Cerebrospinal Fluid Hypocretin-1 (Orexin-A) Level Fluctuates with Season and Correlates with Day Length

Abstract

The hypocretin/orexin neuropeptides (hcrt) are key players in the control of sleep and wakefulness evidenced by the fact that lack of hcrt leads to the sleep disorder Narcolepsy Type 1. Sleep disturbances are common in mood disorders, and hcrt has been suggested to be poorly regulated in depressed subjects. To study seasonal variation in hcrt levels, we obtained data on hcrt-1 levels in the cerebrospinal fluid (CSF) from 227 human individuals evaluated for central hypersomnias at a Danish sleep center. The samples were taken over a 4 year timespan, and obtained in the morning hours, thus avoiding impact of the diurnal hcrt variation. Hcrt-1 concentration was determined in a standardized radioimmunoassay. Using biometric data and sleep parameters, a multivariate regression analysis was performed. We found that the average monthly CSF hcrt-1 levels varied significantly across the seasons following a sine wave with its peak in the summer (June—July). The amplitude was 19.9 pg hcrt/mL [12.8–26.9] corresponding to a 10.6% increase in midsummer compared to winter. Factors found to significantly predict the hcrt-1 values were day length, presence of snow, and proximity to the Christmas holiday season. The hcrt-1 values from January were much higher than predicted from the model, suggestive of additional factors influencing the CSF hcrt-1 levels such as social interaction. This study provides evidence that human CSF hcrt-1 levels vary with season, correlating with day length. This finding could have implications for the understanding of winter tiredness, fatigue, and seasonal affective disorder. This is the first time a seasonal variation of hcrt-1 levels has been shown, demonstrating that the hcrt system is, like other neurotransmitter systems, subjected to long term modulation.

Seasonal affective disorder, winter type: current insights and treatment options

“…In a Danish study on 227 subjects suffering from hypersomnia, a seasonal variation in hcrt was found in cerebrospinal fluid, correlating with day length. This finding might be helpful in the understanding of a physiological basis for fatigue in wintertime or SAD 41. The preliminary conclusion of a small study on SAD patients is that it is possible to find useful biomarkers with gene expression in white blood cells 42.…”

Hypocretin/orexin modulates body weight and the metabolism of glucose and insulin

“…29 Orexin-A has been detected in the cerebrospinal fluid (CSF) and was shown to fluctuate with seasons and the time of the day when measured by radioimmunoassay in a group of Danish subjects. 35 The CSF content of orexins has been used as a diagnostic tool in many conditions related to sleep disorder and or arousal. 36 In addition to the CSF, orexins have been detected in the serum as well.…”

Fatigue in multiple sclerosis – Insights into evaluation and management

“…Such a correlation was absent in the work of Constantinescu et al The remarkable difference in both studies could be attributed to some facts. For instance, orexin-A levels are influenced by day length and seasonal fluctuations [14]; hence, there is a good probability that both trials did not take place in the same season or daytime. Also, methodological difference in measuring orexin-A level might be partly responsible for such an incongruity.…”