Effects of hypocretin-saporin injections into the medial septum on sleep and hippocampal theta

Neurons containing the peptide hypocretin, also known as orexin, were recen tly implicated in the human sleep disorder narcolepsy. Hypocretin neurons a re located only in the lateral hypothalamus from where they innervate virtu ally the entire brain and spinal cord. This peptide is believed to be invol ved in regulating feeding and wakefulness. However, to fully understand wha t other behaviors are regulated by this peptide it is necessary to investig ate each hypocretin target site. In the present study, we focus on one hypo cretin target site, the medial septum, where there is a dense collection of hypocretin-2 receptor-containing cells, and degenerating axons are present here in canines with narcolepsy [J. Neurosci. 19 (1999) 248]. We utilize a saporin toxin conjugated to the hypocretin receptor binding ligand, hypocr etin-2, and find that when this toxin is injected into the medial septum, i t lesions the parvalbumin and cholinergic neurons. We contrast the effects of the hypocretin-saporin with another saporin conjugated toxin, 192 IgG-sa porin, that lesions only the cholinergic neurons in the basal forebrain. 19 2 IgG-saporin reduced theta activity, a finding consistent with previous re ports [J. Neurophysiol. 79 (1998) 1633; Neurodegeneration 4 (1995) 61; Neur oscience 62 (1994) 1033]. However, hypocretin-saporin completely eliminated hippocampal theta activity by day 12, indicating that parvalbumin-containi ng cells in the medial septum generate theta. The daily amount of sleep and wakefulness were not different between hypocretin-saporin, 192 IgG-saporin , or saline-treated rats. The homeostatic response to 12 h prolonged wakefu lness was also not affected in hypocretin-saporin lesioned rats. These find ings suggest that hypocretin neurons could facilitate theta generation duri ng episodes of purposeful behavior by activating GABAergic neurons in the M S/VDB. In this way, hypocretin, which is implicated in feeding, energy meta bolism and wakefulness, serves to influence cognitive processes critical fo r the animal's survival. (C) 2001 Published by Elsevier Science B.V.