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, e sebelisang tlhahiso ea lelapa ea Fos, ke sehlahisoa se theotsoeng sa mofuta oa fosB (Nakabeppu le Nathans, 1991). E bontšoa 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 hlohlelleha ho sa feleng ka lebaka la botsitso ba eona bo ikhethang (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, leseli la neuronal, le mefuta e mengata ea khatello ea maikutlo [bakeng sa tlhahlobo, bona Cenci (2002 ) le Nestler (2008)].
Liphello tse sebetsang tsa ho qhekelloa ha uctionFosB li utloisisoa hantle bakeng sa lithethefatsi tsa tlhekefetso, tse bakang protheine e hlahelletseng ho li-nucleus accumbens (NAc), karabelo e tlalehiloeng bakeng sa mefuta eohle ea lithethefatsi tsa tlhekefetso (Muller le Unterwald, 2005; McDaid et al. , 2006; Nestler, 2008; Perrotti et al., 2008). NAc ke karolo ea ventral striatum mme ke karolo ea bohlokoa ea methapo ea kutlo bakeng sa liketso tse putsang tsa lithethefatsi tse hlekefelitsoeng. Ka hona, bopaki bo ntseng bo eketseha bo fana ka maikutlo a hore ho kenella ha uctionFosB sebakeng sena ho eketsa kutloisiso ea phoofolo litlamorao tse khahlisang tsa lithethefatsi tsa tlhekefetso mme ho ka eketsa le tšusumetso ea ho li fumana. Kahoo, ho tlola maikutlo ho feta ha ΔFosB ho NAc ho etsa hore liphoofolo li hlahise likhetho tsa sebaka sa cocaine kapa morphine, kapa ho iketsetsa k'hok'heine ka litekanyetso tse tlase tsa lithethefatsi, le ho matlafatsa khatello ea lever bakeng sa paradigm e tsoelang pele (Kelz et al., 1999 ; Colby et al., 2003; 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 matha, e tšoarellang libeke tse' maloa, ha ho bapisoa le liphoofolo tse laolang, tseo matha a tsona a fetang libeke tsa 2 (Werme et al ., 2002). Ka mokhoa o ts'oanang, lijo tse nang le mafura a mangata li hlohlelletsa ΔFosB ho NAc (Teegarden le Bale, 2007), athe ΔFosB oxpxpression seterekeng sena e eketsa karabelo e matla bakeng sa moputso oa lijo (Olausson et al., 2006). Ho feta moo, mofuta oa fosB o na le tšusumetso ho boits'ebetso ba bo-mme (Brown 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 ka mokhoa oa 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 meputsong ena ea tlhaho, le hore na ho pepesa moputso o le mong oa tlhaho ho ka ntlafatsa mekhoa e meng ea tlhaho ea moputso.
Lisebelisoa le mekhoa
Tsamaiso eohle ea liphoofolo e amohetsoe ke Komiti ea Tlhokomelo ea Liphoofolo le Ts'ebeliso ea Setsi sa Univesithi ea Texas Southwestern Medical Center.
Boitšoaro ba thobalano.
Linoko tse tona tsa banna ba nang le boiphihlelo ba Sprague Dawley (Charles River) li ile tsa hlahisoa ka ho li lumella ho nyalana le tse tšehali tse amohelang ho fihlela ho emisoa, makhetlo a ∼1-2 ka beke bakeng sa libeke tsa 8-10 bakeng sa libeke tsa 14 kaofela. Boitšoaro ba thobalano bo ile ba hlahlojoa joalo ka ha ho hlalositsoe pele (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 ka thoko, ho ile ha hlahisoa sehlopha se seng sa liteko: banna ba ile ba tsebisoa mosali ea phekoloang oa hormone ea neng a es'o kene estrus. Tse tona li lekile litheko le ho kena lipakeng; leha ho le joalo, hobane basali e ne e se ba boitšoaro bo bobe, boits'oaro ba thobalano ha boa ka ba fumaneha sehlopheng sena. Lihora tse leshome le metso e robeli ka mor'a seboka sa ho qetela, liphoofolo li ile tsa tlotsoa ka oli kapa tsa chesoa, 'me likhoto tsa nkuoa bakeng sa ts'ebetso ea lisele. Bakeng sa sehlopha se seng sa liphoofolo, ∼5 d kamora seboka sa 14th, khetho ea sucrose e ile ea lekoa joalo ka ha ho hlalositsoe ka tlase. Bakeng sa lintlha tse ling, bona Mekhoa e tlatsetsang (e fumanehang ho www.jneurosci.org e le lisebelisoa tse tlatsetsang).
Ts'ebeliso ea pelepele.
Boitekong ba pele (sa feiga. 1a), likhoto li fuoe phihlello e sa lekanyetsoang ea libotlolo tse peli tsa metsi bakeng sa 2 d, tsa lateloa ke botlolo e le 'ngoe ea metsi le sucrose ea 2 d ho eketsa li-sucrose concentrations (0.125-50%). Nako ea 6 d ea libotlolo tse peli tsa metsi e latela feela, ebe 2 d ea botlolo e le 'ngoe ea metsi le botlolo ea 0.125% sucrose. Boitekong ba bobeli (Figs. 1b, c, 2), likhoto li fuoe phihlello e sa lekanyetsoang ea botlolo e le 'ngoe ea metsi le 10% sucrose ea 10 d. Liphoofolo tse laolang li ne li fumana libotlolo tse peli tsa metsi feela. Liphoofolo li ne li sebelisoa ka mokhoa o phethahetseng kapa li tsoa kapele, 'me ho ne ho bokelloa masapo a mokokotlo bakeng sa ho sebetsoa ka tishu.
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 opereishene, ho laola liphapang tse ka khonehang, liphoofolo li ile tsa etsoa pele nakong ea metsotso ea 30 ea pele ea lefifi bakeng sa mokhoa oa ho khetha libotlolo tse peli lipakeng 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 ts'ebetso ea khetho ea libotlolo tse peli tsa 30 min pakeng tsa metsi le 1% sucrose solution.
Liphoofolo tse nang le boiphihlelo ka ho kopanela liphate le ho li laola li ne li se na mokhoa oa 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-e bobebe. 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 khethollo ea sucrose.
Ho koala bophirima.
Litlhotlhollo tsa NAc tse fumanoeng ke punch disgment li ile tsa hlahlojoa ke ho fifala hoa Bophirimela joalo ka ha ho hlalositsoe pejana (Perrotti et al., 2004), ba sebelisa rabi ea polyclonal anti-FosB antib [bakeng sa semelo sa antibody, bona Perrotti et al. (2004)] le anti anti monoclonal ho glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (RDI-TRK5G4-6C5; Research Diagnostics), e sebelitseng e le protheine ea taolo. Maemo a liprotheine tsa ΔFosB a ne a tloaelehile ho GAPDH, mme liteko tsa liteko le taolo li ne li bapisoa. Bakeng sa lintlha tse ling, bona Mekhoa e tlatsetsang (e fumanehang ho www.jneurosci.org e le lisebelisoa tse tlatsetsang).
Immunohistochemistry.
Liphoofolo li ile tsa sebelisoa ka mokhoa o phethahetseng, 'me lisele tsa boko tsa phekoloa ho sebelisoa mekhoa e phatlalalitsoeng ea immunohistochemistry (Perrotti et al., 2005). Hobane ho pepesetsoa hoa tšusumetso e khotsofatsang ho etsahetse 18-24 h pele ho tlhahlobo, re ile ra hlahloba litšebelisano tsohle tsa FosB, tse fumanoeng ka anti-panos FosB (SC-48; Santa Cruz Biotechnology), ho bonts'a ΔFosB (Perrotti et al., 2004 , 2005). Bakeng sa lintlha tse ling, bona Mekhoa e tlatsetsang (e fumanehang ho www.jneurosci.org e le lisebelisoa tse tlatsetsang).
Phetiso ea lefutso e kopaneng le bongata
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 mabapi le likarolo tsa 40 μm cresyl-violet tse nang le litšila. 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 nako ea polelo ea transgene ka hara NAc, liphoofolo li ile tsa lekoa bakeng sa boits'oaro 3-4 libeke kamora ho kenoa ka liente tsa AAV, ha polelo ea transgene e le kholo (Zachariou et al., 2006). Bakeng sa lintlha tse ling, bona Mekhoa e tlatsetsang (e fumanehang ho www.jneurosci.org e le lisebelisoa tse tlatsetsang).
Tlhahlobo ea lipalo.
Bohlokoa bo ile ba lekanyetsoa ho sebelisoa li-ANOVA tsa lintho tse peli tse pheta-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 libotlolo tse peli moo mokokotlo oa sucrose o neng o batla o imena habeli 2 d kamora 2 d ea 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 fokotsa bonyata ba bona ba ho boloka litekanyetso tse tsitsitseng tsa tšebeliso ea sucrose (sa feiga. 1a, sesebelisoa). Kamora 'paradigm ena, liphoofolo li sebelisitse 6 d ka libotlolo tse peli tsa metsi feela, ebe li hlahisoa ka khetho ea botlolo ea 0.125% sucrose kapa metsi a 2 d. Liphoofolo li ile tsa noa metsi a mangata ho feta metsi sebakeng sena, 'me tsa bonts'a khetho e kholo ea sesole ha e bapisoa le ho se ratehe ha se khetholloang kamora ho pepesetsoa mahloriso ana ka letsatsi la 1.
Setšoantšo sa 1.
Li-paradigms tsa khetho ea li-bottle tse peli li bonts'a tšebeliso e ntseng e eketseha ea sucrose. a, Ho eketsa ho tsepamisa mohopolo ha sucrose ho lebisa ho "boits'oaro bo sothehileng ba sebopeho sa U", hammoho le boits'oaro bo ts'oanang le boits'oaro bo matlafatsang kamora nako ea ho hula [phapang e kholo lipakeng tsa metsi le tlhahiso ea sucrose ka 2 d ka bongata ba 0.25% tlhahiso e latelang ea sucrose (t (30) = 4.81; p <0.001; n = 8, e lokisitsoe bakeng sa lipapiso tse ngata)]. Ho kenella, ho kenella ho emetsoe e le ligrama tse felletseng tsa sucrose tse kenngoeng mohopolong o mong le o mong ho feta 2 d, ho bonts'a ho tsitsisa ho kenang maemong a phahameng. b, Liphoofolo tse 10 d tsa libotlolo tse peli tsa khetho ea libotlolo li bonts'a palo e ntseng e eketseha ea tlhahiso ea sucrose ho feta letsatsi la 1 (tlhahiso e bonts'itsoeng letsatsi le le leng feela). Mehato e habeli e phetoang ea ANOVA e senotse phello ea mantlha ea letsatsi (F (3,27) = 42.3; p <0.001), sucrose (F (1,9) = 927.2; p <0.001), le sucrose × day (F (3,27) = 44.8; p <0.001; n = 10 / sehlopha). c, Ho eketsa boima ba 'mele ha ho bapisoa le liphoofolo tse laoloang (metsi feela) tse nang le tlhahiso ea sucrose. Mehato e habeli e phetoang ea ANOVA e bonts'a tšusumetso e kholo ea letsatsi (F (5,70) = 600; p <0.001) eo ka eona lihlopha tsena ka bobeli li nona kamora nako, le tšebelisano e kholo ea sucrose le letsatsi (F (5,70) ) = 17.1; p <0.001; n = 10 / sehlopha), ho fana ka maikutlo a hore sehlopha sa sucrose se fumana boima bo fetang ba nako.
Hobane tšebeliso e phahameng ea palo e fihlile kopanong ea 10%, liphoofolo tse se nang tsebo li fuoe khetho pakeng tsa botlolo e le 'ngoe ea metsi le botlolo e le' ngoe ea 10% sucrose ea 10 d mme ha e bapisoa le sehlopha se laoloang se fuoe libotlolo tse peli tsa metsi feela. Linonyana tsa Sucrose tse hahiloeng ka mokhoa o phahameng oa ho ja li-sucrose ka letsatsi 10 (sa feiga. 1b). Ba bile le boima bo boholo haholo kamora ho pepesetsoa ha li-sucrose ha li bapisoa le liphoofolo tse laoloang, le phapang ea boima ba 'mele ha nako e ntse e feta (fig. 1c).
Ho itlopa joala ba pelehi ho eketsa litekanyetso tsa ΔFosB ho NAc
Re ile ra sekaseka liphoofolo tsena ho 10% sucrose paradigm bakeng sa maemo a ΔFosB ho NAc ka ts'ebeliso ea blotting ea Bophirimela (Fig. 2a) le immunohistochemistry (Fig. 2b). Mekhoa ena ka bobeli e senotse ho kenella ka protheine ea ΔFosB sebakeng sena sa boko ho bo-sucrose bo nang le tsebo ha bo bapisoa le liphoofolo tse laoloang. Hobane tatellano eohle ea ΔFosB ea protheine e teng kahare ho FosB ea bolelele bo felletseng, li-antibodies tse sebelisetsoang ho bona FosB-like immunoreactivity li hlokomela li-protein tsena ka bobeli (Perrotti et al., 2004, 2005). Leha ho le joalo, ho felisoa ha Bophirimela ho senotse hore ke "osFosB feela e susumetsoang haholo ke ho itlopa joala. Sena se bontša hore phapang ea matšoao a bonoang ke immunohistochemistry e emela ΔFosB. Keketseho e hlokometsoeng ho Setšoantšo sa 2b e fumanoe mokokotlong oa NAc le khetla, empa eseng dorsal striatum (data e sa bontsitsoeng).
Setšoantšo sa 2.
Ts'ebeliso ea Sucrose le boits'oaro ba thobalano li eketsa polelo ea ΔFosB ho NAc. a, Ts'ebeliso e sa foleng ea 10% sucrose ka paradigm ea khetho ea libotlolo tse peli, hammoho le boits'oaro ba thobalano, e eketsa polelo ea osBFosB ho NAc ke Western blot (sucrose, t (11) = 2.685; * p = 0.021; n = 5- 8; boitšoaro ba thobalano, t (12) = 2.351; * p = 0.037; n = 6-8). Bolaoli ba taolo ea Olfaction ha bo fapane haholo le taolo ea banna ba bong bo fapaneng (t (10) = 0.69; p> 0.50; n = 4-8). NS, Ha e na thuso. b, Likarolo tsa Brains tse tsoang liphoofolong tse nang le boiphihlelo ba sucrose li bonts'a ts'oaetso ea immunFosB ha e bapisoa le liphoofolo tse laolang ho NAc ka immunohistochemistry. Litšoantšo (10 ×) li emetse likarolo tse ngata tsa boko ho tsoa likhoto tse tšeletseng sehlopheng ka seng sa kalafo. AC, ho qala ka pele. c, Likarolo tsa boko bo tsoang liphoofolong tse nang le boiphihlelo ba thobalano li bonts'a ho qojoa ha osBFosB ha ho bapisoa le balekane ba taolo ho NAc ka immunohistochemistry. Litšoantšo (10 ×) li emetse likarolo tse ngata tsa boko ho tloha likhoto tse tšeletseng ho isa ho tse robeli sehlopheng ka seng sa kalafo.
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 sa taolo (sa feiga. 2a), ntle le maemo a bonoang a bolelele bo felletseng ba FosB. E lumellana le datha tsena, immunohistochemistry e senotse keketseho ea ΔFosB ea lits'oants'o tsa mantlha le khetla ea NAc (Fig. 2c), empa eseng dorsal striatum (ya data e sa bontsitsoeng).
Ho netefatsa hore keketseho ea ΔFosB e bonoang liphoofolong tse nang le thobalano e ne e sa hlahisoe ke ho sebelisana le batho ba bang kapa lintho tse ling tse sa amaneng le tlhalohanyo, re hlahisitse banna ba sa nyalanang, ba neng ba pepesitsoe basali ba tšoeroeng ke li-hormone, empa ba sa lumelloe ho etsisa. Tse tona li bontšitse hore ha li na phapang maemong a ΔFosB ha li bapisoa le mefuta e fapaneng ea liphoofolo tse laoloang ka har'a olfaction. (Fig. 2a), li fana ka maikutlo a hore ho kenella hoa ΔFosB ho etsahala ka karabelo ea boitšoaro ba thobalano eseng likamano tsa sechaba.
Ho tebeloa maikutlo ha ΔFosB ho NAc ho eketsa ho ja haholo
Re sebelisa sistimi e fetelletseng ea tšoaetso ea vaerase, e nolofalletsang polelo e tsitsitseng ea ΔFosB ho feta libeke tse 'maloa (Zachariou et al., 2006) (Setšoantšo sa 3a), re ile ra fuputsa tšusumetso ea maemo a phahameng a osBFosB, haholo-holo e lebisitseng ho NAc, ho seno sa sucrose. boitšoaro (setšoantšo sa 3b). Re qalile ka ho tiisa hore ho ne ho se na liphapang mokhoeng oa mantlha oa boits'oaro ba pele ho ts'ebetso ea opereishene ka mokelikeli o kenang oa 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 etsoa opereishene, ha polelo ea ΔFosB e ne e tsitsitse bakeng sa -10 d, liphoofolo li ile tsa fuoa teko ea posturgery sucrose. 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 pakeng tsa palo ea metsi a kenang lipakeng tsa lihlopha tse peli (AAV-GFP, 0.92 ± 0.019 ml; AAV-ΔFosB, 0.95 ± 0.007 ml; n = 15 / sehlopha; p> 0.15), ho fana ka maikutlo a hore phello ea ΔFosB e totobetse ho sucrose.
Setšoantšo sa 3.
Tlhatlhobo e fetang ea ΔFosB ho NAc e laola likarolo tsa boitšoaro ba moputso oa tlhaho. a, Tlhahiso ea sebaka sa sepheo sa NAc ke phetiso ea liphatsa tsa lefutso e khetholloang ka bongata le mohlala oa polelo ea ΔFosB, e fumanoeng ke immunohistochemistry, kamora ente ea AAV-ΔFosB. b, Ho kenngoa ha AAV-ΔFosB litlamong tsa NAc ho eketsa ho ja hangata ha ho bapisoa le taolo ea AAV-GFP-injected (t (28) = 2.208; * p = 0.036; n = 15 / sehlopha). Ka mokhoa o ts'oanang, libeke tsa 10 tsa boitšoaro ba thobalano, ha li bapisoa le taolo e sa laoleheng ea thobalano, li eketsa ho ja ka mokhoa o ts'oanang (t (14) = 2.240; * p = 0.042; n = 7-9). c, ΔFosB overexpression e fokotseha palo ea maqhubu a hlokahalang ho fihlela tikoloho liphoofolong tse se nang thobalano ha li bapisoa le taolo ea GFP (t (30) = 2.145; * p = 0.04; n = 15-17) 'me e baka tšitiso ea nako e fokotsehileng ea nako ea phomolo ( t (30) = 1.916; #p = 0.065; n = 15-17).
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 tsebeng le tse nang le boiphihlelo. Leha re sa ka ra fumana phapang lipapaling tsa boitšoaro ba thobalano lipakeng tsa liphoofolo tse nang le boiphihlelo ba AAV-osFosB- le -GFP (sheba Tafole ea S1, e fumanehang ho www.jneurosci.org e le lisebelisoa tse tlatsetsang), ho fetella hoa ΔFosB liphoofolong tse sa nahaneng ho fokotsehile haholo palo ea maqhubu a hlokahalang ho fihlela kemiso bakeng sa boiphihlelo ba pele ba boits'oaro ba thobalano. (Sa feiga. 3c). Ho ne ho boetse ho na le tloaelo ea ho fokotseha ha nako ea postejaculatory ea sehlopha sa ΔFosB kamora boiphihlelo ba pele ba thobalano (Fig. 3c). Ho fapana le hoo, ha ho phapang e ileng ea bonoa ho latency bakeng sa litekanyetso, ho kenella, kapa ho nyoloha ho liphoofolo tse sa tsebeng letho kapa tse nang le boiphihlelo (sheba Tafole ea S1, e fumanehang ho www.jneurosci.org e le thepa e tlatsetsang). Ka mokhoa o ts'oanang, ha ho phapano e ileng ea bonoa bakeng sa karo-karolelano ea lipalo [palo ea li-intromissions / (palo ea li-intromissions + palo ea li-mounts)], leha sena e ka ba ka lebaka la phapang e phahameng ea palo ea litefiso sehlopheng ka seng.
Phihlelo ea thobalano e eketsa takatso ea ho ja
Hobane re fumane keketseho ea maemo a ΔFosB ho NAc kamora ho nooa le litloaelo tsa thobalano ka bobeli, mme ΔFosB e tebile ha e fana ka karabelo ea boitšoaro meputsong ka bobeli, ho ne ho khahlisa ho bona hore na ho pepesoa moputsong o mong o ammeng karabelo ea boitšoaro bo botle ho e ngoe. . Pele ho boiphihlelo ba thobalano, liphoofolo tse se nang kelello li ne li abeloa ka boomo ho laola kapa maemo a thobalano. Liphoofolo li ile tsa pepesetsoa boiphihlelo ba thobalano kapa maemo a taolo, joalo ka ha ho hlalositsoe pele, libekeng tsa 8-10. Matsatsi a mahlano kamora seboka sa ho qetela sa thobalano, liphoofolo li ile tsa kenngoa mokokotlong oa khetho ea libotlolo tse peli tsa 30 lipakeng 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 lithulusi (sa feiga. 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; ea nang le thobalano, 1.16 ± 0.159 ml; n = 7-9; p = 0.79), a 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. Moetso oa sucrose (Fig. 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 nepahetseng: khetho pakeng tsa moputso le taolo, karabelo e kentsoeng mofuta oa U-karabelo, karabelo e nkoang kamora ho ikhula, le ts'ebeliso e feteletseng. Moetso ona o boetse o baka phaello e eketsehileng ea boima, e sa 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; o sebelisa mekhoa ka bobeli ho tiisa hore sehlahisoa sa protheine se bonoang e hlile ke ΔFosB ebile ha se FosB ea bolelele bo felletseng, e leng sehlahisoa se seng sa mofuta oa fosB. Tlhahiso e khethiloeng ea ΔFosB 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 (sheba Selelekela). Ho hlokometsoeng, leha ho le joalo, ke tlhokomeliso ea hore tekanyo ea ΔFosB induction ho NAc e hlokometsoeng mona e arabelang meputso ea tlhaho e nyane ho feta e bonoang bakeng sa meputso ea lithethefatsi: ho noesa ho lekana le boitšoaro ba thobalano bo hlahisitse keketseho ea 40-60% maemong a ΔFosB ho induction ea makhetlo a mangata e bonoeng ka 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 o fetileng oa tšusumetso ΔFosB mabapi le moputso oa lithethefatsi o sebelisitse litoeba tse sa sebetseng, moo polelo ea ΔFosB e lebisitsoeng ho NAc le dorsal striatum. Tsena tsa litoeba tsa ΔFosB-overexpressing li bonts'a likarabo tse ntlafalitsoeng tsa boitšoaro ho koae le li-opiate, hammoho le ho phahama ha mabili le karabelo e arabelang bakeng sa lijo (sheba Selelekela). Thutong ena, re sebelisitse sistimi ea phetisetso ea liphatsa tsa lefutso e sa tsoa tsoa ho basali hore e be maemong a bokelletsoeng a likhoto tsa banna (Zachariou et al., 2006). Re fumane mona hore ΔFosB overexpression e eketsa ts'oaetso ea sucrose ha e bapisoa le liphoofolo tse laoloang, 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 boits'oaro 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 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 thobalano (Balfour et al., 2004; Hull and 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 sa tsebeng letho tse nang le ΔFosB overexpression ho NAc li phela joalo ka liphoofolo tse nang le boiphihlelo. Mohlala, litekong tsa boiphihlelo ba khafetsa ba thobalano, liphoofolo li hloka maqhubu a fokolang ho fihlela ejaculation (Lumley le Hull, 1999). Ntle le moo, mokhoa oa ho fokotseha ha nako ea postejaculatory le ΔFosB overexpression o boetse o 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). Ka bobeli, liphumano tsena li fana ka maikutlo a hore ΔFosB ho tlola tekano liphoofolong tse se nang tsebo ho ka nolofalletsa boitšoaro ba thobalano ka ho etsa hore liphoofolo tse se nang tsebo 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 batlisitse hore na ho pepesehela moputso o le mong oa tlhaho pejana ho ama karabelo ea boitšoaro ho e mong joang. Haholo-holo, re nkile phello ea boiphihlelo ba thobalano bo fetileng ho ts'eng ea sucrose. Le ha liphoofolo tse laoloang le tse nang le boiphihlelo ka bobeli li bontšitse khetho e matla ea sucrose, liphoofolo tse nang le boiphihlelo ba thobalano li noa sucrose e ngata, ho se phetoho ea ts'ebeliso ea metsi. Ena ke phumano e khahlisang, ka hore e fana ka maikutlo a hore ho pepesetsoa moputso o le mong pejana ho ka phahamisa boleng bo putsang ba tšusumetso e 'ngoe e putsang, joalo ka ha ho ne ho ka lebelloa haeba ho ne ho na le karolo e arohaneng ea limolek'hule (mohlala, ΔFosB) ea kutloisiso ea moputso. Ka mokhoa o ts'oanang le phuputso ena, li-hamster tsa basali tse neng li pepesitsoe boits'oaro ba thobalano li bonts'itse kutloisiso e ntlafetseng litlamorao tsa boits'oaro ba cocaine (Bradley le Meisel, 2001). Liphuputso tsena li tšehetsa mohopolo oa polasetiki ka har'a potoloho ea moputso ea boko, ka hore boleng bo lemohuoang ba meputso ea hajoale bo thehiloe holima likotsi tse fetileng tsa moputso.
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, tlhatlhobo e fetelletseng ea ΔFosB sebakeng sena sa boko e laola likarabelo tsa phoofolo ho meputso ea tlhaho, joalo ka ha ho hlokometsoe pejana bakeng sa meputso ea lithethefatsi. Liphuputso tsena li fana ka maikutlo a hore ΔFosB e bapala karolo e akaretsang ho taolo ea mekhoa ea meputso, 'me e ka thusa ho tsepamisa mohopolo oa sefapano o hlokometsoeng mefuteng e mengata ea meputso ea lithethefatsi le tlhaho. Hape, liphetho tsa rona li hlahisa monyetla oa hore ho kenella ha uctionFosB ho NAc ho ka se lumellane eseng feela likarolo tsa bohlokoa tsa ts'ebeliso ea lithethefatsi, empa le likarolo tsa seo ho thoeng ke lithethefatsi tsa tlholeho tse kenyelletsang tšebeliso e tlamang ea meputso ea tlhaho.
Mongolo o botlaaseng ba leqephe
• Mosebetsi ona o tšehelitsoe ke lithuso tse tsoang Setsing sa Naha sa Bophelo ba Kelello le Setsi sa Naha sa Tlhekefetso ea Lithethefatsi le Setsing sa Naha sa Patlisiso ho Schizophrenia le khatello ea maikutlo.
• Litaba li lokela ho romelloa ho Carlos A. Bolanos atereseng e kaholimo. [imeile e sirelelitsoe]
• Copyright Copyright XXUMX Mokhatlo oa Neuroscience 2008-0270 / 6474 / 08-2810272 $ 06 / 15.00
Karolo e fetileng
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