November 7, 2012
RedOrbit Exclusive Interview: Professor Elizabeth Buffalo, Emory University’s Buffalo Lab
Jedidiah Becker for redOrbit.com — Your Universe Online
In 2005, Norwegian researchers discovered a previously unknown type of neuron by placing electrodes deep within the cerebral cortex of rats. Dubbed “grid cells,” these specialized neurons were so named because they fire in distinct clusters, each of which constitutes the vertex of a grid-like pattern of equilateral triangles. This recurring triangular, lattice-like firing pattern is what distinguishes grid cells from other similar types of neurons, and in the years that followed their discovery, researchers quickly began to understand that this structure is closely related to their function in helping the brain to encode and navigate 3-dimensional spaces.Until recently researchers had only found direct evidence of the existence of grid cells in studies on rats, bats and mice. Now, however, neuroscientists at Emory University´s Buffalo Lab have demonstrated for the first time the existence of grid cells in primates, a find that is likely to have significant implications for our understanding of how the brain perceives the world as well as for future research into Alzheimer´s disease.
Dr. Elizabeth Buffalo, co-author of the study and an associate professor of neurology at Emory University´s School of Medicine, recently talked with redOrbit about her team´s discovery of grid cells in rhesus monkeys and what it could mean for the future of neuroscience.
Read the original article “Rhesus Monkeys Process Visual Information In A Triangular Grid” first.
RO: So I have to admit, I have a degree in biology and I edit a science news website, yet this is the first time that I´ve heard of grid cells. For those of us unfamiliar with them, could you tell us a bit more about what exactly they are and what we know about them at this point?
Buffalo: To understand grid cells, it helps to start with place cells. In really groundbreaking work in the early 1970's, O'Keefe and Dostrovsky demonstrated the existence of 'place cells' in the rodent hippocampus. These are neurons that emit action potentials whenever the rat is in a specific place in an environment, the neuron's 'place field'. The combined activity of many of these neurons, with distinct place fields, effectively provide a map of the environment and, in more recent research, it was demonstrated that the rat´s trajectory through space could be decoded very accurately by measuring the activity of these neurons. Place cells with the sharpest and most reliable place fields were found in the dorsal part of the rodent hippocampus.
In order to understand what gives rise to these spatial representations, researchers in the laboratory of May-Britt and Edvard Moser in Norway began recording in the medial entorhinal cortex, the part of the brain that provides the strongest input to the dorsal hippocampus. Through this work, in 2005, they identified grid cells. Like place cells, grid cells represent the location of the rat, but each grid cell has multiple place fields. The amazing thing about grid cells is that the multiple place fields are in precise geometric relation to each other and form a tessellated array of equilateral triangles, a 'grid' that tiles the entire environment. A spatial autocorrelation of the grid field map produces a hexagonal structure, with 60º rotational symmetry. In 2008, grid cells were identified in mice, in bats in 2011, and now our work has shown that grid cells are also present in the primate brain.
Although there is much more work to be done in this field, there are several ideas about what might be the function of these neurons, including giving rise to place fields in the hippocampus through summation of their activity, keeping track of an animal's movement through space, and playing a role in memory formation by enabling the association of events or objects with their position in space.
RO: You mentioned that you suspect that grid cells may help to provide a “context or structure” for storing visual experiences in memory. Could you expand on this for us?
Buffalo: We know that structures in the medial temporal lobe, including the hippocampus and the entorhinal cortex, are critical for episodic memory, defined as memory for past events in a person's life. Episodic memory is generally thought to necessarily include three features of a previous experience: what, where, and when. Grid cells, in conjunction with place cells, may provide the spatial context or structure to allow for the association of place with other features of the event. In some really interesting unpublished work from Howard Eichenbaum's lab presented this year at the Society for Neuroscience's annual meeting, it was demonstrated that some neurons in the medial entorhinal cortex of rats show periodic temporal firing, potentially temporal 'grids'. These data suggest that grid cells might provide structure for memories by providing a representation of both spatial and temporal regularities in the environment.
RO: The report on your study also mentioned that researchers have, at this point, only been able to indirectly infer the existence of grid cells in humans. Why has it been difficult to conclusively demonstrate their existence and/or function in people?
Buffalo: Electrophysiological recordings of the activity of individual neurons, which are necessary to demonstrate the existence of grid cells, require the introduction of microelectrodes deep into the brain. This is an invasive procedure that is rarely performed in humans and only under specific conditions. For example, recordings in the human entorhinal cortex are typically only performed in patients with pharmacologically-resistant epilepsy who are undergoing pre-surgical neurophysiological monitoring.
In a very clever study published in Nature in 2010, Doeller et al., presented evidence suggesting the presence of human grid cells. While human subjects navigated through a virtual environment, neural activity throughout the brain was analyzed non-invasively with functional Magnetic Resonance Imaging (fMRI). While fMRI allows us to detect the coordinated activity of thousands of neurons (not individual neurons), this study made use of the fact that the orientation of the grid fields, relative to environmental boundaries, was known to be generally constant across different grid cells. This, along with other features of grid cells, made it possible to detect 60° directional symmetry in the fMRI signal in the human entorhinal cortex.
RO: As noted in the press release, the scientific community has only known about grid cells for a few years, and it seems like the exact role of these specialized neurons is still something of a black box. What do we not know and need to know about grid cells in order to start better understanding their role in visual experience and memory?
Buffalo: That is exactly right, we currently know very little about their function and how they support memory formation and retrieval. Several sophisticated models have been put forward to describe how entorhinal grid cells, along with their afferent and efferent connections in the hippocampal circuitry may play a role in both path integration and episodic memory.
In addition, recent research has demonstrated that the grid fields change in response to experience, suggesting a role for the grid cells in memory formation. It is known that damage to the hippocampus and entorhinal cortex produces impairments in memory. However, we currently lack direct demonstrations of how neuronal representations in grid cells contribute to or are modified by memory. Our study demonstrated that some grid cells modulated their firing rate based on whether a stimulus was novel or repeated. However, this analysis was based on the neurons' activity when the visual stimulus first appeared, and we don't yet know whether this activity was modulated within each grid field. We also don't yet know how or whether the responses of grid cells might guide exploration. In order to clarify the function of grid cells, it would be useful to have experiments that combine spatial or visual exploration with measures of memory formation.
RO: Granted that there is still so much we don't yet know about grid cells, do you have any professional 'hunches' about how they might be affected by Alzheimer's disease?
Buffalo: Grid cells are found predominantly in layer II of the entorhinal cortex, and it is interesting that early and consistent degeneration of the entorhinal cortex is noted in Alzheimer's disease, with a particular build-up of neurofibrillary tangles in layer II. Because layer II neurons provide the major input to the dentate gyrus of the hippocampus, disruption of this layer would effectively cut off the hippocampus from the rest of the cortex, severely disrupting the memory system. There is also some evidence that neurofibrillary tangles in Alzheimer´s are concentrated in layer II in the posterior region of the entorhinal cortex, the part of the primate entorhinal cortex in which we found the largest proportion of grid cells. It seems likely that understanding more about the function of these cells and how they contribute to memory might lead to earlier and more sensitive ways of detecting the onset of cognitive decline in Alzheimer´s disease.
RO: So I have to ask: You mentioned in the press release that you're training monkeys to navigate a virtual 3-dimensional space. What´s that about?
Buffalo: Prior to our study, all of the demonstrations of grid cell firing had been accomplished as subjects navigated either real (in the case of rodents and bats) or virtual (humans) environments. One influential theory about the function of grid cells is that they are useful for path integration, the ability to keep track of one's position in space by integrating linear and angular self-motion. Evidence in support of this theory is that the grid fields remain relatively stable in spite of changes in sensory input, i.e. removal or replacement of major landmarks, and even persist in the dark. One surprising thing about our study was that we were able to identify grid cells in monkeys that were not moving through space, but were simply using their eyes to explore visual scenes. A next obvious question is whether we would see the same types of responses when monkeys are engaged in spatial navigation. It is technically challenging to record neural activity in freely-moving monkeys, so we are currently experimenting with navigation in virtual space, essentially the same technique that was used in the human fMRI experiments. We are training monkeys to use a joystick to navigate a virtual environment that we can easily manipulate with respect to local and environmental cues, and impose different types of spatial memory demands. With this behavioral paradigm, along with other experiments regarding exploration of visual space, we hope to provide more detailed information about the spatial coordinate system of these neurons and how they might contribute to memory.
RO: Dr. Buffalo, thanks very much for taking the time have a chat with us. On behalf of the redOrbit team and our readership, we wish you the best of luck on your continued research in this fascinating field of neurobiology and look forward to reading about your future work.
Elizabeth Buffalo is Associate Professor of Neurology at Emory University School of Medicine and Core Faculty at the Yerkes National Primate Research Center. She received her B.A. in Philosophy from Wellesley College before completing her PhD in Neurosciences at the University of California, San Diego. After her PhD she conducted Postdoctoral Research at the National Institute of Mental Health, and she joined the faculty at Emory in 2005.
Her research investigates the neural mechanisms that support learning and memory. Using neurophysiological and spectral analysis techniques in monkeys and humans, she investigates how individual neurons and synchronized neural ensembles contribute to memory formation and retrieval. Her research has been supported by awards from the National Institutes of Health (NIH), and she was the 2011 recipient of the Troland Research Award from the National Academy of Sciences for her innovative, multidisciplinary study of the hippocampus and the neural basis of memory.