LITLHAKISO: Le ha khatello ea maikutlo ka bobeli, lithethefatsi tsa tlhekefetso le meputso e meng ea tlholeho li baka ho bokellana ha DeltaFosB, khatello ea maikutlo e sebetsa liseleng tse fapaneng tsa molatsoana mme li-receptor le mefuta ea morao-rao e fapaneng. Ka mantsoe a mang, litlamorao le ho hanyetsa khatello ea maikutlo li itšetleha ka mekhoa e fapaneng e fapaneng
J Neurosci. 2010 Oct 27; 30 (43): 14585-92.
Vialou V, Maze I, Renthal W, LaPlant QC, Watts EL, Mouzon E, Ghose S, Tamminga CA, Nestler EJ.
mohloli o moholo
Lekala la Fishberg la Neuroscience, Sekolo sa Bongaka sa Mount Sinai, New York, New York 10029, USA.
inahaneloang
Lisebelisoa tsa limolek'hule tse bakang khatello ea maikutlo le lithethefatsi tse fetotsoeng ke lithethefatsi ha li utloisisehe hantle. Molek'hule e ngoe e kentsoeng phetohong e joalo ke ΔFosB, ntho ea ho ngola e bokellanang sebakeng sa "methapo ea methapo ea methapo", karabelo ea khatello ea maikutlo kapa ho pepesehela lithethefatsi tsa tlhekefetso. To nyolla mekhoa e hatisang ea ΔFosB ka ts'usumetso ea tikoloho ka mekhoa ena ea tikoloho. Mona, re supa karolo e ts'ehetsang ea mongolo o ts'ebetsong, serum reaction factor (SRF), e le 'muelli ea phahameng oa khatello ea maikutlo, empa eseng koae-, e hlohlellelitse ΔFosB. SRF e nyenyefalitsoe ho NAc ea bakuli ba tepelletseng ba batho ba tepelletseng maikutlo 'me ba litoeba tse pepeneneng ba aparetsoe ke khatello ea maikutlo ea maemo a bophelo. Phokotso ena ea SRF ha e eo ho liphoofolo tse ikemiselitseng. Ka ts'ebeliso ea "mutageneis" e sa sebetseng, re bonts'a hore uctionFosB e kenelletsang khatello ea maikutlo, e etsahalang haholo litheteneng tse tiisitsoeng, e itšetlehile ka polelo ea SRF sebakeng sena sa boko. Ntle le moo, ho tlosoa ha genetic ka ho khetheha ha NAF ho khothaletsa mefuta e fapaneng ea protepressant- le proanxonomy-like phenotypes mme e fa liphoofolo tse tsotellang litlamorao tse mpe tsa khatello e sa feleng. Ho fapana le moo, re bonts'a hore SRF ha e nke karolo ea ho bokellana ha ΔFosB ho NAc ho latela ho pepesetsoa ha koae. Ntle le moo, ho tsoa ka ho khetheha ha NAF ha ho na tšusumetso ea boitšoaro bo khothalletsoang ke koae, ho bonts'ang hore khatello ea maikutlo le khatello ea koae e sa khaotseng e laola ho bokellana le ho angoa ke boitšoaro ba ΔFosB ka mekhoa e ikemetseng.
Selelekela
The nucleus accumbens (NAc), sebaka sa moputso oa boko bo bohlokoa, e bohlokoa bakeng sa ho kenyelletsa lipokello tsa kelello le kelello tse tsamaisang boitšoaro bo nepahetseng bo susumetsang ho arabela ka ts'usumetso ea tikoloho (Nestler le Carlezon, 2006; Sesack le Mohau, 2010). NAc le eona e kentse letsoho liketsong tse mpe tsa boitšoaro tse amanang le tšebeliso ea lithethefatsi le khatello ea maikutlo. Ka hona, ho tsepamisa NAc ka ts'usumetso e tebileng ea boko ho bontšitsoe ho fokotsa khatello ea maikutlo- le boits'oaro bo joalo ba tšenyo e joalo ka batho le litoeba (Schlaepfer et al., 2008; Vassoler et al., 2008; Heinze et al., 2009; Kuhn et al., 2009).
Ho pepesetsoa khafetsa ho lithethefatsi tsa tlhekefetso kapa khatello ea maikutlo ho etsa hore mefuta e fetotsoeng ea polelo ea gene e be ho NAc, ka mokhoa o ikhethileng oa khatello ea maikutlo le khatello ea maikutlo (Berton et al., 2006; Krishnan et al., 2007; Maze et al., 2010; Vialou et al. ., 2010). Ho khahlisang ke hore transaction factor ΔFosB, sehlahisoa sa splice sa mofuta oa fosB, se bokellana ho NAc ho araba khafetsa lithethefatsi kapa khatello ea maikutlo (Nestler, 2008; Perrotti et al., 2008; Vialou et al., 2010). ΔFosB e hlahisitsoe e le phetoho ea molek'hule e ka tataisang phetoho ho tloha ts'ebeliso ea lithethefatsi ea boithabiso ho ea ho mmuso o lemaletseng lithethefatsi (Nestler et al., 1999; McClung et al., 2004; Renthal et al., 2009), joalo ka ha e bokelloa ho NAc e ntlafatsa. likarabo tse khotsofatsang ho lithethefatsi tse 'maloa tsa tlhekefetso. Haufinyane tjena, karolo ea ΔFosB ea ho kenya ts'ebetsong NAc kamora khatello ea khatello ea khatello ea sechaba (Nikulina et al., 2008; Vialou et al., 2010) e hlakisitsoe: ΔFosB e khothaletsa likarabo tsa ho sebetsana ka katleho le maikutlo le khatello ea maikutlo.. Leha induction ea ΔFosB e etsahala ka tsela e ts'ehetsang ts'usumetso, lits'ebetso tse ikarabellang bakeng sa ho bokellana ha lithethefatsi le khatello ea maikutlo tsa ΔFosB ho NAc li lula li sa tsejoe.
Sesebelisoa sa karabelo ea Serum (SRF) ke sengoloa se hlokahalang bakeng sa ts'ebetso ea phetolelo e itšetlehileng ka ts'ebetso ea liphatsa tsa lefutso tse 'maloa tsa kapele, ho kenyeletsoa c-fos, fosb, Egr1, le Arc (Knöll le Nordheim, 2009). Boithuto ba morao-rao bo bonts'itse litlamorao tsa SRF ho morphological le cytoarchitectural properties ea li-neuron, ho kenyeletsoa taolo ea ts'ebetso ea synaptic le sebopeho sa potoloho bokong ba batho ba baholo (Knöll le Nordheim, 2009). Liphumano tsena li re hlohlellelitse ho etsa lipatlisiso hore na SRF e laoloa ka nepo ke ho pepesehela lithethefatsi tsa tlhekefetso kapa khatello ea maikutlo, le litlamorao tse ka bang teng taolong e mabapi le ho qalisoa ha osBFosB tlasa maemo ana.
Mona, re hlalosa mochini oa nalane oo ka oona tlolo ea SRF ho NAc e khothalletsang khatello ea maikutlo le khatello ea maikutlo, qetellong e eketsang ts'oaetso ea phoofolo liphellong tse mpe tsa khatello ea maikutlo e sa foleng. Litholoana tsena ke tsa lipakeng, ka karolo e 'ngoe, ke tahlehelo ea uctionFosB ho kenella ho NAc ea liphoofolo tse hatelletsoeng. Ho hlokomeloa ho fokotseha ha polelo ea SRF le ΔFosB posong ea 'mele ea NAc e fumanoeng ho bakuli ba tepelletseng maikutlo e ts'ehetsa bohlokoa ba se re se fumaneng ho khatello ea maikutlo ea motho. Ho khahlisang ke hore mochini ona o laolang pokello ea ΔFosB o bonahala o totobetse khatello ea maikutlo: ho pepeseha ha k'hok'heine e sa foleng ha ho na tšusumetso ho polelo ea SRF, ho tlosoa ha SRF ho NAc ha ho na tšusumetso ho pokello ea ΔFosB kamora ho pepeseha ho sa feleng ha cocaine, mme ho tlosoa ha SRF ho joalo ha ho na tšusumetso ho cocaine- boitšoaro bo susumetsoang. Tšebelisano ena e ncha lipakeng tsa SRF le ΔFosB, maemong a khatello ea maikutlo, e kanna ea emela mochini oa bohlokoa oa homeostatic o laolang maikutlo a motho ho khatello ea maikutlo e sa foleng.
Lisebelisoa le mekhoa
Animals
Limpho tse tona tsa libeke tse robeli tsa C57BL / 6J (Jackson Laborator) li sebelisitsoe liteko tsohle tsa boitšoaro le tsa biochemical. Liphoofolo tsohle li ne li lula sebakeng sa liphoofolo bonyane 1 bekeng pele ho liteko tsa liteko mme li ne li bolokoa 23-25 ° C mochining oa khanya oa 12 h le lefifi (mabone ho tloha 7: 00 AM ho 7: 00 PM) e nang le ad libitum phihlello ea lijo le metsi. Liteko li ile tsa etsoa ho latela tataiso ea Mokhatlo oa Neuroscience le komiti ea tlhokomelo ea liphoofolo le ts'ebeliso ho Mount Sinai School of Medicine.
Bakeng sa liteko tsa k'hok'heine [litoeba tsa Bophirimela le ho putlama ha leqhubu la chromatinit tse ngata tsa (ChIP)], 8- ho 10 ea lilemo li beke ea XXUMXBL / 57J li sebelisitsoe. Liphoofolo li fumane liente tse supileng tse kenang kahare letsatsi le letsatsi tsa saline kapa cocaine (6 mg / kg cocaine-HCl; Sigma). Lice li sebelisitsoe 20 h kamora kalafo ea ho qetela. Bakeng sa liteko tsa boits'oaro, litoeba li ne li kenoa ka mokhoa o khethehileng 'me li alafshoa ka 24 mg / kg (sensomization sensitization) kapa 10 mg / kg (sebaka se ikhethileng) cocaine-HCl ka kotloloho, joalo ka ha ho hlalositsoe ka tlase.
Litoeba tsa Srffl / fl li hlahisitsoe joalo ka ha ho hlalositsoe pele (Ramanan et al., 2005). Ho tsoa hoa Scf ka mokhoa o ikhethileng ho ile ha fumaneha ka ente ea stereotaxic le litlamorao tse latelang tsa vaerase ea Cre recombinase (Cre) e sebelisitseng liprotheine tse tala tsa fluorescent (GFP) li sebelisa li-veenz tse amanang le vaerase. Ho ne ho sebelisoa Cera e sa itlhatsoeng. AAV-GFP e ile ea kenngoa sebakeng sa AAV-Cre-GFP ka litoeba tsa Srffl / Fl joalo ka taolo. Ka bokhutšoanyane, litoeba li ne li sa sebetse li sebelisa motsoako oa ketamine (10 mg / kg) le xylazine (10 mg / kg), ka likhokahano tse latelang tsa li-stereotaxic tse sebelisoang ho tsamaisoa ha vaerase: + 1.6 (anterior / posterior), + 1.5 (lateral), - 4.4 (dorsal / ventral) ka sekhahla sa 10 ° ho tloha bohareng (bo amanang le bregma). Kakaretso ea 0.5 μl ea vaerase e hloekisitsoeng e ile ea isoa habeli ka nako e fetang ea 5 min (0.1 μl / min), ea lateloa ke 5 min ea phomolo. Litsuonyana li ile tsa lekoa libeke tsa 2 kamora ho buuoa, ha tlhahiso ea vaerase e ne e le ngata, 'me libaka tsa ente ea vaerase li tiisitsoe bakeng sa liphoofolo tsohle tse sebelisang mekhoa e tloaelehileng ea nalane. Ho sebetsa hantle ha polelo ea popo e kopaneng le vaerase ho netefalitsoe ke immunohistochemistry le ka re-transcriptase PCR bakeng sa Srf e tsamaisoang ho li-punc tsa microcissected NAc ho liphoofolo tse fuoeng AAV-Cre-GFP le AAV-GFP ho NAc. Likokoana-hloko tsa AAV-GFP le AAV-Cre-GFP li hlahisitsoe joalo ka ha ho hlalositsoe pele (Maze et al., 2010).
Mekhoa ea boitšoaro
Ho imeloa kelellong.
Li-C57BL / 6J litoeba li ne li le tlas'a khatello ea khatello ea maikutlo ea khatello ea khatello ea sechaba bakeng sa matsatsi a 10 a latellanang joalokaha ho hlalositsoe pele (Berton et al., 2006; Krishnan et al., 2007; Vialou et al., 2010). Ka bokhutšoanyane, mouse e 'ngoe le e' ngoe e ile ea pepesetsoa phoofolo ea mohoebi e sa tsoakoeng le e mabifi ea CD1 ka motsotso oa 5 min ka letsatsi. Kamora ho sebelisana ka kotloloho le mohlohlelletsi oa CD1, liphoofolo li ile tsa beoa kamoreng e haufi le terata e le 'ngoe bakeng sa 24 h e latelang ka ho ts'oarana ka maikutlo. Liphoofolo tse laoloang li ne li bolokiloe makaleng a lekanang empa li ne li fuoa litho tsa mofuta o le mong. Liteko tsa tšebelisano ea sechaba li ile tsa etsoa 24 h kamora letsatsi la ho qetela la ho hloloa.
Thibelo ea kahisano ho toeba e tona e sa tsejoeng ea CD1 e ile ea lekoa ho latela melaoana e phatlalalitsoeng (Berton et al., 2006; Krishnan et al., 2007; Vialou et al., 2010). Mouse ea liteko e ile ea qala ho hlahisoa lebaleng le bulehileng le nang le terata e se nang letho ea terata bakeng sa 2.5 min. Nakong ea thuto ea bobeli, toeba e tona e sa tsejoeng ea CD1 e ile ea hlahisoa ka mokoting o nang le mehala. Nako e sebelisitsoeng sebakeng sa tšebelisano (phasejeng e bophara ba lisenthimithara tse 8 e potileng cage) e ne e lekantsoe. Khethollo ea litoeba tse hlotsoeng ka har'a maemo a bonolo le a mamello e entsoe joalo ka ha ho hlalositsoe pejana (Krishnan et al., 2007; Vialou et al., 2010). Kaha boholo ba litoeba li sebelisitse nako e ngata li sebelisana le sepheo sa sechaba ho fapana le sebaka se se nang letho, karolelano ea tšebelisano ea 100 (nako e lekanang e sebelisitsoeng sebakeng sa tšebelisano boteng le ho ba sieo ha sepheo sa sechaba) e ile ea beoa e le cutoff. Litoeba tse nang le lintlha tse <100 li ne li ngotsoe li le bonolo, 'me tse nang le lintlha tse ngata ≥100 li ne li ngotsoe e le tse tiileng. Litlhahlobo tse pharalletseng tsa boits'oaro, biochemical le electrophysiological li tšehetsa bonnete ba likaroloana tsena tse bonolo tse ka hlaseloang habonolo (Krishnan et al., 2007; Wilkinson et al., 2009; Vialou et al., 2010).
Ho hlahloba ho ba kotsing ea likotsi tsa Srffl / fl ho likhathatso tsa khatello ea sechaba, litoeba, tse kentsoeng ka kopanelo le AAV-GFP kapa AAV-Cre-GFP, li ile tsa hloloa ka makhetlo a mararo ka letsatsi le le leng mme tsa lekoa bakeng sa tšebelisano ea sechaba 24 h hamorao. Ts'ebetso ena ea ho hloloa ka submaximal e netefalitsoe pejana ho senola protusceptibility phenotypes e latelang liphatsa tsa lefutso (Krishnan et al., 2007; Vialou et al., 2010).
Ithute ho hloka thuso.
Srffl / Fl mice overexpressing e ka ba AAV-GFP kapa AAV-Cre-GFP ba ile ba kenngoa ts'ebetsong ea ho hloka thuso joalo ka ha ho hlalositsoe pejana (Berton et al., 2007). Ka bokhutšoanyane, litoeba li ile tsa pepesetsoa litšitiso tsa leoto tsa nakoana, tse sa angoeng ke 1 h ka matsatsi a 2 consecutives (0.45 mA, 5 s time). Ka letsatsi la liteko, litoeba li ile tsa hlahisoa hape ka lebokoseng bakeng sa liteko tsa ho baleha tse latellanang tsa 15. Nako le nako ha nyeoe e 'ngoe le e' ngoe e tšoha, ho ts'oaroa ka mokhoa o sa khaotseng 'me litoeba li ne li fuoa monyetla oa ho baleha ka ho kena kamoreng e haufi, e sa khethoang. Kamora ho pholoha ka katleho, lemati le ile la notleloa ka bohona 'me ea rekota ea ho phonyoha. Ha litoeba li sa balehe kahare ho 25 s, nyeoe e ile ea felisoa mme e tlalehiloe e le ho sitoa. Boithuto ba pejana bo bontšitse hore polelo ea vaerase ho NAc le libakeng tse ling ha e na phello ho boits'ireletso ba motheo ba ho se be le khatello ea maikutlo (Newton et al., 2002; Berton et al., 2007).
Sehopotso sa locomotor.
Libeke tse peli kamora liente tsa intra-NAc tsa AAV-GFP kapa AAV-Cre-GFP, litoeba tsa Srffl / fl li ile tsa angoa ke ts'ehetso ea locomotor. Litoeba li ne li tloaetse lebaleng la terene bakeng sa metsotso e 30 ka letsatsi bakeng sa 4 d. Kamora ho tloaela, liphoofolo li ile tsa kenoa kahare ka 10 mg / kg k'hok'heine-HCl ebe e kenngoa ka mabokoseng a terene. Mesebetsi ea baetsi ba liphoofolo e tlalehiloe ho sebelisoa sistimi ea photobeam (San Diego Instruments) joalo ka likhefu tsa ambulense bakeng sa metsotso e 30 ka letsatsi. Ho hlohlelletsa locomotor ho tlalehiloe ka nako ea 6 d.
Sebaka se khethiloeng sa sebaka.
Tsamaiso ea maemo a sebaka e ile ea etsoa joalo ka ha ho hlalositsoe pejana (Maze et al., 2010), ka liphetoho tse latelang. Ka bokhutšoanyane, 18 d kamora infusions ea intra-NAc ea AAV-GFP kapa AAV-Cre-GFP ho Srffl / litoeba, liphoofolo li ile tsa beoa ka likamoreng tsa maemo, tse neng li e-na le libaka tse tharo tse fapaneng. Litoeba tse bonts'ang khetho ea bohlokoa ho e 'ngoe ea likamore tse peli tsa maemo li kentsoe thutong (<10% ea liphoofolo tsohle). Lihlopha tsa maemo li ne li lekantsoe le ho feta ho ikamahanya le khethollo efe kapa efe ea kamore eo e ka bang teng. Matsatsing a latelang, liphoofolo li ile tsa entoa ka letsoai 'me tsa koalloa kamoreng e le ngoe thapama bakeng sa 30 min ebe li entoa ka cocaine (7.5 mg / kg, ip) ebe e koalloa metsotso e 30 kamoreng e' ngoe ka le hlahlamang, ho lekana mekhahlelo e 'meli ea lithupelo tsa mokhatlo kalafo e' ngoe (tse peli tse letsoai le tse peli tse peli tsa cocaine). Letsatsing la teko, litoeba li ile tsa khutlisoa ka har'a lisebelisoa ntle le kalafo bakeng sa metsotso e 20 mme tsa lekoa ho lekola khetho ea lehlakore. Likarabo tsa locomotor ho cocaine li ile tsa hlahlojoa ka likheo tsa boroko likamoreng tse nang le koae ho netefatsa katleho ea kalafo ea lithethefatsi. Bakeng sa lihlopha tsohle, mochini oa mantlha oa karabelo ea letsoai o ile oa hlahlojoa ho netefatsa hore ts'oaetso ha e amehe ke kalafo ea vaerase.
Liteko tse ling tsa boits'oaro.
Litoeba tsa Srffl / Fl li ile tsa lekoa sebakeng se bulehileng, se bobebe / se le lefifi, 'me liteko tsa ho sesa li qobelloa ho latela liprotheine tse phatlalalitsoeng (Vialou et al., 2010). Ts'ebetso ea litoeba lebaleng le bulehileng e tlalehiloe bakeng sa 5 min sebelisa sistimi ea ho lata video (Ethovision) tlasa maemo a bobebe. Bakeng sa teko e bobebe / e lefifi, litoeba li ile tsa lumelloa ho phenya ka bolokolohi lebokose le nang le likamore tse peli le neng le entsoe ka lebaleng le leholo le bonesitsoeng le hokahantsoeng lebaleng le lenyane le koetsoeng. Lice li ile tsa lekoa ka nako ea metsotso ea 5 ho lekola nako e sebelisitsoeng ho eng kapa ho koaloa. Litekong tse bulehileng le tse bobebe / tse lefifi, nako e sebelisitsoeng bohareng le lebaleng la bobebe, ka ho tšoanang, e ile ea hlahlojoa e le index e fapaneng ea likarabo tse amanang le matšoenyeho. Teko e qobelloang ea ho sesa ea 1 d e ile ea etsoa nakoana ea 5 min. Ho eketsa nako ea ho se sebetse hantle nakong ea liteko tse qobelloang ho sesa ho ile ha hlalosoa e le mokhoa o ts'oanang le oa protepressant-like. Teko ea qobello ea ho sesa ea 1 d e sebelisitsoe haholo ho litoeba 'me e netefalitsoe e le mokhoa oa ho nepahala ha maemo, hobane kalafo ea meriana e khahlanong le khatello ea maikutlo e fokotsa linako tsa ho se sebetse hantle.
Immunohistochemistry
Litoeba tsa Srffl / Fl li ne li sa phekoloe li bile li entsoe ka mokhoa o ikhethileng ka 4% paraformaldehyde / PBS. Li-brains li tlositsoe mme li-cryoprotected ho 30% sucrose / PBS. Likarolo tsa Coronal (30 μm) li ile tsa roaloa microtome e se nang chefo 'me tsa sebetsoa bakeng sa tlhahlobo ea immunohistochemical. Netefatso ea Srffl / fl knock-out e entsoe ka ho sebelisa anticl ea polyclonal e lebisitsoeng khahlanong le SRF (1 / 2000; Santa Cruz Biotechnology). Polelo ea Cre e netefalitsoe ka polelo ea GFP (kuku ea polyclonal, 1 / 8000, Aves Labs) ka har'a likelello tse qotsitsoeng, kaha Cre e kopantsoe le GFP. Bakeng sa quanifying of ΔFosB induction kamora khatello ea tlhaselo ea sechaba ho litoeba tsa Srffl / Fl knock-out, ΔFosB e fumanoe e sebelisa rabara ea polyclonal antibody e phahamisitsoeng khahlanong le sebaka sa N-terminal sa protheine (1 / 1000; Santa Cruz Biotechnology). Litšoantšo li ile tsa nkuoa ka microscope e nang le pherekano (tlotliso ea 20 ×; Zeiss). Palo ea lisele tsa immunopositive ea GFP e baloang e le mpe ebile e le ntle bakeng sa ΔFosB immunoreactivity e ile ea hlakisoa litšoantšong tse ngata bakeng sa phoofolo ka 'ngoe, ka boleng bo hlakileng kamora moo e baliloe phoofolo ka' ngoe. Phoofolo e 'ngoe le e' ngoe e ne e nkuoa e le leihlo le nchocho ho lekola lipalo.
Lithane tsa postmortem NAc
Lisele tsa boko ba postmortem li fumanoe ho tsoa ho pokello ea Dallas Brain, moo lisele li bokelloang ho tsoa ho Ofisi ea Mohlahlobi oa Bongaka ea Dallas le University of Texas (UT) Southwestern's Tissue Transplant Program kamora tumello ea beng ka bona. Lisele li ile tsa hlahlojoa ho tloha ho tse tona le tse tšehali li lekana lilemo, nako ea postmortem, nomoro ea RNA botšepehi (RIN) le pH. Lintho tse ikhethang tsa agonal, ho kenyelletsa coma, hypoxia, pyrexia, ho oa, ho felloa ke metsi 'meleng, hypoglycemia, ho hloleha ha litho tse ngata, le ho kenella ha lintho tse nang le methapo ea kutlo ka nako ea lefu li susumetsa bots'epehi ba RNA lithutong tsa boko ba morao (Tomita et al., 2004). Re sebelisitse sekala sa agonal factor (AFS) ho tšoaea mehlala ea lisele maemong ohle a robeli. Ho ba sieo ha karolo ea agonal ho fuoe lintlha tsa 0 mme boteng ba eona bo fumanoe e le 1 ho fana ka lintlha tse felletseng tsa AFS lipakeng tsa 0 le 8. Lisele tse nang le lintlha tsa agonal tsa 0 kapa 1 li bonts'a mehlala ea boleng bo botle; lipalo tsa batho li fanoe ho Tafole ea 1. Boleng bo ikhethang ba lisele bo netefalitsoe ke litekanyetso tse phahameng tsa RIN. Linyeoe li ne li pepesitsoe ka mokhoa o tloaelehileng pele ho qhoqhoa ho -40 ° C isopentane le polokelo ho -80 ° C; ho qhaloa ho eketsehileng ha NAc ho ne ho etsoa ka lisele tse hoamisitsoeng. Boto ea tlhahlobo ea setheo sa Boroa-bophirima e lekotse le ho amohela pokello ea lisele tsena bakeng sa ts'ebeliso ea lipatlisiso. Puisano e tobileng ea tlhaiso-leseling e ile ea etsoa bakeng sa nyeoe e ngoe le e ngoe ea khatello ea maikutlo hamorao, moo tlhaiso-leseling e mabapi le bokuli ba nyeoe e tlalehiloeng; phumano ea tumellano ea lefu le leholo la khatello ea maikutlo e entsoe ho sebelisoa litekanyetso tsa DSM-IV ke lingaka tse peli tsa mafu a kelello tse etsang lipatlisiso. Ha ho linyeoe tse kenyellelitsoeng phuputsong ena tse neng li e-na le li-skrini tsa mali tse nang le chefo bakeng sa lithethefatsi tsa tlhekefetso, joala kapa lithethefatsi tse tlamang ntle le lithibela-mafu. Leha a ne a fuoa kalafo ea ho imeloa kelellong, lithuto tsohle li ne li tepelletse maikutlo nakong ea lefu. Mehlala ea lisele e fanoe ka mokhoa o foufalitsoeng bakeng sa tlhahlobo.
Tafole 1.
Lintlha tsa demographic bakeng sa thuto ea motho ea postmortem
Bophahamo ba Bophirimela
Litšoantšo tsa NAc tsa botho le tsa mouse li ile tsa sebetsoa joalo ka ha ho hlalositsoe pele (Maze et al., 2010). Lithane tse nang le serame li ile tsa kenngoa ka har'a 5 mM HEPES lysis buffer e nang le 1% SDS e nang le proteinase (Roche) le phosphatase inhibitors (Sigma). Ho tsepamisa mohopolo oa liprotheine ho ne ho reriloe ke ts'ebetso ea protheine ea Dc (Bio-Rad). Mefuta e lekanang ea liprotheine e ne e behiloe ho SDS-PAGE le ho blot Western. Ho ile ha batloa lithutsoana tsa Bophirimela ho sebelisoa antibody ho ea ho SRF (1 / 2000; Santa Cruz Biotechnology) kapa GAPDH (1 / 1500; Abcam) 'me ka mor'a moo ea hlahlojoa le ho hlakoloa ka ho sebelisa Odyssey imaging system (Licor).
Ho khetholoha RNA le PCR ea bongata
Ho khetholloa ha RNA, bongata ba PCR (qPCR), le tlhahlobo ea data li entsoe joalo ka ha ho hlalositsoe pele (Maze et al., 2010; Vialou et al., 2010). Ka bokhutšoanyane, RNA e ne e qheletsoe ka thoko le TriZol reagent (Invitrogen) mme e ile ea hloekisoa le ho feta ka li-RITLITTISESEESEESEESESESANGANG TSA TSIETSI TSE TSOANG HO Qiagen. Mehlala eohle ea RNA e ne e ikemiselitse ho ba le 260 / 280 le 260 / 230 boleng values1.8. Mongolo o fetoletsoeng o ne o etsoa ho sebelisoa iScript (Bio-Rad). QPCR e sebelisang SYBR e tala (Quanta) e entsoe ka Sistimi ea Applied Biosystems 7900HT RT PCR e nang le likarolo tse latelang tsa potoloho: 2 min ho 95 ° C; Li-circuits tsa 40 tsa 95 ° C tsa 15 s, 59 ° C bakeng sa 30 s, 72 ° C bakeng sa 33 s; le ho futhumatsa maemo ho ea 95 ° C ho hlahisa li-curve tsa ho itlhatsoa bakeng sa netefatso ea lihlahisoa tse le 'ngoe tsa PCR. Lintlha li ile tsa hlahlojoa ka ho bapisa litekanyetso tsa C (t) tsa boemo ba kalafo (taolo vs. lithaelese tse tsitsitseng kapa tse tsitsitseng, kapa taolo ea motho le bakuli ba tepelletseng) ka ΔΔC (t) mokhoa (Tsankova et al., 2006). Li-primers tsa ΔFosB qPCR: ho fokotseha, AGGCAGAGCTGGAGTCGGATAT le ho khutlisetsa morao, GCCGAGGACTTGAACTTCACTCG.
CHIP
ChIP e entsoe joalo ka ha ho hlalositsoe pele (Maze et al., 2010) ho litla-morao tsa NAc tse kentsoeng ka har'a taolo, lithaelese le litoeba tse matla (tse 'ne tsa 14-gauge punches / mouse) 1 h kamora boiphihlelo ba ho qetela ba ho hloloa le ho tsoa ho saline- le cocaine- tšoara liphoofolo 24 h kamora kalafo ea ho qetela. Lenonyeletso le ne le hokahane le 1% formaldehyde. Ho lokisa ho ile ha kenella ka mor'a moo ka ts'ebeliso ea glycine, 'me thapo e ile ea hlatsuoa' me ea bolokoa ho −80 ° C ho fihlela e sebelisoa. Sheared chromatin e ile ea lula bosiu hang-hang ka anti-SRF antibody (Santa Cruz Biotechnology) eo pele e neng e tlameletsoe lihloeng tsa makenete (Dynabeads M-280; Invitrogen). Kamora ho hokahanya ho kopantseng le ho itlhoekisa ka DNA, ho kopanya ha SRF ho morekisi oa fosb ho tiisitsoe ke qPCR e sebelisang li-primers tse fumanehang sebakeng sa morekisi oa fosb o nang le libaka tse peli tse tlamellang karabelo ea serum. Li-pulldown tsa SRF li ile tsa ruisoa haholo ha li bapisoa le taolo ea anti-antibody. Li-prosers tsa mofuta oa "Mouse fosb gene": pele, CCCTCTGACGTAATTGCTAGG le e khutlisetsang morao, ACCTCCCAAACTCTCCCTTC.
Lipatlisiso tsa sethathamo
Li-ANOVA tsa tsela e le 'ngoe li ne li sebelisetsoa ho bapisa mekhoa lipakeng tsa taolo, litoeba tse bonolo, le tse matlafatsang tlhahlobisong ea biochemical le boits'oaro. Li-ANOVA tsa mekhoa e 'meli li ne li sebelisetsoa ho bapisa indFosB induction ka ho hloloa ke sechaba ho litoeba tsa Srf tsa lehae, hammoho le ho bapisa phello ea Srf ho kokota molemong oa ho hloka thuso le melaoana ea ho hlohlelletsa batho. Liteko tsa baithuti t li ne li sebelisetsoa ho bapisa mekhoa ea phello ea Srf ho tsoa ho indFosB induction, le lipakeng tsa lihlopha tsa tlhahlobo ea motho ea lefu la morao le lefu la toeba ChIP. Liphapang lipakeng tsa maemo a liteko li ne li nkuoa li le bohlokoa ha lipalo li le 0.05.
Results
Polelo ea SRF le ΔFosB mokhatlong oa batho le litoeba tsa sechaba
Ho lekola karolo e ka bang teng ho SRF nts'etsopele ea boits'oaro bo ts'oanang le khatello ea maikutlo, re ile ra qala ho lekola polelo ea protheine ea SRF ho NAc ea bakuli ba motho ba tepelletseng maikutlo kamora lefu la lefu. Lihlooho tse tepelletseng maikutlo li bonts'itsoe haholo li theola maemo a SRF ho NAc ha a bapisoa le taolo ea bona e ts'oanang le lilemo (t (19) = 1.9; p <0.05) (Setšoantšo sa 1A). Ha re fuoa karolo ea SRF ho laoleng ts'ebetsong ea liphatsa tsa lefutso tsa pejana hang-hang (Ramanan et al., 2005), re ile ra nahana hore SRF e ka nka karolo ho laola polelo ea expressionFosB sebakeng sena sa boko. Ho tšehetsa khopolo-taba ena, re hlokometse hore maemo a Δfosb mRNA le 'ona a fokotsoe haholo ho NAc ea batho ba tepelletseng maikutlo (t (16) = 1.8; p <0.05) (Setšoantšo sa 1B). Sena se tsamaellana le liphetho tsa haufinyane tsa maemo a fokotsehileng a protheine ea osBFosB tlasa maemo ana hape (Vialou et al., 2010).
Setšoantšo sa 1.
Khatello e bakoang ke khatello ea maikutlo ea khatello ea maikutlo ea SRF e amanang le phokotso ea sengoloa sa ΔFosB ho NAc. A, B, bakuli ba khatello ea maikutlo ba Postmortem ba bonts'a maemo a fokotsehileng a protheine ea SRF (n = 10 / sehlopha; A) le polelo ea Δfosb mRNA ho NAc (n = 8 / sehlopha; B). C, Litoeba tse nang le khatello ea maikutlo e sa foleng (10 d) ea khatello ea sechaba li ile tsa aroloa ka bongata le ka boiketlo. D, khatello ea maikutlo e sa foleng ea sechaba e fokotsa maemo a protheine ea SRF ho NAc ea litoeba tse bonolo, empa e se litoeba tse matlafatsang, ha li bapisoa le taolo 24 h kamora tlhahlobo ea tšebelisano-'moho e bonts'itsoeng ho C. E, osBfosB mRNA maemo ho NAc a sa fetohe litoeba tse kotsing, empa haholo e laoloang liphoofolong tse tiileng (n = 7-15 / group). F, liprotheine tsa SRF li eketsehile ho tlama ho mohanyetsi oa liphatsa tsa lefutso kamora khatello ea maikutlo e sa foleng ea sechabeng feela ka mamello, eseng ka litoeba tse kotsi, (n = 5 / sehlopha). Lintlha tse bonts'itsoeng li hlahisoa joalo ka ha li ± SEM (tse emeloang e le mekoallo ea liphoso). Con., Taolo; Dep., O sithabetse maikutlo; Sus., Ea angoa habonolo; Res., E tiileng. * p <0.05 khahlanong le taolo; *** p <0.001 khahlanong le taolo; #p <0.05 ha e bapisoa le ts'oaetso; ## p <0.01 khahlanong le ts'oaetso; ### p <0.001 ha e bapisoa le ts'oaetso.
Ho holisa liphuputso tsena, re sebelisitse leano le sa foleng la khatello ea maikutlo ho litoeba. Ho ne ho bonahala lihlopha tse peli tse khetholloang tsa litoeba tse hlotsoeng, tse neng li ka hlaseloa habonolo hape li le bonolo (Krishnan et al., 2007) e ipapisitse le mokhoa oa ho qoba sechaba, moo liphoofolo tse nang le ts'oaetso li bonts'itseng phokotso ea tšebelisano ea sechaba ha e bapisoa le liphoofolo tse laolang le tse matlafatsang (F (2,23, 157.2) = 0.001; p <0.001; t liteko ka tokiso ea Bonferroni, ts'oaetso e khahlano le vs, p <0.05; Resilient vs control, p <0.01; resilient vs susceptible, p <1) (Fig. 2,32C). Matsatsi a mabeli kamora ketsahalo ea ho qetela ea ho hloloa, litoeba tse laoloang habonolo, tse matlafatsang le tse se nang matla li ile tsa hlahlojoa bakeng sa polelo ea SRF ho NAc. Ka mokhoa o ts'oanang le se fumanoeng ke khatello ea maikutlo, litekanyetso tsa protheine tsa SRF li fokotsehile haholo ho NAc ea litoeba tse kotsing ha li bapisoa le taolo, athe maemo a SRF a ne a sa ameha ho NAc ea litoeba tse tiileng (F (4.7) = 0.05; p <0.05; t liteko le a Khalemelo ea Bonferroni, taolo e kotsing ea ho hlaseloa, p <0.05; resilient vs susceptible, p <1) (Setšoantšo sa XNUMXD).
Ka mor'a moo, re ile ra hlahloba polelo ea Δfosb mRNA ho NAc ea lihlopha tsena tse tharo tsa liphoofolo 'me ra bona keketseho e kholo ea polelo ea Δfosb liphoofolong tse matlafatsang feela, ka moetlo empa ha ho na keketseho e kholo e bonoang litoeba tse kotsing (t (14) = 2.1; p <0.05 ) (Setšoantšo sa 1E). Ho etsa lipatlisiso tse tsoelang pele tse ka bang teng lipakeng tsa maemo a SRF le sengoloa sa Δfosb, re sebelisitse ChIP ho lekola hore na SRF e tlamang mohlohlelletsi oa liphatsa tsa lefutso e fetotsoe kamora khatello ea maikutlo e sa foleng ea sechaba ka lihlopha tse arohaneng tsa litoeba tse ka hlaseloang habonolo. Liphoofolo tse matlafatsang li bonts'itse SRF e tlamang haholo ho moetsi oa fosb ho NAc ha a bapisoa le taolo (t (8) = 2.1; p <0.05) hape ha e bapisoa le litoeba tse ka hlaseloang habonolo (t (8) = 2.0; p <0.05). Ha ho phapang e ileng ea bonoa lipakeng tsa taolo le litoeba tse kotsing, mohlomong ho bonts'a khaello ea ho kenella ha SRF ho litoeba tse kotsing (Setšoantšo sa 1F).
Ho netefatsa karolo ea SRF ho taolo ea ΔFosB kamora khatello ea maikutlo e sa foleng ea sechaba, Srffl / litoeba li sebelisitsoe ho lekola phello ea ho tlosoa ha SRF ho NAc mabapi le ho kenya khatello ea kelello ea ΔFosB. Srffl / litoeba li ne li entsoe ka stereotaxically intra-NAc ka li-vector tsa AAV tse hlalosang GFP kapa Cre-GFP. Ho ts'oaroa ha NAF ka ho khetheha ha SRF ho bakoang ke AAV-Cre-GFP ho netefalitsoe immunohistochemically (Setšoantšo sa 2A). Ho joalo, ho ne ho se na lipakeng pakeng tsa litšila tsa SRF le polelo ea Cre, ho bonts'a katleho ea ho kokota. Ho li-punches tsa NAc tse khethiloeng ka microdissected, re fumane phokotso e kholo ea 50% maemong a protheine ea SRF (t (11) = 4.3; p <0.001). Boholo bona bo kanna ba bontša taba ea hore karoloana ea lisele tse microdissection tse joalo ha e na tšoaetso ea vaerase.
Setšoantšo sa 2.
SRF e kenella indFosB e kenella ka khatello ea maikutlo e sa foleng ea ho hlola sechaba. A, Ho entoa ha AAV-Cre-GFP ho NAc ea Srffl / litoeba ho fella ka ho ntšoa ha protheine ea SRF ho li-neurons tse hlahisang Cre. Ho entoa ha AAV-GFP ho ne ho se na phello e hlakileng. B, Ho khetheloa ho khethiloeng ha SRF ho tsoa ho NAc ho thibela ho kenella ha osBFosB ho NAc kamora khatello ea maikutlo e sa foleng ea khatello ea maikutlo sechabeng (n = 4 / sehlopha). Lintlha tse bonts'itsoeng li hlahisoa joalo ka ha li ± SEM (tse emeloang e le mekoallo ea liphoso). * p <0.05 khahlanong le taolo ea AAV-GFP; ** p <0.01 khahlanong le AAV-GFP hloloa.
Ka mor'a moo re ile ra etsa li-immunohistochemistry tse ngata bakeng sa ΔFosB ho NAc ea Srffl / litoeba tse hlotsoeng tse kenngoeng ka intra-NAc ka AAV-Cre-GFP kapa AAV-GFP. Kamora ho imeloa kelellong ke khatello ea maikutlo e sa foleng, polelo ea ΔFosB e ile ea susumetsoa haholo ho NAc ea liphoofolo tse kenngoeng ke AAV-GFP (ts'ebelisano ea kalafo ea kalafo, F (1,12) = 6.4; t e leka ka khalemelo ea Bonferroni, control vs win, p <0.05; AAV-Cre khahlanong le AAV-GFP, p <0.01). Leha ho le joalo, tlhahiso ena ha ea ka ea bonoa ho Srffl / litoeba tse amohelang AAV-Cre-GFP (Setšoantšo sa 2B), ho bonts'a hore ΔFosB e kenella ho NAc ka khatello ea maikutlo e sa feleng e hloka SRF.
Ho buoa ha SRF ho NAc ho phahamisa tlhahiso ea maikutlo le proanxonomy-like phenotypes
Ho tloha ha ΔFosB e qalisoa ke khatello ea maikutlo e sa foleng ea khatello ea sechaba e bonts'itsoe pejana ho mamella botsitso (Vialou et al., 2010), re ile ra nahana hore tlolo ea molao ea SRF, le tahlehelo e hlahisoang ke ΔFosB, liphoofolong tse nang le ts'oaetso li ka emela phetoho e mpe eo qetellong e fanang ka eona liphoofolo tse kotsing ea ho ba le litlamorao tse mpe tsa khatello ea maikutlo. Ho leka khopolo-taba ena, re ile ra etsa hore ho tlosoe mofuta o itseng oa NAc oa liphatsa tsa lefutso tsa Srf ho Srffl / litoeba tsa batho ba baholo joalo ka ha ho hlalositsoe kaholimo, 'me litoeba tse hlahisitsoeng le taolo ea bona li ile tsa lekoa ka betere ea lipalo tsa boits'oaro ho lekola khatello ea maikutlo- le matšoenyeho- joaloka boitšoaro. Ho hlakoloa ha NAc ea lehae ea SRF ho khothaletsa phello e kang ea prodepression joalo ka ha e lekantsoe ka tlhahlobo ea ho sesa e qobelloang (t (30) = 2.5; p <0.05), hammoho le phello ea khatello ea maikutlo joalo ka ha e lekantsoe lebaleng le bulehileng (t (38) = 1.9; p <0.05) le liteko tse bobebe / tse lefifi (t (8) = 1.9; p <0.05). Kahoo, Srffl / litoeba tse amohelang AAV-Cre-GFP ho NAc li bonts'itse ho fokotseha ha latency hore e se ke ea sisinyeha tekong ea ho sesa e qobelloang, nako e nyane bohareng ba lebala le bulehileng, le nako e nyane ka kamoreng e khanyang ea lebone le lefifi / lefifi ha e bapisoa le liphoofolo tse entetsoeng ka AAV-GFP (Setšoantšo sa 3A-C). Leha ho le joalo, ho hlakoloa ha intra-NAc ha SRF ha hoa ka ha fetola methati ea mantlha ea sekhahla, ho fana ka maikutlo a hore litlamorao tsa boits'oaro liphoofolong tsa liphoofolo tsa SRF li ne li sa bakoe ke ho se tloaelehe mesebetsing e akaretsang ea lits'oants'o (Setšoantšo sa 3D). Lintlha tsena lia khahlisa ho latela litlaleho tsa pejana tse fanang ka maikutlo a hore, leha ΔFosB ho NAc e laola boits'oaro bo ts'oanang le khatello ea maikutlo, ha ho bonahale e le karolo ea likarabo tse amanang le matšoenyeho (Vialou et al., 2010). Seo re se fumaneng hajoale sa hore ho lahleheloa ke SRF ho baka likarabo tsa khatello ea maikutlo ho fana ka maikutlo a hore e etsa joalo ka lipheo tse ling ntle le ΔFosB.
Setšoantšo sa 3.
Ho ts'oaroa ha SRF ho tsoa ho NAc ho khothaletsa khatello ea maikutlo le ho ts'oenyeha joalo ka phenotypes. A – C, ho khetheloa ka ntle ho SRF ho tsoa ho NAc, e fihletsoeng ka ente ea AAV-Cre-GFP ho NAc ea Srffl / litoeba, e fokotsa ho lieha ho fetoha ha liteko tsa ho sesa tse qobelloang (n = 14-18 / sehlopha; A) le ho fokotsa nako e sebelisitsoeng bohareng le nako e sebelisitsoeng ka phapusing e khanyang lebaleng le bulehileng (B) le liteko tse bobebe / lefifi (C), ka ho latellana (n = 5-15 / sehlopha). D, Ha ho na phapang ea mesebetsi ea basal locomotor e ileng ea bonoa lebaleng le bulehileng la litoeba tse fumaneng liente tsa intra-NAc tsa AAV-GFP kapa AAV-Cre-GFP. E, F, Keketseho ea ts'oaetso ea ho hloka thuso (n = 7-8 / sehlopha; E) le khatello ea maikutlo ea ho hlola sechaba (n = 5-6 / sehlopha; F), joalo ka ha e lekantsoe, ka ho latellana, ke latency ea ho baleha le nako ea tšebelisano ea sechaba . Lintlha tse bonts'itsoeng li hlahisoa joalo ka ha li ± SEM (tse emeloang e le mekoallo ea liphoso). * p <0.05 khahlanong le GFP kapa khahlanong le sepheo se seng teng; ** p <0.01 khahlanong le GFP; *** p <0.001 khahlanong le GFP.
Ka mor'a moo re ile ra ithuta hore na ho tlosoa ha SRF ho NAc le hona ho eketsa ts'oaetso ea phoofolo litlamorao tse mpe tsa khatello ea maikutlo khafetsa. Srffl / litoeba, tse entetsoeng ka AAV-Cre-GFP kapa AAV-GFP ho NAc, li ile tsa hlahlojoa ka mefuta e 'meli ea khatello ea maikutlo, ba ithuta ho hloka thuso le khatello ea maikutlo e sa foleng ea ho hlola sechaba. Ka ho hloka thuso ho ithutileng, Srffl / liphoofolo tse amohelang AAV-Cre-GFP li bontšitse latency e eketsehileng ho baleha leoto kamora ho pepesetsoa khatello ea maoto e ke keng ea qojoa (kalafo × liteko tsa tšebelisano, F (14,180) = 10.2; t liteko ka tokiso ea Bonferroni, p <0.001; AAV-Cre vs AAV-GFP, p <0.01), e bonts'a ts'oaetso e eketsehileng ea bofokoli bo bakoang ke khatello ea maikutlo (Setšoantšo sa 3E). Ka mokhoa o ts'oanang, ho tlosoa ha SRF ea lehae ho tsoa ho NAc le hona ho ile ha eketsa ts'oaetso ea sechaba (t (10) = 1.8; p <0.05) ha e bapisoa le liphoofolo tse laoloang tse entsoang ke AAV-GFP kamora khatello ea maikutlo e sa foleng ea sechaba (Setšoantšo sa 3F), phello e ts'oanang le khatello ea maikutlo.
Ho haelloa ke ho nka karolo ha SRF ho ΔFosB ho kenella le likarabo tsa boitšoaro ho koae
Kaha FosB e boetse e hlohlelletsoa ho NAc ka lebaka la lithethefatsi tsa tlhekefetso joalo ka cocaine, ho ne ho khahlisa ho hlahloba karolo e ka bang teng ho SRF ts'ebetsong ea cocaine. Ho fapana le khatello ea maikutlo e sa foleng ea khatello ea maikutlo sechabeng, ho pepeseha khafetsa ha "cocaine" ha hoa ka ha fetola polelo ea protheine ea SRF ho NAc (t (14) = 0.8; p> 0.05) (Setšoantšo sa 4A) mme ha e na phello ho SRF e tlamang mohlohlelletsi oa liphatsa tsa lefutso sebakeng sena sa boko. (t (4) = 0.7; p> 0.05) (Setšoantšo sa 4B). Sena se fana ka maikutlo a hore, khahlano le khatello ea maikutlo, ho qalisoa ha ΔFosB kamora hore cocaine e sa foleng e se buisane ka SRF. Re lekile sena ka kotloloho ka ho lekola hore na ΔFosB e bokellana kamora 'cocaine o sa foleng e fetotsoe ho Srffl / liphoofolo tse amohelang AAV-Cre-GFP khahlanong le AAV-GFP ho NAc. Re fumane hore ho hlakoloa ha SRF ho ne ho se na tšusumetso ho bokelleng ba ΔFosB bo bakoang ke k'hok'heine sebakeng sena sa boko (Setšoantšo sa 4C).
Setšoantšo sa 4.
Tahlehelo ea SRF ha ea ka ea ba le tšusumetso ho kenngoeng ha koae ka ΔFosB kapa boitšoaro bo laoloang ke koae. A, B, Phatlalatso ea koae e phetoang (7 d, 20 mg / kg cocaine-HCl) ha e na phello ho polelo ea protheine ea SRF ho NAc (A) kapa ho SRF e tlamang ho morekisi oa gene ea fosB sebakeng sena sa boko (B) 24 h kamora tlhahiso ea litlhare (n = 5 / sehlopha). C, ho bokella ha ΔFosB, ho lekantsoeng immunocytochemically, ho latela ho pepeseha ha koae ho sa tsitsang ha ho anngoe ke NAc e ikhethang ea ho tsoa ha SRF. D, E, Tloso ea lehae ea SRF ho tsoa ho NAc le eona e ne e sena phello mesebetsing ea locomotor kamora ho kenngoa ka ente ea saline (d 1) ts'ebetsong le boitšisinyo ba koae (n = 8 / group) (d 1-7; D) kapa ho khethollo ea sebaka sa koae (e = 8 / group; E). Lintlha tse bonts'itsoeng li hlahisoa e le tsa bohlokoa ± SEM (e emeloang joaloka mekoallo ea liphoso).
Ho latela tlhaiso-leseling ena e makatsang, re ile ra batlisisa hore na SRF e khethiloeng e tsoa ho NAc e fetola likarabo tsa boits'oaro ho cocaine. Tumellanong le khaello ea SRF ea taolo ea ΔFosB ka k'hok'heine, ho ts'oaroa ha NAF ho ikhethileng ha SRF ho ne ho se na tšusumetso ketsahalong ea locomotor e bakoang ke ts'oaetso e matla ea k'hok'heine kapa locomotor e bonoang kamora ho pepeseha khafetsa ha cocaine (kalafo × ho sebelisana ha nako, F (4,80) = 0.3; p> 0.05) (Setšoantšo sa 4D). Ka mokhoa o ts'oanang, ho ts'oaroa ha NAF ho ikhethileng ha SRF ho ne ho se na tšusumetso sebakeng se khethiloeng ke k'hok'heine (t (14) = 0.1; p> 0.05) (Setšoantšo sa 4E), se fanang ka moputso o sa tobang oa moputso oa cocaine.
Puisano
Phuputso ena e senoletse SRF e le mokena-lipakeng oa qoelopele ea ΔFosB ho NAc kamora khatello ea khatello ea maemo a sechaba, mme e kenya letsoho molemong oa boits'oaro bo nyahamisang le bo ts'oenyehileng. Re fana ka bopaki bo tobileng ba hore khatello ea maikutlo ea khatello ea khatello ea sechaba e fokotseha e fokotsa maemo a SRF ho NAc ea ts'oaroang, empa e sa ts'oarella, liphoofolo, le hore ho theoha hona ho thibela ho kenella ha ΔFosB sebakeng sena sa boko, seo re se bonts'itseng se hlokahala bakeng sa ho sebetsana ka katleho le khatello ea maikutlo e sa feleng. ke ho re, ho tiisetsa (Vialou et al., 2010). Phokotso e ts'oanang ea polelo ea SRF e fumanoe ho NAc ea batho ba tepeletseng maikutlo, moo ΔFosB mRNA le polelo ea protheine le eona e fokotsehileng. Ka lehlakoreng le leng, maemo a ΔFosB ha a ka a fokotsoa ho NAc ea litoeba tse senyehang, leha ho le joalo ka ho ngolisoa ka tlase ha SRF, e fanang ka mekhoa e meng ea ho ngola, le joale e sa tsejoeng, ho laola polelo ea ΔFosB. Karolo e tlamang bakeng sa SRF ho kenella ts'ebetsong ea ΔFosB ho NAc kamora khatello e sa feleng e thehiloe ka ts'ebeliso ea tlholeho e sa sebetseng ea liphatsa tsa lefutso tsa SRF sebakeng sena sa boko. Tlhahlobo ea boitšoaro ea litoeba mabapi le litla-morao tsa mofuta ona oa li-SRF e tiisa hore ho bapala karolo ea bohlokoa ho nts'etsopele ea maikutlo le boits'oaro bo bakang khatello ea maikutlo le boits'oaro bo joalo. Ka lehlakoreng le fapaneng, ho tlosoa ha SRF ha ho na ho ba le phello ea ho kenngoa ha ΔFosB ka lebaka la taolo ea koae e sa tsitsang kapa litlamorao tsa boitšoaro ba koae. Liphumano tsena li tšehetsa karolo e ikhethileng ea karolo e matlafatsang ea SRF taolong ea thuto ea ΔFosB le karabelo ea boitšoaro litlotlehong tse fapaneng tsa tikoloho.
Ho hatisoa ha MediF-Mediated ho kile ha bontšoa ho arabela ts'ebetsong ea synaptic, haholo ho bakoa ke ho eketseha ha calcium calcium, hammoho le ts'ebetso e ntlafalitsoeng ea neurotrophic, haholo-holo maemong a neurotrophic factor (BDNF) (Bading et al., 1993; Xia et al., 1996; Johnson et al., 1997; Chang et al., 2004; Kalita et al., 2006; Knöll and Nordheim, 2009). Sena se hlahisa potso e khahlisang ea hore na ke hobaneng ha SRF e theotsoe ka tlase ho NAc ea ts'oaroang, empa e sa tiisehe, litoeba kamora khatello ea maikutlo ea khatello ea sechaba. Taolo ena e nang le phapang e kanna ea se ke ea haptjoa ke dopamine kapa BDNF ho supa, hobane litoeba tse etsahalang habonolo li bonts'a liprotheine tsa BDNF le ho nyoloha ho saena hoa BDNF ho NAc hammoho le ho thunya ho hoholo ha sebaka sa "ventral tegmental" (VTA) dopamine neurons. liphoofolo tse iphehlang li bonts'a maemo a tloaelehileng a BDNF signing le VTA litefiso tsa ho thunya (Krishnan et al., 2007). Monyetla o mong ke oa hore polelo ea SRF e hatelletsoe ho NAc ho arabela ho fetoloa ha glutamatergic ho boloka sebaka sena sa boko, seo re se bonts'itseng se laoloa ka mokhoa o fapaneng maemong a litoeba tse atamelaneng le Viliou et al., 2010). Ho hlokahala mosebetsi o eketsehileng ho ithuta ka kotloloho mekhoa ena le tse ling tse ka khonehang.
Boithuto ba morao-rao bo sebelisang genome-wide le mekhoa e meng bo fana ka maikutlo a hore ∼5-10% ea mefuta ea sepheo sa SRF ho li-neuron ke liphatsa tsa pele tsa lefutso (Philippar et al., 2004; Ramanan et al., 2005; Etkin et al., 2006; Knöll le Nordheim, 2009). Sena se tsamaisana le datha ea rona e bonts'a karolo ea bohlokoa bakeng sa SRF ho kenyeng ΔFosB, sehlahisoa se fokotsoeng sa mofuta oa fosb oa pele, ka khatello e sa feleng. Ho khahlisang, mefuta e mengata ea li-SRF tse lebisitsoeng lithutong tsena tse fapaneng le tsona li emela liphofu tse tsebahalang tsa ΔFosB ho NAc (Kumar et al., 2005; Renthal et al., 2008, 2009; Maze et al., 2010). Har'a mefuta ena e tloaelehileng e laoloang ke tse 'maloa tse tsejoang ho laola neuronal cytoskeleton (mohlala, Cdk5, Arc, le Actb). Sena, se lumellana le litlaleho tsa hore na SRF e susumetsa li-activin dynamic le sephetho sa neuronal mefuteng e 'maloa ea lisele tsa neuronal (Alberti et al., 2005; Ramanan et al., 2005; Knöll et al., 2006), athe ΔFosB e tsejoa ke ama ho hlaha ha dendritic spine ho tsoa ha neurc (Maze et al., 2010). Liphetho tse tloaelehileng tse tšoanang tsa tšebetso li ka supa litlamorao tse kopantsoeng tsa SRF, hammoho le ho kenella ha ΔFosB, ho sebetsa ka bongata letotong la merero e tloaelehileng ho susumetsa morphology ea neuronal mme, qetellong, boitshwaro bo rarahaneng.
SRF e boetse e bontšitsoe e bapala likarolo tsa bohlokoa ho taolo ea polasetiki ea synaptic le polelo ea ts'ebetso ea ts'ebetso ea methapo e itšetlehileng ka ts'ebetso ea methapo. Mohlala, ho lahleheloa ke ts'ebeliso ea ts'ebeliso ea marang-rang ea SRF ea liphatsa tsa lefutso tsa pele ho karabelo mabapi le tlhahlobo ea boithatelo ea tikoloho e ncha kapa ts'ebetso ea neuronal ka ho ts'oaroa ka motlakase ho amahanngoa le tšenyo ea nako e telele ea synaptic ho hippocampus ea Srf mutants (Ramanan et al. , 2005; Etkin et al., 2006). Ntle le moo, ho fokotsoa ha SRF ho hippocampus ho bontšitsoe ho baka khaello ea khatello ea maikutlo ea nako e telele ea synaptic, polelo ea pele ea mofuta oa pele e hlahisoang ke mohopolo oa pale, le ho senyeha ha tikoloho nakong ea ho phenyekolla tikoloho ea nalane (Etkin et al., 2006). Lintlha tsena li tiisa bohlokoa ba SRF ka bokhoni ba phoofolo ba ho ikamahanya hantle le pherekano ea tikoloho, joalo ka taba e boletsoeng kaholimo ea ho ithuta ho tloaela tikoloho e ncha, kapa, maemong a ho ikamahanya le maemo a sithabetsang a khatello, ho thibela phatlalatso ea khatello ea maikutlo bofokoli ba boits'oaro, joalo ka thutong ea rona ea joale. Kahoo, re hlokomela hore liphoofolo tse bonts'ang likhaello ponts'ong ea SRF, ekaba karabelo ea khatello ea maikutlo sechabeng ho batho ba nang le ts'oaetso kapa ka ho otloa ka kotloloho ha SRF, li bonts'a boits'oaro bo ts'oanang ba khatello le khatello. Ka lebaka la hore lithuto tsa batho ba tepelletseng maikutlo le tsona li na le ho fokotseha ha maemo a SRF ho NAc, ho ka nahanoa hore SRF e bapala karolo ea mantlha ho laoleng bokhoni ba motho ba ho ikamahanya le maemo a mabe a tikoloho, karolo e 'ngoe e le ka taolo ea polelo ea ΔFosB ho NAc.
HO FIHLA MAHALA: HO FIHLELA VS STRESS RESISTance
Phello e makatsang ea boithuto ba hona joale ke hore, le ha SRF e hlokahala bakeng sa ho bokelloa ha ΔFosB ho NAc ho arabela khatello ea maikutlo e sa feleng, ha e hlokehe bakeng sa ho kenngoa ha ΔFosB kahare ho sebaka se le seng sa boko ho arabela cocaine e sa foleng. Ka mokhoa o ts'oanang, SRF ha e hlokehe bakeng sa likarabo tse tloaelehileng tsa boitšoaro ho moriana. Lintlha tsena li bonts'a hore, ho sa tsotelehe hore ΔFosB e kentsoe ho NAc ho arabela mefuta e mengata ea ts'usumetso (Nestler et al., 1999; Nestler, 2008), ho bonahala ho na le litsela tse ikhethang tsa limolek'hule tse lebisang ho ΔFosB. Tlhaloso e le 'ngoe e ka fumanoang bakeng sa liphumano tsena ke mefuta e fapaneng ea sele e bonts'a ho bokellana ha ΔFosB ho arabela khatello ea maikutlo le cocaine. Matšoenyeho a sa feleng a etsa ΔFosB hoo e batlang e lekana kahare ho likarolo tse peli tse kholo tsa NAc e pakeng tsa li-spiny neurons, tse hlalosang haholo D1 le D2 dopamine receptors, athe cocaine e sa foleng ea osFosB hangata kahare ho D1 + neurons (Kelz et al., 1999; PNTX. Perrot. . Kahoo, ho ka etsahala hore litsela tse itšetlehileng ka SRF li ka ba tsa bohlokoa bakeng sa ho kenngoa ha ΔFosB ho li-neuron tsa D2004 +. Leha ho le joalo, sena se ne se ke ke sa hlalosa tahlehelo e felletseng ea litheko tsa indFosB ho litoeba tsa DSF kamora ho imeloa kelellong, kaha ho kenella ho etsahala ka bobeli ba li-subtypes tsa neuronal. Tlhaloso e 'ngoe ke hore khatello ea maikutlo le khatello ea koae e sa foleng e kenella ho li-cascade tse ikhethileng, ka mekhoa e fapaneng ea ts'ebetso ho li-neuron tsa narc, ka khatello ea maikutlo e sa foleng mohlomong e sebetsa ka phetiso e fetotsoeng ea glutamatergic, joalo ka ha ho boletsoe pejana, le cocaine e sa foleng e sebetsang haholo ka D1 li-receptor signaling (Nestler, 2008). Monyetla o mong hape ke oa hore ΔFosB ho kenella ka khatello ea maikutlo le cocaine e sa ts'oaneng ho itšetleha ka mekhoa e hlakileng e laoloang ke litlatsetso tse fapaneng tsa neural tse kenyelletsang NAc ho tsoa libakeng tse fapaneng tsa projeke tsa phello ea mahlo, mohlala, libaka tse 'maloa tsa preortalal cortex, hippocampus, le amygdala. Ho hlokahala mosebetsi o mongata ho hlahloba menyetla ena le e meng.
Ka kopanelo, liphumano tsa rona li supa mochine o mocha oa mongolo o sebelisang "ΔFosB" ho kenya letsoho ho ba le karabelo lipuisanong tsa khatello le khatello ea maikutlo. Phuputso ena e boetse e fana ka leseli le lecha la bohlokoa mabapi le karolo e phethoang ke SRF maemong a NAc taolong ea khatello ea maikutlo- le boits'oaro bo kang ba ho tšoenyeha.. Ho utloisisa hamolemo karolo ea phetolelo ea SRF taolong ea boits'oaro bo joalo ho tla thusa ho khetholla sepheo sa liphatsa tsa lefutso tse amanang le mamello ea mathata a amanang le khatello ea maikutlo, mme ho ka thusa nts'etsopele ea nako e tlang ea liphekolo tse loantšang khatello ea maikutlo.
Mosebetsi ona o ne o tšehelitsoe ke lithuso tse tsoang Setsing sa Naha sa Bophelo ba Kelello le Setsi sa Naha ka Tlhekefetso ea Lithethefatsi le ka tumellano ea lipatlisiso le AstraZeneca. Re leboha David D. Ginty ka ho fana ka litoeba tsa Srffl / fl.
Litaba li lokela ho lebisoa ho Eric J. Nestler, Lefapha la Fishberg la Neuroscience, Mount Sinai School of Medicine, Sebaka se le seng sa Gustave L. Levy, Box 1065, New York, NY 10029-6574. [imeile e sirelelitsoe]
Copyright © 2010 bangoli ba 0270-6474 / 10 / 3014585-08 $ 15.00 / 0
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