The overarching conception and goals of the CRC are ambitious, and follow a long-term vision towards better understanding the complexity of the brain on an elementary level. We are convinced that linking such advances with the study of common brain disorders will also lead to a novel understanding of how precisely disease symptoms arise, and how they can be treated.
- Understanding complex behavior: The combination of manipulation of identified neuron types, and in-vivo electrophysiological and imaging techniques now allow examining the contribution of specific neuron types to sensory perception and complex behavior. Multiple groups have adopted one or more of such approaches. We expect that the exchange within the CRC will lead to a further, rapid technological and conceptual development in this direction. In this context, the development of techniques for in-vivo analyses in awake behaving animals will be a key issue for medium-term development of the CRC, that has already been initiated in some participating laboratories.
- Understanding mechanisms of homeostasis and plasticity in neuronal circuits: Synapses have to have a precisely regulated capacity for plastic changes. However, they also have to be capable of maintaining their individual properties over prolonged periods in face of extensive molecular dynamics and the continual renewal of their lipid and proteinacious components. How this dichotomy is regulated is unknown, in particular in intact brain tissue. The CRC will lay the groundwork to understanding basic principles of plasticity vs. tenacity of synapses, the vision then is to extend this understanding to different types of synaptic contacts in the intact brain, and to explore their relevance for learning and memory.
- Combining chemical biology and neuroscience: Understanding neuronal function hinges on the ability to rapidly and reversibly inhibit the function of key signaling molecules or ion channels. Genetic tools are slow, and prone to contamination by compensatory effects. The fundamental ability to inhibit one type of ion channel, and not others in a temporally controlled manner is afforded by methods developed by the Chemical biology groups at LIMES in Bonn. We expect that further development and upscaling of the production of light-based selective inhibitors will be a major and unique tool in life sciences. In addition, the development of novel uncaging tools suitable for multiphoton uncaging will be a major long-term endeavour that will drive a number of neuroscientific projects.
- Treatment of CNS disorders: Many molecular changes in CNS disorders have been identified, and have been used to generate novel therapies. In addition, drug development has been based on simplistic models of brain function. However, candidate drugs have an exorbitantly high rate of failure in clinical translation. We suggest that a detailed knowledge of pathological micronetworks and how therapies work on this level is a prerequisite for rational and more successful design of treatment strategies. We see our CRC as a key consortium that is working in this direction.
General Goals of the SFB 1089
All mammalian behavior relies on the recruitment of neuronal ensembles into precisely orchestrated discharges. How the different cellular and synaptic elements of a neuronal ensemble cooperate to produce characteristic patterns of activity in the central nervous system is a fundamental and important question in neuroscience. Resolving the function of elementary synaptic microcircuits that form a more complex circuitry will therefore significantly advance our understanding of brain function.
We propose to examine the function and disease-related dysfunction of synaptic micronetworks at four interrelated levels of increasing complexity.
- Firstly, at the most elementary level, we will examine the properties of individual synapses interconnecting neurons in specific network motifs on a molecular and functional level, and determine how identified synapses are affected by common CNS disorders.
- Secondly, we will address how the many thousands of individual inhibitory and excitatory synaptic inputs are integrated at the input structures of neurons, neuronal dendrites, and whether these properties are altered in CNS disorders.
- Thirdly, at the level of neuronal ensembles, we want to understand how their behavior is orchestrated by inhibitory or modulatory inputs.
- Finally, we will address how identified types of neurons affect behavior in intact organisms, and how they contribute to the in-vivo manifestations of brain diseases.
Projects that bridge these levels of analysis and their integrating into a CRC will allow us to identify some of the fundamental rules that govern the dynamics of neuronal behavior at the network level, and the translation of neuronal network dynamics to mammalian and human behavior.