HIPPOCAMPUS 25:679–681 (2015)

COMMENTARY

Perspectives on 2014 Nobel Prize Howard Eichenbaum*

ABSTRACT: In celebration of the 2014 Nobel Prize in Physiology or Medicine, this issue of Hippocampus includes a collection of commentaries from a broad range of perspectives on the significance of position coding neurons in the hippocampal region. From the perspective of this student of hippocampal physiology, it is argued that place cells and grid cells reflect the outcome of experiments that strongly select the information available and correspondingly observe singular “trigger features” of these neurons. Notably, however, in more naturalistic situations where multiple dimensions of information are available, hippocampal neurons have mixed selectivity wherein population-firing patterns reflect the organization of many features of experience. Thus, while discoveries on position coding were major breakthroughs in penetrating the hippocampal code, future studies exploring more complex behaviors hold the promise of revealing the full contribution of the hippocampal C 2015 Wiley Periodicals, Inc. region to cognition and memory. V KEY WORDS: coding

place cells; grid cells; mixed selectivity; population

In this issue of Hippocampus, we celebrate the 2014 Nobel Prize in Physiology or Medicine awarded to John O’Keefe and May-Britt and Edvard Moser for their discoveries of position coding neurons in the hippocampus and medial entorhinal cortex. The findings have provided breakthrough observations about the information processing elements of the hippocampal region and their characterizations must influence a comprehensive understanding of its functional circuitry. Here I have asked several of our colleagues to reflect on the significance of these position-coding neurons from the perspective of the areas of research in which they work. I have selected authors from a broad range of foci in hippocampal research, including anatomy, molecular and cellular approaches, basic and behavioral physiology, and function in animals and humans. The commentaries range from Richard Morris’ personal and professional journey with the prize winners, to perspectives from others who work on humans, behaving animals, and slice preparations, and on memory and navigation. I think you will find their comments insightful and reflective of the existing diversity of perspectives on the relevance of position coding toward an understanding of the hippocampal system. Enjoy! I’ll take the opportunity here to begin this series with brief comments from my own perspective as one who studies hippocampal neurons in

Center for Memory and Brain, Boston University, Boston, Massachusetts *Correspondence to: Howard Eichenbaum, Center for Memory and Brain, Boston University, Boston, MA, USA. E-mail: [email protected] Accepted for publication 17 March 2015. DOI 10.1002/hipo.22445 Published online 18 March 2015 in Wiley Online Library (wileyonlinelibrary.com). C 2015 WILEY PERIODICALS, INC. V

animals performing spatial and non-spatial memory tasks. 2014 was a remarkable year for the hippocampus. First, the breakthrough discoveries of Brenda Milner and John O’Keefe were recognized with the Kavli Prize in Neuroscience. Professor Milner studied H.M. the patient who suffered severe and selective amnesia following bilateral hippocampal region removal, and her characterizations of H.M. began the modern era of the cognitive neuroscience of memory. John O’Keefe discovered “place cells” in the hippocampus of rats. These neurons fire when a rat occupied a particular position in the environment, leading O’Keefe along with Lynn Nadel to believe they had found a map-like representation of the physical environment. Then, the 2014 Nobel Prize was awarded to O’Keefe and to the Mosers for their discovery of “grid cells” in the medial entorhinal cortex that fire when rats occupy a spatially periodic array of locations. These neurons, along with discoveries of other neurons in the hippocampal region that encode head direction (James Ranck and Jeff Taube) and border cells (Neil Burgess and others) and other cells with spatial firing characteristics, have bolstered the hypothesis that the hippocampus maps and supports navigation through physical space. Indeed, the Nobel announcement characterized the position coding neurons as elements of the brain’s “inner GPS.” Meanwhile, concurrent years of research in cognitive neuroscience have followed up the pioneering studies of Milner, particularly with the use of neuroimaging. These studies have hugely and impressively supported the work on amnesia that identifies a much broader role of the hippocampal system in memory. With my colleague Neal Cohen, I have recently considered the dilemma posed by apparent disconnects between the “memory” and “GPS” views of the hippocampus (Eichenbaum and Cohen, 2014). Here I will take a different tack on the significance of position-coding by neurons in the hippocampal region. The identification of place cells and grid cells follow a tradition in neuroscience begun by investigators of sensory and motor processing in primary cortical and other brain areas, wherein the aim has been to identify a single “trigger feature” of each neuron, and then model a circuitry that constructs hierarchies of information processing from simple to more complex

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coding features. Perhaps the best known example is Hubel and Wiesel’s Nobel Prize winning discoveries of neurons in early visual cortical areas that have specific visual trigger features (e.g., orientation of visual edge contrast within a small receptive field). At successive stages of visual processing, they and others found neurons with ever larger receptive fields and ever more complex trigger features suggesting a hierarchy that reconstructs object representations. This approach has been elaborated over the years with the identification of a large number of visual areas, each with feature-specific neurons, for which the assumption is that their outputs converge in the hierarchy to represent complex natural images in perception, such as faces. The discoveries of singular trigger features have relied on careful selection of the information provided, in the case of vision, restricted to the presentation of lines, gratings, colors, motion cues, or other isolated dimensions of visual stimuli. However, more recent research has shown that, when presented with natural images in realistic visual contexts, neurons throughout the visual system have very complex firing properties that challenge the explanatory power of these simple trigger features for representation of real-life visual experiences (e.g., Kayser et al., 2004). Furthermore, recent work on other higher order cortical areas, such as the prefrontal cortex, further defy the hope to find simple trigger features in natural situations, because neurons in these areas have highly complex firing patterns that reflect a mixed selectivity to multiple dimensions of ongoing perception, cognition, and behavior. Moreover, it is claimed that mixed selectivity is advantageous to the breadth and flexibility of representation in neural networks especially in higher order areas of the brain (Rigotti et al., 2013). The history of this progress suggests a theoretical revolution underway (Kuhn, 1962). The early pioneering studies indicated that, when only single stimulus dimensions are presented, neurons are impressively selective to a specific element within one dimension, consistent with the single trigger feature hypothesis. Challenges to this came in the form of “modulation” of the trigger feature properties when other salient dimensions are imposed, e.g., attention (Desimone and Duncan, 1995). The notion of feature detectors rapidly becomes too simplistic when the conditions become progressively more multidimensional and naturalistic, and consequently the neurons demonstrate their mixed selectivity that lends to alternative views that characterize representations in terms of neural population coding. This story also characterizes the history of hippocampal place cells. Place cells are selective for a single position in behavioral situations where no salient stimuli other than spatial cues are present and behavior is made homogeneous and ignored (random foraging for food in an open field; Muller et al., 1987). As soon as behavior becomes systematically directed, place cells are “modulated” by velocity and the direction of movement (alleyways in a maze or trajectories in an open field, e.g., McNaughton et al., 1983; Markus et al., 1995). When the animal must learn about important nonspatial stimuli or differential significance of different paths through the same space, the neurons also encode all of the relevant stimuli, contingencies, and accompanying behaviors (e.g., Hippocampus

Wood et al., 1999, 2000). This course of observations challenges as too simplistic the approach in which single spatial trigger features are combined in models to perform navigational calculations of the “inner GPS” (e.g., Barry and Burgess, 2014). Rather, place cells can now take their place among neurons in brain regions that have high-dimensional mixed selectivity, and methods are in development for characterizing the organization of dimensions encoded by hippocampal networks (Mckenzie et al., 2014). Notably, position coding is important in the network representation, but its role is in the spatial organization of memories that can contribute essential information for navigation as it does for many other everyday activities. So, from the perspective of this student of the hippocampus, the significance of place cells is a reflection of the “trigger feature” approach that is very impressive in isolation but only a first step in understanding the role of the hippocampus in cognition and memory. I believe the future will focus on exploring large scale monitoring of neural populations during complex behaviors, and these studies will continue to reveal the organization of multiple dimensions of experience in the hippocampus, a role in which space is important along with time and other relevant organizing dimensions (Eichenbaum, 2014). As for grid cells, we are still at the earliest stage. They have been examined almost exclusively in protocols where only spatial cues are offered and measured. Already, a few studies have shown that, under more complicated circumstances, there is more to their activity patterns than a periodic spatial code (e.g., Derdikman et al., 2009; Kraus et al., 2013), and history predicts a course toward high dimensional representations in neural networks where the grid cells are found. So, while the discoveries of 2014 Nobel Prize winners are to be hailed as the pioneering beginnings, a comprehensive understanding of hippocampal representation will lie in characterizing neural population codes within areas of the hippocampal system and their interactions that support cognition and memory.

REFERENCES Barry C, Burgess N. 2014. Neural mechanisms of self location. Curr Biol 24:R330–R339. Desimone R, Duncan J. 1995. Neural mechanisms of selective visual attention. Annu Rev Neurosci 18:193–222. Derdikman D, Whitlock JR, Tsao A, Fyhn M, Hafting T, Moser MB, Moser EI. 2009. Fragmentation of grid cell maps in a multicompartment environment. Nat Neurosci 12:1325–1332. Eichenbaum H. 2014. Time cells in the hippocampus: A new dimension for mapping memories. Nat Rev Neurosci 15:732–744. doi: 10.1038/nrn3827). Eichenbaum H, Cohen NJ. 2014. Can we reconcile the declarative memory and spatial navigation views of hippocampal function? Neuron 83:764–770. Kayser C, Kording KP, Konig P. 2004. Processing of complex stimuli and natural scenes in visual cortex. Curr Opin Neurobiol 14:468–473. Kraus BJ, Brandon MP, Robinson RJ, Connery MA, Hasselmo ME, Eichenbaum H. 2013. Grid cells are time cells. Society for Neuroscience Abstract 769.19.

PERSPECTIVES ON 2014 NOBEL PRIZE Kuhn TS. 1962. The Structure of Scientific Revolutions, 1st ed. University of Chicago Press, Chicago. Markus EJ, Qin Y-L, Leonard B, Skaggs WE, McNaughton BL, Barnes CA. 1995. Interactions between location and task affect the spatial and directional firing of hippocampal neurons. J. Neurosci 15:7079–7094. McKenzie S, Frank AJ, Kinsky NR, Porter B, Rivie`re PD, Eichenbaum H. 2014. Hippocampal representation of related and opposing memories develop within distinct, hierarchicallyorganized neural schemas. Neuron 83:202–215. McNaughton BL, Barnes CA, O’Keefe J. 1983. The contributions of position, direction, and velocity to single unit activity in the hippocampus of freely-moving rats. Exp Brain Res 52:41–49.

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Muller RU, Kubie JL, Ranck JB Jr. 1987. Spatial firing patterns of hippocampal complex spike cells in a fixed environment. J Neurosci 7:1935–1950. Rigotti M, Barak O, Warden MR, Wang XJ, Daw ND, Miller EK, Fusi S. 2013. The importance of mixed selectivity in complex cognitive tasks. Nature 497:585–590. Wood E, Dudchenko PA, Eichenbaum H. 1999. The global record of memory in hippocampal neuronal activity. Nature 397:613– 616. Wood E, Dudchenko P, Robitsek JR, Eichenbaum H. 2000. Hippocampal neurons encode information about different types of memory episodes occurring in the same location. Neuron 27: 623–633.

Hippocampus

Perspectives on 2014 Nobel Prize.

In celebration of the 2014 Nobel Prize in Physiology or Medicine, this issue of Hippocampus includes a collection of commentaries from a broad range o...
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