Lactate-sensing fibroblasts in stroke
Millions of people suffer from stroke every year, and stroke is the main cause of disabilities among adults. One of the best preventive strategies in stroke is exercise, but no consensus has been reached regarding the optimal exercise regime. We have recently shown that a lactate receptor, HCAR1, is present and active on fibroblasts in the meninges, especially in the pia mater. We further show that activation of these receptors, by high-intensity interval exercise, or lactate injections, induce increased density of capillaries in the brain. This happens at least partly through increased release of growth factors.
Using primary fibroblast cultures, we investigate the intracellular events that occur between receptor activation and release of growth factors. We further use mouse models to investigate the effect of activation of the lactate receptor in the treatment or prevention of stroke. We are studying intracellular signaling pathways, the release of growth factors and signs of oxidative stress and neuroinflammation. The aim of the project is to establish whether lactate-sensing fibroblasts of the meninges represent a novel therapeutic and preventive target in stroke.
Contact: Cecilie Morland
Cell death and cell survival
Different forms of cell death in the CNS can cause permanent disabilities, and in worst case, death. Glutamate is a signaling substance in the brain that causes cell death when found in high extracellular concentrations, e.g. after a stroke. We use glutamate, as well as other methods, to induce cell death in our studies. By studying the mechanisms behind such death, we seek to find new ways to protect the cells. One of several findings so far is that various steroids can protect against glutamate-induced cell death.
Another approach to find out how we can protect nerve cells against cell death, is through studies of the cells’ own mechanisms for survival, and for programmed cell death - so called apoptosis. Hence, we are studying a range of signaling processes, such as pathways including ERK, a MAP-kinase known to be a survival signal, redistribution of the apoptotic inducer NGFI-B, functions of caspase 3, and reactive oxygen species (ROS) and anti-oxidant defence in the form of gluthation (GSH).
Contact: Ragnhild Paulsen
CNS development in the fetus and newborn
Cell death and survival are also important during the development of the CNS. Some cells that are present in early fetal stages are programmed to undergo death by apoptosis at later stages, while other cells are programmed to survive and differentiate. These processes may be disturbed by a variety of substances that the mother is exposed to during pregnancy, or to which the newborn is exposed shortly after birth.
We have established at model using chickens (gallus gallus), in which we can expose the chickens before hatching, and then study potential effects of the exposure in the cerebellum at different stages later during development. We use this model to study possible effects on CNS development of both prenatal exposure to environmental toxins, as well as effects of pharmaceuticals that are prescribed to premature children. We also employ the chicken cerebellum to make primary granule cell cultures for studies of the molecular mechanisms responsible for these processes.
Contact: Ragnhild Paulsen
Effects of exercise in the brain –the search for new drug targets
Physical exercises has beneficial effects on brain function, including enhanced learning/memory and problem solving, and reduced symptoms of anxiety and depression. Mechanisms involve increased synaptic plasticity, neuroneogenesis, synaptogenesis, angiogenesis, and alterations in energy metabolism. We are interested in how different exercise intensities may affect the brain though different mechanisms. We study the beneficial effects of exercise, with the aim of discovering potential new drug targets for the treatment of neurodegenerative diseases, and mood disorders.
Contact: Cecilie Morland