LIPOTSO: Bopaki ba hore deltafosb bo tlohella morao bo latele nako e telele kamora ho lemalla tahi. Ho lemalla ka ho khetheha ho baka liphetoho tsa epigenetic, tse lebisang ho kenngeng kapele ho deltafosb ha ho khutlela morao ho etsahala. Sena se hlalosa kamoo ho oela hape, le kamora lilemo ho ka nyolohang ka potlako ho ba naha e lemaletseng lithethefatsi.
J Neurosci. Sengoloa se ngotsoeng; e fumaneha ho PMC 2013 Januari 25.
inahaneloang
ΔFosB, a Fosb sehlahisoa sa mofuta oa gene, se kenyellelitsoe ho nucleus accumbens (NAc) le caudate putamen (CPu) ka ho pepesehela lithethefatsi tsa tlhekefetso joalo ka koae. Ho kenella hona ho etsa hore ho be le mekhoa e fetelletseng ea polelo ea tlhaho le tlhekefetso ea boitšoaro e bonoang ka ho pepeseha hoa lithethefatsi.
Mona, re ile ra lekola hore na nalane e hole ea phumaneho ea lithethefatsi ho likhoto e ka fetola ho se khonehe hoa Fosb gene e holofalitsoe ke ho pepeseha hoa koae. Re bontša hore pele taolo ea koae e sa foleng e lateloa ke ho khaotsa ho eketsehileng, e eketsa ho se khonehe hoa Fosb ho NAc joalo ka ha ho bonts'oa ts'ebetso e matla ea ΔFosB mRNA le ho bokellana ha protheine ea osFosB ka mor'a ho pepesetsoa koae khafetsa. Ha ho na tseko e joalo Fosb induction e ile ea bonoa ho CPu, ha e le hantle, ho kenella ka morao ho matla ha ΔFosB mRNA ho hatisitsoe ho CPu.
Mekhoa ena e sa tloaelehang ea Fosb polelo e amanang le liphetoho tsa chromatin ho Fosb papatso ea gene. Pele tsamaiso ea koae e sa foleng e etsa hore ho be le keketseho ea nako e telele ea RNA polymerase II (Pol II) Fosb ntšetso-pele ea NAc feela, ho fana ka maikutlo a hore nako ea "II" e "sithabetse" Fosb bakeng sa ho kenella seterekeng sena ha o se o pepesehetse koae hape. Phephetso ea koae e ntan'o etsa hore Pol II e tsoe ho morekisi oa liphatsa tsa lefutso, e lumelle kapele haholo Fosb sengoloa. Phephetso ea koae e boetse e fokotsa liphetoho tse ntlafalitsoeng tsa histone ho Fosb papatso ho NAc, empa e eketsa matšoao a joalo a hatellang mme e fokotse matšoao a sebetsang ho CPu.
Liphetho tsena li fana ka leseli le lecha ka matla a chromatin ho Fosb hlohlelletsa le ho senola mochine o mocha oa mokhoa oa ho ngola Fosb ho kenyelletsa NAc ka mor'a ho hlakeloa hape ke koae.
Selelekela
Bokhoba ba lithethefatsi bo tsebahala ka ho batla lithethefatsi le ho e sebelisa ntle le litlamorao tse mpe (Kalivas le al., 2005; Hyman et al., 2006). Ho pepesehela lithethefatsi tse sa feleng ho baka phetoho e sa khaotseng ea polelo ea mofuta oa tlhaho ho "ventral striatum" (kapa nucleus accumbens; NAc) le dorsal striatum (kapa caudate putamen; CPu), meaho ea litheko e kenang moputsong oa lithethefatsi le ho lemalla. (Freeman et al., 2001; Robinson le Kolb, 2004; Shaham le Hope, 2005; Maze le Nestler, 2011). ΔFosB, protheine e tsitsitseng le e tsitsitseng e kentsoeng ke mofuta oa pele, Fosb, ke sengoloa se tsebahalang se hatisitsoeng ho NAc le CPu ka ho pepesehela lithethefatsi tsohle tsa tlhekefetso, moo se arabelang likarabo tsa boitšoaro mabapi le taolo e pheta-phetoang ea lithethefatsi (Nestler, 2008). Leha ho le joalo, hore na ho pepeseha hoa lithethefatsi tsa tlhekefetso tse fetotsoeng ka morao ho ΔFosB ho ntse ho sa tsejoe.
Re sa tsoa tseba hore liphetoho tse tlisoang ke chromatin ka lebaka la ho pepesoa ha lithethefatsi ka nako e telele li ka fetola ho se khonehe hoa liphatsa tsa lefutso tse ikhethang dikarolong tsa bokong (Robison le Nestler, 2011). Bopaki bo ntseng bo eketseha bo bonts'itse hore lithethefatsi tsa tlhekefetso kamora taolo e sa foleng li fetola sebopeho le phihlello ea ho fumaneha ha chromatin ka mefuta e mengata ea liphetoho, ho kenyelletsa phosphorylation, acetylation, le methylation ea mohatla oa histone. Mosebetsi o sa tsoa feta oa litsamaiso tsa setso sa lisele o tsepamisitse tlhokomelo ho hokeng mefuta ea RNA polymerase II (Pol II) ho morekisi oa mefuta ea "e sa sebetseng" pele ho polelo ea bona, 'me Pol II e ts'oarella ho ea literekeng tse ntlafatsang le tikolohong ea ho qala ea mongolo (TSS ) maemong a "tsitsitseng" (Core le Lis, 2008; Nechaev le Adelman, 2008). Ke ts'ebetso ea Pol II e tsitsitseng joale e nahanoa e le eona e ikarabellang bakeng sa ho pholoha ho tsoa lits'ebetsong tsa papatso le TSS le mongolo oa eona oa mofuta ona oa "primed" (Zeitlinger et al., 2007; Saha et al., 2011; Bataille et al., 2012).
Mona, re bonts'a hore ho pepeseha koae ka ho sa feleng ka mor'a nako, ho lateloe ke nako ea ho khaotsa, ho fetola ho se khotsofale ha Fosb gene ho e latelang ea tsamaiso ea koae, ha NAc e ntse e qholotsoa hore e kenngoe ha CPu e se joalo. Ebe re supa li-signature tse hlakileng tsa chromatin ho Fosb papatso ea gene ho NAc le CPu tse amanang le tlhalohanyo e joalo ea Fosb gene, ho kenyelletsoa le ho haptjoa hoa mofuta oa papali ea II seterekeng Fosb morekisi oa proximal ho NAc feela hammoho le liphetoho liphetoho tse 'maloa tse sebetsang kapa tse hatellang histone ka bobeli ba boko. Liphetho tsena li fana ka temohisiso ea ho ithuta ka matla a chromatin ho Fosb mofuta oa papatso mme o bonts'a ka lekhetlo la pele mochini o ts'oarang nako ea nako ea nako ea II Fosb bakeng sa ts'ebetso e kholo ho NAc mabapi le ho pepesehela k'hok'heine.
Lisebelisoa le mekhoa
Animals
Male Sprague Dawley rats (250-275 g; Charles River Laboratories), e sebelisitsoeng litekong tsohle, e ne e le matlo a mabeli ka phapusing e laoloang ke maemo a leholimo mokokotlong oa 12 hr / potoloho e lefifi (mabone ho 7 AM) ka phihlello ea lijo le metsi ad libitum. Liphoofolo tsohle li ne li kenoa habeli ka letsatsi ka matsatsi a leshome ka koae (15 mg / kg, ip) kapa saline (ip) ka har'a matlo a eona. Liteko tsa liphoofolo li amohetsoe ke Komiti ea Tlhokomelo ea Liphoofolo le Ts'ebeliso (IACUC) thabeng ea Sinai.
Litekanyo tsa locomotor
Liphoofolo li ne li lula ka kamoreng ea locomotor ka letsatsi la pele la 1 hr, ebe li beoa leihlo bakeng sa ts'ebetso ea locomotor kamora ho kenngoa ka ente ea saline e sebelisang Sisteme ea Photobeam Acuction System (San Diego Instruments). Kamora ho lula ha 1 hr ho lula ka kamoreng ea locomotor letsatsi le leng le le leng, cocaine (15 mg / kg, ip) e ne e tsamaisoa letsatsi le leng le le leng bakeng sa matsatsi a 2 'me liphoofolo li ile tsa hlahlojoa hape bakeng sa ts'ebetso ea locomotor bakeng sa 1 hr.
Immunohistochemistry
Liphoofolo li ile tsa sebelisoa ka mokhoa o phethahetseng oa 24 hr ka mor'a ho pepesetsoa lithethefatsi tsa ho qetela. Immunoreactivity ea ΔFosB / FosB e fumanoe joalo ka ha ho hlalositsoe (Perrotti et al., 2004). Ho thibeloa ha Bophirimela ho netefalitse hore immFosB / FosB-like immunoreactivity e hlokometse 24 hr kapa nako e telele kamora ho kenngoa liente tsa cocaine ΔFosB, FosB e sa bonahale (e sa bonts'oa).
Boikhethollo ba RNA, transcript transcript, le PCR
Bilateral 12-gauge punches ea NAc le dorsolateral / dorsomedial CPu li fumanoe joalo ka ha ho hlalositsoe (Perrotti et al., 2004), e hoamisoa leqhoeng le omileng mme e sebetsanoe ho latela protocol e phatlalalitsoeng (Covington et al., 2011). ΔFosB le FosB mRNA e lekantsoe ho sebelisoa PCR e ngata (qPCR) ka li-primers tse khethehileng tsa ΔFosB le FosB (Alibhai et al., 2007). Maemo a ΔFosB le FosB mRNA a ne a etselitsoe maemo a GAPDH mRNA, a neng a sa angoe ke ho pepesetsoa hoa koae (e sa bonts'itsoeng).
Bophahamo ba Bophirimela
Litefiso tsa NAc le CPu li ile tsa bokelloa joalo ka holimo 'me tsa sebetsoa bakeng sa ho thibeloa ha Bophirimela joalo ka ha ho hlalositsoe (Covington et al., 2011), e sebelisa li-antibodies khahlanong le ERK44 / 42 [extracellular sign regated kinase-44 / 42] and phosphoERK44 / 42 (pERK), AKT [thymoma viral proto-oncogene] and p-AKT, SRF (serum reaction factor), and PSF [Karolo ea karabo ea cAMP e tlamang protheine], le pCREB. Lenane la liprotheine tse koetsoeng tseleng ka 'ngoe e ne e le maemong a tloaelehileng a litekanyetso tsa actin kapa tubulin, tse neng li sa koaheloe ke ho pepesetsoa koae.
Chromatin immunoprecipitation (ChIP)
Li-punch tse sa tsoa qaptjoa tse sa tsoa qaptjoa le CPu li lokiselitsoe ChIP joalo ka ha ho hlalositsoe (Maze et al., 2010). Boemo bo bong le bo bong ba liteko bo ile ba hlahlojoa ka makhetlo a mararo ho tsoa ho lihlopha tse ikemetseng tsa liphoofolo. Bakeng sa sampuli e 'ngoe le e' ngoe ea ChIP, li-punch tsa NAc le CPu li ile tsa katoa ho tsoa ho likhoto tse hlano (10 punches). Li-antibodies tse sebelisitsoeng bakeng sa liphetoho tse ikhethang tsa histone li tšoana hantle le tse phatlalalitsoeng (Maze et al., 2010); li-antibodies ho Pol II phosphorylated ho Ser5 ea eona ea "carboxyl terminal domain" (CTD) ea phetolo ea tikoloho (Pol II-pSer5) e fumanoe ho abcam 5131. Likheo tse 'ne tsa li-primers tsa ChIP li etselitsoe Fosb (Lazo et al., 1992; Mandelzys et al., 1997): 1F: GTACAGCGGAGGTCTGAAGG, 1R: GAGTGGGATGAGATGCGTT; 2F: CATCCCACTCGGCCATAG, 2R: CCACCGAAGACAGGTACTGAG; 3F: GCTGCCTTTAGCCAATCAAC, 3R: CCAGGTCCAAAGAAAGTCCTC; 4F: GGGTGTTTGTGTGTGAGTGG, 4R: AGAGGAGGCTGGACAGAACC. Maemo a liphetoho tsa chromatin a bapisoa le a DNA ea ho kenyelletsa joalo ka ha ho hlalositsoe (Maze et al., 2010).
Tlhahlobo ea statistical
Litekanyetso tsohle tse tlalehiloeng li bolela ± sem Data ea ts'ebetso ea motlakase le ho bala lisele li ile tsa hlahlojoa ke li-ANOVA tse peli ka kalafo le ente e le lintlha. Liteko tsa qPCR li ile tsa hlahlojoa ka nako ka nako ke li-ANOVA tsa tsela e le 'ngoe tse nang le kalafo. Ha ho bonoa litlamorao tse kholo (p <0.05), liteko tsa Bonferroni post-hoc li ile tsa etsoa bakeng sa papiso le liphoofolo tse tšoaroang ka letsoai le nang le lithethefatsi (^ ka lipalo) le liphoofolo tse tšoaroang ke cocaine (* lipalo). Liteko tsa baithuti tsa mehatla e 'meli tse se nang mehatla li sebelisitsoe bakeng sa ho hlakola Bophirima le data ea ChIP, ka litokiso bakeng sa papiso e mengata.
Results
E kholoanyane Ho ithutetsoa ha Fosb ho NAc, empa eseng CPu, ea litoeba tse nang le koae
Ho hlahloba tšusumetso ea nako e telele ea koae ea koae, e lateloang ke nako e telele ea ho tlohela, ka ho se khonehe Fosb gene ho latela phephetso e ileng ea latela ea koae, litoeba tse neng li tsoaetsoa habeli letsatsi le letsatsi ka saline kapa cocaine (15 mg / kg) bakeng sa matsatsi a 10 li fuoe litekanyetso tsa phephetso ea lithethefatsi kamora matsatsi a 28 a ho tlohela (Setšoantšo sa 1A). Pele re ile ra lekanya likarabo tsa locomotor sehlopheng se le seng sa liphoofolo ho netefatsa ho kenella ha maikutlo a locomotor ka ho pepesetsoa ha koae, litholoana tse lebelletsoeng tsa taolo ea lithethefatsi. Likhoto tse nang le tsebo ea Cocaine le -naïve li bonts'itse ts'ebetso ea mantlha e tšoanang, ka phephetso ea koae ho liphoofolo tse se nang lithethefatsi tse eketsang thipa ea tsona (Setšoantšo sa 1B. Mehato e phetoang makhetlo a mabeli ANOVA, kalafo: F1,66 = 30.42, p <0.0001; Phephetso ea koae: F2,66= 58.39, p <0.0001; kalafo phephetso ea k'hok'heine: F2,66= 8.56, p = 0.0005, liteko tsa morao-rao tsa Bonferroni ^P <0.001). Phephetso ena ea k'hok'heine e bakile tšebetso e matla haholo ea bo-locomotor, ke hore, ho matlafatsa likhoto tse nang le boiphihlelo ba k'hok'heine (Bonferroni post-liteko * p <0.001).
Ho lekola litlamorao tsa mofuta ona oa "cocaine-pretreatment regimen" ka polelo ea ΔFosB ho NAc le CPu, re lekantse protheine ea ΔFosB ka mekhoa ea immunohistochemical 24 hr kamora hore liphoofolo tse nang le cocaine-naïve le cocaine li tšoaroe ka 0, 1, 3, kapa phephetso ea cocaine ea letsatsi le letsatsi ea cocaine. liente (6 mg / kg; bona Setšoantšo sa 1A). Joalokaha ho thehiloe pele (Nye et al., 1995), Liente tsa 3 tsa koae li ne li lekane ho kenya protheine ea ΔFosB haholo ho NAc le CPu ea liphoofolo-na drugve ea liphoofolo mme ho bokellana ha eona ho ile ha lula ho le bohlokoa kamora matsatsi a 6 ea li-cocaine tsa cocaine (Setšoantšo sa 1C. Mehato e phetoang makhetlo a mabeli ANOVA, NAc mantlha, kalafo: F1,28= 23.5, p <0.0001; Phephetso ea koae: F3,28= 49.16, p <0.0001; kalafo phephetso ea k'hok'heine: F3,28= 6.83, p = 0.0014; NAc khetla, kalafo: F1,28= 18.69, p <0.0001; Phephetso ea koae: F3,28= 31.52, p <0.0001; kalafo phephetso ea k'hok'heine: F3,28= 3.21, p <0.05; CPu, kalafo: F1,28= 9.47, p <0.001; Phephetso ea koae: F3,28= 19.74, p <0.0001; kalafo phephetso ea k'hok'heine: F3,28= 0.94, leq> 0.05. Ka konokono ea NAc, khetla, le CPu, liteko tsa kamora liteko tsa Bonferroni ^P <0.05). Liphoofolong tse nang le boiphihlelo ba k'hok'heine, ho ne ho se na bopaki ba ho phehella ha ΔFosB ho kenella ho NAc kapa CPu kamora matsatsi a 28 a ho tlohela, ho latela litlaleho tsa pejana hore lets'oao la ΔFosB le qhalana ka botlalo ka nako ena (Nye et al., 1995), lebaka leo nako ena e sebelisitsoeng ka lona thutong ena. Ho makatsang, leha ho le joalo, litoeba tse nang le koae ea cocaine tse fuoeng li-3 kapa liente tsa 6 tsa cocaine li ile tsa bonts'a tlhahiso ea protheine ea ΔFosB e kholo ho NAc, phello e hlahang ho likarolo tse tlase tsa mantlha le tsa khetla (Setšoantšo sa 1C. Litlhahlobo tsa poso tsa Bonferroni * p <0.05). Ka lehlakoreng le leng, ha ho ho kenyelletsoa ho hoholo ha protheine ea osBFosB ho CPu; Sebakeng seo, ho kenella ka mokhoa o lekanang oa ΔFosB ho ile ha bonoa sebakeng sena kamora matsatsi a 3 kapa a 6 a liente tsa phephetso ea koae likhopong tsa cocaine-naïve le tse nang le boiphihlelo (Setšoantšo sa 1C).
Ho fumana temohisiso mabapi le liphetoho tse ngotsoeng ho NAc le CPu ho araba phephetso ea koae, re ithutile nako ea (45, 90, le 180 min) ea ho se khonehe ha lingoliloeng tsa ΔFosB le FosB mRNA hodima jarete e le 'ngoe ea cocaine kapa saline e fanoeng ho li-cocaine-naïve le-litekete tse fetotsoeng kamora matsatsi a 28 a ho tlohela (bona Setšoantšo sa 1A). E amanang le phephetso ea letsoai, phephetso ea koae e bakile keketseho e potlakileng ea maemo a ΔFosB le FosB mRNA ka linako tsohle tse tharo maemong a NAc le CPu a liphoofolo tse bitsoang cocaine-naïve (Setšoantšo sa 1D. Mehato e phetoang khafetsa ka tsela e le 'ngoe ANOVA ka nako ea nako; Litlhahlobo tsa kamoso ea Bonferroni ^P <0.05). Ho NAc, re hlokometse hore ΔFosB e kholo le FosB mRNA e kenella liphoofolong tse nang le boiphihlelo ba cocaine ha e bapisoa le liphoofolo tsa cocaine-naïve kamora phephetso ea cocaine, phello e le bohlokoa ho 90 min ha, ka lehlakoreng le leng, ho hloleha ha ΔFosB le FosB mRNA ho CPu ho ne ho le bohlokoa haholo fokotseha liphoofolong tse nang le boiphihlelo ba cocaine (Setšoantšo sa 1D. Litlhahlobo tsa kamoso ea Bonferroni %p = 0.08, * le <0.05).
Tšobotsi ea lits'oaetso tse hloahloa tsa NAC le CPu tsa litoeba tse nang le koae
Tlhaloso e le 'ngoe bakeng sa phetoho e fetotsoeng ea Fosb gene ea NAc le CPu kamora 'nete ea ho tsuba ea koae ke hore nalane ea ho pepesetsoa hoa koae e ka baka liphetoho tse sa feleng lits'ebetsong tse tšoaeang litsela Fosb mofuta oa mofuta oa gene hoo phephetso ea koae e ka kenang ho etsa hore mofuta oa jero e fihle. Ho ithuta khopolo-taba ena, re ile ra sekaseka lintlha tse peli tsa mongolo, SRF le CREB, tse bonts'itsoeng morao tjena hore li hloka ho etsoa ka koae ka ΔFosB libakeng tsena tsa boko (Vialou et al., 2012) hammoho le li-kinases tsa protheine tse nyolohang, ERK le AKT, le tsona li na le tšusumetso ts'ebetsong ea koae.Valjent et al., 2000; Lu et al., 2006; Boudreau et al., 2009). Ha rea atleha ho bona liphetoho lipakeng tsa liprotheine tsena tse fapaneng tse ka hlalosang tšusumetso e fetotsoeng ea Fosb e bonoe, ho kenyelletsa liphetoho lipakeng tsa SRF, CREB, kapa AKT (Feiga 2B, C). Ho haella ha phetoho ho pSRF le pCREB ho NAc ho arabela phephetso ea koae ho tsamaisana le tlaleho ea morao-rao, e fumanoeng ka bobeli e hlahisoa haholo ke cocaine e sa foleng feela (Vialou et al., 2012).
Ho NAc le CPu ea liphoofolo tse nang le lithethefatsi, 20 min kamora ho hlahella ha lithethefatsi tsa pele (Setšoantšo sa 2A), phephetso e le 'ngoe ea cocaine e fokotsehile litekanyetso tsa pERK42 / 44 (Feiga 2B, C. T-teko ea baithuti ba babeli ba tailed: * p <0.05). Ho na le litlaleho tsa pejana tsa litekanyetso tse eketsehang tsa 'mele libakeng tsena kamora tsamaiso e matla ea koae (Valjent et al., 2000). Sena se thata ho se bapisa le lipampiri tse ling tse hlahlobang phosphorylation ea ERK ho NAc nakong ea ho khaotsa ho entoa ka makhetlo a seng makae a cocaine (Boudreau et al., 2007; Shen et al., 2009), joalo ka ha PERK ea rona ea ho ithuta e ile ea hlakoloa kamora matsatsi a 28 a ho tlohela le ka mor'a phephetso ea koae kapa saline. Ho amana le liphoofolo tse nang le lithethefatsi tse nang le koae ka lekhetlo la pele, ho pepesetsoa hape koae ho likhoto tse nang le koae, ka mor'a matsatsi a 28 a ho tlohela, ho bakile keketseho e kholo maemong a PERK42 / 44 ho CPu (Feiga 2B, C. Teko ea moithuti a mabeli a mohatla: * p <0.05).
Chromatin landschap at Morekisi oa mofuta oa Fosb ho NAc le CPu ea litoeba tse nang le koae
Ka mor'a moo re ile ra etsa lipatlisiso tsa hore na liphetoho li teng Fosb ho se sebetse hantle ha liphatsa tsa lefutso ho amana le liphetoho tse teng sebopeng sa eona sa chromatin. ChIP e entsoe ho NAc le CPu e sebelisa li-antibodies tse lebisitsoeng khahlanong le mefuta e meraro e tsebahalang ea liphetoho tsa histone: trimethylation of Lys4 of histone H3 (H3K4me3) amanang le gene activation, le H3K27me3 le H3NUMX le H9NUMXNXXUMUM2NUM28NUMXIUM1 Re ile ra sekaseka likhoto tsa cocaine-naïve le -experienced kamora matsatsi a XNUMX a ho ntsha ka ntle le kapa ka ente ea phephetso ea koae, ha liphoofolo li hlahlobile XNUMX hr hamorao (Setšoantšo sa 3A). Ho NAc, ha rea fumana liphetoho tse kholo tlamong ea liphetoho leha e le life tse tharo tsa histone ho Fosb Morekisi oa mofuta oa gene ha ho na phephetso ea koae, leha ho le joalo ho ne ho e-na le tloaelo ea maemo a fokotsitsoeng a H3K9me2 (Mofuta oa 3B-D. Liteko tse peli tsa teko ea Moithuti. #p = 0.2 ha e bapisoa le taolo e fapaneng ea Drug Naïve). Phello ena e bile ea bohlokoa kamora phephetso ea koae 'me e ne e ikhethile bakeng sa tikoloho e khothalletsang ea mofuta oa gene (Setšoantšo sa 3C. * p <0.05). Le ha maemo a H3K9me2 a le tlase haholo liphatseng tse ling tsa lefutso, Fosb Morekisi oa mofuta o bonts'a maemo a ananeloang a letšoao lena ho NAc tlasa maemo a taolo (Maze et al., 2010, data e sa bontsitsoeng). Ka lehlakoreng le leng, ho CPu, re fumane ho fokotseha ho fokolang empa ho le bohlokoa ho H3K4me3 binding, le ho eketseha ha H3K27me3 binding, Fosb papatso ha ho se na phephetso ea koae, litlamorao tse lahlehileng kamora phephetso (Setšoantšo sa 3D. * p <0.05).
Ka mor'a moo re ile ra etsa lipatlisiso tsa hore na Pol II e amana joang le Fosb gene, e ipapisitseng le liphumano tsa morao-rao litloaelong tsa sele e fumanehang ho Pol II ho TSSs, e tsebahalang ka phosphorylation ho Ser 5 seterekeng sa eona sa pheta-phetiso sa CTD, e amahanngoa le ho bokella liphatsa tsa lefutso (bona matseno). Ka hona re ile ra sekaseka Pol II-pSer5 e tlamehang ho Fosb libakeng tse 'ne tse ikhethang tsa mofuta oa gene (Setšoantšo sa 3B). Tlhahlobo ena e senotse ntlafatso e kholo ea Pol II-pSer5 ho Fosb gene sebakeng sa eona sa proximal promoter le ho potoloha TSS ea eona ho NAc ea liphoofolo tse nang le boiphihlelo ba koae, kamora ho khaotsa nako e telele, ho se phephetso ea phephetso ea koae ha e bapisoa le taolo (3E ea setšoantšo. * p <0.05). Nts'etsopele ena e ne e sa bonahale libakeng tse peli tsa 'mele oa liphatsa tsa lefutso Fosb, e tsamaellanang le maemo a lipalo a II a hlalosoang litsamaisong tse bonolo tsa liteko. Ho khahlisang ke hore, ka mor'a phephetso ea koae, polokeho ea Pol II-pSer5 e ntse e bonts'a matšoao a ho ruisa, leha e se e se a bohlokoa haholo ho Fosb proxer kgothaletsa tikoloho (3E ea setšoantšo. %p = 0.1), empa e khutletse maemong a taolo ho TSS. Se fumanoeng ho CPu se ne se feto-fetoha le ho feta, ho se na sebopeho se hlakileng sa Pol II-pSer5 e hlokometsoeng.
Puisano
Boithuto ba hona joale bo fana ka leseli le lecha mabapi le taolo e tsitsitseng ea Fosb libeke kamora ho khaotsa ho khahloa ke koae khafetsa. Re bontša hore pele tsamaiso e sa foleng ea koae e fana ka Fosb mofuta oa gene o sa sebetseng ho NAc, o lebisang ho bokelleloa ha ΔFosB ka potlako mabapi le moriana hape. Ho fanoa ka tlhaiso-leseling ea bopaki ba hore ΔFosB induction ho NAc e hokahanya likarabo tsa boitšoaro tse amang cocaine (Nestler, 2008), seo re se fumaneng se senola mokhoa o mocha oa ho khutlisetsa kapele likarabo tse joalo tsa maikutlo ka mor'a ho tlohela nako e telele.
Re bonts'a hore induction e ntlafalitsoeng ea ΔFosB ho NAc e amana le liphetoho tsa chromatin ho Fosb gene eo ho ka lebelloang hore e ka e etella pele bakeng sa tlhahiso e kholo. Ka hona, re bonts'a polokeho ea Pol II e tlamang ho proximal promoter le TSS libaka tsa mofuta o teng kamora libeke tsa 4 tsa ho tlohela ho tsoa taolong ea cocaine e sa foleng. Katiso e joalo ea Pol II ho TSS e lahleha ka potlako ho phephetso ea koae le Fosb induction, e lumellanang le mohlala moetlong oa sele e hopotseng hore Pol II e lokollotsoe ho li-TSSs on gene activation (bona Selelekela). Phephetso ea koae e boetse e baka ho fokotseha ka potlako ha H3K9me2 - letšoao la khatello ea gene — ho Fosb morekisi. Ho fapana le hoo, ha re bone hore ho na le ntho e sa feleng e tlisoang ke lintlha tse 'maloa tsa mongolo, kapa tsa mabitso a bona a holimo-limo, a tsejoang ka mokhoa oa ho buisana Fosb tlhahiso ka koae. Liphetho tsena li ts'ehetsa monahano oa rona oa hore ΔFosB e ntlafalitsoeng ho NAc e kopantsoe ka priming ea epigenetic Fosb liphatsa tsa lefutso eseng ka tšohanyetso ea liketsahalo tse hlahelletseng.
Liphetho tse fapaneng haholo li fumanoe bakeng sa CPu. Ho ne ho se na bopaki ba hore o ts'oenyeha ka Pol II Fosb likoteng tse nang le boiphihlelo ba koae pele ho phephetso ea koae, leha ho ne ho e-na le liphetoho tse nyane empa tsa bohlokoa tsa histone tse tsamaellanang le khatello ea mofuta: ho eketsa H3K27me3 ho tlama le ho fokotsa H3K4me3 binding. Hape ha ho na phetoho ea lintlha tse nyolohang tsa transcript kapa li-kinase tse tsamaellanang le tse fokotsehileng Fosb tlhahiso. Liphumano tsena li fana ka maikutlo a hore ka mor'a taolo ea koae e sa foleng, liphetoho tse amanang le epigenetic li thusa ho kokobela Fosb mofuta oa ho se ithute ka mofuta oa CPu, ho fapana le priming e bonoeng ho NAc. Leha ho le joalo, leha litlamorao tsena li hatella tlhahiso ea ΔFosB mRNA ha e pepesetsoa k'hok'heine, ha ho na tahlehelo ea letho ka ho bokella protheine ea BFosB. Mokhoa o thehileng pherekano ena joale o hloka hore ho etsoe lipatlisiso tse ling.
Ka kakaretso, liphetho tsa rona li ts'ehetsa mohlala moo liphetoho tse bang teng tikolohong ea chromatin ka mefuta e ikhethileng mabapi le ts'ebetso ea ts'ebetso ea koae e sa sebetseng kapa e sokolle mefuta eo bakeng sa ho kenella ts'ebelisong ea moriana hape. Liphetoho tse joalo tsa chromatin, tse ka bonoang e le "maqeba a epigenetic," li ka fetoa ha ho hlahlojoa maemo a tsoalo a boemo ba mRNA. Ka tsela ena, ts'oaetso ea epigenome ea ts'ebeliso ea lithethefatsi e ts'episa ho senola tlhahisoleseling bocha mabapi le molek'hule ea pathogenesis ea lefu lena, e ka fokotsoang bakeng sa nts'etsopele ea mekhoa e mecha ea phekolo.
Liteboho
Mosebetsi ona o ile oa tšehetsoa ke lithuso tse tsoang Setsing sa Naha sa Ts'ebeliso e Mpe ea Lithethefatsi.
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