We hypothesize that inappropriate thyroid hormone action in target cells is a common mechanism underlying susceptibility to age-related degenerative diseases and co-morbidities. Although regulation of systemic thyroid status is well understood and underpins treatment of common thyroid disease, it is only in the last decade that the importance of local regulation of thyroid hormone action in tissue development, homeostasis and repair has been identified. During evolution, this complex temporal and cell-specific regulation has been optimized for development and reproductive fitness but NOT for ageing. Humans with their exceptional longevity are thus exposed to a prolonged period of suboptimal local thyroid hormone action. Consistent with this, thyroid status is a continuous variable within the population that is related to fracture risk, muscle mass and cognitive decline. Moreover, in healthy longevity thyroid status is characterized by thyroid stimulating hormone in the upper half of the reference range. In these studies, we will determine how local regulation of thyroid hormone action controls tissue homeostasis and repair, whilst its dysregulation is a common mechanism underlying chronic disease development during ageing. We focus on osteoporosis, osteoarthritis, neurodegeneration and sarcopenia as paradigm age-related, degenerative disorders. Using cutting-edge technology, we will (i) identify thyroid hormone dependent biomarkers for disease susceptibility in bone, cartilage, central nervous system and skeletal muscle, (ii) manipulate cell-specific thyroid hormone action in these tissues and (iii) develop cell-type specific modulators of thyroid hormone action. THYRAGE integrates cross-disciplinary expertise from clinical and basic scientists, endocrinologists, neuroscientists, gerontologists, and industry-based peptide scientists. These studies will identify and validate novel strategies for prevention and treatment of chronic age-related degenerative disease.

We will reveal the neuronal mechanisms of fundamental hippocampal and axonal functions using direct patch clamp recordings from the small axon terminals of the major glutamatergic afferent and efferent pathways of the dentate gyrus region. Specifically, we will investigate the intrinsic axonal properties and unitary synaptic functions of the axons in the dentate gyrus that originate from the entorhinal cortex, the hilar mossy cells and the hypothalamic supramammillary nucleus. The fully controlled access to the activity of individual neuronal projections allows us to address the crucial questions how upstream regions of the dentate gyrus convey physiologically relevant spike activities and how these activities are translated to unitary synaptic responses in individual dentate gyrus neurons. The successful information transfers by these mechanisms ultimately generate specific dentate gyrus cell activity that contributes to hippocampal memory functions. Comprehensive mechanistic insights are essential to understand the impacts of the activity patterns associated with fundamental physiological functions and attainable with the necessary details only with direct recordings from individual axons. For example, these knowledge are necessary to understand how single cell activities in the entorhinal cortex (carrying primary spatial information) contribute to spatial representation in the dentate (i.e. place fields). Furthermore, because the size of these recorded axon terminals matches that of the majority of cortical synapses, our discoveries will demonstrate basic biophysical and neuronal principles of axonal signaling that are relevant for universal neuronal functions throughout the CNS. Thus, an exceptional repertoire of methods, including recording from anatomically identified individual small axon terminals, voltage- and calcium imaging and computational simulations, places us in an advantaged position for revealing unprecedented information about neuronal circuits.

Acetylcholine released by cholinergic neurons in the basal forebrain is a critical component of the modulatory cocktail governing the emergence, stabilization and reorganization of cortical ensembles of co-active neurons representing the environment. In the hippocampus, ACh renders the state of the network optimal for the acquisition of novel information. Deterioration of cholinergic modulation leads to severe deficits in hippocampal function manifested as debilitating cognitive impairments. Despite decades of intense research fundamental questions are still open about the cholinergic modulation of hippocampal information processing: i) how is the behaviour-dependent firing of different neuron types determined by ACh? ii) how does ACh contribute to the emergence of the spatially selective firing of principal cells, their amalgamation into sequences representing the surroundings of the animal and the storage of “relevant” sequences? iii) how does ACh alter the place code in response to salient environmental stimuli? Technological breakthroughs of the past years have opened the possibilities of addressing these long-standing questions about cholinergic modulation. Thus, I aim to combine the latest electrophysiological recording, optogenetic manipulation and behavioural tracking methods to monitor hippocampal neuronal ensembles in freely behaving mice while manipulating the cholinergic input of the hippocampus by light-responsive microbial opsins. Results of the proposed research programme will decipher the role of ACh in hippocampal information processing and inform us how subcortical modulation contributes to the conversion of external inputs from the environment to internal representations. By accomplishing the programme outlined in the proposal I will be acquainted with the cutting edge technologies as well as skills indispensable for starting my independent research group and expanding the research potential of my home institute.

The hippocampus is essential for building episodic memories. Coding of locations, contexts or events in the hippocampus is based on the correlated activity of neuronal ensembles; however, the mechanisms promoting the recruitment of individual neurons into information-coding ensembles are poorly understood. In particular, the recurrent synaptic network of pyramidal cells (PCs) in the hippocampal CA3 area, receiving external inputs from the entorhinal cortex and the dentate gyrus, is thought to be essential for associative memory. Current models of the associative functions of CA3 are mainly based on plasticity of these synaptic connections. Recent work by us and others however suggests that active, voltage-dependent properties of CA3PC dendrites may also promote ensemble functions. Dendritic voltage-dependent ion channels allow nonlinear amplification of spatiotemporally correlated synaptic inputs (such as those produced by ensemble activity) and can even generate local dendritic spikes, which may elicit specific action potential patterns and induce synaptic plasticity. Furthermore, dendritic processing may be modulated by activity-dependent regulation of dendritic ion channels. However, still little is known about the active properties of CA3PC dendrites and their functions during spatial coding or memory tasks. The general aim of my research program is to understand the cellular mechanisms that underlie the formation of hippocampal memory-coding neuronal ensembles. Specifically, we will test the hypothesis that active input integration by dendrites of individual CA3PCs plays an important role in their recruitment into specific context-coding ensembles. By combining in vitro (patch-clamp electrophysiology and two-photon (2P) microscopy in slices) and in vivo (2P imaging and activity-dependent labelling in behaving rodents) approaches, we will provide an in-depth understanding of the dendritic components contributing to the generation of the CA3 ensemble code.

The Human Brain Project (HBP) is a major European scientific research initiative to improve our understanding of the brain and the role it plays in making us human, and to exploit the opportunities offered by the resulting knowledge. The size and complexity of the brain make this an expensive undertaking, but the costs associated with our current ignorance are rising and the potential gains from better insight into the brain are increasing. Brain-related diseases, many of which are age-related, now represent a major part of the global health burden and there are both ethical and economic imperatives to keep the growing number of older people healthier and more productive. Economic advantage is increasingly linked to artificial intelligence (AI), our ability to create technology to extract, manipulate and harness knowledge. The HBP’s comprehension of what makes the human brain so efficient and flexible should help to maintain Europe’s competitiveness and innovation potential in this area. The HBP is one of several brain research initiatives and projects around the world, albeit one of the first, but it is unique in a number of ways. Only the HBP has an explicit focus on both neuroscience and computing. It is also the broadest and most integrated brain initiative, and the only one aiming to build a research infrastructure to accelerate brain research. The HBP is a FET Flagship which started under FP7 and continues under H2020 with a succession of Specific Grant Agreements (SGAs) under a Framework Partnership Agreement (FPA). In its FP7 Ramp-Up Phase (2013-16) and subsequent SGA1 funding period (2016-18), the HBP implemented a scientific project of rare ambition, breadth and scale, and forged its diverse constituents into a functioning entity. On the scientific side, it not only identified critical gaps in our understanding of the brain, but also created tools and obtained data to fill many of them. It designed, built and demonstrated six ICT research platforms, supporting neuroinformatics, brain simulation, high-performance analytics and computing, medical informatics, brain-inspired computing and linking of simulated brains to robotic bodies. The results have been made available to the scientific community. The HBP also learnt to address underperformance and conflicts, and opened up the Project via competitive calls and the integration of Partnering Projects. In the upcoming SGA2 funding period (2018-20), the HBP will continue to strengthen global brain research efforts by extending coordination with other brain initiatives and projects. Internally, it will continue its unique inter-disciplinary co-design approach, developing research infrastructure capabilities via use cases built around specific research needs. This approach will underpin its critical scientific work of understanding how to bridge between the different scales of brain organisation, a key prerequisite to understand the principles of brain organisation. It will include gathering data to support detailed modelling, notably of the human hippocampus, as well as structural, functional and connectivity data to improve systemic understanding of the whole brain. The HBP will also investigate brain similarities and differences between individuals and between species. It will model key brain functions, including visual recognition, slow-wave activity, episodic memory and consciousness in rodents and humans, and elaborate their cognitive architectures. In addition, it will develop simplified brain models to support further development of brain-inspired computing. SGA2 will see the individual infrastructure platforms extended and integrated into the HBP Joint Platform (HBP-JP). The JP will make HBP services more robust and improve the user experience, encouraging wider use of its tools. SGA2 should thus see a shift from supplier-driven to user-driven capabilities, while the infrastructure underpinning them will be tied closely into EU efforts to integrate and stre