I-DeltaFosB: Ukushintshwa kwamangqamuzana omlutha wokulutha (2001)

IMIBUZO: Njengoba izifundo zakamuva zizokwembula iDeltaFosB ingukushintsha okuvamile kwamangqamuzana kokubili ukulutha kwezidakamizwa nokuziphatha. Kuyinto yokubhala okusho ukuthi kuthinta ukuthi yiziphi izakhi zofuzo ezivuliwe noma ezivaliwe. Njengoba kushiwo kwenye indawo, izidakamizwa eziluthayo ziduna kuphela izindlela ezijwayelekile. Kungakho kuwubuwula ukuphakamisa ukuthi ukulutha kokuziphatha akunakubakhona.

 ISIHLOKO ESIFUNDWAYO

Proc Natl Acad Sci US A. 2001 September 25; 98 (20): 11042-11046.

i-doi: 10.1073 / pnas.191352698.

U-Eric J. Nestler *, uMichel Barrot noDavid W. Self

Umnyango Wezokwelapha Nezikhungo Ze-Basic Neuroscience, iNyuvesi yaseTexas Southwestern Medical Center, i-5323 Harry Hines Boulevard, i-Dallas, i-TX 75390-9070

abstract

Ukuphila kwesikhathi eside kokuziphatha okungajwayelekile okubonisa ukulutha kwezidakamizwa kuye kwaphakamisa ukuthi ukulawulwa kwe-genetic neural gene expression kungabandakanyeka enkambisweni lapho izidakamizwa zokuhlukumeza zidala isimo sokulutha. IUbufakazi obungaqapheli bubonisa ukuthi isici sokubhalisa ΔFosB simelela indlela eyodwa izidakamizwa zokuhlukunyezwa ezikhiqiza izinguquko ezinjengezobuchopho ezithintekayo ekuqotheni izidakamizwa. ΔI-FosB, ilungu lomndeni wakwaFos wezici zokubhalisa, iqoqa ngaphakathi kwe-neurons ye-nucleus accumbens ne-dorsal striatum (izizinda zobuchopho ezibalulekile ukulutha) emva kokuphathwa okuphindaphindiwe kwezinhlobo eziningi zezidakamizwa zokuhlukunyezwa. Ukuqoqwa okufanayo kwe-ΔFosB kwenzeka ngemuva kokusebenza ngokucindezela, okubonisa ukuthi i-ΔFosB ingase iqoqe ngokuphendula izinhlobo eziningi zokuziphatha okuphoqelelwe. Okubaluleke kakhulu, i-ΔFosB iphikelela ama-neurons isikhathi eside kakhulu ngenxa yokuzinza okungavamile. Ngakho-ke, i-ΔFosB imelela indlela yamangqamuzana engase iqalise futhi ishintshe izinguquko ezenzweni zegeni eziphikelela isikhathi eside emva kokutholakala kwezidakamizwa kuphelile. Ucwaningo olwenziwe ngamagundane angama-transgenic okungaziwa ukuthi i-ΔFosB noma i-inhibitor enamandla kakhulu yeprotheyini inikeza ubufakazi obuqondile bokuthi i-APF ibangela ukuzwela okukhulu emiphumeleni yokuziphatha kwezidakamizwa zokuhlukunyezwa futhi, mhlawumbe, ukwandisa ukuziphatha kwezidakamizwa. Lo msebenzi usekela umbono wokuthi i-ΔFosB isebenza njengohlobo oluthile lwe-"switch molecule" olwenza kancane kancane izimpendulo ezidakayo zezidakamizwa zibe yizimo ezizimele ezinomthelela ekubambeni kwe-plastic neural and behavioral plasticity.

Ukucwaninga umlutha kugxile ekuqondeni izindlela eziyinkimbinkimbi lapho izidakamizwa zokuhlukumeza ziguqula ubuchopho ukuze kubangele ukukhubazeka okuziphatha okubonisa ukulimala. Enye yezinselelo ezibucayi emkhakheni ukukhomba izinguquko ezinjengezidakamizwa ezizinzile ezibuchosheni ukuze zilandele lezo zimo ezingavamile ezihlala isikhathi eside. Isibonelo, umlutha womuntu kungenzeka ube engozini enkulu yokubuyela emuva ngisho nangemva kweminyaka yokuziyeka.

Ukuzinza kwalezi zimo ezingalungile kuholele ekusikiseni ukuthi bangaphikisana, okungenani ngeyingxenye, ngokusebenzisa izinguquko zesitatimende sezakhi (1-3). Ngokwale mbono, ukuvezwa ngokuphindaphindiwe kwesidakamizwa sokuhlukunyezwa ngokuphindaphindiwe kuphazamisa ukudluliselwa kwamanye ama-syapses ngokukhethekile ebuchosheni obuthinta izidakamizwa. Ukuphazanyiswa okunjalo kugcina kusakaze ngesithunywa se-intracellular esiya endaweni ye-nucleus, lapho kuqala khona bese igcina izinguquko ekukhulumeni kwezakhi zofuzo ezithile. Inqubo eyinhloko lapho izindlela zokudluliswa kwesignali zithinta ukukhuluma kwegenesini kungukulawulwa kwezici zokubhalisa, amaprotheni ahlanganisa izifunda ezilawulayo zezakhi zofuzo futhi aguqule ukubhaliselwa kwawo.

Ngakho-ke, umgomo owodwa wokucwaninga izidakamizwa kuye kwaba ukukhomba izici zokubhalisa eziguqulwa ezindaweni ezibucayi ezibhekiswe ekulutha umlutha emva kokuphathwa okungapheli kwezidakamizwa zokuhlukunyezwa. Kunezici eziningana zokubhalisa ezitholakale kule minyaka eyishumi edlule (1-6). Ukugxila kwalokhu kubuyekezwa kungokwenyama eyodwa ye-transcription factor ebizwa ngokuthi i-ΔFosB.

Ukukhipha i-ΔFosB ngeDrugs of Abuse

I-ΔFosB, ekhonjiswe ifuzo le-fosB, ilungu lomndeni wakwaFos wezici zokubhalisa, ezihlanganisa c-Fos, FosB, Fra1, neFra2 (7). Lezi zeprotheni zomndeni ze-Fos i-heterodimerize nama-protein womndeni wakwaJun (c-Jun, JunB, noma i-JunD) ukwenza ama-AP-1 asebenzayo (izici ze-activator-1) ezithintekayo ezibophezela kumasayithi we-AP-1 (ukulandelana kokuvumelana: TGAC / GTCA). abagqugquzeli bezakhi ezithile zofuzo ukulawula ukubhalwa kwabo.

Lawa maprotheni omndeni wakwaFos ahanjiswa ngokushesha futhi ngokuhamba kwesikhathi ezindaweni ezithile zobuchopho ngemva kokuphathwa kabi kwezidakamizwa eziningi zokuhlukunyezwa (Fig. 1) (8-11). Izifunda ezisemqoka yi-nucleus accumbens ne-dorsal striatum, okubalulekile abaxhumanisi bezimpendulo zokuziphatha ezidakamizwa, ikakhulukazi, imiphumela yabo evuzayo neyakhayo (12, 13). Lawa maprotheni abuyela emazingeni aphansi ngaphansi kwamahora okuphatha izidakamizwa.

 

 

Umfanekiso we-1

I-Scheme ibonisa ukuqongelela kancane kancane kwe-ΔFosB ngokuhambisana nokukhishwa okusheshayo nokuhamba kwesikhathi kwamanye amaprotheni omndeni we-Fos ekuphenduleni izidakamizwa zokuhlukunyezwa. (A) I-autoradiogram ibonisa ukuhlukaniswa okuhlukile kwamaprotheni ahlukahlukene ngokuvuselela okunamandla (i-1-2 hr ngemuva kokutholakala kwezidakamizwa ezilodwa) uma kuqhathaniswa nokugqugquzela okungapheli (usuku lwe-1 ngemva kokuchayeka kwezidakamizwa eziphindaphindiwe). (B) Amaza amaningi amaphrotheni afana ne-Fos (ahlanganisa i-c-Fos (52- kuya kwe-58-kDa isoforms), i-FosB (46- i-50-kDa isoforms), i-FosB (33-kDa isoform), ne-Fra1 noma i-Fra2 ( I-40 kDa)] ifakwe ngaphakathi kwe-nucleus accumbens kanye ne-neorons ehlaselwa yilapho ephethe ukuphathwa kabi kwezidakamizwa zokuhlukunyezwa. Futhi kukhishwe ama-isoforms aguquguqukayo we-ΔFosB (35-37 kDa); nazo, zishintshwa (nangamazinga aphansi) emva kokulawulwa kwezidakamizwa ezimbi, kodwa ziphikelela ebuchosheni isikhathi eside ngenxa yokuzinza kwazo. (C) Ngokuphindaphindiwe (isib., Kabili nsuku zonke) ukuphathwa kwezidakamizwa, ukugqugquzela izidakamizwa ngamunye kudala izinga eliphansi le-ΔFosB isoforms, eliboniswa yi-ephansi elinezingcingo ezithintekayo ezibonisa i-DFF ebangelwa ukugqugquzela ngamunye. Umphumela ukunyuka kancane kancane emazingeni ephelele e-ΔFosB ngokucindezela okuphindaphindiwe phakathi nenkambo yokwelashwa okungapheli, okuboniswa umzila owandayo owegrafu.

Izimpendulo ezihluke kakhulu ziyabonakala emva kokuphathwa okungapheli kwezidakamizwa zokuhlukumeza (Fig. 1). I-isoforms eguquguqukayo ye-biochemically ye-ΔFosB (inqwaba yamangqamuzana i-35-37 kDa) iqoqa ezindaweni ezifanayo zobuchopho ngemva kokudonswa kwezidakamizwa eziphindaphindiwe, kanti zonke ezinye amalungu omndeni wakwaFos zibonisa ukubekezelelana (okungukuthi, ukuncishiswa okunciphisiswe uma kuqhathaniswa nokutholakala kwezidakamizwa zokuqala). Ukuqoqwa okunjalo kwe-ΔFosB kuye kwatholakala i-cocaine, i-morphine, i-amphetamine, i-alcohol, i-nicotine, ne-phencyclidine (11, 14-18). Kunobunye ubufakazi bokuthi lokhu kuhlanganiswa kukhetha i-dynorphin / i-substance engaphansi kwe-P-container ye-neuron ephakathi ephakathi kwezizinda zobuchopho (15, 17), nakuba kuningi okudingekayo ukuze kuqinisekiswe lokhu. I-35- kuya kwe-37-kDa isoforms ye-ΔFosB inciphisa kakhulu i-JunD ukwakha inhlanganisela esebenzayo nehlala njalo e-AP-1 ngaphakathi kwezizinda zobuchopho (19, 20). Lezi zici ze-DFFB zibuthelela ukutholakala kwezidakamizwa ezingapheli ngenxa yempilo yabo engapheli isikhathi eside (21), ngakho-ke ziphikelela emasontweni okungenani amasonto ambalwa emva kokuphela kokuphathwa kwezidakamizwa. Kuyathakazelisa ukuphawula ukuthi lezi zingu-ΔFosB isoforms ziyimikhiqizo eqinile kakhulu ye-gene yangaphambili (fosB). Ukuzinza kwe-ΔFosB isoforms kunikeza inqubo ye-molecular inoveli lapho izinguquko ezibangelwa izidakamizwa ezitshengweni zezinhlayiyana zingaphikelela naphezu kwezikhathi ezide zokuhoxiswa kwezidakamizwa.

Nakuba i-nucleus accumbens idlala indima ebalulekile emiphumeleni emihle yezidakamizwa zokuhlukunyezwa, kucatshangwa ukuthi isebenza ngendlela evamile ngokulawula izimpendulo kubantu abaqinisa imvelo, njengokudla, isiphuzo, ucansi, nokuxhumana kwabantu (12, 13). Ngenxa yalokho, kunesithakazelo esikhulu kunendima engenzeka yalesi sifunda sobuchopho kwezinye izimo zokucindezela (isib. Ukudla ngokweqile, ukugembula, ukuzivocavoca, njll). Ngenxa yalesi sizathu, sihlolisise ukuthi i-ΔFosB ilawulwa yini kwisimo sezilwane sokusebenza ngokucindezela. Ngempela, i-35- kuya kwe-37-kDa isoforms ehleliwe ye-ΔFosB ihanjiswa ngokukhetha ngaphakathi kwe-nucleus accumbens kuma-rats abonisa ukuziphatha okucindezelayo.

Ubunikazi be-Biochemical of Stable ΔFosB Isoforms

Njengoba kushiwo ngenhla, i-ΔFosB isoforms eqoqa emva kokuphathwa okungapheli kwesidakamizwa sokuhlukunyezwa noma ukusebenza ngokucindezela kubonisa inqwaba yamangqamuzana e-35-37 kDa. Zingahlukaniswa kusukela ku-33-kDa isoform ye-ΔFosB ekhishwa ngokushesha kodwa ngemva kokudonswa kwezidakamizwa (Fig. 1) (14, 19, 22). Ubufakazi bamanje bubonisa ukuthi i-33-kDa isoform yiyona uhlobo lwendabuko lweprotheyini, elushintshwayo ukuze lenze izinto eziqinile kakhulu ze-35- kwe-37-kDa imikhiqizo (19, 21). Kodwa-ke, uhlobo lokuguqulwa kwezinto eziphilayo eziguqula i-33-kDa isoform engazinzile ngaphakathi kwe-35- kuya kwe-37-kDa isoforms iye yahlala ingacacile. Kuye kwacatshangwa ukuthi i-phosphorylation ingaba necala (11). Isibonelo, ukungeniswa kwe-ΔFosB kunqanyuliwe ezinkambeni ezingenayo i-DARPP-32, iphrotheni ehlotshisiwe yokubulala (23, 24). Ngenxa yokuthi i-DARPP-32 ilawula umsebenzi we-protein phosphatase-1 ne-protein kinase A (i-25, i-26), imfuneko yale phrotheni yokuqoqwa okujwayelekile kwe-ΔFosB isoforms ibonisa ukuthi kungenzeka ukuthi i-phosphorylation ikwazi ukukhiqiza imikhiqizo emihle.

Indima ye-ΔFosB kuPulasitiki Yokuziphatha kuya Kwezidakamizwa Zokuhlukunyezwa

Ukuqonda ukuthi indima ye-ΔFosB yokulutha izidakamizwa ivela ngokuyinhloko ekutadisheni kwamagundane e-transgenic lapho i-ΔFosB ingenziwa khona ngokukhetha ngaphakathi kwe-nucleus accumbens nezinye izifunda ezibulalayo zezilwane ezikhulile (27, 28). Okubaluleke kakhulu, lezi zinhlanzi ziyi-ΔFosB ngokukhethayo kwi-dynorphin / substance ene-spin neurons ephakathi, lapho izidakamizwa zikholelwa ukuthi zenza iphrotheni. I-phenotype yokuziphatha yama-ΔFosB-overexpressing namiceba, ngezindlela eziningi afana nezilwane emva kokutholakala kwezidakamizwa ezingapheli, kufingqiwe kuThebula 1. Amagundane abonisa izimpendulo ezithengiswayo ezithandwa yi-cocaine ngemuva kokuphathwa okunamandla nokungahleliwe (i-28). Baphinde babonise ukuzwela okuthuthukisiwe kwimiphumela emihle ye-cocaine ne-morphine ezindaweni zokubeka isimo (i-11, i-28) futhi iyozilawula ngokulingana kwama-cocaine kunezintambo ezingenayo i-cocaine ΔFosB. ‡ Ngokuphambene, lezi zilwane zikhombisa ukuhleleka okujwayelekile ukuzwela i-cocaine nokufunda okujwayelekile endaweni yangasese ye-Morris (28). Tidatha ye-hese ikhombisa ukuthi i-ΔFosB yandisa ukuzwela kwesilwane kwi-cocaine futhi mhlawumbe nezinye izidakamizwa zokuhlukumeza futhi ingamela indlela yokuzwela isikhathi eside emithini.

Ithebula 1
I-plasticity yokuziphatha ehlangene ne-ΔFosB ku-nucleus accumbens-dorsalstriatum

 

Ukuvuselelwa kwe-locomotor eyengeziwe ekuphenduleni ukuphathwa okunamandla nokuphindaphindiwe kwe-cocaine.
Ukwandisa izimpendulo ezivuzayo ku-cocaine ne-morphine ezindaweni zokubeka isimo sokuhlala.
Ukuzimela ngokwengeziwe kwemithi ephansi ye-cocaine.
Isisusa esikhulu sokwenza i-cocaine ekuhloleni kokulinganisa isilinganiso.
Izimpendulo ze-anxiolytic ezanda kakhulu.
Ukwandiswa kokuziphatha okuphoqelelwe kokusebenza.

Ngokusekelwe kwedatha ngokucutshungulwa. 28 futhi 29.‡ ‡ §¶

 

I-plasticity yokuziphatha ehlangene ne-ΔFosB ku-nucleus accumbens-dorsal striatum

In Ngaphezu kwalokho, kukhona ubufakazi bokuqala bokuthi imiphumela ye-ΔFosB ingadlulisa ngaphezu komthethonqubo wokuzwela kwezidakamizwa ngesinye sezimo eziyinkimbinkimbi ezihlobene nenqubo yokulutha. Amagundane eveza i-ΔFosB isebenza kanzima ekuziphatheni okwenziwe yi-cocaine ekuzilandeni kwe-self self-administration,ukugcizelela ukuthi i-ΔFosB ingase ivuselele izilwane ekukhuthazeni izakhiwo zokugqugquzela i-cocaine futhi ngaleyo ndlela ziholele ekutheni zibuyele ngemuva kokuhoxiswa kwezidakamizwaI-‡ ΔFosB-amagundane avelayo akhombisa futhi imiphumela ephezulu yokukhathazeka yotshwala, § i-phenotype ehlotshaniswa nokwandiswa kotshwala kubantu. Ngokubambisana, lezi zithole zakuqala ziphakamisa ukuthi i-ΔFosB, ngaphezu kokwandisa ukuzwela kwezidakamizwa zokuhlukunyezwa, iveza izinguquko ezihambisana nokuziphatha okukhuthaza ukuziphatha kwezidakamizwa. Ngakho-ke, i-ΔFosB ingasebenza njenge-"switch switch" eqhubekayo esiza ukuqala bese igcina izici ezibalulekile zombuso onomlutha. Umbuzo obalulekile ngaphansi kokuphenywa kwamanje kungakhathaliseki ukuthi ukuqoqwa kwe-FosB ngesikhathi sokudakwa kwezidakamizwa kukhuthaza ukuziphatha kwezidakamizwa emva kokukhipha isikhathi eside, ngisho nangemva kokuthi ama-FFBB ajwayelekile (bheka ngezansi).

Adult amagundane okwenza i-ΔFosB ngokweqile ngaphakathi kwe-nucleus accumbens ne-dorsal striatum ibonisa nokusebenza okukhulu okuqhathaniswa nokuqhathaniswa nokulawulwa kwezilwanyana. † Lezi ziphakamiso ziphakamisa ukuthi kungenzeka ukuthi i-ΔFosB yokuqoqa ngaphakathi kwalezi zinezi zenza indima ejwayelekile ekubunjweni nasekugcinweni kwemikhumbuzo yokukhubazeka nokucindezela ukuziphatha, mhlawumbe ngokuqinisa ukusebenza kwama-neural circuits lapho lezo zinzwa zisebenza khona.

I-ΔFosB iqoqa ezindaweni ezithile zobuchopho ngaphandle kwe-nucleus accumbens ne-dorsal striatum emva kokuvezwa okungavamile ku-cocaine. Okuvelele phakathi kwalezi izifunda yi-amygdala ne-prefrontal cortex (I-15). Umgomo omkhulu wocwaningo lwamanje ukuqonda iminikelo ye-ΔFosB ukukhishwa kulezi zifunda kuze kube yi-phenotype yomlutha.

Umsebenzi wangaphambilini wamagundane we-fosB knockout uveze ukuthi lezi zilwane zehluleka ukuthuthukisa ukuzwela emiphumeleni ye-cocaine, ehambelana nokutholakele kwamagundane e-ΔFosB-overexpressing okukhulunywe ngenhla (22). Kodwa-ke, izinguquko ze-fosB zikhombise ukuzwela okuthuthukile emiphumeleni emibi ye-cocaine, engahambisani nalokhu okunye okutholakele. Ukuhunyushwa kokutholakele ngezinguquko ze-fosB, noma kunjalo, kuyinkimbinkimbi yokuthi lezi zilwane aziswele i-ΔFosB kuphela, kepha ne-FosB ephelele. Ngaphezu kwalokho, izakhi eziguqukayo zintula amaprotheni womabili ebuchosheni nasezigabeni zokuqala zentuthuko. Ngempela, umsebenzi wakamuva usekela iziphetho ezivela kumagundane e-ΔFosB overexpressing: i-overexpression engachazeki yesigungu esincishisiwe se-c-Jun, esisebenza njengomphikisi ophikisayo omkhulu we-ΔFosB, ngokukhetha kuma-nucleus accumbens nase-dorsal striatum kukhombisa ukuzwela okunciphile kwimiphumela yomvuzo we-cocaine Lokhu okutholakele kugcizelela isexwayiso okufanele sisetshenziswe ekuhumusheni imiphumela evela kumagundane ngokushintshwa okuguqukayo futhi kukhombisa ukubaluleka kwamagundane ngokushintshwa okungaqondakali nohlobo lweseli ezifundweni zepulasitiki ebuchosheni obudala.

Izibalo ezibhekiswe ku-ΔFosB

Ngoba i-ΔFosB iyinhlangano ye-transcription factor, kungenzeka ukuthi amaprotheni abangela ipulasitiki yokuziphatha ngokuguqulwa kwegama lamanye amagciwane. I-FosB ikhiqizwa ngenye indlela yokwehliswa kwegosheni ye-fosB futhi ayinakho ingxenye yesizinda se-C-terminalization transactivation esivela ku-FosB ubude obude. Ngenxa yalokho, ekuqaleni kuhlongozwa ukuthi i-ΔFosB isebenza njengomcindezeli we-transcriptional (29). Kodwa-ke, ukusebenza esitokisini samasiko kuye kwabonisa ngokucacile ukuthi ΔI-FosB kungaba ukudubula noma ukucindezela Ukukhishwa kwe-AP-1-okwenziwe ngokuvumelana nendawo ethile ye-AP-1 esetshenzisiwe (21, 29-31). I-FosB yobude obugcwele inemiphumela efanayo ne-ΔFosB kwezinye izingcezu zokugqugquzela, kodwa imiphumela ehlukile kwabanye. Kudingeka umsebenzi oqhubekayo ukuze uqonde izindlela ezisezenzweni ezihlukahlukene ze-ΔFosB ne-FosB.

Iqembu lethu lisebenzise izindlela ezimbili ukukhomba izakhi zofuzo eziqondiwe ze-ΔFosB. Enye indlela yesakhi sofuzo. Siqale sabheka i-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors njengezinjongo ezibekiwe, ezinikezwe indima ebalulekile yokudluliswa kwe-glutamatergic kuma-nucleus accumbens. Ukusebenza kuze kube yimanje kukhombisile ukuthi i-AMPA glutamate receptor subunit ethile, i-GluR2, ingaba yinhloso eyi-ΔFosB (I-Fig. 2). Isisho se-GluR2, kepha hhayi ukubonakaliswa kwamanye ama-receptor we-AMPA, siyakhuphuka kuma-nucleus accumbens (kepha hhayi i-dorsal striatum) ekuchazeni ngokweqile kwe-ΔFosB (28), kanye nokuvezwa kwesidalwa esibi esibi esinciphisa ikhono le-cocaine lokuheha iphrotheni. Ngaphezu kwalokho, umgqugquzeli wohlobo lweGluR2 uqukethe isiza sokuvumelana se-AP-1 esibopha i-ΔFosB (28). Ukuchazwa ngokweqile kwe-GluR2 kuma-nucleus accumbens, ngokusetshenziswa kokudluliswa kofuzo okuxhumene negciwane, kukhulisa ukuzwela kwesilwane emiphumeleni ezuzisayo ye-cocaine, ngaleyo ndlela kulingise ingxenye ye-phenotype ebonwe kumagundane aveza i-ΔFosB (28). Ukungeniswa kwe-GluR2 kungabangela ukuzwela kwe-electrophysiological kwe-nucleus accumbens neurons kuma-AMPA receptor agonists ngemuva kokuphathwa okungapheli kwe-cocaine (32), ngoba izamukeli ze-AMPA eziqukethe i-GluR2 zibonisa ukwehla kokuziphatha okuphelele futhi kwehlise amandla e-Ca2 +. Ukuphendula okwehlisiwe kwala ma-neuron kokufaka okujabulisayo kungahle kuthuthukise izimpendulo kumuthi wokuhlukumeza. Kodwa-ke, izindlela lapho amasiginali we-dopaminergic ne-glutamatergic kuma-nucleus accumbens alawula khona ukuziphatha okuluthayo ahlala engaziwa; lokhu kuzodinga izinga lokuqonda le-neural, elingakatholakali.

 Umfanekiso we-2

I-AMPA glutamate receptor subunit, i-GluR2, ilitshe lokubeka i-ΔFosB. Kubonisiwe ukuthi ukwenziwa kwe-luFosB-Mediated kwe-GluR2 kungakuguqula kanjani ukuphendula komzimba we-nucleus accumbens neurons futhi kuholele ekuphenduleni okushukumisayo kuzidakamizwa zokuhlukumeza. Ngokusho kwalolu hlelo, izidakamizwa zokuhlukumeza zikhiqiza imiphumela yazo yokuqinisa enamandla ngokuvimbela i-nucleus accumbens neurons. Ngokuvezwa okuphindaphindiwe, izidakamizwa zenza i-ΔFosB, elawula izakhi zofuzo eziningi ezihlosiwe, kufaka phakathi iGluR2. Lokhu kukhulisa inani lama-receptors e-AMPA (AMPA-R) kuma-nucleus accumbens neurons aqukethe i-GluR2 subunit, edala ukwehla kwamanje kwe-AMPA yamanje futhi yehlise i-Ca2 + yamanje. Lokhu kunciphisa ukuthokozisa kungenza ama-neurons azwele kakhulu emiphumeleni emibi yokuvimbela izidakamizwa futhi ngaleyo ndlela kwimiphumela yokuqinisa yezidakamizwa.

Esinye isici sokubeka i-ΔFosB yi-geni encoding dynorphin. Njengoba kushiwo ngaphambili, i-dynorphin iboniswa ku-subset ye-nucleus accumbens e-spin ne-spin medium ekhombisa ukungeniswa kwe-ΔFosB. I-Dynorphin ibonakala isebenza ku-loop-feedback loop: ukukhululwa kwayo kuvimbela i-neurons e-dopaminergic engavumelani ne-neurons ephakathi, nge-receptors ye-opioid ekhona kuma-dopaminergic nerve terminals in the nucleus accumbens kanye nasemzimbeni wesiguli kanye nama-dendrites endaweni ye-ventral tegmental (I-Fig. 3) (33-35). Lo mbono uhambelana nekhono le-κ receptor agonist, ekuphathweni kwesinye salezi zifunda ezimbili zobuchopho, ukunciphisa izidakamizwa ze-drug reward (i-35).

RUmsebenzi we-ecent uye wabonisa ukuthi i-ΔFosB inciphisa ukubonakaliswa kwe-dynorphin, "okungabangela ekuthuthukiseni izindlela zokubukwa ezibonwe nge-DFFB. Ngokuthakazelisayo, esinye isici sokubhalisa izidakamizwa, i-CREB (isakhi sempendulo ye -AMP ebopha amaprotheni) (i-2, i-3), inomphumela ohlukile: ithobisa ukuboniswa kwe-dynorphin ku-nucleus accumbens futhi kunciphisa izindawo ezivuza ze-cocaine ne-morphine (4). **

BUkuvuselelwa okubangelwa izidakamizwa kwe-CREB kuhlakazeka ngokushesha ngemva kokuphathwa kwezidakamizwa, umyalo owenziwe ngokuphindaphindiwe we-dynorphin yi-CREB no-ΔFosB kungachaza ukushintsha kokuziphatha okuqhubekayo okwenzeka ngesikhathi sokuqala nokuphumula kokumiswa, izimpawu ezingezansi zomzwelo nokunciphisa ukuzwela kwezidakamizwa kubangelwa izigaba zakuqala ukuhoxiswa, nokugqugquzela ukuvuza nokuvuselela imiphumela yokugqugquzela yezidakamizwa ezithathwa esikhathini esizayo.

 

 

Umfanekiso we-3

 I-Dynorphin iyinhloso yokubeka i-ΔFosB. Kuboniswe indawo ye-ventral tegmental (VTA) i-dopamine (DA) ye-neuron engayisebenzisi isigaba se-nucleus accumbens (NAc) ye-GABAergic eyenziwe nge-neuron eveza i-dynorphin (DYN). I-Dynorphin isebenzisa indlela yokuphendula kulolu daba: i-dynorphin, ekhishwe kuma-terminals we-NAc neurons, yenza ama-receptors e-opioid asezindaweni zamagciwane nezinzwa zamagciwane e-DA ukuvimbela ukusebenza kwazo. ΔI-FosB, ngokuvimbela ukuboniswa kwe-dynorphin, kungase kube phansi-lawula le loop yombiko futhi kuthuthukiswe izindawo ezivuzayo zezidakamizwa zokuhlukunyezwa. Akuboniswa ukuthi umphumela we-CREB wamukelwa ngalesi simiso: i-CREB ikhulisa ukukhuluma kwe-dynorphin futhi ngaleyo ndlela inqanda izindawo ezivuzayo zezidakamizwa zokuhlukunyezwa (I-4). I-GABA, i-γ-aminobutyric acid; I-DR, i-dopamine receptor; NOMA, i-opioid receptor.

Indlela yesibili esetshenzisiwe ukukhomba izakhi zofuzo eziqondiwe ze-osBFosB ifaka ukuhlaziywa kwe-DNA microarray. Ukuchazwa ngokweqile kwe-ΔFosB kukhuphula noma kunciphise ukubonakaliswa kwezakhi zofuzo eziningi kuma-nucleus accumbens (36). Yize umsebenzi obalulekile manje usudingeka ukuqinisekisa ngasinye salezi zakhi zofuzo njengezinjongo ze-physiologic ze-osBFosB nokuqonda umnikelo wazo ku-phenotype yokulutha, enye inhloso ebalulekile ibonakala njenge-Cdk5 (cyclin-dependent kinase-5). Ngakho-ke, i-Cdk5 yaqale yahlonzwa njenge-ΔFosB-ilawulwa ukusetshenziswa kwama-microarrays, futhi kamuva yaboniswa ukuthi ifakwe ku-nucleus accumbens nase-dorsal striatum ngemuva kokuphathwa okungapheli kwe-cocaine (37). I-osBFosB yenza kusebenze isakhi se-cdk5 ngesiza se-AP-1 esikhona kumgqugquzeli wesakhi (36). Ngokubambisana, le mininingwane isekela uhlelo lapho i-cocaine idala ukubonakaliswa kwe-Cdk5 kulezi zifunda zobuchopho nge-ΔFosB. Ukungeniswa kwe-Cdk5 kubonakala kuguqula ukusayina kwe-dopaminergic okungenani ngokwengxenye nge-phosphorylation eyandisiwe ye-DARPP-32 (37), eguqulwa isibe i-inhibitor ye-protein phosphatase-1 iye ku-inhibitor ye-protein kinase A phezu kwe-phosphorylation yayo yi-Cdk5 (26).

Indima ye-ΔFosB ekuxhumaniseni i-Plasticity "Engunaphakade" ezidakamizwa zokuhlukunyezwa

Nakuba isibonakaliso se-ΔFosB sihlala isikhathi eside, akusiyo unomphela. I-FosB ihlaziya kancane kancane futhi ayisakwazi ukutholakala ebuchosheni ngemva kwezinyanga ezingu-1-2 zokuhoxiswa kwezidakamizwa, yize ezinye izinto ezingajwayelekile ziqhubeka isikhathi eside. Ngakho-ke, i-DFFB ngayinye ayengeke ibonakale ikwazi ukuxhumanisa lezi zimo ezingavamile zokuziphatha. Ukubunzima ekutholeni izimo ezinomzimba ezithinta ukuguquguquka okunamandla kakhulu okuhambisana nokulutha umlutha kufana nezinselele ezibhekene nensimu yokufunda nenkumbulo. Nakuba kunezinhlobonhlobo zezinhlobonhlobo zezinhlobonhlobo zamaselula nokufunda, akukaze kube khona isikhathi sokuthi zikwazi ukujwayela ukuvumelanisa nezimo zamangqamuzana namaselula ezihlala isikhathi eside ukuze zilandele izinkumbulo ezizinzile zokuziphatha. Ngempela, i-ΔFosB iyindlela ehlala isikhathi eside eyaziwa ukuthi yenzeke ebuchosheni obudala, hhayi kuphela ekuphenduleni izidakamizwa zokuhlukunyezwa, kepha nakunoma ikuphi ukuphazamiseka (lokho akubandakanyi izilonda) futhi. Iziphakamiso ezimbili zivele, zombili emkhakheni wokulutha kanye nowokufunda nowenkumbulo, ukuphendula ngalokhu kungahambelani.

Esinye kungenzeka ukuthi izinguquko zesikhashana ezenzakalweni zezakhi zofuzo, njengalezo ezihanjiswa nge-ΔFosB noma ezinye izici zokubhala (isb., I-CREB), ingase ixoxisane nezinguquko ezinde isikhathi eside ku-neuronal morphology kanye nesakhiwo se-synaptic. Ngokwesibonelo, ukwanda kobukhulu bezinhlamba ze-dendritic (ikakhulukazi ukwanda kwezinsipho ezinhlokweni ezimbili) kuhambisana nalokhu ukuphumelela okukhulu kwe-synapses ye-glutamatergic kuma-neurons we-hippocampal pyramidal ngesikhathi eside (38-40), futhi kufana nokuzwela kokuziphatha okuthuthukisiwe ku-cocaine ehlangene ezingeni le-neurons eliphakathi okuphakathi kwe-nucleus accumbens (41). Ayaziwa ukuthi ngabe lezo zinguquko zesakhiwo zihlala isikhathi eside yini ukuze zilandele izinguquko ezizinzile ekuziphatheni, nakuba lokhu kuqhubeka okungenani inyanga ye-1 yokuhoxiswa kwezidakamizwa. Ubufakazi bamuva buphakamisa ukuthi kungenzeka ukuthi i-ΔFosB, kanye nokufakwa kwayo kwe-Cdk5, ingumlamuleli wezinguquko ezibangelwa izidakamizwa esakhiweni se-synaptic ku-nucleus accumbens (Fig. 4). ‡ Ngakho, ukumnika kwe-Cdk5 inhibitor ku-nucleus accumbens kuvimbela ikhono lokuchayeka kwe-cocaine ngokuphindaphindiwe ukwandisa ubukhulu bomgogodla we-dendritic kule ndawo. Lokhu kuvumelana nombono wokuthi i-Cdk5, eyithuthukisiwe ebuchosheni, ilawula isakhiwo se-neural nokukhula (bheka ukucatshangelwa kwe-36 ne-37). Kungenzeka, nakuba kungenakuphikiswa, ukuthi izinguquko ezinjalo kwi-neuronal morphology zingase zivele uphawu lwe-ΔFosB ngokwazo.

 Umfanekiso we-4

Ukulawulwa kwesakhiwo se-dendritic ngezidakamizwa zokuhlukumeza. Kuboniswe ukunwetshwa kwesihlahla se-neuron's dendritic ngemuva kokuchayeka okungapheli emthini wokuhlukumeza, njengoba kubonwe nge-cocaine kuma-nucleus accumbens nase-prefrontal cortex (41). Izindawo zokukhulisa zikhombisa ukwanda kwezinsipho zomzimba ezihlonyelwe ukuthi zenzeke ngokubambisana namatheminali ezinzwa asebenzayo. Lokhu kukhuphuka kokuqina komgogodla we-dendritic kungahle kulamulelwe nge-ΔFosB kanye nokungeniswa okulandelayo kweCdk5 (bona umbhalo). Ushintsho olunjalo esakhiweni se-dendritic, olufana nalolo olubonwe kwamanye amamodeli wokufunda (isib. [Kukhiqizwe kabusha ngemvume evela ku-Ref. 3 (Copyright 2001, Macmillian Magazines Ltd.)].

Okunye okungenzeka ukuthi ukufakwa kwesikhashana kwesici sokubhala (isib., ΔFosB, CREB) kuholele ekushintsheni okuqhubekayo kwesiginja sezakhi ngokusebenzisa ukuguqulwa kwe-chromatin. Lezi zici nezinye eziningi zokubhaliselwa zikholelwa ukuthi zisebenze noma zicindezele ukubhaliselwa kwegciwane lesisulu ngokugqugquzela i-acetylation noma i-deacetylation, ngokulandelana, ye-histones eduze kwegesi (i-42). Nakuba i-acetylation enjalo kanye ne-deacetylation ye-histones kungenzeka ngokusobala kwenzeka ngokushesha kakhulu, kungenzeka ukuthi i-ΔFosB noma i-CREB ingase ikhiqize ukulungiswa okuhlala isikhathi eside emishinini ye-enzymatic elawula i-histone acetylation. I-ΔFosB noma i-CREB ingase iphinde ikhuthaze izinguquko ezihlala isikhathi eside ekukhulumeni kwezakhi zofuzo ngokulawula ezinye izinguquko ze-chromatin (isib. I-DNA noma i-histone methylation) eziye zathinteka ekushintsheni okungapheli kokubhaliswa kofuzo okwenzeka ngesikhathi sokuthuthukiswa (bheka i-42 ne-43) . Yize lezi zindlela zihlala zicatshangelwa, zinganikeza indlela okujwayele ukuzivumelanisa ngayo nezidakamizwa zokuhlukunyezwa (noma ezinye iziphazamiso) ziholela emiphumeleni yokuziphatha yokuphila.

Okubhekwayo

  1. ↵
    1. Nestler EJ,
    2. Ithemba BT,
    3. Widnell KL

(1993) I-Neuron 11: 995-1006.

I-CrossRefI-Medlinekuwebhu weSayensi

  1. ↵
    1. Berke JD,
    2. Hyman SE

(2000) I-Neuron 25: 515-532.

I-CrossRefI-Medlinekuwebhu weSayensi

  1. ↵
    1. I-Nestler EJ

(2001) Nat Rev Neurosci 2: 119-128.

I-CrossRefI-Medlinekuwebhu weSayensi

  1. ↵
    1. UCarlezon WA Jr,
    2. Thome J,
    3. Olson VG,
    4. I-Lane-Ladd SB,
    5. Brodkin ES,
    6. Hiroi N,
    7. Duman RS,
    8. I-Neve RL,
    9. I-Nestler EJ

(1998) Isayensi 282: 2272-2275.

Abstract / Umbhalo ogcwele FREE

    1. U-O'Donovan KJ,
    2. I-Tourtellotte WG,
    3. I-Millbrandt J,
    4. I-Baraban JM

(1999) Amathrendi Neurosci 22: 167-173.

I-CrossRefI-MedlineIwebhu yeSayensi

  1. ↵
    1. UMackler SA,
    2. Korutla L,
    3. Cha XY,
    4. Koebbe MJ,
    5. I-Fournier KM,
    6. Bowers MS,
    7. I-Kalivas PW

(2000) J Neurosci 20: 6210-6217.

Abstract / Umbhalo ogcwele FREE

  1. ↵
    1. Morgan JI,
    2. I-Curran T

(1995) Amathrendi Neurosci 18: 66-67.

I-CrossRefI-MedlineIwebhu yeSayensi

  1. ↵
    1. I-ST encane,
    2. Porrino LJ,
    3. Iadarola MJ

(1991) Proc Natl Acad Sci USA 88: 1291-1295.

Abstract / Umbhalo ogcwele FREE

    1. Greybiel AM,
    2. Moratalla R,
    3. I-Robertson HA

(1990) Proc Natl Acad Sci USA 87: 6912-6916.

Abstract / Umbhalo ogcwele FREE

    1. Ithemba B,
    2. Kosofsky B,
    3. Hyman SE,
    4. I-Nestler EJ

(1992) Proc Natl Acad Sci USA 89: 5764-5768.

Abstract / Umbhalo ogcwele FREE

  1. ↵
    1. Kelz MB,
    2. I-Nestler EJ

(2000) I-Curr Opin Neurol 13: 715-720.

I-CrossRefI-Medlinekuwebhu weSayensi

  1. ↵
    1. I-Koob GF,
    2. Sanna PP,
    3. Bloom FE

(1998) I-Neuron 21: 467-476.

I-CrossRefI-Medlinekuwebhu weSayensi

  1. ↵
    1. I-RA ehlakaniphile

(1998) Ukudakwa Kokudakwa Kokudakwa 51: 13-22.

I-CrossRefI-Medlinekuwebhu weSayensi

  1. ↵
    1. Ithemba BT,
    2. Nye HE,
    3. Kelz MB,
    4. Self DW,
    5. Iadarola MJ,
    6. Nakabeppu Y,
    7. Duman RS,
    8. I-Nestler EJ

(1994) I-Neuron 13: 1235-1244.

I-CrossRefI-MedlineIwebhu yeSayensi

  1. ↵
    1. Nye H,
    2. Ithemba BT,
    3. UK Kelz M,
    4. Ngalokho M M,
    5. I-Nestler EJ

(1995) J Pharmacol Exp Ther 275: 1671-1680.

Abstract / Umbhalo ogcwele FREE

    1. Nye HE,
    2. I-Nestler EJ

(1996) I-Mol Pharmacol 49: 636-645.

abstract

  1. ↵
    1. Moratalla R,
    2. Elibol B,
    3. UVallejo M,
    4. I-Graybiel AM

(1996) I-Neuron 17: 147-156.

I-CrossRefI-Medlinekuwebhu weSayensi

  1. ↵
    1. Khetha i-EM,
    2. Pagliusi SR,
    3. Tessari M,
    4. I-Talabot-Ayer D,
    5. Hooft van Huijsduijnen R,
    6. Chiamulera C

(1997) Isayensi 275: 83-86.

Abstract / Umbhalo ogcwele FREE

  1. ↵
    1. Chen JS,
    2. Nye HE,
    3. Kelz MB,
    4. Hiroi N,
    5. Nakabeppu Y,
    6. Ithemba BT,
    7. I-Nestler EJ

(1995) I-Mol Pharmacol 48: 880-889.

abstract

  1. ↵
    1. Hiroi N,
    2. Brown J,
    3. Ye H,
    4. Saudou F,
    5. Vaidya VA,
    6. Duman RS,
    7. Greenberg ME,
    8. I-Nestler EJ

(1998) J Neurosci 18: 6952-6962.

Abstract / Umbhalo ogcwele FREE

  1. ↵
    1. Chen J,
    2. Kelz MB,
    3. Ithemba BT,
    4. Nakabeppu Y,
    5. I-Nestler EJ

(1997) J Neurosci 17: 4933-4941.

Abstract / Umbhalo ogcwele FREE

  1. ↵
    1. Hiroi N,
    2. Brown J,
    3. Haile C,
    4. Ye H,
    5. Greenberg ME,
    6. I-Nestler EJ

(1997) Proc Natl Acad Sci USA 94: 10397-10402.

Abstract / Umbhalo ogcwele FREE

  1. ↵
    1. Fienberg AA,
    2. Hiroi N,
    3. Mermelstein P,
    4. I-Song WJ,
    5. Snyder GL,
    6. Nishi A,
    7. I-Cheramy A,
    8. U-O'Callaghan JP,
    9. Miller D,
    10. Cole DG,
    11. et al.

(1998) Isayensi 281: 838-842.

Abstract / Umbhalo ogcwele FREE

  1. ↵
    1. Hiroi N,
    2. Feinberg A,
    3. Haile C,
    4. Greengard P,
    5. I-Nestler EJ

(1999) Eur J Neurosci 11: 1114-1118.

I-CrossRefI-Medlinekuwebhu weSayensi

  1. ↵
    1. Greengard P,
    2. U-Allen PB,
    3. I-Nairn AC

(1999) I-Neuron 23: 435-447.

I-CrossRefI-Medlinekuwebhu weSayensi

  1. ↵
    1. Bibb JA,
    2. Snyder GL,
    3. Nishi A,
    4. Yan Z,
    5. Meijer L,
    6. Fienberg AA,
    7. Tsai LH,
    8. Kwon YT,
    9. I-Girault JA,
    10. I-Czernik AJ,
    11. et al.

(1999) Imvelo (eLondon) 402: 669-671.

I-CrossRefI-Medline

  1. ↵
    1. Chen JS,
    2. Kelz MB,
    3. I-Zeng GQ,
    4. Sakai N,
    5. USteffen C,
    6. Shockett PE,
    7. Picciotto M,
    8. Duman RS,
    9. I-Nestler EJ

(1998) I-Mol Pharmacol 54: 495-503.

Abstract / Umbhalo ogcwele FREE

  1. ↵
    1. Kelz MB,
    2. Chen JS,
    3. UCarlezon WA,
    4. Whisler K,
    5. Gilden L,
    6. Beckmann AM,
    7. USteffen C,
    8. Zhang YJ,
    9. Marotti L,
    10. Self SW,
    11. et al.

(1999) Imvelo (eLondon) 401: 272-276.

I-CrossRefI-Medline

  1. ↵
    1. Dobrazanski P,
    2. Noguchi T,
    3. Kovary K,
    4. Rizzo CA,
    5. Lazo PS,
    6. I-Bravo R

(1991) I-Mol Cell Biol 11: 5470-5478.

Abstract / Umbhalo ogcwele FREE

    1. Nakabeppu Y,
    2. Nathans D

(1991) I-Cell 64: 751-759.

I-CrossRefI-Medlinekuwebhu weSayensi

  1. ↵
    1. Yen J,
    2. Ukuhlakanipha RM,
    3. U-Tratner Mina,
    4. I-Verma IM

(1991) Proc Natl Acad Sci USA 88: 5077-5081.

Abstract / Umbhalo ogcwele FREE

  1. ↵
    1. I-White FJ,
    2. I-Hu XT,
    3. Zhang XF,
    4. Wolf ME

(1995) J Pharmacol Exp Ther 273: 445-454.

Abstract / Umbhalo ogcwele FREE

  1. ↵
    1. Hyman SE

(1996) I-Neuron 16: 901-904.

I-CrossRefI-MedlineIwebhu yeSayensi

    1. I-Kreek MJ

(1997) I-Pharmacol Biochem Behav 57: 551-569.

I-CrossRefI-Medlinekuwebhu weSayensi

  1. ↵
    1. Shippenberg TS,
    2. Rea W

(1997) I-Pharmacol Biochem Behav 57: 449-455.

I-CrossRefI-Medlinekuwebhu weSayensi

  1. ↵
    1. Chen JS,
    2. Zhang YJ,
    3. Kelz MB,
    4. USteffen C,
    5. Ang ES,
    6. I-Zeng L,
    7. I-Nestler EJ

(2000) J Neurosci 20: 8965-8971.

Abstract / Umbhalo ogcwele FREE

  1. ↵
    1. Bibb JA,
    2. Chen JS,
    3. Taylor JR,
    4. Svenningsson P,
    5. Nishi A,
    6. Snyder GL,
    7. Yan Z,
    8. I-Sagawa ZK,
    9. I-Nairn AC,
    10. Nestler EJ,
    11. et al.

(2001) Imvelo (eLondon) 410: 376-380.

I-CrossRefI-Medline

  1. ↵
    1. ILuscher C,
    2. I-Nicoll RA,
    3. Malenka RC,
    4. I-Muller D

(2000) Nat Neurosci 3: 545-550.

I-CrossRefI-Medlinekuwebhu weSayensi

    1. Malinow R,
    2. Mainen ZF,
    3. UHayashi Y

(2000) I-Curr Opin Neurobiol 10: 352-357.

I-CrossRefI-Medlinekuwebhu weSayensi

  1. ↵
    1. Scannevin RH,
    2. I-Huganir RL

(2000) Nat Rev Neurosci 1: 133-141.

I-CrossRefI-Medlinekuwebhu weSayensi

  1. ↵

URobinson, TE noKolb, B. (1999) (1997) I-Eur. J. Neurosci.11, 1598-1604.

  1. ↵
    1. UCarey M,
    2. I-Smale ST

(2000) Umthetho wokuThunyelwa kwe-Transcriptional ku-Eukaryotes (iCold Spring Harbor Lab. Cindezela, Plainview, NY).

Sesha i-Google Scholar

  1. ↵
    1. Spencer VA,
    2. Davie JR

(1999) I-Gene 240: 1-12.

I-CrossRefI-Medlinekuwebhu weSayensi

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