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Neocortical long-range inhibition promotes cortical synchrony and sleep

read original get Why We Sleep by Matthew Walker (book) → more articles
Why This Matters

This Nature-style study identifies a rare class of long-range inhibitory neurons in the mouse neocortex (labeled via Sst, Nos1 and Chodl driver lines) that appear to promote cortical synchrony and sleep. Sleep regulation has long been attributed mainly to subcortical circuits, so evidence that cortex-resident inhibitory cells help drive it reframes where sleep control originates. That matters for the long-term hunt for better treatments for insomnia and sleep-disruption disorders.

Key Takeaways
Worth a Look

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Mice

All mouse handling and maintenance was performed according to the regulations of the Institutional Animal Care and Use Committee of the Albert Einstein College of Medicine (protocol 00001393). Sstflp+/+; Nos1creER+/− and Sstflp+/−;Nos1creER+/− mice were used interchangeably in this study, with no differences detected between the two groups (Nos1creER, Jax 014541; Sstflp, Jax 031629). Nos1creER+/− mice were crossed with Sstflp+/+ mice to obtain Sstflp+/−;Nos1creER+/− mice and Sstflp+/−;Nos1creER+/+ were crossed with Sstflp+/+ mice to obtain Sstflp+/+;Nos1creER+/− mice. Sstflp+/+;Nos1creER+/− mice were crossed with Ai210+/+ mice (a gift from the Allen Institute)52 to obtain mice for in vivo imaging experiments. Chodlcre+/+ mice (a gift from the Allen Institute)52 were crossed with Sstflp+/+ or Sstflp+/− mice. Adult male and female mice aged 50 days or older were used in this study. Mice were kept under a 12 h light–dark cycle (lights on 07:00 or lights on 16:00 for ZT18 chemogenetic experiments) under standard housing conditions (20–24 °C and 30–70% humidity).

Cell type classification and sequencing

Data were retrieved from a previous study52.

Abbreviations of brain regions

ACA, anterior cingulate area (d, dorsal); AIp, agranular insular area, posterior; APr, area prostriata; Aud, auditory cortical area (d, dorsal; p, primary; po, posterior; v, ventral); AuT, auditory and temporal cortical area; BS, brainstem; CB, cerebellum; CLA, claustrum; ECT, ectorhinal area; ENT, entorhinal area (l, lateral; m, medial dorsal); EPd, endopiriform nucleus, dorsal; FrM, frontomotor cortex; HPF, hippocampal formation; HVAs, higher visual areas; Mo, motor cortical area (p, primary; s, secondary); NC, neocortex; OB, olfactory bulb; Olf, olfactory areas; PAR, parasubiculum; PERl, perirhinal area; PIR, piriform area; POST, postsubiculum; PRE, presubiculum; RSP, retrosplenial cortical area (agl, lateral agranular; d, dorsal; v, ventral); RSPagl, retrosplenial area, lateral agranular; RSPd, retrosplenial area, dorsal; S1, primary somatosensory cortex; SS, somatosensory cortical area (bfd, barrel field; ll, lower limb; m, mouth; p, primary; ul, upper limb; tr, trunk; un, unassigned; s, supplemental); StP, striatum–pallidum; SUB, subiculum; TEa, temporal association area; V1, primary visual cortex; VIS, visual area (a, anterior; al, anterolateral; am, anteromedial; l, lateral; li, laterointermediate; p, primary; pl, posterolateral; pm, posteromedial; por, postrhinal; rl, rostrolateral); VISC, visceral area.

Surgical procedures

Mice were anaesthetized with isoflurane (5% by volume for induction and 1–2% for maintenance), placed on a stereotaxic frame and kept warm with a closed-loop heating pad. For pain management, mice were given intraperitoneal (i.p.) meloxicam at 2.5 mg kg−1 and local lidocaine on the scalp before skin incision. The following coordinates are distance (in mm) from bregma and dorsoventral (DV) values refer to brain surface.

For viral injections, we minimized brain damage by performing burr holes, keeping a thin layer of the bone intact where the glass micropipettes could penetrate.

For wide-labelling morphological reconstructions, 50 nl viral vector was injected into a burr hole split across two levels (DV −0.25 and DV −0.55) at anteroposterior (AP) −3.3, mediolateral (ML) ±2.7 to target primary visual cortex (V1); or at AP −1, ML ±3 to target primary somatosensory cortex (S1).

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