younger adults. This theoretical program of enquiry will provide insight into the cognitive architecture of VWM and how this system changes with age, and its outcomes will have wide ranging multi-disciplinary applications in applied theory and intervention techniques that may reduce the adverse consequences of aging on memory.

500 000 €

Start date: 2008-09-01, End date: 2011-08-31

DNA replication represents a dangerous moment in the life of the cell as endogenous and exogenous events challenge genome integrity by interfering with the progression, stability and restart of the replication fork. Failure to protect stalled forks or to process the replication fork appropriately contribute to the pathological mechanisms giving rise to cancer, therefore an understanding of the intricate mechanisms that ensure fork integrity can provide targets for new chemotherapeutic assays. Smc5-Smc6 is a multi-subunit complex with a poorly understood function in DNA replication and repair. One of its subunits, Nse2, is able to promote the addition of a small ubiquitin-like protein modifier (SUMO) to specific target proteins. Recent work has revealed that the Smc5-Smc6 complex is required for the progression of replication forks through damaged DNA and is recruited de novo to forks that undergo collapse. In addition, Smc5-Smc6 mediate repair of DNA breaks by homologous recombination between sister-chromatids. Thus, Smc5-Smc6 is anticipated to promote recombinational repair at stalled/collapsed replication forks. My laboratory proposes to develop molecular techniques to study replication at the level of single replication forks. We will employ these assays to identify and dissect the function of factors involved in replication fork stability and repair. We will place an emphasis on the study of the Smc5-Smc6 complex in these processes because of its potential roles in recombination-dependent fork repair and restart. We also propose to identify novel Nse2 substrates involved in DNA repair using yeast model systems. Specifically, we will address the following points: (1) Development of assays for analysis of factors involved in stabilisation, collapse and re-start of single-forks, (2) Analysis of the roles of Smc5-Smc6 in fork biology using developed techniques, (3) Isolation and functional analysis of novel Nse2 substrates.

893 396 €

Start date: 2008-09-01, End date: 2013-08-31

The vast majority of our knowledge about how the brain encodes information has been obtained from recordings of one or few neurons at a time or from global mapping methods such as fMRI. These approaches have left unexplored how neuronal activity is distributed in space and time within a cortical column and how hundreds of neurons interact to process sensory information. By taking advantage of the most recent advances in two-photon microscopy, the proposed project addresses two broad aims, with a particular focus on the function and development of primary visual cortex: 1) to understand how cortical neuronal networks encode visual information, and 2) to understand how they become specialised for sensory processing during postnatal development. For the first aim, we will use in vivo two-photon calcium imaging to record activity simultaneously from hundreds of neurons in visual cortex while showing different visual stimuli to anaesthetised mice. This approach enables us for the first time to characterise in detail how individual neurons and neuronal subsets interact within a large cortical network in response to artificial and natural stimuli. Genetically-encoded fluorescent proteins expressed in distinct cell-types will inform us how excitatory and inhibitory neurons interact to shape population responses during vision. For the second aim, the same approach will be used to describe the maturation of cortical network function after the onset of vision and to assess the role of visual experience in this process. We will additionally use Channelrhodopsin-2, a genetic tool for remote control of action potential firing, to examine the role of correlated neuronal activity on establishment of functional cortical circuits. Together, this work will bring us closer to unravelling how sensory coding emerges on the level of neuronal networks.

1 080 000 €

Start date: 2008-07-01, End date: 2013-06-30

Bacterial dehalorespiration is a microbial respiratory process in which halogenated hydrocarbons, from natural or anthropogenic origin, act as terminal electron acceptors. This leads to effective dehalogenation of these compounds, and as such their degradation and detoxification. The bacterial species, their enzymes and other components responsible for this unusual metabolism have only recently been identified. Unlocking the full potential of this process for bioremediation of persistent organohalides, such as polychlorinated biphenyls (PCBs) and tetrachloroethene, requires detailed understanding of the underpinning biochemistry. However, the regulation, mechanism and structure of the reductive dehalogenase (the enzyme responsible for delivering electrons to the halogenated substrates) are poorly understood. This ambitious proposal seeks to study representatives of the distinct reductive dehalogenase classes as well as key elements of the associated regulatory systems. Our group has been at the forefront of studying the biochemistry underpinning transcriptional regulation of dehalorespiration, providing detailed insights in the protein CprK at the atomic level. However, it is now apparent that only a subset of dehalogenases are regulated by CprK homologues with little known about the other regulators. In addition, studies on the reductive dehalogenases have been hampered by the inability to purify sufficient quantities. Using an interdisciplinary, biophysical approach focused around X-ray crystallography, enzymology and molecular biology, combined with novel reductive dehalogenase production methods, we aim to provide a detailed understanding and identification of the structural elements crucial to reductive dehalogenase mechanism and regulation. At the same time, we aim to apply the knowledge gathered and study the feasibility of generating improved dehalorespiratory components for biosensing or bioremediation applications through laboratory assisted evolution.

1 148 522 €

Start date: 2008-09-01, End date: 2013-08-31

I propose a novel evolutionary approach for studying ecological and demographic factors that affect senescence and lifespan in humans. Women are unique among animals due to menopause and a prolonged lifespan after last birth. Evolutionarily, the quest of everyone is to maximise grandchildren numbers. Hence, human women life-history is enigmatic. One possibility is that older women increase their fitness by directing resources to already produced offspring rather than having more. Thus, although women gain most grandchildren from own reproduction, they also gain more by helping offspring. This has fascinating implications. All animals must split their energy between reproduction vs. self-maintenance. Most continue to reproduce until death and produce maximum grandchildren by optimising investment between current vs. future reproduction. Human women must also optimise investment between mothering and grandmothering. How this is done and affected by ecological, social and demographic factors is unknown, but is essential to understanding the ecological and genetic basis of reproduction, senescence and lifespan. My project has 5 aims: 1. How does reproductive effort affect reproductive and post-reproductive senescence? 2. What proportion of grandchildren is gained post-menopause and how is this modified? 3. Is there heritable variation in life-history traits and their senescence, and how do genetic correlations affect evolution? 4. How do patterns of fitness acquisition account for menopause, prolonged post-reproductive lifespan and age of death in humans? 5. How does fitness maximization differ between men and women and affect their lifespans? The questions will be answered using unique data on three generations of individuals that lived before healthcare and modern contraceptives in Finland. The results will have important implications for predicting demographic structure and will appeal to a wide range of people within and outwith the scientific community.

1 143 824 €

Start date: 2008-07-01, End date: 2014-06-30

A major goal of 21st century science is to protect human health from the growing mismatch between ancient behavioural instincts and modern socio-economic reality. This is especially vital for basic instinctive drives such as appetite, which lead to overeating when food is readily available. The resulting obesity is responsible for 100,000s of premature deaths per year in Europe and North America, and this number is rapidly rising. Sleep is another powerful instinct which substantially contributes to premature human death, for example from car accidents caused by tiredness. Thus “self-destructive” behaviours caused by inappropriate activation of feeding and sleep drives take a devastating social and economic toll in developed countries, and there is a huge unmet need for effective therapies in this area. To design these therapies, we need to understand the brain mechanisms of instinctive drives. However, brain circuits regulating appetite and sleep have only been delineated in the past few years, and their principles of operation are poorly understood at present. The broad aim of my newly-established laboratory is to fill this gap in knowledge. To understand neural signals controlling instinctive drives, and their relationship to well-being and disease, the following questions must be answered: 1) how do neurons that control appetite and sleep generate their electrical and chemical signals? ) how do these neurons interact with each other? 3) how are these neurons altered in disorders of energy balance and sleep? Our objective for the next five years is to address these key unknowns by focusing on neurons known to be unequivocally important for normal sleep and appetite, the orexin and MCH neurons of the lateral hypothalamus.

1 299 999 €

Start date: 2008-10-01, End date: 2013-09-30

The project aims to study learning and volatility in financial markets. We will develop a theoretical market microstructure model to analyze how informational inefficiencies can arise in financial markets even though traders (who have non speculative reasons to trade) are allowed to buy or sell any quantity of an asset (in a continuous action space). In this theoretical framework, we will also analyze the case in which the asset value can change over time (e.g., because of shocks to the economy). We will study how learning occurs in this economy with changing fundamentals and how learning affects price volatility. This will create a bridge between the theoretical literature on learning and the empirical literature on time varying volatility (e.g., ARCH and GARCH). After developing the theoretical analyses, we will test the predictions in experiments, and proceed to a structural estimation of our models. We will run both field and laboratory experiments. The structural estimation will use transaction data in order to shed light on the process of information aggregation and volatility in different markets (e.g., more or less speculative) and different conditions (tranquil times versus financial crises).

765 000 €

Start date: 2008-10-01, End date: 2014-09-30

This research programme aims at understanding the neural mechanisms underlying the manipulation of meaning in the human brain. Throughout this interdisciplinary research programme four complementary research streams will run in parallel: (a) a developmental stream investigating the characteristics of semantic memory development in infants aged 12 to 36 months; (b) a bilingual stream addressing subtle differences in semantic conceptualisation resulting from the handling of different languages by one brain; (c) a nonverbal stream exploring the capacity of the human brain to process complex meaningful information that is not coded in words; and (d) an unconscious stream targeting the processing of meaning triggered by perceptually distorted stimuli processed outside of awareness. As the research programme unfolds, aspects of verbal and nonverbal semantic development in the infant will be compared to second language semantics and to nonverbal processing in the adult. Similarly, differences found between conscious and unconscious aspects of semantic processing will provide an interpretational basis for results obtained in the other three streams. At the end of this research programme an overall synthesis of data collected in the different streams will make it possible to characterize cognitive factors affecting semantic development in early and later life, which can be expected to lead to a completely novel conception of the human semantic system. The series of experiments planned and those generated in the course of this project will enable the research team to establish international leadership in the emerging field of neurosemantics.

961 958 €

Start date: 2008-09-01, End date: 2013-08-31

This project will help to meet the vital need for empirical research into the theory and practice of Payments for Environmental Services (PES). PES approaches to conservation have become rapidly more popular in the last few years, driven by compelling evidence of their effectiveness compared with indirect approaches to financing conservation. This research will exploit a current opportunity to build robust research protocols into the initial design of a PES scheme, thus allowing credible research into its outcomes. This will be undertaken through work with selected communities around the Nyungwe National Park in Rwanda. Communities will be offered cash transfers, contingent on their performance in relation to a set of conservation indicators. One of the great advantages of this project location is the availability of high quality ranger monitoring that, for example, provides regular geo-referenced data on the location of snares, tree-felling and other illicit activities. The outcomes of this experiment will be investigated through interdisciplinary research based on four main types of data. Firstly, data on forest user behaviour, based on the ranger data and additional transect studies; secondly, livelihood surveys that build an understanding of relationships between communities and park resources; thirdly, qualitative data, based on interviews and focus groups, to build an understanding of the social dynamics arising from introduction of the PES scheme; fourthly, public goods games to elicit data on attitudes towards the Park. The research findings will be of use to a wide range of African and international agencies with an interest in better understanding ways of reconciling biodiversity conservation and poverty alleviation. The results will provide a timely input to our understanding of the theory and practice of PES schemes.

1 027 633 €

Start date: 2008-07-01, End date: 2012-09-30