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. 2006 Dec 12;103(50):19170-5.
doi: 10.1073/pnas.0608644103. Epub 2006 Nov 29.

Sleep Deprivation Inhibits Adult Neurogenesis in the Hippocampus by Elevating Glucocorticoids

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Free PMC article

Sleep Deprivation Inhibits Adult Neurogenesis in the Hippocampus by Elevating Glucocorticoids

Christian Mirescu et al. Proc Natl Acad Sci U S A. .
Free PMC article

Abstract

Prolonged sleep deprivation is stressful and has been associated with adverse consequences for health and cognitive performance. Here, we show that sleep deprivation inhibits adult neurogenesis at a time when circulating levels of corticosterone are elevated. Moreover, clamping levels of this hormone prevents the sleep deprivation-induced reduction of cell proliferation. The recovery of normal levels of adult neurogenesis after chronic sleep deprivation occurs over a 2-wk period and involves a temporary increase in new neuron formation. This compensatory increase is dissociated from glucocorticoid levels as well as from the restoration of normal sleep patterns. Collectively, these findings suggest that, although sleep deprivation inhibits adult neurogenesis by acting as a stressor, its compensatory aftereffects involve glucocorticoid-independent factors.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Reduced cell proliferation and adult neurogenesis after prolonged SP exposure. Rats subjected to 72 h of SP, LP, or CC received a single injection of BrdU (200 mg/kg, i.p.) and were perfused 2 h, 1 wk, or 3 wk thereafter. Compared with CC and LP rats, SP rats had fewer numbers of BrdU-positive cells in the subgranular zone/GCL at 2 h (SP, n = 5; LP, n = 4; CC, n = 5). At 1 wk, significantly lower numbers of BrdU-positive cells were found in SP (n = 6), relative to CC (n = 7) and LP (n = 5) rats. By 3 wk, fewer BrdU-labeled cells were evident after SP exposure (n = 6), compared with LP (n = 6) but not CC (n = 4) rats. Error bars indicate the SEM; ∗, P < 0.05, SP vs. CC, LP; ♦, P < 0.05, SP vs. LP.
Fig. 2.
Fig. 2.
Sleep deprivation-induced reduction and subsequent increase in cell proliferation and adult neurogenesis. (A and B) Compared with CC rats (A), stereological estimates of BrdU-labeled cells in the GCL revealed a reduction in cell counts in SP rats (B) 2 h after BrdU administration. (C and D) In contrast, after 1 wk of unrestricted recovery from prolonged sleep deprivation, BrdU cell counts in SP rats (D) were significantly increased compared with CC rats (C). (E and F) By 1 wk after BrdU administration, the majority of BrdU-positive cells showed morphological characteristics of granule cells and were colabeled with TuJ1 (E), a marker of immature and mature neurons. By 3 wk after BrdU administration, most BrdU-positive cells were also colabeled with NeuN (F), a marker of mature neuronal phenotype. (Scale bars: AD, 40 μm; E and F, 20 μm.)
Fig. 3.
Fig. 3.
Elevated CORT levels after prolonged SP exposure. To identify whether changes in CORT levels emerge after acute or prolonged sleep deprivation, blood was collected from animals exposed to LP or SP for 24 h (LP24 h, n = 6; SP24 h, n = 6) and 72 h (LP72 h, n = 6; SP72 h, n = 6), as well as from CC animals (n = 8). Compared with all other groups, animals subjected to 72 h of SP exposure exhibited increased levels of CORT. Error bars indicate SEM; ∗, P < 0.05 compared with control.
Fig. 4.
Fig. 4.
Prevention of sleep deprivation-associated reduction of cell proliferation by CORT normalization. Adult rats underwent bilateral surgical removal of the adrenal glands (ADX) or were Sham-operated. All ADX-treated rats were given drinking water containing CORT (25 μg/ml in 0.9% saline). One week after surgery, ADX and Sham rats either remained as controls (Sham/CC, n = 5; ADX+CORT/CC, n = 5) or were exposed to 72 h on SPs (Sham/SP, n = 7; ADX+CORT/SP, n = 4). Thereafter, all rats received a single injection of BrdU (200 mg/kg, i.p.) and were perfused 2 h later. The suppression of cell proliferation normally associated with extended sleep loss was observed in Sham/SP but not ADX+CORT/SP rats; that is, fewer BrdU-labeled cells were observed in Sham/SP rats compared with all other groups. Error bars indicate SEM; ∗, P < 0.05 compared with control.
Fig. 5.
Fig. 5.
Lasting effects of prolonged sleep deprivation on cell proliferation and adult neurogenesis. Rats that were either subjected to 72 h of sleep deprivation by SP exposure (SP) or maintained as controls (CC) received a single injection of BrdU (200 mg/kg, i.p.) 6 h, 1 wk, or 2 wk later. Rats were then perfused at the 2-h (Upper) or 1-wk (Lower) survival periods to examine changes in cell proliferation and adult neurogenesis, respectively (n = 4–8). SP rats exhibited reduced cell proliferation but no effect on adult neurogenesis 6 h after unrestricted sleep recovery. In contrast, after 1 wk of recovery, both cell proliferation and adult neurogenesis were enhanced in SP animals. By 2 wk of recovery, no difference in neurogenesis was observed. Error bars indicate SEM; ∗, P < 0.05 compared with control. For purposes of comparison, BrdU-labeled cell counts for the 0-h recovery time from Fig. 1 are also presented here.
Fig. 6.
Fig. 6.
Sustained overshoot of cell proliferation after sleep deprivation despite CORT normalization. Adult rats underwent bilateral surgical removal of the adrenal glands (ADX) or were Sham-operated. All ADX-treated rats were given drinking water containing CORT (25 μg/ml in 0.9% saline). One week after surgery, ADX and Sham rats either remained as controls (Sham/CC, n = 4; ADX+CORT/CC, n = 6) or were exposed to 72 h on SPs (Sham/SP, n = 4; ADX+CORT/SP, n = 6). One week later, all rats received a single injection of BrdU (200 mg/kg, i.p.) and were perfused 2 h later. A delayed enhancement of cell proliferation after extended sleep loss was observed in both Sham and ADX+CORT animals. Error bars indicate SEM; ∗, P < 0.05.

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