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Selectively driving cholinergic fibers optically in the thalamic reticular nucleus promotes sleep.

Ni KM, Hou XJ, Yang CH, Dong P, Li Y, Zhang Y, Jiang P, Berg DK, Duan S, Li XM - Elife (2016)

Bottom Line: It does not affect REM sleep.These findings stand in sharp contrast to previous reports of cholinergic activity driving arousal.Our results provide new insight into the mechanisms controlling sleep.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, China.

ABSTRACT
Cholinergic projections from the basal forebrain and brainstem are thought to play important roles in rapid eye movement (REM) sleep and arousal. Using transgenic mice in which channelrhdopsin-2 is selectively expressed in cholinergic neurons, we show that optical stimulation of cholinergic inputs to the thalamic reticular nucleus (TRN) activates local GABAergic neurons to promote sleep and protect non-rapid eye movement (NREM) sleep. It does not affect REM sleep. Instead, direct activation of cholinergic input to the TRN shortens the time to sleep onset and generates spindle oscillations that correlate with NREM sleep. It does so by evoking excitatory postsynaptic currents via α7-containing nicotinic acetylcholine receptors and inducing bursts of action potentials in local GABAergic neurons. These findings stand in sharp contrast to previous reports of cholinergic activity driving arousal. Our results provide new insight into the mechanisms controlling sleep.

No MeSH data available.


Related in: MedlinePlus

MLA decreased spontaneous sleep in the daytime.(A) EEG and EMG trace during 1 hr in the daytime of Chat-ChR2-Saline and Chat-ChR2-MLA mice. (B) Time spent in the wake, NREM and REM stages for Chat-ChR2-Saline and Chat-ChR2-MLA mice. In vivo injection of MLA could decrease spontaneous activity. All data represent mean ± SEM (n = 6 mice, *p < 0.05, **p < 0.01, two-tailed t-test between ChAT-ChR2-MLA and ChAT-ChR2-Saline mice).DOI:http://dx.doi.org/10.7554/eLife.10382.011
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fig6s1: MLA decreased spontaneous sleep in the daytime.(A) EEG and EMG trace during 1 hr in the daytime of Chat-ChR2-Saline and Chat-ChR2-MLA mice. (B) Time spent in the wake, NREM and REM stages for Chat-ChR2-Saline and Chat-ChR2-MLA mice. In vivo injection of MLA could decrease spontaneous activity. All data represent mean ± SEM (n = 6 mice, *p < 0.05, **p < 0.01, two-tailed t-test between ChAT-ChR2-MLA and ChAT-ChR2-Saline mice).DOI:http://dx.doi.org/10.7554/eLife.10382.011

Mentions: Having found that α7-nAChRs mediate cholinergic input to PV-containing GABAergic neurons in the TRN, we tested whether this same pathway was responsible for cholinergic modulation of sleep onset and sleep protection. Half an hour before stimulation, we injected MLA (1 μl, 100 nM) or saline (1 μl, 0.9% NaCl) locally into the TRN of ChAT-ChR2 mice through a cannula implanted in the brain. The mice were then given optical stimulation (200-ms pulses at 6 s intervals, 1.5 mW blue laser) for 1 hr in the TRN. Quantification of the responses indicated that MLA completely blocked light-evoked changes in latency to sleep onset, total sleep time, and sleep architecture (Figure 6). None of the parameters were significantly different from those of WT-Sti mice. In contrast, the saline-injected mice could still be induced to sleep and showed increased NREM by the activation of cholinergic fibers during the 1 hr stimulation, compared with the ChAT-ChR2-Sti-MLA and WT-Sti groups. To further test MLA on spontaneous sleep, we injected saline and MLA into the TRN of ChAT-ChR2 mice in the daytime, and found that in vivo injection of MLA (the antagonist of α7-nAChRs) significantly decreased spontaneous sleep time from 37.2 ± 4.1 min to 27.3 ± 3.2 min (p < 0.01, Figure 6—figure supplement 1). These results indicate that cholinergic promotion of sleep onset and sleep protection are mediated by activating PV-expressing neurons of the TRN through α7-nAChRs.10.7554/eLife.10382.010Figure 6.MLA blocked the decrease in sleep onset time and the increase in sleep duration induced by cholinergic activation.


Selectively driving cholinergic fibers optically in the thalamic reticular nucleus promotes sleep.

Ni KM, Hou XJ, Yang CH, Dong P, Li Y, Zhang Y, Jiang P, Berg DK, Duan S, Li XM - Elife (2016)

MLA decreased spontaneous sleep in the daytime.(A) EEG and EMG trace during 1 hr in the daytime of Chat-ChR2-Saline and Chat-ChR2-MLA mice. (B) Time spent in the wake, NREM and REM stages for Chat-ChR2-Saline and Chat-ChR2-MLA mice. In vivo injection of MLA could decrease spontaneous activity. All data represent mean ± SEM (n = 6 mice, *p < 0.05, **p < 0.01, two-tailed t-test between ChAT-ChR2-MLA and ChAT-ChR2-Saline mice).DOI:http://dx.doi.org/10.7554/eLife.10382.011
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4764559&req=5

fig6s1: MLA decreased spontaneous sleep in the daytime.(A) EEG and EMG trace during 1 hr in the daytime of Chat-ChR2-Saline and Chat-ChR2-MLA mice. (B) Time spent in the wake, NREM and REM stages for Chat-ChR2-Saline and Chat-ChR2-MLA mice. In vivo injection of MLA could decrease spontaneous activity. All data represent mean ± SEM (n = 6 mice, *p < 0.05, **p < 0.01, two-tailed t-test between ChAT-ChR2-MLA and ChAT-ChR2-Saline mice).DOI:http://dx.doi.org/10.7554/eLife.10382.011
Mentions: Having found that α7-nAChRs mediate cholinergic input to PV-containing GABAergic neurons in the TRN, we tested whether this same pathway was responsible for cholinergic modulation of sleep onset and sleep protection. Half an hour before stimulation, we injected MLA (1 μl, 100 nM) or saline (1 μl, 0.9% NaCl) locally into the TRN of ChAT-ChR2 mice through a cannula implanted in the brain. The mice were then given optical stimulation (200-ms pulses at 6 s intervals, 1.5 mW blue laser) for 1 hr in the TRN. Quantification of the responses indicated that MLA completely blocked light-evoked changes in latency to sleep onset, total sleep time, and sleep architecture (Figure 6). None of the parameters were significantly different from those of WT-Sti mice. In contrast, the saline-injected mice could still be induced to sleep and showed increased NREM by the activation of cholinergic fibers during the 1 hr stimulation, compared with the ChAT-ChR2-Sti-MLA and WT-Sti groups. To further test MLA on spontaneous sleep, we injected saline and MLA into the TRN of ChAT-ChR2 mice in the daytime, and found that in vivo injection of MLA (the antagonist of α7-nAChRs) significantly decreased spontaneous sleep time from 37.2 ± 4.1 min to 27.3 ± 3.2 min (p < 0.01, Figure 6—figure supplement 1). These results indicate that cholinergic promotion of sleep onset and sleep protection are mediated by activating PV-expressing neurons of the TRN through α7-nAChRs.10.7554/eLife.10382.010Figure 6.MLA blocked the decrease in sleep onset time and the increase in sleep duration induced by cholinergic activation.

Bottom Line: It does not affect REM sleep.These findings stand in sharp contrast to previous reports of cholinergic activity driving arousal.Our results provide new insight into the mechanisms controlling sleep.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, China.

ABSTRACT
Cholinergic projections from the basal forebrain and brainstem are thought to play important roles in rapid eye movement (REM) sleep and arousal. Using transgenic mice in which channelrhdopsin-2 is selectively expressed in cholinergic neurons, we show that optical stimulation of cholinergic inputs to the thalamic reticular nucleus (TRN) activates local GABAergic neurons to promote sleep and protect non-rapid eye movement (NREM) sleep. It does not affect REM sleep. Instead, direct activation of cholinergic input to the TRN shortens the time to sleep onset and generates spindle oscillations that correlate with NREM sleep. It does so by evoking excitatory postsynaptic currents via α7-containing nicotinic acetylcholine receptors and inducing bursts of action potentials in local GABAergic neurons. These findings stand in sharp contrast to previous reports of cholinergic activity driving arousal. Our results provide new insight into the mechanisms controlling sleep.

No MeSH data available.


Related in: MedlinePlus