A role for inhibition in shaping the temporal flow of information in prefrontal cortex 2002 Nature Publishing Group

Transcription

1 A role for inhiition in shping the temporl flow of informtion in prefrontl cortex Christos Constntinidis, Grhm V. Willims nd Ptrici S. Goldmn-Rkic Deprtment of Neuroiology, Yle University School of Medicine, P.O. Box , 333 Cedr Street, SHM B404, New Hven, Connecticut , USA Correspondence should e ddressed to P.S.G.-R. (ptrici.goldmn-rkic@yle.edu) Pulished online: 22 Jnury 2002, DOI: /nn799 The prefrontl cortex is importnt in guiding or inhiiting future responses, which requires the temporl integrtion of events nd which provides continuity to the thought process. No cellulr mechnism hs een proposed to explin how the mentl representtion of response or ide is linked to the next. Using simultneous recordings in monkeys, we reveled inhiitory interctions etween neurons ctive t different time points reltive to the cue presenttion, dely intervl nd response period of working memory tsk. These findings suggest n importnt role of inhiition in the cererl cortex controlling the timing of neuronl ctivities during cognitive opertions nd therey shping the temporl flow of informtion. The ility of neurons to encode sensory informtion is determined y the unique constelltion of excittory nd inhiitory inputs they integrte. In the cse of the primry visul cortex, inhiition, concurrent with excittion, shpes orienttion preference, lthough the precise contriution of excittory nd inhiitory inputs is still mtter of dete 1 5. Similrly, the specificity for sensory stimuli shown y neurons in extrstrite 6 nd prefrontl 7 res is rodened when inhiitory inputs re negted y γ-minoutyric cid (GABA) ntgonists. By contrst, the neuronl mechnisms responsile for more complex functions, such s those involved with temporl integrtion of events nd with linking the representtion of one ide to the next during the thought process, remin reltively unexplored. The cpcity to process ongoing informtion nd pln pproprite ctions t future time rther thn respond to sensory stimuli in reflexive mnner is highly developed in primtes nd similrly depends on highly developed prefrontl cortex 8,9. We used electrophysiologicl recordings in the prefrontl cortex to test the role of inhiition in the temporl sequencing of ongoing informtion nd the ility to pln motor responses. Monkeys were trined to perform working-memory tsk tht required them to fixte on screen, to rememer the sptil loction of trnsiently presented visul stimulus nd to perform n eye movement towrd the rememered trget fter dely period. Different popultions of neurons re ctivted in sequence during the stimulus presenttion, during the memory intervl nd during the motor components of such tsk Here we report tht inhiition my e involved in shping the temporl pttern of ctivtion seen in these neuronl popultions. Such mechnism could help ridge temporl synchronies etween the perception of stimulus with other susequent stimuli, with mentl ssocitions nd with motor ctions RESULTS Extrcellulr recordings of multiple isolted neurons were performed from the dorsolterl prefrontl cortex of four monkeys trined in the oculomotor delyed response (ODR) tsk 10. We used cross-correltion nlysis to revel inhiitory effective connectivity etween simultneously recorded units Detection of inhiition etween pirs of corticl cells is extremely rre ecuse of the low firing rte of pyrmidl neurons nd the reltively low strength of individul synptic connections 19. Therefore, decrese in firing proility cused y inhiition etween two neurons is difficult to identify in vivo. Nevertheless, we were le to detect such interctions y focusing our recordings within the sphere of corticl column nd y sing our nlysis on lrge smple of 586 simultneously recorded pirs of neurons, 259 recorded from the sme electrode nd 327 from seprte electrodes spced t distnces µm prt, where most excittory interctions etween neurons re lso detected 20. Fifteen pirs of neurons (13 from the sme electrode, 2 from seprte electrodes) showed significnt troughs centered within the centrl 10 ms of the crosscorreltion histogrm (CCH), consistent with inhiitory effective connectivity. In every cse, significnt decrese elow the seline ws oserved in only one side of the CCH. In the cell pirs showing CCH troughs, we oserved tht the two neurons were ctivted during different time intervls of the tril. For exmple, neuron A in Fig. 1 ws ctivted mximlly during the pre-sccdic period, fter the offset of the fixtion point, which instructed the niml to perform sccde towrds the rememered cue loction. The neuron ws rodly tuned for sptil loction, responding est for the 135 loction (Fig. 1c). Neuron B ws recorded from n electrode 300 µm prt nd ws ctivted during the post-sccdic epoch, fter the niml hd devited his gze from the fixtion point. Neuron B displyed similr sptil tuning s neuron A, ut its pek response ws temporlly displced y pproximtely 250 ms (Fig. 1, d nd e). nture neuroscience volume 5 no 2 ferury

2 Fig. 1. Inhiitory interction etween two neurons recorded from seprte electrodes. (,) Rster plots nd peri-stimulus time histogrms for two neurons recorded simultneously from electrodes 300 µm prt., spikes per second. (c,d) The neurons sptil tuning represented y Gussin fit. (e) Co-ctivtion function showed mximum overlp of ctivity corresponding to time lg of 250 ms. (f) Cross-correltion histogrm reveling trough, offset from time zero, consistent with direct inhiition from neuron A onto neuron B. Horizontl lines represent seline nd confidence intervls. Yellow line represents shift predictor. A totl of 29,465 nd 3,950 spikes were used for the construction of the cross-correlogrm from the two neurons, respectively. Bin size, 2 ms. Responses shown were otined with cue ppernce t the 135 loction, reltive to the horizontl meridin (upper left loction). Schemtic digrm illustrtes the concept of inhiitory interction ut should not e tken to imply the ctul circuitry etween the two neurons. On the sis of their seline firing rte nd ction potentil shpe, neuron A ws identified s puttive interneuron nd neuron B s pyrmidl neuron. Cross-correltion nlysis indicted tht the dischrge proility of neuron B decresed following n ction potentil y neuron A, with time lg of 2 4 ms (Fig. 1f). Such pttern of inhiition suggests tht the neuron ctivted erlier in time served to dely the response of the second neuron, cusing c Cue 500 ms Dely Dely 500 ms Fix. off Neuron A c Neuron B d Loction (degrees) Loction (degrees) B A Time (ms) its pttern of ctivtion to e forwrded in time. Another pir of neurons showed inhiition in the opposite temporl direction (Fig. 2 c). Neuron A ws mximlly ctive fter the offset of the cue, wheres neuron B responded with phsic response to the onset of the cue nd therefter decyed in time. A significnt trough ws detected in the cross-correltion histogrm (Fig. 2c), suggesting tht in this cse the neuron ctive lter in the tril helped terminte the ctivtion of the neuron responding erlier. We encountered inhiitory CCH troughs mong pirs of neurons ctive in ny tsk epoch (cue, dely, sccde). We found tht most (9/15) presynptic neurons (s ssessed y cross-correltion) were mximlly ctivted erlier in the time course of the tril thn the postsynptic neurons, ut significnt proportion (6/15) hd their pek ctivtions fter the postsynptic neurons. This retroctive ction suggests role for inhiition in re-entrnt s well s feedforwrd circuitry. To quntify the difference in the temporl response profile etween two neurons nd test whether neurons showing inhiitory CCHs were likely to hve different profiles, we used co-ctivtion function compring the firing rte of neurons cross the durtion of the ehviorl tsk (see Methods). The function indicted the time lg tht produced the mximum overlp of responses for ech pir. Among pirs showing cross-correltion troughs, 46.7% were mximlly ctivted t synchronies etween 200 nd 800 ms, compred to 13.3% mong neurons with no significnt interctions nd 7.6% mong neurons with significnt excittory peks (Fig. 3). The oserved distriution of synchronies ws significntly different from wht would e expected if pirs with CCH troughs were drwn rndomly from our entire smple (chisqured test, p < 0.01). The precise vlues of these synchronies e f Co-ctivtion Spike counts Time (s) Spike counts Time (ms) 25 Fig. 2. Inhiitory interctions etween two neurons recorded from the sme electrode. (,) Rster plots nd peri-stimulus time histogrms for the two neurons. (c) Cross-correltion histogrm. Conventions re the sme s in Fig. 1. Gry verticl r (center ±2 ms) represents n intervl over which synchronous firing etween the two neurons cnnot e resolved. Numer of spikes used for the construction of the CCH, from neuron A, 22,139; neuron B, 6,491. Bin size: 1 ms. 176 nture neuroscience volume 5 no 2 ferury 2002

3 Percentge of pirs 60% - 30% - 0% Temporl difference (s) CCH pek No significnt interction CCH trough re proly determined y key events in our tsk, s the ctivtion of most neurons ws synchronized to the onset or offset of the cue nd the eginning or end of the response window. Evidence tht inhiition ws more prevlent etween neurons ctivted t different time lgs ws not restricted to the pirs with significnt troughs ut could e oserved s more pervsive phenomenon y verging responses from our entire popultion. For ech pir of simultneously recorded neurons, we computed the chnge from seline in the segment of the crosscorreltion histogrm where we hd oserved the mximum reduction mong the neurons with significnt troughs (3 ms durtion, 2 ms offset from zero; see elow). Only one side of the cross-correltion histogrm, the one with the lowest overll sum of in counts, ws used for ech pir. This procedure sought to identify suthreshold troughs nd test whether the mgnitude of inhiition ws relted to the neurons profile of ctivtion. The results confirmed tht neurons mximlly ctivted t different time intervls were more likely to show inhiitory effects (Fig. 4). The mximum CCH reduction from seline cross the popultion ws seen for pirs of neurons with temporl differences etween 200 nd 1400 ms. A regression of CCH chnge on temporl difference of ctivtion confirmed tht CCH reduction from seline ws dependent on temporl difference (p < 0.01). The sme, mximl degree of inhiition for neurons exhiiting temporl ctivtion lgs etween 200 nd 1400 ms nd dependence of CCH decrement on temporl difference (regression nlysis, p < 0.01) ws seen when we restricted our smple to pirs showing no significnt CCH peks or troughs (n = 453), indicting tht there my e sl level of inhiition etween lrge numer of pirs in our smple tht does not rech significnce due to the smll contriution of one neuron onto nother. We lso tested whether inhiition ws strongest etween neurons with different sptil preference y verging responses from ll neurons s descried ove, clssified sed on their difference in sptil tuning (Fig. 4). The results similrly showed significnt dependence of inhiition strength on sptil tuning difference (regression nlysis, p < 0.01). These results suggest tht inhiition is primrily present mong neurons with dissimilr sptil or dissimilr temporl profiles of ctivtion, or oth. A cvet of this nlysis is tht y selecting only one side of the CCH we introduced n overll is towrd inhiition. This would Fig. 4. Inhiitory CCH chnges mong the entire popultion of neurons. () Percent of chnge from CCH seline in n intervl of 2 ms offset nd 3 ms durtion, s function of the neurons temporl difference of ctivtion. Positive vlues indicte overll excittion, negtive vlues, inhiition. () Percent of chnge from CCH seline s function of difference in sptil tuning. Responses re shown for neurons with significntly tuned responses in t lest one common epoch (n = 230). Fig. 3. Neurons showing inhiition were mximlly ctive t different time intervls. Histogrm illustrtes distriution of co-ctivtion lg vlues for pirs exhiiting inhiitory interctions (CCH trough; n = 15), pirs exhiiting significnt excittory interctions (CCH pek; n = 118) nd pirs exhiiting no significnt interctions (n = 453). e expected to overestimte the mgnitude of inhiition ut should hve no effect on the reltionship etween temporl lg nd degree of inhiition. Pirs exhiiting lower in heights on one side of the CCH purely due to rndom vrition would e expected to disply rndom distriution of ctivtion lgs. We estimted the strength of inhiitory interctions mong pirs with significnt troughs y fitting n inverted Gussin curve to 1-ms in CCHs. The verge width (2 stndrd devitions) of significnt trough ws 3.0 ms, nd the position of the center trough in ws offset from zero y 2.1 ms. It is possile tht we overestimted the lg of the trough center, s ins corresponding to the center ±2 ms of the CCH were not ville for pirs recorded from the sme electrode. The totl re of the trough, estimted y the integrl of the Gussin, ws equivlent to 2.2 ± 0.4% (s.e.m.) of the totl numer of spikes for the postsynptic neuron. We lterntively identified the oserved extent of trough s the numer of consecutive ins elow the seline round the lowest in. The verge height of ins in trough defined in this mnner corresponded to 47.8 ± 6.4% decrese elow the cross-correltion seline. This nlysis ws sed on cross-correltion histogrms constructed y summing spikes from ll tsk epochs. Inhiitory troughs were detected, however, when we constructed CCHs using spikes recorded during the fixtion period lone. We quntified the strength of inhiitory interctions in the fixtion period y computing the reduction from the cross-correltion seline in the ins tht defined the trough in the entire-tril CCH, in ech pir. The inhiitory troughs in the fixtion period were very similr to those otined from the entire tril, representing 40.5 ± 8.1% reduction from seline. This result suggests tht lthough the strength of interctions my e dynmiclly modulted during the time course of the tril, constitutive inhiition is property of the underlying ntomicl circuitry. For some pirs, we were le to compute the strength of inhiition throughout the time course of the tril, y plotting peri-stimulus cross-correltion histogrm (PSCCH) 21 (Fig. 5 d). Significnt inhiition ws present in ll tsk epochs nd, despite some modultion round the men vlue, the strength of net inhiition remined greter thn zero over the entire length of the tril (Fig. 5d). In some instnces, we oserved pirs of neurons with firingrte modultion suggestive of inhiition ut no such interction ws confirmed y cross-correltion nlysis. This is not surprising considering tht corticl neurons receive hundreds of CCH chnge 20% 10% 0% 10% 20% Temporl difference (s) Sptil difference ( ) nture neuroscience volume 5 no 2 ferury

4 c d inhiitory inputs, prtly synchronized through electrotonic coupling 22,23. A concerted input from lrge numer of interneurons is therefore likely to ccount for the functionl properties of ech cell, nd the strength of ech inhiitory connection is expected to e firly low on verge. Even when the presence of n inhiitory interction etween pir of neurons ws documented, single inhiitory synpse could not fully ccount for the firing properties of the postsynptic neuron. Indeed, oth in Figs. 1 nd 2, prtil overlp in the two neurons ptterns of excittion is pprent, suggesting tht the two neurons my lso receive some degree of common excittory inputs. DISCUSSION Our results indicte tht inhiition in the prefrontl cortex is most often seen mong neurons ctive t different time intervls during execution of ehviorl tsk. This finding suggests role for inhiition in shping the time course of ctivtion of prefrontl neurons. It hs een known tht individul neurons re mximlly ctivted during different tsk epochs of working memory tsk relted, respectively, to the registrtion of sensory event, the mintennce on line of representtion of tht event, nd the execution, or not, of n pproprite response required y tsk contingencies Our experiments suggest tht the temporl profile of ctivtion of prefrontl neurons is sculpted y inhiitory interctions etween cells ctivted t different phses of the tril, typiclly t trnsition points coincident with the next step in sequence of ctions or stte chnges. This effect of inhiition is different from the shrpening of stimulus selectivity of visul or prefrontl neurons ecuse the ltter involves minly concurrent, not sequentil, responses. A sutle ut Fig. 5. Peri-stimulus cross-correltion histogrm (PSCCH). () Histogrm showing predicted vlue of coincident spikes mong the two neurons depicted in Fig. 2 under the ssumption tht the spike trins were independent, s function of time from the eginning of tril. Dshed, horizontl lines mrk cue, dely nd sccde epochs. Horizontl (PSTH) in size 10 ms, verticl (CCH) in size 1 ms, smoothed y two-dimensionl Gussin kernel with stndrd devitions of 100 ms in the horizontl nd 1 ms in the verticl dimension. The predictor ws estimted y rndomly shuffling the order of tril presenttion nd then clculting the numer of coincident spikes t ech in (verge of 100 rndom shuffles is shown). () Rw PSCCH. Vlues in the ins corresponding to the center ±2 ms of the CCH (gry r) were estimted y liner interpoltion prior to smoothing. (c) Normlized trough. (d) Averge vlue of normlized trough in n intervl 3 ms wide in the verticl dimension, offset y zero y 2 ms. Yellow line represents overll verge of inhiitory decrese. functionlly importnt oservtion is tht inhiition etween pirs of prefrontl neurons ws detected consistently throughout the length of ech ehviorl tril, even during fixtion, efore either neuron ws mximlly ctivted. Although our nlysis cnnot exclude finer degree of modultion such s those descried previously 24,25, our results indicte tht inhiition is engged from the eginning of the tril 26, s result of the underlying pttern of ntomicl circuitry, nd tht the neurl processes of inhiition nd presumly disinhiition re fundmentl to the forwrd flow of opertions. An importnt cvet for our study is tht cross-correltion nlysis does not provide direct evidence of synptic connection etween two neurons, ut cn only revel the effective connectivity etween them. It is therefore possile tht ny of the interctions tht we oserved were indirect, nd in fct, the puttive presynptic neuron in our dt ws not lwys identified s n interneuron. The cell tht we identified s presynptic in ech cse my hve een innervting the ctul inhiitory neuron, or the two my hve shred common input. Such possiilities re not unlikely considering tht prefrontl corticl interneurons receive most of their excittory inputs from nery pyrmidl cells 27 29, forming we of direct nd indirect connections over short distnces 29. However, the low incidence of ctivtion synchronies etween pirs with excittory connectivity s shown in Fig. 3, finding consistent with previous results 20, mkes it highly likely tht even when the underlying connections we oserved were indirect, inhiition ws directed mong neurons with dissimilr timing of pek ctivtions. This conclusion is strengthened y the results of the popultion verge nlysis shown in Fig. 4, which suggests tht inhiition, direct or indirect, is predominntly encountered mong neurons ctive t different time intervls. Direct evidence for role of inhiition in sculpting the neurons temporl profile of ctivtion is provided y experiments involving iontophoretic ppliction of GABA ntgonists. Locl ppliction of icuculline methiodide (BMI) in the prefrontl cortex produces n overll increse in dischrge rte tht is most often mnifested s rodening of receptive fields 7. Anlysis of the time course of neuronl responses reveled, however, tht in mny instnces, drug ppliction produced ctivtion in dditionl tsk epochs, which ws not due to n overll increse in responsiveness ut ws selective for prticulr trget loction nd therefore sptilly tuned. Inhiition serving in the estlishment of receptive field properties hs een descried efore for other corticl res s well s the prefrontl cortex nd it could serve to shpe the memory fields of individul neurons 7,30. A prllel role for inhiition in the temporl domin could e to enle the 178 nture neuroscience volume 5 no 2 ferury 2002

5 prefrontl network to permit the ctivtion of neuron y given stimulus, link the representtion of rememered stimulus to other stimuli nd prevent interference from other ctivtions tht might engge conflicting processes. Neuronl dischrges persisting fter the offset of sensory stimulus re thought to constitute the neurl correlte of mentl representtion, providing mechnism oth for integrting informtion over time nd for insulting motor-generting circuits from sensory stimultion, n essentil feture of higher cognitive functions Theoreticl studies of the temporl orgniztion of ehvior hve modeled the corticl circuitry tht could prtition complex ehviors into discrete components, ech represented y seprte neuronl popultions 33,34, similr to those oserved experimentlly in prefrontl cortex Modeling studies hve further shown tht neuronl firing cn e mintined in the sence of direct stimultion through mesh of recurrent, excittory connections tht llow responses to revererte in the network even fter the originl sensory stimulus is no longer present Recurrent excittion in vivo 20 nd in vitro 40 hs een directly documented in previous experiments from our lortory. Our current results provide new insight into prefrontl circuit functions, suggesting tht feedforwrd nd feedck inhiition my e the proximl opertionl mechnisms for sequencing neuronl ctivity nd occsioning the trnsient ctivtion sttes tht occur during discrete phses of the cognitive opertions involved in working memory. METHODS Behviorl trining, surgery nd electrophysiologicl recordings were performed s descried previously 7,20,32,41. Monkey surgery nd ehviorl testing protocols were in ccord with guidelines set y the Ntionl Institutes of Helth, reviewed nd pproved y the Yle University Animl Cre nd Use Committee. Behviorl tsk. Monkeys st in primte chir with their heds fixed, fcing tngent screen plced typiclly 50 cm wy from them. The nimls initited tril y fixting centrl point of in size. While they mintined fixtion, 1 cue stimulus ppered on the screen for 500 ms. The cue ws followed y dely period of s, t the end of which the fixtion point ws extinguished nd the niml ws trined to shift his gze to the loction of the rememered trget, within 500 ms, in order to receive liquid rewrd. The cue ppered rndomly in ech tril t 1 of 8 possile loctions round the fixtion point, t n eccentricity of For some recordings, either 2 or 25 cue loctions were used insted. Cell clssifiction. We clssified recorded neurons into puttive excittory or inhiitory, relying on ction-potentil wveform nd firing-rte criteri, s descried previously 41,42. For suset of the dt recorded with nrrower nd-pss filter setting of khz, clssifiction ws sed on 2-mens cluster nlysis, using the width of the ction potentil nd the seline firing rte s the 2 relevnt dimensions. The nlysis ws performed with Systt sttisticl softwre (SPSS, Chicgo, Illinois). Cross-correltion nlysis. Cross-correltion histogrms (CCHs) were constructed from the spike trins of simultneously recorded pirs of neurons. We lso constructed shift predictors y first grouping trils depending on cue loction nd then shifting the order of trils y one tril position. For ech neuron pir, we constructed 2-ms-in CCH extending ±100 ms round time zero nd identified troughs in the 10 ms round time zero. Cross-correltion histogrms constructed for neurons recorded from the sme electrode cnnot identify spikes occurring simultneously, s the two superimposed ction potentils produce wveform tht cn e clssified s neither spike. This results in n rtificil trough in the center of the CCH. Our nlysis therefore did not consider CCH ins within ±2 ms from time zero for pirs of neurons from the sme electrode. To evlute the sttisticl significnce of troughs, we computed the seline of the rw correlogrm defined s the verge of hlf the ins in the flnks of the CCH. We then identified troughs tht exceeded the seline y numer of shift-predictor stndrd devitions corresponding to significnce level of This represents the upper ound of significnce, ecuse djcent ins in the cross-correlogrm re likely to e correlted nd ecuse in some cses the confidence intervl corresponded to spike count vlues less thn zero. None of the 586 shift predictors exceeded these confidence intervls. We restricted our nlysis to pirs of neurons tht displyed troughs offset from time zero nd in the sence of significnt offset peks in the sme time scle. Co-ctivtion function. For ech pir of simultneously recorded neurons, we estimted the time lg tht produced the mximum temporl overlp of ctivity. For this purpose we constructed 50-ms-in peristimulus time histogrms (PSTHs) for ll neurons, spnning period of T=5 s (fixtion period through intertril intervl). PSTHs were constructed seprtely for ech of L sptil loctions tested (typiclly 8) nd the seline firing rte computed in the fixtion period ws sutrcted from ech PSTH in. We computed co-ctivtion function C s follows: C AB L T Σ Σ l l ( τ ) = r ( t) r ( t + τ ) A l = 1 t= 1 Here r l A(t) represents the inned firing rte of neuron A t time t from the onset of the PSTH, for stimulus loction l. This is in essence cross-correltion function, operting t the time-scle of ehviorl events, unlike the cross-correltion of spike trins, which is most suited to exmine events in the time scle of synptic interctions. The temporl lg could vry etween 2.5 nd 2.5 s (±T/2). Becuse the fixtion period in one tril followed the intertril intervl of the previous tril, the co-ctivtion function is periodic. For ech neuron pir, we computed the solute vlue of the time lg tht produced the mximum co-ctivtion. Acknowledgements We wish to thnk S. Ro nd M. Frnowicz, who prticipted in these experiments. This reserch ws supported y NIH grnt MH38546 to P.S.G.-R. nd McDonnell-Pew Progrm in Cognitive Neuroscience Awrd to C.C. Competing Finncil Interests The uthors declre tht they hve no competing finncil interests. RECEIVED 12 DECEMBER; ACCEPTED 17 DECEMBER 2001 B 1. Ben-Yishi, R., Br-Or, R. L. & Sompolinsky, H. Theory of orienttion tuning in visul cortex. Proc. Ntl. Acd. Sci. USA 92, (1995). 2. Somers, D. C., Nelson, S. B. & Sur, M. An emergent model of orienttion selectivity in ct visul corticl simple cells. J. Neurosci. 15, (1995). 3. Troyer, T. W., Krukowski, A. E., Priee, N. J. & Miller, K. D. Contrstinvrint orienttion tuning in ct visul cortex: thlmocorticl input tuning nd correltion-sed intrcorticl connectivity. J. Neurosci. 18, (1998). 4. Ferster, D. & Miller, K. D. Neurl mechnisms of orienttion selectivity in the visul cortex. Annu. Rev. Neurosci. 23, (2000). 5. McLughlin, D., Shpley, R., Shelley, M. & Wielrd, D. J. A neuronl network model of mcque primry visul cortex (V1): orienttion selectivity nd dynmics in the input lyer 4Cα. Proc. Ntl. Acd. Sci. USA 97, (2000). 6. Wng, Y., Fujit, I. & Murym, Y. Neuronl mechnisms of selectivity for oject fetures reveled y locking inhiition in inferotemporl cortex. Nt. Neurosci. 3, (2000). 7. Ro, S. G., Willims, G. V. & Goldmn-Rkic, P. S. Destruction nd cretion of sptil tuning y disinhiition: GABA(A) lockde of prefrontl corticl neurons engged y working memory. J. Neurosci. 20, (2000). 8. Goldmn-Rkic, P. S. Topogrphy of cognition: prllel distriuted networks in primte ssocition cortex. Annu. Rev. Neurosci. 11, (1988). 9. Fuster, J. M. The prefrontl cortex nd its reltion to ehvior. Prog. Brin. Res. 87, (1991). 10. Funhshi, S., Bruce, C. J. & Goldmn-Rkic, P. S. Mnemonic coding of visul spce in the monkey s dorsolterl prefrontl cortex. J. Neurophysiol. 61, (1989). 11. Funhshi, S., Bruce, C. J. & Goldmn-Rkic, P. S. Visuosptil coding in nture neuroscience volume 5 no 2 ferury

6 primte prefrontl neurons reveled y oculomotor prdigms. J. Neurophysiol. 63, (1990). 12. Funhshi, S., Bruce, C. J. & Goldmn-Rkic, P. S. Neuronl ctivity relted to sccdic eye movements in the monkey s dorsolterl prefrontl cortex. J. Neurophysiol. 65, (1991). 13. Fuster, J. M. Prefrontl cortex nd the ridging of temporl gps in the perception ction cycle. Ann. NY Acd. Sci. 608, ; discussion (1990). 14. Fuster, J. M. The prefrontl cortex, meditor of cross-temporl contingencies. Humn Neuroiology 4, (1985). 15. Fuster, J. M., Bodner, M. & Kroger, J. K. Cross-modl nd cross-temporl ssocition in neurons of frontl cortex. Nture 405, (2000). 16. Perkel, D. H., Gerstein, G. L. & Moore, G. P. Neuronl spike trins nd stochstic point processes. II. Simultneous spike trins. Biophys. J. 7, (1967). 17. Fetz, E. E., Toym, K. & Smith, W. in Cererl Cortex, Volume 9 (ed. Peters, A.) 1 47 (Plenum, New York, 1991). 18. Reid, R. C. & Alonso, J. M. Specificity of monosynptic connections from thlmus to visul cortex. Nture 378, (1995). 19. Aertsen, A. M., Gerstein, G. L., Hi, M. K. & Plm, G. Dynmics of neuronl firing correltion: modultion of effective connectivity. J. Neurophysiol. 61, (1989). 20. Constntinidis, C., Frnowicz, M. N. & Goldmn-Rkic, P. S. Coding specificity in corticl microcircuits: multiple electrode nlysis of primte prefrontl cortex. J. Neurosci. 21, (2001). 21. Nowk, L. G., Munk, M. H., Nelson, J. I., Jmes, A. C. & Bullier, J. Structurl sis of corticl synchroniztion. I. Three types of interhemispheric coupling. J. Neurophysiol. 74, (1995). 22. Gison, J. R., Beierlein, M. & Connors, B. W. Two networks of electriclly coupled inhiitory neurons in neocortex. Nture 402, (1999). 23. Beierlein, M., Gison, J. R. & Connors, B. W. A network of electriclly coupled interneurons drives synchronized inhiition in neocortex. Nt. Neurosci. 3, (2000). 24. Vdi, E. et l. Dynmics of neuronl interctions in monkey cortex in reltion to ehviourl events. Nture 373, (1995). 25. Riehle, A., Grun, S., Diesmnn, M. & Aertsen, A. Spike synchroniztion nd rte modultion differentilly involved in motor corticl function. Science 278, (1997). 26. Orm, M. W., Htsopoulos, N. G., Richmond, B. J. & Donoghue, J. P. Excess synchrony in motor corticl neurons provides redundnt direction informtion with tht from corse temporl mesures. J. Neurophysiol. 86, (2001). 27. Elhnny, E. nd White, E.L. Intrinsic circuitry: synpses involving the locl xon collterls of corticocorticl projection neurons in the mouse primry somtosensory cortex. J. Comp. Neurol. 291, (1990). 28. Melchitzky, D. S., Sesck, S. R., Puck, M. L. & Lewis, D. A. Synptic trgets of pyrmidl neurons providing intrinsic horizontl connections in monkey prefrontl cortex. J. Comp. Neurol. 390, (1998). 29. Krimer, L. S. & Goldmn-Rkic, P. S. Prefrontl microcircuits: memrne properties nd excittory input of locl, medium, nd wide ror interneurons. J. Neurosci. 21, (2001). 30. Goldmn-Rkic, P. S. Cellulr sis of working memory. Neuron 14, (1995). 31. Funhshi, S., Chfee, M. V. & Goldmn-Rkic, P. S. Prefrontl neuronl ctivity in rhesus monkeys performing delyed nti-sccde tsk. Nture 365, (1993). 32. Constntinidis, C., Frnowicz, M. N. & Goldmn-Rkic, P. S. The sensory nture of mnemonic representtion in the primte prefrontl cortex. Nt. Neurosci. 4, (2001). 33. Dehene, S. & Chngeux, J. P. A hierrchicl neuronl network for plnning ehvior. Proc. Ntl. Acd. Sci. USA 94, (1997). 34. Chngeux, J. P. & Dehene, S. Hierrchicl neuronl modeling of cognitive functions: from synptic trnsmission to the Tower of London. Int. J. Psychophysiol. 35, (2000). 35. Amit, D. J. & Brunel, N. Model of glol spontneous ctivity nd locl structured ctivity during dely periods in the cererl cortex. Cere. Cortex 7, (1997). 36. Lismn, J. E., Fellous, J. M. & Wng, X. J. A role for NMDA-receptor chnnels in working memory. Nt. Neurosci. 1, (1998). 37. Cmperi, M. & Wng, X. J. A model of visuosptil working memory in prefrontl cortex: recurrent network nd cellulr istility. J. Comput. Neurosci. 5, (1998). 38. Compte, A., Brunel, N., Goldmn-Rkic, P. S. & Wng, X. J. Synptic mechnisms nd network dynmics underlying sptil working memory in corticl network model. Cere. Cortex 10, (2000). 39. Guigon, E., Dorizzi, B., Burnod, Y. & Schultz, W. Neurl correltes of lerning in the prefrontl cortex of the monkey: predictive model. Cere. Cortex 5, (1995). 40. Go, W.-J., Krimer, L.S. nd Goldmn-Rkic, P.S. Presynptic regultion of recurrent excittion y D1 receptors in prefrontl circuits. Proc. Ntl. Acd. Sci. USA 98, (2001). 41. Ro, S.G., Willims, G.V. & Goldmn-Rkic, P.S. Isodirectionl tuning of djcent interneurons nd pyrmidl cells during working memory: evidence for microcolumnr orgniztion in PFC. J. Neurophysiol. 81, (1999). 42. Wilson, F.A.W., O Sclidhe, S.P. & Goldmn-Rkic, P.S. Dissocition of oject nd sptil processing domins in primte prefrontl cortex. Science 260, (1993). 180 nture neuroscience volume 5 no 2 ferury 2002