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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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Learn more about virtual reality in rehab

Event is an opportunity to hear from expert Dr Katherine Dawson, Consultant Clinical Neuropsychologist.

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An event later this month will give neuro-rehab professionals an opportunity to learn more about the use of virtual reality in the field. 

The virtual webinar, on 26th January at 1.20pm to 2.30pm, features an in-depth talk by Dr Katherine Dawson, Consultant Clinical Neuropsychologist.

A Guide to Virtual Reality, which can be booked by emailing training@thinktherapy1st.co.uk, will cover:

– Growth of digital health

– Virtual Reality(VR) / Telerehabilitation evidence base

– Virtual tour of the Brain Recovery Zone VR platform

– Where does the Brain Recovery Zone sit in a clinical pathway

– Clinical outcomes, case studies, and research trial

Dr. Katherine Dawson has over 15 years experience working in various rehabilitation settings (both within the NHS and private sector) with individuals who have a wide range of neurological conditions.

She has a particular interest in cognitive rehabilitation, and working with individuals and families to manage emotional and behavioural changes following Acquired Brain Injury (ABI).

She is currently involved in research with the NHS regarding ABI and telerehabilitation, and has recently published a book exploring adjustment to brain injury from the perspectives of clients, family members and clinicians. 

In December 2017, Katherine set up a local neuro-rehab service (Sphere Rehab) with her business partner, focusing on community integration post ABI. She also co-founded the Brain Recovery Zone neuro rehab Virtual Reality platform in the summer of 2019. The team are commissioned by several local CCGs and also work within the private sector.

Ahead of the event, she said: “I just wanted to say a massive thank you to Think Therapy 1st for inviting me to talk about VR and the Brain Recovery Zone. Virtual Reality has great potential in neuro rehab – both to ‘up’ the dosage of rehab, in addition to promoting ongoing engagement and self management.

“I am really looking forward to delivering this webinar and discussing some of the clinical outcomes including the work completed together with Think Therapy 1st and other clients.”

Helen Merfield, Managing Director, Think Therapy 1st, which is organising the event, said: “I am really excited about our VR event we have used Dr Dawson on a number of cases with amazing results and her VR really has changed lives.

“So much so that we are partnering with her company Sphere as a preferred provider for both VR through Brain Recovery Zone and Clinical and Neuro psychology. Close working ties can only improve outcomes which for both our companies are already impressive.”

To register for the event email training@thinktherapy1st.co.uk.

 

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Neuropsychology

Sport and exercise ‘have key role in mental health and wellbeing’

The Moving for Mental Health report highlights the role of physical activity in supporting mental resilience and recovery

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Physical activity and sport can play a key role in supporting mental health and wellbeing and helping people to recover from the ongoing impact of the COVID-19 pandemic, a new report has concluded. 

The Moving for Mental Health report includes better training for health professionals to prescribe movement as a means of effectively tackling the vast growth in people experiencing mental health issues. 

Produced following the onset of the pandemic, the report sets out evidence that developing a healthy relationship with physical activity and being involved in linked programmatic interventions and social networks is beneficial, can improve people’s mental health and wellbeing, and help tackle social isolation.

The project, by the Sport for Development Coalition and Mind, highlights how COVID-19 has exposed the weaknesses of single-sector responses to addressing complex mental health problems and tackling growing health inequalities. 

The report recommends physical activity and community sport be further embedded in health policy and integrated care systems while calling for an enhanced role for experts by experience and diverse communities leading in the design, implementation and evaluation of future strategy and programming.

Launched at an online meeting of the All-Party Parliamentary Group for Sport, it is also designed to support and inspire public bodies, funders, commissioners and policy-makers as well as community-based programme providers aiming to enhance the impact of movement for mental health.

Paul Farmer, chief executive of Mind, said: “While Mind’s research suggests that half of adults and young people have relied on physical activity to cope during the pandemic, we also know that physical activity levels for people with long-term health conditions, including mental health problems, have declined. 

“Considering how vital physical activity is for many people’s mental health, it is clear that we need a collective effort to reach those who need support the most.”

Andy Reed, chair of the Sport for Development Coalition, said: “This report is aimed at supporting and informing policy-makers about how we can maximise the contribution of targeted sport and physical activity-based interventions at this crucial time.”

The research was led by a team of academic researchers from Edge Hill University and Loughborough University, and draws on evidence and submissions from over 70 organisations including sport and mental health organisations, public bodies and Government departments.

Andy Smith, professor of sport and physical activity at Edge Hill University, said: “The impact of Covid-19 on people’s mental health and wellbeing cannot be overstated. 

“It has brought to light the significant mental health inequalities which existed prior to COVID-19, but which have since worsened further, especially among those living in under-served and low-income communities. 

“Our research is calling on the Government and other public bodies to invest in the provision of movement opportunities for mental health across multiple policy sectors, and to use the evidence presented as a basis for making more effective policy decisions which benefit everyone’s mental health and which tackle deep-seated inequalities.”

Moving for Mental Health is the first policy report in a series being published throughout 2022 by the Coalition and relevant partners. The reports are aimed at maximising the contribution of targeted sport-based interventions to helping ‘level up’ communities facing disadvantage and deprivation and tackling deep-seated health and societal inequalities which have been exacerbated by COVID-19.

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Calvert Trust announces new trustees

Louise Dunn, Judith Gate, Emily Flynn and Victoria Notman bring their expertise to the Trust, which also runs Calvert Reconnections

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The Lake District Calvert Trust (LDCT), which runs brain injury rehabilitation centre Calvert Reconnections, has started 2022 by announcing the appointment of four new trustees.

Louise Dunn, Judith Gate, Emily Flynn and Victoria Notman will bring their respective expertise to supporting the further development of the charity and its vital services.

Louise Dunn

Louise Dunn is a communications consultant and academic with over 25 years’ experience of management and leadership roles in the pharmaceutical industry and at Alder Hey Children’s NHS Foundation Trust and Charity.

Commenting on her appointment, Louise said: “As a Keswick resident, I’m delighted to be able to get involved with this extraordinary organisation, that has such a positive impact for people living with disabilities in our community and all over the UK.

“I am looking forward to learning more about how I can help the team and contributing to their exciting plans for the future.”

Judith Gate has extensive experience in the charity and public sectors including leading the volunteering and customer care functions for a national charity.

She currently leads a continuous improvement programme with a focus on delivering efficiency and improved customer experience through business process improvement and digital transformation.

Judith Gate

Judith said: “I applied to be trustee because I wanted to use my skills to deliver as much positive impact as possible. As an outdoor enthusiast I feel a genuine connection to the Calvert Trust‘s mission of making outdoor activity accessible to everyone

“I am really excited to join the board and look forward to using my knowledge and experience to help support the Trust achieve its ambitions over the coming years.”

Emily Flynn has over 21 years’ experience as a military officer and communications-electronics engineer across a wide spectrum of business areas including: senior leadership/board-level management; digital optimisation; resource planning; engineering, operations and risk management; trusteeship; and mountaineering leadership.

Commenting on her appointment, Emily said: “I am delighted to become a trustee of the Lake District Calvert Trust.

“The military introduced me to the benefits of outdoor education as a means of expanding personal confidence and stretching comfort zones in a controlled environment. It also led me to become a mountaineer.

“I hope to be able to bring my previous experience as a leader, mountaineer, engineer and trustee to help the Calvert Trust

Emily Flynn

continue to deliver amazing outdoor education to its participants and to help it grow over the next few years.”

Victoria Notman is legal director at the employment team at Burnetts Solicitors in Carlisle and has over 20 years’ experience as an employment lawyer.

She also has a first-class honours degree in physiotherapy and experience in the rehabilitation and development of adults and young people with mild to severe physical and mental impairments and learning needs.

Victoria said: “I am looking forward to applying my knowledge and skills to become integrated into the fabric of the Trust to such a degree that all the experience I have to offer can really make a difference to the lives and happiness of those accessing Calvert Lakes and Calvert Reconnections.”

Welcoming the charity’s new trustees, Giles Mounsey-Heysham, chairman of the LDCT Trustees, said: “After a detailed recruitment process, we are delighted to welcome our new Trustees.

Victoria Notman

“Together they bring a wealth of skills, experience and shared passion to the Lake District Calvert Trust. We welcome their contributions moving forward.”

The Lake District Calvert Trust has been supporting people with disabilities from its specialist Calvert Lakes residential centre and accessible riding centre near Keswick in the Lake District for almost 45 years.

Calvert Lakes has grown from being the UK’s first dedicated activity centre for people with disabilities, to welcoming around 3,500 visitors to stay each year.

These include individuals, family groups, specialist schools, accessible sports clubs, disability charity groups, supported living organisations and care homes across the UK.

Last year, the charity also opened Calvert Reconnections, the UK’s first residential brain injury rehabilitation programme combining traditional clinical therapies with physical activity in the outdoors.

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