Orexin (hypocretin)/dynorphin neurons control GABAergic inputs to tuberomammillary neurons.
High activity of the histaminergic neurons in the tuberomammillary (TM) nucleus increases wakefulness, and their firing rate is highest during waking and lowest during rapid eye movement sleep. The TM neurons receive a prominent innervation from sleep-active gamma-aminobutyric acidergic (GABAergic) neurons in the ventrolateral preoptic nucleus, which inhibits them during sleep. They also receive an excitatory input from the orexin- and dynorphin-containing neurons in the lateral hypothalamus, which are critically involved in sleep regulation and whose dysfunction causes narcolepsy. We have used intracellular recordings and immunohistochemistry to study if orexin neurons exert control over the GABAergic inputs to TM neurons in rat hypothalamic slices. Dynorphin suppressed GABAergic inputs and thus disinhibits the TM neurons, acting in concert with orexin to increase the excitability of these neurons. In contrast, both orexin-A and orexin-B markedly increased the frequency of GABAergic potentials, while co-application of orexin and dynorphin produced responses similar to dynorphin alone. Thus, orexins excite TM neurons directly and by disinhibition, gated by dynorphin. These data might explain some of the neuropathology of narcolepsy.
Eriksson
Krister S
KS
Department of Neurophysiology, Heinrich-Heine-University Düsseldorf, Germany. kristere@stanford.edu
Sergeeva
Olga A
OA
Selbach
Oliver
O
Haas
Helmut L
HL
D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D004399:Dynorphins / Q000502:physiology*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D007026:Hypothalamic Area, Lateral / Q000187:drug effects / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009479:Neuropeptides / Q000502:physiology*; D000068797:Orexins; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D005680:gamma-Aminobutyric Acid; D004399:Dynorphins