Iinkqubo ze-transcriptional zokulutha: inxaxheba ye-ΔFosB (2008)

IINKCUKACHA: U-Eric Nestler ubeka uninzi lweenkcukacha malunga ne-DeltaFosB kunye neziyobisi. (Okuninzi kuye kwafunyanwa.) Ukubeka nje, i-DeltaFosB inyuka kwisekethe yomvuzo ukuphendula ukusetyenziswa gwenxa kweziyobisi gwenxa kunye nemivuzo ethile yendalo. Injongo yokuvela kwendalo kukuba uyifumane ngelixa ulungile (ukutya kunye nokwabelana ngesondo) -oko kukuthi, ukukhuthaza iziko lomvuzo. Nangona kunjalo, iinguqulelo eziqhelekileyo zemivuzo yendalo zinokukhokelela ekusetyenzisweni kakhulu kunye nasekuqokeleleni i-DeltaFosB… kunye notshintsho lobuchopho olwenza iminqweno emininzi kunye nokubhaka ngakumbi. Into enomdla kukuba, ulutsha luvelisa i-DeltaFosB engaphezulu kakhulu kunabantu abadala, seso sizathu sokuba babe sesichengeni sokulutha.

ISIFUNDO ESIFUNDILEYO

U-Eric J Nestler*

I-10.1098 / rstb.2008.0067 Phil. Trans. R. Soc. B 12 Okthobha 2008 vol. I-363 hayi. I-1507 3245-3255

+ UkuBambisana noMbhali ISebe leNeuroscience, iNtaba yeSinayi yeSikolo seZonyango

ENew York, NY 10029, eU.SA

Abstract

Ummiselo wentetho yemfuza uthathelwa ingqalelo njengesixhobo esikhobokisayo sokulutha iziyobisi, kunikwa uzinzo ekuziphatheni gwenxa okuchaza imeko yobukhoboka. Phakathi kwezinto ezininzi ezikhutshelweyo ezaziwayo ezinefuthe kwinkqubo yokulutha, enye yezona zinto zibonakala kakuhle yi-osBFosB, ethi inyanzeliswe kwimimandla yomvuzo wobuchopho ngokuchaphazeleka okungapheliyo kuwo onke amachiza okuphathwa gadalala kunye nokulamla iimpendulo ezenziweyo ekuvezeni iziyobisi. Kuba i-ΔFosB yiprotein ezinzileyo, imele indlela apho amachiza avelisa utshintsho olusisigxina kwimbonakalo yobuzaza emva kokupheliswa kokusetyenziswa kwesiyobisi. Izifundo ziyaqhubeka ukukhangela iindlela ezichazayo zeemolekyuli apho i-ΔFosB ilawula uhlobo olujolisiweyo kwaye ivelise iziphumo zayo zokuziphatha. Sisondela kulo mbuzo sisebenzisa uluhlu lweDNA ngokudibeneyo nohlalutyo lwe-chromatin remodeling-utshintsho kwi-posttranslational modified of histones at the gene-a-gene promoters gene-kuchonga isini esilawulwa ngamachiza okuphatha gadalala ngokwenza i-ΔFosB kunye nokufumana ukuqonda kwiindlela ezichaziweyo zeemolekyuli. Iziphumo zethu zisekela ukulungisa ngokutsha i-chromatin njengeyona nto ibalulekileyo elawula ukusetyenziswa kweziyobisi, kwaye sithembisa ukuveza ulwazi olusisiseko ngendlela i-osFosB enegalelo ngayo kumlutha ngokulawula ukuchaza uhlobo oluthile lokujolisa kwiindlela zomvuzo wobuchopho.

1. intshayelelo

Uphononongo lweendlela ezikhutshelweyo zolutshintsho lusekwe kwingcamango yophando lokuba ukumiselwa kwento yohlobo lwenyani yenye indlela ebalulekileyo apho ukuveza isigulo sokuchaphazeleka okungapheliyo kubangela iinguqu ezihlala zihleli ezingqondweni, nto leyo echaza imeko yokuziphatha gwenxa echaza imeko yobukhoboka (Nestler 2001). Eyona nto iphambili kule hypothesis kukuba utshintsho olwenziwa ziyobisi kwi dopaminergic kunye ne-glutamatergic transmission nakwi-morphology yeentlobo ezithile zeeseli ze-neuronal kwingqondo, ezihambelaniswe nesebe lomlutha, ziyalungelelaniswa ngokwenxalenye ngotshintsho kwimbonakalo yemfuza.

Umsebenzi kule minyaka ili-15 idlulileyo ubonelele ngobungqina obandayo bendima yokubonakaliswa kwemfuza kwikhoboka leziyobisi, njengezinto ezininzi ezikhutshelweyo- iiproteni ezibophelela kwizinto ezithile zokuphendula kwimimandla yokukhuthaza yeendalo ekujoliswe kuzo kunye nokulawula ukubonakaliswa kofuzo- kuye kwanyanzeliswa inyathelo leziyobisi. Imizekelo ekhuthazayo ibandakanya i-ΔFosB (iprotein yosapho ye-Fos), iprotey yokuphendula eyi-cAMP-i-cAMP, i-cAMP engaphenduliyo (i-ICER), i-activation factor (ATFs), iiprotein zokukhula kokukhula kwangoko (i-EGRs), i-nucleus accumbens 1 (NAC1 ), into yenyukliya κB (NF VerB) kunye ne-glucocorticoid receptor (O'Donovan okqhubekayo. Ngo-1999; Mackler et al. 2000; Ang et al. 2001; UDeroche-Gamonet et al. 2003; UCarlezon et al. 2005; Luhlaza et al. 2006, 2008). Olu hlaziyo lugxile kwi-ΔFosB, ebonakala ngathi idlala indima eyodwa kwinkqubo yokulutha, njengendlela yokubonisa iintlobo zeendlela zovavanyo ezisetyenzisiweyo ukuphanda iindlela zokukhuphela.

2. Ukwenziwa kwe-ΔFosB kwi-nucleus ye-nucleus eqokelelwa ngamachiza okuphatha gadalala

I-FosB ifakwe kwi-fosB gene (Umfanekiso we1) kwaye yabelana nge-homology kunye nezinye izinto zokukhutshelwa kosapho kwi-Fos, ezibandakanya i-c-Fos, FosB, Fra1 kunye ne-Fra2 (UMorgan noCurran 1995). Ezi proteni zosapho zeFos heterodimerize kunye neeprotein zosapho zikaJun (c-Jun, JunB okanye JunD) ukwenza i-activator protein-1 (AP-1) izinto zokukhuphela ezibophelela kwiindawo ze-AP-1 (ukulandelana kokuvumelana: TGAC / GTCA) ekhoyo abaxhasi beentlobo ezithile zemvelo ukuze balawule ukuhanjiswa kwawo. Ezi proteni zosapho ze-Fos zithathwa ngokukhawuleza kwaye zihlale kancinci kwimimandla ethile yobuchopho emva kolawulo olunamandla lweziyobisi ezininzi zokuxhatshazwa (Umfanekiso we2; IGreybiel et al. 1990; Umncinci et al. 1991; Ithemba et al. 1992). Ezi mpendulo zibonwa ngokucacileyo kwi-nucleus accumbens kunye ne-dorsal striatum, ezingabalamli ababalulekileyo kwezenzo zokuvuza kunye ne-locomotor zamachiza. Zonke ezi proteni zosapho ze-Fos, nangona kunjalo, azizinzanga kakhulu kwaye zibuyela kumanqanaba asisiseko ngaphakathi kweeyure zokulawulwa kwamachiza.

Umzobo 1

Isiseko se-Biochemical yozinzo olulodwa lwe-DFB (a) FosB (338 aa, M_r malunga. I-38 kD) kunye (b) ΔFosB (237 aa, M_r malunga. 26 kD) zifakwe kwi-fosB yemfuza. I-osBFosB iveliswa ngolunye uhlobo kwaye iswele i-C-terminal ye-101 amino acid ekhoyo kwiFosB. Iindlela ezimbini zaziwa ngokuba yiakhawunti yozinzo lwe-DFF Okokuqala, i-osBFosB iswele imimandla emibini yeedemon ekhoyo kwi-C-terminus ye-FosB epheleleyo (kwaye ifunyenwe nakwezinye iiproteni zosapho zeFos). Enye yale mimandla yeedemon iithagethi ze-FosB zokuchithwa kunye nokuthotywa kweproteasome. Olunye ugculelo lwedomain ekujolise kuko ekujolisweni kwe-FosB yinkqubo ye-ubiquitin- kunye neproteasome-ezimeleyo. Okwesibini, i-osBFosB iphosphorylated yi-casein kinase 2 (CK2) kwaye mhlawumbi ngamanye amaprotheni kinases (?) Kwi-N-terminus yayo, eqhubeka nokuzinzisa iprotheni. 

Umzobo 2

Isikimu esibonisa ukuqokelelwa kancinci kwe-ΔFosB ngokuthelekisa kunye nexesha elincinci lokungeniswa kwezinye iiprotein zosapho ze-Fos ukuphendula iziyobisi zokuxhatshazwa. (a) I-autoradiogram ibonisa ukwahlula okwahlukileyo kweeproteni zosapho ze-Fos kwinani eliqokelelwa kukukhuthazeka okungathethekiyo (iiyure eziyi-1-2 emva kokuvezwa kwecocaine enye) ngokuchasene nokukhuthaza okungapheliyo (usuku lwe-1 emva kokubhencwa kwakhona kwecocaine). . isiyobisi sokuphathwa gadalala. Okwenziweyo zi-isoforms eziguqulwe ngokubhaliweyo ze-ΔFosB (33-1 kD); bangeniswa kumanqanaba asezantsi ngolawulo lweziyobisi olunamandla, kodwa baqhubeke nengqondo ixesha elide ngenxa yozinzo lwabo. (ii) Ngokuphindaphindiweyo (umz. kabini imihla ngemihla) kulawulo lweziyobisi, isivuseleli ngasinye esibi sisebenza kwinqanaba eliphantsi le-ΔFosB isoforms. Oku kuboniswa kuseti esezantsi yemigca egqithileyo ebonisa ukuba i-ΔFosB ibangelwa yinkuthazo nganye ebukhali. Isiphumo sonyuso ngokuthe ngcembe kumanqanaba e-ΔFosB aphindaphindiweyo ngexesha lokunyanga okungapheliyo. Oku kuboniswa ngumgca okhulayo wokunyuka kwegrafu.

Iimpendulo ezahlukeneyo kakhulu zibonakala emva kolawulo olungapheliyo lweziyobisi zokuxhatshazwa (Umfanekiso we2). I-isoforms eguqulwe ngokwendalo ye-Biochemically ye-ΔFosB (M_r I-35-37 kD) iqokeleleka ngaphakathi kwengqondo efanayo emva kokuchaphazeleka iziyobisi ngokuphindaphindiweyo, ngelixa onke amanye amalungu osapho lweFos abonisa ukunyamezelana (okt ukuncitshiswa kwendalo kuthelekiswa nokwenziwa kweziyobisi kwasekuqaleni.; U-Chen et al. 1995, 1997; UHiroi et al. 1997). Ukuqokelelwa okunjalo kwe-ΔFosB kuye kwaqwalaselwa phantse kuzo zonke iziyobisi zokuxhatshazwa (Itafile 1; Ithemba et al. 1994; UNye et al. 1995; Moratalla et al. 1996; Nye kunye neNestler 1996; UPich et al. 1997; UMuller kunye no-Unterwald 2005; McDaid et al. 2006b), nangona iziyobisi ezahlukeneyo zahluke ngandlel 'ithile kwisilinganiselo sokungeniswa esibonwe kwi-nucleus eqokelele isiseko sokuchasana neqokobhe kunye ne-dorsal striatum (UPerrotti et al. 2008). Ubuncinci kwezinye iziyobisi zokuxhatshazwa, ukufunyanwa kwe-ΔFosB kubonakala kukhetha i-dynorphin-equlethe i-subset ye-kati ye-spiny neurons efumaneka kwezi ndawo zobuchopho (UNye et al. 1995; Moratalla et al. 1996; UMuller kunye no-Unterwald 2005; U-Lee et al. 2006), nangona kufuneka umsebenzi omninzi wokuqinisekisa oku. I-35-37 kD isoforms ye-ΔFosB ilungelelanisa ubukhulu becala nge-JunD ukwenza i-AP-1 engapheliyo yobunzima ngaphakathi kwale mimandla yobuchopho (U-Chen et al. 1997; UHiroi et al. 1998; U-Pérez-Otao et al. 1998). Ukufakwa kweziyobisi ze-ΔFosB kwi-nucleus accumbens kubonakala kuyimpendulo kwimibandela yechemicals kwichiza ngalinye kwaye akuhambelani nokuthatha iziyobisi, kuba izilwanyana ezizisebenzisela ukuzisebenzisa i-cocaine okanye zifumane iziyobisi ezinje ngejekiseni Kule ngingqi yengqondo (UPerrotti et al. 2008).

1 Table

Iziyobisi zokuxhatshazwa ezaziwa ngokubangela i-ΔFosB kwi-nucleus accumbens emva kolawulo olungapheliyo.

·       ↵Isingeniso esinikwe ingxelo ngesiyobisi esisebenzayo ukongeza kwichiza elilawulwa ngumphathi. Ukufakwa kweziyobisi ze-osFosB kuboniswe kumakhonkco kunye nakwiimpuku, ngaphandle kwalokhu kulandelayo: imouse kuphela, ii-cannabinoids; umgca kuphela, i-methamphetamine, i-phencyclidine.

Tyena i-35-37 kD ΔFosB isoforms iqokelelene nokuvezwa kwesiyobisi esinganyangekiyo ngenxa yobomi babo obungaphaya kwesiqingatha sobomi. (U-Chen et al. 1997; UAlibhai et al. 2007). Ngokwahlukileyo, abukho bungqina bokuba ukuprintwa kwe-ΔFosB okanye ukuzinza kwe-mRNA yayo kulawulwa ziyobisi. Ngenxa yokuzinza kwayo, ke ngoko, iprotey ye-ΔFosB iqhubeka kwii-neurons okungenani iiveki ezimbalwa emva kokupheliswa kokuchazwa kweziyobisi. Siyazi ngoku ukuba oku kuzinza kubangelwa zezi zinto zimbini zilandelayo (Umfanekiso we1): (i) ukungabikho kwemimandla emibini ye-defon kwi-ΔFosB, ekhoyo kwi-C-terminus yobude obugcweleyo be-FosB kunye nazo zonke ezinye iiprotein zosapho ze-Fos kwaye ijolise kwezo proteni kulonakaliso olukhawulezileyo kwaye (ii) iphosphorylation ye-ΔFosB yayo I-N-terminus nge-casein kinase 2 kunye nezinye i-protein kinases (Ulery et al. 2006; UCarle et al. 2007). TUzinzo lwe-ΔFosB isoforms lubonelela ngendlela yemolekyuli yentsholongwane apho utshintsho olungene kumachiza kwi-gene expression lungaqhubeka khona nangona ixesha elide lokuyekiswa kwesiyobisi. Siphakamisile ke, ukuba i-ΔFosB isebenze njenge 'molekyuli switch' encedisa ukuqalisa kwaye ilondoloze ilizwe elilikhoboka (Nestler et al. 2001; McClung et al. 2004).

3. Indima ye-ΔFosB kwi-nucleus accumbens kulawulo lweempendulo zokuziphatha kumachiza okuphathwa gadalala

Ukuqonda kwindima ye-ΔFosB kwikhoboka leziyobisi kuza ikakhulu kufundisiso lweempuku ze-bitransgenic apho i-ΔFosB inokungeniswa ngokukhethekileyo ngaphakathi kwe-nucleus ye-nucleus kunye ne-drial striatum yezilwanyana zabantu abadala (UKelz et al. 1999). Ngokubalulekileyo, ezi mbezi I-overexpress ΔFosB ngokukhethekileyo kwi-dynorphin equlethe i-spiny neurons ephakathi, apho amachiza kukholelwa ukuba afaka iprotein. Uhlobo lokuziphatha lweempuku ze-ΔFosB-overexpressing, ethi ngeendlela ezithile ifane nezilwanyana emva kokuchazwa gwenxa kweziyobisi, ishwankathelwe Itafile 2. Iimpuku zibonisa iimpendulo zombane osisiqhelo kwi-cocaine emva kohambo olunzima nolungapheliyo (UKelz et al. 1999). Zikwabonisa uvakalelo oluphuculiweyo kwiziphumo ezinomvuzo ze-cocaine kunye ne-morphine kwimigangatho yemeko yokubeka imeko (UKelz et al. 1999; UZachariou et al. 2006), kunye nokuzilawula ngokwakho kwethamo eliphantsi le-cocaine kunelitha elingahluthisi i-ΔFosB (Colby et al. 2003). Kananjalo, i-ΔFosB overexpression kwi-nucleus eqokeleleneyo igqithisa ukukhula koxhomekeko lomzimba we-opiate kwaye ikhuthaza ukunyanzeliswa kwe-opiate analgesic (UZachariou et al. 2006). Ngokwahlukileyo, iigundane ezibonisa ΔFosB ziqhelekile kwezinye iindlela zokuziphatha, kubandakanywa ukufundwa komhlaba njengoko kuvavanyiwe kwiMazre yamanzi iMorris (UKelz et al. 1999).

Iinkqubo ze-transcriptional zokulutha: inxaxheba ye-ΔFosB

2 Table

I-Beot ye-phenotype kwi-ΔFosB yokungeniswa kwi-dynorphin + i-neurons ye-nucleus accumbens kunye ne-dorsal striatum^a.

·       ↵a Iipototypes ezichazwe kolu luhlu zisekwe phezu kwe-vereFosB engalunganga yeempuku ze-bitransgenic apho ibinzana le-ΔFosB lijolise kwi-dynorphin + neurons ye-nucleus accumbens kunye ne-dorsal striatum; amanqanaba aliqela asezantsi e-ΔFosB abonwa kwi-hippocampus nakwi-cortex yangaphambili. Kwiimeko ezininzi, i-phenotype inxibelelaniswe ngokuthe ngqo kwi-ΔFosB expression kwi-nucleus accumbens se se ngokusebenzisa ugqithiso lwentsholongwane oluhambelana nentsholongwane.

Ujoliso oluthile lwe-ΔFosB overexpression kwi-nucleuseba, ngokusetyenziswa kotshintsho lwe-gene-mediated gene, luvelise idatha efanayo (UZachariou et al. 2006), ebonisa ukuba lo mmandla wengqondo unokuphendula malunga ne-phenotype egcinwe kwiigundane ze-bitransgenic, apho i-ΔFosB ibonakaliswa kwakhona kwi-dorsal striatum kunye nakwindlela encinci kweminye imimandla yobuchopho. Ngaphezu koko, ekujolise kuyo i-enkephalin-equlathe i-spiny neurons ephakathi kwi-nucleus accumbens kunye ne-dorsal striatum kwimigca eyahlukeneyo yeempazamo ze-bitransgenic ezingaphumeleliyo kubonakalisa uninzi lwezi zinto zokuziphatha, zibeka ngokungqongqo i-dynorphin + i-nucleus ibuyisa i-neurons kwezi zinto.

Ngokuchasene ne-overexpression ye ΔFosB, ukugqithiswa kweprotheyini ye-mutant Jun (ΔcJun okanye ΔJunD) -iyasebenza njengesixhobo esichasayo esichazayo sokusetyenziswa kweempuku ze-bitransgenic okanye i-genr-Mediated gene ekhupha ukuchasana. Iziphumo zokuziphatha (Peakman et al. 2003; UZachariou et al. 2006). TIdatha ye-hese ibonisa ukuba ukwenziwa kwe-ΔFosB kwi-dynorphin equkethe i-spiny neurons ephakathi ye-nucleus accumbens inyusa ubuntununtunu besilwanyana kwi-cocaine nakwamanye amachiza okuphathwa gadalala, kwaye inokubonisa indlela yokuziva ixesha elide kwiziyobisi.

Iziphumo ze-ΔFosB zinokwandisa ngaphaya komqathango wokubaluleka kwezidakamizwa ngokubhekiselele ekuziphatheni okunzima okunxulumene nenkqubo yokulawula. Unyango olugqithisileyo lwe-iceFosB lusebenza nzima ukuze likwazi ukuzilawula ngokwalo kunye nokucebisa, licebisa ukuba i-ΔFosB inokwazisa izilwanyana ngenkuthazo ye-cocaine kwaye oko kungakhokelela ekuvuseleleni kwakhona emva kokurhoxiswa kweziyobisi. (Colby et al. 2003). Iimpuku ze-ΔFosB-overexpressing zikwabonisa ifuthe loxinzelelo lwexhala (Picetti et al. 2001), I-phenotype enxulunyaniswa nokwanda kotywala ebantwini. Ngokudibeneyo, ezi ziphumo zakuqala zicebisa ukuba i-ΔFosB, ukongeza kwimvakalelo yokunyanzelwa kwiziyobisi zokuphathwa gadalala, ivelise utshintsho olululo kwimikhwa ekhuthaza isimilo sokufuna iziyobisi, kwaye ixhase umbono, okhankanywe apha ngasentla, ukuba i-ΔFosB isebenza njengento eguqukayo yemolekyuli yomlutha. ilizwe. Umbuzo obalulekileyo phantsi kophando lwangoku kukuba i-ΔFosB ukuqokelelwa ngexesha lokuchazwa kweziyobisi kukhuthaza indlela yokufuna iziyobisi emva kokuyekiswa okongeziweyo, kwanasemva kokuba amanqanaba e-ΔFosB enze imeko yesiqhelo (jonga ngezantsi).

4. Ukwenziwa kwe-ΔFosB kwi-nucleus eqokelelweyo ngemivuzo yendalo

I-nucleus accumbens kukholelwa ukuba isebenza ngesiqhelo ngokulawula iimpendulo kwimivuzo yendalo, njengokutya, isiselo, isini kunye nokuhlangana kwentlalo. Ngenxa yoko, kukho umdla othatyathwayo kwindima enokubakho yommandla wobuchopho kwindawo ebizwa ngokuba ziyobisi zendalo (umz. Ukuxhaphaka kakhulu emzimbeni, ukugembula, ukuzivocavoca njalo njalo). Iimodeli zezilwanyana zeemeko ezinjalo zincinci; Nangona kunjalo, thina nabanye sifumanise ukuba amanqanaba aphezulu okusetyenziswa kweentlobo zemivuzo yendalo akhokelela ekuqokeleleni kozinzo lwe35-37 kD isoforms ye ΔFosB kwi-nucleus accumbens. Oku kubonwe emva kwamanqanaba aphezulu evili lokuqhuba (Werme et al. 2002) nasemva kokusela okungapheliyo kwe-sucrose, ukutya okunamafutha aphezulu okanye isondo (I-Teegarden kunye neBale 2007; Wallace et al. 2007; Teegarden et al. ngokushicilelwa). Ngamanye amaxesha, le induction ikhetha i-dynorphin + i-subset ye-medium spiny neurons (Werme et al. 2002). Izifundo zeempuku ezingafundekiyo, ezingenamqolo kunye nokudluliselwa kohlobo lwentsholongwane ziye zabonisa ukuba ukugcwala kwe-ΔFosB kwi-nucleus accumbens kukonyusa idrive kunye nokusetyenziswa kwezi mbuyekezo zendalo, ngelixa ukuxhaphaka kweproteyini enkulu yeJun kuveza isiphumo esichaseneyot (Itafile 2; Werme et al. 2002; Olausson et al. 2006; Wallace et al. 2007). Ezi ziphumo zibonisa ukuba i-DFFB kule ndawo yengqondo ikhuthaza izilwanyana kungekuphela nje kwemivuzo yezidakamizwa kodwa nembuyekezo yemvelo kunye, kwaye inokuba negalelo ekubhekiseleleni kwimeko yokulutha kwemvelo.

5. Ukwenziwa kwe-ΔFosB kwi-nucleus accumbens ngoxinzelelo olungapheliyo

Ukunikwa ubungqina obuqinisekileyo bokuba i-ΔFosB ifakwa kwi-nucleus accumbens ngokuchana ixesha lokuchazwa kweziyobisi kunye nemivuzo yendalo, kwakumnandi ukuqaphela ukuba i-ΔFosB ikwangeniswa kakhulu kulo mmandla wengqondo emva kweendlela ezahlukeneyo zoxinzelelo, kubandakanya uxinzelelo loxinzelelo, uxinzelelo olungalindelekanga kunye noxinzelelo ukoyiswa kwezentlalo (UPerrotti et al. 2004; UVialou et al. 2007). Ngokungafaniyo neziyobisi kunye nemivuzo yendalo, nangona kunjalo, oku kungeniswa kubonwa ngokubanzi kulo mmandla weengqondo ukuba ubonwa ngokugqwesileyo kuzo zombini i-dynorphin + kunye ne-enkephalin + i-subsets ye-medium spiny neurons. Ubungqina bokuqala bucebisa ukuba le induction ye-ΔFosB isenokubonisa impendulo elungileyo, yokuphendula ukunceda umntu ukuba aqhelane noxinzelelo. Le hypothesis ixhaswa ziziphumo zokuqala zokuba i-ΔFosB iqokelele kwi-nucleus accumbens, ngokusebenzisa inducansgenic, iimpuku ze-bitransgenic okanye udluliselo lwentsholongwane egalelwe emzimbeni, inika iimpendulo ezinje nge-antidepressant-like an assows in behavients yokuziphatha (umz. Ukoyiswa kwentlalo, uvavanyo lokuqubha lokuqubha), ngelixa I-ΔcJun expression ibangela u-pro-ukudana-njengefuthe (UVialou et al. 2007). Ngapha koko, ukulawulwa okungapheliyo kwamayeza e-antidepressant asemgangathweni kunesiphumo esifana noxinzelelo kunye ne-ΔFosB kulo mmandla wengqondo. Ngelixa umsebenzi omninzi uyimfuneko ukuqinisekisa ezi zinto zifunyanisiweyo, indima enjalo iya kuhambelana nokuqaphelekayo oku I-osBFosB yonyusa ubuntununtunu bomvuzo wesekethe kwaye ngaloo ndlela inokunceda izilwanyana zijongane namaxesha oxinzelelo. Into enomdla kukuba, le ndima ye-hypothesised ye-nucleFosB kwi-nucleus accumbens iyafana nale iboniswe kutshanje nge-periaqueductal grey apho into ekhutshelweyo ikwabangela uxinzelelo olungapheliyo (UBerton et al. 2007).

6. Iithagethi zojoliso ze-ΔFosB kwi-nucleuseba

Kuba i-ΔFosB yinto yokukhutshelwa, ivelisa le ndlela yokuziphatha inomdla kwi-nucleus accumbens ngokunyusa okanye ukucinezela ukubonakaliswa kwezinye iintlobo. Njengoko kuboniswe kuyo Umfanekiso we1I-ΔFosB yimveliso ethotyiweyo yohlobo lwe-fosB olungenalo uninzi lwesizinda se-C-terminal transactivation ekhoyo kubude obugcweleyo be-FosB kodwa igcina ubukhulu kunye nemimandla ebopha i-DNA. I-ΔFosB ibophelela kumalungu osapho lakwaJun kunye nesiphumo esibonakalayo sibophelela indawo ye-AP-1 kwiDNA. Olunye uphononongo lwe-in vitro lucebisa ukuba ngenxa yokuba i-ΔFosB isilela kuninzi lwendawo yayo yokudlulisa, isebenza njengomlawuli ongendawo womsebenzi we-AP-1, ngelixa abanye abaninzi babonisa ukuba i-ΔFosB inokuvula ukukhutshelwa kwiindawo ze-AP-1 (I-Dobrazanski et al. 1991; Nakabeppu kunye neNathans 1991; Yen et al. 1991; U-Chen et al. 1997).

Sisebenzisa iimpazamo zethu ezingafundekiyo, ze-bitransgenic ukuba i-overexpress ΔFosB okanye i-ΔcJun engalunganga, kunye nokuhlalutywa kwembonakalo yesini kwi-affymetrix chips, sabonisa ukuba, kwi-nucleus ye-bokski kwi-vivo, Umsebenzi we-ΔFosB ngokuyintloko njengelinge lokukhuphela, ngelixa usebenza njengendawo yokubhala ephantsi kohlobo oluncinci lwendidi (UMcClung kunye noNestler 2003). MnaNgokuncomekayo, lo msebenzi wokwahlula-hlulo we-ΔFosB ngumsebenzi wexesha kunye nenqanaba lokubonisa kwe-ΔFosB, kunye nexesha elifutshane, amanqanaba asezantsi akhokelela ekuphindaphindweni kofuzo kunye nexesha elide, amanqanaba aphezulu akhokelela kuhlobo oluthile lwento yokusebenza. Oku kuyahambelana nokufumanisa ukuba i-ΔFosB yexesha elifutshane kunye nexesha elide i-ΔFosB ibakhokelela kwiziphumo ezichaseneyo yokuziphatha: i-ΔFosB yexeshana elifutshane, njengebinzana le-ΔcJun, iyanciphisa ukuthanda kwe-cocaine, ngelixa ibinzana le-ΔFosB lonyusa ukuthanda kwe-cocaine (UMcClung kunye noNestler 2003). Indlela elawula olu tshintsho ngoku iphantsi kophando; Kunokwenzeka ukuba i-ΔFosB, kumanqanaba aphezulu, inokwenza ii-homeodimers ezenza ukuba kusebenze u-AP-1 (UJorissen et al. 2007).

Iintlobo ezithile ekujoliswe kuzo ze-ΔFosB zisungulwe kusetyenziswa indlela yovavanyo yomgqatswa (Itafile 3). Uhlobo olunye lomenzi yi-GluR2, I-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) i-glutamate receptor subunit (UKelz et al. 1999). I-ΔFosB overexpression kwiigundane ezingenakubaleka ngokukhethekileyo yonyusa ukubonakaliswa kwe-GluR2 kwi-nucleus accumbens, ngaphandle kwesiphumo esibonwe kwezinye i-AMPA ze-glutamate receptor subunits ezihlalutyiweyoNgelixa ibinzana le-ΔcJun livimba amandla e-cocaine ukuya kwi-GluR2 (Peakman et al. 2003). I-AP-1 iyinkimbinkimbi equka i-ΔFosB (kwaye ubukhulu becala isenokuba JunD) ibophelela indawo ye-AP-1 yesivumelwano ekhoyo kwi-GluR2 promoter. Ngapha koko, i-GluR2 i-overexpression ngokudluliselwa yintsholongwane ehambelana nokuchwetheza inyusa iziphumo ezinomvuzo ze-cocaine, ikakhulu njenge-ΔFosB overexpression (UKelz et al. 1999). Kuba iziteshi ze-GluR2-eziqulethe i-AMPA zineendlela zokuziphatha eziphantsi ngokuthelekiswa neendlela ze-AMPA ezingenayo le subunit, i-cocaine- kunye ne-ΔFosB-Mediated upregulation yeGluR2 kwi-nucleus accumbens inokunika ingxelo, ubuncinci ngenxalenye yeempendulo ezincitshisiweyo ze-glutamatergic ezibonwe ku Ezi Neurons emva kokuchazwa gwenxa kweziyobisi (IKauer kunye neMalenka 2007; Itafile 3).

Imizekelo yeethagethi eziqinisekisiweyo ze-ΔFosB kwi-nucleus accumbens^a.

·       ↵Nangona i-ΔFosB ilawula ukubonakaliswa kweentlobo ezininzi zobuchopho kwingqondo (umz.UMcClung kunye noNestler 2003), itafile idwelisa kuphela ezo zofuzo zidibana ubuncinci kwezi ndlela zintathu zilandelayo: (i) inyukile (↑) okanye yehlile (↓) intetho kwi-ΔFosB uxinzelelo, (ii) ukuphindaphinda okanye umgaqo olinganayo ngu-ΔcJun, isithintelo esibi esine-AP-1-ekhutshelweyo, (iii) ΔFosB enezakhiwo ze-AP-1 zibopha kwiindawo ze-AP-1 kwingingqi yokukhuthaza yemfuza, kwaye ( iv) I-osBFosB ibangela umphumo ofanayo kwimisebenzi yokukhuthaza imfuza kwi-vitro njengoko ibonwe kwi vivo.

·       ↵b Ngaphandle kobungqina bokuba i-ΔFosB iyayiphinda-phinda uhlobo lwe-dynorphin kwiimodeli zokusetyenziswa gwenxa kweziyobisi (uZachariou et al. 2006), bukhona obunye ubungqina bokuba inokuthatha isenzo sokulwenza luhlobo lonyango phantsi kweemeko ezahlukeneyo (jonga kwiCenci 2002).

3 Table

Imizekelo yeethagethi eziqinisekisiweyo ze-ΔFosB kwi-nucleus accumbensa.

Olunye udidi lokujolisa kummeli we-ΔFosB kwi-nucleus accumbens ipeptide ye-opioid, dynorphin. Khumbula ukuba i-ΔFosB ibonakala ibangelwa zezi ziyobisi zokuxhatshazwa ngokukodwa kwiiseli ezivelisa idynorphin kule ngingqi yengqondo. Iziyobisi zokuxhatshazwa zineziphumo ezinobunzima ekubonakalisweni kwe-dynorphin, kunye nokunyuka okanye ukwehla okubonakalayo kuxhomekeka kwiimeko zonyango ezisetyenzisiweyo. Uhlobo lwe-dynorphin luqukethe ii-AP-1-ezinje ngeesayithi, ezinokubopha ii-ΔFosB-ezinee-AP-1 complexes. Ngaphaya koko, sibonisile ukuba ukwenziwa kwe-ΔFosB kuyayiphindaphinda ukubonakaliswa kwesidalwa se-dynorphin gene kwi-nucleus accumbens (UZachariou et al. 2006). I-Dynorphin icingelwa ukuba isebenze ii-receptors ze-κ-opioid kwii-VTA dopamine neurons kwaye zithintele ukuhanjiswa kwedopaminergic kwaye ngaloo ndlela zithobe iindlela zomvuzo (IShippenberg kunye neRea 1997). Hence, uxinzelelo lwe-ΔFosB lwentetho ye-dynorphin inokuba negalelo kuphuculo lweendlela zomvuzo eziphakathi kwale nto ikhutshelweyo. Kukho ubungqina ngokuthe ngqo obuxhasa ukubandakanyeka kwengcinezelo yohlobo lwe-dynorphin kwi-ΔFosB yokuziphatha kwe-phenotype (UZachariou et al. 2006).

Ubungqina bamva nje buye babonisa ukuba i-ΔFosB iphinda iphinde ibuyele kuhlobo lwe-c-fos olunceda ukuyila kwimolekyuli-ukusuka ekungenisweni kweeprotein zosapho ezimfutshane ze-Fos emva kokuvezwa kweziyobisi kwi-ΔFosB-Ibhalwe ngaphambili (URenthal et al. ngokushicilelwa). Isixhobo esinoxanduva lokuphindaphinda ΔFosB kwengcaciso ye-c-fos sintsokothile kwaye sogqunywe ngezantsi.

Enye indlela esetyenzisiweyo yokuchonga uhlobo ekujolise kulo lwe-hasFosB ilinganise utshintsho lwenkcazo yemfuza eyenzeka kwi-overexpression engafikelelekiyo ye-ΔFosB (okanye ΔcJun) kwi-nucleus accumbens isebenzisa ukuchaza kweDNA, njengoko kuchaziwe ngaphambili. Le ndlela ikhokelele ekuchongeni iintlobo ezininzi zemfuza eziphakanyiselwe phezulu okanye ezikrokrelwe yi-ΔFosB expression kule ngingqi yengqondo (Chen et al. 2000, 2003; Ang et al. 2001; UMcClung kunye noNestler 2003). Toofuzo obonakala ngathi bubangelwa zizenzo ze-osBFosB njenge-activator ekhutshelweyo exhomekeke kwi-cyclin-kinase-5 (Cdk5) kunye ne-cofactor yayo P35 (Bibb et al. 2001; UMcClung kunye noNestler 2003). I-Cdk5 ikwabangelwa yi-cocaine engapheliyo kwi-nucleus accumbens, isiphumo esivaliweyo kwi-ΔcJun expression, kwaye i-ΔFosB ibopha kwaye isebenze uhlobo lweCdk5 kwindawo ye-AP-1 kwindawo yayo yokunyusa (U-Chen et al. 2000; Peakman et al. 2003). I-Cdk5 lujoliso olubalulekileyo lwe-ΔFosB kuba intetho yayo inxibelelaniswe ngokuthe ngqo notshintsho kwimeko ye-phosphorylation yeeproteni ezininzi ze-synaptic kubandakanya ukuhanjiswa kwe-glutamate receptor (Bibb et al. 2001), kunye nokunyuka kwe-dendritic spine density (UNorrholm et al. 2003; U-Lee et al. 2006), kwi-nucleus accumbens, ezinxulumene nolawulo lwecocaine (URobinson kunye noKolb 2004). Kutshanje, ukumiselwa kwemisebenzi ye-Cdk5 kwii-nucleus ze-nucleus zidityaniswe ngokuthe ngqo kwiinguqu kwiziphumo zokuziphatha kwe-cocaine (UTaylor et al. 2007).

Enye into ekujolise kuyo ΔFosB echongiweyo kukusetyenziswa kwe-Microarrays yi-NF VerB. Le nto yokukhutshelwa ifakwe kwi-nuksi eqokelelweyo yi-ΔFosB oxpxpression kunye ne-cocaine engapheliyo, isiphumo esivaliweyo yi-ΔcJun expression (Ang et al. 2001; Peakman et al. 2003). Ubungqina bamva nje bucebise ukuba ukumiliselwa kwe-NF VerB kunokuba negalelo kumandla e-cocaine yokukhuthaza ukubakho kwe-dendritic spines kwi-nucleus accumbens neurons (URusso et al. 2007). Ukongeza, i-NF VerB ifakelwe impembelelo kwezinye zeempembelelo ze-methotothithamine kwimimandla ye-striatal (I-Asanuma kunye neCadet 1998). Ukuqwalaselwa ukuba i-NF VerB luhlobo ekujolise kulo lwe-ΔFosB kugxininisa ukuntsokotha kweendlela ze-ΔFosB ezilamla phakathi kweziphumo zecocaine kwimo yokubonisa. Ke, ukongeza kwiintlobo zemvelo ezilawulwa yi-ΔFosB ngokuthe ngqo kwiisayithi ze-AP-1 kwizikhuthazi zemfuza, i-ΔFosB kulindeleke ukuba ilawule iintlobo ezininzi ezongeziweyo ngokuchaza okuguqulweyo kwe-NF VerB kunye nezinye iiprotein ezilawulayo ezibhaliweyo.s.

Uluhlu lwegama le-DNA lubonelela ngoluhlu olunobutyebi beentlobo ezininzi ezongeziweyo ezinokuthi zijolise, ngqo okanye ngokungathanga ngqo, yi-ΔFosB. Phakathi kwezi ntlobo zongezwa ii-receptors ze-neurotransmitter, iiprotein ezibandakanyeka kwimisebenzi yaphambi kunye neye-postynaptic, uninzi lweendlela ze-ion kunye neeprotexellular signaling protein, kunye neeproteni ezilawula i-cytoskeleton ye-neuronal kunye nokukhula kweseli (UMcClung kunye noNestler 2003). Umsebenzi ongaphezulu uyafuneka ukuqinisekisa nganye yezi proteni zininzi njengezinto ekujolise kuzo ze-cocaine esebenza nge-ΔFosB kunye nokumisela indima echanekileyo edlalwe yiprotein nganye yokugweba intshukumo entsonkothileyo yokuziphatha neyokuziphatha. Ekugqibeleni, ngokuqinisekileyo, kuya kuba yimfuneko ukuhamba ngaphaya kohlalutyo lwesifo somntu ngamnye kummiselo wamaqela ohlobo oluhlobo lwawo olulungelelanisiweyo mhlawumbi olufunekayo ukuze alamle ilizwe elilikhoboka.

7. Ukwenziwa kwe-ΔFosB kweminye imimandla yobuchopho

Ingxoxo ukuza kuthi ga ngoku ijolise ngokukodwa kwii-nucleus accumbens. Ngelixa le ndawo ingumvuzo wobuchopho ophambili kwaye ibalulekile kwizenzo ezongezelelweyo ze-cocaine kunye nezinye iziyobisi zokuphathwa gadalala, eminye imimandla yobuchopho ibalulekile ekuphuhlisweni nasekugcinweni kwelizwe lokuba likhoboka. Umbuzo obalulekileyo, ke, ngaba i-ΔFosB esebenza kweminye imimandla yobuchopho ngaphaya kwe-nucleus accumbens inokuba nefuthe kwizyobisi. Mnasendikhona, ngoku kukho ubungqina obukhulayo bokuba iziyobisi ezikhuthaza kunye nezixhaphazayo zokuxhaphaza zifundisa i-ΔFosB kwimimandla emininzi yobuchopho ebandakanyayo kwimicimbi eyahlukeneyo yokulutha.n (UNye et al. 1995; UPerrotti et al. 2005, 2008; McDaid et al. 2006a,b; Liu et al. 2007).

Uphononongo lwakutsha nje ngokuthelekisa ngokuthelekisa i-ΔFosB kwezi ndawo zahlukeneyo zobuchopho kuzo zone iziyobisi ezahlukeneyo zokuxhaphaza: i-cocaine; morphine; ii-cannabinoids; kunye ne ethanolItafile 4; UPerrotti et al. 2008). Zonke ezi ziyobisi zine zibangela into yokukhuphela kumanqanaba ahluka-hlukeneyo kwi-nucleus accumbens kunye ne-dorsal striatum kunye nakwi-cortex yangaphambili, i-amygdala, i-hippocampus, i-nucleus yebhedi ye-stria terminalis kunye ne-interstitial nucleus yecala elingasemva le-commissure yangaphandle. Icoocaine kunye ne-ethanol eyodwa ebangela i-ΔFosB kwi-septum esecaleni, onke amachiza ngaphandle kwe-cannabinoids indize uceFosB kwi-periaqueductal grey, kunye necocaine ikhethekileyo ekuphembeleleni i-ΔFosB kwiseli ye-gamma-aminobutyric acid (GABA) yeseli engendawo al. 2005, 2008). Ukongeza, i-morphine ibonakalisiwe ukuba ibangele i-ΔFosB kwi-pralid pallidum (McDaid et al. 2006a). Kuwo ngamnye wale mimandla, yi-35-37 kD isoforms ye-ΔFosB eqokelela ekuvezeni iziyobisi okungapheliyo kwaye iqhubeke ixesha elide ngexesha lokurhoxiswa.

4 Table

Thelekisa imimandla yobuchopho ebonisa i-ΔFosB yokungeniswa emva kokubhenciswa okungapheliyo kumachiza amele ukuphathwa gadalala^a.

·       ↵Itheyibhile ayibonisi imigangatho yokuhlanjwa kwe-ΔFosB ngamachiza awohlukeneyo. Jonga uPerrotti et al. (2008) kolu lwazi.

·       ↵b Isiphumo se-cocaine, i-ethanol kunye ne-cannabinoids kwi-indFosB yokungeniswa kwi-pralidum ye-ventral ayikafundwa, kodwa i-induction enjalo ibonwe ukuphendula i-methamphetamine (McDaid et al. 2006b).

·       ↵I-c ΔFosB yokungeniswa ibonwa kwi-sub subionsal ye-cortex yangaphambili, kubandakanya ne-infralimbic (medial prefrontal) kunye ne-orbitofadal cortex.

Injongo ephambili yophando lwexesha elizayo kukuqhuba izifundo, i-analogous kwezi zichazwe ngasentla kwi-nucleus accumbens, ukumiliselwa kwe-neural kunye nokuziphatha kwe-phenotypes ezixolelweyo yi-ΔFosB kwingingqi nganye yengqondo. Oku kubonisa ukwenziwa okukhulu, kodwa kubalulekile ukuba baqonde impembelelo ye-ΔFosB yehlabathi kwinkqubo yokulutha.

Kutshanje sithathe inyathelo elibalulekileyo kule nto ngokusebenzisa uhlobo lokudluliselwa kuhlobo lwentsholongwane ukuphawula iintshukumo ze-BFosB kwi-subortion yecortex yangaphambili, eyile, ye-orbitofrontal cortex. Lo mmandla uchukunyiswe ngokuqinile kumlutha, ngakumbi, ekufakweni kwento ekunyanzeliswayo nasekunyanzelisweni okubonakalisa ilizwe likhoboka (IKalivas kunye neVolkow 2005). Into enomdla kukuba, ngokungafaniyo ne-nucleus accumbens apho i-cocaine eyenzelwa kwaye iboshwe kwi-cocaine ikhuthaza amanqanaba afanayo e-ΔFosB njengoko kuchaziwe ngaphambili, Siqwalasele ukuba i-cocaine-self-management ibangela i-ΔFosB enkulu kwi-cortex ye-orbitof, iphakamise ukuba le mpendulo inokuba inxulumene nemiba yolawulo lwamachiza. (UWinstanley et al. 2007). Emva koko sisebenzise uvavanyo lweentonga zokunikwa kwengqwalaselo kunye nokwenza izigqibo (umzekelo, ixesha lesi-5 lokukhetha ixesha lokuphendula kunye nokuvavanywa kwezaphulelo) ukumisela ukuba ngaba i-ΔFosB ngaphakathi kwe-cortex ye-orbitofrontal inegalelo kwiinguqu ezibangelwa zezi ziyobisi ekuqondeni. Sifumene ukuba unyango lwe-cocaine engapheliyo lubangela ukunganyamezeli ekungafumanekiyo kwengqondo okubangelwa kukutya okukuko icocaine. I-overexpression ejongene ne-vereFosB ngaphakathi kulo mmandla ilinganisa iimpembelelo ze-cocaine engapheliyo, ngelixa ukubetheka okuchasene nomchasi omubi kakhulu, ΔJunD, kuthintela olu hlobo lokuziqhelanisa nokuziphatha. Ukuchazwa kwe-DNA micrarrayenses ichonge iindlela ezithile ezinokuba zimolekyuli eziphantsi kolu tshintsho lokuziphatha, kubandakanya ukwanda kwecocaine- kunye ne-ΔFosB ekhutshelweyo yokukhutshelwa kwe-metabotrophic glutamate receptor mGluR5 kunye neGABA_A into eyamkelayo kunye nezinto P (UWinstanley et al. 2007). Impembelelo yezi kunye nezinye iinjongo ezininzi zokujolisa ze-ΔFosB zifuna uphando oluthe kratya.

Ezi zinto zifunyanisiweyo zibonisa ukuba i-ΔFosB inceda ekunyamezeleni ukunyamezelana nokuphazamisa ukusebenza kwe-cocaine. Abasebenzisi abafumana ukunyamezelwa kwiziphumo zecocaine, kunokuba lula ukuba baxhomekeke kwi-cocaine, ngelixa abo bafumana ichiza lingaphazamisi emsebenzini okanye esikolweni bengakwazi ukuba likhoboka. (I-Shaffer kunye ne-Eber 2002). Ukunyamezeleka kokuphazamiseka kwengqondo okubangelwa kukungabinamdla kwe-cocaine kubantu abanolwazi lwe-cocaine. Ngale ndlela, i-ΔFosB yokungeniswa kwi-orbitofrontal cortex inokuphakamisa ilizwe elinomlutha, ngokufanayo nezenzo zayo kwi-nucleus accumbens apho i-ΔFosB ikhuthaza ukulutha ngokwandisa imbuyekezo kunye nenkuthazo yempembelelo yechiza.

8. Iindlela ze-epigenetic zesenzo se-ΔFosB

Kude kube kutshanje, lonke uphononongo lommiselo okhutshelweyo kwingqondo luxhomekeke kwimilinganiselo yamanqanaba e-mRNA azinzileyo. Umzekelo, ukukhangela i-ΔFosB ekujolise kuyo kwimfuza kubandakanyeke ekuchongeni i-mRNA ephezulu- okanye ebekelwe ezantsi kwi-osBFosB okanye kwi-JcJun overexpression, njengoko bekutshiwo ngaphambili. Eli nqanaba lohlalutyo lube luncedo kakhulu ekuchongeni iithagethi zokubeka ze-ΔFosB; Nangona kunjalo, isikelwe umda ekunikezeleni ukuqonda kwiindlela ezisisiseko ezichaphazelekayo. Endaweni yokuba, lonke uphononongo lweendlela zixhomekeke kumanyathelo e-vitro anjenge-bFosB ebophelela kulungelelwaniso lomfuziselo kwimfuziselo yokutshintsha kwejeli okanye regulationFosB yolawulo lomsebenzi wentsholongwane okhuthaza inkcubeko yeseli. Oku akonelisi kuba iindlela zomgaqo okhutshelweyo zibonisa umahluko omkhulu kuhlobo lweseli ukuya kuhlobo lweseli, ukushiya kungaziwa ngokupheleleyo ukuba ichiza lokuxhatshazwa, okanye i-ΔFosB, ilawula njani uhlobo lwayo oluthile kwingqondo kwi vivo.

Izifundo zeendlela ze-epigenetic zenza ukuba kwenzeke, okwesihlandlo sokuqala, ukutyhala imvulophu inyathelo elinye ukuqhubela phambili kwaye ukujonga ngqo ukuhanjiswa kokubhaliweyo kwiingqondo zezilwanyana eziphetheyo (UTsankova et al. 2007). Ngokwembali, igama elithi epigenetics lichaza iindlela ezinokuthi zifumaneke njengeeselifayile ngaphandle kotshintsho kulandelelwano lweDNA. Sisebenzisa eli gama ngokubanzi ukubandakanya 'utshintsho lohlengahlengiso lwengingqi ze-chromosomal ukuze ubhalise, umqondiso okanye uhambise imisebenzi etshintshileyo imisebenzi' (Intaka 2007). Ke, ngoku siyazi ukuba imisebenzi yemfuza ilawulwa lutshintsho oluguqukayo (umzekelo, i-acetylation, i-methylation) ye-histones kwindawo ekuyo yofuzo kunye nokugaywa kweentlobo ezahlukeneyo ze-coactivators okanye i-corepressors yokukhuphela. Chromatin immunoprecipitation (ChIP) assays yenza ukuba kunokwenzeka ukuba lusebenzise olu lwazi lukhulayo lwe-chromatin biology ukumisela imeko yovuselelo lomfuzo kwingingqi ethile yobuchopho besilwanyana esinyangwa ngesiyobisi.

Umzekelo wendlela izifundo zommiselo wechromatin ezinokusinceda ngayo ukuba siqonde iinkcukacha zeemolekyuli zesenzo se-cocaine kunye ne-ΔFosB Umfanekiso we3. Njengoko kukhankanyiwe apha ngasentla, i-ΔFosB inokusebenza njengombonisi okhutshelweyo okanye uxinzelelo ngokuxhomekeka kuhlobo ekujolise kulo. Ukufumana ukuqonda kwezi zenzo, sahlalutya imeko ye-chromatin yeethagethi ezimbini zodidi lwe-ΔFosB, i-cdk5 ephenjelelwa yi-ΔFosB kunye ne-c-fos ecinezelweyo kwi-nucleus accumbens. Izifundo ze-chromatin immunoprecipitation zibonise ukuba i-cocaine isebenze cdk5 gene kule ngingqi yeengqondo ngokusebenzisa ikhasco elandelayo: I-ΔFosB ibophelela uhlobo lwe-cdk5 kwaye emva koko iphinda ifumane i-histone acetyltransferases (HAT; eneempawu ze-acetylate ezikufutshane) kunye ne-SWI-SNF. Zombini iintshukumo zikhuthaza ukuguqulelwa kohloboKumar et al. 2005; U-Levine et al. 2005). I-cocaine engapheliyo ikhulisa i-histone acetylation ngokusebenzisa iphosphorylation kunye nokuthintela i-histone deacetylases (i-HDAC; edla ngokufaka uguquko lwendalo; URenthal et al. 2007). Ngokwahlukileyo, i-cocaine icinezela uhlobo lwe-c-fos: xa i-ΔFosB ibophelela kule gene iphinda ifumane i-HDAC kunye ne-histone methyltransferase (HMT; ene-methylate ye-histones ekufutshane), oko ke kuthintela ukukhutshwa kwe-c-fos (Umfanekiso we3; URenthal et al. ngokushicilelwa). Umbuzo ophambili ngulo: yintoni egqiba ukuba ngaba i-ΔFosB iyasebenza okanye iyayicinezela imfuza xa ibophelela kuloo mntu ukhuthazayo?

Umzobo 3

Iindlela ze-epigenetic zesenzo se-ΔFosB. Eli nani libonisa imiphumo eyahlukileyo xa i-ΔFosB ibophelela kuhlobo lwento eyenziwayo (umz. Cdk5) ngokuchaseneyo nokuphindaphinda (umz. C-fos). (a) Kumkhuthazi we-cdk5, u-ΔFosB uqasha imiba ye-HAT kunye ne-SWI-SNF, ekhuthaza kusebenze gene. Kukho ubungqina bokukhutshelwa ngaphandle kwee-HDACs (jonga umbhalo). (b) Ngokwahlukileyo, kumkhuthazi we-c-fos, i-ΔFosB iphinda iqeshe i-HDAC1 kunye ne-HMTs elicinezela uhlobo lwentengiso. I-A, P kunye no-M ibonisa histone acetylation, phosphorylation kunye methylation ngokulandelelana.

Olu phononongo lwangaphambili lweendlela ze-epigenetic zotywala lweziyobisi luyonwabisa kuba zithembisa ukuveza ulwazi olusisiseko ngokubhekisele kwiinkqubo zeemolekyuli apho iziyobisi zokusebenzisa gadalala zilawula ukubonakaliswa kofuzo kwi-nucleus accumbens kunye neminye imimandla yobuchopho. Ukudibanisa uluhlu lweDNA yokucacisa kunye ne-ChIP ekuthiwa kukubizwa kwe-chip (apho kutshintsha khona ubume bechromatin okanye into ekhutshelweyo kunokuhlalutywa ngokubanzi) kuya kukhokelela ekuchongeni iziyobisi kunye nohlobo lokujolisa lwe-ΔFosB ngomgangatho omkhulu wokuzithemba kunye nokugqibelela. Ukongeza, iindlela ze-epigenetic ikakhulu ngabaviwa abanomtsalane ekuthetheleleni eyona nto yenzeka ixesha elide kumbindi wombuso. Ngale ndlela, utshintsho olwenziwe iziyobisi kunye ne-ΔFosB olwenziwe kutshintsho lwe-histone kunye neenguqu ezihambelana ne-epigenetic zibonelela ngeendlela ezinokubakho zokuguqula okukhoyo ngokuqhubeka ixesha elide emva kokuba ukubonakaliswa kweziyobisi kuphelile kwaye mhlawumbi kwanasemva kokuba i-ΔFosB ichithe amanqanaba aqhelekileyo.

9. Izigqibo

Ipatheni yokwenziwa kwe-ΔFosB kwi-nucleus accumbens ngokuvezwa okungapheliyo kwimivuzo yendalo, uxinzelelo okanye iziyobisi zokuxhatshazwa kuphakamisa umbono oqinisekileyo malunga nokusebenza kweprotein kwesiqhelo kwingingqi yengqondo. Njengoko kubonisiwe kwi Umfanekiso we2, kukho inqanaba elincomekayo le-ΔFosB kwii-nucleus accumbens phantsi kweemeko eziqhelekileyo. Oku kwahlukile kwimimandla ye-striatal, njengoko i-ΔFosB ingabonakali nakwezinye iindawo kwingqondo kwisiseko. Sifumanisa ukuba amanqanaba e-osBFosB kwii-nucleus accumbens abonisa ukufundwa kokuvezwa komntu kukhuthazo lweemvakalelo, zombini ezilungileyo nezingalunganga, ezidityanisiweyo kumaxesha amade exesha elinikwe iiprotheyini zexeshana. Umahluko okwahlukileyo kukucaciswa kweselfowuni ye-ΔFosB ngokwenza umvuzo ngokuchaseneyo nesikhuthazo esiqondakalayo asiqondwa kakuhle, kwaye umsebenzi ongaphezulu uyafuneka ukucacisa iziphumo zomsebenzi zokwahlulahlula. Sigxininisa ngakumbi ukuba njengamanqanaba aphezulu okukhuthaza iimvakalelo ukunyusa i-osBFosB kwi-nucleus eqokelela ii-neurons, ukusebenza kwe-neurons kuguqulwa ukuze babe novakalelo ngakumbi kwisikhuthazo esinomvuzo. Ngale ndlela, ukwenziwa kwe-ΔFosB kuya kukhuthaza inkumbulo enxulumene nomvuzo (okt ngokweemvakalelo) ngeeprojekthi ezichaphazelekayo ze-nucleus accumbens. Phantsi kweemeko eziqhelekileyo, ukwenziwa kwamanqanaba aphakathi e-osBFosB ngokunika umvuzo okanye ukuvuselela intsholongwane kuya kulungelelanisa ngokuphucula uhlengahlengiso lwesilwanyana kwimiceli mngeni yokusingqongileyo. Nangona kunjalo, ukumiliselwa okugqithisileyo kwe-ΔFosB kubonwa phantsi kweemeko zophendlo lwezifo (umz.ukuchaphazeleka okungapheliyo kwichiza lokusetyenziswa gwenxa) kungakhokelela kukhuthazo olugqithisileyo lwe-nucleus accumbens circry kwaye ekugqibeleni ibe negalelo ekuziphatheni kwe-pathological (umz. I-osBFosB yokungeniswa kweminye imimandla yobuchopho inokuba negalelo kwimimandla eyahlukileyo yelizwe elinamakhoboka, njengoko kucetyisiwe kwiziphumo zamva nje zesenzo se-osBFosB kwi-orbitofrontal cortex.

Ukuba le hypothesis ichanekile, iphakamisa umdla onomdla wokuba amanqanaba e-osBFosB kwi-nucleus accumbens okanye mhlawumbi eminye imimandla yobuchopho inokusetyenziswa njenge-biomarker ukuvavanya imeko yokusebenza komjikelezo womntu ngamnye, kunye nenqanaba umntu 'ulikhoboka', zombini ngexesha lokuphuhliswa kwesiyobisi kunye nokuncipha kwaso kancinci ngexesha lokurhoxa okanye kunyango. Ukusetyenziswa kwe-ΔFosB njengommakishi wombono wobukhoboka kubonisiwe kwiimodeli zezilwanyana. Izilwanyana ezisebuntwaneni zibonisa ukutyunjwa okukhulu kwe-DFF xa kuthelekiswa nezilwanyana ezindala, ezihambelana nokukhuselwa kwabo kwingozi (U-Ehrlich et al. 2002). Ukongeza, ukumangalelwa kweziphumo ezinomvuzo ze-nicotine nge-GABA_B I-receptor emihle ye-allosteric module inxulunyaniswa ne-blockade ye-nicotine induction ye-ΔFosB kwi-nucleus accumbens (Mombereau et al. 2007). Nangona kucingelwa kakhulu, kucingeleka ukuba i-molecule encinci ye-PET ligand, enobulungu obuphezulu be-ΔFosB, ingasetyenziselwa ukunceda ekuchongeni ukuphazamiseka okunokulutha kunye nokubeka iliso kwinkqubela phambili ngexesha lonyango.

Okokugqibela, i-ΔFosB uqobo okanye naluphi na uhlobo oluninzi olulawulayo-oluchongwe ngokudweliswa kwe-DNA okanye i-ChIP kwi-chip assays -mele iithagethi ezinokubakho kuphuhliso lonyango olusisiseko lonyango lweziyobisi. Siyakholelwa ekubeni kunyanzelekile ukujonga ngaphaya kweethagethi zamayeza esiqhelo (umzekelo, ii-neurotransmitter receptors kunye nabathuthi) bezinto ezinokubakho kunyango lweziyobisi. Imephu ezikhutshelweyo ze-genome ezibanzi ezinokubakho kubuchwephesha banamhlanje zibonelela ngomthombo othembisayo kwezi njongo zijolise kwimizamo yethu yokuphatha ngcono kwaye ekugqibeleni sinyange ukuphazamiseka okuluthayo.

Imibulelo

Ukutyhila. Umbhali uxela akukho kungqubana kwemidla yokulungiselela olu hlaziyo.

Imihlathi

Igalelo elinye le-17 kwiNtetho yeNtlanganiso yeNgxoxo 'I-neurobiology yeziyobisi: vistas ezintsha'.

· © 2008 Umbutho wasebukhosini

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