Obesity: hamsters may hold the clue to beating it

Apply by 28 February for our Research Grants of up to £10,000 (over a 12 to 18-month period). This scheme supports physiologists in their first permanent academic position or returning to a permanent position after a career break, to provide support for their research or to provide seed-funding to start a new project. Gisela Helfer was a 2017 awardee of this grant, and you can read about her research below:

The global obesity crisis shows no signs of abating, and we urgently need new ways to tackle it. Consuming fewer calories and burning more energy through physical activity is a proven way to lose weight, but it’s clearly easier said than done. The problem with eating less and moving more is that people feel hungry after exercise and they have to fight the biologically programmed urge to eat. To develop effective ways to lose weight, we need a better understanding of how these biological urges work. We believe hamsters hold some clues.

Hamsters and other seasonal animals change their body and behaviour according to the time of year, such as growing a thick coat in winter or only giving birth in spring. Some seasonal animals can also adjust their appetite so that they aren’t hungry when less food is available. For example, the Siberian hamster loses almost half its body weight in time for winter, so they don’t need to eat as much to survive the winter months. Understanding the underlying physiological processes that drive this change may help us to understand our own physiology and may help us develop new treatments.

How hungry we feel is controlled by a part of the brain called the hypothalamus. The hypothalamus helps to regulate appetite and body weight, not only in seasonal animals but also in humans.

Tanycytes (meaning “long cells”) are the key cells in the hypothalamus and, amazingly, they can change size and shape depending on the season. In summer, when there is a lot of daylight and animals eat more, tanycytes are long and they reach into areas of the brain that control appetite. In winter, when days are shorter, the cells are very short and few.

These cells are important because they regulate hormones in the brain that change the seasonal physiology of animals, such as hamsters and seasonal rats.

Growth signals

We don’t fully understand how all these hormones in the hypothalamus interact to change appetite and weight loss, but our recent research has shown that growth signals could be important.

One way that growth signals are increased in the brain is through exercise. Siberian hamsters don’t hibernate; they stay active during the winter months. If hamsters have access to a running wheel, they will exercise more than usual. When they are exercising on their wheel, they gain weight and eat more. This is true especially during a time when they would normally be small and adapted for winter. Importantly, the increased body weight in exercising hamsters is not just made up of increased muscle, but also increased fat.

We know that the hamsters interpret the length of day properly in winter, or, at least, in a simulated winter day (the lights being on for a shorter duration), because they still have a white winter coat despite being overweight. We now understand that in hamsters the exercise-stimulated weight gain has to do with hormones that usually regulate growth, because when we block these hormones the weight gain can be reversed.

When people take up exercise, they sometimes gain weight, and this may be similar to what happens in hamsters when appetite is increased to make up for the increased energy being burned during exercise. This doesn’t mean that people shouldn’t exercise during the winter, because we don’t naturally lose weight like Siberian hamsters, but it does explain why, for some people, taking up exercise might make them feel hungrier and so they might need extra help to lose weight.

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We need to find ways to overcome appetite. Lucky Business/Shutterstock.com

What we have learned from studying hamsters so far has already given us plenty of ideas about which cells and systems we need to look at in humans to understand how weight regulation works. This will create new opportunities to identify possible targets for anti-obesity drugs and maybe even tell us how to avoid obesity in the first place.

By Gisela Helfer@gi_helfer and Rebecca Dumbell

(This blog was originally published on The Conversation.)

Life at the Limits: Register now for our extreme environmental physiology conference

By Mike Tipton, @ProfMikeTiptonExtreme Environments Laboratory, Department of Sport and Exercise Science, Portsmouth University

“Ecology”, from the Greek “oikos” meaning home or place to live, is the branch of biology that deals with the relationships of organisms and their physical surroundings. It encompasses the impact of animals on their environment, and the environment on animals. Both sides of the ecology coin are becoming increasingly important and linked.

On one side we are careering, largely unfettered, towards the man-made abyss of the end game of global warming; we are threatening our direct descendants, but at a rate and distance that doesn’t provoke us to action.

On the other side, only 15% of the surface of our planet is not water, desert, ice or mountain. For a tropical, low altitude, air-breathing human, this means most of planet Earth represents an extreme environment, defined as a place where it is difficult to survive. The link between the two is, of course, that global warming will make our planet even more extreme with flooding, erosion, heat waves, cold snaps and desertification.

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Perhaps, therefore, there is no better time for The Physiological Society to plan a specialist conference on Extreme Environmental Physiology (EEP) on 2-4 September.

From origins where EEP research was largely undertaken for occupational groups such as miners and the military, as well as those attempting expeditions to remote parts of the globe, EEP has now become much more “mainstream.” The greatest number of submissions and publications in the journals of The Physiological Society come from the areas of “environmental” and “exercise” physiology; both of which have extreme environmental components.

EEP research continues to examine the responses of humans to environmental stressors such as heat, cold and altitude; these remain important areas in themselves with, for example, at least 1000 people dying from drowning every day around the planet. But EEP research is now also providing insights into a wide range of other conditions such as: responses to hypoxia on intensive care (“survivor phenotypes”); ageing; peripheral vascular disease; osteoporosis; and debilitation caused in critical care patients by bed rest.

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In addition, as we take greater and greater control of our environment through technology, it is becoming increasingly apparent that we need to challenge our homeostatic mechanisms in order to remain functional. At one time we did this naturally by exercise and exposure to the natural world, now we have to employ thermal therapies for a wide range of physiological and mental health pathologies, from microvascular function through autonomic function to depression.

The specialist conference at Portsmouth in September will reflect all of the above, with sessions on cold, heat, hypo- and hyperbaric physiology, micro-gravity and cross-adaptation. To remind us what an eclectic discipline physiology is, each session will include short keynotes on physiology, pathophysiology and comparative physiology, as well as plenty of time for free communications. Finally, it seems appropriate that we should “flip the coin” and spend some time on what the environment might have in store for us if we continue to damage it.

Our exciting keynote speakers include:

References

  1. Martin & McKenna (2017). High Altitude Research and its Relevance to Critical Illness. ICU Management & Practice 17(2): 103-105.
  2. Tipton MJ (2015). GL Brown Lecture: “Extreme Threats” Environmental extremes: origins, consequences and amelioration. Experimental Physiology. doi: 10.1113/EP085362.
  3. Tipton, M. J. (2018) Humans: a homeothermic animal that needs perturbation? Experimental Physiology. https://doi.org/10.1113/EP087450.

Early Career Conference: Join us in December!

Want to run a two-day early career physiology conference? This valuable experience will give you leadership experience and boost your CV! Any Affiliate and/or Undergraduate Members of The Society may apply. Read testimonials from our first Future Physiology conference in 2017 below. 

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Jose L. Areta, Norwegian School of Sport Sciences, Oslo, Norway:

Attending the Future Physiology meeting in Leeds in December 2017, coming all the way from Oslo, Norway, was a privilege I had thanks to a Physiological Society travel grant. I am a post-doctoral researcher in the early stages of what, I think, might turn into a long academic career. I signed up for this conference specifically to get a better overview and insights on what a researcher at my stage could do to make the right choices for his future career. The conference did not fail to provide valuable food for thought.

The attendees included a wide range of representatives of the academic career continuum, from undergraduates to professors. A majority of these were, seemingly, early career researchers (ECRs) and they belonged to a reasonably wide range of areas within the field of physiology. This showed that the purpose of the conference was to go beyond delving into their specific areas of expertise. A dominant topic of interest seemed to be commonalities irrespective of the specific area of expertise, meaning the ins and outs of working in and growing through academia.

Several of the sessions provided examples of more established researchers showcasing how they built their own academic careers in the context of research in physiology. The take-home message for me was that there is no one way to become an established researcher in any given area. The impression that I got is that love for the work you do followed by dedication and a solid network play a key role, immediately followed by serendipity. This seemed to provide some support to the saying ‘the harder you work, the luckier you get’, that I sometimes remind myself of.

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On that note, it was also nice to feel supported by other researchers going through similar difficulties in a research system that seems to very often put high-pressure on individuals and can lead to sub-optimal life quality and, in many cases, burnout. Uncertainty seems to be a common denominator for many researchers in different stages of their careers (more so ECRs). Making this explicit is important to find a solution for it. I think this conference was a good first step to bridge the gap between ECRs who have a lot of questions on how to progress through the ranks, while making meaningful contributions to science and more experienced researchers talking about their specific experiences or professionals providing advice.

Personally, one of my favourite events was a small grant-writing workshop I had the chance to attend that also turned into a bit of a career advice workshop. Transitioning towards being an independent researcher is very significant milestone for anyone in research, I think. Gathering some tools to do so in the context finding one’s place in the field was a nice addition to the experience of the conference.

In conclusion, I think this conference was a good first step to put the uncertainties that ECRs face throughout their development as researchers in the spotlight, and provide them (us!) with tools and networks for better tackling these.

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Dan Brayson, King’s College London, London, UK:

As a member of the Affiliate Working Group of The Society, I was privileged to have the opportunity to help with the planning and execution of the Future Physiology meeting, an early career researcher (ECR) focussed meeting held at the University of Leeds last month. The meeting was ‘by ECRs for ECRs’. This meant that the Affiliate Working Group was placed at forefront of the brainstorming process to come up with a plan for a meeting which facilitated an engaging experience for early career scientists.

What we hoped for was an opportunity for ECR’s to shed their inferiority complex baggage (we all have it), and to feel invigorated by the conference experience rather than being overwhelmed. To this end 20 ECRs were selected for oral presentations whilst five talks were given by senior scientists (for balance, of course). Of these, three were young PIs and shining examples that we don’t have to wait around for professors to retire in order to make significant progress in our careers. We hoped that this would add a motivational slant for attendees. If they can do it, why can’t we?

On a personal note it was a red letter day. I was charged with sharing the chairing and presentation-marking duties with my fellow Affiliate Working Group members, a first for me, and with this, I got to experience the joy of facilitating meeting proceedings rather than merely taking part. At least this was my perception of it, and I would definitely do it again.

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Reflecting now on the meeting I feel that it was a good first crack at a meeting for ECRs. However, I also feel that there is further scope to create the most engaging and immersive experience for young scientists. One idea would be to have facilitated debate workshops on general topics (neuroscience, cardiovascular physiology, gastrointestinal physiology etc.). This would engage people in a relaxed environment to talk more generally about the big issues/questions facing their chosen fields.

Life Sciences 2019: Post-translational modification and cell signalling

Submit your abstract by 21 January 2019 for this exciting meeting on 17-18 March 2019 in Nottingham, UK. 

By Gary Stephens, member of the Organising Committee

Even after proteins are built via transcription and translation, post-translational modifications (PTMs) can change their function. As this has implications throughout the body – such as neuronal signalling, cardiac function, circadian rhythms and in diseases including cancer and psychiatric disorders – post translational modulations are an expanding area of scientific research. All physiologists looking to innovate their science by networking across disciplines should attend Life Science 2019, brought to you by The Physiological Society, the British Pharmacological Society and the Biochemical Society.

In addition to symposia and plenary lectures, the meeting will have training events and an early career researcher (ECR) networking event. If you’re keen to present your research orally, you’re in luck, as a good number of submitted abstracts will be elevated to oral presentations, in particular from ECRs.

PTMs increase the diversity of the protein function, primarily by adding functional groups to proteins, but can also involve the modification of regulatory subunits, or degradation of proteins to terminate effects. PTMs include numerous biologically vital processes such as phosphorylation, glycosylation, ubiquitination, SUMOylation, nitrosylation, methylation, acetylation, lipidation and proteolysis. Identifying and understanding PTMs within major body systems including neuronal, cardiovascular and immune systems is critical in the study of normal physiological function and disease treatment.

As a researcher interested in synaptic function, one symposium that has immediate personal appeal is “PTMs in the regulation of neuronal synapses” will include how PTMs on both sides of the synapse are fundamental to forms of synaptic plasticity. Matt Gold (University College London, UK) will speak on targeting of the calcium/calmodulin-dependent protein phosphatase calcineurin in postsynaptic spines. Moitrayee Bhattacharyya (University of California, Berkeley, USA) will present about the postsynapse, specifically the role of calcium/calmodulin-dependent protein kinase II in driving synaptic long-term potentiation via modifications in postsynaptic spines. For the ion channel aficionados, Annette Dolphin (University College London, UK) will discuss the role of post-translational proteolytic cleavage of α2δ voltage-gated calcium channel subunits in synaptic function.

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Protein methylation in health and disease will feature a presentation from Steven Clarke, (University of California Los Angeles, USA) on cross-talk between methyltransferases to affect the final degree of protein modification and epigenetic control. Kusum Kharbanda (University of Nebraska, USA) will present about how external stimuli such as the consumption of alcohol has important cellular consequences for methyltransferase activity and the development of disease. Pedro Beltran-Alvarez (University of Hull) will detail the combination of biochemical, cell biology, bioinformatics and proteomics methods used to identify the arginine methylome in tissues including platelets and the heart. This has clear functional importance in physiological cardiovascular function.

We hope to see you in Nottingham!

Friends in high places: Researchers go global for answers at high altitude (Part 2)

By Alexandra Williams, @AlexM_Williams

This blog is the second and final part of a series that began here.

Experience

1 July 2018, Day 2 at altitude

The viscometer is being set up in the bloods room and is a key weapon in our arsenal for primary outcome measures in multiple studies. Due to voltage differences (compared to Canada) the unit needs to be connected to a step-down. We connect the viscometer, water bath and the step-down, and at first all seems to be functioning well. A few minutes later, an odd scent emerges. Ah, the step-down is smoking, not good! This unfortunately is not the first fire hazard we’ve encountered. In Nepal, one of our technicians had to rewire most of the outlets to ensure they wouldn’t catch flame. A few days ago, an outlet connected to a locally-made space heater went alight. We are constantly having to double- and triple-check that our equipment doesn’t melt due to poor electrical wiring, or mismatched voltage inputs/ outputs. At the same time, though, we more often find ourselves very thankful that we have electricity to power the large volume of studies being conducted in these remote locations.

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Views from the valleys: descent through Lobuche Pass, Nepal 2016 (top) and Ticlio Pass, Peru 2018 (bottom), both ~4800-5000 m altitude.

These expeditions provide comprehensive research experience and encourage growth amongst the team and its individuals. Things are not always sunshine, rainbows and unicorns, though the many logistical hurdles provide an opportunity for learning and developing our problem-solving abilities.

We often must think outside of the box and utilise our creative capacities to circumvent roadblocks, technical difficulties and unexpected challenges.

Aside from common technical conundrums, there are often cultural barriers that are both interesting and of course region-dependent. One obvious challenge is language – in Nepal, this was less obvious because many of the porters and Sherpa required some English for their work in tourism. Surprisingly to us, Peru has proved much more difficult, as virtually no one in Cerro de Pasco speaks a language other than Spanish. In fact, the local residents have an accent that is ‘poquito’ difficult for our translators to understand, so trying to explain protocols can be tricky. For example, measurements of total blood volume using the carbon monoxide rebreathe technique require the participant to complete a few steps: fully empty the lungs; attach to the spirometer mouthpiece; turn the valve; rapidly fill the lungs and hold for ten seconds; breathe normally for two minutes into the spirometer; then empty the lungs and turn the valve to close the system… all without breaking the glass spirometer (Fig. 2). Simple, right? Not so much. Despite our efforts to perform practice runs and explain the protocol several times over with physical demonstrations and translators, this is notably challenging.

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Members of the Global REACH team, in 2016 at the Ev-K2-CNR Laboratory (5050m) in Khumjung region, Nepal (top) and recently in 2018 at the Institutio de Investigaciones de la Altura (4350m) in Cerro de Pasco, Peru (bottom).

While these international expeditions allow us to become immersed in a different geographical and cultural environment, certain local traditions or values unbeknownst to us can provide unexpected barriers. In Nepal, the Sherpa were incredibly kind, and almost always smiling. They would seldom show negativity or utter complaints. One of our prime focuses on these expeditions is to examine blood markers of inflammation, blood gases and hematocrit concentration. In Nepal we collected serial arterial and venous blood samples at every stop during our ascent, but in Pheriche, one stop before the Pyramid, the Sherpa began to show concern, some requesting to skip the blood draws. We would find out the Sherpa perceived blood as their lifeforce, and that once lost, blood could not be replaced. They believed the loss of blood would weaken them and impair their state of being.

One translator mentioned the word ‘vampire’ and explained the concern that their blood might be sold. Luckily, with the help of our lead Sherpa and a few of the elders, we were able to convey that the bloods were solely used for research purposes and that we would never take more than necessary for study.

1 July 2018, day 2 at altitude; 16:05 h

I look over after completing one great blood volume test on the fourth Andean participant today (we’re getting more effective at translating) and the viscometer is now working, with a step-down that isn’t smoking! Turns out the previous step-down was pulled off the shelves of the Cerro lab. We’ve found one of our own from Canada and it has worked like a charm. With a bit of flexibility and a sprinkle of luck, these things often happen to work out.

Despite the aforementioned challenges, these expeditions provide overwhelmingly positive experiences, opportunities for personal growth and adventure. As researchers, we gain incredible organisational skills: much like a game of Tetris, we learn to schedule participants amongst multiple studies, ensuring a fine balance between efficiency and crossover i.e. that no measures conflict with other studies. Our communication skills grow as we continually coordinate between our local contacts, the P.I.s and the rest of the team. Even when things go completely off-plan, we learn to utilise flexibility and make the best of challenging situations. This field-based research teaches us quick thinking, adaptability (no pun intended) and resourcefulness. The challenges themselves provide strong learning experiences to be applied moving forward.

Perhaps the most obvious and enticing draw of these expeditions is the element of adventure. Not surprisingly, team leader Phil Ainslie’s initial involvement in altitude research was borne from his job as a mountain guide before attending university. ‘The first (trip) was when I was 22 or 23… I was running a trip in northwest India to some peaks at 6,000 m or 7,000 m. Damian (Bailey) was my instructor and he asked, ‘would you collect some blood samples’? And I said, ‘sure’. I spun samples down with a hand-crank centrifuge at 5,000 m on 25 people and took (saturation) measures, just me. And brought it all back. I’ve gone back (to altitude) every few years since.’ Following Phil’s lead, these expeditions allow us to explore incredible regions and share awe-inspiring experiences with our international collaborators. Visiting Everest Base Camp or climbing a (slightly dangerous) hill to look out at the Andes creates a bond of friendship and provides the foundation for long-lasting international collaborations that define Global REACH.

Team

9 July 2018; 21:53 h

Phil Ainslie (University of British Columbia), Mike Stembridge (Cardiff Metropolitan University), Craig Steinback (University of Alberta) and Jonathan Moore (Bangor University) and I are sat in the lobby of our hotel, chatting over a few Cusqueña beers. While discussing the 2016 Nepal Expedition, I explained how impressed I was that a group of 37 individuals had worked so well together, with no obvious dramas despite living in a harsh environment.

‘It’s similar to the New Zealand All Blacks values… basically the ‘no dickheads’ rule’, one of us said. We all laughed, then nodded in agreement. ‘Well, much like in mountaineering leadership, a mantra of the All Blacks rugby team is that they ‘sweep the sheds’, meaning that it doesn’t matter if you’re the star player – everyone on the team cleans the dressing room. If you’re a dickhead, if you’re not a team player, you’re not part of the All Blacks.

Phil has explicitly provided permission to include this conversation in the article, because while blunt, this type of value characterises the core of our collaborations and ensures the success of the expeditions. When everyone works together, dismisses ego and shares positive energy, the team thrives. Sixteen-hour testing days become relatively easy when you’re having fun.

Our team is at the heart of our success. We embrace collaborators with infectious personalities that border on the sides of eclectic and hyperactive: those with a genuine passion for research and zest for life. Team members remind each other to look beyond the academic pressures of funding and publication for the sake of career progression and light a fire and excitement for discovery.

Our peers drive us to new heights, literally and figuratively, in our academic prowess. We find less pride in our individual successes than in those of our teammates.

Our leaders – Phil Ainslie, Mike Stembridge and the late Christopher Willie – continue to inspire us. Their energy brings the continents together to create impressively cohesive and brilliant multidisciplinary collaborations. Their teams will continue to go global and reach for answers to important health-related questions at Earth’s highest altitudes.

(You can read the full article in its original version in Physiology News magazine.)

Friends in high places: Researchers go global for answers at high altitude (Part 1)

By Alexandra Williams, @AlexM_Williams

Global Research Expedition on Altitude Related Chronic Health (or Global REACH) is an international collaboration of academics and physicians from 14 institutions across Canada, the UK, the US, Peru and Nepal. While the “Global REACH” title is relatively new, its leaders have conducted a multitude of expeditions over the last decade to Nepal’s Himalaya, California’s White Mountains and now Peru’s Andes. With a collective interest in heart, lung and vascular health and altitude medicine, Global REACH’s collaborations ultimately aim to understand how the human body adapts, or maladapts, chronically to the low oxygen environments of earth’s highest altitudes.

I am writing this from 4,300 m, at the Laboratorio de Cerro de Pasco and Institutio de Investigaciones de la Altura in Peru. Our team of over 40 researchers, trainees, principal investigators and physicians are currently conducting approximately 20 studies examining heart, lung and brain physiology in lowlanders (us) and Andean highlanders with and without chronic mountain sickness.

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Example of a centrifuged blood sample from an Andean participant with chronic mountain sickness. A normal, healthy lowlander’s hematocrit (i.e. fraction of red cells in the blood) is ~40%; several Andean participants including this one had hematocrit values of 75-80%.

This series of blogs, however, does not intend to outline our experiments or specific scientific findings (which was described in a recent issue of Physiology News). Instead, you will get a raw, behind-the-scenes look at what transpires on these expeditions: the challenges we face, the experiences we gain, and most importantly the team values that drive the success of these international collaborations.

30 June 2018: Day 1 at altitude

Yesterday, the last of three groups of the Global REACH team drove from sea level in Lima up to 4,300 m in Cerro de Pasco, Peru. Amongst the team, some individuals are feeling “okay” (say, a rating of 7/10), while others have been in bed with splitting headaches for more than 24 hours. We would later discover that one, in fact, had a bout of pneumonia. Nevertheless, one thing remains constant across the team – the excitement. It is palpable. Seven lab bays are set up, participants are being scheduled in, the equipment is (mostly) accounted for and working. Data collection has already begun today, and our first Andean participants are coming in tomorrow morning. This is what we came for, and we’re ready for the fun to begin.

For those who haven’t experienced the thin air of Earth’s highest mountain ranges, a 7-hour jump from sea level to over 4,300 m altitude is significant, one which often leaves individuals feeling much worse than “not great.” Yet, with advanced knowledge of the side effects of altitude and hypoxic exposure, Global REACH members have joined forces to answer a plethora of physiological questions. For many, this will mark more than four expeditions to high altitude, a select few even in the double digits. In the first few days, most – including our team leaders – will have headaches, nausea, sleep disturbances and apnoeas. The inter-individual variability of these symptoms is quite high, as a select few may feel fine, most will feel some magnitude and combination of the list, and others will be periodically out of commission.

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Performing a carbon monoxide rebeathe test to measure red cell volume and total blood volume with an Andean participant in Cerro de Pasco. This method is technically challenging, and is made more difficult with a significant language barrier.

So, why do we do it? Why do we involve ourselves with the potential suffering at altitude and any additional risks (i.e. transport, illness) kindred to these trips? From my experience, three fundamental elements outweigh the risks and define the success of expeditions and collaborations like Global REACH: the science, the experience, and the team.

Science

1 July 2018: Day 2 at altitude

“MAS FUERTE, MAS FUERTE, yeah Johnny!” Johnny, our first Andean participant is laying on the bed of testing Bay 1, currently practising a handgrip protocol for a vascular study. Johnny already has a venous catheter placed in his forearm and will be shuttled through a screening circuit: ultrasound imaging (cardiac, ocular and vascular), a maximal exercise test and assessment of total blood volume. Our Spanish skills are currently dismal, but we’re managing to compliment the amazing work of our translators to collect a large cardiovascular dataset on approximately 50 Andean participants.

3 July 2018: Day 4 at altitude

Four of us are working in the bloods room to measure total blood volume, hematocrit and viscosity. We knew from previous reports that Andeans would have augmented total blood volumes and hematocrit levels compared to us lowlanders but seeing those bloods ourselves was staggering. ‘A hematocrit of SEVENTY-EIGHT per cent!’ a colleague yelled, astounded. For reference, a lowlander’s normal hematocrit is ~40%. (Fig. 1) An undeniable passion for physiology underpins collaborations like Global REACH.

The energy amongst the group drives impressive productivity and allows us to complete multiple studies in relatively restricted time periods. During the 2016 Nepal Expedition our team conducted 18 major studies, including a total of 335 study sessions in just three weeks at 5,050 m (further to multiple sea level and ascent testing sessions). This high-density data collection is relatively uncommon outside of field work and is only made possible by the vast breadth of technical fluency, specific expertise and research experience amongst the team. The expeditions allow us to not only answer our current questions but further breed a multitude of ideas for future study.

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‘We could answer that one next, Ethiopia 2020? Another Nepal expedition?’ Of course, these expeditions allow us as trainees and investigators to be productive, and to present and publish high-quality data and exciting findings. They strongly contribute to our development and career progression in academia. But what is undoubtedly most important is the greater aim of Global REACH: to understand altitude health on a ‘global’ scale. This collaboration and research ultimately aims to understand why chronic mountain sickness occurs, how different high-altitude communities have adapted (or maladapted) to low oxygen, and what might ultimately be done to improve the health of individuals exposed to acute or chronic hypoxia.

Stay tuned for Part 2 next week, or read the full article in its original version in Physiology News magazine.

Putting visual information into context

By Nathalie L. Rochefort and Lukas Fischer

The cerebral cortex is the seat of advanced human faculties such as language, long-term planning, and complex thought. Research over the last 60 years has shown that some parts of the cortex have very specific roles, such as vision (visual cortex) or control of our limbs (motor cortex).

While categorizing different parts of the cortex according to their most apparent roles is convenient, it is also an oversimplification. Brain areas are highly interconnected, and studies over the past decade have shown that incoming sensory information is rapidly integrated with other variables associated with a person or an animal’s behavior. Our internal state, such as current goals and motivations, as well as previous experience with a given stimulus shape how sensory information is processed. This can be referred to as the “context” within which a sensory input is perceived. For example, we perceive a small, brightly-colored object differently when we see it in a candy store (where we might assume it is a candy) compared to seeing it in the jungle (where it might be a poisonous animal). In our recent article published in Cell Reports, we investigated the factors that impact the activity of cells in the visual cortex beyond visual inputs as animals learned to locate a reward in a virtual reality environment.

Researchers have known since the 1960s that cells in the primary visual cortex exhibit striking responses to specific features of the visual environment such as bars moving across our visual field or edges of a given orientation. The traditional view of a hierarchical organization of the visual system was that primary visual cortex encodes elementary visual features of our environment, and then forwards this information to higher cortical areas which, in turn, take these individual visual elements and combine them to represent objects and scenes. Our understanding of how an animal’s current behavior influences information processing, however, was limited. Recent studies have started to address this question directly and found that neurons in primary visual cortex show more complex responses than expected. We have set out to use cutting-edge technological advances in systems neuroscience to understand what type of information is processed in the primary visual cortex of awake animals as they learn to find rewards.

A window into the brain, literally

We have combined two recent technologies to record from a large number of individual neurons in primary visual cortex while mice were awake and free to run. An advanced microscopy technique, two-photon calcium imaging, allowed us to visualize the mouse brain and record the activity of hundreds of neurons through a small implanted window.

A key challenge with this technique, however, is that the mouse head has to remain fixed. We, therefore, constructed a virtual reality system in which an animal was placed atop a treadmill, surrounded by computer screens displaying a virtual environment within which they can freely move while their head remains in the same place. The virtual environment consisted of a linear corridor with a black-and-white striped pattern on the wall and a black wall section (visual cue) in which the mouse could trigger a reward (sugar water) by licking a spout. This allowed us to train animals to find rewards at a specific location within the virtual environment while simultaneously recording the activity of neurons in the visual cortex.

More dedicated neurons, more reward

Our first, unexpected, finding was that after learning the task, a large proportion of neurons (~80%) in the primary visual cortex were responding to task-specific elements, with many cells becoming specifically more active when the animal approached the reward area. Interestingly, the number of these “task-responsive” cells strongly correlated with how well the animals performed the task. In other words, the more precisely animals were able to locate the reward location, the more cells we found to be active around that location of the virtual corridor in the visual cortex. This was surprising as neurons in the visual cortex clearly seemed to be as interested in where the animal could get a drop of sugar water, as the visual features of their surroundings. To test the impact that the visual reward cue (black wall section) itself had on the activity, we removed this cue and found that some neurons still responded at the rewarded location. This suggests that these neurons in the visual cortex were no longer only depending on visual information to elicit their responses.

Visual inputs matter, but sometimes motor-related inputs matter more

These results opened up a number of interesting questions about what is driving these responses as it was clearly not only visual inputs. We wanted to understand the factors driving this activity in the visual cortex. Mice could use two strategies to locate the reward when no visual cue was present to indicate the reward point. The first strategy relies on their internal sense of distance based on feedback from the motor systems (motor feedback). In other words, an estimate of how far a mouse has traveled based on how many steps they have taken since the beginning of the corridor. The second strategy would be to rely on an estimate of position based on the way the visual world moves past the animal, known as “optic flow.”

We took advantage of the unique opportunities in experimental design afforded by a virtual reality system to test which information is driving those reward-location specific responses. By creating a mismatch between the animal’s own movement on the treadmill and the visual movement of the external virtual environment, we were able to test whether it is motor feedback or visual flow that determines where the animal thinks it is along the corridor, and, correspondingly, where these neurons representing the reward location become active. The results showed that animals expected the reward location primarily based on motor feedback. This means that there are some neurons in the primary visual cortex that encode information related to the location of a reward, based on an animal’s motor behavior rather than purely visual information.

However, in our final experiment, the importance of visual inputs became clear again: when the visual cue indicating the reward location was put back in, while still maintaining the mismatch between treadmill and virtual movement, the animal’s behavior, as well as the neuronal responses, snapped back to the visual cue, disregarding the number of steps it had taken. This suggests that motor feedback is available to and used by the primary visual cortex, but in a conflict situation, the visual cues indicating a specific location, override other types of information to correctly locate a reward.

Conclusion

These results demonstrate the importance of behavioral context for sensory processing in the brain. The primary visual cortex, a region that was once thought to primarily represent our visual world by detecting elementary visual features such as edges, is also influenced by prior experience, learning, and interactions with our environment. A prominent model proposed to explain sensory cortical function, posits that the cerebral cortex creates a representation of what we expect, based on current sensory inputs and previous experience.

Our results are congruent with this model while emphasizing the large role of contextual factors, such as motor feedback and prior knowledge of a location. Future studies are necessary to determine how different types of inputs to sensory regions of the brain influence the activity of individual neurons and how they shape our perception of the world.

These findings are described in the article entitled The Impact of Visual Cues, Reward, and Motor Feedback on the Representation of Behaviorally Relevant Spatial Locations in Primary Visual Cortex, recently published in the journal Cell ReportsThis work was conducted by Janelle M.P. Pakan from the University of Edinburgh, the Otto-von-Guericke University, and the German Center for Neurodegenerative DiseasesStephen P. Currie and Nathalie L. Rochefort from the University of Edinburgh, and Lukas Fischer from the University of Edinburgh and the Massachusetts Institute of Technology.

This blog originally appeared on the website Science Trends.

Nathalie L. Rochefort has been awarded the 2018 R Jean Banister Prize Lecture. The prize is awarded to early career physiologists in the late stages of a PhD, postdoc or who are in an early faculty position. It was established in 2016 in memory of a former Member of The Physiological Society, (Rachel) Jean Banister who left a legacy to The Society when she passed away in 2013.