Clin Psychopharmacol Neurosci. 2012 Dec; 10 (3): 136-43. Doi: 10.9758 / cpn.2012.10.3.136. Epub 2012 Dec 20.
mohloli o moholo
Lekala la Fishberg la Neuroscience le Friedman Brain Institute, Mount Sinai School of Medicine, New York, USA.
inahaneloang
Taolo ea polelo ea liphatsa tsa lefutso e nkuoa e le mokhoa o hlakileng oa tšebeliso ea lithethefatsi ka lebaka la ts'ebeliso e mpe ea boits'oaro bo hlalosang boemo ba tlhekefetso. Mabaka a mangata a ho ngola, liprotheine tse tsamaeang le likarolo tsa taolo ea liphatsa tse itseng tsa lefutso le litekanyetso tsa taolo ea polelo ea tsona, li bile le tšusumetso ts'ebetsong ea bokhoba lilemong tse leshome tse fetileng kapa tse peli. Mona re lekola bopaki bo ntseng bo hola bakeng sa karolo e phethoang ke lintlha tse 'maloa tse hlahelletseng tsa mongolo, ho kenyelletsa protheine ea lelapa la Fos (ΔFosB), karolo ea karabelo ea cAMP e kopanyang protheine (CREB), le factor factor kappa B (NF VerB), hara ba bang ba bangata, tlatsong ea lithethefatsi. . Joalokaha ho tla bonoa, ntlha ka 'ngoe e bontša melaoana e fapaneng haholo ka lithethefatsi tsa tlhekefetso kahare ho potoloho ea moputso oa boko,' me e le likarolo tse fapaneng tsa phenotype ea lithethefatsi. Boiteko bo teng hona joale bo reretsoe ho utloisisa mefuta ea mefuta ea lipolanete tse hlahisang lintlha tsena tse sebetsang le mekhoa e tlatselletsang ea limolek'hule tse amehang. Mosebetsi ona o ts'episa ho senola leseli le lecha molemong oa ts'ebetso ea molek'hule, e tla kenya letsoho ho ntlafatseng liteko tsa tlhahlobo le litlhare tsa mafu a lemalloang.
SELELEKELA
Boithuto ba mekhoa ea ho lemalla ho sebelisa litlatsetso bo thehiloe khopolong ea hore molaoana oa tšebeliso ea liphatsa tsa lefutso ke mokhoa o mong oa bohlokoa oo ho pepesehela ts'ebeliso ea tlhekefetso ho ka bakang liphetoho tse sa feleng kelellong e ka tlisoang ke tlhekefetso ea boitšoaro e hlalosang boemo ba bokhoba.1,2) Taba-kholo ea khopolo-taba ena ke hore liphetoho li kenngoang ts'ebetsong ea methapo e mengata ea methapo ea kutlo, le ho morphology ea mefuta e meng ea lisele tsa boko bokong, tsamaiso ea lithethefatsi tse sa feleng e kenella ka karolo ka phetoho ea polelo ea gene.
Ho joalo, ha se lipolanete tsohle tse susumetsoang ke lithethefatsi le boits'oaro ba lithethefatsi tse tsamaisanang le maemo a mofuta oa gene, joalo ka ha re tseba liphallelo tsa bohlokoa tsa liphetoho tsa phetolelo le tsa posttranslational le thekiso ea liprotheine tsa liketsahalo tse amanang le bokhoba. Ka lehlakoreng le leng, taolo ea polelo ea liphatsa tsa lefutso ke mokhoa o le mong oa mantlha 'me ho ka etsahala hore ebe ea bohlokoa haholo mesebetsing e meng ea bophelo bohle e tšoereng bokhoba. Ha e le hantle, melaoana ea ho ngola e fana ka thempleite e holim 'a eona e sebelisoang ke mekhoa ena e meng.
Ho sebetsa lilemong tse ~ 15 tse fetileng ho fane ka bopaki bo ntseng bo eketseha ba karolo ea ponahalo ea liphatsa tsa lefutso bokhobeng ba lithethefatsi, joalo ka lintlha tse 'maloa tse ngotsoeng - liprotheine tse tlamang likarabo tse ikhethileng libakeng tsa liphatlalatso tsa liphatsa tsa lefutso le ho laola polelo ea liphatsa tsa lefutso. ts'ebetsong ea lithethefatsi. Ho latela morero ona, o bonts'itsoeng ho Feie. 1, lithethefatsi tsa tlhekefetso, ka liketso tsa bona tsa pele ho synapse, li hlahisa liphetoho ka har'a li-neuron tse bonts'ang khubu le ho laola ts'ebetso ea lintlha tse ngata tsa mongolo le mefuta e meng e mengata ea liprotheine tse tataisang tse ngotsoeng.3) A Liphetoho tsena tsa nyutlelie butle-butle li ntse li haella ka ho pepesehela lithethefatsi khafetsa le liphetoho tse tsitsitseng polelong ea mefuta e ikhethileng eo le eona e tlatsetsang phetohong e sa feleng ea ts'ebetso ea neural e bolokang boemo ba ho lemalla.1,4)
Tlhahlobo ena e shebana le lintlha tse 'maloa tsa sengoloa, tse bonts'itsoeng li bapala karolo ea bohlokoa bokhobeng. Re tsepamisa maikutlo ho feta linthong tse laoloang ke lithethefatsi tse ka har'a potoloho ea moputso, likarolo tsa boko tse tloaetseng ho laola likarabo tsa motho meputsong ea tlhaho (mohlala, lijo, thobalano, tšebelisano 'moho), empa li senngoa ke ho pepeseha ha lithethefatsi ho sa foleng ho baka ho lemalla. Tsamaiso ena ea moputso oa boko e kenyelletsa li-neuron tsa dopaminergic sebakeng sa ventral tegmental sa midbrain le libaka tse 'maloa tsa limbic forebrain tseo ba sa li rateng, ho kenyeletsoa nucleus accumbens (ventral striatum), prefrontal cortex, amygdala le hippocampus, hara tse ling. Joalokaha ho tla bonoa, boholo ba lipatlisiso tse mabapi le mekhoa ea phetisetso ea ho lemalla ho fihlela joale li shebile li-nucleus accumbens.
DFFB
ΔFosB e kentsoe ke FosB gene mme o arolelana homology le lintlha tse ling tsa tlhahiso ea malapa tsa Fos, tse kenyelletsang c-Fos, FosB, Fra1, le Fra2.5) Liprotheine tsena tsa malapa tsa Fos heterodimerize le liprotheine tsa lelapa tsa Jun (c-Jun, JunB, kapa JunD) ho theha lintlha tse sebetsang tsa protheine-1 (AP1) e kopanyang libaka tsa AP1 tse teng lipapatsong tsa mefuta e meng ho laola phetisetso ea tsona. Liprotheine tsena tsa malapa tsa Fos li kenella ka potlako le ka nako e telele libakeng tse itseng tsa boko kamora ho tsamaisoa ha lithethefatsi tse ngata tsa tlhekefetso (Feie. 2).2) Likarabo tsena li bonoa ka mokhoa o hlahelletseng ho li-nucleus accumbens le dorsal striatum, empa li boetse li bonoa libakeng tse ling tse 'maloa tsa boko.6) Li-protein tsena tsa malapa tsa Fos, leha ho le joalo, ha li na botsitso ebile li khutlela maemong a basel ka mor'a lihora tse ngata tsa tsamaiso ea lithethefatsi.
Likarabo tse fapaneng haholo li bonoa kamora taolo e sa feleng ea lithethefatsi tsa tlhekefetso (Feie. 2). Li-isoforms tse fetotsoeng biochemically tsa ΔFosB (Mr 35-37 kD) e bokellana kahare ho likarolo tse tšoanang tsa boko kamora ho pepesetsoa lithethefatsi khafetsa, athe litho tsohle tsa lelapa la Fos li bonts'a mamello (ke hore, ho kenella ka tlase ho bapisoa le tlhahiso ea pele ea lithethefatsi).7-9) Ho bokella ho joalo ha ΔFosB ho hlokometsoe hoo e batlang e le lithethefatsi tsohle tsa tlhekefetso, leha lithethefatsi tse fapaneng li fapana ka tsela e lekanang ea ho kenyelletsa e bonoang ho li-nucleus accumbens core vs. shell, dorsal striatum, le likarolo tse ling tsa boko.2,6) Bonyane bakeng sa lithethefatsi tse ling tsa tlhekefetso, ho qalisoa ha ΔFosB ho bonahala ho khetha seteishene se nang le dynorphin sa li-spiny neurons tse mahareng - tse hlahisang haholo li-D1 dopamine receptors - libakeng tsa striatal. 35-37 kD isoforms ea ΔFosB e fokotseha haholo-holo le JunD ho theha moaho o sebetsang le o tšoarellang oa AP-1 kahare ho libaka tsena tsa boko,7,10) leha ho na le bopaki bo bong bo tsoang a vitro lithuto tse ka angoang ke ΔFosB11) Tlhahiso ea lithethefatsi ea ΔFosB bokong ba li-nucleus e bonahala e le karabelo mefuteng ea bongaka ea lithethefatsi ka bobeli hape ha e amanang le tšebeliso ea lithethefatsi tse sa lekanyetsoang, kaha liphoofolo tse itšelang k'hok'heine kapa li amohela ente ea lithethefatsi tse kopaneng li bonts'a ho kenella ka mokhoa o ts'oanang oa ntho ena e ngotsoeng sebakeng sena sa boko.6) Ka lehlakoreng le leng, ΔFosB induction libakeng tse ling, ho etsa mohlala, orbitofrontal cortex, e hloka taolo ea lithethefatsi ea nakoana.12)
Li-isoforms tsa 35-37 kD ΔFosB li ipokella ka ho pepeseha ha lithethefatsi ka nako e telele ka lebaka la bophelo ba bona bo bolelele bo bolelele ba bophelo.7-13) Ka lebaka la botsitso ba eona, protheine ea ΔFosB e phehella li-neuron bonyane libeke tse 'maloa ka mor'a ho khaotsa ho pepesetsoa lithethefatsi. Joale rea tseba hore botsitso bona bo hlahisoa ke lintlha tse peli: 1) ho se be teng hoa ΔFosB ea libaka tse peli tse senyehileng, tse teng C-terminus ea bolelele bo felletseng ba FosB le liprotheine tsohle tsa malapa tsa Fos mme li shebane le liprotheine tseo hore li senyehe kapele, 'me 2) phosphorylation ea ΔFosB nakong ea N-terminus ea eona ke casein kinase 2 mohlomong le li-protein tse ling tsa protheine.14-16) Ho tsitsa ha ofFosB isoforms ho fana ka mokhoa o mocha oa limolek'hule oo liphetoho tse bakoang ke lithethefatsi liphatseng tsa lefutso li ka tsoelang pele ho sa tsotelehe nako e telele ea ho tlohela lithethefatsi. Ka hona, re kopile hore ΔFosB e sebetse e le "molek'hule" e ts'ehetsang e thusang ho qala le ho boloka boemo ba bokhoba.1,2)
Karolo ea ho lemalla
Tlhahiso ea karolo ea ΔFosB ts'ebetsong ea lithethefatsi tsa lithethefatsi e tsoa haholo ho tsoa thutong ea litoeba tsa bitransgenic moo ΔFosB e ka qobelloang ka mokhoa o ikhethileng ka har'a li-nucleus tse bokellaneng le dorsal striatum ea liphoofolo tse kholo.17) Bohlokoa ke hore litoeba tsena li sebetsa hantle haholo ho li-neuronphin tse nang le "spiny neurons" tse phahameng moo ho lumeloang hore lithethefatsi li hlohlelletsa protheine. IceFosB-overexpressing litoeba li bontsa karabelo ea locomotor ho cocaine ka mor'a taolo e mpe le e sa foleng.17) Li bonts'a kutloisiso e ntlafalitsoeng ea litlamorao tse khahlisang tsa koae le morphine maemong a teng a maemo,17-19) le ho itšireletsa koae e fokolang, le ho sebetsa ka thata ho feta k'hok'heine, ho feta batho ba sa tsubang ho feta ba sa sebetseng haholo.20) Ho ekelletsa moo, ΔFosB overexpression ho li-nucleus e bokella kholo ea nts'etsopele ea 'mele ea opiate mme e khothaletsa mamello ea opiate analgesic.19) Ka lehlakoreng le leng, litoeba tsa iceFosB tse hlalosoang li tloaelehile libakeng tse ling tsa boits'oaro, ho kenyelletsa thuto ea sejoale-leseling joalokaha ho lekiloe mohloling oa metsi oa Morris.17) Ts'ebetso e ikhethileng ea osFosB overexpression ho li-bokellase tsa nucleus, ka ts'ebeliso ea phetisetso ea bongaka-virated, e hlahisitse data e lekanang.19)
Ho fapana le moo, ho lebisa polelo ea ΔFosB ho li-neuron tse tšetsoeng ka har'a sepepahlin tse kenang ka har'a nyutlelie le li-dorsal striatum (tse hlalosang haholo D2 dopamine receptors) ka mela e fapaneng ea litoeba tsa bitransgenic li hloleha ho bonts'a boholo ba mekhoa ena ea phenotypes ea boits'oaro.19) Ho fapana le khatello e fetelletseng ea ΔFosB, khatello e fetelletseng ea protheine ea Mutant Jun (ΔcJun kapa ΔJunD) - e sebetsang e le mohanyetsi ea matla ea hloahloa oa phetisetso e fetisitsoeng ea AP1 - ka ts'ebeliso ea litoeba tsa bitransgenic kapa phetisetso ea liphatsa tsa lefutso tse nang le vaerase, e hlahisa litlamorao tse fapaneng tsa boits'oaro.18,19,21) Lintlha tsena li bonts'a hore ho kenyelletsoa ha ΔFosB ka li-dynorphin tse nang le li-spiny neurons tse mahareng tsa li-nucleus accumbens ho eketsa kutloisiso ea phoofolo k'hok'heine le lithethefatsi tse ling tsa tlhekefetso, mme e kanna ea emela mochini oa ts'ehetso ea nako e telele ho lithethefatsi.
Karolo e bapaloang ke ΔFosB induction libakeng tse ling tsa boko ha e utloisisehe hantle. Boithuto ba morao-rao bo bonts'itse hore ΔFosB induction in orbitofrontal cortex e lumellana le mamello ho tse ling tsa litlamorao tse utloisang bohloko tsa ho pepesetsoa hoa koae e mpe, e ka sebelisang ho phahamisa ts'ebeliso ea lithethefatsi.12,22)
GenesFosB Target gen
Kaha ΔFosB ke ntho e ngotsoeng, ho ka etsahala hore e hlahise mofuta ona o khahlisang oa boits'oaro ba li-nucleus tse bokellanang ka ho matlafatsa kapa ho hatella polelo ea liphatsa tse ling tsa lefutso. Re sebelisa litoeba tsa rona tse sa hlakoheng, tse bitransgenic tse overexpress ΔFosB kapa eona negativecJun e mpe ka ho fetisisa, le ho sekaseka polelo ea liphatsa tsa lefutso ho li-chips tsa Affymetrix, re bonts'itse seo - ka har'a li-nucleus accumbens Ka vivo -ΔFosB e sebetsa haholoholo e le mohatelli ea hatisang, ha e ntse e sebetsa e le mohatelli bakeng sa mofuta o monyane oa mefuta.18) Phuputso ena e boetse e bonts'a karolo e ka sehloohong ea ΔFosB ho loants'eng litlamorao tsa cocaine: ΔFosB e kenella haufi le kotara ea mefuta eohle e susumetsoang ke li-cigineine tse sa sebetseng.
Mokhoa ona o pharalletseng oa genome, hammoho le lipatlisiso tsa liphatsa tsa lefutso tse 'maloa ka ho tšoana, li thehile mefuta e' maloa ea sepheo ea ΔFosB e kenyang tšebetsong ea eona ea boitšoaro. Mofuta o le mong oa mokhethoa ke GluA2, e leng AMPA glutamate receptor subunit, e kenyellelitsoeng ho li-nucleus accumbens ke ΔFosB.17) Kaha liteishene tsa GluA2 tse nang le AMPA li na le ts'ebetso e tlase ka ho fetisisa ha li bapisoa le liteishene tsa AMPA tse senang subunit ena, upoculation ea cocaine- le ΔFosB-mediated ea GluA2 ka li-nucleus accumbens e ka ikarabella, bonyane ka karolo, bakeng sa likarabelo tse fokotsitsoeng tsa glutamatergic tse bonoang ho methapo ena ka mor'a ho pepesetsoa lithethefatsi ka nako e telele.23)
Mofuta o mong o lebisitsoeng ho "ΔFosB" ka li-nucleus accumbens ke opioid peptide, dynorphin. Hopola hore ΔFosB e bonahala e susumetsoa ke lithethefatsi tsa tlhekefetso ka ho khetheha liseleng tse hlahisang dynorphin sebakeng sena sa boko. Lithethefatsi tsa tlhekefetso li na le litlamorao tse totobatsang polelo ea dynorphin, ka keketseho kapa ea fokotseha ho bonahala ho latela maemo a kalafo a sebelisitsoeng. Re bontšitse hore ho kenella ha polelo ea ΔFosB e qobellang polelo ea dynorphin gene ka har'a li-nucleus accumbens.19) Dynorphin ho nahanoa hore e kenya tšebetsong li-ito opioid receptors sebakeng sa ventral tegment (VTA) dopamine neurons le thibelo ea phetisetso ea dopaminergic mme ka tsela eo e nyenyefatse mekhoa ea meputso.24,25) Kahoo, khatello ea ΔFosB ea polelo ea dynorphin e ka kenya letsoho ntlafatsong ea mekhoa ea moputso e lumellanang le ntlha ena ea sengoloa. Hona joale ho na le bopaki bo tobileng bo tšehetsang ho nka karolo ha khatello ea liphatsa tsa lefutso tsa dynorphin ho mofuta oa boitšoaro oa osBFosB.19)
Ho ntse ho khethollotsoe mefuta e meng ea liphooko. ΔFosB e hatella c-Fos liphatsa tsa lefutso tse thusang ho theha phetoho ea limolek'hule - ho tloha ho kenngoe ha liprotheine tse 'maloa tsa lelapa la Fos kamora ho pepeseha hampe ha lithethefatsi ho phello e kholo ea ΔFosB kamora ho pepeseha ha lithethefatsi tse sa foleng - tse boletsoeng pejana.9) Ho fapana le moo, cyclin-wate kinase-5 (Cdk5) e kenella ho li-nucleus bokellwang ke cocaine e sa foleng, phello eo re e bonts'itseng e kopantsoe ka ΔFosB.18,21,26) Cdk5 ke sepheo sa bohlokoa sa ΔFosB kaha polelo ea eona e hokahane ka kotloloho le keketseho ea khatello ea methapo ea mokokotlo oa methapo ea methapo ea methapo ea methapo e kenang bohareng.27,28) bokong ba li-nucleus bo amanang le tsamaiso ea koae e sa foleng.29,30) Kannete, ho kenella ha ΔFosB ho bontšitsoe haufinyane haholo hore ho hlokahala ebile ho lekane bakeng sa kholo ea mokokotlo oa cocaine e hlahisitsoeng ke cendine.31)
Haufinyane tjena, re sebelisitse chromatin immunoprecipitation (ChIP) e lateloang ke papatso ea papatso (ChIP-chip) kapa ka tatellano e tebileng (ChIP-seq) ho tsebahatsa mefuta ea sepheo sa ΔFosB.32) Lithuto tsena, hammoho le li-arrays tsa polelo tsa DNA tse boletsoeng pejana, li fana ka lenane le enneng la liphatsa tsa lefutso tse ling tse ka hlaseloang - ka kotloloho kapa ka tsela e sa tobang - ke ΔFosB. Har'a liphatsa tsena tsa lefutso ho na le li-receptor tsa neurotransmitter tse eketsehileng, liprotheine tse amehang ts'ebetsong ea pre-and postynaptic, mefuta e mengata ea li-ion le liprotheine tse tšoaeang li-intracellular, liprotheine tse laolang cytoskeleton ea neuronal le kholo ea lisele, le liprotheine tse ngata tse laolang sebopeho sa chromatin.18,32) Ho hlokahala mosebetsi o eketsehileng ho netefatsa liprotheine tsena tse ngata e le ea 'nete sepheo sa cocaine e sebelisang ΔFosB le ho theha karolo e nepahetseng eo protheine e 'ngoe le e' ngoe e e phethang ho kopanyeng likarolo tse rarahaneng tsa boiketsetso le boits'oaro ba ketso ea koae.
TREEPO
Karolo ea karabelo ea cyclic AMP e tlamang protheine (CREB) ke e 'ngoe ea lintlha tse ithutoang haholo tsa bongoli ho tsoa ho neuroscience mme e bile le tšusumetso likarolong tse fapaneng tsa polasetiki ea neural.33) E theha li-Homodimers tse ka tlamang ho liphatsa tsa lefutso ho li-cyclic AMP dikarolo tsa karabo (CREs), empa haholo-holo li kenya ts'ebetso phetiso kamora hore e fuoe phosphorylated ho Ser133 (ke efe kapa efe ea liprotheine tse 'maloa tsa protheine), e lumellang ho haptjoa ha protheine e tlamang CREB (CBP) ka nako eo e khothalletsa mongolo. Mokhoa oo ts'ebetso ea CREB e hatellang e hlahisang liphatsa tsa lefutso tse itseng o sa o utloisise hantle.
Li-psychostimulants ka bobeli (k'hok'heine le amphetamine) le li-opiate li eketsa ts'ebetso ea CREB, hantle ebile e sa foleng - joalo ka ha e lekantsoe ke phospho-CREB (pCREB) kapa moqolotsi oa litaba oa liphatsa tsa lefutso litoeba tsa CRE-LacZ - libakeng tse ngata tsa boko, ho kenyeletsoa nucleus accumbens le dorsal striatum .34-36) Nako ea ts'ebetso ena e fapana haholo le e bonts'itsoeng ke ΔFosB. Joalokaha ho bontšoa ka Feie. 2, Ts'ebetso ea CREB e sebetsa butle ha e arabela ts'ebetso ea taolo e mpe ea lithethefatsi 'me e khutlela maemong a tloaelehileng kamora letsatsi kapa a mabeli kamora ho tlohela. Ntle le moo, ts'ebetso ea CREB e etsahala dynorphin le enkephalin subtypes ea methapo ea kutlo e bohareng.34) Ho fapana le cocaine le opiates, CREB e bonts'a likarabo tse thata le tse fapaneng litlhare tse ling tsa tlhekefetso.4)
Liteko tse amanang le khatello e fetelletseng ea "CREB" kapa "mutant" e mpe ka ho fetisisa ho litoeba tsa bitransgenic kapa ka li-vector tsa vaerase li bonts'itse hore ts'ebetso ea CREB - ka ho fapana haholo le ΔFosB - ho li-nucleus accumbens e fokotsa litlamorao tse ntle tsa cocaine le li-opiate joalo ka ha li hlahlojoa maemong a boemo litlhahlobo.37,38) Leha ho le joalo, ts'ebetso ea CREB, joalo ka ΔFosB ho kenya letsoho, e khothaletsa tsamaiso ea lithethefatsi.39) Habohlokoa, litlamorao tse nang le CREB e hlahelletseng li netefalitsoe ka ts'ebetso e sa utloahaleng ea ts'ebetso ea setho sa CREB.39-41) Hoa thahasellisa hore lintlha tsena ka bobeli li tsamaisa tšebeliso e mpe ea lithethefatsi; mohlomong ΔFosB e etsa joalo ka khothaletso e ntle, athe CREB e kenya ts'ebetso ena ts'ebetsong e mpe. Monyetla oa ho qetela o lumellana le bopaki bo bongata ba hore ts'ebetso ea CREB sebakeng sena sa boko e baka boemo bo bobe ba maikutlo.34,42)
Ts'ebetso ea CREB e hokahane ka kotloloho le ts'ebetso e sebetsang ea li-neuron tsa li-spiny neuron tse bohareng. CREB overexpression e eketseha, athe CREB e matla-ngata e ea fokotseha, thabo ea motlakase ea li-neuron tse bohareng tsa kati.43) Phapang e ka bang teng lipakeng tsa dynorphin le enkephalin neuron ha e e-so ho hlahlojoe. Tlhokomeliso ea hore o-na le khatello e matla ea bongaka ea K+ setsi sa subunit se bokellaneng ba methapo ea methapo, se fokotsang thabo ea methapo ea methapo, se ntlafatsa likarabo tsa locomotor ho koae se fana ka maikutlo a hore CREB e sebetsa e le karohano ea maikutlo a boits'oaro ho cocaine ka ho phaellisa thabo ea neuron.43)
Lithethefatsi tsa tlhekefetso li kenya CREB likarolong tse 'maloa tsa boko ho feta li-nucleus. Mohlala o mong ke sebaka sa ho putlama ha 'mele, moo ho nang le ts'ebetso ea "cocaine" kapa "opiates" e sa sebetseng kamehla. Phello ena e bonahala e khothaletsa kapa ho arabela likarabo tse khotsofatsang tsa lithethefatsi tsa tlhekefetso ho ipapisitsoe le subregion ea sebaka se kenang se oelang ka hare.
Ho fumanoe mefuta e mengata ea sepheo ea CREB, ka mekhoa e bulehileng le e haufi le baemeli, e arolelanang litlamorao ho tsena le tse ling ho li-neuron tse bokellanang tsa spiny neuron le sephetho sa CREB sa boitšoaro.18,32,36) Mehlala e hlahelletseng e kenyelletsa "opioid peptide dynorphin"37) e fepa ka morao mme e hatella dopaminergic signing ho li-bokono tsa nucleus joalo ka ha ho boletsoe pejana.24,25) Ho boetse ho na le tšusumetso e tsoang ho li-subunits tse ling tsa glutamate receptor, joalo ka GluA1 AMPA subunit le GluN2B NMDA subunit, hammoho le K+ le Na+ li-subion tsa "ion" li ka lebelloa ho laola maqhubu a li-cellus.43,44) BDNF e ntse e le mofuta o mong oa sepheo bakeng sa CREB ho li-nucleus accumbens, mme le eona e bohlokoa molemong oa ho buella mofuta oa boitšoaro oa CREB.35) K'hamphani ea CREB e boetse e bontšitsoe hore e kenya letsoho ho kenyeng k'hok'heine ea li-dendritic spines ho li-nucleus accumbens medium spiny neurons.45)
CREB ke e 'ngoe ea liprotheine tse amanang le eona tse tlamang li-CRE le ho laola ho fetoloa ha liphatsa tsa lefutso. Lihlahisoa tse 'maloa tsa mofuta oa cyclic AMP reaction element modulator (CREM) li laola sengoloa sa CRE-mediated. Lihlahisoa tse ling (mohlala, CREM) ke li-activator tsa phetolelo, athe tse ling (mohlala, ICER kapa khatello e sa sebetseng ea cyclic AMP) li sebetsa joalo ka bahanyetsi ba hloahloa ba sa feleng. Ntle le moo, lintlha tse 'maloa tse sebetsang tsa sengoloa (ATFs) li ka susumetsa poleloana ea liphatsa tsa lefutso ka ho tlamahanya le libaka tsa CRE. Liphuputso tsa morao-rao li amme lintlha tsena tse fapaneng tsa sengoloa likarabong tsa lithethefatsi. Amphetamine e hlohlelletsa polelo ea ICER ho li-nucleus accumbens, le khatello e fetelletseng ea ICER sebakeng sena, ka ts'ebeliso ea phetisetso ea liphatsa tsa lefutso e tšoaetsang vaerase, e eketsa kutloisiso ea phoofolo litlamorao tsa moriana.46) Sena se lumellana le liphumano tse boletsoeng ka holimo hore ho fetella hoa maikutlo ho matla ka li-CREB tse fetohileng kapa ho putlama ha CREB ho hlahisa litholoana tse tšoanang. Amphetamine e boetse e kenella ho ATF2, ATF3, le ATF4 ho li-nucleus accumbens, ha ho se na phello e bonoang bakeng sa ATF1 kapa CREM.47) ATF2 overexpression sebakeng sena, joalo ka ICER, e eketsa likarabo tsa boits'oaro ho amphetamine, ha ATF3 kapa ATF4 overexpression e na le litlamorao tse fapaneng. Hanyane hanyane ho tsebahala ka mefuta ea sepheo ea liprotheine tsena tsa malapa tsa CREB, tataiso ea bohlokoa bakeng sa lipatlisiso tsa nako e tlang.
NFκB
Nuclear factor-κB (NF VerB), ntho e qalang e hlahisoang ke ts'usumetso e fapaneng ka potlako, e ithutoa hamolemo bakeng sa karolo ea eona ho tsibaneng le likarabo tsa 'mele tsa ho itšireletsa mafung. E sa tsoa bontšoa e le ea bohlokoa ho synaptic plastikiity le memory.48) NF VerB e kenyellelitsoe ka har'a li-nucleus tse bokelloang ke tsamaiso ea khafetsa ea koae,49,50) moo ho hlokehang bakeng sa ho kenoa ha k'hok'heine ea li-dendritic spines tsa nucleus accumbens medium spiny neurons. Ho kenella joalo ha NF VerB ho kenya letsoho ho matlafatseng litlamorao tse khahlisang tsa sethethefatsi.50) Morero o moholo oa lipatlisiso tsa morao-rao ke ho khetholla mefuta eo sepheo sa eona e leng Netefatso e bakang polasetiki ena le boits'oaro.
Ho khahlisang, ts'ebetso ea koae ea NFoB ea cocaine e kopantsoe le ΔFosB: ΔFosB oxpxpression ho li-nucleus e kenella ho NF VerB, ha ts'ebetso e mpe ea "ΔcJun" e le 'ngoe e mpe e thibela thibelo ea koae.21,49) Taolo ea NFκB ke ΔFosB e bonts'a li-Cascade tse rarahaneng tsa ho kenya letsoho tse amanang le ts'ebeliso ea lithethefatsi. Hape, NF VerB e bile le tšusumetso ho tse ling tsa litlamorao tsa methapo ea methamphetamine libakeng tsa striatal.51) Karolo ea NF VerB ho li-spiny neuron spingeneis tsa spiny bo sa tsoa phatlalatsoa ho fana ka mefuta ea khatello ea maikutlo le khatello ea maikutlo,52) ho fumanwa ha bohlokwa ka ho hlaka botle ba ho tepella maikutlo le bokhoba, le ketsahalo e ithutoang hantle ea khatello ea maikutlo e bakiloeng ke ts'ebeliso e mpe ea lithethefatsi.
MEF2
Myocyte e ntlafatsang factor-2 (MEF2) e ile ea fumanoa bakeng sa karolo ea eona ea taolo ea pelo ea pelo. Ka mokhoa o ikhethileng, MEF2 e kentsoe tšebetsong ea boko.53) Li-isoforms tse ngata tsa MEF2 li hlahisoa ka bokong, ho kenyelletsa le li-neuron tse bokellanang tsa spiny neurons, moo li thehang homo- le heterodimers tse ka hlahisang kapa tsa hatisa phetiso ea mofuta oa liphatsa tsa lefutso ho latela mofuta oa liprotheine tseo ba li hapang. Mosebetsi oa morao-rao o bontša mochine o ka khonehang oo ka oona cocaine e sa feleng e hatelletsang ts'ebetso ea MEF2 ho nucleus e kenang karolong e itseng ka thibelo e itšetlehileng ea D1 receptor-cAMP e sebelisang calcineurin, Ca2+-dpostosterone e itšetlehileng ka protheine.28) Taolo ea koae ea Cdk5, eo hape e leng sepheo sa koae le ΔFosB joalo ka ha ho boletsoe pejana, le eona e ka ameha. Phokotso ena ea ts'ebetso ea MEF2 e hlokahala bakeng sa ho koaheloa ka koae ea methapo ea methapo ho dendritic spines. Morero oa bohlokoa oa mosebetsi oa hona joale ke ho khetholla mefuta ea sepheo ka MEF2 e hlahisa phello ena.
MAHLOMOLA MAHALA
Lintlha tse hatisitsoeng tse tšohliloeng ka holimo ke tse 'maloa feela tsa tse ngata tse ithutoang ho theosa le lilemo mefuteng ea ho lemalla. Tse ling tse amehang ho lemalloang li kenyelletsa glucocorticoid receptor, li-nucleus li bokella taba ea mongolo oa 1 (NAC1), lintlha tsa karabelo ea kholo ea pele (EGRs), le li-transducers le li-activator tsa transcript.1,2) Joalo ka mohlala o le mong, "glucocorticoid receptor" e hlokahala li-neuron tsa dopaminocepts bakeng sa ho batla koae.54) Morero oa lipatlisiso tsa nako e tlang ke ho fumana pono e felletseng ea lintlha tse ngotsoeng tse hlahisitsoeng ho li-nucleus bokellanang le likarolo tse ling tsa moputso oa boko ho arabela ho pepesetsoa hoa lithethefatsi tsa tlhekefetso le ho hlalosa mefuta ea mefuta eo ba e susumetsang ho kenya letsoho molemong oa boitšoaro. ya bokhoba.
Morero o mong o moholo oa lipatlisiso tsa nako e tlang ke ho hlakisa mehato e nepahetseng eo lintlha tsena tse fapaneng tsa mongolo li laolang mefuta ea tsona e hlotsoeng. Kahoo, joale rea tseba hore lintlha tse hatisang li laola polelo ea liphatsa tsa lefutso ka ho thaotha mefuta ea tsona e hlophisitsoeng ea li-pro-activator kapa liprotheine tse kopanetsanang tseo ka tsona li laolang sebopeho sa chromatin ho potoloha liphatsa tsa lefutso le ho hira semmuso sa RNA polymerase II e thusang. sengoloa.4) Mohlala, lipatlisiso tsa morao-rao li bonts'itse hore bokhoni ba ΔFosB ho susumetsa mofuta oa cdk5 bo hlaha ka konsarete le ho hloa protheine ea histone acetyltransferase le liprotheine tse amanang le chromatin tse amanang le mofuta oa mofuta.55) Ho fapana le moo, bokhoni ba ΔFosB ba ho hatella mofuta oa c-Fos bo etsahala moketjana oa ho bokelloa ha histone deacetylase le liprotheine tse ling tse ngata tse hatellang tse kang histone methyltransferase (Feie. 3).2,9,31) Ka lebaka la hore liprotheine tse makholo tsa chromatin e laolehang li ka boela tsa ngolisoa ho mofuta oa tumellano le ts'ebetso ea eona kapa ts'ebetso ea eona, ts'ebetso ena ke temana ea leqhubu la tlhahisoleseling e ngata e hlokang ho sibolloa lilemong tse tlang.
Ha tsoelo-pele e ntse e etsoa ho khetholla mefuta ea sepheo bakeng sa lintlha tse ngolisitsoeng ke lithethefatsi, tlhahisoleseling lena le tla fana ka template e felletseng e phethahetseng e ka sebelisoang ho tataisa boiteko ba ho fumana lithethefatsi. Re tšepa hore kalafo e ncha ea meriana e tla ntlafatsoa ho latela tsoelo-pele ena e matla kutloisisong ea rona ea mekhoa ea bongaka e tlasa tahi.