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
(david.foster@jhu.edu).

Discovering the Brains 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 OKeefe, 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 OKeefe, 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, OKeefe and Dostrovsky2 provided the first
evidence that neurons within the hippocampus specifically contribute to a cognitive map by directly representing an animals physical location. In a series of studies using the then-relatively-new technique of in vivo
electrophysiology, OKeefe 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 rats 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-

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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 OKeefe 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 OKeefe, 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 Fosters 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. OKeefe 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. OKeefe J, Nadel L. The Hippocampus as a

Cognitive Map. Oxford, England: Clarendon Press;
1978.

ARTICLE INFORMATION

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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 diseases 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 OKeefe,
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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