LITLHAHISO: Eric Nestler o fana ka lintlha tse ngata mabapi le DeltaFosB le bokhoba ba tahi. (Ho se ho fumanoe tse ling.) Ka mantsoe a bonolo feela, DeltaFosB e phahama ka potoloho ea moputso ho arabela tšebeliso e mpe ea lithethefatsi tsa tlhekefetso le meputso e meng ea tlhaho. Morero oa eona oa ho iphetola ha lintho ke hore u e fumane ha ho ntse ho e-ba hantle (lijo le thobalano) - ke hore, ho matlafatsa setsi sa moputso. Leha ho le joalo, mefuta e sa tloaelehang ea meputso ea tlhaho e ka lebisa ho ts'ebeliso e fetelletseng le ho bokelleng DeltaFosB… le liphetoho tsa boko tse bakang litakatso tse ngata le binging e ngata. Ho khahlisang ke hore bacha ba hlahisa DeltaFosB e ngata haholo ho feta batho ba baholo, ke lona lebaka le leng le etsang hore ba be bonolo ba ho lemalla.
10.1098 / rstb.2008.0067 Phil. Trans. R. Soc. B 12 Mphalane 2008 vol. 363 che. 1507 3245-3255
+ Boikarabello ba Mongoli Lefapha la Neuroscience, Sekolo sa Bongaka sa Mount Sinai
New York, NY 10029, USA
inahaneloang
Molao oa polelo ea liphatsa tsa lefutso o nkuoa e le mokhoa o utloahalang oa ho lemalla lithethefatsi, ka lebaka la botsitso ba boitšoaro bo sa tloaelehang bo hlalosang boemo ba bokhoba. Har'a lintlha tse ngata tsa sengoloa tse tsejoang ho susumetsa ts'ebeliso ea lithethefatsi, e 'ngoe ea tse tsebahalang ka ho fetesisa ke ΔFosB, e kenelletseng libakeng tsa moputso oa boko ka ho pepesehela hoo e batlang e le lithethefatsi tsohle tsa tlhekefetso le ho arabela likarabo tse matlafatsang pontsong ea lithethefatsi. Kaha ΔFosB ke protheine e tsitsitseng, e emela mokhoa oo ka ona lithethefatsi li hlahisang phetoho e sa feleng polelong ea liphatsa tsa lefutso nako e telele kamora ho felisoa ha tšebeliso ea lithethefatsi. Boithuto bo ntse bo tsoela pele ho hlahloba mekhoa e qaqileng ea limolek'hule eo ΔFosB e laolang liphatsa tsa lefutso mme e hlahise litlamorao tsa eona.. Re ntse re atamela potso ena re sebelisa litlhaloso tsa polelo ea DNA, hammoho le tlhahlobo ea tokiso ea chromatin, liphetoho liphetoho tsa nalane ea bongaka ho baphatlalatsi ba gene ba laoletsoeng ke lithethefatsi, ho tseba liphatsa tsa lefutso tse laoloang ke lithethefatsi tsa tlhekefetso ka ts'ebetso ea ΔFosB le ho fumana temohisiso. ka mekhoa e qaqileng ea limolek'hule tse amehang. Liphumano tsa rona li theha ho nchafatsoa ha chromatin e le mokhoa oa bohlokoa oa taolo o khothalletsoang ke lithethefatsi, 'me re ts'episa ho senola temohisiso e ncha mabapi le hore na ΔFosB e kenya letsoho joang tlatsong ka ho laola polelo ea mefuta e ikhethang ea sepheo tseleng ea moputso oa boko.
1. Selelekela
Boithuto ba mekhoa ea ho lemalla ho tlatsana le lithethefatsi bo thehiloe khopolong ea hore molaoana oa tšebeliso ea liphatsa tsa lefutso ke mokhoa o mong o bohlokoa oo ka oona ho pepesetsoa ts'ebetsong ea tlhekefetso ho bakang phetoho ea nako e telele bokong, e tlatselletsang tlhekefetso ea boitšoaro e hlalosang boemo ba bokhoba. (Nestler 2001). Taba-kholo ea khopolo-taba ena ke hore liphetoho tse tlisoang ke lithethefatsi ho fetisetsoa ho dopaminergic le glutamatergic le morphology ea mefuta e meng ea lisele tsa neuronal bokong, e kopantsoeng le boemo ba tlhekefetso, li kopantsoe le karolo ka phetoho ea polelo ea mofuta.
Mosebetsi lilemong tse 15 tse fetileng o fane ka bopaki bo ntseng bo eketseha ba karolo ea ponahalo ea liphatsa tsa lefutso bokhobeng ba lithethefatsi, joalo ka ha lintlha tse 'maloa tsa phetolelo-liprotheine tse amanang le likarolo tse ikhethileng tsa likarabo libakeng tsa liphatlalatso tsa liphatsa tsa lefutso le ho laola polelo ea tsona - li kentsoe letsoho ho ketso ea lithethefatsi. Mehlala e tsebahalang e kenyelletsa ΔFosB (protheine ea lelapa ea Fos), protheine e tlamang (CREB), cAMP-replicationor ea pele (ICER), lintlha tsa ts'ebetso ea ho ngola (li-ATF), liprotheine tsa kholo ea karabelo ea peleho (EGRs), li-protein tsa li-1 (NAC1) ), ntho ea nyutlelie e bitsoang κB (NF VerB) le glucocorticoid receptor (O'Donovan et al. 1999; Mackler et al. 2000; Ang et al. 2001; Deroche-Gamonet et al. 2003; Carlezon et al. 2005; Green et al. 2006, 2008). Tlhahlobo ena e shebile haholo ho ΔFosB, e hlahang e bapala karolo e ikhethileng ts'ebetsong ea bokhoba ba litekanyetso, joalo ka mokhoa oa ho bontša mefuta ea mekhoa ea liteko e sebelisitsoeng ho etsa lipatlisiso tsa mekhoa ea bongoli.
2. Tlhahiso ea ΔFosB ho li-nucleus e bokellanang ka lithethefatsi tsa tlhekefetso
ΔFosB e kentsoe ke mofuta oa fosB (Setšoantšo sa 1) hape o arolelana thuto ea lapeng le lintlha tse ling tsa ho fetisoa ha lelapa la Fos, tse kenyelletsang c-Fos, FosB, Fra1 le Fra2 (Morgan le Curran ka 1995). Liprotheine tsena tsa malapa tsa Fos heterodimerize le liprotheine tsa lelapa tsa Jun (c-Jun, JunB kapa JunD) ho theha li-protocol tse sebetsang tsa protheine-1 (AP-1) tse lumellanang le libaka tsa AP-1 (tatellano ea tumellano: TGAC / GTCA) e teng ka har'a Barekisi ba liphatsa tsa lefutso tse itseng ho laola sengoloa sa bona. Liprotheine tsena tsa malapa tsa Fos li kenella ka potlako le ka nako e telele libakeng tse itseng tsa boko kamora ho tsamaisoa ha lithethefatsi tse ngata tsa tlhekefetso (Setšoantšo sa 2; Graybiel et al. 1990; Mocha et al. 1991; Tšepo et al. 1992). Likarabo tsena li bonoa ka mokhoa o hlahelletseng ho li-nucleus accumbens le dorsal striatum, e leng babuelli ba bohlokoa ba liketso tse thabisang le tsa locomotor tsa lithethefatsi. Li-protein tsena tsa malapa tsa Fos, leha ho le joalo, ha li na botsitso ebile li khutlela maemong a basel ka mor'a lihora tse ngata tsa tsamaiso ea lithethefatsi.
Setšoantšo sa 1
Motheo oa biochemical oa botsitso bo ikhethang ba ΔFosB: (a) FosB (338 aa, Mr joalo ka. 38 kD) le (b) ΔFosB (237 aa, Mr approx. 26 kD) li kentsoe ka har'a mofuta oa fosB. OsBFosB e hlahisoa ka mefuta e meng ea ho qhekella 'me ha e na C-terminal 101 amino acid e teng ho FosB. Ho tsebahala ka mekhoa e 'meli e ikarabellang bakeng sa botsitso ba ΔFosB. Taba ea mantlha, ΔFosB ha e na libaka tse peli tsa bonyaluoa tse fumanehang ho C-terminus ea FosB e bolelele bo felletseng (mme e fumanoe le liprotheineng tse ling tsa malapa tsa Fos hape). E 'ngoe ea libaka tsena tsa degron e shebile FosB bakeng sa ho fumaneha hohle le ho senyeha ha proteasome. Sebaka se seng sa degron se shebile ho senyeha ha FosB ka mokhoa o ikemetseng oa ubiquitin- le proteasome. Taba ea bobeli, osBFosB e entsoe ka phosphorylated ke casein kinase 2 (CK2) mme mohlomong ke li-protein kinases tse ling?? Ho N-terminus ea eona, e tsoelang pele ho tsitsisa protheine.
Setšoantšo sa 2
Morero o bonts'a ho bokella butle-butle ha ΔFosB ha ho bapisoa le ho itšireletsa ka potlako le ka nakoana ha liprotheine tse ling tsa lelapa la Fos ho arabela lithethefatsi tsa tlhekefetso. (a) Autoradiogram e bonts'a ho kenella ka mokhoa o fapaneng oa liprotheine tsa lelapa tsa Fos ka har'a li-nucleus tse bokellanang ka ho hlohlelletsa ho matla (lihora tsa 1-2 kamora ho pepesetsoa ke koae e le 'ngoe) khahlanong le ho hlohlelletsa ho sa feleng (letsatsi la 1 kamora ho pepesetsoa ha koae). (b). tlhekefetso ya tlhekefetso. Ho boetse ho susumetsoa ke li-isoforms tse fetotsoeng biochemically tsa ΔFosB (33-1 kD); ba ts'oaroa ka maemo a tlase ka tsamaiso ea lithethefatsi tse mpe, empa ba phehella bokong nako e telele ka lebaka la botsitso ba bona. (ii) Ka tsamaiso ea lithethefatsi tse pheta-phetoang (mohlala habeli ka letsatsi), ts'usumetso e 'ngoe le e' ngoe e mpe e etsa hore boemo bo tlase ba li-isoforms tsa ΔFosB bo be le botsitso. Sena se bontšoa ke setera se tlase sa mela e fetang moo e bonts'ang ΔFosB e khothalletsoang ke ts'usumetso e 'ngoe le e' ngoe e mpe. Sephetho ke keketseho ea butle-butle maemong ohle a ΔFosB a susumetsoang khafetsa nakong ea kalafo e sa foleng. Sena se bontšoa ke mohala o ntseng o eketseha oa graph.
Likarabo tse fapaneng haholo li bonoa kamora taolo e sa feleng ea lithethefatsi tsa tlhekefetso (Setšoantšo sa 2). Li-isoforms tse fetotsoeng biochemically tsa ΔFosB (Mr 35-37 kD) e bokellana kahare ho likarolo tse tšoanang tsa boko kamora ho pepesetsoa lithethefatsi khafetsa, athe litho tse ling tsa lelapa la Fos li bonts'a mamello (ke hore, ho kenella ka tlase ho bapisoa le ho hlahisoa ha lithethefatsi tsa pele; Chen et al. 1995, 1997; Hiroi et al. 1997). Ho bokella ho joalo ha ΔFosB ho hlokometsoe hoo e batlang e le lithethefatsi tsohle tsa tlhekefetso (tafole 1; Tšepo et al. 1994; Nye, et al. 1995; Moratalla et al. 1996; Nye & Nestler 1996; Pich et al. 1997; Muller le Unterwald 2005; McDaid et al. 2006b), leha lithethefatsi tse fapaneng li fapana ka tekanyo e lekanang ea ho kenella e bonoang ho nucleus e bokella mantlha ha e bapisoa le khetla le dorsal striatum (Perrotti et al. 2008). Bonyane bakeng sa lithethefatsi tse ling tsa tlhekefetso, ho kenngoa ha ΔFosB ho bonahala e le khetho bakeng sa setlhare se nang le "dynorphin" se nang le methapo ea methapo ea kutlo e bohareng e fumanehang libakeng tsena tsa boko (Nye, et al. 1995; Moratalla et al. 1996; Muller le Unterwald 2005; Lee et al. 2006), leha ho hlokahala mosebetsi o mongata ho netefatsa sena. The 35-37 kD isoforms ea ofFosB e nyamela haholo le JunD ho theha mofuta o sebetsang oa nako e telele oa AP-1 ka har'a libaka tsena tsa boko (Chen et al. 1997; Hiroi et al. 1998; Pérez-Otao et al. 1998). Tlhahiso ea lithethefatsi ea ΔFosB bokong ba li-nucleus e bonahala e le karabelo ho lithahasello tsa lithethefatsi ka setheo ka seng mme ha e amana le tšebeliso e mpe ea lithethefatsi, hobane liphoofolo tse itlhommeng koae kapa li amohela liente tsa joala tse kopantsoeng li bonts'a induction e lekanang ea tlhahiso ena sebakeng sena sa boko (Perrotti et al. 2008).
Lethathamo 1
Lithethefatsi tsa tlhekefetso tse tsejoang ho hohela ΔFosB ka li-nucleus tsaqwebu ka mor'a taolo e sa foleng.
| li-opiatesa |
| k'hok'heinea |
| amphetamine |
| methamphetamine |
| bokoalia |
| ethanola |
| phencyclidine |
| cannabinoids |
· ↵tlhahiso e tlalehiloeng bakeng sa lithethefatsi tse itaolang ntle le ts'ebeliso ea lithethefatsi tse laoloang ke lipatlisiso. Tlhahiso ea lithethefatsi ea ΔFosB e bonts'itsoe litoeba le litoeba ka bobeli, ntle le tse latelang: mouse feela, cannabinoids; rat feela, methamphetamine, phencyclidine.
The 35-37 kD ΔFosB e bokellana ka ho pepesetsoa lithethefatsi ka nako e telele ka lebaka la bophelo ba bona bo bolelele bo bolelele ba nako e telele. (Chen et al. 1997; Alibhai et al. 2007). Ka lehlakoreng le leng, ha ho na bopaki ba hore ho qaptjoa ha ΔFosB kapa botsitso ba mRNA ea eona bo laoloa ke tsamaiso ea lithethefatsi. Ka lebaka la botsitso ba eona, protheine ea ΔFosB e phehella li-neuron bonyane libeke tse 'maloa ka mor'a ho felisoa ha lithethefatsi. Joale rea tseba hore khutso ena e bakoa ke lintlha tse peli tse latelang (Setšoantšo sa 1): (i) ho ba sieo hoa libaka tse peli tsa bosholu ho ΔFosB, tse teng C-terminus ea FosB e bolelele bo felletseng le liprotheine tsohle tse ling tsa lelapa la Fos 'me li shebile liprotheine tseo hore li senyehe kapele le (ii) phosphorylation ea ΔFosB ho eona N-terminus ka casein kinase 2 mohlomong le li-protein tse ling tsa liproteine (Ulery et al. 2006; Carle et al. 2007). Tbotsitso ba ΔFosB isoforms e fana ka mochini oa limolek'hule o hlahisoang ke liphetoho tse khothalletsoang ke lithethefatsi ho sa natsoe nako e telele ea ho khaotsa lithethefatsi. Ka hona, re rerile hore ΔFosB e sebetse e le 'switch ea limolek'hule' e thusang ho qala le ho boloka boemo ba ho lemalla (Nestler et al. 2001; McClung et al. 2004).
3. Karolo ea ΔFosB ho li-nucleus bokellanang ho laola likarabo tsa boitšoaro ho lithethefatsi tsa tlhekefetso
Tlhahiso ea karolo ea ΔFosB ts'ebetsong ea lithethefatsi tsa lithethefatsi e tsoa haholo ho tsoa thutong ea litoeba tsa bitransgenic tseo ho tsona ΔFosB e ka qobelloang ka mokhoa o ikhethileng ka har'a li-nucleus tse bokelletsoeng le dorsal striatum ea liphoofolo tse kholo (Kelz et al. 1999). Taba ea bohlokoa, litoeba tsena Overexpress ΔFosB ka mokhoa o ikhethileng methapong ea methapo ea methapo ea methapo, e lumelang e baka proteni. Mokhoa oa boits'oaro oa litoeba tsa ΔFosB-overexpressing, tseo ka tsela tse itseng li tšoanang le liphoofolo kamora ho pepeseha lithethefatsi tse sa foleng, li akaretsoa ho tafole 2. Lintšu li bontša likarabo tse matlafatsoang tsa koae ka mor'a ts'ebetso e mpe le e sa foleng (Kelz et al. 1999). Li bonts'a kutloisiso e ntlafalitsoeng ea litlamorao tse khahlisang tsa koae le morphine litlamong tsa maemo a sebaka ((Kelz et al. 1999; Zachariou et al. 2006), le ho ipeha tekanyetso e tlase ea cocaine ho feta batho ba sa tsubang ba sa feteng thatFosB (Colby et al. 2003). Hape, ΔFosB overexpression ea li-nucleus e bokella kholo ea nts'etsopele ea 'mele ea ts'ebetso mme e khothaletsa mamello ea opiate analgesic (Zachariou et al. 2006). Ka lehlakoreng le leng, litoeba tsa ΔFosB tse hlalosang lintho li tloaelehile libakeng tse ling tsa boits'oaro, ho kenyelletsa thuto ea sejoale-leseling joalokaha ho lekiloe mohloling oa metsi oa Morris (Kelz et al. 1999).
Mekhoa ea phetoho ea ho lemala: karolo ea DFFB
Lethathamo 2
Behavioural phenotype hodima ΔFosB ho dynorphin + li-neurons tsa li-nucleus tse bokellaneng le dorsal striatuma.
| STIMULUS | PHENOTYPE |
| k'hok'heine | eketsa likarabo tsa locomotor ho tsamaiso e mpe |
| keketseho ea sensomotor ho tsamaiso e phetoang | |
| eketseha boemo ba ratang ka ho fetisisa ka litekanyetso tse tlase | |
| ho eketseha ha ts'ebetso ea boikoetliso ba koae ka litekanyetso tse tlase | |
| khothatso e eketsehang ea khothatso tsamaisong e ntseng e eketseha ea keketseho | |
| Morphine | eketseha maemo a rata sebaka ka litekanyetso tse tlase tsa lithethefatsi |
| kholo ea kholo ea kholo ea ho itšepa 'mele le ho tlohela | |
| e fokotsehile likarabo tsa pele tsa li-analgesic, mamello e ntlafalitsoeng | |
| joala | likarabo tse eketsehang tsa ho tšoenyeha |
| wheel wheel | lebili le ntse le eketseha |
| sucrose | keketseho e eketsehileng ea sucrose tsamaisong ea tekanyetso e tsoelang pele |
| mafura a mangata | eketsa likarabo tse kang ho tšoenyeha ha motho a tlohela lijo tse nang le mafura a mangata |
| ho kopanela liphate | boitšoaro bo eketsehileng ba thobalano |
· ↵a The phenotypes e hlalositsoeng ka har'a tafole ena e thehiloe holim 'a litekanyetso tse sa sebetseng tsa ΔFosB ka litoeba tsa bitransgenic moo polelo ea ΔFosB e lebisitsoeng ho dynorphin + neurons ea li-nucleus accumbens le dorsal striatum; maemo a tlase a 'maloa a ΔFosB a bonoa ho hippocampus le frontort cortex. Maemong a mangata, phenotype e hokahane ka ho toba le polelo ea ΔFosB ho li-nucleus bokellase ka sekhahla ka phetiso ea vaerase e bohareng.
Morero o tobileng oa ΔFosB overexpression ho li-bokellase tsa nucleus, ka ts'ebeliso ea phetisetso ea bongaka-virated, o hlahisitse data e lekanang (Zachariou et al. 2006), e bonts'a sebaka sena sa boko se ka ikarabella bakeng sa phenotype e bonoang litoeaneng tsa bitransgenic, moo ΔFosB e hlahisoang hape ka dorsal striatum le ka tekanyo e nyane haholo libakeng tse ling tsa boko. Ho feta moo, e lebisang li-neurepphin tse nang le li-spiny neurons tse mahareng tsa li-nucleus accumbens le li-dorsal striatum ka mela e fapaneng ea litoeba tsa bitransgenic tse sa atleheng ho bonts'a boholo ba liketsahalo tsena tsa phenotypes, ka ho khetheha li beha li-neurons tsa dynorphin + li-nucleus tse bokellanang ka har'a liketsahalo tsena.
Ho fapana le phepelo e fetelletseng ea ΔFosB, ho feteletsoa hoa protheine ea phetoho ea phetoho (ΔcJun kapa ΔJunD) - e sebetsa e le mohanyetsi ea matla oa ho hanyetsoa ha AP-1-mediated transcript ka tšebeliso ea litoeba tsa bitransgenic kapa viral-mediated gene e hlahisa se fapaneng. litlamorao tsa boits'oaro (Peakman et al. 2003; Zachariou et al. 2006). TDintlha tsa hese li bonts'a hore ho kenella ha ΔFosB ho dynorphin e nang le li-spiny neurons tse mahareng tsa li-nucleus accumbens ho eketsa kutloisiso ea phoofolo k'hok'heine le lithethefatsi tse ling tsa tlhekefetso, mme e kanna ea emela mochini oa ho matlafatsa lithethefatsi nako e telele.
Litlamorao tsa ΔFosB li ka holisa ntle le taolo ea kutloisiso ea lithethefatsi ka sethethe ho litloaelo tse rarahaneng tse amanang le ts'ebetso ea bokhoba ba tahi.. IceFosB e sebetsa ka thata ho iphelisa koae ka tekanyo e tsoelang pele ea taolo, e fana ka maikutlo a hore ΔFosB e ka hlokomelisa liphoofolo ka matla a susumetsang a koae 'me ka tsela eo ea lebisa ho ts'oarelleng ha e se e ka khutla ka mor'a ho tlohela lithethefatsi (Colby et al. 2003). Litoeba tsa ΔFosB tse fetang tekano li boetse li bonts'a litlamorao tse matlafatsang tsa botahoa (Picetti et al. 2001), mofuta oa phenotype o amanang le tšebeliso e ngata ea joala ho batho. Ka kopanelo, liphumano tsena tsa pejana li khothaletsa hore ΔFosB, ho ekelletsa ho matlafatseng a kutloisiso ea lithethefatsi tsa tlhekefetso, e hlahisa liphetoho tse loketseng boits'oaro bo khothalletsang boitšoaro bo batlang lithethefatsi, le ho ts'ehetsa pono e boletsoeng ka holimo, hore ΔFosB e sebetsa joalo ka phetoho ea limolek'hule bakeng sa lekhoba la tahi. mmuso. Potso ea bohlokoa tlasa lipatlisiso tsa hajoale ke hore na ho bokelloa ha ΔFosB nakong ea ts'ebetso ea lithethefatsi ho nts'etsapele mekhoa ea ho batla lithethefatsi kamora nako e teletsana ea ho tlohela, le kamora hore maemo a ΔFosB a se a lekantsoe (bona ka tlase).
4. Tlhahiso ea ΔFosB ka har'a li-nucleus tse bokelloang ke meputso ea tlhaho
Li-nucleus accumbens ho lumeloa hore li sebetsa ka tsela e tloaelehileng ka ho laola likarabo ho meputso ea tlhaho, joalo ka lijo, lino, thobalano le litšebelisano tsa sechaba. Ka lebaka leo, ho na le thahasello e kholo ntlheng e ka khonehang ea karolo ena ea boko ho seo ho thoeng ke bokhoba ba tlhaho (mohlala, tšibollo ea mali, ho becha, boikoetliso, jj.). Mefuta ea liphoofolo ea maemo a joalo e lekantsoe; leha ho le joalo, rona le ba bang re fumane hore litheko tse phahameng tsa tšebeliso ea mefuta e mengata ea moputso oa tlhaho li lebisa ho bokelleng ha 35-37 kD isoforms ea ΔFosB ka li-nucleus accumbens. Sena se bonoe kamora maemo a phahameng a mabili a matha (Werme et al. 2002) le kamora ho ts'ebeliso e sa feleng ea sucrose, lijo tse nang le mafura a mangata kapa thobalano (Teegarden & Bale 2007; Wallace et al. 2007; Teegarden et al. ka khatiso). Maemong a mang, ts'ebetso ena e khetha mofuta oa dynorphin + subset ea methapo ea kutlo e bohareng (Werme et al. 2002). Boithuto ba litoeba tse sa sebetseng, tsa litoeba tsa bongaka le tsa phetiso ea vaerase e tsamaeang le vaerase li bonts'itse hore ho qojoa ha ΔFosB ho li-nucleus bokellanya ho eketsa drive le ts'ebeliso bakeng sa meputso ena ea tlhaho, ha ts'ebetso ea protheine e mpe e hlahelletseng e sebetsa ka tsela e fapaneng.t (tafole 2; Werme et al. 2002; Olausson et al. 2006; Wallace et al. 2007). Liphumano tsena li fana ka maikutlo a hore ΔFosB sebakeng sena sa boko e khotsofatsa liphoofolo eseng feela bakeng sa meputso ea lithethefatsi empa le ka moputso oa tlhaho, hape e ka kenya letsoho mefuteng ea bokhoba ba tlhaho.
5. Ho hlahisoa ha ΔFosB ka har'a li-nucleus bokellanang ka khatello ea maikutlo e sa foleng
Ha ho fanoa ka bopaki bo matla ba hore ΔFosB e kenngoa ka har'a li-nucleus bokellanong bo sa foleng ba meputso ea lithethefatsi le ea tlhaho, ho ne ho le monate ho hlokomela hore ΔFosB e boetse e kenella haholo sebakeng sena sa boko ka mora mefuta e mengata ea khatello ea maikutlo e sa feleng, ho kenyelletsa khatello ea maikutlo, khatello ea maikutlo e sa lebelloang le ho hlola sechabeng (Perrotti et al. 2004; Vialou et al. 2007). Ho fapana le lithethefatsi le meputso ea tlhaho, ts'ebetso ena e bonoa haholo tikolohong ena ea kelello ka hore e bonoa haholo mesebetsing ea bo-dynorphin + le enkephalin +. Bopaki ba pele bo fana ka maikutlo a hore tlhahiso ena ea ΔFosB e kanna ea emela karabelo e ntle, ea ho sebetsana le maemo e thusa motho hore a tloaelane le khatello ea maikutlo. Khopolo-taba ena e tšehetsoa ke lipatlisiso tsa pele tsa hore vereFosB e bokellane ka methapo, ka tšebeliso ea litheko tse sa sebetseng, tsa bitransgenic kapa phetisetso ea bong, e fana ka likarabo tse kang tsa antidepressant-liketsong tse 'maloa tsa boits'oaro. Polelo ea ΔcJun e baka litlamorao tse kang tsa khatello ea maikutlo (Vialou et al. 2007). Ntle le moo, taolo e sa foleng ea meriana e thibelang khatello ea maikutlo e fana ka phello e ts'oanang le khatello ea maikutlo le induces ea ΔFosB sebakeng sena sa boko. Ha ho sa ntse ho hlokahala mosebetsi o eketsehileng ho netefatsa liphumano tsena, karolo e joalo e ka tsamaellana le lipono tse OsBFosB e eketsa kutloisiso ea potoloho ea moputso ea boko mme ka hona e ka thusa liphoofolo ho sebetsana ka katleho le linako tsa khatello ea maikutlo. Ho khahlisang, karolo ena ea hypothesised bakeng sa ΔFosB ho li-bokellase tsa nucleus e ts'oana le e bonts'itsoeng morao tjena bakeng sa bohlooho ba periaqueductal moo ntlha ea phetisetso e boetse e hlahisoa ke khatello ea maikutlo e sa foleng.Berton et al. 2007).
6. Mefuta e lebelletsoeng ea ΔFosB ho li-bokellase tsa nucleus
Kaha ΔFosB ke ntho e hatisitsoeng, e hlahisa ka mokhoa o khahlisang boitšoaro ka har'a li-nucleus tse ngata ka ho ntlafatsa kapa ho hatella polelo ea mefuta e meng.. Joalokaha ho bontšitsoe ho Setšoantšo sa 1, ΔFosB ke sehlahisoa se qhekelletsoeng sa mofuta oa fosB se se nang boholo ba sebaka sa C-terminal transactivation se fumanehang ka bolelele bo felletseng ba FosB empa se boloka boemo le maemo a tlamang DNA. ΔFosB e tlamahanya litho tsa lelapa la Jun mme leseling le tlisoang le tlama libaka tsa AP-1 tse ho DNA. Boithuto bo bong ba in vitro bo fana ka maikutlo a hore hobane ΔFosB e haelloa ke sebaka sa eona sa transactivation, e sebetsa joalo ka molaoli ea fosahetseng oa tšebetso ea AP-1, ha ba bang ba mmaloa ba bonts'a hore ΔFosB e ka kenya ts'ebetso khatiso libakeng tsa AP-1 (Dobrazanski et al. 1991; Nakabeppu & Nathans 1991; Yen et al. 1991; Chen et al. 1997).
Re sebelisa litoeba tsa rona tse sa sebetseng, tsa bitransgenic tse orexpress ΔFosB kapa "ΔcJun" ea eona e sa sebetseng, le ho sekaseka polelo ea gene ho li-chips tsa Affymetrix, re bonts'itse hore, bokong bo bokellanang ka vivo, ΔFosB e sebetsa e le motšehetsi oa ho ngola, ha e ntse e sebetsa e le khatello ea phepelo ea mofuta o monyane oa mefuta (McClung le Nestler 2003). Keka thabo, ketsahalo ena e khethollang ea ΔFosB ke ts'ebetso ea nako le polelo ea ΔFosB, e nang le nako e khuts'oane, e tlase e lebisang ho khatello ea mofuta le ts'ebetso ea nako e telele, maemo a holimo a lebisang ts'ebetsong ea mofuta o mong. Sena se tsamaisana le ho fumana hore polelo ea nakoana le ea nako e telele ea ΔFosB e lebisa litlamorao tse fapaneng boits'oarong: polelo ea nakoana ea ΔFosB, joalo ka polelo ea ΔcJun, e fokotsa khetho ea cocaine, ha polelo ea nako e telele ea BFosB e eketsa khetho ea cocaine (McClung le Nestler 2003). Mochine o ikarabellang bakeng sa phetoho ena o ntse o etsoa lipatlisiso; Monyetla o le mong oa tlhahlobo, o ntseng o nahanisisa, ke hore ΔFosB, maemong a phahameng, e ka theha li-Homodimers tse etsang hore tlhahiso ea AP-1 e sebetse (Jorissen et al. 2007).
Mefuta e 'maloa ea sepheo ea ΔFosB e thehiloe ka mokhoa oa mofuta oa motho ea khethang (tafole 3). Mofuta o le mong oa mokhethoa ke GluR2, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glunamate receptor subunit (Kelz et al. 1999). ΔFosB oxpxpression ho litoeba tse sa sebetseng tsa bitransgenic ka boomo e eketsa polelo ea GluR2 ho li-bokellase tsa nucleus, ha ho na phello e bonoang linthong tse ling tse 'maloa tsa AMPA glutamate receptor e hlahlobisisoa, ha polelo ea ΔcJun e thibela bokhoni ba koae ho ntlafatsa GluR2 (Peakman et al. 2003). AP-1 e rarahane e nang le ΔFosB (mme mohlomong JunD) e tiisa sebaka sa tumellano sa AP-1 se teng papatsong ea GluR2. Ntle le moo, ho ba le khatello ea matla ea GluR2 ka ho fetisoa hoa mofuta oa vaerase ho eketsa litholoana tse matlafatsang tsa koae, joalo ka ho qeta nako e telele ho ΔFosB (Kelz et al. 1999). Kaha liteishene tsa GluR2 tse nang le AMPA li na le ts'ebetso e tlase ka ho fetisisa ha li bapisoa le liteishene tsa AMPA tse senang subunit ena, upocaine ea cocaine- le ΔFosB-mediated ea GluR2 ho li-nucleus accumbens e ka ikarabella, bonyane ka karolo, bakeng sa likarabelo tse fokotsitsoeng tsa glutamatergic tse bonoang ho Li-neuron tsena ka mor'a ho pepesetsoa lithethefatsi ka nako e telele (Kauer le Malenka 2007; tafole 3).
Mehlala ea lipehelo tse netefalitsoeng bakeng sa ΔFosB ho li-nucleus accumbensa.
| sepheo | sebakeng sa bokong |
| ↑ GluR2 | ho fokotseha ha kutloano ea khanya |
| ↓ dynorphinb | phokotso ea melaetsa ea likarabo tsa κ-opioid |
| ↑ Cdk5 | katoloso ea lits'ebetso tsa dendritic |
| ↑ NF VerB | katoloso ea lits'ebetso tsa dendritic; taolo ea mekhoa ea ho pholoha ha lisele |
| ↓ c-Fos | phetoho ea limolek'hule ho tsoa liprotheine tsa malapa tsa Fos tse haellang li bile le ΔFosB ka mokhoa o sa tsitsang |
· ↵Le ha ΔFosB e laola polelo ea liphatsa tsa lefutso tse ngata bokong (mohlala, McClung & Nestler 2003), tafole e thathamisa feela liphatsa tsa lefutso tse fihlellang bonyane lintlha tse tharo ho tse latelang: khatello ea maikutlo, (ii) melaoana e ts'oanang le e lekanang ea ΔcJun, inhibitor e mpe e mpe ea phetisetso e kopantsoeng ea AP-1, (iii) ΔFosB e nang le AP-1 meaho e tlamahanya le libaka tsa AP-1 sebakeng sa ts'ehetso sa lefutso, mme ( iv) osBFosB e baka phello e ts'oanang ho ts'ebetso ea liphatsa tsa lefutso in vitro joalokaha ho bonoa vivo.
· ↵b Ntle le bopaki ba hore ΔFosB e hatella mofuta oa dynorphin mehlaleng ea tlhekefetso ea lithethefatsi (Zachariou et al. 2006), ho na le bopaki bo bong ba hore e ka nka bohato ba ho kenya ts'ebetso ea gene tlasa maemo a fapaneng (bona Cenci 2002).
Lethathamo 3
Mehlala ea lipheo tse netefalitsoeng bakeng sa ΔFosB ho nucleus accumbensa.
Mofuta o mong oa sepheo sa sepheo sa osFosB ho li-nucleus kukusanya le opioid peptide, dynorphin. Hopola hore ΔFosB e bonahala e susumetsoa ke lithethefatsi tsa tlhekefetso ka ho khetheha liseleng tse hlahisang dynorphin sebakeng sena sa boko. Lithethefatsi tsa tlhekefetso li na le litlamorao tse totobatsang polelo ea dynorphin, ka keketseho kapa ea fokotseha ho bonahala ho latela maemo a kalafo a sebelisitsoeng. Mofuta oa dynorphin o na le libaka tsa mofuta oa AP-1, tse ka tlama likarolo tsa ΔFosB tse nang le AP-1. Ho feta moo, re bontšitse hore ho kenella ha polelo ea ΔFosB e hatella polelo ea dynorphin gene ka li-nucleus accumbens (Zachariou et al. 2006). Dynorphin ho nahanoa hore e kenya tšebetsong li-ito-opioid receptor ho VTA dopamine neurons le ho thibela phetisetso ea dopaminergic ebe ka tsela eo e nyenyefatsa mekhoa ea moputso (Shippenberg & Rea 1997). Hence, khatello ea ΔFosB ea polelo ea dynorphin e ka kenya letsoho ntlafatsong ea mekhoa ea moputso e lumellanang le ntlha ena ea sengoloa. Hona joale ho na le bopaki bo tobileng bo tšehetsang ho nka karolo ha khatello ea liphatsa tsa lefutso tsa dynorphin ho mofuta oa boitšoaro oa osBFosB (Zachariou et al. 2006).
Bopaki ba morao-rao bo bonts'itse hore ΔFosB e hatella mofuta oa c-fos o thusang ho theha molek'hule - ho tloha ho kenyelletsa liprotheine tse 'maloa tsa lelapa la Fos tse ileng tsa nkuoa nakoana kamora ho pepesetsoa lithethefatsi ho tsoa ho ho bokellana ha lithethefatsi tsa ΔFosB kamora ho pepesetsoa lithethefatsi ho sa feleng—E ngotsoe pejana (Renthal et al. ka khatiso). Mochine o ikarabellang bakeng sa khatello ea ΔFosB ea polelo ea c-fos o rarahane ebile o koahetse ka tlase.
Mokhoa o mong o sebelisitsoeng ho khetholla mefuta ea "ΔFosB" e lekantsoe liphetoho tsa mofuta oa tlhaho tse hlahang ho oFosB kapa (ΔcJun) ka har'a li-nucleus li sebelisa li-expression tsa DNA, joalo ka ha ho hlalositsoe pejana. Mokhoa ona o lebisitse ho khetholloeng liphatsa tsa lefutso tse ngata tse ntseng li phahamisoa kapa li nyenyefalitsoe ke polelo ea ΔFosB sebakeng sena sa boko (Chen et al. 2000, 2003; Ang et al. 2001; McClung le Nestler 2003). TLiphatsa tsa lefutso tse bonahalang li susumetsoa ke liketso tsa ΔFosB joalo ka sehatisi sa sengoloa ke kinase-5 e itšetlehileng ka cyclin (Cdk5) le moqapi oa eona oa P35 (Bibb et al. 2001; McClung le Nestler 2003). Cdk5 e boetse e ts'oaroa ke cocaine e sa foleng ho li-bokellase tsa nucleus, phello e thibetsoeng ho polelo ea ΔcJun, mme ΔFosB e tlama le ho kenya ts'ebetso ea mofuta oa Cdk5 sebakeng sa AP-1 ho morekisi oa eona (Chen et al. 2000; Peakman et al. 2003). Cdk5 ke sepheo sa bohlokoa sa ΔFosB kaha polelo ea eona e hokahane ka kotloloho le liphetoho maemong a phosphorylation ea liprotheine tse ngata tsa synaptic ho kenyelletsa subunits ea glutamate (Bibb et al. 2001), hammoho le keketseho ea letsoalo la mokokotlo oa dendritic (Norrholm et al. 2003; Lee et al. 2006), ka har'a li-nucleus accumbens, tse amanang le tsamaiso ea koae e sa foleng (Robinson & Kolb 2004). Haufinyane, taolo ea ts'ebetso ea Cdk5 ho li-bokellase tsa nucleus e hokahane ka ho toba le liphetoho phetohong ea boitšoaro ba koae (cocaine)Taylor et al. 2007).
Morero o mong oa ΔFosB o khethiloeng ke tšebeliso ea li-Microarrays ke NFκB. Ntho ena e hatisitsoeng e kenyelletsoa ka har'a li-bokellase tsa "nucleus" ka ho qojoa ke ΔFosB oreatxpression le cocaine e sa foleng, e le phello e koetsoeng ke polelo ea ΔcJun (Ang et al. 2001; Peakman et al. 2003). Bopaki ba morao-rao bo bontšitse hore ho kenyelletsoa ha NF VerB ho ka kenya letsoho ho matla a k'hok'heine ea ho hlohlelletsa lesapo la mokokotlo ho li-nucleus accumbens neurons (Russo et al. 2007). Ntle le moo, NF VerB e bile le tšusumetso ho tse ling tsa litlamorao tsa methapo ea methamphetamine libakeng tsa striatal (Asanuma & Cadet 1998). Tlhokomeliso ea hore NF VerB ke mofuta oa sepheo sa ΔFosB e totobatsa ho rarahana ha mekhoa eo ΔFosB e arolelanang litlamorao tsa koae ho polelo ea gene. Kahoo, ntle le mefuta ea lefutso e laoloang ke byFosB ka kotloloho ka libaka tsa AP-1 ho bahlahisi ba mofuta oa gene, wouldFosB e tla lebelloa ho laola mefuta e mengata e eketsehileng ka polelo e fetotsoeng ea NFκB le protheine e meng ea molao e ngotsoeng.s.
Lihlahisoa tsa polelo ea DNA li fana ka lethathamo le letle la mefuta e meng e mengata e tlatselletsang e ka shejoang ka kotloloho kapa ka kotloloho ke ΔFosB. Har'a mefuta ena ho na le li-receptor tse eketsehileng tsa "neurotransmitter", liprotheine tse amehang mesebetsing ea pele le ea postynaptic, mefuta e mengata ea li-ion le protheine ea methapo ea kutlo, hammoho le liprotheine tse laolang li-cytoskeleton tsa neuronal le kholo ea lisele (McClung le Nestler 2003). Ho hlokahala mosebetsi o eketsehileng ho netefatsa liprotheine tsena tse ngata e le sepheo sa 'nete sa "cocaine" se sebelisang ΔFosB le ho theha karolo e nepahetseng eo protheine e' ngoe le e 'ngoe e e sebelisang ho hokahanya likarolo tse rarahaneng tsa tlhaho le boits'oaro ba ketso ea koae. Qetellong, ehlile, ho tla ba bohlokoa ho fetela ka ntle ho tlhahlobo ea liphatsa tsa lefutso tsa motho ka mong ho fetisetsoeng ho lihlopha tsa liphatsa tsa lefutso tseo molao oa tsona o hokahaneng o tlamehang ho boelanya mmuso o lemaletseng.
7. Ho hlahisoa ha ΔFosB libakeng tse ling tsa boko
Puisano ho fihlela joale e shebane feela le li-bokellane tsa nucleus. Le ha hona e le karolo ea bohlokoa ea moputso oa boko 'me e bohlokoa bakeng sa liketso tse tlatsetsang tsa koae le lithethefatsi tse ling tsa tlhekefetso, libaka tse ling tsa boko le tsona li bohlokoa ho nts'etsopele le ho boloka maemo a tlhekefetso. Joale, potso ea bohlokoa ke hore na ΔFosB e sebetsang libakeng tse ling tsa boko ho feta bokapele ba li-nucleus le eona e ka susumetsa tšebeliso ea lithethefatsi. Ihaele hantle, hona le bopaki bo ntseng bo eketseha ba hore lithethefatsi tse susumetsang le tse khothalletsang tlhekefetso li susumetsa ΔFosB libakeng tse fapaneng tsa boko tse kenyelletsang likarolo tse fapaneng tsa bokhoban (Nye, et al. 1995; Perrotti et al. 2005, 2008; McDaid et al. 2006a,b; Liu et al. 2007).
Phuputso ea morao-rao e bapisitse ho kenella ka mokhoa oa ΔFosB libakeng tsena tse fapaneng tsa boko ho lithethefatsi tse 'ne tse fapaneng tsa tlhekefetso: cocaine; morphine; cannabinoids; le ethanol (tafole 4; Perrotti et al. 2008). Lithethefatsi tsohle tse 'ne li kenya taba ea ho ngoloa ho li-degrees tse fapaneng tsa li-nucleus accumbens le dorsal striatum hammoho le cortex ea pele, amygdala, hippocampus, mookotaba oa bethe ea "stria terminalis" le "element" ea karolo ea morao ea mokokotlo oa ka ntle.. Cocaine le ethanol feela e hohelang ΔFosB ka septum ea morao-rao, lithethefatsi kaofela ntle le li-cannabinoids indize uceFosB ka bohloeki ba periaqueductal, mme cocaine e ikhethile ho hohela ΔFosB ho lisele tse mpe tsa gamma-aminobutyric acid (GABA) sebakeng se kotsi sa postterior ventral tegmental. al. 2005, 2008). Ntle le moo, morphine e bontšitsoe ho kenya ΔFosB ho ventral pallidum (McDaid et al. 2006a). Sebakeng ka seng sa libaka tsena, ke 35-37 kD isoforms ea ΔFosB e bokanang ka ho pepeseha hoa lithethefatsi tse sa feleng ebile e phehella nako e telele ha nako ea ho khaotsa.
Lethathamo 4
Papiso ea libaka tsa boko tse bonts'a ho kenella ha ΔFosB kamora ho pepesehela lithethefatsi tse sa emeng tsa tlhekefetsoa.
| k'hok'heine | Morphine | ethanol | cannabinoids | |
| nucleus accumbens | ||||
| konokono | + | + | + | + |
| khetla | + | + | + | + |
| dorsal striatum | + | + | + | + |
| ventral pallidumb | ke | + | ke | ke |
| prefrontal cortexc | + | + | + | + |
| hamorao septum | + | - | + | - |
| medial septum | - | - | - | - |
| BNST | + | + | + | + |
| IPAC | + | + | + | + |
| hippocampus | ||||
| gyrus ea meno | + | + | - | + |
| CA1 | + | + | + | + |
| CA3 | + | + | + | + |
| amygdala | ||||
| basolateral | + | + | + | + |
| bohareng | + | + | + | + |
| e bohareng | + | + | + | + |
| periaqueductal grey | + | + | + | - |
| sebaka sa ventral tegmental | + | - | - | - |
| substantia nigra | - | - | - | - |
· ↵Tafole ha e bonts'e litekanyetso tse lekanang tsa ho kenngoa ha ΔFosB ke lithethefatsi tse fapaneng. Bona Perrotti et al. (2008) bakeng sa tlhaiso-leseling ena.
· ↵b Kameho ea cocaine, ethanol le cannabinoids ho ΔFosB induction ho kenella pallidum ha e e-so ithutoe, empa ho kenella ka mokhoa o joalo ho hlokometsoe ho arabela methamphetamine (McDaid et al. 2006b).
· ↵c ΔFosB induction e bonoa likarolong tse 'maloa tsa cortex ea pele-pele, ho kenyelletsa infralimbic (medial prefrontal) le orbitofrontal cortex.
Morero o moholo oa ho etsa lipatlisiso tsa nako e tlang ke ho etsa lithuto, analogue ho tse hlalositsoeng kaholimo bakeng sa li-nucleus accumbens, ho hlakisa li-phenotypes tsa neural le boits'oaro bo kopaneng le ΔFosB sebakeng ka seng sa libaka tsena tsa boko. Hona ho emela boitlamo bo boholo, leha ho le joalo ho bohlokoa bakeng sa ho utloisisa tšusumetso ea lefats'e ea ΔFosB ts'ebetsong ea bokhoba.
Re sa tsoa nka mohato oa bohlokoa ntlheng ena ka ho fetisetsa liphatsa tsa lefutso tse amanang le vaerase ho khetholla liketso tsa ΔFosB ka subortion ea cortex ea pele, e leng, orbitof Pambal cortex. Sebaka sena se kentse letsoho ka matla ho bokhoba, haholo-holo, ho kenya letsoho ho tsusumetso le ho qobelloang ho khethollang naha e lemalloang (Kalivas le Volkow 2005). Ho khahlisang, ho fapana le li-nucleus tsa li-cocaine moo k'hok'heine e sebetsang le e koaetsoeng ka joko e fana ka maemo a lekanang a ΔFosB joalo ka ha ho boletsoe pejana Re hlokometse hore ts'ebetso ea ts'ebetso ea koae e baka ts'ebetso e ngata ea "osFosB" ho cortex ea orbitofrontal, a fana ka maikutlo a hore karabelo ena e ka amana le likarolo tsa taolo ea lithethefatsi (Winstanley et al. 2007). Ka mor'a moo re ile ra sebelisa liteko tsa ho tsepamisa maikutlo le ho etsa liqeto (mohlala, nako ea ho khetha ka makhetlo a mahlano le liteko tsa ho lieha) ho tseba hore na ΔFosB kahare ho cortex ea orbitofrontal e kenya letsoho phetohong e bakoang ke lithethefatsi tlhokomelong ea batho. Re fumane hore kalafo ea koae e sa foleng e hlahisa mamello ho ts'oaetso ea kelello e bakoang ke cocaine e mpe. Overexpression e atamelaneng le bongata ea "ΔFosB" tikolohong ena e ile ea hlahisa litlamorao tsa koae e sa foleng, ha ho pepeta ho hoholo hoa mohanyetsi ea fosahetseng, ,JunD, ho thibela tloaelo ena ea boits'oaro. Polelo ea Microcarray ea tlhahlobo ea "micarrayes" e hlalositse mekhoa e 'maloa e ka bang molek'hule e bakang phetoho ena ea boits'oaro, ho kenyelletsa keketseho e kopantsoeng le koae- le ΔFosB ea ho fetisoa ha metabotrophic glutamate receptor mGluR5 le GABAA receptor hammoho le ntho P (Winstanley et al. 2007). Tšusumetso ea "sepheo sa" sepheo sa tsena le tse ling tse ngata tsa tlatsetso e hloka hore ho etsoe lipatlisiso tse ling.
Liphumano tsena li bonts'a hore ΔFosB e thusa ho mamellana litlamong tse amang kelello tsa cocaine. Basebelisi ba nang le mamello ho litlamorao tse mpe tsa koae ba kotsing e kholo ea ho sebelisa koae, athe ba fumanang lithethefatsi li le phoso mosebetsing kapa sekolong ba ka ba monyetleng oa ho lemalla. (Shaffer le Eber 2002). Ho mamella pherekano ea kelello e bakoang ke cocaine e mpe ho batho ba nang le boiphihlelo ba koae ka hona ho ka tsamaisa tlhokomeliso ea ho lemalla. Ka tsela ena, ΔFosB induction ho orbitofrontal cortex e ka khothaletsa setjhaba se lemaletseng, se ts'oanang le liketso tsa eona ho li-nucleus accumbens moo ΔFosB e khothalletsang tšebeliso ea litlamorao ka ho ntlafatsa litlamorao le litheko tse susumetsang tsa lithethefatsi.
8. Mehato ea Epigenetic ea ketso ea ΔFosB
Ho fihlela haufinyane, lithuto tsohle tsa melaoana e ngotsoeng bokong li its'etlehile litekanyetsong tsa maemo a tsitsitseng a mRNA. Mohlala, patlo ea liphatsa tsa lefutso tsa ΔFosB e kentse letsoho ho supa hore mRNA e nyolohile kapa e theotsoe holima ΔFosB kapa ocJun overexpression, joalo ka ha ho boletsoe pejana. Boemo bona ba tlhahlobo bo thusitse haholo ho khetholla liphofu tsa putFF; leha ho le joalo, ka tlhaho e na le moeli oa ho fana ka leseli la mekhoa ea mantlha e amehang. Ho fapana le moo, lithuto tsohle tsa mekhoa li ts'epahalletse mehato ea in vitro joalo ka ΔFosB e tlamang ho latellanang ha liphatsa tsa lefutso ka liteko tsa ho fetoha ha gel kapa taolo ea ΔFosB ea ts'ebetso ea liphatsa tsa lefutso moetlong oa sele. Sena ha se khotsofatse hobane mekhoa ea taolo ea sengoloa e bontša phapang e makatsang ho tloha mofuteng oa sele ho isa seleng, ho e tlohella e sa tsejoe ka botlalo hore na sethethefatsi sa tlhekefetso, kapa ΔFosB, se laola liphatsa tsa lefutso tse ikhethileng bokong ho vivo.
Boithuto ba mekhoa ea epigenetic e etsa hore ho khonehe, ka lekhetlo la pele, ho sutumelletsa enfelopo mohato o le mong hape le ho hlahloba ka kotlollo molao o hatisang methapong ea liphoofolo tse boitšoaro.Tsankova et al. 2007). Ho latela nalane, lentsoe epigenetics le hlalosa mekhoa eo lisele tsa semelo li ka fuoang ntle le phetoho ho tatellano ea DNA. Re sebelisa lentsoe lena haholo ho kenyelletsa "litloaelo tsa sebopeho sa libaka tsa chromosomal e le ho ingolisa, ho supa kapa ho ntšetsa pele mesebetsi e fetotsoeng ea liketsahalo '(Nonyana 2007). Kahoo, joale rea tseba hore tšebetso ea liphatsa tsa lefutso e laoloa ke phetoho e kopaneng (mohlala, acetylation, methylation) ea li-histone tse haufi le liphatsa tsa lefutso le ho thaotha mefuta e fapaneng ea li-coactivator kapa li-corepressors tsa sengoloa. Liteko tsa Chromatin immunoprecipitation (ChIP) li etsa hore ho khonehe ho nka monyetla ka tsebo ena e ntseng e hola ea biology ea chromatin ho tseba boemo ba lefutso sebakeng se itseng sa boko sa phoofolo e tšoaroang ka sethethefatsi sa tlhekefetso.
Mehlala ea kamoo lithuto tsa chromatin regulation li ka re thusang ho utloisisa mekhoa e qaqileng ea molek'hule ea ketso ea koae le ΔFosB Setšoantšo sa 3. Joalokaha ho boletsoe kaholimo, ΔFosB e ka sebetsa e le mohatisi ea hatisang kapa mohatelli ho latela mofuta oa morero o amehang. Ho fumana leseli ka liketso tsena, re ile ra sekaseka boemo ba chromatin ba lipehelo tse peli tsa baemeli ba mofuta oa ΔFosB, cdk5 e khothalletsoang ke ΔFosB le c-fos e hatisitsoeng ka li-nucleus accumbens. Boithuto ba chromatin immunoprecipitation bo bonts'itse hore cocaine e kenya mofuta oa cdk5 sebakeng sena sa boko ka mokokotlo o latelang: ΔFosB e tlama ho mofuta oa cdk5 ebe e hira histone acetyltransferases (HAT; histories ea acetylate e haufi) le lintlha tsa SWI-SNF; liketso tseo ka bobeli li khothaletsa mongolo oa liphatsa tsa lefutso (Kumar et al. 2005; Levine et al. 2005). Cocaine e sa feleng e boetse e eketsa histone acetylation ka phosphorylation le thibelo ea histone deacetylases (HDAC; eo ka tloaelo e sebetsang le ho hatella mefuta ea tlhaho; Renthal et al. 2007). Ka lehlakoreng le leng, koae e hatella mofuta oa c-fos: ha ΔFosB e kopana le mofuta ona e boetse e hira HDAC, mohlomong le histonetrylferansase (HMT; eo methylate histones e haufinyane) 'me ka tsela eo e thibela mongolo oa c-fos (Setšoantšo sa 3; Renthal et al. ka khatiso). Potso ea mantlha ke hore: ke eng e khethollang hore na ΔFosB e kenya tšebetsong kapa e hatella liphatsa tsa lefutso ha e tlamahanya le mohokahanyi oa lefutso?
Setšoantšo sa 3
Mehato ea Epigenetic ea ketso ea ΔFosB. Palo e bonts'a litlamorao tse fapaneng haholo ha osFosB e tlama ho gene eo e e sebetsang (mohlala cdk5) khahlanong le khatello ea maikutlo (mohlala, c-fos). (a) Ho morekisi oa cdk5, ΔFosB e hloa lintlha tsa HAT le SWI-SNF, tse khothalletsang ts'ebetso ea gene. Ho boetse ho na le bopaki ba ho kenyelletsoa ha li-HDAC (bona mongolo). (b) Ka lehlakoreng le leng, ho morekisi oa c-fos, ΔFosB e hira HDAC1 hape le HMTs e hatellang polelo ea mofuta. A, P le M li bontša histone acetylation, phosphorylation le methylation ka ho latellana.
Lithuto tsena tsa pele tsa mekhoa ea epigenetic ea bokhoba ba lithethefatsi li ea thabisa hobane li ts'episa ho senola tlhahisoleseling e ncha mabapi le methapo ea limolek'hule eo lithethefatsi tsa tlhekefetso e laolang polelo ea liphatsa tsa lefutso ka har'a li-nucleus aschale le likarolo tse ling tsa boko. Ho kopanya lenane la polelo ea DNA le seo ho thoeng ke ChIP ho li-chip assays (moo liphetoho tse teng sebopeho sa chromatin kapa ntho e tlamang e ka hlahlojoang genome ka bophara) li tla lebisa ho khethollotsoeng lithethefatsi le mofuta oa sepheo sa ΔFosB ka tekanyo e kholo ea kholiseho le phetheho. Ntle le moo, mekhoa ea epigenetic ke khetho e khahlehang haholo ho kenyelletsa mohopolo oa nako e telele oa bohareng ho boemo ba bokhoba. Ka tsela ena, liphetoho tse hlahisitsoeng ke lithethefatsi le ΔFosB litokisetsong tsa histone le liphetoho tse amanang le epigenetic li fana ka mekhoa e meng eo ka eona liphetoho tse ngotsoeng li ka phehellang nako e telele kamora hore tlhahiso ea lithethefatsi e khaotse mme mohlomong le kamora hore ΔFosB e theohe maemong a tloaelehileng.
9. Liphello
Mokhoa oa ho kenyelletsoa ha ΔFosB ka li-nucleus tse bokelloang ke ho pepesehela meputso ea tlholeho, khatello ea maikutlo kapa lithethefatsi tsa tlhekefetso ho hlahisa mohopolo o khahlisang mabapi le tšebetso e tloaelehileng ea protheine tikolohong ena ea boko. Joalokaha ho bontšitsoe ho Setšoantšo sa 2, ho na le boemo ba ΔFosB bo ka ananeloang ka li-nucleus accumbens tlasa maemo a tloaelehileng. Sena se ikhethile libakeng tse sa sebetseng, kaha ΔFosB ha e bonahale kae kapa kae bokong ho ea pele. Re nahana hore maemo a ΔFosB ka li-nucleus accumbens a emela ho baloa ha motho a pepesehetse maikutlo a maikutlo, a matle le a mabe, a kopantsoe ka nako e telele ho fanoa ka boleng ba protheine. Liphapang tse sa lekanyetsoang tsa ho khetholloa ha lisele tsa byFosB ka ho putsa khahlanong le tšusumetso e mpe ha li utloisisoe hantle, 'me ho hlokahala mosebetsi o mong ho hlakisa litlamorao tsa ts'ebetso ena. Re nahana hape hore ha maemo a phahameng a ts'usumetso ea maikutlo a hlohlelletsa ΔFosB e ngata ho li-nucleus tse bokellanang li-neuron, ts'ebetso ea li-neuron e fetotsoe e le hore ba tsebe ho amohela tšusumetso e khotsofatsang. Ka tsela ena, ho kenoa ha ΔFosB ho ka khothaletsa mohopolo o amanang le moputso (ke hore, maikutlo) ka merero e fapaneng ea li-nucleus accumbens. Tlas'a maemo a tloaelehileng, ho kenella ha maemo a itekanetseng a ΔFosB ka ho putsa kapa ho susumetsa maikutlo ho ka fetoha ka ho ntlafatsa liphetoho tsa phoofolo ho mathata a tikoloho. Leha ho le joalo, ho qhekelloa ho fetelletseng ha ΔFosB ho bonoang tlasa maemo a mafu (mohlala, ho pepesehela sethethefatsi sa tlhekefetso) ho ka lebisa tlhokomelong e fetelletseng ea li-nucleus accumbens circry mme qetellong ho tlatsetsa mekhoeng ea boits'oaro (mohlala, ho qobella ho batla lithethefatsi le ho li noa) tse amanang le ho lemalla lithethefatsi. IndFosB e kenngoe libakeng tse ling tsa boko e kanna ea kenya letsoho likarolong tse fapaneng tsa mmuso o lemaletseng joala, joalo ka ha ho bontšitsoe ke liphuputso tsa morao-rao tsa ketso ea osBFosB ka orbitofrontal cortex.
Haeba khopolo-taba ena e nepahetse, e hlahisa monyetla o khahlisang oa hore maemo a ΔFosB ka li-nucleus accumbens kapa mohlomong libaka tse ling tsa boko a ka sebelisoa e le biomarker ho lekola boemo ba ts'ebetso ea moputso oa motho ka mong, le boemo boo motho e 'lemaletse', ka bobeli nakong ea nts'etsopele ea bokhoba ba tahi le ho putlama butle butle nakong ea ho tlohela nako e telele kapa kalafo. Ts'ebeliso ea ΔFosB joalo ka sesupo sa boemo ba tahi e bontšitsoe mefuteng ea liphoofolo. Liphoofolo tse lilemong tsa bocha li bontša tlhahiso e kholo ea DFB ha e bapisoa le liphoofolo tse hōlileng, e lumellanang le kotsing e kholo ea ho lemala (Ehrlich et al. 2002). Ntle le moo, ho nahanisisa ka litlamorao tse thabisang tsa nikotine e nang le GABAB receptor positive allosteric modulator e amana le blockade ea nicotine induction ea ΔFosB ho li-nucleus accumbens (Mombereau et al. 2007). Le ha e le ntho e inahaneloang haholo, ho ka nahanoa hore molek'hule e nyane ea PET, e nang le tumellano e phahameng ea ,FosB, e ka sebelisoa ho thusa ho fumana mathata a lemalloang le ho lekola tsoelo-pele nakong ea kalafo.
Kamora nako, ΔFosB ka boeona kapa efe kapa efe ea liphatsa tsa lefutso tse ngata tseo e li laolang-tse khetholloang ka li-arrays tsa DNA kapa ChIP ho li-chip-li emela lipheo tse ka bang teng bakeng sa nts'etsopele ea kalafo ea mantlha ea bokhoba ba lithethefatsi. Re lumela hore ho bohlokoa ho sheba ka nqane ho lipheo tsa moetlo oa lithethefatsi (mohlala, li-receptor tsa methapo ea pelo le ba tsamaisang thepa) bakeng sa batho bao e ka bang bahlahlobi ba kalafo ba ho lemalla lithethefatsi. Limmapa tse pharalletseng tsa sengoloa sa genome tse khonang ho sebelisa mahlale a morao-rao a kajeno li fana ka mohloli o ts'episang oa sepheo se joalo sa nalane boitekong ba rona ba ho phekola le ho folisa mathata a lemalloang.
lumela hore baa fokola
Ho senola. Sengoli ha se tlalehe maikutlo a ho khahlapetsa tekolo ena.
Mongolo o botlaaseng ba leqephe
· Tlatsetso e le 'ngoe ea 17 ho Taba ea Kopano ea Lipuisano' The neurobiology of addiction: new vistas '.
· © 2008 Mokhatlo oa Royal
References
1. ↵
1. Alibhai KA,
2. Tala TA,
3.Potashkin JA,
4. Nestler EJ
2007 Taolo ea fosB le polelo ea ΔfosB mRNA: lithutong tsa vivo le ho vitro. Brain Res. 1143, 22-33. doi: 10.1016 / j.brainres.2007.01.069.
CrossRefMedlineho web ea Mahlale
2. ↵
1. Ang E,
2. Chen J,
3.Zagouras P,
4.Magna H,
5. Holland J,
6. Schaeffer E,
7. Nestler EJ
Induction ea 2001 ea NFκB ho li-nucleus bokellitsoeng ke tsamaiso ea cocaine e sa foleng. J. Neurochem. 79, 221-224. doi: 10.1046 / j.1471-4159.2001.00563.x.
CrossRefMedlineho web ea Mahlale
3. ↵
1. Asanuma M,
2. Cadet JL
Keketseho e bakiloeng ke 1998 Methamphetamine e bakang tšebetso e kopantseng ea Ntoa ea NF VerB e fumaneha ho litoeba tsa superoxide dismutase transgenic. Mol. Brain Res. 60, 305-309. doi:10.1016/S0169-328X(98)00188-0.
4. ↵
1. Berton O,
2. et al.
Induction ea 2007 ea ΔFosB ka bohloeki ba moea ka khatello ea maikutlo e khothalletsa likarabo tse sebetsang tsa ho sebetsana le maemo. Neuron. 55, 289-300. doi: 10.1016 / j.neuron.2007.06.033.
CrossRefMedlineho web ea Mahlale
5. ↵
1. Bibb JA,
2. et al.
Liphello tsa 2001 tsa ho pepesetsoa ha koae e sa laoleheng li laoloa ke protheine ea neuronal Cdk5. Tlhaho. 410, 376-380. doi: 10.1038 / 35066591.
6. ↵
1. Nonyana A
Polelo ea 2007 ea epigenetics. Tlhaho. 447, 396-398. Doi: 10.1038 / nature05913.
7. ↵
1. Carle TL,
2. Ohnishi YN,
3. Ohnishi YH,
4. Alibhai KA,
5. Wilkinson MB,
6.Kumar A,
7. Nestler EJ
2007 Ho ba sieo ha domain name e bolokiloeng ea C-terminal degron ho tlatsetsa ho botsitso bo ikhethang ba ΔFosB. EUR. J. Neurosci. 25, 3009-3019. doi: 10.1111 / j.1460-9568.2007.05575.x.
CrossRefMedlineho web ea Mahlale
8. ↵
1. Carlezon WA, Jr,
2. Duman RS,
3. Nestler EJ
2005 lifahleho tse ngata tsa CREB. Mekhoa ea Neurosci. 28, 436-445. Doi: 10.1016 / j.tins.2005.06.005.
CrossRefMedlineWebsaense ea Saense
9. ↵
1. Cenci MA
Lintlha tsa phetolelo ea 2002 tse kenyellelitsoeng ho pathogenesis ea l-DOPA e hlahisitsoeng ke dyskinesia ka mohlala oa rat oa lefu la Parkinson. Liamino acid. 23, 105-109.
CrossRefMedlineWebsaense ea Saense
10. ↵
1. Chen JS,
2. Nye HE,
3. Kelz MB,
4. Hiroi N,
5. Nakabeppu Y,
6. Tšepo BT,
7. Nestler EJ
Taolo ea 1995 ea liprotheine tse kang ΔFosB le FosB ka ho ts'oaroa ke motlakase (ECS) le kalafo ea koae. Mol. Pharmacol. 48, 880-889.
11. ↵
1. Chen J,
2. Kelz MB,
3. Tšepo BT,
4. Nakabeppu Y,
5. Nestler EJ
LITLHAKISO TSE KHOLO tsa 1997: mefuta e tsitsitseng ea ΔFosB e kentsoeng bokong ka kalafo e sa foleng. J. Neurosci. 17, 4933-4941.
12. ↵
1. Chen JS,
2. Zhang YJ,
3. Kelz MB,
4. Steffen C.
5.Ang ES,
6.Zeng L,
7. Nestler EJ
Induction ea 2000 ea kinase e itšetlehileng ka cyclin-kinase 5 ho hippocampus ka ho tsitsa ha motlakase o sa feleng: karolo ea ΔFosB. J. Neurosci. 20, 8965-8971.
13. ↵
1. Chen J,
2.Newton SS,
3.Zeng L,
4. Adams DH,
5.Dow AL,
6.Madsen TM,
7. Nestler EJ,
8. Duman RS
2003 Downregulation ea CCAAT-e ntlafatsang beta ea protheine ho litoeba tsa ΔFosB tsa transgenic le ka ho ts'oaroa ke motlakase. Neuropsychopharmacology. 29, 23-31. doi: 10.1038 / sj.npp.1300289.
14. ↵
1. Colby CR,
2.Whisler K,
3. Steffen C.
4. Nestler EJ,
5. Boithati DW
2003 ΔFosB e ntlafatsa ts'usumetso ea koae. J. Neurosci. 23, 2488-2493.
15. ↵
1. Deroche-Gamonet V,
2. et al.
2003 Receptor ea glucocorticoid e le sepheo sa ho fokotsa ts'ebeliso e mpe ea koae. J. Neurosci. 23, 4785-4790.
16. ↵
1.Dobrazanski P,
2.Noguchi T,
3.Kovary K,
4.Rizzo CA,
5.Lazo PS,
6. Bravo R
Lihlahisoa tsa 1991 Ka bobeli lihlahisoa tsa mofuta oa fosB, FosB le mofuta oa eona o mokhuts'oane, FosB / SF, ke li-activator tse sebetsang ka har'a li-fibroblasts. Mol. Cell Biol. 11, 5470-5478.
17. ↵
1. Ehrlich ME,
2. Sommer J,
3. Canas E,
4. EM e sa sebetseng
2002 litoeba tsa Periadolescent li bonts'a ntlafatso ea ΔFosB ha e arabela cocaine le amphetamine. J. Neurosci. 22, 9155-9159.
18. ↵
1. Greybiel AM,
2. Moratalla R,
3. Robertson HA
1990 Amphetamine le cocaine e kenya ts'ebetsong e khethehileng ea lithethefatsi ea gene ea c-fos likopanong tsa striosome-matrix le likarolo tse ka tlase tsa striatum. Proc. Natl Acad. Saense USA. 87, 6912-6916. doi: 10.1073 / pnas.87.17.6912.
19. ↵
1. Tala TA,
2. Alibhai KA,
3. Hommel JD,
4.DiLeone RJ,
5.Kumar A,
6.Theobald DE,
7.Nve ea RL,
8. Nestler EJ
Induction ea 2006 ea polelo ea ICER ho li-nucleus e bokellanang ka khatello ea maikutlo kapa amphetamine e eketsa likarabo tsa boitšoaro ho susumetso ea maikutlo. J. Neurosci. 26, 8235-8242.
20. ↵
1. Tala TA,
2. Alibhai KA,
3.Basebetsi S,
4.Nve ea RL,
5. Ghose S,
6.Tamminga CA,
7. Nestler EJ
Induction ea 2008 ea li-activation transcript factor (ATFs) ATF2, ATF3, le ATF4 ho li-nucleus accumbens le taolo ea bona ea boitšoaro ba maikutlo. J. Neurosci. 28, 2025-2032. doi: 10.1523 / JNEUROSCI.5273-07.2008.
21. ↵
1. Hiroi N,
2. Mofubelu J,
3. Haile C,
4. Uena H,
5. Greenberg ME,
6. Nestler EJ
Litoeba tsa 1997 tsa FosB: tahlehelo ea k'hok'heine e sa foleng ea liprotheine tse amanang le Fos le ho eketsa kutloisiso ho psychomotor ea cocaine le litlamorao tse ntle. Tsamaiso. Natl Acad. Sci. USA. 94, 10 397-10 402. doi: 10.1073 / pnas.94.19.10397.
22. ↵
1. Hiroi N,
2. Mofubelu J,
3. Uena H,
4. Saudou F,
5. Vaidya VA,
6. Duman RS,
7. Greenberg ME,
8. Nestler EJ
Karolo ea Bohlokoa ea 1998 Karolo ea mofuta oa fosB molekong oa lisele, tsa cellular le boits'oaro ba ho ts'oaroa ka motlakase. J. Neurosci. 18, 6952-6962.
23. ↵
1. Tšepo B,
2. Kosofsky B,
3.Hyman SE,
4. Nestler EJ
1992 Taolo ea polelo ea IEG le AP-1 e tlamang ke k'hok'heine e sa foleng ho li-nucleus ea mahlaseli a rat. Proc. Natl Acad. Saense USA. 89, 5764-5768. doi: 10.1073 / pnas.89.13.5764.
24. ↵
1. Tšepo BT,
2. Nye HE,
3. Kelz MB,
4.Wena DW,
5.Iadarola MJ,
6. Nakabeppu Y,
7. Duman RS,
8. Nestler EJ
Induction ea 1994 ea mochine oa AP-1 oa nako e telele o kenyelletsoeng ke liprotheine tse fetotsoeng joaloka Fos bokong ka cocaine le kalafo tse ling tse sa foleng. Neuron. 13, 1235-1244. doi:10.1016/0896-6273(94)90061-2.
CrossRefMedlineho web ea Mahlale
25. ↵
1.Jorissen H,
2.Ulery P,
3. Henry L,
4. Gourneni S,
5. Nestler EJ,
6. Rudenko G
Phokotso ea 2007 le thepa e tlamang DNA ea transcript factor ΔFosB. Biochemistry. 46, 8360-8372. Doi: 10.1021 / bi700494v.
CrossRefMedlineho web ea Mahlale
26. ↵
1.Kalivas PW,
2. Volkow ND
2005 Motheo oa tlhaho oa ho lemalla: thuto ea khothalletso le khetho. Am. J. Psychiatry. 162, 1403-1413. doi: 10.1176 / appi.ajp.162.8.1403.
27. ↵
1. Kauer JA,
2. Malenka RC
2007 Synaptic polasetiki le bokhoba ba tahi. Nat. Moruti Neurosci. 8, 844-858. doi: 10.1038 / nrn2234.
CrossRefMedlineho web ea Mahlale
28. ↵
1. Kelz MB,
2. et al.
Tlhatlhobo ea 1999 ea factor transaction ΔFosB bokong e laola kutloisiso ea cocaine. Tlhaho. 401, 272-276. doi: 10.1038 / 45790.
29. ↵
1.Kumar A,
2. et al.
2005 Chromatin remodeling ke mochini oa bohlokoa o hlahisang polasetiki e kopantsoeng le koae ho striatum. Neuron. 48, 303-314. doi: 10.1016 / j.neuron.2005.09.023.
CrossRefMedlineho web ea Mahlale
30. ↵
1. Lee KW,
2.Kim Y,
3. Kim AM,
4. Helmin K,
5.Nair ea AC,
6. Greengard P
2006 Cocaine-induced dendritic spine form e entsoeng ka lesapo la mokokotlo ka D1 le D2 dopamine receptor e nang le li-spiny neurons tse mahareng tsa li-nucleus tsa li-nucleus. Proc. Natl Acad. Saense USA. 103, 3399-3404. doi: 10.1073 / pnas.0511244103.
31. ↵
1. Levine A,
2. Guan Z,
3. Barco A,
4.Xu S,
5. Kandel E,
6. Schwartz J
2005 CREB e kopanyang liprotheine e laola karabelo ho koae ka ho hlahisa li-histones tse nang le acetylating ho morekisi oa fosB setulong sa mouse. Proc. Natl Acad. Saense USA. 102, 19 186-19 191. doi: 10.1073 / pnas.0509735102.
32. ↵
1.Liu HF,
2. Zhou WH,
3. Zhu HQ,
4. Lai MJ,
5. Chen WS
2007 Microinjection ea M (5) receptor antisense oligonucleotide ho VTA e thibela polelo ea FosB ho NAc le hippocampus ea li-ratin tse khothalelitsoeng. Neurosci. Bull. 23, 1-8. doi:10.1007/s12264-007-0001-6.
33. ↵
1. Mackler SA,
2. Korutla L,
3. Cha XY,
4. Koebbe MJ,
5. Km ea bone,
6.Bowers MS,
7. Kalivas PW
2000 NAC-1 ke protheine ea boko ea POZ / BTB e ka thibelang sensitization e khothalletsoang ke koae ho "rat". J. Neurosci. 20, 6210-6217.
34. ↵
1. McClung CA,
2. Nestler EJ
Molao oa 2003 oa polelo ea tlhaho le moputso oa koae ka CREB le ΔFosB. Nat. Neurosci. 11, 1208-1215. doi: 10.1038 / nn1143.
35. ↵
1. McClung CA,
2.Phatlalatsa PG,
3. Perrotti LI,
4. Zakaria V,
5. Berton O,
6. Nestler EJ
2004 ΔFosB: phetoho ea limolek'hule bakeng sa ho feto-fetoha ha maemo ka nako e telele bokong. Mol. Brain Res. 132, 146-154. Doi: 10.1016 / j.molbrainres.2004.05.014.
36. ↵
1. McDaid J,
2.Dallimore JE,
3. Mackie AR,
4. Napier TC
Liphetoho ho "pumbre" ea "accumbal "le" pallidal pCREB "le" osFosB "" litekong "tse amanang le morphine: litumellano le methapo ea motlakase ea li-receptor-evoke. Neuropsychopharmacology. 31, 2006a 1212-1226.
37. ↵
1. McDaid J,
2. Graham MP,
3. Napier TC
Methamphetamine e susumetsang maikutlo a ho feto-fetoha le maemo ka tsela e fapaneng e fetolang pCREB le ΔFosB ka har'a potoloho ea methapo ea boko ba mammary. Mol. Pharmacol. 70, 2006b 2064-2074. Doi: 10.1124 / mol.106.023051.
38. ↵
1. Mombereau C,
2. Lhuillier L,
3. Kaupmann K,
4. Cryan JF (Phetolelo e Ncha)
2007 GABAB receptor -itive modulation-induction blockade ea thepa e ruisang ea nikotine e amahanngoa le phokotso ea ho bokellana ha li-nucleus ΔFosB. J. Pharmacol. Hlakola Pheko. 321, 172-177. Doi: 10.1124 / jitter.106.116228.
39. ↵
1. Moratalla R,
2. Elibol R,
3.Vallejo M,
4. Greybiel AM
Liphetoho tsa boemo ba sebaka sa marang-rang tsa 1996 molemong oa liprotheine tse sa sebetseng tsa Fos-Jun ka har'a striatum nakong ea kalafo ea koae e sa foleng le ho ikhula. Neuron. 17, 147-156. doi:10.1016/S0896-6273(00)80288-3.
CrossRefMedlineho web ea Mahlale
40. ↵
1. Morgan JI,
2. Curran T
Mefuta ea pele ea 1995: lilemo tse leshome ho ea pele. Mekhoa ea Neurosci. 18, 66-67. doi:10.1016/0166-2236(95)93874-W.
CrossRefMedlineho web ea Mahlale
41. ↵
1.Moller DL,
2. EM e sa sebetseng
2005 D1 dopamine receptors moduction ΔFosB in rat striatum kamora tsamaiso ea nakoana ea morphine. J. Pharmacol. Hlakola Pheko. 314, 148-155. Doi: 10.1124 / jitter.105.083410.
42. ↵
1. Nakabeppu Y,
2. Nathans D
1991 Mofuta oa tlhaho oa FosB o hlahang o thibela mosebetsi oa ho ngola oa Fos / Jun. Sele. 64, 751-759. doi:10.1016/0092-8674(91)90504-R.
CrossRefMedlineho web ea Mahlale
43. ↵
1. Nestler EJ
Motheo oa molek'hule oa 2001 oa polasetiki ea nako e telele e tlisoang ke bokhoba. Nat. Moruti Neurosci. 2, 119-128. doi: 10.1038 / 35053570.
CrossRefMedlineho web ea Mahlale
44. ↵
1. Nestler EJ,
2. Barrot M,
3. Boithati DW
2001 ΔFosB: phetoho e tsoetseng pele ea molek'hule. Proc. Natl Acad. Saense USA. 98, 11 042-11 046. doi: 10.1073 / pnas.191352698.
45. ↵
1. SD ea Norrholm,
2. Bibb JA,
3. Nestler EJ,
4.Ouimet CC,
5. Taylor JR;
6. Greengard P
Keketseho e matla ea coca ea Cocaine e kentsoeng ke 2003 ea li-dendritic spine ka har'a li-nucleus accumbens e itšetlehile ka mosebetsi oa kinase-5 oa cyclin. Neuroscience. 116, 19-22. doi:10.1016/S0306-4522(02)00560-2.
CrossRefMedlineho web ea Mahlale
46. ↵
1. Nye HE,
2. Nestler EJ
Tlhahiso ea 1996 ea li-antigen tse sa foleng (li-antigen tse amanang le Fos) bokong ba rat ka tsamaiso ea morphine e sa foleng. Mol. Pharmacol. 49, 636-645.
47. ↵
1. Nye H,
2. Tšepo BT,
3. Kelz M
4. Iadarola M,
5. Nestler EJ
Boithuto ba 1995 ba lithuto tsa melaoana ea khatello ea kelello ka cocaine of Fra (Fos-antigen) e amanang le "antigen" e fumanehang ho "striatum" le "nucleus accumbens". J. Pharmacol. Hlakola Pheko. 275, 1671-1680.
48. ↵
1. O'Donovan KJ;
2.Tourtellotte WG,
3. Millbrandt J,
4. Baraban JM
1999 Lelapa la EGR la lintlha tse laoloang ke lintlha: tsoelopele sehokelong sa limolek'hule le tsamaiso ea methapo. Mekhoa ea Neurosci. 22, 167-173. doi:10.1016/S0166-2236(98)01343-5.
CrossRefMedlineho web ea Mahlale
49. ↵
1.Olausson P,
2.Jentsch JD,
3. Monyaluoa N,
4.Neve R,
5. Nestler EJ,
6. Taylor JR
2006 ΔFosB e ka har'a nucleus e bokellanang e laola ts'ebetso ea ts'ebetso ea matlafalitsoeng ea sesebelisoa le ts'usumetso. J. Neurosci. 26, 9196-9204. doi: 10.1523 / JNEUROSCI.1124-06.2006.
50. ↵
1.Peakman M.-C,
2. et al.
2003 E sebetsang, polelo ea sebaka se itseng sa bokong phetoho e mpe ea c-Jun ho litoeba tsa transgenic e fokotsa maikutlo a cocaine. Brain Res. 970, 73-86. doi:10.1016/S0006-8993(03)02230-3.
CrossRefMedlineho web ea Mahlale
51. ↵
1. Pérez-Otano I,
2. Mandelzys A,
3. Morgan JI
1998 MPTP-Parkinsonism e tsamaisana le polelo e phehellang ea protheine ea Δ-FosB e tšoanang le litseleng tsa dopaminergic. Mol. Brain Res. 53, 41-52. doi:10.1016/S0169-328X(97)00269-6.
52. ↵
1. Perrotti LI,
2.Hadeishi Y,
3.Ulery P,
4. Barrot M,
5. Monteggia L,
6. Duman RS,
7. Nestler EJ
Induction ea 2004 ea ΔFosB libakeng tse mabapi le moputso tse amanang le moputso ka mora khatello ea maikutlo e sa foleng. J. Neurosci. 24, 10 594-10 602. doi: 10.1523 / JNEUROSCI.2542-04.2004.
53. ↵
1. Perrotti LI,
2. et al.
2005 ΔFosB e bokellana sehlopheng sa lisele tsa GABAergic mohatleng o ka morao oa sebaka sa ho putlama ka hare ho kalafo ka mor'a kalafo ea psychostimulant. EUR. J. Neurosci. 21, 2817-2824. doi: 10.1111 / j.1460-9568.2005.04110.x.
CrossRefMedlineho web ea Mahlale
54. ↵
1. Perrotti LI,
2. et al.
Mekhoa e fapaneng ea 2008 ea ho kenyelletsa ΔFosB bokong ka lithethefatsi tsa tlhekefetso. Synfall. 62, 358-369. Doi: 10.1002 / syn.20500.
CrossRefMedlineho web ea Mahlale
55. ↵
Picetti, R., Toulemonde, F., Nestler, EJ, Roberts, AJ & Koob, litlamorao tsa GF 2001 Ethanol ho litoeba tsa genicFosB. Soc. Neurosci. Abs. 745.16.
56. ↵
1. Pich EM,
2.Pagliusi SR,
3. Tessari M,
4.Talabot-Ayer D,
5. hooft van Huijsduijnen R,
6. Chiamulera C
Li-substrates tsa 1997 tse tloaelehileng tsa neural bakeng sa thepa e lemalloang ea nicotine le koae. Mahlale. 275, 83-86. doi: 10.1126 / science.275.5296.83.
57. ↵
1. Renthal W,
2. et al.
2007 Histone deacetylase 5 epigenetically e laola litloaelo tsa boits'oaro ho susumetsa maikutlo a sa foleng. Neuron. 56, 517-529. doi: 10.1016 / j.neuron.2007.09.032.
CrossRefMedlineho web ea Mahlale
58. ↵
Renthal, W., Carle, TL, Maze, I., Covington III, HE, Truong, H.-T., Alibhai, I., Kumar, A., Olson, EN & Nestler, EJ Ho tobetsa. OsBFosB e buisana le epigenetic desensitization ea c-fos gene ka mor'a amphetamine e sa foleng. J. Neurosci.
59. ↵
1. Robinson TE,
2. Kolb B
Polasetiki ea 2004 polasetiki e amanang le ho pepesehela lithethefatsi tsa tlhekefetso. Neuropharmacology. 47, S33-S46. doi: 10.1016 / j.neuropharm.2004.06.025.
60. ↵
Russo, SJ et al. 2007 NF VerB signaling e laola boitšoaro bo khothalletsoang ke cocaine le polasetiki ea cellular. Motsoalle Neurosci. Abs., 611.5.
61. ↵
1. Shaffer HJ,
2. Eber GB
Keketseho ea nakoana ea mats'oao a ho ts'epa koae ka 2002 ho US National Comorbidity Survey. Ho lemalla. 97, 543-554. doi: 10.1046 / j.1360-0443.2002.00114.x.
CrossRefMedlineho web ea Mahlale
62. ↵
1. Shippenberg TS,
2. Rea W
1997 Sensitization litlamorao tsa boitšoaro ba koae: ho feto-fetoha ha maikutlo ke dynorphin le kappa-opioid receptor agonists. Pharmacol. Biochem. Behav. 57, 449-455. doi:10.1016/S0091-3057(96)00450-9.
CrossRefMedlineho web ea Mahlale
63. ↵
1. Taylor JR;
2.Lynch WJ,
3.Sanchez H,
4.Olausson P,
5. Nestler EJ,
6. Bibb JA
2007 Inhibition ea Cdk5 bokong ba nyutlelie e ntlafatsa sephetho sa cocaine le ts'usumetso ea ts'usumetso ea koae. Proc. Natl Acad. Saense USA. 104, 4147-4152. doi: 10.1073 / pnas.0610288104.
64. ↵
1.Tegarden SL,
2. Bale TL
Ho fokotseha ha 2007 ho khethollo ea lijo ho hlahisa maikutlo a eketsehileng le kotsi ea ho khutla ha lijo. Biol. Psychiki. 61, 1021-1029. doi: 10.1016 / j.biopsych.2006.09.032.
CrossRefMedlineho web ea Mahlale
65. ↵
Teegarden, SL, Nestler, EJ & Bale, TL Ho tobetsa. Liphetoho tse fetotsoeng ke ΔFosB mabapi le ho saena ha dopamine li tloaelehile ka phepo e nepahetseng ea mafura. Tlhaho. Phekolo ea kelello.
66. ↵
1. Tsankova N,
2. Renthal W,
3.Kumar A,
4. Nestler EJ
2007 Epigenetic regulation maemong a mafu a kelello. Nat. Moruti Neurosci. 8, 355-367. doi: 10.1038 / nrn2132.
CrossRefMedlineho web ea Mahlale
67. ↵
1.Phatlalatsa PG,
2.Rudenko G,
3. Nestler EJ
2006 Taolo ea stabilityFosB e tsitsitseng ka phosphorylation. J. Neurosci. 26, 5131-5142. doi: 10.1523 / JNEUROSCI.4970-05.2006.
68. ↵
Vialou, VF, Steiner, MA, Krishnan, V., Berton, O. & Nestler, EJ 2007 Karolo ea ΔFosB ka har'a li-nucleus tse bokellaneng sechabeng se sa foleng. Soc. Neurosci. Abs., 98.3.
69. ↵
Wallace, D., Rios, L., Carle-Florence, TL, Chakravarty, S., Kumar, A., Graham, DL, Perrotti, LI, Bolaños, CA & Nestler, EJ 2007 Tšusumetso ea ΔFosB ka har'a li-nucleus accumbens ka boitšoaro ba moputso oa tlhaho. Soc. Neurosci. Abs., 310.19.
70. ↵
1. Mofuthu M,
2. Mesia C,
3. Olson L,
4. Khahleho L,
5. Thorén P,
6. Nestler EJ,
7. Brené S
2002 ΔFosB e laola mabili a tsamaeang. J. Neurosci. 22, 8133-8138.
71. ↵
1. Winstanley CA,
2. et al.
2007 ΔFosB induction ea orbitofrontal cortex e lumellana le mamello ho se sebetseng hantle ha koae. J. Neurosci. 27, 10 497-10 507. doi: 10.1523 / JNEUROSCI.2566-07.2007.
72. ↵
1. Yen J,
2. Bohlale RM,
3. Tratner I,
4. Verma IM
1991 Sebopeho se seng se fetotsoeng sa FosB ke taolo e mpe ea ts'ebetso ea phetisetso le phetoho ea liprotheine tsa Fos. Proc. Natl Acad. Saense USA. 88, 5077-5081. doi: 10.1073 / pnas.88.12.5077.
73. ↵
1. Mocha ST,
2. Porrino LJ,
3. Iadarola MJ
1991 Cocaine e etsa liprotheine tse matlafatsang tsa c-fos-immunoreactive ka li-receptor tsa dopaminergic D1. Proc. Natl Acad. Saense USA. 88, 1291-1295. doi: 10.1073 / pnas.88.4.1291.
74. ↵
1. Zakaria V,
2. et al.
2006 Karolo ea bohlokoa ea ΔFosB ka har'a nucleus e bokellanang ketsong ea morphine. Nat. Neurosci. 9, 205-211. doi: 10.1038 / nn1636.
CrossRefMedlineho web ea Mahlale
· Ikopanye
· Connotea
· Digg
Lihlooho tse qotsitsoeng sehloohong sena
EW Klee,
o JO Ebbert,
o H. Schneider,
o RD Bohloko,
o le SC Ekker
Zebrafish bakeng sa Tlhahlobo ea Liphello tsa Biological tsa NicotineNicotine Tob Res May 1, 2011 13: 301-312
LA LA Briand,
o FM Vassoler,
RC Pierce,
o RJ Valentino,
o le JA Blendy
Barekisi ba Phapang ea Ventral ho Reinstatement ea Khatello ea Kelello: Karolo ea cAMP Response Element-Binding ProteinJ. Neurosci. December 1, 2010 30: 16149-16159
o V. Vialou,
O I. Maze,
o W. Renthal,
o QC LaPlant,
EL Watts,
o E. Mouzon,
o S. Ghose,
o CA Tamminga,
o le EJ Nestler
Sempe ea Karabo ea Serum e Ntlafatsa Ho tiisetsa ho khatello ea maikutlo ea bophelo bo sa foleng ka tlhahiso ea {Delta} FosBJ. Neurosci. Mphalane 27, 2010 30: 14585-14592
o F. Kasanetz,
o V. Deroche-Gamonet,
O N. Berson,
o E. Balado,
o M. Lafourcade,
o O. Manzoni,
o le PV Piazza
Phetoho ea ho lemalla e amahanngoa le ho senyeha ho sa khaotseng ho Synaptic PlasticityScience June 25, 2010 328: 1709-1712
o Y. Liu,
o BJ Aragona,
O Mocha,
o DM Dietz,
o M. Kabbaj,
o M. Mazei-Robison,
EJ Nestler,
o le Z. Wang
Nyutlelie e bokella dopamine mediates amphetamine-e kenyellelitseng ho senyeha ha litlamo tsa kahare ho mofuta oa monogamous rodent mefutaProc. Natl. Acad. Saense USA January 19, 2010 107: 1217-1222
O I. Maze,
O HE Covington,
o DM Dietz,
O Q. LaPlant,
o W. Renthal,
SJ Russo,
Mechanic ea M.
o E. Mouzon,
o RL Hona joale,
SJ Haggarty,
o Y. Ren,
o SC Sampath,
o YL Hurd,
o P. Greengard,
o A. Tarakhovsky,
o A. Schaefer,
o le EJ Nestler
Karolo ea Bohlokoa ea Histone Methyltransferase G9a ho Cocaine-E tsitsitse PlasticityScience Pherekhong 8, 2010 327: 213-216
SJ Russo,
MB MB Wilkinson,
MS Mazei-Robison,
o DM Dietz,
O I. Maze,
o V. Krishnan,
o W. Renthal,
o A. Graham,
O SG Birnbaum,
o TA Green,
o B. Robison,
o A. Nakoana,
o LI Perrotti,
o CA Bolanos,
o A. Kumar,
MS Clark,
JF Neumaier,
o RL Hona joale,
AL Bhakar,
PA Barker,
o le EJ Nestler
Nuclear Factor {kappa} B Signaling Regulates Neuronal Morphology le Cocaine RewardJ. Neurosci. Hlakubele 18, 2009 29: 3529-3537
Y. Kim,
O MA Teylan,
M. Baron,
o A. Sands,
AC Nairn,
o le P. Greengard
Methylphenidate-indued dendritic spine maleba le {Delta} polelo ea FosB ho nucleus accumbensProc. Natl. Acad. Saense USA February 24, 2009 106: 2915-2920
o RK Chandler,
BW Fletcher,
o le ND Volkow
Ho Phekola Ts'ebeliso e Mpe ea Lithethefatsi le Tlatsetso ho Sisteme ea Toka ea Tlolo ea Molao: Ho ntlafatsa Bophelo ba Sechaba le PolokehoJAMA Pherekhong 14, 2009 301: 183-190
o D. L Wallace,
o V. Vialou,
o L. Rios,
TL Carle-Florence,
o S. Chakravarty,
o A. Kumar,
DL Graham,
o TA Green,
o A. Kirk,
O SD Iniguez,
o LI Perrotti,
M. M. Barrot,
RJ DiLeone,
EJ Nestler,
o le CA Bolanos-Guzman
Tšusumetso ea {Delta} FosB ho Nucleus Accumbens on Natural Reward-BehaeveJ. Neurosci. Mphalane 8, 2008 28: 10272-10277
;
