Download Making New Memories

Making New Memories
The Role of the Hippocampus
in New Associative Learning
WENDY A. SUZUKI
Center for Neural Science, New York University, New York, New York
ABSTRACT: Both aging and Alzheimer’s disease target the hippocampal
formation and can result in mild to devastating memory impairment
depending on the severity of the condition. Understanding the normal
mnemonic functions of the hippocampus and related structures of the
medial temporal lobe is the first step toward the development of diagnostics and treatments designed to ameliorate these potentially devastating
age-related memory deficits. Here I describe findings from behavioral
neurophysiological studies in which we have investigated the patterns
of dynamic neural activity seen in the macaque monkey hippocampus
during the acquisition of new associative memories. We report that hippocampal neurons signal the formation of new associations with dramatic
changes in their firing rate. Because these learning-related signals can
occur just before behavioral learning is expressed, this suggests that these
signals play a role in driving the learning process. Implications of these
findings for understanding the memory deficits associated with aging
and Alzheimer’s disease are discussed.
KEYWORDS: relational memory; medial temporal lobe; changing cells;
macaque monkey
INTRODUCTION
Because both aging and Alzheimer’s disease target the medial temporal
lobe, the study of age-related memory impairment has benefited enormously
from basic research on the memory functions of this region. For example, the
groundbreaking description of the amnesic patient HM in the 1950s1 demonstrated definitively for the first time that the structures of the medial temporal
lobe are critical for our ability to learn and retain new long-term memories
for facts and events. This critical form of memory is referred to as declarative memory in humans2 and relational memory in animals.3 The development of powerful animal models of human amnesia in monkeys4–7 and in
Address for correspondence: Wendy A. Suzuki, Ph.D., Center for Neural Science, New York University, 4 Washington Place Room 809, New York, NY 10003. Voice: 212-998-3734; fax: 212-995-4011.
[email protected]
C 2007 New York Academy of Sciences.
Ann. N.Y. Acad. Sci. 1097: 1–11 (2007). doi: 10.1196/annals.1379.007
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rodents, 8–11 together with detailed neuroanatomical studies 12–15 demonstrated
definitively that the key medial temporal lobe structures important for declarative/relational memory include the hippocampus together with the surrounding
entorhinal, perirhinal, and parahippocampal cortices. While this convergence
of studies in humans and animals has provided detailed information about the
pattern of memory impairment following damage to the medial temporal lobe
(including aging-related damage), less information is available about how individual cells in the intact medial temporal lobe participate in the acquisition,
consolidation, or retrieval of various forms of declarative/relational memory.
A large body of evidence suggests that the medial temporal lobe in general
and the hippocampus in particular are critically involved in the ability to form
fast new associations in memory. For example, amnesic patients with medial
temporal lobe damage are impaired in forming fast new associations between
stimuli in multiple sensory modalities.16–19 The importance of the hippocampus for the ability to form fast new associations is also a key feature of recent
theories of hippocampal function.20 Given these convergent findings, an important question is, how does the hippocampus participate in the formation of
new associative memories? To address this question, we have used single-unit
electrophysiological recording techniques to record neural activity as animals
learn new associations “on-line” with trial and error. We find dramatic changes
in the firing rate of hippocampal neurons that are highly correlated with the
animal’s behavioral learning curve. I will first summarize these neurophysiological findings and then discuss some of the implications of these findings
for the study of aging and age-related memory impairments.
Location-Scene Association Task
To examine the patterns of neural activity during the formation of new associative memories, we recorded the activity of individual hippocampal neurons
as monkeys performed a location–scene association task.21 In this task, animals learned to associate a particular target location with a particular complex
visual scene for reward. We chose this task because several previous studies
had shown that damage to the medial temporal lobe produced impairment in
the ability to learn new location–scene associations.22–27 In this task, each trial
started with the monkeys fixating a central fixation point (FIG. 1). The monkeys
were then presented with four identical targets superimposed on a complex visual scene. Following a delay interval where the visual scene disappears but the
targets remain on the screen, the fixation spot was extinguished, which was the
animal’s cue to making an eye movement to one of four possible targets. Only
one of the targets was rewarded for each new scene. Each day, the animals were
presented with a random mix of two to four new scenes (each associated with
a different rewarded target location) together with two to four highly familiar
“reference” scenes (each also associated with a different rewarded target location). The new location–scene associations were learned in an average of 12 ± 1
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FIGURE 1. Location–Scene Association Task. In this task, following fixation, animals
were shown a set of four identical visual targets superimposed on a complex visual image
(all images used in task were color). Following a delay interval during which time the targets
remained on the screen, but the scene disappeared, the animal was cued to make an eye
movement response (illustrated schematically by the white arrow) to one of the targets.
Only one of the targets was rewarded for each particular scene. Animals learned by trial
and error to associate each new scene with a particular eye movement response. Animals
were also shown highly familiar “reference” scenes that they had seen many times before
and which they performed at ceiling levels.
trials and animals always performed the reference scenes at or near ceiling
levels.
Learning-Related Neural Activity in the Monkey Hippocampus
Many isolated hippocampal neurons were engaged in the performance of this
task with 61% (89) of the 145 isolated cells responding in a scene-selective
fashion during either the scene period, the delay period, or both periods of the
task. We hypothesized that the hippocampal cells that signaled learning would
change their activity when closely correlated with the animal’s behavioral
learning curve for particular learned new location–scene associations, but not
for the reference scenes with the corresponding rewarded target location. To
test this hypothesis, we compared the animal’s behavioral performance to the
hippocampal cell’s firing rate during either the scene or delay period of the
task. Behaviorally, the animal’s performance typically went from chance levels
(i.e., 25% correct) at the beginning of the session to at or near ceiling for
all the scenes learned. FIGURE 2A illustrates a trial-by-trial estimate of the
animal’s probability correct performance (dashed line) together with a trialby-trial estimate of neural activity (solid line) during the delay interval of
the task for the 55 trials that the animal completed for this particular new
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FIGURE 2. Illustration of the trial-by-trial probability correct performance (dotted line
read from the left axis) as a function of the trial-by-trial activity of cells during either the
scene or delay period of the task (solid line read from right axis) for a sustained (A) and
baseline sustained (B) cell. Note the strong positive or negative correlation between neural
activity and learning.
location–scene association. The dashed line (associated with the left y-axis)
shows that the animal exhibited a dramatic increase in behavioral performance
at trial 25. The solid line in the same graph (associated with the right y-axis)
shows that this dramatic shift in behavior was accompanied by an equally
dramatic shift in the cell’s firing rate during the delay interval of the task.
This change in firing rate was highly correlated with learning (r = 0.96).
We found 18% of the total population of sampled hippocampal cells (or 28%
of the cells that responded selectively during at least one phase of the task)
signaled new learning with similar dramatic shifts in firing rate that were
highly correlated with the animal’s behavioral learning curve. We call these
cells changing cells. Approximately half the changing cells increased their
activity during either the scene or delay periods of the task correlated with
learning and this change in neural activity was sustained for as long as we
were able to hold the cell (sustained changing cells; FIG. 2A). Some of the
sustained changing cells started out with very weak or no response during the
early trials of the session and only developed a strong response as the animal
learned a particular association. These cells provide some of the most striking
examples of dynamic changes in neural activity associated with new learning.
The remaining half of the changing cells responded robustly and selectively to a
particular scene early in the session before any association was learned. These
cells signaled learning by decreasing their firing rate to baseline levels and
this decreasing activity was anti-correlated with learning (baseline sustained
changing cells FIG. 2B). The responses of both sustained and baseline sustained
changing cells were highly selective in that the changes in neural activity only
occurred for a particular learned scene.
While we interpreted these changes in neural activity with respect to learning, another possible interpretation is that these changes are related to changes
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in the animal’s motor response. For example, in the changing cell illustrated in
FIGURE 2A, the animal almost never makes the correct response (to the north
target in this case) before trial 25 and always makes a north response after trial
25. Perhaps the change in neural activity simply reflects a preferred direction of
movement. To test this hypothesis, we compared the response of the changing
cell during new learning to the response of the same cell to the reference scenes
with the same rewarded target location (i.e., the same motor response for both
new and reference scenes). In no case did the changing cells respond similarly
to the reference scenes suggesting that the changing signal was not simply
signaling the direction of movement. To determine if the changing cells signal
new learning specific for a particular rewarded target location, we recorded
the activity of a changing cell during learning of two different new scenes with
the same rewarded target location. Typically, the cell would change in parallel
to learning for the first new scene. However, similar changes in activity were
never seen for the second new scene with the same rewarded target location.
Thus, hippocampal changing cells do not appear to signal new learning in a
motor-based or direction-based frame of reference. Instead, these findings suggest that hippocampal cells signal fast associative learning between sensory
stimuli and motor responses or target locations. This interpretation is consistent with theories suggesting that the hippocampus plays a fundamental role
in forming the random associations or relationships between unrelated items.3
These kinds of simple associations may be critical to building up the more
complex associations between the “what,” “where,” and “when” information
that forms the basis of episodic memory.
What Does the Change in Neural Activity Represent?
Previous studies have shown that neurons in both the perirhinal cortex and
visual area TE (Temporal area ”E” of von Bonin and Bailey) signal longterm associations between visual stimuli by responding similarly to the two
items that had been paired in memory.28,29 These findings suggested that the
learning of the paired associates may have “tuned” or “shaped” the sensory
responses of these cells toward a similar response to the two stimuli paired
in memory. Consistent with this idea, several other groups demonstrated that
perirhinal neurons show a shift in response selectivity during the associative
learning process.30–32 These findings suggested that the striking changes in
neural activity observed during the location–scene association task may represent a change in the cell’s stimulus selective response properties with learning. To address this possibility, we examined the average response of a single
changing cell to all new scenes and reference scenes over the course of learning. The changing cell illustrated in FIGURE 3A did not differentiate between
any of the scenes during the scene period of the task early in the learning
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FIGURE 3. (A) Average response to four reference scenes and two new scenes over the
course of the recording session for a sustained changing cell. The learning curve for New
Scene 2 is illustrated as the thick gray line. (B) Graph showing the significant increase in the
selectivity index for sustained changing cells after learning compared to before learning.
(C) In contrast, baseline sustained changing cells decreased their selectivity after learning
compared to before learning.
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FIGURE 4. Scatter plot illustrating the temporal relationship between trial number of
behavioral changing (i.e., learning) and trial number of neuronal change. Note that about
half the cells change before or at the same time as learning while the remaining half of the
cells change before learning.
session. However, this cell appeared to develop a highly selective response to
new scene 2 (black line), which occurred in parallel with learning (thick gray
line). To quantify this observation across the changing cells, we measured selectivity using a selectivity index33 to the responses to all new and reference
scenes before versus after learning. We analyzed the sustained and baseline
sustained changing cells separately. We found that while the sustained cells
exhibited a significant increase in selectivity (FIG. 4B) with learning, the baseline sustained cells exhibited a significant decrease in selectivity (FIG. 4C).
These findings suggest that hippocampal cells signal new associations with a
significant change in their stimulus-selective response properties.
Timing of the Changing Cells Relative to Learning
While the analyses illustrated in FIGURE 2 show a strong correlation between
changing cell activity and learning, a critical question is whether this activity
is causally related to learning. One clue in support of the idea that these signals may underlie learning comes from the lesion studies showing that various
lesions of the medial temporal lobe produce a significant impairment in the
ability of animals to learn new location–scene associations .22–27 If this hypothesis is correct, we further predicted that some of the hippocampal cells should
change their firing rate either at the same time or slightly before behavioral
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learning is expressed, at a time when this activity could drive the changes in
behavior underlying learning. Changes in neural activity that occurred after
behavioral learning is expressed would be consistent with a role in the strengthening of the newly formed association. To address this question, for each cell
that changed for a particular condition, we estimated the trial number of learning as well as the trial number of neural change. FIGURE 4 shows a scatter plot
of this comparison for all changing cells in the hippocampus. This plot shows
that while about half of the changing cells changed before or at the same time
as learning, the remaining half change after learning. These early changing
cells suggest that the hippocampus is among the earliest brain structures to
signal or drive new associative learning. Other recent studies have implicated
other brain areas in new conditional motor association learning including the
caudate,34,35 prefrontal,34,36 as well as premotor areas.35 It will be important
to direct future studies at examining how these different brain areas interact
during the associative learning process.
CONCLUSIONS AND IMPLICATIONS FOR AGING RESEARCH
We have shown that many hippocampal neurons signal learning with dramatic changes in their stimulus-selective response properties. While some
neurons increase their activity (and stimulus selectivity) with learning, others decrease their activity (and stimulus selectivity) with learning suggesting
that these changes represent an overall tuning of the hippocampal network.
The observation that these changes can occur before behavioral learning is
expressed, taken together with the findings of the detrimental effects of medial
temporal lobe lesions on tasks requiring new associative learning, suggest that
the hippocampal changing cells may drive the behavioral changes underlying
learning. We have also shown similar changes in hemodynamic responses in
the hippocampus and other related medial temporal lobe structures in a recent
human fMRI study using a variant of our location–scene association task.37
These findings suggest that associative learning signals can be studied in parallel in both human and nonhuman primate systems.
What are the implications of these basic neuroscience findings for the study
of human aging and Alzheimer’s disease? Given that forming new associations
in memory is highly sensitive to medial temporal lobe damage and this brain
region is also targeted in both aging and Alzheimer’s disease, this suggests that
monitoring brain activity during the location–scene learning task may be a
powerful way of probing and delineating the specific deficits in signaling new
associative learning that are present in both animal models of aging as well as
in both aged and Alzheimer’s patients. More generally, this strategy illustrates
the critical interplay between clinical research efforts and basic experimental
approaches that can provide novel paradigms or hypotheses to test both in
animal models as well as in various patient populations. As we more fully
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define the patterns of normal neural activity seen during associative memory
acquisition not only in the hippocampus proper, but throughout other key
medial temporal lobe structures important for memory, this will provide an
important framework against which we can compare deficits (or lack thereof)
seen in the neurophysiological profiles of aged animals or the fMRI profiles of
aged subjects or patients with Alzheimer’s disease. This experimental approach
suggested by our neurophysiological findings illustrates the point that our best
hope for eventually understanding the specific memory deficits in aging and
Alzheimer’s disease is to keep the channels between basic research and clinic
studies wide open and flowing.
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