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Thalamic dual control of sleep and wakefulness

Abstract

Slow waves (0.5–4 Hz) predominate in the cortical electroencephalogram during non-rapid eye movement (NREM) sleep in mammals. They reflect the synchronization of large neuronal ensembles alternating between active (UP) and quiescent (Down) states and propagating along the neocortex. The thalamic contribution to cortical UP states and sleep modulation remains unclear. Here we show that spontaneous firing of centromedial thalamus (CMT) neurons in mice is phase-advanced to global cortical UP states and NREM–wake transitions. Tonic optogenetic activation of CMT neurons induces NREM–wake transitions, whereas burst activation mimics UP states in the cingulate cortex and enhances brain-wide synchrony of cortical slow waves during sleep, through a relay in the anterodorsal thalamus. Finally, we demonstrate that CMT and anterodorsal thalamus relay neurons promote sleep recovery. These findings suggest that the tonic and/or burst firing pattern of CMT neurons can modulate brain-wide cortical activity during sleep and provides dual control of sleep–wake states.

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Fig. 1: CMT neuron spiking is phase-advanced to cortical UP states.
Fig. 2: CMT neuron spiking is phase-advanced to sensory thalamus and to sleep–wake transitions.
Fig. 3: Optogenetic activation of CMT, but not VB, neurons entrains cortical UP-like states and induces arousal.
Fig. 4: AD neurons relay CMT-induced UP-like states to posterior cortical areas.
Fig. 5: CMT neuron firing is necessary for cortical UP-state synchrony.
Fig. 6: CMT neuron firing increases synchrony of cortical UP states.
Fig. 7: CMT neuron activity promotes sleep recovery.

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Acknowledgements

We thank the Tidis laboratory members for their technical help and comments on a previous version of the manuscript. We thank M. Mameli, S. Brown, and C. Bassetti for helpful comments on the manuscript. We thank the laboratory of H.-R. Widmer and the M.I.C. UNIBE Facility for the use of the microscopes. Optogenetic plasmids were kindly provided by K. Deisseroth (Stanford University) and E. Boyden (MIT). A.R.A. was supported by the Human Frontier Science Program (RGY0076/2012), Inselspital University Hospital, the University of Bern, Swiss National Science Foundation (156156), and the European Research Council (ERC-2016-COG-725850).

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T.C.G. and A.R.A. conceived the study. T.C.G. and C.G.H. collected the data. T.C.G. and M.B. analyzed the data. A.R.A. supervised the project. All authors wrote the manuscript.

Corresponding author

Correspondence to Antoine R. Adamantidis.

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The authors declare no competing interests.

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Integrated supplementary information

Supplementary Figure 1 Spontaneous sleep–wake cycling of instrumented mice.

a, Percentage of time spent in Wake, NREM and REM ± S.E.M. and b, averaged episode duration ± S.E.M. of non-transduced wild-type mice (white; n = 6 animals), AAV2 injection in CMT (blue; n = 15 animals), AAV2 injection in AD (green; n = 6 animals) and AAV2 injection in both CMT and AD (black; n = 8 animals) during the light period. No significant differences were found between groups (Percentage of time: P = 0.91; Episode duration: P = 0.87; two-way ANOVA) demonstrating that virus transduction in does not alter the spontaneous sleep-wake cycle of the mice. c, Averaged power spectra ± S.E.M. from all animals during wake (left), NREM (middle) and REM (right) with corresponding representative EEG/EMG traces (top; n = 6 animals). Frequency domains of the different behavioral states were consistent with previous reports.

Supplementary Figure 2 Dynamic activity of thalamic neurons during sleep–wake states.

Representative EEG/EMG, CMT and VB neuron spiking activity. Averaged neuronal firing rates ± S.E.M. for CMT (black; n = 8 cells) and VB (red; n = 8 cells; from n = 6 animals) neurons are shown across wake-NREM transitions. Vertical lines (red dashed) indicate the onset of cortical slow waves. Filtered delta oscillations are shown.

Supplementary Figure 3 Efferent targets of excitatory neurons in the CMT.

a, Schematic and representative photomicrograph of expression from injection of AAV2-CamKII-ChR2-EYFP in the CMT of wild-type mice. Images of CING (above) and insular (below) cortices are shown. Note the absence of cell body fluorescence in target regions. Scale bar: 100 µm. b, Quantification of cell expression (mean ± S.E.M.; n = 6 animals; P = 0.0006; one-way ANOVA) c, d, Quantification of fluorescence density (mean ± S.E.M.; n = 6 animals; c) and representative photomicrographs (d) of antero-posterior coronal brain sections from wild-type mice transduced with AAV2-CamKII-ChR2-EYFP. Pictures show the distribution of dense ChR2-EYFP-expressing CMT neuron terminals restricted to the CING and insular areas of the cortex. No other cortical areas were labelled. Subcortical labelling was found in zona incerta, amygdala, nucleus accumbens and striatum.

Supplementary Figure 4 Optical activation of CMT neurons entrains CING but not BARR neurons.

a, Schematic of instrumentation for chronic implantation of multi-site tetrode recordings from CMT, CING, and BARR and optic fiber implants over CMT. AAV2-CamKII-ChR2-EYFP was stereotactically injected into CMT. Note that VIS was not recorded in this preparation. Experiments performed on n = 6 animals. b, Representative photomicrographs showing tracts of electrodes targeting neurons in the CMT (left) and CING (right). Arrows identify the tip of electrode. Scale bar: 200 µm. c, Experimental timeline showing blue optical stimulation trains (blue bar) delivered 10 s after the onset of NREM. d, Representative raster plots, averaged traces ± S.E.M. of CMT (n = 6 cells), CING (n = 6 cells) and BARR (n = 7 cells; from n = 6 animals) neuron spiking activity (black) and LFP voltage (red) during optogenetic activation of CMT neurons. One second trains of 5 ms blue light pulses (blue bars) were used to activate ChR2-EYFP-expressing CMT neurons at 5 Hz (left), 20 Hz (center) or 1 s continuous (right). e, Averaged spike fidelity ± S.E.M. of CMT neurons to 1-s optical stimulation at 5 and 20 Hz (n = 10 cells from n = 7 animals).

Supplementary Figure 5 Optical activation of VB neurons entrains BARR but not CING neurons.

a, Schematic of instrumentation for chronic implantation of multi-site tetrode recordings from VB, CING, and BARR and optic fiber implants over VB. AAV2-CamKII-ChR2-EYFP was stereotactically injected into VB. Note that VIS was not recorded in this preparation. Experiments performed on n = 4 animals. b, Representative photomicrographs showing tracts of electrodes targeting neurons in the VB (left) and BARR (right). Arrows identify the tip of electrode. Scale bar: 200 µm. c, Experimental timeline showing blue optical stimulation trains (blue bar) delivered 10 s after the onset of NREM. d, Representative raster plots, averaged traces ± S.E.M. of VB (n = 8 cells), CING (n = 9 cells) and BARR (n = 9 cells; from n = 4 animals) neuron spiking activity (black) and LFP voltage (red) during optogenetic activation of VB neurons. One second trains of 5 ms blue light pulses (blue bars) were used to activate ChR2-EYFP-expressing CMT neurons at 5 Hz (left), 20 Hz (center) or 1 s continuous (right). e, Averaged spike fidelity ± S.E.M. of VB neurons to 1-s optical stimulation at 5 and 20 Hz (n = 9 cells from n = 4 animals).

Supplementary Figure 6 Efferent targets of excitatory neurons in CING.

a, Schematic and representative photomicrograph of expression from injection of AAV2-CamKII-ChR2-mCherry in the CING of wild-type mice. Scale bar: 200 µm. b, c, Quantification of fluorescence density (mean ± S.E.M.; n = 6 animals) (b) and representative photomicrographs (c) of antero-posterior coronal brain sections from wild-type mice transduced with AAV2-CamKII-ChR2-EYFP. Pictures show the distribution of dense ChR2-mCherry-expressing neuron terminals in the antero-dorsal thalamus (AD). Other projection sites include the lateral thalamus and reticular thalamus, periaqueductal grey and pretectal nucleus.

Supplementary Figure 7 Efferent targets of excitatory neurons in the anterodorsal thalamus.

a, Schematic and representative photomicrograph of expression from injection of AAV2-CamKII-ArchT-EYFP in AD of wild-type mice. Scale bar: 100 µm. b, Quantification of cell expression (mean ± S.E.M.; n = 6 animals; P = 0.008; one-way ANOVA). c, d, Quantification of fluorescence density (mean ± S.E.M.; n = 6 animals; c) and representative photomicrographs (d) of antero-posterior coronal brain sections from wild-type mice transduced with AAV2-CamKII-ArchT-EYFP. Pictures show the distribution of dense ArchT-EYFP-expressing neuron terminals in the CING, CA3 hippocampus nucleus accumbens and visual cortex.

Supplementary Figure 8 Dynamics of thalamic and cortical neurons during sleep.

a, Averaged neuron spike rates ± S.E.M. of CMT (red), CING (blue), AD (yellow), BARR (green) and VIS (orange) neurons across spontaneous sleep-wake states. Note the higher spike rates during REM. b, Averaged interspike-intervals of CMT (red), CING (blue), AD (yellow), BARR (green) and VIS (orange) neurons during NREM. c, Averaged spiking rates at the onset of the cortical UP-states (red dashed line). d, Averaged spike rate lag ± S.E.M. of CMT, CING, AD, BARR and VIS neurons at the onset of the cortical UP-states (red dashed line). (CMT: P = 0.003; CING: P = 0.017; BARR: P = 0.015; one-sided t-test).

Supplementary Figure 9 CING neurons relay CMT-induced UP-like states to AD and VIS.

a, Schematic of instrumentation for chronic implantation of multi-site tetrode recordings from CMT, CING, AD, BARR and VIS and optic fiber implants over CMT and CING. AAV2-CamKII-ChR2-EYFP and AAV2-CamKII-ArchT-EYFP were stereotactically injected into CMT and CING, respectively. b, Experimental timeline showing blue optical activation of UP states (5 ms, 300 ms ON, 100 ms OFF, 10 s duration) in CMT neurons and green optical silencing (3 s) of AD neurons, delivered 10 s after the onset of NREM. c, Averaged traces ± S.E.M. of CMT (n = 6 cells), CING (n = 7 cells), AD (n = 5 cells), BARR (n = 6 cells) and VIS (n = 7 cells; from n = 5 animals) neuron spiking activity (black) and LFP voltage (red) during combinatorial optogenetic experiment. Note the high-fidelity of CMT-induced UP-like states travelling along the CING-AD-VIS pathway and the complete blockade of spike transfer to AD and VIS upon CING silencing (arrow).

Supplementary Figure 10 Optical silencing of AD neuronal firing.

a, Schematic of instrumentation for chronic implantation of multi-site tetrode recordings from AD, BARR and VIS and optic fiber implants over AD (unilateral). AAV2-CamKII-ArchT-EYFP was injected into AD (unilateral). b, Representative photomicrographs showing tracts of electrodes targeting neurons in the AD (left) and VIS (right). Arrows identify the tip of electrode. Scale bar: 200 µm. (n = 6 animals) c, Experimental timeline, 10-s optical silencing of ArchT-EYFP-expressing AD neurons was performed with green light (532 nm) 10 s after the onset of a stable NREM episode. d, Averaged spike rates ± S.E.M. of neurons from AD, BARR and VIS cortical neurons during unilateral optical silencing of ArchT-EYFP-expressing AD neurons (ipsilateral: n = 11 cells; contralateral: n = 9 cells), BARR (ipsilateral: n = 8 cells; contralateral: n = 9 cells) and VIS (ipsilateral: n = 12 cells; contralateral: n = 11 cells from n = 6 animals). Note the absence of neuronal firing in ipsilateral AD during optical silencing and the rebound in cell firing following cessation of optical silencing. e, Averaged NREM episode duration ± S.E.M. upon state-specific optical silencing of ArchT-EYFP-expressing AD neurons. (Nat. vs. Unil.: P = 0.0014; Nat. vs. Bilat.: P = 0.0025; one-sided t-test).

Supplementary Figure 11 Dynamics of thalamic and cortical neurons during recovery sleep.

a, Averaged power ± S.E.M. of LFP signals from CMT (red), CING (blue), AD (yellow), BARR (green) and VIS (orange) during recovery sleep, normalized to power during baseline sleep. Data analyzed in 1 s bins. b, Averaged delta power ± S.E.M. are shown (n = 5 animals for each nucleus; CMT: P = 0.035; CING: P = 0.027; AD: P = 0.034; BARR: P = 0.58; VIS: P = 0.030; two-sided t-test). c, Average slope ± S.E.M. of slow wave recorded during baseline (solid fill) and recovery sleep (open) for CMT (red; P = 0.028), CING (blue; P = 0.019), AD (yellow; P = 0.008), BARR (green; P = 0.037), and VIS (orange; P = 0.011). Note that slopes increased for all recorded nuclei except BARR (n = 5 for each nucleus; two-sided t-test). d, Averaged neuron spiking lag ± S.E.M. from CMT (red; n = 8 cells; P = 0.034; two-sided t-test), CING (blue; n = 7 cells; P = 0.042), AD (yellow; n = 8 cells; P = 0.41), BARR (green; n = 8 cells; P = 0.074) and VIS (orange; n = 9 cells; P = 0.35; n = 5 animals) during baseline NREM (solid fill) and recovery sleep (no fill) at the onset of cortical UP-states (dashed red line).

Supplementary Figure 12 Dynamics of thalamic neurons during recovery sleep.

a, Average neuron spikes and LFP ± S.E.M. of midline thalamic nuclei at the onset of the cortical UP-states (dashed red line) during recovery sleep. The phase advancement of the CMT, and other midline thalamus, is similar between baseline and recovery sleep. (CING: Spike: P = 0.052, LFP: P = 0.061; PVT: Spike: P = 0.14, LFP: P = 0.21; IMD: Spike: P = 0.64, LFP: P = 0.89; CMT: Spike: P = 0.008, LFP: P = 0.001; RHO: Spike: P = 0.001, LFP: P = 0.003; REU: Spike: P = 0.002, LFP: P = 0.004; n= 6 animals; one-sided t-test). b, Averaged slope ± S.E.M. of the slow wave for baseline (solid) and recovery sleep (open) at the onset of cortical UP-states during recovery sleep compared to baseline sleep. (CING: P = 0.031; PVT: P = 0.78; IMD: P = 0.63; CMT: P = 0.007; RHO: P = 0.39; REU: P = 0.44; n= 6 animals; one-sided t-test). c, Averaged neuron spike rates (left) and LFPs (right) of CMT (black; n = 8 cells; n = 6 animals) and VB (red; n = 8 cells; n = 6 animals) neurons at the onset of cortical UP-states during spontaneous NREM (dashed red line). d, Averaged lags ± S.E.M. of neuron spike rates (solid fill) and LFPs (open) from CMT (black; Spike: P = 0.0027, LFP: P = 0.0062; n = 8 cells; n = 6 animals) and VB (red; Spike: P = 0.81, LFP: P = 0.82; n = 8 cells; n = 6 animals; two-sided t-test) areas at the onset of cortical UP-states during NREM. CMT neuron spiking was strongly modulated and advanced to cortical UP-states whereas VB neuron spiking was less modulated and in-phase with the onset of cortical UP-states. e, Average changes in slope ± S.E.M of curve fits for neuron spike (solid) and LFP (open) modulation at the onset of cortical UP-states during recovery sleep compared to baseline sleep for CMT (black; Spike: P = 0.0018, LFP: P = 0.02; n = 8 cells; n = 6 animals) and VB (red; Spike: P = 0.024, LFP: P = 0.045; n = 8 cells; n = 6 animals; one-sided t-test). f, Representative EEG/EMG LFP traces of CMT and VB recorded simultaneously during sleep deprived wakefulness. Note the slow activity in VB, but not CMT or EEG, during wakefulness. g, Averaged power spectra showing frequencies of EEG (grey), CMT (black) and VB (red; n = 6 animals) LFPs of wakefulness during the sleep deprivation procedure. Note the high delta power in VB and the predominating theta in EEG and CMT (n = 4 animals). h, Representative EEG/EMG LFP traces of CMT and VB recorded during normal wakefulness. Note the fast frequency low amplitude activity in VB and CMT. i, Averaged power spectra showing frequencies of EEG (grey), CMT (black) and VB (red) LFPs of normal wakefulness (n = 6 animals).

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Gent, T.C., Bandarabadi, M., Herrera, C.G. et al. Thalamic dual control of sleep and wakefulness. Nat Neurosci 21, 974–984 (2018). https://doi.org/10.1038/s41593-018-0164-7

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