Mechanisms underlying cross-orientation suppression in cat visual cortex

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1 Mehnisms underlying ross-orienttion suppression in t visul ortex 6 Nture Pulishing Group Nihols J Priee & Dvid Ferster In simple ells of the t primry visul ortex, null-oriented stimuli, whih y themselves evoke no response, n ompletely suppress the spiking response to optimlly oriented stimuli. This ross-orienttion suppression hs een interpreted s evidene for ross-orienttion inhiition: synpti inhiition mong ortil ells with different preferred orienttions. In intrellulr reordings from simple ells, however, we found tht ross-oriented stimuli suppressed, rther thn enhned, synpti inhiition nd, t the sme time, suppressed synpti exittion. Muh of the suppression of exittion ould e ounted for y the ehvior of geniulte rely ells: ontrst sturtion nd retifition in rely ell responses, when pplied to liner feedforwrd model, predited ross-orienttion suppression of the modultion (F) omponent of exittion evoked in simple ells. In ddition, we found tht the suppression of the spike output of simple ells ws lmost twie the suppression of their synpti inputs. Thus, ross-orienttion suppression, like orienttion seletivity, is strongly mplified y threshold. The feed-forwrd model of visul ortex proposed y Huel nd Wiesel hs endured in lrge prt euse of its simpliity : ortil simple ells derive their orienttion seletivity from the lignment of the reeptive fields of presynpti geniulte rely ells. Where the feed-forwrd model hs trditionlly filed, however, is in ounting for severl nonliner properties of simple ells. One suh property is rossorienttion suppression, wherey stimuli oriented t 9 to ell s preferred orienttion (msk stimuli) suppress the response to simultneously presented stimuli t the preferred orienttion (test stimuli) 7. As n intrinsilly orienttion-seletive mehnism, rossorienttion suppression hs often een interpreted s eing ortil in origin. In the most widely proposed mehnism, ortil ells preferring one orienttion synptilly inhiit ells preferring orienttions 9 wy. This ross-orienttion inhiition is mjor feture of mny reurrent models of ortil funtion, in whih it ontriutes not only to ross-orienttion suppression ut lso to the origin of orienttion seletivity, shrpening the wek orienttion is provided y exittory input from rely ells of the lterl geniulte nuleus (LGN) 8. These models re onsistent with experiments demonstrting tht the ortil pplition of GABA A ntgonists redues orienttion seletivity 4. The intrellulr evidene for ross-orienttion inhiition, however, is somewht equivol 5 8.Ifross-orienttion inhiition is wek or sent in the ortex, then wht is the mehnism underlying ross-orienttion suppression? Some properties of ross-orienttion suppression re more losely ssoited with geniulte rely ells thn with ortil neurons: suppression is lrgely monoulr 5, n e evoked y stimuli of high temporl frequeny,9, is reltively immune to ontrst dpttion 9 nd seems to preede surround suppression. In light of these results, it hs een proposed tht ross-orienttion suppression rises from short-term synpti depression t the thlmoortil synpse. Reent mesurements indite, however, tht thlmoortil depression my not e strong enough to ount for strong rossorienttion suppression,. To investigte the mehnisms underlying ross-orienttion suppression, we reorded intrellulrly from simple ells in t visul ortex. We found tht the ross-oriented msk grting deresed, rther thn enhned, synpti inhiition. At the sme time, the msk deresed the synpti exittion evoked y the test grting t the preferred orienttion. In ddition, we found tht muh of the suppression of exittion ould e ounted for quntittively y the two nonliner properties of geniulte rely ells: spike rte retifition nd response sturtion. When pplied to liner feed-forwrd model, these nonlinerities give rise to ross-orienttion suppression in the modultion (F) omponent of the exittory input to simple ells. This suppression ws omprle in strength to wht we oserved experimentlly in the F omponent of memrne potentil responses of simple ells. The suppression in spike responses, however, ws pproximtely twie the size of the suppression in memrne potentil. Therefore, ross-orienttion suppression, like orienttion seletivity, diretion seletivity nd the distintion etween simple nd omplex ells, is strongly mplified y spike threshold. RESULTS We mde whole-ell pth reordings from simple ells in re 7 of the nesthetized t with potssium (K + )-sed internl solution in the reording pipettes. For eh neuron, we presented drifting grtings t the preferred orienttion (test stimulus) nd the orthogonl Deprtment of Neuroiology nd Physiology, Northwestern University, 45 North Sheridn Drive, Evnston, Illinois 68, USA. Correspondene should e ddressed to D.F. (ferster@northwestern.edu). Reeived 8 Septemer 5; epted Ferury 6; pulished online 5 Mrh 6; doi:.8/nn66 NATURE NEUROSCIENCE ADVANCE ONLINE PUBLICATION

2 6 Nture Pulishing Group V m (mv) Test % Test 8% Test % F mplitude (mv) V m (mv) Time (s) Memrne potentil Msk % Msk 8% Msk % % test F mplitude ms d e f % test % test 8 8 Msk ontrst (%) Msk ontrst (%) Spike rte orienttion (msk stimulus) t two different ontrsts: 8% (low) nd % (high). In ddition, we presented four plid stimuli onsisting of the four omintions of test nd msk stimuli. The grtings were presented in rndom order t the optiml sptil frequeny nd, exept where noted, t temporl frequeny of 4 Hz (Fig. ). The lteny of the response to eletril stimultion of the LGN ws mesured in four neurons; of these, two were identified s reeiving monosynpti exittory input from the LGN nd two s reeiving only polysynpti input 4. Simple ells, y definition, responded to the optimlly oriented test grting with lrge modultion of memrne potentil nd spike rte (Fig. ); the higher ontrst evoked lrger response (left olumn in Fig.,; quntified in Fig. d,e). The orthogonl msk grting eliited little response on its own (top row of Fig.,; quntified in Fig. d,e), ut the msk s effets were lerly reveled when it ws superimposed on the test grting. With the test grting t low ontrst (middle row), the high-ontrst msk redued the modultion of 6 Spike rte % 8% % % test Figure A summry of ross-orienttion effets in the popultion. () Crossorienttion suppression oserved in the memrne potentil responses of simple ells. Memrne potentil modultion (F omponent, fter spikes were removed with medin filter) evoked y plid stimulus s funtion of the response to the orresponding test stimulus lone. The msk stimulus ws lwys % ontrst. The test stimulus ws either 8% ontrst or % ontrst. () Cross-orienttion suppression for spike rte for the 6 ells (out of ) tht spiked relily. Spike rtes were derived from the sme reords s those used for memrne potentil. () The suppression rtio for spike rte s funtion of the suppression rtio for memrne potentil for eh neuron. (d) Suppression rtio derived from predited spike rte s funtion of the suppression rtio mesured from reorded spike rte. Predited spike rtes were otined y pplying the memrne potentil to spike rte trnsformtion for eh ell (s in Fig. f) to the mesured memrne potentil responses (s in Fig. ) spikes per s Mesured Predited Memrne potentil (mv) Figure Cross-orienttion suppression in simple ells of primry visul ortex. () Intrellulrly reorded responses to rndom sequene of the nine grting nd plid stimuli (one lok of stimuli), s shown in the insets ove the tres. Stimuli drifted t 4 Hz. () Cyle-verged memrne potentil responses (fter removl of spikes) to grtings or plids (insets). Contrst of the onstituent test grting (preferred orienttion) nd msk (orthogonl orienttion) re indited. () Cyle-verged spike rtes reorded from the sme ell (lk urves) or predited y the memrne potentil response using the mesured trnsformtion etween memrne potentil nd spike rte (lue fill). (d) Memrne potentil modultion mplitudes (F Fourier omponent) for eh test ontrst plotted s funtion of the msk ontrst. (e) Reorded spike rte responses (lk) nd predited spike rte responses (lue) for eh test ontrst plotted s funtion of msk ontrst. (f) The reltionship etween memrne potentil nd spike rte derived from responses to vriety of visul stimuli. Gry points, spike rte s funtion of men memrne potentil for individul -ms epohs. Open squres, verge of the individul points for -mv ins (error rs indite s.d.). Solid line, power-lw fit to the individul points (eqution ()). memrne potentil y 5% nd the firing rte y over 95%. The highontrst msk lso redued the response to the high-ontrst test grting, lthough y less: memrne potentil ws redued y 4% nd spike rte y 47% (ottom row). For oth test ontrsts, however, the msk-indued redution in spike response ws proportiontely muh lrger thn the orresponding redution in the memrne potentil modultion. It is likely tht this mplifition of suppression rose from the nonliner reltionship etween memrne potentil nd spike rte (Fig. f; see elow). The effets of the low-ontrst test V m F (mv) for plid Suppression rtio for mesured spike rte 5 5 % test 5 5 V m F (mv) for test Spike rte F for test d Spike rte F (sp/s) for plid Suppression rtio for mesured spike rte Suppression rtio for V m Suppression rtio for predited spike rte ADVANCE ONLINE PUBLICATION NATURE NEUROSCIENCE

3 6 Nture Pulishing Group Tle Summry of the suppression rtios High-ontrst msk (%) Low-ontrst test (8%) High-ontrst test (%) F DC F DC V m.48**.7**.9**.89 Spike rte.**.**.7**.68** G e.45**..86*.88* G i.5** Toy model V m LGN predition V m.5**.48**.9**.7** LGN predition V m (X ).54**.5**.9**.9** LGN predition V m (Y ).45**.47**.8**.5 Low-ontrst msk (8%) Low-ontrst test (8%) High-ontrst test (%) F DC F DC V m...5. Spike rte Toy model V m LGN predition V m LGN predition V m (X ).85**..9**.98 LGN predition V m (Y ) Vlues indite the medin suppression rtios derived from either the men (DC) or fundmentl modultion (F) omponent of the response to low-ontrst (8%) or highontrst (%) test grting. Signifine ws determined using ootstrp method 5. *P o.5; **P o.. grting on memrne potentil responses were generlly smll (ompre left nd middle olumns of Fig. ). The effets on spike rte were lrger thn those for memrne potentil (Fig. ; Supplementry Fig. online). To quntify ross-orienttion suppression ross the popultion of reorded simple ells, we plotted the modultion omponent (F) of the response to the plid stimulus (test + high-ontrst msk) s funtion of the response to the test grting lone (Fig. ). For memrne potentil (Fig. ), the medin effet of the msk ws signifint redution in response, to 48% of the test response for the low-ontrst test stimulus (P o., using ootstrp method) nd to 9% for the high-ontrst stimulus (P o.). The differene etween low nd high ontrst in the mgnitude of the suppressive effet ws highly signifint (P o.). The low-ontrst msk grting (8%) hd little effet on the memrne potentil response to the test grting of either ontrst (: % redution; % test: 5% inrese; Supplementry Fig. online). The effets on spike rte (Tle ) did not reh signifine, given the noisiness of the mesurements when stimulus ontrsts nd spikes rtes re low. The suppressive effets of the high-ontrst (%) msk were fr lrger for spike rte (Fig. ) thn for memrne potentil: spike rte ws suppressed to % of the test response for low-ontrst test stimuli (P o.) nd to 7% for high-ontrst test stimuli (P o.). Note tht in mny ells, the spike response to the low-ontrst test stimulus ws ompletely suppressed y the msk (Fig. ). To quntify this differene more diretly, we lulted suppression rtio for eh grting-plid pir the response to the plid divided y the response to the test stimulus lone nd plotted this rtio for spike rte responses ginst the rtio for memrne potentil responses (Fig. ). Most of the points ly elow line of slope (P o.). For the plid omposed of the high-ontrst test grting, the medin mount of suppression ws more thn times lrger for spike rte thn for memrne potentil (9% versus 9%); for the plid omposed of the low-ontrst test grting, the suppression rtio ws.7 times lrger for spike rte thn for memrne potentil (89% versus 5%; Tle ). One likely mehnism tht my mplify the msk-indued suppression in spike rte reltive to the suppression in memrne potentil is the expnsive nonlinerity of spike threshold. To test this possiility, we quntified the threshold nonlinerity, pplied it to the memrne potentil responses to otin predition of spike rte, nd ompred these preditions to the mesured spike rte. Spike threshold ws quntified in eh ell y mesuring, in -ms epohs, the verge firing rte nd memrne potentil during the response to vriety of different visul stimuli (Fig. f; Supplementry Fig. ), together with verges of the individul points ontined in -mv intervls. The individul points were then fit with power-lw: RðV m Þ¼kV m V rest p + ðþ where R is the spike rte, V m is the memrne potentil, V rest is the resting memrne potentil nd the susript + indites retifition (R for V m o V rest is ). The resulting fit losely mthed the verge dt, ounting for t lest 99.5% of the vrine in the verge dt for ll ells. We then pplied the power-lw fit to eh time point in the responses (Fig. ) to derive preditions of spike rte (Fig.,d). These preditions losely mthed the reorded spike rtes (Fig.,d) nd, like them, showed greter ross-orienttion suppression thn the memrne potentil responses themselves: tht is, s result of threshold, reltively modest msk-indued redutions in the memrne potentil modultion led to lrge redutions in firing rte. Note tht the power lw ws hosen for its simpliity 5 9 ut ny numeril formultion of the threshold tht ptures the expnsive nonlinerity, suh s threshold-liner funtion or simple look-up tle, would predit sustntil mplifition of suppression etween synpti input nd spike output. We found tht spike threshold ounted well for the mplifition of the msk-indued effet in most ells (Fig.,d). When the suppression rtio derived from the mesured spike responses (lk tres in Fig. ) ws plotted ginst the predited suppression rtio for spike rte (lue tres in Fig. ), the points generlly fell long line of slope. The men horizontl distne to the digonl ws.8 for memrne potentil (Fig. ) nd.4 for predited spike rte (Fig. d); 47% of the vrine in the spike suppression rtio ws ounted for y the memrne potentil suppression rtio. When threshold ws tken into ount, this perentge rose to 8%. Tht threshold mplifies ross-orienttion suppression mens tht ny ortil model need only ount for out hlf s muh suppression in the synpti inputs to simple ells s is oserved in the spike rte. Beuse the msk grting lters the ontrst of the visul stimuli, one possile mehnism tht ould ontriute to the effets of rossorienttion suppression on memrne potentil is ontrst dpttion. Adpttion uses memrne hyperpolriztion tht develops with time ourse of severl seonds,. We therefore ompred the degree of suppression in the memrne potentil response tht ws present during the first nd lst (fourth) seonds of the response to eh stimulus. Beuse there ws no signifint differene (P ¼.), we onluded tht dpttion does not ontriute to the ross-orienttion effet. Cross-orienttion suppression in g e nd g i Two wys in whih the msk ould derese the memrne potentil responses evoked y the test grting re n inrese in synpti NATURE NEUROSCIENCE ADVANCE ONLINE PUBLICATION

4 6 Nture Pulishing Group V m (mv) g (ns) g i (ns) g e (ns) % msk lnk % test % test + msk.4 na. na.4 na inhiition (tht is, ross-orienttion inhiition) nd msk-evoked derese in synpti exittion. To determine whih (if not oth) of these mehnisms opertes in the ortex, we estimted the stimulusevoked hnges in synpti ondutne: in nine ells, we reorded the memrne potentil while depolrizing nd hyperpolrizing the neuron with different levels of stedy injeted urrent. Voltge-gted sodium (N + )ndk + urrents were loked with esium (Cs + )nd lidoine N-ethyl romide quternry slt (QX-4) in the eletrode solution (Methods). The effets of Cs + nd QX-4 ppered in the first few minutes of eh reording s depolriztion (B mv), n inrese in input resistne (B), rodening of tion potentils (4 ms) nd rise in threshold. Synpti ondutnes were estimted from the memrne eqution t eh time point in the response. Note tht wheres totl ondutne n e mesured in solute terms from the urrent-voltge reltionship, inhiitory nd exittory ondutne n only e mesured reltive to the resting levels, whih re tken to e. (Tht is, negtive vlues of ondutne represent dereses elow the resting levels.) In seven of these nine ells, the lteny of response to eletril stimultion of the LGN ws used to determine whether the ell reeived monosynpti input (six ells) or polysynpti input (one ell) from the LGN (Supplementry Fig. online). Injeted urrent hnged the lne of the hyperpolrizing nd depolrizing omponent of the response (Fig. ). During the strongest hyperpolrizing urrent (lk), the stimuli evoked mostly depolriztion reltive to the lnk stimulus (uniform luminne) (Fig. first olumn); here, the driving fore on exittory postsynpti urrents (EPSCs) ws lrge nd on inhiitory postsynpti urrents (IPSCs) ws smll. With redued urrent (red), the potentil during the lnk stimulus depolrized euse of the Cs + -indued lok of K + hnnels, reduing the driving fore on EPSCs nd inresing the driving fore on IPSCs. The evoked responses were therefore primrily hyperpolrizing + msk ms d f g e F (ns) plid g i F (ns) plid 8% % F 4 g e F (ns) test g e DC (ns) test g i F (ns) test reltive to the lnk. At ll urrents, however, the msk redued the response to the test grtings. Given the reords (Fig. ), we were le to derive stimulus-evoked hnges in totl ondutne from the urrent-voltge reltionship t eh point (Fig. ); we estimted exittory nd inhiitory ondutnes fter ssuming pproprite vlues for their reversl potentils (Fig. ). As noted previously 5,, exittion nd inhiition were evoked in push-pull or lternting pttern. Muh like the memrne potentil responses, synpti exittion nd inhiition were oth redued y the msk stimulus. With the test stimulus t low-ontrst, the suppression rtios (F omponent) were.9 for exittion nd.4 for inhiition; with the test stimulus t high-ontrst, the rtios were.9 nd.9 (Supplementry Fig. 4 online). To onfirm tht the derived mesures of exittory nd inhiitory ondutne were urte, we reonstruted the memrne potentil from the estimtes of ondutne using the memrne eqution (Fig. ). If the derived ondutnes hd een distorted y the tivtion of voltge-gted urrents or y other errors, then the memrne potentil reonstrutions would diverge signifintly. Insted, the mesured nd reonstruted potentils superimposed to the point tht the reonstruted tres were mostly osured (light tres underneth thiker tres in Fig. ). Over the nine ells, the reonstruted potentils ounted for over 98.5% of the vrine of the reorded tres. For the nine tested ells, the medin suppression rtios for the F omponent of the exittory nd inhiitory ondutnes were.45 nd.5 for the low-ontrst test grting, nd.86 nd.88 for the high-ontrst test grting (Fig. d g, Tle ). These redutions were omprle to the redution in mplitude of the memrne potentil modultion (Fig. ). The msk stimulus hd only smll, nonsignifint effets on the men (DC) omponent of the exittion nd inhiition (P 4.). We onluded tht it ws unlikely tht e g g e DC (ns) plid g i DC (ns) plid 4 4 DC 4 g i DC (ns) test Figure Estimtes of exittory nd inhiitory ondutne evoked y grting nd plid stimuli. ( ) In, memrne potentil tres reorded with three different mounts of injeted urrent (red, lue nd lk). The thiker tres, plotted underneth the reorded potentils in light red, light lue nd gry, show the memrne potentil reonstruted from the estimtes of exittory nd inhiitory ondutne shown in. These reonstrutions ounted for t lest 98.5% of the vrine in the reorded memrne potentil tres. () Evoked hnges in totl memrne ondutne. () Chnges in exittory nd inhiitory ondutne reltive to the resting level extrted using the memrne potentil eqution (Methods). (d) The modultion (F omponent) of the hnges in exittory ondutne evoked y the plid stimulus, plotted ginst the hnges evoked y the orresponding test stimulus (gry, ontrst; lk, % test ontrst). (e) Sme s d ut for the men (DC) omponent of the evoked hnges. (f,g) Cross-orienttion suppression in the stimulus-evoked hnges in inhiitory ondutne, s in d nd e. 4 ADVANCE ONLINE PUBLICATION NATURE NEUROSCIENCE

5 6 Nture Pulishing Group Figure 4 Two feed-forwrd models of simple ell nd its responses to grting nd plid stimuli. () In eh model, the simple ell hs one sufield, mde up of the input from four geniulte relys ells whose reeptive field enters re shown superimposed on five different grting nd plid stimuli. () In the first model, the rely ells re ompletely liner. They hve high (5 spikes per s) kground firing, so s to void spike rte retifition t spikes per s, nd liner ontrst response funtions (inset, fourth olumn). Responses re retified t spikes per s. The responses of individul rely ells re olor-oded ording to the reeptive field digrm in. The exittory input to the simple ell is proportionl to the men of the rely ell inputs (lk urve). Note tht the men tre overlies nd osures the individul olored tres in the seond nd fourth olumns (preferred grting). There is no ross-orienttion suppression in this model. The inreses in response mplitude indued y the msk grting in the lue rely ell re extly ompensted for y the redution nd shifts in phse indued in % msk the red, yn nd green rely ells. () Similr to, ut here the rely ells hve lower men rte so tht they undergo response retifition t spikes per s. In ddition, the ontrst response urve shows sturtion with C 5 of 5% (inset, fourth olumn). This model exhiits ross-orienttion suppression in the modultion omponent (F) of the simple ell s exittory input of 6% for the low-ontrst test stimulus (ompre seond nd third olumn) nd 56% for the high-ontrst test stimulus (ompre fourth nd fifth olumns). This suppression ours euse the msk-indued inrese in the response of the lue rely ell is smller (euse of sturtion nd retifition) thn the orresponding dereses nd phse shifts in the red, yn nd green rely ells. Note lso tht the msk indues n inrese in the men exittion for the low-ontrst test stimulus (fifth olumn). inreses in ortil inhiition (tht is, ross-orienttion inhiition) were responsile for the oserved msk-indued suppression of memrne potentil responses (Figs. nd ). A feed-forwrd model of ross-orienttion suppression To investigte the mehnism underlying the msk-indued derese in exittory input to simple ells, we onstruted liner feed-forwrd model, sed entirely on exittory input from rely ells of the LGN. A ritil element of lmost ll models of simple ell orienttion tuning is the synpti input from geniulte rely ells tht hve their reeptive fields rrnged in rows prllel to the simple ell s preferred orienttion 8,,,. For simpliity, we modeled single ON suregion (Fig. 4), onstruted from four rely ells (olored irles) whose reeptive field enters re ligned long the preferred orienttion of the simple ell. (The responses of n dditionl OFF sufield would e identil nd would simply doule the size of the totl input.) We first onsidered the preditions of ompletely liner model, in whih the spike rte of eh rely ell is proportionl to luminne in its reeptive field enter (inset in Fig. 4). To prevent retifition t spikes per s, we set the spontneous rte of eh rely ell to 5 spikes per s, higher thn the mximum mplitude of spike rte modultion. The synpti exittion from eh rely ell is ssumed to e proportionl to its firing rte, nd the inputs from multiple rely ells sum linerly. The totl input to the simple ell is therefore proportionl to the men of the rely ell responses. For the high-ontrst (%) msk stimulus (first olumn in Fig. 4), the luminne modultion of eh rely ell is identil ut out of phse s the grting drifts down the row of reeptive fields (olored tres). The ggregte input to the simple ell (the men of the rely ell responses) therefore shows no modultion (lk tre). For the % test grting (seond olumn), ll rely ells see synhronous modultion of luminne t the sme mplitude (%), s the rs of the grting enounter the geniulte reeptive fields simultneously. The responses of ll four rely ells re therefore Response Response Stimuli % test % test + msk Liner model Nonliner model Resp Resp 5 5 Contrst + msk 5 ms identil nd superimposed. The ggregte input to the simple ell (lk tre) is lso identil nd osures the individul inputs. For the plid stimulus (third olumn), the luminne modultion in the enter of the reeptive field of eh rely ell differs not only in mplitude ut lso in timing (temporl phse). Note tht euse the onstituent grtings of the plid hve the sme temporl frequeny (4 Hz), the plid moves s oherent pttern in diretion 45 to eh grting (Supplementry Video online). The lue rely ell s reeptive field enounters points t whih the rightest nd drkest regions of the two grtings interset; thus, this ell sees the mximum luminne modultion (64% ontrst). The red rely ell s reeptive field enounters the digonl line tht lies etween the right nd drk intersetions Response % msk Test Plid 5 5 Contrst % test + % msk ms Figure 5 A diret omprison of the simple ell input predited y the nonliner model in Figure 4. Here, the simple ell reeives input from eight rely ells with more losely sped reeptive fields. The response to the test grting (gry) nd plid (lk) re superimposed for omprison, long with the response of the rely ells to the plid grting (olored). NATURE NEUROSCIENCE ADVANCE ONLINE PUBLICATION 5

6 6 Nture Pulishing Group of the plid; thus, this ell sees no luminne modultion t ll (% ontrst). The reeptive fields of the green nd yn rely ells see intermedite ontrsts nd phses. Note tht in this ompletely liner model, the plid-evoked exittory input to the simple ell is identil to the input exittion evoked y the %-ontrst test grting lone (lk tres in seond nd third olumns of Fig. 4). The inrese in mplitude of the response of the lue rely ell is extly ompensted y the derese in mplitude of the response of the red rely ell nd y the phse shifts of the response of the green nd yn rely ells. In other words, in liner model there is no ross-orienttion suppression (Supplementry Video online, liner model). The sme onsidertions pply to plid onsisting of n grting nd % msk grting (Supplementry Video online). When the msk is superimposed on the test grting, the modultion in ontrst t the enter of the lue reeptive field rises from 8% to 4% nd t the red rely ell from 8% to 4% (ompre fourth nd fifth olumns of Fig. 4). Beuse of the shifts in phse of the rely ell responses, however, the msk grting hs no net effet on the input to the simple ell (Supplementry Video 4 online, liner model). In relity, rely ell responses re not liner. Among other nonlinerities, the modultion of the firing rte exeeds the spontneous rte so tht the firing rte rehes spikes per s for signifint frtion of the grting yle (retifition). Also, n inrese in stimulus ontrst results in less thn proportionl inrese in the mplitude of modultion (sturtion). We model these nonlinerities y setting the spontneous rte of the rely ells to spikes per s nd setting the ontrst response funtion to R ¼ A C/(C + C 5 ), where R is the modultion of the firing rte, C is the ontrst, A ¼ nd C 5 ¼ 5% (inset in Fig. 4). As it did for the liner model, superimposing the % msk on the % test stimulus neessrily redues the response of the red rely ell to euse the stimulus ontrst flls to. For the lue rely ells, wheres the msk doules stimulus ontrst, the response modultion no longer doules euse of the nonlinerities (seond nd third olumns in Fig. 4 nd Supplementry Video, nonliner model). As result, the input to the simple ell (Fig. 4, lk tres) is smller for the plid thn for the test grting. The derement etween test grting nd plid is smll (out 5%) ut is, in ft, omprle to the redution oserved in the memrne potentil modultion of intrellulrly reorded simple ells, whih verges % (Fig., lk symols). For the grting, the effets of introduing nonlinerities into the rely ell responses re muh lrger. In the nonliner model, the msk grting redues the testevoked input to the simple ell y lmost 5% (fourth nd fifth olumns in Fig. 4 nd Supplementry Video 4, nonliner model). Agin, this redution is omprle to wht is seen in the reorded memrne d F mplitude Phse (deg) % msk potentil responses of simple ells nd in the exittory ondutne to simple ells (Figs. ). Superimposing the plid-evoked nd test-evoked responses of the model simple ell (Fig. 5) mkes ler the msk-indued redution in the modultion mplitude of the exittory input to the simple ell. Here, the simple ell s sufield onsists of eight rely ell inputs, insted of just four, ut with similr spet rtio (length:width ¼.5). Also evident in this figure, the msk evokes % rise in the men (DC) omponent of the response to the grting. For the % test grting, the msk grting indues slight drop in the men omponent (Tle ). These hnges in DC level re not seen in the intrellulr reordings from simple ells. Cross-orienttion suppression predited y rely ell ehvior The toy model (Figs. 4 nd 5) requires two ssumptions out rely ell responses (retifition nd sturtion) nd three free prmeters: the spontneous firing rte of the rely ells, the C 5 of sturtion of the rely ells response nd the spet rtio of the simple ell sufield. To otin more relisti estimte of the input to the simple ell requiring % test % test + % msk Stimulus strt position ( ) spikes per s + % msk ms 8 6 Figure 6 The input to model simple ell derived from the reorded responses of single geniulte rely ell. () The simple ell reeptive field ontins one sufield, whih is mde up of input from eight LGN rely ells (olored irles). () The responses of the reorded rely ell to the stimuli presented t eight different strting positions or, more preisely, with the msk stimulus given eight different strting phses. These responses re ment to simulte the response of eight different rely ells with different reeptive field positions (s indited in ) when the stimulus is given the sme strting position. () The eight rely ell responses (olor oded s in nd ) together with their men (lk), whih is tken to e the exittory input to the simple ell. Like the toy model of Figures 4 nd 5, the predited simple ell shows modest (5%) suppression for the high-ontrst grting (seond nd third olumns) nd stronger (46%) suppression for the low-ontrst grting (fourth nd fifth olumns). (d) F mplitude nd phse of the response of the rely ell to the different stimuli. 6 ADVANCE ONLINE PUBLICATION NATURE NEUROSCIENCE

7 6 Nture Pulishing Group e Proportion of neurons % msk % test + % msk Suppression rtio Cortil V m n = Cortil spikes n = 6 fewer ssumptions, we repled the simulted rely ells with responses reorded from LGN neurons of the t (Fig. 6). The input to the simple ell then depends on only single prmeter: the spet rtio of the simple ell sufield. Idelly, we would hve liked to reord simultneously from numer of different rely ells, eh with its reeptive field slightly displed from its neighor long the model simple ell s orienttion xis. This is diffiult to do in prtie. Insted of reording from different rely ells with different reeptive field positions, we reorded from single rely ell nd moved the stimulus reltive to the reeptive field. More preisely, we systemtilly hnged the initil sptil phse of the msk stimulus, whih disples the strting position of the stimulus long the length of the sufield (Fig. 6). Similr to the toy model (Fig. 4), the reorded responses to the msk grting were identil in mplitude ut differed in phse (Fig. 6, first olumn); the responses to the test grtings were identil in mplitude nd phse (seond nd fourth olumns); nd the responses to the plid differed in oth mplitude nd phse (third nd fifth olumns). When the input to the simple ell ws lulted s the sled sum (men) of the rely ell responses (Fig. 6, lk tres), the rossorienttion effets were similr to those seen in the toy model (Figs. 4 nd 5; for n dditionl rely ell see Supplementry Fig. 5 online): the suppression indies for the high- nd low-ontrst test grting were 5% nd 46%. The msk grting rised the DC omponent of the simple ell s input slightly for eh test ontrst. In ll, we reorded from 4 rely ells nd pplied their responses to the feed-forwrd model. The resulting suppression rtios of the F omponent (Fig. 7,) were omprle to those oserved in the memrne potentil of simple ells (Fig. 7,d) nd smller thn those oserved for spike rte (Fig. 7e,f). The verge suppression for the feed-forwrd model sed on rely ell reordings ws % for the high-ontrst test grting nd 5% for the low-ontrst test grting, ompred to 9% nd 48% for the reorded memrne potentil of simple ells. Note lso tht the rely ell reordings, like the toy d f LGN output n = Figure 7 Mgnitude of ross-orienttion suppression reorded in simple ells nd derived from the feed-forwrd model. () Histogrm of the suppression rtio of the model in Figure 6, s pplied to 4 different reorded rely ells using n grting. () Smes, ut using % test grting. The solid line shows the histogrm for models in whih different, rndomly seleted, reorded rely ell ws hosen to stnd in for one of the eight rely ells in the model. () Histogrms of the suppression rtio for memrne potentil in simple ells (F mplitude), otined using n 8% test grting (gry rs). (d) Smes ut using % test grting. (e,f) Histogrms of the suppression in 6 simple ells for spike rte for 8% (e) nd %(f) test grtings. Arrow, medin vlue. model, predit n inrese in the DC omponent of the predited input to simple ells (48% nd 9%), whih ws not oserved intrellulrly (Tle ). Just s the model predits the effet of the high-ontrst msk grtings on the responses of simple ells, it lso predits the effet, or rther the ner lk of effet, of low-ontrst msk grtings. The lowontrst msk grting hd only smll effets on the memrne potentil nd spike rte responses of simple ells, nd none rehed signifine (Fig., Supplementry Fig. nd Tle ). Only smll effets re predited y the toy model nd only for the low-ontrst test grting; these effets were generlly mthed y rely ell reordings (Tle nd Supplementry Fig. ).With the low-ontrst msk nd lowontrst test, the rely ells ll remin in the more liner portion of the ontrst response urve; thus, inreses nd dereses in rely ell response relted to inreses nd dereses in ontrst losely lne one nother. For high-ontrst test nd low-ontrst msk, the hnges in response of the rely ells lne one nother euse they re smll reltive to the response to the test grting lone. One unrelisti spet of the reording-sed model is tht the ehvior of eh of the eight geniulte inputs is sed on reordings from the sme rely ell. In relity, the ehvior of the rely ell inputs will differ from one nother. We therefore reted version of the model in whih the responses of eh of the eight inputs were drwn from different reorded rely ells. We rndomly hose, sets of eight reorded rely ells from our smple of 4, nd for eh set lulted the suppression rtios for 8%- nd %-ontrst test grtings. Note tht eh rely ell ould e seleted more thn one for eh set of inputs. The resulting distriutions of the suppression rtio for the, sets of inputs (lk urve in Fig. 7,) were omprle to those for the memrne potentil of simple ells (Tle ). In oth the toy model nd the reording-sed model, we ssumed tht the spet rtio of the geniulte sufield is fixed (etween.5 nd ). Aspet rtio hs signifint effet on the width of tuning of the input to model simple ell 9,4,5 : the lrger the spet rtio, the nrrower the width of tuning. It hs little effet on the degree of rossorienttion suppression, however. Inresing the width of simple ell s sufield y dding dditionl prllel rows of rely ell inputs did not ffet the suppression of the modultion mplitude of the input (Supplementry Fig. 6 online). Similrly, lengthening the sufields hd no effet. Thus fr we hve desried only two ontrsts of the test grting: 8% nd % (Figs. 7). Cross-orienttion suppression hs een investigted for lrge rnge of test-grting ontrsts, however, nd it hs een found tht the msk grting effetively shifts the ontrst response urve for the test grting to the right 7,,6,7. For eight rely ells, therefore, we presented plid stimuli onstruted from % msk grting nd rnge of test ontrsts (Fig. 8). The feed-forwrd model s preditions of the synpti input to the simple ell (Fig. 8), like simple NATURE NEUROSCIENCE ADVANCE ONLINE PUBLICATION 7

8 6 Nture Pulishing Group 4% test 6% test % test 45% test Test Plid ell responses, show msk-indued rightwrd shift in the ontrst response funtion, oth for the illustrted ell (Fig. 8) nd for the verged responses of the eight rely ells (Fig. 8d). In ll our experiments nd modeling (Figs. 8), msk nd test grtings were presented t the sme temporl frequeny, resulting in solid plid stimulus tht moved t 45 to either grting orienttion (Supplementry Video ). In mny previous experiments on rossorienttion suppression, the test nd msk grtings were given different temporl frequenies,9,6. The dvntge of mthed temporl frequenies is tht eh prt of the simple ell reeptive field (or eh onstituent rely ell) experienes the sme modultion of ontrst during eh yle of the stimulus. With disprte temporl frequenies, rely ells trde roles from one stimulus yle to the next: on one yle, one rely ell will experiene mximl ontrst nd nother will experiene miniml ontrst; on susequent yle, the different ontrsts will shift mong the set of rely ells. Therefore, the priniples used in the models (Figs. 4 nd 6) tht is, the effets of sturtion nd retifition still pply for plids omposed of disprte temporl frequenies. In eight rely ells, we reorded the responses to suh plids (4 Hz test, nd either 4.5 Hz msk or Hz msk). When pplied to the feed-forwrd model (s in Fig. 6), the predited suppression in the input to simple ells ws omprle to tht otined with mthed temporl frequenies (Supplementry Fig. 7 online). 5 5 d F mplitude (spikes/s) F mplitude (normlized) Test ontrst (%) 4 4 Test ontrst (%) Figure 8 Msk-indued shifts in the ontrst response urves. () Responses to plid stimuli omposed of % ontrst msk grting nd test grting of ontrsts etween 4% nd 45%. Sptil phse of the msk stimulus vries ross rows; ontrst of the test grting vries ross olumns. () The input to the feed-forwrd model ws omputed for test stimulus lone (lk) nd for plids (red; verge of the responses in eh olumn of ). () Contrst response urves for the input to the model simple ell derived from the reords in. (d) Averge ontrst response urves for the input to the model ells derived s in from the responses of eight different rely ells. DISCUSSION Cross-orienttion suppression hs often een interpreted s evidene for inhiitory intertions mong ortil neurons with different orienttion preferenes. Cross-orienttion inhiition, in turn, hs een the ornerstone of severl feedk models for orienttion seletivity,7 9. Our results suggest, however, tht the ross-orienttion suppression oserved in the spike responses of simple ells does not require ross-orienttion inhiition. We found tht ross-orienttion suppression depends on three distint mehnisms, none of whih re themselves orienttion dependent. First, the geometry of the plid stimulus gives rise to speifi pttern of phse nd mplitude in the ontrst modultions seen y the rely ell inputs to simple ells. Wheres the msk stimulus inreses the luminne modultion seen y some rely ells, it proportiontely dereses the modultion seen y others, so tht the men luminne modultion ross the reeptive field does not hnge. Seond, retifition nd ontrst sturtion within the rely ells hve disproportiontely lrge effet on the lrgest of the rely ell responses. As result, the msk-indued dereses in the responses of some rely ells outweigh the dereses tht our in others, suh tht the msk redues the modultion in the ggregte rely ell input to the simple ell. This redution, however, is indequte to ompletely explin the spiking ehvior of simple ells. A third mehnism threshold mplifies the msk-indued redution in synpti input to generte the full effet seen in the spike rte responses. These three mehnisms lso ount for the previously reported msk-indued rightwrd shift in the ontrst response urve 7,6 nd for the effets of high temporl frequeny msks. Our results re in onert with previous work showing tht inhiition nd exittion to simple ells hve similr preferred orienttion nd orienttion tuning width 5,7,4 (ut see ref. 8). This work, however, hd left the phenomenon of ross-orienttion suppression unexplined. In previous study, it ws noted tht the msk stimulus my desynhronize the LGN fferent input, s demonstrted here; further, it ws suggested tht ross-orienttion suppression ould e generted in prt y nonspeifi intrortil inhiition (tht is, inhiition mong ells tht themselves re untuned for orienttion 4 or inhiition tht is tuned for the preferred orienttion ut hs lrge untuned omponent 4 ). The full ross-orienttion effet oserved extrellulrly hs een explined in terms of omintion of response nonlinerities in the LGN, inluding retifition nd sturtion, together with nonspeifi intrortil inhiition (M. Koelling nd M. Shelley, So. Neurosi. Astr. 4.8, 4). In ddition, the timing of ross-orienttion suppression preedes or is oinident with the exittory response to the preferred stimulus 4, onsistent with our onlusion tht feedforwrd nonlinerities underlie ross-orienttion suppression. Our results indite tht ll the ross-orienttion effets on the modultion omponent of ortil responses n e ounted for in terms of nonlinerities in the LGN nd mplifition y spike threshold in the ortex. The one disrepny etween the oserved responses of simple ells nd the predition of purely feed-forwrd model lies in the effets of the msk on the men omponent of the input (Tle ): The feedforwrd model sed on the reorded properties of rely ells (Fig. 6) predits tht the msk will indue up to 5% inrese in the men exittory input, wheres the oserved inrese is only 7% (Fig., 8 ADVANCE ONLINE PUBLICATION NATURE NEUROSCIENCE

9 6 Nture Pulishing Group Tle ). This disrepny ould e ounted for y t lest three possile mehnisms. The first is synpti inhiition. We did not see the msk-indued hnges in inhiitory ondutne tht would e required to suppress inreses in the DC level of exittion (Fig. ). It is possile, however, tht we might hve missed suh inhiition if it were medited y GABA B reeptors, s we inlude Cs + ions in our eletrodes during ondutne mesurements. Cs + is nonspeifi loker of K + hnnels, inluding GABA B reeptor hnnels. The seond possile reson tht we see less msk effet on the men response thn predited is tht simple ells do not reeive ll their exittory input from the LGN (refs. 8,9,,4,,8). Physiologil mesurements of the ontriution of the geniulte to the totl exittory input to simple ells rnge etween % nd 5% (ref. 4), with the remining input oming from ortil ells. Beuse ortil neurons show signifint msk-indued derese in their men response (Tle ), the rise in DC for more omplete model, one with omined ortil nd geniulte input, would e muh smller thn our simplified feed-forwrd model predits. Finlly, ny ontriutions to ross-orienttion suppression from short-term synpti depression t the thlmoortil synpse 9, would lso tend to derese the postsynpti effet of msk-indued rise in the men response of geniulte neurons. Spike threshold is ritil for the expression of numer of ortil properties. The so-lled ieerg effet shrpens the seletivity of the spike output of ortil ells reltive to the seletivity of their synpti inputs for orienttion 4 nd diretion 44, nd enhnes the distintion etween simple nd omplex ells 45. Reent work hs lso implited threshold in the ontrst invrine of orienttion tuning 46 nd the mplifition of the tril-to-tril vriility of response mplitude 47. In eh se, the ortil iruitry is required only to generte reltively wek effet in the synpti inputs to ell nd tht effet is then mplified severlfold y threshold. In the se of stimulus preferene, wek is n e mplified into lmost exlusive seletivity. Thus, the requirements pled on the ortil iruit for estlishing response preferene re muh less stringent thn they first seem to e when judging from the extrellulr responses of ortil ells. The geniuloortil or ortio-ortil onnetions need reltively little stimulus speifiity to give the threshold sustrte on whih to uild. Beuse threshold is universl property of neurons, it my ontriute similrly to neuronl omputtions throughout the neoortex. METHODS Physiologil preprtion. Whole-ell pth reordings in re 7 of nesthetized ts were otined with orosilite glss eletrodes (A-M Systems). For ells, the memrne potentil ws reorded without the injetion of urrent, nd eletrodes were filled with potssium gluonte solution tht inluded C + uffers, ph uffers nd yli nuleotides 4. For 9 ells in whih memrne potentil ws reorded during the injetion of stedy urrent (for lter lultion of memrne ondutne), potssium gluonte ws repled with esium methnesulfonte, nd QX-4 (7 mm, Sigm-Aldrih) ws dded to the solution. All neurons inluded in this study were reorded 48 9 mm from the ortil surfe nd were lssified s simple y the lrge mplitude modultion of response to the optiml grting stimulus 45.ThertiooftheF nd DC omponents of the spike rte responses to n optiml grting rnged from. to 9. (geometri men,.9); the rtio of the F nd DC omponents of the memrne potentil responses rnged from.49 to 4.6 (geometri men,.). Extrellulr reordings in the LGN were otined with stndrd tungsten-in-glss eletrodes (Ainsworth). X nd Y ells were identified ording to the presene of frequeny-douled responses to ounterphse grtings of high sptil frequeny 48. Eletril stimuli to the LGN ( ms, eletrode negtive) were delivered through n ethed tungsten eletrode with n exposed tip of mm. The LGN-stimulting eletrode nd the ortil reording eletrode were pled in orresponding portions of the retinotopi mps. The threshold for evoking lol field potentils ws 5 ma or less. Stimulus presenttion nd dt quisition. Visul stimuli were generted on Mintosh omputer using the Psyhophysis toolox 49 for Mtl nd presented on ViewSoni video monitor pled 48 m from the t s eyes. The video monitor hd men luminne of d m, noninterled refresh rte of Hz nd sptil resolution of pixels, whih sutended 4 m horizontlly nd m vertilly. Drifting grting nd plid stimuli were presented for 4 s, preeded nd followed y 5 ms lnk (men luminne) periods. Orienttion nd sptil-frequeny tuning urves were mde for eh ell. Test stimuli were presented t the optiml orienttion, sptil frequeny nd sptil position; msk stimuli were lso presented t optiml sptil frequeny nd position, ut t 9 to the optiml orienttion. Plid stimuli were reted y interleving the test nd msk grtings on lternte video frmes. Test nd plid grtings were presented t identil temporl frequeny (4 Hz), exept for Supplementry Fig. 7. Reorded memrne potentil ws low-pss filtered, smpled t 496 Hz (6-it resolution) nd stored for susequent nlysis. Dt were nlyzed online to determine when enough trils hd een performed to yield men responses with low noise. Reords were nlyzed for spike rte nd for underlying memrne potentil fter spikes were removed using 5-ms medin filter to remove tion potentils. Extrellulr reords from the LGN were stored long with the eptne pulses from window disrimintor. In ll yle verges, the first yle of response ws disrded. The detils of the ondutne mesurement method hve een presented previously 44. The full memrne eqution ws used to derive ondutne: C m dv m dt ¼ ½g e ðv m V e Þ + g i ðv m V i Þ + g rest ðv m V rest ÞŠ + I inj The memrne eqution reltes the pitne nd the hnge in memrne potentil to ll the urrents entering the neuron. For simpliity we use only three ondutnes: exittion (g e ), inhiition (g i ) nd stedy lek or resting ondutne (g rest ). Reversl potentils for exittion nd inhiition (V e nd V i ) were tken to e mv nd 7 mv. The reversl potentil for inhiition is ment to represent the tion of GABA A,sGABA B urrents were presumly loked y the sustitution of Cs + for K + in the eletrode solution. The resting potentil of the neuron ws estimted from the verge potentil reorded in response to gry (men luminne) sreen. Note tht euse of the kground tivity, the resting urrent ontins oth exittory nd inhiitory synpti inputs. The estimtes of exittory nd inhiitory ondutne in eqution () re therefore not solute estimtes of exittion nd inhiition, ut re hnges in exittory nd inhiitory ondutnes mesured reltive to the kground nd re referred to s Dg e nd Dg i. A potentil wekness of this method of ondutne extrtion is tht voltge-tivted urrents ould distort our estimtes of synpti ondutne. Cs + nd QX-4 were used to lok most voltge-dependent N + nd K + urrents. In ddition, we were le to re-derive the memrne potentil from the lulted urrents with onsiderle ury, n indition tht voltge-gted urrents were not distorting the urrent mesurement proedures. The vrine ounted for is omputed y ompring the distne etween model nd dt reltive to vrine of responses ross stimuli 7. P vlues for ompring medin levels of suppression were lulted with ootstrp method 5. All proedures were pproved y the Northwestern University Animl Cre nd Use Committee. Note: Supplementry informtion is ville on the Nture Neurosiene wesite. ACKNOWLEDGMENTS We re grteful to M.P. Stryker nd J.A. Movshon for omments on the mnusript. We lso thnk J. Hnover for helpful disussions. Supported y grnts from the US Ntionl Institutes of Helth (EY-4499 nd EY-476). COMPETING INTERESTS STATEMENT The uthors delre tht they hve no ompeting finnil interests. ðþ NATURE NEUROSCIENCE ADVANCE ONLINE PUBLICATION 9

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