Sharciga Abaalmarinta Dabiiciga ah ee Daroogada iyo Daroogada ee Nidaamka Nuugyada Soodhaweynta Nafaqada ee leh ΔFosB oo ah dhexdhexaadiye Muhiim (2013)

Daraasadani waxay baartey saameynta abaalmarinta galmada ee DeltaFosB iyo saameynta DeltaFosB ee ku saabsan dhaqanka galmada iyo abaalmarinta. Isbedelada caadiga ah ee molecular-ka ee lagu yaqaan inay ku dhacaan qabatinka maandooriyaha waxaa lagu ogaaday inay la mid yihiin sida ku dhaca galmada. Si kale haddii loo dhigo, DeltaFosB ayaa loo beddelay dhiirrigelinta galmada, laakiin daroogadu waxay afduubtaa farsamadan isku midka ah. Tani waxay soo afjaraysa doodda ku saabsan sida balwadaha maandooriyaha ay uga duwan yihiin balwadaha akhlaaqda, iyo sida balwadaha akhlaaqdu ay yihiin kuwa si fudud qasab looga dhigto (wax kasta oo ay tahay) Isku wareegyo isku mid ah, farsamooyin isku mid ah, isku mid isbeddello gacmeed, dabeecado isku mid ah oo la xiriira - khilaafaadyo yaryar

J Neurosci. 2013 Feb 20;33(8):3434-3442.

WAXBARASHADA DHAQAALAHA

Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM.

source

Waaxda Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, Jaamacadda Western Ontario, London, Ontario N6A 3K7, Canada, Waaxda Molecular & Integrative Physiology, Jaamacadda Michigan, Ann Arbor, Michigan 48109, Fishberg Waaxda Neuroscience iyo Friedman Machadka Maskaxda, Mount Sinai School of Medicine, New York, New York 10029, iyo Waaxyaha Neurobiology iyo Sayniska Cilmiga Jirka iyo Jirka iyo Biophysics, Jaamacadda Mississippi Medical Center, Jackson, Mississippi 39216.

aan la taaban karin

Daroogooyinka xadgudubka ayaa keena neuroplasticity ee waddada abaal-marinta dabiiciga ah, gaar ahaan nukleus accumbens (NAc), taas oo keenaysa horumar iyo muujinta dabeecadaha xariifnimada. Caddaynta dhowaan waxay soo jeedinaysaa in abaalmarinnada dabiiciga ah ay keeni karaan isbaddalo isku mid ah NAc, oo soo jeedinaya in daroogadu ay dhaqdhaqaajinayso qaababka balaastiga la wadaago abaalmarinta dabiiciga ah, isla markaana u oggolaanaya isdhexgalka khaas ah ee u dhexeeya abaalmarinta dabiiciga ah iyo daroogada.

Daraasaddan, waxaan soo bandhignay khibradda jinsiga ee jiirka ragga marka la raaco muddooyin gaaban ama muddo dheer oo lumis ah abaalmarinta jinsiga waxay keenaysaa abaalmarinta amphetamine, oo muujinaysa doorbidista xaalad xasaasi ah oo loogu talagalay qiyaasta hoose (0.5 mg / kg) amphetamine. Waxaa intaa dheer, bilawga, laakiin maaha muujinta muddada dheer, ee abaalmarinta amfitamiin korodhey ayaa la xiriirta kororka ku-oolka ah ee xayiraadda dendritic ee NAc. Marka xigta, kaalin muhiim ah oo ku jirta isbeddelka isweydaarsiga ΔFosB ee khibradda jinsiga ku salaysan ee kordhiyay amfitamiin iyo kordhinta la xiriirta taranka dendritic ee NAc neurons ayaa la aasaasay iyada oo la adeegsanayo gudbinta fayraska viral vector oo ah lammaane-xannibaad xeelad-joojin ah ΔJunD. Waxaa intaa dheer, waxaa la soo bandhigay in abaalmarinta jimicsiga ee hormarinta daroogada, ΔFOSB, iyo spinogenesis ay ku xiran tahay dopamin Dopamin Dopamin Dopamin Diabetes suppression in NAc. Xayiraadda Pharmacological ee Dexiciraha D1, laakiin aan ahayn D1 looyaqaan, NAc inta lagu guda jiro dhaqanka galmoodka ayaa lagu soo bandhigay ΔFOSB induction waxayna ka hortagtay kordhinta lafdhabarta iyo abaalmarinta amfitamin.

THaa, natiijooyinkaas waxay muujinayaan in daroogooyinka xadgudubka iyo dabeecadaha dabeecadda dabiiciga ah ay u dhaqmaan hababka caadiga ah ee unugyada iyo unugyada ee baqshiinka ee xakameynaya u nugulaanta maandooriyaha, iyo in khatarta korodhay ay dhexdhexaadinayso ΔFOSB iyo bartilmaameedkeeda hoose ee isbeddelka.

Hordhac

Dabeecadaha abaalgudka dabiiciga ah iyo abaalmarinta mukhadaraadka waxay kudhisan yihiin wadada nudaha caadiga ah, habka daaweynta mesolimbic dopamine (DA), taas oo nukleus accumens (NAc) ay door weyn ka ciyaaraan (Kelley, 2004). Daroogada xadgudubka ayaa keenta neuroplasticity nidaamka mesolimbic, oo ah door ka qaadashada doorka isticmaalka maandoriyaha ilaa daroogada maandooriyaha (Hyman et al., 2006; Kauer iyo Malenka, 2007; Kalivas, 2009; Chen et al., 2010; Koobka iyo Volkow, 2010; Wolf, 2010a; Mameli iyo Luscher, 2011). Waxaa la qiimeeyay in daroogooyinka iyo abaalmarinta dabiiciga ah aysan u dhaqmin isla jeexjeexyada nidaamka mesolimbic, sidaas daraadeedna daroogadu waxay si iskeed ah u dhaqaajineysaa oo u beddeli kartaa wareegga (Cameron iyo Carelli, 2012). Si kastaba ha noqotee, waxa ay si cad u caddaatay in dabeecadaha dabiiciga ah iyo daroogada ay saameynayaan nidaamka mesolimbic ee labada nooc oo isku mid ah iyo siyaabo kala duwan oo u oggolaanaya dhexda u dhexeeya abaalgudka dabiiciga ah, gaar ahaan abaalmarinta jinsiga, iyo saameynta daroogada xadgudubka (Frohmader et al., 2010a; Pitchers et al., 2010a; Olsen, 2011).

Dabeecadda galmada waa mid aad u fiican (Tenk et al., 2009),

  • iyo waayo-aragnimada galmadu waxay keenaysaa dabeecado la xiriira daroogo la xiriira, oo ay ku jiraan is-dareen-celinta amphetamine (amph) -fiirinaysa dhaqdhaqaaqa firfircoon (Bradley iyo Meisel, 2001; Pitchers et al., 2010a)
  • iyo abaalmarin Amph abaalgud (Pitchers et al., 2010a).
  • Waxaa intaa dheer, waayo-aragnimada galmadu waxay ku dheehan tahay xakamaynta neerfaha ee NAc oo la mid ah taas oo ay sababtay soo-gaadhista maskaxda, oo ay ku jiraan cufnaanta lafdhabarta dendritic (Meisel iyo Mullins, 2006; Pitchers et al., 2010a),
  • isbeddelka gaaban ee garsoorka oo la beddelay, iyo hoos u dhigidda awoodda synaptic ee koontoroolka horay loo yaqaan 'NAc shell neurons (Pitchers et al., 2012).
  • Ugu dambeyntii, mudada dheeraadka ah ee ka fogaanshaha waayo-aragnimada jinsiga waxaa lagu ogaaday in ay muhiim u tahay abaalmarinta Amph ee la kordhiyay, NAc spinogenesis (Pitchers et al., 2010a), iyo ka ganacsiga qashinka gafka (Pitchers et al., 2012).

Natiijooyinkani waxay soo jeedinayaan in khibradaha dabiiciga ah iyo daroogada ay la wadaagaan qaababka caadiga ah ee baqshiinka neuraliska, taas oo saameyn ku yeelanaysa u nugulida maandooriyaha.

Himilada daraasaddan hadda waxay ahayd in la go'aamiyo hababka taleefanka ee dhexdhexaadinta khibradda jinsiga, taas oo iyaduna keenta abaalmarinta daroogada. Gaar ahaan, doorka loo yaqaan 'transposition factor' ΔFOSB ayaa la baaray sababtoo ah waxay ku lug leedahay saamaynta bixinta dabiiciga iyo daawooyinka labadaba (Nestler et al., 2001; Werme et al., 2002; Olausson et al., 2006; Wallace et al., 2008; Hedges et al., 2009; Pitchers et al., 2010b). Waxaa intaa dheer, doorka dopamine D1 Reseptors (D1R) ee loogu talagalay baaxada nudayaasha galmada ee ku salaysan jinsiga ayaa la baaray sababtoo ah NAc indhaha iyo isdabajinta dhabarka oo sii kordhay ka dib markii maamulka maskaxda ee lagu magacaabo D1R-ku jira neurons (Lee et al., 2006; Kim et al., 2009) waxayna ku xiran tahay hawlgelinta D1R (Zhang et al., 2002).

Halkaan, waxaan isticmaalnay fayruska viral-dhexdhexaad ah ee lamaanaha iskudhafka ah ee loogu talagalay ΔFosB, calaamadaha diodhiga, iyo farsamooyinka fayo-dhawrka si loo tijaabiyo khatarta ah in saamaynta is-daba-galinta ee khibradda jinsiga ay raacdo abaal-marin ku sarreysa abaalmarinta amph amaba dhexdhexaadisay D1R-ku-xirnaansho ee ΔFosB ee NAc iyo kororka xiga ee cufnaanta NAc. Wadajir ahaan, natiijooyinka waxay bixiyaan caddayn ah in abaalgudyada dabiiciga ah iyo daroogada ay wadaagaan nidaamyada caamka ah ee nuuralka, iyo ΔFosB oo ah dhexdhexaadiye muhiim ah.

Qalabka iyo Dariiqooyinka

Xayawaanka.

Ragga (225-250 g marka ay timaaddo) iyo dumar (210-220 g) Sprague Dawley jiirarka (Charles River Laboratories) waxay ku yaalaan baqashada Plexiglas isla jinsi isku mid ah oo tijaabooyin ah oo tijaabo ah, heerkulka iyo qiyaasta qoyaanka iyo 12 / 12 h iftiin / mugdi madow oo leh cunto iyo biyo si xor ah loo heli karo. Iskaashatada haweenka ee isu-darka miisaanka ayaa la isku daraa waxaana lagu helaa maqaar-hoosaadyo hooseeya oo ay ku jiraan 5% estradiol benzoate (Sigma-Aldrich) iyo irbadaha 500 μg of progesterone (oo ah 0.1 ml saliidda sisinta; Sigma-Aldrich) 4 h ka hor imtixaanka. Dhammaan nidaamyada waxaa ansixiyay Daryeelka Xoolaha iyo Isticmaalka ee Jaamacadda Western Ontario iyo Jaamacadda Michigan waxayna u hogaansameeyeen Golaha Kanada ee Xannaanada Xannaanada iyo Hay'adaha Qaranka ee Caafimaadka oo ku lug leh xayawaannada xayawaanka ee cilmi baarista.

Dabeecadaha galmada.

Kalfadhiyadaha laysku daray ayaa ka dhacay marxaladda hore ee mugdiga (inta u dhexeysa 2 iyo 6 h ka dib bilawga xilliga madoobaadka) ee hoosta iftiinka casaanka ah, baqashooyinka tijaabada ah ee nadiifka ah (60 45 50 cm). Maydhayaasha labka ah ee la mijo-baxa si ay u neefsadaan inta lagu jiro 4 ama 5 fadhiyada maalinlaha ah. Shan keli ah ayaa loo doortay sababtoo ah waxaan horay u muujinnay in falkani uu keeno fududeyn dhaq-dhaqaaqa muddada dheer ah (Pitchers et al., 2010b), iskuduwidda iskudhufka waxqabadka AmphPitchers et al., 2010a), iyo abaalmarin (Pitchers et al., 2010a). Ejaculation waxaa loo doortay in ay noqoto meesha ugu dambeysa ee mawduucyada kala duwan ee mawqifka sababtoo ah waxaan horey u muujinay inay muhiim u tahay saameynta khibradda galmada ee Amph locomotor sensitization (Pitchers et al., 2010a), taas oo aan dhicin markii xayawaanka loo oggolaaday inay la wadaagaan dheddigga iyada oo aan la soo saarin hawada. Tilmaamaha habdhaqanka galmada (ie, qarsoodi ugu horeysay ee dhagxaanta, raasamaalka iyo shahwadeynta, iyo tirooyinka isdhaafsiga iyo ka hortagga) ayaa la duubay sida hore loogu sharraxay (Pitchers et al., 2010b). Dhammaan tijaabooyinka, kooxo la-soo-galmoodka ah ayaa la isugu geeyay dabeecad jinsi ah (tirada guud ee jahawareerka iyo dhererka neef-xummada inta lagu jiro fadhiga maadada). Ka dib markii shanaad mawduucyada kala duwan, raggu waxay ku sugnaayeen lamaanayaasha isku jinsiga ah, loomana oggolaan inay wadaagaan inta lagu jiro mudada galmada ee 1, 7, ama 28 d. Xayawaanka ku haya jinsiga ah ayaa la qabadsiiyay oo waxay ku yaalliin qolal isku mid ah oo lab ah ragga ragga. Intaa waxa dheer, kantaroolka nadaafadda ayaa lagu dhajiyay baqashooyin tijaabo nadiif ah saacad intii lagu jiray 5 maalmaha isku xigga, iyada oo aan la helin gabar haweeyn ah.

Ereyada ΔFosB.

Xayawaanka ayaa si qoto dheer loo suuxiyey (sodium pentobarbital; 390 mg / kg; ip) iyo udubdhexaad ahaan 50 ml of 0.9% saline, waxaa ku xigay 500 MYXXX% paraformaldehyde (Sigma-Aldrich) 4 m fosfat buffer (PB) wakhtiga dhibcaha iyo tijaabooyinka DR-ka. Xannuunnada ayaa la saarey kadibna dib loogu soo celiyay 0.1 h heerkulka qolka isla xajmiga, kadibna lagu kaydiyey 1 ° C ee 4% sukrose iyo 20% sodium azide ee 0.01 m PB. Wixii tijaabo ah ee DR-da, tijaabooyinka ayaa la saarey oo lagu kala jaray qaybta sagittal sagittal. Hal badh ayaa lagu keydiyay PB waxaana loo isticmaalay DiOlistics, kan kalena waxaa loo shaqeeyay ΔFosB. Qeybta Coronal (0.1 μm) ayaa la jaray microtome microtome (Microm H35R), oo lagu soo ururiyey afar taxane ah oo isku xigxigay xalka dareemaha (400% sukrose iyo 30% ethylene glycol ee 30 m PB) waxaana lagu kaydiyaa -0.1 ° C. Qaybaha bilaashka ah ayaa la dhaqay si ballaadhan oo leh 20 m PBS, pH 0.1, inta u dhaxaysa burinta, iyo tallaabooyinka oo dhan waxay ahaayeen heerkulka qolka. Qeybaha waxaa loo soo gudbiyey 7.35% H2O2 (10 min) iyo xalka uumiifinta (1 h, PBS oo leh 0.1% BSA, Fisher iyo 0.4% Triton X-100, Sigma-Aldrich). Qeybaha ayaa markaa lagu daboolay habeeynimadii habeenimadii barqada-FosB bakteeriyada qashinka ah (1: 5K; sc-48 Santa Cruz Biotechnology), oo hore loo ansixiyey (Perrotti et al., 2004, 2008; Pitchers et al., 2010b). Anti-pan-FosB antibody ayaa laga kiciyay gobol gudaha ah oo ay wadaagaan FosB iyo ΔFosB, waxaana horey loogu sifeeyay in si gaar ah loo arko unugyada ΔFosB waqtiyada loo adeegsaday daraasaddan (> 1 d kadib kicinta)Perrotti et al., 2004, 2008; Pitchers et al., 2010b). Qeybaha waxaa lagu daraa marxaladda biotin-isku-dabiiciga ah ee roodhiga lidka ku ah IgG (1 h; 1: 500 ee PBS +; Shaybaarada Wareegga), avidin-biotin-horseradish peroxidase (1 h; ABC elite; 1: 1000 ee PBS; , iyo 0.02% 3,3'-diaminobenzidine tetrahydrochloride (10 min; Sigma-Aldrich) oo leh 0.02% nikkel sulfate ee 0.1 m PB oo leh hydrogen peroxide (0.015%). Qeybaha waxaa lagu rakibay Supercrost iyo slideshows glass (Fisher) waxaana lagu daboolay kylumfitat fylalate kylene.

Nambarada unugyada ΔFosB-IR ayaa lagu tiriyay qolka NAc iyo asaasiga ah ee gudaha meelaha falanqaynta (400 × 600 μm) sida hore loogu sharaxay (Pitchers et al., 2010b). Laba qaybood ayaa loo tiriyey mid kasta oo NAc ka hooseeya, celcelis ahaan xayawaan kasta. Waqtiga tijaabada ah, tirada nambarada ΔFosB-IR ayaa loo muujiyay inay yihiin isbeddel iskudhaf ah kooxda xakameynaya marka la eego wakhtiga ku haboon iyo marka la barbardhigo kooxaha khibradeysan iyo kuwa khatarta ah ee qowmiyadeed kasta waqti kasta oo shakhsi ah iyada oo la isticmaalayo unug t imtixaannada leh heer muhiim ah p <0.05. Tijaabooyinka 'unJunD-AAV iyo DR antagonist, laba dhinac ama hal dhinac ANOVA, siday u kala horreeyaan, iyo habka Holm-Sidak ayaa loo isticmaalay. Intaa waxaa sii dheer, unugyada 'osFosB-IR' waxaa lagu tiriyay marinka 'dorsal striatum' (aagga falanqaynta: 200 × 600 μm), isla markaaba waxaa loo wareejiyaa NAc oo ku xigta qaybta dambe ee ventricle, dhammaan xayawaannada ku jira tijaabada DR antagonist. Hal-dhinac ANOVA iyo t imtixaannada ayaa loo isticmaalay in lagu barbar dhigo kooxaha.

DiOlistics

Waqtiga xaddiga iyo tijaabada vector vector, ΔJunD tijaabinta fayraska, jiirka ayaa si wacan u dhajiyay xajiinka 50 ml (0.9%), oo ay ku xigto 500 ml 2% paraformaldehyde ee 0.1 m PB. Mucaaradku waxay ahaayeen qaybta (100 μm coronal) iyaga oo isticmaalaya vibratome (Microm) iyo qaybo lagu keydiyo 0.1 m PB leh 0.01% sodium azide at 4 ° C. Daarada qaybta tungsten (Xamux μm, Bio-Rad) oo leh lipophilic carbocyanine dheeer DiI (1.3'-dioctadecyl-1,1'3,3,3'-tetramethylindocarbocyanine perchlorate; Invitrogen) ayaa la sameeyay sida hore loo tilmaamay (Forlano iyo Woolley, 2010). Qalabka tungsten-ka ee la isku qurxiyo waxaa lagu geliyay unugyada 160-180 psi iyada oo la adeegsanayo nidaamka Helios Gene Gun (Bio-Rad) iyada oo loo marayo xaddiga xajmiga 3.0 ee xajmiga (BD Biosciences) waxaana loo oggol yahay in lagu kala qaado xuubyada neuronaliga ee 0.1 m PB 24 h markaad iftiin ku leedahay 4 ° C. Dabadeed, xayawaanka ayaa lagu soo celiyey 4% paraformaldehyde ee PB for 3 h heerkulka qolka, lagu maydhay PB, oo lagu rakibay qollado muuqaal ah (Bio-Rad) leh gelvatol oo ay ku jirto wakiilka qashin-qaadista 1,4-diazabicyclo (2,2) octane ( 50 mg / ml, Sigma-Aldrich) (Lennette, 1978).

Diarriyooyinka loo yaqaan 'DiI-labeled neurons' ayaa lagu sawiray isticmaalkooda Zeiss LSM 510 m mikroskoob isku xiran (Carl Zeiss) iyo helium / neon 543 nm laser. Xayawaan kasta, 2-5 nuuroon kasta ee NAc subregion, ama qolofka (oo ku salaysan meesha ku xiran calaamadaha, oo ay ku jiraan gudniinka dambe iyo jimicsiga gudaha) ee tijaabooyinka ΔJunD-AAV iyo tijaabooyinka DR-ta, ayaa loo isticmaalay inay helaan meel dulsaar dendrite labaad ee qiyaasta lafdhabarta. Mid kasta oo neuron, 2-4 dendrites ayaa lagu falanqeeyey si loo qiyaaso dhererka guud ee dhererka 40-100 μm. Qaybaha dendritic waxaa lagu qabtay iyadoo la adeegsanayo 40 × ujeedo biyo-u-qulqulin ah xilliyada 0.25 μm ee z-axis, iyo sawirka 3D ayaa dib loo dhisay (Zeiss) iyo hoos-u-dhac ku yimid (Autoquant X, Media Cybernetics) iyadoo la isticmaalayo qalab (indhoole) iyo goobta PSF oo lagu taliyey sida lagu taliyey barnaamijka. Cufnaanta lafdhabarta waxaa lagu qiyaasey iyadoo la adeegsanayo moduleka Filam ee xirmooyinka barnaamijka Imaris (version 7.0, Bitplane). Nambarada dhirta 'dendritic' ayaa lagu muujiyay per μmUMX μm, celcelis ahaan qanjir kasta oo kasta kadibna xayawaan kasta. Farogelinta tirakoobka waxaa lagu go'aamiyey iyadoo la adeegsanayo labo hab oo ANOVAs ah oo tijaabo ah marxalado taxane ah oo u dhaxeeya xayawaanka iyo xayawaannada khibradda leh markasta (qodobada: waayo-aragnimada jinsiga iyo NAc subregion) iyo tijaabada ΔJunD (arrimaha: khibradda galmada iyo vektor viral), iyo hal - ANOVA-da tijaabada ah ee tijaabada DR. Isbarbardhigga kooxeed waxaa la sameeyey qaabka Holm-Sidak oo leh heer muhiim ah p <0.05.

Doorashada booska xaalad deg deg ah.

Naqshadaynta tijaabada CPP waxay ahayd mid la mid ah sidii hore loo sharraxay (Pitchers et al., 2010a), iyada oo la adeegsanayo qalabka sadexda qaybood ee aan ku salaysnayn (Med Associates), iyo naqshadda nasiibka ah, oo ay la socoto tijaabo-qaadista keli ah ee d-amph sulfate (Amph; Sigma-Aldrich; 0.5 mg / ml / kg sc oo ku saleysan saldhig bilaash ah) ee qolka labka ah iyo saliin ee qolka aan lakulmeen inta lagu jiro maalmo kala duwan, oo la sameeyey inta lagu jiro qeybtii hore ee wajiga iftiinka. Xakamaynta xayawaanka ee qolalka labka ah.

Dhibcaha CPP waxaa loo xisaabiyay xayawaan kasta sida waqtiga la qaatay (ilbiriqsi) ee qolka labka ah inta lagu guda jiro baaritaanka ka dib markii laga jaray. Hal-dhinac ANOVAs iyo qaabka Holm-Sidak ayaa loo isticmaalay in lagu barbardhigo kooxihii tijaabada ahaa. Iskaashi la'aan t tijaabin muhiimad gaar ah p <0.05 waxaa loo adeegsaday in la isbarbar dhigo Naive-Sal iyo Naive Amph isla markasta oo la muujiyo waqtiga tijaabada, iyo mid kasta oo ka mid ah daaweynta vector-ka ee tijaabada ΔJunD. Tijaabada waqtiga, hal-dhinac ANOVAs iyo habka Holm-Sidak ayaa loo isticmaalay in la isbarbar dhigo kooxaha khibrada u leh galmada (Exp-Sal, 7 d Exp Amph iyo 28 d Exp Amph), oo aan la hagaajin t imtixaan ayaa loo isticmaalay in lagu barbardhigo kooxaha 2 ee naadiyada. Labada dhinac ee ANOVA iyo Habka Holm-Sidak ayaa loo isticmaalay in lagu barbardhigo kooxaha oo dhan ee tijaabadii tijaabada ahaa ee DR. Laba shaqeyn la'aan t baaris ayaa loo isticmaalay in lagu barbardhigo kooxaha Naive-Sal iyo Naive Amph oo leh xaalad daaweyn viral kasta ah (GFP ama ΔJunD), maaddaama xogta ay aad u badanyihiin kooxaha ΔJunD inay u oggolaadaan falanqaynta ANOVA. Dhamaan heerarka muhiimka ah ayaa la dhigay p <0.05.

Tijaabooyinka viral viral.

Mammuucyada labka ah ayaa lagu suuxiyey ketamine (87 mg / ml / kg; ip) iyo xylazine (13 mg / ml / kg ip), oo lagu rakibay qalab qalabeed (Kopf Instruments), waxaana la siiyay laba nooc oo isku-dhafan oo lagu magacaabo 'venectal vectors' GFP oo keliya (borotiinka cagaaran), ama ΔJunD (lammaanaha isku-xiran ee ΔFosB) iyo GFP, oo ku jira NAc (iskudhafid: AP + 1.5, ML ± 1.2 ee bregma; DV-7.6 oo ka soo jeeda), miisaanka 1.5 μl / midisphere ka badan 7 min mining iyadoo la isticmaalayo sirinjeerka Hamilton (Harvard Apparatus). ΔJunD waxay hoos u dhigtaa ΔFosB-dhexdhexaadin ah oo si tartiib tartiib ah u hirgelineysa ΔFOSB taas oo markaa ka hortageysa in ΔFosB loo maro gobolka AP-1 oo ka dhexjirta gobollada dhiirrigeliya genesWinstanley et al., 2007; Pitchers et al., 2010b). Inkasta oo ΔJunD ay ku xidhan tahay ΔFosB, waxaa suurtogal ah in qaar ka mid ah saameynta la ogaaday ee ΔJunD ay dhexdhexaadin karto iyadoo la dhexgelinayo borotiinka kale ee AP-1. Hase yeeshee, waxay u muuqataa in ΔFosB tahay borotiinka hormoodka ah ee AP-1 ee lagu muujiyey shuruudaha lagu baaray (Pitchers et al., 2010b). Toddobaadyadii u dhaxeysay 3 iyo 4, xayawaanku waxay heleen waayo-aragnimo galmo inta lagu jiro 4 kulanno isku xigxigsan oo isdaba-joog ah ama si hagaagsan u-abuuray inay abuuraan kooxo 4 ah: GFP, galmada la-galmoodka GFP, jinsiga kufsiga, iyo jinsiga ku takhasusay ΔJunD. Khibrada galmada waxay ka kooban tahay 4 kulan isku xiga oo maalinle ah. Xayawaanka waxaa lagu tijaabiyay CPP iyo diodhoomiyaal. Xaqiijinta goobaha cirbada ayaa la sameeyay sida hore loogu sharraxay (Pitchers et al., 2010b). Qaybaha NAc (coronal; 100 μm) ayaa lagu xakameynayey GFP (1: 20,000; bakteeriyada anti-GFP; Invitrogen). Faafidda fayraska ayaa ugu horreyn ku koobnayd qaybta qolofka ee NAc, iyada oo faafin dheeraad ah ay ku faafto bartilmaameedka.

D1R / D2R gantaalaha.

Jiirka labka ah ayaa la suuxiyay iyada oo la isku duro oo la isku duro (0.1 ml / kg) oo ketamiin ah (87 mg / ml) iyo xylazine (13 mg / ml), oo lagu rakibay qalab qalafsan (Kopf Instruments). Tilmaamaha 21-tilmaamaha cannulas (Plastics One) ayaa lagu yareeyay NAc ee AP + 1.7, ML ± 1.2 oo ka yimid bregma; -6.4 DV oo ka soo jeeda qallayl oo lagu hubiyo akriliska ilkaha, oo loo hoggaansamey saddex xayiraad oo lagu dhejiyo qalfoofka. Xayawaanka ayaa maalin walba la qabadsiiyaa si ay ula qabsadaan hababka soo galinta inta lagu jiro xilliga ka soo kabashada 2. Shan iyo toban daqiiqo ka hor bilawga mid kasta oo ka mid ah 4 fadhiyada materiga ah ee lagu soo bandhigayo haweenka aqbali kara, ragga labka ah waxay heleen fayrasyo ​​labadaba ah D1R antagonist R (+) SCH-23390 hydrochloride (Sigma-Aldrich), D2 reseptor (D2R) antagonist S- ( -) eticlopride hydrochloride (Sigma-Aldrich) waxaa lagu kala diri jiray salinein sterile (0.9%; mid kasta oo 10gg ah ee 1 μl halkii kiniiniga ah, kala diri 0.9% saline), ama saline (1.0 μl kasta halbeeg yar), xaddiga socodka 1.0 μl / min ka badan 1 min interval waxaa ku xiga 1 min oo leh cannula lagu duro meel ka baxsan xagasha daawada. Miisaanka cirbadani wuxuu ku buufin doonaa labada asaasiga ah iyo qolofka, sida infusions of 0.5 μl ayaa ku xaddidan qaybaha hoose ama qaybta aasaasiga ah (Laviolette et al., 2008). Qiyaasta waxay ku saleysnayd daraasado hore oo muujinaya in kuwan ama qiyaasta hoose ay saameyn ku yeelatay dabeecadda abaalmarinta dabiiciga ahLaviolette et al., 2008; Roberts et al., 2012). Xakamaynta raga ayaa weli galmada kufilan laakiin waxay heshay saline-ka-NAc ka hor inta aan lagu meeleynin qalabka baaritaanka ee madhan, inta lagu jiro 4 kulamada maalinlaha ah. Hal toddobaad ka dib markii la isku daro ama la isku xakameynayo, raga waxaa lagu tijaabiyay Amph CPP, iyo lafdhabarta iyo falanqaynta ΔFosB. Isticmaalka afartii kulan, halkii ay ka badnayn shan kulan oo ka mid ah tijaabooyinka kale, ayaa loo doortay in lagu baabi'iyo dhaawacyada xad-dhaafka ah ee NAc oo sababay soo-celinta soo noqnoqda ee soo noqnoqonaya, sidaas darteedna loo oggolaado in laf-dhabarka iyo falanqaynta ΔFosB. Xaqiiqdii, burburka ma aysan caddayn, iyo falanqaynta lafdhabarka iyo ΔFosB ee NAc ee xayawaanka lafdhabarta ah ayaa muujiyay xog isku mid ah kooxaha kooxaha aan la isticmaalin ee tijaabooyinkii hore. Labada dhinac ee ANOVA iyo Holm-Sidak qaabka muhiimka ah p <0.05 waxaa loo isticmaalay in lagu go'aamiyo khibrada galmada-fududeynta fududeynta dhaqanka galmada.

Natiijooyinka

Jir-dilista ΔFOSB-da waa mid muddo dheer soconeysa

Marka hore, isku-xidhka ku-meelgaarka ah ee isbeddelada galmada ee isbeddelka ku salaysan ΔFosB, xayawaanka dendritic ee NAc, iyo Amph-CPP ayaa lagu go'aamiyey, gaar ahaan ka dib muddooyinka gaaban iyo mudo dheereeya ee ka-dhaafitaanka abaalmarinta jinsiga (7 ama 28 d). Markii hore, waxaa la soo bandhigay in khibradaha galmada ee 5 fadhiyada moodooyinka maalinlaha ah ay sababeen ΔFosB oo dhan nidaamka mesolimbic, gaar ahaan NAc (Wallace et al., 2008; Pitchers et al., 2010b). Daraasooyinkan hore, heerarka ΔFOSB waxaa lagu qiyaasey 1 ka dib markii lagu dhaqmey galmo, loomana ogeyn in isdhaafsiga ΔFOSB uu sii socdey ka dib mudo dheer oo ah abaalmarin la'aan. Dumarka qibrada leh ee galmoodka ah waxay ahaayeen kuwo 1, 7, ama 28 ka dib markii ugu dambeyntii kulammada 5 ee maalinlaha ah ee moodooyinka, kuwaas oo ay raggu ahaayeen hal xayiraad. Kantaroolka galmada ee jinsiga ah ayaa la isku qurxiyo isla waqtigaas ka dib markii finalka 5 ee maalinlaha ah. Lambarrada ΔFosB-IR unugyada NAc iyo xudunta ayaa si weyn uga sarreeya kantaroolka khatarta galmada waqti kasta (Berdihii. 1A, qolof; 1 d, p = 0.022; 7 d, p = 0.015; Berdihii. 1B: asalka; 1 d, p = 0.024; 7 d, p <0.001; 28 d, p <0.001), marka laga reebo qolofka NAc ka dib markii 28 laga fogaado (p = 0.280). Sidaa awgeed, isdhaafinta ΔFOSB waxay sii socotaa inta lagu jiro maqnaanshaha ka dib marka khibrad jinsi ah muddo ugu yaraan 28 d.

Jaantus 1.     

Jaantus 1.     

Khibradda galmada waxay keentay koror degdeg ah oo joogta ah tirada unugyada ΔFosB-IR. Isbedelka tirada ee unugyada ΔFosB-IR ee ku jira qolka NAcA) iyo asaasiga (B) ee xayawaanka ku xeel dheer (xayawaanka) ee la xiiray marka la barbar dhigo kontoroolka jinsiga ah (cadaanka) (n = 4 koox kasta). Xogta ayaa ah kooxi waa SEM. *p <0.05, farqi weyn ayaa u dhexeeya marka la barbar dhigo kontaroolada qaawan. Wakiilka sawirada Naive 1 d (C), Exp 1 d (D), Exp 7 d (E), iyo Exp 28 d (F). ac, bareegga hore. Miiska barafka, 100 μm.

Kororka jinsiga ee soo-kordhay ee xayawaanka dendritic waa mid ku-meel-gaar ah

Pitchers et al. (2010a) horey looga soo sheegey iyadoo la adeegsanayo farsamooyinka goglan oo loo yaqaan 'Golgi impregnation techniques' oo khibrad jinsi ah la socota 7, laakiin aan ahayn 1, oo ka xayirtay abaalmarin la'aantu waxay keentay in si weyn loo kordhiyo ururrada dendritic iyo tirada lafdhabarta dentritic ee NAc khafiifkaPitchers et al., 2010a). Halkan, spinogenesis ee kufsiga galmada iyo ragga qibrada leh waxaa lagu baarey mid ka mid ah 7 d ama 28 d kadib kowada ugu dambeeya ee mating. Natiijooyinka hadda la adeegsanayo habka calaamadaynta calaamadaha ayaa xaqiijiyay in khibradda jinsiga ee xiga ee 7 d ee galmada galmada ay kordhisay tirooyinka dendritic spines (F(1,8) = 9.616, p = 0.015; Berdihii. 2A-C). Gaar ahaan, tirada lafdhabarta dendritic ayaa si aad ah u kordhay xayiraadda NAc iyo xudunta (Berdihii. 2A: qolof, p = 0.011; asaasiga ah, p = 0.044). Hase yeeshee, tani waxay sii kordhisay cufnaanta dhabarka oo aan mar dambe la ogaanin ka dib markii muddo dheer galmo joojin ah ee xNUMX ee NAc subregion (Berdihii. 2B).

Jaantus 2.     

Jaantus 2.    

Khibradda galmada waxay sababtay korodh tiro ka mid ah xayawaanka dendritic ee NAc iyo abaalmarinta amf ee dareenka ah. A, B, Tirada xayiraadaha dendritic ee NAc qolof iyo astaamaha 7 d (A) ama 28 d (DB oo ah galmo kufsi ah [cad] iyo xoolo khibrad leh; n = 4 ama 5). Xogta ayaa ah kooxi waa SEM. #p <0.05, farqi weyn ayaa u dhexeeya marka la barbar dhigo kontaroolada qaawan. C, Qaybaha dendritic qaybaha ka soo Naive 7 d iyo Exp 7 kooxo loo isticmaalo in lagu qiyaaso cufnaanta dhabarka. Miiska barafka, 3 μm. D, Qadarka waqtiga lagu khaarijiyay qolka labiska (amph ama saline) inta lagu guda jiro baaritaanka ka dib marka laga reebo miisaanka (CPP score) ee galmada la jilicsan yahay (caddaan) ama xayawaan (madoow) khibrad leh oo la baaray 7 d ama 28 d kadib kicinta ugu dambeysa ama Kalfadhi qabasho: Naive-Sal (7 d ka dib markaad qabato; n = 8), Naive Amph (7 d ka dib markaad taabato; n = 9), Kalluumeysi (kooxo isku dhafan oo xayawaan ah ayaa lagu tijaabiyay 7 d ama 28 kadib markii la isku daray; n = 7), 7 d Exp Amph (7 d kadib kiisa; n = 9), iyo 28 d Exp Amph (28 d kadib kiisa; n = 11). Kooxaha Sal waxaa la siiyay sal u dhigma labada qol. *p <0.05, farqi weyn ayaa u dhexeeya marka loo eego xakamaynta cusbada galmada ee khibrad u leh galmada.

Jacaylka Amfiga ee soo jiidashada leh ee Amph ayaa ah muddo dheer

Waxaan horay u muujinnay in khibradda jinsiga ee soo raaca 7-10 ee ka-dhaafitaanku keenay natiijada amph amin (Pitchers et al., 2010a). Gaar ahaan, xayawaannada jinsiga ah ayaa abuuray doorbid goob joog ah oo heer sare ah (CPP) ee qiyaasaha hoose ee amph (0.5 ama 1.0 mg / kg) oo aan ku dhicin CPP-da xakamaynta galmada. Daraasaddan hadda la xaqiijiyay oo la kordhiyay natiijooyinka hore ee muujinaysa abaalmarinta Amph ee xayawaanka la xariira jinsiga labadaba ka dib markii 7 d iyo sidoo kale 28 d ee muddada galmada (Berdihii. 2D; F(2,24) = 4.971, p = 0.016). Gaar ahaan, xayawaanno kufilan oo galmo ah oo leh 7 ama 28 d ahmiyad xadidan ayaa waqti badan ku qaatay wakhti aad u ballaadhan qolka amph-paired intii lagu jiray baaritaanka ka dib markii la barbardhigayey kantaroolyo xun oo la xidhiidha galmada oo la helay salinea labadaba (Berdihii. 2D: Exp-Sal vs 7 d Exp AMPH, p = 0.032; 28 d Exp AMPH, p = 0.021). Xaqiijinta natiijooyinka hore, xayawaannada jinsiga ah ee galmada wakhti badan uma aysan bixin qolka amph-paired inta lagu guda jiro baaritaanka ka dib oo aysan ku kala duwanayn doorbididda kooxda ka hortaga uureysiga ee galmada (Berdihii. 2D) (Pitchers et al., 2010a).

Waxqabadka ΔFosB wuxuu muhiim u yahay waayo-aragnimada jinsi-ku-oogidda abaalmarinta amf

Natiijada ilaa hadda waxay muujineysaa in khibradda galmada ay sababtay in muddo dheer socotaa ΔFosB ee NAc neurons oo ku xiran abaalmarinta amph. Si loo go'aamiyo in dhaqdhaqaaqa ΔFosB sii kordhaya uu muhiim u yahay abaalmarinta Amph ee la kordhiyay, ΔJunD, oo ah wada-xeel dheer oo iska xaadiraya ΔFosB oo xakameynaya waraaqaha ΔFOSB-dhexdhexaadin ah (Winstanley et al., 2007), waxay ahayd mid si weyn loo xakameeyay iyada oo loo marayo gudbinta hidda-wadaha-vektor-ku-dhex-dhexaadinta ee NAc (Berdihii. 3A,B). Natiijooyinka baaritaanada Amph CPP waxay muujiyeen in taxaddarinta hawlaha ΔFosB adigoo u sheegaya ΔJunD ee NAc ka hortagay saameynta jinsiga iyo 7 deymo jinsi ah oo ku saabsan amarka abaalmarinta amfi. Xayawaannada qibrada leh ee ΔJunD uma sameysna CPP muhiim ah Amph oo aan ka duwanayn xayawaanka jilicsan ee jimicsiga (ΔJunD xayawaanka (Berdihii. 3B). Taas bedelkeeda, xayawaanka GFP ee xayawaanku waxay sameeyeen CPP Amph sidii ay ku muujiyeen dhibco weyn oo CPP ah marka la barbar dhigo kontoroolka GFP ee jinsiga ah (Berdihii. 3B, p = 0.018).

Jaantus 3.    

Isku darka hawlaha ΔFosB ee NAc xiray abaal-marin AMPH ah oo kordhiyay tirada naabooyinka NAc ee xayawaanka. A, Sawirada Wakiilada ee GFP ee lagu muujinayo saddex xayawaan ah oo qaata cirbadeynta fayruuska 'viral-ΔJunD' ee ku salaysan calaamadaha nucleus, taasoo muujinaysa meelo yaryar (bidix), dhexe (dhexe), iyo goobo waaweyn (midig). ac, Bambo guduud ah; LV, neefsashadooda dambe. Miiska barafka, 250 μm. B, Shematic tusaale u ah meelaha ugu caansan iyo qaababka fidinta fayraska. Dhammaan xayawaanka, GFP ayaa lagu arkay qolofka, hase yeeshee ku faafay furaha ayaa ahaa variable. C, Qadarka waqtiga lagu qaatay qolka amph-paired inta lagu guda jiro baaritaanka ka dib marka laga reebo pretest (dhibcaha CPP) ee jinsiga ah (cadaan) iyo xayawaan khibrad leh (madow) oo la helay cirbadda xakamaynta GFP (Naive, n = 9; Walaac, n = 10) ama vektor ΔJunD (Naive, n = 9; Walaac, n = 9). D, Sawirrada wakiilada ee qaybaha dendritic ee ka soo jeeda GFP ee khibrad ahaan iyo ΔJunD ayaa loo isticmaalay in lagu qiyaaso cufnaanta dhabarka. Miiska barafka, 3 μm. E, Tirada xayiraadaha dendritic ee NAc ee galmada la jilicsan yahay (caddaan) iyo xayawaan khibrad leh (madow) kuwaas oo hela cirbadeynta xakamaynta GFP ama vector ΔJunD. Xogta ayaa ah kooxi waa SEM. *p <0.05, farqi weyn ayaa u dhexeeya marka la barbar dhigo kontaroolada qaawan. #p <0.05, farqi weyn ayaa uga yimid koontaroolada khibradda leh ee GFP.

Saamaynta dhibta ee ΔJunD-ga dulqaad la'aanta ah ma aha natiijada ka dhalatay carqaladaynta dabeecadaha galmada inta lagu gudajirayo helitaanka khibradda jinsiga. Faahfaahinta ΔJunD ee NAc ayaa horay loo soo bandhigay si looga hortago fududaynta dabeecadda galmada kadib khibrad galmo (Pitchers et al., 2010b). Xaqiiqdii, tan ayaa la xaqiijiyay tijaabadii hadda. Xayawaanka xayiraya GFP waxay muujiyeen latans gaaban oo ay ku dhejin karaan, isku-rarid, iyo dheecaan, iyo wax yar yar oo isku-dhafan iyo is-goys ah inta lagu guda jiro maalinta afaraad oo isku xigta ee tijaabooyin isku dhafan, marka la barbardhigo maalinta koowaad ee mate (Shaxda 1). Taas bedelkeeda, xayawaannada ΔJunD-laysku duro ma muujin waayaha gaaban ee qulqulaya ama qulqulin ama tirooyin yar oo la jarayo inta lagu guda jiro maalinta afraad ee mishiinka marka la barbardhigo kuwii hore. Sidaa darteed, faafinta ΔJunD ee NAc ayaa waxay saameyn ku yeelatay saameynta jinsiga. Si kastaba ha ahaatee, ma jirin farqi u dhexeeya mid ka mid ah xuduudaha isku dhafan ee ka dhexeeya kantaroolka GFP iyo kooxaha ΔJunD inta lagu guda jiro mid kasta oo ka mid ah tijaabada isku dhafka, taas oo muujinaysa saameynta ΔJunD infusions ee ku saabsan dareenka jinsiga ee soo jiidashada Amph CPP maaha natiijada kala duwanaanshaha maadinta khibradahaShaxda 1).

Eeg miiskaan:     

Jadwalka 1.    

Qodobada asluubta galmada inta lagu guda jiro helitaanka waayo-aragnimada jinsiga ee kooxo qaadata NAc infusions of GFP- ama ΔJunD-muujinaya vectors virala

ΔFosB waxay muhiim u tahay galmada waayo-aragnimada jinsiga-kordhinta ee NAc dendritic spines

Dhaqdhaqaaqa ΔFosB waxaa sidoo kale looga baahan yahay cufnaanta laftirka ee NAc neurons ka dib khibrad galmo iyo 7 (Berdihii. 3C,D). Falanqaynta dhabta ah ee NAc ee xayawaanka kor lagu sharaxay ee CPP, labada-lugood ee ANOVA waxay muujisay saameyn weyn oo ah khibradda galmada (F(1,34) = 31.768, p <0.001) iyo daaweynta vector viral (F(1,34) = 14.969, p = 0.001), iyo sidoo kale isdhexgalka (F(1,34) = 10.651, p = 0.005). Gaar ahaan, xayawaanka GFP ee xayawaanku waxay yeesheen tiro badan oo NAc ah oo la barbar dhigo kontoroolka GFP (Berdihii. 3D: p <0.001), oo xaqiijinaya raadintayadii hore (Pitchers et al., 2010a). Taa bedelkeed, xayawaanka jimicsiga ΔJunD ayaa si aad ah uga duwan kooxaha kooxaha jinsiga ah, iyagoo aad uga hooseeya marka la barbar dhigo xayawaanka xayawaanka GFP ee khibrada leh (Berdihii. 3D: p <0.001). Sidaa darteed, muujinta ΔJunD ee NAc waxay xannibtay saameynta khibradda galmada iyo abaalmarinta ka fogaanshaha NAc spinogenesis.

D1R antagonist waxay xakameysaa waayo-aragnimada galmada ee ΔFOSB

Si loo go'aamiyo in waxqabadka D1R ama D2R ee NAc inta lagu jiro isu-darka waxaa loo baahan yahay in la isdifaaco ΔFosB-ku-jimicsiga iyo xasaasiyad Amph CPP, xayawaanku waxay heleen infusions gudaha D1R ama D2R antagonist (ama saline) NAc 15 min ka hor intaan mid ka mid ah 4 fadhiyada maalinlaha ah ee isku xigga. Muhiimad weyn, ma ahan D1R ama D2R gardarrada khatarta ah ee NAc ay saameyn ku yeesheen dabacsanaanta ama muujinta dabeecadaha jinsiga ah inta lagu jiro kulamo kasta oo isku dhafan (Berdihii. 4D-F). Sidoo kale, D1R ama D2R daacadnimadu ma aysan horjoogsanayn saamaynta sahlan ee galmada waayo aragnimadooda jinsiga, maaddaama dhammaan kooxuhu ay muujiyeen fududeynta dhaqanka galmada, oo caddaynaya jahawareerka yar-yar ee jimicsiga maalinta 4 marka la barbardhigo maalinta 1 (Berdihii. 4F) (F(1,40) = 37.113, p <0.001; Sal, p = 0.004; D1R Ant, p = 0.007; D2R Ant, p <0.001).

Jaantus 4.    

Argagixisada daawada Dopamine antagonists ee loo geliyey NAc ma saameynayso dhaqanka galmada. Qaybaha NAc Coronal (A, + 2.2; B, + 1.7; C, + 1.2 laga bilaabo bregma) oo tilmaamaya meelo lagu duro gudaha NAc ee xayawaanka oo idil. Cannulas waxay ahaayeen labadaba laakiin waxay si toos ah u matalaan si sahlan ee soo bandhigida dhamaan xayawaanka (Naive-Sal, cad, n = 7; Exp-Saline; guduud mugdi ah, n = 9; D1R Meel, cawl, n = 9; Fadlan D2R Maar, madow, n = 8). ac, Bambo guduud ah; LV, qufacaha lateral; CPu, caudate-putamen. Buurta dhaadheer (D), latency intramination (E), iyo wakhti xaddidan (F) dhammaan kooxaha la-yaqaan ee galmada (Saline, caddaan; D1R Ant, cawl; D2R Ant, madow). Xogta waxay u taagan tahay SEM. *p <0.05, farqi weyn oo u dhexeeya maalinta 1 iyo maalinta 4 ee daaweynta gudaheeda.

Falanqaynta tirada xubnaha ΔFosB-IR ee NAc 7 ka dib markii faleebadii NAc ee ugu dambeysay iyo isugeyn ama la qabtey kalfadhiga ayaa muujiyay faraq wayn oo udhaxeeya labada kooxood ee NAc qolof (F(3,29) = 18.070, p <0.001) iyo xudunta (F(3,29) = 10.017, p <0.001). Marka hore, waayo-aragnimada galmada ee xakamaynta cusbada-cusbada ayaa sababtay isbeddel weyn oo ΔFosB ah marka la barbar dhigo kantaroolka galmada (Berdihii. 5A, qolof p <0.001; Berdihii. 5B: asalka, p <0.001), oo xaqiijinaya natiijooyinka kor ku xusan. Ka soo horjeedka D1R, laakiin maahan D2R, ayaa ka hortagay ama hoos u dhigay qawaaniinta 'osFosB'. Naqshadda NAc, D1R antagonist wuxuu daweeyay ragga khibrad u leh galmada waxay muujiyeen koror ah unugyada ΔFosB-IR marka la barbar dhigo kantaroolka galmada ee galmadaBerdihii. 5A: p = 0.110), iyo ereyada ΔFosB ayaa aad uga hooseeya marka la barbar dhigo ragga labeenta ee khibradda leh (Berdihii. 5A: p = 0.002). Qeybta NAc, D1R waa wax saameyn ah: ΔFosB ayaa si aad ah u kordhay D1R-ga lagu daweeyo ragga ayadoo la barbardhigay kantaroolka shuban (Berdihii. 5B: p = 0.031), laakiin kor u kicitaankan si aad ah ayuu uga hooseeyay marka loo eego raga la isku daaweeyo ee salineedka ah (Berdihii. 5B: p = 0.012). D2R daaweynta antagonist daaweynta ma aysan saameynin indhashareerka ΔFosB sida ragga galmada ku dhasha ee lagu helay D2R antagonist waxay leeyihiin tiro aad u badan oo ah unugyada ΔFosB-IR marka la barbar dhigo kontoroolka shuban (Berdihii. 5A: qolof, p <0.001; Berdihii. 5B: asalka, p <0.001) iyo D1R ragga ladagaalamay antagonist (Berdihii. 5A: qolof, p <0.001; Berdihii. 5B: asalka, p = 0.013), mana ka duwanayn ragga uumiga leh ee la-tacaalay galmada.

Jaantus 5.     

Jaantus 5.     

Xannibaadda D1R ee NAc ayaa waxa ay ka dhigeysaa kororka tirada unugyada ΔFosB-IR ee NAc ee xayawaanka kufsiga. Isbedelka tirada ee unugyada ΔFosB-IR ee ku jira qolka NAcA) iyo asaasiga (B) marka la eego xayawaanka la xariiro (xayawaanka) marka la barbar dhigo kontoroolka jinsiga ah (cadaanka) (Naive-Sal, n = 6; Exp-Saline, n = 7; Fadlan D1R Ant, n = 9; Fadlan D2R Ant, n = 8). Xogta ayaa ah kooxi waa SEM. *p <0.05, farqi weyn ayaa u dhexeeya marka la barbar dhigo kontaroolada qaawan. #p <0.05, farqi weyn ayaa u dhexeeya marka la barbar dhigo cusbada iyo D2R Ant xayawaannada qibrada leh. Wakiilka sawirada Naive Sal (C), Sal Sal (D), Fadlan D1R Ant (E), iyo D2R Ant (F). ac, bareegga hore. Miiska barafka, 100 μm.

Si loo xakameeyo faafitaanka D1R ama D2R ee gantaalaha qallafsan, ereyada ΔFosB ayaa lagu falanqeeyay aagga isla markiiba dhererka NAc iyo kudhaw xariijinta dhinaca dambe, taas oo ah joojinta ΔFosB ee qanjidhada dulinka ah ee maskaxda iyo daawooyinka waxay ku xiran tahay D1R waxqabadka (Zhang et al., 2002; Muller iyo Unterwald, 2005). Daraasada galmada waxay kordhisay tirada unugyada ΔFosB-irbiska ee qanjidhada dulinka ah ee raajada lagu daaweeyo ragga (Naive-Sal: 35.6 ± 4.8 vs Exp-Sal: 82.9 ± 5.1; p <0.001), oo xaqiijinaya warbixinteena hore (Pitchers et al., 2010b). Waxaa intaa dheer, ma ahan D1R ama D2R antagonist fara-gelinta NAc-khibrad jinsi-saameeyn ku salaysan oo loo yaqaan 'ΔFosB oo ku xusan qiyaasta cirbadaynta (Exp-D1R: Unugyada iridaha 82.75 ± 2.64; p <0.001 marka la barbar dhigo kontaroolada Naive-Sal). Natiijooyinkaani waxay soo jeedinayaan in faafitaanka infusions antagonist ay ugu horreyn ku koobnayd NAc.

D1R gantaalaha ee NAc blocks waxay dareemeen abaalmarin Amph

D1R xannibaadda NAc inta lagu jiro falcelinta ayaa sidoo kale xannibay waayo-aragnimo galmo-ku-kordhiyey abaalmarinta Amph, waxay tijaabisay 7 d kadib markii faleebadii NAc ee ugu dambaysay iyo baaritaanka naasaha (F(3,29) = 2.956, p = 0.049). Xayawaannada jinsiga ah ee la helay ee saliida ee NAc inta lagu guda jiro fadhiyada moodooyinka ayaa wakhti aad u ballaadhan ku qaatay qolka amph-paired marka loo eego ragga ragga ah ee jinsiga ah (Berdihii. 6A, p = 0.025), xaqiijinta natiijooyinka kore. Taa bedelkeeda, xayawaannada jinsiga ah ee khibradda leh ee la helay NAc D1R antagonist inta lagu jiro falcelinta ma samaynin CPP Amph. Kama aysan kala duwanaanin kontoroolka jinsiga ah, waxayna si weyn u yaraadeen qolka amph-paired marka la barbardhigo saline (Berdihii. 6A: p = 0.049) ama D2R daandaansi (Berdihii. 6A: p = 0.038) oo loo gudbiyay ragga ragga ah. D2R fara-gelinta argagixisada ma saameynin abaalmarinta amph ee xayawaanka lagu yaqaan xayawaanka jimicsiga leh ee NAc D2R fara-gelinta antagonistku waxay sameeyeen Amph-CPP oo muhiim ah marka la barbar dhigo kumbiyuutarrada saline-da (Berdihii. 6A: p = 0.040) iyo D1R dabiicada khibrad leh (Berdihii. 6A: p = 0.038), mana ka duwanayn ragga uumiga leh ee la-tacaalay galmada.

Jaantus 6.     

Jaantus 6.     

Xakamaynta aaladaha D1 ee NAc waxay tirtirtaa abaalmarinta amph oo ay ku kordhiso xayawaanka dendritic ee xayawaanka la xariira galmada. A, Qadarka wakhtiga lagu qaato qolka amph-paired inta lagu guda jiro baaritaanka ka dib marka laga reebo pretest (dhibcaha CPP, ilbiriqsiyo) galmada laysku daro (cad, n = 6) iyo xayawaan qibrad leh (madow) oo qaata saline (n = 7), D1R daandaansi (n = 9), ama D2R antagonist (n = 8). Xogta ayaa ah kooxi waa SEM. *p <0.05, farqi weyn ayaa u dhexeeya marka la barbar dhigo kontoroolka milixda ee saluugsan. #p <0.05, farqi weyn oo udhaxeeya D1R Ant xayawaan khibrad leh. B, Tirada xayawaanka dendritic (per 10 μm) ee galmada loo yaqaan (cad, n = 7) iyo xayawaan qibrad leh (madow) oo qaata saline (n = 8), D1R daandaansi (n = 8), ama D2R antagonist (n = 8). Xogta ayaa ah kooxi waa SEM. *p <0.05, farqi weyn ayaa u dhexeeya marka la barbar dhigo kontoroolka milixda ee saluugsan. #p <0.05, farqi weyn oo u dhexeeya kontaroolada cusbada cusbada leh.

D1R daaweynta antagonist waxay xakameysaa waayo-aragnimada galmada ee NAc-spinogenesis

Falanqaynta cufnaanta laf dhabarta ee NAc ee xayawaankaas oo kale waxay muujiyeen in firfircoonida D1R inta lagu jiro isku dardarka loo baahnaa si loo kordhiyo cufnaanta NAc ee laf dhabarta ka dib khibrad jinsi ah iyo 7 deymo jinsi galin ah (Berdihii. 6B; F(3,26) = 41.558, p <0.001). Gaar ahaan, xakamaynta cusbada galmada ee khibrada leh iyo xayawaanka D2R antagonist waxay leeyihiin tiro aad u tiro badan oo lafdhabar ah marka la barbar dhigo kantaroolka cusbada galmadaBerdihii. 6B: p <0.001) oo xaqiijinaya natiijooyinkayagii hore (Pitchers et al., 2010a) iyo natiijooyinka la socoshada xakamaynta fayraska ee GFP ee lagu sifeeyey kor. Taa bedelkeeda, xayawaanka D1R-xayawaan-lakabka ah ayaa ka duwanaan jirtey shuban-saliid-shucaac ah (Berdihii. 6B). Waxaa jiray saameyn qayb ah oo faleebo ah ee D2R soo galiyey sida xayawaanka D2R loo soo bandhigay waxay muujiyeen cufnaanta aadka u hooseysa ee kaamilada marka loo eego kumbiyuutarrada salineed ee khibrada leh (Berdihii. 6B: p = 0.02), laakiin tirooyin aad u sarreeya oo ka mid ah basbaaska marka la barbardhigo kantaroolka shubanka ee shahwada leh iyo D1R-la-daaweeyey ragga (p <0.001; Berdihii. 6B). Sidaa daraadeed, D1R xannibaadda NAc inta lagu jiro isku darka iyaga oo xakameynaya saameynta jinsiga iyo khibrad la'aanta NAc spinogenesis.

Dood

Daraasaddan hadda, waxaan ku muujinay dareenka iskudhafka u dhexeeya abaalmarinta dabiiciga ah iyo daroogada, marka abaalmarinta dabiiciga ah ee la socdo mudo aan xad lahayn. Gaar ahaan, waxaan soo bandhignay khibradahaan dhaqan galmoodka, oo ay ku xigto 7 ama 28 ee xannibaadda, waxay sababtaa kor u qaadidda abaalmarinta Amph. Natiijooyinkaasi waxay la mid yihiin doorka muhimka ah ee la xaddiday ee mudada dheeriga ah ee daroogooyinka xadgudubka ee ku saabsan xayiraadda daroogada (Lu et al., 2005; Thomas et al., 2008; Wolf, 2010b, 2012; Xue et al., 2012). Waxaa intaa dheer, ΔFosB abaal-marin ahaaneed ee NAc-ga ayaa muhiim u ah saameynta iskudhafka dabiiciga ah ee ka dhalan kara abaalmarinta dabiiciga ah ee abaalmarinta nafsiga ah, oo laga yaabo inay ka dhalato lafdhabarta NAc muddada mudnaanta abaalmarinta. Waxaan soo bandhignay in ururinta ΔFOSB ee NAc ka dib markii khibrad jinsi ah ay muddo dheer socoto oo ku tiirsan tahay NAc D1R inta lagu jiro wadashaqeyn. Taas bedelkeeda, isweydaarsigan TilfosB ee dhexdhexaadinta ah ee DQNUMXR ee NAc ayaa lagu muujiyay inuu muhiim u yahay abaalmarinta kordhinta Amph oo kordhiyay cufnaanta dhabarka ee NAc, inkastoo natiijooyinka ka soo baxa galmada ay ku xiran tahay mudnaan aan ka ahayn abaalmarinta jinsiga (Pitchers et al., 2010a). Ugu dambeyntiina, waxaan soo bandhignay in NAc spinogenesis ay gacan ka geysan karto horumarinta bilowga ah ee muujinta abaalmarinta Amph amase laakinse ma ahan mid muhiim u ah bandhigida sii kordhinta ee daroogada daroogada, sida cufnaanta kordhay ee NAc uu ahaa mid deg deg ah oo lagu arkay ka dib markii 7, laakiin ma aha 28 d, mudada dheeraadka ah.

Muddo dheer ayaa la ogaaday in dopamine lagu sii daayo NAc inta lagu jiro mudada dabeeciga dabiiciga ah, oo ay ku jiraan habdhaqanka galmada. Marka la hirgeliyo haween qandaraas leh, dopamine-ka ka baxsan ee NAc ayaa kordhay oo wali sarreeya inta lagu jiro isku darka (Fiorino et al., 1997). Daraasadani waxay muujisay in caabuqa daawada dopamine antagonists in lagu daro NAc inta lagu guda jiro mala-awooda oo aan saameyn ku lahayn bilaabista ama waxqabadka galmada, taas oo la socota fekerka ah in dopamine uusan ku lug lahayn qaabka abaal-marinta abaal-marinta, laakiin ee ku saabsan sifeynta dhiirigelinta dhiirrigelinta calaamadaha galmada la xiriira (Berridge iyo Robinson, 1998). Xaqiiqdii, amarrada ku saabsan abaal-marinta jinsiga waxay keeneysaa in lagu kiciyo nuuroonada nidaamka abaal-marinta mesolimbic dopamine, oo ay ku jiraan unugyada dopaminergic-ka ee ku yaala barmaamijka gacanta iyo bartilmaameedkooda, NAc (Balfour et al., 2004). Habdhaqanka jinsi-soo-celinta ee soo noqnoqda wuxuu ku dhacaa ΔFosB ee NAc, taas oo dhexdhexaadinaysa waayo-aragnimada soo-galinta dabeecadaha galmada (Pitchers et al., 2010b). Natiijooyinka iminka jira waxay muujinayaan in hagaajinta ΔFosB-ku-naqashada ay, dhab ahaantii, ku tiirsan tahay firfircoonida D1R ee NAc inta lagu jiro maadada. Natiijadani waxay la socotaa daraasado hore oo muujinaya in maamulka maskaxda ee soo noqnoqda oo si joogta ah u kordhiyay ΔFosB ee NAc dhexdhexaadinta dhexdhexaadinta neer-mareenada oo sheegaya D1R (Lee et al., 2006; Kim et al., 2009) iyo in xakamaynta noocaas ah ee ΔFOSB ay ku xiran tahay dhaqaajinta D1R (Zhang et al., 2002). Waxaa intaa dheer, jawaabaha daroogada ee dareemayaasha ah, sida caadiga ah lagu arkay xayawaan khibrad leh, waxaa la soo saari karaa maqnaanshaha duruufta horay u sii xumaatay ee foosha xun ee ΔFosB ee D1R oo muujinaysa nuuroonada ku jirta striatum (Kelz et al., 1999). THus, labadaba faa'iidooyinka dabiiciga ah iyo daroogada waxay kordhinayaan ΔFosB ee NAc iyada oo adeegsaneysa habka D1R-ku-tiirsanaan si loo dareemo dabeecadaha abaal-marinta.

Waxaa intaa dheer, natiijooyinka iminka muujinaya in ΔFosB ay tahay dhexdhexaadiyaha muhiimka ah ee isdhexgalka udhexeeya khibradda abaalgudka dabiiciga ah iyo abaalmarinta nafsaaniga ah. Sida lagu xusay, waxqabadka ΔFosB ee NAc ayaa horey loogu qeexay jawaabaha daroogada ee xasaasiga ah, sida farqiga NFHS ee NAc dareemayo firfircoonida firfircoonida cocaine ka dib markii hore maamulka ama soo noqnoqday (Kelz et al., 1999), waxay kordhisaa dareenka cocaine iyo morphine CPP (Kelz et al., 1999; Zachariou et al., 2006), waxayna keeneysaa is-maamul-hoosaad hoose oo cocaine ah (Colby et al., 2003). Daraasadani waxay muujineysaa in xannibaadda D1R ama hawlaha ΔFosB ee NAc inta lagu jiro mala-awaalka khaaska ah ee la joojiyey-taas oo sababtay dareenka Amph.

Daraasadani waxay muujisay in mudo aan xadidneyn oo ka timaadda abaalmarinta jinsiga loo baahan yahay marka la dareemayo dareenka Amph iyo NAc spinogenesis. Waxaan u maleyneynaa in ΔFosB inta lagu jiro muddadan xadadani ay saameeyso shaqeynta neuronal by beddelidda muujinta hiddaha hoose ee si loo bilaabo istiraaturojiyeynta iyo isbedelka synaptic. Xaqiiqdii, xannibista joojinta ΔFosB ee NAc inta lagu jiro isku darka ka hortagga in la kordhiyo cufnaanta laf dhabarta ee NAc lagu ogaaday ka dib bixinta abaalmarinta. Waxaa intaa dheer, faleebada D1R antagonist ee NAc ka hor inta kasta oo mawduucyo kale ah ayaa ka hortagay kororka waayo-aragnimada jinsiga ah ee korodhay ee ΔFosB iyo cufnaanta xiga ee sii kordhaya.

ΔFosB waa arrin ku-meel-gaar ah oo u noqon karta firfircooni ku-takbiirsan ama wax-qabad si loo xakameeyo muujinta baaxada ah ee gen ee bartilmaameedka kaas oo laga yaabo inay saameyn ku yeeshaan cufnaanta laf-dhabarka iyo xoogga synaptic ee NAc (Nestler, 2008). Si gaar ah, ΔFosB waxay u hawlgelisaa kinase ku xiran tahay-5 (Bibb et al., 2001; Kumar iyo al., 2005), Nidaamka Nuclearka κ B (NF-QB) (Russo et al., 2009b), iyo qaybta GluA2 ee qaabilsanaha glacamate AMPA (Vialou et al., 2010) iyo rCiriiri-gelinta hargabka ee hiddesidaha hore ee hargabka (Pitchers et al., 2010b) iyo histone methyltransferase G9 (Maze et al., 2010). Ckinase-ku-tiirsan kinase-5 wuxuu xakameynayaa borotiinka cytoskeletal iyo korriinka neurite (Taylor et al., 2007). Intaa waxaa dheer, hawlgelinta NF-κB waxay kordhisaa tirada dendritic spines ee NAc, halka horjoogsiga NF-κB hoos u dhacay basal-dendritic spines iyo blocks xajinta kookeynta sababtoo ah cufnaanta (Russo et al., 2009b). Sidaa awgeed, abaalmarinta galmada waxay kordhineysaa ΔFosB ee NAc, oo laga yaabo inay bedesho NAc laf dhabarta ujeeda bartilmaameedyo kala duwan (ie, kinase-ku-tiirsan kinase-5, NF-κB) iyo in guud ahaan natiijada ay tahay dareenka daroogada, sida la sheegay Russo et al. (2009a) ee ficillada kookeynta soo noqnoqda.

Daraasad lama filaan ah oo daraasaddan lagu sameeyay ayaa ah in kordhinta cufnaanta dhabarka ee NAc uu ahaa mid deg deg ah, oo aan laga helin 28 d ka dib khibrad galmo. Sidaa awgeed, cufka kordhay ee cufka ayaa la xidhiidhay bilawga abaalmarinta Amph oo kor u kaca waxayna ka qayb qaadan kartaa horumarinta bilowga ama muujinta gaaban ee jawaabaha amfor-ka ee xasaasiga ah. Si kastaba ha ahaatee, cufnaanta lafdhabarta looma baahna si joogto ah ujira abaalmarinta Amph abaalmarin kadib muddooyin dheerad ah. Waxaan horey u muujinnay in khibrada galmadu ay sababto waqti gaaban (7, laakiin aan ahayn 28, maalmo kadib maryaha ugu dambeeya) kordhay qiyaasta NMDA sub-NR-1 ee NAc, kaas oo loo rogay heerarka aasaasiga ah ka dib muddooyin dheer oo abaalmarin ah (Pitchers et al., 2012). Tani waxay kor u qaadday muujinta NMDA-yada ayaa lagu qiyaasey inay tahay calaamad muujinaysa sinado la isku halleyn karo (Huang et al., 2009; Brown et al., 2011; Pitchers et al., 2012), iyo soo jeedinta suurtagalnimada in koboca lafdhabarta ee soo-kordhay ay ku xiran tahay waxqabadka NMDA (Hamilton et al., 2012).

Gebogebadii, daraasaddan hadda waxay muujineysaa isdhexgalka daroogada daroogada ee abaalmarinta dabiiciga ah (jinsiga) iyo ku-tiirsanaanta muddada dheer ee abaalmarinta. Waxaa intaa dheer, baqshiman habdhaqanka waxaa dhexdhexaadiyay ΔFosB iyada oo loo marayo dhaqaajinta D1R ee NAc. Sidaa daraadeed, xogta waxay soo jeedinayaan in luminta abaalmarinta dabiiciga ah ka dib khibrad abaalmarin ah ay shakhsiyaadka u nugul tahay horumarinta daroogada maandooriyaha iyo in dhexdhexaadiyaha ah ee korodhkaasi uu sii kordhay waa ΔFosB iyo bartilmaameedkeeda hoose.

Qoraalada

  • La Helay 16, 2012.
  • Dib u eegid ayaa la helay December 12, 2012.
  • La aqbalay December 23, 2012.

  • Shaqadani waxaa taageeray machadyada Kanada ee cilmi-baarista caafimaadka (LMC), Machadka Qaran ee Caafimaadka Maskaxda (EJN), iyo Sayniska Cilmiga Dabiiciga ah iyo Guddiga Cilmi-baarista ee Kanada (KKP iyo LMC). Waxaan u mahadcelinaynaa Dr. Catherine Woolley (Jaamacadda Waqooyi-Galbeed) si loogu caawiyo farsamada calaamadaynta.

  • Qorayaashu ma sheegaan danaha maaliyadeed ee tartanka.

  • Waraaqaha waa in lagu soo hagaajiyaa Dr. Lique M. Coolen, Waaxda Dhaqtarka iyo Biophysics, Jaamacadda Mississippi Medical Center, 2500 North Street Street, Jackson, MS 39216. [emailka waa la ilaaliyay]

tixraacyada

  1. .
    1. Balfour ME,
    2. Yu L,
    3. Coolen LM

    (2004) Dabeecada galmada iyo calaamadaha deegaanka ee la xidhiidha galmoodka waxay u dhaqmaan nidaamka mesolimbic ee jiirka labka. Neuropsychopharmacology 29: 718-730.

  2. .
    1. Berridge KC,
    2. Robinson TE

    (1998) Maxay tahay doorka dopamine ee abaalmarinta: Saameynta racaayada, abaalmarinta waxbarasho, ama salience dhiirigelin leh? Brain Res Brain Res Rev 28: 309-369.

  3. .
    1. Bibb JA,
    2. Chen J,
    3. Taylor JR,
    4. Svenningsson P,
    5. Nishi A,
    6. Snyder GL,
    7. Yan Z,
    8. Sagawa ZK,
    9. Ouimet CC,
    10. Nairn AC,
    11. Nestler EJ,
    12. Greengard P

    (2001) Saameynta saameynta raagida ah ee loo geysto kookeeyaha waxaa qoondeeya borotiinka cudurka neuronal Cdk5. Nature 410: 376-380.

  4. .
    1. Bradley KC,
    2. Meisel RL

    (2001) Dhaqanka galmada dhaqanka ee c-Fos ee nukleus xayawaanka iyo dhaqdhaqaaqa amphetamine-stimulated lumomotor ayaa dareensiiyey waayo-aragnimo galmo hore ee haweenka reer Syria ee hamstrings. J Neurosci 21: 2123-2130.

  5. .
    1. Brown TE,
    2. Lee BR,
    3. Mu P,
    4. Ferguson D,
    5. Dietz D,
    6. Ohnishi YN,
    7. Lin Y,
    8. Suska A,
    9. Ishikawa M,
    10. Huang YH,
    11. Shan H,
    12. Kalivas PW,
    13. Sorg BA,
    14. Zukin RS,
    15. Nestler EJ,
    16. Dong Y,
    17. Schlüter OM

    (2011) Muujin aamusnaan ku salaysan oo loogu talagalay dareenka kookeeynta ee kookeynta. J Neurosci 31: 8163-8174.

  6. .
    1. Cameron CM,
    2. Carelli RM

    (2012) Ka-dhaafitaanka kookayntu waxay bedeshaa nucleus-socodka firfircoonida firfircoonida inta lagu guda jiro dabeecadaha loogu talagalay dabeecada loogu talagalay kookeynta iyo sukrose. Eur Jar Neurosci 35: 940-951.

  7. .
    1. Chen BT,
    2. Hopf FW,
    3. Bonci A

    (2010) Naqshadaynta sinaptic ee nidaamka mesolimbic: saameynta daaweynta ee maandooriyaha maandooriyaha. Ann NY Acad Sci 1187: 129-139.

  8. .
    1. Colby CR,
    2. Whisler K,
    3. Steffen C,
    4. Nestler EJ,
    5. Self DW

    (2003) Nooc-sifeyn nooca "Stratiant" -ka ah ee farsamada gacanta ee "ΔFosB" wuxuu kordhiyaa dhiirigelinta kookeynta. J Neurosci 23: 2488-2493.

  9. .
    1. Fiorino DF,
    2. Coury A,
    3. Phillips AG

    (1997) Isbeddelka isbedbeddelka nucleus wuxuu ku dhacaa dopamine efflux inta lagu guda jiro saameynta Coolidge ee jiirka. J Neurosci 17: 4849-4855.

  10. .
    1. Forlano PM,
    2. Woolley CS

    (2010) Falanqaynta macaamilka ee kala duwanaanshaha galmada ka hor iyo ka horjoogsanaanta galmada ee ku-meel-gaadhka nucleus. J Comp Neurol 518: 1330-1348.

  11. .
    1. Frohmader KS,
    2. Pitchers KK,
    3. Balfour ME,
    4. Coolen LM

    (2010a) Raashin isku dhafan: dib u eegista saameynta daroogooyinka ku saabsan dabeecada galmada ee dadka iyo moodooyinka xayawaanka. Horm Behav 58: 149-162.

  12. .
    1. Frohmader KS,
    2. Wiskerke J,
    3. Wise RA,
    4. Lehman MN,
    5. Coolen LM

    (2010b) Methamphetamine wuxuu wax ka qabtaa subpopulations of neurons oo xukuma dhaqanka jinsiga ee jiirka. Neuroscience 166: 771-784.

  13. .
    1. Hamilton AM,
    2. Oh WC,
    3. Vega-Ramirez H,
    4. Stein IS,
    5. Jahannam JW,
    6. Patrick GN,
    7. Zito K

    (2012) Kobaca dhaqdhaqaaqa ku salaysan ee dareenka cusub ee dendritic waxaa lagu xakumay borotiinka. Neuron 74: 1023-1030.

  14. .
    1. Hedges VL,
    2. Chakravarty S,
    3. Nestler EJ,
    4. Meisel RL

    (2009) Δ Foosha FosB ee xajmiga nukleus wuxuu kor u qaadaa abaalmarinta jinsiga ah ee haweenka reer Suuriya ah. Genes Brain Behav 8: 442-449.

  15. .
    1. Huang YH,
    2. Lin Y,
    3. Mu P,
    4. Lee BR,
    5. Brown TE,
    6. Wayman G,
    7. Marie H,
    8. Liu W,
    9. Yan Z,
    10. Sorg BA,
    11. Schlüter OM,
    12. Zukin RS,
    13. Dong Y

    (2009) Khibrada cocaine-ka ee ku jirta vivo wuxuu abuuraa sinagyo aamusan. Neuron 63: 40-47.

  16. .
    1. Hyman SE,
    2. Malenka RC,
    3. Nestler EJ

    (2006) Hababka maskaxda ee maandooriyaha: doorka abaalmarinta waxbarashada iyo xusuusta. Annu Rev Neurosci 29: 565-598.

  17. .
    1. Kalivas PW

    (2009) Glutamate homeostasis oo ku saabsan mabnuucidda takoorka. Nat Rev Neurosci 10: 561-572.

  18. .
    1. Kauer JA,
    2. Malenka RC

    (2007) Dhaqdhaqaaqa sinaanta iyo takoorka. Nat Rev Neurosci 8: 844-858.

  19. .
    1. Kelley AE

    (2004) Xasuusta iyo takoorka: habka wareegga neuralada iyo hababka molecular. Neuron 44: 161-179.

  20. .
    1. Kelz MB,
    2. Chen J,
    3. Carlezon WA Jr.,
    4. Whisler K,
    5. Gilden L,
    6. Beckmann AM,
    7. Steffen C,
    8. Zhang YJ,
    9. Marotti L,
    10. Self DW,
    11. Tkatch T,
    12. Baranauskas G,
    13. Surmeier DJ,
    14. Neve RL,
    15. Duman RS,
    16. Picciotto MR,
    17. Nestler EJ

    (1999) Faahfaahinta isir-qorista ΔFosB ee maskaxda oo ka ilaalisa dareenka kookaynta. Nature 401: 272-276.

  21. .
    1. Kim Y,
    2. Teylan MA,
    3. Baron M,
    4. Sands A,
    5. Nairn AC,
    6. Greengard P

    (2009) Methylphenidate-ku-abuurka dendritic-abuurka iyo muujinta ΔFosB ee numbleus. Proc Natl Acad Sci USA 106: 2915-2920.

  22. .
    1. Koob GF,
    2. Volkow ND

    (2010) Naas-nuujinta miyir-qabka. Neuropsychopharmacology 35: 217-238.

  23. .
    1. Kumar A,
    2. Choi KH,
    3. Renthal W,
    4. Tsankova NM,
    5. Theobald DE,
    6. Truong HT,
    7. Russo SJ,
    8. Laplant Q,
    9. Sasaki TS,
    10. Whistler KN,
    11. Neve RL,
    12. Self DW,
    13. Nestler EJ

    (2005) Dib-u-hagaajinta Chromatin waa farsamo muhiim ah oo ku saleysan bucshir-cocaine-ku-xiran oo lagu garto striatum. Neuron 48: 303-314.

  24. .
    1. Laviolette SR,
    2. Lauzon NM,
    3. Bishop SF,
    4. Sun N,
    5. Tan H

    (2008) Dopamine signaling iyada oo loo marayo D1-la mid ah duubayaasha D2-sida ee nucleus xarfaha asaasiga ah iyo khudradda kala duwan ayaa beddelaya dareenka abaalmarinta nicotine. J Neurosci 28: 8025-8033.

  25. .
    1. Lee KW,
    2. Kim Y,
    3. Kim AM,
    4. Helmin K,
    5. Nairn AC,
    6. Greengard P

    (2006) Cocaine-ku-abuurka dendritic-xoqidda ee D1 iyo D2 daaweeye dopamine-ku jira nuuro dhexdhexaad ah dhexdhexaad ah ee nucleus. Proc Natl Acad Sci USA 103: 3399-3404.

  26. .
    1. Lennette DA

    (1978) Hagaajinta dhexdhexaadinta ee immunofluorescence microscopy. Am J Clin Pathol 69: 647-648.

  27. .
    1. Lu L,
    2. Hope BT,
    3. Dempsey J,
    4. Liu SY,
    5. Bossert JM,
    6. Shaham Y

    (2005) Xarunta amygdala ee ERK Central bartanku waxay muhiim u tahay soo saaridda cocaine-ka. Nat Neurosci 8: 212-219.

  28. .
    1. Mameli M,
    2. Luscher C

    (2011) Xuduudaha sinagaafiga ah iyo takoorka: hababka barashada ayaa ka baxay. Neuropharmacology 61: 1052-1059.

  29. .
    1. Maze I,
    2. Covington HE 3rd.,
    3. Dietz DM,
    4. LaPlant Q,
    5. Renthal W,
    6. Russo SJ,
    7. Mechanic M,
    8. Mouzon E,
    9. Neve RL,
    10. Haggarty SJ,
    11. Ren Y,
    12. Sampath SC,
    13. Hurd YL,
    14. Greengard P,
    15. Tarakhovsky A,
    16. Schaefer A,
    17. Nestler EJ

    (2010) Doorka muhiimka ah ee methyltransferase G9a ee bucshirada cocaine-induced. Science 327: 213-216.

    1. McCutcheon JE,
    2. Wang X,
    3. Tseng KY,
    4. Wolf ME,
    5. Marinelli M

    (2011) Rugaha ambalaasta ee AMPA waxay ku jiraan nucleus synumbens synapses ka dib markii ay sii dheeraatay ka soo goosashada self-management cocaine, laakiin aan la tijaabin kokaininka. J Neurosci 31: 5737-5743.

  31. .
    1. Meisel RL,
    2. Mullins AJ

    (2006) Khibradda galmada ee jiirka haweenka: hababka gacanta iyo cawaaqibta shaqada. Maskaxda 1126: 56-65.

  32. .
    1. Muller DL,
    2. Unterwald EM

    (2005) Dicin-dopamine D1 reseptors waxay xakameyneysaa ΔFosB induction ee gawaarida rat ka dib markii maaraynta morphine. J Pharmacol Exp Ther 314: 148-154.

  33. .
    1. Nestler EJ

    (2008) Hababka isbeddelka ee mukhaadaraadka: doorka ΔFosB. Philos Trans R Soc London B Biol Sci 363: 3245-3255.

  34. .
    1. Nestler EJ,
    2. Barrot M,
    3. Self DW

    (2001) ΔFosB: waa isbedelka isdaba-joogga ah ee mukhaadaraadka. Proc Natl Acad Sci USA 98: 11042-11046.

  35. .
    1. Olausson P,
    2. Jentsch JD,
    3. Tronson N,
    4. Neve RL,
    5. Nestler EJ,
    6. Taylor JR

    (2006) ΔFosB ee ku-xigeenka nucleus wuxuu xakameynayaa dhaqanka qalabka korontada iyo dhiirigelinta. J Neurosci 26: 9196-9204.

  36. .
    1. Olsen CM

    (2011) Abaalmarinta dabiiciga ah, neuroplasticity, iyo daroogada aan daroogada ahayn. Neuropharmacology 61: 1109-1122.

  37. .
    1. Perrotti LI,
    2. Hadeishi Y,
    3. Ulery PG,
    4. Barrot M,
    5. Monteggia L,
    6. Duman RS,
    7. Nestler EJ

    (2004) Kordhinta ΔFosB ee qaababka abaal-marinta ee abaal-marinnada maskaxda ka dib duuf dabadheeraad ah. J Neurosci 24: 10594-10602.

  38. .
    1. Perrotti LI,
    2. Weaver RR,
    3. Robison B,
    4. Renthal W,
    5. Maze I,
    6. Yazdani S,
    7. Elmore RG,
    8. Knapp DJ,
    9. Selley DE,
    10. Martin Br,
    11. Sim-Selley L,
    12. Bachtell RK,
    13. Self DW,
    14. Nestler EJ

    (2008) Noocyo qotodheer oo ka yimaada ΔFOSB oo maskaxda ku jirta maskaxda iyadoo la isticmaalayo daroogo xadgudub. Synapse 62: 358-369.

  39. .
    1. Pitchers KK,
    2. Balfour ME,
    3. Lehman MN,
    4. Richtand NM,
    5. Yu L,
    6. Coolen LM

    (2010a) Neuroplasticity ee nidaamka mesolimbic oo ay sababto abaalmarin dabiiciga ah iyo abaalmarinta xiga. Dhibaatooyinka maskaxda ee Biol 67: 872-879.

  40. .
    1. Pitchers KK,
    2. Frohmader KS,
    3. Vialou V,
    4. Mouzon E,
    5. Nestler EJ,
    6. Lehman MN,
    7. Coolen LM

    (2010b) ΔFosB ee ku-xirnaanta nucleus waxay muhiim u tahay xoojinta saameynta abaalmarinta jinsiga. Genes Brain Behav 9: 831-840.

  41. .
    1. Pitchers KK,
    2. Schmid S,
    3. Di Sebastiano AR,
    4. Wang X,
    5. Laviolette SR,
    6. Lehman MN,
    7. Coolen LM

    (2012) Waayo-aragnimada abaal-marinta dabiiciga ah waxay bedeshaa qaybinta AMPA iyo NMDA-da iyo qaybta nucleus. QAADO 7: e34700.

  42. .
    1. Roberts MD,
    2. Gilpin L,
    3. Parker KE,
    4. Childs TE,
    5. MJ,
    6. Booth FW

    (2012) Dopamine D1 qaabaynta qaabka naqleus ee nucleus wuxuu hoos u dhigaa gawaarida tabaruca ah ee jiirka jilicsan ee jilicsan si ay u ordaan meelaha fog. Physiol Behav 105: 661-668.

  43. .
    1. Russo SJ,
    2. Mazei-Robison MS,
    3. Ables JL,
    4. Nestler EJ

    (2009a) Calaamadaha neurotrophic iyo baaxadda dhismaha ee takoorka. Neuropharmacology 56 (Qalabka 1): 73-82.

  44. .
    1. Russo SJ,
    2. Wilkinson MB,
    3. Mazei-Robison MS,
    4. Dietz DM,
    5. Maze I,
    6. Krishnan V,
    7. Renthal W,
    8. Graham A,
    9. Birnbaum SG,
    10. Green TA,
    11. Robison B,
    12. Qiyaas ahaan A,
    13. Perrotti LI,
    14. Bolaños CA,
    15. Kumar A,
    16. Clark MS,
    17. Neumaier JF,
    18. Neve RL,
    19. Bhakar AL,
    20. Barker PA,
    21. al et.

    (2009b) Calaamadaha fekerka nukliyeerka ee κB wuxuu xakameynayaa morfoolojiyada neuronaliga iyo abaalmarinta kokainka. J Neurosci 29: 3529-3537.

  45. .
    1. Taylor JR,
    2. Lynch WJ,
    3. Sanchez H,
    4. Olausson P,
    5. Nestler EJ,
    6. Bibb JA

    (2007) Ka hortagga Cdk5 ee ku-xigeenka nucleus wuxuu kor u qaadaa saameynta firfircoonida iyo dhiirigelinta-dhiirigelinta dhiirrigelinta kookeynta. Proc Natl Acad Sci USA 104: 4147-4152.

  46. .
    1. Tenk CM,
    2. Wilson H,
    3. Zhang Q,
    4. Pitchers KK,
    5. Coolen LM

    (2009) Abaalmarinta jinsiga ee jiirka labka ah: saameynta khibradda jinsiga ah ee ku aaddan doorbidka booska ee la xariira jahawareerka iyo galmada. Horm Behav 55: 93-97.

  47. .
    1. Thomas MJ,
    2. Kalivas PW,
    3. Shaham Y

    (2008) Neuroplasticity ee nidaamka dopamine mesolimbic iyo cocaine addiction. Br Jarmalka 154: 327-342.

  48. .
    1. Vialou V,
    2. Robison AJ,
    3. Laplant QC,
    4. Covington HE 3rd.,
    5. Dietz DM,
    6. Ohnishi YN,
    7. Mouzon E,
    8. Rush AJ 3rd.,,
    9. Watts EL,
    10. Wallace DL,
    11. Iñiguez SD,
    12. Ohnishi YH,
    13. Steiner MA,
    14. Warren BL,
    15. Krishnan V,
    16. Bolaños CA,
    17. Neve RL,
    18. Ghose S,
    19. Berton O,
    20. Tamminga CA,
    21. al et.

    (2010) ΔFosB ee wareegyada abaal-marinta maskaxda waxay dhexdhexaad u tahay adkaysiga cadaadiska iyo jawaab-celinta daawada lidka ku ah. Nat Neurosci 13: 745-752.

  49. .
    1. Wallace DL,
    2. Vialou V,
    3. Rios L,
    4. Carle-Florence TL,
    5. Chakravarty S,
    6. Kumar A,
    7. Graham DL,
    8. Green TA,
    9. Kirk A,
    10. Iñiguez SD,
    11. Perrotti LI,
    12. Barrot M,
    13. DiLeone RJ,
    14. Nestler EJ,
    15. Bolaños-Guzmán CA

    (2008) Saameynta ΔFosB ee nukleus waxay ku dhacdaa dabeecadaha dabiiciga ah ee abaalmarinta. J Neurosci 28: 10272-10277.

  50. .
    1. Werme M,
    2. Messer C,
    3. Olson L,
    4. Gilden L,
    5. Thorén P,
    6. Nestler EJ,
    7. Brené S

    (2002) Δ FosB waxay xakameysaa socodka gawaarida. J Neurosci 22: 8133-8138.

  51. .
    1. Winstanley CA,
    2. LaPlant Q,
    3. Theobald DE,
    4. Green TA,
    5. Bachtell RK,
    6. Perrotti LI,
    7. DiLeone RJ,
    8. Russo SJ,
    9. Garth WJ,
    10. Self DW,
    11. Nestler EJ

    (2007) ΔFOSB induction in kortex orbitofrontal dhexdhexaad ah dulqaad u leh caqabada garashada cocaine-sababo. J Neurosci 27: 10497-10507.

  52. .
    1. Wolf ME

    (2010a) Bermuda Saddex geesoodka ah ee kookeynta cocaine-induced neuroadaptations. Isbedelada Neurosci 33: 391-398.

  53. .
    1. Wolf ME

    (2010b) Xeerarka amni-darrada ee AMPA ee nukleus soo galaya by dopamine iyo kokain. Neurotox Res 18: 393-409.

  54. .
    1. Wolf ME

    (2012) Neuroscience: saameyn dabeecadeed ee kakoobiga ayaa ka laabtay. Nature 481: 36-37.

  55. .
    1. Xue YX,
    2. Luo YX,
    3. Wu P,
    4. Shi HS,
    5. Xue LF,
    6. Chen C,
    7. Zhu WL,
    8. Ding ZB,
    9. Bao YP,
    10. Shi J,
    11. Epstein DH,
    12. Shaham Y,
    13. Lu L

    (2012) Habraaca dib u-soo-ceshad-xasilinta si looga hortago daroogada xayiraadda iyo soo noqoshada. Science 336: 241-245.

  56. .
    1. Zachariou V,
    2. Bolanos CA,
    3. Selley DE,
    4. Theobald D,
    5. Xildhibaan Cassidy,
    6. Kelz MB,
    7. Shaw-Lutchman T,
    8. Berton O,
    9. Sim-Selley LJ,
    10. Dileone RJ,
    11. Kumar A,
    12. Nestler EJ

    (2006) Doorka muhiimka ah ee ΔFosB ee nukleus galaya ficilka morphine. Nat Neurosci 9: 205-211.

  57. .
    1. Zhang D,
    2. Zhang L,
    3. Lou DW,
    4. Nakabeppu Y,
    5. Zhang J,
    6. Xu M

    (2002) Dopamin Dexabaha D1 ayaa ah dhexdhexaadiye muhiim u ah muujinta hiddaha cocaine-sababtoo ah. J Neurochem 82: 1453-1464.

Qoraallada soo xigtay qodobkan

  • Ka qayb qaadashada suurtagalka ah ee qaab cusub oo ah balaastigga synaptic ee Aplysia si loogu abaalmariyo, xusuusta, iyo dhibaatooyinkooda ee maskaxda mammalian Barashada & Xusuusta, 18 Sebtember 2013, 20 (10): 580-591

BARASHADA BUUXDA - QAYBTA DOODA:

Daraasaddan hadda, waxaan ku muujinay dareenka iskudhafka u dhexeeya abaalmarinta dabiiciga ah iyo daroogada, marka abaalmarinta dabiiciga ah ee la socdo mudo aan xad lahayn. Gaar ahaan, waxaan soo bandhignay waayo-aragnimadan dhaqanka galmada, oo ay ku xigto 7 ama 28 oo ah xannibaad la'aan, waxay keenaysaa abaalmarin Amph.

Natiijooyinkaasi waxay la mid yihiin doorka muhimka ah ee la xaddiday ee mudada dheeriga ah ee daroogada xadgudubka ee ku saabsan xakamaynta daroogada (Lu et al., 2005; Thomas et al., 2008; Wolf, 2010b, 2012; Xue et al., 2012). Intaa waxaa dheer, abaalmarinta dabiiciga ah ee loo yaqaan 'FosB' ee NAc waxay muhiim u tahay saameynta iskudhafka dabiiciga ah ee ka timaadda abaalmarinta dabiiciga ah ee abaalmarinta nafsaaniga ah, oo laga yaabo in ay ka dhalato lafdhabarta NAc muddada mudnaanta abaalmarinta.

Waxaan soo bandhignay in FoW ka soo baxday NAc ka dib khibrad jinsi ah oo muddo dheer socota oo ku tiirsan NAc D1R inta lagu jiro isafgaradka. Hase yeeshee, D1R-dhexdhexaadin ah? Foosaarinta FosB ee NAc ayaa lagu muujiyey inay muhiim u tahay abaalmarinta la kordhiyay ee Amph iyo kordhinta cufnaanta dhabarka ee NAc, inkastoo natiijooyinka ka soo baxa galmoodka ay ku xiran tahay mudnaan aan ka ahayn abaalmarinta jinsiga (Pitchers et al., 2010a). Ugu dambeyntiina, waxaan soo bandhignay in NAc spinogenesis ay gacan ka geysan karto horumarinta bilowga ah ee muujinta abaalmarinta Amph amase laakinse ma ahan mid muhiim u ah bandhigida sii kordhinta ee daroogada daroogada, sida cufnaanta kordhay ee NAc uu ahaa mid deg deg ah oo lagu arkay ka dib markii 7, laakiin ma aha 28 d, mudada dheeraadka ah.

Muddo dheer ayaa la ogaaday in dopamine lagu sii daayo NAc inta lagu jiro mudada dabeeciga dabiiciga ah, oo ay ku jiraan habdhaqanka galmada. Marka la hirgeliyo haween la aqbali karo, dopamine-ka ka baxsan ee NAc ayaa kordhay oo wali sarreeya inta lagu jiro isu-duwaha (Fiorino et al., 1997). Daraasadani waxay muujisay in caabuqa daawada dopamine antagonists in lagu daro NAc inta lagu guda jiro mala-awooda oo aan saameyn ku lahayn bilaabista ama waxqabadka galmada, taas oo la socota fekerka ah in dopamine uusan ku lug lahayn qaabka abaal-marinta abaal-marinta, laakiin ee ku saabsan sifeynta dhiirigelinta dhiirrigelinta calaamadaha galmada la xiriira (Berridge iyo Robinson, 1998). Xaqiiqdii, rajo laga qabo abaalmarinta jinsiga ayaa dhalinaysa in lagu dhaqdhaqaaqo qanjirada gudaha nidaamka abaalmarinta dopamine, taas oo ay ka mid tahay unugyada dopaminergic-ka ee ku yaala barxadda bedka ah iyo bartilmaameedkooda, NAc (Balfour et al., 2004).

Habdhaqanka jinsi-soo-celinta ee soo noqnoqda ayaa soo-gaadhay? FosB-ga NAc, taas oo dhexdhexaadinaysa waayo-aragnimada soo-saarka dabeecadda jinsiga (Pitchers et al., 2010b). Natiijooyinka iminka jira waxay muujinayaan in macaamilku uu sababay FosB-upregulation, dhab ahaantii, waxay ku tiirsan tahay waxqabadka D1R ee NAc inta lagu jiro maadada. Natiijadani waxay la socotaa daraasado hore oo muujinaya in maamulka joogtada ah ee maskaxda ee joogtada ah uu sii kordhayo? FosB ee NAc dhexdhexaad ah oo dhexdhexaad ah neurons oo muujinaya D1R (Lee et al., 2006; Kim et al., 2009) iyo in sidaas oo kale? FosB upregulation waxay ku xiran tahay dhaqdhaqaaqa D1R (Zhang et al., 2002). Intaas waxaa sii dheer, jawaabaha daroogada ee xasaasiga ah, sida caadiga ah lagu arkay xayawaan khibrad daroogo ah, ayaa la soo saari karaa maqnaanshaha duruufaha horay u sii xumaatay ee foosha 'FosB' ee D1R oo muujinaysa nuucyada ku jira qallalka (Kelz et al., 1999). Sidaa darteed, abaalmarinta dabiiciga ah iyo daroogada labadaba waxay kor u qaadaa FosB ee NAc iyada oo loo marayo habka D1R-ku-tiirsanaan si loo dareemo dabeecadaha abaal-marinta.

Waxaa intaa dheer, natiijooyinka iminka socda ayaa muujinaya in FosB uu yahay dhexdhexaadiyaha muhiimka ah ee iskutallaabta dareenka u dhexeeya khibradda abaalgudka dabiiciga ah iyo abaalmarinta nafsaaniga ah. Falanqaynta FosB ee NAc ayaa horay loogu soo rogay jawaabcelin daroogo ah, sida FosB Faa'idada FosB ee NAc waxay dareensiisaa dhaqdhaqaaqa firfircoonida cocaine ka dib markii hore loo soo celiyey ama soo noqnoqday maamulka (Kelz et al., 1999), wuxuu kordhiyaa xasaasiyadda kookeynta iyo morphine CPP (Kelz et al., 1999; Zachariou et al., 2006), oo keena is-maamulidda qiyaasaha hoose ee daroogada (Colby et al., 2003). Daraasaddan ayaa muujinaysa in xayiraadda D1R ama hawlaha FosB ee NAc inta lagu jiro mala-awaalka jinsiga la joojiyey ee khibrad u leh dareenka Amph. Tnadaafada, dabiiciga ah iyo daroogada maaha kaliya isku duwida jidka isku midka ah ee neerfaha, waxay isku dhajiyaan isla dhexdhexaadiyeyaasha meco (Nestler et al., 2001; Wallace et al., 2008; Hedges et al., 2009; Pitchers et al., 2010b), iyo waxay u badan tahay in isla nuucyada NAc (Frohmader et al., 2010b), inay saameyn ku yeeshaan salience dhiirigalin ah iyo "rabitaan" labada nooc ee abaalmarinta (Berridge iyo Robinson, 1998).

Daraasadani waxay muujisay in mudo aan xadidneyn oo ka timaadda abaalmarinta jinsiga loo baahan yahay marka la dareemayo dareenka Amph iyo NAc spinogenesis. Waxaan ku fekereynaa in FosB inta lagu guda jiro waqtigaan ilbiriqsigu uu saameeyo shaqada neuronal by beddelidda muujinta hiddaha hoose ee si ay u bilaabaan lafdhabarta iyo waxay bedelaan awoodda synaptic. Dhab ahaantii, xannibista joojinta? FosB ee NAc inta lagu guda jiro mala-awaalka ka hortagga in la kordhiyo cufnaanta dhabarka ee NAc lagu ogaaday ka dib bixinta abaalmarinta. Intaa waxaa dheer, anigaNhaajinta D1R daacad u ah NAc ka hor inta aan la isku darin xili kasta oo ka hor istaagay waayo-aragnimadii jinsiga-kordhisay ee FosB iyo cufnaanta kordhay. ? FosB waa arrin ku-meel-gaar ah oo u noqon karta firfircooni ku-takbiirsan ama wax-qabad si loo yareeyo muujinta gogol-dhigga gen ee bartilmaameedka kaas oo laga yaabo inay saameyn ku yeeshaan cufnaanta laf-dhabarka iyo awoodda synaptic ee NAc (Nestler, 2008). FosB waxay u hawlgaleysaa kinase-ku-xiran kinase-5 (Bibb et al., 2001, Kumar et al., 2005), qodobka nukliyeerka? B (NF-? B) (Russo et al., 2009b), iyo qaybta GluA2 ee garsooraha ambalaasta AMPA (Vialou et al., 2010) iyo xanaaqa waraaqaha gawaarida hore ee hargabka (Pitchers et al., 2010b) iyo histone methyltransferase G9 (Maze et al., 2010). Xayawaanka CyclicDependent-5 wuxuu xakameeyaa borotiinka cytoskeletal iyo korriinka neuritis (Taylor et al., 2007). Intaa waxaa dheer, kicinta NF-? B waxay kordhisaa tirada dermiska ee NAc, halka horudhaca NF-B uu hoos u dhacay basal-dendritic spines iyo xayawaanka korriinka kookeynta ee xuubka (Russo et al., 2009b). Sidaa awgeed, abaalmarinta jinsiga ayaa kor u kacaysa? FosB ee NAc, oo laga yaabo inay isbedelaan NAc cufnaanta loona maro bartilmaameedyo badan (ie, kinase ku-xiran kinase-5, NF-? B) aiyo in guud ahaan natiijada ay tahay dareenka daroogada ee dareenka ah, sida laga soo xigtay Russo et al. (2009a) ee ficillada kookeynta soo noqnoqda

Daraasad lama filaan ah oo daraasaddan lagu sameeyay ayaa ah in kordhinta cufnaanta dhabarka ee NAc uu ahaa mid deg deg ah, oo aan laga helin 28 d ka dib khibrad galmo. Sidaa awgeed, cufka kordhay ee cufka ayaa la xidhiidhay bilawga abaalmarinta Amph oo kor u kaca waxayna ka qayb qaadan kartaa horumarinta bilowga ama muujinta gaaban ee jawaabaha amfor-ka ee xasaasiga ah. Si kastaba ha ahaatee, iCufnaanta lafdhabarta oo aan loo baahnayn loogu talagalay joogitaanka Amph abaalmarin dareen ah ka dib muddooyinka dheeriga ah ee ka-dhaafin. Waxaan horey u muujinnay in khibrada galmadu ay sababto waqti gaaban (7, laakiin aan ahayn 28, maalmo kadib maryaha ugu dambeeya) kordhay qiyaasta NMDA sub-NR-1 ee NAc, kaas oo loo rogay heerarka aasaasiga ah ka dib muddooyin dheer oo abaalmarin ah (Pitchers et al., 2012). Tani waxay kor u kacday muujinta NMDA-da oo la yiraahdo waxay muujinaysaa inay muujinayso sinaansho galmo oo la-socdo oo la xariiro (Huang et al., 2009; Brown et al., 2011; Pitchers et al., 2012), iyo soo-jeedin suuragalnimada in waayo-aragnimada galmada kobaca dhabarka waxay ku xiran tahay waxqabadka NMDA ee xajinta (Hamilton et al., 2012).

Gebogebadii, daraasadda hadda waxay muujineysaa isbeddelinta abaalmarinta daroogada ee abaalmarinta dabiiciga ah (jinsiga) iyo ku-tiirsanaanta muddada abaal-marinta ka-dhaafista. Waxaa intaa dheer, baqshimidan habdhaqanka waxaa dhexdhexaadiyay FosB iyada oo loo marayo dhaqaajinta D1R ee NAc. Sidaa darteed, xogta waxay soo jeedinayaan in luminta abaalmarinta dabiiciga ah ka dib khibrad abaal-marineed ay ka dhigi karto shakhsiyaadka u nugul horumarinta daroogada maandooriyaha iyo in hal dhexdhexaadiye ah ee hannaankan korodhka ahi uu yahay 'FosB' iyo bartilmaameedkeeda hoose ee isbeddelka.