Content uploaded by James L Mcgaugh
Author content
All content in this area was uploaded by James L Mcgaugh on Apr 19, 2016
Content may be subject to copyright.
REVIEW: NEUROSCIENCE
Memory—a Century of Consolidation
James L. McGaugh
The memory consolidation hypothesis proposed 100 years ago by Mu¨ller and Pilzecker
continues to guide memory research. The hypothesis that new memories consolidate
slowly over time has stimulated studies revealing the hormonal and neural influences
regulating memory consolidation, as well as molecular and cellular mechanisms. This
review examines the progress made over the century in understanding the time-
dependent processes that create our lasting memories.
Acentury has passed since Mu¨ ller and
Pilzecker proposed the perseveration-
consolidation hypothesis of memory
(1). In pioneering studies with human sub-
jects, they found that memory of newly
learned information was disrupted by the
learning of other information shortly after the
original learning and suggested that processes
underlying new memories initially persist in a
fragile state and consolidate over time. At the
beginning of this new millennium, the con-
solidation hypothesis still guides research in-
vestigating the time-dependent involvement
of neural systems and cellular processes en-
abling lasting memory (2– 4 ).
Retrograde Amnesia and Memory
Enhancement
Clinical evidence that cerebral trauma induc-
es loss of recent memory was reported two
decades before the publication of Mu¨ ller and
Pilzecker’s monograph, and shortly after its
publication, it was noted that the consolida-
tion hypothesis provided an explanation for
such retrograde amnesia (5). Ignored for al-
most half a century, the consolidation hy-
pothesis was reinvigorated in 1949, when two
papers reported that electroconvulsive shock
induced retrograde amnesia in rodents (6, 7),
triggering a burst of studies of experimentally
induced retrograde amnesia (2– 4 ). That same
year, Hebb and Gerard proposed dual-trace
theories of memory, suggesting that the sta-
bilization of reverberating neural activity un-
derlying short-term memory produces long-
term memory (7, 8). The finding that protein
synthesis inhibitors did not prevent the learn-
ing of tasks but disrupted memory of the
training (9) supports the view that there are
(at least) two stages of memory and indicates
that protein synthesis is required only for
consolidation of long-term memory. The is-
sue of whether short- and long-term memory
(and, perhaps, other memory stages) (Fig. 1)
are sequentially linked, as proposed by Hebb
and Gerard, or act independently in parallel
(3, 10) remains central to current inquiry. The
discovery that stimulant drugs administered
within minutes or hours after training en-
hance memory consolidation further stimulat-
ed studies of memory consolidation (3, 10,
11). The use of treatments administered
shortly after training to impair or enhance
memory provides a highly effective and ex-
tensively used method of influencing memo-
ry consolidation without affecting either ac-
quisition or memory retrieval (11).
Endogenous Modulation of
Consolidation
Memory consolidation appears to be a useful
function, because evidence of consolidation is
found in a wide variety of animal species (12,
13). Why do our memories and those of other
animals consolidate slowly? The answer might
simply be that the molecular and cellular ma-
chinery creating memory works slowly. But
that answer is clearly wrong, because “short-
term” or “working” memories are created al-
most immediately. All our cognitive and motor
skills require quickly accessible new memory.
Furthermore, there is no a priori reason to as-
sume that biological mechanisms are not capa-
ble of quickly consolidating memory. Consid-
erable evidence suggests that the slow consoli-
dation of memories serves an adaptive function
by enabling endogenous processes activated by
an experience to modulate memory strength
(14). Emotionally arousing experiences are
generally well remembered (15). Adrenal stress
hormones, epinephrine and cortisol (corticoste-
rone in the rat), released by emotional arousal
appear to play an important role in enabling
the significance of an experience to regulate
the strength of memory of the experience.
Epinephrine (16,17) and corticosterone (13,
18, 19), as well as drugs that activate adren-
ergic receptors and glucocorticoid (type II)
receptors (13, 18, 19), enhance memory for
many kinds of training experiences.
Critical Involvement of the Amygdala
in Memory Consolidation
Epinephrine does not freely pass the blood-
brain barrier and appears to modulate mem-
ory consolidation by activating -adrenergic
receptors located peripherally on vagal affer-
ents projecting to the nucleus of the solitary
tract in the brainstem. Noradrenergic projec-
tions from this region influence neuronal ac-
tivity in other brain regions, including the
amygdala (20). Glucocorticoids released
from the adrenal cortex readily enter the brain
and activate intracellular glucocorticoid re-
ceptors (Fig. 2). Activation of the amygdala,
a brain region important for emotional arous-
al, is critical for mediating the influences of
epinephrine and glucocorticoids, because
amygdala lesions block the effects of these
modulators on consolidation. Most important,
activation of -adrenergic receptors in the
amygdala is essential. Infusions of -adren-
ergic receptor antagonists into the amygdala
The author is at the Center for the Neurobiology of
Learning and Memory and the Department of Neuro-
biology and Behavior, University of California Irvine,
Irvine, CA 92697, USA. E-mail: jlmcgaug@uci.edu
Fig. 1. Memory consolidation
phases. Studies of memory
and neuroplasticity support
Mu¨ller and Pilzecker’s hy-
pothesis proposing that the
consolidation of new memo-
ry into long-term memo-
ry is time dependent (1), but
strongly suggest that short-
term and different stages of
long-term memory are not
sequentially linked, as pro-
posed by the dual-trace hy-
pothesis (9). Evidence that
drugs can selectively block
either short-term (seconds to hours) or long-term memory (hours to months) suggests that
time-dependent stages of memory are based on independent processes acting in parallel. Later
stages of consolidation resulting in memory lasting a lifetime likely involve interaction of brain
systems in reorganizing and stabilizing distributed connections.
SCIENCE’SCOMPASS ●REVIEW
14 JANUARY 2000 VOL 287 SCIENCE www.sciencemag.org248
after training block epinephrine effects,
whereas infusions of -adrenergic receptor
agonists enhance memory (21). Lesions of
the amygdala and infusions of -adrenergic
receptor antagonists into the amygdala also
block the memory-modulating effects of
drugs affecting systems containing ␥-amino-
butyric acid (GABA) and opioid peptides
(20).
The basolateral nucleus of the amygdala
(BLA) mediates the influences of drugs and
hormones on memory consolidation. -Ad-
renergic receptor agonists infused selectively
into the BLA after training enhance memory,
and lesions of the BLA or infusion of -ad-
renergic receptor antagonists into the BLA
block the memory-enhancing effects of sys-
temically administered dexamethasone (a
synthetic glucocorticoid) (22, 23). Modulato-
ry influences on consolidation include release
of norepinephrine (NE) within the amygdala.
For example, foot-shock stimulation induces
NE release in the amygdala; administration of
epinephrine or drugs that enhance consolida-
tion (such as GABA and opioid receptor an-
tagonists) increases NE release in the amyg-
dala; and the use of drugs that impair memory
(such as GABA and opioid receptor agonists)
decreases NE release (24).
Locus of Modulation: Brain Systems
and Forms of Memory
It is increasingly clear that different brain
regions process different forms of memory
(25). Evidence from rat studies indicates that
the hippocampus and striatum process differ-
ent forms of memory (26) and that the amyg-
dala modulates consolidation by regulating
processing in these brain regions. Amphet-
amine infused into the dorsal hippocampus
after training selectively enhances memory of
the spatial localization of a slightly sub-
merged (and thus not visible to the rat) escape
platform in a water-maze, whereas amphet-
amine infused into the striatum selectively
enhances memory of a prominent visual cue
located on an escape platform placed in vary-
ing locations on different training trials. Most
important, amphetamine infused into the
amygdala after training enhances memory of
both types of training. The amygdala is clear-
ly not the locus of the enhanced memory,
because inactivation of the amygdala (with
lidocaine infusions) before the retention test
does not block expression of the enhanced
memory for either type of training (27).
Because glucocorticoid receptors are
densely located in the hippocampus, these
receptors are likely involved in mediating
glucocorticoid influences on consolidation
(19). Evidence that infusions of a glucocorti-
coid agonist into the dorsal hippocampus af-
ter training enhance memory supports this
view. The BLA is critically involved in en-
abling this glucocorticoid influence. BLA le-
sions or infusions of -adrenergic receptor
antagonists into the BLA block the effects of
glucocorticoids either administered systemi-
cally or infused directly into the dorsal hip-
pocampus (23, 28). These findings provide
further evidence that modulating influences
from the BLA regulate memory consolidation
occurring within or mediated by the hip-
pocampus. As discussed below, the molecu-
lar and cellular changes mediating the induc-
tion of long-term potentiation (LTP) in the
hippocampus are widely considered to pro-
vide a basis for memory. Thus, it is of con-
siderable interest that lesions of the BLA or
infusions of a -adrenergic receptor antago-
nist into BLA block the induction of LTP in
the dentate gyrus of the hippocampus and that
stimulation of the BLA enhances such LTP
(29).
It is clear from these findings that memory
consolidation involves interactions among
neural systems, as well as cellular changes
within specific systems, and that amygdala is
critical for modulating consolidation in other
brain regions. Although research has focused
primarily on amygdala influences on memory
related to the caudate nucleus and hippocam-
pus, the modulation is most certainly not
restricted to these brain regions.
Emotional Arousal and Memory
Consolidation in Humans
Although the consolidation hypothesis was
based on human memory results, most re-
search on consolidation has studied memory
in animals. The animal memory findings
have reactivated interest in human memory
consolidation. Amphetamine administered to
human subjects either before or after learning
of word lists enhances memory of the words
(30). Results of human studies, like those of
animal studies, indicate that adrenergic sys-
tems and amygdala activation influence
memory consolidation. Recent studies found
that -adrenergic receptor antagonists block
the memory-enhancing effects of emotional
arousal (31). Studies examined the effects of
-adrenergic receptor antagonists or a place-
bo on the memory of pictures accompanied
by an emotionally arousing story. Subjects
given a placebo before presentation of the
pictures and story remembered best the pic-
tures presented during the most emotional
part of the story. In contrast, in subjects given
a-adrenergic receptor antagonist, memo-
ry for those pictures was not enhanced. -
Adrenergic receptor antagonists (taken as
medication) also blocked arousal-induced en-
hancement of memory in elderly subjects.
Emotional arousal also does not enhance
long-term memory of the arousing material in
human subjects with selective lesions of the
amygdala (32). Additionally, studies using
PET (positron emission tomography) scans to
assess amygdala activity induced by emotion-
ally arousing stimuli (both pleasant and un-
pleasant) found that long-term memory cor-
relates with the degree of amygdala activa-
tion during the original encoding (33).
As Time Goes By: The Orchestration
of Consolidation
Changes in brain activity after learning pro-
vide additional insights into the time course
of consolidation processes. A study of func-
tional brain activity in human subjects (with
PET) revealed shifts in activity among differ-
ent brain regions occurring over a period of
several hours after the learning of a motor
skill, suggesting that consolidation involves
time-dependent reorganization of the brain
representation underlying the motor skill
(34). Studies of learning-induced changes in
receptive fields in the auditory cortex provide
additional evidence that neural processes ac-
tivated by training continue to change for
several days, after completion of training
(35). Neurons in the auditory cortex of ani-
Learning
experience
Basolateral
amygdala
Adrenal gland
Neocortex
Hippocampus
Caudate nucleus
Other brain regions
Glucocorticoid
Epinephrine
NE
Initiation of memory consolidation
Modulating influences
Fig. 2. Neurobiological
systems regulating mem-
ory consolidation. Experi-
ences activate time-
dependent cellular stor-
age processes in various
brain regions involved in
the forms of memory rep-
resented. The experiences
also initiate the release of
the stress hormones from
the adrenal medulla and
adrenal cortex and acti-
vate the release of nor-
epinephrine in the baso-
lateral amygdala, an ef-
fect critical for enabling
modulation of consolida-
tion. The amygdala mod-
ulates memory consolida-
tion by influencing neuro-
plasticity in other brain
regions.
SCIENCE’SCOMPASS
www.sciencemag.org SCIENCE VOL 287 14 JANUARY 2000 249
mals given a brief training session in which a
specific tone was paired with foot shock
subsequently responded more to that tone
and less to other tones. Furthermore, the
degree of selectivity in the “frequency tun-
ing” continued to increase for several days,
suggesting continuing consolidation of the
memory of the tone’s increased signifi-
cance. It would be of considerable interest
to know whether inactivation of the BLA
blocks such consolidation.
Most research on memory consolidation
examined the effects of treatments adminis-
tered within several hours after training. It
cannot be concluded from such research that
consolidation is completed within hours, be-
cause the effectiveness of a treatment in mod-
ulating consolidation depends on the locus
and mechanism(s) of action of the treatment,
as well as the state of consolidation when the
treatment is administered (14). Lesions of the
hippocampus (or adjacent cortical areas) and
sustained drug infusions into the hippocam-
pus impair memory for training given days,
or even weeks, earlier (36). Thus, although
the hippocampus and anatomically related
structures are no doubt involved in consoli-
dation, and may well be a locus of temporary
neural changes that influence the establish-
ment of long-term memory, those brain re-
gions are clearly not unique loci of long-term
memory. This conclusion was first drawn
from studies of the patient H.M. after bilat-
eral surgical excision of his medial temporal
lobes (37) The hippocampus may have a
long-term or perhaps even a sustained role in
consolidating memory (36,38). Such consol-
idation may involve extensive interaction of
the hippocampus and related cortex with the
neocortex as well as other brain regions, serv-
ing to link the sites and enable regions to
strengthen or reorganize connections with the
others, as well as to organize and reorganize
the information being consolidated (38, 39).
Cellular Machinery of Consolidation
Because of evidence suggesting that the hip-
pocampus is active in memory consolidation
(for some forms or aspects of memory), as
well as the hypothesis that cellular and mo-
lecular mechanisms underlying LTP may en-
able memory consolidation, the relation be-
tween hippocampal LTP and memory is the
focus of intense investigation (40,41). It is
important to note that because the cellular
and molecular changes occur mostly within
hours after LTP induction or training, they
are reasonable candidates for consolidation
mechanisms occurring within that time
frame. Different processes occurring in other
brain regions are likely involved in memory
consolidation occurring over days, months, or
years (36).
As discussed above, extensive evidence
indicates that the BLA influences memory
processes and LTP in other brain regions.
Treatments known to affect memory consol-
idation also modulate the maintenance of hip-
pocampal LTP in freely moving rats (42).
Water given to thirsty rats within 30 min after
induction of LTP enhanced the maintenance
of LTP. Foot shock administered after LTP
induction also enhanced LTP. A -adrenergic
receptor antagonist blocked the enhancing
effects of both the water reward and foot
shock on LTP. As with learning in intact
animals, inhibition of protein synthesis after
the induction of LTP in a hippocampal slice
blocks the maintenance (that is, late phase) of
LTP but does not block the induction (that is,
early phase) of LTP (43).
Many recent experiments examined the ef-
fects, on memory consolidation, of drugs regu-
lating specific molecular stages in the develop-
ment and maintenance of LTP. Extensive evi-
dence indicates the involvement of CaMKII
(calcium-calmodulin– dependent protein kinase
II) in both consolidation and LTP. CaMKII is
known to phosphorylate the ␣-amino-3-
hydroxy-5-methyl-4-isoxazolepropionic acid
(AMPA) receptor subunit GluR1. Inhibitors of
CaMKII block the induction of LTP and impair
consolidation when infused into the amygdala
or CA1 region of the hippocampus immediately
after training (41,44). However, CaMKII ap-
pears to have different roles in consolidation in
these two brain regions (44). Infusions of any
of several drugs, including 8-bromo cyclic
adenosine monophosphate (8-Br-cAMP), a do-
pamine D1 receptor agonist, or NE into the
hippocampus (CA1 region) 3 hours after train-
ing attenuate the amnesic effect of a CaMKII
inhibitor infused into the amygdala immediate-
ly after training. In contrast, such treatments
administered 3 hours after training do not block
the amnesia induced by a CaMKII inhibitor
infused into the hippocampus immediately after
training. These findings provide additional ev-
idence that the amygdala plays a modulatory
role in consolidation, whereas the hippocampus
is more likely a locus of memory processing or
consolidation.
Inhibitors of the signal-transducing en-
zyme protein kinase C (PKC) are also known
to block the maintenance of hippocampal
LTP and to induce retrograde amnesia when
infused into the hippocampus of rats after
training. Similarly, inhibitors of protein ki-
nase A (PKA) disrupt the late, protein syn-
thesis– dependent phase of LTP and impair
memory when infused into the hippocampus
several hours after training (45). Additional-
ly, PKA activity and CREB (cAMP response
element– binding protein) immunoreactivity
increase in the hippocampus after training.
Such findings suggest that late-phase LTP
and memory consolidation involve cAMP-
mediated activation, by PKA phosphoryl-
ation, of the CREB transcription factor (46).
Evidence that infusions of CREB antisense
oligonucleotides into the hippocampus block
the consolidation of water-maze learning
without affecting acquisition also supports
this hypothesis (47). Discovering which of
the myriad of CREB-regulated genes is (or
are) selectively involved in memory consoli-
dation will be an interesting quest. Selective
gene activation or inactivation after learning
may regulate consolidation by modulating the
stabilization of synaptic changes required for
long-term memory (4, 48). Neural cell adhe-
sion molecules also appear to play a role in
memory consolidation by regulating time-
dependent processes underlying synaptic sta-
bilization (49).
Memory: The Short and the Long of It
Many treatments affect late LTP and memory
consolidation without affecting early LTP or
short-term or working memory. Although
such findings are consistent with the hypoth-
esis that early and later stages of memory are
serially linked (9), they do not exclude the
possibility that different stages of memory
are based on parallel, independent processes
(3, 10). Moreover, studies of memory in many
species strongly support this latter view (12,
13), and studies of synaptic facilitation in
Aplysia clearly indicate that short-term facil-
itation (STF) and long-term facilitation (LTF)
are not serially linked (50). Drugs and other
conditions that block STF do not block the
expression of LTF and, as with other forms of
plasticity and memory, only LTF requires pro-
tein synthesis. Additionally, evidence that some
drugs infused into the hippocampus and ento-
rhinal cortex after training block short-term
memory without affecting long-term memory
provides critical evidence that short- and long-
term memory processes are independent (51).
Evaluation of this evidence requires sev-
eral caveats. First, it remains a hypothesis
that the synaptic mechanisms of LTP and
LTF underlie memory, whether fleeting or
lasting (or long-lasting). Second, although
studies of the mechanisms of LTP and mem-
ory have focused on the involvement of the
hippocampus, much evidence indicates that
the hippocampus has a time-limited role in
the consolidation or stabilization of lasting
memory, or both. Third, there are forms of
memory that do not involve the hippocampus
and may not use any known mechanisms of
synaptic plasticity. Third, despite theoretical
conjectures, little is as yet known about sys-
tem and cellular processes mediating consol-
idation that continues for several hours or
longer after learning to create our lifelong
memories. These issues remain to be ad-
dressed in this new century of research on
memory consolidation.
References and Notes
1. G. E. Mu¨ller and A. Pilzecker, Z.Psychol.1, 1 (1900).
2. S. E. Glickman, Psychol.Bull.58, 218 (1961); J. L.
McGaugh and M. J. Herz, Memory Consolidation
SCIENCE’SCOMPASS
14 JANUARY 2000 VOL 287 SCIENCE www.sciencemag.org250
(Albion, San Francisco, 1972); H. Weingartner and
E. S. Parker, Eds., Memory Consolidation (Erlbaum,
Hillsdale, NJ, 1984); H. A. Lechner, L. R. Squire, J. H.
Byrne, Learn.Mem.6, 77 (1999); M. R. Polster, L.
Nadel, D. L. Schacter, J.Cogn.Neurosci.3, 95 (1991).
3. J. L. McGaugh, Science 153, 1351 (1966).
4. Y. Dudai, Neuron 17, 367 (1996).
5. T. Ribot, Diseases of Memory (Appleton, New York,
1882); W. McDougall, Mind 10, 388 (1901); W. H.
Burnham, Am. J.Psychol.14, 382 (1903).
6. C. P. Duncan, J.Comp.Physiol.Psychol.42, 32 (1949).
7. R. W. Gerard, Am. J.Psychiatry 106, 161 (1949).
8. D. O. Hebb, The Organization of Behavior (Wiley,
New York, 1949) and (7). It is of interest that Hebb
did not refer to the perseveration-consolidation hy-
pothesis in his seminal 1949 book.
9. B. W. Agranoff, R. E. Davis, J. J. Brink, Brain Res.1, 303
(1965).
10. J. L. McGaugh, in Recent Advances in Learning and
Retention, D. Bovet, F. Bovet-Nitti, A. Oliverio, Eds.
(Accademia Nazionale dei Lincei, Rome, 1968), pp.
13–24.
11. J. L. McGaugh, Annu.Rev.Pharmacol.13, 229 (1973);
Brain Res.Bull.23, 339 (1989).
12. T. M. Alloway and A. Routtenberg, Science 158, 1066
(1967); T. Tully, T. Preat, S. C. Boynton, M. Del
Vecchio, Cell 79, 35 (1994); R. Menzel and U. Mu¨ller,
Annu.Rev.Neurosci.19, 379 (1966); U. Mu¨ller, Neu-
ron 16, 1249 (1996).
13. C. Sandi and S. P. R. Rose, Brain Res.647, 106 (1994).
14. P. E. Gold and J. L. McGaugh, in Short-Term Memory,
D. Deutsch and J. A. Deutsch, Eds. (Academic Press,
New York, 1975), pp. 355–378.
15. S.-A. Christianson, Ed., Handbook of Emotion and
Memory:Current Research and Theory (Erlbaum, Hills-
dale, NJ, 1992).
16. P. E. Gold and R. van Buskirk, Behav.Biol.13, 145
(1975).
17. J. L. McGaugh and P. E. Gold, in Psychoendocrinology,
R. B. Brush and S. Levine, Eds. (Academic Press, New
York, 1989), pp. 305–339.
18. E. R. de Kloet, Front.Neuroendocrinol. 12, 95 (1991);
㛬㛬㛬㛬, S. Kock, V. Schild, H. D. Veldhuis, Neuroen-
docrinology 47, 109 (1988); B. Roozendaal, L. Cahill,
J. L. McGaugh in Brain Processes and Memory,K.
Ishikawa, J. L. McGaugh, H. Sakata, Eds. (Elsevier,
Amsterdam, 1996), pp. 39–54.
19. S. J. Lupien and B. S. McEwen, Brain Res.Rev.24,1
(1997).
20. M. G. Packard, C. L. Williams, L. Cahill, J. L. McGaugh,
in Neurobehavioral Plasticity:Learning,Development
and Response to Brain Insults, N. E. Spear, L. Spear, M.
Woodruff, Eds. (Erlbaum, Hillsdale, NJ, 1995), pp.
149–184; J. L. McGaugh, L. Cahill, B. Roozendaal,
Proc.Natl.Acad.Sci.U.S.A. 93, 13508 (1996). There
is also evidence that epinephrine influences memory
through the release of glucose, which then enters the
brain; however, the effects of glucose on memory
differ from those mediated by the activation of vagal
afferents. P. E. Gold, in Cellular Mechanisms of Con-
ditioning and Behavioral Plasticity, C. D. Woody, D. L.
Alkon, J. L. McGaugh, Eds. (Plenum, New York, 1988),
pp. 329–341.
21. K. C. Liang, R. G. Juler, J. L. McGaugh, Brain Res.368,
125 (1986).
22. B. Roozendaal and J. L. McGaugh, Neurobiol.Learn.
Mem.65, 1 (1996); T. Hatfield and J. L. McGaugh,
Neurobiol.Learn.Mem.71, 232 (1999); B. Ferry and
J. L. McGaugh, Neurobiol.Learn.Mem.72, 8 (1999).
23. G. L. Quirarte, B. Roozendaal, J. L. McGaugh, Proc.
Natl.Acad.Sci.U.S.A. 94, 14048 (1997).
24. R. Galvez, M. Mesches, J. L. McGaugh, Neurobiol.
Learn.Mem.66, 253 (1996); G. L. Quirarte, R. Galvez,
B. Roozendaal, J. L. McGaugh, Brain Res.808, 134
(1998); C. L. Williams, D. Men, E. C. Clayton and P. E.
Gold, Behav.Neurosci.112, 1414 (1998); T. Hatfield,
C. Spanis, J. L. McGaugh, Brain Res.835, 340 (1999).
25. L. R. Squire and E. R. Kandel, Memory from Mind to
Molecules (Scientific American Library, New York,
1999).
26. For example, M. G. Packard and N. M. White, Behav.
Neurosci.105, 295 (1991); M. G. Packard, R. Hirsh,
N. M. White, J.Neurosci.9, 1465 (1989).
27. M. G. Packard, L. Cahill, J. L. McGaugh, Proc.Natl.
Acad.Sci.U.S.A. 91, 8477 (1994); M. G. Packard and
L. Teather, Neurobiol.Learn.Mem.69, 163 (1998).
28. B. Roozendaal and J. L. McGaugh, Euro.J.Neurosci.9,
76 (1997); B. Roozendaal, B.T. Nguyen, A. Power, J. L.
McGaugh, Proc.Natl.Acad.Sci.U.S.A. 96, 11642
(1999).
29. Y. Ikegaya, H. Saito, K. Abe, Brain Res.671, 351
(1995); Neurosci.Res.22, 203 (1995); 㛬㛬㛬㛬,K.
Nakanishi, NeuroReport 8, 3143 (1997). BLA stimu-
lation also induces NMDA-dependent LTP in the in-
sular cortex, a brain region known to be important for
several forms of learning [F. Bermudez-Rattoni, I. B.
Introini-Collison, J. L. McGaugh, Proc. Natl. Acad. Sci.
U.S.A. 88, 5379 (1991); M. L. Escobar, V. Chao, F.
Bermudez-Rattoni, Brain Res. 779, 314 (1998); M. W.
Jones, P. J. French, T. V. P. Bliss, K. Rosenblum, J.
Neurosci 19, RC36 (1999)].
30. E. Soetens, S. Casaer, R. D’Hooge, J. E. Hueting,
Psychopharmacology 119, 155 (1995).
31. L. Cahill, B. Prins, M. Weber, J. L. McGaugh, Nature
371, 702 (1994); A. H. van Stegeren, W. Everaerd, L.
Cahill, J. L. McGaugh, L. J. G. Gooren, Psychopharma-
cology 138, 305 (1998); K. Nielson and R. Jensen,
Behav.Neural Biol.62, 190 (1994).
32. L. Cahill, R. Babinsky, H. J. Markowitsch, J. L. Mc-
Gaugh, Nature 377, 295 (1995); R. Adolphs, L. Cahill,
R. Schul, R. Babinsky, Learn.Mem.4, 291 (1997).
33. L. Cahill et al., Proc.Natl.Acad.Sci.U.S.A. 93, 8016
(1996); S. Hamann, T. Ely, S. Grafton, C. Kilts, Nature
Neurosci.2, 289 (1999).
34. R. Shadmehr and H. H. Holcomb, Science 277, 821
(1997).
35. N. M. Weinberger, in The Cognitive Neurosciences,
M. S. Gazzaniga, Ed. (MIT Press, Cambridge, MA,
1995), pp. 1071–1089; N. M. Weinberger, Trends
Cogn.Sci.2, 271 (1998); T. S. Bjordahl, M. A. Dimyan,
N. M. Weinberger, Behav.Neurosci.112, 467 (1998);
V. V. Galvan, J. Chen, N. M. Weinberger, Soc.Neuro-
sci.Abstr.24, 1422 (1998).
36. G. Winocur, Behav.Brain Res.38, 145 (1990); S.
Zola-Morgan and L. R. Squire, Science 250, 288
(1990); J. J. Kim and M. S. Fanselow, Science 256, 675
(1992); Y. H. Cho, D. Beracochea, R. Jaffard, J.Neu-
rosci.13, 1759 (1993); J. J. Kim, R. E. Clark, R. F.
Thompson, Behav Neurosci.109, 195 (1995); G. Re-
idel et al., Nature Neurosci. 3, 898 (1999).
37. W. B. Scoville and B. Milner, J.Neurol.Neurosurg.
Psychiatry 20, 11 (1957); B. Milner, in Amnesia,
C. W. M. Whitty and O. L. Zangwill, Eds. (Butter-
worths, London, 1966), pp. 109–133.
38. L. R. Squire and P. Alvarez, Curr.Opin.Neurobiol.5,
169 (1995).
39. T. J. Tyler and P. DiScenna, Behav.Neurosci.100, 147
(1986); J. L. McClelland, B. L. McNaughton, R. C.
O’Reilly, Psychol.Rev.102, 419 (1995).
40. T. J. Shors and L. D. Matzel, Behav.Brain Sci. 20, 597
(1997).
41. R. C. Malenka and R. A. Nicoll, Science 285, 1870
(1999).
42. T. Seidenbacher, K. G. Reymann, D. Balschun, Proc.
Natl.Acad.Sci U.S.A. 94, 1494 (1997)
43. U. Frey, M. Krug, K. G. Reymann, H. Matthies, Brain
Res.452, 57 (1988).
44. D. M. Barros et al., Neurobiol.Learn.Mem.71,94
(1999).
45. P. A. Colley, F. -S. Sheu, A. Routtenberg, J.Neurosci.
10, 3353 (1990); Y.-Y. Huang, P. A. Colley, A. Rout-
tenberg, Neuroscience 49, 819 (1992); D. Jerusalinsky
et al., Behav.Neural Biol.61, 107 (1994).
46. Y.-Y. Huang and E. R. Kandel, Proc.Natl.Acad.Sci.
U.S.A. 92, 2446 (1995); R. Bernabeu et al., Proc.Natl.
Acad.Sci.U.S.A. 94, 7041 (1997); G. E. Schafe, N. V.
Nadel, G. M. Sullivan, A. Harris, J. E. LeDoux, Learn.
Mem.6, 97 (1999).
47. J. F. Guzowski and J. L. McGaugh, Proc.Natl.Acad.Sci.
U.S.A. 94, 2693 (1997); T. Tully, Proc.Natl.Acad.Sci.
U.S.A. 94, 4239 (1997).
48. A. Routtenberg, in Four Decades of Memory,P.E.
Gold. and W. T. Greenough, Eds. (American Psycho-
logical Association, Washington, DC, in press); T.
Abel, K. C. Martin, D. Bartsch, E. R. Kandel, Science
279, 338 (1998).
49. K. J. Murphy and C. .M. Regan, Neurobiol.Learn.Mem.
70, 73 (1998); P. Roullet, R. Mileusnic, S. P. R. Rose,
S. J. Sara, NeuroReport 8,1907 (1997).
50. N. J. Emptage and T. J. Carew, Science 262, 253
(1993); J. Mauelshagen, G. R. Parker, T. J. Carew, J.
Neurosci.15, 7099 (1996); U. Mu¨ller and T. J. Carew,
Neuron 21, 1423 (1996).
51. I. Izquierdo, D. M. Barros, T. Mello e Souza, M. M. de
Souza, L. A. Izquierdo, Nature 393, 635 (1998).
52. I thank L. Cahill, I. Izquierdo, A. Routtenberg, G.
Streidter, and N. M. Weinberger for their helpful
comments and N. Collett for assistance in prepara-
tion of the manuscript. Supported by National Insti-
tute of Mental Health grant MH12526.
SCIENCE’SCOMPASS
www.sciencemag.org SCIENCE VOL 287 14 JANUARY 2000 251
