Opinion

VIEWPOINT

Brad E. Pfeiffer, PhD Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland. David J. Foster, PhD Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Corresponding Author: David J. Foster, PhD, Department of Neuroscience, Johns Hopkins University School of Medicine, 725 N Wolfe St, 903 Hunterian Bldg, Baltimore, MD 21205 ([email protected]). jamaneurology.com

Discovering the Brain’s Cognitive Map Identifying our position in space is critical for navigation, and also for our ability to form memories of behavioral episodes, because these occur in a specific time and place. Understanding the neuronal mechanisms underlying these abilities has been an enduring question in neuroscience: how do our brains combine external sensory information with internal self-motion cues to produce a circuit-level representation of spatial location, and how are these representations used to help us understand where we are and to allow us to successfully navigate through our environment? Three neuroscientists, John O’Keefe, May-Britt Moser, and Edvard Moser, were recently awarded the 2014 Nobel Prize in Physiology or Medicine for their seminal research in understanding how 2 neighboring brain regions, the hippocampus and the entorhinal cortex, represent spatial information. Their groundbreaking work not only established these areas as primary sources of spatial processing in the brain but created and sustained a research field within neuroscience dedicated to unveiling the processes by which positional and episodic information is encoded and extracted at the cellular level. Prior to the work of O’Keefe, Moser, and Moser, there was considerable debate and speculation regarding the nature of spatial representation in the brain. In 1948, Edward Tolman coined the term cognitive map to describe the apparent ability of animals to create an internal representation of the external environment.1 This concept was primarily driven by a series of experiments in which rats demonstrated spatial learning behavior that could not be fully explained by simple stimulus-response behavior. Rather, rats appeared to acquire, through experience, a more complex understanding of how their environment was structured. It was hypothesized that access to this mental map allowed animals to create shortcuts or establish novel trajectories to obtain a reward more quickly or effectively. In 1971, O’Keefe and Dostrovsky2 provided the first evidence that neurons within the hippocampus specifically contribute to a cognitive map by directly representing an animal’s physical location. In a series of studies using the then-relatively-new technique of in vivo electrophysiology, O’Keefe demonstrated that single neurons in the dorsal hippocampus of the rat (homologue of the human posterior hippocampus) consistently fired action potentials only when the animal was in a specific, restricted location of an environment. Because the activity of these neurons consistently reflected the rat’s position in space, they were given the moniker place cells. Critically, it was established that although place-cell representations could be influenced by sensory cues in the environment, their activity patterns were not a trivial reflection of primary sensory input but, rather, were more consistent with a represen-

tation of spatial location. The discovery of place cells laid the foundation for a neuronal basis for the cognitive map.3 Decades of continued research, led by O’Keefe and many others, established that the preferred firing location, or “place field,” of a place cell in one environment did not predict the field in another, suggesting that, unlike topographic maps in the brain, the hippocampus “remaps” in new environments, enabling a combinatorial code that represents without interference the thousands of environments an individual might be expected to encounter in life. For several decades following the discovery of place cells, it was postulated that hippocampal neurons obtained their position-specific firing patterns as a result of the intrinsic circuitry within the hippocampus. The work of Jim Ranck and colleagues established that cells in many areas closely connected to the hippocampus represent head direction, providing a compass-like representation.4 However, early results had suggested that spatial location itself was coded more weakly in upstream regions. May-Britt Moser and Edvard Moser decided to record from the specific region that projected to hippocampal place cells, despite the fact that these neurons in layers II and III of the dorsal medial entorhinal cortex could only be targeted with deeply implanted and awkwardly angled electrodes, compared with the more accessible upstream regions that had been studied before. This strategy was transformative; the Mosers discovered “grid cells” in the medial entorhinal cortex that fire in multiple locations within the same environment in a precise grid of equilateral triangles.5 The spatial frequency of grid nodes increases systematically along the dorsoventral axis of the medial entorhinal cortex, while, at any given point along the axis, different grid cells fire at different spatial phases. Thus, while each grid cell fires in multiple locations within an environment, each location in that environment is represented by a unique set of active grid cells. An explosion of interest followed, with observations of grid cells in various species, as well as reports of conjunctive cells that simultaneously code for both grid and head direction and of border cells that code for walls within an environment. Place cells and grid cells reside in the medial temporal lobe, a region best known for its role in memory. Fascinatingly, the spatial mapping firing properties of neurons in these areas appear to provide a scaffold for memory construction. First, hippocampal place cells do not only report current location, but their activity is sensitive to task demands and modulated by the past and future journeys taken. Second, as the technology has advanced to allow recording from large numbers of hippocampal place cells simultaneously, it has become clear that place cells are activated in temporal sequences. During exploration, place cells are modulated by a strong

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Opinion Viewpoint

theta rhythm, and within each theta cycle, place cells are activated in short sequences that can “look ahead” of the current position, exploring multiple different paths at a choice point, for example. In addition, when an animal pauses in an environment, or when it sleeps, large numbers of place cells are activated during an event in the hippocampal electroencephalogram referred to as a “sharp-wave/ ripple.” During these events, place cells are activated in sequences depicting behavioral trajectories as long as 10 m. These sequences can represent previously experienced trajectories but can also represent future paths to a remembered goal location.6 Intriguingly, multiple studies have now shown that hippocampal place-cell sequences can depict novel combinations of experienced places, suggesting a process of imagining as-yet-unexperienced future behaviors. The discoveries of O’Keefe, Moser, and Moser have important implications for human neurological disease. A dramatic loss of episodic memory and a reduction in spatial awareness are both hall-

Published Online: January 5, 2015. doi:10.1001/jamaneurol.2014.4141.

of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Conflict of Interest Disclosures: None reported.

4. Taube JS, Muller RU, Ranck JB Jr. Head-direction cells recorded from the postsubiculum in freely moving rats: I, description and quantitative analysis. J Neurosci. 1990;10(2):420-435.

REFERENCES

Funding/Support: Dr Foster’s research is supported by the National Institutes of Health (grants R01MH085823 and R01MH103325), the Brain Research Foundation, the Brain and Behavior Research Foundation, and the Johns Hopkins Science of Learning Institute.

1. Tolman EC. Cognitive maps in rats and men. Psychol Rev. 1948;55(4):189-208.

5. Hafting T, Fyhn M, Molden S, Moser MB, Moser EI. Microstructure of a spatial map in the entorhinal cortex. Nature. 2005;436(7052):801-806.

2. O’Keefe J, Dostrovsky J. The hippocampus as a spatial map: preliminary evidence from unit activity in the freely-moving rat. Brain Res. 1971;34(1):171-175.

6. Pfeiffer BE, Foster DJ. Hippocampal place-cell sequences depict future paths to remembered goals. Nature. 2013;497(7447):74-79.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, or interpretation

3. O’Keefe J, Nadel L. The Hippocampus as a Cognitive Map. Oxford, England: Clarendon Press; 1978.

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marks of Alzheimer disease, likely resulting from early deterioration of both the entorhinal and hippocampal networks. Thus, a better understanding of how these brain regions function to process spatial and episodic information may unveil future diagnostic tools that can enable the early detection or the precise monitoring of the disease’s progression. Furthermore, direct recordings from these brain regions in various mouse models of Alzheimer disease and other neuropathies can provide a more clear understanding of how these diseases impair spatial awareness and memory. Einstein once wrote: “the most incomprehensible thing about the world is that it is comprehensible.” The discoveries of O’Keefe, Moser, and Moser have revealed an orderly structure in the activity patterns of some of the most remote areas in the brain, far removed from either the peripheral sensory input or the motor output. We are left wondering, with Einstein, how it is that such an intuitive structure exists in these remote, hidden worlds within the brain.

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