By Alexandra Williams, @AlexM_Williams
Stay tuned for Part 2 next week, or read the full article in its original version in Physiology News.
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.
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.
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.
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.
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 Reports. This work was conducted by Janelle M.P. Pakan from the University of Edinburgh, the Otto-von-Guericke University, and the German Center for Neurodegenerative Diseases, Stephen 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.
By Andrew Parker, Oxford University
Stereo vision may be one of the glories of nature, but what happens when it goes wrong? The loss of stereo vision typically occurs in cases where there has been a problem with eye coordination in early childhood. Developmental amblyopia, or lazy eye, can persist into adulthood. If untreated, this often leads to a squint, or a permanent misalignment of the left and right eyes. One eye’s input to the brain weakens and that eye may even lose its ability to excite the visual cortex. If the brain grows up during a critical, developmental period with uncoordinated input from the two eyes, binocular depth perception becomes impossible.
My lab’s work supports a growing tide of opinion that careful binocular training may prove to be the best form of orthoptics for improving the binocular coordination of the eyes. Recent treatment of amblyopia has tended to concentrate on covering the stronger eye with a patch to give the weaker eye more visual experience with the aim of strengthening the weaker eye’s connections to the visual cortex. Now we understand from basic research like ours that there is more to stereoscopic vision than the initial connection of left and right eyes into the primary visual cortex.
Secret Stereo Writing. The great Spanish neuroanatomist Ramon y Cajal developed this technique for photographically sending a message in code. The method uses a stereo camera with two lenses and two photographic plates on a tripod at the left. Each lens focuses a slightly different image of the scene in front of the camera. The secret message is on plate B, whereas plate A contains a scrambled pattern of visual contours, which we term visual noise. The message is unreadable in each of the two photographic images taken separately because of the interfering visual noise. Each photograph would be sent with a different courier. When they arrive, viewing the pair of photos with a stereograph device as in Figure 1, the message is revealed because it stands out in stereo depth, distinct from the noisy background. Cajal did not take this seriously enough to write a proper publication on his idea: “my little game…is a puerile invention unworthy of publishing”. He could not guess that this technique would form the basis of a major research tool in modern visual neuroscience.
Our lab is investigating the fundamental structure of stereoscopic vision by recording signals from nerve cells in the brain’s visual cortex. One of the significant technical developments we use is the ability to record from lots of nerve cells simultaneously. Using this technique, I am excited to be starting a new phase of work that aims to identify exactly how the visual features that are imaged into the left eye are matched with similar features present in the right eye.
The neural pathways of the brain first bring this information together in the primary visual cortex. Remarkably there are some 30 additional cortical areas beyond the primary cortex, all in some way concerned with vision and most of them having a topographic map of the 2-D images arriving on the retinas of the eyes. The discovery of these visual areas started with Semir Zeki’s work in the macaque monkey’s visual cortex. Our work follows that line by recording electrical signals from the visual cortex of these animals. To achieve this, we are using brain implants in the macaques very similar to those being trialed for human neurosurgical use (where implants bypass broken nerves in the spinal cord to restore mobility).
My lab is currently interested in how information passes from one visual cortical area to another. Nerve cells in the brain communicate with a temporal code, which uses the rate and timing of impulse-like events to signal the presence of different objects in our sensory world. When information passes from one area to another, the signals about depth get rearranged. The signals successively lose features that are unrelated to our perceptual experience and acquire new properties, corresponding closer to perceptual experience. So, these transformations eventually come to shape our perceptual experience.
In this phase of work, we are identifying previously unobserved properties of this transformation from one cortical area to another. We are examining how populations of nerve cells use coordinated signals to allow us to discriminate objects at different depths. We are testing the hypothesis that the variability of neural signals is a fundamental limit on how well the population of nerve cells can transmit reliable information about depth.
To be specific, we are currently following a line of enquiry inspired by theoretical analysis that identifies the shared variability between pairs of neurons (that is, the covariance of neural signals) as a critical limit on sensory discrimination. Pursuing this line is giving us new insights into why the brain has so many different visual areas and how these areas work together.
It is an exciting time. We still need to determine whether our perceptual experiences are in any sense localised to certain regions of the brain or represent the activity in particular groups of neurons. What are the differences between types of neural tissue in their ability to deliver conscious perception?
There are many opportunities created by the newer technologies of multiple, parallel recording of neural signals and the ability to intervene in neural signaling brought by the use of focal electrical stimulation and optogenetics. By tracking signals related to specific perceptual decisions through the myriad of cortical areas, we can begin to answer these questions. The prospect of applying these methods to core problems in the neuroscience of our perceptual experience is something to look forward to in the forthcoming years.
By Andrew Parker, Oxford University
The Physiological Society set up the annual, travelling GL Brown Prize Lecture to stimulate an interest in the experimental aspects of physiology. With predecessors such as Colin Blakemore and Semir Zeki, following in their footsteps is a tall order. They are not only at the very top scientifically but also superb communicators.
My lecture series on stereo vision has already taken me around the UK, including London, Cardiff, and Sheffield. I’ll be at the University of Edinburgh on 15 November and Oxford University on 23 November. It’s a nice touch that GL Brown’s career took him around the country too, including Cambridge, Manchester, Mill Hill and central London, before he became Waynflete Professor in my own department in Oxford. The other pleasurable coincidence of giving lectures on stereo vision this year is that there is a 50th anniversary since fundamental discoveries were made about how the brain combines the information from the two eyes to provide us with a sense of depth.
In his 1997 book How the Mind Works Steven Pinker wrote, “Stereo vision is one of the glories of nature and a paradigm of how other parts of the mind might work.” I can’t claim to have written this inspiring sentence myself, but I can at least claim to have chosen stereo vision as my field well before Steven Pinker wrote his sentence.
Stereo vision is, in a nutshell, three-dimensional visual perception. It is the use of two eyes in coordination to give us a sense of depth: a pattern of 3-D relief or 3-D form that emerges out of 2-D images arriving at the left and right eyes. These images are captured by the light-sensitive surface of the eye called the retina. Stereo vision gives us the ability to derive information about how far away objects are, based solely on the relative positions of the object in the two eyes.
The Victorians amused themselves with stereo vision (see Figure 1). Virtual reality is our modern day version of this, but what comes next? The next generation will probably enjoy “augmented reality” rather than virtual reality. With augmented reality, extra computer-generated imagery is projected onto objects in the real world. The aim is to create a perceptual fusion of real objects with virtual imagery. For example, in one prototype I have seen, surgeons perform their operations with virtual imagery (acquired with diagnostic imaging devices) superimposed upon the surgical field in the operating theatre. Needless to say, this places much higher demands on the quality and stability of the virtual imaging systems.
What causes people like Pinker, who are outside the field, to get so excited about stereo vision? Partly it’s just the experience itself. If you’ve been to the 3-D movies or put on a virtual reality headset, you will have the sense of stereoscopic depth. It is vivid and immediate. The other thing that excites Pinker is the way in which the brain is able to create a sense of a third dimension in space out of what are fundamentally two flat images. As a scientific problem, this is fascinating.
We also see parallels between stereo vision and how other important functions of the brain are realised. One straightforward example of that is visual memory. Gaining a sense of stereoscopic depth from two images (left and right) requires matching of visual features from one image to another. Remembering whether or not we have seen something before requires matching of a present image to a memory trace of a previously seen image. Both processes require the nervous system to match visual information from one source to another.
Another aspect that Pinker is highlighting is the way in which the two flat images in stereo are fused to form with a new perceptual quality, binocular depth. A great deal of spatial perception works this way. One obvious example is our ability to use the two ears in combination to form an impression of sound localised in space, based just on the vibrations received by the left and right ear canals.
What is the world like without stereo vision? While you can partly experience this by placing an eyepatch over one eye (try playing a racket sport or carefully making a cup of tea), the difference is most strongly highlighted by the very rare cases when stereo vision appears to have been lost but is then recovered. Susan Barry, professor of neurobiology at Mount Holyoke College, was stereoblind in early life but eventually gained stereo vision with optometric vision therapy.
In a New Yorker article by Oliver Sacks (Stereo Sue, A Neurologist’s Notebook, June 19 2006) Barry describes her newly acquired perception of the world. “Every leaf seemed to stand out in its own little 3-D space. The leaves didn’t just overlap with each other as I used to see them. I could see the SPACE between the leaves. The same is true for twigs on tree, pebbles on the road, stones in a stone wall. Everything has more texture.”
Check back next Wednesday for Part II of Andrew Parker’s blog on stereo vision.
This article originally appeared in our magazine, Physiology News.
By Mike Tipton, @ProfMikeTipton, University of Portsmouth
It can be argued that, in the broadest sense, we would not exist without collaboration. It is also easy to argue that our future health, prosperity, and indeed, survival will be dependent on collaboration. However, collaboration is something of a conundrum. Its meaning and usage are so broad as to be almost meaningless, and as a concept it covers a multitude of scenarios, not all of them good. So how do we foster enduring, productive collaboration in science?
Many people love the idea of collaboration, they pursue it with vigour, offering their services and proclaiming their interest in a project.Others are not keen on collaboration. For most, their view of collaboration largely depends on past experience or worries about future recognition. The problem is that there is a contradiction that runs through “collaboration”, right down to its definitions: a. The action of working with someone to produce something b. Traitorous cooperation with an enemy. Hopefully academic collaboration falls under the former rather than latter definition, but perhaps not always.
Collaboration in nature: lessons for scientists
There is no doubt that collaboration can be a driver for advancement, and even optimal advancement. This is easy to demonstrate in biological terms; for example over a billion years ago one bacteria became host to another, obtaining shelter in return for the production of energy from food and oxygen. Eventually the bacteria merged into a single cell that became the ancestral powerhouses of all multicellular life and the precursors to mitochondria. Today, examples of successful collaboration abound, from the African Oxpecker, and their aquatic equivalent, cleaner fish, to bacteria such as Lactobacillus that inhabit human intestines and help to relieve Irritable Bowel Syndrome, Crohn’s disease and gut dysbiosis. As Darwin said, “in the long history of humankind (and animal kind, too) those who learned to collaborate and improvise most effectively have prevailed.”
What can we learn from the animal kingdom that might help our collaborations with other scientists? The obvious lesson is that those collaborations between organisms that endure are symbiotic rather than parasitic. That is, both collaborators bring something to the relationship and both gain. To coin a cliché, the sum is greater than its constituent parts. Collaborations fail when, in one way or another, they become parasitic. Perhaps we should focus on “symbiosis” rather than “collaboration”?
Scientific collaboration: the benefits
At one level, of course, all science is the product of a collaboration between colleagues within an institution, be they the technicians, students, academics or administrators that enable and conduct research. But what about collaboration across institutions? This is not an insignificant issue; even more so now than previously, successful collaboration is important for the advancement of research areas as well as scientific careers. As science moves unerringly towards complex, multifaceted studies employing advanced and highly specialised techniques, the need to collaborate nationally and internationally increases. This truth is increasingly being reflected in the published literature, where there is a positive relationship between the presence of international collaborating authors on top flight papers and citation impact (Adams & Gurney, 2016).
People are getting the message; as measured by co-authorship on refereed papers, international collaboration grew linearly from 1990-2005, or exponentially if international presentations are assessed (Leydesdorff & Wagner, 2008). In 1981 about 90 % of UK published research output was domestic, by 2014 this figure had fallen to less than 50 %; almost all of the growth in output in the last 30 years was produced by international co-authored collaborations (Adams & Gurney, 2016). In just the last two issues of Experimental Physiology we have published papers from 15 countries, and of the 22 papers published, 13 were collaborations between a total of 34 institutions. Leydesdorff & Wagner (2008) used network analysis to conclude that the growth of international co-authorship can be, at least in part, explained by the organising principle of preferential attachment (“the rich get richer”). Broadening collaboration should therefore be advantageous.
The major driver for collaboration is the need to share, be that ideas, equipment, facilities, techniques, resources or data. Without successful collaboration between experts within different fields, some major problems will either not be solved or will take much longer. For example, it is generally agreed that the battle against cancer cannot be won without such collaboration (Savage, 2018). Looking back, without collaboration we would have been less likely to know of the existence of the Higgs Boson or have sequenced the human genome. It is difficult to imagine the big questions of our time, such as understanding the working of the brain, the origin of the universe or the production of clean sustainable energy, being solved without interdisciplinary collaboration. The need for collaboration to provide the diversity of skills and techniques to answer these questions is paramount.
The UK government is actively encouraging such collaboration through initiatives like the UK Research and Innovation (UKRI) Fellowships Programme. The Industrial Strategy Challenge Fund looks to build collaborations between academics and business. One of the six key areas is “Health and Medicine”. Research England recently invested £67m in 14 collaborative projects to “drive forward world-class university commercialisation across the country”.
Promoting collaboration: opportunities and threats
So, how do we create the conditions that might promote successful symbiotic collaboration within, but even more importantly, across disciplines? We start with an advantage; game theory (e.g. The Prisoners’ Dilemma) research tells us that humans display a systematic bias towards cooperative behaviour in preference to otherwise rational self-interest (Fehr & Fischbacher, 2003). So, we need to foster this altruistic inclination and minimise the threats to collaboration.
Publishing has a role to play in promoting collaboration; since the first issue of the Philosophical Transactions of the Royal Society was disseminated in 1665, potential collaborations have been promoted by the publishing industry reporting what could be done by other people working in the same field. A relatively recent development is the publication of datasets that can be examined and used by others, a new and as yet not fully evolved form of “collaboration”. On the other hand, publication can also be a barrier to collaboration: concerns about recognition of effort, authorship and ownership of ideas or data can introduce anxiety and suspicion. These problems can be minimised by early, open discussion, by scientists, and by journals giving high value to ideas. Following established guidelines for authorship should also help (e.g. International Committee of Medical Journal Editors Guidelines (2017).
Other threats to collaboration come in the form of international politics: BREXIT and access to EU funding, the rise of nationalism, travel bans, language barriers and difficulties in getting work permits. This is a constantly changing canvas within which scientists and leading institutions must lobby and advocate the crucial societal benefits of international collaborative research. Hopefully continued access to international and pan-continental research funding that demands international collaboration will help.
The role of publishing in prompting collaboration is reinforced by scientific meetings where you meet, learn from and socialise with those working in your field. Having determined from the literature and scientific presentations those who you might work with, it is during social exchanges at meetings that you discover people you want to work with. One potentially negative consequence of subject-specific meetings is that they constrain the technical and academic cross-fertilisation, and consequent collaboration, that might be promoted at more multi-disciplinary meetings.
If we continue to use co-authorship with an individual from another institution as the index of collaboration, I have collaborated with 71 people from 15 countries over three decades (e.g. International Drowning Researchers’ Alliance- idra.world). As far as I can recollect, all of these collaborations, and subsequent close friendships, were forged in the conducive atmosphere of a scientific meeting. It follows that any decline in funding to attend scientific meetings will stifle potentially critical collaborations. It also follows that although, as noted above, it is possible to encourage or require collaboration through targeted funding calls, in the absence of such funding it is very difficult to “administer” long-lasting productive collaborations into existence from nowhere. They have to evolve naturally, through interpersonal contact and understanding of the skill sets and capabilities of different people.
That is not to say that people who do not get on personally cannot collaborate; it is simply that the holistic experience and durability of the collaboration is likely to be diminished. Because, in the end, it is about spending time with those you respect, like, need and can communicate freely with. As in so many other things, Shakespeare had it about right,
Those friends thou hast, and their adoption tried,
Grapple them unto thy soul with hoops of steel
For a scientist, as well as society in general, the benefits of collaboration go far beyond science.
I would like to thank Alex Stewart, Sarah Duckering and Joe Costello for their contributions to this article.
By Simone Syndercombe, age 13, Newminster Middle School
I am as deaf as a post; don’t you see,
That’s why hearing is of interest to me.
Pin back your pinna and I will begin,
To tell you how sounds gets from out to within.
When my mum shouts with intention to berate,
Her speech makes the air from her mouth oscillate.
Hitting the pinna the shape does enhance,
The sound which is high pitched, to further advance.
Down through my ear canal, hitting the drum,
The sound is transferred into mechanical vibra-tion!
The eardrum is attached to a bony chain of three,
The malleus, the incus and the stapes, of me.
They act like a lever, enhancing the sound big,
Transferring the signal from middle to inner ear rig.
Through the oval window, the stapes does conduct,
Sound to the snail-shaped cochlear duct.
In this fluid-filled spiral are sensory cell hairs,
Attached to the basilar membrane, which cares,
Whether amplification or attenuation is desired,
Dampening or boosting before the auditory nerve fired,
Transferring the message to brainstem from ear,
The auditory nerve ensures that we can all hear.
I am bionic; I have aids in both ears,
As I have great difficulty hearing my peers.
Remember the mechanisms this poem’s about.
For I’m not ignoring you, you just need to shout!
Hearing is fascinating, I hope you’ll agree.
And that is why hearing is interesting to me.
By Emma Lofthouse, @Emlofthouse, The University of Southampton
I have taken it upon myself to spread the word about the brilliance of the placenta. It’s a fairly tricky task but someone has to do it.
Like all public engagement, this is a two-way dialogue that enables mutual learning between scientists and the public. It both fosters understanding, while providing an opportunity to discuss opinions, questions and concerns in an interactive way.
I created an interactive game called ‘the a-MAZE-ing placenta’, a game of physical skill that demonstrates the complexities of pregnancy and the many roles of the placenta in growing a healthy baby.
The object of the game is to tilt the placenta maze to guide the ball (representing nutrients) to the centre of the maze (the umbilical cord) in the fastest time possible while avoiding obstacles. These represent pregnancy conditions and risks: a ‘smoking forest’ traps the ball, toxins and infections block the path of the ball, and pre-eclampsia makes the ball hit dead ends or narrowed pathways.
During the game, we talk to both parents and children about the Developmental Origins of Health and Disease hypothesis, which suggests that the conditions we experience in utero can impact our adult health and relate this to the obstacles in the game.
Through pick-up on Twitter, ‘the a-MAZE-ing placenta’ has since debuted at conference,; open days, country shows, science festivals and schools.
Public engagement is now strongly encouraged in the research community with many funding bodies requiring public engagement activities as a condition of research grants. Outreach has great benefits for the public but just as many advantages for the scientist. It provides an opportunity to improve your communications skills with all types of audiences and gives you the opportunity to inspire someone.
Many researchers realise the importance of public engagement but are unsure of how to get involved. However, by simply talking to friends and family, you are already sharing your research and encouraging people to consider the relevance of science in their every day lives.
If you are looking to get involved with outreach, have a look at the opportunities that The Physiological Society provide including public engagement grants, Physiology Friday, the public engagement toolkit and ‘I’m a Scientist, Get Me Out of Here!’.
You can also become a STEM ambassador. Their events are designed to educate and more importantly, inspire young people to continue with STEM subjects at school and to help open their eyes to the careers that are available to them.