0306-4522/83/040791-07$33.00/O
Pergamon Press Ltd
0 1983IBRO
NeuroscienceVol. 8, No. 4, pp. 791 to 797, 1983
Printed in Great Britain
TEMPORAL
CONTIGUITY
REQUIREMENTS
FOR LONG-TERM
ASSOCIATIVE POTENTIATION/DEPRESSION
IN THE HIPPOCAMPUS
W. B. LEVY and 0. STEWARD
Department of Neurosurgery, University of Virginia School of Medicine, Charlottesville, VA 22908, U.S.A.
Abstract-A
previous study utilizing the powerful ipsilateral and weak crossed projection from the
entorhinal cortex to the dentate gyrus in the rat revealed that long-term potentiation is an associative
process in these systems. If the weak crossed projection alone receives potentiating stimulation consisting of 8 high-frequency trains 17.5 ms in duration, it does not exhibit long-term potentiation. However,
long-term potentiation can be induced in the crossed projection if it is activated concurrently with the
converging ipsilateral system. The present study is designed to determine the degree of synchrony
required for the associative interactions by varying the timing and order of the potentiating trains
delivered to the two converging systems.
The associative induction of long-term potentiation does not require perfectly synchronous activation
of the converging systems. The order of the trains is crucial, however. Long-term potentiation of the
crossed projection can be induced if activity in the ipsilateral system is concurrent with or follows
activity in the crossed projection. Indeed, there can be as much as 20 ms between the 17.5 ms trains in
the two systems, and long-term potentiation of the crossed projection is still induced. Activation of the
ipsilateral system that precedes activation of the crossed system depresses the responses evoked by the
crossed system. If potentiating stimulation of the ipsilateral system follows activation of the crossed
projection by too long an interval (200 ms, for example), then the crossed projection is depressed rather
than potentiated.
These results are discussed with regard to the nature of the associative process permissive for the
induction of long-term potentiation and lead us to the conclusion that perfect temporal contiguity is not
a requirement of this prototypical elemental memory unit.
It is widely held that some persistent synaptic modification is the elemental basis of memory storage. The
most popular hypothesis is Hebb’s suggestion’ which
forms the central postulate of a variety of associative
memory models.
Hebb proposed that correlated pre- and postsynaptic activity leads to alteration of synaptic strength.
More specifically, he proposed that an increase in
synaptic efficacy occurs with repeated, concurrent activation of a relatively ineffective presynaptic element
and the postsynaptic cell upon which this element
terminates. Since most cells presumably have their
discharge controlled by a population of presynaptic
inputs, this postulate can be transformed into a requirement for co-activity between the relatively ineffective synapse and a number of other presynaptic
elements whose convergent and synchronous activity
exerts a major control upon postsynaptic cell firing.
Thus, the hallmark of a ‘Hebb synapse’ is modifiability as a consequence of co-activity among converging
presynaptic elements.
Address all correspondence to: Dr. W. B. Levy, Department of Neurosurgery, Box 420, University of Virginia
School of Medicine, Charlottesville, VA 22908, U.S.A.
Abbreviations: DG, dentate gyrus; EC, entorhinal cortex; EPSP, excitatory postsynaptic potential; LTP, longterm potentiation of synaptic transmission.
Until very recently, the Hebb synapse was a theoretical construct with no experimental verification.
However, the synapses of entorhinal cortex (EC) upon
the granule cells of the dentate gyrus (DG) possess
features of a Hebb synapse and serve as a prototype
for the class of synapses that could efficiently subserve
associative memory storage.6
Three properties of EC-DG synapses distinguish
them as prototypical elemental synaptic memory
units: (1) a capacity for long-term increases in synaptic efficacy (LTP) which can last for days;‘** (2) an
associative requirement for induction of LTP, that is,
potentiation is a function of the number of active,
converging presynaptic elements$*
and (3) a capacity
for long-term
decreases
of synaptic
strength.6*1 3
These three properties are particularly well revealed
using the sparse crossed EC projection to the DG as
an investigative model6 In the normal rat, activation
of the crossed EC to DG projection results in small
responses.“*r3
Conditioning
stimulation
of the
crossed EC-DG pathway alone induces no measurable potentiation (an insufficient number of synapses
are concurrently active6). However, when this pathway
is conditioned ‘concurrently’ with conditioning of a
convergent and powerful excitatory pathway (the ipsilateral EC projection), the crossed response poten791
79’
W. B. Levy and 0. Steward
tiates.6 On the other hand, this same conditioning
of
the ipsilateral system depresses the crossed pathway
unless that crossed pathway is conditioned
concurrently.
The present study quantitatively
defines the temporal limits of the co-activity requirement for potentiation. Specifically, we were interested in the question: how synchronous
need be the conditioning
coactivity in the converging ipsilateral and contralateral
pathways to induce associative potentiation
in the
contralateral
pathway?
A priori, since conditioning
the ipsilateral EC-DG
pathway both potentiates
and depresses the contralateral input as a function of convergent contralateral
activity during ipsilateral conditioning,
we viewed
conditioning
of the ipsilateral pathway as permissive
for synaptic changes. The expectation
was that a
‘permissive’ period following ipsilateral conditioning
would persist for several milliseconds. Thus, we anticipated LTP of the contralateral
pathway when the
ipsilateral pathway was conditioned immediately preceding conditioning of the contralateral
pathway, but
expected no potentiation
when conditioning
of the
contralateral pathway preceded that of the ipsilateral.
This report shows that, in fact, exactly the opposite
results were obtained.
EXPERIMENTAL
PROCEDURES
Experimental animals were 250-300 g male rats of either
albino or hooded variety obtained from Flow or Blue
Spruce Labs. Although both albino and hooded rats were
analyzed, the data which make up the illustrations come
from hooded animals, since we have found that the \pars~
crossed ECDG
projection is somewhat larger in these :rnmals than in albinos, producing
larger and more c;rs~l!analyzed evoked responses.
The general electrophysiological
methods have been described previously.6,‘2
The animals were acutely anesthrtized with chloralose-urethane
(55 mg/kg and 0.245 g/kg.
respectively).
Stimulating
and recording
electrodes
were
positioned
as diagrammatically
illustrated
in Fig. I. The
bipolar stimulating
electrodes
were positioned
bilaterally
in the angular bundle (the fiber tract carrying EC projections to the dentate gyrus). The final positions of the electrodes were based on their electrophysiological
effectiveness (site of the optimal stimulation
at minimal stimulus
intensity). Current
source density analysis performed
on
animals not used in this study showed that stimulating
electrodes positioned
by this method and/or at this depth
are activating the proximal synapses of the entorhinal
projection in the dentate gyrus. In other words, this position in
the angular bundle is similar to positioning
stimulating
electrodes in the medial entorhinal
cortex. Recording electrodes were positioned
in the ventral blade of the dentate
gyrus to record optimally the negative extracellular
population excitatory
postsynaptic
potential
(EPSP). in the
molecular
layer evoked by the crossed projection,
or the
positive reflection of the population
EPSP at the somatic
level. Following
the experiment,
the recording
electrodes
were re-adjusted
to ensure that they had not shifted from
the optimal recording site during the course of the experiment.
Experimental procedure. To monitor synaptic efficacies, a
single ‘test’ stimulus was delivered once every 30s to the
contralateral
stimulating
electrode. Stimulus intensity was
adjusted so that a near maximal extracellular
EPSP was
evoked with a minimum
of polysynaptic
activity (which
occurs at a longer latency than the monosynaptic
wave).
rf?ec(L)
Test
Cond.
I:+++++&---
SR-FiectL
0
-
L-
EC
EC
Fig. 1. The stimulation and recording set-up is illustrated diagrammatically.
A single recording electrode
(RecL) samples evoked responses generated by the crossed projection from the mtorhinal
cortex (EC) on
the right hand side (indicated by the heavy line). Stimulating
ekctrodes
are positioned on both sides. The
conditioning
contingencies
which we have previously described6 are indicated on the right. Conditioning
stimulation
delivered to the right EC alone induces no (0) potentiation
of the crossed projection
from
that side. Conditioning
stimulation
of the left EC induces dcpreasion
of the responses evoked over the
crossed projection
from the right hand side. Activation of both sides simultaneously
induces associative
potentiation
of the crossed projections.
1
Temporal contiguity requirements for potentiation
Once a stable baseline had been established, the conditioning stimulation was begun. In all cases, stimulus intensity
during conditioning stimulation was the same as that utilized for testing.
The ordering of the stimulus trains delivered to the two
stimulating electrodes varied in different experiments and
within the same experiment. A special advantage provided
by our system is the ability to ‘erase’ potentiation induced
in a crossed pathway, thus permitting repetitive testing of
specific conditioning configurations. After delivery of the
conditioning stimulation, the synaptic efficacy was again
monitored by resuming the test stimulation. A minimum of
seven minutes passed between different conditioning configurations.
In this study, conditioning stimuli were trains of eight
pulses, delivered at 400 Hz and repeated 8 times at 10s
intervals. The experimental variable investigated was the
temporal relationship of individual trains delivered to the
two stimulating electrodes. (For explanatory purposes, we
will consider a single train of the ipsilateral pathway to be
fixed in time, and we will vary the time of the contralateral
conditioning stimulus.) In our previous study, the contralateral conditioning stimulation was delivered nearly simultaneously (kO.l-1.0 ms) with the ipsilateral conditioning
stimulation. In the present study, contralateral conditioning stimulation sometimes precedes and sometimes follows
the ipsilateral conditioning stimulation. When the contralateral conditioning stimulation precedes the ipsilateral
conditioning stimulation, the time between trains will be
the time between the last pulse of the contralateral train
and the first pulse of the ipsilateral train. When the ipsilateral conditioning stimulation precedes the contralateral
conditioning stimulation, the time between conditioning
trains will be measured as the time between the last ipsilateral stimulation pulse and the first contralateral stimulation pulse. Each ‘bout’ of conditioning stimulation at the
appropriate contingency and the following series of test
pulses is termed a conditioning trial. The test periods after
each conditioning bout lasted at least 5 min.
For data analysis, responses were recorded on a 4 channel FM tape recorder and were subsequently analyzed offline with a PDP 11-04 computer. The digitized evoked
responses were quantified by measuring either the amplitude of the negative extracellular EPSP or by measuring
the initial slope of the negative wave. These two measures
are highly correlated and reveal quite comparable changes
induced by potentiation,”
although the amplitude
measure exhibits somewhat less variability than slope
measures when very small responses are analyzed.
RESULTS
The responses evoked by the ipsilateral and sparse
crossed EC-DG projection systems have been extensively described in previous studies.6*7~10~11 At the re-
*While the normal crossed projection of albino rats
does not exhibit LTP, the somewhat larger crossed projection of hooded animals is occasionally sufficiently powerful
to generate limited LTP even when stimulated alone
(unpublished observations). This potentiation does not
complicate the present analysis since it is slight in comparison to the potentiation elicited by co-conditioning with the
ipsilateral system.
793
sponse maximum, the population EPSPs generated
by the crossed system range between 0.5 and 1.2 mV,
with hooded rats exhibiting larger maximal crossed
response amplitudes than albino rats. These responses
are not accompanied by detectable population spikes.
The converging ipsilateral projection system is much
more powerful; the maximal population EPSPs are
typically greater than 8 mV and, at the response maximum, the population EPSPs always evoke large
(several mV) population spikes.
The normal crossed projection of albino rats does
not exhibit LTP when conditioned alone (see footnote*).6*l2 Our normal procedure for inducing potentiation of the crossed projection uses a paired conditioning paradigm in which the stimulus trains to the
powerful ipsilateral and weak crossed projections
overlap, beginning and ending within 1 ms of each
other. Thus, the initial depolarization evoked by each
pathway, as well as each subsequent depolarization,
would occur roughly concurrently (within 1 ms). To
delimit how close in time the stimulus trains must
come, five animals were analyzed. In two animals,
initial conditioning trials had the train to the contralateral afferents follow the train to the ipsilateral afferents. On subsequent trials, the ordering was reversed.
In three other animals, initial trials had the contralaterally-delivered train preceding that of the ipsilateral
side, and again, the ordering was reversed on later
trials. The second of these paradigms is illustrated in
Fig. 2. In each contingency, the train delivered to the
crossed pathway (upper trace) is illustrated as being
held constant, while the order and timing of the train
to the ipsilateral system (lower trace) is varied. (Note
that all figures present, to the right side, the relative
increase of decrease in response amplitude, not the
actual response amplitude. Because each successive
conditioning procedure induces long-term potentiation or depression, changes are calculated relative
to the most immediate sequence of preceding responses. Thus, values less than 100% indicate that the
conditioning train, shown to the left, depressed the
response while values greater than 100% indicate the
conditioning train potentiated the response.) In this
paradigm, the first three conditioning trials had the
ipsilateral train follow the contralateral. As is evident,
the contingency produces potentiation at the 20ms
inter-train interval. Successive conditioning using progressively shorter inter-train
intervals produces
further increases. The lower traces illustrate an unanticipated phenomenon. When the ipsilateral conditioning precedes the contralateral, depression results.
For inducing this depression, the inter-train interval
did not appear critical. Long-term depression invariably occurred so long as the contralateral train
began after the end of the ipsilateral train. Repetition
of depression-inducing contingencies resulted in progressive decreases toward some apparently non-zero
asymptotic level (traces 4-6 of Fig. 2). When this
asymptotic level was reached, further depressioninducing conditioning resulted in no further relative
794
W. B. Levy and 0. Steward
change with respect to preceding responses (see next
to last trace in Fig. 2).
In the 5 animals analyzed, the effects of the order of
the trains were consistent. In the case of the optimal
ordering for inducing potentiation
(contra followed
by ipsi) the maximal inter-train
interval at which
associative
potentiation
was observed varied from
animal to animal. One animal exhibited slight and
statistically insignificant
potentiation
with an intertrain interval of 40ms. Two others (one of which is
illustrated in Fig. 2) exhibited potentiation
with an
inter-train interval of 20ms. The remaining two animals exhibited potentiation
only when the inter-train
interval was decreased to 10 ms and 5 ms, respect-
corldii~
ively. In general, repeating a conditionmg contingency
which had just previously been delivered resulted in
only slight increases in response amplitude.
C‘ompared to repetitive conditioning
with long inter-train
intervals, decreasing inter-train intervals more effectively induced further potentiation.
Long-term
depression was consistently
observed both before and
after the crossed response had been potentiated. confirming our previous observations that the converging
ipsilateral system can decrease the response amplitude
of a ‘control’ crossed projection.6
As noted above, the depression resulting from ipsilateral preceding contralateral
stimulation
was surprising, and was exactly opposite to our expectations.
cotltingemcies
Relative Fbspome Anrplskrde
100%
125’.
150%
1
I
I
Righl -Lett
‘17
,*
R-L
1ms
R
_tttttttt____
-
L*:
L-R
ame
L-R
1 ms
L+R
St imulete Right. Rmrd
Left
Fig. 2. The proper temporal ordering for long-term potentiation. This Figure shows that the contralateral conditioning stimulation must precede (R --+ L) or be synchronized (L + R) with the ipsilateral
conditioning stimulation in order to potentiate the contralateral response. When the order of conditioning trains is reversed (L -+ R), depression results. On the left side of the figure are two traces associated
with each data bar of the right side of the figure. These traces indicate the conditioning protocol used
two minutes prior to the response indicated by the associated bar on the right. Each vertical line
indicates the delivery of a single conditioning pulse. In the case of this experiment the contralateral
stimulating electrode is on the right side of the animal (R = right; L = left). The recording electrode is
on the left side of the animal. The responses plotted on the right half of the figure are from averages
taken over a 5 min time period and are expressed as a percentage of the 5 min average response
amplitude immediately preceding the indicated conditioning protocol. Thus, a response of lOOoJ,indicates no change after the indicated conditioning procedure, while a value lower than lao”/, indicates
depression and a value greater than 100% indicates the associated procedure produces potmtiation. Test
stimuli are delivered l/30 s; conditioning consists of 8 of the indicated train pairs at 1 train per 10 s. The
data are from a single animal. The net changes following R -+ L 8 and 1 ms are significantly larger
relative to the initial baseline. The net changes aher L + R 20, 8 and 1 ms are signi!icantly smaller
compared to the baseline established just prior to the L -+ R 20 ms conditioning procedure. The last
potentiation is significant. All significance values are at P < 0.05, two-tailed t-tests.
795
Temporal contiguity requirements for potentiation
Relative Response Amplitude
100%
200%
3ftO%
Condiiioning Contingencies
t-20mr
Riiht
-wHHH_r
I
t 112’
450
ms
S
450
ms
I
Left
R-luHw
L
R-L
5ms
R-L
200ms
R-L
5ms
R-L
5ms
R+L
Stimulate Right, Record Left
Fig. 3. An upper time limit exists for the potentiating effects of a properly ordered contralateral plus
ipsilateral paired conditioning stimulation. When the contralateral conditioning train precedes the ipsilateral train by as little as 200 ms (R -+ L, 200 ms), depression results. As before, shorter intervals (in one
case here, 5 ms) provide an adequately small interval of separation for the paired conditioning stimulation to potentiate the contralateral response. Details of this figure are the same as in Fig. 2 except that
each response average, taken 2 min after the associated conditioning train, was collected for a period of
10 min. The data are from a single animal. The net depression after the first two conditioning stimulations is significant compared to the initial baseline. The changes following the next three conditioning
stimulations are significant relative to the immediately preceding baseline period. The responses following the last two conditioning stimulations are significantly different relative to the baseline period
preceding R -+ L 5 ms. Significance accepted if P < 0.05 on a two-tailed t-test.
These results were reminiscent, however, of the situation found in classical conditioning paradigms.
By analogy
with classical
conditioning’s
conditioned stimulus and unconditioned
stimulus, the
weak contralateral
stimulation is a very poor excitatory stimulus (an analog of the conditioned
stimulus)
for the postsynaptic
cells, while the ipsilateral stimulus is very effective (an analog of the unconditioned
stimulus). With pairing in which the contralateral
stimulus
precedes
the ipsilateral
stimulus
(conditioned
stimulus-unconditioned
stimulus),
the
contralateral
gains some of the properties of the ipsilateral stimulus, i.e. it becomes more powerful. The
question to answer then was how far this interval
could be extended. From the preceding experiments,
it seemed that 20ms was about the upper limit for
effective pairing. However, to be sure that we were
absolutely outside the effective interval, it should be
possible to increase the interval so that the contralateral and ipsilateral conditioning
stimulations inter-
act not at all. It would be as if there were no contralateral stimulation.
Recall that when just the ipsilateral system is conditioned,
long-term
depression
results. Thus, if no interaction
occurred, one would
anticipate depression with long inter-train intervals.
In these experiments four new animals were used,
and a variety of pairing intervals between 180 and
5OOms were tried. In all cases, profound depression
occurred with these long intervals. Figure 3 gives an
example of a typical experiment.
First, this experiment shows that a 50ms inter-train interval causes
depression of the contralateral
response. When the
delay is shortened to 5 ms, potentiation
is obtained.
Next a long interval is again used (200ms) and depression occurs. Following this second conditioned
depression, potentiation
is again demonstrated
with
short inter-train intervals. These results were significant for changes observed within each individual experiment (P < 0.05;
two-tailed t-test using each test
response as a sampling).
796
W. B. Levv and 0. Steward
DISCUSSION
The results have implications
about the mechanisms of long-term
potentiation
and
long-term
depression and also suggest how potentiationjdepression could contribute
to some information
storage
capabilities.
Considering the mechanisms first, the results provide additional support for the proposition that some
process is set into motion by conditioning
stimulation
of the powerfully depolarizing ipsilateral system that
leads to modification
of the synaptic efficacy of the
crossed pathway,
depending
on the state of the
crossed pathway. If the crossed pathway is active during a critical temporal window, potentiation
occurs. If
the crossed pathway is inactive, or is active at a time
outside the critical temporal
window, depression
occurs. Based on the results here, the critical temporal
window exists simultaneous
with and slightly before
the ‘enabling’ conditioning
stimulation.
The critical
feature here is that both potentiation
and depression
of the crossed system require the same event (conditioning of the converging ipsilateral system), suggesting that some single process is set into motion by this
stimulation which makes the synapses of the crossed
pathway modifiable. The direction of modification, i.e.
potentiation
or depression, of the crossed projection
(or any other weak input) thus is determined
by its
own activity.
We have argued previously that the most likely site
for associative interactions
such as those described
above is the point at which the two pathways converge (the postsynaptic
cell or some portion thereof).
Regardless of whether the critical signal is cell discharge, as Hebb reasoned, or simply a massive local
dendritic
depolarization,
the present results place
several restrictions
upon any postulated
chemical
reaction which may regulate synaptic modifiability.
First, the reaction triggered by strong activation must
differ from the reaction triggered by weak activation,
since the converging
ipsilateral
system must be
strongly activated to induce either associative potentiation or depression of the crossed system.6 This implies that activation of individual spine synapses is
not sufficient, and suggests that perhaps there is some
‘retrograde’ interaction
between a process initiated
within the main dendritic shaft and individual spines.
This dendritic process would begin when a sufficient
number of spines were depolarized concurrently. That
these processes eventually ‘feed back’ to regulate individual synapses is suggested by both our previous
neurophysiological
work and by ultrastructural
experiments (W. B. Levy & N. L. Desmond, unpublished)3 which suggest rather dramatic alterations of
the synaptic interface (i.e. a larger postsynaptic receptive surface).
The present results, by defining the temporal constraints of the postulated
dendritic process, suggest
that there is not enough time for a chemical product
formed in the main dendrite to diffuse or be trans-
ported to the spine head (e.g. 1 pm in 20 ms) \I here
the ultimate reaction occurs. Perhaps a polymerization reaction
of some supersaturated
substance
could move fast enough, but more appealing is ;L
retrograde electrical invasion of the spine structure
(e.g. a Ca2+ spike). However, in line with the preceding logic, such an electrical event would have to be
distinctive from the electrical event associated with
activation of the spine synapse by itself. Recall that a
very weak, high-frequency
conditioning
stimulation
does not potentiate itself. *.12 Yet considering the high
resistance of a spine stem, this stimulation
should
drive the spine head of an active synapse nearly to the
reversal potential of the synapse. Again referring to
the principles discussed in the preceding paragraph,
the retrograde signal from the dendrite and the signal
generated at each specific synapse should be different
to ensure the synapse by synapse specificity of associative potentiation/depression.
Distinctive
critical
events could be accumulation
of ions (Na+ vs Ca2+)
or, in place of one of these ions, a molecule or moiety
released by the associated
presynaptic
terminal of
each synapse (e.g. a derivative of glutamate, ATP, or a
polypeptide, etc.).
Our results also suggest how the processes
of
potentiation/depression
might be used for information storage. As pointed out previously,6 the associative
potentiation/depression
properties
of the
synapses currently being studied are not sufficient for
mediating classical conditioning
by themselves. Additional circuitry is required because the depressioninducing paradigm is not analogous to the extinction
paradigm of classical conditioning.
The present results indicate that even more circuitry is required if this synapse stores classically conditioned memories. Specifically, in trace conditioning
the optimal interval between the conditioned
and
unconditioned
stimuli is a few hundred ms4,9 and
even longer intervals are sufficient. Yet paired conditioning at this optimal interval produced depression
at the synaptic level. Therefore, some type of delay
circuitry is necessary (such as a ‘reverberating’ loop
that allows a response to circulate around the limbic
system several times). This loop would maintain the
activity of a conditioned stimulus during trace conditioning so that, at the cellular level, the conditioned
and unconditioned
stimuli could temporally converge
upon synapses and cells mediating associative potentiation.
Acknowledgements-This
work was supported in part by
NIH Grant No. ROl NS15488 to W.B.L. and NSF Grant
No. BNS80-21865 to OS. O.S. is a recipient of Research
Career Development Award No. NSO0325. The data analysis program utilized in the present study was developed by
R. C. Wilson (Wilson, Levy & Steward, 1981). We would
like to extend special thanks to Dr. L. Gray for his help in
developing this program and for other suggestions whieh
contributed substantially to our off-line data analysis.
Temporal contiguity requirements for potentiation
797
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