DeltaFosB Ho tlōla ho tlōla ho Nucleus Accumbens ho ntlafatsa Moputso oa thobalano Ka Hamsters ea Basyria ea Xyuma (2009)

LINTLHA: DFF ke lik'hemik'hale tse hlokahalang bakeng sa lithethefatsi tse hlahang. Bobeli ba lithethefatsi le boits'oaro ba boitšoaro bo amana le ho bokella Delta FosB. Tlosa Delta FosB le ho lemala ha khaotsa. Mona ho bontšoa hore phihlelo ea thobalano e eketsa Delta FosB, 'me e lebisa tlhokomelong ea setsi sa moputso. Sensitization e etsa hore ho be le tokoloho e phahameng ea dopamine e etsang hore mosebetsi kapa lithethefatsi li ipiletse haholoanyane. Ha e le hantle thobalano ke ts'oaetso ea lithethefatsi. Phuputso ena e boetse e ekelitse lefats'e la Delta FosB, e leng se ileng sa eketsa likarolo tse khotsofatsang tsa thobalano ho feta maemo a tloaelehileng. Na tšebeliso ea litšoantšo tsa bootsoa ba Inthanete e ka baka ho phahama ha Delta FosB holimo le ho feta maemo a tloaelehileng? Na see se ne se tla lebisa ho lemaletseng lithethefatsi le ho sebelisa litsela tsa neural? E bonahala e utloahala.


TLHOLO E TLAHANG: DFFB Ho tlōla ho tlōla ho Nucleus Accumbens ho ntlafatsa moputso oa thobalano ka Hamsters ea Basyria ea Basyria

Genese Brain Behav. 2009 June; 8 (4): 442-449. doi: 10.1111 / j.1601-183X.2009.00491.x.

Li-Hedges tsa VL, 1 S. Chakravarty, 2 EJ Nestler, 2 le RL Meisel1

inahaneloang

Ho pheta-pheta ha monoana o motsoako oa dopamine ho fella ka liphetoho tse tsitsitseng tsa boitšoaro tse tsamaeang le mokhoa oa polasetiki ea neural e nucleus accumbens (NAc). Ha ho bokelloa ha ntho e ngotsoeng ΔFosB e ka 'na ea e-ba karolo ea bohlokoa ea polasetiki ena, potso e botsitsoeng lipatlisisong tsa rona ke hore ΔFosB e laoloa ke phihlelo ea thobalano ho basali. Re bontšitse hore li-hammer tsa Basyria tse nang le phihlelo ea ho kopanela liphate li bontša liphetoho tse 'maloa tsa boitšoaro ho akarelletsa le ho eketseha ha likamano tsa botona le botšehali ka li-hamster tsa banna, litefello tsa thobalano le ho ba le boikarabelo bo eketsehileng ho ba susumetsang maikutlo a kelello (mohlala, amphetamine).

Re sa tsoa bontša hore phihlelo ea thobalano e ekelitse maemong a ΔFosB ho NAc ea hamster ea Basyria. Sepheo sa phuputso ena e ne e le ho hlahloba liphello tse sebetsang tsa tlhahiso ena ka ho etsa qeto ea hore na tlhaloso e kholo ea DFBB ka li-vase tsa NAC tse nang le adeno-associated (AAV) tse ka NAC li ka etsisa liphello tsa boitšoaro ba ho kopanela liphate.

Liphoofolo tse nang le ts'oaetso e kholo ea AAV ea DFFB ho NAc e bontšitse bopaki ba moputso oa ho kopanela liphate sebakeng se khethiloeng sa sebaka paradigm tlas'a maemo ao liphoofolo tse laolang li fumanoang ka eona liente tsa AAV-green fluorescent protheine (GFP) ho NAc ha ea ka ea e etsa. Litlhahlobo tsa boitšoaro ba thobalano li ile tsa boela tsa bontša hore banna ba kopantsoeng le basali ba AAV-ΔFosB ba ne ba eketsehile ka mokhoa o lekanyelitsoeng ha ba lekantsoe ka karolo ea lithaba tse kenyeletsang ho fokotsa ts'oaetso ho bapisoa le banna ba kopanetsoeng le basali ba AAV-GFP. Liphello tsena li tšehetsa karolo ea DFF bakeng sa boitšoaro ba boitšoaro bo susumelletsang tlhaho, tabeng ena boitšoaro bo bobe ba ho kopanela liphate, le ho fana ka temohisiso e ncha ka liketso tsa ho qetela tsa DFFB.

Selelekela

Ho ba le lithethefatsi tsa tlhekefetso, boitšoaro bo susumelletsang batho, boitšoaro bo tsamaeang ka maoto kapa liphello tsa thuto ea li-instrumental ho ts'ebetsong ea tsamaiso ea dopamine ea mesolimbic le liphetoho tse tsitsitseng nucleus accumbens (NAc) (Becker et al a., 2001, Di Chiara et al a., 1998, Harris et al a., 2007, Kumar et al a., 2005, Meisel le Mullins, 2006, Nestler, 2008, Olausson et al a., 2006, Perrotti et al a., 2008, Pierce & Kumaresan, 2006, phiri et al a., 2004). Liphetoho tsa mohaho, haholo-holo ho thehoa ha metsoako ea dendritic, ke karolo ea bohlokoa ea polasetiki ena e nang le phihlelo (Allen et al a., 2006, lee et al a., 2006, Li et al a., 2003, Meisel le Mullins, 2006, Norrholm et al a., 2003, Robinson & Kolb, 2004), e salang nako e teletsana ka mor'a hore phihlelo ea boitšoaro kapa tsamaiso ea lithethefatsi e khaotse (McClung le Nestler, 2008, Meisel le Mullins, 2006, phiri et al a., 2004).

Ntho ea ho ngolisa ΔFosB e na le mehaho ea limolek'hule e etsang hore e be mokhethoa ea khabane bakeng sa ho lumellana le liphetoho tse tsitsitseng tsa boitšoaro le boitšoaro ka lebaka la liphihlelo tsa boitšoaro kapa tsa lithethefatsi (Chen et al a., 1997, Chen et al a., 1995, Colby et al a., 2003, Doucet et al a., 1996, tšepo et al a., 1994, Kelz et al a., 1999, McClung le Nestler, 2003, McClung et al a., 2004, McDaid et al a., 2006, Nakabeppu & Nathans, 1991, Nestler, 2008, Nye et al a., 1995, Olausson et al a., 2006, Perrotti et al a., 2008, Wallace et al a., 2008, Werme et al a., 2002, Zachariou et al a., 2006). DFFB ke sehlahisoa se seng sa sekhahla sa liphatsa tsa lefutso tsa pele fosB (Mumberg et al a., 1991, Nakabeppu & Nathans, 1991) 'me, ho fapana le protheine e feletseng ea FosB e telele, ΔFosB e nang le truncated e na le botsitso bo sa tloaelehang bo bakoang ke ho bokella protheine ka mor'a ho tsosolosa hangata (Chen et al a., 1997, Chen et al a., 1995, tšepo et al a., 1994, Kelz et al a., 1999, Perrotti et al a., 2008, Zachariou et al a., 2006). Le hoja mochine oo fosB ea liphatsa tsa lefutso e ntse e sa tsejoe, truncation ea protheine hammoho le phosphorylation e sireletsa protheine ho tloha ka mokhoa o potlakileng oa proteasomal e hlahisang tšebetso e kholo ea mosebetsi oa phetolelo ha ho bapisoa le litho tsa malapa a FosB ka nako e telele (Carle et al a., 2007, Ulery & Nestler, 2007, Leihlo et al a., 2006). The postulate ke hore pokello ea protein ea ΔFosB e hlahisa mekhoa ea liphatsa tsa lefutso e ka 'nang ea e-ba tlas'a liphello tsa phihlelo ka pentetiki ea nako e telele ea boitšoaro le ea cellular (McClung le Nestler, 2008).

Re sebelisitse boitšoaro bo bong bo hlephileng ba ho kopanela liphate ka li-hamster tsa Syria e le mohlala oa bo-pula-maliboho bo nang le boiphihlelo bokoeng (Bradley et al a., 2005a, Bradley et al a., 2005b, Bradley & Meisel, 2001, Bradley et al a., 2004, Kohlert & Meisel, 1999, Kohlert et al a., 1997, Meisel et al a., 1993, Meisel & Joppa, 1994, Meisel et al a., 1996, Meisel le Mullins, 2006). Molemo oa ho sebetsa ka thobalano ke bokhoni ba ho laola boemo ba liphihlelo tsa liphoofolo ka ho ba le liphoofolo tse fapaneng ka ho feletseng tsa ho kopanela liphate, kapa ka ho pepesa liphoofolo ka tsela e sa tšoaneng ho lihlopha tse fapaneng tsa boiphihlelo ba thobalano. Re kile ra bontša hore ho ba le phihlelo ea ho kopanela liphate ka makhetlo-khetlo ho fella ka ho matlafatsa mokhoa oa mesolimbic dopamine system, o ts'oanang le oa lithethefatsi tsa tlhekefetso (Bradley et al a., 2005b, Bradley & Meisel, 2001, Brenhouse & Stellar, 2006, Cadoni & Di Chiara, 1999, tšepo et al a., 1992, Kelz et al a., 1999, Kohlert & Meisel, 1999, Pierce & Kalivas, 1995, LITLHAKU TSE KHOLO, Litlhaku tsa Pierce & Kalivas, 1997b, Robinson & Kolb, 1999a). Ka mohlala, joaloka liphello tsa lithethefatsi, boiphihlelo bo bongata ba ho kopanela liphate bo eketsa likhahla tsa dendritic li-spin neurons tse bohareng tsa NAc (lee et al a., 2006, Li et al a., 2003, Meisel le Mullins, 2006, Norrholm et al a., 2003, Robinson et al a., 2001, Robinson & Kolb, 1997, Robinson & Kolb, 1999a, Robinson le Kolb, 1999b, Robinson & Kolb, 2004). Ho feta moo, re hlokometse hore ho hloekisa ΔFosB / FosB ho phahame ka nako e kholo ho NAc ho latela phihlelo ea ho kopanela liphate khafetsa (Meisel le Mullins, 2006).

Hobane boiphihlelo ba ho kopanela liphate bo ka hlahisa litho tsa malapa a FosB nako e telele, morero oa thuto ena e ne e le ho sebetsana le maikutlo a ΔFosB ho etsisa liphello tsa boitšoaro ba boiphihlelo bo bongata ba thobalano. Ka mor'a ho ts'oaetsoa ha kokoana-hloko ea DFFB ho NAC, li-hammer tsa Basyria li ile tsa lekoa bakeng sa maemo a ntlafetseng a sebaka seo ho khetholloang ho sona 'me tsa eketseha ka katleho ka li-hamster tse sa tloaelehang, tse peli tse qetellang li bontšitsoe hore li amehile ka phihlelo ea ho kopanela liphate khafetsa (Bradley et al a., 2005b, Meisel & Joppa, 1994, Meisel et al a., 1996, Meisel le Mullins, 2006). We tlaleha mona hore ka ho phehella ho tlosa maikutlo ka ho feteletseng ΔFosB ho NAC ea li-Hamster tse nang le boiphihlelo bo fokolang ba thobalano, re khona ho hlahisa liphetoho tsa boitšoaro tse tšoanang le tsa basali ba nang le phihlelo e tebileng ea thobalano.

Lisebelisoa le mekhoa

Lihlooho tsa Liteko

Majoe a Basyria le a basali a ne a fetisetsoa ka nako e ka bang matsatsi a 60 ho tloha Charles River Breeding Laboratories, Inc. (Wilmington, MA). Basali ba ne ba lula ka botebo ka likotlolo tsa polasetiki (bolelele ba 50.8 cm x × 40.6 cm x xNUMX cm), ha liphoofolo tse tsosang takatso e ne e le lihlopha-li kenngoa ka makhetlo a lekanang ho tse tharo kapa tse 'nè. Kamore ea liphoofolo e ne e lula e le mocheso o laoloang oa 20.3 ° C le 22: Kemiso ea 14 hr-dark (e khantšang pakeng tsa 10: 1 le 30: 11 pm). Lijo le metsi li ne li fumaneha ho liphoofolo ad libitum.

Mekhoa eohle e sebelisoang tlhahlobo ena e ne e le tumellanong le Mekhatlo ea Sechaba ea Bophelo Litaelo tsa tlhokomelo le tšebeliso ea liphoofolo tsa liphoofolo mme ba amoheloa ke Mokhatlo oa Pheliso ea liphoofolo le Komiti ea Sebeliso.

Phekolo

Li-hamster tsa basali li ne li le maemong a mabeli ka tlas'a palo ea pentobarbital anesthesia (Nembutal; 8.5 mg ka 100 gm boima ba 'mele, ip), e fanoeng ka mokhoa o tsoelang pele oa ho phekola manonyeletso ebe e etsoa opereishene ea stereotaxic tse peli bakeng sa ho tsamaisa likokoana-hloko tsa kokoana-hloko. Nakong ea opereishene ea stereotaxic, hlooho e ne e kuta 'me letlalo le mesifa li furalla. Sekoti se senyenyane se ne se khabisitsoe lehata le seringe ea Hamilton ea 5 e ile ea theoleloa ho ea fihla NAc ho tloha 2 ° lateral angle ho netefatsa hore li-ventricle tsa lateral li hlakile. Seringe e ne e boloketsoe sebaka sa 5 pele ho liente ebe joale adeno-associated virusi (AAV) -GFP kapa AAV- ΔFosB (0.7 μL) e nehelanoe ka NAc ka morao 7, e nang le sering e bolokiloeng sebakeng sa tse ling tsa 5 min. Tsamaiso ena e ile ea phetoa ka lehlakoreng le leng la boko.

Li-Vectors tsa Viral

AAV e khetholloa ke bokhoni ba eona ba ho fetola li-neurone hantle le ho boloka lipolelo tse khethehileng tsa nakoana ka nako e telele (Chamberlin et al a., 1998). Li-vectors tsa AAV li na le li-serotypes tse fapaneng tse thehiloeng ho khethollo ea liprotheine tsa bona tsa capsid. Tlhahlobo ena e sebelisitse AAV2 (serotype 2) e tsoang Stratagene e nang le titer ea 108/ μl e hlahisa protheine e tala ea fluorescent (AAV-GFP) hammoho le vector ea AAV e neng e hahile bakeng sa ΔFosB le GFP (AAV-ΔFosB-GFP). Likokoana-hloko tsa kokoana-hloko li ne li kenngoa ka NAc bonyane libeke tsa 3 pele ho tlhahlobo ea boitšoaro ho lumella hore ΔFosB e be bonolo ho hlahisa maikutlo. Litsebi tsena tsa AAV li buisana le litoeba le litoeba tse ngata ka ho fetisisa matsatsing a 10 ea ente 'me li phehella ka nako ena bonyane likhoeli tsa 6 (Winstanley et al., 2007, Zachariou et al., 2006). Habohlokoa, li-vectors li tšoaetsa li-neurone feela 'me ha li hlahise chefo e kholo ho feta koloi ea infusions feela. Lintlha tsa tlhahiso le tšebeliso ea li-vectors tsena li fanoa libukeng tsa pele (Winstanley et al., 2007, Zachariou et al., 2006).

Boiphihlelo ba thobalano

Li-hamster tsohle tsa basali tse nang le mahlo a mangata li ne li amoheloa ka boiphihlelo hang ka beke ka ho fana ka liente tse peli tsa letsatsi le letsatsi tsa estradiol benzoate (10 μg ho 0.1 ml ea oli ea cottonseed) hoo e batlang e le 48 hr le 24 hr pele tlhahlobo ea boitšoaro ba thobalano e lateloa ke "progesterone" (500 μg ho 0.1 ml ea oli e kotsing) 4-6 hr pele ho teko ea boitšoaro ba thobalano. Basali ba ileng ba fumana phihlelo ea ho kopanela liphate ba hlahisitsoe hamster ea banna ba nang le phihlelo ea ho kopanela liphate bakeng sa 10 metsotsoana 4-6 hr ka mor'a hore ho entsoe progesterone. E mong le e mong e motona le e motšehali o ne a kopane feela nakong ea liteko tsa boiphihlelo ba thobalano.

E behiloe Sebaka se Khethollang

Sebaka se khetholloang sebaka sa paradigm se ne se sebelisitsoe tekong ena (Tzschentke, 1998). Lisebelisoa tsa rona tsa maemo a khetholloang (Meisel & Joppa, 1994, Meisel et al a., 1996) e na le kamore e le 'ngoe e mosoeu le e le' ngoe e bohlooho (60 × 45 × 38 cm) e kopantsoeng ke kamore e hlakileng e bohareng (37 × 22 × 38). Likarolo tse ka sehloohong li ne li fapane ka ho eketsehileng ke libethe tsa aspen (Harlan Laboratories, IN) ka kamoreng ea bohlooho le liphahlo tsa li-corncob (Harlan Laboratories, IN) ka kamoreng e tšoeu. Li-hamster tsa basali tse nang le mahlo a mangata li ne li le li-hormone pele li hlahlojoa pele, litekanyetso tsa ho kopanela liphate, le li-post-test. Nakong ea phomolo ea liphoofolo e ne e kenngoa ka kamoreng e hlakileng e ka hare 'me e ne e lokolohile ho phallela likarolo tse fapaneng tsa 10 min ho fumana khetho ea pele bakeng sa kamore e' ngoe le e 'ngoe. Ha liphoofolo tsohle li bontša hore li rata kamoreng e mosoeu, boemo bo ne bo etsoa ka kamoreng ea bohlooho. Hormone e khabisang e ile ea phetoa nakong ea 2 (Lihlopha 2-5) kapa libeke tsa 5 (Sehlopha 1) sa boemo bo botle. Nakong ea boemo bo botle, basali ba filoe boiphihlelo ba thobalano le banna ba karolong ea bohlooho bakeng sa 10 min, ka mekhahlelo ea basali e lekanyelitsoeng (latence lordosis le nako eohle ea lordosis). Hr e le 'ngoe e latela teko ea boiphihlelo ba thobalano, mosali o behiloe a le mong kamoreng e mosoeu bakeng sa 10 min. Sehlopha se nang le taolo sa basali se sa kang sa fumana boiphihlelo ba ho kopanela liphate se ne se entsoe ka bohale empa se behoa se le seng kamoreng e 'ngoe le e' ngoe bakeng sa 10 min. Ho latela libeke tsa 2 kapa 5 tsa boemo bo botle, liphoofolo li ile tsa fuoa tlhahlobo ea kamora 'me li boetse li lokolohile ho phallela likamoreng tsa 10 min. Ho sa tsotellehe sehlopha, litlhahlobo tsohle li ile tsa etsoa ka mor'a libeke tse supileng tsa ho buuoa ka mor'a post-stereotaxic, kahoo liphoofolo tsohle li ne li nyeheloa ka lebelo le le leng la polelo ea kokoana-hloko. Ho ne ho e-na le lihlopha tsa 5 tsa liphoofolo ka teko ena: Sehlopha se nang le matla a ho laola liphoofolo se amohelehileng AAV-GFP le ho fana ka boitšoaro bo hlephileng ba ho kopanela liphate ka 5 bosiu le bong (Group 1, n = 8). Lihlopha tse peli tsa taolo ea boitšoaro bo bobe ha lia ka tsa fuoa boemo leha e le bofe ba ho kopanela liphate libeke tsa 2, mme li amohetse AAV-ΔFosB (Sehlopha 2, n = 5) kapa AAV-GFP (Sehlopha 3, n = 4). Qetellong, ho ne ho e-na le liphoofolo tse ileng tsa amohela libeke tsa 2 tsa boitšoaro bo bobe ba ho kopanela liphate le banna ba nang le meriana e kopanetsoeng ea AAV-ΔFosB (Sehlopha 4, n = 7) kapa AAV-GFP (Sehlopha 5, n = 7).

Boiteko ba banna ba Naïve

Lipatlisiso tse fetileng li bontšitse hore hamsters e nang le phihlelo ea ho kopanela liphate e ka ntlafatsa katleho ea ho sebelisana le banna ba bona ba nang le thobalano (Bradley et al a., 2005b). Tlhahlobo ena e ile ea fanoa hoo e ka bang beke e le 'ngoe ka mor'a lipapali tse peli tsa liphoofolo tse amohetseng libeke tsa 2 tsa likamano tsa botona le botšehali (Lihlopha 4 le 5). Basali ba ne ba amoheloa ke hormonally bakeng sa phihlelo ea thobalano joalokaha ho hlalositsoe. Nakong ea tlhahlobo ea metsotso ea 10, hamster e motona oa ho kopanela liphate e ile ea kenngoa kahare ea ntlo ea basali 'me lenaneo la teko le ne le ngotsoe videotaped bakeng sa tlhahlobo ea morao-rao. Palo ea li-mounts le intromissions (ho kenyeletsa le ejaculations) ke e motona hammoho le palo ea likhahla tsohle tse kenyeletsang ho kena holimo (likhahla tsa hit) li ile tsa khethoa ho tloha videoteng.

Immunohistochemistry

Li-immunostaining li ne li etsoa liphoofolong tsohle ho netefatsa bobeli ba likokoana-hloko le sebaka sa lipalo tsa protheine. Li-females li fanoe ka ho feta tekano ea Sleepaway (0.2 ml ip, Fort Dodge Laboratories, Fort Dodge, IA) mme e sa sebelisoe hantle ka letsoai la 25 mM phosphate (PBS) ea 2 min (hoo e batlang e le 50 ml) e lateloa ke 4% paraformaldehyde ho 25 mM PBS bakeng sa 20 min (hoo e ka bang ka 500 ml). Boko ba ile ba tlosoa 'me ba kenngoa morao bakeng sa 2 hr ho 4% paraformaldehyde ebe ba kenngoa tharolong ea 10% sucrose PBS bosiu bo le bong ho 4 ° C. Liphoofolo tse amohelehang feela AAV-GFP li na le likarolo tse kholo tsa li-coronal (40 μm) tse khaotsoeng ka mahlaseli a serame ho ea ho 25 mM PBS hammoho le 0.1% ea serum albumin (BSA) (ho hlatsoa buffer) ebe e kenngoa ka ho toba ho li-slide ebe e koahetsoe ha 5% n-propyl galate ka glycerin. Liphoofolo tse fumanoeng ka mahlakoreng a AAV-ΔFosB li na le likarolo tse kholo (40 μm) tse khaotsoeng ka mahlaseli a leqhoa, ebe li hlatsoa linako tsa 3 bakeng sa 10 min ka tank. Lihlahisoa tsa AAV-DFFB li ne li hlahlojoa feela bakeng sa polelo ea DFBB ka hona li ne li kenngoa ka antibody e kholo ea ΔFosB / FosB (1: 10000, sc-48 Santa Cruz Biotechnology Inc., Santa Cruz, CA) ho hlakola le 0.3% Triton-X 100 ka mocheso oa mofuthu oa 24 hr ebe o fallela 4 ° C bakeng sa 24 hr. Ts'oaetso ena ea mahlaseli a mantlha e ne e khethiloe kaha e hlahisa litlolo tse fokolang tsa ΔFosB / FosB tse fokolang feela. Ka mor'a ho tsubella likokoana-hloko ho antibody ea motheo, likarolo li ile tsa hlatsoa linako tsa 3 tsa 10 mamineng ea ho hlatsoa, ​​'me li kenngoa kalareng ea motsoako oa li-45 ho 1: 200, Vector, Burlingame, CA). Likarolo li ile tsa hlatsoa linako tse ling tsa 3 bakeng sa 10 min ka tampong ea ho hlatsoa pele e kenngoa ka streptavidin Alexa Fluor 594 conjugate (1: 500, Molecular Probes, Eugene, OR). Ka mor'a ho tsubelloa hona, likarolo li ne li hlatsoa linako tse ling tsa 3 bakeng sa minara ea 10 ha ho hlatsoa li-slides ebe li koahetsoeng ha li ntse li kolobeloa ka 5% n-propyl galate ka glycerin.

Ho hlahlojoa ha Microscopic

Li-slide li ile tsa hlahlojoa ke microscope ea Leica DM4000B e nang le matla a fluorescent hammoho le kamera ea digital ea Leica DFC500. Litšoantšo tsa mechine tsa libaka tse nang le lisebelisoa tse nepahetseng le tse le letšehali tsa karolo e 'ngoe le e' ngoe li ile tsa hlahlojoa ka hloko ka microscopy ea fluorescence ho fumana mochine o kenngoeng NAC. Likarolo tse tsoang ho phoofolo e 'ngoe le e' ngoe li ne li hlahlojoa ho fumana ho phatlalatsoa ha li-viral ho tloha ho likokoana-hloko le ka sebaka sa tlhaho sa boholo bo boholo ba polelo. Ho feta moo, ka hare ho likarolo tsena palo ea lisele tse silafetseng tsa FosB li baliloe ho ImageJ ho tloha litšoantšong tse boloketsoeng tsa digital. Ha sepheo sa rona e ne e le feela ho fumana litekanyo tsa lisele tse lekanyelitsoeng, mekhoa ea li-stereological ha ea sebelisoa.

Results

Nako ea nako e ngata ea tšoaetsano ea kokoana-hloko ea DFFB ho NAc ea li-hammer tsa Basyria

Sehlopha sa liphoofolo tse fapaneng se ne se sebelisetsoa qalong ho fumana nako e ngata ea DFFB e nang le kokoana-hloko ka hamster ea basali. Ho hlahlojoa ha polelo ea ΔFosB ho 3 (n = 5), 6 (n = 6), le 9 (n = 2) lintlha tsa nako ea beke li senotsoe hore libeke tsa 3 ka mor'a ho buuoa ke stereotaxic li hlahisitse ho hlaka ha ΔFosB e bolokiloeng ka 6 le 9 libeke tse 'maloa ka mor'a ho buuoa ke stereotaxic. Mantsoe a likokoana-hloko e ne e le boholo ba nyutlelie, empa a boetse a fumanoa cytoplasm esita le li-dendrites tsa lisele tse ling tse tlokisang matla. Har'a liphoofolo tse leshome le metso e meraro tse neng li e-na le liteko tsa nako ea nako, liphoofolo tse 'nè li ne li e-na le liente tsa kokoana-hloko ea kokoana-hloko ea Nac, e' ngoe ea tsona e neng e hasoa kahare ea bethe ea stria terminalis (BNST). Liphoofolo tse robong tse setseng li ne li e-na le likokoana-hloko tsa caudal, tse supileng mokokotlong oa caudal, le tse peli ka lebokoseng la cauc la NAc. E 'ngoe feela ea li-coal shell e entsoeng ka BNST, ha lijoe tse tšeletseng kahare ea caudal li ne li tšela BNST. Ka karolelano boholo ba li-diameter tsa polelo ea kokoana-hloko bakeng sa nako e 'ngoe le e' ngoe e fumanoe e le 0.9 mm, 1.2 mm, le 1.0 mm bakeng sa li-3, 6 le libeke tsa 9 ka ho latellana. Tsena likhahla tsa boholo-holo li ne li hlahlojoa ka mokhoa o fapaneng 'me li sa fumanoe li fapane haholo. Ka lebaka lena, lits'ebetsong tse latelang tsa boitšoaro, tlhahlobo ea boitšoaro e qalile ho pholletsa le libeke tsa 3 ho etsoa opereishene ea stereotaxic, 'me liphoofolo li ne li etsoa sehlabelo ho pota libeke tsa 9 poso ea stereotaxic ho etsa bonnete ba hore polelo ea likokoana-hloko e bolokiloe ka mokhoa o tsitsitseng.

Tlhahlobo ea immunohistological ea li-virus tsa AAV-ΔFosB le AAV-GFP

Likarolo tsa bokooa ho phoofolo e 'ngoe le e' ngoe e sebelisitsoeng lits'ebetsong tsa boitšoaro li ile tsa hlahlojoa ka sekhahla sefofaneng sa li-coronal bakeng sa sebaka sa anatomical sa ente ea kokoana-hloko. Ka kakaretso liphoofolo tsa 12 li ile tsa hlahlojoa ka lipolelo tsa bona tse peli tsa ΔFosB ka palo ea lisele, le ho kenngoa ka ente, e neng e khethoa ka ho hlahloba litsela tse setseng tsa nale. Le hoja ho kenngoa ka ente ho ile ha hlahlojoa karolong ea likoropo (Setšoantšo sa 1), polelo ea protheine e fetiselitsoe holimo ho rostral-caudal ho tloha sebakeng sa lisebelisoa, 'me e boetse e hasana ka sekhahla sa lensisi-ventral se tsoang sebakeng sa mochine. Har'a liphoofolo tse hlano tse hlahlojoang ke sehlopha sa 2, 70.5% ea lisele tse nang le boithaopo bo boholo li ne li le NAc (lipakeng tsa = lisele tsa 16,864, li-quartile tse tlaase = lisele tsa 7,551, li-quartile tse tlaase = lisele tsa 20,002, interquartile range = 12,451). Liphoofolo tse supileng tse hlahlojoang ho tsoa ho sehlopha sa 4 li bontsitse 65.6% ho feta tekano ho tswa ho NAc (lipakeng tsa = lisele tsa 9,972, quartile e tlaase = lisele tsa 5,683, quartile e phahameng = lisele tsa 11,213, interquartile range = 5530.). Ts'ebetso ena ea lisele li emela li-viral overexpression ho e-na le ho hloekisa mabone ka lebaka la ho hlaphoheloa ha morero oa antibody e kholo.

Setšoantšo sa 1    

Liprotheine li bonts'oa lihlahisoa tsa AAV-GFP kapa AAV-ΔFosB 12 wks kamora 'injection. Ka holimo. Kelello e matla ea GFP e ne e le boholo ba nyutlelie empa hape e fumaneha ho hasana ho cytoplasm le dendrites ea lisele. Ka tlaase. DFFB protheine polelo e etsisitsoe ...

Har'a libaka tsa 24 tse entsoeng ka mahlakoreng a mabeli, tse leshome le metso e 'meli li ne li le karolong ea li-rostral tsa NAC, tse tšeletseng tsa tsona li ne li e-na le li-viral expression tse neng li ka fetisetsoa BNST. Libaka tse ling tse leshome le metso e 'meli tsa lisebelisoa li ne li le Nac ea caudal. E 'ngoe ea liente tse leshome le metso e' meli li ne li le ka lebokoseng la caudal 'me li phatlalatsoa ke BNST. Liwebsaete tsa ho qetela tse leshome le motso o mong li ne li le mokokotlong oa NAC, tse robeli tsa tsona tse jalang BNST. Liente tsohle li ne li le ho pota-potiloe ka ntle ho liphahlo ntle le sekheo se le seng sekhethong sa cauc sa NAC se neng se le se seng se seng se lekanang ho feta sebopeho sa pele (Setšoantšo sa 2). Liphoofolo tsohle li ne li bontša ho ba le maikutlo a loketseng a GFP kapa ΔFosB 'me ka hona li sebelisitsoe ho hlahloba boitšoaro bo latelang. Ha ho liphoofolo tse neng li sa kenyelletsoa thutong ka lebaka la ho beha majoe a futhumetseng a ente. Ho feta moo, hobane liente tsohle li ne li lebisitsoe ho sepakapaka se le seng le se seng se kenyeletsang sekhetla ha ho na lisebelisuoa tsa lisebelisoa tse entsoeng libakeng tse entsoeng ka ente.

Setšoantšo sa 2    

Ho tloaelehile hore libaka tsa liphoofolo li hlahlojoe ke likokoana-hloko tsa likokoana-hloko. Lihlopha li emela sebaka sa AAV-GFP le likarolo tse emelang sebaka sa AAV-ΔFosB. a. Ho kenya mochine oa AAV-GFP bakeng sa liphoofolo tse nang le 5 mksong ea thobalano (sehlopha sa 1). ...

Tlhahlobo e kholo ea AAV ea DFFB ho NAc ea li-hammer tsa Basyria e fella ka moputso o matlafatsang oa thobalano

Ho hlahloba hore na ho tepella ho feteletseng ha DFFB ho NAC ho na le phello ho moputso oa thobalano re sebelisitse sebaka sa maemo a khethollang paradigm. Tekong ena, liphoofolo li ile tsa e-ba 0, 2, kapa libeke tsa 5 tsa boemo ba thobalano. Nakong ea boemo ba thobalano, latency latence le nako e ne e tlalehiloe hamster e 'ngoe le e' ngoe ea basali. Hase le lordosis latency (Sehlopha 1: Sekhahla sa 553 ± 7 sec, Sehlopha 4: Sekhahla sa 552 ± 7 sec, Sehlopha 5: Sekhahla 561 ± 7 sec,) kapa nako ea lordosis (Sehlopha 1: Sekhahla 485 ± 15 sec, Sehlopha 4: 522 sec ± 10 sec, Sehlopha 5: Sekhahla sa 522 ± sekhahla sa 12) nakong ea boemo ba ho kopanela liphate bo fapane haholo har'a lihlopha ho pholletsa le tlhahlobo ho sa tsotellehe jelo ea kokoana-hloko. Ka lebaka leo, ho feteletsa maikutlo ha GFP kapa DFF ha ho na mokhoa leha e le ofe ka boitšoaro bo amohelang ba basali.

Sehlopha se seng le se seng se tsoang sebakeng sa maemo a khetholloang sebaka se ile sa hlahlojoa ka bomong ka tekanyo e phetiloeng ea tekanyo ea tekano pakeng tsa nako ea nako e sebelisoang ka kamoreng ea boemo bo boima (nakong ea pele ho tlhahlobo le tlhahlobo ea tlhahlobo). Tlhaloso ea lipalo ha ea ka ea atolosoa pakeng tsa lihlopha. Phuputso e fetileng e bontšitse hore liphihlelo tse hlano tsa ho kopanela liphate li lekane ho bona liphetoho tse khōlō sebakeng sa khetho ea sebaka (Meisel & Joppa, 1994, Meisel et al a., 1996). Ha e le hantle, sehlopha se ts'oanang sa taolo se nang le liphoofolo tse tšehali tse nang le boikutlo bo botle ba GFP ho NAC tse fanoeng ka liphihlelo tse hlano tsa ho kopanela liphate li ile tsa qeta nako e ngata haholo nakong ea tlhahlobo ea poso ka kamoreng ea bohlooho e nang le phihlelo ea thobalano ha e bapisoa le ts'ebetso ea pele ho boemo, t (8 ) = -3.13, P<0.05. Joalokaha ho lebelletsoe, liphoofolo tse sa fuoeng boiphihlelo ba thobalano ha lia ka tsa fetoha haholo nako ea kamoreng efe kapa efe ho sa tsotelloe ente ea vaerase. Basali ba hatellang GFP ba fuoeng liphihlelo tsa thobalano tse 2 ba ne ba sa bontše boemo ba sebaka sa bolulo, athe basali ba fuoeng liphihlelo tse peli tsa thobalano ka maikutlo a fetelletseng a osBFosB ba qetile nako e ngata haholo ka phapusing e nang le boiphihlelo ba thobalano nakong ea teko ena ea poso, t (7) = 2.48, P <0.05 (Setšoantšo sa 3).

Setšoantšo sa 3    

Sebaka se khethiloeng ka sebaka se latelang ka ente ea kokoana-hloko. Setšoantšo sena se bontša se boleloang (± SEM) palo ea metsotsoana nakong ea tlhahlobo ea pele ho boemo ba pele (Pre) le tlhahlobo ea postconditioning (Post) eo sehlopheng ka seng sa hamsters se se sebelisitseng karolong ea bohlooho. ...

Kakaretso ea AAV e hlakileng ea DFFB ho NAc ea li-hammer tsa Basyria e ntlafatsa katleho ea bona ea ho kopanya le banna ba naïve

Beke e le 'ngoe ka mor'a tlhahlobo ea tlhahlobo ea likamano tsa thobalano, basali ba nang le libeke tsa 2 tsa liteko tsa ho kopanela liphate (Lihlopha 4 le 5) ba ne ba le tlas'a teko ea boitšoaro bo bobe ba ho kopanela liphate. Tlhahlobo ena, AAV-ΔFosB basali ba nang le 2 pele ho liteko tsa thobalano ba ntlafetse haholo mokhoa oa bona oa ho kopanya ho feta ba AAV-GFP ba nang le phihlelo ea pele ea thobalano (2)Setšoantšo sa 4). Sekhahla sa sekhahla (palo ea lithaba tse akaretsang ho kenella) ha banna ba nang le thobalano ba neng ba kopane le basali ba AAV-ΔFosB e ne e phahame haholo ho feta sekhahla sa banna ba naïve ba kopaneng le basali ba AAV-GFP, t (14) = 4.089 p <0.005.

Setšoantšo sa 4    

Ho sebetsana ka katleho le bo-'mametsana ba nang le hamster. Setšoantšo sena se bontša sekhahla se boleloang (± SEM) se lekanang (sebopeho sa likhahla tsohle tse kenyelletsoeng ho kenya letsoho) tsa li-hamster tsa banna tse nang le li-AAV-GFP tsa basali ...

Puisano

Liteko tse fetileng tse neng li sebelisoa ke mahlaseli a AAV bakeng sa ho tepella maikutlo haholo ka ΔFosB li ne li khannoa ka mekhoa ea litoeba tsa rat kapa ea mouse (Wallace et al a., 2008, Winstanley et al a., 2007, Zachariou et al a., 2006). Re netefalitse lipatlisiso tsa likokoana-hloko ka boko ba hamster ka ho hloeka ha immunohistochemical. Tlhahlobo ena e bontšitse pontšo e atlehang ea DFFB e ileng ea hlaha hang ha libeke tse 3 ka mor'a hore e se ke ea kenngoa ka mahlaseli 'me ea lula e phahamisetsoa libeke tsa 9 nakong ea nako ea tlhahlobo le ho fihlela libeke tsa 12 litekong tsa boitšoaro.

Mohlala oa rona oa boiphihlelo ba ho kopanela liphate, ts'ebetsano ea ho kopanya liphate ka banna e lebisa tlhokomelong ea ho lokolloa ha dopamine ka NAc (Kohlert & Meisel, 1999, Kohlert et al a., 1997) e ntseng e matlafatsa liphello sebakeng sa maemo a khethollang paradigm (Meisel & Joppa, 1994, Meisel et al a., 1996). Ho khothaletsoa ha dopamine, hammoho le bokhoni ba li-hamster tsa basali ho laola ho atleha ha banna ka lebaka la ho kopana liphate ka makhetlo-khetlo,Bradley et al a., 2005b). Re bontšitse hore sena se matlafatsa boitšoaro ba thobalano se ka ntlafatsoa ka ho feteletsa maikutlo ka DFFB ho NAc ho latela maemo a ho etsa thobalano, ho tšoana le ho ntlafatsa likarabo tsa li-cocaine, morphine, kapa tšebeliso ea lijo ka mor'a ho hlakolloa ho tšoanang ha ΔFosB (Colby et al a., 2003, Olausson et al a., 2006, Zachariou et al a., 2006). Ts'ebetso ena ea litšebelisano tsa thobalano le banna e latelang boiphihlelo ba thobalano e ne e tšoantšetsoa ke ho fumanoa ha khetho ea sebaka sa boemo bo botle. Kehoa utloahala ho nahana ka DFFB e le sepheo sa ho fetola maikutlo ka nako ea nako e telele boitšoarong le polasetiki ea neuronal e ka sehloohong e lebisang tlhokomelong ea lits'ebetso tse tlaase tsa DFBB.

Kaha ho phahama ha ΔFosB ho hlahisa liphello tsena, mekhoa ea motheo e lokela ho nkoa. Ho na le liphello tse fokolang haholo tsa lik'hemik'hale tse bakoang ke ho bokella ΔFosB. Mlitlhahlobo tsa litoeba tse fokolang maikutlo ΔFosB li bontšitse ho eketseha ha serine / threonine cyclin e itšetlehileng ka kinase-5 (Cdk5), nuclekone factor kappa B (NF-κB), karoloana ea GluR2 ea mokete oa glutamate, le dynorphin (Ang et al a., 2001, Bibb, 2003). Ha ho tsejoe hantle hore na liketsahalo tsena tsa limolek'hule li ka ama pente ea polasetiki joang le sebopeho sa mokokotlo oa mokokotlo, le hoja Cdk5 e tseba karolo ea ho eketsa bongata ba mongobo oa dintritic (Bibb, 2003, Cheung et al a., 2006, Kumar et al a., 2005, Norrholm et al a., 2003), le lihlopha tse nyenyane tsa GluR2 kapa NF-κB li 'nile tsa kenngoa ka synaptic (Ang et al a., 2001, Nestler, 2001, Peakman et al a., 2003). Liphuputsong tsa nakong e tlang re rera ho tsepamisa mohopolo linthong tsena le tse ling tse ka 'nang tsa e-ba teng ka tlaase ho litlhaselo tsa DFFB ho fumana hore na mosebetsi oa bona o fetoha joang ka ho bokella ΔFosB ho latela boitšoaro bo hlephileng ba ho kopanela liphate.

Ho na le lingoliloeng tse ngata tse fanang ka mesebetsi e khethollang eo shell le motheo oa NAc li itšoarang ka eona boitšoarong bo susumetsang (Brenhouse & Stellar, 2006, Cadoni & Di Chiara, 1999, Perrotti et al a., 2008, Pierce & Kalivas, 1995). Phuputso e fetileng ho laboratori ea rona e 'nile ea lemoha liphello tsa lisele tsa ho kopanela liphate mokokotlong oa accumbens (Bradley et al a., 2005a, Bradley et al a., 2005b, Bradley & Meisel, 2001, Bradley et al a., 2004, Kohlert & Meisel, 1999, Kohlert et al a., 1997, Meisel et al a., 1993), ho theha motheo oa ho lebisa tlhokomelo ea NAC ea rona sehloohong sena. Tlhahlobo ea rona ea boholo ba matla a DFFB bo hlalosang maikutlo bo bontšitse hore le hoja lijoelo li ne li lebisitsoe mokokotlong oa NAC, polelo ea ΔFosB e ne e atisa ho jala kahare ho BNST ea rostral. Le hoja nac caud le BSTST rostral ke ka sebele nuclei ka tsela e tloaelehileng, ha e hlile ha e hlile e sebetse hantle ha libaka ka bobeli tsamaisa boholo ba mekhoa ea motheo mekhoa ea ho susumetsa tshebetso (mohlala, Koob et al., 2004). Thupong ea rona ea microdialysis ea hamsters ea basali (Kohlert et al a., 1997), re hlokometse hore ha re khone ho khetholla mekhabiso ea BNST ea majoe a tsoang ho ba nang le NAC ea caudal ka maemo a basal dopamine, likarabo tsa dopamine likamanong tsa thobalano le banna, kapa mekhoa ea dopaminergic afferent innervation. Ho e-na le ho talima ho ata ha tšoaetso ka BNST e le mokhoa o thata, mokhoa ona o tšehetsa khopolo ea ho tsoela pele ho sebetsa pakeng tsa NAc le BNST.

Le hoja re bontšitse hore ho tepella ho hongata ha ΔFosB ka hamsters ea basali ke ho lekane ho hlahisa sebaka se nang le maemo a ratang ho kopanela liphate le ho ntlafatsa likamano tse kopanetsoeng le banna, ha ho tsejoe hore na tlhahiso ea FFB e boetse e tsebahala ho hlokahala bakeng sa liphello tsena tsa boitšoaro tsa boiphihlelo ba thobalano. Liphuputso tsa morao-rao li sebelisitse kokoana-hloko ea AAV-ADJunD, e fokotsang ΔFosB phetolelano e khuts'oetsanoang ka ho hatelloa ka mokhoa o hlōlisanang ka ΔFosB pele e tlama sebaka sa AP-1 liphatsa tsa lefutso (Winstanley et al a., 2007). Ka ho sebelisa mokhoa oa AAV-AJJD ho kokota DFFB, re tšepile ho fumana hore na ΔFosB e hlokahalang bakeng sa polasetiki ea boitšoaro re hlokometse phihlelo ea boitšoaro ba thobalano, e tla tlatsetsa liphello tsa thuto e hlahisitsoeng mona. Haeba ho bokelloa ha ΔFosB le ts'ebetsong ea eona ea ho theoha tlaase ho eona ho baka liphasetiki tsa boitšoaro le tsa cellular, joale kokotla ea ΔFosB e lokela ho felisa liphello tsena.

lumela hore baa fokola

Re rata ho leboha Amanda Mullins, Melissa McCurley le Chelsea Baker bakeng sa thuso ea bona ka tlhahlobo ea boitšoaro, boemo bo botle, le lihlahisoa tsa maiketsetso. Mosebetsi ona o ne o tšehetsoa ke litšebeletso tsa NIH DA13680 (RLM) le MH51399 (EJN).

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