Key brain circuit regulating the entry into hibernation found at last

Amazing stuff!

Notice here the emphasis is on entry into hibernation not hibernation in general.

Notice Google Search was not able to find a news release regarding this discovery neither did the Whitehead Institute for Biomedical Research publish one although many of the authors of this study are affiliated with the WI. That is disappointing.

"... Now, in a preprint posted on bioRxiv, researchers studying hibernating Syrian hamsters have pinpointed for the first time a brain circuit that regulates an animal’s entry into hibernation. The results reveal a “key, really, in the network” and provide “more solid [evidence] than anything we had before” of an ancient hibernation circuit within the mammalian brain ..."

From the abstract:

"Evolution of seasonal hibernation has enabled mammals to survive harsh conditions by entering a state of prolonged hypometabolism and hypothermia with body temperatures as low as 0-4°C1–6.

Despite decades of physiological studies, the genetic tools to study hibernation have remained limited and the mechanisms that induce hibernation entry are still unknown.

Focusing on the brain, we map state-dependent neuronal activity across the hibernation cycle in Syrian hamsters and identify the hypothalamic anterior preoptic area (aPOA) as a key regulator of hibernation entry.

Single-nucleus RNA and chromatin profiling provided a map of neuronal populations present in the hamster POA and enabled the discovery and design of an enhancer AAV that selectively targets hibernation-associated aPOA subpopulations.

Using this genetic approach, we show that Samd3-positive aPOA glutamatergic neurons are necessary for entry into hibernation and that their activation is sufficient to induce a prolonged hypothermic state with associated nesting behavior.

Together, we identify the first neuronal population that controls entry into hibernation, opening new avenues for investigating and manipulating the metabolic and physiological mechanisms underlying this extreme state of “suspended animation” and its potential applications in aging and disease."

Key brain circuit regulating hibernation found at last | Science | AAAS

Preoptic Neurons that Control Entry into Hibernation

Fig. 2: Identification of anterior preoptic area activity as necessary for deep torpor entry.

Unlocking the genetic ‘control switches’ of hibernation

Amazing stuff! When can I go into hibernation to wake up perhaps in the next century? 😴

"New research has identified specific regions of DNA that regulate hibernation by tweaking metabolism. The findings could offer pathways to new treatments for metabolic disorders like type 2 diabetes in humans.

When hibernating animals wake, they reverse dangerous health changes similar to those seen in type 2 diabetes, muscle atrophy, Alzheimer’s disease and stroke. ...

Ferris is co-author of 2 new studies which pinpointed that DNA regions near a gene cluster called the “fat mass and obesity (FTO) locus” play a crucial role in the ability to hibernate. While the FTO locus also appears in humans, hibernating animals use it in a different, and potentially more advantageous way. ...

The hibernator-specific DNA regions (located close to the FTO locus) weren’t genes but DNA sequences called “cis–regulatory elements” (CREs) which contact nearby genes to either turn up or down their expression, ... The researchers found the CREs regulated the activity of neighbouring genes, including those involved in metabolism. ..."

From the editor's summary and abstract:

"Editor’s summary

Metabolic regulation is fundamental to many aspects of health and disease. Two companion papers investigated the genetic bases of mammalian metabolic control by studying the genetic changes associated with hibernation. Ferris et al. performed a comparative analysis of gene expression and chromatin dynamics in a non hibernating mouse and a hibernating squirrel, focusing on the hypothalamus, a brain area involved in metabolic adaptations. They identified a convergent set of cis-regulatory elements (CREs) associated with the adoption of a hibernating lifestyle. Steinwand et al. performed targeted deletion of some of these CREs, determining how these specific alterations translated into distinct metabolic and behavioral phenotypes. These studies suggest that CREs might also play a role in regulating human metabolism. ...

Abstract

Cis-regulatory elements (CREs) drive phenotypic diversity, yet how CREs are causally linked to function remains largely unclear.

Our study elucidates functions for conserved cis elements associated with the evolution of mammalian hibernation and metabolic flexibility.

Genomic analyses revealed topologically associated domains (TADs) enriched for convergent changes in hibernators, including the Fat Mass & Obesity (Fto) locus. In this TAD, we uncovered genetic circuits for metabolic responses and hibernation-linked cis elements forming regulatory contacts with neighboring genes.

Deletions of individual cis elements in mice differentially altered Fto, Irx3, and Irx5 expression, reshaping downstream gene expression programs and affecting metabolism, torpor, obesogenesis, and foraging in distinct ways.

Our findings show how convergent evolution in hibernators pinpoints functional genetic mechanisms of metabolic control, with multiple effects encoded in single CREs."

Unlocking the genetic ‘control switches’ of hibernation

Hibernator “Superpowers” May Lie Hidden in Human DNA (original news release)

Conserved noncoding cis elements associated with hibernation modulate metabolic and behavioral adaptations in mice (no public access)

Conserved Noncoding Cis-Elements Associated with Hibernation Modulate Metabolic and Behavioral Adaptations in Mice (preprint, open access)

Fig. 1 Convergent genomic changes in hibernators identify Fto-Irx TAD cis-elements for functional analysis in knockout mice.

Ultrasound to the brain induces noninvasive and safe hibernation in mice – and maybe humans

Amazing stuff! It also allows for precise control of the depth and duration of ultrasound-induced hypothermia.

"... The team created an ultrasound emitter small enough to be mounted on the heads of mice as they went about their day. This could fire off 10-second pulses of ultrasound directed at the preoptic area of the hypothalamus, which instantly triggered symptoms of torpor in the animals. That includes a drop in body temperature by 3 to 3.5 °C (5.4 to 6.3 °F), as well as reduced heart rate and oxygen consumption. The animals woke up naturally after a few hours. ..."

"... In the rat, which does not naturally go into torpor or hibernation, the team delivered ultrasound to the hypothalamus preoptic area and found a decrease in skin temperature, particularly in the brown adipose tissue region, as well as about a 1 degree C drop in core body temperature, resembling natural torpor. ..."

From the abstract:

"Torpor is an energy-conserving state in which animals dramatically decrease their metabolic rate and body temperature to survive harsh environmental conditions. Here, we report the noninvasive, precise and safe induction of a torpor-like hypothermic and hypometabolic state in rodents by remote transcranial ultrasound stimulation at the hypothalamus preoptic area (POA). We achieve a long-lasting (>24 h) torpor-like state in mice via closed-loop feedback control of ultrasound stimulation with automated detection of body temperature. Ultrasound-induced hypothermia and hypometabolism (UIH) is triggered by activation of POA neurons, involves the dorsomedial hypothalamus as a downstream brain region and subsequent inhibition of thermogenic brown adipose tissue. Single-nucleus RNA-sequencing of POA neurons reveals TRPM2 as an ultrasound-sensitive ion channel, the knockdown of which suppresses UIH. We also demonstrate that UIH is feasible in a non-torpid animal, the rat. Our findings establish UIH as a promising technology for the noninvasive and safe induction of a torpor-like state."

Ultrasound to the brain induces hibernation in mice – and maybe humans (secondary news source)

Induction of a torpor-like state with ultrasound (primary news source) Chen’s team used ultrasound to safely, noninvasively induce a torpor-like state in mice, rats

Induction of a torpor-like hypothermic and hypometabolic state in rodents by ultrasound (open access)

Fig. 2: Ultrasound stimulation of POA induces hypothermia and hypometabolism.

Hibernating Bears Provide Clue to Preventing Serious Clots in Humans

Good news! What brown bears hibernate for six months!

"... researchers found that when bears enter their sleepy winter state, they tamp down on the production of heat-shock protein 47 (HSP47), which typically sits on the surface of platelets and helps them bind to collagen. This phenomenon isn’t unique to bears—humans and pigs also temper HSP47 production in times of immobility, the team discovered. ..."

From the perspective abstract:

"Deep vein thrombosis (DVT) is a common feature of short-term immobilization, which occurs, for example, for patients with acute paralysis. However, in chronic immobilization—e.g., owing to spinal cord injury (SCI)—the incidence of DVT equals that in the general population. The mechanisms that protect against DVT during chronic immobilization in SCI patients are unknown. ....  report an analysis of the thromboinflammatory machinery in hibernating brown bears (Ursus arctos), which rarely suffer from DVT despite 6 months of immobilization during hibernation. They found that platelets from hibernating bears exhibit an antithrombotic signature characterized by decreased expression of heat shock protein 47 (HSP47) and overall reduced biomarkers of thromboinflammation compared with those of active brown bears. Further, this signature is conserved across different animal species, including mice, pigs, and humans, suggesting that this could be a therapeutic target to reduce DVT in immobilized patients."

From the abstract:

"Venous thromboembolism (VTE) comprising deep venous thrombosis and pulmonary embolism is a major cause of morbidity and mortality. Short-term immobility-related conditions are a major risk factor for the development of VTE. Paradoxically, long-term immobilized free-ranging hibernating brown bears and paralyzed spinal cord injury (SCI) patients are protected from VTE. We aimed to identify mechanisms of immobility-associated VTE protection in a cross-species approach. Mass spectrometry–based proteomics revealed an antithrombotic signature in platelets of hibernating brown bears with heat shock protein 47 (HSP47) as the most substantially reduced protein. HSP47 down-regulation or ablation attenuated immune cell activation and neutrophil extracellular trap formation, contributing to thromboprotection in bears, SCI patients, and mice. This cross-species conserved platelet signature may give rise to antithrombotic therapeutics and prognostic markers beyond immobility-associated VTE."

Hibernating Bears Provide Clue to Preventing Serious Clots in Humans | The Scientist Magazine® Low levels of the clotting factor HSP47 protect the sleeping giants from blood clots, and the same may be possible for humans and other mammals.

Sleep like a bear (perspective, no public access) Reduced expression of a platelet protein protects against thrombosis during chronic immobilization

Immobility-associated thromboprotection is conserved across mammalian species from bear to human (no public access)

Outdoor research

Serum from hibernating black bears boosts muscle mass in human cells

Most likely too late for Arnold Schwarzenegger! 😄 This is early stage research! Why does it take so long to research the obvious benefits of hibernation and their implication for humans?

"... Scientists in Japan have made a fascinating discovery in this space, demonstrating how human muscle cells can be infused with serum from hibernating black bears to not just prevent atrophy, but actively promote an increase in mass. ...
This new study focused on skeletal muscle, which is susceptible to wasting caused by immobility. ... the research team took cultured human skeletal muscle cells and infused them with serum drawn from the blood of hibernating black bears, which led to significant protein growth after 24 hours. Importantly, serum collected during the bears' active summer season did not induce these same effects. ..."

"... But what these key blood components are remain unknown. ...

The researchers attributed the diminished capacity of the muscles’ “destruction mechanism” to the suppressed expression of MuRF1 (Muscle RING-finger protein-1), the switch triggering the shredding of unused muscles. According to them, it is likely that suppression of MuRF1 expression was mediated by the activation of the Akt/FOXO3a (protein kinase B/Forkhead box class O 3a) axis responsible for the elevation of protein synthesis.

They also observed increased levels of the growth factor hormone IGF-1 (insulin-like growth factor-1) in the hibernating bear serum. The researchers identified it as a candidate upstream factor that induces activation of the Akt/FOXO3a axis. ..."

From the abstract:

"Hibernating bears remain in their dens for 5–7 months during winter and survive without eating or drinking while staying inactive. However, they maintain their physical functions with minimal skeletal muscle atrophy and metabolic dysfunction. In bears, resistance to skeletal muscle atrophy during hibernation is likely mediated by seasonally altered systemic factors that are independent of neuromuscular activity. To determine whether there are components in bear serum that regulate protein and energy metabolism, differentiated human skeletal muscle cells were treated with bear serum (5% in DMEM/Ham’s F-12, 24 h) collected during active summer (July) and hibernating winter (February) periods. ... Total protein content in cultured skeletal muscle cells was significantly increased following a 24 h treatment with hibernating bear serum. Although the protein synthesis rate was not altered, the expression of MuRF1 protein, a muscle-specific E3 ubiquitin ligase was significantly decreased along with a concomitant activation of Akt/FOXO3a signaling. Increased levels of insulin-like growth factor-1 (IGF-1) were also observed in hibernating bear serum. These observations suggest that protein metabolism in cultured human myotubes may be altered when incubated with hibernating bear serum, with a significant increase in serum IGF-1 and diminished MuRF1 expression, a potential target of Akt/FOXO3a signaling. A protein sparing phenotype in cultured muscle cells by treatment with hibernating bear serum holds potential for the development of methods to prevent human muscle atrophy and related disorders."

Serum from hibernating black bears boosts muscle mass in human cells

Bears got hibernation power in their blood but identity of ‘superhero’ components still a mystery

Supplementing cultured human myotubes with hibernating bear serum results in increased protein content by modulating Akt/FOXO3a signaling (open access)

Fig 1. Alteration of total protein contents in cultured human skeletal muscle cells: Winter-hibernation period vs. summer-active period.

Discovered: Brain Cells that Control Hibernation-Like States

Two papers from different research teams simultaneously report this discovery in about the same region of the brain. Just wondering, do humans also have these brain cells to go into torpor?

"Focusing on the hypothalamus ... the team used a “clever genetic trick,” ... to tag cells activated upon entry into torpor. Later, once the animals were fed and recovered, the genetic trickery enabled the team to reactivate those same neurons, sending the fed animals back into torpor."

" ... were investigating the function of a tiny handful of hypothalamus cells that express a particular neuropeptide called pyroglutamylated RF-amide peptide (QRFP). ... So, when they stimulated the QRFP-producing cells, which they call Q neurons, in mice and found it induced an extended torpor ... Inhibiting Q neurons impaired normal torpor, the team also showed."

Discovered: Brain Cells that Control Hibernation-Like States | The Scientist Magazine® Two independent teams identify neuron populations in the mouse brain that regulate the physiological changes associated with torpor.