New Brain Circuit Helps Recover Lost Sleep

Amazing stuff! When will be able to optimize our sleep for best performance and health? Don't hold your breath! 😊

"... Now, researchers ... identified a subgroup of neurons in the thalamus of the mouse brain are crucial for the homeostatic regulation of sleep, providing insights into how animals recover from lost sleep. ...

Curious to learn more about the neurons that regulate sleep, the researchers first mapped neural circuits upstream of known sleep-promoting brain regions in mice. After identifying 11 candidate regions, they injected mice with clozapine N-oxide, a synthetic molecule, to see if chemical activation of the excitatory neurons in those areas promoted sleep. Of these, the activation of a subset of excitatory neurons in the medial thalamic nucleus reuniens (mRE) led to the greatest increase in [non] REM sleep. ...

To further characterize these mRE neurons, the researchers employed chemogenetic and optogenetic tools. Using either method, they found that stimulated neurons led to mice that exhibited deeper and more prolonged NREM sleep several hours later. This suggested that these neurons do not directly induce sleep but instead regulate sleep homeostasis. The researchers also saw that when they activated mRE neurons with light, the mice engaged in enhanced typical pre-sleep behaviors, such as preparing a spot to sleep (nesting) or self-grooming. ..."

From the abstract of the perspective:

"Most animals regularly undergo an astonishing transformation by cycling between wakefulness and sleep. However, if sleep is disrupted or delayed, sleep “debt” accrues, resulting in longer and deeper sleep. Since the discovery of wake-promoting neurons in the brainstem in the 1940s, a hunt for the control mechanisms of sleep-wake behavior has led to a model of reciprocally connected wake-promoting and sleep promoting cell groups [or nuclei (1, 2)] that achieve discrete brain vigilance states by mutually inhibiting one another (3).

But how sleep loss results in rebound sleep to reestablish homeostasis has remained a mystery. On page 1291 of this issue, Lee et al. (4) report a group of neurons in the thalamus (the brain region that relays incoming sensory information to the cerebral cortex) that increases its activity during sleep deprivation and promotes sleep recovery and depth. The findings suggest that these neurons are responsible for promoting sleep homeostasis."

From the editor's summary and abstract:

"Editor’s summary

Sleep is tightly regulated by homeostatic forces, and sleep deficit leads to persistent and consolidated recovery sleep. However, the pathways underlying the homeostatic control of sleep are still unknown. Lee et al. now describe the first homeostatic sleep circuit in mammals (see the Perspective by Gilette and Lipton). This circuit comprises a cluster of excitatory neurons in the nucleus reuniens that is activated by sleep need and is necessary for recovery sleep. Stimulation of these neurons first triggers presleep behavior, followed by deep and persistent sleep that can last hours. This sleep pattern resembles recovery sleep and suggests that activation of reuniens neurons generates sleep pressure even in animals without sleep debt. Silencing this circuit during sleep deprivation disrupts the amount and quality of recovery sleep, suggesting that its activity signals the accrual of sleep need. ...

Structured Abstract

INTRODUCTION

Sleep is under homeostatic control: After prolonged wakefulness, animals engage in persistent, consolidated, and deep sleep. Although the homeostatic regulation of sleep has been intensely studied over the past century, the biological underpinnings of this process remain enigmatic. Progress is being made delineating molecular pathways that mediate sleep homeostasis. By contrast, the identity of neural circuits that sense and/or transmit homeostatic sleep signals is unclear.

RATIONALE

Sleep can be divided into rapid eye movement (REM) and non-REM (NREM) sleep, which is considered the deeper, more restorative form of sleep. To date, many NREM-promoting neural circuits have been identified. However, the identity of specific neuronal clusters required for the accrual of sleep need remains unclear, and the goal of this study was to identify such a neural circuit.

RESULTS

From a circuit screen in mice, a group of excitatory neurons in the thalamic nucleus reuniens (RE) was identified that projected to multiple downstream NREM-promoting clusters.

Brief optogenetic activation of RE neurons led to an unusual phenotype—persistent, consolidated, and deep NREM sleep after a delay. Notably, during this delay period before falling asleep, the animals engaged in sleep-preparatory behaviors, which included grooming and nesting.

Because the persistent, consolidated, and deep sleep phenotype resembled the homeostatic recovery sleep seen after sleep deprivation, we sought to investigate whether RE neurons participate in the homeostatic regulation of sleep.

Most NREM-promoting neurons exhibit increased activity during NREM sleep. To measure the in vivo activity of RE neurons, chronic Neuropixels recordings were performed during sleep deprivation and recovery sleep.

These recordings revealed that RE activity was greater during sleep deprivation and/or wakefulness and reduced during recovery sleep.

Next, we examined whether this elevated RE activity during sleep deprivation was necessary for the accrual of sleep need.

Chemogenetic inhibition of RE neurons during sleep deprivation decreased subsequent homeostatic recovery sleep amount, consolidation, and depth.

RE neurons promote NREM sleep by signaling to a previously identified NREM-promoting cluster in the zona incerta (ZI).

Unexpectedly, sleep deprivation induced neural plastic changes of the RE-ZI connection. The degree of this RE-ZI plasticity correlated with the amount of subsequent homeostatic recovery sleep.

Moreover, this synaptic plasticity enhanced the morphological and functional connectivity between the RE and ZI neuronal clusters.

Calcium- and calmodulin-dependent protein kinase II (CaMKII) is well described to regulate synaptic plasticity and has been implicated in the homeostatic regulation of sleep.

Inhibition of CaMKII activity in RE neurons reduced the RE-ZI plasticity and subsequent homeostatic recovery sleep triggered by sleep deprivation.

CONCLUSION

Our findings suggest that RE neurons are required for the accrual of sleep need and are able to generate persistent, deep sleep, similar to homeostatic recovery sleep.

Sleep deprivation induces plasticity of the RE-ZI circuit, strengthening the connectivity of this sleep-promoting module. The degree of this plasticity correlates with the amount of homeostatic sleep rebound, which suggests that RE-ZI plasticity serves as a molecular readout for sleep need.

These findings reveal a mechanism by which sleep loss transforms the functional coupling of a sleep circuit to promote persistent, deep sleep."

New Brain Circuit Helps Recover Lost Sleep | The Scientist "How do animals bounce back from sleep deprivation? Scientists found a subset of neurons in the mouse thalamus that repay this “sleep debt.”"

Where the brain pays sleep debt (no public access) "Neurons in the thalamus drive restorative sleep"

Sleep need–dependent plasticity of a thalamic circuit promotes homeostatic recovery sleep (no public access)

Sleep need–dependent plasticity of an RE-ZI circuit promotes homeostatic recovery sleep.

European Birds (crows) trade vigilance for rest while sleeping by keeping one eye less open

Amazing stuff! My conclusion: Smart birds need less vigilance! 😊

However, the scientists appear to have failed to document or mention where the research subjects ( were taken from or located (e.g. natural habitat, laboratory, urban area). This is quite an omission, so bad an omission that it may qualify as junk science. The researchers only mention "European jackdaws". The official news release by the Max Planck Neuroscience institute also does not mention at all where these "European jackdraws" came from.

I believe, it is critically important to mention where (in which environment) these birds were investigated. For example, I would argue that birds in urban areas may need to be less vigilant because there is an overpopulation of birds and fewer predators.

Caveat: I did read the entire article.

"Birds exhibit two types of non-REM sleep: 

symmetric (both brain hemispheres sleeping deeply) and 

asymmetric (one hemisphere sleeping lightly while the other stays alert). 

van Hasselt et al. investigated how birds balance these sleep modes under increased sleep pressure caused by deprivation.

Using high-density EEG on European jackdaws, researchers found that during heightened sleep need, birds prioritize symmetric sleep over asymmetric sleep, sacrificing vigilance to recover from sleep loss. This trade-off highlights the constraints imposed by the need for deep, restorative sleep on the birds’ ability to remain alert for potential threats."

"Summary:

• Birds, unlike humans, can sleep deeply with both halves of their brains (symmetrically) or with one half sleeping lighter than the other (asymmetrically).
• Study of European jackdaws led by an international team of researchers shows that when sleep-deprived, jackdaws were more likely to fall into deep sleep with both brain halves at the expense of keeping one half vigilant – especially early in the night, when the need to recover is greatest.
• Observing how birds navigate the trade-off between vigilance and sleep may help scientists better understand how sleep loss affects brain function more broadly, including in us.

... When humans sleep, our brains cycle through stages, alternating between rapid eye movement (REM) sleep and non-REM sleep roughly every 90 minutes. Birds go through these same stages, but typically in much shorter bursts – and their sleep patterns are far more flexible than ours. ..."

From the highlights and abstract:

"Highlights

• High-density EEG shows local homeostatic responses to sleep loss in the avian brain

• Theta oscillations occur during non-REM sleep in non-hippocampal brain regions

• Non-REM sleep occurs symmetrically and asymmetrically between the hemispheres

• Asymmetric sleep is sacrificed for symmetric sleep when sleep pressure increases

Summary

Sleep is a dangerous part of an animal’s life. Nonetheless, following sleep loss, mammals and birds sleep longer and deeper, as reflected by increased electroencephalogram (EEG) slow-wave activity (SWA; ≈1–5 Hz spectral power) during non-rapid eye movement (NREM) sleep.

Stimulating a brain region during wakefulness also causes that region to sleep deeper afterwards, indicating that NREM sleep is a local, homeostatically regulated process. 

Birds and some marine mammals can keep one eye open during NREM sleep, a behavior associated with lighter sleep or wakefulness in the hemisphere opposite the open eye—states called asymmetric and unihemispheric NREM sleep, respectively.

Closure of both eyes is associated with symmetric NREM or REM sleep.

Birds rely on asymmetric and unihemispheric sleep to stay safe. However, as sleeping deeply with only one hemisphere at a time increases the time required for both hemispheres to fulfill their need for NREM sleep, increased sleep pressure might cause birds to engage in symmetric sleep at the expense of asymmetric sleep. Using high-density EEG recordings of European jackdaws (Coloeus monedula), we investigated intra- and inter-hemispheric asymmetries during normal sleep and following sleep deprivation (SD). The proportion of asymmetric sleep was lower early in the sleep period and following SD—periods of increased sleep pressure. Our findings demonstrate a trade-off between the benefits of sleep and vigilance and indicate that a bird’s utilization of asymmetric sleep is constrained by temporal dynamics in their need for sleep."

In Other Journals | Science

Too tired to stay alert? A difficult trade-off between sleep and vigilance (original press release) "Sleep-deprived European jackdaws trade vigilance for deep sleep – a strategy that could carry risks in the wild."

Sleep pressure causes birds to trade asymmetric sleep for symmetric sleep

(open access)

Graphical abstract

Key players in brain aging: New research identifies age-related damage on a cellular level

Good news! Closing in on the fountain of youth!

"Largest study on brain aging points to possible connections between diet, inflammation, and brain health.

Scientists ... have identified specific cell types in the brain of mice that undergo major changes as they age, along with a specific hot spot where many of those changes occur. ...

Aging hot spot: Scientists discovered a specific hot spot combining both the decrease in neuronal function and the increase in inflammation in the hypothalamus. The most significant gene expression changes were found in cell types near the third ventricle of the hypothalamus, including tanycytes, ependymal cells, and neurons known for their role in food intake, energy homeostasis, metabolism, and how our bodies use nutrients. This points to a possible connection between diet, lifestyle factors, brain aging, and changes that can influence our susceptibility to age-related brain disorders.  ..."

From the abstract:

"Biological ageing can be defined as a gradual loss of homeostasis across various aspects of molecular and cellular function. Mammalian brains consist of thousands of cell types, which may be differentially susceptible or resilient to ageing.

Here we present a comprehensive single-cell RNA sequencing dataset containing roughly 1.2 million high-quality single-cell transcriptomes of brain cells from young adult and aged mice of both sexes, from regions spanning the forebrain, midbrain and hindbrain. High-resolution clustering of all cells results in 847 cell clusters and reveals at least 14 age-biased clusters that are mostly glial types.

At the broader cell subclass and supertype levels, we find age-associated gene expression signatures and provide a list of 2,449 unique differentially expressed genes (age-DE genes) for many neuronal and non-neuronal cell types. Whereas most age-DE genes are unique to specific cell types, we observe common signatures with ageing across cell types, including a decrease in expression of genes related to neuronal structure and function in many neuron types, major astrocyte types and mature oligodendrocytes, and an increase in expression of genes related to immune function, antigen presentation, inflammation, and cell motility in immune cell types and some vascular cell types.

Finally, we observe that some of the cell types that demonstrate the greatest sensitivity to ageing are concentrated around the third ventricle in the hypothalamus, including tanycytes, ependymal cells, and certain neuron types in the arcuate nucleus, dorsomedial nucleus and paraventricular nucleus that express genes canonically related to energy homeostasis. Many of these types demonstrate both a decrease in neuronal function and an increase in immune response. These findings suggest that the third ventricle in the hypothalamus may be a hub for ageing in the mouse brain. Overall, this study systematically delineates a dynamic landscape of cell-type-specific transcriptomic changes in the brain associated with normal ageing that will serve as a foundation for the investigation of functional changes in ageing and the interaction of ageing and disease."

Key players in brain aging: New research identifies age-related damage on a cellular level

Key players in brain aging (original news release) "New research identifies age-related damage on a cellular level"

Brain-wide cell-type-specific transcriptomic signatures of healthy ageing in mice (open access)

Fig. 1: Transcriptomic cell types in young adult and aged mouse brains.

Fig. 6: Decreased neuronal function and increased immune activity as common signatures of ageing across brain cell types.

New pathway found for regulating zinc in E. coli

E. coli is probably one of the most researched subjects in history!

"... researchers have discovered a pathway by which E. coli regulates all-important zinc levels, an insight that could advance the understanding of metal regulation in bacteria generally and lead to antibacterial applications such as in medical instruments and surgical settings. ...

E. coli have evolved mechanisms to bring in more zinc when it’s needed and to get rid of extra to avoid toxicity ... lab has discovered a previously unknown pathway the bacteria can use to control cellular zinc levels. 

The researchers found that the metal-regulating proteins Zur and ZntR – which control uptake and efflux (outflow), respectively – can cross-interact directly through the cell’s DNA, providing another way for the two metalloregulators to coordinate their actions as they control metal concentration in the cell. ...

Studying E. coli DNA, the researchers found that the DNA sequences Zur and ZntR recognize overlap partially, raising the question of whether they really can cross-interact. The experiment proving that they can was the first in-cell study of protein-DNA interaction kinetics as a function of concentration of two proteins.  ..."

From the abstract:

"Transition metals like Zn are essential for all organisms including bacteria, but fluctuations of their concentrations in the cell can be lethal. Organisms have thus evolved complex mechanisms for cellular metal homeostasis. One mechanistic paradigm involves pairs of transcription regulators sensing intracellular metal concentrations to regulate metal uptake and efflux.

Here we report that Zur and ZntR, a prototypical pair of regulators for Zn uptake and efflux in E. coli, respectively, can coordinate their regulation through DNA, besides sensing cellular Zn2+ concentrations. Using a combination of live-cell single-molecule tracking and in vitro single-molecule FRET measurements, we show that unmetallated ZntR can enhance the unbinding kinetics of Zur from DNA by directly acting on Zur-DNA complexes, possibly through forming heteromeric ternary and quaternary complexes that involve both protein-DNA and protein-protein interactions. This ‘through-DNA’ mechanism may functionally facilitate the switching in Zn-uptake regulation when bacteria encounter changing Zn environments, such as facilitating derepression of Zn-uptake genes upon Zn depletion; it could also be relevant for regulating the uptake-vs.-efflux of various metals across different bacterial species and yeast."

New pathway found for regulating zinc in E. coli | Cornell Chronicle

A ‘through-DNA’ mechanism for co-regulation of metal uptake and efflux

Fig. 2: Single-molecule tracking shows that ZntRapo enhances the kinetics of ZurZn unbinding from DNA in cells.

How stem cells organize cellular replacements at a distance

Amazing stuff!

"... it has remained unclear whether stem cells located in different areas of our tissues are able to communicate with each other across distances, telling each other where and how many cells need to be replaced. ...

In a new study ... to show that adult stem cells in skin tissue are able to coordinate calcium signals at surprisingly long distances to prompt the replacement of lost cells.

The ... team ... found that localized groups of up to 10 stem cells initiate communication via calcium signals. As seen in this video (above), these small groups of stem cells, located in a thin layer of the skin known as the epithelial tissue (labelled with magenta with calcium levels in green fluorescence), launch coordinated tissue-wide communications which dictate where and when lost cells are replaced. ...
This biological insight was made possible by a computational method known as “Geometric Scattering Trajectory Homology,” developed by the research team, which captures the patterns of signaling at multiple spatial and temporal resolutions. This method is broadly applicable, and the researchers are now applying it to decipher additional complex signaling in various other biological systems in a follow-up paper. ..."

From the abstract:

"Skin homeostasis is maintained by stem cells, which must communicate to balance their regenerative behaviors. Yet, how adult stem cells signal across regenerative tissue remains unknown due to challenges in studying signaling dynamics in live mice. We combined live imaging in the mouse basal stem cell layer with machine learning tools to analyze patterns of Ca2+ signaling. We show that basal cells display dynamic intercellular Ca2+ signaling among local neighborhoods. We find that these Ca2+ signals are coordinated across thousands of cells and that this coordination is an emergent property of the stem cell layer. We demonstrate that G2 cells are required to initiate normal levels of Ca2+ signaling, while connexin43 connects basal cells to orchestrate tissue-wide coordination of Ca2+ signaling. Lastly, we find that Ca2+ signaling drives cell cycle progression, revealing a communication feedback loop. This work provides resolution into how stem cells at different cell cycle stages coordinate tissue-wide signaling during epidermal regeneration."

How stem cells organize cellular replacements | YaleNews In a new study, Yale scientists reveal insights into how stem cells communicate with one another to coordinate the replacement of lost cells.

Cell cycle controls long-range calcium signaling in the regenerating epidermis (open access)

Fig. 1 The epidermal stem cell layer cohesively carries out coordinated Ca 2+ signaling at long range.