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

Neuroscience. 2007 Aug 10;148(1):34-43. doi: 10.1016/j.neuroscience.2007.05.029. Epub 2007 Jul 6.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Validation Study

MeSH terms

  • Aging / metabolism
  • Animals
  • Animals, Genetically Modified
  • Ataxin-3
  • Disease Models, Animal
  • Female
  • Hypothalamus / metabolism
  • Hypothalamus / physiopathology*
  • Immunohistochemistry
  • Intracellular Signaling Peptides and Proteins / cerebrospinal fluid
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Male
  • Narcolepsy / cerebrospinal fluid
  • Narcolepsy / genetics
  • Narcolepsy / physiopathology*
  • Nerve Degeneration / cerebrospinal fluid
  • Nerve Degeneration / genetics
  • Nerve Degeneration / physiopathology*
  • Nerve Tissue Proteins / genetics
  • Neurons / metabolism*
  • Neuropeptides / cerebrospinal fluid
  • Neuropeptides / genetics*
  • Nuclear Proteins / genetics
  • Orexins
  • Peptides / genetics
  • Peptides / metabolism
  • Promoter Regions, Genetic / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Repressor Proteins / genetics
  • Sleep, REM / genetics
  • Up-Regulation / genetics
  • Wakefulness / genetics

Substances

  • Intracellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • Neuropeptides
  • Nuclear Proteins
  • Orexins
  • Peptides
  • Repressor Proteins
  • polyglutamine
  • ATXN3 protein, human
  • Ataxin-3