Oritofrontl cortex nd solterl mygdl encode expected outcomes during lerning Geoffrey Schoenum 1, Andre A. Chi 2 nd Michel Gllgher 1 1 Deprtment of Psychology, Johns Hopkins University, 3400 North Chrles St, 25 Ames Hll, Bltimore, Mrylnd 21218, USA 2 Cognitive Science Deprtment, University of Cliforni t Sn Diego, 9500 Gilmn Drive - 0515, L Joll, Cliforni 92093, USA Correspondence should e ddressed to G.S. (schoeng@jhu.edu) Reciprocl connections etween the oritofrontl cortex nd the solterl nucleus of the mygdl my provide criticl circuit for the lerning tht underlies gol-directed ehvior. We exmined neurl ctivity in rt oritofrontl cortex nd solterl mygdl during instrumentl lerning in n olfctory discrimintion tsk. Neurons in oth regions fired selectively during the nticiption of rewrding or versive outcomes. This selective ctivity emerged erly in trining, efore the rts hd lerned relily to void the versive outcome. The results support the concept tht the solterl mygdl nd oritofrontl cortex cooperte to encode informtion tht my e used to guide gol-directed ehvior. The prefrontl cortex is importnt for the orgniztion of gol-directed ehvior 1 3. Dysfunction of oritofrontl cortex () is ssocited with disturnces in motivtion nd n inility to nticipte consequences, leding to poor judgment nd mldptive ehvior 4,5. For exmple, in the experimentl setting of gmling tsk in which choices were ssocited with contingencies of monetry rewrds nd penlties, norml sujects lerned to optimize rewrds wheres ptients with dmge to this region of prefrontl cortex performed poorly, unle to djust their ehvior ppropritely to the contingencies of the tsk 6,7. Functions tht require the integrity of re lso dependent on informtion provided through interconnected structures, llowing ccess to informtion regrding the context of cues nd ssocitions formed during lerning through inputs from other systems. One key region, with respect to gol-directed ehvior, is likely to e the solterl mygdl (). The is directly interconnected with 8 11, structure tht is importnt for ssocitive lerning in primtes nd other species 12 17. For exmple, rts with neurotoxic lesions of hve difficulty in lerning to void n versive outcome 13, nd dmge to this structure in oth rts nd monkeys is lso ssocited with deficits in the ility to djust ehvior when the vlue of reinforcers is ltered 14,15. nd my cooperte in circuit tht rings ssocitive lerning to er on decision mking. The current study exmined neurl ctivity in nd during olfctory discrimintion trining, when rts were in the process of lerning n dptive ehviorl strtegy of responding on trils with rewrding outcome nd withholding responses on trils with n versive outcome. Neurons in oth regions fired selectively during dely s the rt wited the outcome of the tril. Moreover, this selective ctivity tht encoded the impending outcome emerged erly in trining, efore rts developed relile ehviorl discrimintion y voiding the versive outcome. Results We recorded neurl ctivity in rts with electrodes positioned in either or (Fig. 1). The rts were trined on series of discrimintion prolems in which the identity of n odor ws informtive out the consequence of mking response. The rt smpled the odor vi smpling port, nd then plced its snout into fluid well locted severl inches elow the odor smpling port (see Fig. 2). Responses t the odor port nd t the fluid well were registered y interruption of photoems tht detected the entry of the rt s snout into ech port. The odor predicted whether the rt would receive rewrding sucrose solution or n versive quinine solution. To exmine the effect of lerning on neurl ctivity, we used novel odors ech dy; thus rts hd to lern the outcomes ssocited with new set of odors in every session. In some sessions, two-odor discrimintion prolem ws presented in which one odor, designted the positive odor, predicted the delivery of sucrose solution, nd second odor, designted the negtive odor, indicted tht the sme response would result in delivery of quinine solution. In other sessions, four-odor discrimintion prolem ws presented tht hd two positive odors nd two negtive odors. Rts were mintined on restricted schedule of wter consumption to motivte ehvior in the tsk. In the process of solving ech new discrimintion, rts initilly responded y entering the fluid well fter odor smpling on every tril (referred to s go response) ut then grdully lerned to withhold this response (referred to s no-go ) fter smpling n odor tht predicted the versive outcome. These sequences of ehvior re schemticlly illustrted in Fig. 2. It is importnt to note tht go response t the fluid well ws not immeditely followed y delivery of the fluid reinforcer, ut rther resulted in short vrile dely period (300 800 ms) efore fluid ws delivered. During this short dely, the rt ws required to mintin its snout in the fluid well. It ws during this intervl (see shded region in Fig. 2), fter the rt mde go response ut efore the outcome ws presented, tht we looked for chnges in neurl ctivity during lerning. nture neuroscience volume 1 no 2 june 1998 155
Fig. 1. Photomicrogrphs of histologicl sections showing the reconstruction of recording sites in representtive sujects in () nd (). The encompsses the oritl regions nd grnulr insulr cortex. In ech photomicrogrph, verticl line represents the dorsoventrl rnge long the electrode trck from which neurons were recorded in the cse shown. Recordings were loclized to ventrolterl nd lterl oritl regions nd ventrl grnulr insulr cortex in the four rts in the group. Recordings were loclized to the solterl nucleus in the three rts in the group. Comprison of neurl ctivity on positive go nd negtive go trils reveled tht sustntil popultion of neurons in oth nd fired differentilly depending on whether the susequent outcome ws to e the rewrding sucrose solution or the versive quinine. This comprison of ctivity ws sttisticlly significnt for 74 (or 22%) of 328 neurons smpled in nd 44 (or 36%) of 121 neurons smpled in. The ctivity of these neurons, illustrted in Fig. 3, differed on positive nd negtive go trils s the rt wited reinforcement in the fluid well. Note tht negtive go trils constitute errors, in which the rt mkes response fter smpling the odor tht predicts delivery of quinine. The development of differentil neurl ctivity is not, therefore, function of difference in ehvior per se. Although the rt hd not yet lerned the dptive ehviorl discrimintion of withholding responses on trils with the versive outcome, these neurons nonetheless hd cquired n ility to discriminte y nticipting the positive or negtive consequences of mking response. Consistent with this interprettion, further nlyses indicted tht selectivity developed s the rt lerned the discrimintion prolem. These nlyses exmined ctivity during n erly segment of trining in ech session, generlly efore the niml showed ny ehviorl lerning (i.e. efore it mde ny correct no-go responses; see methods). The reltive selectivity of these neurons incresed significntly etween tht erly segment of trining nd the remining trils efore the ehviorl criterion ws reched (Fig. 4). These dt show the contrst etween neurl ctivity on positive nd negtive go responses, clculted s the difference etween the firing rtes during positive nd negtive go responses divided y the sum of those rtes. Indeed, comprison of ctivity on positive nd negtive go trils in individul cells for the erly segment of trining reveled tht few neurons were selective t tht point in trining (only 17% or 6 of 35 in nd 15% or 5 of 34 in ). In contrst, for the gret mjority of such neurons, selectivity emerged s trining progressed. These results provide strong evidence tht the cells encode n expectncy for the consequences of the response, sed on experience in the tsk. If the oserved selective ctivity during the dely represents nticipted outcomes, it should depend on whether the odor smpled on tril predicted rewrding or n versive contingency. As expected, numer of neurons in the entire popultion tht we recorded over the trining trils considered in our nlysis did fire differentilly during odor smpling (66 of the 328 neurons in nd 40 of the 121 in ). Considertion of the cells with selective ctivity during the dely, however, reveled tht reltively few of these cells (24% or 18 of 74 in nd 25% or 11 of 44 in ) hd similr selectivity during odor smpling (see Fig. 2 for the intervl of nlysis). Thus severl susets of cells encode informtion in the tsk, ut the mjority of neurons tht exhiited differentil firing during the dely did not fire differentilly erlier in the tril in response to the odor cues. Figure 5 illustrtes neuron tht fired differentilly during the dely fter go responses ut not when the rt ws smpling the odors. Tle 1 shows dditionl fetures of the neurons tht exhiited differentil ctivity, nd provides further indiction of the strong influence of the expected outcome. The popultion of selective neurons is shown with reference to whether greter firing occurred on positive or negtive go trils. In, the gret mjority of these neurons hd selective ctivity ised for negtive go trils; 40 of 44 selective neurons fired more strongly preceding quinine delivery (Tle 1). Such neurons, however, did not increse firing when the rt withheld its response ( no-go) fter smpling the negtive odor. This is consistent with the interprettion tht elevted ctivity is relted to the impending negtive outcome, which is not delivered when decision is mde not to respond (Fig. 5). In ddition, 36% of the cells nd 65% of the cells tht were selective in the four-odor tsk (Tle 1) hd ctivity tht ws elevted to similr degree on trils involving either of two odors ssocited with the sme outcome; these neurons clerly encoded the nticipted outcome independent of which odor hd een smpled. Finlly sustntil numer of the selective neurons in lso responded differentilly during susequent reinforcement; 22 (or 50%) of the 44 neurons tht were selectively ctive during the dely hd similr selectivity during reinforcement. In, the proportion of neurons tht hd prllel selectivity during the dely nd reinforcement ws considerly lower (28%). It is lso evident from Tle 1 tht wheres high proportion of cells were ised for negtive rther thn positive contingencies, this ws not the cse for. Discussion In the current study, neurl ctivity ws recorded s nimls cquired new lerning. During n erly phse of trining on novel odor discrimintion prolems, neurons cquired discrimintive ctivity prior to overt chnges in ehvior. Specificlly, sustntil proportion of cells smpled in nd developed neurl ctivity tht differed relily etween trils with negtive outcome nd trils with positive outcome. This neurl ctivity seemed to reflect n expecttion out the impending consequences of mking response. Such ctivity could provide n importnt component in the lerning process. Expecttions out the occurrence of future events re useful in forming ssocitions tht represent ccurte predictive informtion, nd experience is required to determine whether nticipted outcomes re mtched y ctul outcomes. A susequent dptive chnge cn then e mde sed on the estlished predictive vlue of informtion used to guide ehvior. By this view, the differentil Tle 1. Neurl selectivity during the response dely in pre-criterion trining 2 odor 4 odor Tril Type Negtive Negtive (328) 1 14 16 19 25 (121) 1 1 6 3 34 1 The totl numer of neurons smpled in ech region. 156 nture neuroscience volume 1 no 2 june 1998
Fig. 2. Sequence of ehviors in () positive go, () negtive go, nd (c) negtive no-go trils during cquisition of go, no-go olfctory discrimintion tsk. In this tsk, wter-deprived rt hd to smple n odor presented t port on ech tril (odor smpling) nd then respond (go response) to receive sucrose or withhold the sme response (no-go) to void quinine. Responses t the odor port nd t the fluid well were registered y interruption of photoems tht detected entry of the rt s snout into ech port. When go response ws mde, the rt hd to remin in the fluid well for rief dely efore the reinforcer ws delivered (shded region). Becuse novel odors were presented in ech session, the niml hd to lern new ssocitions ech dy. Lerning ws evident when the rt egn to withhold responses fter smpling the negtive odor to void quinine delivery. Neurl ctivity during the rief dely fter go response ws compred on positive nd negtive go trils s the rts were lerning the discrimintion. During this prt of the session, the rts mde go responses nd lso withheld the response (no-go) on some negtive trils ut hd not yet reched the ehviorl criterion defined under ehviorl methods. As illustrted, the positive go nd negtive go trils tht were compred in our nlysis involved identicl responses nd oth involved requirement tht the rt remin in the well fter the response; thus the nlysis of neurl ctivity during this time period controlled for motor ehvior. ctivity oserved here would provide neurl sustrte tht supports susequent ehviorl chnge. Moreover, these correltes for nticipted outcomes developed erly in the course of trining in two interconnected structures tht re widely viewed s serving importnt functions in dptive ehvior. Clinicl oservtions indicte tht humn ptients with dmge to the oritl region of prefrontl cortex re prone to poor judgment, mking mldptive decisions in complex socil nd nturlistic settings 4. In such cses, it is commonly noted tht the consequences of ptients ctions fil to dequtely influence their ehvior. Mldptive socil ehviors re lso chrcteristic of monkeys with surgicl ltions of the mygdl 18, phenomenon recognized in some of the erliest investigtions of non-humn primte ehvior fter rin lesions 19,20. These oservtions, coupled with ntomicl evidence tht nd re reciproclly connected 8 11, suggest tht these regions function coopertively in the regultion of dptive gol-directed ehvior. The neurophysiologicl findings reported here re comptile with such coopertive reltionship; neurl correltes relted to nticipted outcomes were c found in ech structure. Evidence from clinicl cses nd lortory niml reserch hs lso een tken to indicte tht nd re specilized for somewht different functions. In this context, is widely viewed s criticl for ssocitive lerning 12 17, wheres is implicted in the ility to integrte nd orgnize informtion used in the selection of ehviorl strtegies 4,5,17,21. Accordingly, my function to guide dptive ehvior y ccessing relevnt informtion from fferent structures such s. This view, distinguishing the functions of nd, is consistent with certin fetures of our neurophysiologicl dt. In the present study, the neurl correltes oserved in re consistent with encoding of the criticl ssocitive fetures of the tsk; the gret mjority (91%) of the selective neurons in fired more strongly during errors (i.e. fter responses tht led to the versive quinine solution), nd high proportion of those neurons hd prllel selectivity when the fluid ws susequently delivered (i.e. they fired more strongly on exposure to quinine thn sucrose). Notly this is occurred in go, no-go discrimintion tsk tht required n djustment in ehvior to void the versive outcome. n=51 n=51 % Negtive (error) Negtive (error) n=20 n=28 Negtive (error) Response 1000 ms Fig. 3. Differentil ctivity during the dely following go response on pre-criterion trils in neuron recorded in nd neuron recorded in during two-odor discrimintion trining. () Neurl ctivity during the dely on trils on which the rt mde response prior to chieving criterion performnce, represented s percentge of the pre-tril seline firing rtes (seline rte for = 2.33 spikes/s; for = 0.78 spikes/s). Neurl ctivity during negtive go responses (closed rs) ws significntly higher thn seline in oth cses nd ws elevted when compred to neurl ctivity during positive go responses (open rs): [F(1,69) = 37.4, p<0.001]; nd [F(1,77) = 21.87, p<0.001]. () Rster displys showing neurl ctivity on ten representtive trils from precriterion trining for ech of the neurons during positive go (upper rsters) nd negtive go responses (lower rsters). Neurl ctivity, ounded y the shded region in ech tril, egins with odor offset corresponding to withdrwl from the odor port nd is synchronized on the go response t the fluid well (thin verticl line). Activity is truncted t reinforcement delivery. In these displys, the ctivity is clerly greter for ech neuron during the dely on negtive go trils thn during the dely on positive go trils. nture neuroscience volume 1 no 2 june 1998 157
Activity contrst Erly Lte Erly Lte Fig. 4. Contrst in ctivity on positive nd negtive go trils during the erly (open rs) nd lte (closed rs) segments of pre-criterion trining for popultion of neurons selective during the dely in nd (see Methods for description of erly nd lte segments nd criteri for the nlysis). The ctivity contrst ws clculted s the solute difference in the rtes on positive nd negtive go trils divided y the sum of those rtes, yielding vlues tht rnged from 0 to 1. Note tht these dt include ctivity from the smll suset of neurons tht showed selectivity during the erly segment of the pre-criterion phse. Nevertheless, the ctivity contrst incresed significntly in oth [t(34) = 2.32, p=0.026] nd [t(33) = 3.77, p=0.00065] etween the erly nd lte segments of trining, representing n increse in reltive selectivity of these popultions of neurons. In contrst, hd similr proportions of neurons selective for positive nd negtive outcomes, pttern consistent with more generl function of monitoring the expected consequences of ongoing ehvior, irrespective of need to chnge ehvior. This interprettion grees with prior recording studies using olfctory discrimintion tsks in which lerning ws lredy well estlished; neurl ctivity in oth primte nd rt encoded the identity nd ehviorl significnce of olfctory cues 22 24, s well s fetures of the context 22. Those results nd the current oservtions support the widely held view tht prefrontl cortex serves n executive function, in prt, y representing ongoing events nd the expected consequences of ctions 1 4,21. Selective ctivity during delys is well chrcterized feture of neurons in prefrontl cortex in non-humn primtes. Investigtors Fig. 5. Activity of the neuron in Fig. 3 on positive go, negtive go, nd negtive no-go trils. Ech rster illustrtes ctivity on ten representtive trils from pre-criterion trining. Activity during ech tril in these rsters egins with odor onset nd is synchronized on odor offset, indicted y the thin verticl line. A go response is indicted y rupt termintion of shding t the left of ech rster, nd ctivity is truncted t reinforcer delivery. When no response is mde on negtive no-go trils, ctivity is shown for period of 1500 ms fter odor offset. As illustrted previously, this neuron hd higher ctivity during the dely fter negtive go response, ut exmintion of ctivity prior to odor offset revels tht this selectivity did not reflect ctivtion during smpling of the negtive odor. In ddition, note tht this neuron did not fire during n intervl corresponding to the dely period on no-go trils. Negtive (error) Negtive No hve found such correltes in dorsolterl prefrontl cortex 25 28, nd in some of those studies ctivity during the dely ws clerly relted to the nticiption of specific events 29,30. Here we demonstrte selective ctivity during dely tht is lso relted to future events in region of rt prefrontl cortex, the, nd in n interconnected sucorticl region, the. This dely ctivity seems prticulrly tied to the motivtionl significnce of the expected outcome. Consistent with this concept, recent reserch with humn ptients hs reported deficit in utonomic responses tht provide mrker for the motivtionl properties of nticipted outcomes 6. In contrst to norml sujects, who exhiited n elevted skin conductnce response when mking choices tht could result in negtive outcome, this response ws lcking in ptients with oritl dmge. Interconnections etween nd my e criticl for ccessing informtion out the motivtionl properties of expected consequences when selecting course of ction. The current study offers rodent model tht cn e used to study these nd other ides out the orgniztion of systems tht encode ehviorl contingencies nd govern the selection of dptive ehvior. Methods ELECTROPHYSIOLOGICAL METHODS. Extrcellulr ctivity ws recorded in dult mle Long-Evns rts using drivele undle of ten 25 µm dimeter microwires descried previously 22. A single undle ws implnted in the left hemisphere in oritofrontl cortex of four rts (3.0 mm nterior to regm, 3.2 mm lterl, 4.0 mm ventrl) nd solterl nucleus of mygdl of three rts (3.0 mm nterior to regm, 5.0 mm lterl, 7.5 mm ventrl). The rts were llowed two weeks to recover. Behviorl trining egn therefter nd ws followed y recording once tsk procedures hd een lerned (see cption, Fig. 2). During recording, novel odors were utilized ech dy so tht new lerning could e exmined repetedly, nd fter ech session the electrode undle ws dvnced out 40 or 80 µm to cquire ctivity from new cells for the following dy. Neurl ctivity ws pssed through high-impednce hedstge nd then ctivity on ech microwire ws mplified 5000, ndpss filtered t 300 3000 Hz, nd recorded on nlog tpe long with computer-generted TTL pulses to mrk ehviorl events. Lter, signls were digitized t 25 khz, nd then individul units were discriminted using templte-mtching lgorithm (Cmridge Electronic Design) in concert with exmintion of the oscilloscope trcing. In this mnner, dt were collected in 43 sessions. Recording ws stopped in given rt when the estimted position of the electrode undle ws consistent with pssge eyond the region of interest. The finl electrode position ws mrked y pssge of 15 µa current through ech microwire to crete smll iron deposit, which ws lter visulized histologiclly using 3% potssium ferrocynide solution to produce Prussin lue rection. The electrode trcks were reconstructed to determine pproximte recording sites using these mrks. n=51 n=20 n=17 1000 ms Odor offset BEHAVIORAL METHODS AND RESULTS. Behviorl testing ws performed in n opernt chmer employing go, no-go olfctory discrimintion tsk in which ll ehviorl events nd dt collection were controlled nd monitored y computer s descried 22. Rts were wterdeprived overnight prior to ech recording session nd, therefore, were strongly motivted to perform for fluid rewrd. On ech tril, the rt poked its nose into n odor port to trigger odor presenttion nd then hd 3 s fter withdrwl from the port to respond y entering nery fluid well for reinforcement (go response). After response ws 158 nture neuroscience volume 1 no 2 june 1998
mde, delivery of fluid ws delyed y vrile period of pproximtely 300 800 ms, providing rief period in which neurl ctivity could e exmined independent of reinforcement. In the two-odor tsk, one odor signled tht go response would produce pproximtely 0.05 ml of pltle 10% sucrose solution, wheres the other odor signled tht go response would produce pproximtely 0.05 ml of diststeful 0.03 M quinine solution. In the four-odor tsk, two distinct odors were ssocited with sucrose nd two distinct odors were ssocited with quinine. We exmined neurl ctivity during the cquisition phse of ech session, defined s the trils efore the rt reched ehviorl criterion of 90% ccurte performnce within twenty-tril lock. For the sessions nlyzed in this study, this phse comprised, on verge, 66 trils in the two-odor tsk nd 82 trils in the four-odor tsk. ANALYSIS. Neurl ctivity ws exmined during go responses on trils efore the rt reched the ehviorl criterion within time window extending from 50 ms prior to detection of response t the fluid well until reinforcer delivery. Activity could e exmined during this period independent of the outcome of the response ecuse of the vrile dely instituted etween response nd reinforcement (see cption, Fig. 2). Neurl ctivity (spikes/s) on trils involving positive go response ws compred to tht on trils involving negtive go response using nlysis of vrince. A sttisticlly significnt difference (p<0.05) ws further evluted if the session involved four-odors y post-hoc testing to compre ctivity on trils of ech odor. Neurons with elevted ctivity on trils of single odor or eqully elevted ctivity on trils of either of the pir of odors ssocited with the sme outcome were ctegorized similrly s either positive go- or negtive go-selective. Neurons with differentil ctivity within the dely during pre-criterion trining were further exmined to determine whether selectivity ws present initilly or whether it developed s the rt lerned the discrimintion. To mesure initil selectivity, we defined n erly segment of the pre-criterion phse, including only those trils preceding the sixth negtive go response (error), designed to include only trils efore the rt egn to withhold responses on negtive trils. On verge, this segment included 15 trils (10 18 trils). Only selective neurons from sessions (n=31 sessions) in which the rte of lerning llowed n nlysis of erly ctivity were nlyzed. Criteri for inclusion in the nlysis were the presence of t lest ten errors overll pre-criterion nd five errors efore the third no-go response. In ddition, four neurons in nd two neurons in were excluded due to lck of ctivity in the erly trils tht were the focus of this nlysis. Neurl ctivity in this erly segment of trining ws evluted y nlysis of vrince (p<0.05) in cells tht hd exhiited selectivity in the erlier nlysis. In ddition, the response of the entire popultion of the selective neurons ws evluted y compring the contrst in ctivity on positive nd negtive go trils etween the erly nd lte segments of pre-criterion trining. The contrst ws defined s the solute difference etween the rtes on positive nd negtive go trils divided y the sum of those rtes, nd thus rnged from 0 to 1. The contrsts for the erly nd lte segments of trining were then compred within ech region using t-test for dependent smples (p<0.05). All procedures nd trining ws conducted in ccordnce with niml cre guidelines nd ll protocols were pproved y the institutionl niml cre nd use committee. Acknowledgments We thnk T. Lm for ssistnce in figure preprtion, Dr. M. Burchinl nd E. Neee for sttisticl consulttion. This work ws supported y funding from the NIH. 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