Behavioural Brain Research, 58 (1993) 91-98
© 1993 Elsevier Science Publishers B.V. All rights reserved. 0166-4328/93/$06.00
91
BBR 1509
Memory processing by the limbic system: role of specific neurotransmitter
systems
Ivan Izquierdo ~'*, Jorge H. Medina b, Marino Bianchin a, Roger Walz a, Marilene S. Zanatta a,
Ricardo C. Da Silva a, Marcia Bueno E Silva a, Anelise C. Ruschel a and Natalia Paczko a
a
Centro de Memoria, Departamento de Bioquimica, lnstituto de Biociencias, Universidade Federal do Rio Grande do Sul, 90046-900 Porto Alegre,
R S (Brazil), b Laboratorio de Neurorreceptores, Instituto de Biologia Celular, Facultad de Medicina, Universidad de Buenos Aires, Paraguay
2155, 1121 Buenos Aires (Argentina)
(Received 15 January 1993)
(Accepted 11 October 1993)
Key words: Long-term potentiation and memory; Glutamatergic mechanisms and memory; GABAergic mechanisms and memory; Amygdala
and memory; Hippocampus and memory; Medial septum and memory; Entorhinal cortex and memory
Experiments using localized infusions into selected brain structures of agonists and antagonists of various synaptic receptors, given before
or after behavioral training, have led to the following conclusions: (1) Memory is processed shortly after training in the amygdala, medial septum and hippocampus by glutamatergic NMDA and AMPA receptors activated in that sequence. Cholinergic muscarinic receptors are activated concurrently with the former. GABAA receptors modulated by brain benzodiazepines and by beta-noradrenergic receptors inhibit the
process. (2) The sequential involvement of NMDA and AMPA receptors suggests that long-term potentiation (LTP) of the synapses activated
by the learning experiences in the hippocampus and/or amygdala and medial septum is the crucial event. Expression of this LTP at the time
of testing is necessary for retrieval: AMPA receptor blockade in the hippocampus and amygdala at the time of testing hinders retrieval. This
suggests that the LTP underlies the memory process itself. (3) The amygdala, medial septum and hippocampus mediate different types of memory and/or different components of memories. The entorhinal cortex, through mechanisms that require intact NMDA receptors and are inhibited by GABAA receptors, intervenes in post-training memory processing 90-180 rain after the other limbic regions. The entorhinal cortex
integrates consecutively acquired memories; this role could be maintained by the LTP that is generated after training in the amygdala, hippocampus and medial septum. Post-training intervention of the entorhinal cortex does not occur if this region is inhibited at the time of training.
INTRODUCTION
Like long-term potentiation (LTP) 8'44'54'56,long-term
memories are initially labile and after a few minutes
become stable for very long p e r i o d s 25'33'46. The initial
labile phase of LTP is called the induction phase. It is
mediated by N-methyl-D-aspartate (NMDA) glutamatergic receptors 8, can be modulated by cholinergic
muscarinic and beta-noradrenergic receptors (see refs.
30, 42) and is inhibited by gamma-amino-butyrate type
A (GABAA) receptors (see ref. 8). The late, stable phase
of LTP is expressed through 7-amino-3-hydroxy-5methyl-4-isoxazole propionate (AMPA) glutamatergic
receptors and is called the maintenance phase 8'56. As
* Corresponding author. Centro de Memoria, Departamento de Bioquimica, Instituto de Biociencias, UFRGS (centro), 90050 Porto
Alegre, RS, Brazil. Fax: (55)(51)227-2343.
is the case with long-term memories, the maintenance
phase of LTP can persist for very long periods even if
its expression is withheld or prevented 56. The early,
labile phase of long-term memories is often called the
consolidation phase, because it is believed that it involves a process of strengthening of the underlying neural processes 25"46. LTP, of course, consists of the
strengthening of synaptic transmission 8'27'56. In LTP 56,
as in long-term m e m o r y 25'61'67, re-iteration of the stimuli
that brought them into being will trigger their expression. The expression of memories is called retrieval25,21,67.
Indeed, the two most widely accepted current hypotheses of memory storage are that it involves
L T P 1"54"55 and/or the operation of neural n e t w o r k s 39'43.
These hypotheses are not mutually exclusive. The expression of LTP in the particular synapses that had
been specifically activated during training could sub-
92
serve important functions in amplifying the signals that
are to enter the neural networks 27'37. In addition, LTP
can underlie the function of components of the networks 1. Network theory explains the continued functioning of neural circuits through alternative pathways
in spite of lesions 43, which may in turn explain the
persistence of memories after extensive brain damage
as is seen in the early stages of Alzheimer's disease or
of other organic brain syndromes 21.
Lesion and drug infusion studies have shown that the
main areas involved in consolidation are the amygdala,
the hippocampus, the medial septum and the entorhinal
cortex, which are parts of the so-called limbic
system 16'17"24'25"28"32-35'46. Evidence suggests that other
regions of the brain are involved in parallel 25"64 or alternatively62 to the limbic areas of the temporal lobe.
These parallel or alternative areas include the cerebellum 64, the caudate n u c l e u s 2"68 and various regions of
the cerebral cortex 1'62. It is possible that these extralimbic circuits specialize in types of memory not
handled by the limbic structures referred to a b o v e 2'62.
The present article reviews recent data from our
laboratories on the neurotransmitter mechanisms involved in memory processing by the amygdala, hippocampus and medial septum, and on the interaction of
these structures with the entorhinal cortex in the formation of long-term memories. As will be seen, the data
indicate that LTP in the amygdala, hippocampus and
medial septum is at the core of the memory process.
NEUROTRANSMITTERS
SOLIDATION
INVOLVED IN MEMORY CON-
Previous work in several laboratories had shown that
glutamatergic synapses play a key role in memory. This
is not surprising since glutamatergic synapses are by far
the most abundant excitatory synapses of the brain,
and can generate LTP. The systemic administration of
indirect (i.e. Ca 2+ channel) blockers of N M D A (Nmethyl-D-aspartate) receptors to glutamic acid causes
amnesia for a variety of tasks in rats 59'65. Intracerebroventricular infusion of the indirect N M D A receptor
antagonist, dizolcipine, or of the direct antagonist, D-2amino-5-phosphonopentanoic acid (AP5), hinders retention of spatial learning 54'55. AP5 and its heptanoic
acid analogue, AP7, disrupt retention of a conditioned
startle response when infused into the amygdala prior
to training 51. D-cycloserine, a partial agonist at the glycine modulatory site of N M D A receptors 57, enhances
memory in r a t s 53 and has been proposed as a useful
drug in Alzheimer's disease TM. Sensitivity of the N M D A
receptor complex to glycine is reduced in Alzheimer's
disease s7.
The agonist, glutamate has opposite effects to those
of AP5 and the effects of both are not restricted to the
amygdala. In fact, the two drugs affect memory retroactively when infused into the hippocampus and the
medial septum as well, depending on the task. Posttraining infusion of AP5 into the amygdala, medial septurn or hippocampus blocks the consolidation of stepdown inhibitory avoidance 3235. The infusion of AP5
into the hippocampus but not into the amygdala or
medial septum causes retrograde amnesia for habituation to a novel environment 32'35. The agonist, glutamate,
has effects exactly opposite to those of AP5. Its immediate post-training infusion into the amygdala, medial
septum or hippocampus causes retrograde facilitation
of inhibitory avoidance; its intrahippocampal but not
its intraseptal or intra-amygdala infusion causes retrograde facilitation of habituation 3~.
Recent evidence suggests a role for cholinergic muscarinic receptors in consolidation processes in addition
to glutamatergic receptors. A role for cholinergic
mechanisms in memory had long been suspected mainly
because of the fact that systemic administration of the
cholinergic muscarinic receptor antagonist, scopolamine, causes amnesia in humans and animals (see refs.
26, 38).
The comparative effect on memory consolidation of
cholinergic muscarinic antagonists or agonists given
into specific brain structures was studies for the :first
time by our group. In a step-down inhibitory avoidance
task, post-training intra-amygdala, intraseptal or intrahippocampal scopolamine administration causes retrograde amnesia, whereas that of the agonist, oxotremorine, causes instead retrograde facilitation 32"35. In the
habituation task, the intrahippocampal infusion of scopolamine causes retrograde amnesia and that of oxotremorine causes retrograde facilitation; intraamygdala or intraseptal infusions of these substances
was ineffective32"3s.
It is possible that cholinergic muscarinic transmission may act by facilitating the induction of LTP and
neighboring glutamatergic synapses 42. The amnesia
caused by scopolamine in humans can be alleviated by
D-cycloserine, a modulator of the glycine site of N M D A
receptors 38.
THE ROLE OF GABA A RECEPTORS
The immediate post-training infusion o f the indirect
(C1- channel) blocker of GABAA receptors, picrotoxin, into the amygdala, medial septum or hippocampus causes retrograde memory facilitation of inhibitory
avoidance behaviour and counteracts the amnesic ac-
93
tion of AP5 and/or scopolamine32'35. In the habitation
task, similar effects are found but only in the hippocampus 32'35. The effect of systemic or intra-amygdala
picrotoxin on inhibitory avoidance behavior is shared
by another C1- channel blocker. R05-4864 (4'chlordiazepam) 11. Post-training systemic picrotoxin
administration has long been known to cause memory
facilitation 3'47. The GABA A receptor agonist, muscimol, causes retrograde amnesia when given systemically7 or when infused into the amygdala, medial septum or hippocampus in the case of inhibitory avoidance,
or when infused into the hippocampus but not the
amygdala or septum in the case of habituation to a
novel environment32'35. Post-training infusion of the
GABAA receptor antagonist, bicuculline, into the
amygdala causes retrograde facilitation for aversive behaviors when given post-training either systemically4.
The GABAA receptors involved in memory modulation in the medial septum, amygdala and hippocampus are in turn regulated by benzodiazepines or
benzodiazepine-like molecules released in the same
brain structures 33"7°. The benzodiazepines are released
in relation to the degree of anxiety and/or stress associated with each task ~2. This topic has been recently
reviewed in extenso 31"33'34.
ROLE OF BETA-NORADRENERGIC RECEPTORS AND
OTHER SUBSTANCES
The systemic, intra-amygdala, intraseptal or intrahippocampal adminstration of beta-adrenoceptor antagonists usually has no effect on memory of its own but
hinders the memory enhancing effect of picrotoxin 32.
This suggests that beta-noradrenergic receptors modulate the influence of GABAergic synapses on memory
consolidation 32'3~. Post-training intra-amygdala 32'41,
intraseptal or intrahippocampa132'35 norepinephrine infusion causes memory facilitation, suggesting that, in
addition to their influence on GABAergic terminals,
noradrenergic receptors may also stimulate memory on
their o w n 29. As mentioned above concerning cholinergic muscarinic receptors, it is possible that noradrenergic receptors may also act by promoting the generation of LTP at glutamatergic receptors (see ref. 30).
Other neurotransmitter systems may also participate
in memory consolidation. The systemic or intraamygdala administration of the GABAB receptor
blocker, baclofen, impairs retention 6. This suggests an
involvement of GABAB receptors in the amygdala in
consolidation. Much evidence suggests a role of betaendorphin in post-training memory p r o c e s s e s 25'28'46. Its
effects may be exerted in the medial septum and in the
amygdala25'28 and, at least in the amygdala, are possibly mediated by beta-noradrenergic synapses 46. Recent
data suggest an involvement of dopaminergic synapses
in the caudate nucleus in post-training memory processes 68. It is not known whether dopaminergic synapses in the septum, amygdala or hippocampus are also
involved in memory; there are dopaminergic (and serotonergic) terminals in these structures, and they have
been implicated in a number of functions relevant to
brain psychopathology9'19.
THE MAJOR INTERACTIONS AMONG NEUROTRANSMITTERS INVOLVED IN MEMORY PROCESSING
The major interactions among neurotransmitter
mechanisms in the amygdala, medial septum and hippocampus commented upon above are:
(1) GABA A receptors inhibit the cells that are activated by glutamatergic N M D A and cholinergic muscarinic r e c e p t o r s 3z'35.
(2) The GABAergic synapses are positively modulated by beta-noradrenergic synapses 32'35 and by benzodiazepines, possibly of endogenous origin, released
by the training experiences 29'33'34"49'7°.
(3) Administered norepinephrine may excite the cells
that are excited by glutamatergic and cholinergic muscarinic receptors 3~ and/or promote LTP at the
glutamatergic receptors 3°.
The postulation of these neurotransmitter interactions is supported by histochemical and electrophysiological studies on the three regions4°'5°; see ref. 29.
Interestingly, the interactions are similar in the three
structures despite their anatomical and functional differences. This suggests that similar synaptic mechanisms might develop ontogeneticaUy in structures that
specialize in the processing of one or other kind of
memory35. The amygdala processes alerting 5 or aversive 13 memories or components of memory. The medial
septum and hippocampus process working memory and
spatial and olfactory information52'54, but by virtue of
their different input-output connections they probably
process different data pertaining to these domains, or
the same data differently 16. This specialization of the
amygdala, medial septum and hippocampus explains
their differential involvement in the consolidation of
different behaviors mentioned above 29'32'33'35.
Stress hormones (epinephrine, adrenocorticotropin,
vasopressin) modulate memory consolidation possibly
through influences on central beta-noradrenergic synapses 25'46. The mapping of the effect of the stress hormones, or of the opioid, dopaminergic and serotonergic systems onto the glutamatergic, cholinergic and
94
GABAergic synapses discussed above requires further
investigation. Surely regional differences are to be expected. For example, beta-endorphin-containing terminals are found in the amygdala and medial septum but
not in the hippocampus; the distribution of dopaminergic and serotonergic terminals in these areas is different (Ref. 25, 29; etc.).
For a review of interactions among neurotransmitter
systems involved in memory processing, see refs. 29,
35.
THE ROLE OF LTP IN MEMORY PROCESSES
If consolidation were to be defined in synaptic terms,
it should be a process whereby responses at the synapses involved in each particular experience are
strengthened while in a labile state 29. The best known
process whereby synaptic responses are strengthened is
LTP at glutamatergic synapses; LTP is indeed labile
during its induction phase because of its susceptibility
to inhibition by GABAA receptors 8.
Units in the amygdala, medial septum and hippocampus respond to different sensory modalities, and
each cell has a particular pattern of response 2°'45. Lesion studies by Mishkin and his coworkers indicate that
information pertinent to learning experiences is relayed
from sensory areas onto the amygdala and hippocampus via the perirhinal and the entorhinal cortex, during
or very shortly after acquisition (see refs. 2, 29). Thus,
each learning experience should elicit a pattern of unit
response in the amygdala, medial septum and/or hippocampus that is conceivably unique for each experience 29,37.
LTP induction is mediated by glutamatergic N M D A
receptors and is therefore sensitive to blockade by AP5,
and is maintained through A M P A receptors sensitive
to the antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione
(CNQX) TM. A role of hippocampal LTP in memory
has been suggested by Morris, LynchT M
and others (e.g., refs. 1, 19, 27, 64).
The retention of inhibitory avoidance is hindered by
the infusion of AP5 into the amygdala, hippocampus 37
or the medial s e p t u m 66 immediately but not 90 min
after training, and by C N Q X infused into any of these
three structures 0, 90 or 180 but not 360 min after training 37'66. This strongly suggests that consolidation is mediated by LTP in synapses of the amygdala, medial
septum and hippocampus specifically activated by each
training experience, and that this LTP needs to be expressed during at least 180 min after training in order
for consolidation to Occur 29'37'66. C N Q X specifically
blocks the expression of LTP which is mediated by
A M P A receptors 8'56.
It is possible that the underlying mechanism of LTP
may persist in the medial septum, amygdala and hippocampus beyond the initial 180 min after training during which it is expressed (see ref. 56), and that this
persistence underlies memory storage. If this were so,
memory would be the LTP, and its retrieval would
depend merely on the reactivation (or the renewed expression) of the LTP at the time of testing. A case for
the identity of consolidation and retrieval processes
was made by Spear and Mueller 6~ and Izquierdo 2s with
particular reference to the need to reiterate stimuli that
had been crucial to consolidation, at the time of testing, in order that retrieval may occur > .
Recent findings from the present authors support this
idea. If retrieval depends on the reactivation of the
expression of hippocampal or amygdala LTP by a reiteration of the stimuli that had caused in the first place,
then blockade of AMPA receptors at the cells originally
activated by the learning experience in the hippocampus and amygdala should block both the renewed expression of the LTP and, as a consequence, retrieval.
In recent experiments from our laboratories, it was observed that the bilateral administration of CNQX
(0.5 #g) into the amygdala and hippocampus 10 min
prior to inhibitory avoidance testing, in rats, completely
blocked expression of the memory of this task. Two
hours later, when the effect of the drug had worn olT*~,
retention test performance became fully normal again.
Similar injections of 0.5 or 1.25 #g of CNQX into either the amygdala or hippocampus reduced retention
test performance of this task only by approximately 40
or 500/o . It had been previously shown that memory of
the inhibitory avoidance task depends both on the
amygdala and the hippocampus (and medial septum)
(see above and 32,33,3s). In the habituation task (free
exploration of the training apparatus for 1 rain), which
appears to depend on the hippocampus but not the
amygdala or septum 32'33'3s, the bilateral intrahippocampal administration of CNQX (0.5 #g) 10 min prior
to testing blocked the expression of memory completely;
the intra-amygdala pre-training infusion of 0.5 or
1.25/~g of CNQX had no effect. Davis ~4 showed an
amnestic effect of 0.375/~g of CNQX given bilaterally
before testing in the amygdala, in a fear-potentiated
startle task in which previous data had suggested that
the amygdala was crucially involved in retention13. In
both our and Davis's experiments on pre-test CNQX
the training-test interval was 24 h.
Thus, these findings support the hypothesis that memory is (a consequence of) LTP in limbic structures up
to at least 24 h after training. They do not, however,
provide any hint as to the mechanism of retention or of
retrieval more than 24 h after training. Many data, in-
95
cluding the lack of retrograde amnesia seen in patient
H.M. for memories stored weeks or years prior to bilateral temporal lobectomy, indicate that after some
time temporal lobe structures are no longer important
for the storage or retrieval of many if not most memories 25'62. Storage and retrieval elsewhere in the brain at
long times after acquisition, may or may not involve
LTP ~, but are believed to depend on the operation of
neural n e t w o r k s 27'39"43.
THE ROLE OF THE ENTORHINAL CORTEX
The entorhinal cortex has two-way monosynaptic
connections with the amygdala, hippocampus and medial septum, and is also interconnected, through the
neighboring perirhinal region, with sensory and associative areas of the neocortex 23"36'69. Therefore, it is
strategically located both to convey signals from these
cortical areas to the amygdala, septum and hippocampus (see ref. 2), and to handle memory-relevant information after it has been processed by these structures 16'17. Entorhinal lesions disrupt various types of
spatial and non-spatial learning in different species 60'63'71. The most prominent and most typical lesions of Alzheimer's disease are in the entorhinal cortex 23'36. The early appearance of such lesions signals
the onset of the disintegration of memory and cognition
typical of this disease 15.
We have recently obtained evidence for a delayed
post-training role of the entorhinal cortex in memory,
secondary to amygdala, hippocampal or septal activation. AP5 or muscimol infused bilaterally into the entorhinal cortex 90 or 180, but not 0 or 360 min after
training in habituation or in inhibitory avoidance cause
full retrograde amnesia for both tasks. Thus, the entorhinal cortex is not only important as a relay station
between the sensory cortex and the amygdala and hippocampus 2, but also essential for memory after the
amygdala, medial septum and hippocampus had intervened in it, and for a limited period of time: 90 to
180min from training. Its intervention relies upon
glutamatergic N M D A receptors and is inhibited by
GABAA receptors: the intra-entorhinal infusion of AP5
or muscimol 90 or 180 (but not 0 or 60) min after
training causes amnesia for inhibitory avoidance and
for habituation to a novel environment ~6'17. The late
role of the entorhinal cortex in post-training memory
processing might be secondary to the LTP in the
amygdala, hippocampus 37 and medial septum 66 which
is expressed for up to 180 min after training.
The late intervention of the entorhinal cortex in posttraining memory processing apparently plays an inte-
grative role: the infusion of AP5 or muscimol into this
region 90 min after inhibitory avoidance training prevents the summation of the trace left by this training
with that of a subsequent training session carried out
30 mi later 16'17. Such a role could be of great importance for the formation of memory files25 or complex
memories and, if lacking, could conceivably lead to a
severe disintegration of cognitive processes, such as is
seen in Alzheimer's disease (see refs. 21, 23, 36).
Recent data from our laboratories, obtained in collaboration with Paul Willner of the University of
Swansea, show that if the entorhinal cortex is inhibited
during and immediately after training, it does not participate in the memory processing 90 for 100 min after
training. The infusion of muscimol into discrete brain
regions produces a localized inhibition measurable by
a reduction of 2-deoxyglucose uptake extending for
about 30 mm 3 and lasting for about 60 min 48. In rats
that received a bilateral infusion of muscimol into the
entorhinal cortex, a second infusion of muscimol
100 min after training has no amnestic effect on inhibitory avoidance in animals trained with a high footshock
level (0.5 mA). Further, in animals trained with a low
intensity footshock (0.2 mA) in which two training sessions with a 120 min interval between sessions are
needed in order to obtain good memory (see above), the
pre-training infusion of muscimol into the entorhinal
cortex prevents the summation of the two training sessions. Thus, in the absence of a normally functioning
entorhinal cortex at the time of training or in the immediate post-training period, animals can learn, presumably using other brain areas29; they are, however,
incapable of integrating consecutive memories.
These findings argue in favor of an early role of the
entorhinal cortex in memory, during or very shortly
after training, in addition to its delayed post-training
role referred to above. It is reasonable to think that this
early role consists of conveying learning-related signals
to the hippocampus, amygdala and medial septum from
sensory and polysensory regions of the cortex 2. These
signals could be those that trigger the LTP in the cells
of those limbic structures that had been specifically
activated by each training experience35'37'66, which in
turn maintains the entorhinal cortex active late after
training 16,17.
In addition, these findings on the effect ofpre-training
muscimol given into the entorhinal cortex indicate that
a form of memory (inhibitory avoidance) that is normally processed after training by the entorhinal cortex,
and for which this processing is normally indispensable ~6'17, can be also processed, although defectively,
by other structures when the entorhinal cortex is not
operative during and very shortly after training. This
96
point may be relevant to the observations of Thompson 6 4 that eye-blink conditioning, although normally
processed or modulated by the hippocampus can occur
in the absence of this structure, and to the more general issue of the formation of memories in the absence
of the temporal lobe, which is limited, defective, and/or
restricted to the more simple, primitive and/or gradually acquired forms of memories 2"62.
Mishkin and his group 2 have argued in favor of the
position that procedural memories or 'habits' are processed by cortico-striatal systems, whereas the temporal lobe structures discussed above are involved rather
in the processing of declarative or explicit memories.
Squire and his coworkers 6~'71 support a similar
dichotomy, but suggest a diencephalic locus for the
processing of procedural or implicit memories. These
authors have restricted their analysis mostly to the type
of memories (or components of memories) that humans
or animals with temporal lobe lesions can acquire, however, and neural regeneration and reorganization, and
the entry into play of vicarious circuits are problems
intrinsic to lesion studies 25'58. In fact, entorhinal lesions
are followed after a few days by a reactive synaptogenesis in all surviving afferent systems to the dentate
gyrus 1°'58, which complicates the interpretation of the
behavioral effects of such lesions.
Further research on the role in memory of circuits
parallel and/or alternative to the temporal lobe structures and the medial septum is desirable, if possible
using temporary inhibition of restricted brain regions by
drugs, (e.g., refs. 16, 17, 32, 35, 37, 48, 66) or correlational studies measuring electrical activity concomitantly with behavior (e.g., ref. 55). The so-called 'extended amygdala', which includes cell groups
ontogenetically and neuroanatomically related to the
amygdala in the striatal complex 22 seems particularly
worthy of investigation as part of a possible vicarious
or alternative circuit in memory processing.
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