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Spiers H.J. (2012) Hippocampal Formation. In: V.S. Ramachandran (ed.) The Encyclopedia of
Human Behavior, vol. 2, pp. 297-304. Academic Press.
© 2012 Elsevier Inc. All rights reserved.
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Hippocampal Formation
H J Spiers, University College London, London, UK
ã 2012 Elsevier Inc. All rights reserved.
Glossary
Action potential A nerve impulse, comprising a brief rising
and falling of a cell’s membrane potential.
Episodic memory Memory for events and episodes that
were personally experienced.
Local field potential Local voltage changes in a brain region
due to the combined electrical effects of a synchronously
active population of neurons.
Introduction
The undulating, twisted, interlocking brain structure called the
hippocampal formation has fascinated anatomists from the
dawn of dissection in ancient Egypt. Over the centuries, its
physical appearance has been likened to seahorses, silkworms,
and the horns of a ram. The seahorse stuck, and we know it
today from the Latin for seahorse: hippocampus. The hippocampal formation is composed of the hippocampus, subicular
complex, and entorhinal cortex. It is unparalleled in terms of
its unique circuitry and physiology. Housed within it are some
of the most morphologically spectacular cells in the brain.
Decoding their activity patterns has opened a window into
some of the brain’s fundamental operating characteristics and
uncovered the existence of a map and compass within the
brain. Unlike most of the brain, new neurons are born within
it during adulthood, which must strive to integrate themselves
into an intricate network of existing cells. With the discovery
of dense amnesia following the surgical removal of the hippocampal formation in the famous patient HM, this brain region
has been firmly wedded to memory. But just what ‘type’ of
memory it supports and how it functions remains contentious.
This article aims to distil the key concepts surrounding the
hippocampal formation into a digestible form and provide
a brief overview of its anatomy, physiology, pathology, and
theorized functions.
A Seahorse in the Brain: Anatomy
Like many of the world’s international borders, the borders of
the hippocampal formation are disputed. One view, adopted
in this article, is that the hippocampal formation is composed of
six regions. These are the hippocampus proper, dentate gyrus,
subiculum, presubiculum, parasubiculum, and entorhinal cortex. In other nomenclatures the entorhinal cortex, presubiculum, and parasubiculum are separated from the hippocampal
formation and are gathered under the term ‘parahippocampal
region.’ When the term ‘hippocampus’ is used it often refers to
the hippocampus proper and the dentate gyrus collectively.
A cross-sectional cut through the hippocampal formation
reveals a snugly curled up snaking shape in which the dentate
Medial Toward the midline of the brain.
Neurogenesis The birth of new neurons.
Pyramidal cell The main excitatory cell type in the
neocortex and hippocampal formation, the cell bodies of
which appear pyramidal in shape.
gyrus appears to be ‘biting’ the hippocampus proper (see
Figure 1). The hippocampus proper is divided into three
main subdivisions: CA1, CA2, and CA3. CA stands for ‘Cornu
Ammonis,’ which refers to Amun’s horns, named after the
ancient Egyptian god of the hidden world whose symbol was
ram’s horn. The pyramidal cells in the Cornu Ammonis occupy
a single packed layer, quite unlike the neocortex where pyramidal cells are spread over several layers. By contrast the dentate gyrus contains no pyramidal cells, but is densely packed
with smaller granule cells, 18 million in the human brain.
In addition to these cells, a variety of interneurons are found in
the different structures of the hippocampal formation.
From mouse to man the hippocampus is highly homologous
across all mammals. In primates, the hippocampal formation
is curled inside the medial temporal lobe (Figure 1(a)), alongside the amygdala, perirhinal cortex, and parahippocampal cortex. The entorhinal cortex has been viewed as the neocortical
gate-keeper, sending projections into the structure, receiving
its output and communicating with other neocortical structures. The other major source of communication with the rest
of the brain is the fornix, the white matter pathway connecting the hippocampal formation to various subcortical structures and providing some output to prefrontal cortex. Via this
pathway and other routes the hippocampal formation receives
modulatory input from dopamine, norepinephrine (adrenaline), serotonin, and acetylcholine systems.
Theories of hippocampal function were influenced by
several features of its connectivity. Four important ones are:
(1) information arriving at the hippocampal formation has
been highly processed through various unimodal and multimodal neocortical pathways, (2) there are largely unidirectional connections between its regions, (3) there are dense
projections from the dentate to CA3, and (4) there are highly
self-connected network pyramidal cells in CA3. Unidirectional
connectivity is unusual in the cortex, where pyramidal cells are
usually characterized by dense reciprocal connections to other
cells. A full characterization of connections is beyond the scope
of this article (see Further Reading).
The main flow of information follows four fiber pathways
(see Figure 1(b)). Two arise from the entorhinal cortex.
The first is the perforant path, bringing input from its layer II
to the dentate and CA2/CA3, the second (less dense) is the
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2
1
(a)
Temporoammonic
pathway
CA1
EC
Schaffer
collaterals
LPP
III
MPP
CA3
II
Mossy fibers
Dentate gyrus
Perforant
pathway
(b)
Figure 1 Anatomy of the hippocampal formation. (a) An illustration of the medial surface of the human brain. The front of the brain is to the left.
The position of the hippocampal formation in the medial temporal lobe is highlighted by darker lines, (1) hippocampal formation and (2) fornix. Reprinted
from Amaral DG (1994) Hippocampal formation. In: Ramachandran V (ed.) Encyclopedia of Human Behavior, 1st edn., pp 509–515. Academic Press,
with permission from Elsevier. (b) A diagram of the circuitry in the hippocampal formation. Solid arrows depict the main ‘trisynaptic’ excitatory pathway.
MPP, medial perforant path; LPP, lateral perforant path. II, III refer to layers II and III of the entorhinal cortex (EC). The fornix output pathway
(not shown) arises form the CA1 collaterals and subiculum. Adapted from Figure 1 in Deng W, Amoni JB, and Gage FH (2010) New neurons and
new memories: How does adult hippocampal neurogenesis affect learning and memory? Nature Reviews Neuroscience 11: 339–350, with permission
from Macmillan Publishers Ltd.
temporoammonic pathway from layer III to CA1. From the dentate arises the dense ‘mossy fiber pathway’ which projects exclusively to CA3. The synapses from this pathway are referred to
as ‘detonator synapses,’ because of their strength in driving CA3
cell activity. The CA3 cells project to CA1 via Schaffer collaterals,
and to many other CA3 cells via recurrent collaterals. CA1 cells
project to the subiculum and the deep layer neurons of the
entorhinal cortex and via the fornix to other structures. The subiculum, presubiculum, and parasubiculum have interconnections with the entorhinal cortex and with various other structures.
Spikes and Waves: Physiology
The physiology of the hippocampal formation has played an
important role in providing evidence for its function. A central
idea in neuroscience is that memories are stored in the brain by
the strengthening or weakening of synaptic efficacy between cells
in regions responsible for memory storage. Evidence for this was
first provided by Bliss and Lømo in 1973 with their discovery of
long-term potentiation (LTP) in the hippocampus. LTP refers to
a persistent enhancement in signal transmission between two
neurons resulting from synchronous activity of the neurons. It
has been traditionally studied either ‘in vitro’ (literally: ‘in glass’)
by cutting a living slice from the hippocampus, stimulating fiber
pathways within it and recording cells, or ‘in vivo’ by stimulating
and recording in awake, behaving animals using chronic indwelling electrodes. Since its discovery, it has been studied extensively
and observed in many brain structures. Mounting evidence indicates that memory storage requires LTP. Research focused on its
induction, maintenance, and expression and a wealth of knowledge has been gained about the molecular cascades underlying it.
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Our understanding of hippocampal physiology has been
advanced considerably by the use of extracellular microelectrodes to record the local field potential (LFP) and individual
cell activity in awake, active, and sleeping animals, typically
rats or mice. The LFP is generated by local voltage changes in
the brain region due to the combined electrical effects of a
synchronously active population of neurons. Two predominant LFP states have been observed during awake behavior:
theta state and large irregular activity. When a rat is either alert
or moving, a prominent regular 4–12 Hz ‘theta rhythm,’ oscillation is observed throughout the hippocampal formation;
when resting or eating the LFP is instead dominated by large
irregularly activity. Several interesting aspects of theta are
worth considering. Theta is modulated by the speed of running
and influences the temporal pattern of pyramidal cell activity
in hippocampus proper. The ability to induce LTP varies with
the theta cycle, which has led to the suggestion that encoding
and retrieval may be separated temporally by theta cycles. The
theta oscillations are thought to reflect the combination of
subthreshold membrane potentials and spiking activity, and
appear to synchronize across the hippocampus to create a
traveling wave across its axis. Large irregular activity has also
been associated with synchronization in the bursting activity of
the cells, particularly with the occurrence of sharp wave-ripples
of 150–200 Hz. Evidence indicates that the ripples are generated by CA3, and during these events, brief near synchronous
activity of many hippocampal neurons occurs. This reactivation
of recently active cells may be important for the strengthening
of connections between cells and for transfer of information to
other regions. Sharp wave-ripple events are common in sleep
and their disruption impedes spatial learning.
In addition to studying the LFP, remarkable insights into
the function of the hippocampal formation have been found
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by decoding the activity of individual neurons during awake
behavior. This is discussed in greater detail below.
Maps and Compasses: Neural Coding
Each of us carries in our head an internal map of our world and
a compass to orient within it. These appear to be located within
or near the hippocampal formation. This was discovered by
implanting microwires into the hippocampal formation of
rodents and recording the extracellular activity while the animal explores an environment. By continually recording the
animal’s position together with the neuronal activity it is possible to map the activity of cells to the surface of the environment and to the momentary orientation of the animal within
it. This approach revealed an elegant system dedicated to spatial mapping and orientation.
Because of their distinctive properties, cells in different
regions of the hippocampal formation have been labeled with
names such as ‘place cells,’ ‘head-direction cells,’ ‘grid cells,’ and
‘border cells.’ The first to be discovered were place cells by
O’Keefe and Dostrovsky in 1971. These exist in the hippocampus proper and fire action potentials (a rapid depolarization in
the membrane potential) when an animal is in a particular
location in the environment, but are typically silent otherwise
(see Figure 2(b)). The location in an environment where a cell
fires is called its place field. In a given environment, only a
subset of place cells will be active, with each cell’s place field
occupying a slightly different location, such that their collective, overlapping place fields carpet the whole environment.
Place cells express different activity patterns in different environments, a phenomenon known as remapping. By recording a
large ensemble of cells it has been possible to decode a rat’s
Camera
Recording
system
Activity
High
Rat on arena
(a)
(b)
(c)
Low
Figure 2 Single-unit recording in the hippocampal formation. (a) A diagram of a set up used for in vivo single unit electrophysiology, courtesy of
Kathryn J. Jeffery. A rat is shown in a rectangular flat arena. A cable connects the implanted microwires in the rat’s hippocampal formation to a recording
system. The recording system also receives information about the location of the rat via a camera. (b, c) Top, plots of a rat’s trajectory in the arena
(black lines). Overlaid red dots are the locations at which action potentials were fired by a single place cell in CA3 (b), and a single grid cell in the
dorsomedial entorhinal cortex (c). Below each is shown a false color plot of the spatially smoothed firing rate of each cell, showing the Gaussian peaked
fields of activity. Note that, in this example, the place cell field is large than the grid cell field, but field size can vary substantially along the dorso–ventral
axis. Adapted from Figure 1 in Fyhn M, Hafting T, Treves A, Moser MB, and Moser EI (2007) Hippocampal remapping and grid realignment in entorhinal
cortex. Nature 446(7132): 190–194, with permission from Macmillan Publishers Ltd; Figure 2 in Hafting T, Fyhn M, Molden S, Moser MB, Moser EI
(2005) Microstructure of a spatial map in the entorhinal cortex. Nature 436(7052): 801–806, with permission from Macmillan Publishers Ltd.
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location in an environment to within 1 cm. Unlike the topographic maps in the visual, somatosensory, and motor cortices,
the place cell map is not topographically organized within the
hippocampus. Cells with place fields next to each other in an
environment are not located next to each other in the hippocampus. However, the size of the place field varies from small
in the dorsal hippocampus to large in the ventral hippocampus.
Place cells have several interesting properties. Their response
appears to be a high-level, multimodal conjunction of inputs
that includes information about self-motion. They respond by
remapping predominantly to changes in the boundaries, distant landmarks, and large-scale sensory aspects of the environment, such as the floor and wall colors. They can learn
incidentally (without reward) over several trials to discriminate
very similar environments.
The cells in a number of peri-hippocampal areas such as the
mammillary bodies, anterior thalamus, dorsal presubiculum,
and retrosplenial cortex also produce a spatially tuned response,
but it is not place related. Instead, these cells offer something
akin to an internal compass by expressing activity tuned to
certain head-directions in the current environment. Thus, one
cell might fire maximally when an animal’s head is facing
Northeast, another when facing Southeast, another Northwest,
etc. Collectively the population covers all possible heading
orientations. These cells are referred to as ‘head-direction cells.’
The cells can be modulated both by self-motion information
(such as vestibular or motor signals) and visual information.
When prominent landmarks in an environment are rotated
between visits to an environment, these cells will tend to follow
the rotation, with all cells rotating by the same amount.
‘Grid cells’ and ‘Border cells’ have both been discovered in
the medial entorhinal cortex and more recently in other regions
of the subicular complex. They are similar to place cells in that
they show spatially localized patterns of activity in an environment, but they each differ from place cells in intriguing ways.
Grid cells generate multiple place fields arranged in a tessellating
grid-like pattern across the environment (see Figure 2(c)).
If lines are drawn between all fields, their pattern appears
somewhat like a sheet of graph paper imposed on the environment, but rather than graph lines being at 90 right angles
forming squares, the grid lines are at 60 to each other forming
triangles. Simultaneously recorded grid cells show the same
orientation of their grid pattern within an environment, but
may show different spacing between fields. Mirroring the dorsal
ventral scaling of place field size, cells in the dorsal region have a
small spacing between fields, whereas those in the ventral region
have large spacing between fields. It is thought that grid cells
provide inputs to place cells about the distance traveled in the
environment.
Border cells, referred to as boundary vector cells, likely
provide inputs about the environment, and as their name
suggests, they signal the location of borders in a given environment. Border cells will typically fire along, or just slightly offset
to, a border placed in an orientation matching its preferred
orientation, for example, Northwest. An important facet of the
system is that in addition to the cells described, conjunctive cells
which combine grid or place properties with head-direction
tuning, exist. These cells will only fire in a given place or set of
places and only when an animal is facing a particular direction.
These have been found in the medial entorhinal cortex and
presubiculum, but not the hippocampus proper. Cells in dentate gyrus can express spatially localized patterns of activity, but
in any given environment very few cells are active.
It seems humans too have place cells and grid cells. Evidence for place cells has come from recordings made from
electrodes implanted in patients with drug-resistant epilepsy
while they navigated a virtual reality (VR) environment. Indirect evidence for grid cells has been provided by using functional magnetic imaging (fMRI) to examine brain activity
patterns during VR navigation. Because a proportion of conjunctive head-direction modulated grid cells align to the 60
triangular grid orientations it was predicted that the activity of
such cells might produce a sixfold symmetry of activity patterns. This proved to be true for activity in the right entorhinal
cortex, indicating that this region in humans may contain
grid cells.
Combining human neuroimaging and VR has provided a
number of other insights into the response dynamics of the
hippocampal formation. For example, people who are better
navigators produce more activity in their hippocampus; activity in the right entorhinal cortex increases with the Euclidean
distance to a goal, and hippocampal activity is maximal during
the initial learning of a network of streets. In summary, while
analyses of neural activity have taught us much about the
information processed in the hippocampus, combining such
work with other approaches can help uncover the functions of
the hippocampal formation.
Mapping, Declaring, Relating, Binding, Constructing:
Theories of Function
What is the function of the hippocampal formation? Does it
serve a unique function or multiple functions and does
it operate as part of a wider system? Undoubtedly, it does not
work alone and its contributions to cognition are likely varied.
A full characterization of its function will arguably require
understanding the computational contributions of each subregion in its structure and their interrelations. This is a significant
challenge far beyond current knowledge. However, some constraints on what it may, or may not, be involved in have been
gleaned over the years, but not without considerable debate
and disagreement.
Historically, the hippocampal formation was linked to
olfaction through a supposed strong relationship to the olfactory bulb and later tied to emotion because of its connections
to other brain regions. These views are generally no longer
held. However, there is evidence that the hippocampal formation forms part of a circuit involved in anxiety and this idea was
developed into a theory by Gray. There is expanding interest in
the role the hippocampus plays in stress disorders and depression (see section ‘Dying Cells: Pathology’). However, it was the
discovery of dense amnesia following the surgical bilateral
removal of the hippocampal formation in patient HM in
1953 that firmly cemented its role in memory processing.
Patient HM, now known as Henry Molaison, was reported
(along with several other cases) in a seminal paper by Scoville
and Milner in 1957. He underwent the surgery for the treatment of drug-resistant epilepsy (see section ‘Dying Cells:
Pathology’). The surgery removed the hippocampal formation,
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parahippocampal gyrus and amygdala. From the time he
awoke from the surgery until the time of his death in 2008
he was unable to remember any new events he experienced –
a severe anterograde amnesia. He also suffered a temporally
graded retrograde amnesia, such that he could not remember
events or information from a period just before the surgery, but
the further back in time he was probed, the better he was able
to recall memories. This gradient of retrograde amnesia has
been observed across a large number of amnesic cases.
Despite HM’s dense amnesia he (and other similar patients)
showed a remarkable capacity for short-term memory, procedural memory and priming (the speeded response to a repeated
stimulus). This led to the argument that the hippocampus is
necessary for a ‘special type’ of memory. While numerous theories have been proposed over the past 60 years, this article will
highlight six current and influential theories. The focus of many
of these theories has been on the role played by the hippocampus, as opposed to the hippocampal formation more broadly.
These theories are:
1. Cognitive map: Hippocampus stores a map of the environment supporting flexible navigation and spatial memory
retrieval, and in humans, remembering events.
2. Declarative memory: Hippocampal formation is part of a
medial temporal lobe system which supports memory for
facts and events for a limited time period.
3. Relational memory: The hippocampus is necessary for storing and representing flexible relationships between stimuli
disjointed over space and/or time.
4. Multiple trace: The hippocampus is permanently needed to
support rich detailed episodic memory, but not semantic
memory.
5. Episodic memory (binding – what/where/when): The hippocampal formation is necessary to bind together information
about what happened, where and when, and later retrieving
this memory for such episodes. It plays a time-limited role
in representing these memories.
6. Construction: The hippocampal formation is part of a system supporting the reconstruction of the past or construction of possible future events.
Cognitive map theory was developed by O’Keefe and
Nadel. It argues that the hippocampus forms a flexible cognitive map of the environment to support the recall of what
is located or happened in different places and navigation to
unseen goals. This theory evolved primarily from the idea of a
cognitive map put forward by Tolman in the 1940s, together
with an analysis of the effect of lesions to the hippocampus
and the discovery of place cells. An important aspect of the
cognitive map is that information is learnt rapidly and incidentally, that is, without explicit reward. A criticism leveled at the
theory is that in humans the hippocampus appears to be in
need of remembering nonspatial information, and that spatial
information is just one type of information stored by the
hippocampus. However, it was proposed that the map may
store information about what objects are located in different
places and that for humans the map may have evolved with the
addition of linguistic and temporal inputs to support an episodic memory system. One aspect of cognitive map theory that
is disputed is that it puts no time limit on the involvement of
the hippocampus. Thus, once a map of an environment is
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formed in the hippocampus, the brain is dependent on the
hippocampus indefinitely for the retrieval of the information
in the map or the episodic memory.
Declarative theory, proposed by Cohen and Squire, and
developed by Squire thereafter, contrasts with cognitive map
theory by arguing that: (1) the hippocampus has a time-limited
role in memory retrieval and (2) the hippocampal formation is
part of a unitary medial temporal lobe memory system (which
includes the perirhinal and parahippocampal cortices) for the
conscious encoding and memory for facts and events. The term
‘declarative’ is used because both memory for facts (semantic
memory) and events (episodic memory) can be declared as
either true or false, for example, ‘Socrates was a man,’ ‘I ate eggs
for breakfast today.’ A central idea in the theory is that the
declarative memory system is distinct from several nondeclarative memory systems, which are responsible for procedural
memory, priming, conditioning, and stimulus adaption. Information in these systems is not veridical. For example, knowing
how to move your body to ride a bicycle (a form of procedural
memory) cannot be said to be true or false. Unlike other
theories, declarative theory makes no specific claims about
the contribution of different medial temporal lobe regions to
memory function. Based on the temporal gradient of amnesia,
declarative theory argues for a time-limited role in long-term
memory. Building on a model by Marr, initially declarative
memories are stored in the connections within medial temporal lobe and between it and the neocortex. Gradually, over time
a ‘systems-level consolidation’ occurs such that connections
form and strengthen between neocortical regions and eventually the neocortex rather than the hippocampus is needed to
recall the memories. This view has also been referred to as the
standard model of memory consolidation.
Multiple trace theory (MTT), proposed by Moscovitch and
Nadel disputes the idea that the medial temporal lobe is a
unitary long-term memory system in which all information is
consolidated in the neocortex. MTT agrees with the standard
view with regard to semantic information, but argues that the
rich, vivid reexperiencing of events or episodes always relies on
the hippocampal region. This is based predominately on the
observation that amnesic patients with medial temporal lobe
damage typically report few episodic memories from any time
point before their lesion and those they do are rarely vivid and
detailed. This view is disputed by declarative memory proponents who argue amnesics can recall detailed episodic memories from time points in their remote past.
Relational theory, proposed by Cohen and Eichenbaum,
builds on the idea of a declarative memory system and a
time-limited role in memory. It argues that the specific role of
the hippocampus is in processing the relationships between
stimuli disjointed in space or time and that other regions of the
medial temporal lobe are involved in processing information
about items or contexts. In this view, the hippocampal formation can be used to compare and contrast information held in
the system to extract relationships and apply this information
flexibly to new situations. The focus on processing relationships and flexibility is somewhat similar to the concept of a
cognitive map, since a map is a very good example of this.
However, the key difference is that in relational theory space is
viewed as only one of the many types of relationship that can
be coded by the hippocampal formation.
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The episodic memory theory has multiple proponents and
has evolved from a range of findings. According to this view,
the main purpose of the hippocampal formation is to encode
and store episodic (or episodic-like) memories for weeks,
months, or possibly years. Episodic-like is used to refer to the
fact that while animals can show something like episodic memory, it may be qualitatively different from the sense of mental
time travel that accompanies episodic retrieval in humans.
This view is similar to the MTT view, with the exception that
episodic memories are consolidated in the neocortex. Evidence
that hippocampal formation might be especially crucial for
episodic, but not semantic memory came from the study by
Vargha-Khadem and colleagues in 1997 of several patients with
amnesia due to bilateral hippocampal damage that occurred
in childhood. They all had profound episodic memory problems. Despite this they had all gained a remarkable amount of
semantic knowledge. This was surprising because amnesics
with damage in adulthood do not show such levels of semantic
learning. This led to the view that the neocortex may be able
to slowly incrementally learn about information, and that
the hippocampus normally facilitates this process by providing
information stored in episodic memory. Like many other cases
of amnesia due to relatively selective damage within the hippocampal formation, children were unable to recall past events,
but were unimpaired in their capacity to recognize previously
seen stimuli on some recognition tests. This and results from
lesion studies in primates and rats led to the view, proposed by
Aggleton and Brown, that the hippocampus supports the episodic or episodic-like abilities, and that the perirhinal cortex
imbues the brain with the capacity to determine whether a
stimulus is familiar or not. Evidence for the latter comes from
lesions and single unit recording of perirhinal neurons which
signal whether a stimulus has been encountered before or not.
In addition, some models argue that the parahippocampal
cortex is important for representing context. These ‘binding
into context’ models argue that the role of the hippocampus
is to bind together perirhinal object representations with parahippocampal background context representation, allowing a
rich reexperiencing of the whole event when information is
later recalled. The idea of vivid recollection of the past emphasized by MTT, has led several researchers recently to argue that
the hippocampal formation does more than store and retrieve
memories; it reconstructs the past and even constructs possible
future events.
The ‘construction’ theory is relatively new and based predominantly on neuroimaging and neuropsychological observations. It argues that the hippocampal formation is part of a
‘core network’ required to support episodic memory and navigation, and also imagination. Increased activity in the hippocampus has been observed during periods when subjects were
thinking about the future and amnesic patients with hippocampal damage has been found to struggle to describe new,
imagined situations. Such patients appear to be able to imagine individual objects and colors, suggesting that their problem
lies in creating a rich and coherent mental construction of a
scene. This view also accords with other evidence indicating
that the hippocampus is needed to solve odd-one-out or working memory tasks, which involve holding a mental representation of a room or scene in working memory. Thus, it has been
argued that a function of the hippocampal formation is to
construct rapid online mental representations of scenes and
places. This view offers an alternative explanation for why the
hippocampus may be critical for remembering rich, vivid
events from all time periods of one’s life in that they need
to be reconstructed. It would seem hard to imagine that constructing future scenarios is a function of the rodent or other
nonhuman animal hippocampi. However, recent evidence
suggests that hippocampal place cells can show activity that
might be akin to ‘simulating possible future paths.’ During
some sharp-wave-ripples (see section ‘Spikes and Waves:
Physiology’), a set of cells can briefly fire action potentials in
the order that they would be activated if an animal ran along
a path in the environment. While this ‘sequence replay and
preplay’ might be related to future thinking, an alternative
possibility is that during evolution humans adapted a spatial
memory system to support not only the reconstruction of
episodic memories, but also the construction of fictitious
events and places.
Undoubtedly, pinning the theory on the tail and body of
the hippocampal formation will continue for decades to come.
The study of hippocampal formation has, and will continue to
be, influenced by research conducted with patients who have
suffered some form of pathological damage to the hippocampus. Such pathological states are considered in the next section.
Dying Cells: Pathology
The hippocampal formation appears to be particularly prone
to disruption from a variety of causes. In this section, the effects
of dementia, stress, epilepsy, and schizophrenia are considered. Before we consider these various aberrant states, it is
worth considering the healthy aging. Analysis of the human
brain has revealed mixed results as to whether cell loss occurs
substantially in the hippocampus. In rats, healthy aging is not
associated with significant cell loss, but rather with disrupted
synaptic plasticity, such that LTP is short lasting. Place cells (see
section ‘Maps and Compasses: Neural Coding’) in aged rats
show reduced remapping responses to changes in the environment, suggesting that these cells are less capable of detecting
environment novelty. The place cells can also fail to reestablish
old patterns of activity in familiar environments, suggesting
that they are not capable of detecting a previously visited place
with the same accuracy.
Common causes of substantial cell damage in the hippocampal formation include Alzheimer’s dementia, ischemia/
hypoxia (loss of oxygen supplied by the blood), trauma, hypoglycemia (low blood glucose), and epilepsy. Hippocampal
damage is also associated with rare conditions such as herpes
encephalitis, where an acute infection from the herpes simplex
virus spreads through the hippocampus, amygdala, and associated structures. Due to the relative sparing of other brain
structures that can occur in this disease and in cases of hypoxia,
patients with these pathologies have proved highly important
for the study of hippocampal amnesia.
Epilepsy and Alzheimer’s disease are among the most
common of neurological diseases and are both strongly associated with the dysfunction of the hippocampal formation.
Encyclopedia of Human Behavior, Second Edition (2012), vol. 2, pp. 297-304
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Hippocampal Formation
Alzheimer’s disease is a hugely debilitating disease that typically manifests as an inability to acquire new memories
and disorientation. It has been associated with cell loss, originating in the entorhinal cortex and spreading to the rest of
the hippocampal formation and beyond as the disease progresses. Epilepsy is commonly linked to hippocampal pathology, in the form of hippocampal sclerosis. It is unknown
whether the seizures arising in epilepsy are the result of hippocampal damage or whether they are the cause of the damage. In cases of hippocampal sclerosis, evidence indicates that
the seizures originate from the hippocampus. Links have been
made between its unique anatomy and the origin of the
seizures. Increased connectivity, neurogenesis, loss of inhibitory inputs and increased excitatory drive, among other factors, have all been suggested to contribute to the development
of epilepsy.
Stress can also have a damaging affect on the hippocampal
formation. Stress produces glucocorticoids which then bind to
the dense glucocorticoid receptors inside the hippocampal
formation. They have been found to inhibit neurogenesis
(see section ‘New Birth: Adult Neurogenesis and Morphological Change’), alter gene expression and reduce the excitability
of some classes of cell, and prune the dendrites of CA3 pyramidal cells. Patients suffering posttraumatic stress disorder and
who have experienced extreme stress over long time periods
can show hippocampal atrophy.
Schizophrenia is another disease associated with hippocampal damage in the form of reductions of its volume. It
has been argued this may be the cause of the long-term memory problems many patients show with the disease. Because of
the lack of cell damage markers at autopsy and the presence
of abnormal cytoarchitecture, established prenatally, it has
been suggested that the changes are likely the result of altered
developmental processes rather than due to damage. Also,
altered dopamine levels, central to the syndrome, may be partly
caused by the reduction of hippocampal formation input.
New Birth: Adult Neurogenesis and Morphological
Change
While the hippocampal formation seems particularly fragile,
prone to decay and disease, it is also one of the few brain
regions where the birth of new neurons (neurogenesis) occurs
in adulthood occurs. From the time of the renowned neuroanatomist Ramon y Cajal, a central tenet in the brain was that
no new neurons grow in adulthood. It took many decades
before this view was overturned and the growth of new neurons was identified in two brain areas, the olfactory bulb and
part of the hippocampal formation: the dentate gyrus. This
neurogenesis may help support new learning and memory,
possibly by reducing interference, increased capacity, and tagging memories with temporal information. Despite initial
mixed results, this research is continuing to weigh in favor of
neurogenesis being important for memory.
Does size matter? It would appear to for the hippocampal
formation. In several nonhuman species, its size varies depending on the demands placed on spatial memory. Furthermore,
in some species the volume may change as a function of
303
the seasonal demands. In humans, some jobs place greater
demands on spatial memory than others. An extreme case of
this is the licensed London taxi driver, who must learn the
labyrinth of London’s (UK) 25 000 streets in order to obtain
a license, and navigate to hundreds of destinations on a daily
basis. By examining magnetic resonance imaging scans of
London taxi driver brains, Maguire and colleagues found
greater gray matter volume in the posterior hippocampi
and reduced gray matter volume in their anterior hippocampi
compared with an age-matched control group. In addition,
the longer taxi drivers had navigated in London the greater
the posterior gray matter volume and the more reduced the
anterior gray matter. Thus, suggesting that healthy adult humans
have the capacity to change the structure of their hippocampus
when accruing knowledge of complex environments. The same
changes do not appear to occur in London bus drivers who were
matched for driving experience, indicating that this change is
unlikely to be driven by stress, driving experience, or daily selfmotion. Whether the change in structure is related to neurogenesis, changes in cell morphology, or other factors remains to be
explored in future research.
Summary
From the ancient Egyptian era to present day, people have
written about the hippocampal formation and pondered over
its anatomy and function. In the last 40 years, our knowledge
has leapt forward. Crucial discoveries have been made in
understanding its unique circuitry, physiology, neural code,
and functional properties. This has been made possible by
the development of a wide range of technical innovations
and a creative approach to experimentation. There is a general
consensus that the hippocampal formation is crucial for episodic memory, but how best to characterize its involvement in
this and other functions remains an issue to be resolved.
See also: Amnesia and the Brain; Episodic Memory; Memory, Neural
Substrates; Memory; Our Cognitive Map; Spatial Orientation.
Further Reading
Aggleton JP and Brown MW (2006) Interleaving brain systems for episodic and
recognition memory. Trends in Cognitive Sciences 10(10): 456–463.
Andersen P, Morris RGM, Amaral DG, Bliss T, and O’Keefe J (2007) The Hippocampus
Book. Oxford: Oxford University Press.
Buzsaki G (2006) Rhythms of the Brain. Oxford: Oxford University Press.
Deng W, Amoni JB, and Gage FH (2010) New neurons and new memories: How does
adult hippocampal neurogenesis affect learning and memory? Nature Reviews
Neuroscience 11: 339–350.
Eichenbaum H and Cohen NJ (2001) From Conditioning to Conscious Recollection:
Memory Systems in the Brain. Oxford: Oxford University Press.
Hassabis D and Maguire EA (2007) Deconstructing episodic memory with construction.
Trends in Cognitive Sciences 11(7): 299–306.
Jeffery KJ (2008) Self-localisation and the entorhinal–hippocampal system. Current
Opinion in Neurobiology 17: 1–8.
Moscovitch M, Nadel L, Winocur G, Gilboa A, and Rosenbaum RS (2006) The cognitive
neuroscience of remote episodic, semantic and spatial memory. Current Opinion in
Neurobiology 16(2): 179–190.
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Hippocampal Formation
O’Keefe J and Nadel L (1978) The Hippocampus as a Cognitive Map. Oxford: Oxford
University Press.
Spiers HJ, Maguire EA, and Burgess N (2001) Hippocampal amnesia. Neurocase 7(5):
357–382.
Squire LR (2004) Memory systems in the brain: A brief history and current perspective.
Neurobiology of Learning and Memory 82: 171–177.
Van Strien NM, Cappaert NL, and Witter MP (2009) The anatomy of memory: An
interactive overview of the parahippocampal–hippocampal network. Nature Reviews
Neuroscience 10(4): 272–282.
Vargha-Khadem F, Gadian DG, Watkins KE, Connelly A, Van Paesschen W, and
Mishkin M (1997) Differential effects of early hippocampal pathology on episodic
and semantic memory. Science 18(277(5324)): 376–380.
Relevant Websites
http://www.cognitivemap.net – The Hippocampus as a Cognitive Map.
http://www.ucl.ac.uk/spierslab – Webpage for Dr Hugo Spiers.
Encyclopedia of Human Behavior, Second Edition (2012), vol. 2, pp. 297-304