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by: Marco Wolf


Marco Wolf
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This 14 page Class Notes was uploaded by Marco Wolf on Monday September 7, 2015. The Class Notes belongs to PSY 332C at University of Texas at Austin taught by Staff in Fall. Since its upload, it has received 72 views. For similar materials see /class/181810/psy-332c-university-of-texas-at-austin in Psychlogy at University of Texas at Austin.




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Date Created: 09/07/15
1030 28 F Desdouits J C Siciliano P Greengard J A Girault Proc Ii Acad Sci USA 92 2682 1995 29 A Nishi G L Snyder P Greengard j Neurosci 17 8147 1997 30 G L Snyder A A Fienberg R L Huganir P Cureenr ard j Neurosci 18 10297 1998 on er al Neurosci 84 223 1998 G L Sn der A C Nairn P Greengard j Neurochem 72 2015 1999 33 P Svenningsson er 21 j Neurochem 75 248 2000 34 G L Snyder er alj Neurosci 20 4480 2000 35 A A Fienberg P Greengard Brain Res Rev 31 313 2000 36 P Svenningsson er al Proc Natl Acad Sci USA 97 1855 2000 37 A Nishi eraL Proc Natl Acad Sci USA 97 12840 2000 38 J A Bibb er 21 Nature 410 375 2001 39 H C Hemmings Jr P Greengard H Y L Tung P Cohen Nature 310 503 1984 REVIEW SCIENCE39S COMPASS 40 A A Fienberg er al Science 281 838 1998 41 P E Allen C C Ouimet P Greengard Proc Natl Acad Sci USA 94 9955 1997 Z Yan er al Narure Neurosci 2 13 1999 3 JrA Girault H C Hemmings Jr K R Williams A C Nairn P Greengard j Biol Chem 264 21748 1989 F Desdouits D Cohen A C Nairn P Greengard JrA Girault j Biol Chem 270 8772 1995 5 J A Bi b er 21 Narure 4025752 559 1999 F F da Cruz e Silva er 21 j Neurosci 155 3375 1995 P Greengard J Jen A C Nairn C F Stevens Science 253 1135 1991 LVY Wan M W Salter J F MacDonald Science 25311321991 L HsiehrWilson er al unpublished data C Rosenmund er al Narure 368 853 1994 The work summarized here reflects outstanding cone tributions from many highly gifted associates who be N t masses om im 111 have worked in our laboratory I would particularly like to mention A C Nairn who has been a close colleague and friend for more than 20 years This work has also benefited enormously from collaborar tions with excellent scientists at several omer unir versities Our work on r 39 very generously supported for over 30 years by the National Institutes of Health including the National Institute of Mental Health the National Institute on Drug Abuse and the National Insu39tute on Aging The Molecular Biology of Memory Storage A Dialogue Between Genes and Synapses Eric R Kandel One of the most remarkable aspects of an animal39s behavior is the ability to modify that behavior by learning an ability that reaches its highest form in human beings For me learning and memow have proven to be endlessly fascinating mental processes because they address one of the fundamental features of huma n activity our ability to acquire new ideas from experience and to retain these ideas over time in memory Moreover unlike other mental processes such as thought language and conscious ness learning seemed from the outset to be readily accessible to cellular and molecular analysis I therefore have been curious to know What changes in the brain when we learn And on e something is learned how is that information retained in the brain I have tried to address these questions through a reductionist approach that would allow me to investigate elementary forms of learning and memo ry at a cellular molecular level as specific molecular activities within identified nerve cells ory in 1950 as a result of my readings in psychoanalysis while still an undergraduate at Harvard College Later during medical train ing I began to nd the psychoanalytic approach limiting because it tended to treat the brain the organ that generates behavior as a black box In the mid1950s while still in medical school I began to appreciate that during my lifetime the black box of the brain would be opened and that the problems of memory storage once the ex clusive domain of psychologists and psychoan alysts could be investigated with the me o of modern biology As a result my interest in memory shi ed from a psychoanalytic to a biological approach As a postdoctoral fellow at I rst became interested in the study of mem Howard Hughes Medical Institute Center for Neuro biology and Behavior College of Physicians and Sur geons of Columbia University New Yor State Psy chiatric Institute 1051 Riverside Drive New York NY 10032 USA Email erk5columbiaedu This essay is adapted from the author s address to the Nobel Foundation December 2000 2 NOVEMBER 2001 the National Institutes of Health NIH in Be thesda from 1957 to 1960 I focused on learning more about the biology of the brain and became interested in lmowing how learning produces changes in the neural networks of the brain My ose in translating questions about the psychology of learning into the empirical language of biology was not to replace the logic of psychology or psychoanalysis with the logic of cellular molecular biology but to try to join these two disciplines and to contribute to a new synthesis that would combine the mentalistic psychology of memory storage with the biology of neuronal signaling 1 h pe further that e biological analysis of memory might carry with it an extra bonus that the study of memory storage might reveal new aspects of neuronal signaling Indeed this has proven true A Radical Reductionist Strategy to Learning and Memory At rst thought someone interested in learning and memory might be tempted to mckle the problem in its most complex and interesting form This was the approach that Alden Spen cer and 1 took when we joined forces at NIH in 1958 to study the cellular properties of the 39 pocam us the part of the mammalian brain thought to be most directly involved in aspects of complex memory I We initially asked rather naively Are the electrophysiological properties of the pyramidal cells of the hip pocampus which were thought to be the key hippocampal cells involved in memory storage fundamen ally different from other neurons in the brain With study it became clear to us that all nerve cells including the pyramidal cells of the hi ocam us have similar signaling prop key insights into memory storage unique functions of the hippocampus had to arise not so much from the intrinsic properties of pyramidal neurons but from the pattern of learning To tackl to study not the most complex but the Sim plest instances of memory storage and to study them in aule ma ble experimentally Such a reductionist ap proach was hardly new in 20thcentury biolr ogy eed ink of the use ofDror sophibz in genetics of bacteria and baderior p ages in molecular biology and ofthe squid 39 axon in the study of the conduction of impulses Nevertheless when i c inv were reluctant to use a r omst In lhe19505 and 19605 man brate ones was least likely to succeed They SCIENCE39S COMPASS tem is made up of a small number of nerve cells many of these are gigantic and as a ly identifiable 3 4 Whereas the mamm 39 an brain has a trillion central nerve ce Aplysl39u has only 20000 and the simplest behaviors that can be modified by learning may directly involve less than 100 central nerve cells In addition to being few in numr bers these cells are 39 allr 11s in diameter large enough to be seen with the e0nec r d o ese e naked ey an ecor fr m th larg cells for many hours without any difficulty and the e return to an recorded from over a period of days The cells can easily be dissected out for biochemr irnl hirlip L 39 argued that on y higher esting forms of learning and that these forms require neuronal organizations and neuronal mechanisms qualitatively different from those found in simple animals as my belief however that concerns r sys obtain sufficient mRNA to make a cDNA library Finally these identified cells can readily be injected with labeled compounds antibodies or genetic constructs procedures which opened up the molecular study of sigr about the use of a p tem to study learning were misplaced If elr ementary forms of leamin are common to all imals rvo must be conserved features in the mesh aming at the cell and molecular be studied effectively even in simple invertebrate anim s A Simple Learned Behavior in an Invertebrate A el39 an extensive search for a suitable exr mrim ntai animal T M 4 th 39 t rine snail Aplysl39u Fig 1A because it offers ee important advantages Its nervous sysr A GIII Wlllldrlwll MIX Tactile stimulus Fig 1 A simple learned behavior A A dorsal view opriyrla showing 39 39 39 an A light touc p n the gill me animal Irving Kupfermann and I soon delineate a very simple defensive re ex he withdrawal of the gill upon stimulation of the siphon an action that is like the quick withdrawal of a hand from a hot object stimulus is applied to D a e m 5 g lt7 2 r n in 3 o Er 0 a Tom Carew Robert Hawkins and th th39 39 bemodif three different forms of leamin habituar tion sensitization and classical conditions Sonllllzl on Twila stimulus r S E m 3 ing 57 As we examined these three forms of learning we were struck by the resemblance each had to co forms of learning in higher vertebrates and humans As with vertebrate learning meme ory storage for each type of learning in Aplysl39u has two phases a transient memory 39 utes and an enduring memory that lasts days Conversion of shortrlel39m to longrlel39m memory storage requires spaced t p 39 39 even in snails Fig 1B 678 We focused initially on one type of lean ing Semitl39zutlon IS a form of learned fear in frightened and w l wise innocuous stimulus like a ta shoulder Similarly on rec 39 shock to a part of the bod responses to a variety applied to the siphon even innocuous stimuli Fig 1A 9 The animal remembers the shock and the duration of this memo a function of the number of repetitions of the noxious experience Fig 1B A single shock gives rise to a 39 on y minutes this shorHerm mem 39 the synthesis ofnew protein In contr e paced s ocks to the tail give rise to a memory lasting several days this longrlerm t lt U 3 4 ilnglo sham Duration dfwilhdmal 96 df normal 4 Day alter training tion converts shorHerm memory imo longrlerm memo in lyria Before sensitization training a weak touch 39 a weak brief siphon and giii withdrawal reflex Following a single noxious sensin39zing shock to the tail that same weak touch produces gill ensrnzation of the gillrwnhdrawal reflex b appi ing a noxious a much larger siphon and giii refiex wimdrawai response an enhancer stmuius to anomer part o t e dy such s the tail e ances me rnent that lasts about 1 our ore uai shocks increase the size and wimdrawai reflex of bout the siphon and me giii a Spaced repelir duration of the response Modified from 79 www3ciencemagnrg SCIENCE VOL 294 2 NOVEMBER 2001 1031 1032 memory does require the synthesis of new protein Further training four brief trains a day for four days gives rise to an even more enduring memory lasting weeks which also requires new protein synthesis Thus just as in complex learning in mammals 10 I I the longterm memory for sensitization differs from the shortterm memory in requiring the synthesis of new proteins This was our first clear evidence for the conservation of bio chemical mechanisms between Aplysia and vertebrates Kupfermann Castellucci Carew Hawkins John Byme and I worked out signi cant com ponents of the neural circuit gillwithdrawal re ex Fig2 The circuit is located in the abdom inal ganglion and has 24 central mechanorecep tor sensory neurons that innervate the siphon skin and make direct monosynaptic connections with 6 gill motor cells Fig 2C 12714 The sensory neurons also made indirect connections with the motor cells through small groups of excitatory and inhibitory intemeurons I5 16 In addition to being identi able individual cells also have surprisingly large effects on behavior Fig 2B 4 I4 I 7 As we examined the neural circuit of this re ex we were struck by its invariance In every animal we examined each cell connected only to certain target cells and not to others Fig 2C This also was true in the neural circuitry of other behaviors in Aplysia including inking control of the circulation and locomotion 4 I 8 This raised a key question in A L7 Motor Neuron LE Sensory Neurons Siphon B Gill lm Gill Motor Motor Motor Neuron Neuron 39 Neuron Sensory Sensory Neuron Neuron L sensitizing stimuli From 25 2 NOVEMBER 2001 SCIENCE39S COMPASS the cell biological study of learning How can learning occur in a neural circuit that is so precisely wired In 1894 Santiago Ramon y Cajal pro posed a theory of memory storage according to which memory is stored in the growth of new connections 19 This prescient idea was neglected in good part for half a century as students of learning fought over newer competing ideas First Karl Lashley Wolf gang Kohler and a number of Gestalt psy chologists proposed that learning leads to changes in electric fields or chemical gradi ents which they postulated surround neuro nal populations and are produced by the ag gregate activity of cells recruited by the learning process Second Alexander Forbes and Lorente de No proposed that memory is stored dynamically by a selfreexciting chain of neurons Donald Hebb later championed this idea as a mechanism for shortterm mem ory Finally Holger Hyden proposed that learning led to changes in the base composi tion of DNA or RNA Even though there was much discussion about the merits of each of these ideas there was no direct evidence to support any of them 2 Kupfermann Castellucci Carew Hawkins and I addressed these alternative ideas directly by confronting the question of how learning can occur in a circuit with xed neuronal elements To address this question we examined the neu ral circuit of the gillwithdrawal re ex while the animal underwent sensitization classical condi tioning or habituation Our studies provided clear evidence for the idea proposed by Ramon y Caj al that learning results from changes in the strength of the synaptic connections between precisely interconnected cells 12 20 Thus while the organism s developmental program assures that the connections between cells are invariant it does not specify their precise strength Rather experience alters the strength and effectiveness of these preexisting chemical connections Seen in the perspective of these three forms of learning synaptic plasticity emerged as a fundamental mechanism for infor mation storage by the nervous system a mech anism that is built into the very molecular archi tecture of chemical synapses 21 Molecular Biology of Short and LongTerm Memory Storage What are the molecular mechanisms whereby shortterm memory is established and how is it converted to longterm memory Initially we focused on shortterm sensitization In collabo ration with James H Schwartz we found that the synaptic changes like shortterm behavior were expressed even when protein synthesis was inhibited This nding rst suggested to us that shortterm synaptic plasticity might be me diated by a second messenger system such as cyclic AMP 22 Following up on this idea Schwartz Howard Cedar and I found in 1972 that stimulation of the modulatory pathways Fig 2 The neural circuit of the Aplysia gillwith drawal reflex A In this ll dorsal view of the ab dominal ganglion the six identified motor Siphon cells to the gill are brown and the seven sensory neurons are blue A sensory neuron that synapses on gill motor neuron L7 is 7 Inh stimulated electrically a I IMgsnuel trggs Exc with an intracellular GIquot 7 electrode and a micro l t electrode in the motor n erneurons neuron records the syn aptic potential pro duced by the action po tential in the sensory neuron see middle L trace in The sensory neuron carries the input from the siphon skin the motor neuron makes direct connections onto the gill B Individual cells make significant contributions to IIIIU L the reflex Stimulating a single motor neuron traces on the left produces a detectable change in the gill and stimulating a single sensory neuron produces a large synaptic potential in the motor neuron traces in the middle Repeated stimulation of a single sensory neuron increases the frequency of firing in the motor neuron leading to a visible reflex contraction of the gill traces on the right A single tactile stimulus to the skin normally activates 6 to 8 of the 24 sensory neurons causing each to fire I to 2 action potentials The repetitive firing of 10 action potentials in a single sensory neuron designed to simulate the firing of the total population trace on the right simulates the reflex behavior reasonably well C Diagram of the circuit of the gillwithdrawal reflex The siphon is innervated by 24 sensory neurons that connect directly with the six motor neurons The sensory neurons also connect to populations of excitatory and inhibitory intemeurons that in turn connect with the motor neurons Stimulating the tail activates three classes of modulatory intemeurons serotonergic neurons neurons that release the small cardioactive peptide and the L29 cells that act on the terminals of the sensory neurons as well as on those of the excitatory intemeurons The serotonergic modulatory action is the most important blocking the action of these cells blocks the effects of VOL 294 SCIENCE www5ciencemagorg recruited during heterosynaptic facilimtion led to an increase in CAMP in the abdominal gan glion 23 Cedar and Schwartz found that the neurotransmitter candidates serotonin and do a mine could simulate this action of electrical Later Hawkins Castellucci D and I delineated the modulatory system activat ed by a sensitizing stimulus to the mu I6 25 26 and confirmed that it conmins serotonergic interneurons We next found that serotonin acts on spe cific receptors in the presynaptic terminals of the sensory neuron to enhance transmitter release In 1976 Marcello Brunelli Castel lucci and I injected cAMP directly into the presynaptic cells and found that it too pro duced presynaptic facilitation 27 28 This provided the most compelling evidence then available that cAMP is involved in control ling synaptic strength and gave us our first insight into one molecular mechanism of SCIENCE39S COMPASS shortterm memoryithe regulation of trans mitter release Fig 3 How does cAMP enhance transmitter re lease Serotonin or injected cAMP leads to increased excimbility and a broadening of the action potential by reducing specific Kquot cur rents allowing greate in ux into the presynaptic terminal with each action potential 29 The greater Ca2 in ux could contribute to the enhanced transmitter release Follong the lead of Paul Greengard who had proposed that cAMP produces its action in the rain through the CAMPdependent protein kinase PKA Marc Klein andI suggested that cAMP may cause phosphorylation of this Kquot channel by activating PKA 29 In collaborative exper iments with Paul Greengard in 1980 Castel lucci Schwartz and I found that the active camlytic subunit of PKA by itself produced broadening of the action potential and enhance ment of glummate release 30 Conversely the specific peptide inhibitor of PKA PKI Sensory Neuron Long Term Short Term K Channels 232 Channels Motor Neuron ffects of short and longterm sensitization on the monosynaptic component of the 3 E gr withdrawal reflex of Aplysia In shortterm sensitization lasting minutes to hours a single tail shock causes a transient release of serotonin that lea s to covalent modification of preexisting proteins The serotonin acts on a transmembrane serotonin receptor to activate t e enzyme adenylyl cyclase AC which converts ATP to the second messenger cyclic AMP In turn cAMP recruits the CAMPdependent protein kinase A PKA bindin to the regulatory subunits 39 39 rom and free the catalytic subunits ovals These subunits en phosphorylate substrates channels and exocytosis machinery in the presynaptic termi to rise and persist for several minutes T can then translocate to the nucleus and recruit the mitogenactivated protein kinase MAPK In the nucleus PKA and MAPK phosphorylate and activate the cAMP response elementbinding CREB protein and remove the repressive action 0 CREE2 an inhibitor of CREB I CREE1 in turn activates several immediateresponse genes including a ubiquitin hydrolase necessa for re u lated proteolysis of the regulatory subunit of PKA Cleavage of the inhibitory regulatory subunit results in persistent activity of PKA leading to persistent phosphorylation ofthe substrate proteins 0 A secon immediateresponse gene activated by CREE1 is CEBP which acts both as a homodimer and as a eterodimer with activating factor AF to activate downstream genes including elongation factor 1a EFIoL that lead to the growth of new synaptic connections wwwsciencemagorg SCIENCE VOL 294 2 NOVEMBER 2001 blocked the actions of serotonin These findings provided direct evidence for the role of PKA in shortterm presynaptic facilitation 31 32 elegant series of experiments Steven Siegelbaum Joseph Camar 0 an ic el Schuster identified a novel Kquot channel the type Kquot channel and showed that it too could be modulated by cAMP 33 and that PKA could act on the Stype Kquot channel di rectly 34 Later Byrne showed that serotonin also modulates a delayedrectifier Kquot 32 The Stype channel mediated the increase in excit ability with a minor contribution to broadening whereas the delayedrectifier Kquot channel con tributed little to excimbility but had a major role in spike broadening Finally Hochner Klein and Iiand independently Jack Byrne and his colleaguesishowed that in addition to spike broadening serotonin also enhanced release by an as yetunspecifred action on the release ma chinery Thus serotonin leads to an increase in presynaptic cAMP which activates PKA and leads to synaptic strengthening through en ced transmitter release produced by a com bination of mechanisms Fig 3 32 CREBI mediated transcription By sub stituting puffs of serotonin the transmitter released by tail shocks for the tail shocks mselves Samuel Schacher Pier Giorgio Montarolo Philip Goelet and I modeled sen sitiza ion in a cul e dish consisting of a single sensory cell making synaptic connec tions with a single motor cell 35 We were able to induce both short and longterm fa cilitation and found as with the intact animal that the longterm process differed from the shortterm process in requiring the synthesis of new proteins We used this cell culture to ask What genes are activated to convert the shortterm to the longterm process and what genes are essential for the maintenance of the longterm process We found that five spaced puffs of serotonin simulating five spaced shocks to the tail acti vate PKA which in turn recruits the mitogen activated protein kinase MAPK Both translo cate to the nucleus where they activate a tran scriptional cascade beginning with the tran scription factor CREBl the cAMP response element binding protein 1 so called because it binds to a cAMP response element CRE in the promoters of mget genes Fig 3 The first clue to the impormnce of CREB in longterm mem ory was provided in 1990 by Pramod Dash and Bin 39 ochner 36 They injected into the nucleus of a sensory neuron in culture Oligo nucleotides carrying the CRE DNA element thereby titrating out CREB This treatment blocked longterm but not shortterm facilim tion Fig 3 Later Dusan Bartsch cloned Aply sia CREBla ApCREBla and showed that injection of the phosphorylated form of this transcription factor by itself could initiate the longterm memory process Downstream from ApCREB 37 Cristina Alberini and Bartsch 1033 1034 found two additional positive transcription Tag 8 SCIENCE39S COMPASS liert featrrres are leamed Memory suppressors the mod ulators the CAAT box nhancer brn mg pmr may allow for ulation ofmemory stop tein ApCEBP and activation faraor ApAF age by emotional stimuli as occurs in flash 33 39 CREBJ activates this set of immedi bulb memoriesquot memories of emotionally L39 L 39 A 39 39 a ifa stream genes to give rise to the growth of new 39 connections Fig 3 36 40746 As Orai 39l y Mary Chen havioral memory 45743 As the memory fades the connections retract over time A type rcal sensory neuron in the intact Apbsx39u has about 1200 synaptic varicosities Following longrlielm sensitization the number more than doubles to about 2600 with time the number retrrms to about 1500 complete pizture had been instantly and powr erfully embed in the brain SynapseSpe ty of LongTerm Fac n The finding of a transcriptional cascade ex plained why longrterm memory requires new protein synthesis immediately after training many different target cells Shonrlierm s ynapr tic changes are synapserspeci c Since longr changes Thus despite recruitment of nuclear processes longrlierm chan es in s tic fuch 39 n and structrrre are confined only to those synapses stimulated by serotonin How 39 does this come about Martin n7 ley and I fo d that five puffs of serotonin send a signal to the nucleus to ich e send proteins to all terminals however only those rminals that have been mar ed by serotonin can use these proteins productively for synaptic growth Indeed one puff of see rotonin to the previously unstimulated sync facilitation induced at the other site by five puffs of serotonin Fig 4B rn r s7 1 p and surprising Inhibitory comtraims In 1995 Eartsch and thus the nucleus is longrterm memory insight into shortrlielm facilitation The stimulus 39 39 l half the t 39A p or are there cellr uces e shonrlierm ss storyAhere are also inhibitory constraints on biological mechanisms that maintain the sync functions Fi 4C Whe actrng alone it pror memory 49 Iongrlienn synaptic facilitation apse specificity of longrlierm facilitation idesa l i synapserspeci c enhancement 1 39 39 39 T 39 39 Kelse Martin ofsynaptic strength which contributes to shone er genes h f cultured u cell with a bi lrr term memory lasting minutes When acting in pressor genes Fig 3 One of these the ham cating axon with two motor neurons forming conjunction with the activ of CREE inilir scri 39on r A CREE can rep ess twowidel se atedsynapses ig 4A1nthis amd by a longrlielm process in either that sync CREBrla mediated transcription relieving culture system a single puff of serotonin ape se or in any er s same neur this repression lowers the threshold for the longrlielm process Thus during longrlErm memory storage a tightly controlled cascade of ene activation is swimhed o g n with memoryrsuppressor geres plied to one synapse produces transient facilir 39 seonly asexpemd 50 51 Five u 39 39 produces longrlasting facilitation 72 hours also remitted to the s39 lated synapse Fig ry storage presumably to ensure that only sale A suicn ng synapu39c facilitation w some sy 39 n57 A This phommicrogtaph shows branches The flow of me seromnin can monr wi e dye fast green From 50 Longrlerm facilitan39on is synapserspecific and branch by me sn39mulus mat uat s facilitau39on shown in B This synapserspecific facilitau39on rs not evident at less r v B can be capurred at anomer e are shorHerm process Five puffs of setomnin ap ied at me iniu39au39on site cell A produce a synapserspecific 4B Th39 tion requires CREE and also leads to structural Initiation Capture 5 x 51 QSHT Synuranium Pullman OIII A on 12 2a synpile cptun out a EPBP Amplltude Change is 2 Time h of seromnin r r term memo s Bun 2 NOVEMBER 2001 VOL 294 ron the stimulus locally marks those synapses at which it occurs Th mar ed synapse can then utilize the proteins activated by CREE for synaptic growth to produce a persistent change in synaptic strength Thus the logic for the long4ierm process involves a longrrange inte gration that is different from the shonrlierm c Tun Dilluni Functions of mo snonTunn Prue 1 ShunTenn Mammy slurgo WMQQQ 2 writing tcrttr Clpmuvf LamTm mmmammNNSmpses 99gt Q om 50 2 Two effects of shorHerm tacilr39tan39on shone mrage when acb39ng by itself and marking of me specitic synapse m which it is applied for subsequent mpmre of are proteins wid1 tive pulses m anomer set of terminals SCIENCE wwwsciencemagorg process In the longterm the function of a synapse is not only determined by the history of usage of that synapse It is also determined by the smte of the transcriptional machinery in the nucleus How does one puff of serotonin mark a synapse for longterm change For structural changes to persist local protein synthesis is required 51 Oswald Steward s inrpormnt work in the early 1980s had shown that den drites contain ribosomes and that specific m s are transported to the dendrites an translated there Our experiments showed that one function of these locally translated mRNAs was to stabilize the syn apsespecific longterm functional and struc tural changes Neurotransmitter regulation of local pro tein synthesis These studies thus revealed a new fourth type of synaptic action mediated by neurotransmitter signaling Fig 5 Three of these four have emerged at least in part from the study of learning and memory First in 1951 Katz and Fatt opened up the modern study of chemical transmission with their dis covery of ionotropic receptors that regulate ion ux through transmittergated ion chan nels to produce fast synaptic actions lasting milliseconds 53 Second in the 1970s metabotropic receptors were found to activat secondmessen er athways such as th cAMPPKA pathway to produce slow syn aptic activity lasting minutes 54 As we have seen in Aplysia this slow synaptic ac tion can regulate transmitter release thereby e e Fig 5 Four consequences of the action of neurotransmitters 1 Transmitter activation of a li gandgated ion channel leads to a rapid synaptic action lasting milliseconds Z Transmitter acti vation of a seve transmem rane recepto leads to the translocation of the kinase to the nucleus and to activation of transcription producing a per sistent synaptic action 4 rans synthesis apsespecific facilitation wwwsciencemagorg SCIENCE VOL 294 2 NOVEMBER 2001 SCIENCE39S COMPASS contributing to shortterm memory for sensi tization Third an even more persistent syn aptic action lasting days results from repeat ed action of a modulator transmitter such as nucleus where they activate a cascade of gene induction leading to the growth of new synaptic connections This of course raises the problem of synapse speci ficity that we have considered above Our experiments in the bifurcated culture system revealed a novel fourth action of neurotrans mitters the marking of the synapse and the regulation of local protein synthesis which contributes to the establishment of synapse specifrc longterm facilitation Explicit Memory I have so far considered only the simplest cases of memory storageithose involving re ex esia form called implicit or procedural mem ory Implicit memory is memory for perceptual and motor skills and is expressed through per formance without conscious recall of past epi sodes In contrast the memories we hold near and dear are called explicit or declarative memories These memories require conscious recal and are concerned with memories for people places objects and events Explicit memory 39 vol es a specialized anatomical sys tem in the medial temporal lobe and a structure deep to it the hippocampus Fig 6A 21 55 56 How is explicit memory stored Louis Flexner Bernard Agranoff Sam Barondes and A Dialog Between Genes and Synapses Larry Squire had shown that explicit memory like implicit memory has a shortterm phase that does not require protein synthesis and a longterm phase that does 55 Are these two components of memory storage also represent ed at the cellular level What rules govern explicit memory storage A decade ago when I reached my 603911 birthday I gathered up my courage and re turned to the hippocampus Mario Capecchi and Oliver Smithies by achieving targeted gene ablation in mouse embryonic stem cells provided a superb genetic system for relating individual genes to synaptic plasticity on the one hand and to complex explicit memory storage on the r Mice have a medial temporal lobe system including a hippocam pus that resembles that of humans and they use their hippocampus much as we do to store memory of places and objects Fig 6A Although we still do not lmow much about how information is transformed as it gets into represenmtion of extrapersonal spaceia cogni tive map of spaceiand lesions of the hip pocampus interfere with spatial tasks 5 7 Moreover in 1972 Terje Lomo and Tim Bliss discovered that the perforant path a major path way within the hip ocampus exhibits activity dependent plasticity a change now called long term potentiation LTP Fig 6B In the CA1 region of the hippocampus LTP is induced postsynaptically by activation of an NMDA receptor to glutamate In the late 1980s Richard Morris found that blocking the NMDA receptor pharmacologically not only interfered with LTP but also blocked memory storage 58 59 This earlier work on LTP in hippocampal d most effectively with repeated stimuli Fig 1B So when Uwe Frey Yan You Huang Peter Nguyen and I turned to the hippocampus we examined whether LTP chan ed with re peated stimulation 60762 and found that hip pocampal LTP has phases much like facilita tion in Aplysia The early phase of duced by a single train of stimuli lasts only 1 to 3 hours and does not require new protein syn thesis 62 it involves covalent modifications of preexisting proteins that lead to the strength ening of preexisting connections similar in principle to shortterm facilimtion in Aplysia By contrast repeated trains of electrical stimuli produce a late phase of LTP which has prop erties quite different from early LTP and similar to longterm facilitation in Aplysia Fig 6B The late phase of LTP persists for at least a day and requires both translation and transcription The late phase of LTP like longterm storage of implicit memory requires PKA MAPK and CREB and appears to lead to the growth of new synaptic connections Fig 6C 60769 1035 The bztz phase ofLTP Md explicit meme ory To explore further the specific role of t g genic mice the reduction i hi pocampal activity was paralleled by a significant 39 late while basal s tic transmission and early LTP r mained unr changed Most interesting this de cit in the hase of LTP was paralleled by behave a SCIENCE39S COMPASS ent within minutes E a of the space by the coo population ofplace cells which is normally stable for days The same cell will have the same firing field each time the animal is NMDA receptor antagonist 72 When placed 39 nmen the animals with blocked the strength of the synapsF longterm stabilization o e er a selective deficit that affects only the late phase of LTP causes a he ioral deficits in wquot A longrllerm memory for extrapersonal space whereas 1 39 and shorHlerm memory are unimpair Fig 7 A andB Thus in the storage of explicit memory of extrapersonal 39 malian hippocampus PKA Using the RAB mice we could now ask l L A 39 39 39 PK ire naling have difficulty with space 70 We were in uenced by the classic studies ofJohn O39Keefe and John Dosu39ovsky who In 1971 When now laced in a second environment a new map is formediagajn in minutes 39n part from some ofthe cells that made up the map ofthe first environment and in from p amidal cells that had been silent previously 71 me that the formation ofa new 7 the space and once learned space is retained for days and weeks To first the late phase of LTP were important for the longrlErm stabilization of this map Cliff Kane tros Robert Muller Hawkins and I simply L 39 an discovered that the pyramidal cells of the blocked pharmacologically 1mm a C A l min orallyin mquot collateral pIhwy MaulMm Forbmnfplmwly B 3 m Modulatoryinfut E m Late LTF 4 trains hl amme 5 ca 5 am smallt NMDA amp Early LTP I lulu wIII39Ill E ul 0 I H 30 an In 120 150 I 210 Tllm min MFA in the longrllerm stability of place cells Since only the late phase of LTP requires PKA Alex Rotenberg uller Abel Hawkins and I returned to the RAB transr genic mice with diminished PKA activity and a 39 inished form TP 73 If reduced dim of late L activity of PKA affected the stability of place s that is stable for at hour However the cell eld should be unstable ecorded 24 hours his is precisely r T we found Fig 7C The f ongr term instability in the spatial map an deficit in l gellerm memory paralleled the deficit in the phase of LTP suggested 7 CREE2 CHE J CHE 1035 Fig 6 Longrlenn potenn39an39on LTP in me hippocampus A Three major pamways each of which gives rise a LTP no me gyrus The mony belpathway tormed by me atons ot die ganule cells ot Ihp dpmalp m 39 39 39 CA3 ot die hi pocampus The Scha el collatetal pathway connects die pyramidal cells ot die CA3 region wiui die pyramidal cells in die CA1 region ot die hippocampus B The early and late phases ot LTP in die SChaffer collateral paniway A single nain ot sn39muli tor one second at 100 Hz elicits an early LTP an tour nains at minute intervals elicit are late phase ot LTP The ea y the later lr nain of acn39on potenn39als inin39ates early LTP hy acn39van39ng NMDA recepmts 632 messengers Wim re eated uains of acn39on potenn als illusuated here are GaZT influx also recruits an adenylyl cyclase AC which acn39vates me cAMPdependent protein kinase The kinase is nans mad m are nucleus 39 39 mm acu39vates targets 5 E e F E P wry inputs In addin39on mere are consuaints in red mat inhibit Rprrn al nf 39 A model tor are late phase ot LTP in me SChaffer collateral pamway A single 2 NOVEMBER 2001 VOL 294 old tor LrLTP and enhances merriory smrage SCIENCE www3CienCemagorg mediated gene activation and the synthesis of new protein might be essential for the stabili zation of the spatial map Naveen Agnihotri Kentros Hawkins and I tested this idea and found that inhibiting protein synthesis indeed destabilized the place elds in the longterm much as does inhibiting PKA 81 In the course of this work Kentros and Agnihotri found remarkably that as is the case with explict memories in humans a key feature in the stabilization of PKA and protein synthesisdependent phase of mem ory is attention 82 When a mouse does not attend to the space it walks through the man forms but is unstable after 3 to 6 hours When the mouse is forced to attend to the space however the map invariably is sta ble for days Inhibitory constraints on explicit rnernory Recently we 74 and others 75 have found that the threshold for hippocampal synaptic plasticity and memory storage is determined a ation 74 76 To determine whether the endogenous Caz sensitive phosphatase cal cineurin acts as a constraint on this balance we inhibited calcineurin and examined the effects on synaptic plasticity and memory Isabe le Mansuy Gael Malleret inder Tim Bliss and I found that a transient reduction of calcineurin activity re sulted in facilitation of LTP both in vitro and in vivo 74 This facilitation persisted for Fig7 A The protocol A for context oondition ing consists of e 0 sure to the context fol Trnlnlng mals are then tested 1 hourand 24 hours after training From 70 B1 Mutant mice that express the RAB gene in the hi ocampus blocking the action of PKA have a selective defect for longterm contextual memory Mice that RAB were conditioned to freeze to the con After beooming familiar with the con text the mice heard a sound and received a shock through the elec trified grid in the floor RAB 888 ol lime freezing 5 min 3 0 lmmLeumlng space with shock and to freeze when placed in the box at a future time These mice had good shortterm memory at 1 hour for freezing to context but at 24 hours they no longer froze to context indicating a defect in a form of longterm explicit declarative memory that requires the hippocam pus BZ Wildtype mice exposed to anisomycin an inhibitor of wwwsciencemagorg SCIENCE 4 Exposure to Conlexl Tem1h SCIENCE39S COMPASS several days in the inmct animal and was accompanied by enhanced learning and strengthening of short and longterm mem ory on several spatial and nonspatial tasks requiring the hippocampus These results to gether with previous findings by Winder and Mansuy showing that overexpression of cal cineurin impairs PKAdependent components of LTP and memory 76 77 demonstrate that endogenous calcineurin can act as a neg ative regulator of synaptic plasticity learn ing and memory Fig 6 An Overall View Our studies of the storage component of memory the molecular mechanism whereby information is stored have led to two general conclusions irst our research suggests that the cel lular and molecular strategies used in Aply sia for storing short and longterm mem ory are conserved in mammals and that the same molecular strategies are employed in both implicit and explicit memory storage With both implicit and explicit memory there are stages in memory that are encoded as changes in synaptic strength and that correlate with the behavioral phases of short and longterm memory The short term synaptic changes involve covalent modification of preexisting proteins lead ing to modification ofpreexisting synaptic connections whereas the longterm synap tic changes involve activation of gene ex Context Condlllonlng A Onsel al Sound 05 Onsel of Shock US Context Condltlonlng Is Selecllvely lmpalred In RAB Mlce 32 3 WT Anisomycin I RAB Wildtype mice Teal 24 n lmm Learning Tenn n VOL 294 2 NOVEMBER 2001 pression new protein synthesis and the formation of new connections Whereas shortterm memory storage for implicit and explicit memory requires different signal ing longterm storage of both implicit and explicit memory uses as a core signaling pathway PKA MAPK and CREBl At least in the mouse additional components are likely recruited In both implicit and explicit memory the switch from shortterm to longterm memory is regulated by inhib itory constraints Second the study of learning has revealed new features of synaptic transmission and new cellbiological functions of synaptic sig naling For example different forms of learn ing recruit different modulatory transmitters which then act in one of three ways i They activate secondmessenger kinases that are transported to the nucleus where they initiate processes required for neuronal growth and longterm memory ii they mark the spe cific synapses for capture of the longterm process and regulate local protein synthesis for stabi lization and iii they mediate in ways we are just beginning to understand attentional processes required for memory formation and recall Most important the study of longterm memory has ma e us aware of the extensive dialog between the synapse and the nucleus and the nucleus and the synapse Fig 5 In the longterm process the response of a syn apse is not determined simply by its own Same Co lext 1 hour and 24 hours Place Cell Map Slablllly Is Dependent Upon PKA El Saline RAB El WT I Anlsamydn 04 I RAB 2 g 03 ponm g 392 E a 01 a Tom 24 n 1 h 24 h protein synthesis during training show a similar defect for longterm when tested 24 hours after conditioning From 70 C Place cell stability for RAB and wildtype mice RAB mice with a defect in PKA and late LTP form place fields that are stable at 1 hour These fields are not stable at 24 hours From 73 80 1037 1038 history of activity as in shortterm plastici ty but also by the history of transcriptional activation in the nucleus I smrted this essay by pointing out that 40 years ago at the be innin f my career I thought that a reductionist approach based on the use of a simple experimenml system such as Aplysia might allow us to address fundamenml questions in learning and memory That was a leap of faith for which I have been rewarded beyond my fondest hopes Still the complexity of explicit memory is formi ble and we have only begun to explore it We as yet lmow little about the molecular mechanisms that initiate or smbilize the synaptic growth associated with longterm memory What signa 39 molecules lead to the cytoskeletal rearrangements during synaptic remodeling How do they relate to the olecules that control synapse formation dur ing development In addition we have here only considered the molecular mechanisms of memory storage The more dif cult part of memoryiespecially explicit memoryiis a systems problem e still need to seek answers to a family of impor tant questions How do different regions of the hippocampus and the medial temporal lobei the subiculuni the entorhinal parahippocampal and erirhinal corticesiinteract in the storage of explicit memory How is information in any of these regions transferred for ultimate consol idation in the neocortex We do not for exam ple understand why the initial storage of long term memory requires the hippocampus whereas the hippocampus is not required once a memory has been stored for weeks or months 21 78 What critical information does the hippocampus convey to the neocortex We also lmow very little about the nature of recall of explicit declarative memory a recall that re uire c nscious effort These systems prob ems Will require more the bottomsup approach of molecular biology They will also require the topdown approaches of cognitive psychology neurology and psychiatry Ulti mately we will need syntheses that bridge the two approaches Despite these complexities these and oth er questions in the io o earning no doubt will be vigorously addressed in the near future For the biology of the mind has now captured the imagination of the scientific community of the 21st century much as the biology of the gene fascinated the scientists of the 20th century As the biological study of the mind assumes the central position within biology and medicine we have every reason to expect that a succession of brain scientists will be called to Stockholm and honored for their own leaps of faith 81 References and Notes 1 E R Kandel W A Spencer Ann NY Acad Sci 94 570 1951 E R Kandel W A Spencer Physiol Rev 48 65 1958 2 NOVEMBER 2001 SCIENCE39S COMPASS 3 W T Frazier E R Kandel I Kupfermann R Waziri and E Coggeshall j NeuropIgSiol 30 1288 1957 E R Kandel Cellular Basis of Behavior An Inuoducr rion ro Behavioral Biology Freeman San Francisco 1976 5 H Pinsker I Kupfermann V Castellucci E R Kandel Science 167 1740 1970 6 H M Pinsker W A Hening T J Carew E R Kandel Science 182 1039 1973 Carew H M Pinsker E R Kandel Science 175 451 1972 8 Frost V E Castellucci R D Hawkins E R 5 i Kandel Proc Nari Acad Sci USA 82 8266 1985 9 V E Caste ucci H Blumen eld P Goe et E R Kane delj Neurobiol 20 1 1989 10 H Ebbinghaux Memoiy A Contribution to Experir mental Psychology Dover New York 1885 reprian ed 1963 11 L B Elexner J B Elexner Proc Nari Acad Sci USA 55 359 1955 12 V Castellucci H Pinsker I Kupfermann E R Kandel Science 157 1745 1970 13 J Byrne V Castellucci E 37 1041 1974 14 J H Byme V E Castellucci T J Carew E R Kandel j Neurophysiol 41 402 1978 5 R D Hawkins V E Castellucci E R Kandel Neue ropigxioi 45 304 1981 R D Hawkins V E Castellucci E R Kandel Neur ropIgSiol 45 315 1981 17 J H Byme V E Castellucci E R Kandel Neuroe physiol 41 418 1978 E R Kandel The Behavioral Biology of Aplyxia A Conrriburion ro rhe Comparan39ve Study of Opixrhor branch Molluxcx Freeman San Francisco 1979 19 S R Cajal Proc R S c ndon 55 444 1894 I Kupfermann V Castellucci H Pinsker E R Kandel Science 157 1743 1970 21 B Milner L R Squire E R Kandel Neuron 20 445 1998 22 J H Schwaru V E Castellucci E R Kandel Neue ropIgSiol 34 939 1971 23 H Cedar E R Kandel J H Schwaruj Gen Physiol 50 558 1972 24 H Cedar J H Srhwaru j Gen Physiol 60 570 1972 25 D L Glanzman er al j Neurosci 9 4200 1989 S L Mackey E R Kandel R D Hawkins 1 Neurosci 9 4227 1989 M Brunelli V Castellucci E R Kandel Science 194 1178 1976 28 E R Kandel M Brunelli J Byrne V Castellucci Cold Spring Harbor Symp Quanr Biol 40 455 1975 29 M Klein E R Kandel Proc Natl Acad Sci USA 77 5912 1980 V E Castellucci eralProc Nari Acad Sci USA 77 7492 1980 31 V E Castellucci A Nairn P Greengard J H Schwaru E R Kandel Neurosci 2 1673 1982 J H Byrne E R Kandel j Neurosci 15 425 1995 S Siegelbaum J S Camardo E R Kandel Nature R Kandel Neurophysiol w 0 1010 wN S Camardo S A Siegelbaum E R Kandel Narure 313 392 1985 35 P C Montaroo er al Science 234 1249 1986 P K Dash B Hochner E R Kandel Narure 345 718 1990 D Bartsch A Casadio K A Karl P Serodio E R Kandel Cell 95 211 1998 38 C Albeimi M Cuhirardi R MeII E R Kandel Cell 76 1099 1994 D Bartsch et al Cell 103 595 2000 S Schacher V F Castellucci E R Kandel Science 240 1557 1988 41 B J Bacskai er al Science 260 222 1993 42 K C Martin er al Neuron 18 899 1997 3 Kaang E R Kandel S G N Grant Neuron 10 427 1993 D L Glanzman E R Kandel S Schacher Science 249 799 1990 45 C H Bailey P Montarolo M Chen E R Kandel S Schacher Neuron 9 749 1992 C H Bailey E R Kandel Annu Rev PigSiol 55397 19 93 mm mmbb 850 a no mm mm mm WWV 2 mam m g m WWV m w 2 R G M Mom Narure 319 774 U Frey YrY Huang E R Kandel Science 260 1661 J Yin T Tully Curr E Engert T Bonhoeffer Narure 399 66 T Abel er al Cell 88 515 1997 575 1 R D Bliuer er al Science 280 1940 1 I M Mansuy M Mayford B Kacob E R Kandel M E 9 D C Winderl M C H Bailey M Chen Proc Nari Acad Sci USA 85 2373 1988 euroxci 9 1774 1989 8 7 N o Bartsch er al Cell 83 979 1995 O Steward Neuron 18 9 1 9 7 Eatt B Kau j Physiol Lond 115 320 1951 1 1975 P Greengard Nature 260 10 B J Bacskai er al Science 260 222 1993 V F Castellucci T J Carew E R Kandel Science 202 1305 1978 G N Grant er al Science 258 1903 1992 T V Bliss T Liamo j Physiol 232 331 1973 s E Anderson G S Lynch M Baudly 1985 1 993 R A Nicoll R C Malenka Ann NY Acad Sci 868 5151999 P V Nguyen T Abel E R Kandel Science 265 1104 1994 os akov H Golan E R Kandel S A V Y B l h Siegelbaum Neuron 19 635 1997 L ow E R Kandel S A Siegelbaum Ma Zabl Narure Neurosci 2 24 1999 7 Opin Neurobiol 6 264 1996 1999 I del The Hippocampux a a Cognin39ve Map Clarendon Press Oxford 1978 C Kentros er al Science 280 2121 1998 A Rotenberg T Abel R D Hawkins E R Kandel R U Muller j Neurosci 20 8096 2000 998 Bach Cell 92 39 19 8 Mansuy M Osman T M Moallem E R Kandel Cell 92 25 1998 L Sq ir S ZolarMorgan Science 253 1380 1 rost V E Castellucci Modulation of memory storage Larry Cahill1 and James L McGaugh2 For several decades the concept of modulation of memory storage has significantly influenced research investigating neurobiological memory mechanisms New evidence provides additional support for the view that stress hormones released during emotionally arousing situations modulate memory processes Recent experiments have investigated the role of sympathetic adrenomedullary hormones in emotional memory in humans as well as the role of adrenocortical hormones primarily in animal studies Further it is becoming increasingly clear that the sympathetic adrenomedullary and the pituitary adrenocortical systems interact to modulate memory storage Other new evidence emphasizes the role of peripheral influences to the brain on emotional memory as well as the critical contribution of the amygdaloid complex in modulation of memory by emotional arousal Addresses 1vQCenter for the Neurobiology of Learning and Memory and 9Departments of Psychobiology and Pharmacology University of California Irvine California 927173800 USA 1email lcahiparkerbiouciedu 2email jlmcgauguciedu Abbreviations APV 2amino5phosphonovalerate GABA yaminobutyric acid NMDA NmethyIDaspartate Current Opinion in Neurobiology 1996 6237242 Current Biology Ltd ISSN 09594388 Introduction Not all memories are retained equally well This fact makes sense from an evolutionary and functional perspec tive because animals including humans would appear to bene t little from having memories for trivial events that are as strong as memories for more important events Thus it makes sense that the brain should have evolved mechanisms for storing information that re ect the degree to which the information is worth storing Systems that regulate information storage are clearly as important to an organisms survival as are those neural mechanisms that store the information The concept of modulation of memory storage has guided extensive research into brain mechanisms of learning and memory over the past 30 years This review highlights some of the more important recent developments in this research area and focuses on those systems that appear to be most critical for memory modulation namely endogenous stress hormones released during emotional learning situations and the amygdaloid complex 237 The concept of a memory modulatory system The concept of memory storage modulation grew espe cially from three related discoveries First recently formed memories are susceptible to postlearning in uences eg drug injections brain stimulation for a limited time after they are formed 1 Second many postlearning treatments have the potential to either enhance or impair modulate memory depending on the experimental conditions 2 Finally some posttraining treatments eg injection of sympathetic stress hormones affect memory storage even though they do not directly affect the brain 3 5 From these facts one may infer the existence of endogenous systems that in uence memory storage processes but do not serve as the neural bases of memory storage Compelling evidence that nervous systems contain memorymodulatory mechanisms came from work on invertebrate preparations for discussion see 6 There are several important characteristics of a memory storage modulatory system 78 Perhaps most critically the role of a memory modulatory system is time limited with the passage of suf cient time a modulatory system can be inactivated with no loss of retrieval of stored memories Furthermore such a system can either enhance or impair memory depending on the learning conditions Lastly whereas memory storage mechanisms may serve only speci c forms of memory a memory modulatory system should be capable of in uencing different forms of memory These conclusions and implications are strongly supported by recent ndings Stress hormones I catecholamines Modulation of memory storage has been most exten sively studied in experiments examining the effects of catecholamine stress hormones A very large body of evidence from animal studies indicates that adrenergic stress hormones released peripherally during emotionally arousing events modulate the storage of memory for the events 910 The ndings of two recent studies investigating the role of catecholamines in memory in humans are consistent with the ndings of research with animals In both studies the enhancing effects of arousal on memory were impaired by B adrenergic blocking drugs Cahill et a 11quot studied the effect in healthy volunteers of the Bblocker propranolol on longterm 1 week memory for either an emotionally neutral story or a closely matched but more emotionally arousing story The drug selectively impaired memory for the emotionally arousing story The effect of the drug could not be attributed to effects on attention or sedation nor could it be attributed to a reduction of the emotional reaction of the subjects to the story The ndings support 238 Cognitive neuroscience the view that modulation of memory by emotional arousal depends on the activation of Badrenergic receptors even though such activation is not critical for normal memory under nonemorionally arousing circumstances A second study by Nielson and Jensen 12quot employing physically induced arousal muscle tension to enhance memory for written material reported that young subjects healthy elderly subjects and elderly hypertensive subjects taking nonBblocker medications all showed enhanced retention performance resulting from the arousal manip ulation In contrast elderly hypertensive subjects taking Bblocker medication showed no evidence of enhanced retention with arousal Although this study differs from that of Cahill at a 11 in several key respeCts eg very different retention intervals chronic versus acute dosing both studies support the general conclusion that the enhancing in uence of arousal either emotionally or physically induced on memory depends on Badrenergic receptor activation As noted above these ndings are consistent with studies examining the role of adrenergic activation in memory in animals Other recent work implicates the dopamine system of the prefrontal cortex in modulating memory storage Recording from single neurons in the prefrontal cortex of monkeys performing a shortterm memory task Williams and GoldmanRakic 13quot found that the spatially de ned memory elds of the cells were modi ed by iontophoretic application of antagonists to D1 dopamine receptors More speci cally D1 antagonists increased the size of these memory elds implying that D1 receptors modulate shortterm and possibly longterm mnemonic processing This same group has reported effects of D1 agonists and antagonists on shortterm memory in monkeys 14 An interesting related study reported that lesions of the central amygdaloid nucleus attenuated a stressinduced increase in dopamine turnover in the prefrontal cortex 15 Considered together these studies suggest that the effect of stress on memory may depend on amygdala in uences on Dlrelated activity of the prefrontal cortex Glucose and memory Epinephrine is the stress hormone most extensively implicated to date in memory modulation In recent years considerable evidence has suggested that epinephrine may affect memory at least in part via its well established effects on blood glucose levels For example when admin istered systemically after training both epinephrine and glucose induce invertedU doseresponse enhancement of memory 1617 Glucose has also been shown to enhance memory in elderly humans and in Alzheimer s disease patients 1819 Recent work has focused on the mechanisms by which glucose affects memory The ndings of Kopf and Baratti 20 support the view that the effects of glucose on memory depend on a central cholinergic mechanism They found that central but not peripheral cholinergic manipulations interact with glucose to affect memory subeffective doses of centrally acting cholinergic antag onists impair and agonists augment the action of glucose on memory Related to this Gold and his colleagues 21 found that both systemic and intraseptal injections of glucose augment the release of acetylcholine in the hippocampus It is of particular interest that systemic glucose injections augmented hippocampal acetylcholine release only in a training situation that normally induces acetylcholine release 21 The role of glucose in modulating memory storage is prob ably speci c to learning situations in which epinephrine is released However emotional arousal can in uence memory in the apparent absence of epinephrine release as for example in situations where emotion reduces heart rate 22 Thus in emotionally arousing situations in which epinephrine is not released it seems likely that Badrenergic receptor activation by norepinephrine may be critical to memory enhancement 11quot Because epinephrine is not released in such situations glucose levels are not increased and thus are not likely to in uence memory storage Stress hormones ll corticosteroids In addition to inducing the release of adrenomedullary hormones epinephrine and norepinephrine emotionally stressful events also release adrenocortical hormones Unlike adrenomedullary stress hormones adrenocortical hormones readily enter the brain 23 It is also well established that corticosterone the principle adrenocorti cal hormone in the rat acts at two distinct receptors the mineralocorticoid or type I receptor and the glucocorti coid type II receptor 24 Most recent work into the effects of adrenocortical hormones on memory has focused on the impairing effects of high sustained doses of these hormones produced by multiple injections or chronic stress For example Newcomer et a 25 found that fourday treatment of human subjects with dexamethasone impaired memory In another study Bodnoff et al 26 reported that chronic corticosterone or stress treatment impaired learning of mid age rats in a water maze task The invertedU relationship between dose and retention performance is a well established outcome in studies of drug and hormone action on memory The recent demonstrations of an invertedU relationship between corticosterone levels and electrophysiological activity in the hippocampus thought to be related to learning 2728 suggest that corticosteroid treatments should enhance performance under appropriate conditions such as in studies using lower doses of corticosterone agonists This implication has been supported by ndings of several recent experiments 29 30quot injections of low doses of the synthetic corticoid dexamethasone enhanced retention of one trial avoidance learning and attenuated de cits in watermaze learning produced by adrenalectomy 29quot Because dexamethasone at this dose acts primarily at the glucocorticoid receptor these results indicate that activation of the glucocorticoid receptor which occurs primarily during periods of stressinduced elevations of corticosterone concentration underlies the observed memory enhancement How these ndings relate to the currently more widespread view that glucocorticoid receptor activation typically chronic is related to im paired cognitive functioning see 23 remains to be determined It seems likely that glucocorticoid receptor activation may induce either memory enhancement or memory impairment depending on the degree of receptor activation as well as interactions between glucocorticoid and mineralocorticoid receptors 2431 Neuronal death most studied in the hippocampus probably underlies the memory impairment produced by chronic corticosterone treatments 3233 Recent ndings indicate that adrenocortical suppression blocks the memory enhancing effects of epinephrine and amphetamine 34 These ndings are consistent with con siderable earlier evidence indicating that adrenomedullary and adrenocortical systems interact during stressful learn ing situations to modulate memory the effects of adreno medullary hormones depend on the levels of adrenocorti cal hormones 31quot However the speci c nature of this interaction remains controversial 2431quot Other modulatory influences Many other neuromodulatory substances are released in response to stress including Bendorphin vasopressin adrenocorticotropic hormone substance P and cholecys tokinin The ndings of research investigating the effects of these hormones on memory are summarized in several reviews 1031quot353639 Evidence of peripheral nervous system modulation of memory Considerable evidence indicates that memory modulation is initiated by in uences from the PNS to the CNS Most fundamental to this conclusion is the fact that many of the peptide and catecholamine hormones implicated in memory modulation do not readily pass the bloodbrain barrier An early indication of the importance of peripheral in uences on memory came from the nding that periph eral but not central injections of the Bblocker propranolol attenuated the amnesia produced by stimulation of the frontal cortex 37 More recent evidence indicates that the effect of epinephrine on memory is blocked by sotalol a peripherally acting Badrenergic antagonist 4 A number of Studies have suggested that afferents of the vagus nerve mediate the memorymodulating effects of peripherally administered drugs and hormones 3839 A recent study reported that direct electrical stimulation of the vagus can modulate memory storage Clark at a 40 implanted rats with a cuff through which the vagus nerve could be stimulated Stimulation of the vagus immediately Modulation of memory storage Cahill and McGaugh 239 after onetrial avoidance learning enhanced subsequent retention and in an important parallel to drug and hormone studies the stimulus intensity effect on memory had an invertedU relationship Memory enhancement induced by epinephrine is also blocked by injections of a local anesthetic into the nucleus of the solitary tract the brain stem region to which the vagus nerve projects 41 Modulation of memory in the brain sites of action of peripheral influences Amygdaloid complex The amygdaloid complex is the brain region most clearly implicated to date in the modulatory effects of peripheral drugs and hormones on memory It has long been known that direct stimulation of the amygdaloid complex can modulate enhance or impair memory and that the effects of amygdaloid complex stimulation on memory depend on the integrity of adrenal hormones 4243 Recent evidence from humans with selective amygdaloid complex lesions indicates that the effects of emotional arousal on conscious memory depend on the amygdaloid complex 44453946 A consistent body of evidence from animal studies indi cates that lesions of the amygdaloid complex or the stria terminalis a major amygdaloid complex afferentefferent pathway block the effects of many drugs and hormones on memory 8 This is true not only for memory enhancing agents but for amnestic agents as well Several recent studies have con rmed this view Consistent with much earlier work Roozendaal and McGaugh 29 reported that the memorymodulatory effects of glucocorticoids depend on an intact stria terminalis and on the integrity of the basolateral nucleus of the amygdaloid complex 30 However lesions of the central amygdaloid complex nucleus did not block glucocorticoidinduced memory enhancement 30 Flood and colleagues 47 reported that the memoryenhancing effects of both epinephrine and the gut peptide cholecystokinin depend on an intact stria terminalis However they also reported that stria terminalis lesions did not block memory enhancement produced by the cholinergic agonist arecoline suggesting that the effect of this drug on memory does not critically depend on the integrity of the amygdaloid complex This nding conflicts with earlier evidence indicating that stria terminalis lesions attenuate the effects of the cholinergic drugs atropine and oxotremorine on memory 48 As described earlier two important criteria for a memory modulatory system are rst a timelimited involvement in memory and second an ability to in uence different forms of memory A recent report by Packard Cahill and McGaugh 49 suggests the functioning of the amygdaloid complex in learning and memory satis es both criteria Rats were trained in either a spatial hidden platform or cued visible platform water maze task Earlier studies had demonstrated a double dissociation between the hippocampus and the caudate nucleus in the effects of both lesions and injections of dopamine 240 Cognitive neuroscience agonists on the learning of these two tasks In this experiment 49 rats received unilateral injections of Damphetamine into either the hippocampus the caudate nucleus or the amygdaloid complex immediately after training in one of the two tasks Retention of the tasks was tested one day later As expected Damphetamine injection into the hippocampus enhanced retention of the spatial but not cued tasks Conversely Damphetamine injection into the caudate nucleus enhanced retention of the cued but not spatial tasks In contrast Damphetamine injection into the amygdaloid complex enhanced retention of both tasks Furthermore the enhanced retention produced by posttraining D amphetamine injection into the amygdaloid complex was not affected by inactivation of the amygdaloid complex via infusions of lidocaine immediately before the retention test This nding sug gests that locus of change underlying enhanced memory after amygdaloid complex stimulation is not within the amygdaloid complex Packard e a 49 thus suggest that amygdaloid complex stimulation probably enhances memory in spatial and cued water maze tasks by influenc ing memory processes mediated by the hippocampus and caudate nucleus respectively Evidence supporting this view comes from recent experiments using c Fos immunochemistry showing that amygdaloid complex stimulation can functionally affect both the hippocampus and caudate nucleus L Cahill unpublished data 8 both of which have been im plicated in some forms of memory 49quot50 Ikegaya and colleagues 5152 have also recently shown that normal hippocampal longterm potentiation depends on in uences from the basolateral amygdaloid complex They report that both reversible 51 and permanent 5239 lesions of the basolateral amygdaloid complex nucleus attenuate the induction of longterm potentiation in the dentate gyrus in vivo Collectively the studies just described support the view that the amygdaloid complex modulates memory processes in other brain regions especially the hippocampus Recent research has further implicated the amygdaloid complex in the modulation of memory storage by benzodiazepines eg valium The well established ability of these compounds to impair memory consolidation acquires heightened importance given the growing body of evidence for the existence of endogenous benzodiazepines 53 The basolateral but not central amygdaloid complex nucleus has been implicated in benzodiazepineinduced amnesia S4 A recent report supports this view diazepam ie valium causes amnesia in rats for inhibitory avoidance learning when injected into the basolateral but not central amygdaloid complex nucleus 5539 Injection of another benzodiazepine midazolam into the basolateral amygdala also impairs conditioned avoidance responding and conditioned hypoalgesia 56 Amygdaloid complex dependent mechanisms are further implicated in memory modulation by benzodiazepines by the recent obser vation that intraamygdaloid complex injections of the GABAergic antagonist bicuculline block the amnesia induced by systemically administered midazolam 57 Finally recent research further implicates NMDA dependent mechanisms within the amygdaloid complex in memory modulation Liang Hon and Davis 58 found that antagonism of NMDA receptors within the amygdaloid complex with APV produces a dose and timedependent retrograde amnesia for one trial avoidance learning but exerts no effect on retrieval of this task once learned NMDA receptor blockade within the amygdaloid complex has also recently been shown to impair aversively motivated tastepotentiated odor conditioning S9 The septahippocampal system Although the amygdaloid complex is the brain region most implicated to date in drug and hormone mod ulation of memory other brain regions including the septahippocampal system also appear to be involved The timelimited involvement of the septohippocam pal system in long term memory is well established 60 6162 and is consistent with a memorymodulatory role Also the septo hippocampal system possesses a high number of receptors for many known memorymodulating agents such as corticosterone discussed earlier and benzodiazepines 63 Indeed a recent report suggests that the septo hippocampal system is involved in benzo diazepine modulation of spatial memory injection of the benzodiazepine chlordiazepoxide into the medial septum impaired working memory in a radial arm maze task 64 In addition both GABAergic 6566 and opiatergic 67 dependent mechanisms in the septahippocampal system appear to be important in regulating longterm memory storage in a several learning situations Each of these experiments is consistent with a modulatory role for the hippocampus in longterm memory storage Conclusions The concept of memory modulation continues to guide research into the neurobiology of memory This research is helping to reveal how emotional arousal affects longterm memory storage in both animal and human studies Recent research has reinforced the evidence that two factors at minimum are critical to the effects of emotion on memory Badrenergic activation centrally andor peripherally and the amygdaloid complex However the evidence also suggests that complex interactions among many hormones and brain systems regulate the storage of longterm memory Understanding these interactions is now a major goal of studies investigating the modulation of memory storage Acknowledgements This research supported by USPHS grant MH12526 from the National Institute of Mental Health and the National Institute on Drug Abuse JL McGaugh References and recommended reading Papers of particular interest published within the annual period of review have been highlighted as o of special interest 00 of outstanding interest 1 McGaugh JL Timedependent processes in memory storage Science 1966 1531351 1358 2 McGaugh JL Herz MJ Eds Memory Consolidation San Francisco Albion Publishing Company 1972 3 Gold P Van Buskirk R Enhancement and Impairment of memory processes with posttrlal injections of adrenocorticotroplc hormone Behav Biol 1976 16387400 4 IntroiniCollison IB Saghafi D Novack G McGaugh JL Memory enhanclng effects of posttralnlng dlplvefrln and epinephrine involvement of peripheral and central adrenerglc receptors Brain Res 1992 5728186 5 McGaugh JL Affect neuromodulatory systems and memory storage in Handbook of Emotion and Memory Current Research and Theory Edited by Christianson SA New Jersey Erlbaum Associates 1992245 268 6 Krasne FB Extrinsic control of Intrinsic neuronal plasticity an hypothesis from work on simple systems Brain Res 1978 140197216 7 Gold PE McGaugh JL A singletrace two process view of memory storage processes In ShortTerm Memory Edited by Deutsch D Deutsch JA New York Academic Press 1975355 378 8 Packard MG Williams CL Cahili L McGaugh JL The anatomy of a memory modulatory system from periphery to brain In Neurobehavioral Plasticity Learning Development and Response to Brain Insults Edited by Spear N Spear L Woodruff M New Jersey Lawrence Erlbaum Associates 1995149 184 9 McGaugh JL Involvement of hormonal and neuromodulatory systems in the regulation of memory storage Annu Rev Neurosci 1989 12255287 10 McGaugh JL Gold PE Hormonal modulation of memory In Psychoendocrinoogy Edited by Brush RB Levine S New York Academic Press 1989305 339 11 Cahili L Prins B Weber M McGaugh JL Betaadrenerglc u activation and memory for emotional events Nature 1994 371 702 704 Examines the effects of a Badrenergic blocking drug on relatively emo tional and nonemotional memory Presents evidence of a selective role for Badrenergic receptors in memory for emotional events in humans 12 Nielson KA Jensen RA Betaadrenergic receptor antagonist 0 antihypertenslve medications impair arousalinduced modulation of werklng memory In elderly humans Behav Neural Biol 1994 62190200 Provides further evidence see 1 1quot to support the view that the influence of arousal on memory in humans depends on Badrenergic receptor activa tion 13 Williams GV GoldmanRakic PS Modulation of memory fields 00 by dopamine D1 receptors in prefrontal cortex Nature 1995 376572575 An electrophysiological analysis of memory modulation at the cellular level The findings suggest that memory modulation depends on D1 receptor activity within the prefrontai cortex and help explain how dopaminergic agents given systemically influence memory storage 14 Amsten AF Cai JX Murphy BL GoldmanRakic PS Dopamine D1 receptor mechanisms in the cognitive performance of young adult and aged monkeys Psychopharmacology 1994 116143 151 15 Davis M Hitchcock JM Bowers MB Berridge CW Melia KR Roth RH Stressinduced activation of prefrontal cortex dopamine turnover blockade by lesions of the amygdala Brain Res 1994 664207210 Modulation of memory storage Cahili and McGaugh 241 16 Gold PE Modulation of emotional and nonemotional memories same pharmacological systems different neuroanatomlcal systems in Brain and Memory Modulation and Mediation of Neural Plasticity Edited by McGaugh JL Weinberger NM Lynch G New York Oxford University Press 1 99541 74 1397 Messier C White NM Memory Improvement by glucose fructose and two glucose analogs a possible effect on peripheral glucose transport Behav Neural Biol 1987 48104127 18 Parsons M Gold P Glucose enhancement of memory in elderly humans an invertedU dose response curve Neurobiol Aging 1992 131401 404 19 Manning C Ragozzino M Gold P Glucose enhancement of memory In patients with probable senile dementia of the Alzheimer39s type Neurobiol Aging 1993 14523 528 20 Kopf SR Baratti CM Memoryimproving actions of glucose involvement of a central cholinerglc mechanism Behav Neural Biol 1995 62237 243 21 Ragozzino ME Unick KE Gold PE Hippocampal acetylcholine o release during memory testing In rats augmentation by glucose Proc Natl Acad Sci USA 1996 in press Provides evidence for the view that glucose modulates memory by affecting cholinergic processes within specific brain regions Furthermore suggests that the effects of glucose on cholinergic processes are specific to learning situations that themselves activate cholinergic mechanisms 22 Heuer F Reisberg D Vlvld memories of emotional events the accuracy of remembered minutiae Mem Cognition 1990 18496506 23 McEwen BS Sapolsky RM Stress and cognitive function Curr Opin Neurobiol 1995 5205 216 24 De Kloet E Brain corticosteroid receptor balance and homeostatic control Front Neuroendocrinol 1991 1295 164 25 Newcomer JS Craft S Hershey T Askins K Bardgett ME Glucocortlcoidinduced Impairment in declarative memory performance In adult humans J Neurosci 1994 142047 2053 26 Bodnoff SR Humphreys AG Lehman JC Diamond DM Rose GM Meaney MJ Enduring effects of chronic corticosterone treatment on spatial learning synaptic plasticity and hippocampal neuropathology in young and midaged rats J Neurosci 1995 1561 69 27 Bennett MC Diamond DM Fleshner M Rose GM Serum corticosterone level predicts the magnitude of hippocampal primedburst potentlatlon and depression In urethane anesthetized rats Psychobiology 1991 19301 307 28 Diamond DM Bennett MC Fleshner M Rose GM InvertedU relationship between the level of peripheral corticosterone and the magnitude of hippocampal primed burst potentlatlon Hippocampus 1992 2421 430 29 Roozendaal B McGaugh JL The memorymodulating effects of 00 glucocortlcolds depend on an Intact strla terminalls Brain Res 1996 709243 250 See annotation 30 30 Roozendaal B McGaugh iL Amygdalold nuclei lesions differentially affect glucocortlcoldInduced memory enhancement In an inhibitory avoidance task Neurobiol Learn Mem 1996 6518 Together with 29 demonstrates memory


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