I-DeltaFosB Ukugqithisa kwi-Nucleus Accumbens kuphucula umvuzo wobulili kwi-Hamster yamaSyhinikazi (i-2009)

IZIMVO: ΔFosB yikhemikhali eyimfuneko ukuze umlutha wenzeke. Zombini iziyobisi kunye neziyobisi zokuziphatha zihambelana nokuqokelelwa kweDelta FosB. Vimba i-Delta FosB kwaye umlutha uyayeka. Apha kuboniswa ukuba amava ngesondo anyusa i-Delta FosB, kwaye ikhokelela ekukhuthazeni iziko lokuvuza. Ukuqonda kubangela ukukhutshwa okuphezulu kwe-dopamine eyenza umsebenzi okanye ichiza libe nomtsalane ngakumbi. Ngokwenyani, isondo yinkqubo yokulutha. Olu phononongo lukwanyuse ngokwemfuza i-Delta FosB, eyonyuse imiba evuzayo yesini ngaphezulu nangaphaya kwamanqanaba aqhelekileyo. Ngaba ukusebenzisa i-porn ye-Intanethi kunokubangela ukunyuka kwe-Delta FosB ngaphezulu nangaphaya kwamanqanaba aqhelekileyo? Ngaba oku kungakhokelela kumlutha kunye nokuphinda kufakwe i-neural pathways? Kubonakala kusengqiqweni.

ISIFUNDO ESIPHELELEYO: I-ΔFosB i-Overexpression kwi-Nucleus Accumbens iphucula umvuzo wesondo kwi-Hamsters yaseSyria yabasetyhini

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

VL Hedges,1 S. Chakravarty,2 EJ Nestler,2 kunye neRL Meisel1

Abstract

Ukwenziwa kusebenze okuphindaphindiweyo kwenkqubo ye-mesolimbic dopamine kubangela utshintsho oluqhubekayo lokuziphatha olukhatshwa yipatheni ye-neural plasticity kwi-nucleus accumbens (NAc). Njengoko imfumba yento ekhutshelweyo i-ΔFosB inokuba yinxalenye ebalulekileyo yale plastikhi, umbuzo oxutyushwayo kuphando lwethu kukuba ingaba i-ΔFosB ilawulwa ngamava ezesondo kwabasetyhini. Sibonisile ukuba iihamster zaseSyria zabasetyhini zinikwe amava ezesondo zibonisa utshintsho oluninzi lokuziphatha kubandakanya ukonyuka kwezesondo kunye neehamster zamadoda angama-naïve, umvuzo wesondo, kunye nokuphendula okuphuculweyo kwizivuseleli zengqondo (umzekelo, i-amphetamine).

Kutshanje sibonise ukuba amava ngesondo andise amanqanaba e-ΔFosB kwi-NAc yeehamster zaseSyria zabasetyhini. Ugqaliselo lolu phononongo yayikukuphonononga iziphumo ezisebenzayo zolu lwazi ngokumisela ukuba ngaba ukuchazwa okugqithisileyo kwe-ΔFosB nge-adeno-associated viral (AAV) vectors kwi-NAc inokulinganisa iziphumo zokuziphatha zamava ngokwesondo.

Izilwanyana ezine-AAV-mediated overexpression ye-ΔFosB kwi-NAc ibonise ubungqina bomvuzo wesondo kwindawo ekhethiweyo i-paradigm phantsi kweemeko apho izilwanyana zokulawula ezifumana i-injection ye-AAV-green fluorescent protein (GFP) kwi-NAc ayizange. Uvavanyo lokuziphatha ngokwesondo luphinde lwabonisa ukuba amadoda adityaniswe ne-AAV-ΔFosB yabasetyhini yonyuse ukusebenza kakuhle kokukopana njengoko kulinganiswe ngomlinganiselo weentaba ezibandakanya ukungena ngaphakathi xa kuthelekiswa namadoda adityaniswe ne-AAV-GFP yabasetyhini. Ezi ziphumo zixhasa indima ye-ΔFosB ekulawulweni kweendlela zokuziphatha ezikhuthazayo, kule meko yokuziphatha kwabasetyhini ngokwesondo, kunye nokubonelela ngembono entsha ngezenzo ezinokwenzeka ze-ΔFosB.

Yiya e:

intshayelelo

Amava ngeziyobisi zokusetyenziswa gadalala, indlela yokuziphatha ekhuthazayo, ivili eliqhubayo okanye ukufundwa kwezixhobo zokwenza kusebenze inkqubo ye-mesolimbic dopamine kunye notshintsho oluqhubekayo kwi-nucleus accumbens (NAc) (Becker okqhubekayo., 2001, UDi Chiara okqhubekayo., 1998, Harris okqhubekayo., 2007, Kumar okqhubekayo., 2005, Meisel & Mullins, 2006, Nestler, 2008, Olausson okqhubekayo., 2006, Perrotti okqhubekayo., 2008, Pierce & Kumaresan, 2006, ingcuka okqhubekayo., 2004). Utshintsho lwezakhiwo, ngokukodwa ukubunjwa kwe-dendritic spines, yinxalenye ebalulekileyo yala mava asekelwe kwiplastiki (Allen okqhubekayo., 2006, Lee okqhubekayo., 2006, Li okqhubekayo., 2003, Meisel & Mullins, 2006, Norrholm okqhubekayo., 2003, URobinson kunye noKolb, ngo-2004), ehlala ixesha elide emva kokuba amava okuziphatha okanye ulawulo lweziyobisi luphelile (McClung & Nestler, 2008, Meisel & Mullins, 2006, ingcuka okqhubekayo., 2004).

Into ekhutshelweyo ΔFosB ineempawu zemolekyuli ezenza ukuba ibe ngumgqatswa olungileyo ukulamla uhlengahlengiso oluhlala luhleli lwesakhiwo kunye nokuziphatha ngenxa yamava okuziphatha okanye eziyobisi.Chen okqhubekayo., 1997, Chen okqhubekayo., 1995, Colby okqhubekayo., 2003, Doucet okqhubekayo., 1996, Ithemba okqhubekayo., 1994, UKelz okqhubekayo., 1999, McClung & Nestler, 2003, McClung okqhubekayo., 2004, McDaid okqhubekayo., 2006, Nakabeppu & Nathans, 1991, Nestler, 2008, Nye okqhubekayo., 1995, Olausson okqhubekayo., 2006, Perrotti okqhubekayo., 2008, Wallace okqhubekayo., 2008, Werme okqhubekayo., 2002, Zachariou okqhubekayo., 2006). I-ΔFosB yenye imveliso yesplice yegene yangoko yangoko iifosB (Mumberg okqhubekayo., 1991, Nakabeppu & Nathans, 1991) kwaye, ngokungafaniyo nobude obupheleleyo beprotein ye-FosB, i-ΔFosB ecuthiweyo inozinzo olungaqhelekanga olukhokelela ekuqokeleleni kweprotheyini elandela ukuvuselela okuphindaphindiweyo (Chen okqhubekayo., 1997, Chen okqhubekayo., 1995, Ithemba okqhubekayo., 1994, UKelz okqhubekayo., 1999, Perrotti okqhubekayo., 2008, Zachariou okqhubekayo., 2006). Nangona indlela apho i iifosI-gene ye-B ngenye indlela i-spliced ​​ayikaziwa, ukunqunyulwa kweprotheyini kunye ne-phosphorylation ikhusela iprotheyini ekuwohlokeni okukhawulezayo kweproteasomal ivelisa inqanaba elikhulu lomsebenzi wokubhaliweyo xa kuthelekiswa namalungu osapho lwe-FosB ahlala okwethutyana.Carle okqhubekayo., 2007, Ulery & Nestler, 2007, Ulery okqhubekayo., 2006). I-postulate kukuba ukuqokelelwa kweprotheyini ye-ΔFosB ivelisa iipatheni zendlela yokuchazwa kofuzo enokuthi ibe phantsi kweempembelelo zamava ekuziphatheni kwexesha elide kunye neplastiki yeselula.McClung & Nestler, 2008).

Sisebenzise ukuziphatha ngokwesondo kwabasetyhini kwiihamster zaseSyria njengemodeli yeplastiki esekwe kumava engqondweni (Bradley okqhubekayo., 2005a, Bradley okqhubekayo., 2005b, UBradley noMeisel, ngo-2001, Bradley okqhubekayo., 2004, Kohlert & Meisel, ngo-1999, Kohlert okqhubekayo., 1997, Meisel okqhubekayo., 1993, Meisel kunye neYopa, ngo-1994, Meisel okqhubekayo., 1996, Meisel & Mullins, 2006). Inzuzo yokusebenza ngokuziphatha ngokwesondo kukukwazi ukulawula umgangatho wamava esilwanyana ngokuba nezilwanyana ezizii-naïve ngokupheleleyo, okanye ngokubeka izilwanyana ngokwahlukileyo kumanqanaba ahlukeneyo okwabelana ngesondo. Ngaphambili siye sabonisa ukuba amava esondo aphindaphindiweyo abangela uvakalelo lwenkqubo ye-mesolimbic dopamine, efana naleyo yeziyobisi zokuxhatshazwa.Bradley okqhubekayo., 2005b, UBradley noMeisel, ngo-2001, UBrenhouse kunye neStellar, ngo-2006, UCadoni kunye noDi Chiara, ngo-1999, Ithemba okqhubekayo., 1992, UKelz okqhubekayo., 1999, Kohlert & Meisel, ngo-1999, Pierce & Kalivas, ngo-1995, Pierce & Kalivas, 1997a, Pierce & Kalivas, 1997b, URobinson kunye noKolb, ngo-1999a). Ngokomzekelo, njengeempembelelo zeziyobisi, amava esondo aphindaphindiweyo anyusa i-dendritic spines kwi-medium spiny neurons ye-NAc (Lee okqhubekayo., 2006, Li okqhubekayo., 2003, Meisel & Mullins, 2006, Norrholm okqhubekayo., 2003, URobinson okqhubekayo., 2001, URobinson kunye noKolb, ngo-1997, URobinson kunye noKolb, ngo-1999a, URobinson kunye noKolb, ngo-1999b, URobinson kunye noKolb, ngo-2004). Ngapha koko, sifumene ukuba i-ΔFosB/FosB staining ihlala inyuswa kwi-NAc kulandela amava esondo aphindaphindiweyo (Meisel & Mullins, 2006).

Ngenxa yokuba amava ngesondo anokuvelisa ukubonakaliswa okuhlala ixesha elide kwamalungu osapho lwe-FosB, injongo yolu phononongo yayikukukhohlisa imbonakalo ye-ΔFosB ukulinganisa iziphumo zokuziphatha zamava esondo aphindaphindiweyo. Ukulandela ukunyanzeliswa kwentsholongwane ye-ΔFosB kwi-NAc, ii-hamster zaseSyria zabasetyhini zavavanywa ukuze ziphuculwe indawo ekhethwayo kunye nokwandisa ukusebenza kakuhle kokubambisana kunye nee-hamster zamadoda angama-naïve, iziphelo ezibini eziye zaboniswa ngaphambili ukuba zichatshazelwa ngamava esondo aphindaphindiweyo.Bradley okqhubekayo., 2005b, Meisel kunye neYopa, ngo-1994, Meisel okqhubekayo., 1996, Meisel & Mullins, 2006). Wenika ingxelo apha ukuba ngokuzingisa ngokugqithisileyo i-ΔFosB kwi-NAc yee-hamsters zabasetyhini ezifumana amava amancinci ngokwesondo, siyakwazi ukuvelisa utshintsho lokuziphatha olufana nalaa manina anamava abanzi ngokwesondo.

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Impahla nenkqubo

Imixholo yoMfuniselo

Iihamster zaseSyria zamadoda nabasetyhini zanikezelwa malunga neentsuku ze-60 ubudala ukusuka kuCharles River Breeding Laboratories, Inc. (Wilmington, MA). Iimazi zazihlaliswa ngabanye kwiikheji zeplastiki (ubude be-50.8 cm × 40.6 cm ububanzi × 20.3 cm ukuphakama), ngelixa izilwanyana ze-stimulus zamadoda zazihlala kwiqela-zifakwe kwiikheji ezifanayo ngamanani amathathu okanye amane. Igumbi lezilwanyana lagcinwa kwiqondo lokushisa elilawulwayo le-22 ° C kunye neshedyuli ye-14: 10 hr ukukhanya-mnyama (izibane zivaliwe phakathi kwe-1: 30 kunye ne-11: 30 ntambama). Ukutya namanzi zazifumaneka kwizilwanyana ad adum.

Zonke iinkqubo ezisetyenzisiweyo kolu vavanyo zihambelana namaZiko ezeMpilo eSizwe Izikhokelo zoKhathalelo kunye nokuSetyenziswa kwezilwanyana zaselebhu kwaye zamkelwa yiPurdue Animal Care and Use Committee.

Ukuhlinzwa

Iihamster zabasetyhini zaye zenziwa i-ovariectomized phantsi kwe-sodium pentobarbital anesthesia (Nembutal; 8.5 mg nge-100 gm ubunzima bomzimba, ip), inikwe i-anesthetic eyongezelelweyo kwaye emva koko yenziwa utyando lwe-bilateral stereotaxic ukuhanjiswa kwe-viral vectors. Ngexesha lotyando lwe-stereotaxic, intloko yayichetywe kwaye ulusu kunye nezihlunu zihlehlisiwe. Kwagrunjwa umngxuma omncinane kukhakhayi kunye ne-5 μL yesirinji ye-Hamilton yathotywa yaya kumgangatho we-NAc ukusuka kwi-engile esecaleni ye-2 ° ukuqinisekisa ukucoceka kwee-ventricles ze-cerebral ezisecaleni. Isirinji yagcinwa isendaweni kangangemizuzu emi-5 phambi kokutofwa kwaye emva koko intsholongwane ehambelana ne-adeno-associated (AAV)-GFP okanye i-AAV- ΔFosB (0.7 μL) yasiwa kwi-NAc ngaphezulu kwe-7 min, kunye nesirinji emva koko yagcinwa endaweni yayo. eyongezelelweyo 5 min. Le nkqubo yaphinda yaphindwa kwicala le-contralateral yengqondo.

IVictors Viral

I-AAV ibonakaliswe ngokukwazi ukutshintshela ngokufanelekileyo i-neurons kunye nokugcina intetho ethile ye-transgene ixesha elide.Chamberlin okqhubekayo., 1998). Iivektha ze-AAV zikhona kwii-serotypes ezahlukeneyo ngokusekwe kuphawu lwedyasi yeprotheyini ye-capsid. Olu lingelo lusebenzise i-AAV2 (serotype 2) esuka kwiStratagene enesihloko esingaphezulu kwe-10.8/μl echaza iprotein eluhlaza yefluorescent (AAV-GFP) kunye neVektha ye-AAV eyayinolwakhiwo kuzo zombini i-ΔFosB kunye ne-GFP (AAV-ΔFosB-GFP). Iivektha zentsholongwane zafakwa kwi-NAc ubuncinci kwiiveki ze-3 ngaphambi kovavanyo lokuziphatha ukuvumela ukuba i-ΔFosB ikhule ngokugqithisileyo. Ezi vectors ze-AAV zilamla ukubonakaliswa kwe-transgene kwiimpuku kunye neempuku eziye zibe zezona zininzi phakathi kweentsuku ezili-10 zenaliti kwaye ziqhubeke kweli nqanaba kangangeenyanga ezi-6 (Winstanley et al., 2007, Zachariou et al., 2006). Okubalulekileyo, ii-vectors zosulela ii-neuron kuphela kwaye azivelisi tyhefu enkulu kunokufakwa kwisithuthi kuphela. Iinkcukacha zemveliso kunye nokusetyenziswa kwezi zixhobo zinikwe kupapasho lwangaphambili (Winstanley et al., 2007, Zachariou et al., 2006).

Amava ngesondo

Zonke ii-hamster ze-ovariectomized zabasetyhini zaqhutyelwa kumava ngokwesondo kanye ngeveki ngokunika iinaliti ezimbini zemihla ngemihla ze-estradiol benzoate (i-10 μg kwi-0.1 ml yeoli ye-cottonseed) malunga ne-48 hr kunye ne-24 hr ngaphambi kovavanyo lokuziphatha ngokwesondo olulandelwa yinaliti engaphantsi kwe-progesterone. (500 μg kwi-0.1 ml yeoli ye-cottonseed) 4-6 iyure ngaphambi kovavanyo lokuziphatha ngokwesondo. Abasetyhini abafumana amava ngesondo banikwa i-hamster yesini enamava ngokwesondo kwiseshoni ye-10 min i-4-6 hr emva kwe-injection ye-progesterone. Indoda nganye kunye nemazi yayidityaniswe kanye kuphela ngexesha lovavanyo lwamava ngesondo.

Ukukhetha indawo ekhethiweyo

Kusetyenziswe iparadigm enomkhethe kwindawo ekhethiweyo kolu lingelo (Tzschentke, 1998). Izixhobo zethu zokukhetha indawo esemgangathweni (Meisel kunye neYopa, ngo-1994, Meisel okqhubekayo., 1996) iqulethwe enye emhlophe kunye ne-gray compartment (60 × 45 × 38 cm) edityaniswe ngendawo ephakathi ecacileyo (37 × 22 × 38). Awona macandelo aphambili aye ahlulwa ngakumbi ngomandlalo we aspen (Harlan Laboratories, IN) kwigumbi elingwevu kunye nesikhwebu somandlalo (Harlan Laboratories, IN) kwigumbi elimhlophe. I-hamster yabasetyhini eyenziwe nge-ovariectomized i-hormonally primed phambi kovavanyo lwangaphambili, iiseshini zokulungisa ngokwesondo, kunye novavanyo lwasemva. Ngethuba lokuvavanywa kwangaphambili isilwanyana safakwa kwigumbi eliphakathi elicacileyo kwaye lalikhululekile ukuzulazula amacandelo ahlukeneyo kwi-10 min ukuseka ukhetho lokuqala lwegumbi ngalinye. Njengoko zonke izilwanyana zibonise ukhetho lokuqala lwegumbi elimhlophe, ukulungiswa kwenziwa kwigumbi elingwevu. I-hormone priming yaphindwa kwakhona ngexesha le-2 (Amaqela 2-5) okanye iiveki ze-5 (Iqela le-1) le-conditioning. Ngexesha lokulungiswa kwemeko, abafazi banikwa amava ngesondo kunye nendoda kwindawo egrey ye-10 min, kunye neeparitha zokulinganisa zamabhinqa ezilinganisiweyo (i-lordosis latency kunye nobude be-lordosis epheleleyo). Iyure enye emva kovavanyo lwamava ngesondo, ibhinqa labekwa yodwa kwigumbi elimhlophe le-10 min. Iqela elilawulayo labasetyhini abangazange bafumane amava okwabelana ngesondo benziwa i-hormonally primed kodwa babekwe bodwa kwigumbi ngalinye le-10 min. Ukulandela i-2 okanye i-5 iiveki zokumisela, izilwanyana zanikwa uvavanyo emva kokuba ziphinde zikhululeke ukuzulazula kumagumbi kwi-10 min. Kungakhathaliseki ukuba liphi iqela, zonke iimvavanyo zasemva zenziwe iiveki ezisixhenxe emva kokuhlinzwa kwe-stereotaxic, kwaye ngoko ke zonke izilwanyana zabingelelwa ngezinga elifanayo le-viral expression. Kwakukho amaqela ezilwanyana ezi-5 kolu vavanyo: Iqela elilungileyo lokulawula izilwanyana lifumene i-AAV-GFP yamazwe amabini kwaye linikwe i-5 yeveki yokuziphatha kwesondo kunye nendoda (Iqela le-1, n = 8). Amaqela amabini olawulo olubi awazange anikwe nayiphi na imeko yezesondo kwiiveki ze-2, kwaye afumene i-AAV-ΔFosB (iQela 2, n = 5) okanye i-AAV-GFP (iQela 3, n = 4). Okokugqibela, bekukho izilwanyana ezifumene iiveki ze-2 zokuziphatha ngokwesondo kunye nendoda enenaliti yamacala amabini nokuba yi-AAV-ΔFosB (iQela 4, n = 7) okanye i-AAV-GFP (iQela 5, n = 7).

Naïve Male Experiment

Uphando lwangaphambili lubonise ukuba i-hamster yabasetyhini abanamava ngesondo inokuphucula ukusebenza kakuhle kokunxibelelana kunye namaqabane abo angamadoda angama-naïve ngokwesondo (Bradley okqhubekayo., 2005b). Olu vavanyo lwanikezelwa malunga neveki enye emva kovavanyo olukhethiweyo lwendawo emva kovavanyo kumaqela amabini ezilwanyana ezifumene iiveki ze-2 zesini (Amaqela 4 kunye ne-5). Ababhinqileyo babelungiselelwe ihomoni kumava ngokwesondo njengoko kuchaziwe. Ngexesha lovavanyo lwemizuzu eyi-10, i-hamster yesini esine-sexual naïve yaziswa kwi-cage yasekhaya yabasetyhini kwaye iseshoni yovavanyo yafakwa kwividiyo ukuze kuhlalutywe kamva. Inani leenyuka kunye ne-intromissions (kubandakanywa ne-ejaculations) yindoda kunye nomlinganiselo wee-mounts ezipheleleyo ezibandakanya i-intromission (i-hit rate) inqunywe kwi-videotape.

Immunohistochemistry

I-Immunostaining yenziwa kuzo zonke izilwanyana ukuze kuqinisekiswe indawo yokutofa kwentsholongwane kunye nobungakanani be-anatomical yokubonakaliswa kweprotheyini. Abasetyhini banikwa i-overdose ye-Sleepaway (0.2 ml ip, i-Fort Dodge Laboratories, i-Fort Dodge, i-IA) kunye ne-intracardially perfused nge-25 mM i-phosphate buffered saline (PBS) nge-2 min (malunga ne-50 ml) ilandelwa yi-4% paraformaldehyde kwi-25 mm PBS. imizuzu engama-20 (malunga ne-500 ml). Ubuchopho bususiwe kwaye bulungiswe emva kwe-2 hr kwi-4% ye-paraformaldehyde emva koko ifakwe kwisisombululo se-sucrose ye-10% kwi-PBS ngobusuku kwi-4 ° C. Izilwanyana ezifumene i-AAV-GFP yamacala amabini kuphela zineziqephu ze-coronal (40 μm) zisikwe kwizicubu ezikhenkcezisiweyo ukuya kwi-25 mM ye-PBS kunye ne-0.1% ye-albumin ye-bovine serum (BSA) (i-buffer yokuhlamba) emva koko ifakwe ngqo kwizilayidi kwaye igqunywe ngexa isamanzi nge-5%. n-propyl galate kwi glycerin. Izilwanyana ezifumene amacala amabini i-AAV-ΔFosB zineziqendu ze-coronal (40 μm) zisikwe kwiithishu ezikhenkcezileyo, zaze zahlanjululwa ka-3 kangangemizuzu eli-10 kwisithinteli sokuhlamba. Izilwanyana ze-AAV-ΔFosB zihlalutyelwe kuphela imbonakalo ye-ΔFosB kwaye ke zafakwa kwi-ΔFosB/FosB i-antibody ephambili (1:10000, sc-48 Santa Cruz Biotechnology Inc., Santa Cruz, CA) kwindawo yokuhlamba kunye ne-0.3% Triton-X 100 e- Iqondo lobushushu begumbi le 24 hr kwaye emva koko lifudukele kwi-4 °C kangangeyure ezingama-24. Olu xinaniso lwe-antibody ephambili lukhethwe njengoko luvelisa kuphela ubuncinci obuncinci be-ΔFosB/FosB. Ukulandela ukufukanyelwa kwi-antibody ephambili amacandelo aye ahlanjululwa ka-3 ngemizuzu eyi-10 kwisithinteli sokuhlamba, aze emva koko afakelwe kwi-antibody ye-biotinylated-secondary imizuzu engama-45 kwiqondo lobushushu begumbi (1:200, Vector, Burlingame, CA). Emva koko amacandelo ahlanjwe ngamaxesha e-3 kwi-10 min kwi-buffer yokuhlamba ngaphambi kokuba ifakwe kwi-streptavidin Alexa Fluor 594 conjugate (1: 500, i-Molecular Probes, i-Eugene, OR). Ukulandela oku kuqanduselwa, amacandelo ayehlanjwa amaxesha ama-3 ngemizuzu eli-10 kwisithinteli sokuhlambela aze axhonywe kwizilayidi kwaye agqunywe ngexa emanzi nge-5% ye-n-propyl galate kwi-glycerin.

Uhlalutyo lweMicroscopic

Izilayidi zahlalutywa ngemakroskopu yokukhanya yeLeica DM4000B enekhono lefluorescent idityaniswa nekhamera yedijithali yeLeica DFC500. Imifanekiso yedijithali yazo zombini iindawo zokutofa zasekunene nezasekhohlo zecandelo ngalinye zahlalutywa ngokulandelelana yi-fluorescence microscopy ukuze kufumaneke indawo yokutofa kwi-NAc. Amacandelo asuka kwisilwanyana ngasinye ahlalutywa ukufumana i-rostral ukuya kwi-caudal ye-virus expression kunye nendawo ye-anatomical ye-diameter enkulu yokubonakalisa. Ngaphaya koko, kula macandelo amanani e-FosB eneeseli ezinamabala abalwe kwi-ImageJ kwimifanekiso yedijithali egciniweyo. Njengoko injongo yethu yayikukufumana uqikelelo lokubala lweeseli, iindlela zestereological azizange zisetyenziswe.

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iziphumo

Ixesha lexesha lokudityaniswa kwentsholongwane ye-ΔFosB kwi-NAc yeehamster zaseSyria zabasetyhini

Iqela elahlukileyo lezilwanyana lasetyenziswa ekuqaleni ukufumana ikhosi ye-ΔFosB edityaniswe yintsholongwane kwi-hamster yabasetyhini. Uhlalutyo lwentetho ye-ΔFosB kwi-3 (n = 5), 6 (n = 6), kunye ne-9 (n = 2) amanqaku eveki abonise ukuba iiveki ezi-3 emva kotyando lwe-stereotaxic zivelise inqanaba le-ΔFosB overexpression eyagcinwa nge-6 kunye ne-9. kwiiveki emva kotyando lwestereotaxic. Inkcazo yentsholongwane ubukhulu becala yayiyinyukliya, kodwa yafunyanwa nakwi-cytoplasm kunye nakwi-dendrites yezinye iiseli ezigqithisileyo. Kwizilwanyana ezilishumi elinesithathu eziquka ilingelo lekhosi, izilwanyana ezine zine-rostral NAc iinaliti zentsholongwane ezingundoqo, enye yazo yasasazeka kwinucleus yebhedi ye-stria terminalis (BNST). Izilwanyana ezisithoba eziseleyo zine-caudal injection yokubekwa, ezisixhenxe kwi-caudal core, kunye nesibini kwi-caudal shell ye-NAc. Inye kuphela yenaliti yeqokobhe le-caudal yawela i-caudally kwi-BNST, ngelixa i-injection ezintandathu kwi-caudal core yawela i-caudally kwi-BNST. Umyinge omkhulu we-diameter ye-viral expression kwi-point time nganye ifunyenwe yi-0.9 mm, i-1.2 mm, kunye ne-1.0 mm ye-3, i-6, kunye ne-9 yeeveki, ngokulandelanayo. Le mitha ye-avareji yayiphantsi kohlalutyo lokungafani kwaye ayifumanekanga ukuba yahluke kakhulu. Ke ngoko, kolu vavanyo lokuziphatha lulandelayo, uvavanyo lokuziphatha lwaqala malunga neeveki ze-3 emva kotyando lwe-stereotaxic, kwaye izilwanyana zabingelelwa malunga neeveki ze-9 emva kotyando lwe-stereotaxic ukuqinisekisa ukuba ukubonakaliswa kwentsholongwane kugcinwe kwinqanaba elifanayo.

Uhlalutyo lwe-Immunohistological ye-AAV-ΔFosB kunye ne-AAV-GFP yentsholongwane yentsholongwane

Amacandelo obuchopho kwisilwanyana ngasinye esisetyenziswe kwiimvavanyo zokuziphatha zahlalutywa ngokuphindaphindiweyo kwinqwelomoya ye-coronal indawo ye-anatomical ye-injection ye-viral. Izilwanyana ezili-12 zizonke zahlalutywa ukubonakaliswa kwazo kumacala amabini e-ΔFosB ngokubalwa kweeseli, kunye nokubekwa kwesitofu, okuye kwamiselwa ngokulandela umkhondo weenaliti ezishiyekileyo. Nangona ukufakwa kwesitofu kwahlalutywa kwicandelo le-coronal (Umzobo 1), ukubonakaliswa kweprotheyini kwandiswe kwi-rostral-caudal ellipse ukusuka kwindawo yokutofa, kwaye iphinde isasazeke kwi-dorsal-ventral ellipse ukusuka kwindawo yokutofa. Kwizilwanyana ezihlanu ezihlalutyelwe kwiQela le-2, i-70.5% yeeseli ezigqithisiweyo ezingaphezulu kwi-NAc (i-median = iiseli ze-16,864, i-quartile ephantsi = iiseli ze-7,551, i-quartile ephezulu = iiseli ze-20,002, i-interquartile range = 12,451). Izilwanyana ezisixhenxe ezihlalutywe kwiQela le-4 zibonise i-65.6% ye-viral overexpression kwi-NAc (i-median = i-9,972 iiseli, i-quartile ephantsi = iiseli ze-5,683, i-quartile ephezulu = iiseli ze-11,213, i-interquartile range = 5530.). Ezi zibalo zeeseli zimele ukugqithiswa kwentsholongwane endaweni ye-endogenous stain ngenxa yokuhlanjululwa okunenjongo kwe-antibody yokuqala.

Umzobo 1    

Amanqanaba okubonakaliswa kweeprotheyini ahlanganiswe yi-AAV-GFP okanye i-AAV-ΔFosB 12 wks emva kokutofa. Phezulu. I-GFP overexpression yayininzi yenyukliya kodwa yafunyanwa ukuba isasazeke kwi-cytoplasm kunye ne-dendrites yeeseli. Ezantsi. ΔFosB iprotein yokubonakalisa ilinganisiwe ...

Kwiindawo ze-24 zeendawo zokutofa zamazwe amabini, ishumi elinesibini lalikwi-rostral core ye-NAc, ezintandathu kuzo zazinentetho yentsholongwane eyasasazeka kwi-BNST. Iziza ezilishumi elinambini eziseleyo zenaliti zazikwi-caudal NAc. Enye yeenaliti ezilishumi elinambini yayikwiqokobhe le-caudal kwaye yasasazeka nge-caudally kwi-BNST. Iziza zokugqibela zenaliti ezilishumi elinanye zazikumbindi we-caudal we-NAc, ezisibhozo zazo zasasazeka nge-caudally kwi-BNST. Zonke iinaliti zazigxile kwi-anterior commissure ngaphandle kwenaliti enye kwigobolondo le-caudal ye-NAc eyayiphakathi kancinci kune-commissure yangaphambili (Umzobo 2). Zonke izilwanyana zibonise ukugqithisa okufanelekileyo kwe-GFP okanye i-ΔFosB kwaye ke zasetyenziswa kuhlalutyo lokuziphatha olulandelayo. Akukho zilwanyana ziye zakhutshelwa ngaphandle kuphononongo ngenxa yokungafakwa kakuhle kwesitofu se-anatomical. Ukuqhubela phambili, ngenxa yokuba zonke iinaliti zazijoliswe kwi-accumbal core kunye nenaliti enye kuphela yayibandakanya iqokobhe akukho lucazululo lwamanani lwenziwa kwiindawo zokutofa.

Umzobo 2    

I-anatomical localization yokubeka inaliti yentsholongwane yezilwanyana zokulinga. Izangqa zimele ukubekwa kwe-AAV-GFP kwaye izikwere zimele i-AAV-ΔFosB yokubekwa. a. I-AAV-GFP yokubeka i-injection yezilwanyana ezine-5 wks ngokwesondo (iQela 1). ...

I-AAV vector overexpression ye-ΔFosB kwi-NAc ye-hamsters yabasetyhini baseSyria iphumela kumvuzo wesondo ophuculweyo

Ukuvavanya ukuba ngaba ukugqithiswa kwe-ΔFosB kwi-NAc kunempembelelo kumvuzo wesondo sisebenzise indawo ekhethiweyo yeparadigm. Kolu vavanyo, izilwanyana zahamba nokuba yi-0, i-2, okanye i-5 yeeveki zesini. Ngexesha lokulungiswa ngokwesondo, i-lordosis latency kunye nobude bexesha zabhalwa kwi-hamster nganye yabasetyhini. Ayikho i-lordosis latency (iQela 1: 553 isekhondi ± 7 isekhondi, iQela 4: 552 isekhondi ± 7 isekhondi, iQela 5: 561 isekhondi ± 7 sec,) okanye ixesha le-lordosis (Iqela 1: 485 isekhondi ± 15 isekhondi, Iqela lesi-4: 522 imizuzwana ± i-10 sec, iQela 5: i-522 sec ± 12 sec) ngexesha le-sex conditioning yahluke kakhulu phakathi kwamaqela kulo lonke uvavanyo kungakhathaliseki ukuba i-viral injection. Ke ngoko ukuchazwa okugqithisileyo kwe-GFP okanye i-ΔFosB ayinayo nayiphi na impembelelo kwindlela yokwamkela yabasetyhini.

Iqela ngalinye elivela kwinkqubo yokukhetha indawo ekhethiweyo yahlalutywa ngabanye kunye novavanyo oluphindaphindiweyo lwe-t-test phakathi kwexesha elichithwe kwi-conditioning compartment (i-gray compartment) ngexesha lovavanyo lwangaphambili kunye novavanyo lwasemva. Uhlalutyo lwamanani aluzange lwandiswe phakathi kwamaqela. Uphando lwangaphambili lubonise ukuba amava amahlanu anesimo sezesondo anele ukufumana utshintsho olubalulekileyo kwindawo yokukhetha (Meisel kunye neYopa, ngo-1994, Meisel okqhubekayo., 1996). Enyanisweni, iqela elilungileyo lokulawula elibandakanya izilwanyana zabasetyhini ezigqithise i-GFP kwi-NAc eziye zanikwa amava amahlanu e-sexual conditioning achitha ixesha elininzi ngexesha lovavanyo lweposi kwigumbi elingwevu elidibene namava ezesondo xa kuthelekiswa nokusebenza kwangaphambili, t (8) ) = -3.13, P< 0.05. Njengoko bekulindelekile, izilwanyana ezingakhange zinikwe nayiphi na imeko yamava ezesondo azizange zitshintshe kakhulu isixa sexesha kulo naliphi na igumbi ngaphandle kwenaliti yentsholongwane. Abasetyhini abagqithisa i-GFP abanikwe amava e-2 abonisa imeko yezesondo ayizange ibonise imeko yendawo, ngelixa abafazi banikwe amava amabini abonisa ngokwesondo ngokugqithiswa kwe-ΔFosB bachitha ixesha elingakumbi kwigumbi elidibene namava ngokwesondo ngexesha lovavanyo lweposi, t(7) = -2.48, P< 0.05 (Umzobo 3).

Umzobo 3    

Indawo ene-conditioning ekhethwayo emva kwesitofu sentsholongwane. Le grafu ibonisa inani eliqhelekileyo (±SEM) lemizuzwana ngexesha lovavanyo lwangaphambili lwe-conditioning (Pre) kunye novavanyo lwe-postconditioning (iPost) iqela ngalinye le-hamster elichithwe kwi-gray compartment. ...

I-AAV vector overexpression ye-ΔFosB kwi-NAc yeehamster zaseSyria zabasetyhini ziphucula ukusebenza kakuhle kwazo kunye namadoda angama-naïve

Kwiveki enye emva kovavanyo olukhethiweyo lwendawo emva kovavanyo, abasetyhini abaneeveki ze-2 zovavanyo lwe-sexual conditioning (Amaqela 4 kunye ne-5) baphantsi kovavanyo lwe-naïve yokuziphatha ngokwesondo. Kolu vavanyo, abasetyhini be-AAV-ΔFosB abaneemvavanyo ezi-2 zangaphambili zesondo baphucule kakhulu ukusebenza kwabo kokukopa ngaphezu kwe-AAV-GFP yabasetyhini abane-2 yangaphambili yamava ngesondo.Umzobo 4). Umlinganiselo wokubethelwa (umyinge weentaba zizonke ezibandakanya ukungeniswa) kwamadoda angama-naïve ngokwesondo awayedityaniswe ne-AAV-ΔFosB yabasetyhini yayiphezulu kakhulu kunomgangatho wokubethelwa kwamadoda angama-naïve adityaniswe nabafazi be-AAV-GFP, t(14)= 4.089 p. <0.005.

Umzobo 4    

Ukusebenza kakuhle kwe-Copulatory yamaqabane e-hamster yamadoda angama-naïve. Le grafu ibonisa intsingiselo (± SEM) ireyithi yokubetha (umyinge weentaba zizonke ezibandakanya ukungena) kweehamster zamadoda ezinaïve ezidityaniswe nokuba ngabafazi be-AAV-GFP ...
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Imifuniselo yangaphambili esebenzise iivektha ze-AAV zoxinzelelo olugqithisileyo lwe-ΔFosB zaqhutywa kwiinkqubo zempuku okanye zemouse (Wallace okqhubekayo., 2008, Winstanley okqhubekayo., 2007, Zachariou okqhubekayo., 2006). Siye saqinisekisa iipateni zokubonakaliswa kwentsholongwane kwingqondo ye-hamster ngokungcoliswa kwe-immunohistochemical. Olu hlalutyo lubonise ukubonakaliswa okusebenzayo kwe-ΔFosB evele kamsinya kwiiveki ezi-3 emva kokutofa nge-intracranial kwaye yahlala iphakamile iiveki ze-9 kuhlalutyo lwekhosi yethu kunye nokuya kuthi ga kwiiveki ze-12 kuvavanyo lokuziphatha.

Kwimodeli yethu yamava esondo, ukusebenzisana okuphindaphindiweyo yindoda kukhokelela ekuvuseleleni ukukhutshwa kwe-dopamine kwi-NAc (Kohlert & Meisel, ngo-1999, Kohlert okqhubekayo., 1997) eneziphumo ezomelezayo kwindawo elungiselelwe iparadigm (Meisel kunye neYopa, ngo-1994, Meisel okqhubekayo., 1996). Le dopamine sensitization, kunye nekhono leehamster zabasetyhini ukulawula ukungena okuphumelelayo yindoda ekhuphukayo ngenxa yokudibana ngokwesondo okuphindaphindiweyo, kubonisa impendulo yobudlelwane (Bradley okqhubekayo., 2005b). Sibonise ukuba oku kuqiniswa kokuziphatha ngokwesondo kunokongezwa ngokugqithisileyo kwe-ΔFosB kwi-NAc kumxholo we-subthreshold yamava ezesondo, afanayo nokuphucula iimpendulo zesixhobo kwi-cocaine, i-morphine, okanye ukusetyenziswa kokutya okulandela ukugqithiswa okufanayo kwe-ΔFosB.Colby okqhubekayo., 2003, Olausson okqhubekayo., 2006, Zachariou okqhubekayo., 2006). Oku kunyuswa kobudlelwane bezesondo kunye nendoda elandelayo kumava ezesondo kubonakaliswe kukufumana indawo elungiselelweyo. It kunengqiqo ukuthathela ingqalelo i-ΔFosB njengesebenza njenge-transcriptional nexus elamla zombini uhlengahlengiso lwexesha elide kwindlela yokuziphatha kunye nesiseko seplastiki ye-neuronal esisiphumo sokusebenza kokujoliswe kuko okusezantsi kwe-ΔFosB.

Ngenxa yokuba ukuphakama kwe-ΔFosB kuvelisa ezi ziphumo, iindlela ezisisiseko kufuneka zithathelwe ingqalelo. Zimbalwa kakhulu iziphumo ezichongiweyo zemolekyuli eziphuma kuqokelelo lwe-ΔFosB. MIzifundo ze-icroarray zeempuku ezibonisa ngokugqithisileyo i-ΔFosB ibonise ukonyuka kwe-serine/threonine cyclin exhomekeke kwi-kinase-5 (Cdk5), i-nuclear factor kappa B (NF-κB), i-GluR2 subunit ye-glutamate receptor, kunye ne-dynorphin (Ang okqhubekayo., 2001, Bibb, 2003). Akucaci ukuba ezi ziganeko zemolekyuli zinokuchaphazela njani iplastiki kunye ne-dendritic spine formation, nangona i-Cdk5 iyazi indima ekwandiseni i-dendritic spine density.Bibb, 2003, Cheung okqhubekayo., 2006, Kumar okqhubekayo., 2005, Norrholm okqhubekayo., 2003), kunye ne-GluR2 subunits okanye i-NF-κB ifakwe kwi-synaptic (Ang okqhubekayo., 2001, Nestler, 2001, Peakman okqhubekayo., 2003). Kuphononongo lwexesha elizayo siceba ukugxila kwezi kunye nezinye izinto ekujoliswe kuzo ezinokubakho zokukhutshelwa ezantsi kwe-ΔFosB ukujonga ukuba umsebenzi wabo uguquguquka njani noqokelelo lwe-ΔFosB kulandela ukuziphatha okuphindaphindiweyo ngokwesondo.

Kukho uncwadi oluninzi oluthumela iindima ezahlukileyo ezidlalwa yiqokobhe kunye nesiseko se-NAc kwiindlela zokuziphatha ezikhuthazayo (UBrenhouse kunye neStellar, ngo-2006, UCadoni kunye noDi Chiara, ngo-1999, Perrotti okqhubekayo., 2008, Pierce & Kalivas, ngo-1995). Uphando lwangaphambili kwibhubhoratri yethu luchonge ngokuqhubekayo iziphumo zeselula zamava ngokwesondo kumbindi we-accumbens (Bradley okqhubekayo., 2005a, Bradley okqhubekayo., 2005b, UBradley noMeisel, ngo-2001, Bradley okqhubekayo., 2004, Kohlert & Meisel, ngo-1999, Kohlert okqhubekayo., 1997, Meisel okqhubekayo., 1993), esenza isiseko sokujolisa kwethu undoqo we-NAc kolu phononongo. Uhlalutyo lwethu lobungakanani be-anatomical ye-ΔFosB overexpression ibonise ukuba nangona iinaliti bezijolise kwi-caudal core ye-NAc, intetho ye-ΔFosB ihlala isasazeka kwi-rostral BNST. Nangona i-caudal NAc kunye ne-rostral BNST ngokuqinisekileyo ziyi-nuclei eyahlukileyo ye-anatomically, azifani ngokufanelekileyo njengoko zombini imimandla imodareyitha uninzi lwezinto ezingundoqo kwiinkqubo zenkuthazo (umz., Koob et al., 2004). Kwizifundo zethu ze-microdialysis ze-hamster zabasetyhini (Kohlert okqhubekayo., 1997), siqaphele ukungakwazi ukwahlula ukubekwa kwe-rostral ye-BNST yeprobe ukusuka kwabo bakwi-caudal NAc ngokwemigangatho yamanqanaba e-basal dopamine, iimpendulo ze-dopamine ekusebenzisaneni ngokwesondo namadoda, okanye iipatheni ze-dopaminergic afferent innervation. Endaweni yokujonga ukusasazeka kosulelo kwi-BNST njengengxaki yendlela, ezi ziphumo zixhasa umbono wokuqhubekeka okusebenzayo phakathi kwe-NAc kunye ne-BNST.

Nangona sibonisile ukuba ukugqithiswa kwe-ΔFosB kwiihamster zabasetyhini kunjalo ngokwaneleyo ukuvelisa indawo emiselweyo ekuphenduleni ngokwesondo kunye nokuphucula intsebenziswano kunye namadoda, ayaziwa ukuba i-FosB ibonakaliso nayo. kuyimfuneko kwezi ziphumo zokuziphatha zamava okwabelana ngesondo. Uphononongo lwakutsha nje lusebenzise intsholongwane ye-AAV-ΔJunD, eyehlisa i-ΔFosB ngokukhuphisana ngokukhuphisanayo nge-heterodimerizing kunye ne-ΔFosB ngaphambi kokubophelela ummandla we-AP-1 kwiijeni.Winstanley okqhubekayo., 2007). Ngokusebenzisa i-AAV-ΔJunD ukunkqonkqoza i-ΔFosB ekhutshelweyo, sinethemba lokufumanisa ukuba i-ΔFosB iyafuneka kwi-plasticity yokuziphatha esiyibonileyo emva kwamava okuziphatha ngokwesondo, okuza kuhambelana neziphumo zophononongo oluthiwe thaca apha. Ukuba uqokelelo lwe-ΔFosB kunye nokusetyenziswa kwayo okulandelayo kweethagethi ezisezantsi kubangela zombini ukuziphatha kunye neplastiki yeselula, ngoko ke ukuthotywa kwe-ΔFosB kufuneka kuphelise ezi ziphumo.

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Imibulelo

Sithanda ukubulela u-Amanda Mullins, uMelissa McCurley, kunye no-Chelsea Baker ngoncedo lwabo ngokuvavanya ukuziphatha, ukulungiswa, kunye nokulungiswa kwezicubu. Lo msebenzi uxhaswe yi-NIH izibonelelo ze-DA13680 (RLM) kunye ne-MH51399 (EJN).

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Ucaphulo

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