Relationship between CSF hypocretin levels and hypocretin neuronal loss

The sleep disorder narcolepsy may now be considered a neurodegenerative disease, as there is a massive reduction in the number of neurons containing the neuropeptide, hypocretin (HCRT). Most narcoleptic patients have low to negligible levels of HCRT in the cerebrospinal fluid (CSF), and such measurements serve as an important diagnostic tool. However, the relationship between HCRT neurons and HCRT levels in CSF in human narcoleptics is not known and cannot be directly assessed. To identify this relationship in the present study, the neurotoxin, hypocretin-2-saporin (HCRT2-SAP), was administered to the lateral hypothalamus (LH) to lesion HCRT neurons. CSF was extracted at circadian times (ZT) 0 (time of lights-on) or ZT8 at various intervals (2, 4, 6, 12, 21, 36, 60 days) after neurotoxin administration. Compared to animals given saline in the LH, rats with an average loss of 73% of HCRT neurons had a 50% decline in CSF HCRT levels on day 60. The decline in HCRT levels was evident by day 6 and there was no recovery or further decrease. The decline in HCRT was correlated with increased REM sleep. Lesioned rats that were kept awake for 6 h were not able to release HCRT to match the output of saline rats. As most human narcoleptics have more than 80% reduction of CSF HCRT, the results from this study lead us to conclude that in these patients, virtually all of the HCRT neurons might be lost. In those narcoleptics where CSF levels are within the normal range, it is possible that not all of the HCRT neurons are lost and that the surviving HCRT neurons might be increasing output of CSF HCRT.