Molecular and Cellular Mechanisms of Neural Homeostasis
The nervous system is characterized by a remarkably elaborate cellular architecture able to receive, integrate, store information, and to orchestrate appropriate responses of the rest of the body.
One of the most important functions of this complex system is its ability to change its structure and function in response to altered external information input.
With this in mind, the guiding principles of this initiative are to explore the fundamental molecular and cellular processes that lead the nervous system to be able to:
- Acquire and maintain a homeostatic state during development.
- Achieve homeostasis during adult life.
- Adjust to new set-points in response to a harmful event.
Our initiative is ready to take up the challenge of investigating and understanding how “the unstable stuff of which we are composed has learned the trick of maintaining stability” (Cannon, 1932).
Summary of the Research Programme
The guiding principle of the research performed in the CRC1080 can be summarized as follows: We explore the fundamental molecular-cellular, circuit- and systems-level processes that enable the nervous system to maintain the functionality, adaptability and flexibility of its network components during adult life. We not only seek to understand how “the unstable stuff of which we are composed has learned the trick of maintaining stability” (from Cannon, 1932) but also how it remains an open and flexible system. We are aware that numerous mechanisms operating on different scales are involved here; therefore, our approach includes projects which analyze molecular mechanisms of circuit maintenance and, as a consequence, diverse classes of genes, including those that encode transcription factors, signaling molecules, transporters, or molecules that control cell-cell interaction and communication (Area A and B). In a new section developed for the next period of funding (Area C) we aim to link the molecular and cellular levels to projects analyzing circuit- and systems-level homeostatic mechanisms.
Our research is not limited to a single set of genes, cell types, pathological processes or structures. Instead, we draw on the strengths of different experimental approaches to elucidate the chain of events that constitutes homeostasis in the nervous system. Together, our laboratories offer expertise in molecular and cell biology, biochemistry, morphology, imaging, electrophysiology, clinical as well as computational competence. Nevertheless, we are aware that the issue of neural homeostasis cannot be answered comprehensively within one research network alone, and therefore, as a consortium, we also interact with international centers including the Institute de Neurobiologie de la Méditerranée (INMED), Yale University School of Medicine, Columbia University, California Institute of Technology, Harvard Medical School, NeuroCentre Magendie, Université Bordeaux, University of California Berkeley, Hebrew University, Jerusalem, and Hôpital de la Pitié-Salpêtrière. Within this research network, it is the ultimate goal of this collaborative research center to understand the importance of homeostatic mechanisms for the brain.
Already throughout the first funding period, important insights on neuronal homeostatic mechanisms and their limits in pathophysiological brain states as well as improved methods how to study homeostatic with cellular and subcellular resolution (e.g. tom Dieck et al., 2015) have been published by members of the consortium. These include for example the role of GRIP/14-3-3 pathway in dendrite development and homeostasis (Geiger et al., 2014), the function of PRG-mediated lipid signaling in synaptic homeostasis (Unichenko et al., 2016; Vogt J et al., 2015) and the failed homeostatic in vivo firing rate control via impaired potassium channel function in dopamine neurons in Parkinson Disease (Subramaniam et al., 2014).
The CRC1080’s achievements are in synchrony with global developments in the field of neuronal homeostasis, which has considerably matured in the last few years. In particular, the study of neural homeostasis has moved from simple in vitro system to in vivo studies in intact animals, where homeostatic mechanisms are shaped by global brain states such as distinct sleep states (Hengen et al., 2016; Watson et al., 2016). Moreover, understanding homeostatic mechanisms of the brain has become even more essential to fully understand brain dynamics in response to transient – mostly optogenetic – network manipulation (Otchy et al., 2015). These will need to be fully resolved before attempting to capture major brain diseases as essential failures of homeostatic regulation (Mullins et al., 2016). Finally, the contributions of theoretical and computer modeling to understand neural homeostasis have become comprehensive and refined (e.g. O-leary et al., 2014). As will become evident in the detailed presentation of the research program, the CRC has responded to these developments and challenges in the field.
A major goal of this CRC is to accelerate the exchange of our combined experimental resources so as to arrive at a detailed analysis of the morphological, cellular and biochemical processes associated with a homeostatic mechanism.
As a single laboratory cannot be proficient in all aspects of analysis of the nervous system, an alliance between work groups investigating molecular and cellular homeostasis in the nervous system opens up significant long-term possibilities.
To this end the CRC is made up of the following institutes:
Amparo Acker-Palmer, Thomas Deller, Alexander Gottschalk, Jochen Roeper, Irmgard Tegeder.
Johannes Gutenberg-University Mainz
Christian Behl, Benedikt Berninger, Albrecht Clement, Jonathan Kipnis, Yonatan Loewenstein (The Hebrew University of Jerusalem), Heiko Luhmann, Beat Lutz, Thomas Mittmann, Simon Rumpel, Mirko Schmidt, Susann Schweiger, Anne Sinning, Johannes Vogt, Jakob von Engelhardt, Frauke Zipp.
Max Planck-Institute for Brain Reseach
Erin Schuman, Gilles Laurent, Tatjana Tchumatchenko.
Institute for Molecular Biology Mainz (IMB)