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Scientists identify neurons that control hibernation-like behaviour

The dream of suspended animation has long captivated the human imagination, reflected in countless works of mythology and fiction, from King Arthur and Sleeping Beauty to Han Solo.

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By effectively pausing time itself for an individual, a state of stasis promises to enable the repair of lethal injuries, prolong life and allow for travel to distant stars.

While suspended animation may seem a fantasy, a strikingly diverse array of life has already achieved a version of it.

Through behaviours like hibernation, animals such as bears, frogs and hummingbirds can survive harsh winters, droughts, food shortages and other extreme conditions by essentially entering into biological stasis, where metabolism, heart rate and breathing slow to a crawl and body temperature drops.

Now, Harvard Medical School neuroscientists have discovered a population of neurons in the hypothalamus that controls hibernation-like behaviour, or torpor, in mice, revealing for the first time the neural circuits that regulate this state.

The team demonstrated that when these neurons are stimulated, mice enter torpor and can be kept in that state for days. When the activity of these neurons is blocked, natural torpor is disrupted.

Another study published simultaneously by the University of Tsukuba in Japan also identified a similar population of neurons in the hypothalamus.

By better understanding these processes in mice and other animal models, the authors envision the possibility of one day working toward inducing torpor in humans—an achievement that could have a vast array of applications, such as preventing brain injury during stroke, enabling new treatments for metabolic diseases or even helping NASA send humans to Mars.

“The imagination runs wild when we think about the potential of hibernation-like states in humans. Could we really extend lifespan? Is this the way to send people to Mars?” said study co-lead author Sinisa Hrvatin, instructor in neurobiology in the Blavatnik Institute at HMS.

“To answer these questions, we must first study the fundamental biology of torpor and hibernation in animals,” Hrvatin said. “We and others are doing this—it is not science fiction.”

To reduce energy expenditure in times of scarcity, many animals enter a state of torpor. Hibernation is an extended seasonal form of this. Unlike sleep, torpor is associated with systemic physiological changes, particularly significant drops in body temperature and suppression of metabolic activity.

While common in nature, the biological mechanisms that underlie torpor and hibernation are still poorly understood.

The role of the brain, in particular, has remained largely unknown, a question that drove the research efforts of Hrvatin and colleagues, including co-lead author Senmiao Sun, a graduate student in the Harvard Program in Neuroscience, and study senior author Michael Greenberg, the Nathan Marsh Pusey Professor and chair of the Department of Neurobiology in the Blavatnik Institute at HMS.

Neural TRAP

The researchers studied mice, which do not hibernate but experience bouts of torpor when food is scarce and temperatures are low.

When housed at 22 C (72 F), fasting mice exhibited a sharp drop in core body temperature and significant reduction in metabolic rate and movement. In comparison, well-fed mice retained normal body temperatures.

As mice began to enter torpor, the team focused on a gene called Fos—previously shown by the Greenberg lab to be expressed in active neurons. Labeling the protein product of the Fos gene allowed them to identify which neurons are activated during the transition to torpor throughout the entire brain.

This approach revealed widespread neuronal activity, including in brain regions that regulate hunger, feeding, body temperature and many other functions.

To see if brain activity was sufficient to trigger torpor, the team combined two techniques—FosTRAP and chemogenetics—to genetically tag neurons that are active during torpor. These neurons could then be re-stimulated later by adding a chemical compound.

The experiments confirmed that torpor could indeed be induced—even in well-fed mice—by re-stimulating neurons in this manner after the mice recovered from their initial bout of inactivity.

However, because the approach labelled neurons throughout the entire brain, the researchers worked to narrow in on the specific area that controls torpor. To do so, they designed a virus-based tool that they used to selectively activate neurons only at the site of injection.

Focusing on the hypothalamus, the region of the brain responsible for regulating body temperature, hunger, thirst, hormone secretion and other functions, the researchers carried out a series of painstaking experiments.

They systematically injected 54 animals with minute amounts of the virus covering 226 different regions of the hypothalamus, then activated neurons only in the injected regions and looked for signs of torpor.

Neurons in one specific region of the hypothalamus, known as the avMLPA, triggered torpor when activated. Stimulating neurons in other areas of the hypothalamus had no effect.

“When the initial experiment worked, we knew we had something,” Greenberg said. “We gained control over torpor in these mice using FosTRAP, which allowed us to then identify the subset of cells that are involved in the process. It’s an elegant demonstration of how Fos can be used to study neuronal activity and behavioural states in the brain.”

Worthwhile goal

The team further analysed the neurons that occupy the region, using single-cell RNA sequencing to look at almost 50,000 individual cells representing 36 different cell types, ultimately pinpointing a subset of torpor-driving neurons, marked by the neurotransmitter transporter gene Vglut2 and the peptide Adcyap1.

Stimulating only these neurons was sufficient to induce rapid drops in body temperature and motor activity, key features of torpor. To confirm that these neurons are critical for torpor, the researchers used a separate virus-based tool to silence the activity of avMLPA-Vglut2 neurons. This prevented fasting mice from entering natural torpor, and in particular disrupted the associated decrease in core body temperature. In contrast, silencing these neurons in well-fed mice had no effect.

“In warm-blooded animals, body temperature is tightly regulated,” Sun said. “A drop of a couple of degrees in humans, for example, leads to hypothermia and can be fatal. However, torpor circumvents this regulation and allows body temperatures to fall dramatically. Studying torpor in mice helps us understand how this fascinating feature of warm-blooded animals might be manipulated through neural processes.”

The researchers caution that their experiments do not conclusively prove that one specific neuron type controls torpor, a complex behaviour that likely involves many different cell types. By identifying the specific brain region and subset of neurons involved in the process, however, scientists now have a point of entry for efforts to better understand and control the state in mice and other animal models, the authors said.

They are now studying the long-term effects of torpor on mice, the roles of other populations of neurons and the underlying mechanisms and pathways that allow avMLPA neurons to regulate torpor.

“Our findings open the door to a new understanding of what torpor and hibernation are, and how they affect cells, the brain and the body,” Hrvatin said. “We can now rigorously study how animals enter and exit these states, identify the underlying biology, and think about applications in humans. This study represents one of the key steps of this journey.”

The implications of one day being able to induce torpor or hibernation in humans, if ever realized, are profound.

“It’s far too soon to say whether we could induce this type of state in a human, but it is a goal that could be worthwhile,” Greenberg said. “It could potentially lead to an understanding of suspended animation, metabolic control and possibly extended lifespan. Suspended animation in particular is a common theme in science fiction, and perhaps our ability to traverse the stars will someday depend on it.”

Additional authors include Oren Wilcox, Hanqi Yao, Aurora Lavin-Peter, Marcelo Cicconet, Elena Assad, Michaela Palmer, Sage Aronson, Alexander Banks and Eric Griffith.

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No higher risk of pregnancy complications in women with MS – study

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Women with multiple sclerosis (MS) may not be at a higher risk of pregnancy complications like gestational diabetes, emergency caesarean section or stillbirth than women who do not have the disease, new research has found.

However, the study did find that babies born to mothers with MS had a higher chance of being delivered by elective caesarean section (c-section) or induced delivery, and of being small for their age when compared to babies of women who did not have the disease.

“Women with multiple sclerosis may be understandably concerned about the risks of pregnancy,” says study author Professor Melinda Magyari, of the University of Copenhagen.

“While previous research has shown there is no higher risk of birth defects for babies born to women with MS, there are still a lot of unknowns around pregnancy and MS.

“We wanted to find out if women with MS are at risk for a variety of pregnancy complications.

“We found overall their pregnancies were just as healthy as those of the mothers without MS.”

The study involved 2,930 pregnant women with MS who were compared to 56,958 pregnant women without MS. All women gave birth between 1997 and 2016.

Researchers found no difference in risk of several pregnancy complications between women with MS and women without it.

No differences were found in risk of pre-eclampsia, gestational diabetes, placenta complications, emergency c-section, instrumental delivery, stillbirth, pre-term birth, congenital malformations or low Apgar score. Apgar score is a test of a newborn’s health, including measures like heart rate, reflexes and muscle tone immediately after birth.

Researchers did find that 401 of the 2,930 women with MS, or 14 per cent, had an elective c-section, compared to 4,402 of the 56, 958 women without MS, or eight per cent, who had an elective c-section.

After adjusting for other factors that could increase the likelihood of having an elective c-section, such as prior c-section and mother’s age, women with MS were 89 per cent more likely to have an elective c-section.

Researchers also found women with MS were 15 per cent more likely to have an induced delivery than women without the disease.

Also, women with MS were found to be 29 per cent more likely to have babies that were born small for their gestational age compared to women without MS.

Overall, 3.4 per cent of women with MS had babies small for their gestational age, compared to 2.8 per cent of women without MS.

“We think the reason more women with MS have babies by elective c-section or induced delivery may have to do with MS-related symptoms such as muscle weakness, spasticity or fatigue that might affect the birth,” Professor Magyari says.

“Any of these could make a mother more tired and lead to delivery complications that could prompt the clinician and woman to take extra precautions.”

Researchers also found that mothers with MS were 13 per cent less likely to give birth to babies with signs of being deprived of oxygen, or asphyxia.

Professor Magyari said the higher prevalence of elective c-sections among women with MS most likely explains the corresponding lower odds of asphyxia.

A limitation of the study is the lack of data on the mothers’ smoking, which could cause babies to be born small for their gestational age.

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Neuro physio

Community neurorehab gym continues to expand

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The West Berkshire Therapy Centre was established on the back of £145,000 worth of fundraising

A community therapy centre which enables neuro patients access to the physio-led exercise which can support their recovery continues to expand in response to demand for its services.

West Berkshire Therapy Centre was opened in 2014 to bridge the gap in existing community resources, and initially opened for 20 hours a week with ten items of equipment.

Since that time, the Thatcham centre has expanded into premises twice the size of its initial home, and now has 17 items of equipment which clients can access 35 hours each week.

While the centre has been forced to close during lockdown periods, the investment in its offering has continued, with a further £17,500 being spent to upgrade equipment.

In addition to its regular clientele of around 260 people, around 200 more will be referred to the centre from the Berkshire Long COVID Integrated Service, led by Dr Deepak Ravindran, who has worked closely with the centre for several years.

As well as the anecdotal evidence from clients who attest the positive effect West Berkshire Therapy Centre has, the centre’s work has been proven to improve client mobility by an average of ten per cent, psychological outlook by 15 per cent and weight loss by three per cent.

All clients are assessed by the centre’s physio before being prescribed an individual exercise programme. The centre prides itself on its client-centred approach and some of the equipment in the gym has been designed and built specifically in response to what clients said were important to them.

West Berkshire Therapy Centre was created by the West Berkshire Neurological Alliance, a group of 23 local neuro charities, which recognised the need for greater specialist provision for people living with neurological conditions in the area.

John Holt was instrumental to the creation of both the Alliance and the Centre. Having supported his wife in living with MS for over 40 years, he took the lead on ensuring greater provision and support was there for those who needed it.

“I’m not from a medical background, I’m a food technologist, and while I was chair of a trade association during my career, I was used to working with competitors and business enemies, that was just what happened for the greater good of us all,” he says.

“So I was rather shocked when I got involved with the local voluntary sector and found that wasn’t the case. I was very proactive in all of our charities working together as I know the importance of working as one alliance.

“People who were living with neurological conditions were often having to fend for themselves when it came to community rehab, and that’s why we wanted to create the West Berkshire Therapy Centre.”

Having been established on the back of £145,000 in fundraising, five years later the demand for its services was such it had to expand into larger premises and invest in more equipment.

The centre – which is funded by voluntary contributions for sessions and through fundraising – now has eight part-time staff and a core of volunteers to support clients with whatever rehabilitation issues they have.

While most clients have neurological conditions – including stroke, Parkinson’s, MS and Post-Polio Syndrome – the centre has broadened its reach to include large numbers of people with arthritis, heart and lung conditions, sight impairments as well as amputees.

“We’re completely pan-disability and will support anyone who needs us. Our clients talk to us and we listen and adapt,” says John.

“I think many clients come to us because we are a safe place for them and they’re among people who understand the challenges they face.

“It is very important that we talk about things openly. For example, we talk about how hard it is when you can’t get to the bathroom in time and you wet yourself.

“When you face issues like that, it can be the start of a spiral downhill, you might then stop going to work or stop leaving the house, but we share these kinds of things.

“By having this interaction, it becomes a place people aren’t afraid to open up.”

With the centre having been closed for much of the past year, John and the team are ready to welcome back regular and new clients, including the many who are recovering from Long COVID.

“Many of our clients won’t have exercised for several months, but we hear very often that people have waited 20 years for a centre like this, so a few months hasn’t been long in comparison,” says John.

“But we are very much looking forward to re-opening and supporting our clients in regaining any progress and fitness they may have lost. Hopefully we are on the right track now after three lockdowns and clients can come back to us regularly.

“Long COVID is a new condition for us, as it has only come into being in the past few months, but we are ready to support people with their symptoms and in them using exercise as part of their recovery.”

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Brain tech company secures funding to increase support post COVID-19

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CBS Health will help clinicians utilise more digital services

An online brain assessment platform has secured funding to enable its work in telehealth to continue to support people as the world emerges from the COVID-19 pandemic.

Cambridge Brain Sciences (CBS) is planning to expand its operation through a funding round from Canadian Shield Capital, a Toronto-based private equity investment firm, closely aligned to Hatch, a global engineering consultancy.

The investment will allow Candian-based CBS to further its work in digital health, especially around mental health, and respond to the need for accurate and reliable quantified measures of brain function and brain health – hailed as being essential to so many people who have suffered psychologically from the effects of COVID-19.

The funds will allow CBS to grow its sales and customer support teams rapidly, which will enable it to roll out its flagship product, CBS Health, further.

It will also enable it to expand on CBS Health features to help continue to refine and develop its cognitive care platform for healthcare professionals treating the growing mental health, brain injury and ageing patient populations.

The COVID-19 global pandemic has seen many healthcare practitioners to adopt platforms such as CBS Health to manage patients remotely.

As a result of lockdowns and ‘stay at home’ guidance, there has been exponential growth in patients seeking treatment for mental health conditions brought on, or exacerbated by, the pandemic, as well as individuals recovering from COVID-19 suffering with longer term neurological symptoms.

CBS Health has also grown as a result, and offers a web-based platform or integration which allows healthcare professionals to administer the CBS tasks standalone or alongside other established and validated complementary assessments (such as the PHQ-9, a standard scale for assessing the severity of depressive symptoms).

Assessments can be combined into a single session and administered in person or remotely via email—an option from which clinicians have benefitted greatly throughout the COVID-19 global pandemic.

The investment also contemplates further collaboration between CBS and Hatch, building upon an earlier successful pilot for a dedicated CBS platform to address corporate workplace mental health and safety at large scale industrial operations, construction sites and infrastructure projects.

“CBS is excited to be closing this round of financing which builds upon a long-term relationship with Canadian Shield and an earlier successful pilot with Hatch,” says Marc Lipton, president and CEO of Cambridge Brain Sciences.

“The funding will allow us to further accelerate the growth of our core CBS Health product especially amongst mental health practitioners, as well as to strategically explore, with Hatch, large corporate applications for workplace mental health and safety.”

“CBS brings many years of academic discipline and rigorous digital measurement of cognitive health, with applications in mental health, brain injury recovery, healthy ageing, and soon workplace safety,” says Andrew W. Dunn, managing partner at Canadian Shield Capital.

“The growing awareness of, and attention to, mental health conditions and CBS’ engaging and efficient approach gives it enormous runway.”

James Marzocca, global managing director for project delivery at Hatch, adds: “We see great potential to apply CBS testing as a non-invasive diagnostic to assess fitness for duty for individuals reporting to worksites where mental alertness is essential for their own safety and the safety of others.”

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