The adverse effects of sleep problems in humans manifest themselves in many ways. Sleep deprivation causes slower response times, reduced learning acquisition in cognitive tasks, loss of situational awareness, and involuntary bouts of microsleeps (Durmer et al, 2005). Moreover, patients with chronic sleep disturbances have significantly worse memory consolidation overnight as compared to control subjects (Backhaus et al, 2006). Using positron emission tomography, Riemann et al (2007) found that hippocampus volume is substantially larger in good sleepers as compared to patients with primary insomnia. Given that the 20% of adults are estimated to have insufficient sleep (Durmer et al, 2005), there is an urgent need to understand the neurophysiology of the situation. One consistent finding from rodent models is that sleep deprivation of longer than 24 hours reduces neurogenesis in the dentate gyrus (DG) of the hippocampus, mainly as a function of decreased REM sleep (Guzman-Marin et al, 2008). A mechanism for this attenuation, if found, could yield insight into developing treatments to reduce the adverse effects of sleep deprivation in humans. One potential pathway is a change in the level of glucocorticoids, high levels of which have been associated with decreased neurogenesis (Cameron et al, 1999). Mirescu et al (2006) propose that sleep deprivation inhibits neurogenesis because of its effects as a general stressor on stress hormone levels. This paper will critically evaluate this claim in light of recent developments and propose a framework for further research.
It is well documented across species and across stressors that increased levels of stress decreases neurogenesis in the DG, and there is good reason to suspect that glococorticoids such as corticosterone (CORT) are involved (Mirescu and Gould, 2006). If stress is the sole reason for diminished neurogenesis and increased CORT is the neurophysiological consequences of stress, then rodents with controlled CORT levels will not show the normal decreased neurogenesis following sleep deprivation. By using adrenalectomized (ADX) rats and controlling their intake of CORT with drinking water, Mirescu’s team was able to test this prediction. They measured CORT levels with radioimmunassay at the time of death, which was seven hours into the light cycle, and they measured the amount of newly differentiated cells in the DG by injecting BrdU. They found no significant difference in CORT levels at the time of death between control and sleep deprived ADX rats, implying that their attempt to normalize glucocorticoid levels in sleep deprived animals was successful. Additionally, they found that normal rats had significantly fewer newly differentiated cells in the DG following sleep deprivation but that the ADX+CORT sleep deprived rats had similar amounts to those of controls. On the basis of these results, Mirescu et al concluded that the stressful nature of sleep deprivation is what accounts for the suppression of neurogenesis.
Since its publication, this conclusion has been called into question on a number of fronts. Guzman-Marin et al (2007) used a sleep fragmentation method that results in suppression of REM sleep without inducing elevations in CORT levels, because it does not require postural support. They tested for the effects of ADX with CORT replacement on the suppression of neurogenesis and found that ADX and intact rats had similar reductions in neurogenesis as compared to control rats of the same type, contra Mirescu et al. Mueller et al (2008) used subcutaneous minipumps to normalize CORT levels in ADX rats, and also found that sleep deprivation inhibits neurogenesis independently of stress hormone levels. Methodologically, they noted that CORT intake is 70-80% nocturnal and that the half life of blood CORT is less than 30 minutes, so a single blood sample drawn 7 hours after the lights were turned on is unlikely to be representative of actual group differences in CORT levels. Mueller et al then measured the levels of CORT twice daily in sleep deprived ADX rats receiving CORT normalization via either the minipump or drinking water. They found a 60% decrease of CORT levels in sleep deprived rats receiving CORT via the drinking water, but no difference in CORT levels of rats receiving via the minipump. This suppression of CORT levels in rats given CORT with drinking water can account for Mirescu et al’s results, because the reduction in stress hormone levels could upregulate neurogenesis by enough to offset the decrease in neurogenesis due to sleep deprivation.
Given the preponderance of evidence against their results, there is reason to doubt the conclusion of Mirescu et al that sleep deprivation causes diminished neurogenesis through its action as a simple stressor. It is possible and indeed likely that, to the extent that sleep deprivation is stressful, changes in the level of stress hormones contribute to a downregulation of neurogenesis in the DG, but they are not the only reason for the change. The primacy of behavioral paradigm over changes in the level of stress hormones is similar to the contradictory findings that enriched environments simultaneously enhance neurogenesis and increase glucocorticoid levels in rats. Mirescu and Gould (2006) propose that the positive influence of the enriched environment must override the negative effect of elevated glucocorticoids on neurogenesis. Likewise, in the sleep deprivation paradigm described here, the attenuation of neurogenesis through the behavioral change of sleep deprivation is not eliminated by normalizing CORT levels. The stress hormone system is complex and it is difficult to parse out the effects of glucocorticoids from the various behavioral paradigms they are associated with. One possibility is that the effects of stress hormones are so intricately associated with the brain region in which they are released that overall levels of stress hormones in the blood is not a good measure of their action. As for the actual mechanism driving the reduction in neurogenesis following extended sleep deprivation, more trial-and-error research will be necessary to pinpoint the cause, which may never be adequately explained by one isolated system.
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