Abstract
During sleep and awake rest, the neocortex generates large-scale slow-wave (SW) activity. Here, we report that the claustrum coordinates neocortical SW generation. We established a transgenic mouse line that enabled the genetic interrogation of a subpopulation of claustral glutamatergic neurons. These neurons received inputs from and sent outputs to widespread neocortical areas. The claustral neuronal firings mostly correlated with cortical SW activity. In vitro optogenetic stimulation of the claustrum induced excitatory postsynaptic responses in most neocortical neurons, but elicited action potentials primarily in inhibitory interneurons. In vivo optogenetic stimulation induced a synchronized down-state featuring prolonged silencing of neural activity in all layers of many cortical areas, followed by a down-to-up state transition. In contrast, genetic ablation of claustral neurons attenuated SW activity in the frontal cortex. These results demonstrate a crucial role of claustral neurons in synchronizing inhibitory interneurons across wide cortical areas for the spatiotemporal coordination of SW activity.
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Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Code availability
The custom-written analysis code is available from the corresponding author upon reasonable request.
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Acknowledgements
We thank S. Tonegawa for valuable comments; C. Yokoyama for critical reading of the manuscript; H. Hioki (Juntendo University), J. Sohn and S. Okamoto (Kyoto University) for PV/myrGFP-LDLRct transgenic mice; I. R. Wickersham (MIT), H. S. Seung (Princeton University) and E. M. Callaway (Salk Institute) for modified rabies virus; K. Deisserroth (Stanford University) and E. S. Boyden (MIT) for AAV plasmids; S. Amemiya for help in statistical analyses; S. Mitsui, Y. Mishima and RIKEN CBS Research Resources Division for technical assistance; and members of the Yoshihara Lab for discussion. This work was supported by research funds from RIKEN to Y.Y., grants-in-aid for Scientific Research on Innovative Areas ‘Memory Dynamism’ (25115005) and ‘Brain Information Dynamics’ (18H05146) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and a grant from the Uehara Memorial Foundation to Y.Y.
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K.N., R.M., A.A. and Y.Y. conceived the study. Y.Y. developed the Cla-Cre mouse. R.M., M.S., H.H., J.P.J. and Y.Y. performed the anatomical experiments. A.A. performed the in vitro electrophysiological experiments. K.N. performed the in vivo electrophysiological experiments. K.N., R.M., A.A., K.M. and Y.Y. wrote the paper.
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Extended data
Extended Data Fig. 1 A representative example of presynaptic input neurons to Cre-expressing claustral neurons.
Presynaptic input neurons to Cre-expressing claustral neurons were visualized with a modified rabies virus-mediated mono-synaptic retrograde tracing method. AON, anterior olfactory nucleus; Au, auditory cortex; BLA, basolateral amygdala; Cg, cingulate cortex; Cla, claustrum; DEn, dorsal endopiriform nucleus; DR, dorsal raphe nucleus; DTT, dorsal tenia tecta; Ect, ectorhinal cortex; Ent, entorhinal cortex; FrA, frontal association cortex, IC, insular cortex; LH, lateral hypothalamic area; M1, primary motor cortex; M2, secondary motor cortex; MD, mediodorsal thalamic nucleus; MnR, median raphe nucleus; OFC, orbitofrontal cortex; PaS, parasubiculum; Pir, piriform cortex; PrL, prelimbic cortex; PRh, perirhinal cortex; RS, retrosplenial cortex; S1, primary somatosensory cortex; S2, secondary somatosensory cortex; SI, substantia innominate; V1, primary visual cortex; V2, secondary visual cortex. The antero-posterior coordinates are indicated in each section (mm from the bregma). Scale bar, 1 mm. Similar results were obtained in four independent experiments.
Extended Data Fig. 2 A representative example of axonal trajectories of Cre-expressing claustral neurons.
Axonal trajectories of Cre-expressing claustral neurons were visualized with Cre-dependent tdTomato-expressing AAV. AON, anterior olfactory nucleus; Au, auditory cortex; BLA, basolateral amygdala; Cg, cingulate cortex; Cla, claustrum; DEn, dorsal endopiriform nucleus; DR, dorsal raphe nucleus; DTT, dorsal tenia tecta; Ect, ectorhinal cortex; Ent, entorhinal cortex; FrA, frontal association cortex, IC, insular cortex; LH, lateral hypothalamic area; M1, primary motor cortex; M2, secondary motor cortex; MD, mediodorsal thalamic nucelus; MnR, median raphe nucleus; OFC, orbitofrontal cortex; PaS, parasubiculum; Pir, piriform cortex; PrL, prelimbic cortex; PRh, perirhinal cortex; RS, retrosplenial cortex; S1, primary somatosensory cortex; S2, secondary somatosensory cortex; SI, substantia innominata; V1, primary visual cortex; V2, secondary visual cortex. The antero-posterior coordinates are indicated in each section (mm from the bregma). Scale bar, 1 mm. Similar results were obtained in four independent experiments.
Extended Data Fig. 3 A representative example of synaptic vesicle distributions of Cre-expressing claustral neurons.
Synaptic vesicle distributions of Cre-expressing claustral neurons were visualized with Cre-dependent synaptophysin-GFP (sypGFP)-expressing AAV. Coronal sections of the brain were immunolabeled with anti-GFP (white in left panels, green in right panels) and anti-NeuN (red in right panels) antibodies. The antero-posterior coordinates are indicated in each section (mm from the bregma). Similar results were obtained in four independent experiments. Scale bar, 200 μm.
Extended Data Fig. 4 Claustral activation drives PV-positive fast-spiking neurons in the insular cortex.
Three examples (a–c) of the PV-positive neurons in the insular cortex of PV/myrGFP-LDLRct transgenic mice. Upper panels show the morphology of the recorded neurons filled with biocytin (red) and immunostained with anti-GFP antibody (green). Scale bar, 50 μm. Arrows indicate the PV-positive recorded neurons. Lower panels show firing patterns induced by inward current pulse injection for 1 s (200 and 400 pA in a and b, respectively) or 250 ms × 3 (270 pA in c) and responses to optogenetic stimulation of the claustrum. Blue arrows and red asterisks indicate the timing of photostimulation (5 ms) and the evoked action potentials. The horizontal black bar on the left of each voltage trace indicates membrane potential at −60 mV. The photostimulation-evoked action potentials were observed in 48% (10/21) of the GFP-positive neurons recorded from 10 mice.
Extended Data Fig. 5 Claustral stimulation drives fast-spiking interneurons in the frontal cortex.
a, Current-clamp recordings of regular-spiking neurons in the frontal cortex. Firing patterns induced by inward current pulse injection for 1 s (top), and responses to the optogenetic stimulation of the claustral axons (bottom). b, Percentage of regular-spiking neurons (n = 90) that showed EPSP with action potential (red), EPSP without action potential (blue), and no response (white) upon the optogenetic claustral stimulation. c, Recordings from fast-spiking neurons. Firing patterns induced by inward current pulse injection for 1 s (top), and responses to the optogenetic stimulation of the claustral axons (bottom). d, Percentage of fast-spiking neurons (n = 27) that showed an EPSP with action potential (red), EPSP without action potential (blue), and no response (white) upon the optogenetic claustral stimulation. The horizontal black bar on the left of each voltage trace, −60 mV; the vertical black scale bar on the right of each top voltage trace, 10 mV; the blue arrow below each trace, photostimulation (5 ms); red asterisk, action potential.
Extended Data Fig. 6 Spike latencies of claustral and cortical neurons after photostimulation.
Top, Claustral photostimulation-triggered PSTHs (1-ms bins, smoothed by 3 bins moving average) of claustral units (Cla, n = 42, magenta), cortical narrow-spike waveform units (NS, n = 8, blue) and cortical wide-spike waveform units (WS, n = 5, brown). Bottom, the group average of each PSTH. The line graph shows mean ± s.e.m.
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Narikiyo, K., Mizuguchi, R., Ajima, A. et al. The claustrum coordinates cortical slow-wave activity. Nat Neurosci 23, 741–753 (2020). https://doi.org/10.1038/s41593-020-0625-7
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DOI: https://doi.org/10.1038/s41593-020-0625-7
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