title: ATP-sensitive potassium channel-mediated lactate effect on orexin neurons: implications for brain energetics during arousal.
abstract: Active neurons have a high demand for energy substrate, which is thought to be mainly supplied as lactate by astrocytes. Heavy lactate dependence of neuronal activity suggests that there may be a mechanism that detects and controls lactate levels and/or gates brain activation accordingly. Here, we demonstrate that orexin neurons can behave as such lactate sensors. Using acute brain slice preparations and patch-clamp techniques, we show that the monocarboxylate transporter blocker alpha-cyano-4-hydroxycinnamate (4-CIN) inhibits the spontaneous activity of orexin neurons despite the presence of extracellular glucose. Furthermore, fluoroacetate, a glial toxin, inhibits orexin neurons in the presence of glucose but not lactate. Thus, orexin neurons specifically use astrocyte-derived lactate. The effect of lactate on firing activity is concentration dependent, an essential characteristic of lactate sensors. Furthermore, lactate disinhibits and sensitizes these neurons for subsequent excitation. 4-CIN has no effect on the activity of some arcuate neurons, indicating that lactate dependency is not universal. Orexin neurons show an indirect concentration-dependent sensitivity to glucose below 1 mm, responding by hyperpolarization, which is mediated by ATP-sensitive potassium channels composed of Kir6.1 and SUR1 subunits. In conclusion, our study suggests that lactate is a critical energy substrate and a regulator of the orexin system. Together with the known effects of orexins in inducing arousal, food intake, and hepatic glucose production, as well as lactate release from astrocytes in response to neuronal activity, our study suggests that orexin neurons play an integral part in balancing brain activity and energy supply.
authors.affiliation: Division of BioMedical Sciences, Faculty of Medicine, Memorial University, St. John's, Newfoundland and Labrador A1B 3V6, Canada.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Parsons
authors.forename: Michiru
authors.initials: M
authors.lastname: Hirasawa
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D003373:Coumaric Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005463:Fluoroacetates / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007031:Hypothalamus / Q000166:cytology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007476:Ionophores / Q000494:pharmacology; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D019344:Lactic Acid / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D000068797:Orexins; D018408:Patch-Clamp Techniques / Q000379:methods; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D003373:Coumaric Acids; D005463:Fluoroacetates; D007004:Hypoglycemic Agents; D047908:Intracellular Signaling Peptides and Proteins; D007476:Ionophores; D054086:KATP Channels; D009479:Neuropeptides; D000068797:Orexins; D026941:Sodium Channel Blockers; C007175:alpha-cyano-4-hydroxycinnamate; D019344:Lactic Acid; D013779:Tetrodotoxin; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D005947:Glucose; D005905:Glyburide