The brain decade in debate: III. Neurobiology of emotion

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Braz J Med Biol Res 34(3) 2001

Neurobiology of emotionBrazilian Journal of Medical and Biological Research (2001) 34: 283-293ISSN 0100-879X

The brain decade in debate:III. Neurobiology of emotion

Departments of 1Neurobiology and 2Psychology, University of Hawaii,Honolulu, HI, USA3Computational Neurobiology Laboratory, The Salk Institute, Biological Studies,La Jolla, CA, USA4Departamento de Fisiologia, Faculdade de Medicina de Ribeirão Preto,Universidade de São Paulo, Ribeirão Preto, SP, Brasil5Department of Psychology, University of Wisconsin, Madison, WI, USA6Center for Neural Science, New York University, New York, NY, USA7Center for Neurobiology of Learning and Memory andDepartment of Neurobiology and Behavior, University of California, Irvine, CA, USA8University of Delaware, Neuroscience Program, Newark, DE, USA9Laboratório de Neurobiologia, Departamento de Ciências Fisiológicas,Centro de Biomedicina, Universidade Federal do Espírito Santo, Vitória, ES, Brasil10Laboratório de Neurobiologia 2, Instituto de Biofísica Carlos Chagas Filho,Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil11Laboratório de Fisiologia e Farmacologia do Sistema Nervoso Central,Departamento de Farmacologia, Universidade Federal do Paraná, Curitiba, PR, Brasil

C. Blanchard1,R. Blanchard2,J.-M. Fellous3,

F.S. Guimarães4,W. Irwin5,

J.E. LeDoux6,J.L. McGaugh7,

J.B. Rosen8,L.C. Schenberg9,E. Volchan10 and

C. Da Cunha11

Abstract

This article is a transcription of an electronic symposium in whichactive researchers were invited by the Brazilian Society of Neurosci-ence and Behavior (SBNeC) to discuss the advances of the last decadein the neurobiology of emotion. Four basic questions were debated: 1)What are the most critical issues/questions in the neurobiology ofemotion? 2) What do we know for certain about brain processesinvolved in emotion and what is controversial? 3) What kinds ofresearch are needed to resolve these controversial issues? 4) What isthe relationship between learning, memory and emotion? The focuswas on the existence of different neural systems for different emotionsand the nature of the neural coding for the emotional states. Is emotionthe result of the interaction of different brain regions such as theamygdala, the nucleus accumbens, or the periaqueductal gray matteror is it an emergent property of the whole brain neural network? Therelationship between unlearned and learned emotions was also dis-cussed. Are the circuits of the former the underpinnings of the latter?It was pointed out that much of what we know about emotions refersto aversively motivated behaviors, like fear and anxiety. Appetitiveemotions should attract much interest in the future. The learning andmemory relationship with emotions was also discussed in terms ofconditioned and unconditioned stimuli, innate and learned fear, con-textual cues inducing emotional states, implicit memory and theproperty of using this term for animal memories. In a general way itcould be said that learning modifies the neural circuits through whichemotional responses are expressed.

CorrespondenceC. Da Cunha

Laboratório de Fisiologia e

Farmacologia do SNC

Departamento de Farmacologia

UFPR

Caixa Postal 19.031

81531-990 Curitiba, PR

Brasil

E-mail: [email protected]

Publication supported by FAPESP.

The names of the authors are

presented in alphabetic order,

except for the last who was the

symposium organizer.

Received August 21, 2000

Accepted January 30, 2001

Key words· Emotion· Fear· Anxiety· Learning· Memory· Amygdala· Nucleus accumbens· Periaqueductal gray matter

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Introduction

Emotion has long being recognized as animportant drive for behaviors important tothe survival of animal species. In humans itcontributes to welfare and suffering, with animportant role in psychiatric diseases. Theefforts of psychologists and neuroscientiststo create a scientific theory of emotion canbe viewed in the theories and studies ofCharles Darwin, William James, SigmundFreud, James Papez, and Paul McLean,among others. The advances introduced bythese scientists were followed by a longperiod of time in the middle of the 20thcentury during which both neuroscience andcognitive science neglected the emotionalnature of the mind. Hopefully, in the so-called �Decade of the Brain�, a step forwardwas made by the attempts to join the progressof the cognitive neuroscience approach andemotion in a unified theory of mind (see, forexample, the books of Damasio (1) andLeDoux (2)). Antonio Damasio (3) calledthis movement �a second chance for emo-tion�, in spite of the fact that today there aremore disagreements than fully accepted theo-ries for emotions (4). Nevertheless, someconsensus has been reached in particularissues, like the role attributed to the amygda-la in emotion. In order to discuss the scien-tific advances and views achieved in thisfield over the last decade, the Brazilian Soci-ety of Neuroscience and Behavior (SBNeC)organized a virtual symposium held on April24, 2000. The chat site was provided by theConselho Nacional de DesenvolvimentoCientífico e Tecnológico (CNPq). The pre-sent article is based on the transcription ofthis symposium.

What are the most critical questionsin the neurobiology of emotion?

Luiz Carlos Schenberg: From my pointof view there are two sets of problems thatshould be worked out in the next years. The

first set is conceptual: Few areas of sciencehave a conceptual framework as loose andimprecise and so influenced by commonsense as the field of emotion. What are emo-tions? What are the differences betweenemotion, mood, drive, temperament and per-sonality? Are drives and emotions distinctentities? How many emotions do we have?What are the differences between sadness,anxiety, fear, panic, happiness, love, sexualarousal, hunger, pleasure, aversion, etc.? Arethere basic emotions? Is pain a sensation oran emotion? What is suffering? What do wemean by stress? How do these entities relateto each other? The second set of problems isexperimental and deals with the specific con-tribution of any neural system to the genesisof emotions. Conversely, it also addressesthe question if one neural system can expresstwo or more kinds of emotions depending onits mode of operation. For instance, are anxi-ety and panic generated by different systemsor by the different functioning of a singleneural system? Hopefully, the solution ofthe second set of problems will help us an-swer the above theoretical questions.

Jean-Marc Fellous: Is there one emo-tional system, or are there several emotionalsystems? Is there an animal model of emo-tion (or of a particular emotion)?

Claudio Da Cunha: In my opinion themost critical questions in the neurobiologyof emotion are: 1) What is emotion in aneurobiological perspective? 2) Which arethe basic neurobiological systems involvedin specific kinds of emotion? Which brainstructures participate in the expression ofdifferent types of emotion and how do theydo so? Is an emotion encoded in a specificbrain region or is it a property of the interac-tion of the whole brain neural network? Whatis the participation of the different emotionalbrain systems in psychiatric diseases?

Joseph LeDoux: I will start with twoobvious questions. First, are there differentneural systems for different emotions? Sec-ond, how do we get from our understanding

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of emotional reactions in the brain to emo-tional feelings?

Francisco Guimarães: What is the in-teraction between emotion and memory?How do emotional experiences induce last-ing behavioral changes? What is the role ofthe hippocampal formation in emotion? Whatabout the neurobiology of other emotionalstates (since a large part of the research hasbeen done with a specific emotional state:fear)? And what is the neurochemistry ofemotion, particularly the role of neuropep-tides found in huge concentration in areasrelated to emotion?

Robert & Caroline Blanchard: We�reat home with only one computer so ournames will appear together. One critical is-sue is - What are the emotions? Taking theexample of fear, we don�t know if this in-volves one or several systems and if the latterhow to differentiate and classify them. Itprobably will be possible to create a unifiedview of emotions, their evolutionary func-tioning and all, but to obtain a solid resultthis is going to have to rest on adequateanalyses for at least some focal systems.

Jeffrey Rosen: Are there common neu-roanatomical substrates for different emo-tions or are there separate systems? For ex-ample, the amygdala is important for fearconditioning, but evidence suggests it is alsoinvolved in appetitive conditioning. Are theseoverlapping systems using the same circuitsor separate parallel circuits?

Joseph LeDoux: We all seem to be onthe same track. The question then is what isthe best way to figure this out. We havedecent models of emotional behavior forstudying fear, but less good models for otheremotions. Appetitive conditioning, for ex-ample, doesn�t have the same face validityfor human emotion the way fear condition-ing does.

Robert & Caroline Blanchard: We canmuster a case for good models of aggression,as well as fear, the latter possibly involvingmore than one system anyway. Certainly

there is growing evidence for differentialinvolvement of different aspects of (systemswithin) fear/defense in different psychiatricconditions.

James McGaugh: I think that we need toexpress some caution about concluding thatwe have good models for studying any emo-tion in animals. We have to consider both theautonomic expression and other aspects ofexpression of emotions.

William Irwin: In part related to Joseph�scomment, at least at the human level, it isimportant to distinguish between the pro-cesses underlying the perception of emo-tionally salient stimuli from the neural sub-strates that �generate� emotion.

Luiz Carlos Schenberg: Jeffrey - Atleast in the periaqueductal gray matter thereseems to be a great overlapping of systems, ifnot in the periaqueductal gray matter itself,systems elsewhere in the brain that are trig-gered by activation of a single site within theperiaqueductal gray (5,6).

Jeffrey Rosen: Yes, the periaqueductalgray matter seems to be divided at least intoactive (escape) and passive (freezing, immo-bility) behavioral coordinating areas; how-ever, these may be activated by differentforebrain neural systems, one with projec-tions from the hypothalamus and the otherfrom the amygdala, respectively.

William Irwin: In part the route for pre-served responses will be sense modality spe-cific.

Luiz Carlos Schenberg: William, I agreewith you but I would add to your commentthat we should also differentiate processesthat generate emotions from those which aremerely executive of hard-wired behaviors(releasing mechanisms).

James McGaugh: I agree with Irwin�scomment.

William Irwin: Getting back to the issueof different neural systems for different emo-tions, if you take the perceptual processes (inhumans) with regard to facial expressions,then the amygdala appears not to be in-

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volved with certain emotional states (e.g.,anger).

James McGaugh: I think it is importantto distinguish between the learning of anemotion (emotional response) and the influ-ence of emotion on learning and memory.This is a critical distinction. I think it highlyunlikely that an emotion is encoded in anyspecific brain region. Interactions amongbrain regions seem to be required.

Claudio Da Cunha: I agree with you, butsometimes it is not what it seems to peoplethat are not working in this area but who areinterested in reading the papers.

William Irwin: Indeed, McGaugh�s dis-tinction is important. Relatedly, Davis� group(7) have reported that there are differentneural systems (e.g., amygdala) that are re-sponsible for conditioned vs unconditionedfear responses.

Claudio Da Cunha: Dr. LeDoux, do youagree with Dr. McGaugh�s opinion?

Joseph LeDoux: Yes, I do agree withJim McGaugh about the difference betweenbrain mechanisms of emotion and emotionalinfluences on memory mechanisms.

James McGaugh: I agree with Irwin thatit is important to distinguish between learnedand unlearned emotional responses.

What do we know for certain aboutbrain processes involved in emotionand what is controversial?

Jean-Marc Fellous: One possible ap-proach is to focus on a particular emotionand study it exhaustively (from neurochem-istry to behavior). This is the most conserva-tive/traditional way and it brought about al-ready plenty of information (fear condition-ing, for example). But I am wondering ifsuch an approach will not bias a priori thescope of research... What if there were noemotional centers/circuits per se, but ratheremotion is an emergent property of existingcomputations...

Claudio Da Cunha: With respect to Jean-

Marc�s comment, in our last chat (on neuro-biology of learning and memory, see Ref. 8),Joaquin Fuster said that he believes we areliving times of �a new phrenology more orless legitimized by the scientific method�. Isthis the case for the neurobiology of emotion?

Jeffrey Rosen: In reply to Jean-Marc�searlier comment, I agree that the brain prob-ably did not develop as emotion systems perse, but as systems for rapid appraisal (neuralcomputation) of incoming stimuli and gen-eration of appropriate responses. Emotionmay be an emergent property of this neuralactivity. For learning or rapid evaluation ofalready learned fear, the amygdala is per-forming many of these computations. Forunlearned or innate fear I think it is not clearwhat the role of the amygdala is. Much of theappraisal of unconditioned emotional stimulimay be taking place in the sensory organs,thalamus or cortex.

Joseph LeDoux: Jean-Marc, it could eas-ily be the case for emotion if you only look athuman work, imaging, and lesions. I think itmay be less of a criticism of the animal workthat looks at mechanisms within and be-tween cells as opposed to brain areas.

James McGaugh: I think we need toconsider much more seriously the intercon-nectedness of brain systems mediating emo-tional responses and emotional influences.Several recent papers have reported that fearcan be and is expressed in rats lacking anamygdala. Also, Joseph, you have shownthat different aspects of fear are mediated bydifferent amygdala nuclei (9).

Joseph LeDoux: Jim is right on target.We are very good at focusing on small piecesof the puzzle in neuroscience (on memory orperception or emotion or attention) and havedone less well in understanding how all ofthese things come together to make us whowe are.

Jean-Marc Fellous: It seems to me thatin addition to asking �what are the neurons/centers involved in emotion?�, we shouldalso ask �how a particular set of neurons

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computes during an apparent emotional state�(i.e., fast, slow, using synaptic changes, re-cruiting more/less cells...).

James McGaugh: Another importantcontroversy is that of whether the same pro-cesses underlay learned and unlearned emo-tional responses. What do we know aboutthat?

Joseph LeDoux: Almost everything iscontroversial. Regarding learned vs unlearnedmechanisms, my own view is that learningmodifies the circuits through which unlearnedresponses are expressed.

William Irwin: Regarding LeDoux�s laststatement about learning modifying a cir-cuit, can you say a bit more about the natureof that modification? Is it more like a param-eter adjustment? Do certain structures go�off line� and do certain structures go �online� (i.e., a transfer of function)?

Joseph LeDoux: I had in mind the switch-ing of inputs. Natural stimuli turn the systemon and through learning novel stimuli gainaccess. I base this in part on Blanchard�searly work with rat fear of cats (10). But JeffRosen�s new data question this to some ex-tent. We need more work on what �uncondi-tioned� fear is.

Eliane Volchan: If an unlearned visualfear response like that for looming does notinvolve the amygdala, it is difficult to imag-ine the switching of inputs needed for condi-tioning to novel stimuli. Shouldn�t the samebasic circuit be involved in order to be modi-fied by the learning experience?

James McGaugh: I heartily agree thatwe need to know more about the nature ofunlearned emotions (including but not re-stricted to fear).

Robert & Caroline Blanchard: Whilethe learned-unlearned fear distinction is im-portant (go to it, guys), we sense a disturbinglack of attention to the specifics of the neuro-behavioral systems that regulate defense perse (never mind emotion, until you get thebasics down). These are beautifully complexsensorimotor systems and should provide

the basis for analyses of the neurobehavioralsystems controlling at least one type of emo-tion.

Jeffrey Rosen: In regard to learned andunlearned emotional responses, I think thecircuits may be different. We have lesiondata showing that the lateral, basolateral andcentral nuclei of the amygdala are importantfor conditioned fear (freezing), but not forfreezing to a predator odor. We�re not yetsure what the systems are for freezing topredator odor.

Luiz Carlos Schenberg: Jeffrey, may bethere is an involvement of the medial amyg-dala. Unpublished data from our laboratorysuggest an important role of the medial amyg-dala in fear-like behaviors (immobility, trot-ting). The Blanchards have convincing dataas well (11,12).

Eliane Volchan: Joseph, going back tothe issue of learning modifying unlearnedcircuits: How does a learning fear experi-ence (which involves the amygdala) modifya circuit of unlearned fear, if the amygdalawas not involved in the first place?

Joseph LeDoux: The way I see it is thatthe emotional responses elicited by danger-ous stimuli are hard-wired outputs of theamygdala. These outputs are engaged whenthe amygdala is turned on. Some things thatturn on the amygdala do so because of evolu-tionary wiring. Others do so because of learn-ing. The natural or unlearned or evolution-ary stimuli are prewired to access the hard-wired response circuits. Other things canenter those circuits if they activate the cir-cuits at the same time that a natural stimulusdoes. Electric shock, being a form of painelicited by tissue damage, naturally activatesthe amygdala. Amygdala cells are respon-sive to shocks and also to tones. And if theshock comes on while the tone is activatingthe amygdala, the tone acquires the ability toactivate the amygdala as well. This is a stan-dard Hebbian interpretation of plasticity.

Eliane Volchan: Joseph, in that case, thesame basic circuit should be involved to be

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modified by the learning experience. Whathappens if the amygdala is not involved inthe first place?

Joseph LeDoux: I think I sort of an-swered this above. But basically, for any partof the brain to learn an association betweentwo stimuli, those two stimuli have to havesome impact on that part of the brain. In thissense the amygdala has to be involved in thefirst place (which I assume means it re-sponds to the unconditioned stimulus) if it isto be involved in the second place (if it is tolearn).

Claudio Da Cunha: Talking about con-troversy - why do medial amygdala nucleiparticipate in fear behavior but not modulatememory? Are these two processes correlatedor not?

Joseph LeDoux: I am not sure of the roleof the medial amygdala in fear. Damage hasno effect on fear conditioning, at least whenwe have done it, but the medial amygdala isconnected with the paraventricular nucleusand may be involved in stress hormone re-lease.

Luiz Carlos Schenberg: Stimulation ofthe medial amygdala elicits responses re-sembling those of the periaqueductal graysuch as immobility and trotting and Blan-chard and colleagues (11) showed taming ofwild rats by lesioning the medial amygdala.

James McGaugh: Have brain imagingstudies revealed anything critical about dif-ferential brain systems involved in differenttypes of emotion?

Claudio Da Cunha: From what I haveread, I agree with the opinion of Dr. Baddeleyin the other chat (8): at present brain imaginghas just proved what we already knew aboutthese processes. Now it is time to use it toanswer new questions.

Joseph LeDoux: Jim, there are someimaging studies that show different activa-tions to different emotional stimuli (faces)(13). I am not sure if this really addressesyour question but I think that may be all thatexists.

William Irwin: Could McGaugh com-ment further on this point: We know that�emotion enhances memory� but does themagnitude of the emotion correlate with thedegree of memory enhancement?

James McGaugh: The strength of memo-ry varies with the intensity of stimulationused to induce the memory and with thedegree of release of catecholamines - par-ticularly norepinephrine in the amygdala.

Francisco Guimarães: Related to Wil-liam�s question another issue is: Could anegative emotional experience introduce abias in memory (for example, facilitatingmemories of other negative events)? Thereare some studies with depressive patientssuggesting this.

William Irwin: At the human level, it isimportant for us to systematically examinethe relation between �self-reported� emo-tion (that is, at a neural level it is importantwhat people say/feel about their emotionalstates) and brain systems. We are examiningthis with neuroimaging techniques. Also,note the obvious statement that this can�t bedone in non-human animals.

Joseph LeDoux: It is true you can�t use�self-reporting� in animals but it�s importantto also remember that just because you canuse �self-report� in humans doesn�t meanthat�s the key to emotions or other aspects ofmental life (other than the aspects that areaccessible to self-report). I am sure that�swhat you meant but I just wanted to make itclear.

William Irwin: Yes, thank you for thatclarification. To further add (and related toyour comments about learning modifying aneural circuit), the (human) process of feel-ings may be an important component thatmodifies the underlying neural substrata (ofcourse, an obvious territory would be theprefrontal cortex).

James McGaugh: But, we can do a rea-sonably good job of getting at something like�self-reporting� in animals by asking them alot of questions that they can answer behav-

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iorally (i.e., by testing them in various ways).There are a lot of ways, for example to findout what animals like and whether they knowhow to find what they like and rememberwhere it is. This is a bit like self-reporting butprobably more believable!

What kinds of research are neededto resolve these controversial issues?

Claudio Da Cunha: It would be a goodidea if each of us stated in a few words whatwe are doing in our laboratories to addressthese controversial issues on neurobiologyof emotion.

James McGaugh: We find that lesionsof the basolateral amygdala block thememory-modulating (enhancing or impair-ing) effects of post-training drug and hor-mone infusions into other brain regions -including, but not restricted to, the dorsalhippocampus. The same effects are foundwith beta-adrenergic antagonists infused se-lectively into the basolateral amygdala (14).Similar effects have been reported by sev-eral other laboratories studying basolateralamygdala influences on dentate gyrus long-term potentiation. Basolateral amygdala le-sions block the long-term potentiation andbasolateral amygdala stimulation enhancesit (15,16).

Jeffrey Rosen: In our laboratory we arestudying immediate early gene expression inthe lateral nucleus of the amygdala with fearconditioning. Early growth response gene 1(EGR-1; also called zif268) mRNA increaseswith conditioning, but not during retrieval(17). Does that mean the amygdala playsdifferent roles in acquisition and retrieval offear?

Claudio Da Cunha: In my laboratory wedid some experiments showing that �anx-ious� and �non-anxious� rats present corre-lated behavior in learning and memory tasks(18). I suppose this is in agreement withJean-Marc�s view of an interconnected net-work. More recently I started to study rats

with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) lesions in the substantianigra pars compacta. It seems to me thatsome �emotional� aspect may also be en-compassed by the prefrontal cortex/striatecircuitry (unpublished data).

Francisco Guimarães: We found thatpoststress facilitation of 5-HT1A (19) orblockade of NMDA-mediated neurotrans-mission in the dorsal hippocampus inhibitsthe decrease in open arm exploration found24 h after a 2-h period of restraint stress.

Luiz Carlos Schenberg: I do believethat anxiety and panic are triggered by phe-nomena within the amygdala and periaque-ductal gray, respectively. Similar to theblunted neuroendocrine response of panicattacks in humans (20,21), our recent resultsshowed that neither plasma ACTH nor pro-lactin levels change following a 1-min full-blown defense reaction induced by stimula-tion of the dorsal periaqueductal gray mat-ter. Moreover, the dorsal periaqueductal graymatter-induced defense reaction was attenu-ated by 21-day administration of clomipra-mine (22).

Francisco Guimarães: An interestingfinding with clomipramine. What do youthink about the initial worsening that thisdrug might cause in panic patients?

Luiz Carlos Schenberg: There was no�worsening�, i.e., threshold reduction, in in-termediate sessions. In turn, fluoxetine (1mg kg-1 day-1) which is a less efficientpanicolytic but a selective 5-HT reuptakeinhibitor, attenuated galloping only.

Robert & Caroline Blanchard: Was thatacute fluoxetine? In our laboratory acute andchronic fluoxetine have opposite and strongeffects on flight, so your �galloping� is veryinteresting.

Luiz Carlos Schenberg: Chronic fluox-etine test trials were performed before thedaily dose so as to avoid the acute effect.Robert, it is interesting that neither acutediazepam and buspirone nor a 10-day treat-ment with buspirone caused any threshold

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increase in periaqueductal gray matter-in-duced defensive responses.

Robert & Caroline Blanchard: Whichperiaqueductal gray matter-induced defen-sive responses?

Luiz Carlos Schenberg: Immobility, trot-ting, galloping, micturition, defecation, jump-ing, and exophthalmus.

Robert & Caroline Blanchard: Relatedto panic, we have been examining resultsfrom a wide array of panic �models� and onepossible interpretation of these is that anti-panic and panicolytic drugs work very selec-tively on flight, but that when flight is elic-ited lower and lower in the system (i.e.,experimentally vs stimulation of dorsome-dial hypothalamus vs periaqueductal graymatter) some variability creeps into the sys-tem, suggesting that these drugs may actalong the route, having less effect near theend (23).

William Irwin: I think there are different(likely overlapping) neural substrata thatgovern �preferences� (as you describe) ver-sus �feelings� (self-reported). Note that ifwe are going to be honest with ourselves, atruly comprehensive neural theory of emo-tion is necessarily going to have to deal with�feelings� (whatever they may be).

James McGaugh: Much of the focus ofemotional research has, of course, been onaversively induced emotional states. Howare we to study positive emotional states?Any guess about the brain processes in-volved?

Claudio Da Cunha: Talking about posi-tive reinforcers, could the nucleus accum-bens play a more important role than theamygdala in this case?

James McGaugh: The nucleus accum-bens is certainly involved. Nucleus accum-bens lesions produce effects like those ofstria terminalis and basolateral amygdala le-sions in blocking the effects of stress hor-mones on memory - even if the stress hor-mone agonists are infused into the dorsalhippocampus.

Jean-Marc Fellous: Claudio - It does goin the direction of emotion as an interactingcircuit. But I would like to push further...The fact that two regions are communicatingduring an emotional state is interesting andimportant to know. What I was trying to sayis that very little research is done on param-etrizing the communication (is it fast, slow,how many neurons are involved, what is thetiming of spikes, what neuromodulators areinvolved?) Perhaps this level of descriptioncould be useful to characterize/understandthe emotional state... For example, the amyg-dala is involved in fear conditioning to toneand the hippocampus is involved in condi-tioning to context: Are stimuli routed withrespect to their complexity? Can this bechanged/modulated in cases where �fear� isnot involved? This surely would help a com-putational neurobiologist like me...!

James McGaugh: Although we knowthat the amygdala is involved in fear condi-tioning the meaning of �involved� needsserious consideration. Our findings (24,25)and those of many other recent studies (26,27)clearly indicate that the amygdala has a modu-latory role in influencing storage in otherbrain systems. We find no evidence that theamygdala is a site of storage for any kind offear conditioning (28).

Jean-Marc Fellous: I do think that modu-lation of activity, rather than activity itself, iswhere a lot can be learned about emotion...Very much in your line of thought...

Jeffrey Rosen: For positive emotions, Ithink the nucleus accumbens is probablyinvolved. Interestingly, LeDoux and others(9) are finding that learning of active avoid-ance behavior seems to involve the basalnucleus of the amygdala, but not the centralnucleus. Because the basal nucleus projectsto the nucleus accumbens, it is possible thatthe nucleus accumbens plays a role in activeavoidance. Since avoidance is a coping re-sponse to an aversive event there are prob-ably positive emotions associated with it. Ifthe nucleus accumbens is part of an avoid-

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ance circuit, positive emotions should emergeduring avoidance.

Claudio Da Cunha: Related to Dr.McGaugh�s proposition, a long time ago Iread some papers suggesting that the amyg-dala and some processes may be equallyinvolved in both positive (reward) and aver-sive behaviors (29).

Joseph LeDoux: The work of Everittand Robbins (30) has helped clarify the roleof the amygdala and nucleus accumbens.The amygdala seems important for learningabout incentives and the nucleus accumbensis where dopamine amplifies the incentivevalue of the stimulus coming from the amyg-dala, if I have got their ideas right.

William Irwin: With regard to the amyg-dala/accumbens interactions, I believe it isthe case that while there are no amygdalofugalprojections to the ventral striatum, there areprojections in the reverse. It�s not clear ex-actly how to interpret these findings, but Ithink they are important to consider.

Claudio Da Cunha: Other evidence forthe participation of the amygdala in bothaversive and reward tasks is that the actionsof benzodiazepines are mediated by the ba-solateral amygdala and they block the ex-tinction of an aversive conditioning causedby the learning of a secondary task (31).What do you think about it?

James McGaugh: As benzodiazepinesinduced amnesia in humans (32) - for allkinds of learning - it seems reasonable toconclude that they affect positive as well asnegative learning.

Jeffrey Rosen: Do benzodiazepineschange thresholds in the amygdala?

Luiz Carlos Schenberg: I did not test iton thresholds, but it was shown long ago thatmicroinjection releases punished behavior(33).

James McGaugh: Benzodiazepines donot affect memory in animals with basolat-eral amygdala lesions (34). Thus, the benzo-diazepine receptors in the amygdala are criti-cal for memory effects.

Luiz Carlos Schenberg: Interestingly,stimulation of the central nucleus of theamygdala produces only immobility (unpub-lished data).

Claudio Da Cunha: Does this immobil-ity mean an emotional state? Is it related tothe memory processes modulated by the ba-solateral nucleus of the amygdala?

Luiz Carlos Schenberg: I do not know ifthis is tense immobility such as in freezing,not quiescent immobility.

Jeffrey Rosen: So how do you see therole of the amygdala and periaqueductal graymatter in fear (anxiety) vs panic?

Luiz Carlos Schenberg: Flight is thetypical response of periaqueductal gray mat-ter, not of the amygdala, and is the responsemost sensitive to panicolytics (22).

What is the relationship betweenlearning, memory and emotion?

Robert & Caroline Blanchard: Relatedto learning, we think some attention to anadditional distinction might be profitable.Typical paradigms explore the relationshipbetween pain and contextual or point stimuli.What about nonpain stimuli such as preda-tors as the unconditioned stimulus in contextor other types of learning? Predator-contextassociations constitute a significant para-digm in the real world and have the advan-tage of enabling us to systematically addpain activation to analyses.

Jeffrey Rosen: Predator odor does notseem to act as a good unconditioned stimu-lus. We don�t get context conditioning to apredator odor, although the predator odorelicits robust freezing (35).

James McGaugh: Have you tried manykinds of odors and intense odors?

Jeffrey Rosen: Jim, fox odor (trimethyl-thiazoline) elicits robust freezing for longperiods of time (at least 15 min). We also geta very nice dose-response curve with smallamounts of fox odor. We have tried to elicitfreezing with butyric acid, caproic acid and

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isoamyl acetate at amounts 100 times morethan the fox odor. Only isoamyl acetate givesus moderate levels of freezing when used invery large amounts (35). We have tested twoother animal odors (besides caproic acid).Fox urine elicited freezing, while mouse urinedid not.

Luiz Carlos Schenberg: Odors are im-plicit memory, we can recognize them butnot recall, may be this is the point.

Joseph LeDoux: Most things that hu-mans are emotional about are things we havelearned about in one way or another. Memoryis therefore very important in emotion. Bothexplicit and implicit memory, and vice-versa.Emotions, once aroused, strongly influencememory, but Jim should talk about that.

James McGaugh: We can certainly learnto be emotional in the presence of cues thatpreviously induced the emotion. We all agreeon that. But emotion can also, as discussedabove, modulate the degree of memory ofthe specific events (i.e., declarative memory)that elicited the emotional arousal. And, weknow that this involves the release of stresshormones, the activation of the basolateralamygdala (release of norepinephrine) andactivation of other brain regions includingthe insular cortex and hippocampus.

William Irwin: Are the emotion-enhanc-ing effects on explicit/declarative types ofmemory the same for implicit types of memory?

James McGaugh: Does anyone knowhow to study implicit memory in animals?We would need to know that in order toanswer Irwin�s question.

Joseph LeDoux: Jim, did you mean im-plicit or explicit memory in your questionabout animals?

James McGaugh: I meant �implicit� butI said that because it is not clear to me howwe can clearly distinguish between implicit

and explicit memory in animals - can wespecify those prior to conducting any par-ticular experiment? In the case of humansubjects the distinction is clear on the basisof priming experiments. But do we have thesame clear evidence for animal studies?

Joseph LeDoux: I tend to think of mostmemory in animals and humans as implicit.In humans we have some sense that explicitmemory is what happens when informationthat was encoded by the hippocampus isretrieved and placed in working memory. Atmost, then, we should think of explicitmemory in animals as this kind of hippocam-pal based memory. But it is also possible thatother animals have little or no explicitmemory (at least the kind of explicit memorythat we talk about in humans). So for memost memory in animals is implicit. Thisterminology is sort of backwards since im-plicit can only be defined by contrast toexplicit, and it is likely that explicit camelater in evolution.

Eliane Volchan: Does anyone know therole of the superior colliculus in the circuit ofpositive and negative emotions? For the vi-sual system it is known that the superiorcolliculus feeds the pulvinar on the way tothe amygdala.

Luiz Carlos Schenberg: Michael Davis(36) showed that the superior colliculus isinvolved in fear potentiation of acousticstartle by visual cues.

Acknowledgments

The SBNeC organizers are grateful toHidevaldo Machado and Roberto Andreatinifor help with the organization of the chat, andto Simone Alencar for technical assistanceduring the chat. CNPq-Prossiga is also ac-knowledged for providing the chat web room.

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The brain decade in debate: III. Neurobiology of emotion

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