I-DeltaFosB ku-Nucleus Accumbens yiyona Eyimbangela Yokuvuselela Imiphumela Yomvuzo Wezocansi. (I-2010)

IMIBUZO: IDelta FosB iyimpawu yazo zonke izidakamizwa, zokuziphatha nezamakhemikhali. Njengoba le molekyuli inyuka esifundeni somvuzo kanjalo nokuziphatha okuluthayo. Ngenye yama-molecule abandakanyeka kuzinguquko ze-neuroplastic. Lokhu kuhlolwa kukhombisa ukuthi kuyanda ngokuhlangenwe nakho kocansi, ngokufanayo nokuthi kwenzeka kanjani ngokulutha kwezidakamizwa. Ekuhlolweni basebenzise ubunjiniyela bezakhi zofuzo ukukhuphula amazinga ayo ngaphezu "kokujwayelekile". Lokhu kuholele ekwenzeni lula ukwenza umsebenzi wezocansi. Sicabanga ukuthi lokhu kwenzeka ngokulutha kocansi.

ISIHLOKO ESIFUNDWAYO

Pitchers KK, Frohmader KS, Vialou V, Mouzon E, Nestler EJ, Lehman MN, Coolen LM.

I-Genesin Brain Behav. I-2010 Oct; 9 (7): 831-40 i-doi: 10.1111 / j.1601-183X.2010.00621.x. I-Epub 2010 Aug 16.

Umnyango we-Anatomy ne-Cell Biology, iSchool School of Medicine kanye namaDentistry, eNyuvesi yaseWestern Ontario, eLondon, e-Ontario, eCanada.

UKUQALA

Ukuziphatha ngokobulili kumagundane wesilisa kuvuza futhi kuqinisa. Kodwa-ke, kuncane okungaziwa mayelana nezinsizakalo ezithile zamaselula nezindlela zamakhemikhali ezixazulula umvuzo wezocansi noma imiphumela yokuqinisa umvuzo ekuboniseni okulandelayo kokuziphatha ngokobulili. Lolu cwaningo luvivinya ukuthi i-ΔFosB, ifomu elimiswe ngokucacile le-FosB, lidlala indima ebalulekile ekuqinisekiseni ukuziphatha ngokocansi kanye nokugqugquzelwa kwezenzo zesisusa nokusebenza kocansi.

Okuhlangenwe nakho kobulili kuboniswe ukuthi kubangele ukuqoqwa kwe-FosB ezindaweni eziningana zobuchopho ezingxenyeni ezihlanganisa i-nucleus accumbens (NAc), i-prefrontal cortex yangaphakathi, indawo ye-ventral tegmental kanye ne-caudate putamen kodwa hhayi i-nucleus yangaphambili ye-preoptic.

Okulandelayo, ukufakwa kwe-c-Fos, isici esingaphansi (esiphenduliwe) se-ΔFosB, silinganiselwe izilwane ezitholakalayo ngokobulili nezilwane. Inombolo yamaseli c-Fos-immunoreactive eyenziwe ngokuxubanisa ahlaselwe kakhulu ekuzilwaneni okubhekwa ngokocansi uma kuqhathaniswa nezilawuli zobulili.

Okokugcina, amazinga we-FosB kanye nomsebenzi walo ku-NAc basebenziselwa ukusebenzisa ukudluliswa kwegciwane lesandulela ngculazi ukuze bafunde indima yawo engaba khona ekuxhumaniseni isipiliyoni socansi kanye nokusizwa okuhlangenwe nakho kohlelo lokusebenza kocansi. Izilwane ezine-ΔFosB ngokweqile ziboniswa ukuthuthukiswa okuthuthukisiwe kokusebenza kocansi ngesipiliyoni socansi ngokuphathelene nezilawuli. Ngokuphambene nalokho, ukubonakaliswa kwe-AJunD, umlingani obophezelayo obophezelayo we-ΔFosB, okwehlisiwe okuhlangenwe nakho kobulili-ukugqugquzelwa kokusebenza kocansi nokulondolozwa okwesikhashana isikhathi eside sokwenza ngcono uma kuqhathaniswa namaprotheni aluhlaza okwedlulele namaqembu e-FosB overexpressing.

Ngokubambisana, lezi zithole zisekela indima ebalulekile ye-ΔFosB inkulumo e-NAc yokuqinisa imiphumela yokuziphatha ngokocansi kanye nokuhlangenwe nakho kobulili-ukugqugquzelwa kokusebenza kocansi.

ISINGENISO

Ukuziphatha ngokobulili kuvuza kakhulu futhi kuqinisa ama-rodents wesilisa (Coolen et al. I-2004; Pfaus et al. 2001). Ngaphezu kwalokho, isipiliyoni socansi siguqula ukuziphatha ngokocansi okulandelayo nokuvuza (Tenk et al. 2009). Ngokuhlangenwe nakho okuphindiwe okuphindaphindiwe, ukuziphatha kocansi kusetshenziselwa noma "kuqiniswa", kuboniswe ukunciphisa ama-latencies ukuze kuqaliswe ukulinganisa nokusekela ukusebenza kocansi (Balfour et al. 2004; Pfaus et al. 2001). Kodwa-ke, izindlela ezisetshenziswayo zamangqamuzana nezindlela zamakhemikhali zomvuzo wobulili nokuqiniswa aziqondakali kahle. Ukuziphatha ngokocansi kanye namagama afanelekile okubikezela ukuthi ukubeletha kukhonjisiwe kukhonjiswe ngokuphindaphindiwe ukuveza inkulumo ye-gene-c-fos esheshayo esimisweni se-mesolimbic samantombazane (Balfour et al. 2004; Pfaus et al. 2001). Ngaphezu kwalokho, kusanda kuboniswa ukuthi isipiliyoni socansi senza i-neuroplasticity ehlala isikhathi eside ohlelweni lwesilwane samasilonda (i-rat eyelimbic system)Frohmader et al. 2009; Pitchers et al. 2010). Ngaphezu kwalokho, kumagundane wesilisa, isipiliyoni socansi siye saboniswa ukuthi senze i-ΔFosB, a Ilungu lomndeni wakwaFos, ku-nucleus accumbens (NAc) (Wallace et al. 2008). I-FosB, i-FosB eyisiqephu esinqunyiwe, iyilungu eliyingqayizivele lomndeni wakwaFos ngenxa yokuzinza okukhulu (I-Carle et al. 2007; Ulery-Reynolds et al. 2008; Ulery et al. 2006) futhi idlala indima ekugqugquzelweni okuthuthukisiwe kanye nomvuzo wezidakamizwa zokuhlukumeza kanye ne-plastic neural plastic mediating the addiction (Nestler et al. 2001). I-ΔFosB ihlanganisa i-heteromeric transcription factor complex (i-activator protein-1 (AP-1)) nama-proteins kaJun, okungcono uJunD (Chen et al. 1995; Hiroi et al. 1998). Nge-inducible over-expression ye-ΔFosB, ngokuyinhloko ivinjelwe ku-striatum isebenzisa amagundane we-bi-transgenic, i-phenotype edlalwa izidakamizwa ezinjengezidakamizwa ikhiqizwa naphezu kokungabikho kwezidakamizwa ezedlule (McClung et al. 2004). Le phenotype yokuziphatha ihlanganisa impendulo yokuvakasha etholakalayo ku-cocaine (Kelz et al. 1999), ukhetho olwandayo lwe-cocaine (Kelz et al. 1999) kanye ne-morphine (Zachariou et al. 2006), futhi ukwanda kwe-cocaine self-administration (I-Colby et al. 2003).

Ngokufana nomvuzo wezidakamizwa, i-API ihlukunyezwa ngokuziphatha okuvuzayo kwemvelo iphinde ixoxisane nalokho okushiwo ukuziphatha. Ukubhekwa ngokweqile kwe-ΔFosB ku-NAc usebenzisa ama-rodent models kwenza i-wheel voluntary isebenze (Werme et al. 2002), i-instrumental ephendula ngokudla (Olausson et al. 2006), siphunga ukudla (Wallace et al. 2008), futhi kusiza owesilisa (Wallace et al. 2008) futhi owesifazane (Bradley et al. 2005) ukuziphatha ngokocansi. Ngakho-ke, i-ΔFosB ingase ibandakanyeke ekuxhumaniseni imiphumela yemiphumela evuzayo yemvelo. TUcwaningo lwamanje luyaqhubeka ngezifundo zangaphambilini ngokuphenya ngokubheka indima ye-ΔFosB ku-NAc emiphumeleni yesikhathi eside yesazi ocansini ngokuziphatha okulandelanayo okulandelayo nokusebenza kwe-neural ohlelweni lwe-mesolimbic.

  • Okokuqala, kwakhiwe ukuthi iziphi izifunda zobuchopho ezibandakanyekile emjikelezweni wesifunda kanye nokuziphatha ngokobulili okuvezwa ngokocansi-kubangele i-ΔFosB.
  • Okulandelayo, umphumela wesipiliyoni socansi-owenziwe i-ΔFosB ekuboniseni okufakwe ukulinganisa kwe-c-Fos, ilitshe elingezansi elicindezelwe i-ΔFosB (Renthal et al. 2008), waphenywa.
  • Okokugcina, umphumela wokwenza umsebenzi we-FosB ku-NAc (ukukhulunywa ngokwezakhi zofuzo kanye nokuboniswa komlingani obambelele kabi) ekuziphatheni ngokocansi kanye nokusizwa okuhlangenwe nakho kwezenzo zesisusa nokusebenza kocansi kunqunyelwe ukusebenzisa ubuchwepheshe be-vector delivery technology.
Iya ku:

IZINDLELA

Izilwane

Amantombazane amadala aseSprague Dawley (ama-200-225 amagremu) atholakala kuCharles River Laboratories (Senneville, QC, Canada). Izilwane zahlala emagodini e-Plexiglas ngebhayisikili yomhubhe ephakathi kwezilinganiso ezifanayo zobulili phakathi nokuhlolwa. Ikamelo lekoloni lalibusheshisa-lilawulwa futhi ligcinwe ku-12 / 12 hr umjikelezo omnyama omnyama nokudla namanzi atholakalayo isikhangiso ngaphandle kokuhlolwa kokuziphatha. Ama-stimulus females (ama-210-220 amagremu) okwenziwa ngezikhathi zokulinganisa athola isitshalo esincane esine-5% estradiol benzoate kanye ne-95% ye-cholesterol elandela i-ovariectomy ephakathi kwamabili ngaphansi kwe-anesthesia ejulile (0.35g ketamine / 0.052g Xylazine). Ukwamukelwa ngokocansi kwabangelwa ukuphathwa kwe-500μg progesterone ku-0.1 mL yamafutha esameya cishe amahora angu-4 ngaphambi kokuhlolwa. Yonke inqubo yamukelwa yi-Animal Care kanye namakomidi asetshenziswayo eNyuvesi yaseWestern Ontario futhi ihambisane nemikhombandlela yeCACAC ehilela izilwane ze-vertebrate ekucwaningweni.

Ukuziphatha ngokocansi

Izikhathi zokuxubana zenzeke ngesikhathi sesimnyama (phakathi kwamahora angu-2-6 ngemva kokuqala kwesikhathi esimnyama) ngaphansi kokukhanya okubomvu okubomvu. Ngaphambi kokuzama, izilwane zahlukaniswa ngezigaba ngezigaba. Ngesikhathi sokulinganisa izimpondo zamadoda zavunyelwa ukuba zilandele ukujula noma ihora le-1, futhi imingcele yokuziphatha ngokocansi ibhalwe phansi kufaka: ukuphakama kwe-latency (i-ML; isikhathi kusukela kokusungulwa kwabesifazane kuze kube sekuqaleni), i-latency intromission (i-IL; isikhathi kusukela ekungenisweni i-feminine kuze kube yilapho iqala ukufaka ukungenwa kwesisu), i-ejaculation latency (i-EL; isikhathi kusukela ekungeneni kokuqala ukuya ekujuleni), isikhathi sokuthunyelwa kwe-ejaculation (i-PEI; isikhathi esivela ekujuleni kuya kokungeniswa kokuqala okulandelayo), inani lezintaba (M; ukungena), inombolo ye-intromissions (i-IM; ukukhuphuka kufaka ukungena kwesisindo) nokusebenza kahle kwamandla (CE = IM / (M + IM)) (I-Agmo 1997). Izinombolo zezintaba nokungahambanga kahle akuhlanganisiwe ekuhlaziyweni kwezilwane ezingazange zibonise ukujula. Izintaba ze-Mount ne-intromission yizimpawu ezibonisa ukugqugquzela ngokocansi, ngenkathi i-ejaculation latency, inani lezintaba nokusebenza kahle kwe-copulation kubonisa ukusebenza kocansi (I-Hull 2002).

Isivivinyo 1: Ukuveza kwe-ΔFosB

Amagundane angamadoda angaziwa ngokocansi avunyelwe ukuba abambisane namakheji ahlanzekile (60 × 45 × 50 cm) ye-5 imihlangano elandelanayo, yokulinganisa nsuku zonke noma ehlala engavumelani ngokobulili. Ithebula Lokungezelela 1 iveza i-paradigm yokuziphatha yamaqembu okuhlola: i-naïve no-sex (NNS; n = 5), ubulili be-naïve (NS; n = 5), abangekho ucansi (ENS; n = 5) kanye nobulili obuhlangenwe nakho (ES; n = 4). Izilwane ze-NS ne-ES zanikezwa ihora le-1 ngemuva kokukhishwa kwesikhashana ngosuku lokugcina lokubambisana ukuphenya ukukhuluma okukhulunywe nge-c-Fos. Izilwane ze-NNS zanikelwa ngesikhathi esifanayo ne-ENS izilwane ze-24 amahora ngemva kokugcina kokuhlangana kokuhlola ukuhlola ubulili-okubangelwa i-ΔFosB. Amaqembu ahlangene ngokobulili afanelwe ukuziphatha ngokocansi ngaphambi kokuhlolwa okulandelayo. Akukho ukungafani okuphawulekayo okutholakala phakathi kwamaqembu nganoma yiziphi izinyathelo zokuziphatha ngaphakathi kweseshini lokuxuba esifanelekile kanye nokuqeqeshwa okuhlangenwe nakho kobulili-ukugqugquzelwa kokuziphatha ngokobulili kuboniswe ngamabili amaqembu ahlangene (Ithebula Lokungezelela 2). Izilawuli zazibandakanya abesilisa abathandana nabo ngokobulili abanjwe ngesikhathi esifanayo nezilwane eziqhamukayo ukuqinisekisa ukuvezwa kwamakha amahhala kanye nokuqanjwa kwamagama ngaphandle kokuxhumana ngqo kwabesifazane.

Ukuhlatshwa kwemfuyo, izilwane zazixoshwa ngokujulile zisebenzisa i-sodium pentobarbital (270mg / kg; ip) futhi zenziwe ngokungenasisekelo nge-50 mL ye-0.9% saline, ilandelwe i-500 mL ye-4% ye-paraformaldehyde ku-0.1 M i-phosphate buffer (PB). Ama-Brain asusiwe futhi ashintshwe ngemuva kwe-1 h ekamelweni lokushisa endaweni efanayo, bese efakwe ku-20% sucrose no-0.01% sodide azide ku-0.1 M PB futhi agcinwe ku-4 ° C. Izigaba ze-coronal (35 μm) zazinqunywa nge-microtome efrijini (H400R, i-Micron, eJalimane), iqoqwe ngochungechunge ezine oluhambisana nesikhambi se-cryoprotectant (30% sucrose ne-30% ethylene glycol ku-0.1 M PB) futhi igcinwe ku-20 ° C. Izigaba ezihambayo zamahhala zihlanziwe kakhulu nge-0.1 M i-phosphate-buffered-saline (PBS; pH 7.3-7.4) emkhatsini wokukhushulwa. Izigaba zavezwa ku-1% H2O2 i-10 min ekamelweni lokushisa ukubhubhisa i-peroxidase engapheli, ivinjelwe ku-PBS + yokuxubha ukuxubusha, okuyi-PBS equkethe i-0.1% ye-serum albinini (into yohlu lwe-005-000-121; i-Jackson ImmunoResearch Laboratories, i-West Grove, i-PA) ne-0.4% iTriton X -100 (ikhathalogu into ethi BP151-500; Sigma-Aldrich) ye-1 h. Ngakho-ke izingxenye zazingeniswa ebusuku ngo-4 ° C ku-anti-rabbit ye-pan-FosB ye-rabbit polyclonal (i-1: i-5K; i-sc-48 i-Santa Cruz Biotechnology, i-Santa Cruz, i-CA, e-USA). I-anti-panic FosB ikhuliswe ngokumelene nesifunda sangaphakathi esabelwe yiFosB no-ΔFosB. Amaseli e-ΔFosB-IR ayeyi-ΔFosB-positive ngokuqondile ngoba ngesikhathi sokuthutha emva kwesikhathi (amahora angu-24) yonke i-FosB eyenziwe yikhuthazo ehlonishwayo (i-FosB)I-Perrotti et al. 2004; I-Perrotti et al. 2008). Ngaphezu kwalokho, kulolu cwaningo, izilwane ezixubha ngosuku lokugcina (NS, ES) zanikelwa ngo-1 h ngemuva kokuxubana, ngaleyo ndlela ngaphambi kokukhuluma kwe-FosB. Ukuhlaziywa kwe-Western blot kuqinisekisile ukutholakala kwe-ΔFosB cishe ne-37 kD. Ngemuva kokunciphisa ama-antibody okuyisisekelo, izingxenye zihanjelwe i-1 h ku-IgG ye-bi-gog imbuzi ehlanjululwe yi-biotin-1 e-PBS; i-Vector Laboratories, i-Burlingame, i-CA, e-USA) bese i-500 i-avidin-biotin-hoseradish peroxidase (ABC elite ; 1: 1K ku-PBS; i-Vector Laboratories, i-Burlingame, i-CA, e-USA). Ukulandela lezi zigaba zokufakelwa ukucubungula kwacutshungulwa ngenye yezindlela ezilandelayo:

I-1. Ukubhalisa kwe-single peroxidase

Izigaba zezilwane ze-NNS ne-ENS zisetshenziselwe ukuhlaziywa kobuchopho obuningi obuncatshangelwa ucansi lwe-DFFB. Ukulandela ukuxubha kwe-ABC, inkimbinkimbi ye-peroxidase iboniswe ngokulandela ukwelashwa kwemizuzu ye-10 kwisixazululo se-chromogen esine-0.02% 3,3'-diaminobenzidine tetrahydrochloride (DAB; Sigma-Aldrich, St. Louis, MO) ethuthukiswe nge-0.02% nickel sulfate ku-0.1 M PB i-hydrogen peroxide (i-0.015%). Izigaba zagezwa kahle ku-0.1 M PB ukuze ziqede ukusabela futhi zifakwe kwiSlides ebizwa nge-Superfrost plus glass glass (Fisher, Pittsburgh, PA, USA) ne-0.3% gelatin ku-ddH2I-0. Ngemva kokuphelelwa amandla kwamanzi, wonke amaslayidi ayemboziwe-alayishwe nge-DPX (dibutyl phthalate xylene).

I-2. I-immunofluorescence ephindwe kabili

Izingxenye ezivela kumaqembu amane okuhlola aqukethe i-NAc ne-mPFC zisetshenziselwe ukuhlaziywa kwe-ΔFosB ne-c-Fos. Ukulandela ukuqhutshwa kwe-ABC, izingxenye zihanjiswe ngamaminithi we-10 nge-tyramide eyi-biotinylated (BT; 1: 250 ku-PBS + 0.003% H2O2 I-Tyramid Signal Amplification Kit, i-NEN Life Sciences, i-Boston, MA) kanye ne-30 min nge-Alexa 488-conjugated strepavidin (i-1: 100; i-Jackson Immunoresearch Laboratories, i-West Grove, i-PA). Ngakho-ke izingxenye zazingenwa ngobusuku obubusuku nge-anti-rabbit anti-rabbit ngokuqaphela ngqo i-c-Fos (i-1: i-150; i-sc-52; i-Santa Cruz Biotechnology, i-Santa Cruz, i-CA), ilandelwa i-30 min incubation ne-anti-rabbit ye-goat anti-rabbit i-Cy3-conjugated antibody (I-1: i-200; i-Jackson Immunoresearch Laboratories, i-West Grove, i-PA, e-USA). Ukulandela ubuningi, izigaba zahlanzwa kahle ku-0.1 M PB, zifakwe kwi-slides engilaziwe nge-0.3% gelatin ku-ddH2I-0 ne-cover-igxiliwe nge-medium aqueous mounting (i-Gelvatol) equkethe i-agent anti-fading i-1,4-diazabicyclo (2,2) octane (i-DABCO; i-50 mg / ml, i-Sigma-Aldrich, iSt. Louis, MO). Ukulawulwa kwama-immunohistochemical kufaka phakathi ukungabikho kokubili kwamagciwane okuqala noma okubili okuholela ekungabikho kwe-labeling ku-wevelength efanelekile.

Ukuhlaziya Data

Ukuhlaziywa kwengqondo kwe-ΔFosB

Abahlolwayo ababili abaphuphuthekisiwe ukwelashwa okwenziwe ubuchopho obubanzi kwi-slide ekhodiwe. Amaseli e-FosB-immunoreactive (-IR) kuwo wonke ubuchopho ahlaziywe ngokulingana-quantitatively esebenzisa isikali ukumela inani lama-ΔFosB-cells ashiwo Ithebula 1. Ngaphezu kwalokho, ngokusekelwe ekutholeni okulinganiselwe kwamanani, izinombolo zama-ΔFosB-IR amaseli zibalwa ngokusebenzisa izindawo ezijwayelekile zokuhlaziywa ezindaweni ezibucayi ezibandakanya umvuzo nokuziphatha ngokocansi besebenzisa ikhamera yekhamera yokudweba i-leica DMRD microscope (Leica Microsystems GmbH, Wetzlar , EJalimane): i-NAc (core (C) negobolondo (S); i-400 × 600μm) ihlaziywe emazingeni amathathu e-rostral-caudal (Balfour et al. 2004); indawo ye-ventral (VTA; 1000 × 800μm) ihlaziywe emazingeni amathathu we-rostral-caudal (Balfour et al. 2004) nomsila we-VTA (I-Perrotti et al. 2005); i-prefrontal cortex (indawo yangaphakathi ye-cinglulate (ACA); i-prelimbic cortex (i-PL); i-corral (inf) ye-infralimbic (i-IL); i-600 × 800μm ngayinye); i-caudate putamen (CP; 800 × 800μm); futhi i-nucleus yangaphambili ye-preoptic (MPN; 400 × 600 μm) (Amanani Ezingeziwe 1-3). Izigaba ezimbili zazibalwa ngaphansi kwesifunda ngasinye, futhi isilwane ngasinye esilinganiselwe ukubalwa kweqembu kusho. Amaphesenti amaqembu e-Sexual naïve futhi anolwazi ngama-ΔFosB-IR amelelwelwa kunoma yiyiphi indawo engaphansi kokusebenzisa ukuhlolwa kwe-t okungaphelele.

Ithebula 1    

Ukufingqa kwe-ΔFosB inkulumo ezithombeni zobulili ezingenazicansi kanye nolwazi olunempilo
Ukuhlaziywa kwe-ΔFosB ne-c-Fos

Izithombe zithunjwe ngokusebenzisa ikhamera yeCCD ehlile (i-Microfire, i-Optronics) exhunywe ku-microscope yeLeica (i-DM5000B, i-Leica Microsystems; i-Wetzlar, i-Germany) kanye ne-software ye-Neurolucida (MicroBrightfield Inc) ngezilungiselelo ezimele ezikhamera kuzo zonke izifundo (usebenzisa izinhloso ze-10x). Inani lamaseli abonisa i-c-Fos-IR noma i-DFF-IR ezindaweni ezijwayelekile zokuhlaziywa ku-NAc core kanye negobolondo (400 × 600μm ngayinye; I-Supplementary Figure 1) ne-ACA ye-mPFC (600 × 800μm; I-Supplementary Figure 3) zibalwe ngomuntu obhekene nezimpumputhe kumaqembu okuhlola, ezingxenyeni ze-2 ngesilwane ngasinye esebenzisa isofthiwe ye-Neurolucida (MBF Bioscience, Williston, VT) nesilwane ngasinye esilinganiselwe. Amaphesenti amaqembu we-c-Fos noma i-ΔFosB amaseli aqhathaniswa esebenzisa i-ANOVA emibili (izici: isipiliyoni socansi kanye nomsebenzi wobulili) ne-Fisher LSD yokuqhathanisa okuthunyelwe okuthunyelwe ngezinga lokubaluleka kwe-0.05.

Hlola i-2: ΔFosB ukudluliswa kokukhuluma

I-Gene Transfer ye-Viral Vector-Mediated

Amantombazane ama-sprague Dawley abesilisa abesilisa ngokobulili ahlukaniswe ngamaqembu ngamaqembu ngaphambi kokuhlinzwa okwe-stereotaxic. Zonke izilwane zithole ama-microinjections angamazwe amabili we-adeno-associated associated viral (rAAV) okufakela i-GFP (control; n = 12), uhlobo olusendle ΔFosB (n = 11) noma umlingani obophezelayo ongenamandla we-ΔFosB okuthiwa i-JunD (n = 9) ku-NAc. Ukunciphisa i-ΔFosB ukubhalisana okuhlanganisiwe nge-heterodimerizing ngokuncintisana ne-ΔFosB ngaphambi kokubopha isifunda se-AP-1 ngaphakathi kwabagqugquzeli bezakhi (Winstanley et al. 2007). I-Virus titer inqunywe yi-qPCR futhi ihlolwe vivo ngaphambi kokuqala ukutadisha. I-Titer yayingu-1-2 × 1011 izinhlayiya ezithathelwanayo nge-mL ngayinye. I-vAAV vectors zafakwa nge-1.5 μL / eceleni emaminithini we-7 (izixhumanisi: AP + 1.5, ML +/- 1.2 kusuka ku-Bregma; DV-7.6 kusuka ku-skull surface ngokusho kwe-Paxinos ne-Watson, i-1998) usebenzisa isilenze se-Hamilton (5μL ; UHarvard Apparatus, Holliston, MA, eU.SA). Ama-vectors akhiqi uketshezi olungaphezu kokulawulwa kwe-infusions yedwa (I-Winstanley et al, i-2007; ukuze uthole imininingwane yokulungiselela i-AAV, bheka Hommel et al., 2003). Izivivinyo zokuziphatha ziqalile amasonto e-3 ngemuva kokungena kwe-vector okuvumela ukutheleleka okubangelwa yi-viral (optimal and infectious infection)Wallace et al. 2008). Ukuboniswa kwe-Transgene ezinhlobonhlobo ze-murine kuphakama ezinsukwini ze-10 kanye nezinsalela eziphakanyisiwe okungenani izinyanga ze-6 (Winstanley et al. 2007). Ekupheleni kokuhlolwa, lezi zilwane zazingcoliswa nge-transcardially futhi izingxenye ze-NAc zazingenwa yi-GFP (i-1: 20K; anti-GFP antibody; i-Molecular Probes) isebenzisa ukuphendula kwe-ABC-peroxidase-DAB (njengoba kuchazwe ngenhla) ngokwemvelo qinisekisa ukujola amasayithi usebenzisa i-GFP njengomaka (I-Supplementary Figure 4). I-FosB kanye nama-VCD angenawo ingxenye ebonisa ukuhlukaniswa kwe-GFP nge-intanethi yangaphakathi yokungena, okuvumela ukuqinisekiswa kwesayithi ngomjovo ngokubukwa kwe-GFP kuzo zonke izilwane. Izilwane kuphela ezinezindawo zokujola kanye nokusabalalisa igciwane elibhekiswe ku-NAc zifakiwe ekuhlaziyweni kwezibalo. Ukusabalala kwegciwane ngokuvamile kulinganiselwe engxenyeni ye-NA futhi ayizange isakaze i-rostral-caudally kuyo yonke i-nucleus. Ngaphezu kwalokho, ukusabalala kwegciwane kubonakala ikakhulukazi kunoma yikuphi igobolondo noma ingqikithi. Kodwa-ke, ukuhlukahluka kwamasayithi okujola nokusabalalisa ngaphakathi kwe-NA akuzange kuthinte imiphumela ekuphatheni. Okokugcina, ukujova kwe-GFP akuthintanga ukuziphatha ngokocansi noma ukuhlinzekwa okuhlangenwe nakho okuhlangenwe nakho kobulili uma kuqhathaniswa nezilwane ezingekho-ukuhlinzwa ezifundweni zangaphambilini (Balfour et al. 2004).

Ukuziphatha ngokocansi

Amasonto amathathu elandela ukulethwa kwevolonti ye-viral, izilwane ezihambisana ne-ejaculation eyodwa (noma ngehora le-1) ze-4 ezilandelanayo, izikhathi zokubuthana zansuku zonke ukuze zithole isipiliyoni socansi (amaseshini okuhlangenwe nakho) bese zihlolwe ukuboniswa kwesikhathi eside kwesikhashana ukugqugquzelwa kokuziphatha kokuziphatha ngokobulili 1 namaviki e-2 (amaseshini wokuhlola i-1 ne-2) ngemuva kweseshini yokugcina isipiliyoni. Imingcele yokuziphatha ngokocansi ibhalwe phansi phakathi nayo yonke imihlangano yokulinganisa njengoba kuchazwe ngenhla. Ukungafani kwesitatimende kuzo zonke izilinganiso phakathi nesigaba ngasinye sokulinganisa kuqhathaniswa ngaphakathi naphakathi kwamaqembu besebenzisa izinyathelo ezimbili eziphindaphindiwe ze-ANOVAs (Izinto: ukwelapha kanye neseshini yokuxhuma) noma indlela eyodwa ye-ANOVAs (i-ejaculation latency, inombolo ye-mounts kanye ne-intromissions; iseshini) kulandelwa ukuhlolwa kwe-Fisher LSD noma i-Newman-Keuls yokuqhathanisa okuthunyelwe okuthunyelwe ngezinga lokubaluleka kwe-0.05. Ngokukodwa, imiphumela ekhuthazayo yocwaningo lobulili emiphakathini yokulinganisa iqhathaniswa phakathi kwesipiliyoni sesipiliyoni 1 (naïve) kanye neseshini yokuhlangenwe nakho 2, 3, noma i-4 ngayinye, kanye naphakathi kwamaqembu okuhlola ngaphakathi kweseshini lesipiliyoni. Ngaphezu kwalokho, ukuhlaziya imiphumela yokwelashwa (vector) ekusebenzeni isikhathi eside kwendlela yokuziphatha ngokobulili, imingcele yokulinganisa iqhathaniswa phakathi kwesipiliyoni sesiseshini 4 kanye neseshini yokuhlola i-1 ne-2 ngaphakathi kweqembu ngalinye lezokwelapha, futhi kuqhathaniswa phakathi kwamaqembu okuhlola ngaphakathi kweseshini ngasinye sokuhlola.

Iya ku:

IZIPHUMA

Okuhlangenwe nakho ngokobulili kubangela ukuqoqwa kwe-FosB

Ekuqaleni, uphenyo olulinganiselwe lwe-ΔFosB ukuqoqwa kulo lonke ubuchopho kubantu besilisa abathandana nabo ngokocansi uma kuqhathaniswa nokulawulwa ngokobulili. Isifinyeto sokuthola konke okuhlinzekwayo kuhlinzekwe Ithebula 1. Ukuhlaziywa kwe-FosB-IR kuhloswe ngokunquma izinombolo zama-ΔFosB-IR amangqamuzana ezindaweni eziningana eziphathelene nobuchopho ezihambisana nezimbungu esebenzisa izindawo ezijwayelekile zokuhlaziywa. Umfanekiso we-1 ibonisa izithombe ezimele ze-DAB-Ni ezonakalisa i-NAc yezilwane ezizibandakanya ngokobulili nezilwane ezinolwazi. I-ΔFosB phezulu-umthethonqubo obaluleke kakhulu itholakala emiphandleni ye-mPFC (Umfanekiso 2A), I-NAc core negobolondo (i-2B), i-caudate putamen (i-2B) ne-VTA (i-2C). E-NAc, umehluko omkhulu wawukhona kuwo wonke amazinga we-rostral- caudal ku-NAc core kanye negobolondo, kanye nedatha ekhonjisiwe Umfanekiso we-2 isilinganiso ngaphezu kwamazinga e-rostro-caudal. Ngokuphambene nalokho, kwakungekho ukwanda okuphawulekayo ku-ΔFosB-IR engxenyeni ye-hypothalamic medial preoptic (NNS: Avg 1.8 +/- 0.26; ENS: Avg 6.0 +/- 1.86).

Umfanekiso we-1    

 

Izithombe ezimele ezibonisa i-API-I-cell (i-black) e-NAc ye-naïve engekho ucansi (A) futhi ayikho amaqembu e-sex (B). i-aco: ukukhishwa kwangaphakathi kwesibalo Ibha yokulinganisa ibonisa i-100 μm.
Umfanekiso we-2     

Inani lama-ΔFosB-IR amaseli ku: A. infralimbic (IL), prelimbic (PL) kanye namaphandlela angaphansi kwe-cingulate cortex (ACA) we-prefrontal cortex; B. I-Nucleus iqoqa isisekelo kanye negobolondo, kanye ne-caudate putamen (CP); C. Rostral, maphakathi, caudal nomsila ...

Okuhlangenwe nakho ngokobulili kunciphisa c-Fos ekwenzeni ukulingana

Umphumela wesipiliyoni socansi kumazinga we-FosB ku-NAc aqinisekisiwe ngokusebenzisa ama-stainrescence staining techniques. Ngaphezu kwalokho, imiphumela yezocansi ekuboniseni c-Fos yahlaziywa. Umfanekiso we-3 ibonisa izithombe ezimele ze-ΔFosB- (green) kanye ne-c-Fos (obomvu) -Iziyingqamuzana -IR kuzo zonke amaqembu okuhlola (A, NNS; B, NS; C, ENS; D, ES). Okuhlangenwe nakho ngokobulili kwanda kakhulu i-API ye-FosB e-NAc core (Umfanekiso 4A: F1,15 = 12.0; p = 0.003) negobolondo (Umfanekiso we-4C: F1,15 = 9.3; p = i-0.008). Ngokuphambene, ukulinganisa ihora le-1 ngaphambi kokukhipha ama-perfusion, akuzange kube nethonya ku-ΔFosB inkulumo (Umfanekiso 4A, C) futhi akukho ukuxhumana phakathi kokuhlangenwe nakho kocansi nokuxubana ngokushesha ngaphambi kokukhipha imfucuza kwatholakala. Kube khona umphumela jikelele wokulinganisa ngaphambi kokukhipha imfucuza ekuboniseni kwe-c-Fos kokubili kwe-NAc core (Umfanekiso we-4B: F1,15 = 27.4; p <0.001) negobolondo (Umfanekiso 4D: F1,15 = 39.4; p <0.001). Ngaphezu kwalokho, umphumela jikelele wesipiliyoni socansi utholwe kumgogodla we-NAc (Umfanekiso we-4B: F1,15 = 6.1; p = 0.026) negobolondo (Umfanekiso 4D: F1,15 = 1.7; p = 0.211) futhi ukuxhumana phakathi kokuhlangenwe nakho kocansi nokuxubana ngaphambi kokukhipha imfucuza kwatholakala ku-NAc core (F1,15 = 6.5; p = 0.022), ngesimo segobolondo (F1,15 = 1.7; p = i-0.211; F1,15 = 3.4; p = i-0.084). Ukuhlaziya okuthunyelwe okuboniswa ukuboniswa kwe-c-Fos ekwenzeni ukuxubha okusemkhathini kanye negobolondo labesilisa abathandana nabo ngokocansi (Umfanekiso 4B, D). Kodwa-ke, kumadoda abesilisa ngokobulili, i-c-Fos ayizange ikhuliswe kakhulu ku-NAc core (Umfanekiso we-4B) futhi ishicilelwe kakhulu kugobolondo (Umfanekiso 4D). Ngakho-ke, isipiliyoni socansi senze ukunciphisa ukukhulunywa kwe-c-Fos okubangelwa ukulingana. Amanani e-P wokufanisa okubili okuhlakaniphileyo asemabhalweni esithombeni.

Umfanekiso we-3     

Izithombe ezimele zibonisa i-FosB (green) ne-c-Fos (obomvu) ku-NAc eqenjini ngalinye lokuhlola. Ibha yokukala ibonisa i-100 μm.
Umfanekiso we-4     

Ukwaziswa kocansi-okubangelwa i-ΔFosB kanye ne-c-Fos eyenziwe ngokulingana. Izinombolo ze-ΔFosB (I-Core, A; I-Shell, C; i-ACA, E) noma i-c-Fos (I-Core, B; Shell, D; ACA, F) amaseli angasebenzi okuqenjini ngalinye: NNS (n = 5), NS (n = I-5), ENS (n = 5) noma i-ES (n = 4). Idatha ivezwa ...

Umphumela wesipiliyoni socansi kumazinga we-c-Fos akhonyelwe ukulinganisa akugcini kuphela ku-NAc. Ukunciphisa okufanayo kwe-c-Fos ukuboniswa kuboniswe ku-ACA ezilwaneni ezibhekene nocansi uma kuqhathaniswa nokulawulwa ngokobulili. Okuhlangenwe nakho ngokocansi kwaba nethonya elikhulu ku-ΔFosB inkulumo ku-ACA (Umfanekiso 4E: F1,15 = 154.2; p <0.001). Ukukhwelana ngaphambi kokugcotshwa akuzange kube nomthelela enkulumweni ye-ΔFosB (Umfanekiso we-4C) kodwa kwanda kakhulu c-Fos (Umfanekiso 4F: F1,15 = 203.4; p <0.001) ku-ACA. Ngaphezu kwalokho, ukubonakaliswa kwe-c-Fos okubangelwa ukukhwelana ku-ACA kwehle kakhulu ngokuhlangenwe nakho kocansi (Umfanekiso 4F: F1,15 = 15.8; p = i-0.001). Ukuxhumana okuphakathi kokubili phakathi kwesipiliyoni socansi kanye nokulingana ngaphambi kokukhipha imfucumfucu kutholakale ngenkulumo ye-c-Fos (Umfanekiso 4F: F1,15 = 15.1; p <0.001). Amanani we-P wokuqhathanisa okuqonde ukuhlakanipha okukabili asezinganekwaneni zesibalo. Ekugcineni, bekungekho ukuncipha okukhulu ekuvezweni kwe-c-Fos okubangelwa ukukhwelana ku-medial preoptic nucleus (NS: Avg 63.5 +/− 4.0; ES: Avg 41.4 +/− 10.09), indawo lapho isipiliyoni sokukhwelana singabanga khona umphumela obalulekile ukwanda kwenkulumo ye-ΔFosB, ekhombisa ukuthi ukubonakaliswa kwe-c-Fos okubangelwa ukukhwelana akuzange kuthinteke kuzo zonke izindawo zobuchopho.

I-FosB e-NAc ihlanganisa ukuqiniswa kokuziphatha ngokocansi

Ukuhlola indlela engase ibe nayo yamangqamuzana ekuqiniseni ukuziphatha ngokobulili njengoba kuboniswe ukusizwa okuhlangenwe nakho okuhlangenwe nakho kokuziphatha ngokocansi, imiphumela yokuhlukumeza kwendawo yamazinga we-FosB kanye nomsebenzi wayo wokubhalisa kunqunywe. Okuhlangenwe nakho ngokocansi ngesikhathi sesinezikhathi zokuhlangenwe nakho okulandelanayo kwaba nomthelela omkhulu ekugcineni kwe-mount (Umfanekiso 5A: F1,23 = 13.8; p = i-0.001), i-latency latency (Umfanekiso we-5B: F1,23 = 18.1; p <0.001), kanye ne-ejaculation latency (Umfanekiso we-5C: GFP, F11,45 = 3.8; p = i-0.006). Izilwane zokulawula ze-GFP zibonise ukuhlelwa okuhlangenwe nakho okufakwe ekuhlangenwe nakho kobulili futhi kuboniswe ama-latencies aphansi kakhulu ekukhunjweni kokuqala, ukungena kokuqala nokukhishwa kwe-ejaculation phakathi neseshini lesipiliyoni 4 kuqhathaniswa neseshini lesipiliyoni 1 (Umfanekiso 5A-C; bheka isithombe sekhanda lamanani we-p). Lokhu kuhlinzekwa okwenziwe ngokuhlangenwe nakho kokuziphatha ngokobulili kwaphinde kwaphawula eqenjini le-ΔFosB lokukhishwa kwe-intromission kanye ne-intromission latencies, kepha kwakungekho umehluko omkhulu otholakale ekugcineni kwe-ejaculation (Umfanekiso 5A-C). Ngokuphambene nalokho, izilwane ze-JUN zibonisa ukuhleleka okunamandla; nakuba ama-latencies we-mounts, ama-intromissions, nama-ejaculations wehle ngohlelo lokuphindaphinda ngokuphindaphindiwe, ayikho yalezi zimingcele ezifinyeleleke ekubaleni uma kuqhathaniswa phakathi kwama-sessions we-1 ne-4 (Umfanekiso 5A-C). Phakathi kokuqhathaniswa kweqembu kwenkathi ngayinye yesifundo kubonisa ukuthi i-JUND yayinezikhathi eziningana kakhulu zokukhuphuka, ukuzibandakanya kanye nokwehliswa ngesikhathi sesipiliyoni sesipiliyoni uma kuqhathaniswa ne-FosB ne-GFP (Umfanekiso 5A-C). Ukwengeza, kokubili isipiliyoni socansi kanye nokwelashwa kwaba nemiphumela ebalulekile ekusebenzeni ngokubambisana (Umfanekiso 5F: isipiliyoni socansi, F1,12 = 22.5; p <0.001; ukwelashwa, uF1,12 = 3.3; p = i-0.049). Ama-FosB abesilisa ayekhuphuke ukusebenza kahle ngesikhathi sokufunda isipiliyoni 4 kuqhathaniswa nesipiliyoni sesiseshini 1 (Umfanekiso 5F). Ngaphezu kwalokho, izilwane ze-FosB zazinamaphesenti ambalwa ngaphambi kokujula ngesikhathi sosuku lwesifundo 4, uma kuqhathaniswa nesipiliyoni sesikhathi 1 (Umfanekiso 5D: F10,43 = 4.1; p = i-0.004), nokuthi amadoda angama-JunD ayekhuphuka kakhulu kakhulu ngaphambi kokukhishwa kwe-ejaculation, ngaleyo ndlela yanciphisa kakhulu ukusebenza kwe-copulation, kunamanye amaqembu amabili (Umfanekiso 5D no-F). Ngakho-ke, i-GFP ne-ΔFosB izilwane ziboniswa ukuqeqeshwa okuhlangenwe nakho okuhlangenwe nakho kokuqaliswa kokuziphatha ngokocansi kanye nokusebenza kocansi, kanti izilwane ze-AD azizange zenze.

Umfanekiso we-5     

Ukuziphatha ngokocansi kwe-GFP (n = 12), ΔFosB (n = 11) kanye nezilwane ze-JunD (n = 9): i-latency (A), i-latency latency (B), i-ejaculation latency (C), inani lezintaba (D), inombolo ye-intromissions (E) nekhono lokukopisha (F). Idatha ivezwa ...

Ukuhlola i-hypothesis ukuthi i-ΔFosB inkulumo ebalulekile ekuboniseni isikhathi eside kokuhlelwa okuhlangenwe nakho kwezenzo zokuziphatha ngokobulili, izilwane zahlolwa iviki le-1 (iseshini lokuhlola i-1) namaviki angu-2 (iseshini sokuhlola i-2) ngemuva kweseshini yokugcina. Ngempela, ukuziphatha kobulili okuqhutshisiwe kwagcinwa kokubili kumaqembu we-GFP nama-ΔFosB ngoba akukho mingcele yokuziphatha eyahlukana phakathi kwezikhathi zokuhlolwa 1 noma i-2 kanye neseshini yokugcina ye-4, ngaphakathi kwamaqembu we-GFP nama-FosB (Umfanekiso 5A-C; ngaphandle kwe-ejaculation latency kanye nokusebenza ngokuphumelelayo ngesikhathi sokuhlolwa i-1 yezilwane ze-FosB). Ukungafani okuphawulekayo phakathi kwezilwane ze-JunD ne-GFP noma i-ΔFosB amaqembu atholakala kuzo zombili izikhathi zokuhlola kuzo zonke izilinganiso zokuziphatha ngokocansi (Umfanekiso 5A-F). Kubekho ukungafani okutholakala phakathi noma phakathi kwamaqembu uma kuqhathaniswa nezinombolo zokungena kwamaphutha, i-PEI, noma amaphesenti ezilwane ezakhiwe (i-100% yabesilisa kuwo wonke amaqembu ahlanganisiwe phakathi nezinhlelo zokugcina ezine zokugcina).

Iya ku:

UKUKHULUMA

Ucwaningo lwamanje lubonise ukuthi isipiliyoni socansi kubangela ukuqoqwa kwe-ΔFosB ezindaweni eziningana eziphathelene nobuchopho, ezibandakanya i-NAc core negobolondo, i-mPFC, i-VTA ne-caudate putamen. Ngokungeziwe, isipiliyoni socansi sagcizelela ukuboniswa kwe-c-Fos e-mating ku-NAc ne-ACA. Ekugcineni, i-ΔFosB e-NAc iboniswe ukuthi ibalulekile ekuxhumaniseni ukugqugquzela ukuxubana ngesikhathi sokuthola ulwazi lwezocansi kanye nokubonakaliswa kwesikhathi eside kokuhlelwa kwezenzo zokuziphatha ngokobulili. Ngokuqondile, ukunciphisa ukuguqulwa kwe-ΔFosB-mediated okwenziwe ngokuhlangenwe nakho okwenziwe ngokuhlangenwe nakho kocansi nokusebenza, ngenkathi kubonakala ngaphezulu kwe-ΔFosB i-NAc yabangela ukuthuthukiswa okuthuthukisiwe kokuziphatha ngokocansi, ngokwenza ukwanda kocansi nokuhlangenwe nakho okuncane. Ngokubambisana, ukutholakala kwamanje kusekela ukucabanga ukuthi i-FosB iyisidlali esiphambanayo se-molecular for the long-term neural and plastical behavioral eyenziwa ngukuhlangenwe nakho kobulili.

Okutholakele kwamanje kwandisa izifundo zangaphambilini ezibonisa ukuhlangabezana nesimo socansi-okubangelwa i-ΔFosB ku-NAc kwamagundane angamadoda (Wallace et al. 2008) kanye nama-hamsters wesifazane (AmaHedges et al. 2009). Wallace et al. (I-2008) wabonisa ukuthi i-rAAV-I-FOSB evezwe ngaphezulu kokuziphatha kocansi okuthuthukisiwe kwe-NAc ngezilwane zobulili ezingenayo ngokocansi ngesikhathi sokuqala kokuhlangana, njengoba kuboniswe ukungena okuncane kokungenelela ekujuleni kwegazi kanye nezikhathi ezincane zokuthutha, kodwa akubanga nomthelela kumadoda abesilisa ocansini (Wallace et al. 2008).

Ngokuphambene nalokho, isifundo samanje asikhombisi imiphumela ye-ΔFosB ngaphezulu-okukhulunywa ngayo emadodeni abesilisa ocansini ngesikhathi sokuhlolwa kokuqala, kodwa kunalokho ngesikhathi sokulandela nokutholakala kwesipiliyoni socansi. I-FosB ngaphezulu-izakhamuzi ibonise ukusebenza okwenyuka kobulili (ukwandisa ukusebenza kahle kwe-copulation) kuqhathaniswa nezilwane ze-GFP.

Ngaphezu kwalokho, isifundo samanje sivivinye indima ye-ΔFosB ngokuvimbela i-ΔFosB-transcription transcription esebenzisa i-ΔJunD-evingayo vector vira. Ukuvimbela ukukhula okuhlangenwe nakho okuhlangenwe nakho kwe-ΔFosB ukukhulisa ukuvinjelwa okuhlangenwe nakho okuhlangenwe nakho kwesisusa socansi (ukukhuphuka kwentamo nokuvama kokungenayo) kanye nokusebenza kocansi (ukukhula kwe-ejaculation latency kanye nenani lezintaba) nokuboniswa kwesikhathi eside kwezenzo zokuziphatha zobulili.

Ngakho-ke, le datha yiyona yokuqala yokubonisa indima ephoqelekile ye-ΔFosB ekutholeni ukuqeqeshwa okuhlangenwe nakho okuhlangenwe nakho kobulili. Ngaphezu kwalokho, lemininingwane ibonisa ukuthi i-ΔFosB nayo ihileleke ngokujulile ekuboniseni isikhathi eside kokuziphatha okwenziwe ngokuhlangenwe nakho. Siphakamisa ukuthi le nkulumo yesikhathi eside yendlela yokuziphatha eqondiswayo imelela uhlobo lokukhumbula umvuzo wemvelo, ngakho-ke i-FosB ku-NAc ingumlawuli wememori yomvuzo. Okuhlangenwe nakho ngokobulili kwandise amazinga e-FosB ku-VTA nase-mPFC, izindawo ezibandakanya umvuzo nomemori (Balfour et al. 2004; Phillips et al. 2008). Ucwaningo lwesikhathi esizayo luyadingeka ukuze luqaphele ukubaluleka okungaba khona kwe-ΔFosB phezulu-isimiso kulezi zindawo zokukhumbula imemori.

I-FosB expression ibonakala igxilile, ngakho-ke inamandla amakhulu njengombhalisi wamangqamuzana wokuguquguquka okuqhubekayo kobuchopho obulandela ukuphazamiseka okungapheli (Nestler et al. 2001). I-FosB iye yaboniswa ukuthi ikhuphuke kancane kancane ku-NAc ngaphezu kwezigciwane eziningi ze-cocaine futhi iqhubeka kuze kube amasonto amaningana (Ithemba et al. 1992; Ithemba et al. 1994). Lezi zinguquko ku-NAc ΔFosB inkulumo zihlotshaniswa nokuqwashiswa komvuzo nezidakamizwa (UChao noNestler 2004; UMcClung noNestler 2003; McClung et al. 2004; I-Nestler 2004, 2005, 2008; Nestler et al. 2001; Zachariou et al. 2006). Ngokuphambene nalokho, indima ye-ΔFosB ekuxhumaniseni umvuzo wemvelo iye yahlushwa. Ubufakazi bamuva buye bufakazela ukuthi i-ΔFosB induction ku-NAc ibandakanyeka emvuzweni wemvelo. Amazinga e-FosB ayenyuka ngendlela efanayo ku-NAc elandela ukudla ne-wheelrose. Ukuvezwa ngokweqile kwe-ΔFosB ku-striatum besebenzisa ama-bitransgenic amagundane noma ama-viral vectors kuma-rats kubangela ukwanda kwe-sucrose, isisusa esithuthukisiwe sokudla kanye nokwanda kwevili elisebenza ngokuzenzekelayo (Olausson et al. 2006; Wallace et al. 2008; Werme et al. 2002). Idatha yamanje ingeza kakhulu kule mibiko futhi iphinde isekele umqondo wokuthi ΔFosB ungumxhumanisi obalulekile ekuqiniseni umvuzo kanye nememori yomvuzo wemvelo.

I-FosB ingase ixoxisane nokuvuselelwa kohlelo lokuziphatha ngokobulili ngokufakwa kwe-plasticity ohlelweni lwe-mesolimbic. Ngempela, isipiliyoni socansi sibangela izinguquko eziningana ezihlala isikhathi eside ohlelweni lwe-mesolimbic (UBradley & Meisel 2001; Frohmader et al. 2009; Pitchers et al. 2010). At Izinga lokuziphatha, impendulo yokuvakasha ekhuthazwayo ku-amphetamine kanye nomvuzo othuthukisiwe we-amphetamine kuye kwaboniswa kumagundane angamadoda avela ocansi (Pitchers et al. 2010); impendulo yokuguqula i-amphetamine iphinde ibonwe nama-hamster wesifazane (UBradley & Meisel 2001). Ngaphezu kwalokho, kuye kwatholakala ukukhuphuka kwezinombolo ze-dendritic kanye nokubunzima kwama-dendritic arbors ngokulandela isikhathi sokuziqeda ekuhlangenwe nakho kobulili kumantombazane wesilisa (Pitchers et al. 2010). Ucwaningo lwamanje lubonisa i-ΔFosB ingaba umlamuleli othile wezinambuzane zemiphumela yesikhathi eside yocwaningo lobulili. Ngokuvumelana, i-ΔFosB isanda kuboniswa ukuthi ibalulekile ekunciphiseni izinguquko zemigodi ye-dendritic ekuphenduleni ukuphathwa okungavamile kwe-cocaine (I-Dietz et al. 2009; Maze et al. 2010).

Akucaci ukuthi iyiphi i-neurotransmitter (ama) ephezulu enomthwalo wokunciphisa i-ΔFosB ku-NAc, kodwa i-DA iphakanyisiwe njengomuntu ozobhapathizwa (Nye et al. 1995). Cishe zonke izidakamizwa zokuhlukunyezwa, kubandakanya i-cocaine, i-amphetamine, i-opiates, i-cannabinoids, ne-ethanol, kanye nemivuzo yemvelo, ukwandisa i-ΔFosB ku-NAc (I-Perrotti et al. 2005; Wallace et al. 2008; Werme et al. 2002). Kokubili izidakamizwa zokuhlukumeza kanye nemivuzo yemvelo zandisa ukuhlushwa kwe-DA e-NAc (Damsma et al. 1992; UHernandez noHoebel 1988a, b; UJenkins noBecker 2003). I-FosB ukungeniswa kwezidakamizwa zokuhlukunyezwa kuboniswe kwi-receptor ye-DA equkethe amangqamuzana ne-cocaine-i-ΔFosB ivaliwe yi-D1 DA receptor antagonist (Nye et al. 1995). Ngakho-ke, ukukhululwa kwe-DA kuhloswe ukugqugquzela i-ΔFosB ukukhuluma futhi ngaleyo ndlela kuhambisane neuroplasticity ehambisana nomvuzo. Ngokuqhubekayo ukusekela umqondo wokuthi ama-FosB amazinga ase-DA atholakala ukuthi izindawo zokucubungula lapho isipiliyoni sezocansi sashintsha amazinga e-FosB athola ama-dopaminergic anamandla avela ku-VTA, kufaka phakathi i-prefrontal cortex kanye ne-basolateral amygdala.

Kodwa, ngokuphambene, i-ΔFosB ayinyuswanga endaweni yangaphambili ye-preoptic yize le ndawo ithola ukungena kwe-dopaminergic, naphezu kwemithombo ye-hypothalamic (IMiller & Lonstein 2009). Ucwaningo lwesikhathi esizayo luyadingeka ukuze kuhlolwe uma ukukhulunywa kwe-ΔFosB okufakwe ekuhlanganyeleni kanye nemiphumela yesipiliyoni socansi ngesisusa nokusebenza kocansi kuxhomeke ekusebenzeni kwe-DA. Indima ye-DA ekusizeni ngokocansi kuma-rats wesilisa okwamanje ayicacisi ngokuphelele (I-Agmo neBerenfeld 1990; I-Pfaus 2009). Kukhona ubufakazi obuningi bokuthi i-DA ikhishwa ku-NAc ngenkathi kuvezwa owesifazane noma ukubeletha (Damsma et al. 1992) ne-neurons ze-DA zenziwa ngesikhathi sokuziphatha ngokocansi (Balfour et al. 2004). Kodwa-ke, ukujova okuhlelekile kwe-DA receptor antagonist akuvimbeli ukuthanda indawo yendawo ehlelwe ngumvuzoI-Agmo neBerenfeld 1990) kanye ne-hypothesis ukuthi i-DA ibaluleke kakhulu ekuqinisekiseni ukulingana okuhlangenwe nakho okuhlangenwe nakho okungahlanganiswanga.

Akucaci nokuthi yiziphi abalamuleli abaphansi be-ΔFosB imiphumela yokuziphatha ngokobulili. I-FosB iye yaboniswa ukuba isebenze njengomshini wokuqalisa we-transcriptional kanye nokucindezela ngokusebenzisa uhlelo lokusebenza oluxhomeke ku-AP-1 (UMcClung noNestler 2003; I-Peakman et al. 2003). Kunezinhlobonhlobo zamagciwane ezihlosiwe eziveziwe, kufaka phakathi i-geni ngokushesha c-fos (Ithemba et al. 1992; Ithemba et al. 1994; UMorgan noCurran 1989; Renthal et al. 2008; Zhang et al. 2006), cdk5 (Bibb et al. 2001), i-dynorphin (Zachariou et al. 2006), i-sirtuin-1 (Renthal et al. 2009), Amanunithi we-NFκB (Ang et al. 2001), aI-AMPA glutamate receptor GluR2 subunit (Kelz et al. 1999). Imiphumela yamanje ibonisa ukuthi amazinga e-c-Fos akhuthaza ukukhushulwa ayancishiswa ngesipiliyoni socansi ezindaweni ezibucayi ngokwanda kwe-ΔFosB (NAc ne-ACA). Ukukhishwa kwe-c-Fos kubonakala kuncike esikhathini sokusukela kokugcina ukuhlangana nokuphindaphindiwe kwezikhathi zokuxubana, njengasesezifundweni zangaphambilini, ukunciphisa okunjalo ku-c-Fos akutholakalanga kumazinyo wesilisa evivinywa iviki le-1 ngemuva kweseshini yokuqeda ukugcina (Balfour et al. 2004) noma ngemuva kwesipiliyoni socansi esineseshini esisodwa sokulinganisa (ILopez ne-Ettenberg 2002). Ngaphezu kwalokho, ukutholakala kwamanje kuhambisana nobufakazi bokuthi i-ΔFosB igcizelela isakhi segciwane c-fos ngemuva kokungabonakali kwe-amphetamine engapheli (Renthal et al. 2008). Ngokuvumelana nalezi zitholakele, ukufakwa kwezimbungulu ze-geneRNAs ezincane (c-fos, fosB, c-jun, junB, ne-zif268) ezincishisiwe zancishiswa ngemuva kokujova ngokuphindaphindiwe kwe-cocaine uma kuqhathaniswa nezijovo ezidakamizwa (Ithemba et al. 1992; Ithemba et al. 1994), futhi i-amphetamine-eyenziwe i-c-fos yaxoshwa ngemva kokuhoxiswa kokuphathwa okungapheli kwamamthetamine (I-Jaber et al. 1995; Renthal et al. 2008). Ukubaluleka komsebenzi we-down-regulation of expression c-Fos ngemuva kokuphathwa kwezidakamizwa ezingapheli noma okuhlangenwe nakho kocansi kungabonakali kahle, futhi kuphakanyisiwe ukuthi kube yindlela ebalulekile ye-homeostatic yokulawula ukuzwela kwesilwane ukuphindaphinda ukuvuleka komvuzo (Renthal et al. 2008).

Ekuphetheni, isifundo samanje sibonisa ukuthi i-ΔFosB e-NAc idlala indima ebalulekile ekukhunjweni kobulili, exhasa ukuthi kungenzeka ukuthi i-ΔFosB ibalulekile ekuqiniseni umvuzo jikelele kanye nokukhumbula. Ukuthola okuvela esicwaningweni samanje kuqhubeka nokuqonda ukuqonda kwethu kwezinhlelo zamaselula nezama-molecular ezithintana nomvuzo wezocansi nesisusa, futhi engeza emzimbeni wezincwadi ezibonisa ukuthi ΔFosB ngumdlali obalulekile ekuthuthukiseni umlutha, ngokubonisa i-ΔFosB indima emvuzweni wemvelo ukuqinisa.

Iya ku:

Izinto ezengeziwe

Supp Fig S1-S4 & Ithebula S1-S2

Iya ku:

Ukubonga

Lolu cwaningo lusekelwa yizibonelelo ezivela e-Canada Institutes of Health Research kuya ku-LMC, iNational Institute of Health Mental kuya ku-EJN, ne-Natural Sciences kanye ne-Engineering Research Council yaseCanada eya eKKP naseLMC.

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