The development of hypocretin (OREXIN) deficiency in hypocretin/ataxin-3 transgenic rats

S. Zhang, L. Lin, S. Kaur, S. Thankachan, C. Blanco-Centurion, M. Yanagisawa, E. Mignot, P. J. Shiromani

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Narcolepsy is linked to a widespread loss of neurons containing the neuropeptide hypocretin (HCRT), also named orexin. A transgenic (TG) rat model has been developed to mimic the neuronal loss found in narcoleptic humans. In these rats, HCRT neurons gradually die as a result of the expression of a poly-glutamine repeat under the control of the HCRT promoter. To better characterize the changes in HCRT-1 levels in response to the gradual HCRT neuronal loss cerebrospinal fluid (CSF) HCRT-1 levels were measured in various age groups (2-82 weeks) of wild-type (WT) and TG Sprague-Dawley rats. TG rats showed a sharp decline in CSF HCRT-1 level at week 4 with levels remaining consistently low (26%±9%, mean±S.D.) thereafter compared with WT rats. In TG rats, HCRT-1 levels were dramatically lower in target regions such as the cortex and brainstem (100-fold), indicating decreased HCRT-1 levels at terminals. In TG rats, CSF HCRT-1 levels significantly increased in response to 6 h of prolonged waking, indicating that the remaining HCRT neurons can be stimulated to release more neuropeptide. Rapid eye movement (REM) sleep in TG rats (n=5) was consistent with a HCRT deficiency. In TG rats HCRT immunoreactive (HCRT-ir) neurons were present in the lateral hypothalamus (LH), even in old rats (24 months) but some HCRT-ir somata were in various stages of disintegration. The low output of these neurons is consistent with a widespread dysfunction of these neurons, and establishes this model as a tool to investigate the consequences of partial hypocretin deficiency.

Original languageEnglish (US)
Pages (from-to)34-43
Number of pages10
JournalNeuroscience
Volume148
Issue number1
DOIs
StatePublished - Aug 10 2007

Keywords

  • REM sleep
  • ataxin
  • hypocretin
  • hypothalamus
  • narcolepsy
  • sleep

ASJC Scopus subject areas

  • Neuroscience(all)

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    Zhang, S., Lin, L., Kaur, S., Thankachan, S., Blanco-Centurion, C., Yanagisawa, M., Mignot, E., & Shiromani, P. J. (2007). The development of hypocretin (OREXIN) deficiency in hypocretin/ataxin-3 transgenic rats. Neuroscience, 148(1), 34-43. https://doi.org/10.1016/j.neuroscience.2007.05.029