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Understanding the function of the brain is a central goal of modern life sciences. However, our knowledge about the most complex organ of the human body is still very limited. Rough estimates suggest that the human central nervous system consists of approximately 1011 neurons. Each of these neurons communicates with approximately 10,000 other neurons. This enormous complexity of the human brain raises several questions. What, for example, are the functional properties of communication sites between different types of neurons? How is information in brain networks encoded, stored, and retrieved? What are the mechanisms underlying disorders of neuronal network function? Even seven years after the end of the "decade of the brain", we are still far away from having definitive answers to these fundamental questions.
Communication between neurons in the brain takes place at specialized contact sites, termed synapses. These synapses play a decisive role for the encoding of information and for the dynamics of network activity. Excitatory synapses releasing the transmitter glutamate typically generate subthreshold signals that are integrated to generate an action potential output in the target neuron. Excitatory synapses are also thought to store information as an increase or decrease in synaptic strength through spike timing-dependent plasticity. In contrast, inhibitory synapses constrain the activity level of neuronal networks, control synaptic plasticity, and contribute to the generation of network oscillations that can serve as reference signals for temporal encoding of information. The functional balance between excitatory and inhibitory synapses is a key factor for the stability of the network, and the failure of inhibition is thought to contribute to several diseases of the brain, including epilepsy and schizophrenia.
A substantial amount of work has been done on the characterization of synapses. However, several pieces of key information are still lacking. First, analysis of synaptic transmission in many cases has remained at a qualitative level. A quantitative understanding, as suggested in the current application, is an essential long-term goal. Second, analysis thus far has either been performed at unidentified synapses or concentrated on a very limited number of “models” with highly specialized properties. However, it is well established that synapses can be extremely diverse, even within the same circuit, and can vary substantially, depending on the nature of the presynaptic neuron and the postsynaptic target cell. Third, the structure of synapses has not been sufficiently described, and the relation between structure and function of synaptic transmission often has remained unclear. Fourth, little is known about neuromodulatory synapses. As the output synapses of neuromodulatory systems have important roles in disease (e.g. the dopaminergic system in Parkinson’s disease and schizophrenia; the cholinergic system in Alzheimer’s disease), it is essential to obtain more basic information about these synapses. Fifth, the mechanisms of synaptic plasticity at cortical synapses remain incompletely understood. This holds for both functional plasticity (such as long-term potentiation and depression) and structural plasticity (such as neurogenesis), and particularly applies to the interface between these two forms of plastic changes. Again, it is essential to fill these gaps in our knowledge to enable us to develop novel therapeutic strategies, such as those based on stem cell transplantation. Finally, it is largely unclear how complex phenomena (such as network oscillations) and functions (such as episodic memory) ultimately emerge form the specific functional properties of neurons and synapses. A logical approach to address this question is to develop models of neuronal networks based on realistic assumptions about neuronal and synaptic properties, and to calibrate these models using in vivo observations. However, most existing network models have too abstract properties for this purpose and do not comply with biological reality. The new SFB 780 can bridge these gaps and thus provide an important contribution to the field of Neuroscience both in Germany and at the international level.
The proposed research program attempts to address synaptic transmission at three different levels: (A) At the level of single identified synapses, their pre- and postsynaptic components, and their molecular machinery, (B) at the level of neuromodulation, functional plasticity, and structural plasticity, and (C) at the level of computational models and neuronal networks in vivo.

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Research Area A (Synaptic structure and function) addresses the basic mechanisms of exocytosis and transmission at identified central synapses. Project A1 (Klugbauer) characterizes Cav2.1 Ca2+ channels, which are the major channels mediating the Ca2+ inflow necessary for transmitter release at central synapses. A major focus is the generation of conditional Cav knockout mice. Project A2 (Kulik) investigates the subcellular distribution of metabotropic receptors (e.g. GABAB receptors) and inwardly rectifying K+ channels at hippocampal synapses and their functional role in slow inhibition of postsynaptic principal neurons and interneurons. Project A3 (Fakler) proposes a proteomic analysis of N-Type (Cav2.2) Ca2+ channels and their interaction partners, which are important for both transmitter release and neuromodulation at pre- and postsynaptic sites. Project A4 (Frotscher and Jonas) aims to correlate structure and function at a plastic glutamatergic presynaptic terminal, the mossy fiber bouton in the hippocampal CA3 region. This project will examine release site topography and localization of presynaptic proteins at these boutons by improved electron microscopy techniques. Project A5 (Jonas) examines the coupling between action potential, presynaptic Ca2+ inflow, and exocytosis in synaptic terminals of GABAergic interneurons (basket cells) in the hippocampus. The major aim of this project is to functionally characterize the output synapses of identified types of GABAergic interneurons, and thus to provide information essential for the development of realistic network models (Research Area C).

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Research Area B (Synaptic modulation and plasticity) targets the mechanisms of synaptic modulation and plasticity. Project B1 (Baumeister) focuses on the functional role of α-synuclein and LRRK2 in cytoskeletal organization and vesicular trafficking in dopaminergic presynaptic terminals. Projects B2, B3, and B4 address different aspects of synaptic plasticity. Project B2 (Krieglstein) will examine the role of TGF-β in the modulation and plasticity of respiratory and cortical networks. Project B3 (Bischofberger) will determine the properties of dendritic signal integration and action potential backpropagation in dentate gyrus granule cells and their consequences for the induction of synaptic plasticity at the glutamatergic input synapses. Project B4 (Klöcker) plans to characterize AMPA receptor protein complexes and to examine the role of AMPA receptor interaction partners for the regulation of synaptic strength. Together, B3 and B4 address important aspects of plasticity at glutamatergic synapses in a complementary manner. Project B5 (Herz, Bock, and Frotscher) examines how the Reelin signaling cascade controls structural and functional plasticity in the hippocampus, using a second generation conditional knockout mouse of the Reelin gene. Finally, Project B6 (Driever and Friedrich) will develop techniques to label dopaminergic axons and analyze the effects of their activation on plasticity and network activity in the olfactory bulb, using the zebrafish brain as a model. Together with project B1, this project addresses a major neuromodulatory pathway, which is highly relevant to our understanding of brain diseases (e.g. Parkinson’s disease and schizophrenia).

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Research Area C (Networks and network models) addresses the function of synapses in the context of a neuronal network, concentrating on the hippocampus and the neocortex. Project C1 (Staiger and Hennig) proposes a combined approach using electrophysiology and in vivo imaging (functional MRI; diffusion tensor imaging, DTI) to investigate topographic maps and map plasticity in the barrel cortex. Project C2 (Wolfart and Haas) proposes to study the mechanisms of signal integration in dentate gyrus granule cells under physiological and pathophysiological conditions in a new kainate model of epilepsy. Project C3 (Schulze-Bonhage) will perform recordings in vivo in epileptic patients. Field potentials and single-unit activity will be recorded during physiological (e.g. memory task related) and pathological (ictal and interictal) gamma and high-frequency oscillations. Together with research areas A and B, results from C1 – C3 will provide the experimental basis for the development of reality-based models of neuronal networks. Realistic modeling is the explicit purpose of project C4 (Aertsen, Boucsein, and Rotter). This project plans to characterize synaptic connections within and across layers in the neocortex (by multiple electrode recording) in vitro and in vivo, and to incorporate anatomical and functional information about neocortical connections into network models. The project will provide major clues regarding the question how structure shapes function of neuronal networks. Finally, project C5 (Weiller and Lange) will examine cortical network plasticity in vivo. The aim of this project is to examine polysynaptic inhibitory pathways from the contralateral to the ipsilateral primary motor cortex, and polysynaptic excitatory pathways from the cerebellum to the primary motor cortex using fMRI imaging. The project proposes to work out the underlying synaptic pathways and to exploit this information for the treatment of patients with apoplectic insults.

The innovative scientific strategy of the SFB comprises both hypothesis-driven research and approaches of “systems biology”. At the level of synapses, we want to test specific hypotheses about mechanisms of synaptic transmission, but at the same time obtain the data to provide a complete description of the molecular and subcellular elements of a synaptic system. This will ultimately lead to a quantitative model of transmitter release and receptor activation for a subset of hippocampal and neocortical synapses. At the level of circuits, we will test specific hypotheses about the dynamic behavior of neuronal networks, but at the same time collect data about cellular and synaptic properties, databasing hippocampal and neocortical neuronal networks. This information will be used to develop increasingly realistic network models. A detailed analysis of the models, in turn, will help to generate new hypotheses about network function.
The proposed collaborative research center combines several techniques, often used simultaneously in the same preparation. These include genetic techniques such as second generation conditional knockout mice, transgenic mice with EGFP tagging in subpopulations of cells, siRNA techniques to knockdown specific proteins in culture and in vivo, channelrhodopsin-mediated activation of single neurons, light and electron microscopy, immunohistochemistry, immunogold localization of channels and receptors, quick freezing and freeze fracture electron microscopy, paired recordings from synaptically connected neurons in slices, recording from presynaptic terminals, Ca2+ imaging, imaging of second messengers and lipids, proteomic analysis (mass spectrometry), fMRI to examine global network activity, DTI for fiber tracking of axonal pathways in vivo, field, unit, and intracellular recording in vivo, simulations of network activity, and methods of computational neuroscience. The combination of the different techniques clearly goes beyond the expertise of a single laboratory or a small group of researchers, but requires intense interdisciplinary collaboration, as supported by the platform of the new SFB 780.
As we ultimately want to understand how higher brain functions are implemented, we will concentrate on cortical networks, with special focus on the hippocampus and the neocortex. The hippocampus is believed to be critically involved in the formation of declarative-explicit memory. The hippocampus also offers the technical advantage of a clearly defined layering, which makes cell identification easier. Finally, the hippocampus also facilitates analysis of network function in vivo, because its neurons show spatial firing characteristics (“place cells”). One long-term vision of the planned SFB is to fully understand learning and memory in the cortico-hippocampal network system.
Rigorous testing of hypotheses requires a certain degree of flexibility in the choice of the experimental model, to allow the selection of the best model for each scientific question. The species studied in the projects of the new SFB range from simple organisms, such as C. elegans and zebrafish, to more complex organisms such as rats, mice, and humans. In the present application, in vivo recording in humans is only performed in two projects (C3, Schulze-Bonhage and Hefft; C5, Weiller and Lange). However, we envisage that during the second and the third funding period of the SFB 780, the focus may shift towards recording in the human brain.
An extensive network of collaborations already exists between the listed projects, both within and among the three research areas. Project A1 (Klugbauer), A3 (Fakler), A4 (Frotscher and Jonas) and A5 (Jonas) work closely together to address the role of presynaptic Ca2+ channels in transmitter release at the molecular and functional level. Project A5 (Jonas), which examines interneurons and inhibitory synapses in vitro, will closely cooperate with project C3 (Schulze-Bonhage and Hefft) and C4 (Aertsen, Boucsein, and Rotter), which examine principal neuron-interneuron networks in vivo and assemble realistic network models based on the experimental data. Project A4 (Frotscher and Jonas), which examines the structural machinery for transmitter release at glutamatergic synapses, will closely collaborate with B3 (Bischofberger) and B4 (Klöcker), which examine glutamatergic synaptic plasticity from a postsynaptic perspective. Project B3 (Bischofberger), which addresses dendritic integration and synaptic plasticity in hippocampal granule cells, will collaborate with C2 (Wolfart and Haas) to reveal how the integrative properties of granule cells change under pathophysiological conditions. Project C4 (Aertsen, Boucsein, and Rotter), which develops network models, will use the in vitro data of C1 (Staiger and Hennig) as well as the in vivo data of C3 (Schulze-Bonhage and Hefft) and C5 (Weiller and Lange) to calibrate and iteratively refine the models.

Criteria for further inclusion of projects into the new SFB 780 are:
·    Analysis of synaptic transmission at identified synapses at the molecular, cellular, and network level,
·    Correlated analysis of structure and function of synapses,
·    Analysis of excitatory glutamatergic synapses, inhibitory GABAergic synapses, and neuromodulatory synapses,
·    Analysis of function of inhibitory interneurons,
·    Analysis of polysynaptic pathways involving excitatory or inhibitory synapses with fMRI and DTI,
·    Development of neuronal network models with realistic properties.

Criteria for future exclusion of projects from the new SFB 780 are:
·    Experiments on non-neuronal cell types,
·    Analysis of undefined or unidentified synapses,
·    Purely descriptive projects, not addressing the mechanisms of synaptic transmission or network function,
·    Analysis of abstract neuronal network models unrelated to experimental observations,
·    Clinical studies exclusively developing therapeutic strategies, without addressing the underlying mechanisms.

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