LITLHAHISO: Delta FosB ke e 'ngoe ea limolek'hule tse ka sehloohong tsa bokhoba ba tahi. E phahama, kapa ea bokellana, nakong ea ts'ebetso ea ho lemalla lithethefatsi, e matlafatsa boits'oaro ba bokhoba le ho pheta-pheta ha boko. Hoa phahama hore na bokhoba boo ke ba lik'hemik'hale kapa ba boitšoaro. Phuputso ena e bonts'a hore e bokellana nakong ea thobalano le ts'ebeliso ea tsoekere. Bafuputsi ba fumane hape hore thobalano e eketsa tšebeliso ea tsoekere. Delta FosB e kanna ea ameha bokhobeng bo le bong ho matlafatsa bokhoba bo bong. Potso ke hore na "ho noa" litšoantšo tsa bootsoa ho ama Delta FosB joang? Kaha ke dopamine e rahelang DeltaFosB, ho its'etleha holima bokong ba hau.
J Neurosci. 2008 Mphalane 8; 28 (41): 10272–10277. doi: 10.1523 / JNEUROSCI.1531-08.2008.
Deanna L Wallace1,2, Vincent Vialou1,2, Loretta Rios1,2, Tiffany L. Carle-Florence1,2, Sumana Chakravarty1,2, Arvind Kumar1,2, Danielle L. Graham1,2, Thomas A. Green1,2, Anne Kirk1,2I, LLXXL, DXXUM, DIX3L, XVXXL, RGXXL, XV. J. DiLeone1,2,4, Eric J. Nestler1,2,5, le Carlos A. Bolaños-Guzmán1,2,6 +
+ Lingoliloeng tsa Sengoli
Aterese ea hajoale ea DL Wallace: Helen Willis Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720.
Aterese ea hajoale ea TL Carle-Florence: Mary Kay Research Laboratories, Dallas, TX 75379.
Aterese ea hajoale ea DL Graham: Merck Laboratories, Boston, MA 02115.
Aterese ea hona joale ea TA Green: Virginia Commonwealth University, Richmond, VA 23284.
Aterese ea hajoale ea EJ Nestler: Lefapha la Neuroscience, Mount Sinai School of Medicine, New York, NY 10029.
inahaneloang
Transcript factor deltaFosB (ΔFosB), e kenyellelitsoeng ho nucleus accumbens (NAc) ka ho pepesehela lithethefatsi tsa tlhekefetso, e bonts'itsoe ho fana ka likarabo tse khothatsang litlamong tsena. Leha ho le joalo, ha ho tsejoe letho ka karolo ea ΔFosB ho laola likarabo ho meputso ea tlhaho. Mona, re bonts'a hore litloaelo tse peli tse matla tsa moputso oa tlhaho, ho nwa ka ho lekana le boitšoaro ba thobalano, li eketsa maemo a levelsFosB ho NAc. Joale re sebelisa phetiso ea liphatsa tsa lefutso ea bongata hore re ithute ka tsela eo indFosB induction e susumetsang karabelo ea boitšoaro liputsong tsena tsa tlholeho. Re bonts'a hore khatello e feteletseng ea ΔFosB ho NAc e eketsa mokhoa oa ho ja le ho phahamisa likarolo tsa boitšoaro ba thobalano. Ntle le moo, re bonts'a hore liphoofolo tse nang le boiphihlelo ba pele ba thobalano, tse bonts'ang litekanyetso tsa ΔFosB, le tsona li bonts'a keketseho ea tšebeliso ea sucrose. Mosebetsi ona o fana ka maikutlo a hore BFosB ha e qobelloe feela ho NAc ka lithethefatsi tsa tlhekefetso, empa hape e susumetsoa ke ts'usumetso e ntle ea tlhaho. Ho kenyelletsa moo, liphumano tsa rona li bonts'a ho pepeseha ho sa feleng ho susumetsang ho susumetsang osFosB ho NAc ho ka eketsa tšebeliso ea meputso e meng ea tlhaho.
Selelekela
ΔFosB, ntho ea ho reka ea lelapa ea Fos, ke sehlahisoa se qhekelletsoeng sa fosB mofuta (Nakabeppu le Nathans, 1991). E hlahisoa ka maemo a tlase haholo ha a bapisoa le liprotheine tse ling tsa lelapa la Fos ha li arabela ka tšusumetso e mpe, empa e ipokellela maemong a phahameng bokong kamora ho hlohlella ho sa feleng ka lebaka la botsitso ba eona bo ikhethang (bona Nestler, 2008). Ho bokellana hona ho etsahala ka tsela e ikhethileng ea tikoloho ho arabela mefuta e mengata ea ts'usumetso e sa foleng, ho kenyelletsa le taolo e sa foleng ea lithethefatsi tsa tlhekefetso, ho ts'oaroa, lithethefatsi tsa antidepressant, lithethefatsi tsa antipsychotic, lesapo la mokokotlo, le mefuta e mengata ea khatello (bakeng sa tlhahlobo, bona Cenci, 2002; Nestler, 2008).
Liphello tsa ts'ebetso ea ΔFosB ho utloisisoa hamolemo bakeng sa lithethefatsi tsa tlhekefetso, tse susumetsang protheine ka mokhoa o hlahelletseng ho li-nucleus accumbens (NAc), karabelo e tlalehiloeng hoo e batlang e le mefuta eohle ea lithethefatsi tsa tlhekefetso (bona McDaid et al., 2006; Muller le Unterwald, 2005; Nestler, 2008; Perrotti et al., 2008). NAc ke karolo ea "ventral striatum" mme ke karolo ea bohlokoa ea neural bakeng sa liketso tse ntle tsa lithethefatsi tse hlekefelitsoeng. Ka hona, bopaki bo ntseng bo eketseha bo fana ka maikutlo a hore ho kenella ha ΔFosB sebakeng sena ho eketsa maikutlo a phoofolo ka litlamorao tse khotsofatsang tsa lithethefatsi tsa tlhekefetso mme hape ho ka eketsa takatso ea ho li fumana. Kahoo, overexpression ea ΔFosB ho NAc e etsa hore liphoofolo li hlahise lithahasello tsa koae kapa morphine, kapa ho itaola k'hok'heine, ka tekanyetso e tlase ea lithethefatsi, le ho ntlafatsa khatello ea "cocaine" ka tekanyo e tsoelang pele ea karo-karolelano (Colby et al., 2003; Kelz et al., 1999; Zachariou et al., 2006).
Ntle le karolo ea eona ea ho kenyelletsa moputso oa lithethefatsi, NAc e kentse letsoho ho laola likarabo ho meputso ea tlhaho, mme mosebetsi oa morao-rao o supile kamano lipakeng tsa meputso ea tlhaho le ΔFosB hape. Ho tsamaisoa ha lebili la boithatelo ho bontšitsoe ho eketsa maemo a ΔFosB ho NAc, 'me ho pepeseha ha ΔFosB ka hare ho sebaka sena sa boko ho baka keketseho e tsitsitseng ea ho tsamaisa e tsoelang libeke tse' maloa ho bapisoa le ho laola liphoofolo tseo matala a tsona a fetang libeke tse peli (Werme et al., 2002). Ka mokhoa o ts'oanang, phepo e phahameng ea mafura e etsa hore ΔFosB e NAc (Teegarden le Bale, 2007), ha ΔFosB e tebelitsoe ka botlalo tikolohong ena e eketsa karabelo e matla bakeng sa moputso oa lijo (Olausson et al., 2006). Ntle le moo, the fosB liphatsa tsa lefutso li na le tšusumetso ho boits'ebetso ba bo mmeBrown et al., 1996). Leha ho le joalo, tlhaiso-leseling e nyane e teng ka kamano lipakeng tsa ΔFosB le boitšoaro ba thobalano, e leng o mong oa meputso e matla ea tlhaho. Ho feta moo, ho sa hlakileng le ho feta ke ho nka karolo ha "FosB maemong a qobelloang, leha e le ho" eketsa ", mekhoeng ea moputso oa tlhaho. Mohlala, litlaleho tse 'maloa li bonts'itse karolo e ts'oanang le temallo ho litekanyetso tsa ho ja li-sucrose (Avena et al., 2008).
Ho eketsa tsebo ea rona ea ketso ea ΔFosB ka boits'oaro ba meputso ea tlhaho, re fuputse kenyelletso ea ΔFosB ho NAc ka mekhoa e fapaneng ea ho noa le boitšoaro ba thobalano. Re boetse re bone hore na qoelopele ea ΔFosB ea NAc e fetola likarabo tsa boitšoaro joang ho moputso ona oa tlhaho, mme haeba ho pepesetsoa moputso o le mong oa tlhaho ho ka ntlafatsa mekhoa e meng ea tlhaho ea moputso.
Lisebelisoa le mekhoa
Ts'ebetso tsohle tsa liphoofolo li amohetsoe ke Komiti ea Tlhokomelo ea Liphoofolo le Ts'ebeliso ea Setsi sa kalafo sa UT Southwestern.
Boitšoaro ba thobalano
Likhoto tsa banna ba nang le boiphihlelo ba li-Sprague-Dawley tse nang le thobalano (Charles River, Houston, TX) li hlahisitsoe ka ho li lumella ho nyalana le basali ba amohelang ho fihlela ho emisoa, makhetlo a ka bang 1-2 ka beke bakeng sa libeke tsa 8. Boitšoaro ba thobalano bo ile ba hlahlojoa joalo ka ha ho hlalositsoe (Barrot et al., 2005). Ba batona ba taolo ba ne ba hlahisoa ka ho pepesetsoa lebaleng le liketsong tsa boroko, ka nako e lekanang, joalo ka banna ba nang le boiphihlelo. Ha ho mohla basali ba kileng ba hlahisoa lebaleng le bana ba banna ba laolang. Ha ho etsoa liteko tse fapaneng, ho ile ha hlahisoa sehlopha se eketsehileng sa liteko: banna ba ile ba tsebisoa mosali ea nang le phekolo ea li-hormone ea neng a e-so ka a kenella. Tse tona li lekile liso le ho kena lipakeng, leha ho le joalo kaha basali e ne e se ba amohelehang, boitšoaro ba thobalano ha boa ka ba fumaneha sehlopheng sena. Li-hrs tse leshome le metso e robeli kamora seboka sa ho qetela, liphoofolo li ile tsa tlotsoa ka oli kapa tsa tlosoa, 'me masapo a nkuoa bakeng sa ts'ebetso ea lisele. Bakeng sa sehlopha se seng sa liphoofolo, matsatsi a ka bang 5 ka mor'a 14th Seboka, boikhethelo ba sucrose bo ile ba lekoa joalo ka ha ho hlalositsoe ka tlase. Bona Mekhoa ea Tlatsetso bakeng sa lintlha tse eketsehileng.
Ts'ebeliso ea pelepele
Teko ea pele (Setšoantšo sa 1a), likhoto li fuoe phihlello e sa lekanyetsoang ea libotlolo tse peli tsa metsi bakeng sa matsatsi a 2, tsa lateloa ke botlolo e le 'ngoe ea metsi le sucrose bakeng sa matsatsi a 2 libakeng tsohle tse ntseng li eketseha tsa sucrose (0.125 ho 50%). Nako ea matsatsi a 6 ea libotlolo tse peli tsa metsi e latela feela, joale matsatsi a mabeli a botlolo e le 'ngoe ea metsi le botlolo ea 0.125% sucrose. Teko ea bobeli (Setšoantšo sa 1b-c, Setšoantšo sa 2), likhoto li fuoe phihlello e sa lekanyetsoang ea botlolo e le 'ngoe ea metsi le 10% sucrose bakeng sa matsatsi a 10. Liphoofolo tse laolang li ne li fumana libotlolo tse peli tsa metsi feela. Liphoofolo li ile tsa sebelisoa ka mokhoa o phethahetseng kapa tsa lahleloa ka potlako 'me tsa bokelloa bakeng sa ts'ebetso ea lisele.
Teko ea likhetho tsa libotlolo tse peli
Paradigm ea likhetho tsa libotlolo tse peli e entsoe joalo ka ha ho hlalositsoe pele (Barrot et al., 2002). Pele ho ts'ebetso ea bongaka, ho laola phapang e ka khonehang, liphoofolo li ile tsa hlahlojoa pele ho nako ea 30 min ea mokhahlelo o lefifi bakeng sa mokhoa oa khetho oa libotlolo tse peli pakeng tsa metsi le 1% sucrose. Libeke tse tharo kamora ho fetisoa ha liphatsa tsa lefutso tsa vaerase (bona ka tlase) le pele ho tlhahlobo efe kapa efe ea boits'oaro e eketsehileng, liphoofolo tse fuoang metsi feela li ile tsa lekoa bakeng sa mokhoa oa khetho ea libotlolo tse peli tsa 30-min pakeng tsa metsi le 1% sucrose solution.
Liphoofolo tse nang le tsebo ea ho kopanela liphate le ho laola li ne li se na mokhoa oa tlhahlobo ea pele ho boitšoaro ba thobalano. Matsatsi a mahlano ka mor'a seboka sa 14th sa boitšoaro ba thobalano (kapa taolo), liphoofolo li ile tsa fuoa tlhahlobo ea likhetho tse peli pakeng tsa metsi le 1% sucrose tharollo nakong ea metsotso ea pele ea 30 ea potoloho ea bona e lefifi. Lihlopha tse arohaneng tsa liphoofolo tse nang le tsebo ea thobalano le tse laoloang li ne li sebelisoa ho lekanya maemo a ΔFosB kamora boitšoaro ba thobalano le ho ithuta ka litlamorao tsa boitšoaro ba thobalano ho rateng batho ba bangata.
Bophirimela ba Blotting
Lisebelisoa tsa NAc tse fumanoeng ke punch disgment li ile tsa hlahlojoa ke ho fifala ha Bophirimela joalo ka ha ho hlalositsoe pele (Perrotti et al., 2004), o sebelisa antibu ea polyclonal anti-FosB antib (bona Perrotti et al., 2004 bakeng sa semelo sa antibody) le anti anti monoclonal ho glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (RDI-TRK5G4-6C5; research Diagnostics, Concord, MA, USA), e neng e sebetsa e le protheine ea taolo. Maemo a liprotheine tsa ΔFosB a ne a tloaelehile ho GAPDH, le liteko tsa liteko le taolo ha li bapisoa. Bona Mekhoa ea Tlatsetso bakeng sa lintlha tse eketsehileng.
Immunohistochemistry
Liphoofolo li ile tsa sebelisoa ka mokhoa o phethahetseng 'me lisele tsa boko tsa phekoloa ho sebelisoa mekhoa ea phatlalatso ea immunohistochemistry (Perrotti et al., 2005). Ho tloha ha ho hlaha tšusumetso ea ho qetela ea sepheo se khotsofatsang se etsahetse 18-24 hrs pele ho tlhahlobo, re ile ra hlahloba litšebeliso tsohle tsa FosB, tse fumanoeng ka anti-panos FosB (SC-48; Santa Cruz Biotechnology, Santa Cruz, CA, USA), ho bonahatsa ΔFosB (Perrotti et al., 2004, 2005). Bona Mekhoa ea Tlatsetso bakeng sa lintlha tse eketsehileng.
Phetisetso ea Gene-Mediated Mediene
Ho buoa ho ile ha etsoa ho likhoto tsa banna tsa Sprague-Dawley. Litholoana tsa vaerase tse amanang le kokoana-hloko ea Adeno (AAV) li ile tsa kenngoa ka kotloloho, 1.5 µl ka lehlakoreng le leng, ho NAc joalo ka ha ho hlalositsoe pele (Barrot et al., 2005). Ho beoa ka nepo ho netefalitsoe kamora liteko tsa 40 µm cresyl-violet likarolo tse lits'oants'o. Bareki ba ne ba kenyelletsa taolo e hlalosang feela protheine e tala ea fluorescent (GFP) (AAV-GFP) kapa AAV e bontšang mofuta oa mofuta oa wildFosB le GFP (AAV-ΔFosB) (Zachariou et al., 2006). Ho ipapisitsoe le kemiso ea nako ea transgene kahara NAc, liphoofolo li ile tsa lekoa bakeng sa boits'oaro 3-4 libeke kamora ho kenoa ka ente ea lijana tsa AAV, ha polelo ea transgene e le kholo (Zachariou et al., 2006). Bona Mekhoa ea Tlatsetso bakeng sa lintlha tse eketsehileng.
Tlhahlobo ea statistical
Bohlokoa bo ile ba lekanyetsoa ho sebelisoa li-ANOVA tsa lintho tse peli tse phetoang hammoho le liteko tsa Baithuti t, tse ileng tsa lokisoa moo ho tsejoang ka lipapiso tse ngata. Lintlha li hlahisoa e le mekhoa ± SEM. Bohlokoa ba lipalo-palo bo hlalositsoe e le * p <0.05.
Results
Ho pepeseha ho sa feleng ha li-sucrose induces ho eketsa mokhoa oa ho ja oa sucrose le boits'oaro ba maikutlo
Re sebelisitse paradigm ea likhetho tsa botlolo eo ho eona ho ts'oaroang ha sucrose ho neng ho batla ho imenne habeli ka mor'a matsatsi a 2 a libotlolo tse peli tsa metsi. Khokahano ea sucrose e qalile ho 0.125% mme e eketsehile ho 50%. Liphoofolo ha lia ka tsa bontša khetho ea sucrose ho fihlela 0.25% ea sucrose, mme joale e nooa ho feta metsi ho feta maemong ohle a phahameng. Ho qala phutuhong ea 0.25%, liphoofolo li ile tsa noa litekanyetso tse ntseng li eketseha tsa sucrose ho fihlela palo e phahameng ea sucrose e fihlile ho 5 le 10%. Ka 20% le holimo, ba ile ba qala ho theola molumo oa bona oa "sucrose" ho boloka litheko tse tsitsitseng tsa ts'ebeliso ea sucrose (Setšoantšo sa 1a le inset). Kamora pherekano ena, liphoofolo li qetile matsatsi a 6 ka libotlolo tse peli tsa metsi feela, ebe li fuoa khetho ea botlolo ea metsi a 0.125% kapa metsi matsatsi a mabeli. Liphoofolo li noelehile ho feta metsi sebakeng sena, 'me li bonts'itse khetho ea bohlokoa ea sucrose ha e bapisoa le ho se khetholloe ha ho pepesetsoa mahloriso a qalang ka letsatsi la 1.
Hobane tšebeliso e phahameng ea molumo o fihlile kopanong ea 10%, liphoofolo tsa naïve li fuoe khetho pakeng tsa botlolo e le 'ngoe ea metsi le botlolo e le' ngoe ea 10% sucrose bakeng sa matsatsi a 10 mme ha e bapisoa le sehlopha se laoloang se fuoe libotlolo tse peli tsa metsi feela. Linonyana tse futhumetseng tse hahiloeng ka mokhoa o phahameng oa ho ja li-sucrose ka letsatsi 10 (Setšoantšo sa 1b). Ba bile le boima bo boholo haholo kamora ho iponahatsa ho tsoelapele ha sucrose ha ho bapisoa le ho laola liphoofolo, mme phapang ea boima bo eketseha ha nako e ntse e feta (Setšoantšo sa 1c).
Ho itlopa joala ba pelehi ho eketsa litekanyetso tsa ΔFosB ho NAc
Re ile ra sekaseka liphoofolo tsena 10% sucrose paradigm bakeng sa maemo a ΔFosB ho NAc ka ts'ebeliso ea blotting ea Bophirimela (Setšoantšo sa 2a) le immunohistochemistry (Setšoantšo sa 2b). Mekhoa ena ka bobeli e senotse ho kenella ka protheine ea ΔFosB sebakeng sena sa boko ho sucrose e nang le boiphihlelo ha e bapisoa le ho laola liphoofolo. Kaha tatellano eohle ea ΔFosB ea protheine e teng kahare ho FosB ea bolelele bo phethahetseng, li-antibodies tse sebelisoang ho bona liente tsa "FosB-like" li amohela liprotheine tsena ka bobeli (Perrotti et al., 2004, 2005). Leha ho le joalo, ho felisoa ha Bophirimela ho senotse hore ke ΔFosB feela e ileng ea susumetsoa haholo ke ho itlopa joala. Sena se bontša hore phapang ea matšoao a bonoang ke immunohistochemistry e emela ΔFosB. Keketseho e hlokometsoeng Setšoantšo sa 2b e fumanoe mokokotlong oa NAc le khetla, empa eseng dorsal striatum (ha e bontšoe).
Boitšoaro ba thobalano bo eketsa maemo a ΔFosB ho NAc
Ka mor'a moo re ile ra etsa lipatlisiso ka litlamorao tsa boitšoaro bo sa feleng ba thobalano mabapi le ho kenya ΔFosB ho NAc. Liroto tsa banna tse nang le tsebo ea thobalano li ne li lumelloa ho fihlella ho sa lekanyetsoang le mosali ea amohelang ho fihlela kemiso ea linako tsa 14 nakong ea beke ea 8-10. Habohlokoa, liphoofolo tse laoloang e ne e se taolo ea likhopo tsa lehae, empa ho e-na le hoo li ne li hlahisoa ke ho sebetsana le matsatsi a teko le ho pepesehela lebaleng le bulehileng moo ho qopitsoang ho bileng teng ka nako e lekanang empa ntle le ho pepesehela mosali ea amohelang, ho laola bakeng sa olfaction le litlamorao tsa ho sebetsana. Re sebelisa mokhoa oa ho koala Bophirimela, re fumane hore boiphihlelo ba thobalano bo ile ba eketsa maemo a ΔFosB haholo ha a bapisoa le sehlopha se laolang (Setšoantšo sa 2a), e sena maemo a bonyane a FosB e boletsoeng ka botlalo. E lumellana le datha tsena, immunohistochemistry e senotse keketseho ea ΔFosB ea ho boloka maemo maemong a mantlha le khetla ea NAc (Setšoantšo sa 2c), empa eseng dorsal striatum (ha e bontšoe).
Ho netefatsa hore keketseho ea ΔFosB e bonoang liphoofolong tse nang le thobalano e ne e se ka lebaka la tšebelisano ea setjhaba kapa tšusumetso e 'ngoe e sa amanang le bong bo tšoanang, re hlahisitse banna ba sa kopaneng le basali ba ileng ba pepesetsoa basali ba tšoaroang ke li-hormone, empa ba sa lumelloe ho etsisa. Tse tona li bontšitse hore ha li na phapang lipakeng tsa ΔFosB ha li bapisoa le liphoofolo tse laoloang lebaleng la olfaction.Setšoantšo sa 2a), ho fana ka maikutlo a hore ho qalisoa ha ΔFosB ho etsahala ka karabelo ea boitšoaro ba thobalano eseng litloaelo tsa kahisano kapa tse seng tsa bong bo fapaneng.
Ho tebeloa maikutlo ha ΔFosB ho NAc ho eketsa ho ja haholo
Ho sebelisa sistimi e matlafatsang ea bongata bo botle e ka thusang ho fana ka maikutlo a tsitsitseng a ΔFosB libeke tse 'maloa (Zachariou et al., 2006) (Setšoantšo sa 3a), re fuputse tšusumetso ea maemo a holimo a ΔFosB, re tobile haholo ho NAc, ka boits'oaro bo bobe ba ho noesa (Setšoantšo sa 3b). Re qalile ka ho tiisa hore ho ne ho se na liphapang mokhoeng oa motheo oa sucrose pele ho opereishene ka tlhahlobo ea pele ea teko ea sucrose (AAV-GFP: 6.49 ± 0.879 ml; AAV-ΔFosB: 6.22 ± 0.621 ml, n = 15 / sehlopha, p> 0.80 ). Libeke tse tharo kamora ho buuoa, ha polelo ea ΔFosB e ne e tsitsitse ka matsatsi a ~ 10, liphoofolo li ile tsa fuoa tlhahlobo ea sucrose ea kamora 'ho buuoa. Sehlopha sa AAV-ΔFosB se noele haholo sucrose ho feta sehlopha sa taolo ea AAV-GFP (Setšoantšo sa 3b). Ho ne ho se na phapang palong ea phepelo ea metsi lipakeng tsa lihlopha tsena tse peli (AAV-GFP: 0.92 ± 0.019 ml; AAV-ΔFosB: 0.95 ± 0.007 ml, n = 15 / group, p> 0.15), ho fana ka maikutlo a hore phello ea ΔFosB e totobetse ho sucrose.
Tlhatlhobo e fetang ea ofFosB ea NAc e susumetsa boitšoaro ba thobalano
Kamora moo, re ile ra hlahloba hore na oFosB overexpression ho NAc e laola boitšoaro ba thobalano ba liphoofolo tse sa naïve le tse nang le boiphihlelo. Leha re sa ka ra fumana phapang lipapaling tsa boitšoaro ba thobalano lipakeng tsa AAV-ΔFosB le -GFP tsa liphoofolo tse nang le boiphihlelo (bona Letlapa la Tlatsetso S1), ho tebella ha ΔFosB ho liphoofolo tsa naïve ho fokotsehile haholo palo ea maqhubu a hlokahalang ho fihlela kemiso bakeng sa boiphihlelo ba pele ba boits'oaro ba thobalano (Setšoantšo sa 3c). Ho ne ho boetse ho e-na le tloaelo ea ho fokotseha ha nako ea kamora ho qeta ho sebelisa mmele bakeng sa sehlopha sa ΔFosB kamora boiphihlelo ba pele ba thobalano (Setšoantšo sa 3c). Ka lehlakoreng le leng, ha ho phapano e ileng ea bonoa litulong tsa mounts, tse kenang kapa tse tsoang ka har'a liphoofolo tse hlometseng kapa tse nang le boiphihlelo. (bona Letlapa la Tlatsetso S1). Ka mokhoa o ts'oanang, ha ho phapano e ileng ea bonoa bakeng sa karo-karolelano ea kenella (palo ea maqhubu / [palo ea maqhubu + a lipalo]), leha sena e ka ba ka lebaka la phapang e kholo ea palo ea litefiso sehlopheng ka seng.
Phihlelo ea thobalano e eketsa takatso ea ho ja
Kaha re fumane keketseho ea maemo a ΔFosB ho NAc kamora ho nooa le litloaelo tsa thobalano ka bobeli, mme osFosB e tebile maikutlo e susumetsa karabelo ea boits'oaro meputsong ka bobeli, ho ne ho khahlisa ho bona hore na ho pepesetsoa o mong oa meputso e ammeng karabelo ea boitšoaro bo botle haholo ho e 'ngoe.. Pele ho boiphihlelo ba thobalano, liphoofolo tsa Naïve li ne li abeloa ka mokhoa o sa laoleheng ho laola kapa maemo a thobalano. Liphoofolo li ile tsa pepesetsoa boiphihlelo ba thobalano kapa maemo a taolo, joalo ka ha ho hlalositsoe pejana, ho feta libeke tsa 8-10. Matsatsi a mahlano kamora seboka sa ho qetela sa thobalano, liphoofolo li ile tsa beoa mokokotlong oa khetho ea botlolo ea 30-min tse peli pakeng tsa botlolo e le 'ngoe ea metsi le e' ngoe ea sucrose. Re fumane hore liphoofolo tse nang le thobalano li noele haholo ho feta taolos (Setšoantšo sa 3b). Ha ho na phapang lipakeng tsa liphoofolo tse nang le tsebo ea thobalano le taolo tse ileng tsa bonoa ka tšebeliso ea metsi (Taolo: 1.21 ± 0.142 ml; Phihlelo ea Thobalano: 1.16 ± 0.159 ml, n = 7-9, p = 0.79), e fana ka maikutlo a hore phello e ikhethile ho sucrose.
Puisano
Boithuto bona bo koala lekhalo le fetileng la lingoliloeng ho hlakisa karolo ea ΔFosB litloaelong tsa moputso oa tlhaho tse amanang le thobalano le boits'oaro. Re ile ra qala ho tseba hore na ΔFosB e bokellana sebakeng sa NAc, e leng sebaka sa bohlokoa sa moputso oa boko kamora ho pepesehela meputso ea tlhaho. Karolo ea bohlokoa ea mosebetsi ona e ne e le ho fa liphoofolo khetho ea tsona, ka ho bapisa lipapatso tsa taolo ea lithethefatsi. Sena e ne e le ho etsa bonnete ba hore phello efe kapa efe maemong a ΔFosB e amana le tšebeliso ea boithatelo ba moputso. Mohlala oa sucrose (Setšoantšo sa 1) e bonts'a likarolo tsa boits'oaro bo joalo ba bokhoba ha bo bapisoa le mefuta e meng ea ho ja ka mokhoa o itseng: khetho pakeng tsa moputso le taolo, karabelo ea karabelo e entsoeng ka sebopeho sa U, karabelo e ananeloang kamora ho ikhula, le ho ja ho tlontlolla. Tmohlala oa hae o boetse o baka ho eketseha ha boima ba 'mele, ha o bonoe mefuteng e meng e kang ea tsoekere ea letsatsi le letsatsi (Avena et al., 2008).
Re hlahisa data, ka lekhetlo la pele, hore mefuta ea bohlokoa ea meputso ea tlhaho, sucrose le thobalano, ka bobeli e eketsa maemo a ΔFosB ho NAc. Keketseho ena e ile ea bonoa ke West blotting le immunohistochemistry; sebelisa mekhoa ka bobeli e tiisa hore sehlahisoa sa protheine se hlokometsoeng ehlile ke ΔFosB mme ha se FosB ea bolelele bo felletseng, sehlahisoa se seng sa fosB mofuta. Khetho e khethiloeng ea BFosB ka sucrose le thobalano e ts'oana le mokhoa o khethiloeng oa ΔFosB ho NAc kamora ts'ebetso e sa fetoheng ea mefuta eohle ea lithethefatsi tsa tlhekefetso (bona Selelekela). Ho hlokometsoeng, leha ho le joalo, ke tlhokomeliso ea hore tekanyo ea ΔFosB ho kenya ts'ebetsong ea NAc e bonoang mona ha e arabela meputso ea tlhaho e nyane ha e bapisoa le e bonoang bakeng sa meputso ea lithethefatsi: ho nwa ka ho lekana le boitšoaro ba thobalano ho hlahisitse keketseho ea 40-60% maemong a inFosB ho phapang e fapaneng le e 'ngoe ea induction e bonoang le lithethefatsi tse ngata tsa tlhekefetso (Perrotti et al., 2008).
Morero oa bobeli oa thuto ena e ne e le ho etsa lipatlisiso mabapi le litlamorao tse sebetsang tsa ΔFosB ho NAc mabapi le boitšoaro bo amanang le moputso oa tlhaho. Boholo ba mosebetsi oa rona oa pele ho tšusumetso ea ΔFosB mabapi le moputso oa lithethefatsi o sebelisitse litoeba tse sa sebetseng, moo polelo ea ΔFosB e lebisitsoeng ho NAc le dorsal striatum. Litoeba tsena tsa ΔFosB li bontša likarabo tse ntlafalitsoeng tsa koae le li-opiates, hammoho le ho phahama ha mabili le karabelo e arabelang bakeng sa lijo (bona Selelekela). Thutong ena, re sebelisitse sistimi ea phetisetso ea liphatsa tsa lefutso e sa tsoa tsoa ho basali ho kenya likarolo tsa mantlha tsa boko ho likhoto tsa banna (Zachariou et al., 2006). Re fumane mona hore ΔFosB everexpression e eketsa ts'ebetso ea sucrose ha e bapisoa le ho laola liphoofolo, ho se na phapang ea tšebeliso ea metsi lipakeng tsa lihlopha tsena tse peli.
Hape re ithutile hore na ΔFosB e susumetsa boitšoaro ba thobalano joang. Re bontšitse hore ΔFosB overexpression ho NAc e fokotsa palo ea ho kenella ho hlokoang hoa liphoofolo tse amanang le thobalano. Sena se ne se sa tsamaellane le liphapang tse ling tsa boitšoaro bo bobe ba botona le botšehali, ho kenyelletsa le liphetoho tsa ho nyoloha, ho kenella kapa ho nyamela. Ntle le moo, ΔFosB oeverxpression ha e a ka ea ama karolo efe kapa efe ea boitšoaro ba thobalano ho liphoofolo tse nang le bohlola. Bokhoni ba ho qhekella ho NAc ho susumetsa boitšoaro ba thobalano ha ho makatse ha ho fanoe ka bopaki bo ntseng bo hola ba hore sebaka sena sa moputso oa boko se laola boitšoaro ba thobalanor (Balfour et al., 2004; Hull le Dominguez, 2007). Ho fokotseha ho tlisoang ke ΔFosB ho bakiloeng ke ho kenella ka bongata ho ka bonts'a ntlafatso ea boitšoaro ba thobalano, ka hore liphoofolo tse naïve tse nang le ΔFosB overexpression ho NAc li phela joalo ka liphoofolo tse nang le boiphihlelo. Mohlala, litekong tsa boiphihlelo bo kopaneng ba thobalano, liphoofolo li hloka ho kenella kahare ho fihlela kemolo (Lumley le Hull, 1999). Ntle le moo, tloaelo ea ho fokotseha ha nako ea ho emisoa ka morao ho sebopeho (PEI) e nang le ΔFosB everexpression e boetse e bonts'a boits'oaro bo bonoang ho batona ba nang le takatso e matla ea thobalano, ba nang le boiphihlelo (Kippin le van der Kooy, 2003). Tka kakaretso, lipatlisiso tsena li fana ka maikutlo a hore ΔFosB Boitšoaro bo feteletseng ba liphoofolo tsa naïve bo ka nolofalletsa boitšoaro ba thobalano ka ho etsa hore liphoofolo tse hlaha li tšoane le liphoofolo tse nang le boiphihlelo kapa tsa thobalano. Ka lehlakoreng le leng, ha re ka ra bona phello ea bohlokoa ea ΔFosB ho tlola tekano boits'oarong ba bootsoa. Lithuto tse rarahaneng tsa boits'oaro ba thobalano (mohlala, khetho ea sebaka se ikhethileng) li ka khetholla hamolemo litlamorao tsa ΔFosB.
Qetellong, re fuputse hore na ho pepesetsoa moputso o mong oa tlhaho ho ama karabo ea boitšoaro ho e mong. Ka ho khetheha, re tsebisitse phello ea boiphihlelo ba pele ba thobalano ka ho ja batho ba bangata. Le ha liphoofolo tse laolehileng le tsa thobalano li bontšitse khetho e matla bakeng sa ho ikama, liphoofolo tse nang le thobalano li noele haholo, ntle le phetoho ea ts'ebeliso ea metsi. Ena ke phumano e khahlisang, ka hore e fana ka maikutlo a hore ho pepesehela moputso o le mong ho ka phahamisa boleng bo hlasimollang ba khothatso e 'ngoe e ntle, joalo ka ha ho ne ho ka lebelloa haeba ho na le karolo e arolelanoang ea molek'hule (mohlala, ΔFosB) ea maikutlo a moputso. Hoa tšoana le thutong ena, li-hamsters tsa basali tse neng li pepesitsoe boitšoaro ba thobalano bo bonts'itsoeng maikutlo a ntlafalitsoeng a amang litlamorao tsa boitšoaro ba koae (Bradley le Meisel, 2001). Liphumano tsena li ts'ehetsa maikutlo a polasetiki ka har'a potoloho ea moputso, ka hore boleng bo fumanoeng ba meputso ea hona joale bo thehiloe holim'a keketso ea moputso oa nakong e fetileng.
Ka kakaretso, mosebetsi o hlahisitsoeng mona o fana ka bopaki ba hore, ntle le lithethefatsi tsa tlhekefetso, meputso ea tlhaho e baka maemo a ΔFosB ho NAc. Ka mokhoa o ts'oanang, ts'ebetso ea ΔFosB sebakeng sena sa boko e laola karabelo ea boitšoaro ba phoofolo melemong ea tlhaho joalo ka ha e kile ea bonoa pejana bakeng sa meputso ea lithethefatsi. Liphumano tsena li fana ka maikutlo a hore ΔFosB e bapala karolo e akaretsang taolo ea mekhoa ea meputso, hape e ka thusa ho natefisa maikutlo a sefapano a hlokometsoeng mefuta eohle e mengata ea meputso ea lithethefatsi le ea tlhaho. Hape, sephetho sa rona se hlahisa monyetla oa hore ΔFosB e kenelle ho NAc e kanna ea arola likarolo tsa bohlokoa tsa bokhoba ba lithethefatsi, empa le likarolo tsa seo ho thoeng ke bokhoba ba tlhaho bo kenyelletsang tšebeliso e tlamang ea meputso ea tlhaho.
Boitsebiso bo Eketsehileng
Boitsebiso bo Eketsehileng
Letlapa la S1
Liteboho
Mosebetsi ona o tšehelitsoe ke lithuso tse tsoang Setsing sa Naha sa Bophelo ba Kelello le Setsi sa Naha sa Tlhekefetso ea Lithethefatsi le ho tsoa ho National Alliance bakeng sa Patlisiso ho Schizophrenia le khatello ea maikutlo.
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