ANR Multimodel – Task 2 – Modélisation du couplage neuro-glio-vasculaire : Un premier modèle simple

Justifications des hypothèses RESUME - Une région du cerveau (d'un organe en général) peut être Productrice OU Consommatrice de Lactate [Orban 2010], il y a donc un switch - Ce switch est l'acide ascorbique qui est relié au glutamate [Castro09R] - Ce switch va également faire le distingo entre glycolyse aérobique et anaérobique pour les neurones (glycolyse forcément anaérobique pour les astrocytes) Sur le sens du transport en Lactate [Orban 2010] Régions (d’un organe, entre organes) productrices OU consommatrices de Lactate  Hypothèses ANLS et NALS controversées peuvent être reliées Le lien = Le glutamate via l’acide ascorbique [Castro 2009R] Ascorbic acid stimulated by glutamate, ascorbic acid inhibits Glucose use and stimulates Lactate use in neurons Donc [Glu]E increase  (ascorbic acid release from astrocytes  ) NALS hypothesis becomes ANLS hypothesis Changement d’hypothèse en pratique Lac production by neurons (NALS)  Lac consumption by neurones (ANLS) inhibition of Glucose uptake by neurons [Lac]E dégagé dans le sang  [Lac]V extrait du sang Ce que cela implique au niveau de la glycolyse Consommation de lactate = réoxydation en pyruvate Production de lactate : Anaérobie = Glc  Lac, aérobie = Glc  Pyr  Lac [Lin10a] Third, the two metabolic pathways (oxidative and non-oxidative) are co-existent, dissociable, and serve different purposes in maintaining neuronal functions during visual stimulation. [Vaishnavi10] These striking regional variations in aerobic glycolysis in the normal human brain provide an opportunity to explore how brain systems differentially use the diverse cell biology of glucose in support of their functional specializations in health and disease. [Takata04] switching from anaerobic to aerobic glycolysis = response to Ca2+ flux = distinct roles (switch may depend on NMDA) [Zwingmann03] In astrocytes, glucose is utilized predominantly anaerobically. Glycolysis is interrelated to the astrocytic TCA cycle via bi-directional signals and metabolic exchange processes between astrocytes and neurons. Besides glucose oxidation, neuronally released glutamate is metabolized through the glial TCA cycle. The flexibility of glutamate metabolism, depending on ammonia and energy homeostasis, and the discovered pyruvate recycling pathway in astrocytes, modulates the glutamine–glutamate cycle.

Modèle NGV initial : changement NALS … (neurones producteurs de Lac) Main cells compartment 1 1 PPSEpyr PPSIpyr Relations vert  rouge: activation fct ([Glu]E) 6 Ox. processes 2 7 8 ATP 13 9 ana. 10 Anaerobic glycolysis in neurons when O2 falls (threshold) on considere pour l’instant que O2 en quantité partout FRpyr [Glc]NE [pyr]NE [Lac]NE ana. Apport via Glu-Gln cycle 15 14 [Glu]N [Glu]E Recup pour GABA shunt 15 19 16 MCT2 GLUT3 17 MCT1 Extracellular space [Lac]E [Lac]V [Glu]E 18 [Glc]E [Glc]V GLUT1 (55k) MCT1,4 GLUT1 (45k) Ox. Processes = pyr dehydrogenase + krebs via acetyl-CoA + Ox. Phosphorylation 17 pumpA 16 20 [Glc]A Apport via GABA shunt 18 12 21 [Glu]A [pyr]A [Glc]A 19 ana. 11 temporary Glycogen stock ana. Recup pour Glu-Gln cycle [Lac]A Vascular compartment Astrocytes compartment

Modèle NGV initial : … vers ANLS (neurones consommateurs de Lac) 1 Main cells compartment PPSIpyr 1 PPSEpyr 6 Questions modélisation : activation ANLS, GlcE vers GlcA rapide  GlcE diminue  moins pour GlcNE GlcV vers GlcA non représenté donc pas de représentation pour GlcE diminue et rerempli par astrocytes plus loin (gap-junction) ou apport direct from blood Ox. processes 8 2 ATP 13 + 7 O2 10 FRpyr 14 [pyr]NE [Glc]NE [Lac]NE ana. Apport via Glu-Gln cycle 15 14 [Glu]N [Glu]E Recup pour GABA shunt - pumpN 19 15 16 MCT2 GLUT3 MCT1 17 Extracellular space [Lac]E [Lac]V [Glu]E 18 [Glc]E [Glc]V GLUT1 (55k) MCT1,4 GLUT1 (45k) 17 pumpA 16 + 20 [Glc]A 12 Apport via GABA shunt 18 21 [Glu]A [pyr]A [Glc]A + 19 ana. 11 temporary Glycogen stock + ana. Recup pour Glu-Gln cycle [Lac]A Vascular compartment Astrocytes compartment

Ajout des interneurones = ajout GABA shunt Main cells compartment Interneurons compartment [GABA]N pumpN [Glu]N [GABA]E Extracellular space + Réplication glycolysis (relations interneurons/extracell space) + Relations interneurons/main cells n°3 FRpyr  PPSEint n°4 PPSEint  FRint n°5 FRint  PPSIpyr [GABA]A Recup GABA shunt via TCA cycle 18 [Glu]A Astrocytes compartment

Astrocytes compartment Respiration Main cells compartment [CO2]NI [CO2]E [CO2]NE Ox. Processes + from Lac to Pyr when ANLS Ox. Processes + from Lac to Pyr when ANLS 13,14 [O2]NI [O2]E [O2]NE FR FR Interneurons compartment Extracellular space [O2]V [CO2]E [CO2]V [O2]A [CO2]A TCA Astrocytes compartment Vascular compartment

Relations Neurones-Vaisseaux Vascular compartment PPSEpyr FRint FRpyr Only functional hyperemia PPSIpyr PPSEint Couplage à définir [travaux Nicole] BP Fin Fout Vv(=HbT) [Lac]V [O2]V dHb [Glc]V