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Plasticity, Hippocampal Place Cells, and Cognitive Maps
Matthew Shapiro, PhD
Arch Neurol. 2001;58:874-881.
ABSTRACT
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Memory of even the briefest event can last a lifetime. Thus, learning
and memory require neuronal mechanisms that allow rapid, yet persistent, changes
to brain circuits. Hippocampal neuropsychology, synaptic and cellular electrophysiology,
pharmacology, and molecular genetics converge and begin to reveal these mechanisms.
Lesions of the hippocampus profoundly impair memory for recent events in humans
and rodents. Circuits within the hippocampus are remarkably plastic, and this
plasticity is mediated in part through changes in synaptic strength and revealed
by long-term potentiation (LTP) and long-term depression (LTD). N-methyl D-aspartate (NMDA) receptors, a subtype of glutamate receptor,
are crucial for inducing these plastic changes, and blocking these receptors
reduces plasticity and impairs learning in tasks that require the hippocampus.
Molecular genetic alterations that disrupt signaling mechanisms downstream
of the NMDA receptor also prevent LTP induction and impair hippocampus-dependent
learning. N-methyl D-aspartate receptor mechanisms
have also been linked to information coding by hippocampal neurons. Hippocampal
cells fire selectively in specific and restricted locations (place fields)
as rodents move through open environments. Place fields form within minutes
and persist for months. N-methyl D-aspartate receptor
antagonists prevent the establishment of stable place fields. The same molecular
genetic manipulations that interfere with hippocampal NMDA receptor function,
prevent LTP induction, and impair spatial learning also disrupt the formation
of stable hippocampal place fields. Finally, learning has been improved in
mice with genetically modified NMDA receptors that enhance LTP induction.
Thus, hippocampal cells "learn" to encode the salient features of experience
through NMDA receptor–dependent synaptic plasticity mechanisms, and
this rapid and persistent neuronal encoding is a crucial step toward the formation
of long-term memory. Disruption of these plasticity mechanisms may underlie
age-related memory deficits.
MEMORY AND AMNESIA
In 1957, Scoville and Milner1 described
a patient whose medial temporal lobes were removed as an experimental treatment
for epilepsy. The surgery reduced the patient's seizures, but also caused
severe amnesia. After his surgery, the patient was unable to learn new facts
or remember recent events, though both his short-term memory and childhood
memories remained intact. Neuropsychological studies of other temporal lobe
lesion cases suggested that damage to the hippocampus caused this anterograde
amnesia. Research since then focused upon how medial temporal lobe structures,
the hippocampus in particular, contribute to memory.
ANIMAL MODELS OF AMNESIA
Memory, in the everyday sense of the word, hinges on remembering events:
what happened in a place once upon a time? People can describe episodes in
words, and the accuracy of their memory can be verified. People with amnesia
cannot remember recent events. The ability to remember the personal, spatial,
and temporal context of events has been called episodic memory, described
in detail by Endel Tulving.2
A major challenge to the neuroscience of memory was to establish valid
animal models of amnesia in nonverbal species. This limitation of animal behavior
forced researchers to define memory in terms of abstract cognitive processes
such as information encoding, manipulation, storage, and retrieval, and to
translate those ideas into behavioral tests. Rapid progress followed the discovery
of dissociations among multiple memory systems during the 1970s and 1980s.
We know now that several special-purpose memory systems process and store
different types of information. O'Keefe and Nadel's The
Hippocampus as a Cognitive Map3 helped
establish the idea of multiple memory systems by emphasizing that animals
could represent the same physical stimuli differently using different neuronal
systems. They showed that locations are defined not by single items, but rather
by the unique set of spatial relationships among common items, so that the
perspective from one place distinguishes that location from any other. Hippocampal
lesions impair many tasks that require memory for spatial relationships. In
contrast, rats learn to approach or avoid simple stimuli (eg, a light) with
brain circuits that require the dorsal striatum but not the hippocampus.4 This dissociation has been shown in the radial maze
devised by David Olton and colleagues (Figure
1C).5 To test hippocampus-independent
memory, hungry rats are trained to enter arms that are marked by a light to
obtain food and to avoid unlit arms that contain no food. In this cue approach
task, lesions of the neostriatum impair learning, but rats with hippocampal
damage learn faster than normal ones. To test hippocampus-dependent spatial
memory, a piece of food is placed at the end of each arm at the start of a
trial. To obtain the food efficiently, the rat must enter each arm once and
only once each day. Normal rats remember visited arms for 12 hours or more
with no decrement in performance, so this ability is not simply one of short-term
memory. As long as the animal is prevented from learning a stereotyped response
pattern (eg, always turning left), hippocampal lesions made by any method,
before or after training, permanently impair performance. This and other dissociations
among different memory systems show that motivation, perception, motor ability,
and other variables that are common among the tasks cannot explain the effects
of hippocampal lesions. Rather, the dissociations show that the effects of
hippocampal lesions are selective for memory—in this case, memory for
recently entered locations.
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Figure 1. Synaptic plasticity and behavior.
A, The anatomy of the hippocampus, at increasing magnifications from left
to right (adapted from Amaral and Witter6).
The hippocampal slice, circled in the lower left figure, is expanded to show
the trisynaptic circuit. At the top right, a single cornu ammonis 1 (CA1)
pyramidal neuron and the hippocampal synapse are shown. Axons from CA3 pyramidal
neurons form glutamatergic synapses on CA1 neurons. N-methyl
D-aspartate (NMDA) receptors are colocalized in synapses that also contain
non-NMDA (eg, AMPA [ -amino-3-hydroxy-5-methyl-4-isoxazole propionic
acid]) glutamate (GLU) receptors. Simultaneous GLU binding to NMDA receptors
and postsynaptic depolarization leads to calcium (Ca) influx. This dual gating
of the NMDA receptor provides a mechanistic explanation for many of the induction
properties of long-term potentiation (LTP), including associativity and synaptic
specificity. Calcium influx through the NMDA receptor initiates an enzyme
phosphorylation cascade that includes the activation of Ca-calmodulin–dependent
kinase II (CaMKII), protein kinases, and CREB (cyclic adenosine monophosphate–responsive
element binding protein). Metabolic poisons or molecular genetic manipulations
that interfere with these different enzymes either reduce the duration of
LTP or block LTP induction altogether. Longer-term LTP maintenance requires
protein synthesis, but more specific mechanisms required for such prolonged
synaptic change are not fully known. Anatomy: The rat hippocampus is shown
in a cut-away view. The hippocampus is formed by 2 sheets of cells folded
into interlocking Cs. The outer C is the CA (or Ammon horn); the inner C is
the dentate gyrus (DG). Cortical axons make synapses on cells in the DG, which
in turn innervate the CA, which returns input to the cortex. Highest-order
association cortices (eg, visual association area TE) converge onto parahippocampal
and perirhinal cortices in the medial temporal lobe. These areas innervate
the entorhinal cortex (EC), which in turn connects to the hippocampus. The
hippocampal output to the cortex is conveyed by CA1 and subiculum, which project
back to the EC and parahippocampal cortex. Within the hippocampus, axons from
the EC travel in the perforant path (pp) and make synapses on the granule
cells of the DG. Granule cell axons, called mossy fibers (mf), enter the CA
and make synapses on CA3 pyramidal cells, which in turn send Schaffer collateral
axons to CA1 pyramidal cells. Together with related subicular cells (called
CA0 by some anatomists), CA1 neurons innervate the EC. S indicates the septal
pole of the hippocampus; trans, the transverse axis of the hippocampus; S-comm,
Schaffer collaterols/commissural inputs. B, Hippocampal circuits support rapidly
induced and persistent synaptic plasticity, such as LTP and long-term depression.
The sketch of a hippocampal slice shows a stimulating electrode in the hippocampal
commissure and a recording electrode in the pyramidal cell layer of CA1 (left).
Stimulating the commissure activates CA3 axons, which release GLU on the dendrites
of CA1 cells, which respond with excitatory postsynaptic potentials and action
potentials, and these evoked potentials are recorded easily in vivo (center).
Stimulation patterns that mimic rhythmic complex spiking, such as brief high-frequency
bursts, potentiate CA3-CA1 synapses. The traces illustrate the baseline (solid
lines, ±1 SD) and potentiated (dashed lines) responses recorded in
a behaving rat. The downward population spike amplitude doubled after brief
high-frequency bursts. Potentiation of CA3-CA1 synapses typically requires
NMDA receptor function (right). Thus, the NMDA receptor antagonist CPP ((+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic
acid) or aminophosphonovalerate (APV) completely prevents LTP. The figure
on the right shows the complete block of synaptic potentiation in area CA1
produced by the NMDA receptor antagonist CPP (10 mg/kg). In this experiment,
primed burst potentiation was used to induce a short-lived form of plasticity.
C, NMDA receptor antagonists prevent normal spatial learning in the radial
maze. The figure on the left depicts a rat in an 8-arm radial maze surrounded
by distal cues. The task for the rat is to enter each arm once to obtain food
placed at the end of each arm at the start of the daily trial. Probe tests
have shown that rats remember which arms they have visited on the basis of
the distal cues. Hippocampal lesions made by any method permanently impair
performance on this task. The graph on the right illustrates the effects of
NMDA receptor antagonists on radial maze performance. The vertical axis shows
repeated arm entries, while the horizontal axis shows blocks of trials. In
this experiment, 2 groups of rats were trained under normal conditions to
perform the radial maze task. Thus, in blocks 1 through 4, no rats were given
drugs, and all rats learned to perform the task well. During block 5, some
rats were given injections of the NMDA receptor antagonist MK801 (62.5 µg/kg,
a dose that had impaired new learning in prior experiments). The drug had
no effect on performance in this familiar environment. In blocks 6 through
8, the same rats given the same drug were tested in an identical maze situated
in another, unfamiliar room. The rats given saline performed well in the new
room within a few trials. The rats given the NMDA receptor antagonist, however,
performed poorly in this unfamiliar environment. The results show that NMDA
receptor antagonists do not impair recent memory for familiar items, but rather
prevent the establishment of new memories.
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As reviewed by Eichenbaum and colleagues,7
many tasks that require memory for nonspatial relationships are also impaired
by hippocampal lesions. Thus, spatial memory is an important and useful example
of a more general memory capacity provided by the hippocampus across species.
The refinement of animal models allows specific aspects of memory to be tested,
which in turn requires specific neural circuitry and provides a crucial step
toward the evaluation of memory mechanisms at neuronal, synaptic, and molecular
levels of analysis.
SYNAPTIC PLASTICITY IN HIPPOCAMPAL CIRCUITS
Learning and memory require persistent changes in neuronal circuits.
These changes, according to Donald Hebb's hypothesis,8
occur when the connections between coactive cells change and thereby store
a record of an event. Indeed, hippocampal circuits support rapidly induced
and persistent synaptic plasticity (Figure
1A). Bliss et al9, 10
discovered that high-frequency electrical stimulation of hippocampal circuits
produced an enhancement of synaptic responses that lasted for hours in vitro
and days to weeks in vivo. They named this enduring response long-term potentiation (LTP).
The discovery of LTP and its inverse, long-term depression (LTD), in a brain structure associated with memory and amnesia suggested
a biological implementation of Hebbian synapses. The link between LTP and
learning could not be tested, however, unless and until LTP could be manipulated
independently from normal synaptic transmission. Fortunately for the neuroscience
of memory, the mechanisms of LTP induction can be separated from normal synaptic
transmission, at least in the hippocampus. (The induction, maintenance, and
expression of LTP are defined operationally and refer to the moment when evoked
potentials are measured.) In the hippocampus, LTP induction requires the N-methyl D-aspartate (NMDA) type of glutamate receptor
and is blocked by NMDA receptor antagonists, whereas LTP expression and normal
neurotransmission are conveyed by non-NMDA (AMPA [-amino-3-hydroxy-5-methyl-4-isoxazole
propionic acid]) glutamate receptors.11 The
NMDA receptor is required to induce LTP because Ca2+ influx through
the NMDA receptor channel is the first signal that ultimately changes synaptic
strength. The NMDA-associated Ca2+ channel is gated by both voltage
and ligand. To open the channel, the postsynaptic membrane must be strongly
depolarized at the same time that glutamate occupies the receptor site. Thus,
the NMDA receptor detects presynaptic and postsynaptic coactivation, much
as predicted by Hebb.8 If presynaptic and postsynaptic
elements are coactive and calcium influx is sufficient, then the strength
of the synapse increases. Note that the NMDA receptor is only crucial for
this induction step and that normal synaptic transmission, including that
through potentiated synapses, does not require NMDA receptors. Thus, while
blocking NMDA receptors prevents the induction of LTP, it does not prevent
the expression of LTP.
SPATIAL LEARNING AND ENDURING RECENT MEMORY REQUIRE NMDA
RECEPTOR–DEPENDENT SYNAPTIC PLASTICITY
Psychopharmacology
Research on LTP accelerated after Richard Morris and colleagues12 demonstrated that blocking NMDA receptors impaired
learning in tasks that require the hippocampus. Long-term potentiation induction
in the dentate gyrus and spatial learning in the water maze were impaired
by the NMDA receptor antagonist aminophosphonovalerate (APV).12
In contrast, neither the expression of previous learning nor visual discrimination
learning in the same apparatus was impaired by the drug. Direct infusion of
APV into the hippocampus produced the same pattern of effects. These findings
established a testable link between a biophysical mechanism and memory formation
in the mammalian brain.
N-methyl D-aspartate receptor antagonists also
impair spatial learning, but not performance, in the radial maze. Doses that
reduce potentiation in hippocampal circuits prevent rats from learning the
task. The same doses do not impair memory performance, as long as rats are
first trained and then tested in the same, familiar environment. The drugs
therefore do not alter motivation, perception, or sensorimotor function enough
to disrupt memory performance. Furthermore, the same animal that performs
the radial maze task well when drugged and tested in a familiar room performs
poorly when tested in an unfamiliar room. The simplest interpretation of these
results is that the drug impairs learning about the particulars of an environment.
This view is bolstered by the fact that NMDA receptor antagonists also prevent
the establishment of new neuronal representations in the hippocampus.
Molecular Genetics
The effects of NMDA receptor antagonists on learning in rodents have
been confirmed by molecular genetics experiments in mice. Two classes of mutations
show that NMDA receptor activation is required for synaptic plasticity mechanisms
in the hippocampus that mediate hippocampus-dependent learning: localized
NMDA receptor elimination and disruption of signaling pathways downstream
of the NMDA receptor (Figure 2A).
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Figure 2. Hippocampal place fields, learning,
and synaptic plasticity. A, Cornu ammonis 1 (CA1) and CA3 pyramidal neurons
have distinct complex-spike action potentials whether recorded intracellularly
or extracellularly. These signature complex-spike cells occasionally fire
in bursts of 2 to 7 action potentials with decreasing amplitude. Advances
in microelectrode recording methods allow these cells to be discriminated
with high accuracy by the unique pattern of waveforms across 2 (stereotrode)
or 4 (tetrode) adjacent electrode wires. Place cells: When rats explore open
environments, eg, a 4-arm maze surrounded by stimuli, hippocampal pyramidal
cells fire in restricted locations called place fields, shown in a computer-generated
place field "map" (right). A computer combines the action potentials fired
by a single hippocampal cell with the animal's location, detected by an overhead
video camera; each small square represents an area on the radial maze visited
repeatedly by the rat during a 10-minute recording period. The small squares
in the map show locations entered by the rat, and filled squares show that
significantly elevated firing rates occurred in a restricted region (southwest
maze arm). The cells respond to relationships among distal cues, in particular,
to the distance between the rat and a relatively small subset of the available
stimuli. S-comm indicates Schaffer collaterols/commissural inputs; mf, mossy
fivers; DG, dentate gyrus; PP, perforant path; and EC, entorhinal cortex.
B, Place fields form rapidly and persist. The figure shows the spatial distribution
of neuronal activity recorded from a pyramidal neuron in the CA1 region of
a rat during the first 2 days it explored a new environment. The environment
was an enclosed square arena. Locations entered by the rat are shown by small
squares, the firing rate is shown by line density, and the waveforms show
stereotrode recordings taken at the beginning of each day's recording session.
The left-hand panel shows the firing during the rat's first 5 minutes of exploration
in the recording chamber; the right-hand panel shows the first 5 minutes of
firing 24 hours later. The scattered firing that appears during the first
day begins to focus by the end of the first recording session, and the region
with highest firing, the middle right-hand wall, persists through the second
day. The visual impression of focusing is verified by statistical measures
including spatial information that measure the likelihood that the rat occupied
a pixel given that the cell fired (from left to right, 0.47, 0.85, and 1.3
bits per pixel). C, N-methyl D-aspartate (NMDA) receptor
antagonists do not prevent normal place cell activation. Normal rats have
place-stable fields. In a familiar environment, the same fields can be recorded
for months. When normal rats are placed in a novel environment, however, the
firing maps change rapidly to form new place field maps. Within 30 minutes
or less, these new fields become stable. Place fields were recorded in rats
as they explored a square, enclosed, and highly familiar recording chamber.
Place fields recorded in the chamber were stable and unchanged (a and b) in that environment when the rats
were given doses of an NMDA receptor antagonist (NPC-17742 or CPP [(+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic
acid]) that had prevented induction of long-term potentiation (LTP) in previous
experiments. Thus, the drugs that blocked LTP induction and learning but neither
LTP expression nor memory retrieval did not impair the sensory, motor, motivational,
or other information-processing functions that are required for normal place
field activation. Establishing stable place fields in unfamiliar environments
requires NMDA receptor function. A cylinder introduced into the recording
chamber defined a new and unfamiliar environment for the animals and produced
new spatial firing patterns. This normal remapping was not prevented by NMDA
receptor antagonists (c, day 1). The drugs prevented
the establishment of stable place fields; the next day, the same cell was
remapped again and had yet another field. Thus, blocking NMDA receptors prevents
the establishment of stable place fields, but does not prevent either the
activation of previously established stable fields or the formation of temporary
fields (Kentros et al13). CCD indicates charge-coupled
device.
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Joe Tsien and colleagues,14 then in Susumo
Tonegawa's laboratory at the Massachusetts Instutute of Technology, created
mice that lost their NMDA receptors selectively in the cornu ammonis 1 (CA1)
layer 3 weeks after birth. Because the receptor elimination was both region
selective and postnatal, the mutation was less likely to disrupt either normal
development or widespread brain circuits. The mice without CA1 NMDA receptors
had normal neurotransmission but no LTP in CA1 and were severely impaired
in the hippocampus-dependent, spatial version of the Morris water maze (a
task in which a platform that can be found only by learning and remembering
its spatial location is hidden underwater). In contrast, the mice learned
to escape the water onto a visible platform, demonstrating that motivation,
sensation, perception, motor function, and extrahippocampal learning systems
were intact. More recently, a mutation was produced in which CA1 NMDA receptors
can be deleted and reinserted through the use of tetracycline (a so-called inducible/reversible mutation). These mice learn the spatial
version of the water maze task only when CA1 NMDA receptors are available
and become impaired after the receptors are eliminated. This class of experiments
provides perhaps the strongest evidence that links NMDA receptor function,
synaptic plasticity, and hippocampus-dependent learning ability.
Similar results were reported by Alcino Silva and others15, 16
in mice with mutations that altered intracellular signaling downstream of
the NMDA receptor. Mice without or with mutated forebrain calcium-calmodulin–dependent
kinase II (CaMKII) have abnormal hippocampal LTP and impaired hippocampus-dependent
learning. CaMKII is activated by calcium influx through the NMDA channel and
is necessary for LTP induction. Other mutations prevent the induction or persistence
of LTP by impairing other signaling pathways downstream of the NMDA receptor,
and each mutation prevents new spatial learning in the water maze. These include
mutations to CREB (cyclic adenosine monophosphate–re sponsive element
binding protein) and protein kinases C and A. Mice with these mutations are
impaired in several tasks that require the hippocampus, such as contextual
fear conditioning and social transmission of food preferences.11
Again, cue approach learning that is unimpaired by hippocampal damage is not
impaired by either NMDA receptor antagonists or mutations to LTP induction
pathways.
Mutations in CREB and protein kinase A (PKA) pathways reduce the persistence,
rather than the induction of LTP and provide especially powerful evidence
of the importance of NMDA-dependent plasticity mechanisms for learning (Figure 2A). Ted Abel and others,17 then in Eric Kandel's laboratory, and Alcino Silva
and others15, 16 showed that mice
with such mutations learn normally and perform well when tested shortly after
training, but perform at chance levels after 24 hours.The time course of intact
and impaired performance parallels LTP duration. Together, the behavioral
pharmacological studies and the more recent molecular genetics experiments
converge to support the hypothesis that NMDA receptor activation contributes
to synaptic plasticity mechanisms in the hippocampus that are necessary for
hippocampus-dependent learning.11
Better Learning Through Molecular Genetics?
If the NMDA receptor is crucial for learning and memory, can its function
be altered to improve memory? In a fascinating counterpoint to these molecular
genetic "lesions," Ya-Ping Tang and colleagues18
in Joe Tsien's laboratory at Princeton University describe improved learning
and memory in mice engineered to overexpress the NR2B subunit of the NMDA
receptor. N-methyl D-aspartate receptors are complexes
that contain various combinations of NR1 and NR2 subunits. The NR2 subunit
regulates the duration of Ca2+ influx through the NMDA ion channel.
Hippocampal cells taken from mice that overexpressed the NR2B subunit had
prolonged NMDA currents and more easily induced LTP than normal cells. The
mutant mice learned the Morris water maze, contextual fear conditioning, and
novel object discriminations more rapidly than normal, wild-type mice. Most
impressively, the NR2B mice showed more rapid extinction to the fear conditioning
than wild-type mice, implying that the enhanced learning was flexible. The
NR2B mice, therefore, had both enhanced synaptic plasticity in the hippocampus
and more rapid learning than normal mice. These results provide important
evidence that helps to link NMDA receptor function, synaptic plasticity, and
hippocampus-dependent learning. The results also raise many questions: Can
learning-enhanced mice show the same behavioral flexibility as normal mice,
or are they "sticky," ie, learning rapidly but then perseverating? Do they
have supernormal storage capacity, or do they just "fill up" their memory
space more quickly? Does the enhanced memory improve problem solving beyond
memory itself? The creation of these and other engineered species promises
to illuminate the neuroscience of memory more brightly than ever before.
Hippocampal Neuronal Activity and Behavior
The activity of hippocampal neurons correlates with the salient features
of virtually every situation in which hippocampal cells are recorded. Hippocampal
neurons respond robustly and selectively in relation to either the discriminative
stimuli or the behavioral responses that constitute task performance or both
in every experimental situation in which an animal behaves.7
The wide-ranging correlates of cell firing, together with the effects of hippocampal
lesions, are consistent with an episodic memory function of the hippocampus.
One of the most striking correlates of hippocampal neuronal activity is the
place field—the location-specific firing of single hippocampal cells
observed as rodents explore open environments. These spatial correlates have
been studied extensively, are closely linked with spatial memory, and provide
crucial insights into hippocampal neurobiology.
HIPPOCAMPAL PLACE FIELDS
Discovery
In 1971, O'Keefe and Dostrovsky19 discovered
that, as a rodent moves about a large environment, the firing rate of hippocampal
cells correlates with the animal's location (Figure 1A). This spatially selective firing pattern led O'Keefe
and Dostrovsky to call such neurons place cells and
to suggest that place cells encoded a map-like representation of a rat's location
in its environment.1 Most hippocampal cells
are almost silent in most places, firing less than 1 spike per second, while
in other areas, the firing rate can exceed 100 Hz. A typical cell fires predominantly
in one contiguous region; this is the cell's place field (Figure 1A). Recent experiments by Matthew Wilson and Bruce McNaughton20 have shown that as few as 60 simultaneously recorded
cells can predict a rat's location to within 1 cm.
Recording and Analytic Methods
Modern place field studies typically use a video camera to record the
location of the animal and a computer to store action potentials along with
the camera output. Together, these data allow location-related firing to be
assessed rapidly as time-averaged "firing maps" that show the mean firing
rate (spikes per second) in each X-Y coordinate (pixel) of a spatial array.
These firing maps usually depict place fields from an overhead view of an
environment or maze, with color, line density, or a 3-dimensional perspective
showing cell-firing rates. The visual impression of place field maps can be
quantified. Place field borders can be defined as contiguous regions of pixels
with firing rates that exceed a predetermined threshold (eg, 3 SEs above the
mean firing rate). These "in-field" regions can then be measured for area,
"volume" (the sum of pixel rates within an area), and other spatial statistics.
To quantify the spatial signal without place field thresholding, which is
somewhat arbitrary, spatial coherence (spatial autocorrelation) or information
content (in bits per spike) can also be calculated from the firing maps. To
quantify the spatial stability of firing over time, the correlation between
place field maps is calculated. Stable place fields will produce similar firing
maps with high spatial correlations.
Coding Properties
Quantitative methods have allowed detailed explorations of hippocampal
place field properties. Within any one environment, place fields are consistent
from day to day, with the correlation among place field maps recorded on consecutive
days typically exceeding 0.7. The location of a place field in one environment,
however, does not predict either the existence or location of a place field
in any other environment. About 30% of hippocampal pyramidal cells have place
fields in any one environment; the rest are silent. Anatomically adjacent
cells in the hippocampus do have correlated firing fields, but they do not
consistently overlap, nor do they form a spatiotopic map in the way adjacent
neurons in the primary visual cortex respond to stimuli in adjacent retinal
locations. Rather, neighboring hippocampal cells can fire in widely different
places, and anatomically distant cells can fire in identical locations in
the same environment. Together, the firing properties suggest that locations
are represented by a distributed population code: Each location in an environment
is indicated by an anatomically distributed pattern of activity of many hippocampal
cells, and each cell contributes to the encoding of many places. Recent experiments
have shown that, in open environments, place cells fire as a function of the
distance between the animal and a subset of available cues.
How Do Place Fields Form?
Place fields form within minutes when a rat first explores a new environment,
and the same fields persist for months for familiar places (Figure 2B). In new and unfamiliar environments, place fields form
and stabilize quickly. Initially, the cells fire in an unfocused or unstable
pattern. After about 5 to 30 minutes, the place fields are stable and focused,
and they remain consistent for as long as they are recorded. In familiar,
unchanging environments, hippocampal neurons have been shown to have the same
place fields for months.21
Synaptic Plasticity and Place Fields
Pharmacology
The rapid formation of persistent place fields requires NMDA receptors.13 The NMDA receptor antagonist CPP ((+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic
acid), 10 mg/kg, blocks LTP induction in the CA1 region of behaving rats.
The same dose impairs spatial learning and long-term spatial working memory
in the radial maze, and prevents the formation of stable place fields in new
and unfamiliar environments (Figure 2B). In contrast, this drug dose does not prevent LTP expression, short-term working
memory in the radial maze, or the activation of previously established place
fields in familiar environments (Figure 2B).13 Thus, NMDA receptor–dependent
synaptic plasticity is necessary for establishing stable neuronal representations.
Molecular Genetics
As described above, mutations in the NMDA receptor or enzymes downstream
of the receptor channel cause reduced LTP in CA1 and poor spatial learning.
The same mutations produce noisy and unstable place fields. The mutations
include region-selective NMDA receptor knockouts, altered CaMKII (CaMKII-Asp286, CaMKII
T286A), CREB (CREB  2), and PKA (PKA RAB). Thomas McHugh et al22 in Matthew Wilson's laboratory showed that mice with
NMDA receptors "knocked out" only in area CA1 (no LTP in CA1 and impaired
spatial learning) had abnormally large place fields compared with wild-type
littermates. The enlarged fields are reportedly caused by instability within
a place field that may be established by normal plasticity in regions upstream
from CA1, including CA3 and the dentate gyrus. Alex Rotenberg et al23 in Bob Muller's laboratory and Yoon Cho et al24 in Howard Eichenbaum's laboratory showed that, unlike
wild-type mice, those with CaMKII or CREB mutations have place fields that
change from one recording session to the next, sometimes within minutes, in
the same environment. PkA mutations alter the persistence, not the induction,
of LTP, so that normal LTP returns to baseline within a few hours, even after
strong induction. Mice with protein kinase A mutations also have transient
memory in hippocampus-dependent tasks (eg, contextual fear conditioning) and
place cells that are stable within a day but unstable across days. Thus, synaptic
plasticity is necessary for establishing stable neuronal representations in
the hippocampus. The clear inference is that these representations, in turn,
are required for enduring spatial memory.
RELEVANCE TO THE PRACTICE OF NEUROLOGY
The hippocampal contribution to memory provides a direct link between
the analysis of memory in experimental animals and the neurology of memory
and amnesia in humans. The mechanisms of information coding and synaptic plasticity
described herein may provide insight into the most common cause of human amnesia,
age-related memory loss, including Alzheimer disease. Subsets of aged (24-month-old)
rats have memory deficits, and these rats have either transient LTP or a reduced
sensitivity to stimulation that produces LTP in young adult rats.25 Hippocampal place fields in these aged rats are both
less sensitive to environmental changes and more unstable in unchanging environments.
Indeed, Carol Barnes et al26 showed that old,
memory-impaired rats had place fields that were as unstable as those of young
rats given NMDA receptor antagonists. In efforts to directly model the causes
of Alzheimer disease, transgenic mice have been designed either to overexpress ß-amyloid
or presenilins or to produce abnormal ß-amyloid sequences. Some strains
of these mutant mice also have impaired memory, attenuated LTP, and normal
LTD. The clear prediction is that these mice will have transient place fields
and that the place field instability will correlate with memory impairments.
AUTHOR INFORMATION
Accepted for publication November 10, 2000.
From the Kastor Neurobiology of Aging Center, the Fishberg Research
Center for Neurobiology, and the Department of Geriatrics and Adult Development,
Mount Sinai School of Medicine, New York, NY.
Corresponding author and reprints: Matthew Shapiro, PhD, Kastor Neurobiology
of Aging Center, Mount Sinai School of Medicine, One Gustave L. Levy Place,
Box 1639, New York, NY 10029-6574 (e-mail: matthew.shapiro{at}mssm.edu).
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