Summary of the Research Programme
Neural homeostasis refers to one of the most remarkable features of the nervous system, i.e. its ability to maintain a balanced and stable internal state in response to a constant flow of input from an ever-changing environment. This continuous adaptation is ensured by homeostatic feedback mechanisms acting at the molecular, cellular and circuit levels to maintain nervous system functions around flexible set-points. Brain homeostasis is proposed to prevent damaging or inefficient states by adjusting neuronal function and keeping neurons in an optimal operating regime supporting information transfer and processing across neuronal circuits. Homeostatic adaptation is thus critical for the stability of the nervous system, while simultaneously allowing for a certain degree of structural, functional and organizational flexibility as a platform for development and adaptation to new environments and experiences. In other words, homeostatic stability and flexibility can be considered as two complementary and mutually dependent design principles of the brain.
Neural homeostasis covers many areas of neuronal function, such as proteostasis, synaptic transmission, neuronal morphology and connectivity, or neurogenesis. At the single cell level, these homeostatic adaptive mechanisms regulate transcriptional programs, protein translation, trafficking and subcellular localization, as well as post-translational signaling pathways, to modify cellular morphology and/or physiology; subsequently, they modulate the interaction with neighbouring neurons and the transmission of information within the network. Similarly, cell proliferation and cell death are also key mechanisms of homeostasis and adaptation in the developing and adult brain, as they control cell numbers and hence shape connectivity and brain function. At the circuit level, homeostatic processes are co-regulating the intrinsic function of multiple neuronal and non-neuronal cell types, their communication and their integration into a common network, thus supporting the stability of brain function and computation in response to new experiences. By maintaining neuronal function around a set-point and avoiding pathological extremes, all these homeostatic processes at the molecular, cellular and circuit levels also help preserving the ability of our brain to adapt to stimulus- and task-induced changes.
The guiding principle of the research performed in the CRC1080 can thus be summarized as follows: We explore the fundamental processes enabling the nervous system to maintain the functionality, adaptability and flexibility of its network components during physiological conditions, and also how these mechanisms are altered in pathological situations. We seek to understand not only 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. As described above, we are aware that numerous players and mechanisms operating on different scales are involved, and that they are not acting independently, but interact to implement neural homeostasis. Therefore, our approach includes projects that analyze the molecular mechanisms of circuit maintenance through the regulation of apoptosis, neurogenesis, ribostasis and proteostasis, as well as neuronal morphology and synaptic transmission from the pre- and post-synaptic side (Areas A and B). After its implementation in the second funding period, we are now strengthening the study of the regulation of network function at a circuit level in physiological and altered conditions using experimental and computational angles (Area C). Across all areas, we are also including non-neuronal cells (glia, endothelial cells and perivascular cells), which are newly emerging key players in the modulation of homeostatic mechanisms.