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The Journal of Neuroscience, September 15, 2001, 21(18):7273-7283
Hypocretin-2-Saporin Lesions of the Lateral Hypothalamus Produce Narcoleptic-Like Sleep Behavior in the Rat
Dmitry Gerashchenko1, Matthew D. Kohls4, MaryAnn Greco1, Nahid S. Waleh3, Rafael Salin-Pascual1, 2, Thomas S. Kilduff3, Douglas A. Lappi4, and Priyattam J. Shiromani1 1 West Roxbury Veterans Affairs Medical Center and Harvard Medical School, West Roxbury, Massachusetts 02132, 2 Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico 04510, 3 SRI International, Menlo Park, California 94025, and 4 Advanced Targeting Systems, San Diego, California 92121
Hypocretins (Hcrts) are recently discovered peptides linked to the human sleep disorder narcolepsy. Humans with narcolepsy have decreased numbers of Hcrt neurons and Hcrt-null mice also have narcoleptic symptoms. Hcrt neurons are located only in the lateral hypothalamus (LH) but neither electrolytic nor pharmacological lesions of this or any other brain region have produced narcoleptic-like sleep, suggesting that specific neurons need to be destroyed. Hcrt neurons express the Hcrt receptor, and to facilitate lesioning these neurons, the endogenous ligand hypocretin-2/orexin B (Hcrt2) was conjugated to the ribosome-inactivating protein saporin (SAP). In vitro binding studies indicated specificity of the Hcrt2-SAP because it preferentially bound to Chinese hamster ovary cells containing the Hcrt/orexin receptor 2 (HcrtR2/OX2R) or the Hcrt/orexin receptor 1 (HcrtR1/OX1R) but not to Kirsten murine sarcoma virus transformed rat kidney epithelial (KNRK) cells stably transfected with the substance P (neurokinin-1) receptor. Administration of the toxin to the LH, in which the receptor is known to be present, eliminated some neurons (Hcrt, melanin-concentrating hormone, and adenosine deaminase-containing neurons) but not others (a-melanocyte-stimulating hormone), indicating specificity of the toxin in vivo. When the toxin was administered to the LH, rats had increased slow-wave sleep, rapid-eye movement (REM) sleep, and sleep-onset REM sleep periods. These behavioral changes were negatively correlated with the loss of Hcrt-containing neurons but not with the loss of adenosine deaminase-immunoreactive neurons. These findings indicate that damage to the LH that also causes a substantial loss of Hcrt neurons is likely to produce the multiple sleep disturbances that occur in narcolepsy.
Key words: hypothalamus; peptides; lesion; sleep; REM sleep; circadian rhythm
Copyright © 2001 Society for Neuroscience 0270-6474/01/21187273-11$05.00/0
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