Research on largest network of cortical neurons to date published in Nature

Robust network of connections between neurons performing similar tasks shows fundamentals of how brain circuits are wired

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Even the simplest networks of neurons in the brain are composed of millions of connections, and examining these vast networks is critical to understanding how the brain works. An international team of researchers, led by R. Clay Reid, Wei Chung Allen Lee and Vincent Bonin from the Allen Institute for Brain Science, Harvard Medical School and Neuro-Electronics Research Flanders (NERF), respectively, has published the largest network to date of connections between neurons in the cortex, where high-level processing occurs, and have revealed several crucial elements of how networks in the brain are organized. The results are published this week in the journal Nature.

A network of cortical neurons whose connections were traced from a multi-terabyte 3D data set. The data were created by an electron microscope designed and built at Harvard Medical School to collect millions of images in nanoscopic detail, so that every one of the “wires” could be seen, along with the connections between them. Some of the neurons are color-coded according to their activity patterns in the living brain. This is the newest example of functional connectomics, which combines high-throughput functional imaging, at single-cell resolution, with terascale anatomy of the very same neurons. Image credit: Clay Reid, Allen Institute; Wei-Chung Lee, Harvard Medical School; Sam Ingersoll, graphic artist

“This is a culmination of a research program that began almost ten years ago. Brain networks are too large and complex to understand piecemeal, so we used high-throughput techniques to collect huge data sets of brain activity and brain wiring,” says R. Clay Reid, M.D., Ph.D., Senior Investigator at the Allen Institute for Brain Science. “But we are finding that the effort is absolutely worthwhile and that we are learning a tremendous amount about the structure of networks in the brain, and ultimately how the brain’s structure is linked to its function.”

“Although this study is a landmark moment in a substantial chapter of work, it is just the beginning,” says Wei-Chung Lee, Ph.D., Instructor in Neurobiology at Harvard Medicine School and lead author on the paper. “We now have the tools to embark on reverse engineering the brain by discovering relationships between circuit wiring and neuronal and network computations.” 

“For decades, researchers have studied brain activity and wiring in isolation, unable to link the two,” says Vincent Bonin, Principal Investigator at Neuro-Electronics Research Flanders. “What we have achieved is to bridge these two realms with unprecedented detail, linking electrical activity in neurons with the nanoscale synaptic connections they make with one another.”

“We have found some of the first anatomical evidence for modular architecture in a cortical network as well as the structural basis for functionally specific connectivity between neurons,” Lee adds. “The approaches we used allowed us to define the organizational principles of neural circuits. We are now poised to discover cortical connectivity motifs, which may act as building blocks for cerebral network function.”

Lee and Bonin began by identifying neurons in the mouse visual cortex that responded to particular visual stimuli, such as vertical or horizontal bars on a screen. Lee then made ultra-thin slices of brain and captured millions of detailed images of those targeted cells and synapses, which were then reconstructed in three dimensions. Teams of annotators on both coasts of the United States simultaneously traced individual neurons through the 3D stacks of images and located connections between individual neurons.

Analyzing this wealth of data yielded several results, including the first direct structural evidence to support the idea that neurons that do similar tasks are more likely to be connected to each other than neurons that carry out different tasks. Furthermore, those connections are larger, despite the fact that they are tangled with many other neurons that perform entirely different functions.

“Part of what makes this study unique is the combination of functional imaging and detailed microscopy,” says Reid. “The microscopic data is of unprecedented scale and detail. We gain some very powerful knowledge by first learning what function a particular neuron performs, and then seeing how it connects with neurons that do similar or dissimilar things.

“It’s like a symphony orchestra with players sitting in random seats,” Reid adds. “If you listen to only a few nearby musicians, it won’t make sense. By listening to everyone, you will understand the music; it actually becomes simpler. If you then ask who each musician is listening to, you might even figure out how they make the music. There’s no conductor, so the orchestra needs to communicate.”

This combination of methods will also be employed in an IARPA contracted project with the Allen Institute for Brain Science, Baylor College of Medicine, and Princeton University, which seeks to scale these methods to a larger segment of brain tissue. The data of the present study is being made available online for other researchers to investigate.

This work was supported by the National Institutes of Health (R01 EY10115, R01 NS075436 and R21 NS085320); through resources provided by the National Resource for Biomedical Supercomputing at the Pittsburgh Supercomputing Center (P41 RR06009) and the National Center for Multiscale Modeling of Biological Systems (P41 GM103712); the Harvard Medical School Vision Core Grant (P30 EY12196); the Bertarelli Foundation; the Edward R. and Anne G. Lefler Center; the Stanley and Theodora Feldberg Fund; Neuro-Electronics Research Flanders (NERF); and the Allen Institute for Brain Science.

About the Allen Institute for Brain Science

The Allen Institute for Brain Science, a division of the Allen Institute (alleninstitute.org), is an independent, 501(c)(3) nonprofit medical research organization dedicated to accelerating the understanding of how the human brain works in health and disease. Using a big science approach, the Allen Institute generates useful public resources used by researchers and organizations around the globe, drives technological and analytical advances, and discovers fundamental brain properties through integration of experiments, modeling and theory. Launched in 2003 with a seed contribution from founder and philanthropist Paul G. Allen, the Allen Institute is supported by a diversity of government, foundation and private funds to enable its projects. Given the Institute’s achievements, Mr. Allen committed an additional $300 million in 2012 for the first four years of a ten-year plan to further propel and expand the Institute’s scientific programs, bringing his total commitment to date to $500 million. The Allen Institute’s data and tools are publicly available online at brain-map.org.

About Harvard Medical School

HMS has more than 7,500 full-time faculty working in 10 academic departments located at the School’s Boston campus or in hospital-based clinical departments at 15 Harvard-affiliated teaching hospitals and research institutes: Beth Israel Deaconess Medical Center, Boston Children’s Hospital, Brigham and Women’s Hospital, Cambridge Health Alliance, Dana-Farber Cancer Institute, Harvard Pilgrim Health Care Institute, Hebrew SeniorLife, Joslin Diabetes Center, Judge Baker Children’s Center, Massachusetts Eye and Ear/Schepens Eye Research Institute, Massachusetts General Hospital, McLean Hospital, Mount Auburn Hospital, Spaulding Rehabilitation Hospital and VA Boston Healthcare System.

About NERF

Neuro-Electronics Research Flanders (NERF; www.nerf.be) is a neurotechnology research initiative is headquartered in Leuven, Belgium initiated by imec, KU Leuven and VIB to unravel how electrical activity in the brain gives rise to mental function and behaviour. Imec performs world-leading research in nanoelectronics and has offices in Belgium, the Netherlands, Taiwan, USA, China, India and Japan. Its staff of about 2,200 people includes almost 700 industrial residents and guest researchers. In 2014, imec's revenue (P&L) totaled 363 million euro. VIB is a life sciences research institute in Flanders, Belgium. With more than 1470 scientists from over 60 countries, VIB performs basic research into the molecular foundations of life. KU Leuven is one of the oldest and largest research universities in Europe with over 10,000 employees and 55,000 students.

ORIGINAL: Allen Institute

March 28th, 2016

Peeking into the brain's filing system

Aspects of a single memory can be scattered throughout the outer "cortex" of the brain

Storing information so that you can easily find it again is a challenge. From purposefully messy desks to indexed filing cabinets, we all have our preferred systems. How does it happen inside our brains?

Somewhere within the dense, damp and intricate 1.5kg of tissue that we carry in our skulls, all of our experiences are processed, stored, and - sometimes more readily than others - retrieved again when we need them.

It's what neuroscientists call "episodic memory" and for years, they have loosely agreed on a model for how it works. Gathering detailed data to flesh out that model is difficult.

But the picture is beginning to get clearer and more complete.

A key component is the small, looping structure called the hippocampus, buried quite deep beneath the brain's wrinkled outer layer. It is only a few centimetres in length but is very well connected to other parts of the brain.

People with damage to their hippocampus have profound memory problems and this has made it a major focus of memory research since the 1950s.

Quick learning

It was in the hippocampus, and some of its neighbouring brain regions, that scientists from the University of Leicester got a glimpse of new memories being formed, in a study published this week.

Single brain cells in the hippocampus can form associations very rapidly

They used a rare opportunity to record the fizz and crackle of single human brain cells at work, in epilepsy patients undergoing brain surgery.

Individual neurons that went crazy for particular celebrities, like Clint Eastwood, could be "trained" to respond to, for example, the Statue of Liberty as well - as soon as the patients were given a picture of Clint in front of the statue.

It seemed that single brain cells, in the hippocampus, had been caught in the act of forming a new association. And they do it very fast.

But that outer wrapping of the brain - the cortex - is also important. It is much bigger than the hippocampus and does myriad jobs, from sensing the world to moving our limbs.

When we have a particular experience, like a trip to the beach, different patches of the cortex are called up to help us process different elements: recognising a friend, hearing the seagulls, feeling the breeze.

So traces of that experience are rather scattered across the cortex.To remember it, the brain needs some sort of index to find them all again.

And that, neuroscientists generally agree, is where the hippocampus comes in.

"Think of the [cortex] as a huge library and the hippocampus as its librarian," wrote the prominent Hungarian neuroscientist Gyorgy Buszaki in his 2006 book Rhythms of the Brain.

Does the brain have a librarian?

The elements of our day at the beach might litter the cortex like specific books along miles of shelving; the hippocampus is able to link them together and - if all goes well - pull them off the shelf when we want to reminisce.

Completing patterns

Another brand new study, out this week in the journal Nature Communications, looks inside the brain using fMRI imaging to see this filing system in action.

By getting people to learn and remember imaginary scenarios while inside a brain scanner, Dr Aidan Horner and his colleagues at University College London collected the first firm evidence for "pattern completion" in the human hippocampus.

Pattern completion is the mechanism behind a phenomenon we all recognise, when one particular aspect of a memory - the smell of salt in the air, perhaps - brings all the other aspects flooding back.

"If you have an event that involves the Eiffel tower, your friend and, say, a pink balloon… I can show you a picture of the Eiffel tower, and you remember not only your friend, but also the pink balloon," Dr Horner told the BBC.

While his volunteers had just this sort of experience inside the scanner, Dr Horner saw interplay between different parts of the cortex, associated with different parts of a memory, and the hippocampus.

The brain activity flowed in a way that showed "pattern completion" was indeed underway - and the cortex and the hippocampus were working just like the library and the librarian in Prof Buzsaki's analogy.

The hippocampus (darker brown) is centrally located and very well connected

"If I cue you with the location, and I get you to explicitly retrieve the person, what we also see is activation in the region that's associated with the object for that event," Dr Horner explained. "So even though it's task-irrelevant, you don't have to retrieve it, it seems that we still bring that object to mind.

"And the extent to which we see that activation in the 'object' region correlates with the hippocampal response. So that suggests that it's the hippocampus that's doing the pattern completion, retrieving all these elements.

"It's able to act as an index, I suppose, by linking these things together - and doing it very very quickly, that's the key thing."

If the cortex were left to make its own connections between the fragments of a memory, he added, it would be far too slow.

"That's clearly not a system we want, if we're going to remember a specific event that happens once in a lifetime."

Beat this: Episodic memory is a key challenge for artificial intelligence systems

Dr Horner said the findings also dovetail nicely with the single-neuron, celebrity-spotting results from the Leicester study.

"We can look across the cortex and the hippocampus, and we can relate it to recollection. But what they can do is say look, these cells [in the hippocampus] have learned really quickly.

"So that's the sort of underlying neural basis of what we're looking at, at a slightly broader scale."

Science, it seems, is finally managing to unpick the way our brains record our lives. It is a remarkable, beautiful, fallible system.

Building some sort of memory storage like this is regarded as one of the next key challenges for researchers trying to build intelligent machines.

Our own memories, for all their flaws, are a hard act to follow.

ORIGINAL: BBC

By Jonathan WebbScience reporter, BBC News

5 July 2015