Rare brain cells that can switch on sleep identified in mouse cortex

For decades, neuroscientists assumed the cerebral cortex was a follower when it came to sleep — a region that displayed the slow, rolling rhythms of deep sleep but did not generate them. The signals that put the brain to sleep, the thinking went, came from deeper, older structures. A study published in Nature now challenges that picture, identifying a population of cortical cells so rare they amount to roughly one neuron in every thousand in the cortex, yet capable of triggering sleep on their own.

The cells are called Sst-Chodl neurons, named for two genes — somatostatin (Sst) and chondrolectin (Chodl) — that are simultaneously active in them. The research, led by Geoffrey Terral and Renata Batista-Brito at the Albert Einstein College of Medicine in New York, found that selectively switching these neurons on in mice was enough to induce sleep.

Usually, sleep is associated with being controlled by subcortical regions.— Geoffrey Terral, neuroscientist, Albert Einstein College of Medicine

What our work shows is that the cortex can not only see this rhythm but also initiate it by itself, and this is sufficient to promote sleep.— Geoffrey Terral, neuroscientist, Albert Einstein College of Medicine

Finding these cells at all required years of technical work. Inhibitory neurons make up about a fifth of all cortical neurons, and Sst-Chodl cells represent only around one percent of those — making them roughly 0.1 percent of the cortex overall. Targeting them with a single gene marker is impossible: both Sst and Chodl individually label far larger, more varied families of neurons. Batista-Brito's team spent years building a strategy that only labels a cell when both genes are active at once.

Going after these cells was really a high-risk project because the likelihood of seeing anything with 0.1 percent of neurons in the cortex is really low. I wrote a bunch of grants on these projects that were always rejected because it was too high-risk.— Renata Batista-Brito, neuroscientist, Albert Einstein College of Medicine

The payoff came immediately when Batista-Brito first examined the cells' anatomy. Despite their scarcity — just two or three cell bodies visible across an entire brain section — each neuron sent branches sprawling across the visual cortex and dispatched long axons to regions responsible for touch, hearing, spatial memory, navigation, and voluntary movement. This is highly unusual: inhibitory neurons almost always work locally, suppressing activity in their immediate neighborhood. Sst-Chodl neurons do the opposite.

At first, I saw two or three cell bodies in the whole brain. Despite that, there was massive, massive arborization all over the visual cortex, like I never saw with any other neuron.— Renata Batista-Brito, neuroscientist, Albert Einstein College of Medicine

Sst-Chodl neurons are kind of the opposite. They are receiving inputs that are quite precise, but then they are broadcasting that information everywhere.— Renata Batista-Brito, neuroscientist, Albert Einstein College of Medicine

To track when the cells fire naturally, the team imaged them while simultaneously monitoring pupil size, muscle tone, facial movement, running, and the cortex's electrical activity. Of 111 cells imaged, 95 lit up during slow-wave sleep and quiet, motionless wakefulness, and went silent during running and REM sleep. Their firing pattern during slow-wave sleep was also distinctive: while the cortex normally alternates between bursts of activity (UP states) and near-silence (DOWN states), Sst-Chodl neurons ramped up precisely as other neurons were winding down at the end of an UP state — and skipped the rebound that other cells show coming out of a DOWN state.

Their activity is even higher at the termination of the UP state. Once all the other neurons start to decrease their activity, those neurons start to increase it even more.— Geoffrey Terral, neuroscientist, Albert Einstein College of Medicine

To test what the cells actually do, the team used optogenetics — inserting a gene for a light-activated ion channel so the neurons could be made to fire on command. Stimulating Sst-Chodl cells in the visual cortex drove up delta power (the slow, high-amplitude brain waves characteristic of deep, restorative sleep) across every cortical layer, made DOWN states more frequent and longer, and tightened the timing of when other neurons fired together. Crucially, the overall firing rate of surrounding neurons barely changed — the cells were reorganizing coordination, not simply silencing the cortex.

Those neurons are not changing so much the firing rate. They change just the coordination — whether the neurons fire together or not.— Geoffrey Terral, neuroscientist, Albert Einstein College of Medicine

The effect also proved remarkably frequency-independent. Regardless of whether the researchers stimulated the cells with a flat signal, a delta-frequency pulse, or a 60-hertz burst, the same slow oscillation emerged. Something in the intrinsic properties of the cells locks them onto a single output frequency — though the researchers say they do not yet know the mechanism.

If we did a flat stimulus, or delta, or 20 hertz, or 60 hertz, you still induced the same kind of oscillation. There's something about the intrinsic properties of these cells that, once they trigger, they go on this one frequency.— Renata Batista-Brito, neuroscientist, Albert Einstein College of Medicine

The reach of the effect matched the cells' anatomy. Direct inhibitory currents appeared in a third of neurons recorded two millimeters from the stimulation site, and effects were measurable as far away as the frontal motor areas — even though the stimulated cell bodies sat in the visual cortex.

The findings place the cortex alongside established subcortical structures as an active participant in sleep regulation, not merely a downstream display. According to the Nature paper, Sst-Chodl cells constitute 'a sparse and genetically distinct class of neocortical GABAergic inhibitory neurons' whose long-range axons 'target multiple regions simultaneously' — a wiring diagram that gives a handful of cells outsized influence over brain-wide synchrony. The study was conducted in mice, and whether the same population plays the same role in humans remains to be established.

Why it matters — Identifying a cortical cell type that can actively initiate sleep — rather than merely reflect it — opens a potential new target for treating insomnia and sleep disorders without going through the brain's deeper, harder-to-reach structures.

Reported by arstechnica.com, nature.com, mountsinai.org