UNews - Dr. Bruce McNaughton

New research reveals central role of the hippocampus in instructing the neocortex in spatial navigation and memory

caroline.zentner — Mon, 16 Jul 2018 16:52:45 +0000

A research collaboration between Dr. Bruce McNaughton’s lab at the Canadian Centre for Behavioural Neuroscience at the ��Ѹ��Դ��߿�Ƭ of Lethbridge and Dr. Vincent Bonin’s lab at the Neuro-Electronics Research Flanders (NERF, VIB-KU Leuven-imec) in Belgium has provided new insight into how the brain learns about the environment and why the hippocampus, a key part of the brain, is so important in this process.

Dr. Bruce McNaughton

“This is quite a major breakthrough in understanding and supporting a long-standing theory for which there was virtually no neurophysiological evidence, mostly just behavioural evidence and conjecture,” says McNaughton.

A 2017 study conducted by Dr. Dun Mao (PhD ’17), then a graduate student working in the labs of McNaughton and Bonin, was the first to show that cells in the cerebral neocortex, specifically the retrosplenial cortex, look very much like ‘place cells’ in the hippocampus. Place cells are involved in navigation and learning. However, the researchers didn’t know whether the retrosplenial cortex developed activity patterns on its own or relied on instructions from the hippocampus.

Dr. Dun Mao wears U of L doctorate regalia for his convocation in 2017.

“Navigating and remembering rely on extensive interactions between the hippocampus and the neocortex,” says Mao, now a post-doctoral fellow at Baylor College of Medicine in Houston, Texas. “This study provides the first direct evidence of the role of the hippocampus in sending a continuous, sequential code to the neocortex. I think it will inspire a new direction of research in the field.”

The study, Hippocampus-dependent emergence of spatial sequence coding in retrosplenial cortex, has been published in PNAS (Proceedings of the National Academy of Sciences of the United States of America).

The idea of the study stemmed from the long-held hippocampal indexing theory. Neuroscientists have proposed the indexing theory to explain how the hippocampus interacts with the cortex. Since the brain’s cortex has many cells, distant regions of the cortex don’t communicate strongly with each other. However, each part of the cortex is able to store information in its own domain.

Indexing theory proposes that, each time an animal has a unique experience, the hippocampus creates a unique pattern of neural activity that it sends to the rest of the cortex. That unique pattern acts like a context code and is stored in different regions of the cortex, along with the raw data the regions are responsible for encoding, such as shapes, sounds and motion. If the hippocampus recreates that index, it will simultaneously appear in all the cortical regions involved at the time, thereby retrieving the individual parts of the experience to create an integrated memory. Although this theory was initially proposed more than 30 years ago, direct neurophysiological evidence has been lacking.

In the current study, Mao damaged very precise locations in the hippocampus in mice so that the hippocampus was no longer functional but the cortex remained intact. He then used 2-photon calcium imaging to track the activity of neurons in the cortex as the mice navigated and learned about the environment. This allowed him to witness how retrosplenial activity develops and to determine the role of the hippocampus in that learning.

“In those mice, we found that there was a loss of this place-cell like activity in the cortex, thereby strongly supporting the conclusion that the cortex gets its spatial code, or its index code, from the hippocampus itself,” says McNaughton.

“Most compelling are the strength and specificity of the effects,” says Bonin. “The effects are stunning. With an intact hippocampus, activity in the retrosplenial cortex is precise and orderly. In the absence of it, it’s a complete mess, as if the animal had never been exposed to the environment. Having such a strong phenomenon to rely on will be helpful in basic studies but also in studies of brain disorders and neurodegeneration.”

The results pave the way for further studies to determine how general the phenomenon is and determine how and if indexing activity helps the cortex retrieve stored information.

“We need to know the circuit mechanisms,” says McNaughton. “We need to know how those particular indexing cells are connected to the other cells in those regions of the cortex. Very detailed neuroscience needs to be done in order to get a complete picture of how this memory- or knowledge-creating system actually works at the level of the nuts and bolts of the brain.”

McNaughton looks forward to these future studies as new high-tech tools should be available in the next five years that will allow for deeper exploration of the brain, as well as techniques that will allow for simultaneous recording of the activity of tens of thousands of brain cells, rather than the few hundred currently possible.

Students benefit from training opportunities through U of L’s partnership with the ��Ѹ��Դ��߿�Ƭ of California Irvine

caroline.zentner — Thu, 14 Sep 2017 20:08:02 +0000

Dr. Bruce McNaughton, a neuroscientist and recipient of the 10-year Alberta Innovates Health Solutions Polaris Award in 2008, has been somewhat of a double agent for the past few years.

As the province’s only Polaris-award winner, he’s been teaching and conducting research at the Canadian Centre for Behavioural Neuroscience (CCBN) at the ��Ѹ��Դ��߿�Ƭ of Lethbridge. Then in 2014, McNaughton was jointly appointed a distinguished professor at the ��Ѹ��Դ��߿�Ƭ of California, Irvine (UCI) at their Center for the Neurobiology of Learning and Memory (CNLM).

“The idea here was that, by having a joint appointment at UCI, I could expand my research funding, my collaborations and my ability to train graduate students and post-doctoral fellows, as well as my research funding,” says McNaughton. “Since that time, we’ve had at least five visits by students and post-docs in California getting trained on our advanced imaging technology here, and I’ve had one technician and three trainees do rotations down there. These opportunities for CCBN trainees and faculty members will clearly enrich the U of L’s education and research efforts.”

Part of the Polaris mandate was to expand international collaborations and UCI was a good fit, based on McNaughton’s research interests in learning, memory and memory disorders associated with aging and brain diseases. A recent area of interest for McNaughton is something called cognitive reserve, which is one of the best predictors of healthy brain aging. This phenomenon describes a situation in which two brains may show the same level of pathology, such as plaques and tangles, yet the one that has had more education, leads an active and varied lifestyle, speaks multiple languages and engages in exercise will show fewer behavioural signs of dementia.

“We’re interested in understanding the neural circuit mechanisms that underlie cognitive reserve,” says McNaughton. “It’s a complicated question; it involves studying the dynamics of the interaction of brain cells, how efficiently they represent data and things of that nature.”

Thanks to the hiring of Dr. Majid Mohajerani, infrastructure support from the Polaris award and the Canada Foundation for Innovation (CFI), the CCBN is equipped with a two-photon optical imaging system that allows researchers to analyze how the brain codes and stores information by monitoring hundreds of individual neurons simultaneously while animals are behaving. This involves placing mice in a virtual reality setup where they run on a treadmill with their head fixed under the microscope.

“It’s like they’re running around in the world. The fact that they’re running causes the hippocampus — the part of the brain that is essential for creating new memories and retrieving them, at least initially — to update its pattern as though the animal were running in a real world,” says McNaughton.

Sandra Gattas looks to map cognitive reserve through neural activity

One of McNaughton’s students at UCI, Sandra Gattas, wants to know if cognitive reserve can be seen at the neural level. Gattas, a student in the MD/PhD program, is currently at the U of L implementing an experiment she designed to answer that question. She’s working with a mouse model and comparing differences in neural activity between a group of mice participating in environmental enrichment activities and a group receiving no enrichment. As her research progresses, she also intends to perform the same experiment with mice genetically designed to mimic Alzheimer’s disease.

Sandra Gattas, a UCI student in the MD/PhD program, has been researching cognitive reserve at the CCBN.

“I’m measuring brain activity with the two-photon microscope as I gradually increase or enrich the experiences of these animals,” says Gattas. “This then gives me a gradual measure of how cognitive reserve can lead to a change in the neural activity. In the end, I expect to see some difference that helps me identify a very smart brain from a very naïve brain.”

While her study is still in the early stages, the results could have implications for Alzheimer’s disease in the future.

“If we can quantify what the neural activity looks like in a brain with high cognitive reserve, this could inform how deep brain stimulation can be used as treatment for Alzheimer’s disease,” she says.

While UCI also has two-photon imaging systems, the CCBN lab is already set up for running mice in the virtual reality system, allowing her to get a big head start on her research by coming to the U of L. At the end of September, she will have an armload of data and analysis completed. She will have a perspective of the direction of the study before starting her PhD coursework in Irvine.

“Getting good quality data and having access to the resources, which we do have here, is a big benefit,” says Gattas. “What’s neat about the CCBN is that all the labs are together in one place and they’re all asking different questions. People come from all over the world to study here. Bringing all that together in one building is mentally stimulating.”

Dr. Ivan Skelin observes memories in the making

The partnership between the U of L and UCI has also benefitted Dr. Ivan Skelin, who has a medical degree obtained in his homeland of Croatia. He wanted to combine clinical work with research into how memories are formed. He began doctoral studies at the ��Ѹ��Դ��߿�Ƭ of Zagreb and completed much of the work at Montreal’s McGill ��Ѹ��Դ��߿�Ƭ, where he first heard about McNaughton’s work. After completing his PhD, he came to the U of L to do post-doctoral work with funding from Alberta Innovates Health Solutions.

Dr. Ivan Skelin, a U of L post-doctoral fellow, has been researching memory formation at UCI.

The U of L’s partnership with UCI gave Skelin an opportunity to conduct research in the UC Irvine Health Comprehensive Epilepsy Program, in collaboration with the program’s director, Dr. Jack Lin. He works with patients who have exhausted all treatment options except surgery to remove the part of the brain where the seizures occur. To locate the appropriate area for surgery, surgeons insert electrodes both directly on the cortical surface and deep into the brain.

“Most of the human electrical activity recordings these days are done using scalp electroencephalography, which provides low-resolution, summed activity of large populations of neurons scattered over multiple brain structures,” says Skelin. “We are recording the activity of single neurons — functional units of brain computation — from the electrodes placed directly inside the brain structures relevant for memory formation and retrieval. The big advantage of this approach is that you can correlate the human subjective experience with recorded brain activity.”

Skelin can observe how memories are encoded and retrieved by asking patients to recall a short five-second video they’ve watched and comparing the activity evoked by recall with activity present at the time of memory formation. As the memory-consolidation process of gradual strengthening of selected memories occurs during sleep, overnight recordings allow Skelin to follow the dynamics of memory traces during sleep. Bit by bit, Skelin is mapping the spatiotemporal dynamics of memory in the human brain.

Without the U of L’s partnership with UCI, Skelin would not have had the chance to record directly from the human brain.

“UCI is one of a handful of places in the world where we have the ability to record single neurons from the human brain,” says Skelin. “This is a unique opportunity that I am extremely grateful for. My experiences here have contributed a lot to my career.”

Partnership gaining strength amid future uncertainty

The momentum has been building since the Polaris award began, especially over the past two to three years. Thanks to an NSERC (Natural Sciences and Engineering Research Council) Collaborative Research and Training Experience Program grant, we have been able to support excellent trainees and, with additional support from CFI (Canada Foundation for Innovation), the CCBN has advanced supercomputing equipment, microscopes and electrophysiology setups. Several trainees have gone to attend workshops and training camps in European labs through the Polaris award. The partnership is also enabling new collaborations for CCBN faculty who have had opportunities to spend time at UCI. So far, Drs. Robert Sutherland and Mohajerani have taken advantage of visits to UCI. UCI hosted a joint meeting with CCBN, ��Ѹ��Դ��߿�Ƭ of Alberta and ��Ѹ��Դ��߿�Ƭ of Toronto faculty members to develop a strategic plan for collaborative research projects.

As McNaughton looks ahead to the time when the Polaris award, which is non-renewable, will finish in 2018, his brows furrow.

“I am deeply concerned about what happens then because we will be going from a budget that’s supported about 40 trainees and staff to what can be supported on a regular NSERC grant. We have acquired world-class instrumentation and infrastructure, and are just reaching our peak productivity, but I will have to lay off a lot of people,” says McNaughton. “It won’t end suddenly this time next year because I’ve saved enough in the budget to stretch it another year maybe, a least at a reduced scale, so the door doesn’t slam shut all at once. And, of course, I’m spending a lot of my time applying for other sources of funding, but support for this kind of basic research has been steadily shrinking worldwide. This is a very disturbing trend. Most advances in medicine have, at their root, fundamental discoveries that were made in the context of basic, curiosity-driven scientific research, the impact of which might not be seen in the discoverer’s lifetime. Clinical translation represents the apex of a pyramid, at the base of which is discovery science.”

Navigation and spatial memory — brain region newly identified to be involved

caroline.zentner — Wed, 16 Aug 2017 17:56:08 +0000

Research conducted in a collaboration between Drs. Dun Mao, a researcher in Dr. Bruce McNaughton’s lab at the Canadian Centre for Behavioural Neuroscience at the ��Ѹ��Դ��߿�Ƭ of Lethbridge, and Steffen Kandler, a researcher in Professor Vincent Bonin’s lab at Neuro-Electronics Research Flanders (NERF) in Belgium, has found neural activity patterns that may assist with spatial memory and navigation.

Their study, Sparse orthogonal population representation of spatial context in the retrosplenial cortex, has been published in Nature Communications.

Dr. Dun Mao, who received his PhD in neuroscience this spring, is now a postdoctoral fellow at Baylor College of Medicine in Houston, Texas.

“Previously, we knew little about how spatial information is encoded in large neuronal populations outside of the hippocampal formation,” says Mao (PhD ’17), who’s now a postdoctoral fellow at Baylor College of Medicine in Houston, Texas. “Now we have revealed that the retrosplenial cortex, which is highly connected with the hippocampus, encodes spatial signals in a way similar to the hippocampus. These results will help us understand how the hippocampus and neocortex interact to support spatial navigation and memory.”

Navigation in mammals, including humans and rodents, depends on specialized neural networks that encode the animal’s location and trajectory in the environment, serving essentially as a GPS (global positioning system). Failure of these networks, as seen in Alzheimer’s disease and other neurological conditions, results in severe disorientation and memory deficits.

When an animal enters a specific place in its environment, ‘place cells’ in the hippocampus, a brain area known for its role in navigation and memory formation, begin firing. At any given location, only a few place cells are active, with the remaining neurons being largely silent. This sparse firing pattern maximizes information storage in memory networks while minimizing energy demands.

In addition to the hippocampus, the retrosplenial cortex is involved in spatial orientation and learning and has dense connections with the hippocampus. To better understand its role, Mao and Kandler measured activity in the retrosplenial cortex in mice as they moved on a treadmill fitted with tactile stimuli. As they precisely tracked the animal’s behaviour and location, they used highly sensitive live microscopic techniques to compare the activity of neurons in the retrosplenial cortex and the hippocampus.

The researchers discovered a new group of cells that fire in smooth sequences as the animals run in the environment. While the activity resembled that of place cells in the hippocampus, the retrosplenial neurons responded differently to sensory inputs.

“We found these two functional cell types in the retrosplenial cortex, one devoted to spatial mapping and the other devoted to visual processing. We are now studying how these two information streams interact in the retrosplenial cortex,” Mao says.

The results show that the retrosplenial cortex carries rich spatial activity, the mechanisms of which may be partially different from that of the hippocampus. While more research is needed to investigate the relationship between retrosplenial activity and the hippocampus, the results pave the way for a better understanding of how the brain processes spatial information.

Three U of L professors elected to the Fellowship of the Royal Society of Canada

caroline.zentner — Wed, 07 Sep 2016 16:03:02 +0000

A renowned neuroscientist, an accomplished anthropologist and a leading biologist from the ��Ѹ��Դ��߿�Ƭ of Lethbridge have been elected to the Fellowship of the Royal Society of Canada (FRSC). Their election acknowledges the remarkable accomplishments of Drs. Louise Barrett, Bruce McNaughton and Joe Rasmussen in advancing knowledge and scholarship.

Barrett, a U of L psychology professor, has been elected by her peers in the Anglophone division of the Academy of Social Sciences. Her innovative approaches to evolutionary anthropology and psychology have contributed to an exciting and fruitful interdisciplinary research program. Her training in ecology and anthropology led her to accept a Canada Research Chair in Evolution, Cognition, and Behaviour as well as the publication of influential books and articles on the social nature of cognition. Her research is firmly grounded in world-class empirical field study of social interaction in primate populations.

Dr. Louise Barrett poses with one of her research subjects.

“It is an enormous honour to be elected, and a great thrill to be recognized in this way by my adopted country, but I would never have been able to achieve it without the support and hard work of my collaborator, Peter Henzi, our students and our other research collaborators, so much of the credit must also go to them,” says Barrett. “It also meant a great deal to me to be nominated by Linda Fedigan, as she is without doubt Canada’s leading biological anthropologist, and someone whose work I have long admired.”

“I nominated Dr. Louise Barrett for membership in the FRSC because she is a recognized leader in the field of social cognition. She focuses mainly on social dynamics in wild, non-human primates, specifically baboons and vervets, as models of how animals conceptualize and interact adaptively in their social worlds,” says Dr. Linda Fedigan, FRSC, C.M., ��Ѹ��Դ��߿�Ƭ of Calgary professor emerita.

Rasmussen, a biology professor, joins the Earth, Ocean and Atmospheric Sciences division of the Academy of Science. He has contributed significantly to the development of tracer approaches to modelling energy flow in food webs, based on fractionation and kinetics of naturally occurring isotopes. These approaches have yielded fresh insights and technical inroads into important ecological problems such as the biomagnification of persistent contaminants and the impacts of heavy metals and mining practices. Rasmussen’s research has important applications to conservation problems, including invasive species, habitat modelling and fragmentation.

Dr. Joe Rasmussen's research has implications for important ecological problems.

“It feels very special to be honoured in this way by colleagues for all these years of doing something that is so much fun. I’m a lucky guy,” says Rasmussen.

“Joe is most deserving of being elected to the Royal Society of Canada. I nominated him because he is a scientist with a broad interdisciplinary scope and strong quantitative skills. He knows the potential that exists in applying theory, tools and modelling approaches from physical sciences to ecology and he’s brave enough to venture into uncharted waters,” says U of L President Mike Mahon.

McNaughton, a neuroscience professor, has been elected to the Life Sciences division of the Academy of Science. His ground-breaking discoveries in systems neuroscience have been the basis for thousands of studies and publications focused on how the world thinks about synaptic plasticity, spatial cognition and long-term memory. His research has dramatically impacted neuroscience theory and his experimental and conceptual work contributed significantly to the work upon which the shared 2014 Nobel Prize in Physiology and Medicine was awarded.

Dr. Bruce McNaughton is a world leader in systems neuroscience.

“Generals get medals for battles won through the courage and sacrifices of their troops. Senior scientists get elected to prestigious societies for much the same reason,” says McNaughton. “It is a pleasure and honour to have been nominated and elected, but the main credit goes to the many talented trainees and research staff who have made any achievement I have made possible.”

“Bruce is truly a world leader in systems neuroscience and he’s made major advances in several areas and pioneered new technologies and new conceptual approaches. He continues to have a huge impact on neuroscience theory, research and methods. I was pleased to nominate him and his election to the Fellowship of the Royal Society recognizes his many accomplishments,” says Mahon.

Distinguished scholars and artists are elected to the Fellowship of the Royal Society of Canada every year based on their exceptional contributions to Canadian intellectual life. The Society was established through an Act of Parliament in 1883 as Canada’s National Academy for senior scholars, artists and scientists.

UNews - Dr. Bruce McNaughton

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