|PI of the laboratory: Jean-Yves Chatton |
Tel: 021 692 51 06
Direct supervisor (assistant): Christophe Lamy
Tel 021 692 51 17
Department: DBCM & Dépt. Physiologie
Address: Rue du Bugnon 9, CH-1005 Lausanne
Cellular, molecular and functional elements of astrocyte neuron lactate shuttle in the hypothalamus
Description of project:
Astrocytes are central players of neurometabolic coupling by taking up glucose from blood vessels to provide neurons with energy equivalents. The astrocyte neuron lactate shuttle hypothesis (ANLS) proposes that during neuronal activity astrocytes export glycolysis-derived lactate to neurons (Magistretti et al, 1999). Recent data show that in parallel to their function in brain energy supply, astrocytes might also have a major role in the body energy homeostasis. How these two different functions are articulated by the same cell type is not yet understood.
Central nervous system pathways involved in glucose and energy metabolism regulations form a complex and heavily interconnected network. A major integrating site in this circuitry is the medial basal hypothalamus (arcuate nucleus, ventromedial nucleus). This area of the brain responds to peripheral signals and metabolites, and regulates important functions such as feeding behavior, insulin production, and energy expenditure. For a long time, these circuits have been thought to rely mainly on metabolite and hormone-sensing neurons. However, there is increasing evidence that the primary cells involved are astrocytes. These cells, as their counterparts in other brain areas, can process glucose to produce lactate and export it to neighboring neurons. In this case, lactate would act as a signal to change neuronal excitability and hypothalamic output.
This project will ask the question of whether ANLS is taking place in hypothalamus, by characterizing the cellular and molecular components of this pathway and probe their interactions. If ANLS does not appear to be present in the hypothalamus, we will explore alternative modes of astrocyte to neuron coupling. Ultimately, this project will test for a role of astrocyte-neuron interactions in peripheral metabolite sensing.
This project will rely on experiments done on acute brain slices to record physiological parameters at a cellular resolution in real time with electrophysiology and optical imaging. It will also require performing immunohistochemical labeling on brain tissue. Below is a list of main techniques provided:
• Preparation and use of acute brain slice model
• Dynamic fluorescence imaging (calcium and sodium imaging)
• Whole-cell electrophysiology, extracellular field potential measurements
• Immunohistochemistry on brain slices
• Widefield and confocal fluorescence imaging
• Signal and image processing and analysis
This project asks important --but hardly explored-- questions on the regulation of energy homeostasis by the brain. Considering the high prevalence of the metabolic syndrome (obesity, diabetes) in our societies, the questions addressed by this project are timely and focused on original hypotheses of the brain involvement in food intake and expenditure. Results from these experiments will document anatomical and functional aspects of the astrocyte to neuron coupling related to this physiology in the form of: characterization of cell types and molecular markers, cellular calcium and sodium dynamics, electrophysiological responses, pharmacology of responses. Results will be published as soon as available in international meetings and peer-reviewed papers.
Bernardinelli Y, Magistretti PJ and Chatton J-Y (2004) Astrocytes generate Na+-mediated metabolic waves. Proc. Natl. Acad. Sci. USA 101:14937-14942.
Magistretti PJ, Pellerin L, Rothman DL and Shulman RG (1999) Energy on demand. Science 283:496-497.
Voutsinos-Porche B, Bonvento G, Tanaka K, Steiner P, Welker E, Chatton J-Y, Magistretti PJ and Pellerin L (2003) Glial glutamate transporters mediate a functional metabolic crosstalk between neurons and astrocytes in the mouse developing cortex. Neuron 37:275-286.
Lam TK, Gutierrez-Juarez R, Pocai A and Rossetti L (2005) Regulation of blood glucose by hypothalamic pyruvate metabolism. Science 309:943-947.
Song Z and Routh VH (2005) Differential effects of glucose and lactate on glucosensing neurons in the ventromedial hypothalamic nucleus. Diabetes 54:15-22.
Link to the group web site