Behavioural neuroscienceThe development of hypocretin (OREXIN) deficiency in hypocretin/ataxin-3 transgenic rats
Section snippets
Animals
The TG rats are derived from the Sprague–Dawley strain. Two independent groups of rats were used in the present study, one maintained at the West Roxbury VA hospital and the other at Stanford University. However, both groups of rats were derived from rats obtained from the original colony in University of Texas Southwestern Medical Center, Dallas, TX, USA (Beuckmann et al., 2004). Genotype analysis of tail snips was used to confirm that the ataxin-3 transgene was present. Since the previous
Age-related changes in CSF and brain tissues
Fig. 1 summarizes the age-related changes in HCRT-1 level in CSF and brain tissues in WT and TG rats. Fig. 1A shows the CSF HCRT-1 levels in each rat. In WT rats, CSF HCRT-1 was detectable at 2 weeks, when the samples could be reliably collected. CSF HCRT-1 then increased gradually over the next few weeks to reach a stable level at week 5. In contrast, HCRT-1 levels in TG rats continuously decreased from week 2 to week 4, to stabilize at a low level after the fourth week. This decrease was
Discussion
The primary finding of this study is that the TG rats, which represent a rat model of the HCRT neuronal degeneration seen in human narcolepsy, have a 74% decline in CSF levels of HCRT-1. The TG rats showed a significant and precipitous decline in CSF HCRT-1 levels around 4 weeks of age, consistent with a previous study reporting cell death during this developmental period (Beuckmann et al., 2004). In the TG rats HCRT neurons were evident even in old (60–124 weeks) rats, but the rich axonal and
Acknowledgments
We thank Suraiya Begum for providing technical assistance, E. Winston for analyzing the sleep data, and Shelley Dixon for expert managerial assistance. Supported by NIH grants NS30140, NS52287, MH55772, MH01600, NS23724, MH073435 and Medical Research Service of the Department of Veterans Affairs. E.M. and M.Y. are HHMI investigators.
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