Non-redundant odor coding by sister mitral cells revealed by light addressable glomeruli in the mouse

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1 Non-reunnt oor oing y sister mitrl ells revele y light ressle glomeruli in the mouse Ashesh K Dhwle,2, Akri Hgiwr 3, Upiner S Bhll 2, Venktesh N Murthy 3 & Dinu F Alenu 2 Nture Ameri, In. All rights reserve. Sensory inputs frequently onverge on the rin in sptilly orgnize mnner, often with overlpping inputs to multiple trget neurons. Whether the responses of trget neurons with ommon inputs eome eorrelte epens on the ontriution of lol iruit intertions. We resse this issue in the olftory system using newly generte trnsgeni mie tht express hnnelrhoopsin-2 in ll of the olftory sensory neurons. By seletively stimulting iniviul glomeruli with light, we ientifie mitrl/tufte ells tht reeive ommon input (sister ells). Sister ells h highly orrelte responses to oors, s mesure y verge spike rtes, ut their spike timing in reltion to respirtion ws ifferentilly ltere. In ontrst, non-sister ells orrelte poorly on oth of these mesures. We suggest tht sister mitrl/tufte ells rry two ifferent hnnels of informtion: verge tivity representing shre glomerulr input n phse-speifi informtion tht refines oor representtions n is sustntilly inepenent for sister ells. The responses of neurons in sensory iruit epen on the intertion etween iret input reeive from sensory fferents, lterl input from neurons in the sme iruit, s well s feek from other rin res. In mmmls, olftory sensory neurons (OSNs) sen their xons to the olftory ul, where there is hrteristi physil lyout of inputs t the glomerulr lyer. Eh glomerulus reeives onvergent fferents from lrge numer of OSNs expressing the sme oornt reeptor 2,3. The prinipl neurons in the olftory ul, the mitrl n tufte (mitrl/tufte) ells, typilly hve only one primry enrite tht projets to single glomerulus. A few ozen mitrl/tufte ells shre input from the sme prent glomerulus. Mitrl/tufte ells lso reeive lterl GABAergi n opminergi inputs from vriety of interneurons in the glomerulr n externl plexiform lyers, thus llowing them to smple informtion from severl funtionlly iverse glomeruli. To wht extent is the output of mitrl/tufte ells shpe y the input from the prent glomerulus versus lterl signls originting from other glomeruli in the ul? Do mitrl/tufte ells tht hve their primry enrites in the sme glomerulus, referre to s sister ells, rry reunnt informtion out oors to higher rin enters? Progress in nswering these questions out reunny n the topogrphy of lterl onnetivity hs een slowe y the nture of oor representtions t the input lyer n the ntomy of the ul. Ativting iniviul input elements (glomeruli) seletively is iffiult euse iniviul oors ten to tivte istriute popultions of glomeruli 4,5 n not ll glomeruli n e tivte, even with lrge plette of oors 6. We evelope new tools for tivting glomeruli optilly with high sptil n temporl preision. We engineere trnsgeni mouse lines tht express the light-tivte ion hnnel hnnelrhoopsin-2 (ChR2) 7 speifilly in OSNs. Then, using igitl mirror evie (DMD) to eliver ptterne light stimultion onto the olftory ul in onjuntion with extrellulr reorings, we otine the glomerulr reeptive fiel mps of iniviul mitrl/tufte ells. By ientifying the prent glomeruli, we were le to iretly exmine the similrity of oor responses of sister n non-sister mitrl/tufte ells. RESULTS We generte trnsgeni mie tht express ChR2-EYFP (enhne yellow fluoresent protein) in ll mture OSNs using the olftory mrker protein (Omp) promoter (ORC mie), suh tht ll glomeruli were light sensitive (Fig. ). We hrterize the ORC mie in vitro using ute rin slies n lser-snning photostimultion 8. Whole-ell pth lmp reorings from mitrl ells (Fig.,) showe relile lightevoke urrents only in response to photostimultion of the glomerulr lyer. These responses were loke y ionotropi glutmte reeptor ntgonists 6-yno-7-nitroquinoxline-2,3-ione (CNQX) n ( )-2-mino-5-phosphonovleri i (AP5) (n = 5 ells; Fig. ). Furthermore, when stimulting t suglomerulr inter-foi sping (5 μm), exittory urrents (Fig. ) were otine y stimultion of only single glomerulus for eh reore ell (Fig. ). Fluoresent ye (Alex 546) loe into the reore mitrl ell onfirme tht its pil enrite projete to the sme glomerulus whose stimultion evoke urrents (Fig. ). Inresing the stimultion intensity le to lrger urrents (Supplementry Fig. ), s well s to spre of the hotspot to res jent to the input glomerulus (Supplementry Fig. ), presumly s result of tivtion of ChR2 in xons of pssge. These results onfirm tht tivtion of ChR2 in olftory sensory xons in single glomeruli oul epolrize their terminls effetively, using glutmte relese to tivte postsynpti neurons. Col Spring Hror Lortory, Col Spring Hror, New York, USA. 2 Ntionl Centre for Biologil Sienes, Tt Institute of Funmentl Reserh, Bnglore, Ini. 3 Deprtment of Moleulr n Cellulr Biology, n Center for Brin Siene, Hrvr University, Cmrige, Msshusetts, USA. Corresponene shoul e resse to V.N.M. (vnmurthy@fs.hrvr.eu) or D.F.A. (lenu@shl.eu). Reeive 4 July; epte 24 Septemer; pulishe online 7 Otoer 2; oi:.38/nn.2673 nture NEUROSCIENCE vne online pulition

2 2 Nture Ameri, In. All rights reserve. Figure ORC trnsgeni expression pttern. Lser-snning photostimultion ientifie prent glomeruli for mitrl ells in ORC mie olftory ul slies. () Confol mirogrph of olftory ul sgittl setion from ORC mie showing EYFP fluoresene. A, nterior; AOB, essory olftory ul; D, orsl; GL, glomerulr lyer; MCL, mitrl ell oy lyer; P, posterior; V, ventrl. Sle r represents μm. Inset, higher mgnifition view, rrow inites OSN xons. Sle r represents 5 μm. () Bth pplition of glutmte reeptor ntgonists CNQX n AP5. The three tres for eh of the onitions orrespon to three jent photostimultion foi 5 μm prt (re tre, efore rug pplition; lk tre, uring rug pplition; rrow inites the time of photostimultion). () Phse (top left) n re fluoresene imge (ottom left) of one mitrl ell fille with Alex 546; the ox inites the fiel of photostimultion. Top right, primry enrite n tuft projeting to glomerulus. Bottom right, mthing 2DLAM (6 6), inter-foi istne = 5 μm, photostimultion urtion = ms. Note the fiuiry irle on the two pnels. Color Ientifition of prent glomeruli of mitrl/tufte ells y light We pte DMD from ommeril igitl light projetion (DLP) projetor (see Online Methos) to onstrut n instrument tht llowe us to illuminte the olftory ul surfe with ritrry light ptterns (t ~47 nm, see Online Methos) n photo-tivte glomeruli in vivo (Fig. 2). Thus, we were le to optilly ontrol neuronl tivity t suglomerulr resolution, with eh pixel on the DMD orresponing to ~5-μm spot on the ul surfe. We simultneously reore mitrl/tufte ell tivity using tetroes tht were inserte t epth of 25 3 μm in the olftory ul of nesthetize ORC mie (Online Methos). The surfe of the ul ws tessellte into squre gri n eh squre pixel ws illuminte sequentilly y single fol spots of light in pseuo-rnom sptil orer (Fig. 2). The stimulting light spots were of the sme size or smller (2 75 μm) thn the verge mouse glomerulus (~75 μm) 6,9. Light stimultion inue rpi n relile hnges in firing, peking t 25 5 ms n lsting for ms on verge (Fig. 2). For eh single unit (Fig. 2) stisfying our seletion riteri (Online Methos), we onstrute two-imensionl light tivtion mp (2DLAM) t suglomerulr resolution (75 μm own to 2 μm; Fig. 2 n Online Methos). The light intensity ws suessively lowere until no light-triggere tivity ws seen in ny unit eing reore (own to intensities lower thn 2 mw mm 2 ). This ensure tht we were operting in the regime of miniml glomerulr tivtion (Fig. 2) with negligile nonspeifi tivtion of xons of pssge, s oserve in ute slie experiments. Beuse ny given mitrl/tufte ell in the ult mouse olftory ul reeives exittory inputs from only one glomerulus, we interprete the hotspots to e prent glomeruli for the orresponing mitrl/tufte ells. This ws supporte y the oservtion tht reuing light levels le to single hotspot on the 2DLAMs for ll 4 units tht were light responsive. In ition, the verge size of the hotspot t the lowest intensity of stimultion (73.6 ± 3.9 μm, n = 4) ws omprle to the size of the verge mouse glomerulus (74.2 ±.2 μm), s mesure P D V A GL AOB MCL GL Before rug pplition CNQX, AP5 represents the pek mplitue of the light-inue urrents. ONL, olftory nerve lyer. Sle r represents μm. () Currents reore in the mitrl ell y lser-snning photostimultion in re shown t lotions orresponing to eh point in the 6 6 gri. Tres were verge ross four repets,.6-mw lser power ws use. Sle rs represent 5 pa n ms. 5 µm 5 pa 5 ms ONL GL EPL MCL µm µm 5 pa ms 5 µm in OMP-synptopHluorin (OMP-spH) mie (572 glomeruli n 9 hemiuls; Fig. 2e), onsistent with ntomil stuies 9. Furthermore, tking vntge of YFP expression in glomeruli, we overli funtionl hotspots (n = 9) otine from light mpping onto multiphoton z stk projetions of imges of YFP glomeruli tken in the sme niml (Online Methos). The hotspots ololize well with ntomil glomeruli (Fig. 3 n Supplementry Fig. 2) n the full with t hlf mximum (FWHM) of the hotspots fitte in the ntomil ounries of mthing glomeruli (Fig. 3). Furthermore, the jitter etween the entrois of hotspots n ntomil glomeruli ws sustntilly smller thn the orresponing glomerulr withs (Fig. 3 n Online Methos). The prent glomerulus for eh isolte mitrl/tufte unit ws thus ientifie optilly, just s it ws one in vitro. Glomeruli re generlly li out in single row on the ul surfe, ut osionlly they n e stke on top of eh other. As it oul ffet the orret ssignment of prent glomeruli to mitrl/tufte units, we quntifie the frequeny of this over-stking. Multiphoton z stks of ORC n OMP-spH glomeruli otine vi the sme surgil onfigurtion use for the physiology experiments revele tht only ~6% of glomeruli overlppe on the orsl surfe (5.94 ±.45%, 558 glomeruli, 4 ORC-M hemiuls; 6.2 ±.6%, 875 glomeruli, 7 OMP-spH hemiuls; Fig. 3 n Supplementry Fig. 2). Ientifition of sister n non-sister mitrl/tufte ells y light Using tetroes or ul-tetroes, we reore oor responses simultneously from multiple mitrl/tufte units with efine prent glomerulr ientities. On verge, we were le to isolte ~4 single units per reoring site. We ompre ll possile pirs of light-responsive units otine t eh reoring site (n = 35 pirs) y tking the ifferene of 2DLAMs orresponing to eh unit (Fig. 4 ). In some pirs, the hotspots were lerly sptilly seprte (Fig. 4), wheres in others they were overlpping (Fig. 4). Thus, some units ppere to reeive inputs from ifferent neighoring glomeruli (Fig. 4), wheres others shre the sme glomerulr territory (Fig. 4). 5 pa vne online pulition nture NEUROSCIENCE

3 vi v iv viii vii M A P L iii ii 5 µm i Tetroe hnnel Trils Spikes per in µv Time (ms) e 3 µv 28 Hz A P M µm 5 Hz mw mm 2 Proportion of totl sph glomeruli Hotspots FWHM (µm) 2 L µm 2 Nture Ameri, In. All rights reserve. Figure 2 DMD ptterne illumintion in ORC mie mps the prent glomeruli of mitrl/tufte ells in vivo. () Left, shemti of the DLP projetor se photostimultion setup. Top right, orsl surfe of the ul with tetroe positione in the mitrl ell lyer. One squre light spot n e seen projete onto the ul surfe. Sle r represents 5 μm. Inset, rtoon shemti of glomeruli showing suglomerulr size light spot n ul-tetroes positione in the mitrl ell lyer. i, DLP projetor; ii, fousing lens; iii, lue exittion filter; iv, ihroi mirror; v, emission filter; vi, CCD mer; vii, ul-tetroe; viii, olftory ul. () Top, rw voltge tres orresponing to the four hnnels of tetroe uring photostimultion. Center, rster plot of spikes from n isolte single unit. Bottom, peri-stimulus time histogrm (PSTH) with 2-ms time ins. () Left, exmple spike wveform of single unit ross the eight hnnels of ul-tetroe. Drk tres represent iniviul spikes n the white line represents the verge wveform. Center, 2DLAM showing the hnge in firing rte of the mitrl/tufte unit uring photostimultion over ten repets. Sle r represents μm (light spot size, 5 μm). Right, 2DLAM re-smple y interpoltion. () 2DLAMs otine t ifferent stimultion intensities (spot size, 5 μm). All mps were normlize to the highest in in the 2.8 mw mm 2 2DLAM. (e) Distriution of 2DLAM hotspot withs (FWHM) for ll units (n = 4) otine in miniml photostimultion regime (lk rs). The istriution of synptophluorin-lele glomerulr withs (FWHM) from OMP-spH mie (re line, n = 572) is shown. We neee n ojetive riterion for lssifying the reore mitrl/ tufte units s sister ells or non-sister ells (Fig. 4e). For eh pir, we lulte the Eulien istne etween the enters of the hotspots, normlize y the men with (FWHM) of the two hotspots onsiere (Fig. 4f). We foun tht the size of glomeruli ws greter thn or equl to one FWHM of the funtionl hotspots (Figs. 2e n 3 ). Therefore, pirs of mitrl/tufte units whose prent glomeruli were 2DLAM 6.5 Hz Multiphoton imge z projetion Overly ple less thn one men FWHM prt were lssifie s eing sister ells n the rest s eing non-sister ells. Two istint popultions emerge (Fig. 4f) tht were unmiguously seprte y the FHWM riterion. Out of the 35 mitrl/tufte pirs tht we onsiere, 2 were foun to e sisters. In seon strtegy, we ompute the orreltion etween the 2DLAMs for eh mitrl/tufte pir (Supplementry Fig. 3 n Supplementry Note ); this pproh yiele the sme ChR2-YFP glomeruli Hotspot FWHM (µm) Hz Normlize hotspot-glomerulus jitter Glomerulr with (µm) Glomerulr with (µm) µm Numer of hotspots 5 µm Figure 3 Funtionl hotspots orrespon to ntomilly ientifie glomeruli. () Left, funtionl hotspot from representtive 2DLAM. Center, z stk imge projetion of ntomil glomeruli from the sme fiel of view s the 2DLAM otine vi multiphoton mirosopy. Right, overly of the 2DLAM n the z projetion. Yellow otte lines inite the ounries of the 2DLAM. () Hotspot FWHMs plotte ginst orresponing ntomil glomerulr withs. () Normlize sptil jitter etween the entrois of funtionl hotspots n the orresponing ntomil glomeruli plotte ginst ntomil glomerulr withs. The sptil jitter ws normlize y the men with of the ntomil glomerulus n the hotspot ( vlue of orrespons to jitter of glomerulr with). () Exmple z stk imge projetions of OMP-ChR2-YFP glomeruli otine vi multiphoton mirosopy. Eh imge shown is 2-μm thik projetion, tken 2 μm prt in the z xis from the susequent one. Drwing illustrtes ontours of the glomeruli in the fiel of view. Arrows inite overstke glomeruli. nture NEUROSCIENCE vne online pulition

4 Figure 4 Light mpping sorts mitrl/tufte ells into sister n nonsister pirs. () Exmple spike wveforms on iniviul tetroe hnnels for two isolte non-sister mitrl/tufte ell units. () 2DLAMs for the units shown in t ifferent light intensities use for stimultion. The olor sle to the right of the highest intensity mps inites the rnge of firing rte hnges with respet to seline. All light mps for prtiulr unit re sle to this rnge. Differene mp refers to the ifferene etween the normlize 2DLAMs of the two units, plotte for eh of the light intensities use. Sptil sle r represents μm. () Exmple wveforms for two isolte sister mitrl/tufte ell units. () 2DLAMs for the units shown in t ifferent light intensities use for photostimultion. The olor sle is s esrie in. The sptil sle r represents μm. (e) Crtoon shemti of prent glomerulr onnetivity for sister n non-sister mitrl/tufte ells. (f) Seprtion of mitrl/tufte ells into sisters n non-sisters se on Eulien istne etween the enters of light hotspots on 2DLAMs otine in miniml photostimultion regime. The istne etween the enters of hotspots is expresse in units of the men full with t hlf mximum (FWHM) of Gussin fits to the two hotspots for eh pir. Dotte line mrks the seprtion etween sister n non-sisters mitrl/tufte ells n is ple t FWHM mw mm mw mm mw mm mw mm 2 Unit 7 µv Unit Unit 2 2 Hz L 5 Hz A P µm Hz Hz M Unit 2 4 µv Hz µm Hz 2 Hz Differene mp Hz 7 µv Differene mp 2 Nture Ameri, In. All rights reserve. results. The high proportion of sister pirs is result of two ftors: heterogeneity in light exitility of glomeruli n pre-seletion is to overome the intrinsilly low hne (2 3%) of reoring sister pirs (Supplementry Note ). We onlue tht the physil seprtion etween 2DLAM hotspots n e use to etermine whih mitrl/tufte units shre input from the sme prent glomerulus. Oor response iversity in sister mitrl/tufte ells We next investigte the oor response properties of these mitrl/ tufte unit pirs to set of 42 oor stimuli. Mitrl/tufte firing is often loke to respirtion 2 (Fig. 5,); tht is, mitrl/tufte ells ten to spike preferentilly t prtiulr phse of the respirtory yle. In response to n oor, mitrl/tufte ell firing rtes n inrese or erese from resting vlues n the timing of spikes in reltion to respirtion n e ltere 3 5. We ivie eh yle of respirtion into five ins n populte these ins with spikes (Fig. 5,). The resulting vetor, referre to s the phse tuning urve, ws otine for eh mitrl/tufte unit seprtely for the ir perio n oor perio ross mny respirtory yles (Fig. 5,) for ll 42 oors. For exmple, one unit spike relily t the eginning n towr the en of the respirtory yle uring fresh ir, ut shifte its phse preferene to ifferent point in the yle, n unerwent reution in firing rte one llyl-tiglte ws presente (Fig. 5,). Responses to multiple oors were ompre in simultneously reore sister mitrl/tufte ells (Fig. 5). p-nis lehye inrese the firing rtes of oth units, with oor-triggere spikes ourring t ll phses of the respirtory yle. For heptnl, however, the firing rte inrese for unit, ut ws suppresse for unit 2. In response to 2-heptnone, lthough oth units inrese their firing rtes, the phses of the respirtory yle t whih they preominntly spike were ifferent. Thus, we oserve similrities n ifferenes in the oor responses of sister mitrl/tufte ells. Oors inue orrelte firing rte hnges in sister ells For eh mitrl/tufte unit, we lulte the verge hnge in firing rte on oor presenttion for ll 42 stimuli n onstrute firing rte se oor response spetrum (F-ORS; Fig. 6,, see Online Methos). Sister mitrl/tufte units tene to e similr in their firing rte hnges (Fig. 6), s quntifie y the Person orreltion oeffiient etween the F-ORSs (.68 ±.5, n = 2; Fig. 6,). In ontrst, the F-ORSs of non-sister pirs were 2.8 mw mm mw mm 2 e GL EPL f Numer of mitrl/tufte ell pirs 5 MCL Inter-hotspot istne (FWHM units) iverse (Fig. 6) n h lower orreltions (.23 ±., n = 5, P = 2.4 4, two-smple unpire t test; Fig. 6,). To otin mesure of reliility for iniviul units ross ifferent trils, we split the oor repets n lulte self F-ORS orreltions, whose verge vlue ws.67 ±.4 (n = 4). Sister pirs F-ORS n self orreltions were not signifintly ifferent (P =.8, lso true when using mthe numer of trils, t not shown). However, some oors i trigger ifferent hnges in the firing rtes of sister ells (Figs. 5 n 6). Sister mitrl/tufte ells re esynhronize y oors For eh mitrl/tufte ell, we onstrute phse tuning urves uring ir n oor perios (Fig. 7) for ll stimuli. As mesure of similrity, we ompute the orreltion oeffiient etween the phse tuning urves in ir n oor perios for eh stimulus. We terme this the phse response, nlogous to firing rte response. The phse responses for ll 42 oors then yiele phse oor response spetrum (P-ORS; Fig. 7) for eh ell. For given stimulus, high vlue of the phse response (lose to ) inites tht oor presenttion i not use sustntil hnge in the phse tuning urve ompre to the preeing ir perio. How similr re phse responses for sister n non-sister pirs? We foun tht for sister pirs the verge P-ORS orreltion ws only.8 ±.7 (n = 2; Fig. 7), higher thn, ut not signifintly ifferent from, the verge orreltion for non-sister pirs (.5 ±.6, n = 5, P =.6). These low orreltion vlues were not the result of lk of reprouiility of phse response spetr ross trils, s self P-ORS orreltion ws.6 ±.5 (n = 4), whih is signifintly 5 vne online pulition nture NEUROSCIENCE

5 2 Nture Ameri, In. All rights reserve. Figure 5 Exmples of similrities n ifferenes in oor responses of sister mitrl/ tufte ells. () Exmple oor response of mitrl/tufte unit. Top, five oor stimultion trils re shown for this unit; vertil lines mrk the time of spike ourrene. Showe re inites the oor presenttion winow (5 s). Bottom, respirtion tre. One respirtory yle (lele to ) ws typilly ~5 ms long. Inset, expne tres showing three respirtory yles uring ir n oor presenttion perios for one tril. () Top, phse-time plot of the oor response of the sme mitrl/tufte unit in, shown over five repets of llyl tiglte. Note the hnge in the preferre phse uring oor stimultion (showe re). To the right of the phse-time plot re phse tuning urves lulte uring ir (otte line) n oor (ontinuous line) presenttion in whih eh respirtory yle ws ivie into five time ins. Bottom, PSTH of the sme unit showing rop in firing rte triggere y oor onset (in with, 5 ms;, normlize spike ount). () Exmple oor responses to p-nis lehye, heptnl n 2-heptnone for two sister mitrl/ tufte ells (unit n unit 2) shown s phse plots, PSTHs n phse tuning urves s in. Left, note the strong inrese in firing, spre ross ll respirtion yle phses for oth units. Center, the exittory versus inhiitory response triggere y oor onset in the two units. Right, the hnge in preferre phse of unit 2 triggere y the oor onset. higher thn oth sister n non-sister P-ORS orreltions (P < 5 n P < 7, respetively). Thus, unlike in the se of firing rte hnges esrie ove (Fig. 6), oors inue ifferentil phse responses in oth sister n non-sister mitrl/tufte pirs. How o oors inue istint phse responses in sister ells? Do they strt with similr phse tuning urves tht iverge on oor stimultion or o they strt with ifferent phse tuning urves even t rest (ir perio)? To etermine the phse reltionship etween units, we lulte the orreltion oeffiient etween the phse tuning urves of the two units of mitrl/tufte pir, for ll stimuli use. We lulte this inter-unit phse similrity (PS) seprtely for ir n oor perios (Fig. 7). Over the entire popultion of sister mitrl/tufte ells, the verge phse similrity for ll stimuli ws high uring ir n ws signifintly reue when oors were presente (verge PS ir =.45 ±.2, verge PS oor =.27 ±.2; n = 2 pirs times 42 oors, P < 7, two-smple Kolmogorov-Smirnov test; Fig. 7 f). This rop in phse similrity on oor presenttion ws not result of lk of reprouiility of phse tuning urves ross trils, s the self phse similrity ws high in oth ir n oor onitions (verge self PS ir =.45 ±., verge self PS oor =.45 ±.; P =.5, two-smple Kolmogorov-Smirnov test; Fig. 7f). Non-sister pirs h ro, polymol istriution of phse similrities t rest (ir), with moes t positive n negtive similrity vlues (Fig. 7e), lerly ifferent from the istriution of sister pirs (P =.4, twosmple Kolmogorov-Smirnov test). This implies tht ifferent pirs of non-sister units fire onsistently with ifferent phse lgs. Oor presenttion flttene the istriution of phse similrity etween the non-sister mitrl/tufte units (Fig. 7e). Trils Air Oor Air Respirtion Unit Unit 2 Respirtory phse Spikes Respirtory phse Spikes 3 3 p-nis lehye 2 2 s Respirtory phse Spikes per in We otine similr results if we fouse on just the men firing phse inste of the entire phse tuning urve for eh stimulus (Supplementry Fig. 4 n Supplementry Note 2). We lso exmine the spiking reltionship (Supplementry Fig. 5 n Supplementry Note 3) etween pirs of mitrl/tufte units with the more ommonly use spike time orreltion nlysis. This nlysis inite tht oor presenttion le to signifint roening of the pek n rop in pek height of the mitrl/tufte units uto-orrelogrms, s well s of sister pirs ross-orrelogrms (Supplementry Fig. 4). Closer inspetion revele perioi moultion of spike timing in the et n gmm frequeny rnge for some mitrl/tufte pirs, s seen previously 6 (Supplementry Fig. 6), ut on verge we i not etet sustntil power in these ns vi oherene mesurements t popultion level (Supplementry Note 4). The oor-inue rop in phse similrity oserve etween sister units i not epen on the qulity of unit isoltion, the with of their hotspots or the istne etween them (Supplementry Figs. 7 n 8 n Supplementry Note 5). Oornts ten to tivte multiple glomeruli. To investigte the effets of tivting only the prent glomerulus on the phse properties of sister mitrl/tufte pirs, we use the miniml light-stimultion strtegy (Figs. 2 n 4) to moulte tivity of single glomeruli Normlize spike ount Heptnl Time (s) Time (s) Time (s) Time (s) 2 2-heptnone Oor Air nture NEUROSCIENCE vne online pulition

6 2 Nture Ameri, In. All rights reserve. Figure 6 Sister mitrl/tufte ells hve orrelte hnges in oor inue firing rtes. (,) Exmples of F-ORSs otine using set of 42 oors for three pirs of sister () n three pirs of non-sister mitrl/tufte (M/T) ells (). Arrows in enote ifferentil responses ross pirs of sister units. () A stter plot of the similrity (orreltion oeffiient) of oor-inue firing rte hnge ginst the Eulien istne etween the enters of the hotspots in the 2DLAMs for eh pir of mitrl/tufte units tht we onsiere. Gry inites non-sister mitrl/tufte ells n lk inites sister mitrl/tufte ells. The mrginl istriutions re shown s histogrms on the top n right xes. Top, seprtion of units into sister n non-sister mitrl/tufte ells, s shown in Figure 3f. Right, histogrms of sister (n = 2) n non-sister pirs (n = 5) F-ORS orreltions. () Averge F-ORS orreltions for sister n non-sister mitrl/tufte ells; self refers to the sme unit (n = 4) proe ross ifferent loks of oor repets y splitting the totl numer of trils in two. # P <.5 for F-ORS orreltions, ross groups with respet to sister mitrl/tufte pirs (for exmple, sister versus non-sister mitrl/tufte units). Error rs represent s.e.m. (Online Methos), y presenting light pulses ontinuously for 2-ms perios. As expete, light tivtion of iniviul glomeruli signifintly inrese the firing rte of sister mitrl/tufte units ompre to seline (verge 2.63 ±.47 Hz in the ir perio versus 9. ±.72 Hz in the light perio, P <. y two-smple pire t test). The phse similrity etween sister pirs ws inistinguishle etween ir n light onitions (verge PS ir =.43 ±.4, verge PS light =.42 ±.2, n = 2 pirs, P =.88, two-smple Kolmogorov-Smirnov test; Fig. 7g,h), even in instnes in whih light stimultion hnge the phse preferene of the sister mitrl/tufte units (Fig. 7g). These t inite tht sister mitrl/tufte units re entrine y respirtion to fire synhronously t rest, ut eome esynhronize (in terms of their firing reltion to respirtion) y oors. However, light tivtion of just the prent glomerulus ltere the phse properties of sister units in similr mnner. Non-sister mitrl/tufte units fire with onsistent phse lgs with respet to eh other when t rest. On oor stimultion, these preitle phse reltionships were lso isrupte. Oor-inue firing rte n phse hnges re inepenent Are the ifferentil firing rte n phse responses in sister mitrl/ tufte units (Figs. 6 n 7) tht we oserve use y the sme oors? To nswer this question, we ientifie oors tht ffete one unit in istint mnner ompre with the other (Online Methos). More oors h ifferentil effets on phse thn on firing rte in sister pirs (8.7 ± 3.% versus 9.3 ± 2.3% of oors, P =.2, Wiloxon signe-rnk test, Fig. 8), s ntiipte (Figs. 6 n 7). Notly, the perentge overlp etween oors tht use ifferentil responses in firing rte n phse ws.6 ±.6%, not ifferent from hne (.4 ±.5%, P =.68, y Wiloxon signe-rnk test; Fig. 8 n see Supplementry Note 6). For non-sister mitrl/tufte pirs, similr perentges of oors use oth firing rte n phse similrity hnges (9. ± 3.9% versus 8. ± 5.4%), lso overlpping only to hne levels (P =.95, Wiloxon signe-rnk test). It is noteworthy tht similr perentge of oors use erese in phse similrity for sister (8. ± 3.%) n non-sister pirs (9. ± 3.9%, P =.5, two-smple Kolmogorov-Smirnov test). These results inite tht oors n inue ifferentil hnges in the phse of sister mitrl/tufte ells without inuing ifferentil hnges in firing rtes. Thus, hnges in phse n firing rte re inepenent. DISCUSSION We engineere trnsgeni mie with optilly exitle glomeruli, whih offer mny possiilities for isseting the iruitry of the erly Pir 3 Pir 2 Pir Numer of M/T ell pirs Firing rte hnge orreltion Sister M/T ells Oor numer Hz Hz olftory system. We use these mie to ientify sister mitrl/tufte ells n foun tht their oor responses re not reunnt. 2 Optil tivtion of inputs to the olftory ul The expression of ChR2 in the OSNs provies unpreeente ontrol over glomeruli, the elementry input units of the ul. This is n importnt vne in the stuy of olftion, s it hs een iffiult to seletively tivte every glomerulus in region with oors. This pproh oul e extene to mp the surroun for eh mitrl/ tufte neuron, unovering glomeruli tht provie inhiitory input n thus otin the glomerulr reeptive fiel for eh mitrl/tufte ell, whih hs not een possile until now 5. Beyon iruit mpping, these mie oul lso e use for ehviorl stuies to test hypotheses out oor oing n pereption 7,8. The ORC mouse ontrsts with the Thy-ChR2 mouse 9, whih expresses ChR2 in lrge frtion of mitrl/tufte ells. Light ontrol of neuronl tivity in these Thy- ChR2 mie ypsses the first level of proessing n is gnosti to importnt trnsformtions on the inputs tht tke ple in the glomerulr lyer, inluing feeforwr inhiition 2,2. The two trnsgeni lines re likely to provie omplementry informtion on iruits in the olftory ul. The DMD ptterne illumintion strtegy tht we pte hs een employe extensively in vision reserh 22, s well s to ontrol neuronl tivity in other systems 23. In omprison to lser-snning photostimultion, DMDs n stimulte multiple foi in prllel to eliver rnge of stimuli from single spots to sptio-temporlly omplex nturl (oor like) or even ritrry tivity ptterns. Finlly, ifferent stimultion wvelengths n e esily o-projete to trigger exittory n inhiitory responses in prllel, for multi-olor ontrol of neuronl iruits 24,25. Pir 3 Pir 2 Pir Non-sister M/T ells 3 Hz 2 Hz Inter-hotspot istne (FWHM units) 7 Numer of M/T ell pirs..8 2 Hz Hz Oor numer Firing rte hnge orreltion # Self vne online pulition nture NEUROSCIENCE

7 2 Nture Ameri, In. All rights reserve. Unit Unit 2 g Air perio Respirtory phse Respirtory phse Air Oor Phse similrity spetr Sister units Oor numer Unit Unit 2 Air perio Respirtory phse Oor perio e Counts Counts Oor response properties of sister mitrl/tufte ells In vivo stuies using extrellulr reorings in the olftory uls of roents me to ivergent onlusions out the similrities in oor responses of neighoring mitrl/tufte ells 26,27. This ws presumly euse, in ontrst with our stuy, they oul not ifferentite etween sister n non-sister pirs. We foun tht sister ells were orrelte in their firing rte hnges. This is onsistent with the prevlent view tht the glomerulus is homogenous in terms of reeptor type innervtion 3 ; thus, sister ells shoul reeive ommon exittory input. In vitro stuies hve provie eviene for strong oupling etween the primry enrites of sister mitrl ells, through gp juntions 28,29 or glutmte spillover 3,3. Slie experiments lso suggest tht tivtion of the olftory nerve les to highly orrelte tivtion of sister mitrl/tufte ells 2,32. A reent in vivo stuy sequentilly reore from mouse mitrl ells onnete to the sme glomerulus rete y n etopilly expresse rt reeptor. Consistent with our results, they foun tht mitrl/tufte ell firing rte responses re orrelte with eh other n mirror presynpti tivity in their prent glomerulus 33. Correlte firing of prinipl ells in the olftory ul or its nlog rin strutures ppers to e ommon theme ross speies. In the ntennl loe of Drosophil, genetilly ientifie homotypi Air Oor Phse similrity Light perio Respirtory phse Phse response spetr Sister units Oor numer f Phse similrity h Correltion oeffiient Air Oor Nonsisters Sister units Air Phse response orreltion * Phse response # # * Light Phse similrity # # * Self # Self Figure 7 Oors isrupt phse orreltions of sister n non-sister mitrl/tufte ells. () Exmple phse tuning urves for two mitrl/ tufte units (unit n unit 2) uring ir n oor. () Phse response spetr for one representtive sister mitrl/tufte unit pir. Arrows inite exmple mismthes etween the spetr. () Averge phse response spetr orreltions etween sister n non-sister mitrl/tufte pirs. () Exmple phse similrity spetr for two sister mitrl/tufte ells uring ir (lue) n oor (re) for 42 stimuli. (e) Histogrms of phse similrity uring Air (lue) n Oor (re) for ll sister (n = 2, top) n non-sister (n = 5, ottom) mitrl/tufte unit pirs for 42 stimuli. (f) Averge phse similrity for sister n non-sister mitrl/tufte pirs. (g) Exmple phse tuning urves for two mitrl/tufte units (unit n unit 2, ifferent from ) uring ir n light tivtion of single prent glomeruli. Note tht light inue similr hnges in phse for oth units. (h) Left, verge phse response etween ir n light for iniviul sister mitrl/tufte units. Right, verge phse similrity etween sister mitrl/tufte pirs uring ir (otte line) n light (ontinuous line). Self refers to similrity etween phse tuning urves generte from the sme unit y splitting the numer of trils into two. *P <.5 for omprisons within the sme group (sister or non-sister mitrl/tufte units) ross onitions (oor versus ir), # P <.5 for sme onition (ir or oor), ross groups (sister versus non-sister mitrl/tufte units) with respet to sister mitrl/tufte pirs. projetion neurons, the fly nlogs of sister mitrl/tufte ells, fire in synhrony t rest n oor presenttion triggers further inrese in spiking orreltions 34. In experiments on the tpole olftory ul 35, imging tivity of lrge popultions of mitrl/tufte ells using lium-sensitive yes ientifie lusters of highly similr mitrl/tufte ells tht were shown in some instnes to e onnete to the sme glomerulus. Our oservtion tht oors esynhronize pirs of sister mitrl/tufte ells is t os with these finings from other speies. Possile resons for this inlue the limite numers of oors use in these previous stuies, n expne role of lol interneurons in sulpting ulr tivity ptterns n the tive smpling of oors y sniffing in mmmls. It is importnt to stress tht we presente ifferent oornts t single nominl liqui ilution (:, Online Methos). It woul e interesting to systemtilly explore the effet of oor onentrtion on the firing n phse properties tht we hve tlogue. Origin of sister mitrl/tufte ells ifferentil phse responses Where n how oes the non-reunny in phse properties of sister mitrl/tufte ells rise? One possiility is tht OSNs innervting the sme glomerulus re heterogeneous in their phse responses y virtue of their sptil positioning in the olftory epithelium 36. Per ontr, ifferenes in the timing of sensory xon inputs in glomerulus hve not een foun 37. In ition, we i not oserve onsistent phse reltionship etween sister units in terms of one ell systemtilly leing or lgging nother (Supplementry Fig. 4), whih woul e expete if sister units reeive signls from sptilly istint groups nture NEUROSCIENCE vne online pulition

8 Figure 8 Oors trigger firing rte n phse hnges in n inepenent mnner. () Averge numer of oors tht inue ifferentil responses in units of the sme pir, onsiere in terms of firing rte hnges or phse similrity. Overlp refers to the numer of oors tht inue signifint hnges in oth firing rte n phse etween units. Expete overlp refers to the numer of oors tht woul inue signifint hnges in oth firing rte n phse if the two were inepenent. Dt re shown for sister (left) n non-sister (right) mitrl/tufte pirs (*P <.5). () Left, rtoon representtion of the iversity of sister mitrl/tufte ell surroun fiels. Right, exmple spike trins of two moel sister mitrl/tufte ells (re n lue) uring ir n oor perios with respet to the respirtory yle (top tre). Stimulus eliite ifferent phse shifts etween the two neurons, ut their firing rtes were unhnge. Stimulus 2 eliite similr firing rte hnges in oth neurons n their firing times remine orrelte. Stimulus 3 eliite the sme firing rte hnge in oth neurons, ut ifferent phse shifts. Perentge of oors using ifferentil response 3 2 Firing rte Phse similrity * Overlp Expete overlp Perentge of oors using ifferentil response Respirtion Stimulus 3 2 Firing rte Phse similrity Overlp Expete overlp Stimulus 2 2 Nture Ameri, In. All rights reserve. of OSNs. Alterntively, ifferenes in mitrl/tufte ells intrinsi properties, suh s vrying spiking threshols or ifferenes in the expression n istriution of vrious ion hnnels, my ount for the unpreitle effets of ifferent oors on sister units. However, it is hr to envision ny oor-speifi effets in these senrios. Furthermore, using light stimuli to tivte only the prent glomerulus of sister units proue oorinte moultion of the phse tuning urves of sister units (Fig. 7g,h). Therefore, it is unlikely tht the ifferenes in phse properties of mitrl/tufte sisters oserve on oor stimultion re relte to ifferenes in intrinsi properties of the units. A iruit-level explntion seems more plusile. The phse of spiking my e influene y the lterl input mitrl/tufte ell reeives vi interneurons in the glomerulr lyer 2 n/or the grnule ell lyer 38. The non-reunny in oor responses of sister mitrl/tufte ells oul rise from the unique set of lterl surroun input onnetions tht eh ell reeives. As the numers of oors tht reue phse similrities of sister n non-sister mitrl/tufte pirs re omprle (Fig. 8), we suggest tht the surrouns of sister ells re s istint s those of non-sister ells. In our moel, ommon input n intrglomerulr intertions ominte mitrl/tufte spiking t rest, leing to sister ell synhroniztion. Surroun inhiition eomes preeminent uring oor presenttion euse of stronger overll input to the ul. This les to esynhroniztion of preferre spiking phse of sister mitrl/tufte units n further ltertion of phse reltionships etween non-sister units. Wht re the mehnisms tht n unouple firing rte hnges n phse hnges? One possiility is tht the exittory sensory inputs rive the overll exitility of mitrl ells, wheres lterl inhiition rrives t ifferent times 39, even for sister mitrl/tufte ells, to sulpt the pttern of firing (Fig. 8). This requires tht sister mitrl/tufte ells reeive synpti inputs from ifferent popultions of interneurons, whih is plusile, ut remins to e estlishe. Spike ounts n spike timing rry inepenent informtion A single sniff is suffiient for roent to istinguish losely relte oors 4, thus the sniff hs een thought of s representing snpshot of the outsie olftory worl. Mitrl/tufte ells n onvey oor informtion to higher rin regions y moultion of either the numer of spikes in eh respirtory yle or the timing of these spikes in the yle. The first strtegy woul e form of rte oe, wheres the seon woul e time oe. Our fining tht sister ells re similr with respet to firing rte hnges, ut issimilr with respet to the timing of their spikes suggests tht oth types of oes my e use in n inepenent mnner. Stimulus 3 This implies tht the mitrl/tufte ells re ple of onveying ifferent kins of informtion y multiplexing rte n time oes in the sme spike trin. Wht re these ifferent kins of informtion? Beuse the phse of spiking is proly influene y the lterl input n mitrl/tufte ell reeives, one possiility is tht the temporl oe is representtion of the suset of glomeruli in the surroun tht re tivte y the stimulus, wheres the rte oe might onvey the tivity level of the OSNs projeting to the primry glomerulus. In other wors, the temporl oe my represent ross-reeptor reltionships tht frequently iffer etween oors tivting the sme oornt reeptor, wheres the rte oe my e more speifi to tivtion levels of n iniviul reeptor tht is likely to sle similrly for ll oors tht tivte the sme reeptor. These two oes re lrgely inepenent (Fig. 8 n Supplementry Fig. 9). How o ownstrem iruits re out the ifferent timing of spikes? Olftory ortil neurons re very sensitive to timing of inputs oming from mitrl/tufte ells euse of preisely time feeforwr inhiition 4,42. Therefore, sister mitrl/tufte ells with ifferent spike times my tivte ifferent popultions of neurons. Other ownstrem rin regions tht re less sensitive to timing ifferenes my t in more integrtive moe. It will e interesting to etermine whether there re suh ifferenes in ulr trget res suh s the olftory tuerle, nterior olftory nuleus n even the mygl. The non-reunny tht we foun in the temporl hrteristis of sister mitrl/tufte ell tivity suggests tht mny more informtion output hnnels re leving the olftory ul thn the numer of OSN types entering it. Suh n expnsion of outputs suggests tht the ul is not just rely sttion. On the ontrry, interesting omputtions our here tht my e importnt for extrting vrious fetures from the inputs n onveying them to the ortex. Methos Methos n ny ssoite referenes re ville in the online version of the pper t Note: Supplementry informtion is ville on the Nture Neurosiene wesite. Aknowlegments We thnk the Genome Mnipultion Fility t Hrvr University for help with generting the ORC mie. We re grteful to M. Meister, A. Kepes, G. Turner, A. Khn, S. Kumri n P. Gupt for omments on the mnusript. B. Burh, vne online pulition nture NEUROSCIENCE

9 2 Nture Ameri, In. All rights reserve. H. Cho, R. Eifert n M. Dvis provie exellent tehnil support. We thnk G. Otzu n S. Rne for vie on uiling tetroes n H. Ovieo n A. Zor for ess to the lser-snning photostimultion rig. Our speil thnks go to Megus for swift trnsporttion n to the House of Mrks. A.K.D. n D.F.A. were supporte y the Col Spring Hror Lortory Fellows Progrm. Aitionl support for A.K.D. ws provie y the Interntionl Soiety for Neurohemistry, Srojini Dmorn fellowship (Tt Institute of Funmentl Reserh) n Merk. AUTHOR CONTRIBUTIONS A.K.D. n D.F.A. esigne the stuy. D.F.A. engineere the ORC trnsgeni mie in the lortory of V.N.M. A.H. hrterize the expression pttern of ORC mie n performe ute slie reorings. A.K.D. n D.F.A. uilt the DLP stimultion rig n performe in vivo experiments. A.K.D. wrote ustom softwre for reoring n nlysis. A.K.D. n D.F.A. nlyze the t. U.S.B. n V.N.M. provie expert vie on t nlysis n guine with experimentl esign. A.K.D., U.S.B., V.N.M. n D.F.A. wrote the mnusript. COMPETING FINANCIAL INTERESTS The uthors elre no ompeting finnil interests. Pulishe online t Reprints n permissions informtion is ville online t reprintsnpermissions/.. Shepher, G.M. The Synpti Orgniztion of the Brin (Oxfor University Press, New York, 998). 2. Vssr, R. et l. Topogrphi orgniztion of sensory projetions to the olftory ul. Cell 79, (994). 3. Momerts, P. Axonl wiring in the mouse olftory system. Annu. Rev. Cell Dev. Biol. 22, (26). 4. Stewrt, W.B., Kuer, J.S. & Shepher, G.M. Funtionl orgniztion of rt olftory ul nlyse y the 2-eoxygluose metho. J. Comp. Neurol. 85, (979). 5. Ruin, B.D. & Ktz, L.C. Optil imging of oornt representtions in the mmmlin olftory ul. Neuron 23, (999). 6. Souy, E.R., Alenu, D.F., Fntn, A.L., Murthy, V.N. & Meister, M. Preision n iversity in n oor mp on the olftory ul. Nt. Neurosi. 2, 2 22 (29). 7. Boyen, E.S., Zhng, F., Bmerg, E., Ngel, G. & Deisseroth, K. Milliseontimesle, genetilly trgete optil ontrol of neurl tivity. Nt. Neurosi. 8, (25). 8. Shepher, G.M.G., Pologruto, T.A. & Svoo, K. Ciruit nlysis of experieneepenent plstiity in the eveloping rt rrel ortex. Neuron 38, (23). 9. Royet, J.P., Souhier, C., Journ, F. & Ploye, H. Morphometri stuy of the glomerulr popultion in the mouse olftory ul: numeril ensity n size istriution long the rostroul xis. J. Comp. Neurol. 27, (988).. Bozz, T., MGnn, J.P., Momerts, P. & Whowik, M. In vivo imging of neuronl tivity y trgete expression of genetilly enoe proe in the mouse. Neuron 42, 9 2 (24).. Hrtwih, K., Pollk, T. & Kluserger, T. Distint firing ptterns of ientifie sket n enrite-trgeting interneurons in the prefrontl ortex uring hippompl thet n lol spinle osilltions. J. Neurosi. 29, (29). 2. Mries, F. & Chorover, S.L. Olftory ul units: tivity orrelte with inhltion yles n oor qulity. Siene 75, (972). 3. Mereith, M. Ptterne response to oor in mmmlin olftory ul: the influene of intensity. J. Neurophysiol. 56, (986). 4. Khn, A.G., Thtti, M. & Bhll, U.S. Oor representtions in the rt olftory ul hnge smoothly with morphing stimuli. Neuron 57, (28). 5. Fntn, A.L., Souy, E.R. & Meister, M. Rt olftory ul mitrl ells reeive sprse glomerulr inputs. Neuron 59, (28). 6. Kshiwni, H., Sski, Y.F., Uhi, N. & Mori, K. Synhronize osilltory ishrges of mitrl/tufte ells with ifferent moleulr reeptive rnges in the rit olftory ul. J. Neurophysiol. 82, (999). 7. Mouly, A.M. & Holley, A. Pereptive properties of the multi-site eletril mirostimultion of the olftory ul in the rt. Behv. Brin Res. 2, 2 (986). 8. Mono, B., Mouly, A.M., Vigouroux, M. & Holley, A. An investigtion of some temporl spets of olftory oing with the moel of multi-site eletril stimultion of the olftory ul in the rt. Behv. Brin Res. 33, 5 63 (989). 9. Arenkiel, B.R. et l. In vivo light-inue tivtion of neurl iruitry in trnsgeni mie expressing hnnelrhoopsin-2. Neuron 54, (27). 2. Aungst, J.L. et l. Center-surroun inhiition mong olftory ul glomeruli. Nture 426, (23). 2. Gire, D.H. & Shopp, N.E. Control of on/off glomerulr signling y lol GABAergi miroiruit in the olftory ul. J. Neurosi. 29, (29). 22. Engert, F., To, H.W., Zhng, L.I. & Poo, M. Moving visul stimuli rpily inue iretion sensitivity of eveloping tetl neurons. Nture 49, (22). 23. Guo, Z.V., Hrt, A.C. & Rmnthn, S. Optil interrogtion of neurl iruits in Cenorhitis elegns. Nt. Methos 6, (29). 24. Zhng, F. et l. Multimol fst optil interrogtion of neurl iruitry. Nture 446, (27). 25. Hn, X. & Boyen, E.S. Multiple-olor optil tivtion, silening, n esynhroniztion of neurl tivity, with single-spike temporl resolution. PLoS ONE 2, e299 (27). 26. Buonviso, N. & Chput, M.A. Response similrity to oors in olftory ul output ells presume to e onnete to the sme glomerulus: eletrophysiologil stuy using simultneous single-unit reorings. J. Neurophysiol. 63, (99). 27. Egñ, J.L., Aylwin, M. & Mlono, P. Oor response properties of neighoring mitrl/tufte ells in the rt olftory ul. Neurosiene 34, 69 8 (25). 28. Christie, J.M. et l. Connexin36 meites spike synhrony in olftory ul glomeruli. Neuron 46, (25). 29. Kosk, T. & Kosk, K. Neuronl gp juntions etween intrglomerulr mitrl/ tufte ell enrites in the mouse min olftory ul. Neurosi. Res. 49, (24). 3. Nioll, R.A. & Jhr, C.E. Self-exittion of olftory ul neurones. Nture 296, (982). 3. Urn, N.N. & Skmnn, B. Reiprol intrglomerulr exittion n intr- n interglomerulr lterl inhiition etween mouse olftory ul mitrl ells. J. Physiol. (Lon.) 542, (22). 32. Shopp, N.E. & Westrook, G.L. Glomerulus-speifi synhroniztion of mitrl ells in the olftory ul. Neuron 3, (2). 33. Tn, J., Svigner, A., M, M. & Luo, M. Oor informtion proessing y the olftory ul nlyze in gene-trgete mie. Neuron 65, (2). 34. Kzm, H. & Wilson, R.I. Origins of orrelte tivity in n olftory iruit. Nt. Neurosi. 2, (29). 35. Chen, T.W., Lin, B. & Shil, D. Oor oing y moules of oherent mitrl/tufte ells in the verterte olftory ul. Pro. Ntl. A. Si. USA 6, (29). 36. Miymihi, K., Serizw, S., Kimur, H.M. & Skno, H. Continuous n overlpping expression omins of oornt reeptor genes in the olftory epithelium etermine the orsl/ventrl positioning of glomeruli in the olftory ul. J. Neurosi. 25, (25). 37. Whowik, M., Denk, W. & Frierih, R.W. Funtionl orgniztion of sensory input to the olftory ul glomerulus nlyze y two-photon lium imging. Pro. Ntl. A. Si. USA, (24). 38. Jhr, C.E. & Nioll, R.A. Denroenriti inhiition: emonstrtion with intrellulr reoring. Siene 27, (98). 39. Kpoor, V. & Urn, N.N. Glomerulus-speifi, long-lteny tivity in the olftory ul grnule ell network. J. Neurosi. 26, (26). 4. Uhi, N. & Minen, Z.F. Spee n ury of olftory isrimintion in the rt. Nt. Neurosi. 6, (23). 4. Lun, V.M. & Shopp, N.E. GABAergi iruits ontrol input-spike oupling in the piriform ortex. J. Neurosi. 28, (28). 42. Poo, C. & Isson, J.S. Oor representtions in olftory ortex: sprse oing, glol inhiition, n osilltions. Neuron 62, (29). nture NEUROSCIENCE vne online pulition

10 2 Nture Ameri, In. All rights reserve. ONLINE METHODS Generting the ORC mie. Mie were engineere to express ChR2 fuse to EYFP in ll mture OSNs uner the ontrol of 2-k frgment of the rt Omp promoter 43. Two trnsgeni lines (#32, #33) h expression restrite to the vomeronsl orgn n essory olftory ul. A thir line (#2, or ORC-M, use for this stuy) expresse ChR2-EYFP in oth the olftory epithelium n the min olftory ul, s well s in the vomeronsl orgn n essory olftory ul. Sujets. We use totl of 89 ult ORC-M trnsgeni n 2 OMP-spH heterozygous mie (postntl y 6 4, g). Eh mouse ws nesthetize with oktil of ketmine:xylzine (initil ose of 6:6 mg per kg of oy weight, intrperitonel), tthe susequently to n nesthesi pump (Hrvr Apprtus, Pump Plus) n thermo regulte with heting p (FST TR- 2). Flow of the nesthetis oktil ws kept t 4 7 μl h throughout typil 2 5-h ute experiment. Low melting-point grose (.5%, Sigm, Type III) ws poure in thin lyer ove the ul surfe, fter performing rniotomy n urtomy. Cortex uffer 44 ws onstntly irulte vi perfusion pump (ColePlmer Msterflex C/L) ove the exposure. All niml proeures were performe in orne with the guielines of the US Ntionl Institutes of Helth n were pprove y the Institutionl Animl Cre n Use Committee t Col Spring Hror Lortory. Slie eletrophysiology n light stimultion. We reore intrellulrly from mitrl ells in 3-μm-thik horizontl olftory ul slies from postntl y 5 3 mie, in voltge lmp moe, holing the memrne potentil t 7 mv. We use ~5-MΩ impene pth pipettes fille with internl solution ontining esium gluonte n Alex 546 fluoresent ye. Lser-snning photostimultion 8 (DPSS Lsers, 35-, 354 nm, ~5-μm em imeter t the speimen) through 4 ojetive (Olympus, UPlnApo, NA.6) ws use to etermine the position of the prent glomerulus. An ultrviolet lser ws use euse it ws lrey in opertion in the experimentl sttion for glutmte unging n we foun tht the ro exittion spetrum of ChR2 llowe for its exittion t 354 nm. Gris of 8 8, 8 6 or 6 6 stimultion foi were superimpose onto the slie, mking sure tht the glomerulr lyer ws properly smple. We typilly use. 4-mW lser power (mesure t the k fol plne of the ojetive), ms of light stimultion n 5 5-μm inter-foi sping. Eh ell we reore from ws fille with Alex 546 ye n imge t 4 n 6 mgnifitions. In vivo eletrophysiology. We reore mitrl/tufte ell tivity in the olftory ul using gol-plte tetroes 45. Tetroes were onstrute y twisting together four 2.5-μm polyimie-ote nihrome wires (Knthl Plm Cost) n fusing their insultion using het gun. To inrese single unit yiel, we lso employe lusters of eight eletroes. These were me either y gluing together two tetroes using Lotite 42 or y twisting together n het-fusing eight nihrome wires. The tip of the tetroe ws ut t n ngle to mke penetrtion into rin tissue esier n eh eletroe ws gol plte to n impene of 4 6 kω t khz. The eletroes were lowere into the ul (Sutter MP-285) until they rehe the orsl mitrl ell lyer, hrterize y the presene of multiple units with oorinte, rhythmi respirtory tune tivity t epth of pproximtely 25 3 μm from the pil surfe. Eletrophysiologil signls were mplifie 2-fol (RHA6, Intn Tehnologies LLC), filtere (n pss, 3 Hz to 5 khz), n igitize t 32 khz (PCI-6259, Ntionl Instruments). The respirtory yle of the mouse ws reore using piezo-eletri stress trnsuers (RioShk uzzer or Kent Sientifi TRN28 piezo-eletri stress sensor) ple uner the mouse, mplifie vi ustom eletronis n igitize in prllel with the neurl signls. In vivo light stimultion. To tivte iniviul glomeruli in ORC mie, we use DLP projetor (Optom EP727 or EP774) with its olor wheel remove n inserte lue filter (Emun Inustril Optis NT52-532) in the emission pth. One single lens reflex (SLR) photo lens (Nikor 5 mm, f/.4, AF) ws ple in front of the projetor n ouple to n hromti oulet (Thorls, AC58-5-A, fol length (FL) = 5 mm) positione so s to projet the stimulus imge t infinity. A seon SLR photo lens (Voigtläner, Nokton 35 mm FL, f/.2) ws then use to fous the imge onto the ul (Fig. 2). One pixel of projete imge orrespone to 4 μm on the x xis n 5 μm on the y xis. A ihroi mirror (Chrom 53xr, roun, 2-inh imeter) ws use to guie lue light to the tissue. To get timestmp of the light stimulus, we use n LED (Luxeon V, Lumiles) s photoioe n ple it in the optil pth fter the first SLR lens. Two SLR lenses (the sme Nokton 35 mm FL n Nikkor 5 mm FL, f/2., AF, see Fig. 2) ouple front to front n ppene to n emission filter (Chrom, HQ5LP) were use to imge the olftory ul onto the CCD hip of mer (Vosskuhler 3-QF) with pixel size of μm. Light stimuli were generlly squre in shpe n were presente for 2 ms in 5-ms trils. Oor stimultion. We ilute 42 oornts 46 in minerl oil (typilly :) n loe them into ustom-uilt oor-elivery mhine 6 (Supplementry Tle ). We use photo-ioniztion etetor (Auror Sientifi) to etermine the onentrtion of some of the oornts. Air ws psse through Whtmn filters soke in pure oornts n susequently ilute to lirte the photoioniztion etetor signls. The mesure onentrtions rnge etween. to 2%. If t lest two units isplye light-triggere tivity in the fine-sle light mpping, the pnel of oornts ws serilly presente to the mouse over three to five repetitions. Eh tril onsiste of s of ir followe y 5 or s of oor exposure n 5 s of ir. An intertril intervl of or 5 s ws institute to prevent olftory pttion. Sptil omprison of funtionl hostpots to ntomil glomeruli. Imge projetions from multiphoton z-stks tessellting the ul were stithe together using ImgeJ. Bloo vessel rnhing ptterns were employe s lnmrks for utomte imge registrtion using elsti eformtions (UnwrpJ 47 ) etween the multiphoton z stk imge projetions n right fiel imges of the ul surfe. The 2DLAMs were registere first to the right fiel imges n the overly onto the multiphoton imges ws susequently onstrute. Counting frequeny of over-stke glomeruli. The orsl surfe of ORC-M n OMP-spH hemiuls ws smple systemtilly vi multiphoton mirosopy. For eh fiel of view, z stks of the glomerulr lyer were otine n the orresponing two imensionl (x-y) glomerulr ontours were rwn mnully. Glomeruli shring nonzero numer of pixels in x-y were onsiere over-stke. Dt proessing. All offline nlysis ws rrie out in MATLAB (Mthworks) n Igor Pro (Wvemetris). Single units were ientifie y mnul spike sorting using MClust (MClust-3.5, A.D. Reish). The sorting fetures use were the energy, pek height, pek to vlley ifferene n the first two prinipl omponents of the spike wveform. The interspike intervl histogrm ws use to test for single unit isoltion, imposing the riterion tht the perentge of events seprte y less thn 2 ms shoul e elow % of the totl spike intervl ount, initing well-efine refrtory perio. To etermine single unit luster qulity, we employe isoltion istne, ommonly use metri 48. Three wveform prmeters were use to ompute the isoltion istne: energy, pek-vlley ifferene n the first prinipl omponent. More thn 85% of the single unit lusters use h isoltion istnes exeeing 2, whih is stnr threshol vlue 49,5 (Supplementry Fig. 7). 2DLAMs were onstrute y etermining the verge firing rte hnge etween the stimulus n pre-stimulus perios for eh spot in the gri. In these mps, eh pixel represents the verge hnge in firing rte uring 2-ms light-stimultion perio for the orresponing spot on the ul surfe (Fig. 2). A two-smple Kolmogorov-Smirnoff test ws use to test whether the istriution of spike ounts in the 2-ms light perio ross repets ws signifintly ifferent (P <.) from the spike ounts in the 2-ms pre-stimulus perio ross ll trils n repets. If mp ontine t lest one signifint pixel, it ws sujete to further nlysis. To etermine the sptil extent of the light hotspots, we selete the 2DLAMs otine t the lowest lser intensity tht still moulte tivity in the reore units. These light mps were re-smple t -μm resolution y interpoltion (Fig. 2) n the hotspots fitte with two-imensionl Gussins (Fig. 2e). The full with t hlf mximum (FWHM) of this two-imensionl Gussin fit ws tken s the with of the hotspot. nture NEUROSCIENCE oi:.38/nn.2673

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