I-Journal of Neuroscience, i-6 Septemba 2006, i-26 (36): i-9196-9204; i-doi: 10.1523 / JNEUROSCI.1124-06.2006
UPeter Olausson1, J. David Jentsch2, Natalie Tronson1, Rachel L. Neve3, U-Eric J. Nestler4, Futhi UJane R. Taylor1
1.Ukuxhumana kumele kuhanjiswe kuJane R. Taylor, uMnyango wezeMpilo, i-Division of Molecular Psychiatry, i-Yale University School of Medicine, iRicicoff Research Facilities, isikhungo sezempilo se-Connecticut, i-34 Park Street, iNew Haven, i-CT 06508.[i-imeyili ivikelwe]
abstract
Izinguquko ekugqugquzelweni ziye zathinteka ekutheni i-pathophysiology yezinkinga eziningana zezifo zengqondo, kuhlanganise nokusebenzisa kabi izidakamizwa nokucindezeleka. Ukwehliswa okuphindaphindiwe kwezidakamizwa zokuhlukunyezwa noma ukucindezeleka kuyaziwa ngokuqhubekayo ukufaka isici sokubhalisa ΔFosB ku-nucleus accumbens (NAc) ne-dorsal striatum, imiphumela ethinteka ekubambeni izinqubo ezingenayo i-dopamine-ukuqondiswa okulawulwayo. Kodwa-ke, okuncane akuyazi ngokubandakanyeka okuqondile kwe-ΔFosB ekuhlukunyezweni kokuziphatha okukhuthazayo okufisa inhliziyo. Siyabonisa lapha ukuthi ukucindezeleka okungajwayelekile kwe-ΔFosB ku-NAc kanye ne-dorsal striatum yamagundane we-bitransgenic, noma ikakhulukazi ku-NAc yengqikithi yamagundane ngokusebenzisa ukusetshenziswa kwegciwane lesandulela ngculaza, ukusebenza okuthuthukisiwe kokudla kwe-instrumental kanye nokuphendula kwesilinganiso sokuqhubeka. Imiphumela yokuziphatha efana kakhulu itholakale ngemuva kokuvezwa okuphindaphindiwe okuphindaphindiwe kwe-cocaine, i-amphetamine, i-MDMA [(+) - 3,4-methylenedioxymethamphetamine], noma i-nicotine kumazinyo. Le miphumela ibonisa ukulawulwa okunamandla kwezinqubo zokugqugquzela ngu-ΔFosB, futhi inikeze ubufakazi bokuthi ukuguqulwa kwezidakamizwa ekukhulumeni kwegenesheni ngokufakwa kwe-ΔFosB ngaphakathi kwe-NAc kungabamba iqhaza elibalulekile emthethweni wokuthonya okugqugquzelayo ekusebenzeni kwezinsimbi.
Isingeniso
Ukwehliswa kwezidakamizwa okuphindaphindiwe kubangela ukuguqulwa kwamandla okwesikhashana ekuguqulweni kwegesi okukhiqiza izikhathi ezingapheliyo ngaphakathi kwe-nucleus accumbens (NAc) (I-Nestler, i-2004). Lesi sifunda sobuchopho sidlala indima ebalulekile kokubili izidakamizwa kanye nezinqubo zokuqiniswa kwemvelo (UKelley noBerridge, i-2002), nakuba okuncane kuyaziwa ngezici zokubhalisa ezithinta ukuziphatha okugqugquzelwa yi-nondrug, abaqinisayo abanenkinga njengokudla. I-FosB isici se-transcription esasetshenziswa ngaphakathi kwe-NAc ne-dorsal striatum ngokutholakala kwezidakamizwa ezingapheli (Konradi et al., 1994; Nye et al., 1995; Chen et al., 1997; I-Pich et al., I-1997; Shaw-Lutchman et al., 2003) nokucindezela isondo-egijima (Werme et al., 2002). Kuphinde kuhanjiswe kulezi zifunda ngezinhlobo eziningana zokucindezeleka okungapheli (I-Perrotti et al., I-2004). Ukuthuthukiswa kwezinqubo zokuqinisa izidakamizwa ezihlobene nokufakelwa kwe-ΔFosB ezibulalayo kusungulwe kahle (Kelz et al., 1999; I-Colby et al., I-2003; UZachariou et al., 2006). Imiphumela yemiphumela ephakeme ye-DFFB kulezi zindawo ngokuziphatha kwezinsimbi ezithonywa yiziqinisi zemvelo, kodwa aziwa.
Ukusebenza kwezimpendulo zezinsimbi kuyisici esidingekayo sokuziphatha kwezidakamizwa ezingasetshenziswa ukuhlukumeza noma ukungathandeki kahle njengoba ukuguqulwa kokulutha umlutha kuqhubeka (UJentsch no-Taylor, i-1999; I-Berke no-Hyman, i-2000; IBerridge noRobinson, i-2003; Everitt noRobbins, i-2005). I-NAc ibandakanyeka ezinkambeni eziningi zokuziphatha kwezinsimbi ngokuhambisana nokulutha (I-Balleine ne-Killcross, i-1994; I-Corbit et al., I-2001; de Borchgrave et al., 2002; I-Di Ciano no-Everitt, i-2004b; Everitt noRobbins, i-2005). Ngakho-ke kungenzeka ukuthi izinkinga ezibangelwa izidakamizwa ngaphakathi kwe-NAc zingathinta ukusebenza kwezenzo zezinsimbi. Ngempela, ukuchayeka kwe-cocaine okungapheli kuthuthukisa ukusebenza kwe-instrumental (I-Miles et al., I-2004) kanye nezinqubo ezicatshangelwe ukuvimbela ukungasebenzi kwegazi ngaphakathi kwengqalasizinda ye-NAc, kuhlanganise nokuvinjelwa kwe-PKA (protein kinase A) noma amaprotheni synthesis, ukuphazamisa izimpendulo ze-instrumental ezikhokhelwa ukudla (I-Baldwin et al., 2002a; Hernandez et al., 2002). Inhloko ye-NAc iphinde ihambisane nomthelela wokugqugquzela wamathonya afanele ekusebenzeni kwezinsimbi (I-Parkinson et al., I-1999; I-Corbit et al., I-2001; I-Hall et al., I-2001; I-Di Ciano no-Everitt, i-2004a; Ito et al., 2004), ukuhlinzeka nge-neurobiological substrate lapho i-DFFB induction ingase ithinte ngamandla ukusebenza kwama-instrumental kanye nesisusa sabanqamuli abanenkinga njengokudla, amanzi, noma izidakamizwa zokuhlukunyezwa.
Lapha, siphumelele imiphumela ye-ΔFosB ekuziphatheni kwezinsimbi zokugqugquzela ukudla usebenzisa izindlela ezimbili ezihambisanayo zofuzo: (1) ngokweqile ukungatholakali kwe-ΔFosB ngaphakathi kwe-NAc ne-dorsal striatum yamagundane we-bitransgenic (NSE-tTA × TetOp-ΔFosB) nokuxhumayo okukhulu kwe-2 ye-ΔFosB ekhoneni le-NAc ngokukhethekile ngokusetshenziswa kwegciwane lokuguqula i-viral-mediated in rats. Siphinde sahlola ukuthi ukutholakala okuphindaphindiwe okuphindaphindiwe ku-cocaine, i-amphetamine, (+) - i-3,4-methylenedioxymethamphetamine (i-MDMA), noma i-nicotine, ngaphansi kwemibandela ebikwe ukwandisa i-FosB, izokwenza ngcono ukuphendula kwe-instrumental ukudla kanye / noma isisusa ngokusebenzisa isimiso sokukhula kwesilinganiso, njengoba kuye kwaboniswa ukuzithuthukisa izidakamizwa eziqinisekisiwe (I-Horger ne-al., I-1990, 1992; Piazza et al., 1990; Vezina et al., 2002; I-Miles et al., I-2004). Imiphumela yethu ibonisa imiphumela ephikisanayo ye-ΔFosB ngokuziphatha kwezinsimbi futhi iphakamise ukuthi lesi sici sokubhaliselwa singase senze ku-NAc core njengoba umlawuli wokusebenza okugqugquzelayo.
Izimpahla nezindlela
Izilwane nokunakekelwa kwezilwane
Amagundane e-Sprague Dawley ayengama-naive atholakala kuCharles River Laboratories (Wilmington, MA). Amantongomane angama-bitransgenic ama-11A atholakala esiphambanweni phakathi kwamagundane e-homozygous transgenic eveza i-neuron-enolase (NSE) -TTA tetracycline transactivator amaprotheni (umugqa A) kanye namagundane aveza i-TetOp (umgqugquzeli we-tetracycline-responsive) -AFosB (umugqa 11); imigqa yabazali yayigcinwe ngemuva kwesizinda esixubekile (50% ICR ne-50% C57BL6 × SJL) (Chen et al., 1998; Kelz et al., 1999). Lezi zinambuzane ze-bitransgenic ze-11A ziveza i-DFFB kuphela uma: (1) kokubili i-transgenes zikhona esitokisini esifanayo, futhi (2) ukusebenziselwa kwe-transcription nge-T akuvinjelwe ukutholakala kwama-antibiotic e-tetracycline afana ne-doxycycline. Ukuphathwa kwe-doxycycline kulezi zinhlanzi kungasebenzisa ukulawula okwesikhashana phezu kwe-ΔFosB futhi kusetshenziswe ukuvimbela le nkulumo ngesikhathi sokuthuthukiswa; empeleni, ukuphathwa kwe-doxycycline kuhlotshaniswa nengekho inkulumo ebonakalayo yokuvuza ye-ΔFosB (Chen et al., 1998; Kelz et al., 1999). Ngaphezu kwalokho, umugqa we-11A wezinambuzane ze-bitransgenic okhethwe ukuhlolwa okwamanje, ngoba ubonisa iphethini yokubonisa okuyiwona kuphela owenzelwe i-dynorphin equkethe neurons ezibulalayo (kokubili i-NAc ne-dorsal striatum), efana kakhulu nephethini ye-ΔFosB yokukhishwa kwesidakamizwa esingapheli ukuchayeka (Kelz et al., 1999). Ngaphezu kwalokho, i-quantification yalesi sibonakaliso sokuzala sika-ΔFosB iye yaqanjwa ngaphambilini (Chen et al., 1998; Kelz et al., 1999). Amagundane akhiqizwa eNyuvesi yaseTexas Southwestern futhi agcinwa futhi ahlolwe ezindaweni zaseYale. Kuzo zonke izinsizakalo nokuthuthukiswa, wonke amagundane agcinwe ku-doxycycline kuze kuphele amasonto e-8-9 ekuxilongweni kwe-100 μg / ml emanzini okuphuza, izimo ezaziwa ukugcina ama-transgenes aqhutshwa yi-TetOp e-"off" state, futhi asetshenziselwa ukuqala i-6 amasonto angenayo i-doxycycline lapho i-ΔFosB inkulumo iba khona kakhulu (Kelz et al., 1999). Zonke izivivinyo zazibandakanya ukuqhathaniswa kwamagundane we-bitransgenic okubhebhethekayo okungahambisani ne-doxycycline, eyodwa ayinayo impumelelo ekuphatheni okukhuthazayo (Kelz et al., 1999; UMcClung noNestler, i-2003; UZachariou et al., 2006).
Zonke izifundo zokuhlola zazihlelwe ngamabili (amagundane) noma ngamaqembu (amagundane; ama-four kuya ku-5 ngehora) ngaphansi kwezimo ezibusayo zokushisa nemiswakama ngaphansi kwe-12 h ukukhanya / umjikelezo omnyama (ukukhanya ku-7: 00 AM futhi kuvaliwe ku-7: 00 PM). Bavunyelwe ukuthi okungenani i-7 d ivumelane nezakhiwo zezindlu ngaphambi kokufunda. Izilwane zazikwazi ukungena emanzini ngezikhathi zonke nokufinyelela okunqunyelwe kokudla njengoba kucacisiwe ngezansi. Yonke ukusetshenziswa kwezilwane kwaqhutshwa ngokuhambisana neNational Institutes of Health Guide ekuNakekelweni nasekusetshenzisweni kwezilwane zaseBathole futhi yavunyelwa yiKomidi Yokunakekelwa Kwezilwane kanye Nokusebenzisa Amakomidi eNyuvesi yaseTexas Southwestern and Yale University.
Izidakamizwa
I-Cocaine hydrochloride [ngomusa ehlinzekwa yiNational Institute on Drug Abuse (NIDA)], i-d-amphetamine sulfate (Sigma, iSt. Louis, MO), i-MDMA hydrochloride (ngomusa ehlinzekwa yi-NIDA), kanye (-) - nicotine hydrogen tartrate (Sigma ) zahlakazwa ngosawoti womzimba oyinyumba (0.9%) futhi zijowe ngaphakathi kwe-5 ml / kg (amagundane) noma i-2 ml / kg (amagundane). I-pH yesisombululo se-nicotine ishintshwe nge-bicarbonate ye-sodium ngaphambi kokujova.
Vectors viras
Ukudluliswa kwegciwane lesandulela ngculaza kwenziwa njengoba kuchazwe ngaphambilini (I-Carlezon et al., I-1998; I-Perrotti et al., I-2004). Ngamafuphi, i-cDNA encoding amaprotheni ethize yayifakwe ku-herpes simplex virus (HSV) amplicon HSV-PrPUC futhi ifakwe ku-virus ngokusebenzisa umsizi 5dl1.2. Ama-vectors asho ukushayela kwe-HSV-LacZ, ukukopisha iphrotheni yokulawula i-β-galactosidase, noma i-HSV-ΔFosB, ikhodi ye-ΔFosB, kamuva ibanjwe ngaphakathi kwe-NAc ngokwezifiso zokuhlola.
Inqubo yokuhlola
Uhlaka.
Isivivinyo i-1 ihlolile imiphumela yokudonswa kwezidakamizwa ezedlule ngokuphindaphindiwe kokusebenza kwe-instrumental yokudla kanye nokuphendula kwesilinganiso sokuqhubeka. Amagundane ayehlukaniswa ngezigaba ngamaqembu amahlanu okuhlola (n = 9-10 / iqembu). Lawa maqembu athola injection kabili ngosuku (intraperitoneally; ku-9: 00 AM no-5: i-00 PM) nge-saline noma enye yezidakamizwa ezilandelayo: i-nicotine, i-0.35 mg / kg; I-MDMA, i-2.5 mg / kg; i-cocaine, i-15 mg / kg; noma i-amphetamine, i-2.5 mg / kg ngezinsuku ezingu-15 ezilandelanayo. Amanani akhethwe ngokusekelwe kwedatha yethu eshicilelwe ngaphambilini (U-Taylor noJentsch, i-2001; I-Olausson et al., I-2003), futhi ukukhuthazwa okuqhutshwa izidakamizwa okwenziwe izidakamizwa kwaqashwe ngezinsuku zokwelashwa i-1 ne-15. Ngemuva kwe-5 d yokuhoxiswa, izilwane zaqeqeshwa ekuphenduleni izinsimbi zezinsuku ezingu-10 ezilandelanayo futhi zihlolwe ngokulinganisa isilinganiso sokuphendula ngosuku olulandelayo. Izilwane ezimbili zazingeniswa ekuhlaziyweni kwezibalo ngoba azizange zithole impendulo yezinsimbi, zingenzi impendulo engaphezulu kweyodwa esebenzayo yempembelo kulezi zinsuku ezintathu zokugcina zokuqeqeshwa.
Ukuhlolwa kwe-2 no-3 bahlolisise imiphumela ye-ΔFosB engapheliyo ematheni we-bitransgenic ekusebenzeni kwezinsimbi futhi ephendula ngesilinganiso esiqhubekayo sokuqiniswa. Ukwehliswa okukhulu kwe-ΔFosB kulawa makhambi kuye kwaboniswa ngaphambilini ukulingisa imiphumela yokuchayeka kwezidakamizwa eziphindaphindiwe emsebenzini wokuqasha kanye nama-paradigms okhethwe yindawo ehleliwe (Kelz et al., 1999; UZachariou et al., 2006). Lezi zinambuzane zingahlinzeka ngolwazi olubalulekile mayelana nomnikelo we-ΔFosB obulalayo emisebenzini ethile yokuziphatha. Amagundane wesilisa asetshenziselwe ukugcinwa e-doxycycline noma ashintshiwe ukuze athathe amanzi kumasonto e-8. Izivivinyo zaqaliswa emva kwamasonto e-6 wokuhoxiswa kwe-doxycycline, ngaleso sikhathi ukukhuluma ngokweqile kukhulu kakhulu (Kelz et al., 1999). Ekuhlolweni i-2, izilwane (n = 16) zazivinjelwe ukudla futhi zaqeqeshwa ngenqubo yensiza echazwe ngezansi (bheka ngezansi, ukuphendula kwe-Instrumental nokuhlolwa kwesilinganiso sokuqhubeka) kwezinsuku ezingu-10 ezilandelanayo. Ngemuva kokuthi kuqedwe ukuhlolwa kwezinsimbi, ukugqugquzelwa kwe-cocaine-stimulated locomotor kwahlolwa kulezi zinhlanzi. Ekuvivinyweni kwe-3, iqembu elihlukile lezinkampani (n = 18) zaqeqeshwa ekuphenduleni kwezinsimbi zezinsuku ezingu-10 ezilandelanayo ngaphansi kwezimo lapho isikhulu se-50 sithunyelwa khona. Ngosuku 11, wonke amagundane ahlolwe ekuphenduleni kwenani eliqhubekayo. Ngosuku lwe-12, sithole imiphumela yokuqinisa ukuhlaziywa ngokuqhathanisa nokuqhubeka kwesilinganiso sokuphendula.
Ukuhlola i-4 no-5 bahlolisise imiphumela yokucindezeleka okunamandla kwe-ΔFosB ngokuqondile ngaphakathi kwe-NAc. Ukuhlolwa i-4 ihlolwe imiphumela ye-ΔFosB ngokweqile ngokusebenza kwezinsimbi. Lapha, amagundane afakwe nge-HSV-ΔFosB (n = 8) noma i-HSV-LacZ (n = 8) enqenqemeni ye-NA futhi yaqeqeshwa ngenqubo yensiza eqala i-40 kamuva. Ngemuva kwemihlangano yokuqeqeshwa yansuku zonke ye-10, amazinga womsebenzi wokuqala ahlolwe kuzo zonke izilwane emishini yokuqapha imisebenzi yomsebenzi njengoba kuchazwe ngezansi (bheka ngezansi, umsebenzi wokwenza indawo). Ukuhlola i-5 ihlolwe imiphumela ye-NAc ΔFosB ngokweqile ngokucacile ngokuphendula okuqhubekayo kwesilinganiso. Lapha, amaphuzu aqale aqeqeshwa ngezinsuku ze-15 ezilandelanayo, ezabeliswa emaqenjini okuhlola, futhi kamuva afakwa nge-HSV-ΔFosB (n = 8) noma i-HSV-LacZ (n = 7) ku-NAc core. Izilwane zishiywe ngaphandle kokuhlolwa futhi zingaphenduliwe nge-4 d ukuvumela ukuba i-ΔFosB ivezwe ngaphezulu. Ngosuku 5 ngemuva kokumnika, zonke izilwane zahlolwa i-lever ngokucindezela esimweni sokukhula kwesilinganiso. Ngemuva kosuku lokugcina lokuhlolwa, wonke amagundane abulawe futhi ukufakwa kwama-cannula e-infusion ku-NAc okuqinisekisiwe kuqinisekisiwe. Ngokusekelwe kokubekwa kwama-cannulas wokukhipha, ama-rats amabili akhishwe ekuhlolweni kwe-4 kanye nomlingisi owodwa kusuka kokuhlolwa kwe-5.
Ukufaniswa kwezakhi zofuzo kwenzelwa iqembu elihlukile lezilwane. Lapha, i-HSV-LacZ yafakwa ngaphakathi kwe-NAc futhi izilwane zabulawa nge-3 d kamuva. Inkulumo ye-β-galactosidase yabuye yahlolwa nge-immunohistochemically.
Umsebenzi wokwenza indawo.
Umsebenzi wokwenza indawo ulinganisiwe usebenzisa amamitha womsebenzi (i-Digiscan i-monitor yomsebenzi wezilwane; i-Omnitech Electronics, iColumbus, OH). Amamitha womsebenzi afakwe imigqa emibili yama-photosensors we-infrared, irowu ngayinye elinezinzwa ze-16 ezibekwa eceleni kwe-2.5 cm. Amamitha womsebenzi ayelawulwa yi-data yamamitha womsebenzi aqoqwe ikhompyutha ye-PC esebenzisa uhlelo lwe-Micropro (Omnitech Electronics).
Izilwane zokuhlola zifakwe emabhokisini e-plastic avela (25 × 45 × 20 cm) afakwa emamitha womsebenzi. Izilwane ekuqaleni zavunyelwa ukuba zijwayele imishini yokuqopha yomsebenzi we-30 min. Kwezinye izilingo, izilwane zabe sezikhishwa, zijowe nge-cocaine, i-amphetamine, i-nicotine, noma imoto ngokusho kwendlela yokuhlola, futhi ibuyiselwe emabhokisini. Umsebenti wokuhlelwa wabhalwa nge-60 iminithi, uqala i-5 min ngemuva kokujoza izidakamizwa ukuze ugweme i-hypermotility engenalutho. Zonke izivivinyo zenziwa ngesikhathi sokukhanya kwesilwane (phakathi kwe-9: 00 AM ne-6: i-00 PM).
Ukuphendula kwe-Instrumental nokuhlolwa kwesilinganiso okuqhubekayo.
Ukuphendula kwe-Instrumental kwahlolwa ngokusebenzisa amakamelo asebenzayo amakhompuyutha (30 × 20 × 25 cm) noma amagundane (16 × 14 × 13 cm) elawulwa yi-Software MedPC (Med Associates, St. Albans, VT). Ikamelo ngalinye lalihlelwe ekamelweni elingaphandle lokuqapha umsindo eligcwele umshini womsindo omhlophe nomoya wokunciphisa umthelela womsindo wangaphandle. Ukukhanya kwendlu okubekwe phezu kwodonga lwangemuva kwakhanyisa ikamelo. Umphakeli we-pellet wanikeza izipelisi zokudla (20 noma i-45 mg; i-Bio-Serv, i-Frenchtown, NJ) njenge-reinforcer kumagazini. Okufakiwe kwekhanda kutholwe ngesikhangiso se-photocell esithunyelwe ngenhla kwesithandwa se-reinforcer. Kulomagazini kwakuwukukhanya okukhuthazayo. Amakhompi, elinye lever libekwa eceleni komagazini ngamunye. Amagundane, ama-twopopoke apertures afakwa ebhodini elingemuva lamakamelo (okungukuthi, ngokumelene nomagazini we-reinforcer).
Ngesikhathi i-5 d ngokushesha ngaphambi kokuqala kokuqeqesha, izilwane zazivinjelwe ukufinyelela kweminye ye-90 ekudleni ngosuku futhi zivezwe ezinqolobaneni zokudla okusanhlamvu (izigaxa, i-20 mg, izinja, i-45 mg) emakamelweni abo. Phakathi nesikhathi sokuhlola, iziphazamisi zokudla zazitholakala phakathi kwamakamelo asebenzayo ngokuvumelana nenqubo yokuziphatha (bheka ngezansi) kanye namanani angenamkhawulo emgodini wasekhaya we-90 min, uqale i-30 min ngemuva kweseshini yokuhlola nsuku zonke. Lolu hlelo lokufinyelela kokudla luvumela isilwane ngasinye ukuba sifinyelele iphuzu lazo lokuzikhethela futhi kunciphise ukuhlukahluka okubangelwa ukuncintisana phakathi kwezilwane ezidumile nezingaphansi. Ezandleni zethu, lolu hlelo luvumela ukuthola inzuzo yesisindo esincane emva kokulahlekelwa kwesisindo sokuqala ~I-85-90% yezisindo zokudla mahhala. Izisindo zezilwane zaziqashwe kulo lonke ukuhlolwa.
Zonke izifundo ziqale zijwayele izixhobo zokuhlola ze-2 d; phakathi nalezi zinsuku, amaphilisi okudla adluliselwa kumagazini we-reinforcer ngesikhathi esimisiwe se-15 s (FT-15) schedule. Kusukela ngosuku olulandelayo, lezi zihloko zithole ukuqeqeshwa kwansuku zonke kwezinsuku ze-10 ezilandelanayo. Ukusabela kokudla kuhlolwe ngokusekelwe ezinkambisweni zokusungula izinsimbi ezishicilelwe ngaphambili (I-Baldwin et al., 2002b). Ukuphendula ngesibindi (okungukuthi, esebenzayo) isibindi / i-nosepoke yaqiniswa, kanti ukuphendula ngesinye (ukungasebenzi) lever / nosepoke kwakungekho nemiphumela ehleliwe. Isikhundla se-nosepoke esebenzayo noma i-lever (kwesobunxele / kwesokudla) sinokulinganisela kuwo wonke amaqembu okuhlola. Ukugcwaliswa kwemfuneko yokuphendula (bheka ngezansi) kuholele ekuqaliseni ukukhanya komagazini, kulandela i-1 s kamuva ngokuletha isikhwama esisodwa sokudla. Emasekhondi amabili kamuva, ukukhanya kokuvuselela kuvaliwe. Ama-reinforcers wokuqala e-10 atholakale ngemva kokuphothulwa ngokuphumelelayo kokuphendula ngokuvumelana nesimiso esinqunyiwe (FR1) isimiso, ngemuva kwalokho amapelulethi ayatholakala ngemuva kokuphendula esimisweni sokuhluka kwesilinganiso (VR2). Isikhathi siphelelwe isikhathi se-15 min.
Ukuhlolwa kwe-3 (amagundane) kanye ne-5 (amagundane) basebenzisa ama-schedule amaningi wokuqeqesha ukugwema impembelelo engaba khona yokwehlukana kokusebenza kwezinsimbi ngenkathi kuqeqeshwe ukulinganisa isilinganiso esilandelayo esilandelayo (okuningiliziwe ngezansi). Ekuhlolweni kwe-3, amagundane aqeqeshiwe ohlelweni lwe-FR1 ye-2 d bese ku-schedule ye-FR2 ye-8 d. I-3 yokuqala yokuqala yokuhlolwa isebenzisa izikhathi ze-60 min. Ezinsukwini zokugcina ze-7, iseshini sinqanyuliwe lapho ama-reinforcers e-50 atholakale. Ekuvivinyweni kwe-5, amagundane aqeqeshiwe kuhlelo lwe-FR1 / VR2 ku-15 imizuzu encane njengoba kuchazwe ngenhla kuzo zonke ezinye izivivinyo ngezingaphandle ezimbili. Okokuqala, inani eliphezulu lama-pellets / iseshini ye-150 ihanjisiwe. Okwesibili, lezi zilwane zithole izinsuku ezingu-5 ezengeziwe zokuqeqesha (okungukuthi, inani le-15 d) ukuvumela ukusungulwa kokusebenza okusimeme ngaphambi kwanoma yikuphi ukuphathwa kokuhlola.
Izilwane nazo zavivinywa ekuphenduleni ukudla kuhlelo lokuqhubekela phambili lwezinga lokuqiniswa. Kulesi sivivinyo, izidingo zokuphendula ukuthola ukudla zaqaliswa njengezinhlelo ze-FR1 kepha zanda kancane nge-2 ukuthola ukuvuselelwa okulandelayo (ie, 1, 3, 5, 7 ..., X + 2 izimpendulo). Ekuhlolweni kokwelashwa kwezidakamizwa usebenzisa amagundane, isimiso senyuke kancane ngo-5, sinikeza isimiso sokugcina se-1, 6, 11, 16 ..., X + 5. Yonke enye imingcele yayigcinwe efanayo nenqubo yokuqeqesha eningiliziwe ngenhla. Ukuhlolwa kwaqedwa lapho kungekho impendulo esebenzayo okwenzelwe i-5 min.
Ukuqagela kabusha kwe-Reinforcer.
Umthelela wokuhlaziywa kwe-reinforcer wahlolwa ngokusetshenziswa kwesibindi esithile. Lapha, amagundane avunyelwe ukuba adle izinqolobane zokudla okusanhlamvu okungenamkhawulo endlini yokugoma ekhaya ngesikhathi se-3 h ngaphambi kokuhlola esimisweni sokukhula kwesilinganiso sokuqiniswa njengoba kuchaziwe ngenhla.
Amasu okuhlinza.
Izilwane zazixoshwa nge-Equithesin [ingxube equkethe i-pentobarbital (35 mg / kg) ne-hydrate ye-chloral (183.6 mg / kg) ku-ethanol (i-10% v / v) ne-propylene glycol (i-39% v / v); ilawulwa ku-4.32 ml / kg, ip]. Ama-cannulas (i-Plastics One, i-Roanoke, i-VA) yafakwa ngokugcizelela okuhloswe ngenhla kwe-NAc, esebenzisa i-Kopf imishini yokugcina amandla. Izixhumanisi zesimo se-stereotactic ezisetshenziselwa ukuhlukumeza zimi kanje: i-anterior / posterior, + 1.5 mm; i-lateral / medial, ± 1.5 mm; i-ventral / i-dorsal, -6.0 mm (I-Paxinos ne-Watson, i-1986). I-cannulas yayinamathele ku-skull isebenzisa izikrini kanye nesimenti samazinyo. Ama-Obturators afakwe emathonjeni wokuqondisa ukuvimbela ukuvimbela. Ngemuva kokuhlinzwa, izilwane zenziwa ngaphansi kokunakekelwa okujwayelekile kwe-postoperative futhi zavunyelwa ukubuyiselwa i-5 d ngaphambi kokuqala kwanoma yikuphi ukuhlolwa.
Infusions.
I-Intracerebral infusions ye-vector viral yenziwa nge-40 h ngaphambi kokuqala kokuqeqeshwa (bheka ngezansi). Izilinganiso ezingenayo (i-31 gauge), ukukhulisa i-1 mm ngezansi kwendwangu ye-cannulas yomhlahlandlela, zancipha kancane kancanekanye ngakwesobunxele ne-NAc, ne-1.0 μl / eceleni zifakwe esikhathini esincane se-4 ngesilinganiso sokungeniswa kwe-0.25 μl / iminithi usebenzisa ipompo ye-microinfusion (PHD-5000; i-Harvard Apparatus, Holliston, MA). Izinaliti zokumnika zishiywe endaweni ye-1 min ngemuva kokukhipha ukumiswa, futhi ama-cannulas amancane ashintshwa. Ukufakwa kwe-Cannula kwaqinisekiswa ngokweqile ngemuva kokuqedwa kokuhlolwa kokuziphatha (bheka Fig. 6B), futhi izilwane kuphela ezine-cannulas ezibekiwe kahle zifakiwe ekuhlaziyweni kwezibalo zedatha yokuhlola.
Ukuhlaziywa kwakhe ngokwemvelo nokuzivikela kwe-immunostaining.
Ngemuva kokuthi kuqedwe ukuhlolwa, izilwane ezazitholiwe ukuhlinzekwa njengengxenye yokuhlolwa zazixiliswe nge-Equithesin futhi zenziwe nge-transcardially nge-0.1 m PBS (i-5 min) ne-10% formalin (i-10 min) ngokwezinqubo ezijwayelekile. Ama-Brains ayefakwe efomini e-formalin futhi kamuva afakwa ku-solution ye-sucrose ephunywe yi-phosphate (30%). Konke ubuchopho bubekwa ngaphansi kwezigaba ze-40 μm kwi-microtome futhi kusetshenziselwa ukuhlaziywa kwakhe kwa-cantolo nokuchazwa kwamaphrotheni.
Ukufakwa kwe-Cannula kwenziwa ngezigaba eziphikisana nokubomvu okungahambisani nendawo futhi zifakwe kuma-slidescope ama-slides ku-plasticizer e-distyrene ne-xylene (i-DPX) ngemva kokudambisa amanzi ethanol. I-Immunohistochemistry yenziwa njengoba kuchazwe ngaphambilini (Hommel et al., 2003). Ngamafuphi, ukubonakaliswa kwe-β-galactosidase ngemuva kokumnika kwe-HSV-LacZ kwakunqunywa ngokugaya okungafani nokusebenzisa i-anti-β-galactosidase primary antibody (1: 5000; Biogenesis, Kingston, NH). Ngemuva kokugxilwa kwamabili, izigaba zahlanjululwa futhi ziphinde zakhiwe nge-donkey fluorescent anti anti-imfuyo yesikhumba esiphezulu i-Cy2 (1: 200; i-Jackson ImmunoResearch, i-West Grove, i-PA). Izigaba zahlanzwa futhi zilandelwa i-ethanol dehydration futhi zikhuphuka ku-DPX. Izigaba zokulawula ezenzakale zaziphathwa ngokungafani ngaphandle kokufakwa kwamagciwane okuqala. I-Immunofluorescence yahlolwa ku-520 nm isebenzisa i-a Zeiss (I-Oberkochen, eJalimane) i-microscope ne-FITC isihlungi kanye nezithombe ezithathwe ngesikhathi esifanayo zokuchayeka Zeiss Uhlelo lwe-imagery ye-Axiovision.
Izibalo
Imininingwane evela kuzo zonke izivivinyo ihlolwe kusetshenziswa i-ANOVA yendlela eyodwa, ezimbili, noma ezintathu ezilandelwe ukuhlolwa kukaScheffe noma okukaDunnett, okulungisa ukuqhathanisa okuningi lapho kufanele khona kusetshenziswa ukuhlolwa kokulandulwa okulandelanayo kukaHolm. Inani le-p ≤ 0.05 lithathwa njengelibalulekile ngezibalo.
Imiphumela
Isivivinyo i-1: imiphumela yokuchayeka kwezidakamizwa eziphindaphindiwe ekusebenzeni kwezinsimbi nokuphendula isilinganiso sokuqhubeka
Ukuze siqinisekise ukuthi i-paradigm yethu yokuchayeka kwezidakamizwa eziphindaphindiwe zenza izinzwa ezibonakalayo ezibalulekile, siqale sahlola ukukhushulwa kwezinto zokuziqhenya njengendlela yokuziphatha yokuziphatha yezidakamizwa ezingapheli. Amagundane anikwe kabili ukujova kwansuku zonke kwe-nicotine (0.35 mg / kg), i-MDMA (5 mg / kg), i-cocaine (i-15 mg / kg), noma i-amphetamine (i-2.5 mg / kg), nomsebenzi wokuqashwa wahlolwa ngemva kokujova kokuqala izinsuku zokwelapha i-1 ne-15 (isibalo esengeziwe se-1A-E, etholakalayo www.jneurosci.org njengezinto ezengeziwe ezengeziwe). Ukuhlaziywa kwesitatimende kubonise ukwelashwa okubalulekile ngokusebenzisana nosuku (F(4,42) = 9.335; p ≤ 0.0001). Ngaphandle kwe-MDMA (p = 0.62), zonke izidakamizwa zenze umsebenzi omkhulu wokukhiqiza (okungukuthi, ukugqugquzela) ngosuku 15 kuqhathaniswa nosuku 1 (i-nicotine, p ≤ 0.001; i-cocaine, p ≤ 0.001; i-amphetamine, i-≤ 0.01). Amapayipi okuphinda aphindaphindiwe awazange abe nomthelela. Ayikho yokwelashwa kwezidakamizwa okushintshe umsebenzi wokwenza umsebenzi wokulinganisa olinganiswe ngesikhathi sokuhlala ngosuku 15 (isibalo esengeziwe se-2A, esitholakalayo www.jneurosci.org njengezinto ezengeziwe ezengeziwe).
Ngemva kwezinsuku ezinhlanu umjovo wokudakamizwa wokugcina izidakamizwa, sahlola imiphumela ye-nicotine ephindaphindiwe, i-MDMA, i-cocaine, noma i-amphetamine ekuvezeni kokudla kwe-instrumental. Idatha inikezwa ngomuthi ngamunye ngokwehlukile Umfanekiso we-1I-H isebenzisa iqembu elifanayo lokulawulwa kwe-saline yokuqhathanisa. Sithole ukuthi ukuchayeka kwangaphambilini kulezi zidakamizwa kakhulu futhi ukhethe ukwandisa ukudla okuqinisiwe kokudla ukudla (ukwelashwa nge-lever ngokuqeqeshwa ngosuku, F(36,378) = 1.683; p ≤ 0.01; Ukuhlaziywa kwe-post hoc: i-nikotine, p ≤ 0.01; I-MDMA, p ≤ 0.05; i-cocaine, p ≤ 0.01; amphetamine, p ≤ 0.001). Ukuphakama okuphikisanayo ekuphenduleni kwezinsimbi okubheke ekusebenzeni njenge-asymptotic kusiphakamise ukuthuthukiswa okungenzeka kube khona ekugqugquzelweni, okuhambisana nokunyuka okubikiwe ngaphambili ngemuva kokuvezwa kwe-psychostimulant ephindaphindiwe (bheka Ingxoxo). Ngakho-ke sihlolisise ukuthi ukuchayeka kwezidakamizwa eziphindaphindiwe okuphindaphindiwe ngokuphindaphindiwe kusetshenziselwa ukugqugquzela okuthuthukisiwe usebenzisa isimiso sokukhula kwesilinganiso Kube nomthelela wokubalwa kwezidakamizwa ezedlule ekuphenduleni lever esebenzayo (ukwelashwa ngokusebenzisana kwe-lever, F(4,42) = 3.340; p ≤ 0.05) (I-Fig. 2A) kanye nephuzu lokugcina (F(4,42) = 5.560; p ≤ 0.001) (I-Fig. 2B). Ukuhlaziywa okungeziwe kubonise ukuthi zonke izifo zanda ukwanda kwenombolo yezimpendulo ezisebenzayo (nicotine, p ≤ 0.001; MDMA, p ≤ 0.05; cocaine, p ≤ 0.001; i-amphetamine, p ≤ 0.001) nephuzu lokuphumula (i-nicotine, p ≤ 0.001; i-MDMA , p ≤ 0.01; i-cocaine, i-≤ 0.0001; i-amphetamine, i-≤ 0.0001) ehambisana nomthelela walezi zonyango ngokugqugquzela. Njengoba kunikezwe amandla okusebenza kwezidakamizwa emisebenzini yokuqashwa okuyisisekelo, nokungabi namthelela emishini yokusebenza engasebenzi, cishe akunakwenzeka ukuthi ukuphendula okwandayo kokudla ngaphansi kwalezi zimo kubonisa ukukhushulwa okungajwayelekile emisebenzini yemoto.
Umfanekiso we-1.
Imiphumela ye-injection ephindaphindiwe ye-nicotine (0.35 mg / kg), i-MDMA (i-2.5 mg / kg), i-cocaine (i-15 mg / kg), noma i-amphetamine (2.5 mg / kg) kabili nsuku zonke i-15 d ekuziphatheni okulandelayo. Izilwane zahlolwa ndawonye, kodwa ngokucacile imiphumela yomuthi ngamunye ihanjiswe ngokwehlukana, isebenzisa iqembu elilawulayo elilawulwa u-saline. A (izimpendulo ezisebenzayo) no-B (izimpendulo ezingasebenzi) kubonisa imiphumela ye-nicotine yangaphambili yokudalwa; C, D, i-MDMA; E, F, i-cocaine; G, H, i-amphetamine. Idatha imelwe njengezindlela ± SEM.
Umfanekiso we-2.
Umphumela wokwelashwa okuphindiwe okwedlule (kabili nsuku zonke, i-15 d) nge-saline, i-nicotine (0.35 mg / kg), i-MDMA (2.5 mg / kg), i-cocaine (15 mg / kg), noma i-amphetamine (2.5 mg / kg) ekuphenduleni ngensimbi kusheduli yesilinganiso sokuqhubeka sokuqiniswa. Imininingwane imelwe njengezindlela ± SEM. *** p <0.001; ** p <0.01; * p <0.05. USal, uSaline; Nic, nicotine; Coc, i-cocaine; Amph, amphetamine; PR, isilinganiso esiqhubekayo.
Ukutholakala kwezidakamizwa zangaphambilini akuzange kube nomthelela ekutheni umzimba urekhodiwe ngaphambi kokuvinjelwa kokudla, ngosuku lokugcina noma lokugcina lokuqeqeshwa kwezinsimbi, noma ngokushesha ngaphambi kokuhlolwa kwesilinganiso sokukhula (isibalo esengeziwe se-2B, esitholakalayo www.jneurosci.org njengezinto ezengeziwe ezengeziwe). Ukufinyelela okuvinjiwe kokudla kwe-3 d kwanciphisa ekuqaleni isisindo somzimba ngamaphesenti angu-91-92 wezinsimbi zokudla mahhala. Ekupheleni kokuhlolwa kokuziphatha, isisindo sabuyele ku-97-99% yesisindo somzimba sokuguqulwa, futhi akukho ukungafani okwakubhekwa phakathi kwezidakamizwa ezidalulwe izidakamizwa nezidakamizwa. Ukuguqulwa kwesisindo somzimba kanye nokungafani kwendlala noma isifiso akufanele kube negalelo elikhulu ekuthuthukiseni ukusebenza kwezinsimbi noma isisusa.
Ukuzama i-2: ukugqithisa okungaqondakali kwe-ΔFosB kumagundane we-bitransgenic; ukusebenza komculo
Silandela ukuthi ngabe ukusebenza kwama-instrumental kwandiswe yini namagundane we-bitransgenic okwenza ukuthi i-FFBB isetshenziselwe ukuphazamiseka okuphawulekayo ku-NAc ne-dorsal striatum (Kelz et al., 1999). Kulolu cwaningo, ama-ΔFosB-overexpressing amagundane ayeqhathaniswa nokulawulwa kwezidakamizwa ezingaphazamisi i-ΔFosB ngoba zigcinwe ku-doxycycline (bheka Izinto Zokusebenza Nezindlela). Sithole ukuthi ukuphazamiseka okukhulu kwe-ΔFosB kwandisa kakhulu ukuphendula okuqinisiwe kokudla (isenzo segeneshini nge-lever ngokuqeqeshwa usuku, F(9,126) = 3.156; p ≤ 0.01) (I-Fig. 3A). Inombolo yezimpendulo ze-nosepoke ezenziwe ekuvuleni okungasebenziyo azifani phakathi kwamaqembu amabili (I-Fig. 3B). Ngokubodwa, le datha ikhombisa ukuthi i-ΔFosB ngokucindezela okukhulu ku-NAc ne-dorsal striatum ekhethiwe yokwenza izinsimbi zokusebenza
Umfanekiso we-3
Umphumela we-inducible ngokweqile kakhulu kwe-ΔFosB kumagundane e-bitransgenic ekusebenzeni kwezingoma. A, Izimpendulo ezisebenzayo. B, izimpendulo ezingasebenzi. Idatha imelwe njengezindlela ± SEM.
Ukuqaphela ukuthi ukuthuthukiswa kokusebenza kwezinsimbi ezidalweni ze-ΔFosB-overexpressing kungachazwa ngokuguqulwa kokudla noma ukulamba, isisindo somzimba sarekhodwa ngaphambi kokuvinjelwa kokudla futhi ezinsukwini zokuqala zokugcina zokuqeqeshwa. I-FosB ayizange ibe nomthelela kwisisindo somzimba ngaphambi kokuvinjelwa kokudla, futhi kwakungekho nethonya ngesisindo somzimba ngesikhathi sokuhlolwa kokuziphatha. Lapha, ukufinyelela kokuvinjelwa kokudla kwe-3 d kuncishisiwe isisindo somzimba kuya ku-87-89% yezinsimbi zokudla mahhala. Ekupheleni kokuhlolwa kokuziphatha, izilinganiso zezilwane zaziyi-97-99% yezinsipho zomzimba zokugandelelwa, nezinguquko ezilinganayo ezibonwe ku-ΔFosB kanye namagundane wokulawula (i-Fig. 3A eyengeziwe, etholakala www.jneurosci.org njengezinto ezengeziwe ezengeziwe). Ngakho-ke akunakwenzeka ukuthi imiphumela engaba khona ye-ΔFosB ngokweqile ekulaleni noma ekudleni kungabhekana nezithuthukisi ekuphenduleni izinsimbi.
Lapho ukuhlolwa kokusebenza kwezinsimbi sekuphelile, i-ΔFosB ngokweqile akuzange ishintshe umsebenzi wokuqala wokulinganisa olinganiselwe ngesikhathi se-30 min (isibonisi esengeziwe se-3B, esitholakalayo www.jneurosci.org njengezinto ezengeziwe ezengeziwe). Lokhu kubheka kusekela umbono wokuthi ukungaguquki okwedlulele emisebenzini akubambi iqhaza ekuthuthukiseni ukusebenza kwezinsimbi ezitholakala kulezi zilwane. Noma kunjalo, i-ΔFosB-overexpressing bitransgenic amagundane kuye kwabikwa ukuthi ibonise izimpendulo ezithuthukisiwe zokukhiqiza ku-cocaine esicacile futhi ephindaphindiwe (Kelz et al., 1999). Ngenxa yokuthi sisebenzise isimiso esithile esihlukile sokuhoxiswa ku-doxycycline ukuze senze isenzo sefule (amasonto we-6 ngesimiso sokudla), sabeka ukuqinisekisa lesi sici. Ngempela, ama-ΔFosB-overexpressing amagundane abonise ukwanda okukhulu kakhulu komsebenzi wokukhiqiza lapho kujojowe nge-cocaine uma kuqhathaniswa nokulawulwa kwabo okungahambisani naso okugcinwe ku-doxycycline (ukwelashwa ngokwegama lesiginci, F(1,44) = 4.241; p ≤ 0.05) (isibalo esengeziwe se-3C, esitholakalayo www.jneurosci.org njengezinto ezengeziwe ezengeziwe).
Ukuzama i-3: ukugqithisa okungaqondakali kwe-ΔFosB kumagundane we-bitransgenic; isilinganiso sokuqhubeka
Njengoba kunikezwe ukuthi ukutholakala kwezidakamizwa zangaphambilini kudala i-ΔFosB ebulalayo (Nestler et al., 2001) futhi watholakala lapha ukuze ukwandise izinga lokuphendula okuqhubekayo, sivame ukuhlolwa ukuthi ukuphelelwa ngokweqile kokudala kwe-ΔFosB kwandisa nokusebenza kwesikhathi esimisweni esimisiwe sokuqiniswa. Iqembu elisha lamagundane laqeqeshwa ekuphenduleni izinsimbi ngaphansi kwezimo (bheka Izinto Zokusebenza Nezindlela) ezingazange zenze umehluko omkhulu ekusebenzeni kwezinsimbi ngaphambi kokuvivinya ekuphenduleni isilinganiso sokuqhubeka (F(1,16) <1). Kodwa-ke, esivivinyweni sesilinganiso esiqhubekayo sabona isakhi sofuzo esibalulekile ngokusebenzisana kwe-lever (F(1,16) = 5.30; p ≤ 0.05) (I-Fig. 4A) futhi wathola ukuthi i-ΔFosB-overexpressing amagundane, uma kuqhathaniswa namagundane okulawulwa kwezidakamizwa agcinwe ku-doxycycline, enza inombolo enkulu yezimpendulo ezisebenzayo (p ≤ 0.05), kanti inani leempendulo ezingasebenzi ezingavumelekile. Amagundane e-FosB-overexpressing nawo afinyelele endaweni ephakeme yokuphumula (F(1,16) = 5.73; p ≤ 0.05) (I-Fig. 4B). Le datha ibonisa ukuthi, njengokudlulela kwengqondo yangaphambilini, ukuphazamiseka okukhulu kwe-ΔFosB kwandisa isisusa. Ngoba inani lezimpendulo ezingasebenziyo alishintshiwe kuma-ΔFosB-overexpressing namagundane, ukunyuka okungajwayelekile emisebenzini akumele kube negalelo kule miphumela. Lo mbono wabuye wesekelwa ukuhlolwa komsebenzi wokuqalwa okuyisisekelo lapho kwakungenalo umehluko phakathi kwamagundane okwedlula isikhathi ΔFosB kanye namagundane okulawulwa kwezidakamizwa agcinwe ku-doxycycline. Akukho ukungezwani okukhulu kwesisindo somzimba phakathi kwe-ΔFosB-overexpressing nokulawula izilwane kubonakala njengoba kulinganiswa ngosuku lokuhlolwa. Ngakho-ke, nakuba izidakamizwa ze-FosB-overexpressing zizokhipha izimpendulo ezithintekayo zokudla, azibonakali ukuthi zidla ukudla okuningi uma zitholakala ngokukhululekile. Incazelo eyinhloko yalokho okushiwo yilokho, nakuba ukugqugquzela kunquma ukuthi isilwane esiyinkimbinkimbi sizosebenza kanjani ukuze sithole amandla, izici eziningi ezengeziwe (isifiso sokudla, isisu, isimo somzimba, njll) sithonya ukuziphatha kokudla kanye nokusetshenziswa kwangempela kokudla.
Umfanekiso we-4.
Umphumela we-overexpression engafinyeleleki ye-FosB kumagundane e-bitransgenic ekuphenduleni okunamandla kusheduli yesilinganiso sokuqina, ngaphambi nangemva kokuncipha kokuqiniswa kwe-satiety. A, B, Isisekelo: izimpendulo ze-lever (A), iphuzu lokuphumula (B). C, D, Ngemuva kokuqiniswa kwe-reinforcer: izimpendulo ze-lever (C), iphoyinti lekhefu (D). Imininingwane imelwe njengezindlela ± SEM. * p <0.05.
Ama-ΔFosB ama-bitransgenic amagundane asetshenziswe lapha aveza i-DFFB kulo lonke i-striatum. Nakuba i-ventral striatum (kuhlanganise ne-NAc) ifakwe ezinkambisweni zokugqugquzela, i-dorsal striatum ichazwe ukuthi ihileleke ekuthengeni imikhuba yezinsimbi (Yin et al., 2004; I-Faure et al., I-2005). Nakuba singazange sibone ukungezwani kokusebenza kwezinsimbi ngesikhathi sesigaba sokuqeqesha usebenzisa uhlelo oluphansi lokulinganisa nemikhakha yokuqinisa amandla, izimo ezingahambisani nokuthuthukiswa kwemikhuba yezinsimbi (U-Dickinson, i-1985), kungenzeka ukuthi ukusungulwa kwemikhuba kungathonya ukuphendula ngaphansi kwesimiso sokukhula kwesilinganiso. Lokhu kungenzeka kwahlolwe ngqo ngokuhlolisisa umphumela wokuqhathanisa ukuhlaziywa ngokuqeda ukuqhubeka kwesilinganiso sokuphendula. Ukuqhathaniswa okunjalo kwasusa umphumela we-ΔFosB ngokuphindaphindiwe kwesilinganiso sokuphendula, ngaphandle kokungafani ekuphenduleni noma ekuphuleni amaphuzu aphakathi kwe-ΔFosB-overexpressing kanye nokulawula amagundane (F(1,16) <1) (I-Fig. 4C, D). Ngokubambisana, le datha ibonisa ukuthi ukucindezeleka okuphezulu kwe-ΔFosB akuzange kushintshe ukuzwela ekushintsheni kokubaluleka kwemiphumela evuzwe ngokusebenzisa lolu hlelo lokuhlola. Esikhundleni salokho, ukuphendula okusemqoka ekubonweni kokuhlolwa kwesilinganiso kubonakala sengathi kuyinhloso-eqondiswayo futhi iphuzu lokuphumula elibhekwe e-ΔFosB-overexpressing amagundane cishe linomphumela wokugqugquzela okungeziwe futhi hhayi ukuphakamisa ukuphendula okufana nomkhuba.
Ukuhlola i-4: ukucindezeleka okungeziwe nge-viral-mediated of ΔFosB kwinhloko ye-NAc: ukusebenza kwe-instrumental
Ukuze uhlole ukuthi i-ΔFosB ngokweqile ngokucacile ku-NAc ingabangela ukuziphatha okuphawulwe kumagundane we-bitransgenic, sifake i-HSV-ΔFosB, noma i-HSV-LacZ njengendlela yokulawula, ngokukhetha phakathi kwe-NAc yengqungquthela yamagundane futhi yahlola umphumela walokhu kusetshenziselwa ukudla Ukusebenza kwe-instrumental okuqinisiwe (I-Fig. 5A, B). Ngemuva kokuqeqeshwa komagazini, i-HSV-ΔFosB noma i-HSV-LacZ yafakwa ngaphakathi kwe-NAc core 40 h ngaphambi kokuqala kokuhlolwa kokuziphatha. Indawo yokwehliswa kanye nobukhulu bezinkulumo zegenesithini ehambelana negciwane kuboniswa kuyo Umfanekiso we-6, I-A kanye ne-B. NAc infusions ye-HSV-ΔFosB yakhiqiza ukwanda okuqhubekayo kwenani leempendulo ezisebenzayo ezenziwe (isenzo segeni nge-lever, F(1,12) = 8.534; p ≤ 0.05) (I-Fig. 5A), okuqhubekayo kulo lonke uhlolo. Le miphumela yayikhetha, ngoba kwakungekho nemiphumela ebalulekile ye-ΔFosB ngokweqile ngaphakathi kwe-NAc ngenombolo yezimpendulo ezingasebenzi (I-Fig. 5B) noma kumsebenzi wokuqala wokuqasha oqoshiwe usuku olwedlule ukuqedwa kohlolo (idatha engaboniswa). Ukucindezeleka okukhulu kwe-ΔFosB ku-NAc ngaleyo ndlela kwahlukana nemiphumela yokuziphatha yokudalwa kwezidakamizwa zangaphambilini noma ukuphazamiseka okukhulu kwe-ΔFosB.
Umfanekiso we-5.
Imiphumela ye-HSV-ΔFosB engxenyeni ye-NA ngaphambi kokuqeqeshwa ngokuphendula izinsimbi. A, Izimpendulo ezisebenzayo. B, izimpendulo ezingasebenzi. Idatha imelwe njengezindlela ± SEM.
Umfanekiso we-6.
A, Ukufakwa kwamasayithi okungenisa ukuhlolwa kwamagciwane we-vector. Phezulu, imibuthano emnyama egcwele ihambelana nesayithi elihlosiwe lokukhipha. Amagciwane kuphela enza ngaphakathi ~I-0.5 mm yalendawo (okungukuthi, ngaphakathi kwe-NAc core), njengoba kuboniswe ngumbuthano, kwakubhekwa njengamukelekile. Izilwane ezine-infusions ezenziwe ngaphandle kwalendawo zazingekho ezihlaziyweni zezibalo. Indawo engaphansi, ukuxhunyezwa ngaphakathi kwe-NAc esilwaneni esimele. B, ukuqinisekiswa kwama-immunohistochemical of protein expression emva kokukhipha kwe-HSV-LacZ. Amaphaneli aphezulu abonisa inkulumo ye-β-galactosidase ngaphakathi kwe-NAc core (2.5 ne-10 × ukukhulisa). Ama-panels aphansi abonisa ukungabi khona kwe-immunofluorescence ezigabeni zokulawula eziseduze usebenzisa inqubo efanayo ye-immunohistochemical ngaphandle kokufakwa kwe-antibody yokuqala.
Isivivinyo i-5: ukucindezeleka okukhulu kwe-viral-mediated of ΔFosB kwinhloko ye-NAc: isilinganiso sokuqhubeka
Ukuhlolwa kokugcina kunqume ngokuqondile ukuthi ukucindezeleka okukhululekile kwe-ΔFosB ku-NAc core usebenzisa indlela yokudlulisa i-viral-mediated mediation okwanele ukuthuthukisa ukugqugquzelwa kwamagundane. Lapha, i-HSV-ΔFosB yafakwa kuphela emva kokuqeqesha izinsimbi kwase kuqediwe, ukuqeda noma yikuphi ukuthonya okungase kube khona kwe-ΔFosB ngokweqile ngesikhathi sokuqeqeshwa kokuhlolwa kwesilinganiso sokuqhubeka. Iqembu elisha lamagundane laqeqeshwa, njengangaphambili, futhi lahlukaniswa ngamaqembu alinganiselayo ngokulinganisa ukusebenza kwabo ezinsukwini zokugcina zokuqeqeshwa. Izilwane zatholwa ngamagciwane angama-HSV-ΔFosB noma i-HSV-LacZ enqenqemeni ye-NAc futhi yahlolwe ekuphenduleni kwenani eliqhubekayo ngemuva kwe-5 d yokucindezela okukhulu. Ukuhlaziywa kwesitatimende kuveze indlela ephawulekayo yezakhi zofuzo ngokusebenzisana kwe-lever (F(1,12) = 14.91; p ≤ 0.01) (I-Fig. 7A). Amathanga afakwe nge-HSV-ΔFosB enza izimpendulo ezisebenzayo (p ≤ 0.01) uma kuqhathaniswa nalabo abathintekayo nge-HSV-LacZ, kanti ukuphendula nge-lever engasebenzi akuthintekile. Ngokuvumelana nalokhu kwanda, amagundane afakwe ne-HSV-ΔFosB nayo yayinephuzu eliphakeme kakhulu (F(1,12) = 18.849; p ≤ 0.001) (I-Fig. 7B) kunezilwane ezifakwe ne-HSV-LacZ. Kube khona umphumela we-ΔFosB kumsebenzi wokuqala wokuhlola ohlolwe i-1 h ngaphambi kokuhlolwa kwesilinganiso sokukhula (isibalo esengeziwe se-4A, esitholakalayo www.jneurosci.org njengezinto ezengeziwe ezengeziwe). Kwakungenjalo ukungafani ngesisindo somzimba ngosuku lokuhlolwa kwesilinganiso okuqhubekayo (isibonisi esengeziwe se-4B, etholakalayo www.jneurosci.org njengezinto ezengeziwe ezengeziwe). Lezi zithole zisekela ukubonwa kwethu ngama-perengenic ΔFosB-overexpressing amagundane, futhi kubonisa ukuthi ukucindezeleka okukhethiwe kwe-ΔFosB ku-NAc kwanele ukuthuthukisa isisusa esihambisana nokudla.
Umfanekiso we-7.
Imiphumela ye-infusions ye-HSV-ΔFosB 5 d ngaphambi kokuhlolwa ekuphenduleni kwensimbi kusheduli yesilinganiso sokuqina sokuqina. A, izimpendulo ze-Lever. B, Break iphuzu. Imininingwane imelwe njengezindlela ± SEM. *** p <0.001; ** p <0.01.
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Ucwaningo lwamanje lubonisa ukuthi ukucindezeleka okukhulu kwe-ΔFosB ngaphakathi kwe-NAc kuthuthukisa ukuziphatha kwe-instrumental reinforcedr. Ukwehla kwangaphambili kwe-cocaine, i-amphetamine, i-MDMA, noma i-nicotine eyakhiwe kwenyusa ukwanda okuqhubekayo kokusebenza kwezingoma ezilandelayo. Lezi zidakamizwa ezikhungethe izidakamizwa nazo zandisa ukuziphatha okugqugquzelwa kokudla ngaphansi kwesimiso sokuqhubeka kwesilinganiso sokuqiniswa. Lezi zindlela zokudonswa kwezidakamizwa zangaphambilini zazilingiswa ngokucindezeleka okukhululekile kwe-ΔFosB ku-striatum, ngokusebenzisa izintambo ze-Bitransgenic (NSE-tTA × TetOP-ΔFosB) ezingenayo i-inducible (i-NSE-tTA × TetOP-ΔFosB) amagundane noma ukusebenzisa i-vector ye-virtual novel ukuveza i-ΔFosB ngokukhethayo ku-NAc. Ngokuphawulekayo, ukucindezeleka ngokweqile kwe-ΔFosB ku-NAc core, ngemuva kokuphendulwa kwezinsimbi kwase kutholakale, ukugqugquzelwa okuthuthukisiwe kokudla ngaphansi kwesimiso sokukhula kwesilinganiso. Ngokubambisana, okutholakala kwethu kubona i-FosB enqenqemeni ye-NA njengomlamuleli wezinkinga ezibangelwa izidakamizwa ezingakhuthaza ukuziphatha kwezinsimbi, nokwandisa indima yalesi sici sokubhalisa ukufaka izinqubo ezihambisana nokuthonya okugqugquzelayo ekusebenzeni kokuziphatha okuqinisiwe kokudla. Babuye baphakamise ukuthi kungenzeka ukuthi izimo ezenza ukuthi i-API ibonise ukuthi i-NAc ingathonya izakhiwo ezikhuthazayo zombili izidakamizwa zemvelo nezidakamizwa.
I-ΔFosB iqoqa ama-neuron e-dynorphin-avela aphakathi kwe-NAc kanye ne-dorsal striatum emva kokungapheli, kodwa hhayi okuvelele, ukuvezwa kwezidakamizwa zokuhlukunyezwa. Le ndlela yokufunda yesifunda iphinda ikhiqizwe kuma-bitransgenic ΔFosB-overexpressing amagundane asetshenziswe lapha. Kulezi zimice, amazinga aphezulu e-striatal e-ΔFosB akhulisa ukuzwela kwezilwane ku-cocaine ne-morphine njengoba kukalwa ngokuthandwa kwendawo enesimo (Kelz et al., 1999; UZachariou et al., 2006). Iphinde ibeke isilinganiso sokuqhubeka kwesilinganiso sokuphendula i-cocaine esikisela ukuthi isisusa sokuziphathisa i-cocaine sithuthukiswa ngokweqile kwe-ΔFosB ngokweqile (I-Colby et al., I-2003). Lapha, sithole ukuthi i-ΔFosB yokuhlukumeza ngokweqile kulezi zinambuzane futhi yanda isilinganiso sokuqhubeka ngokuphendula ngokuqinisa ukudla futhi ukuthi le miphumela yenziwa ngokugqithisa okungekho emthethweni kwe-ΔFosB ku-NAc core in rat. Idatha yethu ibonisa ukuthi i-ΔFosB ingasebenza njenge-modulator modulator yokugqugquzela abaqinisi bokuqala, kungaba ukudla, izidakamizwa, noma mhlawumbe ukuzivocavoca, umqondo ohambisana nokuqaphelwa kokuqala ukuthi ukubhekwa kwe-ΔFosB kwandiswa ngemuva kwesondo elingapheli eliqhutshwayo noma i-sucrose yokuphuza (McClung et al., 2004). Le datha ibonisa ukuthi ukucindezeleka kwe-NAc kwe-ΔFosB kungathuthukisa umthelela wokugqugquzela kokubili izidakamizwa zemvelo nezidakamizwa.
Izifundazwe ze-NAc ziye zatshengiswa ukuhlukanisa ngokwehlukana ithonya lezinqubo zokuvuselela i-pavlovian noma izinsimbi ekusebenzeni kwezinsimbi (I-Corbit et al., I-2001; de Borchgrave et al., 2002), kanti ezinye izithonya ezivusa amadlingozi ekusetshenzisweni kwezinsimbi zingabhaliswa yizinye izifunda ezifana ne-central nucleus ye-amygdala (I-Corbit ne-Balleine, i-2005). Kodwa-ke, i-NAc core iye yahlongozwa ukuba ibe indawo ebalulekile yokuthola ukufundwa kwezinto zokuqondiswa kwezinhloso (USmith-Roe noKelley, i-2000; I-Baldwin et al., 2002a,b; Kelley, 2004). Sibonisa imiphumela elinganayo yokudalwa kwezidakamizwa zangaphambilini kanye nokuphazamiseka okukhulu kwe-ΔFosB okuphazamisayo ekuthuthukiseni ukuziphatha kwezinsimbi. Ama-infusions we-HSV-ΔFosB ayenqunyelwe ku-NAc core nawo ayanda ukuphendula kwe-instrumental ukudla. Nakuba lezi zivivinyo zingabandakanyi umnikelo we-dorsal striatum kulezi zindlela zokuziphatha, ziphakamisa ngokuqinile ukuthi ukuguqulwa kwe-FosB-okubangelwa ukuguqula izakhi zofuzo ngaphakathi kwe-NA kuyanele ukwandisa ukuphendula okugqugquzela ukudla. Ngoba ukuphendula okuqhubekayo kwesilinganiso kwaphinde kwathuthukiswa lapho i-ΔFosB iboniswa ngemuva kokusebenza okuqinile okusezingeni eliphezulu ngaphambili, kuyingxenye yethonya lokugqugquzela ukuziphatha kwezingoma. Ukuthi kungenzeka ukuthi izinqubo zethu zokufunda ezithinta izinsimbi zingasuswa ngokuphelele. Ukusekela iziphetho zethu, ukwanda kokwenziwa kwezinsimbi kubonwe ngemuva kokudalwa komlomo we-cocaine wangaphambili (I-Miles et al., I-2004) kuye kwachazwa ukuthi kuhilela ukuguqulwa kokugqugquzela okuhambisana nokukwazi ukwelashwa okungapheliyo kwe-nicotine ukwandisa isilinganiso sokuqhubekayo esabela kumagundane (Brunzell et al., 2006). Ngaphezu kwalokho, i-dopamine transporter idonsa amantongomane, lapho amazinga e-extracellular dopamine ekhuphuka khona, abonisa kokubili i-DFamB immunoreactivity nokugqugquzela ukudla okuqinisiwe, kodwa hhayi ukuguqulwa kokufunda (UCagniard et al., 2006). Ngaphezu kwalokho, sithole ukuthi ukuphazamiseka okukhulu kwe-ΔFosB yokubeletha emasimini akuthinti ukusebenza uma ukudla "kuqhathaniswa" ngokufeza. Le datha ibonisa ukuthi izilwane zazizwela ngokubaluleka kokugqugquzelwa kwe-reinforcer nokuthi ukuphendula kwakuyi-target eqondiswe.
Ukwehliswa kwezidakamizwa eziphindaphindiwe kwangaphambilini kungaphinde kuthuthukise ukulawulwa kokuziphatha okusetshenziselwa isifiso esimisiwe esihambisana nama-reinforcers yemvelo, kulinganiswa indlela ye-pavlovian (I-Harmer ne-Phillips, i-1998; U-Taylor noJentsch, i-2001; I-Olausson et al., I-2003), ukuqinisekiswa okusimisiwe (U-Taylor no-Horger, i-1999; I-Olausson et al., I-2004), nokudluliswa kwe-pavlovian-to-instrumental (I-Wyvell ne-Berridge, i-2001). Manje kukhona ubufakazi obunamandla bokuthi i-NAc core, ngokuphambene negobolondo, ihilelekile ekulawuleni ukuziphatha okubangelwa izidakamizwa yi-stivol ehambisana nesimo se-pavlovian (I-Parkinson et al., I-1999, 2002; I-Hall et al., I-2001; I-Dalley et al., I-2002; Ito et al., 2004). Imiphumela yethu ingase isikisele ukuthi ukungeniswa kwezidakamizwa kwe-ΔFosB ku-NAc kungase kube yindlela eyodwa okulawulwa ngayo ukuziphatha kokuziphatha kulezi zinqubo. Kungenzeka nokuthi ukuguqulwa kwesimo se-pavlovian, okwenza njengabaqinisekisile, kufaka isandla emiphumeleni yokuziphatha yamanje. Ukulawulwa okuthuthukisiwe ekuphatheni yizimo ezinjalo ezihlelelwe ukwanda kwe-ΔFosB ezibulalayo zingase zenze nomthelela emthonjeni weprotheyini ekuthandweni kwezindawo ezifakwe izidakamizwa (Kelz et al., 1999; UZachariou et al., 2006) kanye nesilinganiso sokuqhubeka sokuphendula i-cocaine (I-Colby et al., I-2003). Izinguquko ezinkambisweni zokugqugquzela ziye zaxilongwa ukuze zenze intuthuko nokugcinwa kokuziphatha okuluthayo (I-Robinson ne-Berridge, i-1993; UJentsch no-Taylor, i-1999; URobbins no-Everitt, i-1999; I-Nestler, i-2004). Idatha yamanje ibuye ihambisane nezinye izinkomba ezigcizelela izinqubo eziningi ze-instrumental ne-pavlovian ekuziphatheni komlutha (Everitt noRobbins, i-2005). Umsebenzi owengeziwe manje udinga ukuchaza indima yezidakamizwa ezibangelwa izidakamizwa nezidakamizwa ze-FosB e-NAc nakwezinye izindawo ezingaphansi kwe-limbic-striater ngokuphathelene nezici ezithile zokubambisana noma ezishukumisayo ezingase zibe lula ukwenza ukusebenza kwama-instrumental futhi zibe negalelo ekuziphatheni okuphoqelekile.
Yize izindlela eziqondile eziyizakhi zamangqamuzana ezishintsha ngaphakathi kwe-NAc ithonya lokuziphatha eligqugquzelwa yiziqinisekisi eziyisisekelo noma eziqinisekisiwe ezingaziwa (UKelley noBerridge, i-2002), i-GABAergic neurons spiny medium springs ye-NA ibhekwa njenge-substrate ebalulekile ye-plasticity ne-plastic dependence-dependent. Lapha, ukufakelwa kwe-dopaminergic kusuka endaweni ye-ventral kanye ne-glutamatergic okuvela kuma-corticolimbic afferents kuguqulela kuma-dendrites ajwayelekile nezinsiza ze-dendritic (USesack no-Pickel, i-1990; USmith noBlamlam, i-1990). Ukuvezwa kwe-psychostimulant engapheli ukwandisa ubukhulu bezinsipho ezinjalo kwi-neurons kugobolondo le-NAc kanye nenhloko (URobinson noKolb, 1999; URobinson et al., 2001; Li et al., 2003, 2004). Muva nje, ukusungulwa kokugqugquzelwa kokuziphatha kwahlotshaniswa ngokunyuka kwezimpande ze-dendritic ngaphakathi kwe-NAc core (Li et al., 2004). Ngokuphawulekayo, ukwandiswa kwe-cocaine-okwenziwe ukwanda kwamagogasi kuqhubeka kuphela ku-D1I-neurons ephikisayo eyenza i-ΔFosB (URobinson noKolb, 1999; U-Lee et al., 2006). I-FosB e-NAc core ingase ibe nomthelela eklasini le-synaptic elihlala njalo elingathinta ukuziphatha kwezinsimbi. Ngempela, indima ebalulekile ye-dopamine-glutamate neurotransmission (USmith-Roe noKelley, i-2000), amaprotheni kinase A umsebenzi (I-Baldwin et al., 2002a), no de novo amaprotheni synthesis (Hernandez et al., 2002) ngaphakathi kwe-NAc esemqoka ekusebenzeni kwezinsimbi kuye kwabikwa ngaphambilini. Manje sibheka i-ΔFosB njengesici se-transcription esingakwazi ukuqhubeka nokuphendula ukuphendula okuqinisiwe kokudla uma kuphazamisekile ku-NAc core. Izakhi zofuzo ezithile noma amaprotheni ahilelekile kulezi zimo zihlala zichazwe ngokuqondile. I-FosB ilawula ukubonakaliswa kwamaprotheni amaningi e-NAc abandakanyeka ekutheni i-neuroplastiality ishicilelwe (UMcClung noNestler, i-2003). Ukuhlaziywa kwe-microarray yakamuva kuboniswe amaphethini okukhuluma ngegenesheni ku-NAc yamagundane we-bitransgenic eveza i-ΔFosB esebenziwe lapha, futhi ahlonza i-subset yezakhi zofuzo ezilawulwa yi-ΔFosB (UMcClung noNestler, i-2003). I-BDNF yayingenye yezakhi zofuzo, futhi i-BDNF kulolu hlelo lwesigodi se-neural yaziwa ngokuthuthukisa ukuphendula ngezinkulumo ezihlobene nezidakamizwa nokudla (I-Horger ne-al., I-1999; I-Grimm et al., 2003; Lu et al., 2004). Ijethi eyengeziwe yenzalo i-cyclin-dependent kinase 5 (Bibb et al., 2001), eliphinde lihoxiswe ngu-ΔFosB, futhi lingalawula kokubili i-plasticity eyenziwe nge-cocaineNorrholm et al., 2003) kanye nesisusa esilinganiselwe isilinganiso sokuqhubeka nesiphenduli sezinsiza zemvelo noma izidakamizwa (JR Taylor, ukuphawula okungashicilelwe). Okwamanje ukhetho olungeziwe yi-GluR2 subunit yama-glutamate receptors (Kelz et al., 1999) kanye ne-factor factor NFKBB (nuclear factor κB) (I-Ang et al., I-2001). Kungabalulekile ukuhlola lezi kanye namanye amaprotheni alawulwayo ema-subregion ase-NA njengabazongenela ukuxazulula imiphumela yokuziphatha ye-ΔFosB ngokusebenza kwezingoma nokugqugquzela.
The Uchungechunge lwamanje lwamavivinyo lunikeza ubufakazi bokuthi ukucindezeleka okukhulu kwe-ΔFosB ngaphakathi kwe-NAc kungakuthuthukisa ukuziphatha okugqugquzela ukudla futhi ngaleyo ndlela kulawulwe ukusebenza kwezinsimbi, njengoba kukhonjisiwe ngaphambilini ngenxa yemivuzo yezidakamizwa. Lezi zedatha zinikeza ubufakazi obusha bokuthi i-ΔFosB ingase isebenze njengenguquko ejwayelekile yamangqamuzana ehlotshaniswa nezithuthukisi ezinkambisweni zokugqugquzela eziqinisayo ekuziphatheni okuqondiswe umgomo. Izinto esizifunayo ziphakamisa ukuthi kungenzeka ukuthi ukufakwa kwe-NAc ΔFosB, ngezidakamizwa, izidakamizwa eziluthayo, ukucindezeleka, noma ukudla okunomvuzo kakhulu, kungase kube indlela ebalulekile ekugqugquzeleni ukungasebenzi okubangelwa ukukhathazeka kwengqondo okuhambisana nokuziphatha okuphoqelelwe.
Imibhalo yaphansi
o Itholwe ngo-March 15, i-2006.
o Ukubuyekeza kutholiwe ngo-Juni 23, i-2006.
o Yamukelwe ngo-Agasti 2, i-2006.
Lo msebenzi wawusekelwa izibonelelo ezivela eNational Institute on Drug Abuse, iNational Institute of Health Mental, kanye neNational Institute of Alcohol Abuse and Alcoholism. Siyazisa ngokubaluleka usizo olubalulekile lukaDalja Krueger, uDrew Kiraly, uDkt. Ralph DiLeone, uRobert Sears, noDkt. Jonathan Hommel eMnyangweni Wezokwelapha, iYale University. Sibonga futhi uDkt. Jennifer Quinn noDkt. Paul Hitchcott ngokunikeza imibono ewusizo kulo mqulu wesandla.
Ukuxhumana kumele kuhanjiswe kuJane R. Taylor, uMnyango wezeMpilo, i-Division of Molecular Psychiatry, i-Yale University School of Medicine, iRicicoff Research Facilities, isikhungo sezempilo se-Connecticut, i-34 Park Street, iNew Haven, i-CT 06508.[i-imeyili ivikelwe]
I-copyright © 2006 Society for Neuroscience 0270-6474 / 06 / 269196-09 $ 15.00 / 0
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