Umthetho Wemihlahlandlela Yokwemvelo Nezidakamizwa Ngezinqubo Ezivamile Ze-Neural Plasticity ne-ΔFosB njenge-Key Mediator (2013)

Lolu cwaningo luhlolisise imiphumela yomvuzo wobulili ku-DeltaFosB nemiphumela ye-DeltaFosB ekuziphatheni kocansi nasemvuzweni. Izinguquko ezijwayelekile zamangqamuzana ezaziwayo ukuthi zenzeka ngokuluthwa yizidakamizwa zitholwe zifana nokuthi zenzeka nocansi. Ngamanye amagama, iDeltaFosB yavela ngenxa yezenzo zocansi, kepha izidakamizwa ziyayiduna le ndlela efanayo. Lokhu kuphelisa impikiswano yokuthi ukulutha kwezidakamizwa kuhluke kanjani ekuluthweni kokuziphatha, nokuthi ukulutha kokuziphatha kumane nje kuyimpoqo (noma ngabe kusho ukuthini lokho). Amasekethe afanayo, izindlela ezifanayo, izinguquko ezifanayo zamaselula, izindlela ezifanayo zokuziphatha ezihambisana –nomehluko omncane.

J Neurosci. 2013 Feb 20;33(8):3434-3442.

ISIHLOKO ESIFUNDWAYO

Pitchers KK, I-Vialou V, I-Nestler EJ, I-Laviolette SR, Lehman MN, Coolen LM.

Umthombo

UMnyango We-Anatomy & Cell Biology, iSchulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario N6A 3K7, Canada, Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, Fishberg Department of Neuroscience and Friedman IBrain Institute, iMount Sinai School of Medicine, eNew York, eNew York 10029, kanye neMinyango yeNeurobiology neAnatomical Sciences kanye nePhysology kanye neBiophysics, University of Mississippi Medical Center, Jackson, Mississippi 39216.

abstract

Izidakamizwa zokuhlukumeza zidala ukungasebenzi kahle emgwaqweni wemvelo, ikakhulukazi i-nucleus accumbens (NAc), ngaleyo ndlela kubangele ukuthuthukiswa nokuveza ukuziphatha okuluthayo. Ubufakazi bamuva bubonisa ukuthi imivuzo yemvelo ingabangela ushintsho olufanayo ku-NAc, okuphakamisa ukuthi izidakamizwa zingase zisebenzise izindlela ze-plasticity ezabelwana ngemiklomelo yemvelo, futhi zivumela ukusebenzisana okuyingqayizivele phakathi kwemivuzo yemvelo nezidakamizwa.

Kulolu cwaningo, sibonisa ukuthi isipiliyoni sezocansi emakhompini abesilisa lapho kulandelwa isikhathi esifushane noma eside sokulahlekelwa umvuzo wezocansi kubangela umvuzo owenziwe ngcono we-amphetamine, oboniswe ngendawo ehlonishwayo yendawo okumele ibekwe ngayo (i-0.5 mg / kg) i-amphetamine. Ngaphezu kwalokho, ukuqala, kodwa hhayi ukukhuluma kwesikhathi eside, umvuzo wamamthetamine othuthukisiwe wawuhambisana nokunyuka kwesikhashana kwezimpande ze-dendritic ku-NAc. Okulandelayo, indima ebalulekile yesici sokubhalisa ΔFosB ekunikeni umvuzo we-amphetamine othuthukisiwe ngocansi kanye nokunyuka okuhambisanayo emithonjeni ye-dendritic ku-NAc neurons yasungulwa usebenzisa ukudluliswa kwegciwane lesandulela ngculaza lomlingani obophezelayo ongathintekiyo. Ngaphezu kwalokho, kuboniswe ukuthi umvuzo wokuvuselelwa kwezidakamizwa owenziwe ngocansi, i-ΔFosB, ne-spinogenesis kuxhomeke ekusebenziseni ukutholwa kwe-Dopamine ye-D1 ku-NAc. Ukuvinjwa kwamaphilisi kwe-D1 receptor, kodwa hhayi i-receptor ye-D2, ku-NAc ngenkathi ukuziphatha ngokobulili kunqatshelwe i-DFFB ukukhishwa futhi kuvinjelwe ukukhula kwe-spinogenesis nokuvuza okunamandla kwe-amphetamine.

Tkonke lokhu kutholakala ukuthi izidakamizwa zokuhlukumeza kanye nokuziphatha komvuzo wemvelo zisebenzisana nezinqubo ezivamile zamangqamuzana namaselula we-plasticity okulawula ukubhekela ekubhekaneni nezidakamizwa, nokuthi lokhu kukhishwa kwengozi kuhlanganiswa yi-ΔFosB kanye nezinhloso zayo ezingezansi.

Isingeniso

Ukuziphatha komvuzo wemvelo kanye nomvuzo wezidakamizwa kuguqula indlela ejwayelekile ye-neural, uhlelo lwe-mesolimbic dopamine (DA), lapho i-nucleus accumbens (NAc) idlala indima ebalulekile (Kelley, 2004). Izidakamizwa zokuhlukumeza zenza i-neuroplasticity ohlelweni lwe-mesolimbic, elidlala indima yokufaka ekushintsheni ekusetshenzisweni kwezidakamizwa kuya ekulweni kwezidakamizwa (I-Hyman et al., I-2006; U-Kauer noMalenka, i-2007; I-Kalivas, i-2009; Chen et al., 2010; U-Koob no-Volkow, i-2010; Wolf, 2010a; Mameli noLuscher, i-2011). Kuye kwacatshangelwa ukuthi izidakamizwa nemiklomelo yemvelo ayisebenzisi ama-neurons afanayo ohlelweni lwe-mesolimbic, ngakho-ke ukuthi izidakamizwa zivuselele ngokukhethekile futhi ziguqule lesi sifunda (UCameron no-Carelli, i-2012). Kodwa-ke, sekucacile ukuthi imivuzo yemvelo nezidakamizwa ithinta uhlelo lwe-mesolimbic ngazo zombili izindlela ezifanayo nezingafani ezivumela ukuxhumana phakathi komvuzo wemvelo, ikakhulukazi umvuzo wezocansi, nemiphumela yezidakamizwa zokuhlukunyezwa (I-Frohmader et al., 2010a; Pitchers et al., 2010a; U-Olsen, i-2011).

Ukuziphatha ngokobulili kuvuza kakhulu (Tenk et al., 2009),

Lokhu okutholakele kusikisela ukuthi okuhlangenwe nakho kwemiphumela yemvelo kanye nezidakamizwa kubelana ngezindlela ezivamile zepulasitiki ye-neural, okumele ibenze ithonya ekubhekaneni nokusetshenziswa kabi kwezidakamizwa.

Umgomo wesifundo samanje kwakuwukuba kunqume izindlela zamaselula ezixhumanisa ubuciko be-plasticity eyenziwe ngesifo sobulili, okubangela ukuthi kuthuthukiswe umvuzo wezidakamizwa. Ngokuyinhloko, indima yezinto ezibhaliwe ΔFosB iphenywe ngoba ihileleke emiphumeleni yomvuzo nemvelo yezidakamizwa (Nestler et al., 2001; Werme et al., 2002; I-Olausson et al., I-2006; Wallace et al., 2008; Hedges et al., 2009; Pitchers et al., 2010b). Ngaphezu kwalokho, indima ye-dopamine D1 receptors (i-D1R) ye-plastic neural plasticity eyenziwe ngesipiliyoni ihlolwe ngoba i-NAc ΔFosB isungulwa futhi yanda ubukhulu bomgogodla ngemuva kokuphathwa kwengqondo kwe-psychostimulant kuboniswe kwi-neurons ene-D1R (U-Lee et al., 2006; Kim et al., 2009) futhi kuncike ekusebenzeni kwe-D1R (Zhang et al., 2002).

Lapha, sisebenzisa inkulumo ye-vector-mediated yomlingani obophezelayo ongenamandla we-ΔFosB, i-diolistic yokubeka uphawu, kanye nokusebenza kwemithi ukuze avivinye ukucabanga ukuthi imiphumela ehlukumezayo yesipiliyoni sobulili elandelwe ukuzithiba ekuzikhulumeni ku-Amph ukukhuliswa okuthuthukisiwe kuhanjiswe Ukufakwa kwe-D1R ngokwe-ΔFosB ku-NAc nokunyuka okulandelayo kwe-NAc spine mass. Ngokubambisana, lokho okutholakele kuhlinzeka ubufakazi bokuthi imivuzo yemvelo kanye nezidakamizwa ibelana ngezindlela ezivamile ze-plastic neural, futhi i-ΔFosB njengomlamuleli obalulekile.

Izimpahla nezindlela

Izilwane.

Amadoda amadala (i-225-250 g lapho efika) ne-female (210-220 g) Ukuphambanisa amagundane e-Dawley (iCharles River Laboratories) babehlala emigodini ye-Plexiglas ngamabhanzana afanayo ocansini kulo lonke ukuhlolwa, ngaphansi komthetho wokushisa nomswakama kanye ne-12 / 12 h umjikelezo okhanyayo / omnyama nokudla namanzi atholakalayo ngokukhululekile. Abalingani besifazane okwenziwe ngezikhathi zokulinganisa babenama-ovariectomized futhi bathola izimpande ezincane eziqukethe i-5% estradiol benzoate (Sigma-Aldrich) kanye nokujova kwe-500 μg ye-progesterone (ku-0.1 ml ye-sameame; Sigma-Aldrich) 4 h ngaphambi kokuhlolwa. Yonke inqubo yamukelwa yi-Animal Care kanye namaKomidi asetshenziswayo eNyuvesi yaseWestern Ontario naseYunivesithi yaseMichigan futhi ivumelana neCanada Council on Animal Care kanye neziqondiso zikazwelonke zezeMpilo zeZempilo ezibandakanya izilwane ze-vertebrate ekucwaningweni.

Ukuziphatha ngokocansi.

Izikhathi zokuxubha zenzeke ngesikhathi sesimnyama (phakathi kwe-2 ne-6 h emva kokuqala kwesikhathi esimnyama) ekukhanyeni okubomvu okumnyama, emakhenjini okuhlola ahlanzekile (60 × 45 × 50 cm). Amagundane abesilisa abanjwe ukujula ngesikhathi se-4 noma i-5 sessions yokubamba nsuku zonke. Kuye kwakhethwa amaseshini amahlanu ngoba ngaphambilini sibonise ukuthi le paradigm ibangela ukusizwa kwesikhashana isikhathi sokuziphatha kobulili (Pitchers et al., 2010b), ukunqamuleka okuphambene nomsebenzi we-Amph locomotor (Pitchers et al., 2010a), nomvuzo (Pitchers et al., 2010a). Ukukhethwa kwe-Ejaculation kukhethwe njengophawu lokuphela kweseshini ngayinye yokubuthana ngoba ngaphambili sabonisa ukuthi kubalulekile emiphumeleni yocansi lesimo socansi ku-Amph locomotor sensitization (Pitchers et al., 2010a), okwakungeke kwenzeke lapho izilwane zivunyelwe ukuba zithandane nabesifazane ngaphandle kokuboniswa kwe-ejaculation. Amapharamitha wokuziphatha ngokocansi (okungukuthi, i-latency kuya kokuqala kokuqala, ukukhishwa kwe-intanethi nokukhishwa kwe-ejaculation, kanye nenani lezintaba nezintambo) kubhalwe njengoba kuchazwe ngaphambili (Pitchers et al., 2010b). Kuzo zonke izivivinyo, amaqembu ahlangene ngokobulili afanelwe ukuziphatha ngokobulili (inani eliphelele le-ejaculations kanye ne-latency kuya ku-ejaculation phakathi neseshini ngayinye yokuhlangana). Ngemuva kweseshini yesihlanu yokulinganisa, abesilisa bahlala behlala nabo abalingani abafanayo bobulili futhi abavunyelwe ukushada nabo ngesikhathi sokuzibandakanya ngocansi lwe-1, 7, noma i-28 d. Izilwane ezahlala ziphila ngokocansi zaphathwa futhi zahlala emakamelweni afanayo njengamadoda abesilisa ocansini. Ngaphezu kwalokho, ukulawulwa kwe-naive kuye kwafakwa ezigodini zokuhlola ezihlanzekile ngehora phakathi nezinsuku ze-5 ezilandelanayo, ngaphandle kokufinyelela kumfazi owemukelayo.

Ukukhuluma kwe-FosB.

Izilwane zazixoshwa kakhulu (i-pentobarbital ye-sodium; i-390 mg / kg; ip) futhi ingasetshenziswanga ngokungahambisani ne-50 ml ye-0.9% saline, ilandelwa i-500 ml ye-4% ye-paraformaldehyde (Sigma-Aldrich) ku-0.1 m phosphate buffer (PB) ngaleso sikhathi iphuzu kanye nezivivinyo ze-DR eziphikisayo. Ama-Brains asusiwe futhi afakwe ngemuva kwe-1 h ekamelweni lokushisa endaweni efanayo, bese agcinwe ku-4 ° C ku-20% sucrose no-0.01% sodium azide ku-0.1 m PB. Ukuhlolwa kwe-DR okuphikisayo, ubuchopho basusiwe futhi bube yingxenye yesigamu eceleni kwe-axis sagittal. Ingxenye eyodwa igcinwe ku-PB futhi isetshenziselwa i-DiOlistics, kanti enye isetshenziselwa i-ΔFosB. Izigaba ze-Coronal (35 μm) zazinqunywa nge-microtome yamahhala (Microm H400R), ziqoqwe ngochungechunge ezine oluhambisanayo kwisisombululo se-cryoprotectant (30% sucrose ne-30% ethylene glycol ku-0.1 m PB) futhi igcinwe ku-20 ° C. Izigaba ezingenazifutho zihlanziwe kakhulu nge-0.1 m PBS, i-pH 7.35, phakathi kwezinguquko, futhi zonke izinyathelo zisezingeni lokushisa. Izigaba zavezwa ku-1% H2O2 (I-10 min) nesisombululo sokuxubha (i-1 h; i-PBS equkethe i-0.1% BSA, i-Fisher; ne-0.4% i-Triton X-100, i-Sigma-Aldrich). Izigaba zabe seziqhutshwa ngobusuku obubodwa ku-pan-FosB i-rabbit polyclonal antibody (1: 5K; sc-48 Santa Cruz Biotechnology), eqinisekisiwe ngaphambilini (I-Perrotti et al., I-2004, 2008; Pitchers et al., 2010b). I-anti-pan-FosB antibody yakhuliswa ngokumelene nesifunda sangaphakathi esabiwe yi-FosB ne-osBFosB, futhi ngaphambili ibibonakaliswe ukubona ngeso lengqondo amaseli e-ΔFosB ngesikhathi samaphuzu asetshenziswe kulolu cwaningo (> 1 d ngemuva kwesikhuthazi) (I-Perrotti et al., I-2004, 2008; Pitchers et al., 2010b). Okulandelayo, izigaba zafakwa ngaphakathi kwe-IgG ye-goat-anti-rabbit (i-1 h; i-1: 500 ku-PBS +; i-Vector Laboratories), i-peroxidase ye-avidin-biotin-horseradish (i-1 h; i-ABC elite; i-1: i-1000 ku-PBS; i-Vector Laboratories) , ne-0.02% 3,3'-diaminobenzidine tetrahydrochloride (10 min; Sigma-Aldrich) ne-0.02% nickel sulfate ku-0.1 m PB ene-hydrogen peroxide (0.015%). Izigaba zafakwa kwi-Superfrost plus glass slides (Fisher) futhi zenziwe nge-dibutyl phthalate xylene.

Amanani we-ΔFosB-IR amaseli ayebalwa kugobolondo le-NAc kanye nenhloko ezindaweni ezijwayelekile zokuhlaziywa (400 × 600 μm) njengoba kuchazwe ngaphambilini (Pitchers et al., 2010b). Izigaba ezimbili zabalinganiselwe ngaphansi kwe-NAc, ngaphansi kwesilwane ngasinye. Esikhathini sokuhlola kwesikhawu, izinombolo zama-ΔFosB-IR amaseli ziboniswa njengenguquko ye-fold yeqembu lokulawula i-naive ngesikhathi sokufaneleka esifanele futhi kuqhathaniswa phakathi kwamaqembu anolwazi namaqembu angaphansi kwesinye isikhathi ngasinye ngesikhathi sokusebenzisa isikhathi esingasebenzi t ukuhlolwa ngezinga lokubaluleka p <0.05. Ekuhlolweni kwe-ΔJunD-AAV ne-DR kwabamelene nayo, kusetshenziswe indlela yezindlela ezimbili noma eya ngakunye i-ANOVA, ngokulandelana, nangendlela yeHolm-Sidak. Ngaphezu kwalokho, amaseli e-ΔFosB-IR abalwa ku-dorsal striatum (indawo yokuhlaziya: 200 × 600 μm), ngokushesha kwehliselwa i-NAc futhi kusondelene ne-lateral ventricle, kuzo zonke izilwane ekuhlolweni kwabamelene ne-DR. Indlela eyodwa ye-ANOVA ne- t kusetshenziswa izivivinyo ukuqhathanisa phakathi kwamaqembu.

I-DiOlistics.

Ngephuzu lesikhathi nokuhlolwa kwe-veJunD vector viral, amagundane asetshenziswa ngokungenabungozi nge-50 ml saline (0.9%), kwalandelwa yi-500 ml ye-2% paraformaldehyde ku-0.1 m PB. AmaBroins ahlukaniswe ngezigaba (i-100 μm coronal) kusetshenziswa i-vibratome (Microm) kanye nezingxenye ezigcinwe ku-0.1 m PB nge-0.01% sodium azide ku-4 ° C. Ukuhlanganiswa kwezinhlayiya ze-tungsten (1.3 μm ubukhulu, i-Bio-Rad) nge-lipophilic carbocyanine dye DiI (1,1'-dioctadecyl-3,3,3'3'-tetramethylindocarbocyanine perchlorate; Attitrogen) kwenziwa njengoba kuchaziwe ngaphambili (U-Forlano no-Woolley, 2010). Izinhlayiya ze-DiI-coated tungsten zilethwe ku-tishu e-160-180 psi zisebenzisa uhlelo lwe-Helios Gene Gun (Bio-Rad) ngesihlungi esine-3.0 μm pore usayizi (i-BD Bioscience) futhi zavunyelwa ukuvela ngokusebenzisa ulwelwesi lwama-neuronal ku-0.1 m PB ye I-24 h ngenkathi ivikelwe ukukhanya ku-4 ° C. Okulandelayo, izingcezu zabhalwa kabusha ku-4% paraformaldehyde ku-PB ye-3 h kumazinga okushisa amakamelo, wageza ku-PB, futhi wafakwa emakamelweni afakwe uphawu (i-Bio-Rad) nge-gelvatol equkethe i-ejenti elwa nokuphelelwa amandla i-1,4-diazabicyclo (2,2) octane ( I-50 mg / ml, i-Sigma-Aldrich) (ULennette, i-1978).

Ama-neurons anelebuli ye-DiI aboniswa isithombe Zeiss I-LSM 510 m microscope eyimfihlo (Carl Zeiss) kanye ne-helium / neon 543 nm laser. Kwisilwane ngasinye, ama-neuron we-2-5 ku-subcion ngayinye ye-NAc, noma egobolondweni (kususelwa endaweni ehlobene nezimpawu zomhlaba, kufaka phakathi i-latricle ne-anterior commissure) ekuhlolweni kwe-ΔJunD-AAV kanye ne-DR antagonist. inzalo kwi-dendrite ye-oda lesibili yokuvalwa komgogodla. Kwi-neuron ngayinye, kwahlaziywa ama-dendrites ama-2-4 ukuthola isilinganiso sobude besibalo se-40-100 μm. Izingxenye ezi-Dendritic zathunjwa kusetshenziswa injongo ye-40 × yokuntywiliselwa emanzini ngezikhathi ze-0.25 μm z-axis, futhi isithombe se-3D sakhiwa kabusha (Zeiss) futhi kwenziwe i-deconvolution (i-Autoquant X, i-Media cybernetics) isebenzisa i-adaptiv (blind) kanye ne-theoretical PSF setting njengoba kunconywe yisoftware. Ubuningi be-spine buqanyulwe kusetshenziswa imodyuli yeFilament ye-Imaris software package (inguqulo 7.0, Bitplane). Izinombolo zemigqa eyenziwe nge-dendritic yavezwa nge-10 μm, okulinganiselwa kuyo i-neuron ngayinye bese kuthi isilwane ngasinye. Ukwahluka kwezibalo kunqunywe kusetshenziswa ama-ANOVA wezinhlandla ezimbili ocwaningweni lwesikhathi phakathi kwezilwane ezinobuhlakani nezocansi nesipiliyoni ngesikhathi ngasinye (amaphuzu: okuhlangenwe nakho kwezocansi kanye nokuzithoba kwe-NAc) nasekuhlolweni kwe-ΔJunD (izici: isipiliyoni sobulili kanye nevayirasi ye-viral), kanye neyodwa -way ANOVA ekuhlolweni kwe-DR antagonist. Ukuqhathaniswa kweqembu kwenziwa ngendlela yeHolm-Sidak enamazinga abalulekile we p <0.05.

Ukuthanda indawo okuthandayo.

Idizayini yokulinga ye-CPP yayifana nalena echazwe ngayo ngaphambili (Pitchers et al., 2010a), kusetshenziswa i-comparatus enezinto ezintathu zama-compartment (iMedi Associates), kanye nokuklama okungashintshiwe, ngesilingo esisodwa sokufaka isimo ku-d-Amph sulfate (Amph; Sigma-Aldrich; 0.5 mg / ml / kg sc kubalwe ngesisekelo samahhala) egunjini elibhangqiwe nosawoti egumbini elingakhokhelwanga phakathi kwezinye izinsuku, futhi kwenziwe phakathi kwengxenye yokuqala yesigaba sokukhanya. Izilwane ezilawulayo zithole usawoti kuwo womabili amakamelo.

Izikolo ze-CPP zabalwa isilwane ngasinye njengoba isikhathi esichithwe (ngemizuzwana) egumbini lokubhanqana ngesikhathi sokuvivinya sokususa umenzi. Ama-ANOVA asendleleni eyodwa kanye neHolm-Sidak indlela yasetshenziselwa ukuqhathanisa amaqembu ocwaningweni lwamaphuzu wesikhathi. Akukhokhelwa t vivinya ngokubaluleka okusethwe ku- p <0.05 isetshenziselwe ukuqhathanisa i-Naive-Sal ne-Naive Amph ngaphakathi kwesikhathi ngasinye ekuhlolweni kwephoyinti lesikhathi, nangaphakathi kwelashwa ngalinye le-vector ku-experimentJunD. Esivivinyweni sesikhathi, kwasetshenziswa ama-ANOVA wendlela eyodwa kanye nendlela yeHolm – Sidak ukuqhathanisa amaqembu anolwazi ngocansi (i-Exp-Sal, i-7 d i-Exp Amph ne-d engu-28 ye-Exp Amph), futhi engakhokhiwe t isivivinyo sisetshenziselwe ukuqhathanisa amaqembu we-2 naive. I-ANOVA enezindlela ezimbili kanye ne-Holm-Sidak indlela yasetshenziselwa ukuqhathanisa wonke amaqembu ekuhlolweni kwe-DR antagonist. Ababili abangakhokhelwa t kusetshenziswe isivivinyo ukuqhathanisa amaqembu we-Naive-Sal neNaive Amph nesimo ngasinye sokwelashwa kwevithamini ye-viral (GFP noma ΔJunD), njengoba idatha yayihluka kakhulu emaqenjini we-ΔJunD ukuvumela ukuhlaziywa kwe-ANOVA. Wonke amazinga abalulekile asethelwe ku p <0.05.

Ukuhlolwa kwesivivinyo segciwane.

Amagundane amaduna abulawa nge-ketamine (i-87 mg / ml / kg; ip) ne-xylazine (i-13 mg / ml / kg ip), ifakwe endaweni yokusebenza ye-stereotaxicaratarat (Kopf Instrsets), yathola nama-virinjection angama-bilateral we-recombinant adeno-ahambelana nama veges encoding I-GFP kuphela (iprotheni eluhlaza ye-fluorescent), noma i-ΔJunD (ebopha kakhulu i-ΔFosB) ne-GFP, kwi-NAc (izixhumanisi: AP + 1.5, ML ± 1.2 kusuka ku-bregma; DV −7.6 kusuka kugebhezi), ngevolumu ye-1.5 I-μl / hemisphere ngaphezulu kwe-7 min isebenzisa isirinji yeHamilton (iHarvard Apparatus). I-ΔJunD inciphisa ukubhalwa kwe-ΔFosB-Mediated byoncintisana heterodimerizing nge-andFosB futhi ngenxa yalokho kuvimbela ukubopha kwe-ΔFosB esifundeni se-AP-1 ezingxenyeni zokuphromotha zezinhlobo zokuqondisa (I-Winstanley et al., I-2007; Pitchers et al., 2010b). Noma i-ΔJunD ibopha ngokuhambisana okukhulu ne-ΔFosB, kungenzeka ukuthi eminye imiphumela ebonwe yi-ΔJunD ingahle iqondaniswe nokuphikisana namanye amaphrotheni we-AP-1. Kodwa-ke, kuvela ukuthi i-ΔFosB yiprotheni ebaluleke kakhulu ye-AP-1 eboniswe ngaphansi kwezimo ezihloliwe (Pitchers et al., 2010b). Phakathi kwamaviki we-3 ne-4 kamuva, izilwane zathola okuhlangenwe nakho kwezocansi ngesikhathi sokuhlangana kwe-4 noma zahlala zinenkani ukudala amaqembu e-4: i-GFP engenacala ngocansi, i-GFP enezifiso zocansi, i-ΔJunD engenacala ngokobulili, nomuntu onolwazi lwezocansi ΔJunD. Umuzwa wezocansi wawenziwe ngeseshini yokulandelana yansuku zonke ye-4. Izilwane zahlolwa i-CPP ne-diOlistics. Ukuqinisekiswa kwezindawo zokujova kwenziwa njengoba kuchaziwe phambilini (Pitchers et al., 2010b). Izingxenye ze-NAc (i-coronal; i-100 μm) zacutshungulwa zasebenza ngenxa ye-GFP (1: 20,000; unogwaja anti-GFP antibody; Invitrogen). Ukusakazwa kwegciwane kwakuvinjelwe kuphela engxenyeni yegobolondo ye-NAc, nokusakazeka okwengeziwe emgogodleni.

Abaphikisi be-D1R / D2R.

Amagundane angamaduna awafakwa ngomjovo we-intraperitoneal (0.1 ml / kg) we-ketamine (87 mg / ml) ne-xylazine (13 mg / ml), futhi afakwa kwizixhobo ze-stereotaxic (Kopf Instrsets). Ama-cannulas we-Bilateral 21-gauge guide cannulas (Plastics One) ehliselwe kwi-NAc e-AP + 1.7, ML ± 1.2 kusuka bregma; I-−6.4 DV kusuka kugebhezi futhi ivikelwe nge-acrylic yamazinyo, inamathele kwizikulube ezintathu ezisethwe kugebhezi. Izilwane zaziphathwa nsuku zonke ukuze kuthathwe izinqubo zokungenela ngesikhathi sokulungiswa kwamasonto e-2. Imizuzu eyishumi nanhlanu ngaphambi kokuqala kwesikhathi ngasinye sokukhula kwe-4 nsuku zonke ngokwethula insikazi etholayo, amagundane amaduna athola ama-microinjections we-D1R antagonist R (+) SCH-23390 hydrochloride (Sigma-Aldrich), D2 receptor (D2R) -) i-eticlopride hydrochloride (Sigma-Aldrich) yachithwa ku-saline oyinyumba (i-0.9%; ngayinye ku-10 μg ku-1 μl nge-hemisphere; encibilikisiwe e-0.9% saline), noma i-saline (1.0 μl per hemisphere). I-μl / min ngaphezulu kwesikhathi sokuphumula se-1.0 imizuzu elandelwa ngamaminithi we-1 nge-cannula yomjovo esele endaweni yokufakwa kwezidakamizwa. Umthamo walejojekithi uzofaka i-both core and igobolondo, njengoba infusions ye-1 μl ikhawulelwe ekuhlukaniselweni kwegobolondo noma okuyi-core (Laviolette et al., 2008). Imithamo yayisuselwa ocwaningweni lwangaphambilini olukhombisa ukuthi le noma imithamo ephansi ithinta ukusebenza kwezidakamizwa noma komvuzo wemvelo (Laviolette et al., 2008; URoberts et al., I-2012). Abesilisa abalawulayo bahlala bengazi lutho ngokocansi kepha bathola usawoti we-intra-NAc ngaphambi kokubekwa ekhejini lokuhlola elingenalutho, ngesikhathi sokusingathwa kwansuku zonke kwe-4. Isonto elilodwa ngemuva kokulunga kokugcina noma ukuphatha isikhathi, abesilisa bahlolwa i-Amph CPP, nokuhlaziywa komgogodla kanye ne-ΔFosB. Ukusetshenziswa kwamaseshini amane, esikhundleni sezinsuku ezinhlanu njengakwezinye izivivinyo, kukhethwe ukuqeda ukulimala ngokweqile kwi-NAc okubangelwe yi-infusions ephindaphindwayo ngakho-ke kuvumele ukuhlaziywa komgogodla kanye ne-ΔFosB. Ngempela, umonakalo awuzange ubonakale, futhi ukuhlaziya komgogodla kanye ne-BFosB ku-NAc yezilwane ezifakwe usawoti kukhombisa idatha efanayo njengamaqembu angazange afakwe kokulinga kwangaphambilini. Izindlela ezimbili ze-ANOVA neHolm-Sidak ezinokubaluleka okubekwe kuyo p <0.05 isetshenziselwe ukunquma ukuqhutshwa kokuhlangenwe nakho kobulili kokuziphatha kocansi.

Imiphumela

Ukuvuselelwa kokuhlangenwe nakho kocansi ΔFosB kuhlala isikhathi eside

Okokuqala, ukuhlangana kwesikhashana phakathi kokushintsha okunesifiso sokuya ocansini kwesimo se-ΔFosB, izindawo ezi-dendritic ku-NAc, ne-Amph-CPP kunqunywe, ikakhulukazi ngemuva kwezikhathi ezimfushane nezesikhathi eside zokuziyeka emvuzweni wobulili (7 noma 28 d). Phambilini, kwaboniswa ukuthi ulwazi lwezocansi lwe-5 nsuku zonke zokuzalela kokubeletha lubangele ukunqwabelana kwe-ΔFosB kulo lonke uhlelo lwe-mesolimbic, ikakhulukazi ku-NAc (Wallace et al., 2008; Pitchers et al., 2010b). Kulezi zifundo ezedlule, amazinga we-ΔFosB alinganiswa ngaphakathi kwe-1 d ngemuva kokuziphatha kocansi, futhi akukwaziwa ukuthi ukuqoqeka kwe-ΔFosB kuphikekile ngemuva kokukhishwa isikhathi eside komvuzo. Abesilisa abanolwazi ngocansi benziwa i-1, 7, noma i-28 d ngemuva kokugcina kwamaseshini wokuzala we-5 nsuku zonke, lapho abesilisa besangana beya ejacweni elilodwa. Izilawuli ze-sex naive zalungiswa ngesikhathi esifanayo ngemuva kokugcina kwamaseshini we-5 wokuphatha nsuku zonke. Amanani amaseli we-ΔFosB-IR kuseli le-NAc igobolondo nokuphakama kwakuphakeme kakhulu kunokulawulwa kwabesifazane abanocansi ngaso sonke isikhathi amaphuzu (I-Fig. 1A, igobolondo; I-1 d, p = 0.022; I-7 d, p = 0.015; I-Fig. 1B: umongo; I-1 d, p = 0.024; I-7 d, p <0.001; 28 d, p <0.001), ngaphandle kwegobolondo le-NAc ngemuva kokuyeka i-28 d (p = 0.280). Ngakho-ke, ukukhiqizwa kwe-ΔFosB kuphikelela ngesikhathi sokungabinaki ngemuva kokuhlangenwe nakho kocansi isikhathi okungenani se-28 d.

Umfanekiso we-1.     

Umfanekiso we-1.     

Umuzwa wezocansi ubangele ukwanda okuqhubekayo nokwandayo kwenani lamaseli we-BFosB-IR. Ukushintshwa okumbalwa kwenombolo yamaseli we-ΔFosB-IR kwigobolondo le-NAc (A) nomongo (B) ezilwaneni ezinolwazi lwezocansi (ezimnyama) uma ziqhathaniswa nezilawuli ze-naive (ezimhlophe) zocansi (n = 4 iqembu ngalinye). Imininingwane yeqembu isho ± SEM. *p <0.05, umehluko ophawulekayo uma uqhathaniswa nezilawuli ezingenamqondo. Ummeleli wezithombe zeNaive 1 d (C), Exp 1 d (D), Exp 7 d (E), ne-Exp 28 d (F). ac, Isithasiselo se-Anterior. Ibha yesikali, i-100 μm.

Ukwanda okwenziwe ngezocansi okuphathelene nocansi kuhamba kancane

Pitchers et al. (2010a) ngaphambilini kubikwa ngokusebenzisa amasu okufakwa kweGolgi ukuthi isipiliyoni socansi esilandelwa yi-7 d, kodwa hhayi i-1, yokuzibamba ukukhokhela umvuzo kubangele kakhulu ukwandisa i-dendritic branching kanye nenani lezinhlavu ze-dendritic kugobolondo le-NAc kanye ne-core neurons (Pitchers et al., 2010a). Lapha, i-spinogenesis kubantu abesilisa nabesifazane abanesifo socansi kanye nabesilisa abanolwazi bahlolwe noma yi-7 d noma i-28 d ngemva kokugcina kokuhlangana kokugcina. Ukutholakala kwamanje ngokusebenzisa indlela yokubhalisa i-diOlistics kuqinisekisile ukuthi isipiliyoni socansi esilandelwa yisikhathi sokuqeda ubulili be-7 senyuke izinombolo zemifino ye-dendritic (F(1,8) = 9.616, p = 0.015; I-Fig. 2A-C). Ngokuqondile, inani lezinhlamba ze-dendritic landa kakhulu kwigobolondo le-NAc kanye nenhloko (I-Fig. 2A: igobolondo, p = 0.011; okuyisisekelo, p = 0.044). Noma kunjalo, lokhu kwanda kwe-spine density kwakunesikhashana futhi akusatholakali ngemva kwesikhathi sokuhlala isikhathi socansi lwe-28 d kunoma iyiphi indawo ye-NAc (I-Fig. 2B).

Umfanekiso we-2.     

Umfanekiso we-2.    

Okuhlangenwe nakho ngokobulili kubangele ukwanda kwenani lezinhlanzi ze-dendritic ku-NAc nokubuyekezwa kwe-Amph. A, B, Inombolo yezimpande ze-dendritic kugobolondo le-NAc kanye nenhloko ye-7 d (A) noma i-28 d (DB yezilwane [ezimnyama] ezitholakalayo ngokobulili nezilwane [ezimnyama]; n = 4 noma i-5). Idatha yiqembu elisho ± SEM. #p <0.05, umehluko omkhulu uma uqhathaniswa nezilawuli ezingenamqondo. C, Izingxenye ezimele ze-dendritic ezisuka ku-Naive 7 nama-Exp 7 amaqembu asetshenziselwa ukulinganisa ubukhulu bomgogodla. Ibha yokulinganisa, i-3 μm. D, Isikhathi esichithwa ekamelweni elihlangene (i-Amph noma i-saline) ngesikhathi sokuhlolwa kwe-post-test ngaphandle kwe-pretest (amaphuzu we-CPP) wezilwane zobungqingili (ezimhlophe) noma izilwane ezinolwazi (ezimnyama) ezihlolwe noma i-7 d noma i-28 ngemuva kokuqeda kokugcina noma Isixazululo sokuphatha: i-Naive-Sal (i-7 d ngemuva kokuphatha; n = 8), i-Naive Amph (i-7 d ngemuva kokuphatha; n = 9), i-Exp-Sal (amaqembu ahlangene ezilwane ahlolwe noma i-7 d noma i-28 d ngemva kokulingana; n = 7), i-7 d Exp Amph (i-7 d ngemva kokulingana; n = 9), ne-28 d Exp Amph (i-28 d ngemva kokulingana; n = 11). Amaqembu e-sal athola uSol ahlangene nawo womabili amakamelo. *p <0.05, umehluko ophawulekayo uma uqhathaniswa nezilawuli zikasawoti ezinolwazi ngocansi.

Ubulili obunenzuzo obangelwa u-Amph umvuzo buhlala njalo

Esikhathini esidlule sibonise ukuthi isipiliyoni socansi esilandelwa yi-7-10 d yokuziqeda kubangele ukuvuza okuthuthukisiwe (Pitchers et al., 2010a). Ngokucacile, izilwane ezitholakale ngokobulili zakha indawo enhle kakhulu ye-Amp (0.5 noma i-1.0 mg / kg) engazange iqhube i-CPP ekulawuleni ubulili. Ucwaningo lwamanje luqinisekisile futhi lwandise lemiphumela yangaphambilini ngokubonisa ukuvuselelwa okuthuthukisiwe kwe-Amph ezilwaneni ezihlangene ngokobulili kokubili emva kwe-7 d kanye ne-28 d isikhathi sokuqeda ucansi (I-Fig. 2D; F(2,24) = 4.971, p = 0.016). Ngokuqondile, izilwane ezitholakale ngokobulili ezine-7 noma i-28 d yokuchitha isikhathi zasebenzisa isikhathi esiningi kakhulu ekamelweni lama-Amph ngesikhathi sokuhlolwa kokuhlolwa uma kuqhathaniswa nokulawulwa okungalungile kobulili okwakuthola u-saline kumabili amakamelo (I-Fig. 2D: I-Exp-Sal vs 7 d Exp AMPH, p = 0.032; vs 28 d Exp AMPH, p = 0.021). Ukuqinisekisa ukutholakala kwangaphambilini, izilwane ezingenayo ubulili azizange zisebenzise isikhathi esiningi ekamelweni elihlangene le-Amph ngesikhathi sokuhlolwa kokuhlolwa futhi azifani nakakhulu kusukela eqenjini lokulawulwa kwe-saline lobulili lobuzweli (I-Fig. 2D) (Pitchers et al., 2010a).

Umsebenzi we-FosB ubalulekile ekuziphatheni kocansi-okubangelwa u-Amph ukuvuselelwa

Imiphumela kuze kube manje ikhombise ukuthi isipiliyoni socansi sabangela ukuqoqwa okuhlala njalo kwe-ΔFosB ku-NAc neurons ehambisana ne-Amph eyathuthukisiwe. Ukuze unqume ukuthi umsebenzi we-ΔFosB wanda kakhulu yini ekuzuzeni ukuvuselelwa kwe-Amph, i-AJunD, umlingani obophezelayo obophezelayo we-ΔFosB ovimbela ukubhalwa kwe-ΔFosB-mediated (I-Winstanley et al., I-2007), yayidlulele ngokweqile nge-viral vector-mediated transfer gene ku-NAc (I-Fig. 3A,B). Imiphumela ye-Amph CPP yokuhlola ibonise ukuthi ukucatshwa kwemisebenzi ye-FosB ngokubonisa ukuthi i-NAY i-NAc ivimbele imiphumela yesipiliyoni socansi ne-7 d ubulili bezocansi ekuzinikeleni kokuncintisana kwe-Amph. Izidakamizwa ezitholakale ngokobulili Izilwane ze-JIN azizange zenze i-CPP ebalulekile ye-Amph futhi azifani nezilwane ezingenabulili izilwane ze-JUND (I-Fig. 3B). Ngokuphambene nalokho, izilwane zokulawulwa kwe-GFP ngokobulili zakha i-CPP ye-Amph njengoba kuboniswe ngamaphesenti aphezulu we-CPP uma kuqhathaniswa nokulawulwa kwe-GFP ngokobulili.I-Fig. 3B, p = 0.018).

Umfanekiso we-3.    

Ukuvimbela umsebenzi we-FosB ku-NAc uvinjelwe ukubuyiswa kwe-AMPH nokwandiswa kwenani lezinhlavu ze-NAc ezilwaneni ezihlangene ngokobulili. A, Izithombe ezimele ze-GFP ekuboniseni izilwane ezintathu ezithola umjovo we-adeno-ehlobene ne-viral-ΔJUND eqondiswe ku-nucleus accumbens, ebonisa amancane amasayithi amancane (kwesobunxele), aphakathi (aphakathi), namakhulu (kwesokudla). ac, ukukhishwa kwe-Anterior; I-LV, i-ventricle yangasese. Ibha yokulinganisa, i-250 μm. B, Umfanekiso wesimiso wezindawo ezivelele kakhulu namaphethini okusakazeka kwegciwane. Kuzo zonke izilwane, i-GFP itholakale kugobolondo, kodwa isakazeka kumgogodla wawuguqukile. C, Isikhathi esichithwa ekamelweni elihlangene le-Amph ngesikhathi sokuhlolwa kokuhlolwa ngaphandle kokulinganisa (amaphuzu we-CPP) wezilwane ezimhlophe ezingenayo ubulili kanye nezilwane (ezimnyama) ezitholwe umjovo we-GFP control vector (Naive, n = 9; Exp, n = 10) noma i-VectorJunD (i-Naive, i- n = 9; Exp, n = 9). D, Izithombe ezimele zamacandelo e-dendritic avela ku-GFP ocansini ngokobulili futhi i-JUND isetshenziselwa ukulinganisa ubukhulu bomgogodla. Ibha yokulinganisa, i-3 μm. E, Inani lezinhlamba ze-dendritic ku-NAc yezinhlamba zobungqingili (ezimhlophe) nezilwane ezinolwazi (ezimnyama) ezithola umjovo we-vector control GFP noma i-VIDJ vector. Idatha yiqembu elisho ± SEM. *p <0.05, umehluko omkhulu uma uqhathaniswa nezilawuli ezingenamqondo. #p <0.05, umehluko omkhulu kusuka kuzilawuli ezinolwazi ze-GFP.

Imiphumela yokuqeda ukukhukhumeza ngokweqile akuzange kube umphumela wokuphazanyiswa kokuziphatha ngokocansi ngesikhathi sokuthola isipiliyoni socansi. Ukubonakaliswa kwe-IJJD ku-NAc iye yaboniswa ngaphambilini ukuvimbela ukuziphatha kokuziphatha ngokocansi ngemuva kokuhlangenwe nakho kocansi (Pitchers et al., 2010b). Ngempela, lokhu kuqinisekisiwe ekuhlolweni kwamanje. Izilwane zokulawula ze-GFP zibonise ama-latencies amfushane ukufaka, ukungaxhunyiwe, nokukhishwa kwe-ejaculation, nezintaba ezimbalwa nokungeniswa phakathi nosuku lwesine olulandelanayo lokuhlolwa kokulinganisa, uma kuqhathaniswa nosuku lokuqala lokuqasha (Ithebula 1). Ngokuphambene nalokho, izilwane ezingenayo i-JUND azizange zibonise kakhulu izikhathi ezincane zokuvuthwa noma ukukhishwa kwezinhlamvu noma izinombolo ezincane zezintaba phakathi nosuku lwesine lokuqhathaniswa uma kuqhathaniswa neyokuqala. Ngakho-ke, ukuxhaswa kwe-NA ku-NAc kunqande imiphumela yezobulili. Kodwa-ke, kwakungekho ukungafani okuphawulekayo kunoma yimiphi imingcele yokulinganisa phakathi kokulawulwa kwe-GFP namaqembu a-JIND okwehlisiwe phakathi kwanoma yikuphi ukuhlolwa kokulingana, okubonisa ukuthi imiphumela ye-AUDs infusions ngokuzizwa kocansi-okubangelwa ukuzwela kwe-Amph CPP akuwona umphumela wokungafani Ukuhlangenwe nakho okuhlangene nge-se (Ithebula 1).

Buka leli tafula:     

Ithebula 1.    

Izilinganiso zokuziphatha ngokocansi ngesikhathi sokuthola ulwazi lwezocansi emaqenjini athola i-NAc infusions ye-GFP- noma i-ΔJunD-eveza izivunguvungu ezibangelwa amagciwanea

I-FosB ibalulekile ekukhuleni okwenziwe ngabafundi ngezocansi emahlathini we-NAc dendritic

Umsebenzi we-FosB nawo wawudingeka ukuba ukwanda komgogodla we-NAc neurons ngemuva kokuhlangenwe nakho kocansi kanye nokuhlukunyezwa kocansi lwe-7 d (I-Fig. 3C,D). Ukuhlaziywa kwesihluthulelo ku-NAc yezilwane ezichazwe ngenhla nge-CPP, i-ANOVA emibili yenza imiphumela ephawulekayo kokubili kwezocansi (F(1,34) = 31.768, p <0.001) kanye nokwelashwa kwe-vector virus (F(1,34) = 14.969, p = 0.001), kanye nokuxhumana (F(1,34) = 10.651, p = 0.005). Ngokuqondile, izilwane zokulawula ze-GFP zobulili zinezikhulu eziningi ze-NAc uma kuqhathaniswa nokulawulwa kwe-GFP ngokocansiI-Fig. 3D: p <0.001), eqinisekisa ukutholwa kwethu kwangaphambilini (Pitchers et al., 2010a). Ngokuphambene, izilwane ze-ΔJunD ezinolwazi lwezocansi zazingahlukile kakhulu emaqenjini ama-naJunD anobuhlakani, futhi zaziphansi kakhulu uma ziqhathaniswa nezilwane ezilawula ucansi nge-GFP (I-Fig. 3D: p <0.001). Ngakho-ke, ukubonakaliswa kwe-unJunD ku-NAc kuvimbele imiphumela yesipiliyoni socansi futhi kwavuza ukuzithiba ku-NAc spinogenesis.

Umphikisi we-D1R uvimbela ukuhlangenwe nakho kocansi-okubangelwa ukuguqulwa kwe-ΔFosB

Ukuze unqume ukuthi ukusebenza kwe-D1R noma i-D2R ku-NAc ngesikhathi sokuxubungela kuyadingeka ukukhishwa kwe-ΔFosB nokwehliswa kwe-Amph CPP, izilwane zithole izifo zendawo zengxabano ye-D1R noma i-D2R (noma i-saline) ku-NAc 15 min ngaphambi kwe-4 ngayinye amaseshini wokulandelana nsuku zonke. Okubaluleke kakhulu, noma i-D1R noma i-D2R engqubuzanayo ingenelela ekuqalweni okuthintekayo kwe-NA noma ukuveza ukuziphatha ngokobulili ngesikhathi sokuhlanganyela kokuhlangana (I-Fig. 4D-F). Ngokufanayo, Ukuphikisana ne-D1R noma i-D2R akuzange kuvimbele imiphumela eyakhayo yokuhlangenwe nakho kwezocansi ekuxhumaneni, njengoba wonke amaqembu akhombise ukulekelela kokuziphatha kobulili, okuboniswa ukulandelana okufutshane kwe-ejaculation ngosuku 4 kuqhathaniswa nosuku lwe-1 (I-Fig. 4F) (F(1,40) = 37.113, p <0.001; Sal, p = 0.004; I-D1R Ant, p = 0.007; I-D2R Ant, p <0.001).

Umfanekiso we-4.    

Ama-Dopamine receptor antagonists afakwe kwi-NAc awuzange athinte indlela yokuziphatha kwezocansi. Izingxenye ze-Coronal NAc (A, + 2.2; B, + 1.7; C, + 1.2 kusuka ku-bregma) ekhombisa ama-intra-NAc injection sites for zonke izilwane. Ama-cannulas ayengamazwe angaphandle kodwa amelelwe ngokubambisana ukuze kube lula ukuveza zonke izilwane (Naive-Sal, ezimhlophe, n = 7; Exp-Saline; mpunga omnyama, n = 9; I-Exp D1R Ant, i-gray gray, n = 9; I-exp D2R Ant, omnyama, n = 8). ac, ukukhishwa kwe-Anterior; I-LV, i-ventricle yamuva; I-CPu, i-caudate-putamen. Mount latency (D), i-latency latency (E), kanye ne-ejaculation latency (F) kuwo wonke amaqembu ahlangene ngokobulili (i-Saline, emhlophe; i-D1R Ant, imfucuza; i-D2R Ant, emnyama). Ukumelwa kwedatha kusho ± SEM. *p <0.05, umehluko omkhulu phakathi kosuku 1 nosuku 4 ekwelashweni.

Ukuhlaziywa kwenombolo yamaseli we-ΔFosB-IR kwi-NAc 7 d ngemuva kokufakwa kwe-NAc kokugcina nokungena kwesikhathi noma kokusingathwa kwembula umehluko obalulekile phakathi kwamaqembu kulawo magobolondo e-NAc (F(3,29) = 18.070, p <0.001) nengqikithi (F(3,29) = 10.017, p <0.001). Okokuqala, ulwazi lwezocansi kuzilawuli ezifakwe ngosawoti lubangele ukwanda okuphawulekayo kwe-ΔFosB ngokuqhathaniswa nezilawuli ezingenamqondo zocansi (I-Fig. 5A, igobolondo p <0.001; I-Fig. 5B: core, p <0.001), eqinisekisa imiphumela ngenhla. Ukuphikisana kwe-D1R, kepha hhayi i-D2R, kuvinjelwe noma kunciphise lokhu kukhushulwa kwe-ΔFosB. Egobolondeni le-NAc, umphikisi we-D1R waphatha abesilisa abanolwazi ngocansi akazange akhombise ukwanda kwamaseli e-ΔFosB-IR uma kuqhathaniswa nezilawuli ezingenangqondo zocansiI-Fig. 5A: p = 0.110), futhi i-ΔFosB inkulumo yayingaphansi kakhulu uma kuqhathaniswa nabesilisa abafana nocansi (I-Fig. 5A: p = 0.002). Esikhathini se-NAc, ukuphikisana kwe-D1R kunomphumela owodwa: ΔFosB yanda kakhulu kuma-D1R abesilisa abathintekayo abaqhathaniswa nokulawulwa kwe-saline naine (I-Fig. 5B: p = I-0.031), kodwa lokhu kuguqulwa kwakuphansi kakhulu uma kuqhathaniswa nabesilisa abathintekayo ngocansi (I-Fig. 5B: p = 0.012). Ukwelashwa kwe-D2R ukuphatha kabi akuzange kube nomthelela wokungeniswa kwe-ΔFosB njengoba abesilisa abanolwazi lwezocansi abathola i-D2R antagonist babenenombolo enkulu kakhulu yamaseli we-ΔFosB-IR uma kuqhathaniswa nezilawuli ze-saline ezine-naive (I-Fig. 5A: igobolondo, p <0.001; I-Fig. 5B: core, p <0.001) nabesilisa abaphathwe ngabaphikisi be-D1R (I-Fig. 5A: igobolondo, p <0.001; I-Fig. 5B: core, p = 0.013), futhi bekungehlukani nabesilisa abanolwazi lwe-saline.

Umfanekiso we-5.     

Umfanekiso we-5.     

Ukuvimba i-D1R kwi-NAc kukhombisa ukwanda kwenani lamaseli we-ΔFosB-IR kwi-NAc yezilwane ezinolwazi ngocansi. Ukushintshwa okumbalwa kwenombolo yamaseli we-ΔFosB-IR kwigobolondo le-NAc (A) nomongo (B) ezilwaneni ezitholakale ngokobulili (ezimnyama) uma kuqhathaniswa nokulawulwa kobulili (white) (Naive-Sal, n = 6; Exp-Saline, n = 7; I-Exp D1R Ant, n = 9; I-Exp D2R Ant, n = 8). Imininingwane yeqembu isho ± SEM. *p <0.05, umehluko omkhulu uma uqhathaniswa nezilawuli ezingenamqondo. #p <0.05, umehluko ophawulekayo uma uqhathaniswa nosawoti kanye nezilwane ezinolwazi lwe-D2R Ant. Ummeleli wezithombe zeNaive Sal (C), I-Exp Sal ​​(D), I-Exp D1R Ant (E), ne-Exp D2R Ant (F). ac, Isithasiselo se-Anterior. Ibha yesikali, i-100 μm.

Ukulawula ukusabalala okungahle kwenzeke kwabaphikisi be-D1R noma abaxhasi be-D2R ku-dorsal striatum, i-ΔFosB inkulumo yahlaziywa endaweni lapho ihlehla khona ku-NAc futhi ihambisana ne-ventricle yangasese, njengoba ukufakwa kwe-ΔFosB ku-dorsal striatum yi-psychostimulants nama-opiates kuncike ku-D1R umsebenzi (Zhang et al., 2002; U-Muller no-Unterwald, i-2005). Isipiliyoni sokuya ocansini sanda amanani we-ΔFosB-ir cell ku-dorsal striatum emadodeni abaphathwa ngosawoti (Naive-Sal: 35.6 ± 4.8 vs Exp-Sal: 82.9 ± 5.1; p <0.001), eqinisekisa umbiko wethu wangaphambilini (Pitchers et al., 2010b). Ngaphezu kwalokho, no-D1R noma umphikisi we-D2R abathintekayo ku-NAc isipiliyoni socansi esithintekile-kuqukethe i-ΔFosB ku-dorsal striatum (Exp-D1R: 82.75 ± 2.64 ir cells; Exp-D2R: 83.9 ± 4.4 ir cells; p <0.001 iqhathaniswa nezilawuli zeNaive-Sal). Lokhu okutholakele kusikisela ukuthi ukusakazeka kokungeniswa kwabaphikisi kwakukhawulelwe ikakhulukazi kwi-NAc.

Umphikisi we-D1R ku-NAc uvimba ukubuyekezwa kwe-Amph

I-D1R ivinjelwe ku-NAc ngenkathi kuqhathaniswa nokuvinjelwa kobulili-okukhushulwa okuthuthukisiwe kwe-Amph, kuhlolwa i-7 d ngemuva kokukhipha kokugcina kwe-NAc nokuhlolwa kokulinganisa (F(3,29) = 2.956, p = 0.049). Izilwane ezitholakale ngokocansi ezithola u-saline ku-NAc ngesikhathi sokuqhathanisa zasebenzisa isikhathi esiningi kakhulu ekamelweni elinama-Amph uma kuqhathaniswa namadoda angama-sex (I-Fig. 6A, p = 0.025), eqinisekisa imiphumela ngenhla. Ngokuphambene nalokho, izilwane ezitholakale ngokobulili ezithola umphikisi we-intra-NAc D1R ngesikhathi sokubambisana azange zenze i-CPP ye-Amph. Babengafani nokulawula ukuhlukunyezwa ngokobulili, futhi bachitha isikhathi esincane kakhulu ekamelweni elinama-Amph kuqhathaniswa ne-saline (I-Fig. 6A: p = 0.049) noma umphikisi we-D2R (I-Fig. 6A: p = I-0.038) igxile amadoda abesilisa ocansini. Ukuhlukunyezwa kwe-D2R akuzange kuthinte i-Amph yokukhuliswa okukhulunywe ngayo njengoba izilwane ezitholakale ngokobulili ezine-NAc D2R eziphikisanayo zenzeke i-Amph-CPP ephawulekayo ngokuqhathaniswa nokulawulwa kwe-saline naive (I-Fig. 6A: p = 0.040) no-D1R abaphikisanayo nezilwane (I-Fig. 6A: p = 0.038), futhi bekungehlukani nabesilisa abanolwazi lwe-saline.

Umfanekiso we-6.     

Umfanekiso we-6.     

Ukuvimbela ama-receptors e-D1 ku-NAc aqeda ukuvuselelwa kwe-Amph enomqondo okwandisa izimpande ze-dendritic ezilwaneni ezihlangene ngokobulili. A, Isikhathi esichithwa ekamelweni elihlangene le-Amph ngesikhathi sokuhlolwa kokuhlolwa ngaphandle kokulinganisa (amaphuzu we-CPP, imizuzwana) yezinkinga zokuziphatha ngokocansi (ezimhlophe, n = I-6) nezilwane ezinolwazi (abamnyama) abathola isiline (n = 7), umphikisi we-D1R (n = 9), noma umphikisi we-D2R (n = 8). Imininingwane yeqembu isho ± SEM. *p <0.05, umehluko ophawulekayo uma uqhathaniswa nezilawuli ezinosawoti ezingenamqondo. #p <0.05, umehluko ophawulekayo kusuka ezilwaneni ezinolwazi lwe-D1R Ant. B, Inani lezinhlamba ze-dendritic (nge-10 μm) ye-naive enobulili (ezimhlophe, n = I-7) nezilwane ezinolwazi (abamnyama) abathola isiline (n = 8), umphikisi we-D1R (n = 8), noma umphikisi we-D2R (n = 8). Imininingwane yeqembu isho ± SEM. *p <0.05, umehluko ophawulekayo uma uqhathaniswa nezilawuli ezinosawoti ezingenamqondo. #p <0.05, umehluko ophawulekayo kusuka ekulawulweni kasawoti onolwazi.

Ukwelashwa okuphikisanayo kwe-D1R kuvimbela isipiliyoni sobulili-kubangelwa i-NAc spinogenesis

Ukuhlaziywa komgogodla we-spine ku-NAc yalezi zilwane ezifanayo kubonise ukuthi ukuvuselelwa kwe-D1R ngesikhathi sokubuthana kwakudingeka ukunyuka kwesisindo somzimba we-NAc ngemuva kokuhlangenwe nakho kobulili kanye ne-7 d yokuzilahla kocansi (i-abstinence)I-Fig. 6B; F(3,26) = 41.558, p <0.001). Ngokuqondile, izilawuli zikasawoti ezinolwazi ngocansi kanye nezilwane eziphikisayo ze-D2R zazinenani elikhulu kakhulu lezinsipho uma kuqhathaniswa nokulawulwa kasawoti okungenamqondo ngokocansiI-Fig. 6B: p <0.001) eqinisekisa okutholakele kwethu kwangaphambilini (Pitchers et al., 2010a) nokuthola okutholakala ne-GFP yokulawula i-viral vectors echazwe ngenhla. Ngokuphambene nalokho, izidakamizwa ezithintekayo nge-D1R ezithintekayo ngokobulili azizange zihluke ekulawuleni izicathulo zobulili ezingenalo ubulili (I-Fig. 6B). Kube khona umphumela okhethekile we-D2R ukumelana nokuphikisana okuhambisana nomuntu njengoba i-D2R egxilise izilwane kubonisa ukucindezeleka komgogodla ophansi kakhulu kunokulawulwa kosawoti ocansini (I-Fig. 6B: p = 0.02), kodwa izinombolo eziphakeme kakhulu zezinhlayiya uma kuqhathaniswa nokulawulwa kosawoti ngokobulili kanye nabesilisa abathintekayo be-D1R (p <0.001; I-Fig. 6B). Ngakho-ke, i-D1R ivinjelwe ku-NAc ngenkathi ukuxubha kuvinjelwe imiphumela yezobulili kanye nokuzibamba ukuzithiba ku-NAc spinogenesis.

Ingxoxo

Esifundweni samanje, sibonise ukuzwelana phakathi kwemiphumela yemvelo nemithi, lapho umvuzo wemvelo ulandelwa yisikhathi sokuziyeka. Ngokuqondile, sibonise lolo phiko ngokuziphatha kobulili, kulandelwa i-7 noma i-28 d yokuzilahla, kubangela ukuvuselelwa kwe-Amph okuthuthukisiwe. Lezi zitholakele zifana nendima ebaluleke kakhulu yokuqeda izidakamizwa zokuhlukunyezwa ekukhulisweni kwezifiso ezidakamizwa (Lu et al., 2005; Thomas et al., 2008; I-Wolf, i-2010b, 2012; Xue et al., 2012). Ngaphezulu kwalokho, i-ΔFosB emkhatsini wemivuzo yemvelo ku-NAc ibaluleke kakhulu emiphumeleni ye-cross-sensitizing yemiphumela yemvelo yokuziyeka ekunikeni umvuzo we-psychostimulant, okungenzeka nge-spinogenesis ku-NAc phakathi nenkathi yokuzigwema. Sikhombise ukuthi ukuqoqwa kwe-ΔFosB ku-NAc ngemuva kokuhlangenwe nakho kocansi kuhlala isikhathi eside futhi kuncike emsebenzini we-NAc D1R ngesikhathi sokulingana. Futhi, lokhu kuguqulwa kwe-DFNUMXR e-DFNB e-NAc kuboniswe ukuthi kubaluleke kakhulu ekuvuseleleni umvuzo we-Amph nokwandisa ubukhulu bomgogodla ku-NAc, nakuba lezi ziphumo zobulili zixhomeke esikhathini sokuziqeda umvuzo wezocansi (Pitchers et al., 2010a). Okokugcina, sibonise ukuthi i-NAc spinogenesis ingabangela ekuthuthukiseni kokuqala kwesikhashana se-Amph ukukhuthazwa kodwa akuyona into ebalulekile ekukhulumeni okuqhubekayo komvuzo wokudakwa kwezidakamizwa, njengoba ukukhula komgogodla okwandisiwe ku-NAc kwakudlule futhi kugcinwa ngemuva kwe-7, kodwa hhayi i-28 d, isikhathi sokuziqeda.

Kuye kwaziwa isikhathi eside ukuthi i-dopamine ikhishwa ku-NAc ngesikhathi sokuziphatha komvuzo wemvelo, kuhlanganise nokuziphatha ngokocansi. Ngemuva kokwethulwa kwesifazane otholayo, i-extracellular dopamine ku-NAc yanda futhi ihlala iphakanyisiwe ngesikhathi sokubuthana (Fiorino et al., 1997). Ucwaningo lwamanje lubonise ukuthi ukufakaza abaphikisi be-dopamine e-NAc ngesikhathi sokuxubana akuzange kube nomthelela ekuqalisweni noma ekusebenzeni kokuziphatha ngokocansi, okuhambisana nomqondo wokuthi i-dopamine ayihileleki ekuboniseni umvuzo wokuziphatha nge-se, kepha kunalokho ukuze kube nomthelela wokugqugquzela izici ezihlobene nobulili (IBerridge noRobinson, i-1998). Ngempela, ukukhomba ukubikezelwa kobulili kubangelwa ukuvuselelwa kwe-neurons ngaphakathi kwesimiso somvuzo we-dopamine we-mesolimbic, kufaka phakathi amaseli we-dopaminergic endaweni ye-ventral ne-target yayo, i-NAc (I-Balfour et al., I-2004). Ukuziphatha okuphindaphindiwe ngokobulili kudonsa i-ΔFosB ku-NAc, ebuye ihlangane nokuqiniswa kokuziphatha kobuliliPitchers et al., 2010b). Imiphumela yamanje ibonisa ukuthi ukuguqulwa kwe-ΔFosB okwenziwe ukuxubanisa, ngokuqinisekile kuncike ekusebenzeni kwe-D1R ku-NAc ngenkathi kuqhathaniswa. Lokhu kutholwa kuyahambisana nezifundo zangaphambilini ezibonisa ukuthi ukuphathwa kwe-psychostimulant okuphindaphindiwe kwandiswe ngokuqhubekayo ΔFosB kuma-nec medium spiny neurons eveza i-D1R (U-Lee et al., 2006; Kim et al., 2009) nokuthi ukuguqulwa kwe-ΔFosB encike ekusebenziseni kwe-D1R (Zhang et al., 2002). Ngaphezu kwalokho, izimpendulo ezidakamizwa zezidakamizwa, ezivame ukubonwa esilwaneni esibhekene nezidakamizwa, zingenziwa ngaphandle kokutholakala kwezidakamizwa ngaphambi kokudlulela ngokweqile kwe-ΔFosB ku-D1R eveza i-neurons e-striatum (Kelz et al., 1999). TI-FosB ku-NAc nge-D1R encike ekusebenzeni ukuvuselela ukuziphatha komvuzo.

Ngaphezu kwalokho, ukutholakala kwamanje kubonisa ukuthi i-ΔFosB ingumlamuleli obaluleke kakhulu we-cross-sensitization phakathi kokuhlangenwe nakho kwemvelo nomvuzo we-psychostimulant. Njengoba kuphawuliwe, imisebenzi ye-FosB e-NAc iye yafakwa ngaphambili ekuphenduleni izidakamizwa ezithandwayo, njengoba i-ΔFosB ngokucacile ku-NAc yenza inqubo yokusebenzisa i-cocaine isebenze ngemuva kokuphatha okusheshayo noma okuphindaphindiwe (Kelz et al., 1999), kwandisa ubuzwe be-cocaine ne-morphine CPP (Kelz et al., 1999; UZachariou et al., 2006), futhi kubangele ukuphathwa kwezinga eliphansi le-cocaine (I-Colby et al., I-2003). Ucwaningo lwamanje lubonisa ukuthi ukuvimbela umsebenzi we-D1R noma i-ΔFosB ku-NAc ngenkathi kuqhathaniswa nokuqeda ukuhlukunyezwa kwesimo socansi-okubangelwa ukuvuselelwa kwe-Amph.

Ucwaningo lwamanje lubonise ukuthi isikhathi sokuziqeda kusuka kumvuzo wesondo kuyadingeka ukuze kuqinisekiswe u-Amph ukuvuza kanye ne-NAc spinogenesis. Sifisa ukuthi i-ΔFosB ngalesi sikhathi sokuziqeda sithinta umsebenzi we-neuronal ngokushintsha umqondo wezakhi zofuzo ukuze uqale i-spinogenesis futhi ushintshe amandla ase-synaptic. Ngempela, ukuvimbela ukungeniswa kwe-ΔFosB ku-NAc ngenkathi kuqhathaniswa nokuvinjelwa kuvinjelwe ukwanda kwesibindi somzimba ku-NAc esitholakale ngemuva kokuyeka ukuziphindisela. Ngaphezu kwalokho, ukungeniswa komphikisi we-D1R ku-NAc ngaphambi kweseshini ngasinye sokubambisana kuvimbele ukukhushulwa kwesipiliyoni socansi ku-ΔFosB kanye nokwanda kwesibindi somzimba.

I-ΔFosB iyinhlangano ye-transcription engenza njengomsunguli we-transcriptional noma ukucindezela ukuthonya inkulumo yezinhlobonhlobo zezakhi zofuzo ezingase zibe nomthelela ekutheni ubukhulu bomzimba nobukhulu be-synaptic ku-NAc (I-Nestler, i-2008). Ngokuqondile, I-FosB isebenzisa i-kinase-5 encike emhlane (Bibb et al., 2001; Kumar et al., 2005), isisombuluzi κ B (NF-κB) (Russo et al., 2009b), kanye nengxenye ye-GluA2 ye-glutamate AMPA receptor (I-Vialou et al., 2010) futhi rihlose ukubhaliselwa kwe-gene esheshayo c-fos (Pitchers et al., 2010b) futhi i-histone methyltransferase i-G9 (Maze et al., 2010). Ci-kinc-dependent kinase-i-5 ilawula amaprotheni we-cytoskeletal kanye ne-neurite outgrowth (U-Taylor et al., I-2007). Ngaphezu kwalokho, ukuvuselela i-NF-κB kwandisa inani lezinhlavu ze-dendritic ku-NAc, kanti ukuvinjelwa kwe-NF-κB kunciphise izimpande ze-dendritic ezisemngceleni futhi kuvimbela ukukhushulwa kwe-cocaine emithonjeni (Russo et al., 2009b). Ngakho-ke, umvuzo wezocansi ukwandisa i -ΔFosB ku-NAc, engase ishintshe i-NAc spine wiziningi ngamakhamera amaningi (ie, kinclic-dependent kinase-5, NF-κB) nokuthi umphumela jikelele ngumvuzo wokudakwa wezidakamizwa, njengoba kwadalwa Russo et al. (2009a) ngezenzo ze-cocaine ephindaphindiwe.

Ukuqashelwa obekulindelekile ocwaningweni lwamanje ukuthi ukwanda kokuqina komgogodla ku-NAc kwakudlula isikhashana, futhi kungasatholakali ku-28 d ngemuva kokuhlangenwe nakho kwezocansi. Ngakho-ke, ukuqina komgogodla okwandisiwe kwahlanganiswa nokuqala komvuzo we-Amph othuthukisiwe futhi kungaba nomthelela ekukhuleni kokuqala noma ukubizelwa kwezimpendulo zesikhashana ze-Amph. Kodwa-ke, ukwanda kokuqina komgogodla bekungadingeki ekuqhubekeleni phambili komvuzo we-Amph ngemuva kokuchitha isikhathi eside. Sike sabonisa ngaphambili ukuthi ulwazi lwezocansi lubangela isikhathi esifushane (i-7, kepha hhayi i-28, izinsuku ngemuva kokuganana kokugcina) ukwanda kwe-NMDA receptor subunit NR-1 ku-NAc, ebuyela kumazinga okuqala ngemuva kwezikhathi ezinde zokukhishwa komvuzo (Pitchers et al., 2012). Lokhu kwanda ukukhulumisana kwe-NMDA yokutholwa kwakunenkolelo yokukhombisa ukuthi ucansi lwama-synapses alungele ukuthula (I-Huang et al., 2009; Brown et al., 2011; Pitchers et al., 2012), futhi kuphakamisa ukuthi kungenzeka ukuthi ubulili-obangele ukukhula komgogodla kuxhomeke kumsebenzi we-NMDA wokwamukelwa (U-Hamilton et al., 2012).

Ekuphetheni, isifundo samanje sikhombisa ukukhuthazwa kwemithi yezidakamizwa ngomvuzo wemvelo (ubulili) nokuxhomekeka kwayo ngesikhathi sokuziphindisela. Ngaphezu kwalokho, le plastiki yezokuziphatha yayiphambene ne-ΔFosB nge-activation ye-D1R ku-NAc. Ngakho-ke, idatha ibonisa ukuthi ukulahlekelwa komvuzo wemvelo emva kokuhlangenwe nakho kokuvuza kungenza abantu babe nobungozi ekuthuthukiseni ukulutha izidakamizwa nokuthi lowo mlamuleli oyedwa wezokukhushulwa kakhudlwana yi-ΔFosB kanye nezinhloso zayo ezingezansi zokubhala.

Imibhalo yaphansi

  • Itholwe ngo-Okthoba 16, i-2012.
  • Ukubuyekeza okutholiwe ngo-December 12, 2012.
  • Yamukelwe ngo-December 23, i-2012.

  • Lo msebenzi wawusekelwa yi-Institutes of Health Research (LMC) yaseCanada, i-National Institute of Mental Health (EJN), ne-Natural Sciences kanye ne-Engineering Research Council yaseCanada (iKKP neLMC). Siyabonga uDkt. Catherine Woolley (eNyakatho-ntshonalanga Yunivesithi) ukusizwa nge-diOlistic yezokwelapha.

  • Abalobi basho ukuthi akukho okuthintana nezimali.

  • Ukuxhumana kufanele kudluliselwe kuDkt. Lique M. Coolen, uMnyango wePhysical and Biophysics, Isikhungo sezokwelapha saseYunivesithi saseMississippi, i-2500 North State Street, i-Jackson, i-MS 39216. [i-imeyili ivikelwe]

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Izihloko ezikhuluma ngalesi sihloko

  • Iminikelo engenzeka yenqubo yombhalo we-plastic synaptic e-Aplysia ukuvuza, ukukhumbula, kanye nezidakamizwa zabo ebuchosheni bamaMammalian Ukufunda nokukhumbula, ngomhlaka 18 Septhemba 2013, 20 (10): 580-591

ISIFUNDO ESIPHELELE - ISIGABA SOKUXOXA:

Ocwaningweni lwamanje, sikhombise ukuzwela phakathi komvuzo wemvelo nowezidakamizwa, lapho umvuzo wemvelo ulandelwa isikhathi sokuyeka. Ngokuqondile, sakhombisa ukuthi okuhlangenwe nakho ngokuziphatha kobulili, okulandelwa yi-7 noma i-28 d yokuziyeka, kubangela ukuxhaswa komvuzo we-Amph.

Lokhu okutholakele kunokufana neqhaza elibalulekile lesikhathi sokungazidli izidakamizwa zokuhlukumeza ekufakweni kokufiswa yizidakamizwa (Lu et al., 2005; Thomas et al., 2008; Wolf, 2010b, 2012; Xue et al., 2012). Ngaphezu kwalokho, oklonyeliswa ngomvuzo wemvelo? I-FosB ku-NAc ibaluleke kakhulu ekuthambekiseni imiphumela yemvelo yokuvinjwa komvuzo wemvelo kumvuzo we-psychostimulant, ngokunokwenzeka nge-spinogenesis ku-NAc ngesikhathi sokuvinjezelwa komvuzo.

Sikhombisile lokho? Ukuqongelela i-FosB ku-NAc ngemuva kokuhlangenwe nakho kocansi kuhlala isikhathi eside futhi kuncike emsebenzini we-NAc D1R ngesikhathi sokukhula. Futhi, le D1R-mediated? Ukuqanjwa kabusha kwe-FosB ku-NAc kuboniswe njengokubalulekile kumvuzo othuthukisiwe we-Amph futhi kwandise nokuxinana komgogodla ku-NAc, noma ngabe le miphumela yesipiliyoni sokuya ocansini incike esikhathini sokuziyeka emvuzweni wezocansi (ama-Pitchers et al., 2010a). Ekugcineni, sikhombisile ukuthi i-NAc spinogenesis ingahle ifake isandla ekuthuthukisweni kokuqala kokubekezela okufushane komvuzo we-Amph kodwa akubucayi ukuthi inkulumo eqhubekayo yokuthola umvuzo wezidakamizwa ithuthukisiwe, njengoba ukukhuphuka kokuqina komgogodla ku-NAc kwakuhamba kancane futhi kwaqapheleka ngemuva kwe-7 d, kepha hhayi i-28 d, isikhathi sokukhipha.

Kudala kwaziwa ukuthi i-dopamine ikhishwa kwi-NAc ngesikhathi sokuziphatha kwemivuzo yemvelo, kubandakanya nokuziphatha kocansi. Lapho kwethulwa insikazi etholayo, i-dopamine ye-extracellular ku-NAc iyanda futhi ihlala iphakanyisiwe ngesikhathi sokuzalela komzimba (i-Fiorino et al., 1997). Ucwaningo lwamanje lubonise ukuthi ukufakaza abaphikisi be-dopamine e-NAc ngesikhathi sokuxubana akuzange kube nomthelela ekuqalisweni noma ekusebenzeni kokuziphatha ngokocansi, okuhambisana nomqondo wokuthi i-dopamine ayihileleki ekuboniseni umvuzo wokuziphatha nge-se, kepha kunalokho ukuze kube nomthelela wokugqugquzela izici ezihlobene nobulili (IBerridge neRobinson, 1998). Ngempela, izintambo ezibikezela ngomvuzo wezocansi zibangela kusebenze ama-neurons ngaphakathi kohlelo lomvuzo we-mesolimbic dopamine, kufaka phakathi amaseli we-dopaminergic endaweni ye-ventral tegmental kanye nesitshe sabo, i-NAc (Balfour et al., 2004).

Ukuzibandakanya ocansini okuphindaphindwayo kuyayifinyelela? I-FosB ku-NAc, yona futhi eqondisa ukuqiniswa okwenziwe yisifiso sokuziphatha kocansi (Pitbers et al., 2010b). Imiphumela yamanje ikhombisa ukuthi ukukhuthaza ukukhula kwe-matos? Ukufakwa phansi kwe-FosB ngempela, kuxhomeke ekusebenzeni kwe-D1R ku-NAc ngesikhathi sokuzala. Lokhu okutholakele kuyahambisana nezifundo ezedlule okubonisa ukuthi ukuphathwa kwe-psychostimulant okuphindaphindayo kuye kwanda njalo? I-FosB ku-NAc medium spiny neurons eveza i-D1R (U-Lee et al., 2006; uKim et al., 2009) nokuthi lokho? Ukubhalwa kwe-FosB kuncike esenzweni se-D1R (Zhang et al., 2002). Ngaphezu kwalokho, izimpendulo zezidakamizwa ezifakwayo, ezijwayele ukubonwa esilwaneni esinolwazi ngezidakamizwa, zingakhiqizwa lapho kungekho khona ukudalulwa kwezidakamizwa kwangaphambili yi-overexpression ye? FosB ku-D1R eveza ama-neurons ku-striatum (Kelz et al., 1999). Ngakho-ke, imivuzo yemvelo nezidakamizwa iyakhuphuka? I-FosB ku-NAc ngokusebenzisa inqubo exhomeke ku-D1R ukuthola amakhono yokuziphatha.

Ngaphezu kwalokho, okutholakele njengamanje kukhombisa ukuthi? I-FosB ngumlamuleli obucayi we-sensitization yesiphambano phakathi kokuhlangenwe nakho komvuzo wemvelo kanye nomvuzo we-psychostimulant. Njengoba kuphawuliwe, umsebenzi we-FosB ku-NAc phambilini ubukade uthinteka ezimpendweni zezidakamizwa eziqondakalayo, njengoba? Ukuqothulwa kwe-FosB ku-NAc kuthola ukwenziwa kwe-locomotor ku-cocaine ngemuva kokuphatha okubi kakhulu noma okuphindaphindwe njalo (uKelz et al., 1999), kwandisa ukuzwela ku-cocaine kanye ne-morphine CPP (uKelz et al., 1999; Zachariou et al., 2006), futhi kubangela ukuzilawula kwemithamo ephansi ye-cocaine (Colby et al., 2003). Ucwaningo lwamanje lukhombisa lokho blockade of D1R or? FosB umsebenzi in the NAc ngesikhathi sokuqeda inkanuko yezocansi okuqediwe komvuzo we-Amph. TI-hus, imivuzo yemvelo nezidakamizwa ayihlanganisi kuphela emzileni ofanayo we-neural, ihlangana nabalamuli bemilingo efanayo (UNestler et al., 2001; Wallace et al., 2008; Hedges et al., 2009; Pitchers et al., 2010b), futhi mhlawumbe e-neurons efanayo ku-NAc (Frohmader et al., 2010b), ukuthonya isisenge sokukhuthaza kanye “nokufuna” kwazo zombili izinhlobo zemivuzo (IBerridge neRobinson, 1998).

Ucwaningo lwamanje lukhombisa ukuthi isikhathi sokukhipha emvuzweni wobulili siyadingeka ekuzwisiseni umvuzo we-Amph ne-NAc spinogeneis. Sifaka i-hypothesize lokho? I-FosB ngalesi sikhathi sokuphuza umzimba ithinta ukusebenza kwe-neuronal ngokuguqula ukubonakaliswa kofuzo kokwehla komzimba ukuqala i-spinogenesis namandla e-alter synaptic. Impela, Ukuvimbela ukungena kwe-FosB ku-NAc ngesikhathi sokutshala kuvimbele ukwanda kokuxinana komgogodla ku-NAc etholakele ngemuva kokukhishwa kwemivuzo. Ngaphezu kwalokho, iukunqunyelwa komphikisi we-D1R kwi-NAc ngaphambi kweseshini ngayinye yokuqhathanisa kuvimbele ukwanda okubangelwa ubulili? I-FosB kanye nokuqina okwandayo komgogodla. I-FosB iyisici sokubhaliwe esingasebenza njenge-activator transrital noma i-repressor ukuthonya ukubonakaliswa kwezinhlobo eziningi zezakhi zelitshe ezingaphenduka zibe nomthelela ekuqineni komgogodla nokuqina kwe-synaptic ku-NAc (Nestler, 2008). Ngokucacile,? I-FosB isebenza nge-cyclic-based kinase-5 (Bibb et al., 2001; Kumar et al., 2005), factor yenuzi? B (NF-? B) (URusso et al., 2009b), kanye ne-GluA2 subunit ye-glutamate AMPA receptor (Vialou et al., 2010) iphinde icindezele okubhaliwe kohlobo lwangempela lwensalela c-fos (Pitchers et al., I-2010b) ne-histone methyltransferase G9 (Maze et al., 2010). I-cyclicdependent kinase-5 ilawula amaprotheni we-cytoskeletal kanye nokuphuma kwe-neurite (Taylor et al., 2007). Ngaphezu kwalokho, ukusebenza kwe-NF-? B kukhuphula inani le-dendritic spines ku-NAc, kanti ukuvimbela kwe-NF-? B kunciphise imisebe eyisisekelo ye-basal dendritic futhi kuvimbe ukwanda okubangelwa yi-cocaine (i-Russo et al., 2009b). Ngakho-ke, umvuzo wezocansi uyakhuphuka? I-FosB ku-NAc, engahle iguqule ukuqina komgogodla we-NAc ngokusebenzisa imigomo eminingi (ie, i-cyclic-wate kinase-5, NF-? B) aNgiyaqonda ukuthi imiphumela iyonke izuzwe umvuzo wezidakamizwa, njengoba kwaqhathaniswa noRusso et al. (2009a) ngezenzo ze-cocaine eziphindaphindwayo

Ukuqashelwa obekulindelekile ocwaningweni lwamanje ukuthi ukwanda kokuqina komgogodla ku-NAc kwakudlula isikhashana, futhi kungasatholakali ku-28 d ngemuva kokuhlangenwe nakho kwezocansi. Ngakho-ke, ukuqina komgogodla okwandisiwe kwahlanganiswa nokuqala komvuzo we-Amph othuthukisiwe futhi kungaba nomthelela ekukhuleni kokuqala noma ukubizelwa kwezimpendulo zesikhashana ze-Amph. Noma kunjalo, iUkuxineka komgogodla okuhlanganisiwe kwakungadingeki ekuqhubekeni komvuzo we-Amph ozwelayo ngemuva kwezikhathi zokuvalwa isikhathi eside. Sike sabonisa ngaphambili ukuthi ulwazi lwezocansi lubangela isikhathi esifushane (i-7, kepha hhayi i-28, izinsuku ngemuva kokuganana kokugcina) ukwanda kwe-NMDA receptor subunit NR-1 ku-NAc, ebuyela kumazinga okuqala ngemuva kwezikhathi ezinde zokukhishwa komvuzo (Pitchers et al., 2012). Le nkulumo eyandayo ye-receptor ye-NMDA yaconjululwa ukuthi ibe yinkomba yama-synapses ocansini atholwe ocansini (uHuang et al., 2009; uBrown et al., 2011; uPitchers et al., 2012), futhi ebonisa ukuthi kungenzeka ucansi luvuseleleke ukukhula komgogodla kuncike emsebenzini othuthukisiwe we-NMDA receptor (Hamilton et al., 2012).

Ekuphetheni, ucwaningo olukhona manje luqokomisa ukuhlukaniswa ngokweqile komvuzo wezidakamizwa ngomvuzo wemvelo (ubulili) kanye nokuncika kwayo esikhathini sokuvinjezelwa komvuzo. Ngaphezu kwalokho, lokhu kuziphatha okuhlelekile kuqondwe yi-FosB nge-D1R activation ku-NAc. Ngakho-ke, imininingwane iphakamisa ukuthi ukulahleka komvuzo wemvelo ngemuva kokuhlangenwe nakho komvuzo kungenza abantu abathile babe sengozini yokuthuthukisa umlutha wezidakamizwa nokuthi umlamuleli oyedwa walokhu kuba sengozini okungaphezulu? I-FosB nezinjongo zayo zokuloba eziphansi.