Research Area: Brain energy metabolism, Glial cell biology, Mitochondrial biology
Most if not all functions of the mature central nervous system essentially depend upon a highly coordinated activity of several cell types constituting the so-called neurovascular unit. Besides endothelial cells, which form the actual blood-brain-barrier (BBB), and the critical recruitment of pericytes during BBB formation, astrocytes have recently emerged for their possible co-regulatory role on vasculature permeability aiding neurovascular coupling and brain energy metabolism1. Following brain injury, the coordinated activity of these cell types becomes disrupted, eventually resulting in vascular dysfunction, BBB breakdown, neuroinflammation and spreading of secondary degeneration2. In this setting, astrocytes invariably enter a state of reactivity (astrogliosis) which has been reported to underlie important functions in the progression of the injury and its possible resolution, including confining macrophage extravasation and spread of pro-inflammatory mediators. Interestingly, during this response astrocytes exhibit traits of pronounced structural plasticity by acquiring polarized morphologies and – in a subset of juxtavascular cells – resuming proliferation. They also undergo major changes in their metabolic state, including mitochondrial energy metabolism3, mirroring corresponding alterations in gene expression. Very little is known on the actual changes reactive astrocytes may experience with regard to their perivascular compartment in vivo, and in particular whether these changes can contribute to regulate or even restore the microvascular network after injury.
We have been recently able to reveal that injury-induced reactive astrocytes in vivo undergo differential and time-dependent structural changes of their mitochondrial network, mirroring corresponding alterations in their energy state4. While so far the ultimate significance of this network reorganization has remained elusive, in scar-forming astrocytes this distinctive metabolic state may presumably support their capacity to elongate polarized branches towards the lesion site or to sustain locally metabolic/energy needs functional to the resolution of the lesion. In a project being currently finalized in the lab, we have collected evidence demonstrating that this is indeed the case, with some candidate pathways having emerged for being particularly important during the resolution phase of the injury in astrocytes.
The candidate student will address the significance of signaling pathways triggered by brain injury and inflammation in astrocytes. In particular, the role of these pathways during tissue repair will be assessed in mouse models. As one of these pathways involves calcium signaling, we have optimized techniques to monitor calcium dynamics in specific intracellular compartments in astrocytes in situ. The student will take advantage of these innovative tools to investigate how different organelles (mitochondria and endoplasmic reticulum) contribute to calcium micro-domains in astrocytes and how these dynamics modulate tissue recovery after injury. Manipulation of calcium and other key pathways will be achieved via intracranial virus delivery in mice, and by the use of dedicated transgenic animals. The project may extend to other target pathways during the course of the studies.
The model of election will be rodents (mouse), and the project will require experiments to be performed in transgenic mice in vivo, as well as in fresh mouse brain tissue isolated for analysis ex vivo and in vitro. The candidate will make extensive use of mouse genetics and imaging techniques (e.g., confocal, 2-photon and electron microscopy), besides general basic approaches in molecular biology. Training in mouse brain surgery and stereotactic injections4,5,6 is offered and warmly recommended as a central approach to achieve genetic manipulation in experiments in vivo as part of this project.
The lab focuses on mechanisms of brain plasticity in physiology and disease. Therefore, the candidate must first of all be driven by a strong interest in research areas close to our main topic. Previous experience work with anything of the following would be most welcome: handling of rodents, handling of mouse brain tissue, preparation of primary cultures of brain cell types, imaging approaches, methods to manipulate and visualize mitochondrial dynamics. The candidate is expected to already possess basic knowledge in standard laboratory techniques.