Long-term modification of cortical synapses improves sensory perception

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1 Long-term modifition of ortil synpses improves sensory pereption Roert C Froemke 1 4,8, Ion Cre 1 3,8, Alison J Brker 4, Kexin Yun 4, Bryn A Seyold 4, An Rquel O Mrtins 1 3,5, Ntly Zik 1,2, Hnnh Bernstein 1,2, Megn Whs 6, Philip A Levis 6, Dniel B Polley 7, Mihel M Merzenih 4 & Christoph E Shreiner 4 npg 213 Nture Ameri, In. All rights reserved. Synpses nd reeptive fields of the ererl ortex re plsti. However, hnges to speifi inputs must e oordinted within neurl networks to ensure tht exitility nd feture seletivity re ppropritely onfigured for pereption of the sensory environment. We indued long-lsting enhnements nd derements to exittory synpti strength in rt primry uditory ortex y piring ousti stimuli with tivtion of the nuleus slis neuromodultory system. Here we report tht these synpti modifitions were pproximtely lned ross individul reeptive fields, onserving men exittion while reduing overll response vriility. Deresed response vriility should inrese detetion nd reognition of ner-threshold or previously impereptile stimuli. We onfirmed oth of these hypotheses in ehving nimls. Thus, modifition of ortil inputs leds to wide-sle synpti hnges, whih re relted to improved sensory pereption nd enhned ehviorl performne. Reeptive fields of sensory ortil neurons re highly strutured. The ntomil rrngement nd strength of synpti inputs ontriute to the funtionl orgniztion of reeptive fields, whih in turn underlie the pereption of the externl world 1 4. Cortil reeptive fields re plsti, mening tht the feture seletivity of individul neurons nd ell ssemlies n e modified in mnner tht depends on the ptterns of eletril tivity 5 8, sensory experiene 9 18 nd enggement of neuromodultory systems suh s the holinergi nuleus slis Furthermore, vrious forms of ehviorl onditioning nd lerning re often, though not lwys, orrelted with hnges in ortil orgniztion, synpti strength nd response properties. Reeptive field plstiity llows ortil neurons to t s dynmi filters, djusting tuning urves nd response properties depending on novelty or ehviorl signifine of ertin inputs 25,26. These hnges re elieved to e dptive in tht they my underlie pereptul lerning, filitting the identifition nd disrimintion of relevnt environmentl fetures nd sensory ojets. However, there is little experimentl evidene in support of this hypothesis 27,28. Behviorl trining n improve some pereptul ilities without ovious hnges in ortil responses 24,29, nd studies tht hve diretly exmined ortil reeptive field plstiity in ehviorl ontext hve vriously found enhnements 24,3,31, redutions 32 or no orresponding effet on pereptul ilities 6,3. Given the preision of reeptive field orgniztion in the mture nervous system, persistent modifitions of synpti strength in vivo must e refully orhestrted nd oordinted within the overll ortil network to emphsize ertin fetures while preserving the reltive struture nd seletivity of ortil tuning. These hnges re often studied in the ontext of ehviorl onditioning or repetitive exposure to sensory stimuli. In these ses, speifi responses to pired or exposed stimuli re generlly enhned One of the min mehnisms thought to underlie this enhnement is longterm potentition (LTP) of intrortil exittory inputs 7,8,17,22. However, theoretil studies hve shown tht forms of ompetitive synpti modifitions suh s LTP or long-term depression (LTD) re, y themselves, destilizing influenes on network tivity. LTP nd LTD re positive-feedk proesses tht drive neurl networks into hyper- or hypo-exitle sttes, respetively, nd seem to e insuffiient for ehviorlly meningful memory storge 33,34. Although vrious tivity-dependent nd tivity-independent mehnisms hve een proposed to ountert these prolems nd help normlize reeptive fields inluding homeostti ontrol of neurotrnsmitter reeptor nd ion hnnel expression 35, heterosynpti plstiity 36, nti- Hein plstiity 37 nd metplsti modifition of synpti lerning rules 11 it is unknown how the synpti drive onto ortil neurons is monitored nd lirted in the intt rin to llow hnges in sensory representtion to positively influene pereption nd ehvior. RESULTS Synpti modifitions onserve net exittion We investigted the oordintion of synpti reeptive field plstiity ross multiple inputs nd stimulus prmeters y mking whole-ell 1 Moleulr Neuroiology Progrm, The Helen nd Mrtin Kimmel Center for Biology nd Mediine t the Skirll Institute for Biomoleulr Mediine, Deprtment of Physiology nd Neurosiene, New York University Shool of Mediine, New York, New York, USA. 2 Deprtment of Otolryngology, New York University Shool of Mediine, New York, New York, USA. 3 Center for Neurl Siene, New York University, New York, New York, USA. 4 Colemn Memoril Lortory nd W.M. Kek Foundtion Center for Integrtive Neurosiene, Neurosiene Grdute Group, Deprtment of Otolryngology, University of Cliforni, Sn Frniso, Cliforni, USA. 5 PhD Progrm in Experimentl Biology nd Biomediine, Center for Neurosienes nd Cell Biology, University of Coimr, Portugl. 6 Computer Systems Lortory, Deprtments of Eletril Engineering nd Computer Siene, Stnford University, Plo Alto, Cliforni, USA. 7 Eton-Peody Lortory, Msshusetts Eye nd Er Infirmry, Deprtment of Otology nd Lryngology, Hrvrd Medil Shool, Boston Msshusetts, USA. 8 These uthors ontriuted eqully to this work. Correspondene should e ddressed to R.C.F. (roert.froemke@med.nyu.edu). Reeived 19 Deemer 211; epted 2 Otoer 212; pulished online 25 Novemer 212; doi:1.138/nn.3274 nture NEUROSCIENCE VOLUME 16 NUMBER 1 JANUARY

2 npg 213 Nture Ameri, In. All rights reserved. Figure 1 Exmple of A1 synpti reeptive field modifition indued y nuleus slis piring. () Experimentl preprtion. Re, reording; Stim, stimultion; NB, nuleus slis. () Exmple of synpti tuning urve modifition indued y nuleus slis piring. Top, intensity sensitivity t 4 khz. Bottom, frequeny tuning t 3 db SPL. Responses to pired stimulus (3 db SPL, 4 khz; rrows) re enhned, wheres responses to pek level nd est frequeny (rrowheds) re redued. () Frequeny-intensity synpti reeptive field for sme ell s in. Top, efore (left) nd fter (right) piring. Color, EPSC mplitude. Blue lines, threshold. Bottom, hnge in EPSCs (post-piring pre-piring). Exittion (ex) t pired tone (irle) inresed from 14.8 ± 3.6 pa to 46.8 ± 6.6 pa (P <.1, Student s pired two-tiled t-test); exittion t originl est stimulus (8 db SPL, 16 khz; squre) deresed from 98.6 ± 15.4 pa to 43.3 ± 8.1 pa (P <.1). Net exittion ross stimuli ws similr efore nd fter piring (efore, 1.68 na; fter, 1.51 na; P >.4). Sle rs: 5 pa, 4 ms. Error rs show s.e.m. reordings from 29 neurons of dult rt primry uditory ortex (A1) in vivo 17,2,23,38. To rpidly nd relily reorgnize synpti reeptive fields of A1 neurons, we omined reordings with eletril stimultion of the holinergi nuleus slis 2 24 (Fig. 1), mimiking the tivtion of this neuromodultory system during direted ttention or rousing ehviorl episodes 39,4. Exittory synpti reeptive fields were mesured in voltge-lmp y plying pseudorndom sequenes of pure tones, vrying in intensity from 1 to 8 db sound pressure level (SPL) nd frequeny from.5 to 32 khz. hrterizing seline responses for 5 15 min, we indued modifitions of A1 synpti reeptive fields y repetitively piring nuleus slis stimultion with tone of speifi intensity nd frequeny for 1 5 min ( nuleus slis piring ), using optimized prmeters for piring first identified with extrellulr reordings (Supplementry Fig. 1) nd onfirmed with intrellulr reordings (Supplementry Fig. 2). piring ended, we monitored reeptive fields for s long s reording qulity remined stle (see Online Methods). Nuleus slis piring indued set of highly orgnized hnges ross the entire frequeny-intensity synpti reeptive field (Fig. 1, nd Supplementry Fig. 3). In prtiulr, inreses in exittion t the pired inputs were mthed losely y orresponding dereses t the originl est stimuli (tht whih initilly evoked the lrgest response), leding to onservtion of exittory input reeived y A1 neurons. In the exmple reording shown in Figure 1, 4-kHz tones of 3 db SPL were pired with nuleus slis stimultion for 3 min. piring, the pek intensity ws 8 db SPL nd the est frequeny ws 16 khz. piring, exittion inresed mrkedly t the pired stimulus (Fig. 1,). Additionlly, lthough only 3 db SPL, 4-kHz tones were presented during nuleus slis stimultion, exittion t the originl est stimulus (8 db SPL, 16 khz) deresed (Fig. 1,; for three other exmples, see Supplementry Fig. 3). Although hnges to some individul unpired tones ould e oserved, responses to unpired stimuli on verge were not signifintly different fter piring (P >.5). The net result of these modifitions ws to shift the preferred sound level nd frequeny tuning of this neuron while preserving the totl strength of exittory input ross ll stimuli (Fig. 1). For 29 reordings, these long-term hnges in synpti strength were on verge speifi to prtiulr stimuli ross dimensions of oth intensity (Fig. 2) nd frequeny (Fig. 2). For intensity sensitivity, we oserved mximum enhnements t the pired vlue, lthough inreses often spred to lower intensities s well (Fig. 2, top, nd Supplementry Figs. 2,). Inresed exittion t pired stimuli ws mthed y deresed exittion t originl Re A Tone NB Ex (efore) Stim Synpti reeptive field est stimuli (Fig. 2,, ottom), leit with somewht slower time ourse (~1 2 min; Fig. 2). These piring-indued hnges to synpti strength ooperted to shift intensity sensitivity profiles of A1 neurons, mking them less monotoni with regrd to sound intensity (Supplementry Fig. 4), nd onserved the net exittory drive reeived y A1 neurons, suh tht the reltive mgnitudes of individul enhnements were pproximtely lned y n equivlent mount of redution (Fig. 2d). These hnges seemed to e speifi to ortil neurons, s indited y three sets of experiments. First, we mde seven multiunit reordings from the ventrl division of the medil geniulte ody (MGB), the min uditory thlmus. We did not oserve long-term hnges of MGB responses fter nuleus slis piring (Supplementry Fig. 1,d), suggesting tht thlmi spiking output is not persistently ffeted y piring. However, under different onditions, it is possile tht thlmi responses re modified, nd it remins possile tht piring n indue plstiity in other prts of the MGB, suh s the medil division. Seond, piring lso indued long-term hnges in tone-evoked inhiitory responses of A1 neurons (Supplementry Fig. 5,), suh tht inhiitory responses t the pired stimulus nd originl est stimulus were redued. In prtiulr, in the exmple shown in Supplementry Figure 5, redutions in tone-evoked inhiition were oserved t oth the pired nd originl est frequeny. Over the popultion of 29 reordings, however, inhiition t the pired input egn to reover (Supplementry Fig. 5) nd, s previously reported, eventully reovered to mth nd relne the strength of exittion 22. As inhiitory inputs to A1 neurons re intrortil, this provides more evidene, together with lol Exittion (pa) Ex (efore fter) pa t 4 khz t 3 db Ex (fter) 5 pa 1 8 VOLUME 16 NUMBER 1 JANUARY 213 nture NEUROSCIENCE

3 npg 213 Nture Ameri, In. All rights reserved. Figure 2 Conservtion of totl exittion fter piring. () Intensityspeifi hnges. Top, summry of hnges reltive to pired level over ll reordings (rrow; inrese of 66.7% ± 1.3%, n = 29 neurons, P < 1 6, Student s pired two-tiled t-test). Signifint potentition lso ourred to responses evoked y stimuli of the pired frequeny nd 1 db lower in intensity (29.7% ± 12.4%, P <.4). Bottom, hnges to originl pek level (rrowhed; derese of 19.% ± 5.2%, P < 1 4 ). () Frequeny-speifi hnges. Top, hnges reltive to pired frequeny. Bottom, hnges to originl est frequeny ( 21.9% ± 5.7%, P <.1). Sme reordings s in. () Time ourse of hnges to pired (irles) nd originl est (squres) stimuli. Horizontl r, piring. Sme reordings s in. (d) Conservtion of totl exittion fter piring. nd fter piring, reltive mounts of inreses (lk) nd dereses (white) in synpti strength were similr ross the entire frequeny-intensity synpti reeptive field (RF) (exittion inresed y ftor of 3.2 ±.9 nd deresed y 4.5 ± 1.2; n = 29 neurons, P >.6, Mnn-Whitney), ross intensity t pired frequeny (inrese, 1.2 ±.3; derese, 1.3 ±.2; P >.6) nd ross frequeny t pired intensity (inrese, 1.1 ±.1; derese, 1.1 ±.2; P >.5). Sme reordings s. Error rs show s.e.m. mirostimultion experiments of thlmi nd intrortil inputs 22, for ortil lous of synpti modifition. Third, we found tht topil pplition of holinergi or NMDA reeptor ntgonists to A1 prevented modifitions of exittory nd inhiitory tuning urves y nuleus slis piring. Applition of the musrini reeptor ntgonist tropine (1 mm; Supplementry Fig. 6) loked short- nd long-term hnges, suggesting tht, despite GABAergi nd peptidergi projetions from nuleus slis 41,42, musrini reeptor tivtion is required for oth the immedite nd the enduring effets of nuleus slis piring. Exmple exittory nd inhiitory tuning urves from the sme neuron re shown in Supplementry Figure 6, efore nd 1 min fter piring; results from five experiments re summrized in Supplementry Figure 6, ottom. Similrly, ortil pplition of the NMDA reeptor loker (2R)-mino-5-phosphonovleri id (AP5, 1 mm; Supplementry Fig. 6) lso prevented the long-term (ut not the immedite) effets of piring on exittion nd inhiition in six neurons, demonstrting tht exittory nd inhiitory modifitions re onsolidted downstrem of NMDA reeptor tivtion. Therefore, s with frequeny tuning 21,22, the pek sound levels nd overll intensity sensitivity profiles of A1 synpti responses re plsti nd n e regulted onjointly. These hnges t together to lolly enhne pired stimuli while glolly normlizing exitility ross frequeny-intensity synpti reeptive fields. Suh synpti modifitions re longer-term onsequenes of omplex proesses engged y neuromodultion nd nuleus slis piring, similr to wht might hypothetilly our during episodes of direted ttention to slient or ehviorlly meningful stimuli Seletive ttention might, however, engge other mehnisms lso importnt for proessing sensory informtion, suh s deorrelting tivity ptterns ross different neurons or ell ssemlies 23,4, stimuli re dynmilly determined How re neurons or lol networks le to sense nd seletively modify responses to their originl est stimuli? Previous studies of ortil reeptive field plstiity in the visul system hve exmined the influene of homeostti modifitions of synpti trnsmission nd exitility on reeptive field remodeling, espeilly fter prolonged periods of monoulr deprivtion 11,33,35. However, here, suh homeostti mehnisms my e too protrted nd nonspeifi to ount for the redution t the originl est stimulus, whih dereses over 1 2 min. Given tht the est stimulus itself is n empirilly determined lol mximum, we next sked whether this Normlized exittion (%) Normlized exittion (%) Normlized intensity tuning 2 Reltive to pired level Reltive to est level Intensity differene (db SPL) Time ourse 2 Piring Time (min) suppression of synpti strength ws n tivity-dependent proess sensitive to the reent stimulus history. To ssess to wht degree the redution of synpti strength t the originl est stimulus ws experiene dependent, we plyed restrited stimulus set (generlly 1 6 db SPL tones t.5 32 khz) for pproximtely 1 min fter piring, exluding the originl est stimulus (usully t 7 8 db SPL). We then plyed the full stimulus set for the reminder of the reording, to rehrterize the synpti reeptive field nd determine whether post-piring presenttion of the originl est stimulus ws neessry for the oserved redution in exittion evoked y those tones. The solute est stimulus for one exmple reording ws n 8 db SPL, 1 khz pure tone, with strong responses to nery, reltive est stimuli of 1 2 khz t 6 8 db SPL (exittory responses, Fig. 3; inhiitory responses, Supplementry Fig. 5). Tones of 3 db SPL, 4 khz were used during piring for this reording. piring, only stimuli of 1 6 db SPL were plyed for 1 min (thus exluding solute est stimuli). We then resumed mesuring the frequeny-intensity synpti reeptive field with the full stimulus set nd found tht, lthough exittory responses to the pired tone hd inresed, exittory responses to the originl solute est stimulus were unhnged (Fig. 3). However, nlysis of post-piring hnges throughout the synpti reeptive field reveled redutions to reltive est stimuli tht were inluded in the restrited stimulus set. Responses to 6 db SPL, 2 khz tones (the reltive est stimulus; tht is, whihever stimulus of <7 db SPL evoked the lrgest pre-piring responses) were depressed 1 2 min fter piring (Fig. 3). The redution of responses t the solute est or reltive est stimuli ( est stimuli depression ) thus seemed to require presenttion of those tones in prolonged period fter the piring proedure. For 13 reordings, responses evoked y reltive est stimuli t lower intensity levels (usully t 6 db SPL) were onsistently redued when inluded in the restrited stimulus set (exittion, Fig. 3, left; inhiition, Supplementry Fig. 5d), wheres originl solute est stimuli t higher intensities were unhnged when those stimuli were not Normlized exittion (%) d Normlized exittion Normlized frequeny tuning 2 Reltive to pired frequeny Reltive to est frequeny Frequeny differene (otves) Totl exittion Full RF Intensity Inreses Dereses Frequeny nture NEUROSCIENCE VOLUME 16 NUMBER 1 JANUARY

4 npg 213 Nture Ameri, In. All rights reserved. Figure 3 stimuli depression depends on reent sensory experiene. () Exmple reording in whih, for 1 min fter piring, no stimuli >6 db SPL were presented (hthing). Responses to pired tone (3 db SPL, 4 khz; irles) inresed (efore, 21.3 pa; fter, 4.7 pa); responses to solute est stimulus (8 db SPL, 1 khz) were unhnged (efore, 79.4 pa; fter, 81.1 pa; squres); responses to 6 db SPL, 2-kHz tones (reltive est stimuli) deresed (efore, 54.3 pa; fter, 26. pa; dimonds). () Summry of redued stimulus set experiments. Left, EPSCs evoked y reltive est stimuli were depressed ( 23.6 ± 5.9%, n = 13 neurons, P <.6, Student s pired two-tiled t-test), while solute est stimuli were unhnged ( 6.2 ± 4.3%, P >.1). Right, est stimuli depression ws equivlent fter 51 6 presenttions, regrdless of rte (lk rs;.5 Hz: 27.2 ± 4.7%, n = 7 neurons, P <.2;.1 Hz: 39.5 ± 5.8%, n = 5 neurons, P <.3;.5 Hz: 31.9 ± 7.2%, n = 1 neurons, P <.3; equivlent mgnitudes ross rtes, P >.4, Kruskl-Wllis H = 1.51). No depression ws mesurle fter 11 2 presenttions (open rs). Error rs show s.e.m. presented. These results indite tht the est stimulus of neuron is dynmilly determined fter periods of reeptive field reorgniztion, likely requiring severl minutes of stimulus presenttion to ssess the sttistis of sensory input. This regultory proess of est stimuli depression ould require ertin durtion (for exmple, pproximtely 1 min) to elpse, regrdless of the numer of stimulus itertions. Alterntively, est stimuli depression ould require ertin numer of tones to e presented, independent of durtion. To resolve this issue, we vried the intervls etween pure tone presenttion fter piring, plying stimuli either t slower rte (~1 per 2 s, or.5 Hz), moderte rte (~1 per 1 s,.1 Hz) or fster rte (~1 per 2 s,.5 Hz). We then monitored the hnge in response t est stimuli t two different times: fter 11 2 stimulus presenttions or fter 51 6 stimulus presenttions. If est stimuli depression ws stritly time dependent, then we expeted tht, fter 6 presenttions, responses should e progressively more depressed from fster to slower presenttion rtes, s more time would hve elpsed over the slower rte. Conversely, if est stimuli depression ws retive, then similr mounts of depression should e oserved fter 6 presenttions, irrespetive of rte over this rnge. We found tht the mgnitude of est stimuli depression ws equivlent fter 51 6 stimulus presenttions regrdless of rte (Fig. 3, right), ut not fter 11 2 presenttions in ny of the three ses. These results demonstrte tht 2 6 presenttions of these tones were required for est stimuli depression, t lest when presented within ~1 2 min. Furthermore, these dt strengthen the hypothesis tht est stimuli depression, nd the resulting normliztion of net exittion onto A1 neurons fter piring, is input speifi nd tivity dependent. Thus, lthough mture A1 reeptive fields re usully very stle 46, events suh s nuleus slis piring trnsiently destilize ortil tuning y enhning responses to pired, possily ehviorlly relevnt stimuli. To ompenste for suh hnges in exittion, stimulus history ppers to e monitored for minutes to hours fterwrd, llowing ortil networks to preserve exitility nd reeptive field struture y reduing the empirilly determined lrgest evoked responses mong the unpired stimuli. Furthermore, pired stimuli themselves my e proteted from this depression. Redued vriility improves signl proessing Long-term hnges in ortil synpti reeptive field orgniztion might hve importnt onsequenes for informtion proessing nd pereption of sensory stimuli. In the reminder of this study, we used three different methods to evlute hnges in ortil funtion nd signl proessing fter piring: nlytil (omputing mutul informtion nd vriility of synpti responses), eletrophysiologil Exittion (%) Synpti reeptive field Ex (efore) Ex (efore fter) 8 2 Asolute est 6 Reltive est ** Reltive est Asolute est 3 pa.5 Hz Ex (fter) ** ** ** (exmining spiking reeptive fields) nd psyhophysil (performing nuleus slis piring in ehving nimls). Two min tsks tht sensory systems must omplish re signl detetion nd reognition 47,48. These funtions n e hllenging even in reltively quiet, ontrolled environments euse, in ortil iruits, sensory-evoked exittory responses our in noisy kground of spontneous tivity (Fig. 4, top), with vrile singletril mplitudes lose in size to those triggered y other stimuli (Fig. 4, top). We notied tht, prtiulrly fter piring nuleus slis stimultion with low-intensity tones, the mgnitude of initilly smll responses to pired stimuli inresed in prllel with dereses of the lrgest responses (Fig. 1, top). This oservtion suggested tht while the men exittory postsynpti urrent (EPSC) size over ll stimuli remined unhnged, the totl vrine of A1 synpti tuning urves nd reeptive fields might e redued. Detetion of sensory input requires the ility to relily resolve tone-evoked events from spontneously ourring synpti events. At the sme time, ortil representtions of sensory perepts must e sttistilly distint for orret reognition of stimuli nd disrimintion etween different inputs. To exmine whether hnges to signl detetion nd reognition pities might e represented t the level of synpti inputs to A1 nd therefore ould e mintined for minutes to hours fter piring, we quntified hnges to distriutions of tone-evoked ( signl ) nd spontneous ( noise ) EPSCs over frequeny-intensity reeptive fields. mesuring these distriutions efore nd fter piring, we omputed two different metris: n index of vriility q, the vrine of synpti mplitudes normlized y men mplitude 38, nd the mutul informtion etween the signl nd noise distriutions 48. In this ontext, mutul informtion is relted to the proility tht, t ny time, given synpti response ws either stimulus evoked or ourred spontneously..1 Hz.5 Hz 8 4 pa 11 2 stim 51 6 stim 82 VOLUME 16 NUMBER 1 JANUARY 213 nture neuroscience

5 npg 213 Nture Ameri, In. All rights reserved. Figure 4 Piring dereses synpti vrine to enhne detetion nd reognition of sensory stimuli. () Exmple of detetion hnges. Top, responses to pired frequeny (tone presenttion, red). Sle rs: 4 pa, 6 ms. Bottom, distriutions of tone-evoked nd spontneous EPSCs efore (left, dshed) nd fter (right, solid) piring. piring, signl nd noise distriutions overlpped (mutul informtion MI pre,.17 its) nd hd higher vriility q in signl distriution (q pre, 24.8 pa; men µ pre, 3.7 pa; σ 2 pre, pa 2 ). piring, vriility deresed nd MI inresed (MI post,.26 its; q post, 15.1 pa; µ post, 26.2 pa; σ 2 post, pa 2 ). () Exmple of reognition hnges. Top, responses evoked y tones of different frequenies (pired tone, red). Sle rs: 5 pa, 3 ms. Bottom, EPSC distriutions for pired (red) nd unpired tones (gry). Initilly (left), pired nd unpired responses were similr (MI pre,.7 its; q pre, 69. pa; µ pre, 42.2 pa; σ 2 pre, 2,911.3 pa 2 ). piring, mens inresed while vriility deresed, enhning MI etween pired nd unpired distriutions (MI post,.18 its; q post, 25.9 pa; µ post, 72.2 pa; σ 2 post, 1,871.7 pa 2 ). () Chnges to detetion. Top left, MI etween signl nd noise inresed fter piring (efore,.19 ±.2 its; fter,.23 ±.3 its; z = 2., n = 29, P <.5, two-tiled pired Wiloxon signed-rnk test). Top right, q deresed fter piring (efore, 19.2 ± 4.6 pa; fter, 12.7 ± 3.3 pa; z = 2.8, P <.5). Bottom left, men mplitudes of signl distriutions were unhnged fter piring (efore, 33.4 ± 5.3 pa; fter, 34. ± 5.2 pa; z =.7, P >.5). Bottom right, s.d. of signl distriutions deresed fter piring (efore, 24. ± 4.8 pa; fter, 19.3 ± 3.8 pa; z = 2.4, P <.2). (d) Chnges to reognition. Top left, MI etween pired nd unpired stimuli inresed (efore,.5 ±.1 its; fter,.8 ±.1 its; z = 3., P <.3). Top right, q deresed fter piring (efore, 11.2 ± 3.1 pa; fter, 6.2 ± 2. pa; z = 2.5, P <.2). Bottom left, men mplitudes of pired stimuli responses inresed fter piring (efore, 27.9 ± 4.2 pa; fter, 44.5 ± 6.9 pa; z = 4.4, P < 1 4 ). Bottom right, s.d. of pired stimuli responses were unhnged (efore, 15.6 ± 3.2 pa; fter, 14.2 ± 3.1 pa, z =.9, P >.3). We found tht nuleus slis piring inresed mutul informtion nd deresed q. Distriutions of tone-evoked nd spontneous EPSCs for the reording in Figure 1 re shown in Figure 4, ottom. piring, there ws onsiderle overlp etween these distriutions (Fig. 4, ottom left). piring low-intensity tones with nuleus slis stimultion, the distriution of spontneous tivity ws essentilly unhnged, wheres the s.d. of the tone-evoked response distriution sutly ut signifintly deresed, lthough men mplitude ws onserved (Fig. 4, ottom right). As result, the mutul informtion for signls inresed; tht is, the unertinty out the presene of signl in the noise ws redued, s there ws less overlp etween signl nd noise distriutions. Although these effets my e modest in individul reordings, smll gins in single ells my hve sustntil effets t the popultion level. This suggests tht quiet sounds would eome esier to detet. Over 29 reordings, mutul informtion etween signl nd noise distriutions inresed (Fig. 4, top left, nd Supplementry Fig. 7) nd q deresed (Fig. 4, top right), owing to redutions in s.d. (Fig. 4, ottom right) with little hnge in men mplitudes (Fig. 4, ottom left). In 22 of 29 reordings, signl distriutions eme more sttistilly distint from noise distriutions fter piring (mesured with Numer of events MI post (its) post (pa) Detetion of evoked responses Exittion (pa) Numer of events d Reognition of response identity Signl Noise Unpired Informtion.4.8 MI pre (its) 3 Men pre (pa) q post (pa) post (pa) Vriility q pre (pa) Std. devition pre (pa) MI post (its) post (pa) Informtion MI pre (its) Men 1 Exittion (pa) Student s pired two-tiled t-tests). In five ses, signl distriutions were initilly sttistilly similr to noise distriutions (P >.5) ut eme signifintly different (P <.5) fter piring. Similr nlyses indited tht reognition of pired versus unpired stimuli would lso e enhned y piring, lthough y omplementry mehnism: inrese in distriution men (Fig. 4, ottom). piring, responses to tones hosen for piring were pproximtely the sme s responses to most other tones. piring, responses tht were initilly wek eme stronger, inresing mutul informtion onveyed y pired versus non-pired tones (Fig. 4d, top left, nd Supplementry Fig. 7). Piring lso deresed q for responses to pired inputs (Fig. 4d, top right), y inresing men mplitude (Fig. 4d, ottom left) while s.d. ws not signifintly ffeted (Fig. 4d, ottom right). As the sizes of pired distriutions ould e muh smller thn the unpired distriutions, we ross-vlidted this nlysis using t-tests. We found tht 17 of 29 reordings showed lower P-vlues etween pired nd unpired distriutions fter piring (1 of 29 ses hnging from sttistilly similr to sttistilly distint t the P <.5 level), nd 16 of 29 reordings showed lower P-vlues etween pired nd noise distriutions fter piring (7 reordings hnging from sttistilly similr to sttistilly distint). 2 q post (pa) pre (pa) post (pa) Vriility q pre (pa) Std. devition pre (pa) nture NEUROSCIENCE VOLUME 16 NUMBER 1 JANUARY

6 npg 213 Nture Ameri, In. All rights reserved. Spikes per tone Spikes (%) (8 db SPL) t 16 khz Chnge in spiking 2 ** ** (5 db SPL) Net Synpti modifitions ffet spike output To e useful for improving pereptul ilities in ehving nimls, ltertions in ortil reeptive fields nd signl proessing t the level of synpti inputs should lso e represented y hnges to spiking Figure 6 Nuleus slis piring improves uditory detetion. () Exmple of enhned detetion fter nuleus slis (NB) piring. Hits (irles) t 3 db SPL) inresed fter piring (efore piring, 28.9 ± 6.6%; fter, 66.7 ± 1.%; P <.5). Responses to foils (tringles) were unhnged (flse lrms t 3 db SPL efore, 18.7 ± 3.2%; fter, 16.7 ± 5.7%; P >.7). d inresed (.3 to 1.4). Arrow indites pired stimulus throughout. () Crhol piring enhned detetion without NB stimultion. Hits inresed (efore, 36.7 ± 6.6%; fter, 74.1 ± 7.8%; P <.1); flse lrms were unhnged (efore, 32.4 ± 7.6%; fter, 27.2 ± 4.1%; P >.5). d inresed (.1 to 1.3). () Summry of d vlues efore nd fter piring NB stimultion with sline (d efore,.7 ±.2; fter, 1.5 ±.3; N = 9 nimls, P <.3), or rhol (r) piring without NB stimultion (d efore, 1. ±.5; fter, 2. ±.5; N = 7, P <.3). Sline piring without NB stimultion hd no effet (d efore, 1.2 ±.6; fter, 1.2 ±.7; N = 4, P >.8). (d) Chnges to men response rte ross nimls. Response rte inresed fter piring t the pired intensity level (hits efore piring, 47.7 ± 4.7%; fter, 7.6 ± 4.%; N = 9, P <.2) nd 1 db SPL from pired level (efore, 28.9 ± 6.4%; fter, 42.4 ± 6.7%; P <.3) ut not t higher intensities (P >.1). Flse lrms were unhnged (efore, 25.2 ± 4.6%; fter, 22.1 ± Spikes per tone d MI post (its) (4 khz) d g (16 khz) NB + sline Hits t 6 db SPL Detetion MI pre (its) Reognition.5 1. MI pre (its) Flse lrms NB piring NB + tropine reeptive fields. To determine whether piring improved informtion proessing t the level of tion potentil genertion, we mde urrent-lmp reordings from A1 neurons in vivo nd mesured tone-evoked suprthreshold responses. For intensity sensitivity (Fig. 5) nd frequeny tuning (Fig. 5), piring enhned spike ounts evoked y pired tones nd redued spiking evoked y originl est stimuli. As with synpti strength, the net effet of these djustments ws tht the totl numer of 5.5%; P >.3). (e) d for pired stimuli ross nimls ws enhned fter piring (efore,.7 ±.2; fter, 1.5 ±.3; P <.3). (f) Comprison of detetion etween first nd seond dys, efore piring (d dy 1,.6 ±.2; d dy 2,.8 ±.2; N = 9, P >.4) nd for nimls reeiving only sline (d dy 1, 1.2 ±.6; d dy 2, 1.3 ±.6; N = 4, P >.2). (g) Atropine prevented effets of piring. Hits, flse lrms nd d were unhnged (P >.6). (h) AP5 prevented effets of piring (P >.5). (i) Summry of effets of tropine (d efore,.7 ±.4; fter, 1. ±.2; N = 4, P >.2) nd AP5 (d efore,.9 ±.2; fter,.7 ±.4; N = 4, P >.4). Error rs show s.e.m Intensity differene (db SPL) Figure 5 Nuleus slis piring modifies spiking reeptive fields. () Suprthreshold intensity sensitivity (t 16 khz) is modified fter piring. Exmple reording in whih responses t pired intensity (5 db SPL, rrow) inresed (efore, 1.3 ±.3 spikes per tone; fter, 2.6 ±.6 spikes per tone; P <.3, Student s pired two-tiled t-test), responses t 8 db SPL (rrowhed) deresed (efore, 3.1 ±.6 spikes per tone; fter, 1.9 ±.4 spikes per tone; P <.5). Sle rs: 5 mv, 5 ms. () Exmple of hnges to suprthreshold frequeny tuning (t 6 db SPL) fter piring (for pired frequeny 16 khz: efore,.5 ±.1 spikes per tone; fter, 1.6 ±.1 spikes per tone; P < 1 4 ; for est frequeny 4 khz: efore, 1.8 ±.1 spikes per tone; fter, 1.2 ±.1 spikes per tone; P <.1). Sle: 2 mv, 25 ms. () Summry of urrent-lmp reordings. Spiking responses to pired tones inresed (65.2 ± 17.6%, n = 14 neurons, P <.3), responses to originl est stimuli deresed ( 26.7 ± 7.4%, P <.4); there ws no net hnge in spiking (.2 ± 1.3%, P >.9). (d) Summry of hnges to MI fter piring. Piring inresed MI for detetion (efore,.29 ±.6 its; fter,.46 ±.8 its; z = 2.3, P <.2; left) nd reognition (efore,.16 ±.4 its; fter,.29 ±.5 its; z = 2.9, P <.4; right). Error rs show s.e.m. e h Crhol N = 9 1. N = 9 d NB + AP NB + tropine NB + AP5 5 NB piring Intensity differene (db SPL) d fter f Dy 2 d efore i d fter NB + sline Cr Sline d efore NB + sline Sline Dy 1 d efore d efore 84 VOLUME 16 NUMBER 1 JANUARY 213 nture neuroscience

7 npg 213 Nture Ameri, In. All rights reserved. Figure 7 Nuleus slis piring improves reognition. () Responses from one niml. Nuleus slis piring did not improve widend performne (d efore, 3.5; fter, 2.8). Arrow indites pired stimulus throughout. () Responses from nother niml. Piring improved nrrownd performne (d efore, 1.3; fter, 2.3). () Summry of widend (d efore, 2.7 ±.3; fter, 2.3 ±.3; N = 12, P >.3) nd nrrownd (d efore,.5 ±.1; fter, 1. ±.2; N = 12, P <.5). (d) Widend performne ws unhnged fter piring (hits efore piring, 9.3 ± 2.8%; fter, 84.5 ± 5.%; N = 12, P >.1). (e) Nrrownd performne ws improved fter piring (hits efore piring, 5.1 ± 6.6%; fter, 69.9 ± 9.%; N = 12, P <.5). (f) d efore nd fter piring for widend (efore, 2.7 ±.3; fter, 2.3 ±.3; P >.3) nd nrrownd (efore,.5 ±.1; fter, 1. ±.2; P <.5) tsks. (g) Atropine infused into A1 prevented piring from improving nrrownd ehvior (hits efore piring, 72. ± 16.4%; fter, 63.6 ± 9.5%; P >.6; flse lrms efore, 23.4 ± 6.5%; fter, 14.6 ± 6.4%; P >.3; d efore, 1.3; fter, 1.4). (h) When only lower intensity (<5 db SPL) stimuli were presented 3 min fter piring, nrrownd ehvior tsk performne ws unffeted (hits efore, 23.3 ± 15.4%; fter, 11.5 ± 9.5%; P >.3; flse lrms efore, 11.9 ± 4.5%; fter, 7.5 ± 1.8%; P >.3; d efore,.4; fter,.2) (i) Summry of results for A1 tropine (d efore,.7 ±.3; fter,.8 ±.3; N = 5, P >.5), systemi (sys) tropine (d efore, 1.2 ±.7; fter, 1. ±.6; N = 5, P >.3) or when only quiet stimuli were presented fter piring (d efore,.7 ±.2; fter,.3 ±.1; N = 6, P >.5). Error rs show s.e.m. evoked spikes ross ll presented stimuli ws kept onstnt (Fig. 5) nd mutul informtion for oth signl detetion nd reognition inresed (Fig. 5d). Synpti modifitions improve pereption Attention nd rousl filitte sensory proessing, nd the nuleus slis neuromodultory system is ritilly linked to tivtion of ttentive ehviorl sttes 25,4. Our nlyses of synpti distriutions (Fig. 4) nd mesurements of spiking tuning urves (Fig. 5) oth indited tht the hnges to exittory reeptive fields indued y few minutes of nuleus slis piring should improve uditory pereption, prtiulrly for suliminl stimuli with initilly wek, suthreshold responses. Therefore, in our finl experiments, we exmined the psyhophysil ilities of dult nimls to pereive speifi tonl stimuli ( trgets ), fousing on two seprte spets of sensory pereption: detetion of trget stimuli over rnge of intensities nd disrimintion of trget stimuli from non-trget tones ( foils ) (Fig. 6). Rts were operntly onditioned to nose-poke for food rewrd in response to trget stimuli (4-kHz tones, ny intensity) while withholding responses to foil tones of other frequenies. Animls hd stimultion eletrodes implnted into right nuleus slis nd nnuls for drug delivery implnted unilterlly into ipsilterl A1. 2 weeks of trining, nimls rehed performne plteus for reltively loud, slient trget stimuli. The psyhophysil detetion ilities of two representtive nimls re shown in Figure 6,, nd the performnes of ll nimls re individully shown in Supplementry Figure 8. Animls hieved high hit rtes for trgets nd low numer of flse lrm responses to foils (Fig. 6). Consequentilly, vlues of the disriminility index d were good for louder tones onsiderly ove pereptul threshold, wheres tones elow ~5 db SPL were deteted less relily. g Widend Flse lrms Atropine Hits Flse lrms h 1 5 Nrrownd d e f 1 5 N = N = min quiet determining response rtes nd d, we repetitively pired 4-kHz tones t single lower intensity (etween 3 45 db SPL) with nuleus slis stimultion for 3 5 min while nimls were wke in the trining ox. We then retested their pereptul ilities to detet 4-kHz tones. At the pired stimulus intensity, detetion ws muh higher, with verge d more thn douling 3 12 min fter piring (Fig. 6,e). This ws due to n inrese in hit rte t the pired intensity, with no signifint hnge in flse lrms (Fig. 6,d). Dt shown re verged ross 2 d of trining; s shown in Figure 6f, seline dily performne of individul nimls ws pproximtely the sme t the strt of the first dy nd the seond dy. Thus piring nuleus slis tivtion with presenttion of low-intensity sounds mkes it esier for nimls to pereive nd operte on these initilly hrd-to-her stimuli, perhps y seletive redution in thresholds for spike genertion nd/or pereption. Chnges to A1 networks ould led to sustntil pereptul improvements in initilly trined nimls. We found tht, insted of nuleus slis stimultion, piring low-intensity tones with diret A1 infusion of the holinergi gonist rhol (1 mm) lso ws effetive t inresing detetion of the pired tone (Fig. 6,). This demonstrted tht hnges lolized to or initited diretly in A1 ould enhne uditory pereption, fter the si udiomotor ssoition for the tsk hd een formed. As ontrol, sline infusion pired with low-intensity tones hd no effet (Fig. 6). In ontrst, infusion into A1 of either the musrini reeptor ntgonist tropine or the NMDA reeptor loker AP5 (1 mm eh) prevented inrese in detetion ilities fter nuleus slis piring, inditing tht long-term modifition of A1 synpses is required for enhned tone detetion (Fig. 6g i). We further tested whether piring in wke nimls would improve reognition ilities (Fig. 7). Initilly, foil stimuli were spetrlly d fter d i d fter Widend Nrrownd d efore 4. piring piring Widend Nrrownd Atropine, A1 Atropine, sys Quiet d efore nture NEUROSCIENCE VOLUME 16 NUMBER 1 JANUARY

8 npg 213 Nture Ameri, In. All rights reserved. Figure 8 Piring under nesthesi improves pereption. () Detetion; niml nesthetized with pentoritl (pento) during nuleus slis (NB) piring. Hits inresed fter piring (efore, 3.6 ± 16.3%; fter, 67.3 ± 6.5%; P <.4). Flse lrms were unhnged fter piring (efore, 27.2 ± 5.2%; fter, 27.3 ± 1.9%; P >.4), inresing d from.4 to.8. Arrow indites pired stimulus throughout. () Nrrownd; pentoritl nesthesi during piring. Hits inresed (efore, 39. ± 2.7%; fter, 63.5 ± 7.9%; P <.3); flse lrms were unhnged (efore, 2.9 ± 2.9%; fter, 22.4 ± 3.5%; P >.7), inresing d from.6 to 1.1. () Widend; pentoritl nesthesi during piring (hits efore, 54.8 ± 11.9%; fter, 75.1 ± 1.1%; P >.1; flse lrms efore, 6.8 ± 1.7%; fter, 4.3 ± 2.%; P >.3; d efore, 1.7; fter: 1.8). (d) Summry of experiments with pentoritl nesthesi during nd 1 3 h fter piring. Performne on widend, nrrownd nd detetion tsks ws ssessed 3 6 min efore piring nd 1 2 h fter reovery. Performne improved on detetion (d efore,.9 ±.1; fter, 1.3 ±.2; N = 7, P <.3) nd on nrrownd (d efore,.4 ±.1; fter,.7 ±.2; N = 5, P <.2) ut not widend (d efore, 1.6 ±.2; fter, 2. ±.4; N = 5, P >.5) reognition. (e) Detetion; niml nesthetized with isoflurne (iso) efore piring. Hits inresed fter piring (efore, 53.3 ± 3.3%; fter, 83.3 ± 9.6%; P <.3) nd flse lrms were unhnged (efore, 15.1 ± 2.6%; fter, 2.7 ± 4.%; P >.1), inresing d from.8 to 1.4. (f) Nrrownd reognition; niml nesthetized with isoflurne during piring. Hits inresed (efore, 36.8 ± 5.5%; fter, 62.1 ± 9.4%; P <.4) nd flse lrms were unhnged (efore, 3.6 ± 3.6%; fter, 36.1 ± 4.2%; P >.1), inresing d from.2 to.7. (g) Widend reognition; niml nesthetized with isoflurne during piring. Behvior ws unhnged (hits efore, 69.4 ± 12.3%; fter, 74.7 ± 5.4%; P >.7; flse lrms efore, 9.2 ± 1.9%; fter, 11.9 ± 2.2%; P >.3; d efore piring, 1.8; fter, 1.8). (h) Summry of experiments with isoflurne nesthesi during piring. Performne improved on detetion (d efore, 1.1 ±.4; fter, 1.7 ±.5; N = 6, P <.4) nd nrrownd (d efore,.2 ±.2; fter,.5 ±.1; N = 5, P <.5) ut not widend (d efore, 1.5 ±.2; fter, 1.9 ±.1; N = 3, P >.1) reognition. Error rs show s.e.m. dissimilr from the trget stimulus of 4 khz, seprted t 1-otve intervls t 7 db SPL. Animls ould esily respond to trgets nd withhold responses to foils on this widend tsk efore piring, s shown for one exmple niml (Fig. 7) nd for ll 12 nimls tested on this tsk (Fig. 7d). Unsurprisingly, piring with 4-kHz tones filed to improve reognition (exmple niml, Fig. 7; ll nimls, Fig. 7,d,f), s nimls were lredy performing lose to optimum. We then mde this tsk more hllenging, y ompressing the spetrl rnge of the foils from six otves to one otve, suh tht the foils were muh more similr to the trget tone. piring, ehviorl performne on this nrrownd tsk ws low (exmple niml, Fig. 7; ll nimls, Fig. 7,e,f), ut piring gretly improved frequeny reognition (exmple niml, Fig. 7; ll nimls, Fig. 7,e,f). This inrese in performne ws prevented y dministrtion of tropine, either diretly into A1 y mens of nnul (Fig. 7g,i) or given systemilly (Fig. 7i). Overll, 7 of 9 nimls showed signifintly higher hit rte (P <.5, Student s pired two-tiled t-test) in the detetion of the trget tone t the pired intensity fter piring (Supplementry Fig. 8). On the nrrownd reognition tsk, 7 of 12 nimls showed signifintly higher hit rte on the trget frequeny fter piring (Supplementry Fig. 9), wheres only 1 of 12 nimls improved performne on the widend reognition tsk (Supplementry Fig. 1). We then tested whether hnges to pired inputs lone ould enhne pereptul ilities; lterntively, perhps est stimuli depression nd orresponding hnges in full synpti reeptive field vrine re required for improved sensory pereption. In ehving nimls, we found tht nuleus slis piring enhned reognition on the nrrownd tsk for tones t 7 db SPL only when we plyed the full stimulus set fter piring. If, insted, we presented for 3 min e g NB piring (pento) Hits Flse lrms NB piring (pento) NB piring (iso) NB piring (iso) fterwrd redued set of trgets nd foils tht did not ontin ny tones over 5 db SPL, piring filed to improve trget reognition t higher intensity levels (exmple niml, Fig. 7h; ll nimls, Fig. 7i). Therefore, lthough nuleus slis piring indued enhnements in responses to pired stimuli, wide-sle reeptive field reorgniztion medited y lrge rnge stimulus exposure leding to deresed response vriility ws required for these hnges to e pereptully useful. Given the reltively rpid gins in performne, our results indite tht est stimulus depression is required for ortil reeptive field reorgniztion to hve funtionl signifine. Without it, pereptul improvement is limited nd the enefits of ortil plstiity my e ompromised. Lstly, lthough these ehviorl hnges were oserved when nuleus slis piring ws performed in wke nimls, the eletrophysiologil dt were otined in nesthetized nimls. To more losely onnet the physiologil nd ehviorl effets of piring, we onduted further ehviorl experiments, performing piring in nimls tht were temporrily nesthetized. We monitored seline ehviorl performne of trined, implnted nimls for 3 6 min. We then nesthetized them with either pentoritl (Fig. 8 d) or isoflurne (3 5%; Fig. 8e h) nd performed 5 min of piring with 4-kHz tones ws performed. Animls were llowed to reover (usully fter 1 2 h for isoflurne or 3 5 h for pentoritl) nd post-piring ehviorl performne ssessed for 1 2 h. We oserved signifint d d fter f h d fter 1 5 NB piring (pento) Pento piring summry d efore NB piring (iso) Iso piring summry d efore Detetion Widend Nrrownd Detetion Widend Nrrownd 86 VOLUME 16 NUMBER 1 JANUARY 213 nture neuroscience

9 npg 213 Nture Ameri, In. All rights reserved. improvements on the detetion nd nrrownd reognition tsks even when piring ws performed in nimls tht were nesthetized (Fig. 8). Thus the hnges in neurl iruits initited y nuleus slis piring persist nd n ffet ehviorl performne even fter mjor hnges in rin stte. DISCUSSION The entrl nervous system remins plsti throughout life, dpting to ehviorlly relevnt hnges in the externl environment. Previous studies hve doumented ltertions to ortil iruits nd elsewhere in the rin tht re orrelted with periods of ehviorl trining nd onditioning 1,49. Here we used different pproh to ssess the usl vlue of suh modifitions to ortil synpti reeptive fields, tking dvntge of the powerful neuromodultory system of the holinergi nuleus slis to mimi the neurl proesses engged y nd importnt for ttention. Nuleus slis piring modifies intrortil synpses in sene of hnges to thlmoortil trnsmission 22, llowing us to seletively proe the ehviorl nd network effets of diret hnges to ortil synpses nd reeptive fields. Our dt demonstrte how exittory inputs to the ererl ortex re oordinted in vivo to ommodte hnges in sensory representtions for pereptul lerning. Severl prmeters of A1 reeptive fields were rpidly hnged y piring speifi input with nuleus slis tivtion. In prtiulr, neurons tht initilly prefer higherintensity tones ould e retuned to prefer lower-intensity stimuli. Synpti enhnements t pired inputs were oupled with redutions in responses to previously strong inputs, in mnner tht depended on the sttistis of the ousti environment experiened immeditely fter eh episode of nuleus slis piring. We predit tht these hnges serve to trnsiently inrese the similrity etween ortil neurons y enhning responses to the shred, pired input nd deresing responses to originlly preferred (possily distint) inputs. As onsequene of hving more similr reeptive fields, we speulte tht stimulus nd noise orreltions etween neuronl firing ptterns my e higher, possily improving signl proessing nd informtion trnsmission to downstrem sttions. Further experiments will e neessry to lrify this issue of the effets of synpti plstiity nd ttentionl modultion on ortil orreltion 23, Our experiments indite tht, in ddition to the tone presented during nuleus slis stimultion, the sttistis of the post-piring ousti environment influene how A1 synpses nd tuning urves re djusted fter piring. In prtiulr, it seems tht ells nd networks re le to ompute their lol mximl est stimulus, to redue those responses nd ompenste for the inrese of exittion t the pired input. The integrtive time for this proess seemed to e t lest 1 min, nd future studies re required to determine the durtion of this sensitive period for est stimulus depression, the ellulr mehnisms nd reltion to phenomen suh s heterosynpti LTD, nd the pereptul impt of hnges to input sttistis. Notly, reent study of ousti pereptul lerning in humns demonstrted tht pssive stimuli presented fter trining ould lso influene the degree of lerning 5. However, stimuli presented more thn 15 min fter period of prtie were less effetive, nd stimuli presented 4 or more hours fter prtie were found to e ineffetive. Funtionlly, hnges to A1 synpses lone re presumly insuffiient to generte ehviorl modifition in untrined nimls, whih require extensive trining on the proedurl spets of the tsks. However, one the initil udiomotor ssoitions hve een formed, modifitions of A1 iruitry n led to superior ehviorl performne for reognizing pired tones from spetrlly similr unpired tones nd enhne the pereption of liminl, low-intensity stimuli. Methods Methods nd ny ssoited referenes re ville in the online version of the pper. Note: Supplementry informtion is ville in the online version of the pper. Aknowledgments We thnk L.F. Aott, T. Bok, M. Berry, E. Chng, Z. Chen, E. de Villers- Sidni, A.L. Dorrn, P. Dutt, A. Firhll, S.P. Gndhi, G. Glssner, C.A. Hoeffer, K. Imizumi, B.J. Jones, N. Kopell, R. Liu, G. Myers, P. O Hr, J. Shih, A.Y. Tn, C.-L. Teng nd L. Wilreht for omments, disussions nd tehnil ssistne. J. Pivkov reted the rtwork in Figure 1. This work ws supported y the US Ntionl Institute on Defness nd Other Communition Disorders (grnt DC9635 to R.C.F., grnt DC9836 to D.B.P. nd grnt DC226 to C.E.S.), US Ntionl Siene Foundtion (grnts nd to P.A.L.), Intel Reserh (P.A.L.), DoCoMo Cpitl nd Foundtion Cpitl (P.A.L.), the Conte Center for Neurosiene Reserh t the University of Cliforni, Sn Frniso (grnt MH7797 to M.M.M. nd C.E.S.), Hering Reserh In. (C.E.S.), the John C. nd Edwrd Colemn Fund (M.M.M. nd C.E.S.) nd the US Ntionl Ademies Kek Future Inititives (R.C.F. nd P.A.L.). A.J.B. is supported y US Ntionl Siene Foundtion Predotorl Fellowship. M.W. is supported y Sequoi Cpitl Stnford Grdute Fellowship. I.C. is supported y n US Ntionl Institute of Mentl Helth trining grnt. P.A.L. is supported y Mirosoft Reserh New Fulty Fellowship. R.C.F. is supported y Slon Reserh Fellowship. AUTHOR CONTRIBUTIONS R.C.F., I.C., D.B.P., M.M.M. nd C.E.S. designed the experiments. R.C.F., I.C. nd A.R.O.M. performed the eletrophysiologil experiments. R.C.F., I.C., A.J.B., K.Y., B.A.S., N.Z. nd H.B. performed the ehviorl experiments. M.W. nd P.A.L. designed nd uilt the wireless devie. R.C.F. wrote the mnusript. All uthors disussed the mnusript. COMPETING FINANCIAL INTERESTS The uthors delre no ompeting finnil interests. Pulished online t Reprints nd permissions informtion is ville online t reprints/index.html. 1. Huel, D.H. & Wiesel, T.N. Reeptive fields, inoulr intertion nd funtionl rhiteture in the t s visul ortex. J. Physiol. 16, (1962). 2. Hirsh, J.A. & Mrtinez, L.M. Ciruits tht uild visul ortil reeptive fields. Trends Neurosi. 29, 3 39 (26). 3. Huermn, A.D., Feller, M.B. & Chpmn, B. Mehnisms underlying development of visul mps nd reeptive fields. Annu. Rev. Neurosi. 31, (28). 4. Ye, C.Q., Poo, M.M., Dn, Y. & Zhng, X.H. Synpti mehnisms of diretion seletivity in primry uditory ortex. J. Neurosi. 3, (21). 5. Frégn, Y., Shulz, D., Thorpe, S. & Bienenstok, E. A ellulr nlogue of visul ortil plstiity. Nture 333, (1988). 6. 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