The Journal of Neuroscience, 6 September 2006, 26 (36): 9196-9204; Doi: 10.1523 / JNEUROSCI.1124-06.2006
Peter Olausson1, J. David Jentsch2, Natalie Tronson1, Rachel L. Neve3, Eric J. Nestler4, 'me Jane R. Taylor1
1.Litaba li lokela ho lebisoa ho Jane R. Taylor, Lefapha la Psychiatry, Karolo ea Molekolo oa Mahlale, Sekolo sa Bongaka sa Yale University, Lisebelisoa tsa Patlisiso tsa Ribicoff, Setsi sa Tleliniki ea Connecticut, 34 Park Street, New Haven, CT 06508.[imeile e sirelelitsoe]
inahaneloang
Liphetoho tse susumetsang li bile le tšusumetso ho pathophysiology ea mafu a 'maloa a kelello, ho kenyelletsa tlhekefetso ea lithethefatsi le khatello ea maikutlo. Ho pepesehela khafetsa lithethefatsi tsa tlhekefetso kapa khatello ea maikutlo ho tsejoa ho phehella ho hatisa ntlha ea ho ngola ΔFosB ho li-nucleus accumbens (NAc) le dorsal striatum, litlamorao tse kenyellelitsoeng ho kenya letsoho ho neuroadaptations ho dopamine e laoloang ke dopamine. Ha ho tsejoehale, leha ho le joalo ka ho kenella ha ΔFosB ka kotloloho ho boits'oaro bo bobe ba boits'oaro. Re bonts'a mona hore ouffxpression e sa sebetseng ea ΔFosB ho NAc le dorsal striatum ea bitransgenic litoeba, kapa ka kotloloho mokokotlong oa NAc oa likhoto ka ts'ebeliso ea phetisetso ea bongaka e bohareng, ts'ebetso e matlafalitsoeng ea ts'ebetso ea sistimi e matlafalitsoeng le karabelo e tsoelang pele. Litlamorao tse tšoanang le tsa boits'oaro li fumanoe kamora ho pepesetsoa koae ka makhetlo a mangata, amphetamine, MDMA [(+) - 3,4-methylenedioxymethamphetamine], kapa nikotine ho likhoto. Liphetho tsena li senola taolo e matla ea lits'ebetso tse susumetsang ke ΔFosB, hape e fana ka bopaki ba hore liphetoho tse tlisitsoeng ke lithethefatsi ho polelo ea gene ka ho kenella ha ΔFosB ka har'a motheo oa NAc li ka bapala karolo ea bohlokoa ho phello ea tšusumetso ea ts'usumetso ea ts'ebetso ea ts'ebeliso ea matla.
Selelekela
Ho pepesetsoa ha lithethefatsi khafetsa ho baka liphetoho tse matlafatsong ea bongaka ea gene e hlahisang li-neuroadaptations tse sa feleng kahare ho li-nucleus accumbens (NAc) (Nestler, 2004). Sebaka sena sa boko se bapala karolo ea bohlokoa lits'ebetsong tsa ho matlafatsa litlhare le tsa tlhaho (Kelley le Berridge, 2002), leha e le tse nyane tse tsejoang ka lintlha tsa phetisetso tse amang boitšoaro bo susumetsoang ke li-nondrug, li-khothalletso tsa takatso ea lijo joalo ka lijo. ΔFosB ke ntho e qobelloang ho kenella kahare ho NAc le dorsal striatum ka ho pepeseha ho sa feleng hoa lithethefatsi (Konradi et al., 1994; Nye et al., 1995; Chen le al., 1997; Pich et al., 1997; Shaw-Lutchman et al., 2003) le ho matha ha mabiliWerme et al., 2002). E boetse e kenngoa libakeng tsena ka mefuta e mengata ea khatello ea maikutlo e sa feleng (Perrotti et al., 2004). Ntlafatso ea lits'ebetso tsa ho matlafatsa litlhare tse amanang le ho kenyelletsa striatal ΔFosB e thehiloe hantle (Kelz et al., 1999; Colby et al., 2003; Zachariou et al., 2006). Liphetho tsa maemo a phahameng a ΔFosB libakeng tsena mabapi le boits'oaro bo matla ba khothalletsoang ke tlatsetso ea tlholeho ha li tsejoe.
Ts'ebetso ea likarabo tsa makolopetso ke karolo e hlokahalang ea boits'oaro ba tšebeliso ea lithethefatsi e ka bang tahi kapa ea feto-fetoha le phetoho ha ts'ebeliso ea lithethefatsi e ntse e tsoela pele (Jentsch le Taylor, 1999; Berke le Hyman, 2000; Berridge le Robinson, 2003; Everitt le Robbins, 2005). NAc e kenya letsoho likarolo tse ngata tsa boits'oaro ba methapo e amanang le bokhoba ba tahi (Balleine le Killcross, 1994; Corbit et al., 2001; de Borchgrave et al., 2002; Di Ciano le Everitt, 2004b; Everitt le Robbins, 2005). Ho ka etsahala hore ebe li-neuroadaptations tse entsoeng ke lithethefatsi kahare ho NAc li ka ama ts'ebetso ea liketso tse matla. Ka sebele, ho pepesetsoa ha koae e sa foleng ho ntlafatsa ts'ebetso ea ts'ebetso ea scrose (Miles et al., 2004) le ho qhekella ho nahanoang ho thibela neuroplasticity kahare ea NAc, ho kenyelletsa le thibelo ea PKA (protein kinase A) kapa synthetiki, e kena-kenana le likarabo tsa sesebelisoa se abeloang lijo (Baldwin et al., 2002a; Hernandez et al., 2002). Bohlokoa ba NAc bo boetse bo hokahanya tšusumetso ea lits'usumetso tse nang le tšusumetso ho boits'oaro bo sebetsang (Parkinson et al., 1999; Corbit et al., 2001; Hall et al., 2001; Di Ciano le everitt, 2004a; Ito et al., 2004), e fana ka substrate ea neurobiological eo ho eona ΔFosB induction e ka amang matla a ts'ebetso ea ts'ebetso le khothaletso bakeng sa litlatsetso tsa takatso e kang lijo, metsi kapa lithethefatsi tsa tlhekefetso.
Mona, re fuputse litlamorao tsa ΔFosB mabapi le ts'ebeliso ea sesebelisoa se khothalletsoang ke lijo ka ho sebelisa mekhoa e 'meli e tlatselletsang ea liphatsa tsa lefutso: (1) oudexpression e sa sebetseng ea ΔFosB ka har'a NAc le dorsal striatum ea litoeba tsa bitransgenic (NSE-tTA × TetOp-ΔFosB) le (2) ea ΔFosB ea mantlha ea NAc ka kotloloho ka ts'ebeliso ea phetiso ea bongaka e lipakeng ka likhoto. Re boetse re lekotse hore na ho pepesoa ha "cocaine" khafetsa, amphetamine, (+) - 3,4-methylenedioxymethamphetamine (MDMA), kapa nicotine, tlasa maemo a tlalehiloeng ho eketsa ΔFosB, ho ka matlafatsa karabelo e matlafalitsoeng ea lijo le / kapa ts'usumetso ho sebelisa kemiso e tsoelang pele ea tekanyo, joalo ka ha ho bonts'itsoe ts'ebetso ea boithati e matlafatsang ea lithethefatsi (Horger et al., 1990, 1992; Piazza et al., 1990; Vezina et al., 2002; Miles et al., 2004). Liphetho tsa rona li bonts'a litlamorao tse sa feleng tsa ΔFosB mabapi le boits'oaro bo sebetsang mme re fana ka maikutlo a hore ntlha ena e ngotsoeng e ka sebetsa mohoareng oa NAc joalo ka molaoli oa tšebetso e susumetsang.
Lisebelisoa le mekhoa
Liphoofolo le tlhokomelo ea liphoofolo
Ka mokhoa o mong, litoeba tsa Sprague Dawley tse se nang kelello li ile tsa nkuoa ho Charles River Laboratories (Wilmington, MA). Maleke a bitransgenic 11A litoeba li ne li nkiloe sefapanong lipakeng tsa litoeba tsa homozygous transgenic tse hlahisang protheine ea neuron e ikhethileng (NSE) -tTA tetracycline transactivator protein (mola A) le litoeba tse buang ka TetOp (tetracycline-reactionive promoter) -ΔFosB (line 11); mela ea botsoali e ne e bolokiloe mothating o sa tsoakoang (50% ICR le 50% C57BL6 × SJL) (Chen le al., 1998; Kelz et al., 1999). Litoeba tsena tsa bitransgenic 11A li bua ka ΔFosB ha feela: (1) bobeli ba transgene ba le teng seleng e le 'ngoe, mme (2) ts'ebetso ea transcriptal ka tTA ha e thibeloe ke ho ba teng hoa lithibela-mafu tsa tetracycline tse kang doxycycline. Tsamaiso ea doxycycline ho litoeba tsena e ka fana ka taolo ea nakoana holim'a polelo ea ΔFosB mme ea sebelisoa ho thibela polelo nakong ea nts'etsopele; ka sebele, tsamaiso ea doxycycline e amahanngoa le polelo efe kapa efe e sa bonoeng ea ΔFosB (Chen le al., 1998; Kelz et al., 1999). Ho feta moo, mohala oa 11A oa litoeba tsa bitransgenic o ile oa khethoa bakeng sa liteko tsa hona joale, hobane li bonts'a mokhoa oa ho hlahisa maikutlo o thibelitsoeng feela ho li-dynorphin tse nang le li-striatal neurons (ka bobeli NAc le dorsal striatum), tse ts'oanang le mohlala oa ho kenngoa ha ΔFosB ke lithethefatsi tse sa foleng. tlhahiso (Kelz et al., 1999). Ntle le moo, moelelo oa polelo ena e tiileng ea ΔFosB e hlakotsoe pele (Chen le al., 1998; Kelz et al., 1999). Litoeba li hlahisitsoe Univesithing ea Texas Southwestern mme li hlokometsoe le ho hlahlojoa litsing tsa Yale. Nako eohle ea nts'etsopele le nts'etsopele, litoeba tsohle li ile tsa bolokoa ho Doxycycline ho fihlela libeke tsa 8-9 li le lilemo li le setsing sa khatello ea 100 /g / ml metsing a nooang, maemo a tsejoang ho boloka transgen e tsamaisoa ke TetOp seterekeng sa "theoha", mme e sebelisitsoe ho qala 6 beke ho buuoa ka doxycycline ha polelo ea ΔFosB e fetoha kholo (Kelz et al., 1999). Liteko tsohle li kenyelletsa papiso ea litoeba tsa littermate bitransgenic ho bapisoa le doxycycline, eo ka boyona e se nang tšusumetso ho boitšoaro bo susumetsoang (Kelz et al., 1999; McClung le Nestler, 2003; Zachariou et al., 2006).
Lithuto tsohle tsa liteko li ne li behiloe ka bobeli (likhoto) kapa ka lihlopha (litoeba; tse 'ne ho isa ho tse hlano ka koung) tlas'a mocheso o laoloang le maemo a mongobo tlasa 12 h light / potoloho e lefifi (lebone ho 7: 00 AM le ho tima 7: 00 PM). Ba ne ba lumelletsoe bonyane 7 d ho ikamahanya le meaho ea matlo pele ho thuto. Liphoofolo li na le phihlello ea ho amohela metsi ka linako tsohle le ho fihlella lijo tse fokolang joalokaha ho hlalositsoe ka tlase. Ts'ebeliso eohle ea liphoofolo e entsoe ho latela Lenane la Naha la Litaba tsa Bophelo bakeng sa Tlhokomelo le Ts'ebeliso ea Liphoofolo tsa Laboraro mme e amohetsoe ke Likomiti tsa Tlhokomelo ea Liphoofolo le Ts'ebeliso Univesithing ea Texas Southwestern le Yale University.
lithethefatsi
Cocaine hydrochloride [e fanoe ka mosa ke National Institute on Drug Abuse (NIDA)], d-amphetamine sulfate (Sigma, St. Louis, MO), MDMA hydrochloride (e fanoe ka mosa ke NIDA), le (-) - nicotine hydrogen tartrate (Sigma ) li ne li qhibilihile ka har'a letsoai le omileng la 'mele (0.9%) le ho tsoa kotsi ka bongata ho 5 ml / kg (litoeba) kapa 2 ml / kg (likhoto). PH ea tharollo ea nikotine e ile ea fetoloa ka sodium bicarbonate pele ho ente.
Litholoana tsa vaerase
Ho fetisoa ka bongata ba mofuta oa vaerase ho entsoe joalo ka ha ho hlalositsoe pele (Carlezon et al., 1998; Perrotti et al., 2004). Ka bokhutšoanyane, li-cDNA tse kenyang liprotheine tse khethehileng li ile tsa kenngoa ka har'a vaerase ea herpes rahisix (HSV) amplicon HSV-PrPUC mme tsa kenngoa ka har'a vaerase li sebelisa mothusi 5dl1.2. Litholoana tse tsamaisang mofuta oa HSV-LacZ, li-coding tsa protheine ea taolo ea β-galactosidase, kapa HSV--FosB, li ile tsa kenngoa mokokotlong oa NAc ho latela protocol ea liteko.
Ts'ebetso ea liteko
Bolela.
Teko 1 e ile ea hlahloba litlamorao tsa ho pepesetsoa hoa lithethefatsi khafetsa mabapi le ts'ebetso e matlafalitsoeng ea sesebelisoa le karabelo e tsoelang pele ea karolelano. Likhoto li ile tsa aroloa ka mokhoa o sa khetholloang ka lihlopha tse hlano tsa liteko (n = 9-10 / group). Lihlopha tsena li fumane liente habeli ka letsatsi (intraperitoneally; ho 9: 00 AM le 5: 00 PM) ka saline kapa e 'ngoe ea lithethefatsi tse latelang: nicotine, 0.35 mg / kg; MDMA, 2.5 mg / kg; koae, 15 mg / kg; kapa amphetamine, 2.5 mg / kg bakeng sa matsatsi a 15 a latellanang. Litekanyetso li ile tsa khethoa ho ipapisitse le data eo re e phatlalalitseng pele (Taylor le Jentsch, 2001; Olausson et al., 2003), le ts'usumetso ea tšusumetso ea lithethefatsi e entsoeng ka lithethefatsi e ne e behiloe leihlo ka matsatsi a kalafo 1 le 15. Kamora 5 d ea ho tlohela, liphoofolo li ile tsa koetlisetsoa ho arabela ka mokhoa o hlakileng bakeng sa matsatsi a 10 a latellanang 'me ka mor'a moo tsa lekoa mabapi le karabelo e tsoelang pele ka letsatsi le hlahlamang. Liphoofolo tse peli ha lia ka tsa kenyelletsoa tlhahlobisong ea lipalo hobane li sa fumane karabo ea bohlokoa, 'me ha ho a fetisa karabelo e le' ngoe ea "lever" e 'ngoe le e' ngoe ea lithuto tse tharo tsa ho qetela tsa thupelo.
Liteko 2 le 3 li ile tsa hlahloba litlamorao tsa ho se sebetse hantle ha litheko tsa riFosB ho litoeba tsa bitransgenic mabapi le ts'ebetso ea ts'ebetso le ho arabela ka tekanyo e tsoelang pele ea matlafatso. Ho hlohlona ho sa lekanyetsoang hoa ΔFosB litoeba tsena ho kile ha bontšoa ho etsisa litlamorao tsa ho pepesetsoa lithethefatsi khafetsa ketsahalong ea methati le maemo a khetholloang a sebakaKelz et al., 1999; Zachariou et al., 2006). Litoeba tsena li ka fana ka tlhaiso-leseling e tebileng mabapi le tlatsetso ea "striatal ΔFosB" lits'ebetsong tse itseng tsa boits'oaro. Litoeba tse tona tsa genotyped li ne li bolokoa ho doxycycline kapa li ne li chencheloa ho pompela metsi ka libeke tsa 8. Liteko li ile tsa qalisoa kamora libeke tsa 6 tsa ho tlosoa ha doxycycline, ka nako eo polelo ea transgene e leng e phahameng haholo (Kelz et al., 1999). Ho liteko 2, liphoofolo (n = 16) li ne li thibetsoe ho lijo le ho koetlisetsoa ts'ebetso ea ts'ebetso e hlalositsoeng ka tlase (bona ka tlase, Ho arabela ka lisebelisoa le tlhahlobo e tsoetseng pele ea tekanyo) bakeng sa matsatsi a 10 a latellanang. Kamora ho phethoa ha liteko tsa bohlokoa, ho hlohlelletsoa hoa koae ka koae ho litoeba tsena. Ho leka 3, sehlopha se arohaneng sa litoeba (n = 18) li ile tsa koetlisoa ka karabelo ea matla bakeng sa matsatsi a latellanang a 10 tlas'a maemo ao ho fanoeng ka boholo ba li-reinforcers tsa 50. Letsatsing la 11, litoeba tsohle li ile tsa lekoa ho li-ratio tse tsoelang pele. Letsatsing la 12, re ile ra tseba litlamorao tsa ho khothaletsoa ho matlafatsoa ka ho itšunya-tšunya ho arabela ka tekanyo e tsoelang pele.
Liteko 4 le 5 li ile tsa hlahloba litlamorao tsa viral-Mediated overexpression ea ΔFosB ka kotloloho kahare ho NAc. Teko 4 e ile ea leka litlamorao tsa ΔFosB overexpression mabapi le ts'ebetso ea ts'ebeliso. Mona, likhoto li ile tsa kenngoa ka HSV-ΔFosB (n = 8) kapa HSV-LacZ (n = 8) mokokotlong oa NAc mme ea koetlisetsoa ts'ebetso ea sesebelisoa ho qala 40 h hamorao. Kamora linako tsa koetliso ea letsatsi le leng le le leng la 10, maemo a ts'ebetso ea mantlha a ile a hlahlojoa bakeng sa liphoofolo tsohle tse ts'ebetsong ea ho hlokomela mesebetsi ea locomotor joalo ka ha ho hlalositsoe ka tlase (bona ka tlase, ts'ebetso ea locomotor). Teko 5 e hlahlobile litlamorao tsa NAc ΔFosB overexpression ka ho khetheha ho arabeloeng ke keketseho ea karo-karolelano ea karabelo. Mona, likhoto li ne li koetliselitsoe matsatsi a 15 ka ho latellana, li abeloa lihlopha tsa liteko, 'me ka mor'a moo li tšoaetsoa HSV-ΔFosB (n = 8) kapa HSV-LacZ (n = 7) mokokotlong oa NAc. Liphoofolo li ile tsa tloheloa li sa hlahlojoe ebile li sa phekoloe bakeng sa 4 d ho lumella polelo ea ΔFosB hore e be sehlohlolong. Letsatsing la 5 ka mor'a ho kenngoa, liphoofolo tsohle li ile tsa lekoa bakeng sa khatello ea lever ho hatela pele lenaneong la tekanyo e tsoelang pele. Kamora letsatsi la ho qetela la liteko, likhoto tsohle li ile tsa bolaoa le ho kenngoa ha li-cannulas tsa mantlha mokokotlong oa NAc e netefalitsoe histochemically. Ho ipapisitsoe le tlhahiso ea li-cannulas tsa infusion, likhoto tse peli li ile tsa qheleloa ka thoko 4 le rat e le 'ngoe ho tsoa ho liteko tsa 5.
Tšobotsi ea polelo ea tlhaho e entsoe ka sehlopha se arohaneng sa liphoofolo. Mona, HSV-LacZ e ile ea kenngoa mokokotlong oa NAc mme liphoofolo tsa bolaoa 3 d hamorao. Polelo ea β-galactosidase e ile ea hlahlojoa kamora moo e le immunohistochemically.
Ts'ebetso ea locomotor.
Ts'ebetso ea locomotor e ne e lekantsoe ho sebelisoa metara ea ts'ebetso (paki ea Digiscan ea phoofolo e sebetsang; Omnitech Electronics, Columbus, OH). Methati ea tšebetso e ne e na le mela e 'meli ea lifoto tsa infrared, mola o mong le o mong o nang le li-sensor tsa 16 o behiloe 2.5 cm ka thoko. Limithara tsa tšebetso li ne li laoloa ke data le ho tsoa ho li-metres tsa tšebetso tse bokelitsoeng ke khomphutha ea PC sebelisa software ea Micropro (Omnitech Electronics).
Liphoofolo tsa liteko li ile tsa beoa mabokoseng a pepeneneng a polasetiki (25 × 45 × 20 cm) tse neng li kentsoe metsing a ts'ebetso. Liphoofolo li ne li lumelloa ho lula sebakeng sa polokeho ea lisebelisoa tse rekotiloeng tsa 30 min. Litekong tse ling, liphoofolo li ile tsa ntšoa ka mor'a moo, tsa kenngoa ka koae, amphetamine, nikotine, kapa koloi ho latela sebopeho sa liteko, 'me tsa khutlisoa ka har'a mabokose. Ts'ebetso ea locomotor e ile ea rekisoa bakeng sa 60 min, ho qala 5 min kamora ho kenngoa ka ente ea lithethefatsi ho qoba hypermotility e sa tsubeng. Liteko tsohle li entsoe nakong ea leseli la liphoofolo (pakeng tsa 9: 00 AM le 6: 00 PM).
Ho arabela ka sesebelisoa sa thulusi le tlhaiso e tsoelang pele ea tekanyo.
Ho araba ka lisebelisoa ho ile ha hlahlojoa ho sebelisoa likamore tse sebetsanang le maemo a likhoto (30 × 20 × 25 cm) kapa litoeba (16 × 14 × 13 cm) tse laoloang ke software ea MedPC (Med Associates, St. Albans, VT). Kamore e 'ngoe le e' ngoe e ne e behiloe ka kamoreng e kantle e nang le molumo e kenyelletsang jenereithara e tšoeu ea molumo le fan e le ho fokotsa lerata la lerata la kantle. Leseli la ntlo le neng le behiloe leboteng le ka morao le bonesitse kamore eo. Mohlophisi oa pellet o ne a isa li-pellets tsa lijo (20 kapa 45 mg; Bio-serv, Frenchtown, NJ) e le setsi sa makasine. Mananeo a hlooho a fumanoe ke fotokopi e behiloeng ka holim'a sethala sa thepa e tšehetsang. Makasineng ona e ne e le lebone la tšusumetso. Bakeng sa likhoto, mokokotlo o le mong o ne o behiloe ka lehlakoreng le leng la makasine. Bakeng sa litoeba, apertures tse peli tsa nosepoke li ile tsa beoa leboteng le ka morao la likamore (ke hore, ka thoko ho makasine ea matlafatso).
Nakong ea 5 d hang-hang pele ho qalo ea boikoetliso, liphoofolo li ne li sa lumelloe ho fihlella lijo tsa 90 min ka lijo mme li pepesoa le li-pellets tsa lijo tse tsoang ka mabele (litoeba, 20 mg; litoeba, 45 mg) ka malapeng a bona. Nakong ea liteko, li-pellets tsa lijo li ne li fumaneha ka linako tsohle likamoreng tse sebetsang ho latela ts'ebetso ea ts'ebetso (bona ka tlase) hammoho le litefiso tse se nang moeli ka kolecheng ea lapeng bakeng sa 90 min, ho qala 30 min kamora seboka sa letsatsi le letsatsi la tlhahlobo. Lenaneo lena la phihlello ea lijo le lumella phoofolo e 'ngoe le e' ngoe hore e fihle boemong ba eona ba ho satiety le ho fokotsa phapang e bakoang ke tlholisano lipakeng tsa liphoofolo tse kholo le tse tlasa tlase. Ka matsohong a rona, kemiso ena e lumella phaello e nyane butle ka mor'a ho theola boima ba pele ho ∼85-90% ea boima ba lijo tsa mahala. Boima ba liphoofolo bo behiloe leihlo ho pholletsa le liteko.
Lithuto tsohle li ne li lula malapeng a liteko tsa 2 d; nakong ea li-program tsena, li-pellets tsa lijo li ile tsa tlisoa makasineng oa ntlafatso ka kemiso ea nako e tsitsitseng ea 15 s (FT-15). Ho qala ka letsatsi le hlahlamang, lithuto li ile tsa fumana lithupelo tsa letsatsi le letsatsi tsa 10 matsatsi a latellanang. Ho arabela lijo ho ile ha lekoa ho ipapisitsoe le lits'ebetso tsa maemo a phepelo a neng a phatlalalitsoe nakong e fetileng (Baldwin et al., 2002b). Ho arabela ka lever e nepahetseng (ke hore, e sebetsang) lever / nosepoke e ile ea matlafatsoa, athe ho araba ka lever (e sa sebetseng) lever / nosepoke ho ne ho se na litlamorao tse boletsoeng. Boemo ba "nosepoke" kapa "lever" bo sebetsang bo ne bo lekane bakeng sa lihlopha tsohle tsa liteko. Ho phethoa ha tlhoko ea karabelo (bona ka tlase) ho hlahisitse ho qaleha ha leseli la tšusumetso ea makasine, ho lateloang 1 s hamorao ka ho tlisa pellet e le 'ngoe ea lijo. Metsotsoana e mmedi hamorao, lebone la tsusumetso le ile la tima. Lits'ireletso tsa pele tsa 10 li ile tsa fumanoa kamora ho phethoa ka katleho ho araba ho latela kemiso e tsitsitseng (FR1), kamora hore li-pellets li fumanehe ka mor'a ho araba ka li-ratio tse fapaneng (VR2). Seboka se tšoareletse metsotso ea 15.
Liteko 3 (litoeba) le 5 (likhoto) li sebelisitse likemiso tse ling tsa koetliso ho qoba tšusumetso e ka bang teng phapusing ea ts'ebetso ea sesebelisoa nakong ea thupelo holima karabelo e latelang (e hlalositsoeng ka tlase). Ho leka 3, litoeba li ile tsa koetlisoa lenaneong la FR1 bakeng sa 2 d mme ea ba lenaneong la FR2 la 8 d. 3 d ea pele ea liteko e sebelisitse linako tsa 60 min. Matsatsing a ho qetela a koetliso ea 7, seboka se ile sa felisoa ha li-50 tsa li-supplement li se li fumanoe. Ho liteko 5, likhoto li ile tsa koetlisoa lenaneong la FR1 / VR2 ka linako tsa 15 min joalokaha ho hlalositsoe ka holimo bakeng sa liteko tsohle tse ling ntle le tse peli. Taba ea pele, ho ile ha tlisoa palo e phahameng ea li-pellets tsa 150. Taba ea bobeli, liphoofolo tsena li fumane matsatsi a eketsehileng a koetliso ea 5 (ke hore, 15 d) ho lumella ho thehwa ha ts'ebetso e tsitsitseng pele ho mofuta o fe kapa o fe oa ho leka.
Liphoofolo li ile tsa boela tsa lekoa mabapi le ho arabela bakeng sa lijo lenaneong le tsoelang pele la matlafatso. Thutong ena, tlhoko ea karabo ea ho fumana lijo e qaliloe e le kemiso ea FR1 empa e ntse e eketseha butle-butle ke 2 ho fumana thekiso e latelang (ke hore, 1, 3, 5, 7…, X + 2 likarabo). Boitekong ba kalafo ea lithethefatsi bo sebelisang likhoto, kemiso e ile ea eketseha butle-butle ke 5, e hlahisa kemiso ea ho qetela ea 1, 6, 11, 16…, X + 5. Meetso eohle e meng e ne e bolokiloe e ts'oana le ts'ebetso ea koetliso e boletsoeng ka holimo. Teko e ile ea felisoa ha ho se karabelo e sebetsang bakeng sa 5 min.
Matlafatso ea boleng.
Matla a ho matlafatsa boleng bo matlafatso a ile a hlahlojoa ho sebelisoa preforcer e ikhethang. Mona, litoeba li ne li lumelloa ho ja lijo tse se nang moeli tsa lijo-thollo tse fumanehang ka har'a koti ea bona ea lapeng nakong ea 3 h pele ho hlahlojoa lenaneong la ts'ebetso ea tsoelo-pele joalo ka ha ho hlalositsoe kaholimo.
Mekhoa ea ho buoa.
Liphoofolo li ne li sa rueloe li sebelisa equithesin [motsoako o nang le pentobarbital (35 mg / kg) le chloral hydrate (183.6 mg / kg) ho ethanol (10% v / v) le propylene glycol (39% v / v); e tsamaisoa ho 4.32 ml / kg, ip]. Cannulas (Plastics One, Roanoke, VA) li ile tsa kenngoa ka mokhoa oa ts'ebetso kaholimo ho mantlha ea NAc, ho sebelisoa lisebelisoa tsa Kopf stereotactic. Litlhophiso tsa li-stereotactic tse sebelisitsoeng ho amanang le bregma li ne li le latelang: anterior / posterior, + 1.5 mm; lateral / medial, ± 1.5 mm; ventral / dorsal, −6.0 mm (Paxinos le Watson, 1986). Linokoane li ne li khokhisitsoe ke lehata ho sebelisoa lereko le samente ea meno. Bareki ba ile ba kenngoa ka har'a li-cannulas tsa tataiso ho thibela ho thibeloa. Kamora ho buuoa, liphoofolo li ile tsa fuoa tlhokomelo e tloaelehileng ea postoperative mme tsa lumelloa ho fola bakeng sa 5 d pele ho qala teko efe kapa efe.
Infusions.
Litla-morao tsa methapo ea methapo ea vaerase li ne li etsoa habeli 40 h pele ho qala koetliso (bona ka tlase). Li-syringes tsa ente (31 gauge), li atolosa 1 mm ka tlase ntlheng ea li-cannulas tsa tataiso, li theotsoe butle ka nako e ts'oanang ka lehlakoreng le letšehali le le letona la NAc, mme 1.0 μl / lehlakore le ile la kenngoa nakong ea metsotso ea 4 anl / Min ho sebelisa pompo ea microinfusion (PHD-0.25; Lisebelisoa tsa Harvard, Holliston, MA). Li-needle tsa infusion li ile tsa siuoa sebakeng sa 5000 min kamora hore ts'elo e phethoe, 'me li-cannulas tsa dummy li ile tsa nkeloa sebaka. Ho beoa ha Cannula ho netefalitsoe ka nalane kamora ho phethoa hoa liteko tsa boits'oaro (bona sa feiga. 1B), ke liphoofolo feela tse nang le li-cannulas tse kentsoeng hantle li kenyellelitsoeng tlhaisong ea tlhahlobo ea tlhahlobo ea tlhahlobo ea tlhahlobo ea tlhaiso-leseling.
Tlhahlobo ea nalane le nalane ea boits'oaro.
Kamora ho phethela liteko, liphoofolo tse neng li fumane lingaka tse buoang joalo ka karolo ea teko li ne li sa anngoe ka mokhoa oa Exithesin 'me li entsoe ka transporter ka 0.1 m PBS (5 min) le 10% formalin (10 min) ho latela lits'ebetso tse tloaelehileng. Li-brains li ne li hatisoa ka mokhoa oa semmuso ebe ka mor'a moo li kenngoa ka tharollo ea sucrose (30%). Ka linako tsohle, likelello tsohle li ne li khaoloa ka likarolo tsa 40 μm ka microtome mme li sebelisetsoa tlhahlobo ea nalane ea ho bea cannula le polelo ea protheine.
Cannula e kentsoe ka likarolo tse hokahaneng le bofubelu bo sa nkeng lehlakore 'me ea beoa ka li-slide tsa microscope ho distyrene plasticizer le xylene (DPX) kamora ho felloa ke metsi ka bongata. Immunohistochemistry e entsoe joalo ka ha ho hlalositsoe pele (Hommel et al., 2003). Ka bokhutšoanyane, polelo ea β-galactosidase kamora ho ts'oaroa ha HSV-LacZ e ile ea khethoa ke lits'oants'o tsa immunofluorescent ho sebelisa anti-β-galactosidase antibody ea mantlha (1: 5000; Biogenesis, Kingston, NH). Kamora ho ts'oaroa bosiu bo le bong, likarolo li ile tsa ts'oaroa tsa ba tsa kenngoa ka morao-rao ka anti-poli ea anti-poli ea anti-poli e kopantsoeng le Cy2 (1: 200; Jackson ImmunoResearch, West Grove, PA). Likarolo li ile tsa hlatsuoa hape tsa lateloa ke ho nyekeloa ke ethanol le ho eketseha hoa DPX. Likarolo tse haufi tsa taolo li ile tsa tšoaroa ka mokhoa o ts'oanang ntle le ho kenyelletsa li-antibodies tsa mantlha. Immunofluorescence e ile ea hlahlojoa ho 520 nm e sebelisa a Seiss (Oberkochen, Jeremane) microscope e nang le sefahleho sa FITC le litšoantšo tse nkuoang ka linako tse tšoanang le Seiss Sistimi ea ho nahana ka maqhubu ea dijithale.
Lipalo-palo li
Lintlha tse tsoang litekong tsohle li ile tsa hlahlojoa ho sebelisoa ANOVA ea tsela e le 'ngoe, tse peli, kapa tse tharo e lateloang ke teko ea Scheffe kapa ea Dunnett, ho lokisa lipapiso tse ngata moo ho loketseng ho sebelisa tlhahlobo ea tatellano ea Holm ea tatellano. Boleng ba p ≤ 0.05 bo ne bo nkuoa e le ba bohlokoa.
Results
Teko 1: litlamorao tsa ho pepesetsoa ha lithethefatsi khafetsa ts'ebetsong ea sesebelisoa le karabelo e tsoelang pele ea karabelo
Ho netefatsa hore paradigm ea rona e pepesitsoeng ea lithethefatsi e hlahisa li-neuroadaptations tsa bohlokoa, re qalile ka ho hlahloba sensomization ea boitšoaro bo sa rateheng ba ts'ebetso ea lithethefatsi tse sa feleng. Likhoto li ile tsa fuoa ente ea habeli ea letsatsi le letsatsi ea nicotine (0.35 mg / kg), MDMA (5 mg / kg), koae (15 mg / kg), kapa amphetamine (2.5 mg / kg), le ts'ebetso ea locomotor e ile ea lekoa kamora ho ente ea pele matsatsi a kalafo 1 le 15 (tlatsetso ea feiga. 1A-E, e fumanehang ho www.jneurosci.org joalo ka thepa e tlatsetsang). Tlhahlobo ea lipalopalo e senotse kalafo ea bohlokoa ka ho sebelisana ha motšehare (F(4,42) = 9.335; p ≤ 0.0001). Kantle ho MDMA (p = 0.62), lithethefatsi tsohle li kentse ts'ebetso e kholo haholo ea locomotor (ke hore, sensitization) ka letsatsi 15 bapisoa le letsatsi 1 (nicotine, p ≤ 0.001; cocaine, p ≤ 0.001; amphetamine, p ≤ 0.01). Liente tsa khafetsa tsa letsoai li ne li sena phello. Ha ho na kalafo ea lithethefatsi e fetotsoeng tšebetso ea mantlha ea nako e lekantsoeng nakong ea ho aha ka letsatsi 15 (tlatsetso ea feiga. 2A, e fumanehang ho www.jneurosci.org joalo ka thepa e tlatsetsang).
Matsatsi a mahlano ka mor'a ente ea ho qetela ea lithethefatsi, re ile ra hlahloba litlamorao tsa nicotine e fetileng e phetoang, MDMA, cocaine, kapa phello ea amphetamine ka ts'ebeliso ea matla a khothalletsoang ke lijo. Lintlha li hlahisoa bakeng sa lithethefatsi ka bomong ka thoko ho Setšoantšo sa 1A-H o sebelisa sehlopha se le seng sa taolo ea letsoai ho bapisa. Re fumane hore ho pepesehela e 'ngoe le e' ngoe ea lithethefatsi tsena ka mokhoa o matla le ka mokhoa o ikhethileng ho eketsa karabelo e matlafalitsoeng ea lijo (kalafo ke lever ka letsatsi la thupelo, F(36,378) = 1.683; p ≤ 0.01; tlhahlobo ea post hoc: nicotine, p ≤ 0.01; MDMA, p ≤ 0.05; koae, p ≤ 0.01; amphetamine, p ≤ 0.001). Ho phahamisoa ho sa khaotseng ha karabelo ea mohopolo ho bonahala ts'ebetsong ea asymptotic ho khothalelitse ntlafatso e ka khonehang molemong oa ts'usumetso, e lumellanang le keketseho e tlalehiloeng ea pele ka mor'a ho pepesetsoa hangata psychostimulant (bona Puisano). Ka hona, re ile ra leka hore na tšebeliso ea lithethefatsi e sa khaotseng e sebelisitsoeng khafetsa re sebelisa kemiso e tsoelang pele ea karolelano ea litekanyetso. Ho bile le phello ea lipalo ea ho pepesetsoa hoa lithethefatsi nakong e fetileng ha a arabela ho lever e sebetsang (kalafo ka tšebelisano ea lever, F(4,42) = 3.340; p ≤ 0.05) (Feie. 2A) hammoho le ntlha ea khefu ea ho qetela (F(4,42) = 5.560; p ≤ 0.001) (Feie. 2B). Tlhahlobo e eketsehileng e bontšitse hore liphekolo tsohle li eketsehile ka bobeli palo ea likarabo tse sebetsang (nicotine, p ≤ 0.001; MDMA, p ≤ 0.05; cocaine, p ≤ 0.001; amphetamine, p ≤ 0.001) le sebaka sa khefu (nicotine, p ≤ 0.001; MDMA , p ≤ 0.01; cocaine, p ≤ 0.0001; amphetamine, p ≤ 0.0001) e lumellana le phello ea liphekolo tsena mabapi le tšusumetso. Ka lebaka la ho haella ha litlamorao tsa lithethefatsi mesebetsing ea mantlha ea seteraeke, le ho se sebetse hantle ha likhatiso tse sa sebetseng tsa lever, ha ho na monyetla oa hore karabelo e eketsehang ea lijo tlasa maemo ana e bonts'a keketseho e sa utloahaleng ea ts'ebetso ea makoloi.
Setšoantšo sa 1.
Kameho ea liente tse phetoang tse fetileng tsa nicotine (0.35 mg / kg), MDMA (2.5 mg / kg), koae (15 mg / kg), kapa amphetamine (2.5 mg / kg) habeli ka letsatsi bakeng sa boits'oaro bo latelang ba 15 d. Liphoofolo li ile tsa lekoa hammoho, empa bakeng sa ho hlaka litlamorao tsa lithethefatsi ka seng li hlahisoa ka thoko, li sebelisa sehlopha se le seng se laoloang ke letsoai. A (likarabo tse mafolofolo) le B (likarabo tse sa sebetseng) li bonts'a litlamorao tsa ho pepeseha ha nicotine e fetileng; C, D, MDMA; E, F, koae; G, H, amphetamine. Lintlha li hlahisoa e le mokhoa oa ± SEM.
Setšoantšo sa 2.
Phello ea kalafo e fetileng e phetoang (habeli ka letsatsi, 15 d) ka saline, nicotine (0.35 mg / kg), MDMA (2.5 mg / kg), cocaine (15 mg / kg), kapa amphetamine (2.5 mg / kg) ho arabeleng ka seletsa lenaneong le tsoelang pele la karolelano ea matlafatso. Lintlha li emeloa e le mekhoa ± SEM. *** p <0.001; ** p <0.01; * p <0.05. Letsoai, Saline; Nic, nikotine; Coc, k'hok'heine; Amph, amphetamine; PR, karo-karolelano e tsoelang pele.
Ho pepesetsoa lithethefatsi hape ho ne ho sena phello ho boima ba 'mele bo tlalehiloeng pele ho thibelo ea lijo, ka letsatsi la pele kapa la ho qetela la thupelo ea maiketsetso, kapa hang-hang pele ho tlhahlobo ea tekanyo e tsoelang pele (tlatsetso ea feiga. 2B, e fumanehang ho www.jneurosci.org joalo ka thepa e tlatsetsang). Phokotso ea lijo tse thibetsoeng bakeng sa 3 d qalong e ile ea theola boima ba 'mele ho ba 91-92% ea boima ba' mele ea mahala. Qetellong ea liteko tsa boitšoaro, boima bo ne bo khutletse ho 97-99% ea boima ba 'mele oa prerestriction, mme ha ho phapang e ileng ea bonoa lipakeng tsa liphoofolo tse pepesitsoeng ke lithethefatsi le tse tšoaroang ka letsoai. Liphetoho tsa boima ba 'mele le liphapang tsa tlala kapa takatso ea lijo ha lia lokela ho kenya letsoho haholo ntlafatsong e bonts'itsoeng ea ts'ebetso ea ts'ebetso kapa khothatso.
Teko ea 2: Ho fetelletsa litaba ho sa amaneng ha ΔFosB ka litoeba tsa bitransgenic; ts'ebeliso ea lisebelisoa
Ka mor'a moo re ile ra hlahloba hore na tšebetso ea tšebetsong e boetse e eketsehile ho litoeba tsa bitransgenic tse sa hlokeng hore overexpress ΔFosB e nang le khethollo e tšoaeang ho NAc le dorsal striatum (Kelz et al., 1999). Boitekong bona, litoeba tsa ΔFosB-overexpressing li ile tsa bapisoa le taolo ea littermate tse sa hlokeng ho bua ΔFosB hobane li bolokiloe ho doxycycline (bona Lisebelisoa le Mekhoa ea Ts'ebetso). Re fumane hore overexpression ea ΔFosB e eketsehile haholo karabelo e matlafatsang ea lijo (polelo ea liphatsa tsa lefutso ka lever ka letsatsi la thupelo, F(9,126) = 3.156; p ≤ 0.01) (Feie. 3A). Palo ea likarabo tsa nosepoke tse entsoeng ka har'a aperture e sa sebetseng e ne e sa fapana lipakeng tsa lihlopha tsena tse peli (Feie. 3B). Ka bobeli, tlhaiso-leseling ena e bonts'a hore oFosB overexpression ho NAc le dorsal striatum ka mokhoa o ikhethileng oa ts'ebetso ea ts'ebetso
Setšoantšo sa 3
Phello ea ho ba leqeba ho feteletseng ha boiketsetso ba ΔFosB ho litoeba tsa bitransgenic mabapi le ts'ebetso ea sebetsa. A, Likarabo tse sebetsang. B, Likarabo tse sa sebetseng. Lintlha li hlahisoa e le mokhoa oa ± SEM.
Ho etsa qeto ea hore ntlafatso ea ts'ebetso ea bohlokoa ho liphoofolo tsa inFosB tse fetang tekano li ka hlalosoa ka phetoho litakatsong tsa tlala kapa tlala, boima ba 'mele bo ne bo tlalehiloe pele ho thibelo ea lijo le ka matsatsi a pele le a ho qetela a koetliso. ΔFosB ha e na phello ho boima ba 'mele pele ho thibelo ea lijo, hape ha ho na phello ho boima ba' mele nakong ea liteko tsa boitšoaro. Mona, phihlello ea lijo e thibetsoeng bakeng sa 3 d e theotse boima ba 'mele ho ba bohareng ba 87-89% ea boima ba' mele bo fepang mahala. Qetellong ea liteko tsa boits'oaro, boima ba liphoofolo e ne e le 97-99% ea boima ba 'mele ea prerestriction, ka liphetoho tse ts'oanang tse bonoang ho ΔFosB le litoeba tsa taolo (feiga ea tlatsetso ea 3A, e fumanehang ho www.jneurosci.org joalo ka thepa e tlatsetsang). Kahoo ha ho na monyetla oa hore litlamorao tsa ΔFosB ho feta tlala kapa takatso ea lijo li ka baka lintlafatso molemong oa ho arabela ka matla.
Ha liteko tsa ts'ebetso ea ts'ebeliso ea lisebelisoa li se li phethiloe, ΔFosB overexpression ha ea ka ea fetola tšebetso ea motheo ea methati e lekantsoeng ka nako ea metsotso ea 30 (tlatsetso ea feiga X. 3B, e fumanehang ho www.jneurosci.org joalo ka thepa e tlatsetsang). Tlhahlobo ena e ts'ehetsa pono ea hore liphetoho tse sa hlokeng tšebetso tšebetsong ha li kenye letsoho ts'ebetsong e matlafalitsoeng ea ts'ebeliso e bonoang liphoofolong tsena. Leha ho le joalo, litoeba tsa ΔFosB-overexpressing bitransgenic li tlalehiloe hore li bonts'a likarabo tse ntlafalitsoeng tsa koae ka koae e mpe le e phetoang hangata (Kelz et al., 1999). Hobane re sebelisitse kemiso e fapaneng hanyane ho tsoa ho doxycycline ho kenya mofuta oa liphatsa tsa lefutso (Libeke tsa 6 ka thibelo ea lijo), re ikemiselitse ho netefatsa mofuta ona oa phenotype. Ka sebele, litoeba tsa ΔFosB-overexpressing li bonts'itse keketseho e kholo haholo ea ts'ebetso ea locomotor ha e kenngoa ka koae ha e bapisoa le taolo ea littermate e bolokiloeng ho doxycycline (kalafo ka polelo ea gene, F(1,44) = 4.241; p ≤ 0.05) (Setšoantšo sa tlatsetso sa X. 3C, se fumanehang ho www.jneurosci.org joalo ka thepa e tlatsetsang).
Teko ea 3: Ho fetelletsa litaba ho sa amaneng ha ΔFosB ka litoeba tsa bitransgenic; karolelano e tsoelang pele
Fuoa hore ho pepesetsoa lithethefatsi nakong e fetileng ho etsa hore riFosB (Nestler et al., 2001) mme e fumanoe mona ho eketsa tekanyo e tsoelang pele ea karabelo, re ile ra leka hape hore na transgenic striatal overexpression ea ΔFosB le eona e eketsa ts'ebetso lenaneong la ts'ebetso ea tsoelo-pele. Sehlopha se secha sa litoeba se koetliselitsoe ho araba ka mokhoa o sebetsang tlasa maemo (bona Lisebelisoa le Mekhoa ea Ts'ebetso) e sa hlahiseng phapang e kholo tšebetsong ea ts'ebetso pele ho lekoa mabapi le karabelo ea mohato o tsoelang pele (F(1,16) <1). Leha ho le joalo, tekong e tsoelang pele ea karolelano re hlokometse polelo ea bohlokoa ea liphatsa tsa lefutso ka ho sebelisana le lever (F(1,16) = 5.30; p ≤ 0.05) (Feie. 4A) mme a fumana hore litoeba tsa ΔFosB-overexpressing, ha li bapisoa le litali tsa taolo ea littermate tse bolokiloeng ho doxycycline, li entse likarabo tse ngata tse sebetsang (p ≤ 0.05), athe palo ea likarabo tsa lever tse sa sebetseng e ne e sa fapana. Litoeba tsa iceFosB-overexpressing le tsona li fihlile sebakeng se phahameng sa khefu (F(1,16) = 5.73; p ≤ 0.05) (Feie. 4B). Lintlha tsena li fana ka maikutlo a hore, joalo ka ho pepesetsoa ha psychostimulant ea nakong e fetileng, ho ts'oaroa ho matla ha riFosB ho eketsa ts'usumetso. Hobane lipalo tsa likarabo tse sa sebetseng li ne li sa fetoloe ho litoeba tsa ΔFosB-overexpressing, ho eketseha ho sa lebelloang ha mosebetsi ho ka se be le karolo ho litlamorao tsena. Pono ena e ts'ehelitsoe hape ke liteko tsa ts'ebetso ea mantlha ea locomotor moo ho neng ho se na phapang pakeng tsa mFosB ea litoeba tse feteletseng le litoeba tsa taolo ea littermate tse bolokiloeng ho doxycycline. Ha ho liphapang tse tebileng boima ba 'mele lipakeng tsa ΔFosB-overexpressing le liphoofolo tse laoloang li ne li bonahala joalo ka ha li lekantsoe ka letsatsi la liteko. Kahoo, le ha liphoofolo tse ΔFosB-oxpxpress li tla sebelisa likarabo tse matlafatsoang ke lijo, ha li bonahale li ka ja lijo tse ngata ha li fumaneha ka bolokolohi. Tlhaloso e kholo ka ho fetisisa bakeng sa tlhokomeliso ena ke hore, le ha ts'usumetso e nka hore na phoofolo e tla sebetsa ka thata hakae ho fumana matlafatso, lintlha tse ngata tse eketsehileng (takatso ea lijo, satiety, metabolic state, jj.) E susumetsa boitšoaro ba ho fepa le tšebeliso ea sebele ea lijo.
Setšoantšo sa 4.
Phello ea khatello e fetelletseng ea FosB ho litoeba tsa bitransgenic mabapi le ho arabela ka mokhoa o bonolo lenaneong le tsoelang pele la matlafatso, pele le kamora ho satiety e matlafalitsoeng. A, B, Motheo oa motheo: likarabo tsa lever (A), ntlha ea khefu (B). C, D, Kamora 'matlafatso ea matlafatso: likarabo tsa lever (C), ntlha ea khefu (D). Lintlha li emeloa e le mekhoa ± SEM. * p <0.05.
Litoeba tsa ΔFosB bitransgenic tse sebelisitsoeng mona li bontša ΔFosB ho pholletsa le striatum. Le ha li-ventral striatum (ho kenyelletsa le NAc) li kentse letsoho lits'ebetsong tse susumetsang, ho boleloa hore dorsal striatum e nka karolo ho fumantseng litloaelo tse matla (Yin et al., 2004; Faure et al., 2005). Leha re sa ka ra bona ho se tšoane ha ts'ebetso ea bohlokoa nakong ea thupelo re sebelisa kemiso e tlase ea tekanyetso le meeli e matlafatsang ea maemo, maemo a hanana le nts'etsopele ea litloaelo tse hlokahalang (Dickinson, 1985), ho ka etsahala hore ho thehwa ha mekhoa ho ka susumetsa ho arabela tlasa kemiso e tsoelang pele ea karolelano ea maemo. Monyetla ona o ile oa lekoa ka kotlolloho ka ho lekola phello ea boitlamo ba ho matlafatsa ka ho hatella karabelo ea karo-karo e tsoelang pele. Prefeeding e joalo e felisitse phello ea ΔFosB mabapi le karabelo e tsoelang pele ea karo-karolelano, ntle le karohano ea ho araba kapa ho hlakola lintlha tse bonngoeng lipakeng tsa ΔFosB-overexpressinging le control litoeba (F(1,16) <1) (Feie. 4C, D). Ka bobeli, tlhaiso-leseling ena e fana ka maikutlo a hore ts'ebetso ea ΔFosB ha e fetole maikutlo a ho fetoha ho boleng ho sephetho sa moputso ka ho sebelisa kemiso ena ea liteko. Ho fapana le moo, karabelo ea mohopolo e hlokometsoeng tekong e tsoetseng pele ea karo-karolelano e bonahala e tataisoa ke sepheo 'me sebaka sa khefu se eketsehang se bonoang ho litoeba tsa ΔFosB se ka tlisoa ke tšusumetso e matla eseng ho arabela ka mokhoa o joalo.
Teko ea 4: Ho fetella ho bongata ha botlaaseng ba ΔFosB mokokotlong oa NAc: ts'ebetso ea ts'ebetso
Ho lekola hore na ΔFosB overexpression ka boikhethelo ho NAc e ka ikarabella bakeng sa boits'oaro bo bonoang ho litoeba tsa bitransgenic, ra kenya HSV-ΔFosB, kapa HSV-LacZ e le taolo, ka mokhoa o ikhethileng oa mantlha ea NAc ea likhoto mme ra ithuta phello ea ho qhekella hona ho lijo Ts'ebetso e matlafalitsoeng ea mochini (Feie. 5A, B). Kamora boikoetliso ba limakasine, HSV-ΔFosB kapa HSV-LacZ e ile ea kenngoa mokokotlong oa NAc konokono 40 h pele ho qalisoa tlhahlobo ea boitšoaro. Sebaka sa infusion le boholo ba polelo ea gene-Mediated gene li bontšitsoe ho Setšoantšo sa 6, Infusions ea A le B. NAc ea HSV-ΔFosB e hlahisitse keketseho e tsitsitseng ea palo ea likarabo tse sebetsang tse hlahisitsoeng (polelo ea gene ke lever, F(1,12) = 8.534; p ≤ 0.05) (Feie. 5A), e ileng ea phehella nakong ea liteko. Litlamorao tsena li ne li ikhethile, hobane ho ne ho se na litlamorao tse kholo tsa ΔFosB overexpression kahare ho motheo oa NAc palong ea likarabo tse sa sebetseng (Feie. 5B) kapa ketsahalong oa mantlha oa ho paka tse tlalehiloeng letsatsi kamora ho phethoa hoa tlhahlobo (ya data e sa bonts'ang). Tlhatlhobo e fetisisang ea ΔFosB ho NAc ke kahoo e ileng ea bapisa litlamorao tsa ho pepeseha hoa lithethefatsi kapa khatello e feteletseng ea ΔFosB.
Setšoantšo sa 5.
Tšusumetso ea infusions ea HSV-ΔFosB mokokotlong oa NAc pele ho koetliso ea ho araba ka mokhoa o lerato. A, Likarabo tse sebetsang. B, Likarabo tse sa sebetseng. Lintlha li hlahisoa e le mokhoa oa ± SEM.
Setšoantšo sa 6.
A, Ho beoa ha libaka tsa infusion bakeng sa liteko tsa vaerase ea vaerase. Holimo, Liroto tse ntšo tse tlatsitsoeng li tsamaellana le sebaka sa infusion se reriloeng. Ke infusions feela e entsoeng ka hare ho ∼0.5 mm ea sebaka sena (ke hore, kahara motheo oa NAc), joalo ka ha ho bonts'itsoe ke potoloho, e ne e nkuoa e amoheleha. Liphoofolo tse nang le infusions tse entsoeng ka ntle ho sebaka sena li ne li sa kengoe tlhahlobisong ea lipalo. Ka tlase, sebaka sa ts'oaetso kahare ho NAc ka phoofolo ea boemeli. B, netefatso ea Immunohistochemical ea polelo ea liprotheine kamora ho kenngoa ha HSV-LacZ. Li-panels tse kaholimo li bonts'a polelo ea β-galactosidase kahare ho NAc konokono (2.5 le 10 × ho holisa). Liphanele tse ka tlase li bonts'a ho haella ha immunofluorescence likarolong tse haufi tsa taolo ho sebelisa ts'ebetso e ts'oanang ea immunohistochemical ntle le ho kenyelletsoa ha antibody ea mantlha.
Teko ea 5: Ho fetella ka bongata ha botlaaseng ba ΔFosB mokokotlong oa NAc: tekanyo e tsoelang pele
Teko ea hoqetela e nkile qeto ka kotloloho ea hore na BFosB e thibelitsoeng ho mantlha ea NAc e sebelisang mokhoa oa ho fetisetsa liphatsa tsa lefutso e ne e lekane ho matlafatsa ts'usumetso litekeng. Mona, HSV-ΔFosB e ile ea kenngoa feela kamora hore koetliso ea matla e phethetsoe, e tlosa tšusumetso efe kapa efe ea tšusumetso ea ΔFosB overexpression nakong ea thupelo litekong tse latelang tsa keketseho ea tekanyo e latelang. Sehlopha se secha sa likhoto se ile sa koetlisoa, joalo ka pele, 'me sa aroloa ka lihlopha tse lekang tsa liteko tse ipapisitseng le tšebetso ea tsona matsatsing a ho qetela a thupelo. Liphoofolo hamorao li ile tsa amohela infusions ea naha e 'ngoe ea HSV-ΔFosB kapa HSV-LacZ ka mokokotlong oa NAc mme ea lekoa ka tekanyo e tsoelang pele ho arabela ka mor'a 5 d ea overexpression. Tlhahlobo ea lipalopalo e senotse polelo ea bohlokoa ea mofuta oa lipuisano ka ho sebelisana le lever (F(1,12) = 14.91; p ≤ 0.01) (Feie. 7A). Liroto tse kentsoeng HSV-ΔFosB li entse likarabo tse sebetsang haholoanyane (p ≤ 0.01) ha li bapisoa le tse fuoang le HSV-LacZ, athe ho araba ka leiring e sa sebetseng ho ne ho sa amehe. Tumellanong le keketseho ena, likhoto tse tlisitsoeng ka HSV-ΔFosB le tsona li ile tsa ba le sebaka se phahameng sa khefu (F(1,12) = 18.849; p ≤ 0.001) (Feie. 7B) ho feta liphoofolo tse fuoeng HSV-LacZ. Ha ho na phello ea ΔFosB ho ts'ebetso ea mantlha ea locomotor e ileng ea lekoa 1 h pele ho liteko tse tsoelang pele tsa tekanyo (tlatsetso ea feiga. 4A, e fumanehang ho www.jneurosci.org joalo ka thepa e tlatsetsang). Ho boetse ho ne ho se na phapang ea boima ba 'mele ka letsatsi la tlhahlobo e tsoelang pele ea tekanyo (tlatsetso ea feiga. 4B, e fumanehang ho www.jneurosci.org joalo ka thepa e tlatsetsang). Liphumano tsena li ts'ehetsa maikutlo a rona ka litoeba tsa transgenic ΔFosB-overexpressing, hape li bonts'a hore ho khetha ho feteletseng hoa ofFosB ho NAc ho lekane ho matlafatsa sepheo se amanang le lijo.
Setšoantšo sa 7.
Phello ea infusions ea HSV-ΔFosB 5 d pele e lekoa ka karabelo ea sesebelisoa ka mokhoa o tsoelang pele oa sekhahla sa matlafatso. A, likarabo tsa Lever. B, Ntlha ea khefu. Lintlha li emeloa e le mekhoa ± SEM. *** p <0.001; ** p <0.01.
Puisano
Boithuto bo teng hona joale bo bonts'a hore ho ba le qoelopele ea ΔFosB ka hara NAc e matlafatsa boits'oaro bo matlafalitsoeng ba ts'ebeliso ea lijor. Ho pepesetsoa ha koae, amphetamine, MDMA, kapa nikotine e ntlafalitsoeng ho hlahisitse keketseho e sa feleng ea ts'ebetso e latelang ea ts'ebetso. Litlhahiso tsena tsa lithethefatsi li boetse li matlafalitse boitšoaro bo susumetsoang ke lijo tlasa kemiso e tsoelang pele ea matlafatso. Litlamorao tsena tsa ho pepesetsoa lithethefatsi nakong e fetileng li ile tsa emisoa ke thibelo e fetelletseng ea ΔFosB seterekeng, ho sebelisa litoeba tse sa sebetseng (NSE-tTA × TetOP-ΔFosB) kapa ho sebelisa vector viral vevel ho bontša expressFosB ka boikhethelo ho NAc. Haholo-holo, ho hlonama ha ΔFosB ka sehlohlolong sa NAc, kamora hore ho arabe ka mokhoa o matla ho se ho fumanoe, khothatso e ntlafalitsoeng ea lijo tlasa kemiso e tsoelang pele ea tekanyo. Hammoho, liphumano tsa rona li supa ΔFosB mokokotlong oa NAc e le mokena-lipakeng oa li-neuroadaptations tse entsoeng ke lithethefatsi tse ka khothaletsang boits'oaro bo matla, e phahamisa karolo bakeng sa ntlha ena ea ho kenyelletsa ho kenyelletsa lits'ebetso tse amanang le tšusumetso ea ts'usumetso ts'ebetsong ea boitšoaro bo matlafatsoang ke lijo. E boetse e phahamisa monyetla oa hore maemo a susumetsang expressionFosB polelo ho NAc a ka susumetsa likarolo tsa matlafatso tsa tlatsetso ea tlholeho le ea lithethefatsi.
ΔFosB e bokellana ka har'a methapo ea kutlo e lipakeng tsa dynorphin le ea bobeli ea NAc le dorsal ka mor'a nako e telele, empa eseng e mpe, ho pepesehela lithethefatsi tsa tlhekefetso. Mokhoa ona oa tikoloho o hlahisoa hape ho litoeba tse sa sebetseng tsa rFosB-overexpressing tse sebelisitsoeng mona. Litseng tsena, Maemo a phahameng a striatal a ΔFosB a eketsa kutloisiso ea liphoofolo ho cocaine le morphine joalo ka ha e lekantsoe ke sebaka seo e se ratang (Kelz et al., 1999; Zachariou et al., 2006). E boetse e phahamisa keketseho e tsoelang pele ea karabo ea koae e fanang ka maikutlo a hore tšusumetso ea ho ithekha ka koae e ntlafatsoa ke ho tebela ho feteletseng ha riFosBColby et al., 2003). Mona, re fumane hore ts'ebetso ea "striatal ΔFosB overexpression" ea litoeba tsena e ile ea eketseha ka keketseho e tsoelang pele ea karabelo ea lijo le hore litlamorao tsena li hlahisitsoe hape ke thibelo e matla ea bongaka ea ΔFosB ka sehlohlolong sa NAc ho rat. Lintlha tsa rona li fana ka maikutlo a hore ΔFosB e ka sebetsa e le mochine o susumetsang oa khothatso ea mantlha ho batho ba matlafatsang, ekaba lijo, lithethefatsi kapa mohlomong ho ikoetlisa, mohopolo o lumellanang le maikutlo a qalang a hore polelo ea "atFosB" ea eketseha kamora ho khanna ho tsamaisoa ka mabili kapa ho choachoasela ka sekhahla (McClung et al., 2004). Lintlha tsena li fana ka maikutlo a hore NAc overexpression ea ΔFosB e ka ntlafatsa tšusumetso ea matlafatso ea tlhaho le ea lithethefatsi.
Subregions ea NAc ho phehisanoe khang ea hore e arolelane ka mokhoa o fapaneng ts'usumetso ea lits'ebetso tsa ts'ebetso ea pavlovian kapa ea ts'ebetso ea ts'ebetso ea ts'ebeliso ea matla (Corbit et al., 2001; de Borchgrave et al., 2002), athe litšusumetso tse ling tsa ts'ebetso ea ts'ebetso ea ts'ebeliso e matla li ka fokotsoa ke libaka tse ling tse joalo ka konopo e bohareng ea amygdala (Corbit le Balleine, 2005). Bohlokoa ba NAc, leha ho le joalo, bo boetse bo hlahisitsoe ho ba sebaka sa bohloka sa ho fumana thuto ea maano a tataisitsoeng ka sepheo (Smith-Roe le Kelley, 2000; Baldwin et al., 2002a,b; Kelley, 2004). Re bonts'a litlamorao tse ts'oanang tsa litlatsetso tsa lithethefatsi tse fetileng le transgenic striatal ΔFosB overexpression mabapi le ho ntlafatsa boits'oaro. Infusions ea HSV-ΔFosB e lekantsoeng mookotong oa NAc le eona e ile ea eketsa karabelo e matlafalitsoeng ea lijo. Le ha liteko tsena li sa qhele karolo e tlatsetsang tlatsong ea dorsal boits'oarong bona, li khothaletsa ka matla hore liphetoho tse susumetsoang ke ΔFosB ka polelo ea mofuta oa NAc li lekane ho eketsa karabelo e khothalletsoang ke lijo. Hobane ho arabela ka tekanyo e tsoelang pele ho boetse ho ntlafalitsoe ha ΔFosB e hlahisoa kamora ts'ebetso e tsitsitseng ea ts'ebeliso ea ts'ebetso pele e fihlelletsoe, karolo ea tšusumetso ea ts'usumetso molemong oa boits'oaro ba ts'ebeliso e bonahala e ka etsahala. Monyetla oa hore manong a rona a amehang le a amehang mekhoa ea ho ithuta e ke keng ea qheleloa ka thoko. Ho ts'ehetsa liqeto tsa rona, keketseho ea tšebetsong ea ts'ebeliso ea ts'ebeliso ea ts'ebetso kamora ho pepesetsoa ha koae ka molomo (Miles et al., 2004) ho phetoa khang ea hore e kenyelletsa liphetoho tse susumetsang tse lumellanang le bokhoni ba kalafo ea nicotine e sa feleng ho eketsa keketseho ea karabelo ea litoeba (Brunzell et al., 2006). Ntle le moo, litoeba tsa "dopamine transporter", moo litekanyetso tsa dopamine li eketsoang, li bonts'a mesebetsi e ntlafalitsoeng ea ΔFosB le tšusumetso e matla ea lijo, empa ha e fetole ho ithuta.Cagniard et al., 2006). Ho feta moo, re fumane hore ho fetella ha "striatal ΔFosB" litokollong ha ho ame ts'ebetso ha lijo li "felisoa" ka ho fetisoa. Lintlha tsena li bonts'a hore liphoofolo li ne li ela hloko boleng ba khothalletso le hore karabelo e ne e tataisoa.
Ho pepesetsoa lithethefatsi khafetsa ho ka boela ha ntlafatsa taolo ea boits'oaro e fanoang ke maemo a susumetsang a kopantsoeng le li-reinforcers tsa tlhaho, tse lekantsoeng ke mokhoa oa pavlovian (Harmer le Phillips, 1998; Taylor le Jentsch, 2001; Olausson et al., 2003,, e tiisa maemoTaylor le Horger, 1999; Olausson et al., 2004), le phetisetso ea pavlovian-to-instrumental (Wyvell le Berridge, 2001). Hona joale ho na le bopaki bo kholisang ba hore mantlha ea NAc, ho fapana le khetla, e kentse letsoho taolong ea boitšoaro bo susumetsoang ke lithethefatsi ke tšusumetso ea tlhaho ea pavlovia (Parkinson et al., 1999, 2002; Hall et al., 2001; Dalley et al., 2002; Ito et al., 2004). Liphetho tsa rona li kanna tsa fana ka tlhahiso ea hore uctionFosB e khothalletsoang ke lithethefatsi ho NAc e ka ba mokhoa o le mong oo taolo ea boitšoaro e ntlafalitsoeng lits'ebetsong tsena. Hape ho ka etsahala hore tšusumetso ea "pavlovia" e sebetsang e le bathusi ba maemo, e kenya letsoho litlamorao tsa boitšoaro. Matlafatso a taolo ea boits'oaro a susumetsoang ke maemo a joalo a susumetsoang ke keketseho ea ΔFosB le eona e ka kenya letsoho phello ea protheine ho khethoa ke maemo a lithethefatsi (Kelz et al., 1999; Zachariou et al., 2006) le karo-karolelano ea karabelo ea koae (cocaine)Colby et al., 2003). Liphetoho tsa ts'ebetso ea tšusumetso li ntlafalitsoe ho kenya letsoho kholisong le phepelong ea boitšoaro bo tlatsetsang (Robinson le Berridge, 1993; Jentsch le Taylor, 1999; Robbins le Everitt, 1999; Nestler, 2004). Lintlha tsa hona joale li boetse li lumellana le likhopolo tse ling tse hatisang ts'ebetso ea methapo e mengata ea ts'ebetso le pavlovia ka boits'oaro bo bobebe (Everitt le Robbins, 2005). Hona joale ho hlokahala mosebetsi o eketsehileng ho hlalosa karolo ea li-neuroadaptations tsa lithethefatsi le tsa BFosB ho NAc le likarolo tse ling tsa semmuso tse mabapi le likarolo tse ikhethileng tse ka tsamaisang ts'ebetso ea ts'ebetso le ho kenya letsoho boits'ebetsong bo qobelloang.
Leha mekhoa e hlakileng ea limolek'hule e fetohang kahare ho NAc e susumetsa boits'oaro bo khothalletsoang ke basebeletsi ba mantlha kapa ba boemo bo tlase ha e tsejoe (Kelley le Berridge, 2002), li-neurons tsa "GABAergic medium spiny neurons" tsa "Nc li nkoa e le karoloana ea bohlokoa bakeng sa polasetiki e itšetlehileng ka lithethefatsi le boiphihlelo. Mona, ho kenngoa ha dopaminergic ho tsoa sebakeng sa ho kenella ka mokokotlo oa moea le ho kenngoa ha glutamatergic ho tsoa ho li-corticolimbic tse amanang le tsona li fetohela ho li-dendrites le li-spendritic spine tse tloaelehileng. (Sesack le Pickel, 1990; Smith le Bolam, 1990). Ho pepeseha hoa psychostimulant e sa foleng e eketsa letsoalo la methapo e joalo ho li-neuron ka mokokotlong oa NAc le konokono (Robinson le Kolb, 1999; Robinson et al., 2001; Li et al., 2003, 2004). Haufinyane, kenyelletso ea maikutlo a boitšoaro e ne e amahanngoa ka ho khetheha le keketseho ea methapo ea methapo (dendritic spines) kahara motheo oa NAc (Li et al., 2004). Haholo-holo, keketseho e bakoang ke koaeine mokokotlong e ntse e eketseha ho D1Li-neuron tse ntle tse sebetsang coFosB (Robinson le Kolb, 1999; Lee le al., 2006). ΔFosB mokokotlong oa NAc ka hona e ka kenya letsoho ho polasetiki ea synaptic e tsitsitseng e ka bang le tšusumetso ho boits'oaro bo sebetsang. Ka sebele, karolo ea bohlokoa bakeng sa dopamine-glutamate neurotransication (Smith-Roe le Kelley, 2000), protein proteinase shughuliBaldwin et al., 2002a), le "novovo synthesis"Hernandez et al., 2002) kahare ho motheo oa NAc ts'ebetsong ea ts'ebetso ea ts'ebetso e tlalehiloe pele. Ha joale re khetholla ΔFosB e le ntho e ngotsoeng e ka ntlafatsang karabelo e ntlafalitsoeng ea lijo ha o hlakisoa ke mantlha ea NAc. Mefuta kapa liprotheine tse ikhethang tse amehang liphellong tsena li lula li sa hlalosoe hantle. ΔFosB e laola tlhahiso ea liprotheine tse ngata ho NAc tse amehang ho neuroplasticity (McClung le Nestler, 2003). Tlhahlobo ea morao-rao ea microarray e bonts'itse mekhoa ea liphatsa tsa lefutso ho NAc ea litoeba tsa bitransgenic tse hlalosang ΔFosB e sebelisitsoeng mona, mme e bonts'a semmuso sa mefuta e neng e laoloa ke polelo ea nakoana ea ΔFosB (McClung le Nestler, 2003). BDNF e ne e le mofuta o joalo, 'me BDNF potolohong ena ea neural e tsejoa ho ntlafatsa ho arabela bakeng sa lintlha tse amanang le lithethefatsi le lijo (Horger et al., 1999; Grimm et al., 2003; Lu et al., 2004). Mofuta o mong oa phaello ke cyclin-based kinase 5 (Bibb et al., 2001), eo hape e susumetsoang ke ΔFosB, hape e khona ho laola li-polasetiki tse susumetsoang ke koaeNorrholm et al., 2003) khothatso e lekantsoeng ke keketseho e tsoelang pele ea karabelo bakeng sa litlatsetso tsa tlholeho kapa tsa lithethefatsi (JR Taylor, litlhahlobo tse sa phatlalatsoang). E ntse e le likhetho tse eketsehileng ke GluR2 subunit ea AMPA glutamate receptors (Kelz et al., 1999) le "trans factor factor" (NF factor)Ang et al., 2001). Ho ka ba bohlokoa ho hlahloba liprotheine tsena le tse ling tse laoloang maemong a NAc e le likhetho bakeng sa ho ahlola litlamorao tsa boitšoaro ba ΔFosB ts'ebetsong ea ts'ebetso le ts'usumetso.
The tlhahlobo ea hajoale ea liteko e fana ka bopaki ba hore oxpxpression ea ΔFosB ka hara NAc e ka ntlafatsa boits'oaro bo khothalletsoang ke lijo 'me ka tsela eo e laola taolo ea ts'ebetso, joalo ka ha ho kile ha bonts'oa moputso oa lithethefatsi. Lintlha tsena li fana ka bopaki bo bocha ba hore ΔFosB e ka sebetsa e le phetoho e akaretsang ea limolek'hule tse amanang le tlhabollo maemong a hlohlelletsang a khothalletso mabapi le boits'oaro bo lebisitsoeng ho sepheo. Seo re se fumaneng se hlahisa monyetla oa hore ho kenella ha NAc ΔFosB ka mohlala, lithethefatsi tse lemalloang, khatello ea maikutlo, kapa lijo tse nang le moputso o moholo, e ka ba mokhoa o thata oo ka ona lits'ebetso tsa kelello tse sa sebetseng li qetellang li baka mathata a kelello a amanang le boits'oaro bo qobelloang..
Mongolo o botlaaseng ba leqephe
o E amohetse March 15, 2006.
o Phetolelo e amohetse ka June 23, 2006.
o E amohetse August 2, 2006.
Mosebetsi ona o tšehelitsoe ke lithuso tse tsoang Setsing sa Naha sa Tlhekefetso ea Lithethefatsi, Setsi sa Naha sa Bophelo ba Kelello, le Setsi sa Naha sa Tšebeliso e Mpe ea Joala le Tahi. Re leboha ka thabo thuso ea bohlokoa ea Dilja Krueger, Drew Kiraly, Dr. Ralph DiLeone, Robert Sears, le Dr. Jonathan Hommel Lefapheng la Psychiatry, Yale University. Re boetse re leboha Dr. Jennifer Quinn le Dr. Paul Hitchcott ka ho fana ka maikutlo a thusang mabapi le mongolo ona.
Litaba li lokela ho lebisoa ho Jane R. Taylor, Lefapha la Psychiatry, Karolo ea Molekolo oa Mahlale, Sekolo sa Bongaka sa Yale University, Lisebelisoa tsa Patlisiso tsa Ribicoff, Setsi sa Tleliniki ea Connecticut, 34 Park Street, New Haven, CT 06508.[imeile e sirelelitsoe]
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