DeltaFosB e laoloa ka Wheel Running (2002)

LITLHAKU: DeltaFosb ke phetoho ea limolek'hule e bokellanang bokong ka mokhoa o sa feleng oa ho sebelisa lithethefatsi tse nang le lithethefatsi, mafura a mangata, tsoekere e phahameng le lebili le mathang. E fetola boko ho etsa hore maikutlo a ntho efe kapa efe eo motho a e jang haholo. Ke taba ea ho ngola e fetolang le ho tima mefuta e fetolang sebopeho le puisano potolohong ea moputso oa kelello. Qeto: Lintlha li senola ho ts'oana ho ts'oanang lipakeng tsa lithethefatsi tse lemalloang le ho matha ha mabili mme li fana ka maikutlo a bohlokoa ho ΔFosB ho laola meputso ea tlhaho le e khothalletsoang ke lithethefatsi..

The Journal of Neuroscience, 15 September 2002, 22 (18): 8133-8138;

Werme M, Messenger C, Olson L, Gilden L, Thorén P, Nestler EJ, Brené S.

+ Lingoliloeng tsa Sengoli

1. Mafapha a 1 a Neuroscience le

2. 2 Physiology and Pharmacology, Karolinska Institutet, Stockholm, S-171 77 Sweden, le

3. 3 Lefapha la Psychiatry le Setsi sa Neuroscience ea Motheo, Univesithi ea Texas Southwestern Medical Center, Dallas, Texas 75390-9070

inahaneloang

ΔFosB ke ntho e tsoang ho mongolo e bokellanang ka tsela e ikhethileng ea sebaka ka bokong kamora ho lits'oaetso tse sa foleng. Mohlala, taolo e pheta-phetoang ea lithethefatsi tsa tlhekefetso e eketsa maemo a ΔFosB striatum. Thutong e teng hona joale, re hlahlobisitse phello ea ho matha ka lebelo la koloi, joalo ka mohlala oa boits'oaro bo nang le moputso oa tlhaho maemong a ΔFosB libakeng tsa litereke. Ho feta moo, litoeba tse fetelletseng ka mokhoa o sa hlakangFosBka litlatsetso tse ikhethang tsa li-neuron tsa striatal li sebelisitsoe ho ithuta karolo eo ho ka khonehang ea ΔFosB hodima boits'oaro. Lieu e fuoeng ad libitum phihlello ea mabili a 30 d e koahetse se neng se ka tsamaellana le ∼10 km / d mme e bonts'a maemo a eketsehang a ΔFosB bokaholimo ba letsoho bo bapisoa le likhoto tse senotsoeng mabili a tsamaeang. Lintle tse oxpxpressress ΔFosB ka mokhoa o khethehileng li-neuron tse nang le "driorphin" tse nang le li-neuron tse matlafatsang ts'ebetso ea tsona ea letsatsi le leng le le leng ha li bapisoa le batho ba lahliloeng kherehloa, athe litoeba tse tlotsang matla ΔFosB Haholo-holo li-neuron tse nang le li-neuron tse nang le litheko li ile tsa theoha haholo ho feta taolo. Lintlha tse tsoang thutong ea hona joale li bonts'a hore joalo ka lithethefatsi tsa tlhekefetso, ho sebetsa ka boithaopo ho eketsa maemo a ΔFosB litseleng tsa moputso oa boko. Ho feta moo, overexpression ea ΔFosB ka karolo e ikhethileng ea phello ea li-neuronal palo ea baahi e eketsa boitšoaro bo mathang. Hobane mosebetsi o fetileng o bontšitse seoFosB Tlhatlhobo e fetelletseng kahare ho palo ena e ts'oanang ea li-neuronal e eketsa likarolo tse khotsofatsang tsa lithethefatsi tsa tlhekefetso, liphetho tsa lipatlisiso tse teng li fana ka maikutlo a hore ΔFosB e ka bapala karolo ea bohlokoa ho laoleng moputso oa tlhaho le o susumetsoang ke lithethefatsi.

Previous KaroloE 'ngoe Karolo

Selelekela

ΔFosB ke oa lelapa la Fos la lintlha tse hatisitsoeng mme o tsoa ho mofuta oa fosb ka ho sebelisa mantsoe a mefuta. Ho fapana le liprotheine tse ling tsohle tsa Fos, tse nang le halofo e khutšoanyane ea bophelo, 35 le 37 kDa isoforms ea ΔFosB bokella ka tsela e ikhethileng e lebisang bokong ka mora mefuta e mengata ea tšohanyetso, mohlomong ka lebaka la botsitso bo phahameng haholo ba li-isoforms (Tšepo et al., 1994a; Chen le al., 1997; Nestler et al., 1999). Taolo ea ΔFosB libakeng tsa litereke kamora ho buoa khafetsa tsa lithethefatsi tsa tlhekefetso ho ithutoe haholo (Tšepo et al., 1994b; Moratalla et al., 1996; Chen le al., 1997; Nestler et al., 1999). Tsela ea mesolimbic dopamine e na le karolo ea mantlha moputsong oa lithethefatsi (Koob et al., 1998). E simoloha sebakeng se pharalletseng sa 'mele ea bohareng' me se fela karolong e ka hare ea striatum, e bitsoang li-nucleus accumbens. Ts'ebetso e matla ea lithethefatsi leha e le life tse 'maloa tsa tlhekefetso butle-butle e etsa liprotheine tse ngata tsa malapa tsa Fos ka har'a nucleus ea methapo le dorsal striatum. Liprotheine tsena li theha li-heterodimers ka liprotheine tsa lelapa la Jun ho theha activator protein-1 (AP-1) transaction factor complication ka nako e khutšoane ea bophelo. Ka lehlakoreng le leng, kamora kalafo e sa khaotseng ea lithethefatsi, ho kenngoa ha lihlahisoa tsa pele tsa gene hoa fokotseha, mme ho e-na le hoo, ho bokelloa butle-butle ha stable e tsitsitseng ea ΔFosB isoforms. ΔFosB heterodimerizes haholo le JunD le ho isa tekanyong e nyane le JunB (Hiroi et al., 1998; Perez-Otano et al., 1998) ho theha meralo ea AP-1 ea nako e telele libakeng tse itseng tsa boko. Ho reriloe hore li-AP-1 tsena tsa nako e telele li fetole tse ling tsa litlamorao tsa nako e telele tsa lithethefatsi tsa tlhekefetso litseleng tsa moputso oa boko tse tlatsetsoang ho tsona.Nestler et al., 2001).

Lithuto tsa boitšoaro li bontša hore ho tsamaea ka mabili ho litoeba hoa putsa. Mohopolo ona o ipapisitse le liteko tse bonts'ang mochini o hatisang likhoto bakeng sa phihlello ea mabelo mme o ntšetsa pele maemo a ratang tikoloho e amanang le sephetho sa mabili a mathang (Iversen, 1993; Belke, 1997; Lett et al., 2000). Ho feta moo, likhoto tse tsamaeang maeto a malelele letsatsi le leng le le leng li bonts'a lipontšo tsa ho khaola, joalo ka ho eketseha ha mabifi, ha ho hanoa ho fihlella mabili a mathang (Hoffmann et al., 1987). Lipatlisiso pakeng tsa limathi tsa batho tse ikemiselitseng haholo li bonts'a hore ho matha ke mokhoa o lemalloang ho batho ba bangata (Rudy le Estok, 1989; Chapman le De Castro, 1990; Furst le Germone, 1993). Ho joalo, ho tsamaisoa ho bonts'a mekhoa e mengata e kenyelelitsoeng ho Diagnostic Statistical Manual (Mokhatlo oa Mahlale oa Amerika, 1994) bakeng sa tlhahlobo ea bokhoba ba tahi.

Morero oa thuto e teng hona joale e ne e le ho etsa lipatlisiso hore na maemo a Δ aFosB e fetoloa ke boitšoaro bo botle ba tlhaho bo kang ho matha le hore na o qoqoa ka mokhoa o sa hlaloseheng oa ΔFosBlibakeng tsa litereke li ka laola boitšoaro bo tsamaeang. Re bontša mona hore, joalo ka lithethefatsi tsa tlhekefetso, kalafo e sa foleng e kenang ucFosB ka har'a li-nucleus accumbens; ka ntle ho moo, overexpression ea ΔFosB ka har'a li-subset tse peli tse fapaneng tsa li-striatal projene neurons li na le litlamorao tse fapaneng le ho matha ha wheel. Lintlha li senola ho ts'oana ho ts'oanang lipakeng tsa lithethefatsi tse lemalloang le ho matha ha mabili mme li supa karolo ea bohlokoa bakeng sa ΔFosB taolong ea meputso ea tlhaho le ea lithethefatsi.

Karolo e fetilengKarolo e latelang

LISEBELISOA LE MEKHOA

Liphoofolo. Male Lewis rats (Setsi sa Tsoalo ea Møllegaard, Skansved, Denmark) tse boima ba 250 gm qalong ea liteko li ile tsa sebelisoa. Likhoto li ne li fumaneha ad libitum ho metsi, lijo le mabili a matha. Ba ne ba le lebollong la 12 hr leseli / lefifi, le mabone ho 10 AM mme mabone a tima ho CNUMX PM Cages (10 × 43 × 22 cm) e ne e na le lebili le tsamayang le bophara ba 20 cm; kahoo, phetoho e le 'ngoe e lumellanang le 34 m. Kamora libeke tsa 1.07 tsa ho tsamaea ka mabili a boithatelo, likhoto li ile tsa bolaoa ka ho sesa, 'me lithapo tsa nkuoa bakeng sa ho thibeloa kapa ho tlotsoa ka moriana mme tsa sebetsoa bakeng sa immunohistochemistry le in situnyallelloa.

Mela e 'meli ea litoeba tsa bitransgenic tse ka fetisang mokhoa o tebileng oa vereFosB ka mokhoa o ikhethileng libakeng tse nang le taolo tlasa taolo ea kemiso ea liphatsa tsa lefutso le tsona li ile tsa sebelisoa (Chen le al., 1998). Moleng o le mong, o bitsoang 11A, ΔFosB e hohliloe ka mokhoa o sa hlakeheng ho li-neuron tsa "striatal proion" tsa "neuropeptide dynorphin" kamora ho tlosoa ha doxycycline (Kelz et al., 1999). Moleng o mong o bitsoang 11B, ΔFosB e hohliloe ka mokhoa o sa hlakeheng ho li-neuron tsa provenatal proionat tse hlalosang neuropeptide enkephalin kamora ho tlosoa ha doxycycline, leha polelo e itseng e bonoa ho li-neurons tsa dynorphin. Tsamaiso le ΔFosBLi-litoeba -verexpressing ke litterling kahare ho mola o mong le o mong (11A le 11B) mme li na le mofuta o tšoanang oa kaho oa li-bitransgenic, o ka qalisoang ka ho tlosa doxycycline. Litoeba tsohle li ile tsa emoloa tsa ba tsa holisoa ka letheba la tetracycline derivative doxycycline ka tekanyetso ea 100 μg / ml metsing a nooang. Ha e se e le batho ba baholo, halofo e le ngoe ea lithaole tse hlahisitsoeng e ile ea bolokoa ho doxycycline (taolo); halofo e 'ngoe e ne e tlositsoe doxycycline (ΔFosB oxpxpressers) bakeng sa liteko tse ling kaofela. Libeke tse ts'eletseng kamora ho tlosoa ha doxycycline, ka nako efe ΔFosB polelo e tsejoa e le boholo bo phahameng (Chen le al., 1998; Kelz et al., 1999), mabili a neng a matha a ile a buleloa litoeba ka bobeli ka tetracycline (li-control) le litoeba metsing a pompo (ΔFosB bahlahisi ba bangata), le ho qala ho ithaopa ho qalile. Ho ahlola menyetla ea hore Doxycycline ka boeona e amme boitšoaro ba mabili, re ile ra sekaseka likoloi tse tsamaeang ka litoeba tsa C57BL / 6 (Charles River, Uppsala, Sweden) ka kalafo ea 100 μg / ml doxycycline bakeng sa libeke tsa 6 pele ba lumelloa ho fihlella mabili. Joale litoeba li ne li kenngoa ka mekotleng le ad libitum phihlello ea mabili a tsamaeang mme o lutse ho tetracycline nakong ea liteko tsohle. Sehlopha sa taolo se ile sa fumana metsi a nooang a tloaelehileng nakong ea tlhahlobo eohle. Li-cage tsa mouse (22 × 16 × 14 cm) e ne e na le lebili le tsamayang le bophara ba 12.4 cm; kahoo, phetoho e le 'ngoe e lumellanang le 0.39 m. Lintlha tse tsamaeang ho tsoa ho likhoto le litoeba li ne li nkuoa metsotso e meng le e meng ea 30 li sebelisa software e etselitsoeng likhomphutha.

Ho koala bophirima. Masapo a tlositsoeng kapele a ne a tsoa litlamong tse litšila a ba a chesoa ke serame sa 'mele. Li-punches tse nang le bophara ba 2 mm li ne li sebelisetsoa ho etsa sampole ea lisele tse tsoang mothong o bokellaneng le litsoeng tsa moea tsa morao-rao le tsa morao-rao tsa 1-mm-thick-coronal ka tekanyo ea bregma 0.7-1.7 mm (Paxinos le Watson, 1997). Mehlala ea brain e ile ea homogenized ho 1% SDS, mme liqeto tsa liprotheine li entsoe ka mokhoa oa Lowry. Li-Homogenates tse nang le lipakeng tsa 5 le 50 μg tsa protheine li ile tsa kenngoa ho li-gels tsa SDS-polyacrylamide mme li kenngoa ka har'a electrophoresis joalo ka ha ho hlalositsoe. Anti-anti-Fos antibody (1: 4000; MJ Iadarola, National Institutes of Health, Bethesda, MD) kapa anti-FosB (N-terminal) antibody (1: 4000; Santa Cruz Biotechnology, Santa Cruz, CA) e sebeliselitsoe ho lemoha ha ΔFosB. Liprotheine li fumanoe li sebelisa li-antibodies tsa Igeradish peroxidase-conjugated (1: 2000; Vector Laboratories, Burlingame, CA) e lateloe ke chemiluminescence (DuPont NEN, Boston, MA). Maemo a thibelo ea bokhachane (IR) a ne a hlakotsoe ho sistimi ea litšoantšo e thehiloeng ho Macintosh, 'me maemo a liprotheine a mehlala ea liteko a ne a bapisoa le a taolo. Liroto li ne li entsoe ka lehare le letšo ho netefatsa ho laolla le phetisetso ea lijusi. Li-blots li ne li boetse li immunolabeled bakeng sa 68 kDa neurofilament protein, e sa kang ea bonts'a phapang lipakeng tsa lihlopha tsa liteko le taolo (data e sa bonts'itsoeng).

Immunohistochemistry. Likhoto tsa Lewis tse neng li se li qetile libeke tsa 4 le li-taolo tse nang le mabili a notletsoeng li ne li sa anngoe ka ho teba ka pentobarbital mme li entsoe ka mokhoa o ikhethileng ka 50 ml ea Ca2+Tharollo ea mahala ea Tyrode (mocheso oa kamore) ho kenyelletsa le 0.1 ml ea heparin. Sena se ile sa lateloa ke 250 ml ea fixative (4% paraformaldehyde le 0.4% picric acid ho 0.16m PBS, pH 7.4, mocheso oa kamore). Boko bo ile ba aroloa 'me ba bolokoa bo lokisoa bakeng sa hora e le' ngoe 'me ba hlatsoa ka 1m PBS ka 0.1% sucrose le 10% ea sodium azide makhetlo a' maloa ho feta 0.1 hr ho 24 ° C bakeng sa ts'ireletso. Boko bo ne bo hoamme, mme likarolo tsa 4 μm coronal li ile tsa bokelloa maemong a pakeng tsa bregma 14 le 0.70 mm. Likarolo li hlatsoitsoe makhetlo a mararo bakeng sa 1.70 min ho PBS pele ho tsubella bosiu bo le bong (10 ° C ka phapusing ea mongobo) ka lesole la mmele la mantlha la anti-FosB (N-terminal) (4: 1; Santa Cruz Biotechnology) ho 500% Triton-PBS (0.3 μl ka karolo). Sena se ile sa lateloa ke li-rinses tse tharo tse nang le PBS bakeng sa 150 min pele ho kenella bakeng sa 10 hr mocheso oa kamore le anti-mmutla oa anti-mmutla oa IgG (1: 1; Vector Laboratories) ho 200% Triton-PBS (0.3 μl ka sekhahla). Li-rinses tse ling tse tharo ho PBS bakeng sa 150 min li entsoe pele mochini oa avidin-biotin o eketsoa (10: 1 le 100: 1, ka ho latellana, ho 100 m PBS; 0.1 μl ka karolo). Kamora ho hlatsoa metsotso e meraro ea 150 min, moaho o ile oa bonoa kamora ho emisoa ha 10 min le substrate ho latela protocol ea moetsi (Vector Laboratories). Likarolo li ile tsa hlatsuoa makhetlo a mararo bakeng sa metsotso e 7.

a situ nyallelloa. Bakeng sa immunohistochemistry lein situ liteko tsa hybridization, likarolo tsa boko tse neng li sebetsitsoe bakeng sa immunohistochemistry li ile tsa kenngoa hang-hangin situ hybridization, e ileng ea etsoa hantle joalo ka ha ho hlalositsoe pele (Seroogy et al., 1989; Dagerlind et al., 1992). Li-oligonucleotide tse mashome a mane a metso e robeli tsa li-oligonucleotide e ikhethang dynorphin (296-345) (Douglass et al., 1989) le enkephalin (235-282) (Zurawski et al., 1986) li-mRNA li ne li ngotsoe ka seea-le-moea ka [cy-35S] dATP (DuPont NEN) ho 3 ′ ea bona e sebelisa terminal deoxynucleotidyl transferase (Attitrogen, San Diego, CA) ketsahalong e itseng ea ∼1 × 109 cpm / mg. Lebenkele la lebasetere le ne le na le 50% formamide, 4 × SSC (1 × SSC ke 0.15m NaCl le 0.015 sodium citrate, pH 7.0), tharollo ea 1 × Denhardt, 1% sarcosyl, 0.02 mNa3PO4, pH 7.0, 10% dextran sulfate, 0.06 m dithiothreitol, le 0.1 mg / ml sheared salmon sperm DNA. Hybridization e ile ea etsetsoa 18 hr ka phapusing e le mongobo ho 42 ° C. Kamora ho nyalisoa, likarolo li ile tsa hlakoloa makhetlo a mane bakeng sa 20 min e 'ngoe le e ngoe ho 1 × SSC ho 60 ° C. Kamora moo, likarolo tseo li ile tsa tšeloa ka metsing a iketlileng bakeng sa 10 sec, a tšeloa metsi a nooang hape a omisitsoe ke moea. Kamora nako, NTB2 track track emulsion (e kentsoeng 1: 1 ka metsi; Kodak, Rochester, NY) e ile ea kenngoa ka ho tšela. Kamora ho qeta libeke tsa 2-4, li-slide li ntlafalitsoe le D19 (Kodak) mme li hlophisitsoe le Unifix (Kodak).

Lipalo tsa lisele tse nang le FosB-IR le lisele li colocalizing FosB-IR le dynorphin mRNA kapa enkephalin mRNA ka likhoto kamora libeke tsa 4 tsa ho matha (n = 8) le lits'ebetsong (n = 8) li ne li etsoa ka slide e le 'ngoe ka phoofolo ke bashebelli ba ikemetseng ba foufalitseng sebopeho sa liteko. Ts'ebetso e entsoe ho boemo ba bregma 1.2 mm (Paxinos le Watson, 1997).

Tsamaiso ea lipalo. Ho sekaseka phapang ho ΔFosB maemo lipakeng tsa taolo le limathi ho liteko tsa Bosholu le boits'oaro ba bohloeki, t liteko li entsoe. Liphello tsa ho tlola ho feteletseng ha ΔFosB mabapi le boitšoaro bo tsamaeang ho litoeba tsa transgenic ho ile ha hlahlojoa ho sebelisoa ANOVA e habeli ka litekanyo tse phetoang, ho sekasekwa kahare ho sehlopha le liphetho tsa lipakeng tsa sehlopha (Statistica version 99; StatSoft, Tulsa, OK).

Karolo e fetilengKarolo e latelang

LIPOTSO

Taolo ea ΔFosB ho liqhubu tsa maqhubu ka lebelo la mokokotlo

Lirats e kentsoeng mabokoseng a nang le mabili a matha e eketsehile palo ea eona ea letsatsi le letsatsi e tsamaeang ka tatellano ho fihlela ka letsatsi la 13, ha e tsitsa ho 10.210 ± 590 m / d (bolela ± SEM). Boemo bona bo ile ba bolokoa hantle nakong ea 32 ea letsatsi, ha liphoofolo li ne li sebelisetsoa tlhahlobo ea biochemical. Nakong ea 4 d ea ho qetela, likhoto li ile tsa matha 8.910 ± 900 m / d. Boitšoaro bona bo tsamaeang ho likhoto tsa Lewis bo ts'oana le bo bonoang pele (Werme et al., 1999). Kamora moo, maemo a ΔFosB li ile tsa hlahlojoa ke ho fifala ha Bophirimela ho li-nucleus bokellanong le litlamong tsa morusu le tsa morao-rao tsa caudate ho sebetsa (n = 7) le taolo (n = 7) likhoto. Joalokaha ho bontšitsoe Setšoantšong 1, lebelo la mokokotlo le eketsehile ΔFosB maemo a 37 le 35 kDa isoforms ho li-nucleus accumbens (p <0.05). Ka lehlakoreng le leng, ho ne ho se na phapang ho ΔFosB maemo lipakeng tsa limathi le taolo ho medam kapa tsa morao-rao caudate putamen (ya data ha e bontšoe).

Setšoantšo sa 1.

Sheba tlhahiso e kholoanyane:

Setšoantšo sa 1.

Taolo ea ΔFosB ka wheel wheel. Maemo a li-isoforms tsa 35-37 kDa ea ΔFosB li ne li lekantsoe ka har'a li-nucleus tse bokelletsoeng li sebelisa blotting ea Bophirimela ho litoeba tsa taolo (C) le likotong tse tsamaeang le libeke tsa 4 libeke tse tsamaeang ka boikhethelo (R). Top, Moemeli litselana ho tloha lithunthung. Lintlha li hlahisitsoe joalo ka S mean SEM (lihlopha ka bobeli, n = 7). *p <0.05.

Immunohistochemistry e senotse boteng ba ΔFosB- Lisele tse bokellaneng ka har'a li-nucleus li bokellana ka taolo (n = 8) hape ea sebetsa (n = 8) likhoto. Liphetho tsa ΔFosB- Lisele tse sebetsang hantle ka ho fetisisa mokokotlong le khetla li senotse keketseho ea palo ea lisele tse hlalosang ΔFosB-IR ka sehlohlolong (p <0.05) empa eseng ka har'a khetla ea li-nucleus accumbens kamora ho sebetsa (sa feiga.2). Li-immunohistochemistry tse kopaneng tsa ΔFosB-IR le in situ hybridization ea enkephalin kapa dynorphin mRNA bokong ba li-nucleus bo ile ba sebelisoa hamorao ho supa mofuta oa sele kahare ho sebaka sena sa boko moo ΔFosB e susumetsoa ke ho matha (sa feiga.3). Ha palo ea lisele tse bontšang dynorphin mRNA le FosB-IR e ne e phahame ho limathi.n = 8) ho feta ho li-control (n = 8) (Lethathamo1), palo ea lisele tse hlalosang li-enkephalin mRNA le FosB-IR ka limathi li ne li le tlase ho feta litulong (Lethathamo 1). Litlamorao tsena li ne li bonahala kahare ho karohano ea mantlha ea sebaka sena sa boko (Tafole 1). Liphetho tsena li bonts'a hore induction ea ofFosB ka ho matha ho etsahala hangata ho dynorphin e nang le karolo e ka tlase ea li-nucleus e bokellang li-neuron.

Setšoantšo sa 2.

Sheba tlhahiso e kholoanyane:

Setšoantšo sa 2.

Ho matha ha Wheel ho ama palo ea ΔFosB- Lisele tse bokellaneng ka har'a li-nucleus li bokellana.Top, Lifoto tse emelang likarolo tsa boko ba rat li bonts'a keketseho ea palo ea ΔFosB- Lisele tse bohlokoa tse ka har'a khubu li bokellanang boteng ha limathi ((Matha) li bapisoa le taolo (Ctr). aca, Ntlafatso ea kahare ea kahare.Bottom, Bar graph ea lipalo tsa lisele tse ntle bakeng sa ΔFosB-IR ka likarolo tsa medial tsa mantlha le khetla ea li-nucleus e bokellana ho likhoto le ho litoeba tse tsamaeang le libeke tsa 4 tsa wheelchair tse tsamaeang. Lintlha li hlahisitsoe joalo ka S mean SEM (lihlopha ka bobeli, n = 8). *p <0.05.

Setšoantšo sa 3.

Sheba tlhahiso e kholoanyane:

Setšoantšo sa 3.

Ho tsebahala ha selefouno ka ΔFosBho kenyelletsoa ke wheel wheel. Lifoto tse emelang likarolo tsa boko ba rat ho tsoa ho batho ba robeli ba bonts'a colocalization ea ΔFosB-IR (soene e nang le 'mala o sootho) le dynorphin mRNA (lijo-thollo tse ntšo) (a) kapa ΔFosB-IR le enkephalin mRNA ho konokono e bokellanang (b).

Sheba tafole ena:

Tafole 1.

ΔFosB liseleng tsa dynorphin le enkephalin tse bokellaneng ea li-nucleus

Kameho ea ΔFosB ka wheel wheel

Ho ithuta karolo e ka khonehang ea ΔFosB taolong ea lebili le tsamaeang, re sebelisitse mela e 'meli ea litoeba tsa bitransgenic tse orexpress overexpress ΔFosB kahare ho liphoofolo tse kholo (Chen le al., 1998; Kelz et al., 1999). Mohala oa 11A oa bitransgenic o ka ba boima bo fetelletseng ba ΔFosB feela kahare ho li-neuron tse nang le dynorphin e nang le striatum (Kelz et al., 1999), athe mohala oa "11B" oa bitransgenic o ka feta tekanyo e fetisisangFosB Haholo-holo ka har'a li-neuron tse nang le enkephalin sebakeng sena, ka polelo e 'ngoe e bonoang ho li-neurons tsa dynorphin hape (sa feiga. 4). Ka bobeli mela e ne e emisitsoe le ho holisoa holima Doxycycline ho boloka ΔFosBpolelo e felile (sa feiga. 4) (Kelz et al., 1999), 'me halofo e le' ngoe ea barekisi ba ile ba tlosoa doxycycline e le batho ba baholo ho bulela ΔFosB polelo.

Setšoantšo sa 4.

Sheba tlhahiso e kholoanyane:

Setšoantšo sa 4.

Pontšo ea ΔFosB ka litoeba tsa 11B. Likarolo tsa bongo li ile tsa hlahlojoa bakeng sa ΔFosB-IR (nko e nang le 'mala o sootho) e lateloa ke in situ halemi bakeng sa dynorphin mRNA (A) kapa enkephalin mRNA (B) (lijo-thollo tse ntšo). Ela hloko polelo e khethollang ea ΔFosB-IR ka har'a enkephalin-positive empa eseng lisele tse ntle tsa dynorphin. Ea 214 ΔFosBLisele tse 'nileng tsa baloa ho litoeba tse tharo tsa 11B, 73 ± 11% le tsona li ne li le enkephalin ntle,' me 22 ± 6% le tsona li ne li le dynorphin ntle. Ha ho mabitso a habeli a bonoeng pakeng tsa ΔFosB le matšoao a mahareng a litaba.

11A litoeba tse overexpress ΔFosB (ha ho na doxycycline) (n = 7) li fumanoe li eketsa sebaka sa tsona sa ho matha ka ho fetisa libeke tsa 3 tsa pele ha li bapisoa le taolo ea littermate (e fuoeng doxycycline) (n = 8), e bonts'itseng sehlaba se maemong a bona a ho matha kamora libeke tsa 2 (sa feiga.5 A). Ka lehlakoreng le fapaneng, litoeba tsa 11B tse ileng tsa hatella ΔFosB (n = 7) e bonts'itse ts'ebetso e fokolang haholo nakong ea libeke tsa 2 le 3 ho feta taolo ea littermate tsa bona (n = 6) (sa feiga. 5 B). Ho etsa lipatlisiso ka taba ea hore na doxycycline ka boeona e ka fetola tsela eo u tsamaeang ka eona, re bapisitse lebelo la lintja tsa C57BL / 6 lithaelese tsa bona tsa metsi a nooang. Ha ho phapano lipakeng tsa lihlopha tse fumanoeng (ya data ha e bontšoe).

Setšoantšo sa 5.

Sheba tlhahiso e kholoanyane:

Setšoantšo sa 5.

Kameho ea ΔFosB overexpression mabapi le ho tsamaea ha mabili ho litoeba tsa bitransgenic. A, Metsi a pompo ea litoeba tsa Bitransgenic a na le tšenyo e fetelletseng ea ΔFosB ka striatal dynorphin neurons (metsi) mme e bonts'a ho eketseha hoa ho matha (sebaka ka letsatsi) bakeng sa libeke tsa 3 tsa pele tsa phihlello ea mabili. Ho fapana le hoo, liphatsa tsa lefutso tse tšoanang ka lefutso li na le Doxycycline metsing a tsona a nooang tse sa feteleng ΔFosB (Dox) e bonts'itse ho eketseha ha libeke tsa 2 tsa pele feela. B, Mohala o mong oa khatello ea litoeba tsa bitransgenic, e bitsoang 11B, e nang le tšenyo e fetelletseng ea ΔFosB haholo-holo ka striatal enkephalin neurons (metsi) e bonts'e ha e sebetse haholo nakong ea libeke tsa bona 2 le 3 bapisoa le lipalo tse ts'oanang le liphatsa tsa lefutso tse sa amaneng Δ ΔFosB (Dox). # e bonts'a keketseho ea ho matha (sebaka ka beke) ka har'a sehlopha. * e bontša phapano ea ho matha pakeng tsa ΔFosBbahatisi (metsi) le taolo (Dox). Mehala e otlolohileng supa meeli pakeng tsa libeke tsa 1 le 2, hammoho le libeke tsa 2 le 3. Mehala e otlolohileng le lets'oao la # hlalosa phapang lipalo lipakeng tsa beke le beke har'a sehlopha. Lintlha li hlahisitsoe e le tse mpe (11A dox,n = 8; 11A metsi, n = 7; 11B dox, n = 6; 11B metsi, n = 7).# p <0.05;## p <0.01;### p <0.001; *p<0.05.

Karolo e fetilengKarolo e latelang

TŠOHLOA

Thutong ena, re bonts'a hore ho pepesehela lithethefatsi tsa tlhekefetso, ho matha lebili le sa feleng, mokhoa o atlehileng oa tlhaho, ho hohelang.FosB bokong ba li-nucleus, karolo ea bohlokoa ea meputso ea kelello. Re boetse re bonts'a hore overexpression ea ΔFosB ka striatal dynorphin neurons ea liphoofolo tsa batho ba baholo e eketsa boitsoaro bo tsamaeang, athe ΔFosB polelo haholo-holo ka striatal enkephalin neurons e na le litlamorao tse fapaneng. Lintlha tsena li tšehetsa pono e thatFosB e nka karolo ka botebo litlamorao tsa nako e telele tsa meputso ea tlhaho le lithethefatsi ebile e hatisa karolo ea bohlokoa ea ΔFosB taolong ea ts'ebetso ea striatal.

Likarabo tse tšoanang tsa limolek'hule lithethefatsing tsa tlhekefetso le tse mathang

Lithethefatsi tsa tlhekefetso tse fapaneng joaloka psychostimulants, opiates, joala, nicotine le phencyclidine e eketsa maemo a ΔFosB ho bokellane (Tšepo et al., 1994b; Nye et al., 1995; Nye le Nestler, 1996; Nestler et al., 1999), mme mona re bonts'a hore boitsoaro bo sa foleng bo tsamaeang le karabelo e tšoanang. Cocaine e sa foleng le ho tsamaisa phetoho e tloaelehileng e tloaelehileng, mohlala, ho kenyelletsa dynorphin mRNA libakeng tse ling tsa striatum (Werme et al., 2000). Joalokaha ho hlokometsoe pejana bakeng sa koae (Hiroi et al., 1997), tlhahiso ea ΔFosB ka ho matha ho na le matla bohareng ho feta karohanong ea khetla ea li-nucleus. Leha ho le joalo, ΔFosBho kenella ka ho matha ho lekantsoe ho li-nucleus accumbens, athe lithethefatsi tsa tlhekefetso li kenya protheine ho caudate putamen hape. Lithuto tse fetileng li bontšitse hore ΔFosB e hlahisoa feela ka li-neuron tsa proionatum, le hore cocaine e sa foleng e eketsa ΔFosB ka ho khetheha ho kenella ts'ebetsong ea li-neuron tsa projeke tse bontšang dynorphin (Moratalla et al., 1996). Thutong ea hona joale, ka tšebeliso ea li-immunohistochemistry lein situ lebasetere ka likarolo tse tšoanang tsa lithane, re bonts'a hore wheel wheel also induces ΔFosB ka ho khetheha ka har'a li-neuron tsa dynorphin.

Ho fumana hore moputso oa lithethefatsi le moputso oa tlhaho ho etsa hore le molek'hule e tšoanang e sebetse hantleFosB) kahare ho mofuta o tšoanang oa sele ea neuronal o fana ka maikutlo a hore bobeli ba bona bo ka sebetsa ka mochine o mong o tloaelehileng. Mokhoa o mong o tloaelehileng o hlakileng ke ho fetisetsa dopaminergic phepong ea li-nucleus. Ts'ebetso ea mathang le e matla ea lithethefatsi tse tlatsetsang e eketsa litekanyetso tsa extracellular tsa dopamine sebakeng sena sa boko (Ho lokolotsoe le Yamamoto, 1985; Di Chiara le Imperato, 1988; Wilson le Marsden, 1995). Pheta khafetsa le D1 dopamine receptor agonist (+/−) - 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin hydrobromide e le 'ngoe kapa e kopane le D2 receptor agonist quinpirole e tla eketsa maemo a ΔFosB ka har'a nucleus bokellaneng le dorsal striatum (Nye et al., 1995). Lithethefatsi tse lemalloang ke Psychostimulant tse kang cocaine le amphetamine, tse seng ka ho toba dopamine agonists le tsona li eketsa ΔFosB maemo maemong a litereke (Jaber et al., 1995; Nye et al., 1995). Ntle le moo, tsamaiso e sa fetoheng ea "dopamine transporter antagonist" 1- [2- (bis [4-fluorophenyl] methoxy) ethyl] -4- (3-hydroxy-3-phenylpropyl) piperazinyl decanoate li-inhibitors tse khethiloeng, induces ΔFosB libakeng tsena tsa boko (Nye et al., 1995). Liphumano tsena li bonts'a tlhahiso ea ΔFosB ho striatum ka mor'a kalafo e fapaneng e itšetlehileng ka dopamine.

Liphetoho tse hanyetsanang tsa ΔFosB overexpression ho drioral dynorphin bapisoa le enkephalin neurons ka boits'oaro bo matha ka lebelo

Litoeba tsa bitransgenic le ΔFosB Tlhatlhobo e tebileng e bakoang ke ho tlosoa ha doxycycline ho liphoofolo tse kholo ha e bonts'e litlatsetso tse kholo tsa tlhabollo. Ho litoeba moo ΔFosBoverexpression e khetha li-neurons tsa "striatal dynorphin", boitšoaro bo tsamaeang bo eketsehile nakong ea libeke tsa 3 tsa pele tsa ho matha, sebakeng sa libeke tsa 2 tsa pele joalo ka ha li bonoa bakeng sa barekisi ba litter. Ka lehlakoreng le leng, litoeba li feta tekanyo ΔFosB Haholo-holo ka har'a li-neuron tsa striatal enkephalin neurons li ne li sa sebetse haholo ho feta li -terterter tsa bona tsa taolo nakong ea libeke tsa 2 le 3 ea ho sebetsa. Ho khahlisang, mela e 'meli ea litoeba tsa bitransgenic tse ithutoang mona le tsona li bontša likarabelo tse fapaneng tsa boitšoaro ho lithethefatsi tsa tlhekefetso. Athe oxpxpression ea ΔFosB ho dynorphin neurons e eketsa litholoana tse matlafatsang tsa koae le morphine (Kelz et al., 1999; Nestler et al., 2001), overexpression ea ΔFosB Haholo-holo ka har'a li-neuron tsa enkephalin ha e fetole melemo ea lithethefatsi tsena.

Litlamorao tse fapaneng tsa boitšoaro bo mathang tse bonoang mefuteng e 'meli ea litoeba li ka hlalosoa ke karohano e fapaneng ea likarolo tse peli tse ikhethileng tsa li-neuron tsa striatal. Ho feta 90% ea li-neuron tsa "striatal neurons" ke li-neurone tsa "medium spiny" tse sebelisang GABA joalo ka neurotransmitter. Hoo e ka bang halofo e le 'ngoe ea li-neuron tsena le tsona li bontša maemo a phahameng a dynorphin le ntho P (le ho isa boholeng bo itseng D1 dopamine receptor)Gerfen et al., 1990; Le Moine et al., 1991) le projeke ka kotlolloho ho mokhachane. Halofo e 'ngoe e bontša maemo a phahameng a enkephalin (le D2dopamine receptor)Gerfen et al., 1990; Le Moine et al., 1990) le ho its'oara ka kotlolloho bohareng ba "midbrain" ka "globus pallidus" le subthalamic nucleus. Ts'ebetso ea tsela e otlolohileng e eketsa ts'oarelo, athe ts'ebetso ea tsela e sa tobang e fokotseha ha pina. Kahoo, liphetoho tse khutlisetsang ts'ebetsong tsa boitšoaro tse bonts'itsoeng ke mela e 'meli ea ΔFosBLisebelisoa tse fetotsang kelello tse sebelisoang litekong tsena li ka supa ΔFosBLiphetoho tse fetotsoeng ho thabo ea tsela e ikhethileng khahlanong le tsela e sa tsejoeng. Mabapi le mela ena, hoa thabisa ho hakanya hore phokotseho ea lebelo la mabili le bonoang ho litoeba tse feteletseng tsa iceFosB Haholo-holo ka enkephalin neurons e kanna ea lumellana le taba ea hore lithethefatsi tsa "antipsychotic" tsa pele, tse fokotsang ts'ebetso ea locomotor, induct ΔFosB ka mokhoa o ikhethileng onaHiroi le Graybiel, 1996; Atkins et al., 1999).

Mefuta ea sepheo e laoloang ke ΔFosB

Litlamorao tsa ΔFosB tšebetso ea methapo ea methapo ea methapo e ka hokahanngoa ka taelo ea liphatsa tse ling tsa lefutso. Ka lebaka la hore mefuta e mengata e na le libaka tsa tumellano ea li-complexes tsa AP-1 libakeng tsa bona tsa papatso, ho ka etsahala hore ketso tsa ΔFosB ho methapo ea kutlo e kenyelletsa mathata a mefuta e mengata. Ke ba seng bakae feela ba khethiloeng ho tla fihlela joale. AMPA glutamate receptor subunit 2 (GluR2) e ngolisitsoe ka ΔFosB ka har'a li-nucleus bokellitsoeng, phello e sa bonoeng ho dorsal striatum (Kelz et al., 1999). Cyclin e itšetlehileng ka kinase 5 (Cdk5) e ngolisitsoe ka bobeli ka har'a li-nucleus accumbens le dorsal striatum (Bibb et al., 2001). Litlamorao tsena li ka kopanngoa ka libaka tsa AP-1 tse teng libakeng tsa lipapatso tsa mefuta ena (Brene et al., 2000; Chen le al., 2000). Taolo ea GluR2 e ka lebelloa ho fetola thabo ea motlakase ea li-neuron tsa striatal ka ho fetola kutlo ea bona ea AMPA receptor. Taolo ea Cdk5 e ka boela ea fetola thabo ea li-neurons tsena ka tsela e kenyelletsang dopamine le phofo e laoloang ke cAMP-phosphoprotein-32, e matlafalitsoeng haholo har'a li-neuron tsa "spriatal medium spiny neurons"Brene et al., 1994; Bibb et al., 1999). Leha ho le joalo, ho hlokahala mosebetsi o eketsehileng ho tseba mekhoa e nepahetseng ea limolek'hule ka eonaFosB, ka liphetoho phetohong ea liphatsa tse ling tsa lefutso, e fetola boemo bo sebetsang ba dynorphin le enkephalin neurons.

Nahanisisa

Liphumano tsa hore liphetoho tse tšoanang tsa limolek'hule li etsahala ka har'a li-nucleus tse bokellaneng maemong a moputso oa tlhaho le o khothalletsoang ke lithethefatsi li bontša hore mekhoa e tloaelehileng ea neurobiological e ka laola mefuta e 'meli ea boits'oaro bo atlehileng. Ntho e 'ngoe e tšoanang lipakeng tsa boitšoaro bona ke bokhoba ba bona ba ho lemalla. ΔFosB e ts'oaroa ke boits'oaro ka bobeli mme e ntlafatsa boits'oaro ka bobeli ha e ikemetse ka mokhoa o ikemetseng ho li-neurons tsa "driorphin neurons". Mohlomong ΔFosB, ha e hlahisoa ka li-neuron tsena, e lemoha potoloho ea neural e amanang le boits'oaro bo qobelloang. Leha e le monahano, tsebo e ntseng e eketseha ka ΔFosB e fana ka maikutlo a hore, kapa mekhoa e fapa-fapaneng ea limolek'hule eo e e laolang, e ka ba sepheo se nepahetseng bakeng sa nts'etsopele ea meriana ea meriana bakeng sa mafu a fapaneng. Mehlala ea tsena e ka ba boitshwaro bo qobelloang, ho kenyelletsa eseng feela lithethefatsi tsa lithethefatsi empa hape le mathata a ho ja, ho becha ka methapo, ho ikoetlisa ka mokhoa o feteletseng, mme mohlomong le bothata bo fetelletseng.

Karolo e fetilengKarolo e latelang

Mongolo o botlaaseng ba leqephe

  • E amohetse January 29, 2002.
  • Phetolelo e amohetse ka June 11, 2002.
  • E amohetse June 12, 2002.
  • Mosebetsi ona o tšehelitsoe ke Lekhotla la Lipatlisiso la Sweden (03185, 11642, le 04762), Centrum för idrottsforskning (CIF 86 / 01), National Institute on Drug Abuse, le Mokhatlo oa Sechaba oa Botsofali. Re leboha Karin Pernold le Karin Lundströmer ka thuso e ntle ea thekniki.
  • Litaba li lokela ho lebisoa ho Stefan Brené, Lefapha la Neuroscience, Karolinska Institutet, Stockholm, S-171 77 Sweden. Lengolo-tsoibila: [imeile e sirelelitsoe].
  • Copyright © 2002 Mokhatlo oa Neuroscience

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