Hababka isdaba-marinta ee mukhaadaraadka: doorka ΔFosB (2008)

Faallooyin: Eric Nestler wuxuu bixiyaa faahfaahin badan oo ku saabsan DeltaFosB iyo qabatinka. (Inbadan ayaa tan iyo markii la helay.) Ujeeddadeeda isbeddelka ayaa ah inaad hesho inta helitaanku wanaagsan yahay (cuntada iyo jinsiga) - taasi waa, wacyi gelinta xarunta abaalmarinta. Si kastaba ha noqotee, noocyada caadiga ah ee abaalmarinta dabiiciga ah waxay u horseedi kartaa cunno xad dhaaf ah iyo uruurinta DeltaFosB… iyo isbeddelada maskaxda ee sababa jahwareer badan iyo foorar badan Si xiiso leh, dhalinyarada waxay soo saaraan wax ka badan DeltaFosB marka loo eego dadka waaweyn, taas oo ah hal sabab oo ay ugu nugul yihiin qabatinka.

WAXBARASHADA ISKUULKA

Eric J Nestler*

10.1098 / rstb.2008.0067 Phil. Trans. R. Soc. B 12 Oktoobar 2008 vol. 363 maya. 1507 3245-3255

+ Abaalmarinta Is-bahaysiga Waaxda Neuroscience, Mount Sinai School of Medicine

New York, NY 10029, USA

aan la taaban karin

Shuruucda muujinta hidda-wadaha waxaa loo tixgeliyaa farsamo macquul ah oo balwadda maandooriyaha ah, iyadoo la siinayo xasilloonida cilladaha dabeecadda ee qeexaya xaalad qabatin leh Waxyaabaha badan ee transcript loo yaqaan inay saameyn ku yeeshaan habka balwadda, mid ka mid ah kuwa ugu wanaagsan ee lagu garto waa ΔFosB, oo lagu soo rogo gobollada abaalmarinta maskaxda iyadoo si joogta ah loogu soo bandhigo dhammaan daroogooyinka xadgudubka iyo dhexdhexaadinta jawaabaha xasaasiga ah ee soo-gaadhista daroogada. Sababtoo ah ΔFosB waa borotiin aad u deggan, waxay u taagan tahay habka ay daawooyinka u keenaan isbeddel joogto ah ee muujinta hidda-dheer ka dib joojinta isticmaalka daroogada. Daraasado ayaa la socdaa si ay u sahamiyaan farsamooyinka farsamo ee farsamaysan oo ay ΔFosB u hoggaansamayso gen genes bartilmaameed iyo soo saartaa saameynteeda dhaqanka. Waxaan ku soo dhoweynaynaa su'aashan iyada oo la adeegsanayo qoraallada DNA-ga ee la xidhiidha falanqaynta is-beddelka isudheellitirka ee is-beddelka ah ee isbeddelka dambe ee histos ee daawooyinka hiddaha-daaweeyayaasha-si loo ogaado hidaha lagu xakamaynayo daroogada xadgudubka iyada oo loo marayo ΔFOSB iyo si loo helo aragti galay farsamooyinka farsamada ee faahfaahsan. Natiijooyinkeenu waxay aasaaseen nidaam is-beddelaad ah oo ah nidaam sharciyaysan oo ku salaysan daroogo anshax-darro ah, iyo ballan-qaad si loo muujiyo fahamka aasaasiga ah ee ku saabsan sida ay ΔFosB gacan ugu geysato isticmaalka mukhaadaraadka iyada oo la xakameynayo muujinta geedka bartilmaameedka ee maskaxda abaal marinta.

1. Hordhac

Daraasada farsamooyinka mukhaadaraadka ee mukhaadaraadka waxay ku saleysan tahay sharraxa ah in qawaaniinta hiddaha hiddaha ay tahay mid ka mid ah habka muhiimka ah ee soo noqnoqoshada soo noqnoqoshada daroogada xadgudubka sababa isbeddel dheer oo maskaxda ah, taas oo hoosta ka jirta habdhaqanka habdhaqanka ee qeexaya xaaladda haysashada (Nestler 2001). Waxyaabaha ka muuqda aragtidan ayaa ah in isbeddelada daroogada ay sababaan isbitaallada iyo glutamaterka iyo in qaab-dhismeedka noocyada unugyada neuronal ee maskaxda, kuwaas oo lagu xidhiidhiyey xaalad xad-dhaaf ah, ay dhexdhexaadinayaan qaybo ka mid ah isbeddelka muujinta gene.

Shaqada 15-kii sano ee la soo dhaafay waxay soo bandhigtay caddeyn sii kordheysa oo ku saabsan doorka muujinta hidda-wadaha ee daroogada maandooriyaha, iyadoo dhowr arrimood oo qoraal ah - borotiinno ku xiraya cunsurro jawaab gaar ah ka leh gobollada dhiirrigeliyaha ee hiddo-wadaha bartilmaameedka ah iyo nidaaminta muujinta hiddo-wadahaas - waxaa lagu ficilka daroogada. Tusaalooyinka caanka ah waxaa ka mid ah: ΔFosB (protein Fos family), borotiinka cAMP-jawaab-celinta protein (CREB), ciribtiraha hore ee curiyaha CAMP (ICER), firfircoonida tarjumooyinka transcription (ATFs), borotiinka jawaab celinta hore (EGRs), nucleus waxay ku dhacdaa 1 (NAC1 ), waxyaallaha nukliyeerka ee NFB (NFBB) iyo soo-qaadaha glucocorticoid (O'Donovan et al. 1999; Mackler et al. 2000; Ang et al. 2001; Deroche-Gamonet et al. 2003; Carlezon et al. 2005; Green et al. 2006, 2008). Dib-u-eegidani wuxuu diiradda saarayaa ΔFosB, oo u muuqda inuu kaalin ka ciyaarayo habka mukhadaraadka, si loo muujiyo noocyada hababka tijaabada ah ee loo isticmaalay in lagu baaro hababka isdabajoogga ee maandooriyaha.

2. Kordhinta ΔFosB ee nucleus ayaa soo galaya daroogooyinka xadgudubka

ΔFosB waxaa lagu calaamadeeyaa hiddaha fosB (Tirada 1) oo la wadaagaan shuruudaha kale ee Qoyska, oo ay ku jiraan C-Fos, FosB, Fra1 iyo Fra2 (Morgan & Curran 1995). Cudurrada Fosiyada Qoyska waxay heterodimer ka sameeyaan borotiinta qoysaska Jun (c-Jun, JunB ama JunD) si ay u sameeyaan borotiinka firfircoon ee firfircoon-1 (AP-1) ee ku xirma goobaha AP-1 (isku xirnaanshaha: TGAC / GTCA) dhiirrigeliyeyaasha jaangooyooyinka qaarkood si ay u xakameeyaan buugaagtooda. Barootinnada qoysaska ee Fosiyada ayaa si degdeg ah u socda oo si ku-meel-gaar ah u ah gobollo gaar ah oo maskaxda ka dib markii ay si degdeg ah u maamulaan daroogo badan oo xadgudub ah (Tirada 2; Graybiel et al. 1990; Young et al. 1991; Hope et al. 1992). Jawaabyadani waxay u muuqdaan kuwa ugu caansan nucleus xajmiga iyo cirbadeynta, kuwaas oo ah dhexdhexaadiyeyaasha muhiimka ah ee falalka abaalmarinta iyo firfircoonida daawooyinka. Si kastaba ha noqotee, borotiinka qoysaska ee Fos, si kastaba ha ahaatee, waa kuwo aan xasillooneyn oo ku soo noqda heerarka asalka ah saacadaha daawada maandooriyaha.

Jaantuska 1

Astaamaha bayoolaji ee xasiloonida gaarka ah ee ΔFosB: (a) FosB (338 aa, M_r qiyaastii. 38 kD) iyo (b) ΔFosB (237 aa, M_r qiyaastii. 26 kD) waxaa lagu kaydiyaa hidda-wadaha fosB. 'OsFosB waxaa lagu soo saaraa kala-soocid kale oo ka maqan C-terminal 101 amino acids oo ku jira FosB. Laba hanaan ayaa la ogyahay in lagu xisaabtamo xasiloonida ΔFosB. Marka hore, ΔFosB waxaa ka maqan laba meelood oo degro ah oo ku yaal C-terminus ee dhererka buuxa ee FosB (waxaana laga helaa dhammaan borotiinka kale ee qoyska Fos sidoo kale). Mid ka mid ah aagaggan degron ayaa bartilmaameedsanaya FosB si loo meeleeyo loona nabaad-dejiyo proteasome-ka. Qeybta kale ee degron waxay bartilmaameedsaneysaa hoos u dhaca FosB iyadoo loo adeegsanayo ubiquitin- iyo farsamo madax-bannaan oo madax-bannaan. Marka labaad, ΔFosB waxaa fosforylated by casein kinase 2 (CK2) iyo malaha kinase protein kale (?) N-terminuskeeda, oo sii xasiliyo borotiinka. 

Jaantuska 2

Qorshaha muujinaya isku-dhajinta tartiib-tartiib ah ee ΔFosB oo ka soo horjeeda soo-kicinta degdegga ah ee ku-meel-gaadhka ah ee Fosiyada qoysaska kale ee ka jawaabista daroogooyinka xadgudubka. (a) Autoradiogram waxay muujineysaa kala-soocida Fos ee qoysaska ee nukleus accumbens by kicinta degdega ah (1-2 ka dib markii hal kiniin-kicinta hal mar) oo ka soo horjeeda kicinta daba-galka ah (maalinta 1 ka dib soo-gaadhista kookeynta). (b) (i) Dhowr hirar oo ah Fosiyada Qoyska Qoyska (oo ka kooban C-Fos, FosB, ΔFosB (33 kD isoform), iyo suurta galnimada (?) Fra1, Fra2) ayaa lagu soo bandhigay nucleus accumers iyo norson norsis nourons daroogada xadgudubka. Waxaa sidoo kale lagu soo bandhigay istiraatiijiyado kala duwan oo loo yaqaan 'ΔFosB (35-37 kD); waxaa lagu sababeeyaa heerarka hooseeya by maamulka daroogada khatarta ah, laakiin joogta maskaxda muddo dheer sabab u ah xasiloonida. (ii) Marka lagu celceliyo (tusaale ahaan laba goor maalinle ah) maamulka daroogada, kicin kasta oo xasaasiyad leh waxay hoos u dhigtaa heerka hoose ee ΔFosB xasilloon. Tani waxaa lagu muujiyey qadarka hoose ee khadadka isku dhafan ee tilmaamaya ΔFosB oo ay sababtay kicin kasta oo kedis ah. Natiijadu waa kordhay tartiib tartiib ah heerarka guud ee ΔFosB oo leh dareemo soo noqnoqota inta lagu jiro mudada daaweyn dabadheeraad ah. Tan waxaa lagu tilmaamayaa khadka sii kordhaya ee garaafka.

Jawaabyo aad u kala duwan ayaa loo arkaa ka dib markii si joogto ah loo maamulo daawooyinka xadgudubka (Tirada 2). Biochemically modified isoforms of ΔFosB (M_r 35-37 kD) waxay ku ururaan isla gobollada maskaxda ka dib markay soo noqdaan daroogada soo noqnoqda, halka dhammaan xubnaha Qoyska ee Fos ay muujiyaan dulqaadka (ie hoos u dhigis marka la barbardhigo astaamaha daroogada bilowga ah; Chen et al 1995, 1997; Hiroi iyo al. 1997). Rugta noocan ah ee loo yaqaan 'ΔFosB' waxaa lagu arkay dhammaanba daroogooyinka xadgudubka ah (jadwalka 1; Hope et al. 1994; Nye et al. 1995; Moratalla et al. 1996; Nye & Nestler 1996; Pich et al. 1997; Muller & Unterwald 2005; McDaid iyo al. 2006b), inkasta oo daroogooyinka kala duwan ay ku kala duwan yihiin heerka qiyaasta soo-baxa ee lagu arko nucleus waxay soo saartaa muusikada ka soo horjeeda qolofka iyo qallalka gawaarida (Perrotti et al. 2008). Ugu yaraan daroogooyinka xad-dhaafka ah, soo-saarista ΔFosB waxay u muuqataa mid xushmad u ah qaybta dynorphin-ka kooban ee dhexdhexaadiyaha dhexdhexaadka ah ee ku yaala gobollada maskaxda (Nye et al. 1995; Moratalla et al. 1996; Muller & Unterwald 2005; Lee et al. 2006), inkastoo loo baahan yahay shaqo dheeraad ah si loo xaqiijiyo arrintan. 35-37 kD istiraatiijiyasha ΔFOSB waxay u badan tahay inay la mid noqoto JunD si ay u sameyso xeelad firfircoon oo muddo dheer socota oo ku yaala gobollada maskaxda (Chen et al 1997; Hiroi iyo al. 1998; Pérez-Otao et al. 1998). Kala soocista daroogada ee ΔFosB ee ku-soo-galayaasha nucleus waxay u muuqdaan inay jawaab u yihiin sifooyinka daawooyinka ee daawada ee daawada ee maandooriyaha aan la xiriirin daawooyinka is haysta, sababtoo ah xayawaannada is-maamulaya cocaine ama la qaato cirbadaha daroogada ah ayaa muujinaya isbarbardhiga udubdhexaadinta gobolka maskaxda (Perrotti et al. 2008).

Shaxda 1

Daroogooyinka xadgudubka ee loo yaqaan 'ΔFosB' ee nucleus ayaa soo galaya ka dib markii la xannibmay.

·       .Induction oo lagu soo warramey daroogo iskiis loo maamulo marka lagu daro daroogada loo isticmaalo daroogada. Kobcin faafinta ee ΔFosB ayaa lagu muujiyey jiirka iyo jiirarka labadaba, marka laga reebo kuwa soo socda: mouse kaliya, cannabinoids; jiir keliya, methamphetamine, phencyclidine.

T35-37 kD ΔFosB isoforms waxay ku urursan yihiin daroogada daba-dheeraadka ah ee ay sabab u tahay noloshooda aan caadi ahayn (Chen et al 1997; Alibhai iyo al. 2007). Taas bedelkeeda, ma jirto wax caddayn ah in fekerka ΔFOSB ama xasilloonaanta mRNA ay tahay mid lagu maamulo maamulka daroogada. Sababtoo ah xasillooni, sidaas darteed, borotiinka ΔFOSB wuxuu ku jiraa nuuroon ugu yaraan dhowr toddobaad ka dib joojinta isticmaalka daroogada. Hadda waxaan ognahay in xasilladani ay sabab u tahay laba arrimood oo soo socda (Tirada 1): (i) Maqnaanshaha laba meeldhexaad oo ku yaalla ΔFosB, kuwaas oo ku jira C-terminus dhererka dheer ee FosB iyo dhammaan qiyaasaha Qoysaska Qoysaska oo bartilmaameed u ah barootiga si deg deg deg deg ah iyo (ii) fosforyaalka ΔFosB ee N-terminus by casein kinase 2 iyo laga yaabee kale kinase protein (Ulery et al. 2006; Carle et al. 2007). Twuxuu xasilooni ka haystaa ΔFosB isoforms wuxuu bixiyaa farsamo cusub oo loo yaqaan 'molecular mechanism' kaas oo isbeddelka daroogada sababay ee muujinta hiddaha ku sii jiri karto inkastoo muddooyinka muddada dheer ee daroogada laga saarayo. Sidaas awgeed, waxaannu soo jeedinay, in ΔFosB u shaqeyneyso 'isbeddel sheyba' joogtada ah kaas oo ka caawinaya bilawga iyo ka dibna ilaaliya xaalad xad-dhaaf ah (Nestler et al. 2001; McClung et al. 2004).

3. Doorka ΔFosB ee nucleus wuxuu ku dhacaa nidaaminta habdhaqanka habdhaqanka daroogooyinka xadgudubka

Fahminta doorka ΔFosB ee daroogada maandooriyaha ayaa inta badan ka timid daraasadda jiirka jilicsan ee loo yaqaan "ΔFosB" oo si ku-meel-gaar ah loogu dhex-dhex-dhex-dhexaadin karo nukleus accumens iyo qoryaha ciriiriga ee xayawaanka qaangaarka ah (Kelz iyo al. 1999). Muhiimad ahaan, jiirarkan ΔFosB oo si xushmad leh u doorbideysa xuubka dhexdhexaadka ah ee naqshadaha dhexdhexaadinta ee dynorphin, halkaas oo daawooyinka la rumaysan yahay inay ku dhaliyaan borotiinka. Dabeecadda dabeecadda ee ΔFosB-jareecada jilicsan, taas oo siyaabo gaar ah u egtahay xayawaanka ka dib soo-gaadhista daroogada, ayaa lagu soo koobay jadwalka 2. Jadeecadu waxay muujinaysaa jawaabaha lafdhabarta ee kookaynta ka dib markii ay noqoto mid deg deg ah oo joogto ah (Kelz iyo al. 1999). Waxa kale oo ay muujiyaan dareen xoog leh si ay saameyn ku yeelato saameynta cocaine iyo morphine ee baaritaannada meelaynta (Kelz iyo al. 1999; Zachariou et al. 2006), iyo is-maamulida qiyaasaha hoose ee daroogada oo ka badan kuwa littermates oo aan si weyn u badneyn ΔFosB (Colby et al. 2003). Sidoo kale, ΔFosB daacadnimo ku jirta nucleus wuxu kor u qaadayaa horumarinta xaddiga jidhka ee jidhka oo xaddidan oo dhiirrigeliya dulqaadka dulqaadka xanuunka (Zachariou et al. 2006). Taas bedelkeeda, jiirarka ΔFosB ayaa muujinaya caadooyin kale oo badan oo ka mid ah habdhaqanka, oo ay ka mid tahay barashada maaddooyinka sida lagu qiimeeyay labiska biyaha morris (Kelz iyo al. 1999).

Hababka isbeddelka ah ee maandooriyaha: doorka ΔFosB

Shaxda 2

Dabeecadda dabeecadda ah ee ku dhacda ΔFosB induction in dynorphin + neurons of nucleus accumbens iyo cirbadeynta dhirta^a.

·       .a Xaaladaha astaamaha ee lagu sharraxay jaantuskan waxaa lagu aasaasay sharaf badan oo ka soo horjeeda ΔFosB ee jiirarka xajmiga ah halkaasoo tilmaamaha ΔFosB lagu beegsanayo dynorphin + neurons ee nucleus xajmiga iyo ciriiriga dhirta; heerarka hoose ee hoose ee ΔFosB waxaa lagu arkay hippocampus iyo kortex hore. Xaalado badan, faytoomiinku wuxuu si toos ah ugu xiran yahay ereyada ΔFosB ee nucleus oo ku soo baxa halkii adoo isticmaalaya xayawaan fayrus ah oo fayrus ah.

Tilmaamaha gaarka ah ee ΔFosB-dul-dhaafka ah ee ku-xirnaanta nucleus, iyadoo la adeegsanayo wareejinta hargabka fayruuska ah, waxay keentay xog la mid ah (Zachariou et al. 2006), taas oo muujinaysa in gobolkan maskaxda ee khaaska ah uu ku xisaabtami karo calaamad muujinaysa jiirka jilicsan, halkaasoo ΔFosB sidoo kale lagu muujiyo qanjidhada dhererka iyo heerar ka hooseeya gobollada kale ee maskaxda. Intaa waxaa dheer, bar-tilmaameedka maskaxda ee enkephaline-ka dhexdhexaad ah ee nucleus xajmiga iyo ciriiriga qanjidhada kala duwan ee jiilalka kala duwan ee jiirarka xajmiga ah ee ku fashilmay inay muujiyaan inta ugu badan dabeecadaha habdhaqanka ah, gaar ahaan waxay tilmaamaysaa dynorphin + nucleus xayawaanka nuuroon ee dhacdooyinkan.

Marka la barbardhigo fara badan oo ka mid ah ΔFosB, qadarin dheellitirnaanta borotiinka mutantinka ah (ΔcJun ama ΔJunD) -waxay ka shaqeynayaan antagonisto xun oo khadadka ah AP-1-dhexdhexaadin ah - iyadoo la isticmaalayo jiirka jooniska ah ama hargabka fayruska ee fayruska ah saameyn dabeecadeed (Peakman et al. 2003; Zachariou et al. 2006). Txogta hese waxay muujineysaa in soo-kicinta 'osFosB' ee dynorphin-ay kujirto dhexdhexaad-dhexdhexaad dhexdhexaad ah ee nukleus accumens ay kordhiso xasaasiyadda xayawaanka ee cocaine iyo daroogooyinka kale ee xadgudubka, waxayna u matali kartaa farsamo loogu talagalay dareenka dheer ee daroogada.

Dhibaatooyinka ka yimaada ΔFOSB ayaa laga yaabaa inay si fiican u siyaadin karaan xeerka dareenka daroogada marka loo eego dabeecado badan oo adag oo la xariira geedi socodka takoorka. Mice qadarinta badan ee ΔFOSB waxay u shaqeysaa sidii loo kantarooli lahaa daroogada kakoobka ee baaritaanka iskudhaca isirka, taasoo soo jeedinaysa in ΔFOSB ay dareemeyso xayawaan si loogu isticmaalo dhiirigelinta dhiirigelinta kookeynta ee kobcinta, taasina waxay horseedi kartaa dib u soo noqoshada dib u soo noqoshada ka dib (Colby et al. 2003). ΔFosB-jeebka badan ee jiirarka ayaa sidoo kale muujiya saameynta aan fiicnayn ee khamriga (Picetti iyo al. 2001), Xaalad caadi ah oo lala xiriiriyay isticmaalka khamriga ee kordhinta bani-aadamka. Si wadajir ah, natiijooyinkan hore waxay soo jeedinayaan in ΔFOSB, ayadoo dheeraad u ah kordhinta dareenka daroogada xadgudubka, soo saartaa isbeddel tayo leh oo dhiirigeliya dabeecadaha dhiirigeliya dabeecada daroogada, iyo taageerida aragtida, kor ku xusan, in ΔFosB u shaqeyso sidii isbeddel sheyba joogta ah gobolka. Su'aasha muhiimka ah ee baaritaanka hadda jira waa haddii ay dhacdo ΔFOSB inta lagu jiro jiritaanka daroogada waxay kor u qaadeysaa dhaqanka daroogada raadsashada ka dib markii mudada ka-soo-baxsan, xitaa ka dib markii heerarka ΔFOSB uu caadi yahay (fiiri hoos).

4. Kicinta ΔFosB ee nucleus waxay ku dhacdaa abaalmarin dabiici ah

Qaybaha nucleus waxaa la rumeysan yahay in ay si caadi ah u shaqeeyaan adoo u hoggaansamaya jawaabaha abaalmarinta dabiiciga ah, sida cunto, cabitaan, jinsi iyo isdhexgalka bulshada. Natiijo ahaan, waxaa jira xiiso badan oo ku saabsan doorka suurtagalka ah ee gobolka maskaxda ah ee lagu magacaabo dabiiciga dabiiciga ah (Tusaale ahaan, quudinta neefta, khamaarka, jimicsiga, iwm.). Moodooyinka xayawaanka ee xaaladaha noocaas ah waa kuwo xadidan; hase yeeshee, annaga iyo kuwo kale ayaa ogaaday in heerarka sarreeya ee isticmaalka dhowr nooc oo abaalmarin dabiiciga ah ay keenayaan raasamaalka 35-37 KD oo ah xannibaadaha ΔFosB ee nucleus accumbens. Tani waxa la arkay kadib heerarka sare ee gawaarida (Werme et al. 2002) iyo sidoo kale ka dib isticmaalka raashinka ah ee sukrose, cunto dufan badan ama galmo (Teegarden & Bale 2007; Wallace et al. 2007; Teegarden et al. saxaafadeed). Xaaladaha qaarkood, is-goysyadani waxay xushmeyneysaa dynorphin + hoos-u-dhac dhexdhexaad ah oo dhexdhexaad ah (Werme et al. 2002). Cilmi-baarista jiirka, xargaha jooniska iyo xayawaanka fayruska ee fayruuska ah ayaa muujiyay in sharraxaad dheeraad ah oo ka soo baxday ΔFosB ee nucleus accumens ay kordhinayso isticmaalka iyo isticmaalka faa'iidooyinka dabiiciga ah, halka feejignaanta badan ee maskaxda xun ee jinsiga ah ee Junt (jadwalka 2; Werme et al. 2002; Olausson et al. 2006; Wallace et al. 2007). Natiijooyinkaasi waxay soo jeedinayaan in ΔFosB ee gobolka maskaxda ahi dareemayo xayawaanka maaha oo kaliya abaalmarinta daroogada laakiin abaalmarinta dabiiciga ah, sidoo kale waxay gacan ka geysan kartaa xaaladaha khatarta dabiiciga ah.

5. Kicinta ΔFosB ee nucleus waxay ku dhacdaa cadaadiska daba dheeraaday

Marka la eego caddaymaha muhiimka ah ee ah in ΔFosB ay sababtay nucleus soo galootiga khatarta soo noqnoqoshada ee daroogada iyo abaalmarinta dabiiciga ah, waxay ahayd mid xiiso leh in la ogaado in ΔFOSB ay sidoo kale si weyn u soo jiidatay gobolka maskaxda kadib markii dhowr nooc oo dareen-celin daba-dheer, oo ay ka mid tahay cadaadiska xakamaynta, cadaadiska joogtada ah ee aan la saadaalin karin iyo jabinta bulshada (Perrotti et al. 2004; Vialou et al. 2007). Si kastaba ha ahaatee, maandooriyaha iyo abaalmarinta dabiiciga ah, si kastaba ha ahaatee, isdifaaciddu waxa ay si weyn uga muuqataa gobolka maskaxda ah ee loo arko in si cad loogu arkay labadaba dynorphin + iyo enkephalin + hoos udhaca dhexdhexaadiyeyaasha dhexdhexaadka ah. Caddaynta hore waxay soo jeedinaysaa in isdhexgalka ee ΔFOSB uu meteli karo jawaab celin waxtar leh, oo ka caawinaya qofku inuu la qabsado diiqada. Tilmaamahan waxaa lagu taageeray natiijooyin hordhac ah oo muujinaya in ΔFosB ay ka dhexjirto nucleus, iyadoo adeegsanaysa jiirka, ama jadeecada xayawaanka ah ee loo yaqaan 'genetic nostruated', ayaa lagu dabiqi karaa jawaabaha liddi ku ah antidepressant-ka ee baaritaano dabeecadeed oo badan (tusaale ahaan guul darrada bulsheed, imtixaanka qasabka ah) Dhacdooyinka ΔcJun ayaa keena saameyn nacayb-niyad jabka ah (Vialou et al. 2007). Waxaa intaa dheer, maamulka daba-galka daaweynta diiqadda caadiga ah waxay saameyn ku yeelataa walaaca iyo waxay u keentaa ΔFosB gobolka maskaxda. In kasta oo shaqo dheeraad ah loo baahan yahay si loo ansixiyo natiijooyinkaas, doorka noocan oo kale ah waxay ku xirnaan doontaa aragtidaas ΔFosB waxay kordhisaa xasaasiyadda wareegga abaalmarinta maskaxda waxaana laga yaabaa inay taasi ka caawiso xayawaanka inay la qabsadaan xilliyada walaaca. Arrinta xiisaha leh, doorka nooca loo yaqaan 'ΔFosB' ee astaamaha nucleus wuxuu la mid yahay tan dhowaan loo soo bandhigay ciriiri-bararka iyada oo miisaanka loo yaqaan 'transcription' uu sidoo kale keeno cadaadiska daba dheeraadka ah (Berton et al. 2007).

6. Noocyada Target ee loogu talagalay ΔFosB ee nucleus accumbens

Sababtoo ah ΔFosB waa arrin ku-meel-gaar ah, waxay u muuqataa inay soo saari karto ficilkan dabeecad ee dabeecadda ah ee nucleus galaya iyadoo kor loo qaadayo ama hoos u dhigayo muujinta jinsiyada kale. Sida lagu muujiyey Tirada 1, ΔFosB waa badeeco la taaban karo ee hiddaha fosB ee ka maqan inta badan C-terminal transactivation domain ee buuxa FosB buuxa laakiin waxay xajisaa xajinta iyo xuduudaha DNA-saaridda. ΔFosB waxay ku xidhan tahay xubnaha qoyskooda Jun iyo maxsuulkii soo-baxa waxay ku xiraan goobaha AP-1 ee DNA. Qaar ka mid ah baaritaanada vitamin waxay soo jeedinayaan in sababta oo ah ΔFosB ay ka maqan tahay qaybo badan oo ka mid ah xayiraadaha, waxay u shaqaysaa sida dhaqdhaqaaqa xun ee waxqabadka AP-1, halka qaar kale oo kale ay muujinayaan in ΔFosB ay dhaqdhaqaajin karaan xarumaha AP-1 (Dobrazanski et al. 1991; Nakabeppu & Nathans 1991; Yen et al. 1991; Chen et al 1997).

Isticmaalaan jiirkeena maskaxeed ee maskaxda ah oo si weyn u xoojinaya ΔFosB ama xakameyntiisa xun ee ΔcJun, oo lagu falanqeynayo muujinta hiddaha ee jajabka Affymetrix, waxaan soo bandhignay, in nukleus soo galo gudaha vivo, ΔFosB wuxuu u shaqeeyaa sida ugu dhaqsaha badan oo ah dhaqdhaqaaqa beddelka ah, iyada oo u adeegta sidii wax loo yaqaan 'repressor' si loo yareeyo hoos (McClung & Nestler 2003). AnigaHawlaha kala duwan ee hawlaha kala duwan ee ΔFosB waa farsameynta muddada iyo heerka ΔFosB, oo leh heerar gaaban, heerar hoose oo keena cadaadiska hiddaha iyo waqti dheer, heerar sarreeya oo keena hindhisto badan. Tani waxay la socotaa raadinta mudada gaaban iyo muddada fog ee ereyada ΔFosB waxay keenaysaa saameynta soo horjeeda dabeecadaha: ereyga 'ΔFosB', sida erayga ΔcJun, wuxuu yareynayaa doorbididda kokainimada, halka mudada dheer ee ΔFosB ku kordhinayso kookeynta (McClung & Nestler 2003). Nidaamka mas'uulka ka ah isbeddelkan ayaa hadda la baadhayaa; hal suurtagal oo cusub, oo weli kufilan, ayaa ah in ΔFosB, heerarka sare, laga yaabo inay sameeyaan homodimers kuwaas oo dhaqdhaqaaqa warqadda AP-1 (Jorissen et al. 2007).

Noocyada bartilmaameedka ee ΔFOSB waxaa lagu aasaasay iyadoo la adeegsanayo hannaanka musharraxiinta musharaxnimada (jadwalka 3). Mid ka mid ah hiddaha musharaxiinta waa GluR2, alfa-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) qaybta qaabilsan ee glutamate (Kelz iyo al. 1999). ΔFosB sarreysa oo ku saabsan jiirka jilicsan doorasho xaddidan ayaa muujinaysa in GluR2 ay muujinayso xajmiga nucleus, iyada oo aan wax saameyn ah laga helin dhowr meelood oo kale oo ah AMPA glutamate reseptor-ka la falanqeeyay, halka ΔcJun ay muujinayso awoodda cocaine si loo kiciyo GluR2 (Peakman et al. 2003). Qalabyada AP-1 oo ka kooban ΔFosB (iyo ugu badnaana JunD) waxay isku xiraan isku xirka AP-1 oo ku yaala GluR2 promoter. Waxaa intaa dheer, GluR2 ciribtirka xawilaadda iyadoo la adeegsanayo gudbinta hidda-wareerka fayruuska oo sii faa-iideynaya saamaynta wax-qabadka ee kookeynta, sida fareerka dheeriga ah ee ΔFosB (Kelz iyo al. 1999). Maaddaama GluR2-ku jira Nidaamka AMPA ay leeyihiin hoos u dhigis guud marka loo eego kanaalada AMPA oo aan ka koobnayn kan hoose, daroogada kookeynta iyo ΔFOSB-dhexdhexaadinta ee GluR2 ee nucleus accumens ayaa laga yaabaa inay xisaabtamaan, ugu yaraan qayb ahaan, jawaab celinta glutamatergic ee lagu arkay nuucyadaas ka dib markii la soo gaadhsiiyo daroogo joogto ah (Kauer & Malenka 2007; jadwalka 3).

Tusaale ahaan bartilmaameedyada asaasiga ah ee loogu talagalay ΔFosB ee nukleus accumbens^a.

·       .a Inkasta oo ΔFosB ay nidaamiso muujinta hiddo-wadayaal badan oo maskaxda ah (tusaale McClung & Nestler 2003), jadwalka waxaa ku taxan oo keliya hiddo-wadayaasha buuxiya ugu yaraan saddex ka mid ah shuruudaha soo socda: (i) korodhay (↑) ama hoos u dhaca (↓) muujinta ΔFosB xad-dhaaf ah, (ii) is-beddel ama qaanuunka u dhigma ee ΔcJun, oo ah ka-hortagga diidmada weyn ee ka-hortagga AP-1-dhexdhexaadinta, (iii) ΔFosB-ka kooban isku-xirka AP-1 waxay ku xidhan yihiin goobaha AP-1 ee dhiirrigeliyaha hidda-wadaha, iyo iv) ΔFosB wuxuu saameyn la mid ah ku leeyahay dhaqdhaqaaqa dhiirrigeliyaha hidda-wadaha ee vitro sida lagu arko vivo.

·       .b Inkastoo ay jirto caddaynta in ΔFosB ay ku faafinayso hiddo-hufnaanta hormuudka ku salaysan xadgudubka mukhadaraadka (Zachariou et al. 2006), waxaa jira caddayn kale oo sheegaya in ay u dhaqmi karto hirgelinta hiddaha xaaladaha kala duwan (eeg Cenci 2002).

Shaxda 3

Tusaale ahaan bartilmaameedyada la xaqiijiyey ee loogu talagalay ΔFosB ee nucleus accumbensa.

Dhiig kale oo lagu bartilmaameedsanayo musharaxnimada ΔFosB ee nukleus accumens waa peptide opioid, dynorphin. Xasuuso in ΔFosB u muuqato in ay sabab u yihiin daroogo xadgudub gaar ah oo ku jira unugyada hormoonada ee dynorphin ee gobolka maskaxda. Daroogooyinka xadgudubku waxay leeyihiin saamayn adag oo ku saabsan muujinta dynorphin, iyadoo la kordhiyo ama la yareeyo aragtidooda iyadoo ku xiran xaaladaha daaweynta ee loo isticmaalo. Geedka dynorphin wuxuu ka kooban yahay xarumaha AP-1-sida, taasoo xiri karta xarumaha ΔFosB ee ku jira dhismooyinka AP-1. Waxaa intaa dheer, waxaan soo bandhignay in indha-indheynta ΔFosB ay tarjumayso hannaanka hiddaha ee dynorphin ee nucleus accumens (Zachariou et al. 2006). Dynorphin waxaa loo maleynayaa in uu dhaqdhaqaaqaayo qeeybta opioid ee dareenka qanjirka 'VTA dopamine' iyo in la joojiyo gudbinta dopaminergic taas oo hoos u dhigaysa hababka abaal-marinta (Shippenberg & Rea 1997). Hmarka la eego, cadaadiska osFosB ee muujinta dynorphin wuxuu gacan ka geysan karaa kor u qaadista hababka abaalmarinta ee dhexdhexaadinta qaybtan transcript. Hadda waxaa jira caddayn toos ah oo taageeraya ka-qaybgalka cadaadiska hidda-wadaha dynorphin ee dabeecadda dabeecadda ΔFosB (Zachariou et al. 2006).

Caddaymihii dhowaa ayaa muujiyay in ΔFosB ay sidoo kale cambaareeyso hiddo-wadaha-fosho oo caawisa abuurista is-beddelka molecular -ka laga bilaabo soo-saarka dhawr faayrood oo qoyan oo Fos qoys ah ka dib markii ay soo gaadhay daroogada khatarta ah ee ka soo raynaysa xajmiga badan ee ΔFosB ka dib markii la sii daayo daroogada joogtada ah- ayaa hore loo soo diray (Renthal et al. saxaafadeed). Farsamada mas'uulka ka ah fara-gelinta "ΔFosB" ee c-fos waa qallafsan waana hoos ku xusan.

Hab kale oo loo isticmaalo in lagu aqoonsado genuska bartilmaameedka ee ΔFosB ayaa qiyaastay isbeddelka muujinta hidda-galka ee ka dhacaya kororka xakamaynta ee ΔFosB (ama ΔcJun) ee nucleus soo galaya iyada oo la adeegsanayo arrimo la xidhiidha DNA, sida hore loo sharraxay. Nidaamkan wuxuu keeney aqoonsiga unugyada badan ee kor u kacay - ama hoos u dhigeen faahfaahinta ΔFosB ee gobolka maskaxda (Chen et al. 2000, 2003; Ang et al. 2001; McClung & Nestler 2003). Two gen oo u muuqda in lagu soo rogay ficillada ΔFosB iyada oo loo adeegsanayo dhaqdhaqaaqa dhaqdhaqaaqa ayaa ah ku-tiirsanaanta kinase-5 (Cdk5) iyo isku-duwaha P35 (Bibb et al. 2001; McClung & Nestler 2003). Cdk5 waxaa sidoo kale sabab u ah kookeer joogta ah oo ku jira xajmiga nucleus, saameyntana waa la xakameeyay ΔcJun, iyo ΔFosB waxay ku xidhan tahay oo hirgelisaa hiddaha Cdk5 iyada oo loo marayo barnaamijka AP-1 ee ku jira hindisaheeda (Chen et al 2000; Peakman et al. 2003). Cdk5 waa bartilmaameed muhiim ah oo ka mid ah ΔFosB maaddaama ay muujinayso isbedelka xaaladaha fosforyaalka ee borotiinno badan oo synaptic ah oo ay ka mid yihiin subagyada glutamate (Bibb et al. 2001), iyo sidoo kale kordhinta cufnaanta lafdhabarta dendritic (Norrholm et al. 2003; Lee et al. 2006), oo ku jira baayacmushtarada nucleus, kuwaas oo la xiriira maamulka cocaine-daRobinson & Kolb 2004). Dhawaan, xeerka Cdk5 ee ku-xirnaanta nucleus ayaa si toos ah ugu xiran isbedelka saameynta dhaqanka ee kookeynta (Taylor et al. 2007).

Mashruuc kale oo ΔFOSB lagu qeexay isticmaalka mareeriyada waa NFBB. Waxyaalaha bukaan-socodka ah ee loo yaqaan 'transcontinental' ayaa lagu soo koobay nucleus oo ay soo saartey ΔFosB xumada iyo kookeynta joogtada ah, saameyntani waxay xakamaysay ereyga ΔcJun (Ang et al. 2001; Peakman et al. 2003). Caddaymihii ugu dambeeyay waxay soo jeediyeen in soo-saarista NFBB ay sidoo kale gacan ka geysan karto awoodda kookeynta si ay u soo jiido muruqyada dendritic ee Nucleus accumbens neurons (Russo et al. 2007). Waxaa intaa dheer, NFBB ayaa lagu soo bandhigay qaar ka mid ah saamaynta neurotoxiciga ee methamphetamine ee gobollada dhimirka (Asanuma & Cadet 1998). Kormeerka NFBB-gu waa hindisaha bartilmaameedka loogu talagalay ΔFosB wuxuu xoojinayaa isku dhafka qaababka ay ΔFosB dhexdhexaadinayso saameynta kookaynta ku jirta bandhigga hidda. Sidaa darteed, marka laga reebo hiddo-yada ay ΔFosB si toos ah ula xariirtaan goobaha AP-1 ee kuyaala taageerayaasha hiddaha, ΔFOSB waxaa laga filayaa in ay xakamayso gen genes dheeraad ah iyada oo la beddelayo muujinta NFBB iyo bedelka kale ee proteins.

Nidaamka qoraallada DNA wuxuu bixiyaa liis dheer oo ah hiddaha dheeraadka ah ee dheeraadka ah ee lala beegsan karo, si toos ah ama si aan toos ahayn, ΔFosB. Xubnahan waxaa ka mid ah soo-saareyaasha neurotransmitter dheellitiran, borotiinada ku lug leh hawlaha hore iyo post-postsinaptic, noocyo badan oo ka mid ah ion channels iyo borotiinnada jaaniska ku-soo-baxa, iyo sidoo kale borotiinka xukuma jimicsiga neuronal iyo koritaanka unugyada (McClung & Nestler 2003). Hawlaha dheeraadka ah ayaa loo baahan yahay si loo xaqiijiyo mid kasta oo ka mid ah borotiinnada badan ee ka mid ah bartilmaameedyada daroogada ee kakoobiga ah ee loo marayo ΔFosB iyo in la dhiso doorka saxda ah ee borotokool kastaa uu ku ciyaarayo dhexdhexaadinta dhinacyada culeyska iyo dabeecada ee cocaine. Ugu dambeyn, dabcan, waxay noqon doontaa mid aad muhiim u ah in laga gudbo falanqaynta shakhsiyaadka bartilmaameedka u ah qawaaniinta udubdhexaadka ah ee jinsiyada kuwaas oo sharcigooda isku-duwani laga yaabo inay ubaahdaan inay dhexdhexaadiyaan gobolka xad-dhaafka ah.

7. Kordhinta ΔFosB ee gobollada kale ee maskaxda

Wadahadalka ilaa hadda waxa uu diiradda saarey kaliya halbeegyada nucleus. Inkastoo tani ay tahay mid muhiim u ah gobolka abaalmarinta maskaxda iyo muhiim u ah tallaabooyinka wax lagu kobciyo ee daroogada iyo daroogooyinka kale ee xadgudubka, gobollo kale oo badan oo maskaxeed ayaa sidoo kale muhiim u ah horumarka iyo dayactirka xaalad cabsida. Su'aal muhiim ah, ka dibna waa, in ΔFosB ku socoto meelo kale oo maskaxeed oo ka baxsan xajmiga nucleus waxay sidoo kale saameyn kartaa maandooriyaha maandooriyaha. Anigandeed, hadda waxaa jira caddayn dheeraad ah oo kicinta iyo daroogooyinka daroogada ah ee xadgudubka ah ay keento ΔFosB gobolo badan oo maskaxda ah oo ku lug leh dhinacyo kala duwan ee addiction (Nye et al. 1995; Perrotti et al. 2005, 2008; McDaid iyo al. 2006a,b; Liu et al. 2007).

Daraasad dhowaan la sameeyay ayaa si isdaba joog ah u barbar dhigta ΔFosB indho-indheynta kuwan kala duwan ee maskaxda ku salaysan afar daroogo kala duwan oo xadgudub ah: kookayn; morphine; cannabinoids; iyo ethanol (jadwalka 4; Perrotti et al. 2008). Dhammaan afarta dawo ayaa soocaya isugeynta warqadaha kala duwan ee qiyaasaha kala duwan ee numbaska xajmiga ah iyo qanjirrada duleelka ah iyo sidoo kale kortex doorbid, amygdala, hippocampus, sariirta sariirta ee terminaalka stria iyo nucleus nudleus oo ka soo baxa xuubka dambe ee bambada hore. Cocaine iyo ethanol oo keliya ayaa keena ΔFosB in septum lateral, dhammaan daroogooyinka, marka laga reebo cannabinoids marka laga reebo xashiishada iswidishka ah ee kudheerka ah, iyo daroogada cocaine waa mid gaar ah oo loogu talagalay ΔFosB oo ah unugyada gamma-aminobutyric acid (GABA) unugyada xuubka hoose (Perrotti et al. 2005, 2008). Waxaa intaa dheer, morphine ayaa lagu muujiyey in ay u soo jiidaan ΔFosB oo ku taala ventral pallidum (McDaid iyo al. 2006a). Mid kasta oo ka mid ah gobolladan, waa 35-37 kD istiraatiijiyaadka ΔFOSB ee ku urursan daroogada dabadheeraadka ah waxayna sii jirtaa mudo dheer inta lagu jiro mudada.

Shaxda 4

Isbarbardhiga gobollada maskaxda ee muujiya ΔFosB induction ka dib soo-gaadhis joogto ah ee daroogooyinka wakiil ee xadgudubka^a.

·       .a Miiska ma muujinayso heerarka murugada ee ΔFosB ee daawooyinka kala duwan. Eeg Perrotti et al. (2008) macluumaadkan.

·       .b. Saamaynta kookeynta, ethanol iyo cannabinoids ee ku jirta indhaha ΔFosB ee ventral pallidum ayaan wali la baadhin, laakiin indho-furiddan ayaa lagu arkay iyada oo laga jawaabayo methamphetamine (McDaid et al. 2006b).

·       .Calaamadeynta ΔFosB waxaa lagu arkaa dhowr subagro kortex leh, oo ay ku jiraan infralimbic (prefrontal medial) iyo kortex orbitofrontal.

Hadafka ugu weyn ee cilmi baarista mustaqbalka waa in lagu fuliyo daraasad, taas oo la mid ah kuwa kor lagu sharaxay ee soo-saarka nucleus, si loo jaro jimicsiga maskaxda iyo dabeecadaha ee dhexdhexaadinta ΔFosB mid kasta oo ka mid ah gobollada maskaxda. Tani waxay ka dhigan tahay ballanqaad weyn, hase yeeshee waa muhiim in la fahmo saameynta caalamiga ah ee ΔFOSB ee habka mukhadaraadka.

Waxaan dhawaanahan qaadnay tallaabo muhiim ah oo ku saabsan arrintan iyada oo la adeegsanayo wareejinta hiddo-wareerka fayruuska ah si loo muujiyo ficilada ΔFosB ee hoos-u-kaca ah ee kiliyaha hore, oo ah kortex orbitofrontal. Gobalkan waxaa si aad ah loola xiriiriyey mukhaadaraadka, gaar ahaan, in uu gacan ka geysto xasilooni-darrida iyo qasdigeeda taasoo muujinaysa dawlad xad-dhaaf ah (Kalivas & Volkow 2005). Arrin xiiso leh, ka duwan nukleus accumbens meesha kookeeynta self-administration iyo lumiso kakoobiga ayaa keena heerarka la midka ah ee ΔFosB sida hore loo sheegay, waxaan ogaanay in is-maamulidda kookeynta ay sababto dhowr isbuuc ka weyn oo ka soo baxa ΔFosB kortex orbitofrontal, taas oo soo jeedinaysa in jawaabtan ay la xiriiri karto dhinacyada kala duwan ee maamulka daroogada (Winstanley et al. 2007). Kadib waxaanu isticmaalnay baadhitaano jiirka ah iyo go'aan-qaadasho (tus., Tusaale ahaan marxaladaha jawaab celinta ee shan jeer ah iyo dib-u-dhimista-dhimista) si loo go'aamiyo in ΔFosB gudaha koonfureed orbitofrontal-kortex ay wax ka beddesho isbeddelada daroogada ee ku jirta garashada. Waxaan ogaanay in daaweynta cocaine joogtada ah ay soo saartey dulqaad garaadka caqabadaha garashada ee ay keento kookayn daran. Viral-dhexdhexaad ah ee ΔFosB gobolka gudaheeda ayaa saameyn ku yeeshay saameynta cocaine joogtada ah, iyada oo sharraxaad xoog leh ee dhexdhexaad xumo, ΔJunD, waxay ka hortagtaa isbedelka habdhaqanka. Falanqaynta DNA-ga micneheedu waxa uu tilmaamey dhowr farsamood oo midab-kala-soocid ah oo hoosta ka ah isbedelka habdhaqanka, oo ay ku jiraan kookeynta-iyo ΔFOSB-dhexdhexaad ah oo kordhiyey soo-celinta maaddada 'metabotrophic glutamate resume mGluR5 iyo GABA_A qaataha iyo sidoo kale walaxda P (Winstanley et al. 2007). Saamaynta waxyaalahan iyo waxyaabo kale oo badan oo ka mid ah ΔFOSB ayaa waxay u baahan yihiin baaritaan dheeraad ah.

Natiijooyinkaasi waxay tilmaamayaan in ΔFOSB ay ka caawiso dhexdhexaadinta saameynta garashada iyo saameynta cocaine. Isticmaalayaasha oo dareema inay u dulqaadanayaan saameynta xun ee cocaine ayaa waxay u badan tahay inay noqdaan kuwa daroogada kakoobiga ah, halka kuwa hela daroogada khalkhal geliya shaqada ama dugsiga aysan u badneyn inay noqdaan kuwo qabatimay (Shaffer & Eber 2002). Ku tiirsanaanta garashada fahamka ee ay keento kookeenta daran ee dadka ku shaqeeya kokaininka ayaa sidaas darteed u sahlaya ilaalinta maandooriyaha. Sidan, ΔFosB induction in kortex orbitofrontal waxay dhiirigelin kartaa gobolka xad-dhaaf ah, oo la mid ah tallaabooyinka ay ku jiraan soo-saaraha nucleus halkaas oo ΔFosB kor u qaadashada maandooriyaha by kordhinta saameynta dhiirigelinta iyo dhiirigelinta dhiirigelinta daroogada.

8. Farsamooyinka Epigenetic ee ficilka ΔFosB

Ilaa dhowaan, dhammaan daraasadaha ku saabsan qawaaniinta qoraalka ee maskaxda waxay ku tiirsan yihiin cabbiraadda heerarka joogtada ah ee gobolka mRNA. Tusaale ahaan, raadinta hiddo-wadaha 'osFosB gen gen' waxay ku lug leedahay aqoonsiga mRNA ee kor u kaca ama hoos loogu dhigay 'osFosB' ama 'JcJun xad-dhaaf ah, sida horay loo sheegay. Heerka falanqayntaani wuxuu ahaa mid aad waxtar ugu leh aqoonsiga bartilmaameedyada ativeFosB; si kastaba ha noqotee, asal ahaan way ku xaddidan tahay bixinta aragti ku saabsan farsamooyinka aasaasiga ah ee ku lug leh. Taa baddalkeeda, dhammaan daraasadaha farsamooyinka waxay ku tiirsan yihiin tallaabooyinka loo yaqaan 'vitro tallaabooyinka' sida 'osFosB' oo ku xiran isku-darka dhiirrigelinta hidda-wadaha ee baaritaanka isbeddelka gel ama regulationFosB qawaaniinta waxqabadka dhiirrigeliyaha hiddaha ee dhaqanka unugyada. Tani waa mid aan ku qanacsaneyn maxaa yeelay qaababka qawaaniinta qoraalka ayaa muujinaya kala duwanaansho weyn oo ka yimaada nooca unugyada ilaa unugyada unugyada, taas oo ka dhigeysa mid gebi ahaanba aan la ogeyn sida daroogada xadgudubka, ama ΔFosB, ay u xakameyso hiddo-wadaha gaarka ah ee maskaxda ku jirta vivo.

Daraasadaha farsamoyinka farsamada ayaa suurtagal ah, markii ugu horeysay, si aad u riixdo baqshadda hal talaabo oo dheeri ah oo si toos ah u eegta qawaaniinta isdabajoogga ee maskaxda xayawaanka (Tsankova et al. 2007). Taariikh ahaan, ereyga "epigenetics" wuxuu qeexaa hababka ay u adeegsan karto qaababka unugyada leh iyada oo aan la beddelin isbeddelka DNA-da. Waxaan u adeegsaneynaa ereyga si ballaaran si looga dhigo 'qaabaynta qaabdhismeedka gobollada koromosoomyada si loo diiwaangeliyo, calaamad u ah ama loo sii gudbo xaaladaha waxqabadka dhaqdhaqaaqa' (Bird 2007). Marka, waxaan hadda ognahay in waxqabadka hiddo-wadaha ay xakameyso is-beddelka wada-jirka ah (sida acetylation, methylation) ee histones ee agagaaraha hiddo-wadaha iyo qoritaanka noocyada kala duwan ee wada-hawlgalayaasha ama xuddun-wadaha qoraalka. Tijaabinta tallaalka 'Chromatin immunoprecipitation (ChIP)' waxay suurtagal ka dhigeysaa in laga faa'iideysto aqoontaan sii kordheysa ee bayoolajiga chromatin si loo go'aamiyo xaaladda firfircoonida ee hidda-wade ee gobol maskaxeed gaar ah oo xayawaan ah oo lagu daweeyo daroogo xadgudub ah.

Tusaalooyinka sida daraasadaha xeerka chromatin ayaa naga caawin kara in aan fahanno farsamooyinka farsameysan ee farsamada ee kookeynta iyo ΔFOSB la bixiyo Tirada 3. Sida kor ku xusan, ΔFosB waxay u shaqeyn kartaa mid ka mid ah dhaqdhaqaaqa beddelka ama bareeraha taas oo ku xiran hannaanka udubdhexaadka ah. Si loo helo aragti ficilkan ah, waxaan ku falanqeynay xaalad nacas ah oo laba ujeeddo oo loo yaqaano "hinds" oo loogu talagalay ΔFosB, cdk5 oo ay sababtay ΔFosB iyo c-fos oo lagu naqdiyo xajmiga nucleus. Daraasaadaha baaritaanka shukulaatika ee kiniiniga ayaa muujinaya in cocaine-da ay hirgeliso hiddaha cdk5 ee kuyaal gobolka maskaxda iyada oo loo marayo xajinta soo socota: ΔFosB waxay ku xidhan tahay hiddo-wadaha CD-ka ka dibna waxay qoraysaa histone acetyltransferases (HAT, taas oo asetilate dhow dhow) iyo isirrada SWI-SNF; Labada tallaabo waxay sare u qaadayaan tallaalka hidda (Kumar iyo al. 2005; Levine et al. 2005). Cocaine-ka dheer ee cocaine-ka soo-saara histone acetylation iyada oo loo marayo phosphorylation iyo joojinta histone deacetylases (HDAC, oo sida caadiga ah daasetilate iyo jinsiga; Renthal et al. 2007). Marka la barbardhigo, kookeeynku wuxuu cambaareeyaa hindhada c-fososka: marka ΔFosB ku xidhan tahay hidde-yaashaas waxa ay qortaa HDAC iyo suurto galka miyirka methyltransferases (HMT, oo ah methylate near histones) oo sidaas ku xakameysa qoraalka c-fos (Tirada 3; Renthal et al. saxaafadeed). Su'aasha dhexe waa: maxaa go'aaminaya haddii ΔFosB dhaqaajiso ama cadaadiso hidda-wadaha markuu ku xidho dhiirrigeliye hidda-wade?

Jaantuska 3

Farsamooyinka Epigenetic ee ficilka ΔFosB. Sawirku wuxuu muujinayaa cawaaqibo aad u kala duwan marka ΔFosB ay ku xidhan tahay hiddaha uu ku shaqeynayo (sida cdk5) oo ka soo horjeeda cadaadiska (tusaale c-fos). (a) Ka-qaybgalaha cdk5, ΔFosB wuxuu qorayaa calaamadaha HAT iyo SWI-SNF, kaas oo kor u qaadaya hirgelinta hiddaha. Waxaa sidoo kale jira caddayn ah in laga reebo HDAC (eeg qoraalka). (b) Taas bedelkeeda, taageeraha c-fos, ΔFosB wuxuu qortaa HDAC1 iyo sidoo kale malaha HMT-yada oo dhaleeceynaya hidda-gensiga. A, P iyo M oo muujinaya taariikhda asaasiga ah, phosphorylation iyo methylation, siday u kala horreeyaan.

Daraasadan hore ee farsamoyaqaanada daroogada maandooriyaha waa mid xiiso badan, sababtoo ah waxay ballanqaadayaan inay muujiyaan faahfaahin faahfaahsan oo cusub oo ku saabsan hababka molecular ee daroogooyinka xad-gudubka lagu maareeyo muujinta hiddaha ee nucleus accumbens iyo gobollada kale ee maskaxda. Isku-darka DNA-ga ee lagu magacaabo "Chip" oo lagu magacaabo baadhitaano chip ah (meesha wax laga beddelo qaabka loo yaqaan 'chromatin' ama 'transcription factor') ayaa keeni kara aqoonsiga daroogooyinka iyo ΔFOSB bartilmaameedyo heer sare ah oo kalsooni iyo buuxda. Waxaa intaa dheer, hababka epigenetic waa musharaxyo gaar ah oo soo jiidasho leh si ay u dhexdhexaadiyaan mudaharaadyo aad u dheer oo ku salaysan xaaladda gobolka. Sidan oo kale, isbeddelada daroogada iyo isbeddelada ee ΔFOSB ee isbeddelka histone iyo isbeddelada isbedelka epigenetic ayaa bixiya habab ay suuragal tahay in isbeddelada isbeddelka ahi sii socdo muddo dheer ka dib markii daroogada soo-gaadhista joojiso iyo xitaa kadib ΔFosB hoos u dhigto heerarka caadiga ah.

9. Gabagabo

Qaabka soo-saarista ΔFosB ee nukleus soo-gaadhista soo-gaadhista joogtada ah ee abaalmarinta dabiiciga ah, diiqadda ama daroogooyinka xadgudubka ayaa kor u qaadaya mala-awaal xiiso leh oo ku saabsan shaqada caadiga ah ee borotiinka ee gobolka maskaxda. Sida lagu sawiray Tirada 2, waxaa jira heer la mahadiyo oo ah 'osFosB ee' nucleus accumbens xaaladaha caadiga ah. Tani waa mid u gaar ah gobollada murugada leh, maadaama 'osFosB' gebi ahaanba aan la ogaan karin meel kasta oo maskaxda ku jirta. Waxaan ku qiimeyneynaa in heerarka 'osFosB' ee 'nucleus accumbens' ay u taagan yihiin akhrinta ka-soo-baxa shaqsiyeed ee shucuurta shucuurta, labadaba mid togan iyo mid taban, oo isku dhafan muddada dheer ee muddada la siiyay astaamaha ku meel gaarka ah ee borotiinka. Kala duwanaanshaha qayb ahaanta gaarka ah ee unugyada 'osFosB induction' iyadoo lagu abaalmarinayo dhiirrigelinta ka soo horjeedka ayaa si liidata loo fahmay, waxaana loo baahan yahay shaqo dheeri ah si loo caddeeyo cawaaqibka shaqeynaya ee kala soocnaantan. Waxaan sii qiimeyneynaa in sida heerarka sare ee kicinta shucuurta ay u keento moreFosB badan oo ka mid ah nucleus accumbens neurons, shaqada neerfaha ayaa la beddelay si ay u noqdaan kuwo xasaasi u ah dhiirrigelinta abaalmarinta. Sidan oo kale, soo-kicinta ΔFosB waxay dhiirrigelin doontaa xusuusta la xidhiidha abaalmarinta (ie dareenka) iyada oo loo marayo mashruucyo kala duwan oo ka mid ah nukleus accumens. Xaaladaha caadiga ah, soo-saarista heerarka dhexdhexaadka ah ee 'osFosB' iyadoo lagu abaalmarinayo ama lagu dhiirrigelinayo dhiirrigelin waxay la-qabsan doontaa iyadoo la xoojinayo hagaajinta xayawaanka ee caqabadaha deegaanka. Si kastaba ha noqotee, soo-kicinta xad-dhaafka ah ee 'osFosB' ee lagu arko xaaladaha cudurada (tusaale ahaan soo-gaadhista joogtada ah ee daroogada xadgudubka) waxay u horseedi doontaa dareen-celin xad-dhaaf ah oo ku saabsan wareegga 'nucleus accumbens circuitry' oo ugu dambeyntii gacan ka geysata dabeecadaha cudurada (sida daroogada khasabka ah ee loo raadsado iyo qaadashada) ee la xidhiidha daroogada daroogada. Soo-kicinta osFosB ee gobollada kale ee maskaxda ayaa laga yaabaa inay gacan ka geysato dhinacyada kala duwan ee gobolka la qabatimay, sida lagu soo jeediyay natiijooyinkii ugu dambeeyay ee ficilka ΔFosB ee kortex orbitofrontal.

Haddii fikraddani ay sax tahay, waxay sare u qaadeysaa suurtagalnimada xiisaha leh ee ah in heerarka 'osFosB' ee nucleus accumbens ama laga yaabee in gobollada kale ee maskaxda loo isticmaali karo biomarker si loo qiimeeyo xaaladda waxqabadka shaqsiga abaalmarinta wareegga, iyo sidoo kale heerka shaqsi waa 'la qabatimay', labadaba inta lagu gudajiro horumarinta balwadda iyo tartiib tartiib tartiib tartiib tartiib tartiib tartiib tartiib tartiib ah ama daaweyn Isticmaalka ΔFosB oo ah calaamadeeyaha xaalad qabatinka ayaa lagu muujiyey moodooyinka xayawaanka. Xayawaannada qaangaarka ah waxay muujinayaan ΔFOSB badan marka la barbar dhigo xoolaha waayeelka ah, ayadoo la waafaqsaneyn jaahwareerkooda ugu weyn ee qabatinka (Ehrlich et al. 2002). Intaa waxaa dheer, soocista saameynta abaalmarinta nicotine leh GABA_B naqshadeeyaha habboon ee naqotinka xambaarsan ee xayawaanka ku jira ayaa lala xiriirinayaa xannibaadda nikotiinta indhaha ee ΔFosB ee nucleus accumens (Mombereau et al. 2007). Inkasta oo ay tahay wax aad u macquul ah, waxay u muuqataa in molecule PET ligand, oo leh qotodheer waxtar leh oo loogu talagalay ΔFosB, ayaa loo isticmaali karaa in lagu caawiyo baaritaanka xanuunka addictive iyo sidoo kale la socoshada horumarka daaweynta.

Ugu dambeyntiina, ΔFosB lafteeda ama mid ka mid ah hiddo-wadaha fara badan ee ay maamusho - oo lagu caddeeyo qaababka muujinta DNA ama ChIP on assays chip - waxay u taagan yihiin bartilmaameedyo suurtagal ah oo loogu talagalay horumarinta daaweynta aasaasiga ah ee daaweynta maandooriyaha. Waxaan aaminsanahay inay lama huraan tahay in laga fiirsado bartilmaameedyada daroogada ee soojireenka ah (tusaale ahaan soo-saareyaasha neurotransmitter-ka iyo gaadiidleyda) ee loogu talagalay wakiilada daweynta ee balwadda leh. Khariidadaha guud ee hiddo-wadaha ah ee karti u leh tikniyoolajiyadda casriga ah maanta waxay bixiyaan ilo lagu kalsoonaan karo oo ah bartilmaameedyada noocan oo kale ah ee dadaalkeenna loogu jiro in si wanaagsan loo daaweeyo oo ugu dambeyn loo daaweeyo cudurada balwadda leh.

Mahadnaq

Bixinta. Qoraaga qoraa ma jiro wax khilaaf ah oo xiiso u leh diyaarinta dib u eegistaan.

Qoraalada

· Hal wax ku biirinta 17 ee ku saabsan Wadahadalka Kulan Isweydaarsiga 'Cudurka neerfaha ee balwadda: vistas cusub'.

· © 2008 Ururka Boqortooyada

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