I-DeltaFosB ilawula i-Wheel Running (i-2002)

IZIMVO: I-DeltaFosb sisitshixo seemolekyuli eziqokelelana ebuchotsheni ngolawulo olungapheliyo lweziyobisi ezikhobokisayo, amanqatha amaninzi, iswekile ephezulu kunye nokubaleka kwamavili. Iguqula ingqondo ukuba ibangele uvakalelo kuyo nayiphi na into esetyenziswa kakhulu. Yinto ekhutshelweyo evula kwaye ivale iijini eziguqula ubume kunye nonxibelelwano kwisekethe yomvuzo wengqondo. Isiphelo: Idatha ityhila ukufana okumangalisayo phakathi kweziyobisi ezikhobokisayo kunye nokubaleka kwevili kwaye icebisa indima ebalulekileyo ye-ΔFosB ekulawuleni imbuyekezo yendalo kunye neyeziyobisi..

I-Journal ye-Neuroscience, i-15 Septemba 2002, i-22 (18): 8133-8138;

Werme M, UMbusi C, UOlson L, UGilden L, Thorén P, Nestler EJ, Brené S.

+ Ukubambisana Kwombhali

1. AmaSebe e-1 ye-Neuroscience kunye

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

3. I-3 iSebe le-Psychiatry kunye neZiko le-Neuroscience eyiSiseko, iYunivesithi yaseTexas Southwestern Medical Centre, eDallas, eTexas 75390-9070

Abstract

ΔFosB yinto ekhutshelweyo eqokelela kwindawo ethile kwingqondo emva kokuphazamiseka okungapheliyo. Ngokomzekelo, ukulawulwa ngokuphindaphindiweyo kweziyobisi zokuxhatshazwa kwandisa amanqanaba e-ΔFosB kwi-striatum. Kwesi sifundo sikhoyo, sihlalutye isiphumo sokubaleka kwevili ngokuzenzekelayo, njengomzekelo wokuziphatha okuvuzayo ngokwendalo, kumanqanaba ΔFosB kwimimandla ye-striatal. Ngaphaya koko, iimpuku ezenza overexpress ΔFosBkwii-subpopulations ezithile ze-striatal neurons zasetyenziselwa ukufunda indima enokwenzeka ye-ΔFosB kwindlela yokuziphatha. Lewis iimpuku zinikwe ad adum ufikelelo kumavili abalekayo kangange 30 d ezigqunyiweyo ezinokuhambelana ne ~ 10 km/d kwaye ibonise amanqanaba awondisiweyo e-ΔFosB kwi-nucleus accumbens xa kuthelekiswa neempuku ezivezwe kumavili abalekayo atshixiweyo. Iimpuku ezibonisa ngokugqithisileyo ΔFosB ngokukhethiweyo kwi-striatal dynorphin-equlathe i-neurons yonyuse ukusebenza kwayo kwemihla ngemihla xa kuthelekiswa ne-littermates yolawulo, kanti iimpuku ezi-overexpress ΔFosB ubukhulu becala kwi-striatal enkephalin-equlethe i-neurons ibaleke kakhulu kunolawulo. Idatha evela kuphononongo lwangoku ibonisa ukuba njengeziyobisi zokuxhatshazwa, ukubaleka ngokuzithandela kwandisa amanqanaba e-ΔFosB kwiindlela zomvuzo wengqondo. Ngaphaya koko, ukuchazwa ngokugqithisileyo kwe-ΔFosB kwisiphumo esicacileyo sokubulawa kwabantu be-neuronal yonyusa indlela yokuziphatha. Kuba umsebenzi wangaphambili ubonise ukuba ΔFosB Ukugqithisa kakhulu ngaphakathi kwesi sibalo esifanayo se-neuronal kwandisa iimpawu ezivuzayo zeziyobisi zokusetyenziswa kakubi, iziphumo zolu phononongo lwangoku zibonisa ukuba ΔFosB inokudlala indima ephambili ekulawuleni umvuzo wendalo kunye neziyobisi.

egqithileyo IcandeloOkulandelayo Icandelo

intshayelelo

ΔFosB yeyosapho lweFos lwemiba yoshicilelo kwaye luthatyathwe kuhlobo lwe-fosb ngokudibanisa okunye. Ngokungafaniyo nazo zonke ezinye iiproteni ezinjenge-Fos, ezinobomi obufutshane obufutshane, i-35 kunye ne-37 kDa isoforms ye-ΔFosB ziqokelele ngendlela ethile kwingqondo emva kokuphazamiseka okungapheliyo, mhlawumbi ngenxa yozinzo oluphezulu kakhulu lwezi isoforms (Ithemba et al., 1994a; Chen et al., 1997; Nestler et al., 1999). Ummiselo we-ΔFosB kwimimandla ebulalayo emva kokulawulwa ngokuphindaphindiweyo kweziyobisi zokusetyenziswa kakubi kuye kwafundwa kakuhle (Ithemba et al., 1994b; Moratalla et al., 1996; Chen et al., 1997; Nestler et al., 1999). Indlela ye-mesolimbic dopamine inendima ephambili kumvuzo weziyobisi (Koob et al., 1998). Isuka kwindawo ye-ventral tegmental ye-midbrain kwaye iphela kwindawo ye-ventral ye-striatum, ebizwa ngokuba yi-nucleus accumbens. Ulawulo olungqongqo lwalo naliphi na iziyobisi ezininzi zokuxhatshazwa okwethutyana libangela iiproteni zosapho ezininzi ze-Fos kwi-nucleus accumbens nakwi-dorsal striatum. Ezi proteni zenza i-heterodimers kunye neeprotheni zentsapho zikaJun ukwenza i-activator protein-1 (AP-1) i-transcription factor complexes kunye nesiqingatha sobomi obufutshane. Ngokwahlukileyo, emva kokunyangwa kweziyobisi ngokuphindaphindiweyo, ukwenziwa kwezi mveliso zofuzo kwangoko ziyehla kwaye, endaweni yoko, kukho ukuqokelelwa ngokuthe ngcembe kwesitali ΔFosB ii-isoforms. ΔFosB i-heterodimerizes ikakhulu nge-JunD kwaye ukuya kumlinganiselo omncinci nge-JunB (Hiroi et al., 1998; Perez-Otano et al., 1998) ukwenza ii-AP-1 ezihlala ixesha elide kwiindawo ezithile zengqondo. Kuye kwacetywa ukuba ezi zixhobo zihlala ixesha elide ze-AP-1 zilamla ezinye zeziphumo zexesha elide zokusetyenziswa kakubi kweziyobisi kwiindlela zomvuzo wengqondo ezenza umlutha (Nestler et al., 2001).

Izifundo zokuziphatha zibonisa ukuba ukubaleka kwevili kwiimpuku kunomvuzo. Olu qikelelo lusekwe kwiimvavanyo ezibonisa ukuba iimpuku zicinezela i-lever-press ukufikelela kumavili abalekayo kwaye ziphuhlisa indawo ekhethwayo kwindawo ehambelana neziphumo zokuhamba kwevili (Iversen, 1993; Belke, 1997; Lett et al., 2000). Ngaphezu koko, iigundane ezibaleka imigama emide imihla ngemihla zibonisa iimpawu zokurhoxa, ezinje ngokunyuka komsindo, xa ukufikelela kumavili abalekayo kunqatshelwe (Hoffmann et al., 1987). Uphononongo phakathi kweembaleki ezingabantu ezizinikeleyo lucebisa ukuba ukubaleka yindlela yokuziphatha ekhobokisayo kubantu abaninzi (URudy no-Estok, ngowe-1989; UChapman kunye noDe Castro, ngo-1990; UFurst kunye neGermone, ngo-1993). Ewe, ukuqhuba kubonisa ezininzi zeendlela ezibandakanyiweyo kwi-Diagnostic Statistical Manual (Umbutho we-Psychiatric Association, i-1994) ukufumanisa ukuba likhoboka.

Injongo yolu phononongo lwangoku yayikukuphanda ukuba ingaba amanqanaba ΔFosB zitshintshwa yindlela yokuziphatha enomvuzo yendalo efana nokubaleka nokuba inducible overexpression ye-ΔFosBkwimimandla ebethwayo inokulawula indlela yokuziphatha. Sibonisa apha ukuba, njengeziyobisi zokuxhatshazwa, ukuqhutywa okungapheliyo kubangela ΔFosB kwi-nucleus accumbens; ukongeza, ukuchazwa ngokugqithisileyo kwe-ΔFosB kwiiseti ezimbini ezahlukeneyo ze-striatal projection neurons zineziphumo ezichaseneyo ekusebenzeni kwevili. Idatha ityhila ukufana okumangalisayo phakathi kweziyobisi ezikhobokisayo kunye nokubaleka kwamavili kwaye icebisa indima ebalulekileyo ye-ΔFosB ekulawuleni zombini imbuyekezo yendalo kunye neziyobisi.

Icandelo langaphambiliIcandelo elilandelayo

IMPAHLA NENKQUBO

Izilwanyana. Iimpuku zaseLewis eziyindoda (iZiko lokuzalela iMøllegaard, eSkansved, eDenmark) ezinobunzima obungama-250 gm ekuqaleni kovavanyo zasetyenziswa. Iimpuku zazinokufikelela ad adum emanzini, ukutya, kunye namavili ahambayo. Baye kwi-12 hr ukukhanya / umjikelezo omnyama, kunye nezibane kwi-10 AM kunye nezibane ezivaliweyo kwi-10 PM Cages (43 × 22 × 20 cm) iqulethe ivili eliqhubayo kunye nobubanzi be-34 cm; kungoko, inguqu enye ihambelana ne-1.07 m. Emva kweeveki ze-4 zokuhamba ngesondo ngokuzithandela, iigundane zabulawa ngokuchithwa, kwaye izicubu zathathwa ngenxa yokuchithwa kwe-Western okanye i-perfused kunye ne-fixative kunye ne-processed for immunohistochemistry kunye. in situukuxubana.

Imigca emibini yeempuku ze-bitransgenic ezinokuthi zigqithise i-inducibly overexpress ΔFosB ngokukhethiweyo kwimimandla ye-striatal phantsi kolawulo lwenkqubo yokulawula imfuza ye-tetracycline nayo yasetyenziswa (Chen et al., 1998). Kumgca omnye, obizwa ngokuba yi-11A, ΔFosB I-inducibly overexpressed kuphela kwi-striatal projection neurons echaza i-neuropeptide dynorphin emva kokususwa kwe-doxycycline (UKelz et al., 1999). Komnye umgca, obizwa ngokuba yi-11B, ΔFosB i-inducibly overexpressed kakhulu kwi-striatal projection neurons echaza i-neuropeptide enkephalin emva kokususwa kwe-doxycycline, nangona enye intetho ibonakala kwi-dynorphin neurons nayo. Ulawulo kunye ΔFosB-i-overexpressing mice i-littermates ngaphakathi komgca ngamnye (i-11A kunye ne-11B) kwaye inokwakhiwa kwe-bitransgenic efanayo, enokuthi isebenze ngokususwa kwe-doxycycline. Zonke iigundane zakhulelwa kwaye zaphakanyiswa kwi-tetracycline derivative doxycycline kwi-dose ye-100 μg / ml emanzini okusela. Njengabantu abadala, isiqingatha seelitha ezibangelwayo zigcinwe kwi-doxycycline (ulawulo); esinye isiqingatha saye sasuswa kwi-doxycycline (ΔFosB overexpressers) kulo lonke ulingo. Kwiiveki ezintandathu emva kokususwa kwe-doxycycline, ngelo xesha ΔFosB intetho yaziwa njengowona mkhulu (Chen et al., 1998; UKelz et al., 1999), amavili abalekayo aye avulelwa zombini iimpuku kwi-tetracycline (ulawulo) kunye neempuku kumanzi etephu (Δ)FosB overexpressers), kwaye ukubaleka ngokuzithandela kwaqala. Ukuthintela ukuba kungenzeka ukuba i-doxycycline ngokwayo ichaphazele ukuziphatha kwesondo, sihlalutye ivili elisebenza kwiigundane ze-C57BL / 6 (uCharles River, i-Uppsala, eSweden) iphathwe nge-100 μg / ml doxycycline kwiiveki ze-6 ngaphambi kokuvunyelwa ukufikelela kwiivili ezihambayo. Iimpuku zaye zafakwa kwiikheji nge ad adum ukufikelela kumavili asebenzayo kwaye yahlala kwi-tetracycline ngexesha lonke lovavanyo. Iqela lolawulo lifumene amanzi okusela aqhelekileyo ngexesha lovavanyo lonke. Iikheji zeMouse (22 × 16 × 14 cm) ziqulethe ivili eligijimayo kunye nobubanzi be-12.4 cm; kungoko, ujikelezo olunye luhambelana no-0.39 m. Idatha eqhubayo kwiimpuku zombini kunye neempuku zathathwa rhoqo ngemizuzu engama-30 kusetyenziswa isoftware yekhompyuter eyenziwe ngokwezifiso.

Western blotting. Ubuchopho basuswa ngokukhawuleza kwiimpuku ezinqunyulwe iintloko kwaye zapholiswa kwi-ice-cold physiological buffer. Iipuntshi ezinobubanzi be-2 mm zisetyenziselwa ukukhangela izicubu ezivela kwi-nucleus accumbens kunye ne-medial and lateral caudate putamen kwi-1-mm-thick coronal slices yengqondo kwinqanaba le-bregma 0.7-1.7 mm (I-Paxinos ne-Watson, i-1997). Iisampulu zobuchopho zenziwe nge-homogenized kwi-1% ye-SDS, kwaye ukuzimisela kweprotheni kwenziwa ngokusebenzisa indlela ye-Lowry. I-Homogenates equkethe phakathi kwe-5 kunye ne-50 μg yeprotheni yalayishwa kwi-SDS-polyacrylamide gels kwaye iphantsi kwe-electrophoresis njengoko kuchaziwe. I-anti-Fos antibody yomvundla (1:4000; MJ Iadarola, National Institutes of Health, Bethesda, MD) okanye i-anti-FosB (N-terminal) antibody (1:4000; Santa Cruz Biotechnology, Santa Cruz, CA) yasetyenziselwa ubhaqo lwe-ΔFosB. Iiprotheyini zifunyenwe zisebenzisa i-horseradish peroxidase-conjugated IgG antibodies (1: 2000; Vector Laboratories, Burlingame, CA) elandelwa yi-chemiluminescence (DuPont NEN, Boston, MA). Amanqanaba e-immunoreactivity (IR) aqikelelwe kwinkqubo yohlalutyo lwemifanekiso esekelwe kwi-Macintosh, kwaye amanqanaba eprotheyini kwiisampuli zokulinga afaniswa nezo zolawulo. Amablothi adyojwe yi-amido emnyama ukuqinisekisa ukulayisha ngokulinganayo kunye nokudluliselwa kweegel. I-Blots nayo i-immunolabeled ye-68 kDa neurofilament protein, engazange ibonise umahluko phakathi kwamaqela okulinga kunye nokulawula (idatha engaboniswa).

Immunohistochemistry. Iimpuku ze-Lewis eziqhube iiveki ezi-4 kunye nolawulo olunamavili atshixiweyo zaye zafakwa i-anesthetized kakhulu nge-pentobarbital kwaye zixutywe ngaphakathi nge-50 ml ye-Ca.2+Isisombululo seTyrode esikhululekile (iqondo lokushisa kwegumbi) kuquka i-0.1 ml ye-heparin. Oku kwalandelwa yi-250 ml ye-fixative (4% paraformaldehyde kunye ne-0.4% ye-picric acid kwi-0.16m PBS, i-pH 7.4, kwindawo yokushisa). Ubuchopho buhlulwe kwaye bugcinwe kwi-fixative ye-1 hr kwaye emva koko buhlanjululwe kwi-0.1m ye-PBS kunye ne-10% ye-sucrose kunye ne-0.1% ye-sodium azide ngamaxesha amaninzi ngaphezu kwe-24 hr kwi-4 ° C ye-cryoprotection. Ubuchopho benziwe ngumkhenkce, kwaye i-14 μm amacandelo e-coronal aqokelelwa kumanqanaba aphakathi kwe-bregma 0.70 kunye ne-1.70 mm. Amacandelo ahlanjululwe kathathu ngemizuzu eyi-10 kwi-PBS ngaphambi kokufukamela ebusuku (4 ° C kwigumbi lokufuma) kunye ne-polyclonal ephambili ye-anti-FosB (N-terminal) antibody (1:500; i-Santa Cruz Biotechnology) kwi-0.3% i-Triton-PBS (150) μl kwicandelo ngalinye). Oku kulandelwa ngamahlambi amathathu ane-PBS yemizuzu eyi-10 ngaphambi kokufukanyelwa kwi-1 hr kwiqondo lobushushu begumbi kunye ne-antibody ye-IgG yesibini ye-biotinylated echasene nemivundla (1:200; iVector Laboratories) kwi-0.3% ye-Triton-PBS (150 μl kwicandelo ngalinye). Ezinye iirinse ezintathu kwi-PBS ye-10 min zenziwa ngaphambi kokuba i-avidin-biotin complex yongezwa (1: 100 kunye ne-1: 100, ngokulandelanayo, kwi-0.1 m PBS; 150 μl kwicandelo ngalinye). Emva kokuhlanjululwa kwemizuzu eyi-10, i-complex yabonwa emva kwe-7 min incubation kunye ne-substrate ngokweprotocol yomenzi (iVector Laboratories). Amacandelo emva koko ahlanjululwe kathathu ngemizuzu emi-5.

Endaweni yokuhlala ukuxubana. Kuba i-immunohistochemistry edibeneyo kunyein situ imifuniselo ye-hybridization, amacandelo obuchopho aye acutshungulwa kwi-immunohistochemistry athotyelwa ngokukhawulezain situ ukuxubana, okwenziwa ngokwenyani njengoko kuchaziwe ngaphambili (Seroogy et al., 1989; Dagerlind et al., 1992). Amashumi amane anesibhozo eemer DNA oligonucleotide probes ezithile zedynorphin (296-345) (Douglass et al., ngo-1989) kunye ne-enkephalin (235–282) (Zurawski et al., 1986I-mRNAs zaye zabhalwa ngokusasazwa nge- [α-35S]dATP (iDuPont NEN) kwi-3′ yabo iphela usebenzisa i-terminal deoxynucleotidyl transferase (Invitrogen, San Diego, CA) kumsebenzi othile we ~ 1 × 109 cpm/mg. I-cocktail ye-hybridization iqulethe i-50% ye-formamide, i-4× i-SSC (i-1× i-SSC yi-0.15m NaCl kunye ne-0.015 citrate ye-sodium, i-pH 7.0), i-1× isisombululo se-Denhardt, i-1% sarcosyl, i-0.02 mNa3PO4, pH 7.0, 10% dextran sulfate, 0.06 m dithiothreitol, kunye ne-0.1 mg/ml i-sheared salmon sperm DNA. I-Hybridization yenziwa i-18 hr kwigumbi elifumileyo kwi-42 ° C. Emva kokuxutywa, amacandelo ahlanjululwe kane kwimizuzu engama-20 nganye kwi-1 × SSC kwi-60 ° C. Emva koko, amacandelo ahlanjululwe ngamanzi a-autoclaved kwi-10 sec, aphelelwe ngamanzi ngotywala, kwaye omiswe ngomoya. Ekugqibeleni, i-emulsion ye-nuclear ye-NTB2 (i-diluted 1: 1 ngamanzi; i-Kodak, i-Rochester, i-NY) isetyenziswe ngokudipha. Emva kweeveki ezi-2-4 zokuvezwa, iislayidi zaphuhliswa nge-D19 (Kodak) kwaye zilungiswe kunye ne-Unifix (Kodak).

Amanani eeseli ezilungileyo ze FosB-IR kunye neeseli ezidibanisa i-FosB-IR kunye ne-dynorphin mRNA okanye i-enkephalin mRNA kwiigundane emva kweeveki ze-4 zokugijima (n = 8) kunye nolawulo (n = 8) zenziwa kwisilayidi esinye kwisilwanyana ngasinye ngumbukeli ozimeleyo owamfamekiswa kuyilo lokulinga. Uhlalutyo lwenziwa kwinqanaba le-bregma 1.2 mm (I-Paxinos ne-Watson, i-1997).

Iinkqubo zamanani. Ukuhlalutya umahluko kwi-ΔFosB amanqanaba phakathi kolawulo kunye neembaleki kuvavanyo lwe-Western blotting kunye ne-immunohistochemistry, t iimvavanyo zenziwa. Isiphumo sokuchazwa ngokugqithisileyo kwe-ΔFosB ekuqhubeni ukuziphatha kwiigundane ze-transgenic zahlalutywa kusetyenziswa i-ANOVA yeendlela ezimbini kunye nemilinganiselo ephindaphindiweyo, ukuhlalutya ngaphakathi kweqela kunye nemiphumo yeqela (i-Statistica version 99; StatSoft, Tulsa, OK).

Icandelo langaphambiliIcandelo elilandelayo

IINKCUKACHA

Ummiselo we-ΔFosB kwinucleus accumbens ngokubaleka kwamavili

Iimpuku ze-Lewis ezifakwe kwiikheji ezinamavili ahambayo zonyuse umthamo wazo wemihla ngemihla wokubaleka ngokulandelelana de kube yimini ye-13, xa bezinza kwi-10.210 ± 590 m/d (ithetha ± SEM). Eli nqanaba ligcinwe ngokufanelekileyo ngosuku lwe-32, xa izilwanyana zisetyenziselwa uhlalutyo lwe-biochemical. Ngexesha lokugqibela le-4 d, iigundane zibaleke 8.910 ± 900 m/d. Le ndlela yokuziphatha kwiimpuku zikaLewis iyafana naleyo ibikhe yabonwa ngaphambili (Werme et al., 1999). Emva koko, amanqanaba e-ΔFosB zahlalutywa ngokucinywa kweNtshona kwi-nucleus accumbens nakwi-medial and lateral caudate putamen ekusebenzeni (n = 7) kunye nokulawula (n = 7) iimpuku. Njengoko kubonisiwe kuMfanekiso 1, ukubaleka kwevili kunyukile ΔFosB amanqanaba e-37 kunye ne-35 kDa isoforms kwi-nucleus accumbens (p <0.05). Ngokwahlukileyo, kwakungekho mahluko ku-ΔFosB amanqanaba phakathi kweembaleki kunye nolawulo kwi-medial okanye i-lateral caudate putamen (idatha engaboniswa).

Umzobo 1.

Jonga inguqu enkulu:

Umzobo 1.

Ummiselo we-ΔFosB ngokubaleka kwevili. Amanqanaba e-35–37 kDa isoforms ye-ΔFosB zilinganiswe kwi-nucleus accumbens kusetyenziswa i-Western blotting kwiigundane zokulawula (C) nakwiimpuku eziqhube iiveki ezi-4 zokuqhutywa kwevili ngokuzithandela (R). umphezulu, Ummeli iindlela ukusuka kumabala. Idatha ichazwa njengentsingiselo ± SEM (amaqela omabini, n = 7). *p <0.05.

I-Immunohistochemistry iveze ubukho be-ΔFosB-iiseli ezilungileyo kwi-nucleus accumbens yolawulo (n = 8) kunye nokusebenza (n = 8) iimpuku. Amanani e-ΔFosB-iiseli ezilungileyo kumbindi kunye neqokobhe ziveze ukwanda kwenani leeseli ezibonisa ΔFosB-IR kumbindi (p <0.05) kodwa hayi kwiqokobhe lenucleus accumbens emva kokubaleka (Fig.2). Idityanisiwe i-immunohistochemistry ye-ΔFosB-IR kunye in situ Ukuxutywa kwe-enkephalin okanye i-dynorphin mRNA kwi-nucleus accumbens yasetyenziswa emva koko ukuchonga uhlobo lweseli ngaphakathi kommandla wobuchopho apho ΔFosB yenziwe ngokubaleka (Fig.3). Ngelixa inani leeseli ezibonisa zombini idynorphin mRNA kunye neFosB-IR yayiphezulu kwimbaleki (n = 8) kunolawulo (n = 8) (Itheyibhile1), inani eliphakathi kweeseli ezivakalisa zombini i-enkephalin mRNA kunye ne-FosB-IR kubagijimi yayiphantsi kunolawulo (Itheyibhile 1). Ezi ziphumo zabonakala kulwahlulo olungundoqo lwalo mmandla wobuchopho (Itheyibhile 1). Ezi ziphumo zibonisa ukuba ukuqaliswa kwe-ΔFosB ngokubaleka kwenzeka ikakhulu kwi-dynorphin-equlethe i-subset ye-nucleus accumbens neurons.

Umzobo 2.

Jonga inguqu enkulu:

Umzobo 2.

Ukubaleka kwevili kuchaphazela inani le ΔFosB-iiseli ezilungileyo kwi-nucleus accumbens.umphezulu, Ummeli weefotomicrographs zamacandelo engqondo yempuku ebonisa ukwanda kwenani ΔFosB-iiseli ezilungileyo kwi-nucleus accumbens core xa abagijimi (Run) zithelekiswe nolawulo (Ctr). aca, I-Anterior commissure ngaphambili.ezantsi, Ibar yegrafu yamanani eeseli ezilungileyo ze ΔFosB-IR kwimiba ye-medial ye-core kunye negobolondo ye-nucleus accumbens kwiigundane zokulawula kunye neegundane ezithatha iiveki ze-4 zokuhamba ngesondo ngokuzithandela. Idatha ichazwa njengentsingiselo ± SEM (amaqela omabini, n = 8). *p <0.05.

Umzobo 3.

Jonga inguqu enkulu:

Umzobo 3.

Iinkcukacha zeSelula ze-ΔFosBukwaziswa ngokubaleka kwevili. Ummeli weefotomicrographs zamacandelo engqondo yegundane ukusuka kubantu abasibhozo ababonisa ukuhlanganiswa kwe-ΔFosB-IR (iinuclei ezimdaka ngebalakunye nedynorphin mRNA (iinkozo ezimnyama) (a) okanye ΔFosB-IR kunye ne-enkephalin mRNA kwi-nucleus accumbens core (b).

Jonga le tafile:

Ithebula 1.

ΔFosB kwiiseli ze-dynorphin kunye ne-enkephalin kwi-nucleus accumbens

Isiphumo se-ΔFosB kwivili ukubaleka

Ukufunda indima enokwenzeka ka-ΔFosB ekulawuleni ukubaleka kwevili, sisebenzise imigca emibini yeempuku ze-bitransgenic ezidityaniswe ne-overexpress ΔFosB ngaphakathi kwemimandla ebulalayo yezilwanyana ezindala (Chen et al., 1998; UKelz et al., 1999). Umgca we-bitransgenic 11A unokwenza i-inducibly overexpress ΔFosB kuphela ngaphakathi kwe-dynorphin-equlethe i-neurons kwi-striatum (UKelz et al., 1999), kanti umgca we-bitransgenic we-11B unokugqithiswa ngokugqithisileyo ΔFosB ubukhulu becala kwi-enkephalin-equlethe i-neurons kulo mmandla, kunye nembonakalo ethile ebonwa kwi-dynorphin neurons ngokunjalo (Fig. 4). Yomibini imigca yeempuku yakhawulwa kwaye yaphakanyiswa kwi-doxycycline ukugcina i-ΔFosBintetho icinyiwe (Fig. 4) (UKelz et al., 1999), kunye nesiqingatha se-littermates sasuswa kwi-doxycycline njengabantu abadala ukuvula i-ΔFosB ibinzana.

Umzobo 4.

Jonga inguqu enkulu:

Umzobo 4.

Ukuchazwa kwe-ΔFosB kwiimpuku eziyi-11B. Amacandelo obuchopho ahlalutyelwe ΔFosB-IR (iinuclei ezimdaka ngebala) ilandelwe ngu in situ ukuxutywa kwedynorphin mRNA (A) okanye enkephalin mRNA (B) (iinkozo ezimnyama). Qaphela intetho ekhethiweyo ye ΔFosB-IR kwi-enkephalin-positive kodwa kungekhona iiseli ze-dynorphin-positive. Kwi 214 ΔFosB-iiseli ezintle ezibalwe kwiigundane ezintathu ze-11B, i-73 ± 11% nayo i-enkephalin enhle, kwaye i-22 ± 6% nayo yayiyi-dynorphin positive. Akukho mbhalo-mbini uboniweyo phakathi kwe-ΔFosB kunye neziphawuli ze-interneuron.

11Iimpuku ezibonisa ngokugqithisileyo ΔFosB (akukho doxycycline) (n = 7) zifunyenwe ukwandisa umgama wabo wokuhamba imihla ngemihla kwiiveki zokuqala ze-3 xa kuthelekiswa nokulawulwa kwe-littermate (enikwe i-doxycycline) (n = 8), ebonise i-plateau kwizinga labo lokugijima emva kweeveki ze-2 (Fig.5 A). Umahluko omangalisayo, iimpuku eziyi-11B ezichaze ngokugqithisileyo ΔFosB (n = 7) ibonise umsebenzi ophantsi kakhulu wokubaleka kwiiveki ze-2 kunye ne-3 kunolawulo lwabo lwe-littermate (n = 6) (umzobo. 5 B). Ukuphanda ukuba kungenzeka ukuba i-doxycycline ngokwayo inokuguqula indlela yokuziphatha, siye sathelekisa ukubaleka kwevili le-C57BL/6 iimpuku kunye nangaphandle kwe-doxycycline emanzini azo okusela. Akukho mahluko phakathi kwamaqela ufunyenwe (idatha ayiboniswanga).

Umzobo 5.

Jonga inguqu enkulu:

Umzobo 5.

Isiphumo se-ΔFosB ukubonakalisa ivili elibalekayo kwiimpuku ze-bitransgenic. A, iimpuku ze-Bitransgenic ezisela amanzi epompo zine-inducible overexpression ye-ΔFosB kwi-striatal dynorphin neurons (amanzi) kwaye ubonise ukunyuka kokubaleka (umgama ngosuku) kwiiveki zokuqala ze-3 zokufikelela kumavili asebenzayo. Ngokwahlukileyo, ulawulo lwe-littermate olufana nofuzo kunye ne-doxycycline emanzini abo okusela angenayo i-overexpress ΔFosB (dox) ibonise ukunyuka kokubaleka kwiiveki ezi-2 zokuqala kuphela. B, Omnye umgca we-bitransgenic strain yeempuku, ebizwa ngokuba yi-11B, ene-inducible overexpression ye-ΔFosB ngokuyintloko kwi-striatal enkephalin neurons (amanzi) babonise ukubaleka kancinci ngexesha leeveki zabo ze-2 kunye ne-3 xa kuthelekiswa ne-littermates efana nemfuzo engabonakalisi ΔFosB (dox). # ibonisa ukunyuka kokubaleka (umgama ngeveki) phakathi kweqela. * ibonisa umahluko ekusebenzeni phakathi kwe ΔFosBii-overexpressers (amanzi) kunye nolawulo (dox). Imigca efana bonisa imida phakathi kweveki yoku-1 neye-2, kunye neveki yesi-2 neyesi-3. Imigca ehambayo kunye nesimboli # chaza umahluko wamanani phakathi kokuqhuba ngeveki phakathi kweqela. Idatha ichazwa njengentsingiselo (11A dox,n = 8; 11Amanzi, n = 7; 11B dox, n = 6; 11B amanzi, n = 7).# p <0.05;## p <0.01;### p <0.001; *p<0.05.

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UKUQALA

Kolu phononongo, sibonisa ukuba njengokuvezwa ngokuphindaphindiweyo kwiziyobisi zokusetyenziswa kakubi, ukuhamba kwevili elingapheliyo, ukuziphatha okuvuzayo kwendalo, kubangela ΔFosB kwi-nucleus accumbens, inxalenye ebalulekileyo yeendlela zomvuzo wengqondo. Sikwabonisa ukuba ukugqithiswa kwe-ΔFosB kwi-striatal dynorphin neurons yezilwanyana ezikhulileyo zonyusa ukuziphatha okusebenzayo, ngelixa i-ΔFosB intetho ngokuyintloko kwi-striatal enkephalin neurons inesiphumo esichaseneyo. Ezi data zixhasa imboniselo ΔFosB ibandakanyeka kakhulu kwiziphumo zexesha elide zembuyekezo yendalo kunye neziyobisi kwaye igxininisa indima ebalulekileyo ye-ΔFosB kulawulo lomsebenzi wokubethelwa.

Iimpendulo zemolekyuli ezifanayo kwiziyobisi zokuxhatshazwa kunye nokusebenza

Iziyobisi zokusetyenziswa gadalala ngokwahlukeneyo njengee-psychostimulants, opiates, alcohol, nicotine, kunye nephencyclidine zonyusa amanqanaba e-ΔFosB kwi-nucleus accumbens (Ithemba et al., 1994b; Nye et al., 1995; UNye noNestler, ngo-1996; Nestler et al., 1999), kwaye apha sibonisa ukuba ukuziphatha okungapheliyo kubangela impendulo efanayo. I-cocaine engapheliyo kunye nokusebenza kubangela uhlengahlengiso olongezelelweyo oluqhelekileyo, umzekelo, ukufakwa kwe-dynorphin mRNA kwimimandla ethile ye-striatum (Werme et al., 2000). Njengoko bekutshiwo ngaphambili ngecocaine (Hiroi et al., 1997), ukwenziwa kwe ΔFosB ngokubaleka kunamandla kumbindi kunakwiqokobhe lolwahlulo lwenucleus accumbens. Nangona kunjalo, ΔFosBUkuqaliswa ngokubaleka kuthintelwe kwi-nucleus accumbens, ngelixa iziyobisi zokuxhatshazwa zikhuthaza iprotein kwi-caudate putamen ngokunjalo. Izifundo zangaphambili zibonise ukuba ΔFosB ibonakaliswa kuphela kwi-neurons ye-striatum, kwaye i-cocaine engapheliyo yonyuka ΔFosB ngokukhethekileyo kwi-subpopulation ye-neuron ebonisa i-dynorphin (Moratalla et al., 1996). Kwisifundo esikhoyo, ngokusetyenziswa kwe-immunohistochemistry edibeneyo kunyein situ ukuxubana kumacandelo eethishu ezifanayo, sibonise ukuba ivili elibalekayo nalo libangela u-ΔFosB ngokukhethekileyo ngaphakathi kwedynorphin neurons.

Ukufumanisa ukuba umvuzo wechiza kunye nomvuzo wendalo ukhuthaza ukulungelelaniswa kwemolekyuli efanayo (ukwenziwa kwe-ΔFosB) kuhlobo lweeseli ze-neuronal lucebisa ukuba ezi zimbini zinokusebenza ngendlela eqhelekileyo. Enye indlela eqhelekileyo eqhelekileyo kukwandisa ukuhanjiswa kwe-dopaminergic kwi-nucleus accumbens. Ukubaleka kunye nolawulo olungqongqo lweziyobisi eziluthayo kwandisa amanqanaba angaphandle kwe-dopamine kulo mmandla wobuchopho (Ukhululekile kunye no-Yamamoto, i-1985; I-Di Chiara kunye ne-Imperato, i-1988; UWilson noMarsden, i-1995). Unyango oluphindaphindiweyo kunye no-D1 i-dopamine receptor agonist (+/-)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin hydrobromide iyodwa okanye idibene ne-D2 i-receptor agonist quinpirole iya kwandisa amanqanaba e-ΔFosB kwi-nucleus accumbens kunye ne-dorsal striatum (Nye et al., 1995). Iziyobisi zePsychostimulant ezikhobokisayo ezifana necocaine kunye ne-amphetamine, eziyi-dopamine agonists ezingathanga ngqo, nazo zonyusa ΔFosB amanqanaba kwimimandla yestriatal (UJaber et al., ngo-1995; Nye et al., 1995). Ukongeza, ulawulo olungapheliyo lwe-dopamine transporter antagonist 1- [2- (bis [4-fluorophenyl] methoxy) ethyl] -4- (3-hydroxy-3-phenylpropyl) ipiperazinyl decanoate, kodwa hayi ye-serotonin- okanye i-norepinephrine- ezikhethiweyo zokuthutha inhibitors, yenza ΔFosB kule mimandla yobuchopho (Nye et al., 1995). Ezi ziphumo zibonisa ukuba ukwenziwa kwe-ΔFosB kwi-striatum emva konyango olwahlukeneyo luxhomekeke kwi-dopamine.

Iziphumo ezichasayo ze-ΔFosB Uxinzelelo kakhulu kwi-striatal dynorphin ngokuchasene ne-enkephalin neurons kwindlela yokubaleka kwamavili

Iimpuku ze-bitransgenic ezine ΔFosB ukubonakaliswa okugqithisileyo okubangelwa ukususwa kwe-doxycycline kwizilwanyana ezikhulileyo akubonisi ukungaqhelekanga kophuhliso. Kwiimpuku apho ΔFosBUkugqithisa ngokugqithiseleyo kukhetha i-striatal dynorphin neurons, ukuziphatha okusebenzayo kunyukile kwiiveki zokuqala ze-3 zokugijima, endaweni yeeveki zokuqala ze-2 njengoko zibonwa kulawulo lwe-littermates. Ngokuchaseneyo, iimpuku ezibonisa ngokugqithisileyo ΔFosB ngokuyinhloko kwi-striatal enkephalin neurons iqhube ngaphantsi kwe-littermates yabo yokulawula ngexesha leveki ye-2 kunye ne-3 yokusebenza. Okubangela umdla kukuba, le migca mibini yeempuku ze-bitransgenic efundwe apha ikwabonisa iimpendulo ezahlukeneyo zokuziphatha kwiziyobisi zokuxhatshazwa. Ngexa ukuchazwa ngokugqithisileyo kwe-ΔFosB kwi-dynorphin neurons yonyusa iziphumo ezinomvuzo ze-cocaine kunye ne-morphine (UKelz et al., 1999; Nestler et al., 2001), ukuchazwa ngokugqithisileyo kwe-ΔFosB ngokuyinhloko kwi-neurons ye-enkephalin ayitshintshi imiphumo evuzayo yala machiza.

Iziphumo ezichaseneyo ekuziphatheni okubonakalayo kwimigca emibini yeempuku zinokuchazwa ngokwahlukana kokujikeleza kwezi zimbini zahlukileyo ze-neurons ezibulalayo. Ngaphezulu kwe-90% ye-striatal neurons yi-medium spiny projection neurons esebenzisa i-GABA njenge-neurotransmitter. Ngokumalunga nesiqingatha sezi neurons zikwabonakalisa amanqanaba aphezulu edynorphin kunye ne-substance P (kwaye kwinqanaba elithile i-D1 i-dopamine receptor) (UGerfen et al., 1990; Le Moine et al., 1991) kwaye iprojekthi ngqo kwi-midbrain. Esinye isiqingatha sichaza amanqanaba aphezulu e-enkephalin (kunye noD2i-dopamine receptor) (UGerfen et al., 1990; Le Moine et al., 1990) kunye neprojekthi ngokungathanga ngqo kwi-midbrain ngeglobus pallidus kunye ne-subthalamic nucleus. Ukusebenza kwendlela ethe ngqo kwandisa ukuhamba, ngelixa ukusebenza kwendlela engathanga ngqo kunciphisa ukuhamba. Ke ngoko, utshintsho oluhambelanayo kwindlela yokuziphatha eboniswe yimigca emibini ye-ΔFosB-Iimpuku ezivezwa ngokugqithisileyo ezisetyenziswe kule mifuniselo zinokubonisa ΔFosB-utshintsho oluye lwenziwa kwi-excitability yendlela ethe ngqo ngokuchasene nendlela engathanga ngqo. Ngayo le migca, inika umdla ukuqikelela ukuba ukucutha kwevili ukubaleka kubonwa kwiimpuku ezigqithisa ngokugqithisileyo ΔFosB ngokuyinhloko kwi-enkephalin neurons inokuhambelana nenyaniso yokuba izidakamizwa ze-antipsychotic zesizukulwana sokuqala, ezinciphisa umsebenzi we-locomotor, zenza i-ΔFosB ngokukhethiweyo ngaphakathi kolu luhlu lwe-neuronal (UHiroi noGreybiel, i-1996; Atkins et al., 1999).

Ufuzo ekujoliswe kulo lulawulwa ngu ΔFosB

Iziphumo ze-ΔFosB kumsebenzi we-neuronal kuqikelelwa ukuba zilamlwa ngolawulo lwezinye iijini. Ngenxa yokuba izakhi zofuzo ezininzi ziqulethe iindawo zemvumelwano ze-AP-1 kwizakhiwo kwiindawo zabo zokukhuthaza, kunokwenzeka ukuba izenzo ze-ΔFosB kwii-neuron zibandakanya iziphumo ezinzima kwiijini ezininzi. Bambalwa abachongiwe ukuza kuthi ga ngoku. I-AMPA glutamate receptor subunit 2 (GluR2) ilawulwa ngu-ΔFosB kwi-nucleus accumbens, umphumo ongabonakali kwi-dorsal striatum (UKelz et al., 1999). I-Cyclin-dependent kinase 5 (Cdk5) iphakanyiswe kuzo zombini i-nucleus accumbens kunye ne-dorsal striatum (Bibb et al., 2001). Ezi ziphumo zinokulamlwa ngokusebenzisa iisayithi ze-AP-1 ezikhoyo kwimimandla yokukhuthaza ezi genes (Brene et al., 2000; Chen et al., 2000). Ukulawulwa kwe-GluR2 kuya kulindeleka ukuba kutshintshe ukonwaba kombane kwi-striatal neurons ngokuguqula i-AMPA receptor sensitivity. Ukulawulwa kwe-Cdk5 kunokutshintsha kwakhona ukuba mnandi kwezi neurons ngendlela ebandakanya i-dopamine kunye ne-cAMP-elawulwa yi-phosphoprotein-32, etyetyiswe kakhulu kwi-striatal medium spiny neurons.Brene et al., 1994; Bibb et al., 1999). Nangona kunjalo, umsebenzi owongezelelweyo uyafuneka ukuchonga iindlela ezichanekileyo zemolekyuli apho ΔFosB, ngotshintsho kwintetho yezinye izakhi zofuzo, iguqula imeko yokusebenza ye-striatal dynorphin kunye ne-enkephalin neurons.

izigqibo

Iziphumo zokuba uhlengahlengiso olufanayo lwemolekyuli lwenzeka kwi-nucleus accumbens kwiimeko zomvuzo wendalo kunye neziyobisi zicebisa ukuba iindlela eziqhelekileyo ze-neurobiological zinokulawula zombini iintlobo zokuziphatha okuvuzayo. Undoqo wokufana phakathi kwezi ndlela zokuziphatha yindalo yazo ekhobokisayo. ΔFosB Uchukunyiswa zizo zombini iindlela zokuziphatha kwaye uphucula zombini izimilo xa ngokuzimeleyo uxinezeleke kakhulu kwi-striatal dynorphin neurons. Mhlawumbi ΔFosB, xa ichazwa kwezi neurons, ivuselela i-neural circuit ehambelana nokuziphatha okunyanzelekileyo. Nangona kuqikelelwa, ukwanda kolwazi malunga ΔFosB icebisa ukuba yona, okanye iindlela ezahlukeneyo zemolekyuli eyilawulayo, inokuba yinto ekujoliswe kuyo efanelekileyo kuphuhliso lonyango lwamachiza kuluhlu lwezifo. Imizekelo yoku inokuba kukuziphatha okunyanzelekileyo, kubandakanywa kungekuphela nje ukukhotyokiswa ziziyobisi kodwa kunye nokuphazamiseka kokutya, ukungcakaza ngezifo, umthambo ogqithisileyo, kunye nokuba nengxaki yokunyanzelisa.

Icandelo langaphambiliIcandelo elilandelayo

Imihlathi

  • Ifumene ngoJanuwari 29, 2002.
  • Uhlaziyo olufunyenwe ngoJuni 11, 2002.
  • Yamkelwa ngo-Juni 12, 2002.
  • Lo msebenzi uxhaswe liBhunga loPhando laseSweden (03185, 11642, kunye ne-04762), iCentrum för idrottsforskning (CIF 86/01), iZiko leSizwe lokuSetyenziswa gwenxa kweZiyobisi, kunye Isizwe seSizwe sokuguga. Sibulela uKarin Pernold kunye noKarin Lundströmer ngoncedo olubalaseleyo lobugcisa.
  • Imbalelwano kufuneka ibhekiswe kuStefan Brené, iSebe leNeuroscience, iKarolinska Institutet, iStockholm, iS-171 77 Sweden. I-imeyile: [imeyile ikhuselwe].
  • Copyright © 2002 Society for Neuroscience

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