Dhiirranaanta DeltaFosB ee nucleus galbeed waxay la jaanqaadaysaa muuqaal-celinta walxaha ilaalinta, laakiin maaha dabeecadda niyad-jabka ee dareen-celinta deegaanka (2014)

Front Behav Neurosci. 2014; 8: 297.

Loo soo daabacay internetka Aug 29, 2014. doi:  10.3389 / fnbeh.2014.00297

PMCID: PMC4148937

aan la taaban karin

Kobcinta bey'ada waxay soo saartaa xakameyn iyo walaac ku dhaca jiirka. ΔFosB waa shey la soo qoro oo maareysa abaalmarinta maskaxda isla markaana ay ku dhacdo culeys maskaxeed iyo sidoo kale daroogada si xun loogu isticmaalo. Si kastaba ha noqotee, doorka ay ka cayaartay ΔFosB ee ka hortagga dabeecadaha ilaalinta ee deegaanka si wanaagsan looma baran. Halkan, waxaan ku muujineynaa ΔFosB in si ka duwan loogu habeeyay jiirka lagu soo qaaday xaalad go’doonsan (IC) marka loo barbar dhigo kuwa ku jira xaalad hodan ah (EC) iyadoo laga jawaabayo xakameynta walaaca ama cocaine.

Welwelka daba-dheeraada ama daaweynta muddada-dheer ee cocaine ayaa midkasta sare uqaadda levelsFosB-ga borotiinka ee burooyinka Nucleus-ka (NAc) ee jiirka IC, laakiin aan ka imaanin jiirka EC sababo la xiriira aruurinta aasaaska sare ee 'osFosB' oo lagu arkay xaaladaha EC..

Xad-dhaafka dhexdhexaadka ah ee 'osFosB' ee duqeynta NAc ee jiirka lammaanaha leh (sida, ka madax banaan kobcinta / go'doominta) waxay kordhineysaa howl wadeenada wax ka qabashada guulaha marka ay gaajada gaarto, laakiin waxay yareysaa wax ka qabashada xayawaanka ku daalay. Intaa waxaa dheer, oveFosB xad-dhaafka ah wuxuu hoos u dhigaa is-maandorinta maandooriyaha, wuxuu wanaajiyaa baabi'inta raadinta kookaha, wuxuuna yareynayaa dib-u-soo-kicinta maandooriyaha is-maandhaafka ah; dhammaan natiijooyinka dabeecadda oo la jaan qaada kobcinta 'phenotype'.

Taas bedelkeeda, si kastaba ha noqotee, oveFosB xad-dhaafka ma uusan beddelin jawaabihii jiirka labada-hoy ku jira ee dhowr tijaabo oo walaac ah- iyo dabeecadda niyad-jabka.

Markaa, ΔFosB ee NAc qolofta miciinka astaamaha xakamaynta balwadda, laakiin ma aha dabeecadda niyad-jabka ee kobcinta deegaanka.

Keywords: [kordhin]FosB, kobcinta deegaanka, niyad jab, maamulka maandooriyaha ee cocaine, fayraska la xiriira adeno-ka (AAV), xad-dhaafka

Hordhac

Khibradda nolosha, gaar ahaan marxaladaha hore ee nolosha, waxay ku leedahay saameyn qoto dheer dabeecadda xayawaanka inta lagu jiro nolosha. Deegaanku wuxuu door muhiim ah ka ciyaaraa nuglaanta iyo caabbinta cudurada maskaxda ee ka dhaca aadanaha (Elisei et al., 2013; Akdeniz et al., 2014; Kato iyo Iwamoto, 2014; van Winkel et al., 2014). Moodooyinka noocan ah, ee ku nool bey'ad hodan ah ilaa naas-nuujinta ilaa qaangaarnimada ayaa la soo sheegay inay soo saaraan balwadda ilaalinaysa iyo waxyaabaha murugada leh. (Cagaarka et al., 2002, 2003, 2010; Laviola et al., 2008; Solinas et al., 2008, 2009; El Rawas et al., 2009; Thiel et al., 2009, 2010). Qaabkan, xayawaannada waxaa loo xilsaarayaa xaalad hodan ah (EC) oo ay xayawaanku ku hoydaan oo ay maalin kasta marin karaan aaladda sheeyada cusub, ama xaalad go'doon ah (IC) oo xayawaanku hal meel ku nool yihiin oo aan lahayn sheeko ama xiriir bulsheed. Xayawaanku waxay ku koreen xaalad qani ah, oo ay ku jiraan xiriir bulsheed, jimicsi iyo sheeko cusub, waxay muujinayaan xoojin yar iyo raadinta kookaha ama amphetamine-ga ee maandooriyaha is-xakamaynta maandooriyaha. (Cagaarka et al., 2002, 2010). Ka sokow balwad-xumada balwada leh, soo-gaadhista noocan ah ee kobcinta waxay soo saartaa saamayn murugo-u leh qaababka xayawaannada niyad-jabka (Cagaarka et al., 2010; Jha et al., 2011). Gaar ahaan, xayawaanada hodanka ah waxay muujiyeen hoos u dhac dabeecadeedka anhedonia-u eg ee imtixaanka doorbidida, ka laabashada bulshada ee imtixaanka is dhexgalka bulshada, iyo yaraanshaha awooda tijaabada dabaasha qasabka ah (FST). In kasta oo ka hortagga balwadda iyo saameynta dabiiciga-lidka ku ah kobcinta, hababka salka ku haya ka hortagida dabeecadahaan kobcinta deegaanka si buuxda aan loo fahmin, in kasta oo baaritaankeenna hore uu saameyn ku yeeshay dhaqdhaqaaqa hoos u dhaca natiijada qoritaanka, CREB, ee kujira qanjirayaasha Nucleus (NAc) ) dhexdhexaadinta qaar ka mid ah saamaynta kobcinta deegaanka (Cagaarka et al., 2010; Larson et al., 2011). Markaa, hadafka daraasadaha kala duwanaanshahaani waa in la isticmaalo dariiqa sayniska ee aasaasiga ah si loo ogaado hababka moodeelka ah ee adkeysiga oo markii dambe loo tarjumi karo rugta caafimaadka. Habkaani waa bey'ada u dhiganta istiraatiijiyad hidaha sida wanaagsan loo dejiyay sida taranka xulashada (McBride et al., 2014).

Halkaan waxaan diirada saareynaa qodobo kale oo la isku qori karo, ΔFosB, oo si xad dhaaf ah ay ugu kiciso NAc noocyo walaac ah ama gabi ahaanba daroogada oo dhan, oo ay ku jiraan kookaha, morphine, aalkolada, nikotiinta, iyo amphetamine (Hope et al., 1992; Kelz iyo Nestler, 2000; Perrotti et al., 2004, 2008). Maaddaama ay tahay qayb isweydaarsi ah, ΔFosB waxay hoos u dhigeysaa ilaalinta borotiinka qoyska ee qoyska, gaar ahaan JunD, si ay u sameyso isku dhaf AP-1 firfircoon oo ku xirma qeybta jawaab-celinta AP-1 si kor loogu qaado ama loo xakameeyo qorista hidde-sideyaasha bartilmaameedka ah (Nestler, 2001), in kasta oo cilmi-baaris cusub ay soo jeedisay in ΔFosB sidoo kale u dhaqmi karo homodimer (Wang et al., 2012). Borotiinka 'osFosB' waa nooc kala duwanaansho kabay kala duwan oo ah FosB hiddo-wadaha, oo sababa borotiinka 'osFosB' inuu ka maqnaado laba qaybood oo ah C-terminal degron, kana hortago proteinFosB borotiinka xawaaraha deg degga ah ee lagu arko FosB iyo dhammaan borotiinka kale ee qoyska Fos. Sababtoo ah ΔFosB si aad ah ayey ugu xasilisan tahay NAc, ΔFosB waxay u dhaqantaa si aad u kala duwan ugana jawaab celisa xaaladaha degdegga ah marka la barbar dhigo borotiinka Fos kale. Soo-noqosho joogto ah oo loo sameeyo daroogada xadgudubka ama walaaca proteinFosB borotiinka ayaa si tartiib tartiib ah u urursada oo sii jiraya maalmo ilaa toddobaadyo, halka FosB iyo borotiinada kale ee Fos la kiciyay muddo gaaban oo keliya (saacado) oo ay yeeshaan horumar ku-kicinta ka-soo-if-baxa xiga (Nestler et al., 2001; Nestler, 2008).

Muhiimadda ΔFosB ma aha oo keliya in ay si weyn u horseeddo daroogada si xun ula dhaqanka iyo walaaca, laakiin in ku takri-falidda ΔFosB ee maskaxda ayaa la muujiyay inay saameyn ku leedahay dhaqanka xoolaha. Xulashada 'osFosB' ee 'dynorphin spiny dhexdhexaad neurons' ee jiirka dadka waaweyn waxay kordhisaa dareenka miyir-qabka iyadoo laga jawaabayo cocaine-ka daran iyo soo noqnoqda, iyo sidoo kale jawaabaha abaalmarinta leh ee ku saabsan xaaladda doorbidista doorka xaaladda iyo xaaladda xoojinta is-maamulka is-maamul. (Kelz et al., 1999; Kelz iyo Nestler, 2000; Colby et al., 2003).

In kasta oo dabeecadaha kahortaga qabatinka iyo niyad jabka loo sharxay jiirka deegaanka hodanka ku ah, doorka suurtagal ee ΔFosB ee dhexdhexaadinta dhacdooyinkan ilaalintiisa si buuxda looma qiimeynin. Daraasadihii hore ee kobcinta bey'ada ayaa muujisay, marka la barbar dhigo jawiga caadiga ah (SE), bey'ad hodan ah waxay kordhisaa heerarka 'basal ΔFosB' labadaba D1 iyo D2 dhexdhexaadka cirifka dhexe ee gobollada jiirka ee jiirarka. (Solinas et al., 2009; Lobo et al., 2013). Intaa waxaa sii dheer, jiirka Wistar ee hodanka ah waxay muujiyeen unugyada togan ee ΔFosB sare ee NAc iyo kiliyaha prefrontal marka loo barbar dhigo SE-da, iyagoo soo jeedinaya doorka suurtagalka ah ee ΔFosB ee balwadda kahortagga walaxda nikotiinta. (Venebra-Muñoz et al., 2014). Intaas waxaa sii dheer, isticmaalka 'extrarexpressing ΔFosB' ee dusha sare ee jiirka ayaa kordhinaya socodka maalinlaha, kaasoo laga yaabo inuu u dhigmo dhaqdhaqaaqa kordhay ee jiirka ee bay'ad hodan ah (Werme et al., 2002).

Daraasadda hadda socota, waxaan qiyaasahay in: (1) kobcinta deegaanka ay kordhineyso aruurinta heerarka 'basal alFosB' ee NAc; iyo (2) ururintan ΔFosB waxay gacan ka geysan doontaa saameynta ka hortagga kobcinta deegaanka.

Qalabka iyo hababka

Xayawaanka

Kobcinta deegaanka, Ragga Sprague-Dawley jilayaasha (Harlan, Houston, TX, USA) si aan kala sooc lahayn ayaa loo xilsaaray mid ka mid ah guryaha EC ama IC laga bilaabo maalinta umusha 21 ilaa maalinta 51. Jiirka EC ayaa koox ahaan loo habeeyay (20 halkii qafis) oo ku yaal bakhaaro waaweyn oo bir ah (70 × 70 × 70 cm) oo ay ku jiraan dhowr waxyaabo adag oo caag ah (alaabada carruurta, weel caag ah, tuubooyinka PVC, iwm). Walxahan waxaa lagu bedelay waxyaabo cusub waxaana dib loogu habeeyay qaabeynta sheeko maalinle ah. Jiirka IC ayaa kelidii lagu hayaa xirmooyinka caadiga ah ee polycarbonate. Jiirka ayaa ku sii jiraya shuruudahan dhammaan tijaabooyinka iyo dhammaan tijaabooyinka dabeecadda iyo tijaabooyinka bayoolojiyeed ayaa bilaabmay ka dib markii maalmo 51 ah (ie, uguyaraan 30 maalmood oo kobcinta / go'doominta). Xaddiga xad-dhaafka ah ee 'osFosB', ragga Sprague-Dawley rats (Harlan, Houston, TX, USA) waxaa laga helay xajmiga 225 – 250 g waxaana la isugu geeyay xirmooyin heer sare ah oo polycarbonate ah kahor intabadan si rasmi ah loogu duray faayraska firfircoon ee adeno-ka (AAV2) overrexpressing ΔFosB oo leh borotokoolka cagaaran (GFP) ama kaliya GFP sidii kontorool (eeg hoos). Cowga caadiga ah ee jiirka iyo biyaha ayaa si xor ah u heli kara dhammaan jiirka marka laga reebo inta lagu jiro tijaabooyinka dabeecadda iyo sharciyeynta cuntada. Dhammaan jiirka ayaa lagu ilaaliyaa deegaan la xakameeyay (heerkulka, 22 ° C; huurka qaraabada, 50%; iyo 12 h iftiin / wareegga mugdiga ah, nalalka 600 h) oo ku jira Ururka Qiimeynta iyo Aqoonsiga Daryeelka Shaybaarka Xayawaanka (AAALAC) ogolaaday gumeysi . Dhammaan tijaabooyinka waxay waafaqsan yihiin Tusaha NIH ee Daryeelka iyo Adeegsiga Xayawaanka Shaybaarka iyo Guddiga Xannaanada Xayawaanka iyo Adeegga Jaamacadda ee Jaamacadda Texas.

Kobcinta Deegaanka waa isku duubni iskuxirnaan oo ka kooban cusub, xiriir bulsheed iyo jimicsi. Guriyeynta lammaanaha waxay bixisaa xiriir bulsheed sidaas darteed waxay matalaysaa EC (eeg Tilmaanta NIH). Markaa, kooxda xakameynta ku habboon ee leh xaalad cusub, xiriir bulsheed iyo jimicsi ayaa noqon doonta koox bilaa fal ah, xiriir bulsheed ama jimicsi, xaaladda IC. Jiirka IC ayaa muujinaya astaamo ka yar buufiska daba-dheeraada marka loo eego jiirka EC. Gaar ahaan, EC jiirku waxay leeyihiin tilmaamo balaaran (Mlynarik et al., 2004), jawaabaha CORT blunded (Jaranjarooyinka et al., 2011), oo ay soo ifbaxday bilawgii dhaqsaha-hore ee hiddaha (Zhang et al., qoraal gacmeedkii diyaarinta) iyo uruurinta ΔFosB (Solinas et al., 2009; Lobo et al., 2013), dhammaan calaamadaha walaaca joogtada ah (Crofton et al., dib u eegis).

Murugo nafsi ah

Jiirka waaweyn iyo kuwa go'doonsan waxaa la galiyay meelayaal jilicsan oo jilicsan oo caag ah (DecapiCone®, Braintree Scientific Inc., MA, USA) oo loogu talagalay 60 min labada 1 maalin (ba'an) ama 9 maalmood (soo noqnoqda). Imtixaannada mRNA-ga gaaban ee muuqaalka, jiirka 30 (jiirka 5 kooxdiiba) ayaa loo gooyey 30 min ka dib bilowgii muddadii ugu dambeysay ee xannibaadda, aaladaha jiirka ayaa la soo saaray oo NAc loo faafiyay falanqaynta mRNA. Wixii loogu talagalay immunohistochemistry, jiirka 12 ayaa lagu caddeybay cusbada iyo 4% paraformaldehyde, maskaxda ayaa la soo saaray, dib loo hagaajiyaa 4% paraformaldehyde waxaana lagu keydiyaa 20% glycerol ee 1xPBS 4 ° C. Maskaxda raatka waxaa lagu jarjaray 40 μm oo leh microtome qabow. Maskaxda ayaa la goostay 24 h kadib walaackii ugu dambeeyay si loogu oggolaado in borotiinka FosB-dhererkiisu buuxiyo (Perrotti et al., 2008).

Is xakamaynta maandooriyaha kookaha oo la kobciyo deegaanka

Galinta tuubada galinta galinta

Jiirka ayaa la suuxiyay iyadoo la isticmaalayo ketamine (100 mg / kg IP) iyo xylazine (10 mg / kg IP) iyo kateetarka Silastic ayaa la galiyay oo lagu keydiyey xididdada jugular, oo laga saaray maqaarka dhabarka xayawaanka. Maalin kasta kateetariyada waxaa lasiiday 0.1 ml oo ah biyo cusbo oo saafi ah oo ay kujiraan heparin (30.0 U / ml), penicillin G potassium (250,000 U / ml) iyo streptokinase (8000 IU / ml) si looga hortago caabuqa loona ilaaliyo kateetarka kateetarka mudada oo dhan ee tijaabooyin.

Is-maamulida maandooriyaha ee kobcinta deegaanka

Labaatan maalqabeen ah iyo jiinooyin go'doon ah oo loo yaqaan '20' oo go'doon ah ayaa lagu meeleeyay qolal ku shaqeeya 30 × 24 × 21 cm (Med-Associates, St. Albans, VT) oo loo oggolaaday inay riixaan libaax ku saabsan infusions cocaine ah (0.5 mg / kg / infusion, NISA oo ah dawada, Machadka Triangle Research, NC, USA) ama cusbada iyada oo la raacayo jadwalka go'an ee 1 (FR1) jadwalka 2 h maalin kasta wadarta guud ee maalmaha 14. Si loo joogteeyo qaadashada isku-midka ah ee loo yaqaan 'cocaine qaadashada' ee u dhexeysa kooxaha EC iyo kooxaha IC waxaa jiray ugu badnaan infusions 30 galaaskiiba. Awoodda maareynta garka ayaa ku koobneyd saamiyada '30', sidaa darteed jiirka ugu hooseeya ee jawaab bixiya koox kasta looma baaraandegayn, taasoo ka tagaysa Ns ee 8 ee kookaha iyo 7 ee loogu talagalay kooxaha cusbada. Markaa, ma jirin kala duwanaansho EC / IC wadarta guud ee qaadashada ama waqti qaadashada infusus ee udhexeeya jiirka EC iyo IC. Maskaxda Rat-ka ayaa laga soo saaray 3 h wixii ka dambeeyay bilowgii kalfadhiga is-maamul ee ugu dambeeyay iyo NAc waxaa loo faaqiday mRNA iyo falanqaynta borotiinka. Mid ka mid ah NAc waxaa loo adeegsaday 'West blot', dhinaca kalena waxaa loo isticmaalay qPCR.

Maamulka maandooriyaha kahortagga ah ee kobcinta deegaanka

Isbarbardhiga tooska ah ee suugaanta hore loo daabacay (Hope et al., 1994; Chen et al., 1995), EC (N = 12) iyo jiirka IC (N = 12) waxaa lagu duray cusbada ama 20 mg / kg cocaine intraperitoneally (IP) oo loogu talagalay maalinta 1 (ba'an) ama 9 maalmood (soo noqnoqda). Hal muunad EC ah ayaa la waayey intii howsha la waday. Kooxda degdegga ah waxay heshay mudisyo cusbo leh maalmo 8 iyo hal duriin ah maandooriyaha maalinta 9 si ay dhammaan jiirku u helaan tiro isku duriin ah. Maskaxda ayaa laga soosaaray 30 min ka dib mudistii ugu dambeysay waxaana NAc faafisay falanqaynta mRNA.

Qeexitaanka mRNA iyadoo la adeegsanayo qPCR

RNA waxaa laga soo saaray isku-dhiska 'RNA STAT-60' (Teltest, Friendwood, TX), RNA oo laga soocay DNA iyo borotiinka iyadoo la adeegsanayo chloroform, iyo saadaasha wadarta guud ee RNA oo leh 'isopropanol'. Wasakhaynta DNA ayaa laga saaray (TURBO DNA-Free, Teknolojiyadda Nolosha, CA, USA) iyo 5 ug oo ah RNA la daahiriyey ayaa loo rogay cDNA (SuperScript III Khariidadda Maqaalka 1aad ee 'Invitrogen katalog # 18080051). ΔFosB mRNA waxaa lagu tiriyay iyadoo la adeegsanayo PCR-waqtiga dhabta ah oo tiro ahaaneed (SYBR Green: Applied Biosystems, Foster City, CA) oo loo adeegsado qalabka loo yaqaan 'Biosystems 7500 fast thermocycler' oo ay weheliso kuwa u ololeeya in lagu garto oo keliya ΔFosB (horay: AGGCAGAGGGGGTCGGAGAT; u beddelidda: GCCGAGGACCGGDCGGDCGGGTDGGGTGGGTIG) si loo ogaado jiirka GAPDH (hore: AACGACCCCTTCATTGAC; rogid: TCCACGACATACTCAGCAC). Dhammaan ra'iisul-wasaaraha waxaa la ansaxiyay oo la falanqeeyey gaar ahaanta iyo jaangooynta ka hor tijaabooyinka (Alibhai et al., 2007).

Reer Galbeedka

Dhinaca midig ee NAc laga bilaabo cocaine ama cusbada iskood u maareynta EC iyo IC rats waxaa lagu sameeyay isku xirnaan ay kujirto haro, Hepes buffer, sodium fluoride, 10% SDS, iyo ka ilaaliyayaasha borotokoolka iyo fosfoolka dawada loo yaqaan (Sigma-Aldrich: P-8340, P -2850, P-5726). U fiirsashada borotiinka waxaa lagu qiimeeyay iyadoo la adeegsanayo Qalabka 'Proteind Assay Kit' ee Pierce BCA (Thermo Scientific, IL, USA). Sababtoo ah borotiinka laga soo saaray hal jiir kuma filneyn falanqaynta, samballada '2' oo ka socda isla kooxdii ayaa wada liitay, iyagoo soo saaraya samballo '4' koox kasta. Shaybaarada borotiinka 'protein' waxaa lagu diidey 95 ° oo loogu talagalay 5 min waxayna ku socotaa 10 – 20% polyacrylamide gradient gel (Criterion TGX, Bio-Rad Laboratories, CA, USA) ka dibna waxaa loo gudbiyay membrane polyvinylidene (PVDF) membrane (Millipore, MA, USA) ). Maska ayaa lagu xayirmey xannibaadda heerka-qallafsan (caano aan qallalan ahayn), oo lagu sameeyay ΔFosB anti antibody (bakaylaha, 1: 1000, #2251, Teknolojiyada Calaamadaha Taleefanka, MA, USA) iyo anti-aasaasiga ah antibody (jiirka, 1: 1000) , Teknolojiyada Digniinta Qalabka, MA, USA), waxay ku maydhay TBST ka dibna waxay ku dartay walxaha ka hortaga ee fluorescent Second (anti-bakaylaha (780 nm)), dameerka anti-jiirka (680 nm), 1: 15000, Li-Cor Biosciences, NE, USA). Nuqullada reer galbeedka ayaa markaa la hirgaliyay (Odyssey, Li-Cor Biosciences, NE, USA) iyo heerarka borotiinka oo ay kuxiran yihiin barnaamijka Odyssey.

Immunohistochemistry

Sawirka Jaantus11 (N = 3), unugyada ay ka kooban tahay 'osFosB' waa la daawaday waxaana lagu tirinay astaamaha immunohistochemical ee sumadda 'ΔFosB' ee NAc xaashiyaha lagu dhejiyay DAB (Xirmada qalabka 'DAB peroxidase, Vector Laboratories, CA, USA'). Maskaxda ayaa la soo saaray, la dhajiyay ka dib, la sii daayay oo loo kala qaybiyay xaleefyo 40 μm ah oo ay ka kooban tahay NAc oo ku taal meel lagu keydiyo microtome (Leica Biosystems, IL, USA). Xaleefyadu way sii qulqulayaan waxaana lagu maydhay 1xPBS ka hor inta aan la baabi'in peroxidases, kahor intaan la xerin 3% riyaha caadiga ah (Jackson ImmunoResearch, PA, USA) oo leh 0.3% triton iyo avidin D (Vector Laboratories, CA, USA). Xaleefyada NAc waxaa lagu soo rogay FosB antibody Primbody habeen Habeen ah (1: 1000, Santa Cruz Biotechnology, Dallas, TX, USA) oo leh xNUMX% riyaha, 3% triton, 0.3xPBS, iyo xalka biotin (Vector Laboratories, CA, USA). In kasta oo antibody uu aqoonsan yahay labadaba FosB iyo ΔFosB, daraasadihii hore ee daraasadaha reer galbeedka waxay muujiyeen in 1 h boostada kicinta, tirada badan ee astaanta immunohistochemical ay ka kooban tahay ΔFosB maxaa yeelay FosB si fiican ayey hoos ugu dhacday kahor 24 h (Perrotti et al., 2008). Ka dib maydhashada, xaleefyada waxaa lagu soo daray ariga biotinylated anti-bakaylaha antibody bakteeriyada IgG (Vector Laboratories, CA, USA), riyaha riyaha, iyo 1xPBS. Kadib, xaleefyada waxaa lagu soo rogay avidin-biotin complex (ABC) peroxidase wasakh oo loogu talagalay 15 min (Thermo Scientific, IL, USA). Ugu dambeyntiina, xaleefyada ayaa lagu rakibay, fuuq-baxa iyadoo la isticmaalayo ethanol iyo CitriSolv (Fischer Scientific, MA, USA) waxaana ku daboolan DPX (Fisher Scientific). Tirinta unugyada, qeybaha ayaa laga soo qaaday Bregma + 1.80 to + 1.44 xayawaan kasta. Tirada guud ee unugyada talaalka 'osFosB' ayaa laga tiriyay afar qeybood oo NAc ah xudunta iyo qolofta jiir kasta.

Jaantuska 1  

Cadaadiska iyo [kordhin]FosB ee EC iyo jiirka IC. (A – D) Wakiilka immunohistochemistry DAB oo cillad ka muujinaya ΔFosB ee NAc qolofka iyo xudunta u ah IC (A iyo B) iyo EC (C iyo D) jiirka leh (B iyo D) iyo la'aanteed (A iyo C) walaac soo noqnoqda (N = 3). (E) Tirinta ...

Fayraska la xidhiidha Adeno ee xad-dhaafka ah [kordhin]FosB

A -V2 ku saleysan fallaaraha oo muujinaya ΔFosB iyo humanized renilla GFP (hrGFP; Winstanley et al., 2007, 2009a,b) ama kontaroolada kantaroolka hrGFP (N = 10 midkastoo) waxaa lagu durayaa si kadis ah jiirka NAc. Sababta oo ah majiraan bini'aadamka IC, labada jiir-habeysan ayaa loo adeegsaday bedellada jiirka IC daraasaddan si loo kordhiyo muhiimadda ay u leedahay bulshada sayniska iyadoo la muujinayo saameynta 'ΔFosB madax bannaan muuqaalka EC / IC. AAV muujinaya hrGFP laakiin aan ka badneyn pressFosB ayaa loo adeegsaday xakameyn. Muujinta ΔFosB in vivo waxaa ansaxiyay immunofluorescence wasakheynta antios koowaad ee FosB (1: 200, Rabbit, Teknolojiyada Calaamadaha Taleefanka, MA, USA). Fallaaraha AAV ayaa lagu duray NAC qolofka laba geesood ah (1 μl / dhinaca 10 min) iyadoo la isticmaalayo isku duwayaasha (AP = 1.7, L = 2.0, D = −6.5). Imtixaannada habdhaqanka waxay bilaabeen toddobaadyo 3 ka dib qalliinka stereotaxic. Meelaynta saxda ah ayaa loo go'aamiyay immunohistochemically ka dib gabagabadii imtixaanka dabeecadda.

Sucrose neophobia

RaFosB doolshaha xayawaanka lagu buufiyo (N = 10) iyo kontoroolka jiirka (N = 8) waxaa gacanta loo galiyay usbuuca 1 kahor bilowga tijaabooyinka hab dhaqanka. Si loo tijaabiyo dabeecadda walaaca-la mid ah, jiirka ayaa loo qiimeeyay cudurka neophobia ilaa dhadhanka cusub (sucrose). Jiirka ayaa loo kala qaybiyey qaanso-shaqsiyeedka waxaana biyaha laga saaray 1600 h. Dhalooyinka biyaha ee caadiga ah ee jiirka waxaa laga buuxiyay xNUMX% w / v sucrose oo ah biyaha jiirka "caadiga ah" biyaha oo miisaan ayaa la galiyay ka hor intaan la dul dhigin qafis kasta oo ku yaal 1 h. Ka dib 1800 min dhalooyinka ayaa la saaray oo dib loo miisaamay, iyo farqiga miisaanka dhalada ku-guuleysta ka hor iyo kadib imtixaanka xisaabinta. Dabadeed, sucrose ayaa lagu beddelay baqshadda maalmo dheeri ah oo ah 30 si loogu oggolaado jiirka inay u bartaan dhadhanka sucrose ka hor imtixaanka doorbidida sucrose.

Sare u kacay oo ay weheliyaan

Tijaabad kale oo ah dabeecadda walwalka-walaaca leh, oo kacsan oo lagu daray maze (EPM), ayaa la tijaabiyay 2 maalmood kadib guushii ka soo baxday neophobia. EPM waxay cabbirtaa dabeecadda sahaminta ee habaynta sahaminta ee sheeko cusub iyo jawi soo saare walaac ah (Green et al., 2008). Laba gacmood oo xidhan iyo laba gacmood oo furan (Med Associates Inc., VT, USA) oo cabbiraya 12 × 50 cm waxay ahaayeen 75 cm dabaqa sare waxayna lahaayeen sawiro laga soo galo albaabka gacan kasta. Waqtiga lagu qaatay gacmaha furan waxaa isha lagu hayaa 5 min iyadoo la adeegsanayo jebinta sawirada iyadoo la adeegsanayo barnaamijka 'Med-PC'.

Qabatinka walaaca ee qabowga

Maalintii ka dambeysey EPM, waxaa la isticmaalay tijaabadii sedexaad ee walwalka walaaca: kala goynta ka jawaab celinta jawiga aadka u walaaca (qabow). Xirmooyinka jeelka polycarbonate (33 × 17 × 13 cm) ayaa horay loogu qaboojiyay barafka loogu talagalay 10 min. Jiirka ayaa la dhigay baqshadda barafka loogu talagalay 30 min oo tirada fecal boli waxaa lagu duubay daqiiqad kasta oo ah 5.

Xiriirka bulshada

Maalintii xigtay, dabeecadda murugo-la mid ah ayaa lagu cabiray iyadoo la adeegsanayo tijaabada is dhexgalka bulshada. Jiirka ayaa loo kala soocay 24 h kahor baaritaanka. Maalinta imtixaanka ee jiirka ayaa lagu meeleeyay bey'ad cusub (weel caag ah, 45 × 40 × 45 cm) oo ay weheliyaan qafiskooda qafiska iyo dabeecadda ayaa loo duubay fiidiyoowga 30 min. Waqtiga ay lammaaneyaasha jiirka cunayaan midba midka kale waxaa cabiray baarayaal indha indheeya xaaladda jiirka.

Sucrose doorasho

Xiriir bulsheed ka dib, imtixaanka doorbidida sucrose waxaa loo isticmaalay sidii moodada ahedonia. Jiirka labada-isku duuban ayaa loo kala soocay 1600 h oo cunto ah laakiin lama oggola in marin biyo loo helo 2 h. 1800 h laba dhalo biyo ah oo hore loo miisaamay ayaa la dul saaray qafis kasta, mid biyo ku jirta, tan kalena ah 1% xalka ku-guuleysiga biyaha. Dhalooyinka biyaha waxaa lagu meeleeyay booska caadiga ah halka kujirka la dhigey qiyaastii 10 cm fog. Dhalooyinka ayaa laga saaray oo dib loo miisaamay ka dib 15 min.

Waxqabadka Locomotor

Saddex maalmood ka dib doorbida ku-meelgaarka, nashaada dhaqdhaqaaqa waxaa lagu qiimeeyay xaaladaha iftiinka caadiga ah iyada oo lagu meeleeyo jiirka kuwa ku yaal qolalka Plexiglas cad (40 × 40 × 40 cm) oo leh lakab khafiif ah oo gogosha sariirta ah, oo ku hareereysan laba 4 × 4 matoor sawir qaadis ah, hal 4 cm kor dhulka iyo hal xNUMX cm oo dhulka korkiisa ah si loo diiwaan geliyo dhaqdhaqaaqa taagan iyo dhaqdhaqaaqa toosan (korinta). Fasaxyada sawir-qaadista waxaa lagu kormeeray 16 h oo ah nidaam hawleed furan oo wax laga beddelay (San Diego Instruments, CA, USA).

Imtixaanka qasabka ah ee khasabka ah

Imtixaankii ugu dambeeyay ee dabeecadda laf-dhabarta waxay ahayd FST, oo ah nooc u nugul daawooyinka murugada. Rats waxaa la galiyay santuuqa Plexiglas oo ay ka buuxaan ku dhowaad 14 L oo heerkulka qolka ah (24 ± 0.5 °) biyaha loogu talagalay 15 min Session 1, iyo 5 min maalinta Kalfadhiga 2 maalinta ku xigta. Jiirleydu way qallaleen oo dib ayaa loogu celiyey xirmooyinka guryahooda. Waxqabadka dabaasha ayaa loo duubay fiidiyoow iyo daahfurnaanta muddada ugu horreysa ee karti la'aanta (1 s) iyo wadarta waqtiga halista ah waxaa loo go'aamiyay kulanka "2" oo uu baaruhu indhatirey xaaladaha.

Howl wadeenka sucrose

Kontoroolka AAV iyo jiirka raFosB-overrexpressing waxaa loo habeeyay 85% culeyska quudinta-bilaashka ah maalmaha 7. Dhammaan jiirka ayaa loo tababaray inay ka horjoogsadaan saxaafadda si ay u xalliyaan mashiinnada suufka (Bio-Serv, NJ, USA) jadwalka FR1 ee xoojinta loogu talagalay fadhiyada min 15 min maalmaha 5 oo isku xiga. Rats ka dibna waxaa lasiiyay helitaan bilaash ah oo cuntada loogu talagalay maalmaha 3 oo mar kale loo oggolaaday inay u ololeeyaan si loo helo mashiinnada ku-meel-gaarka ah ee jadwalka FR1 ee 15 min, markan oo ah 100% miisaanka quudinta-bilaashka ah.

Isku-kalsoonaanta kookeeynta

Helida

Hal usbuuc ka dib qalliinka kateetarka (sida kor lagu sharaxay), dhammaan jiirka (jiirka xakameynaya 7 andFosB reFosB overrexpressing, hal jiirka xakameynta ayaa laga waayey qalliinka kateetarka) waxaana lagu meeleeyay qolalka qalliinka 10 × 30 × 24 cm (Med-Associates, St. Albans, VT) oo loo oggol yahay inuu iskiis u maareeyo 21 mg / kg / infusion unit dose ee koocaha loogu talagalay 0.2 h kalfadhiga maalmaha 2; ka dibna 4 mg / kg / faleebo maalmaha 0.5 ee jadwalka FR3. Faleebo kasta waxaa loo geeyay si xaddidan oo mug ah 1 ml ka sarreysa 0.01 s. Dhexgalka waxaa loo calaamadiyay iftiiminta laba nalal oo iftiin ah oo loogu talagalay 5.8 s, oo calaamad u ah waqti xaddidan oo aan hadda laga faa'iideysan karin infusions.

eynu

Sababtoo ah soo-gaadhista cocaine-ka daba-joogga ah waxay u horseedi kartaa inuu uruursado ΔFosB ee jiirka kantaroolka, taas oo sababi doonta jiirka labada xaaladood ee 'vector' inay lahaadaan heerar sare ΔFosB maskaxda, jiirku wuxuu ku xaddidan yahay baqashada guryahooda maalmaha 4 iyada oo aan maamulku iskiis u oggolaanin. LevelsFosB heerarka borotiinka si loo yareeyo jiirka kantaroolka-fekerka. Ka dib markii laga reebay maalmo 4, jiir ayaa lagu meeleeyay qolka qalliinka waxaana loo oggolaaday inay iskood u maareeyaan cusbada halkii ay ka isticmaali lahaayeen jadwalka 'FR1' oo loogu talagalay kalfadhiyada 1 h ee 3 maalmood oo isku xiga.

Qiyaasta saamiga saamiga

Jiir kasta (xakameyn iyo ΔFosB overrexpressing) ayaa loo oggol yahay inuu iskiis u maamulo 0.00325, 0.0075, 0.015, 0.03, 0.06, 0.125, 0.25, 0.5 mg / kg / infusion cocaine si kor loogu qaado nidaamka jadwalka FR1 maalin kasta oo loogu talagalay maalmo isku xigxiga 5. Rats iskood u maamuli jiray qiyaas kasta oo ah kookaha loogu talagalay 30 min.

Dib-u-soo-kicinta Cocaine-ka

Jiirka ayaa maray nidaamka dib u soo celinta kal-fadhiga gudahiisa. Rats waxay heleen 0.5 mg / kg / infusion jadwalka FR1 ee loogu talagalay 60 min oo ay ku xigto 3 h oo ah tirtirid (oo ay weheliso baaqyada korantada cocaine). Marka xigta waxay heleen mudis IP (Green et al., 2010) ee kookaha ee mid ka mid ah shan qiyaasood (0, 2.5, 5, 10, ama 20 mg / kg) si nidaamsan oo aan kala sooc lahayn jiir kasta inta lagu jiro kalfadhiyada 5 ee dib u soo celinta. Wejigii ugu dambeeyay ee 3 h ee kalfadhiga ayaa dib loo soo celiyay isagoo ka jawaabaya, mar labaad iyadoo la raacayo tixraacyada loo yaqaan 'cocaine' laakiin weli iyada oo aan la soo qaadin. Ka dib kulan kasta oo dib-u-kicinta kookaha ah, jiirku wuxuu helay maalmo dhex-dhexaadin ah 2 oo ah qiyaasta sare (0.5 mg / kg / infusion) kocaine jadwalka FR1 ee loogu talagalay 2 h si loo ilaaliyo heerar sare oo ka jawaab celinta kalfadhiyada oo dhan. Intii lagu guda jiray howsha maamulka maareynta ee kookaha, kateetariyada qaar ka mid ah jiirka ayaa si tartiib tartiib ah u lumay sharafteeda sidaa awgeed, xogaha jiirka kontoroolka ee 6 iyo 7 ΔFosB-overrexpressing jiirka ayaa loo adeegsaday falanqayntaan.

Falanqaynta tirakoobka

Falanqaynta laba-nooc ee kala duwanaanshaha (ANOVAs) iyo laba-ka-laab-cabbir-tallaabooyin ANOVAs ah ayaa la sameeyey si loo barbardhigo afarta koox ee daaweynta iyo isbarbardhigyada qorshaysan ayaa la isticmaalay in la isbarbar dhigo kala duwanaanshaha xaaladaha. Muhiimadda udhaxeysa laba xaaladood oo keliya ayaa lagu falanqeeyay iyadoo la adeegsanayo ardayga t- ugu dambeyntii. Dhammaan tXogta ugu badan waxay ka gudubtay imtixaanka Shapiro-Wilk ee caadiga ah. Macluumaadka oo dhan waxaa loo muujiyaa inay yihiin 'SEM'. Muhiimada tirakoobka waxaa lagu dejiyay at p <0.05. Dhammaan jiirka lagu taajiray ee hal tijaabo waxaa lagu xareeyay hal qafis laakiin waxaa loola dhaqmay sidii maadooyin gooni ah, iyagoo bixinaya saameyn ku saabsan arinta ku saabsan been abuurka.

Natiijooyinka

Jiirka EC wuxuu muujiyaa heerarka aasaasiga ah ee sare ee [kordhin]FosB gudaha NAc marka loo fiirsado jiirka IC

Marka loo barbar dhigo jiirka IC, jiirka EC waxay leeyihiin tiro aad u sareysa oo ah unugyada ΔFosB togan ee NAC labadaba (t(4) = -3.31, p <0.05) iyo qolof (t(4) = -6.84, p <0.05) (Sawirada 1A, C, E, F), soo jeedinta in codka asalka ah ee 'osFosB' uu ka sarreeyo qiimeeyeyaasha EC marka la barbar dhigo jiirka IC. Intaa waxaa sii dheer, natiijooyinka caleema saarka ee reer galbeedka waxay muujiyeen isbeddel xoog leh ee jiirka cusbada EC ee leh heerka ugu hooseeya ee borotiinka 'osFosB' ee NAc marka loo barbar dhigo jiirka cusbada IC.t(6) = -2.03, p = 0.089; Jaantuska Jaantus2A) 2A) adeegsiga tijaabin laba-laba ah. Si kastaba ha noqotee, marka la eego muujinta kordhay ee Sawir-barayaasha 1A – F iyo kororka lagu arkay waraaqaha kale (Solinas et al., 2009), waxaan ku kalsoon nahay saameyntaan. Natiijooyinka 'West blot' waxay kaloo xaqiijinayaan in ku dhawaad ​​dhammaan FosB-like immunoreactivity laga helo immunohistochemistry ay ahayd 'osFosB oo aan ahayn FosB, oo aan lagu ogaan karin 24 h.

Jaantuska 2  

Qaxwada iyo [kordhin]FosB ee EC iyo jiirka IC. (A – B) Waxaa loola jeedaa borotiinka 'osFosB' (A) iyo mRNA (B) Heerka (± SEM) ee NAc kadib 14 maalmood ee cusbada ama maareynta koocaha ee IC iyo EC (N = 7 – 8). Xargaha gaduudka ah gudiga ayaa ah tilmaam ...

[kordhin]FosB si gaar ah ayey ula falgashaa EC iyo calaamadaha IC cadaadiska

Waxa ku dhacay saamayn weyn oo muhiim ah walaaca xakamaynta soo noqnoqda ee labada qolof (F(1, 8) = 16.6, P <0.005) iyo xudunta (F(1, 8) = 7.9, P <0.05) ee NAc iyo saameynta ugu weyn ee kobcinta deegaanka ee qolofka (F(1, 8) = 22.3, P <0.005; Sawirada 1A – F). Waxaa taas ka sii muhiimsan, is-dhexgalka u dhexeeya walaaca iyo kobcinta deegaanka ayaa sidoo kale muhiimad weyn ku yeeshay labada qolof (F(1, 8) = 25.6, P <0.01) iyo xudunta (F(1, 8) = 6.7, P <0.05). Isdhexgalka wuxuu ahaa sida, kadib culeys xakameyn ah oo soo noqnoqday, tirada unugyada positiveFosB ee togan ayaa si weyn ugu kordhay jiirka IC, halka tiradaani aysan isbadalin jiirka EC ka dib diiqad soo noqnoqotay.

Si loo sii baaro sida 'osFosB si firfircoon loogu habeeyo xaalufka daran iyo walaaca soo noqnoqda iyo in loo oggolaado isbarbardhigga baaritaan hore (Alibhai et al., 2007), bilaabida ΔFosB mRNA waxaa lagu bartay walaac xaddidan iyo xakamaynta xakamaynta (Jaantuska (Sawirka1G) .1G). Waxaa jiray saameyn muhiim ah oo walaac badan leh (F(2, 24) = 31.9, P <0.001) iyo kobcinta deegaanka (F(1, 24) = 5.1, P <0.05). Jiirka IC, ΔFosB mRNA si xoog leh ayaa loo soo jiiday ka dib cadaadis xakameyn daran. Si kastaba ha noqotee, walaac soo noqnoqday, soo-kicinta ΔFosB mRNA si aad ah ayaa loo yareeyay marka la barbar dhigo soo-kicinta ba'an. Waxaa sidoo kale jiray is dhexgal muhiim ah (F(2, 24) = 4.6, P <0.05), oo muujineysa in soo-kicinta ba'an ee ΔFosB mRNA ay ka yar tahay jiirka EC marka la barbar dhigo jiirka IC. Markaa, jiirka EC waxay leeyihiin heerar aasaasi ah oo 'ofFosB' ah protein gudaha NAc, laakiin ka yar ΔFosB mRNA la qabsashada si looga jawaabo walaaca daran.

[kordhin]FosB waxaa si ka duwan u kallifa inay ku dhacdo NAC ee EC iyo jiirka IC

Si loo go'aamiyo in jiirka EC iyo IC ay si kala duwan ugu jawaabaan maandooriyaha, waxaan baranay qaanuunka 'osFosB protein' iyo mRNA ee jiirka NAc ka dib is-maandhaafka cocaine (Jaantus 2A, B siday u kala horreeyaan). Xaraashka reer galbeedka ayaa muujiyey saameyn muhiim ah oo weyn oo ah cocaine (F(1, 12) = 24.9, P <0.001) iyo isdhexgal muhiim ah (F(1,12) = 5.5, P <0.05). Isdhexgalka wuxuu ahaa sida 'osFosB ay uga kordheen jiirka IC-ga in ka badan jiirka EC (Jaantus (Figure2A) .2A). Xaqiiqdii, ka dib markii maareynta is-maamulidda ΔFosB ee borotiinka ay si weyn kor ugu kacday oo keliya jiirka IC. Marka la eego heerarka mRNA, natiijooyinka qPCR waxay sidoo kale shaaca ka qaadeen saameyn weyn oo weyn oo ah cocaine (F(1, 26) = 47.1, P <0.001) iyo saameynta ugu weyn ee kobcinta deegaanka (F(1, 26) = 13.8, P <0.005). Inkasta oo heerarka guud ay ka hooseeyeen jiirka EC, labada kooxba waxay kordhiyeen ΔFosB mRNA (Jaantus (Sawirka2B2B).

In kasta oo xogta borotiinka ay taageertay aragtida asalka ah, waxaa laga soo qaatay Jaantus Sawirka1G1G in jiirka EC uu muujiyo wax ka yar mRNA laadlaadista ka badan jiirka go'doonsan ee tijaabada kookaha ee kore, oo aan dhicin, waxay u badan tahay sababta oo ah Jaantuska Sawirka1G1G adeegsaday daqiiqad daqiiqad ah oo ah 30 iyo tijaabada maandooriyaha ayaa loo isticmaalay saacad 3 h ah. Si loo sii wareysto fikirka 'mRNA hypothesis', daqiiqad daqiiqad ah oo ah 30 waxaa loo isticmaalay in lagu sahamiyo labadaba daaweynta ba'an ee soo noqnoqda iyo soo noqnoqda iyadoo loo barbardhigi karo sifiican Sawirka1G.1G. Sababta oo ah maareynta kookaha degdegga ah waa dhibaato xagga dabiiciga ah (tusaale ahaan, helitaanka barashada), EC iyo jiirka 'IC' waxaa lasiiyay maalmo aad u xun ama 9 maalmood oo ah soo noqnoqoshada maandooriyaha kookaha IP (20 mg / kg). Sida la qiyaaso, waxaa jiray saameyn weyn oo weyn oo ah kobcinta deegaanka (F(1, 17) = 14.3, P <0.005), laakiin daaweynta kookaha saameyn weyn (F(2, 17) = 3.4, P = 0.057) iyo is dhexgalka (F(2, 17) = 3.4, P = 0.055) kaliya waxay muujisay isbeddello xoog leh oo leh labo-taayir oo imtixaan ah. Si kastaba ha noqotee, marka la eego in aan ka helnay fikradaha tilmaamaha jaantuska Jaantus1G, 1G, aad ayaan ugu qanacsanahay aragtideena in jirooyinka EC ay muujiyaan indu ka yar yihiin jiirka IC (Jaantus (Jaantus2C2C).

Dheecaan badan [kordhin]FosB ee NAc qolofta waxay la mid tahay ka hortagga balwad-ku-kordhin-qabatinka balwadda leh ee loo yaqaan 'phenotype'

Si loo baaro saameynta "osFosB" ee dabeecadda jiirka ee ka madax bannaan kobcinta / go'doominta (ie, si natiijooyinkaan looga dhigo mid ku habboon daraasadaha aan EC / IC ahayn), fayraska la xiriira adeno-ka (AAV) ayaa loo isticmaalay in lagu daro 'reFosB laba-geesoodka ah ee NAC dhexdeeda dooliga aan-hodan ahayn ee labada jiirka ah. Sida laga soo xigtay daraasadihii aan horay u sameynay, qolofka NAc wuxuu aad ugu nugul yahay xakameynta niyadjabka iyo daroogada qaadashada / raadinta dabeecadda sidaas daraadeed AAV vectors waxaa lagu duray qaybta NAc ee daraasaddan (Green et al., 2006, 2008, 2010). Sawirro 3A, B Muuji wakiilka immunohistofluorescence ee ΔFosB oo leh koontaroolka kantaroolka (guddiyada A; ie, endogenous ΔFosB express) iyo ΔFosB-overrexpressing vector (panel B) qolofka NAc.

Jaantuska 3  

Dheecaan badan [kordhin]FosB ee NAc qolof waxay la mid tahay kahortaga balwada leh ee kobcinta deegaanka. (A – B) Wakiilka immunohistochemistry ee ΔFosB ee xakameynta hrGFP (A) iyo ΔFosB-overrexpressing (B) Actor-ka AAV. ...

Markuu ansaxiyay go to go, in vivo muujinta iyo meelaynta guud ee fayraska fayraska, waxaan marka hore baarnay saamaynta culeyska xad dhaafka ah ee ΔFosB ee moodooyinka walaaca. Cadaadiska xad dhaafka ah ee 'osFosB ee qolofka NAc kuma filna inuu soo saaro saameynta jirka ee kobcinta deegaanka neophobia iyo calaamadaha qabow-walaacyada ee sababay jajabinta taranka. (Xogta lama tusin). Intaa waxaa sii dheer, ma jirin wax saameyn ah oo ku saabsan EPM (xogta aan la muujin). Sababtoo ah kobcinta bey'ada waxay soo saartaa saameyn dabiici ah oo ku saabsan jiirka, waxaan marka xigta sameynay baaritaanno la xiriira niyad-jabka oo ku saabsan jiirka ΔFosB-overrexpressing. Natiijooyinka la mid ah moodooyinka walaaca, natiijooyinka waxay muujiyeen in xad-dhaafka 'osFosB' ee NAc qolofka uusan ku filneyn yareynta dabeecadda niyad-jabka ee imtixaanka doorbidida guusha, imtixaanka is-dhexgalka bulshada, ama FST (Xogta lama tusin).

Qaabka kobcinta bey'ada, Jirooyinka EC waxay muujinayaan waxqabad hoose oo aasaaska u hooseeya kan jiirka IC (Bowling et al., 1993; Bowling iyo Bardo, 1994; Smith et al., 1997; Cagaarka et al., 2003, 2010). Si loo baaro saameynta xad-dhaafka ah ee reFosB ee duqeynta NAc, waxqabadka iskiis u dhaca waxaa lagu tijaabiyay 120 min. Isticmaalka tijaabinta laba-taayir ah natiijooyinka ayaa shaaca ka qaaday in xad-dhaafka 'reFosB' ee loo yaqaan 'NAc' uu ka dhashay isbadal xoog leh oo ku yimid hoos u dhac ku yimaada waxqabadka aasaasiga ah ee jiirka (Jaantuska.) (Figure3C; 3C; t(16) = 1.84, p = 0.084). In kasta oo aan ahayn tiro ahaan tiro ahaan laba geesood ah, haddana xogtan ayaa wali soo jiidasho leh iyada oo la waafajinayo aragtideena tooska ah ee tilmaanta leh ee ku saleysan Green et al. (2010), kaas oo la jaan qaada saamaynta kobcinta deegaanka.

In marka loo eego moodooyinka niyadjabka iyo walaaca, culeyska xad dhaafka ah ee ΔFosB ee NAc qofeed wuxuu awood u yeeshay inuu soo saaro EC-like phenotype noocyo badan oo balwadaha / xoojinta ah. Anigan tijaabada isukeenida maareynta ee 'prolet pellet', waxaa jiray is-dhexgal weyn oo ka dhexeeya ΔFosB xad-dhaafka ah iyo dhiirigelinta gaajada ee jiirka (F(1, 16) = 7.4, P <0.01). Jiirka xad-dhaafka ah ee ΔFosB ee qolofka NAc ayaa si weyn u qaatay dheeraad ah pellerose pellets oo ku hoos jira xaalado dhiirigelinaya gaajada (ie, 85% quudinta jirka ee miisaanka yar), laakiin kaabal yar oo ka hooseeya xaaladda dhiirigelinta yar (ie, 100% culayska quudinta oo bilaash ah; Jaantus Jaantus3D), 3D), oo sifiican u dhigaya dabeecadda ECotype (Green et al., 2010).

Qaabka kobcinta bey'ada, jiir EC ayaa soo bandhigay dabeecad raadinta maandooriyaha yareynta ee baabi'inta iyo dib u soo celinta maandooriyaha. (Cagaarka et al., 2010). Markaa, qaadashada cocaine iyo dhaqanka raadinta ayaa lagu cabiray ΔFosB-muujinta jiirka iyadoo la adeegsanayo maareynta kookaha ee maareynta iswada. Sida nooc ka mid ah jeceshahay, muuqaalka baabi'inta maandooriyaha ayaa shaaca ka qaaday in 'xad-dhaafka xad-dhaafka ah ee duqeynta NAc ay hoos u dhacday dabeecadda maandooriyaha.r (F(1, 15) = 6.7, P <0.05; Jaantus Jaantus3E) .3E). Waxa kale oo jiray saamayn weyn oo muhiim ah fadhiga (F(2, 30) = 74.0, P <0.001). Dayactirka ka jawaab celinta jadwalka FR1, waxaa jiray saameyn weyn oo weyn oo qiyaasta ah (F(7, 105) = 222.6, P <0.001) iyo isdhexgal muhiim ah (F(7, 105) = 2.3, P <0.05) qaadashada isku darka kookeynta. Dabeecadda isdhexgalka waxay ahayd in kala duwanaanta ay muuqatay kaliya qiyaasta kookeynta ee ugu badan (Jaantus (Sawirka3F) .3F). Ugu dambeyntiina, dib u soo celinta maandooriyaha waxaa ku dhacay saameyn weyn oo muhiim ah qiyaasta qaadashada (F(4, 44) = 15.5, P <0.001) iyo isbeddelka saameynta ugu weyn ee ΔFosB xad-dhaafka ah iyadoo la adeegsanayo tijaabo laba-dabo ah (F(1, 11) = 4.1, P = 0.067). Si kastaba ha noqotee, marka la eego fikirka jihada ee ka soo jeeda Green et al. (2010) iyo natiijooyinka xisaabta ee la taaban karo ee isugeynta leh 3D, E, F, waxay u egtahay in osFosB ay yareynayso dib u soo kabashada (Jaantus (Sawirka3G) .3G). Jawaab-celinta qiyaasta 10 mg / kg ayaa si weyn hoos ugu dhacday raFosB-muujinta jiirka. Natiijooyinka guud ahaan waxay muujinayaan in xad-dhaafka ΔFosB ee jiirka NAc qoqobku uu yareynayo qaadashada cocaine iyo raadinta dabeecadda, taas oo la jaan qaadi doonta saameynta dabeecadda ee kobcinta deegaanka.

Dood

U nuglaanta dadka shaqsiyaadka la qabatinka iyo murugada waxaa si xoogan u saameeya arrimaha deegaanka. Kobcinta deegaanka waa muuqaal u janjeera deegaanka xoolaha xayawaanka, soo saaraya saameyn kahortag xaalado badan oo xagga dhimirka ah. ΔFosB waxay door muhiim ah ka ciyaaraysaa hagaajinta shaqada abaalmarinta qaybo badan oo maskaxda ah, oo ay ka mid yihiin NAc iyo dorsal striatum (Koob et al., 1998; Xigmad, 1998; Wallace et al., 2008; Grueter et al., 2013; Pitchers et al., 2013). Mashruucan, waxaan ku baranay qawaaniinta firfircoon ee ΔFosB adoo xakameynaya walaaca iyo kookaha ee jiirka kobcinaya iyo kuwa go'doonsan. Waxyaabaha ugu waaweyn ee laga helay mashruucan ayaa ah:

(1) Jiirka EC ayaa sare u qaaday heerarka ΔFosB ee NAc-gundhigga marka loo barbar dhigo jiirka IC;

(2) kaliya ee loo yaqaan 'IC rad' ayaa uruursada borotiinka ΔFosB dheeraad ah oo leh walaaca soo noqnoqda;

(3) Jiirka EC wuxuu soo bandhigayaa lasocodka inFosB mRNA ee ku xiga walaaca ama kokain; iyo

(4) xad-dhaafka ΔFosB ee NAc ee jiirka lammaanaha leh ee la habeeyay waxay u ekaysiinayaan dabeecadda kahortagga balwadda, laakiin ma aha dabeecadda murugada ilaalinaysa.

Mid ayaa laga fili karaa suugaanta la daabacay, taasoo muujineysa in jiirarka 'osFosB' ee jiirarka burooyinka badan ay muujinayaan feejignaan kor u qaadista abaalmarinta cocaine iyo is-maamulidda ee qiyaasta daawada yar (Kelz et al., 1999; Colby et al., 2003; Vialou et al., 2010; Robison et al., 2013), in jiirka 'osFosB-overrexpressing ee tijaabada hadda jirta ay muujineyso kororka u nugul maareynta maandooriyaha iyo raadinta. In Tijaabooyinka hadda jira, si kastaba ha noqotee, xad-dhaafka 'osFosB' ee ku dhaca NAc qolofta ayaa yareysay qaadashada qaadashada iyo kocaine-ka inta lagu gudajiray baabi'inta iyo dib u soo celinta, taasoo muujineysa yaraynta dhiirrigelinta cocaine. Farqiga ayaa u dhici kara sababta oo ah in jiirarka transgenic-ka loo muujiyo ΔFosB inta lagu gudajiro dhammaan mawjadaha, laakiin kaliya unugyada 'dynorphin + (Colby et al., 2003). Baadhitaanka hadda jira ee 'FosB' waxaa si xad dhaaf ah loogu buufiyay iyada oo loo marayo 'vero AAV' kaas oo saameeya dynorphin + iyo enkephalin + neurons. Midda labaad, daraasada hada socota waxay diirada saareysaa NAC qolof halkii ay ka ahaan laheyd gobolka oo idil.

Marka lagu daro daweynta 'addototpepe', kobcinta bey'ada waxay soo saartaa dawada lidka ku ah antioxidant iyo astaamo-dabiicadaha u eg faylka (Cagaarka et al., 2010; Vialou et al., 2010). Daraasadda hadda socota, xad-dhaafka ah ee 'osFosB' ee NAc ayaa ku guuldareystay inuu soo saaro saameyn saddaxdii niyad jab ama seddex baaritaan oo walaac ah.. In kasta oo ay jiraan qodobo badan oo suurtagal ah oo gacan ka geysan kara ΔFosB oo la mid ah qabatinka maandooriyaha laakiin aan ahayn murugada 'depression', waxaa macquul ah in NAc qofeed ay u badan tahay dabeecad laxiriirta maandooriyaha halka dabeecadda laxiriirta niyad jabka ay si xoogan ugu dhexdhexaadin karto gobollada kale. Natiijooyinka hadda la joogo waxay la jaanqaadi karaan daraasadaha gudaha jiir halkaas oo ΔFosB xad-dhaafka ah ee NAc (meesha qofku isku hallayn karin kala-soocida sheyga iyo kan ugu weyn) ay ka soo saartay saameyn aad u xoog badan oo lidi ku ah lidka-antidepressant-ka dhowrka dabeecadood ee dabeecadda ah (Vialou et al., 2010). Hal sabab oo macquul ah ayaa ah in ay sahlan tahay in la arko saameynta 'osFosB' oo ku dhacda moodooyinka dabeecadda daran ee walaaca leh sida jahwareerka bulshada. Daraasadda hadda xad-dhaafka ah ee xad-dhaafka ah waxay baaris ku sameysay dabeecad-xumada sida dabeecadda murugada leh markii aysan jirin walaac daran.

Si isdaba joog ah inta lagu jiro daraasaddan, heerarka aasaasiga ah ee “osFosB” (tusaale ahaan, kobcinta, walaaca soo noqnoqda ama kokain) waxay la xiriirtaa firfircoonida xigta ee ΔFosB. Tani waxay ka dhigan tahay saamaynta saqafka, iyada oo aan sii kicitaan dheeraad ah lagu suurta gelin karin heerarka sare ee saldhiga borotiinka. Waxaa kale oo suuragal ah in heerarka uruurinta 'osFosB' ay dib u soo kaban karaan si ay uga horjoogsadaan gelitaanka dambe ee 'osFosB mRNA ka dib walaaca ama cocaine-ka oo ah jawaab celin taban. Tusaale ahaan, EC R waxay yeelanayaan heerar sare 'ΔFosB waxayna muujiyeen soo kicinta' osFosB 'ka dib culeyska ama kookaha. Tani waxay hoosta ka xariiqaysaa xiriirka xun ee ka dhexeeya heerarka borotokoolka ΔFosB iyo bilowgeeda mRNA. Jawaab celinta taban ee 'uruurinta' isku-urursiga 'ΔFosB' waxay sidoo kale mas'uul ka tahay qaadista attFosB ee culeyska soo noqnoqda ee jiirka IC.

Si aan u caddeyno, uma sheegno sheegashada in kobcinta bey'ada bey'adu leedahay xiriir toos ah oo xagga tarjumidda ah, maaddaama ay jiraan carruur aad u tiro yar oo ku barbaarey xaalad la aanta dhabta ah (waa in la ogaadaa in yaraanta dhaqan-dhaqaale aysan u dhigmin wax u dhicidda deegaanka). Adeegga qaabkan ayaa ah in ay tahay dawooyin aan dawooyin ahayn, aan qalliin ahayn, oo khalkhal galmo aan caadi ahayn ahayn oo soo saaraysa dabeecad ilaalin dabeecadeed oo balwadda iyo niyad-jabka lagu isticmaali karo deegaanka shaybaarka lagu xakameeyo iyada oo loo adeegsanayo aaladda sayniska aasaasiga ah ee lagu garto hababka moodeelka u adkeysiga adkeysiga xaaladaha dhimirka. Daraasad hore ayaa si faahfaahsan u sharaxday dabeecadaha dabeecadda (Bowling et al., 1993; Bowling iyo Bardo, 1994; Bardo et al., 1995; Cagaarka et al., 2002, 2003; El Rawas et al., 2009) iyo daraasadihii ugu dambeeyay (Solinas et al., 2009; Cagaarka et al., 2010; Lobo et al., 2013), oo ay weheliso daraasada hada socota, waxay soo bandhigayaan tilmaamo ku saabsan qaababkii gudbinta ee salka ku haya dabeecadan dabeecadeed. Bartilmaameedka hiddo-wadeyaasha hiddaha / borootiinka ee soo saaraya noocyada is-difaaca ayaa hadda la baarayaa (Fan et al., 2013a,b; Lichti et al., 2014).

Fikradeenna kobcinta deegaanka ayaa ah in kobcinta ay tahay wadis go'doon ah dhamaadka hoose iyo kobcinta buuxda ee dhamaadka sare. “Kobcinta buuxda ee kiiskan waxaa lagu qeexay bii'ad maadooyinku u muuqdaan kuwo cusub, xiriir bulsheed oo aan khatar ku jirin xidhiidhka bulshada, isla markaana loo oggol yahay boos iyo waxyaabo lagu jimicsado. These sedex arimood dhamaantood waxay matalaan xaalada iskudarsan ee "kobcinta" maxaa yeelay waa midkasta abaal marin ah oo midkastoo lagu sii daayo ee NAc, iyo sida oo kale, waxay dhaqdhaqaaqaan astaamaha 'neurobiological circuitry' (Louilot et al., 1986; Calcagnetti iyo Schechter, 1992; Crowder iyo Hutto, 1992; Rebec et al., 1997; Bevins et al., 2002). Fikraddan fikradda, go'doominta waxaa loo arkaa inay tahay kooxda kantaroolka maxaa yeelay waxay metelaysaa maqnaanshaha khalkhalgelinta (ie, kobcinta; Crofton et al., Dib u eegista). Si kastaba ha noqotee, fikradaha kale ee suurtagalka ah waa suurtagal. Hal fikrad oo is beddel ah, isugeynta ayaa isku mid ah, laakiin kooxda go'doominta ayaa ah kooxda tijaabada ah kooxda kobcisaana waa xakameynta. Anigan Qaabkan, oo laga reebay maadooyinka kobcinta caadiga ah is khalkhalgelinta dhabta ah. In kiiskan, intii la odhan lahaa kobcinta waa difaac, qofku wuxuu dhihi karaa in go'doomku yahay mid nugul. Weli fikradda saddexaad ayaa muujineysa inaysan jirin wax sii soconaya iyo in kobcinta iyo go'doominta ay yihiin labo isdabamarin aasaasiyan ah. Muuqaalkan, kobcinta iyo go'doominta waa in la kala saaraa oo labadaba la barbar dhigaa kontoroolka laba-hoyga ah. La'aanta heshiis guud oo caalami ah oo ku saabsan nooca kobcinta waxay ka dhigan tahay xaddidaadda astaamaha, wali waxay bixisaa jiheyn loogu talagalay daraasadaha mustaqbalka. Si kastaba ha noqotee, natiijooyinka tijaabooyinkan ayaa ah kuwo taagan iyada oo aan loo eegin tarjumaadda xigta.

Deegaanka iyo waaya-aragnimada nolosha waxay saameyn xoog leh ku leeyihiin horumarka iyo muujinta xaalado badan oo xagga dhimirka ah. Fahmitaanka habka kahortaga qabatinka iyo walwalka murugada ee kobcinta bey'adda ayaa ka jawaabaya su’aal aasaasi ah oo ku saabsan cilmi-baarista ciladda maskaxda - taas oo ah kaqeybgalka deegaanka ee u nugul ama u adkeysiga xaaladaha dhimirka. Daraasadani waxay hoosta ka xariiqday ahmiyada "osFosB" u habeynayso dabeecadaha la xiriira balwadaha. Daraasadaha mustaqbalka, ficilka ΔFosB iyo firfircoonidiisa iyo saameynteeda xannibaadda hidda-wadeyaasha gaarka ah waxay u baahan yihiin in si dheeraad ah looga baaraan dego nooca kobcinta deegaanka.

Maalgelinta iyo bixinta

Yafang Zhang, midna; Elizabeth J. Crofton, midna; Dingge Li, midna; Maryan Kay Lobo, midna; Xiuzhen Fan, midna; Eric J. Nestler, R37DA007359; Thomas A. Green, DA029091.

Khilaafka dulmiga xiisaha

Qorayaashu waxay caddeeyeen in cilmi-baaristaan ​​lagu sameeyey maqnaansho xiriir ganacsi ama dhaqaale oo laga yaabo inay noqon karto khilaafka xiisaha leh.

Mahadnaq

Tijaabooyinkan waxaa lagu maalgeliyey deeq ka timid Machadka Qaranka ee Ku Xadgudubka Daroogada, DA029091 iyo R37DA007359. Cocaine oo ay soo saartay Machadka Qaranka ee Xadgudubka Maandooriyaha.

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