Zvinyorwa zveTranscriptional zvekusvuta: basa reAFosB (2008)

ZVIMBVUNZO: Eric Nestler anoisa yakawanda yeizhinji nezve DeltaFosB uye kupindwa muropa. (Zvimwe kubvira zvawanikwa.) Zvichitaurwa zviri nyore, DeltaFosB inokwira mudunhu remubairo mukupindura kusingaperi kwemishonga yekushandisa zvisina kufanira uye mimwe mibayiro yechisikigo. Chinangwa chayo chekushanduka-shanduka ndechekuti iwe uwane panguva yekuwana kwakanaka (chikafu uye bonde) - ndiko kuti, kurudzira nzvimbo yemubairo. Nekudaro, akanyanya-akajairwa mavhezheni echisikigo mibairo anogona kutungamira mukuwedzeredza-kudyiwa uye kuunganidzwa kweDeltaFosB… uye huropi shanduko dzinokonzeresa zvakawanda zvishuwo uye zvimwe kubheja. Sezvineiwo, vechidiki vanoburitsa yakanyanya DeltaFosB kupfuura zvinoita vanhu vakuru, chinova chimwe chikonzero nei vari mukana wekupindwa muropa.

YOKUDZIDZA KUNYAYA

Eric J Nestler*

10.1098 / rstb.2008.0067 Phil. Trans. R. Soc. B 12 October 2008 vol. 363 no. 1507 3245-3255

+ Author Affiliations Dhipatimendi reNeuroscience, Mount Sinai School of Medicine

New York, NY 10029, USA

ngovepo

Mirau yekutaura kwemajini inoonekwa seyakajeka nzira yekushandisa zvinodhaka, zvichipiwa kugadzikana kwehunhu husina kujairika hunotsanangura mamiriro akapindwa muropa. Pakati pezvakawanda zvinyorwa zvekunyorwa zvinozivikanwa kuti zvinokonzeresa kupindwa muropa, imwe yeakanyanya kuzivikanwa ndiAFosB, inoiswa munzvimbo dzemubairo wehuropi nekuratidzwa kusingaperi kune zvese zvinodhaka zvekushungurudzwa uye inopindirana mhinduro dzinokurudzirwa pakuratidzwa kwezvinodhaka. Sezvo ΔFosB iine protein yakasimba, inomiririra nzira iyo madhiragi anounza kuchinja kusingaperi mukutaura kwemajeri kwenguva refu mushure mokuguma kwekushandisa zvinodhaka. Zvidzidzo zviri kuenderera mberi kuti zviongorore nzira dzakanyatsorongeka dzemakemikari iyo ΔFosB inotarisa chinangwa chemajini uye inounza maitiro ayo. Tiri kutarisa mubvunzo uyu tichishandisa DNA kutaura mazita akabatanidzwa nekuongororwa kwekromatin kugadzirisa-kuchinja mu posttranslational kugadziriswa kwe histones pane zvinodhaka-zvakarongedzwa gadzi vanokurudzira-kuziva zvirwere zvinotungamirirwa nemishonga yekudzvinyirirwa kuburikidza nekuiswa kweAFosB uye kuwana ruzivo kusvika mune tsanangudzo yakawanda inoshandiswa. Zvatinowana zvinogadzira chromatin kugadziriswa sechinhu chinokosha chekugadzirisa nzira iri pasi pezvinodhaka-induced behavioral plasticity, uye inovimbisa kuzarura ruzivo rutsva rwekuita kwokuti ΔFosB inobatsira kukanganisa nekugadzirisa kutaura kwezvimwe zvinangwa zvemajeni mumigwagwa yezvipo zveupfungwa.

1. ziviso

Kuongorora nzira dzekushandura zvinokonzerwa nehutano hwokuti mutemo wekutaura kwemajeni ndiyo imwe nzira inokosha iyo kusingagumi kushandiswa kwechirwere chekushungurudzwa kunokonzera kuchinja kwenguva refu muuropi, iyo inowedzera kuipa kwezviito zvinorondedzera mamiriro ekutsamwa (Nestler 2001). A corollary of this hypothesis is that the drug-induced changes in dopaminergic and glutamatergic transmission and in the morphology of some neuronal cell types in the brain, iyo yakabatana neyechirwere, inopindirana muchikamu kuburikidza nekushandura kwemazwi emagetsi.

Kushanda pamusoro pemakore gumi nemashanu apfuura kwakapa humbowo hunowedzera hwechimiro chemageneti mukutsvaira zvinodhaka, sezvakanyorwa zvinoverengeka - mapuroteni anosunga kune mamwe madanho ekupindura mumatunhu ekusimudzira emageneti uye kudzora kutaura kwemajeni - akaiswa mukati chiito chemishonga. Mienzaniso yakakosha inosanganisira ΔFosB (mhuri yeFos protein), cAMP-response element-binding protein (CREB), inducible cAMP rinoporesa (ICER), kuita zvinhu zvinyorwa zvekunyora (ATFs), mapurogiramu ekutanga ekukura maitiro (EGRs), nucleus accumbens 1 (NAC1 ), nyukireya chinhu κB (NFκB) uye glucocorticoid receptor (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). Kuongorora uku kunotarisa paAFosB, iyo inoita seinoita basa rakasiyana-siyana mukugadzirisa zvinodhaka, senzira yekuenzanisira mhando dzemhando dzekuedza dzakave dzichishandiswa kuongorora nzira dzekunyorwa kwekunyadzisa.

2. Kunyunyuta kweAFosB mu nucleus inowanikwa nemishonga yekutsvaga

ΔFosB inokodhwa ne fosB gene (chimiro 1) uye kugoverana chibvumirano nedzimwe nhengo dzeFos dzemhuri dzinyorwa, dzinosanganisira c-Fos, FosB, Fra1 uye Fra2 (Morgan & Curran 1995). Iyi Fos family proteins heterodimerize naJun family mapuroteni (c-Jun, JunB kana JunD) kuti vashandise activator protein-1 (AP-1) zvinyorwa zvinyorwa zvinosungirirana kune nzvimbo dze AP-1 (kubvumirana kwekuenderana: TGAC / GTCA) iripo mu vanosimudzira mamwe majee ega kuti vateerere kudhinda kwavo. Aya mapuroteni emhuri eFos anokurudzirwa nokukurumidza uye kwenguva pfupi mune dzimwe nzvimbo dzeuropi dzakapera mushure mekugadziriswa kwemishonga yakawanda yekushandiswa zvisina kunaka (chimiro 2; Graybiel et al. 1990; Young et al. 1991; Hope et al. 1992). Iyi mhinduro inowanikwa zvakanyanya mu nucleus accumbens uye dorsal striatum, iyo inokosha ivo vamiririri vezvipo zvinokomborera uye zvinogadzirisa zvemishonga. Zvose izvi mapuroteni emhuri dzeFos, zvisinei, hazvina kugadzikana uye zvinodzokera kumiganhu yepamusoro kwemaawa mashoma ekushandisa zvinodhaka.

Mufananidzo 1

Biochemical hwaro hweAFosB hwakasimba hwakasimba (a) FosB (338 aa, M_r approx. 38 kD) uye (b) ΔFosB (237 aa, M_r approx. 26 kD) akanyorwa neiyo fosB geni. OsBFosB inogadzirwa neimwe nzira yekutsikisa uye inoshaya iyo C-terminal 101 amino acids aripo muFosB. Maitiro maviri anozivikanwa iyo account yeAFosB kugadzikana. Kutanga, osBFosB inoshaya madhimoni madomeni aripo muC-terminus yehurefu hwakazara FosB (uye inowanikwa mune mamwe mapuroteni emhuri eFos futi). Imwe yeaya madhimoni maseru anotarisa FosB yeiyo ubiquitination uye kudzikisira muproteasome. Iyo imwe degron domain inonanga FosB kusvibiswa neiyo ubiquitin- uye proteasome-yakazvimirira mashandiro. Chechipiri, osBFosB inonzi phosphorylated ne casein kinase 2 (CK2) uye pamwe nemamwe mapuroteni kinases (?) PaN-terminus yayo, inoenderera ichigadzirisa protein. 

Mufananidzo 2

Chirongwa chinoratidza kuwedzera kwekuunganidza kweAFosB maererano nekukurumidza nekugadziriswa kwekugadzirwa kwevamwe mapuroteni emhuri yeFos mukupindura zvinodhaka zvekushungurudzwa. (a) Chirongwa chekutsvaga chinoratidzira kusiyanisa kushandiswa kwevaFos mapuroteni emumusha mumusana unounganidza nekugadzirisa kwakanyanya (1-2 maawa pashure pekushandiswa kwekodhaine imwechete) zvichienderana nekusimudzirwa kwenguva refu (Zuva re1 mushure mekudzokidzwa kwechicaine). (b) (i) Mafungu akawanda eFos mapuroteni emhuri (anosanganisira c-Fos, FosB, ΔFosB (33 kD isoform), uye zvichida (?) Fra1, Fra2) inokonzerwa mumusana wekuunganidza uye kushandiswa kwekwenyuka kunotyisa chirwere chekushandisa zvisina kunaka. Zvimwe zvakakonzerwa zvipenyu zvakashandurwa isoforms yeAFosB (35-37 kD); vanoderedzwa pasi zvakaderera nehutachiona hwehutachiona hwehutano, asi huri kuramba huri muuropi kwenguva refu nekuda kwekugadzikana kwavo. (ii) Nokudzokorora (semuviri kaviri zuva rimwe nerimwe) kushandiswa kwezvinodhaka, rimwe nerimwe rinokurudzira rinoita kuti pasi yakaderera ΔFosB isoforms. Izvi zvinoratidzirwa nechezasi yezvidimbu zvinoputika zvinoratidza ΔFosB inokonzerwa nechimwe chinhu chinokurudzira. Mhedzisiro inowedzera zvishoma nezvishoma muzvikamu zvose zveAFosB zvinokurudzirwa kakawanda munguva yechirwere chisingaperi. Izvi zvinoratidzirwa nemutsara unowedzera uri mumurongo.

Mhinduro dzakasiyana zvakasiyana dzinoonekwa mushure mekusagadzwa kwezvinodhaka zvekushungurudzwa (chimiro 2). Biochemically modified isoforms yeAFosB (M_r 35-37 kD) inounganidza mukati memaitiro europi imwechete mushure mokudzokorora kudengenyeka kwezvinodhaka, asi dzimwe dzose nhengo dzemhuri dzeFos dzinoratidza kushivirira (kureva kuti kuderedzwa kuderedzwa kuenzaniswa nekuenzaniswa kwekutanga kwezvinodhaka; Chen et al. 1995, 1997; Hiroi et al. 1997). Kuunganidzwa kwakadaro kweAFosB kwave kuchicherechedzwa kwezvinenge zvose zvinodhaka zvekushungurudzwa (tafura 1; Hope et al. 1994; Nye et al. 1995; Moratalla et al. 1996; Nye & Nestler 1996; Pich et al. 1997; Muller & Unterwald 2005; McDaid et al. 2006b), kunyange zvazvo mishonga yakasiyana yakasiyana pane imwe yehuwandu hwezvinyorwa zvakaratidzwa mu nucleus accumbens core ne shell uye dorsal striatum (Perrotti et al. 2008). Kunyanya kune mamwe madhiragi ekudzvinyirirwa, kubudiswa kweAFosB kunoita sekusarudza dynorphin-ine subset inonzi medium spiny neurons iri munzvimbo idzi dzeuropi (Nye et al. 1995; Moratalla et al. 1996; Muller & Unterwald 2005; Lee et al. 2006), kunyange zvazvo mamwe mabasa aidiwa kuti aise izvi nekuvimbika. I35-37 kD isoforms yeAFosB inowedzera zvikuru neJunD kuti iumbe sangano reA AP-1 rinoshanda uye rinogara kwenguva refu mukati mezvikamu zveuropi (Chen et al. 1997; Hiroi et al. 1998; Pérez-Otao et al. 1998). Mushonga wezvinodhaka weAFosB mu nucleus accumbens inoratidzika kuva mhinduro kumaprojeni emiti yemishonga pari uye kwete maererano nekutengesa zvinodhaka zvinodhaka, sezvo mhuka dzinozvipira kugovera cocaine kana kugamuchira mishonga yemishonga yakakodzwa dzinoratidza zvakaenzana zvekunyorwa kwechinyorwa ichi munharaunda iyi yeuropi (Perrotti et al. 2008).

Tafura 1

Zvinodhaka zvekushungurudzwa zvinozivikanwa kuti zvinokonzera ΔFosB mu nucleus accumbens mushure mekugara kwenguva refu.

·       ↵Induction inonzi yakagadzirwa nemishonga inoshandiswa pakuzvipira pamwe chete nemuongorori-anotungamirirwa nemishonga. Kushandiswa kwezvinodhaka kweAFosB kwakaratidzwa mumakumbo maviri nemakonzo, kunze kweiyi inotevera: mutezo chete, zvinokonzerwa nemhando dzemawere; karoti chete, methamphetamine, phencyclidine.

Tiye 35-37 kD ΔFosB isoforms inounganidza nekugara kwenguva refu kwezvinodhaka nekuda kwerufu rwavo rwakareba kwenguva refu (Chen et al. 1997; Alibhai et al. 2007). Kusiyana neizvi, hakuna humwe uchapupu hwokuti kupatsanurwa kweAFosB kana kuti kugadzikana kwemRNA yacho kunotungamirirwa nekutengesa zvinodhaka. Somugumisiro wekugadzikana kwayo, saka, ΔFosB protein inopfuurira mune neurons kwemavhiki mashomanana mushure mokuguma kwemishonga inodhaka. Iye zvino tava kuziva kuti kugadzikana uku kunokonzerwa nezvinhu zviviri zvinotevera (chimiro 1): (i) kusabatwa kwemashoko maviri emadhemoni muAFosB, ayo aripo paC-terminus yeFosB yakazara-refu uye mamwe mapuroteni emhuri yeFos uye anotarisa mapuroteni iwayo kukurumidza kukuvadza uye (ii) phosphorylation yeDFBB pairi N-terminus ne casein kinase 2 uye zvichida dzimwe protein kinases (Ulery et al. 2006; Carle et al. 2007). Tkusimba kweAFosB isoforms inopa inoverengeka yemakemikari inoshandiswa nemishonga-iyo inokonzerwa kuchinja kwemazwi ekugadzirisa inogona kuramba ichienderera pasinei kwenguva yakareba kwenguva yekuderedza zvinodhaka. Saka, isu, takasarudza kuti ΔFosB inoshanda sechisimbiso che "molecular switch" iyo inobatsira kutanga uye nekuchengetedza mhirizhonga (Nestler et al. 2001; McClung et al. 2004).

3. Basa reAFosB mu nucleus rinogadziriswa mukuraira maitiro ekuzvibata kune zvinodhaka zvekushungurudzwa

Kuongorora kunzvimbo yeAFosB mukunyanyisa zvinodhaka kwakauya zvikuru kubva pakudzidza bitransgenic mbeve umo ΔFosB inogona kushandiswa kusarudzwa mukati memushumo accumcums uye dorsal striatum yezvikara zvevanhu vakuru (Kelz et al. 1999). Zvinonyanya kukosha, mutsara aya overexpress ΔFosB inosarura mu dynorphin-ine-spiny neurons, iyo madhiragi anotendwa kuti aite puroteni. Maitiro e phenotype eAFosB-overexpressing pice, iyo mune dzimwe nzira yakafanana nemhuka mushure mokugara kwenguva refu kwemishonga, inopfupikiswa mu tafura 2. Iyo mbeve inoratidza kuwedzera kwekuita zvinokonzerwa nemakwikwi kune cocaine mushure mekurwa uye kusingaperi kwehutongi (Kelz et al. 1999). Vanoratidzawo kuwedzerwa kunzwisisika kunokonzerwa nemigumisiro inobatsira ye cocaine uye morphine munzvimbo-conditioning assays (Kelz et al. 1999; Zachariou et al. 2006), uye kuzvidzora kuderedza cocaine kudarika zvinodhaka zvisinganyanyi kuwedzera ΔFosB (Colby et al. 2003). Uyezve, DFBB inodzokorora mumusikisi yakawanda inowedzera kukwidziridzwa kweipiate kuderedza muviri uye inosimudzira opiate analgesic tolerance (Zachariou et al. 2006). Kusiyana neizvi, ΔFosB-tsvina inotaura inowanzoonekwa mune dzimwe nzvimbo dzakasiyana-siyana dzekuzvibata, kusanganisira kudzidza kwepakati sezvinoongororwa mumvura maze Morris (Kelz et al. 1999).

Zvinyorwa zvekushandura zvinokonzerwa nekudhakwa: basa reAFosB

Tafura 2

Maitiro e phenotype pane ΔFosB kuiswa mu dynorphin + neurons ye nucleus accumbens uye dorsal striatum^a.

·       ↵a Iyo phenotypes inotsanangurwa mutafura ino inogadziriswa painotisiform inducible yeAFosB mumakonzo e bitransgenic apo ΔFosB kutaura inotarisirwa kune dynorphin + neurons ye nucleus accumbens uye dorsal striatum; mamiriyoni-ezasi mazinga eAFosB anowanikwa mu hippocampus uye mberi cortex. Muzviitiko zvizhinji, phenotype yakabatanidzwa zvakananga neAFosB kutaura mu nucleus accumbens per se kuburikidza nekushandiswa kwehutachiona hunopindirana.

Kunyatsotarisa kweAFosB kunyanya kutsvaga kusvika kune nucleus accumbens, kuburikidza nekushandiswa kwehutachiona hunopindirana nehutachiwana, yakapa dhiyano yakaenzana (Zachariou et al. 2006), iyo inoratidza kuti iyi ingano yenharaunda inogona kukonzera fenotype inowanikwa mumakonzo e bitransgenic, apo ΔFosB inoratidzwawo mune dorsal striatum uye nechepakati mune dzimwe dzipi dzehupi. Uyezve, chinotarisa ekephalin-ine midzi spiny neurons iri mumusana wekuunganidza accumbens uye dorsal striatum mumitsara yakasiyana yezvinonzi bitransgenic zvinokanganisa kuratidza zvizhinji zvezviito zve phenotypes, kunyanya zvinoreva dynorphin + nucleus accumbens neurons muzviitiko izvi.

Kusiyana nekunyanya kufungidzirwa kweAFosB, kunyanya kufungidzirwa kweJune protein (ΔcJun kana DJJD) inoshandiswa-iyo inoshanda somunhu anonyanya kushorwa neA-AP-1-kupindirana-kunyoresa-kushandiswa kwemakonzo echiBitransgenic kana kuti yevirari-mediated gene transfer inogadzira zvakasiyana behavioral effects (Peakman et al. 2003; Zachariou et al. 2006). These data inoratidza kuti kuiswa kweAFosB mune dynorphin-ine yepakati spiny neurons yenucleus accumbens inowedzera kunzwisisika kwemhuka kune cocaine nemamwe madhiragi ekushungurudzwa, uye inogona kumiririra mashandiro ekukurudzira kwenguva refu kumishonga.

Migumisiro yeAFosB inogona kupfuurira mberi kwekugadzirisa kwekushungurudzwa kwezvinodhaka pane imwechete kune dzimwe nzira dzakaoma dzakabatana nehutachiona hwehutano. Nhengo dzekudzivirira hupenzi ΔFosB dzinoshanda zvakaoma kuzvitorera checaine muzvikwidziro zvinowedzera kuzvienzanisa, zvichiratidza kuti ΔFosB inogona kukurudzira mhuka kune zvinokurudzirwa zvinokurudzira zve cocaine uye zvichidaro zvinotungamirira kumudziro wekudzokerazve shure kwekuregererwa kwemishonga (Colby et al. 2003). ΔFosB-overexpressing panya inoratidzawo kukurudzirwa kwezvinokanganisa zvinokonzerwa nedoro (Picetti et al. 2001), imwe phenotype iyo yave ichibatanidzwa nekuwedzerwa doro kunowanikwa nevanhu. Pamwe chete, izvi zvitsva zvinowanzoitika zvinoratidza kuti ΔFosB, kunze kwekuwedzera kukurudzira kune zvinodhaka zvekushungurudzwa, inounza kuchinja kwehutano muhutano hunokurudzira maitiro ekutsvaga zvinodhaka, uye kutsigira maonero, ataurwa pamusoro apa, kuti ΔFosB inoshanda sekuchengetedzeka kwema molecular for the addicted state. Mubvunzo unokosha pasi pekuongororwa kwezvino ndeyekuti ΔFosB kuunganidza panguva yekutsvaga zvinodhaka kunokurudzira maitiro ekutsvaga zvinodhaka mushure mekuwedzera kwekusiya nguva, kunyange mushure mokunge maFosB maitiro akagara aripo (ona pasi apa).

4. Kunyunyuta kweAFosB mumukati kunowanikwa nezvipo zvepanyama

Nucleus accumbens inotendwa kuti inoshanda nenzira yakajeka kuburikidza nekugadzirisa mhinduro kune mibairo yepanyama, zvakadai sokudya, kunwa, zvepabonde uye kushamwaridzana kwevanhu. Somugumisiro, kune ruzivo rwakakura mune imwe nzvimbo inogona kuita yehutano huno munzvimbo dzinonzi zvinodhaka zvinokonzerwa nemasikirwo (semuenzaniso kutengesa kudya, kubhejera, kurovedza muviri, nezvimwewo). Mienzaniso yezvipfuwo yemitemo yakadaro haigone; zvisinei, isu uye vamwe takaona kuti kuwanda kwekushandiswa kwemhando dzakawanda dzemararamiro echisikigo kunounza kuunganidza kwezvigaro 35-37 kD isoforms yeAFosB mu nucleus accumbens. Izvi zvakaratidzwa mushure mekukwirira kwemavhiri ekufamba (Werme et al. 2002) uyewo shure kwekusingaperi kushandiswa kwe sucrose, kudya kwemafuta akawanda kana zvepabonde (Teegarden & Bale 2007; Wallace et al. 2007; Teegarden et al. in press). Mune zvimwe zviitiko, iyi induction inosarudza dynorphin + subset yepakati spiny neurons (Werme et al. 2002). Zvinyorwa zveinducible, bitransgenic mice uye yeviral-mediated gene transfration zvakaratidza kuti kunyanya kufungidzira kweAFosB mumusikisi accumbens kunowedzera kuendesa nekushandisa kwezvikomborero zvepanyama, nepo kunyanya kufungidzira kweJune protein yakaipa kunobata zvakasiyanat (tafura 2; Werme et al. 2002; Olausson et al. 2006; Wallace et al. 2007). Izvi zvitsva zvinoratidza kuti ΔFosB munharaunda iyi yeuropi inokurudzira mhuka kwete zvekupa mishonga yemishonga chete asi nemigumisiro yemhuka zvakare, uye inogona kuwedzera kune zvinyorwa zvekudhakwa kwepanyama.

5. Kunyunyuta kweAFosB mu nucleus inounganidza nekusingaperi kushungurudzika

Zvichipa humwe humwe uchapupu hunoratidza kuti DFFB inokonzerwa mumusana inounganidza nekusingaperi kusvibiswa nemishonga nemararamiro ezvisikwa, zvakange zvichifadza kuchengeta kuti ΔFosB inonyanya kukonzerwa munharaunda iyi yeuropi mushure memhando dzakawanda dzekusagadzikana kusingaperi, kusanganisira kuzvidzora kunetseka, kusingaperi kusingafungidziki kunetseka uye social defeat (Perrotti et al. 2004; Vialou et al. 2007). Kusiyana nemishonga nemishonga yemasikirwo, zvisinei, izvi zvinyorwa zvinowonekwa zvakanyanya muhutano huno munharaunda iyi zvokuti inowanikwa zvakananga mune zvose dynorphin + uye enkephalin + subsets ye medium spiny neurons. Uchapupu hwepakutanga hunoratidza kuti uku kuiswa kweAFosB kunogona kureva zvakanaka, kugadzirisa mhinduro iyo inobatsira munhu kuti agadzikane nekunetseka. Iyi pfungwa inotsigirwa nezvakaitika kare izvo zvakanyanya kufanirwa kweAFosB mu nucleus accumbens, kuburikidza nekushandiswa kweinducible, bitransgenic mice kana chirwere chetachiona-mediated, inoshandisa mhirizhonga-yakafanana nenzira dzakasiyana-siyana dzekuita maitiro (sekukurudzirwa kwevanhu, kusamanikidzwa kushambira test), panguva Kutaurirana kweChino kunokonzera pro-kudzvinyirira-semigumisiro (Vialou et al. 2007). Uyezve, chirwere chisingaperi chemishonga inopesana nemishonga inogadzirisa zvinokonzera kushanda kwakafanana nekudzvinyirira uye inokurudzira ΔFosB munharaunda iyi yeuropi. Kunyange zvazvo basa rinowedzera richidikanwa kuti ribatsire izvi zvakawanikwa, basa rakadaro raizove rakapesana nezvinocherechedza izvo OsBFosB inowedzera kunzwisisika kwemubairo wehuropi wedunhu uye nekudaro inogona kubatsira mhuka kurarama panguva dzekunetseka. Zvinonakidza, basa iri rekufungidzirwa kweAFosB mu nucleus accumbens rakafanana neyo yakaratidzwa munguva pfupi yapfuura ye periaqueductal grey apo gwaro rekunyora kunokonzerwawo nekusingaperi mupfungwa (Berton et al. 2007).

6. Target majenera eAFosB mu nucleus accumbens

Sezvo ΔFosB ichinyorwa chechinyorwa, zvinonzwisisika zvinokonzera izvi zvinonakidza zvinoita phenotype mu nucleus accumbens kuburikidza nekusimudzira kana kuderedza maitiro emamwe magenhi. Sezvinoratidzwa chimiro 1, ΔFosB chigadzirwa chetatu che fosB gene iro risina zvakawanda zveC-terminal transactivation domain iripo muFosB yakazara-refu asi inoramba iine dimerization uye DNA-inogadzirisa domains. ΔFosB inosunga kuJun nhengo dzemhuri uye iyo inogadzirisa dimer inosunga nzvimbo dze AP-1 muDNA. Dzimwe dzidzo mu-vitro dzinoratidza kuti ΔFosB haina zvakawanda zvayo zvekugadzirisa nzvimbo, inoshanda semutongi asina kunaka weAAP-1 basa, nepo dzimwe dzakawanda dzichiratidza kuti ΔFosB inogona kushandura kunyoresa panzvimbo dze AP-1 (Dobrazanski et al. 1991; Nakabeppu & Nathans 1991; Yen et al. 1991; Chen et al. 1997).

Tichishandisa zvinyorwa zvedu, bitransgenic mice dzinofadza ΔFosB kana kuti dzakaipa zvayo zvakanyanya ΔcJun, uye kuongorora mazita emagetsi paAffymetrix chips, takaratidza kuti, mu nucleus accumbens in vivo, ΔFosB inonyanya kushanda semushandisi wechinyorwa, iyo inoshumira sekunyepedzera kamudiki kadiki kwemajini (McClung & Nestler 2003). Izvisinganzwisisiki, izvi zvakasiyana-siyana zveAFosB inoshanda kwenguva uye chiyero che ΔFosB kutaura, nekanguva shoma, mazinga mashoma anotungamirira kuwedzerwa kuderedza geni uye kwenguva refu, mazinga akakwirira anotungamirira kune mamwe gene ekugadzirisa. Izvi zvinopindirana nekuwana kuti nguva pfupi uye kwenguva refu ΔFosB kutaura kunotungamirira kune zvinopesana nemigumisiro pamusoro pemufambiro: pfupi-pfupi ΔFosB kutaura, sekureva kweAcJun, kunoderedza kunakidzwa kwekodineine, kana nguva yakareba ΔFosB kutaura kunowedzera cocaine (McClung & Nestler 2003). Iyo nzira inokonzera kuchinja uku ikozvino iri pasi pekutsvakurudza; imwe rivheti inogona, iyo inoramba ichinyatsofungidzira, ndeyokuti ΔFosB, pamatunhu akakwirira, inogona kuumba ma-homodimers anoshanda AP-1 kunyorwa (Jorissen et al. 2007).

Zviverengeka zvinokonzerwa nemajeni eAFosB ave achishandiswa achishandisa chikwata chinokodzera (tafura 3). Chimwe chinonzi gene gluR2, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor subunit (Kelz et al. 1999). ΔFosB kufungisisa mune zvinyorwa zvitsva zvinonzi bitransgenic kusarudzwa kunowedzera GluR2 kutaurira mu nucleus accumbens, pasina chiitiko chinowanikwa kune dzimwe dzakawanda dzimwe AMPA glutamate receptor subunits yakaongororwa, apo ΔcJun kutaura inogadzirisa kukwanisa kwekodineini kuwedzera GluR2 (Peakman et al. 2003). AP-1 complexes inosanganisira ΔFosB (uye inowanzove JunD) inosunga chibvumirano AP-1 site iripo muGluR2 anokurudzira. Uyezve, GluR2 kunyanya kuderedza nehutachiona-medived gene gene transfer inowedzera zvinokonzera zvinokonzera cocaine, zvakadai seAFosB nguva refu (Kelz et al. 1999). Sezvo GluR2-ine-AMPA chiteshi ine rutivi rwepamusoro huno mufambiro huenzaniswa neAimPA nenzira dzisingabatanidzi nhengo iyi, iyo cocaine- uye ΔFosB-kupindirana kweGluR2 mu nucleus accumbens inogona kureva, pamwe chete muchikamu, nokuda kwezvakaderedzwa glutamatergic mhinduro dzinoonekwa mu idzi neuroni mushure mekugara kwenguva refu kwemishonga (Kauer & Malenka 2007; tafura 3).

Mienzaniso yezvinangwa zvakagadziriswa zveDFBB mu nucleus accumbens^a.

·       ↵Kunyangwe hazvo osBFosB inodzora kutaurwa kwemajini akawanda muuropi (semuenzaniso McClung & Nestler 2003), tafura yacho inongorongedza chete magene anosangana matatu matatu anotevera maitiro: (i) yakawedzera (↑) kana kuderera (↓) kutaura pane ΔFosB kudzvinyirira, (ii) kudzokorora kana yakaenzana mirawo neJcJun, inonyanyisa yakaipa inhibitor yeAP-1-yakagadziriswa transcript, (iii) ΔFosB-ine AP-1 zvivakwa zvinosunga kunzvimbo dzeAP-1 munzvimbo inosimudzira dunhu, uye ( iv) osBFosB inokonzeresa mhedzisiro yakafanana pane inosimudzira geni chiitiko mu vitro sezvinoonekwa mu vivo.

·       ↵b Pasinei neuchapupu hwokuti DFFB inoderedza dynorphin geni mumhando dzekushandisa zvinodhaka (Zachariou et al. 2006), pane humwe uchapupu hwokuti hunogona kuita kuti hupenyu huve mumamiriro ezvinhu akasiyana (ona Cenci 2002).

Tafura 3

Mienzaniso yezvinangwa zvakagadziriswa zveDFBB mu nucleus accumbensa.

Chimwe chikwata chinotarisa geni reDFBB mu nucleus accumbens ndiyo opioid peptide, dynorphin. Yeuka kuti ΔFosB inoratidzika inokonzerwa nezvinodhaka zvekushungurudzwa zvakananga mumasero ekubudisa dynorphin munharaunda iyi yeuropi. Zvinodhaka zvekushungurudza zvinokonzera zvinetso pane dynorphin kutaura, pamwe nekuwedzera kana kuderera kunoonekwa zvichienderana nemamiriro ekurapa anoshandiswa. Dynorphin geni ine nzvimbo dze AP-1-iyo, iyo inogona kusunga ΔFosB-ine AP-1 complexes. Zvakare, takaratidza kuti kuiswa kweAFosB kunosimbisa dynorphin geni kutaura mumusikisi accumbens (Zachariou et al. 2006). Dynorphin inofungidzirwa kushandura κ-opioid receptors paVTA dopamine neurons uye inhibit dopaminergic transmission uye nenzira iyo inoderedza nzira dzekupa mubayiro (Shippenberg & Rea 1997). Hence, iyo ΔFosB kudzvinyirira kwe dynorphin expression inogona kubatsira mukuwedzera kwenzira dzemubairo dzakapindirana neichi chinyorwa chinhu. Ikozvino kune humbowo hwakananga hunotsigira kubatanidzwa kwe dynorphin gene kudzvinyirira muAFosB's behaviour phenotype (Zachariou et al. 2006).

Uchapupu huchangobva kuitika hwakaratidza kuti ΔFosB inodzvinyirirawo g-c-fos geni inobatsira kuumba shanduko yemasomendi-kubva pakubvambiswa kwemapurotini emhuri akawanda kwemazuva mashomanana mushure mekunyanya kushandiswa kwezvinodhaka kune zvakanyanya kuunganidza ΔFosB mushure mokunge zvirwere zvisingaverengeki-Akataurwa kare (Renthal et al. in press). Iyo nzira inokonzerwa neDFBB kudzvinyiririka kwe c-fos kutaura kwakaoma uye inowanikwa pasi apa.

Imwe nzira yakashandiswa kuzivisa chinangwa chemajeni eAFosB yakayera mazita ekushandurwa kwemashoko anowanika painducible kunyanya kufungidzirwa kweAFosB (kana kuti ΔcJun) mumusana inounganidza achishandisa DNA kutaura mavara, sezvakatsanangurwa kare. Nzira iyi yakatungamirira pakuzivikanwa kwemajini akawanda ari kumusoro-kana kutsetseka neAFosB kutaura mumamiriro aya europi (Chen et al. 2000, 2003; Ang et al. 2001; McClung & Nestler 2003). Tmagene majini anoita kunge anokonzereswa kuburikidza nezviito zveAFosB seyakagwinyisa activist maccylin-anoenderana kinase-5 (Cdk5) uye cofactor P35 (Bibb et al. 2001; McClung & Nestler 2003). Cdk5 inokonzerwawo nekodekine isingaperi mu nucleus accumbens, chiitiko chakavharwa pane ΔcJun kutaura, uye ΔFosB inonamatira uye inobatsira gwaro reCdk5 kuburikidza neApp-1 site mumutsigiri wayo (Chen et al. 2000; Peakman et al. 2003). Cdk5 chinhu chinonyanya kukosha cheAFosB sezvo kutaura kwacho kwave kwakabatana zvakananga nekushandurwa kwenyika ye phosphorylation yemasikirini akawanda emaprotiniti kusanganisira glutamate receptor subunits (Bibb et al. 2001), pamwe nekuwedzera mu dendritic spine density (Norrholm et al. 2003; Lee et al. 2006), mu nucleus accumbens, iyo inobatanidza nekugara kwenguva refu cocaine (Robinson & Kolb 2004). Munguva pfupi yapfuura, mutemo weCdk5 mutambo mu nucleus accumbens wakabatanidzwa zvakananga nekuchinja kwehutano hwekuita kwecocaine (Taylor et al. 2007).

Chimwe chinyorwa cheFFBB chinoratidzwa nekushandiswa kwema microarrays ndiNFBBB. Ichi chinyorwa chinokonzerwa chinokonzerwa nucleus chinowanikwa neAFosB overexpression uye chronic cocaine, chiitiko chakavharwa neAcJun kutaura (Ang et al. 2001; Peakman et al. 2003). Hwazvino humbowo hwakaratidza kuti kuburitswa kweNF VerB kunogona zvakare kubatsira mukukwanisa kwecocaine yekukonzeresa dendritic spines mu nucleus accumbens neurons (Russo et al. 2007). Mukuwedzera, NFKB yave ichibatanidzwa mune dzimwe nzira dzeuropheno ye methamphetamine munzvimbo dzinouraya (Asanuma & Kadheti 1998). Kuona kuti NFKBB inoratidzirwa geni yeAFosB inotsanangura kuoma kwemichina iyo ΔFosB inopindira nayo migumisiro yekodineine pamagumo ejeni. Nokudaro, kuwedzera kune majeni anotungamirirwa neAFosB zvakananga nema AP-1 nzvimbo pavanokurudzira geni, ΔFosB inotarisirwa kutonga mazamu akawanda akawanda kuburikidza nekushandurwa kweNFκB uye zvichida zvimwewo mapuroteni anonyora zvinyorwas.

Izwi reDNA rinowedzera huwandu hwepfumi yemamwe majini ezvijeni angangotarirwa, zvakananga kana kuti zvisina kukodzera, neAFosB. Pakati peiyo majeni kune mamwe mapurogiramu anonzi neurotransmitter, mapuroteni anobatanidzwa mushure mekupedzisira uye mushure memazuva ano, mamwe marudzi eIon channels uye intracellular signaling proteins, uyewo mapuroteni anodzora neuronal cytoskeleton uye masero ekukura (McClung & Nestler 2003). Imwezve basa rinodiwa kusimbisa imwe neimwe yemapurotini akawanda seona fide targets ye cocaine inoshanda kuburikidza neDFBB uye kuti iite basa rakakwana iro purotini imwe neimwe inobatsira mukuronga zvinorema neural uye maitiro ekuita cocaine. Pakupedzisira, zvichange zvakakosha kuti tifambise mberi kwekutsvaga kwezvinangwa zvemajeni kusvika kumagadziro emapoka ejeni ane mutemo wakarongeka unenge uchidikanwa kuti uwirirane nemhirizhonga.

7. Kunyunyuta kweAFosB mune dzimwe nzvimbo dzeuropi

Iyo hurukuro kusvika iyezvino yakangotarisa chete pane nucleus accumbens. Kunyange zvazvo ichi chiri chipiro chepfungwa chinokonzera nzvimbo uye chakakosha nokuda kwezviito zvinodhaka zve cocaine nemamwe madhiragi ekudzvinyirirwa, dzakawanda dzimwe nzvimbo dzeuropi dzakakoshawo pakugadzirisa nekugadzirisa kwehutano hwehutano. Mubvunzo unokosha, naizvozvo, ndewekuti ΔFosB inoshanda mune dzimwe nzvimbo dzeuropi dziri mberi kwechikamu chekuunganidza inogonawo kukanganisa zvinodhaka zvinodhaka. Ikusungirirwa, kune ikozvino kuwedzera huchapupu hunokurudzira uye opiate zvinodhaka zvekushungurudzwa zvinokonzera ΔFosB mune hutano humwe nzvimbo dzakabatanidzwa mune zvakasiyana-siyana zveAddiction (Nye et al. 1995; Perrotti et al. 2005, 2008; McDaid et al. 2006a,b; Liu et al. 2007).

Kuongorora kwechangobva kuitika kwakarongeka kuenzanisa ΔFosB kuiswa muzvikamu zvakasiyana-siyana zvehuropi pamativi mana emishonga yakasiyana-siyana ekudzvinyirirwa: cocaine; morphine; cannabinoids; ethanol (tafura 4; Perrotti et al. 2008). Mishonga mina yose inokonzera gwaro rekunyora kune zvidimbu zvakasiyana muyucleus accumbens uye dorsal striatum uyewo mu prefrontal cortex, amygdala, hippocampus, nheyo yemubhedha we stria terminalis uye nhengo yepamusoro yechitubu chemberi chekutanga. Cocaine neEthanol chete zvinokonzera ΔFosB mune dzimwe nguva, iyo yose yemishonga kunze kweiyo inokonzerwa ne cannabinoid inokonzera ΔFosB mune periaqueductal grey, uye cocaine yakasiyana mukuderedza ΔFosB mumagina-aminobutyric acid (GABA) ergic masero mu posterior ventral tegmental (Perrotti et al. 2005, 2008). Mukuwedzera, morphine yakaratidzwa kuti inokurudzira ΔFosB mukuderedza pallidum (McDaid et al. 2006a). Munzvimbo imwe neimwe yezvikamu izvi, ndeye 35-37 kD isoforms yeAFosB iyo inounganidza nekugara kwenguva refu kwemishonga uye inopfuurira kwenguva yakareba panguva yekurega.

Tafura 4

Kuenzaniswa kwehuropi nzvimbo dzinoratidza ΔFosB kuiswa mushure mushure mekutsvaga kwenguva refu kune zvinomiririra zvinodhaka zvekushungurudzwa^a.

·       ↵A Tafura haina kuratidzira zviyero zveAFosB kudhevedzwa nemishonga yakasiyana-siyana. Ona Perrotti et al. (2008) nekuda kwemashoko aya.

·       ↵b Kukonzerwa kwekodineine, ethanol uye cannabinoids paAFosB kubudiswa mumhepo inonzi ventral pallidum haisati yadzidzwa, asi kuiswa kwakadaro kwakaratidzwa mukupindura methamphetamine (McDaid et al. 2006b).

·       ↵c ΔFosB inductions inowanikwa munzvimbo dzakasiyana-siyana dze prefrontal cortex, kusanganisira infralimbic (medial prefrontal) uye orbitofrontal cortex.

Chinangwa chikuru chekutsvakurudza mune ramangwana ndechokuita zvidzidzo, zvakaenzana kune avo vanorondedzerwa pamusoro apa nekuda kwekugumira accumbens, kujekesa neural uye behavioral phenotypes inopindirana neAFosB kune imwe neimwe yezvikamu zveuropi. Izvi zvinomirira basa rakakura, asi zvakakosha kuti uchinzwisise simba repasi rose reAFosB pamusana pekuita zvinodhaka.

Tangobva kutora danho rinokosha munyaya iyi nekushandiswa kwehutachiona-hutachiwana hutachiona hunoshandiswa kuratidza zviito zveAFosB mune imwe nharaunda ye prefrontal cortex, kureva, orbitofrontal cortex. Iyi nharaunda yave yakanyatsoratidzirwa mukutengesa, kunyanya, pakuita kuti kusagadzikana uye kusagadzikana kunoratidzira mhirizhonga (Kalivas & Volkow 2005). Zvinofadza kuti, kusiyana neyucleus accumbens iyo inogadziriswa uye yejoka cocaine inokura mazinga akaenzana eAFosB sezvakataurwa kare, takacherechedza kuti cocaine self-administration inokonzera huwandu hwakawanda huwandu hweAFosB mu orbitofrontal cortex, zvichiratidza kuti mhinduro iyi inogona kunge yakabatana nezvimwe zvikamu zvehutano hwezvinodhaka (Winstanley et al. 2007). Takabva tashandisa kuongorora kwekodent yekucherechedza nekugadzirisa kusarudzwa (semuenzaniso kusarudzwa kwemashure mashanu kusarudza nguva uye kunonoka-kutengesa kuongororwa) kuongorora kana ΔFosB mukati memasitorio e-orbitofrontal cortex inobatsira kushandiswa kwezvinodhaka zvinokonzerwa nemishonga mu cognition. Takawana kuti kusingaperi kwekodineine kurapa kunobatsira kutsungirira kushaya njodzi kwepfungwa kunokonzerwa neacute cocaine. Viral-mediated expression of ΔFosB munharaunda ino inoenzanisa migumisiro yenguva refu yekodhaine, nepo kunyanya kufungidzirwa kwevanhu vanonyanya kukwikwidza zvakaipa, ΔJunD, kunodzivisa izvi kuchinja maitiro. DNA inonzi microarray inorondedzera yakawanda yakawanda inogona kuisa maitiro emakemikari anokonzera shanduko iyi yekuchinja, kusanganisira cocaine- uye ΔFosB-kuwedzerwa kuwedzerwa kwechinyorwa che metabotrophic glutamate receptor mGluR5 uye GABA_A receptor pamwe chete nezvinhu P (Winstanley et al. 2007). Kufurirwa kweizvi nezvimwe zvakawanda zvinokonzera ΔFosB zvinotarisirwa zvinongowedzera kuongororwa.

Izvi zvitsva zvinoratidza kuti ΔFosB inobatsira kuratidzira kushivirira kune pfungwa-yekuvhiringidza migumisiro ye cocaine. Vashandi vanotambura nemigumisiro yakaipa yekodineine inowanzova cocaine inotarisirwa, asi avo vanowana mishonga inovhiringidza kushanda kana kuchikoro havakwanisi kuva mishonga (Shaffer & Eber 2002). Kutsungirira kunetseka kwepfungwa kunokonzerwa neacuteine ​​cocaine muvanhu vekocaine-vane ruzivo vanogona kuita kuti kugadziriswa kwekusagadzikana kuve nyore. Nenzira iyi, ΔFosB induction in the orbitofrontal cortex inogona kukurudzira dambudziko remamiriro ezvinhu, zvakafanana nezviito zvaro mu nucleus accumbens apo ΔFosB inokurudzira kusagadzikana nokusimudzira kubhadhara uye kukurudzira zvinokonzera kushandiswa kwechirwere.

8. Epigenetic nzira dzeAFosB chiito

Kusvikira nguva pfupi yadarika, zvese zvidzidzo zve transcriptional mutemo muuropi zvakavimba nezviyero zveyakagadzikana-mamiriro mRNA mazinga. Semuenzaniso, kutsvaga kweAFosB inotarisirwa majeni kwakabatanidza kuzivisa mRNA kumusoro- kana kuderedzwa paAFosB kana ΔcJun overexpression, sezvambotaurwa. Iyi nhanho yekuongorora yanga ichinyanya kubatsira mukutarisa zvinangwa zvekuisa zveAFosB; zvisinei, zvakasikwa zviripo pakupa nzwisiso yehunhu hwenzira hunobatanidzwa. Asi, zvese zvidzidzo zvemaitiro zvinovimba nema vitro zviyero senge osBFosB inosunga kune inoteedzana negene mukuchinja kwejeli kana ΔFosB kudzora kweiyo genere inosimudzira chiitiko mumasero tsika. Izvi hazvigutsikane nekuti nzira dzekutapa manyorerwo dzinoratidza kusiyana kukuru kubva pasero rerudzi kuenda kurudzi rwechitokisi, kuchisiya zvichinyatso kuzivikanwa kuti mushonga wekushungurudzwa, kana ΔFosB, inodzora sei majeni ayo muuropi mu vivo.

Zvidzidzo zvepigenetic systems zvinogonesa, kwekutanga, kukwezva vhokupepe imwe danho rinopfuurira uye kunyatsoongorora mutemo wekunyora kwepamusoro muhupenzi hwekubata mhuka (Tsankova et al. 2007). Nhoroondo yekare, izwi rokuti epigenetics rinotsanangura nzira iyo maitiro emagetsi anogona kupiwa nhaka kunze kwekushandurwa kweDNA maererano. Isu tinoshandisa izwi racho zvakazara kuti tive ne "maitiro ekugadzirisa maitiro echromosomal kuitira kuti vanyora, zviratidzo kana kuti kupfuurira basa rakachinjwa rinoti" (Shiri 2007). Nekudaro, isu ikozvino tave kuziva kuti chiitiko chemagen'a chinotariswa neiyo covalent modification (semuenzaniso acetylation, methylation) ye histones munzvimbo yemageneti ari padyo nekutorwa kwemhando dzakasiyana dzevanobatanidza kana corepressors ezvekunyora. Chromatin immunoprecipitation (ChIP) assays inoita kuti zvikwanisike kushandisa irwo ruzivo rwuri kukura rwechromatin biology kuona iyo yekumisikidza mamiriro ejeni mune imwe nzvimbo yeuropi yemhuka inorapwa nemushonga wekushungurudzwa.

Mienzaniso yekuti zvidzidzo zvekugadzirwa kwechromatin zvingatibatsira sei kunzwisisa tsanangudzo dzemakemikorasi emabasa ekucocaine uye ΔFosB anopiwa mu chimiro 3. Sezvakataurwa pamusoro apa, ΔFosB inogona kushanda semushanduri wezvinyorwa kana kudzvinyirira zvichienderana nechinangwa chemajini. Kuti tive nekunyatsonzwisisa nezvezviito izvi, takaongorora chromatini yenyika mbiri inomiririra maitiro eAFosB, cdk5 iyo inokonzerwa neFFB uye c-fos iyo inopindurwa mu nucleus accumbens. Chromatin immunoprecipitation studies yakaratidza kuti cocaine inobatsira cdk5 gene munharaunda iyi yeuropi kuburikidza nechikwata chinotevera: ΔFosB inonamatira kune cdk5 gene uye inotora histone acetyltransferases (HAT; iyo inogadzirisa pedo histones) uye SWI-SNF zvinhu; zvose zviito zvinokurudzira gene transcription (Kumar et al. 2005; Levine et al. 2005). Chronic cocaine inowedzera kuwedzera histone acetylation kuburikidza ne phosphorylation nekudzivirirwa kwe histone deacetylases (HDAC; iyo inowanzosazvidzivirira uye kudzvinyirira mazamu; Renthal et al. 2007). Kusiyana neizvi, cocaine inodzvinyirira g-c-fos geni: apo ΔFosB inosunga kune iri geni inoshandisa HDAC uye zvichida histone methyltransferase (HMT; iyo inoshandisa inonzi histones iri pedyo) uye inodzivisa c-fos transcription (chimiro 3; Renthal et al. in press). Mubvunzo wepakati ndewekuti: chii chinogadza kuti ΔFosB inomutsa kana kudzvinyirira geni kana ichisunga kune iye anosimudzira geni?

Mufananidzo 3

Epigenetic nzira dzeAFosB chiito. Nhamba yacho inoratidzira migumisiro yakasiyana zvikuru apo ΔFosB inosungira kune geni iyo inoshandisa (semuenzaniso cdk5) kana isiridzika (semuenzaniso c-fos). (a) Kune cdk5 anokurudzira, ΔFosB inoshandisa HAT uye SWI-SNF zvinhu, izvo zvinokurudzira kuve nekushandisa. Panewo uchapupu hwekuregwa kweHCDACs (ona mashoko). (b) Kusiyana neizvi, pa-c-fos vanokurudzira, ΔFosB inotora HDAC1 uye pamwe pamwe neHMTs iyo inodzvinyirira mazwi emagetsi. A, P uye M inorondedzera histone acetylation, phosphorylation uye methylation, maererano.

Izvi zvidzidzo zvekutanga zvepigenetic nzira dzekushandisa zvinodhaka zvinonakidza nekuti vanovimbisa kubudisa ruzivo rwemashoko matsva pamusoro pemagadzirirwo emakemikari anoshandiswa nemishonga yekushandiswa kwechisimba kuronga mazwi ekugadzirisa mumagetsi ekuunganidza yakawanda uye mamwe maitiro europi. Kubatanidza DNA kutaura mazita ane chinzi chinonzi ChIP pane chip assays (apo kushandurwa mu chromatin chimiro kana kunyorwa kwechinyorwa chinobatanidza kunogona kuongororwa genome yakazara) kunotungamirira pakuzivikanwa kwezvinodhaka uye ΔFosB chinangwa chemajini nemazinga akawanda akawanda ekuvimba uye kukwana. Mukuwedzera, zvirongwa zvepigenetic zvinonyanya kukoshesa vanhu vanoita kuti vatarise nguva yakareba-yekare inoratidzira hurumende yehutachiona. Nenzira iyi, kushandiswa kwemishonga-uye DFB-inokonzerwa kuchinja kwe histone nekugadzirisa kwakafanana epigenetic kunopa nzira dzingangodaro dzinoshandiswa pakuchinja kwechinyorwa dzinogona kupfuurira kwenguva yakareba mushure mekunyadziswa kwezvinodhaka zvinoguma uye zvichida kunyange pashure pekuti ΔFosB inonyadzisa kune zviyero zvakakwana.

9. Mhedziso

Iyo pateni yekunyorwa kweAFosB mu nucleus accumbens nekugara uchionekwa kune zvakasikwa mibairo, kushushikana kana zvinodhaka zvekushungurudzwa zvinomutsa inonakidza fungidziro ine chekuita neyakajairika mashandiro munzvimbo ino yeuropi. Sezvinoratidzwa mu chimiro 2, pane mwero unokosheswa weAFosB mune nucleus accumbens pasi pechinyakare mamiriro. Izvi zvakasarudzika kumatunhu anouraya, sezvo ΔFosB isingaonekwe kumwe kunhu mukati mehuropi pakutanga. Isu tinofungidzira kuti iwo mazinga eAFosB mune nucleus accumbens anomiririra kuverengerwa-kubva kwekuratidzwa kwemunhu kune zvinokanganisa manzwiro, zvese zvakanaka nezvakaipa, zvakabatanidzwa kwenguva yakareba yenguva yakapihwa iwo epanguva epuroteni. Misiyano yakasarudzika mune yakasarudzika maseru eAFosB kudzoreredzwa nekupa mubayiro maringe neanopokana nechisimba hazvinzwisisike, uye rimwe basa rinodiwa kujekesa mhedzisiro yekuita kweiyi misiyano. Isu tinofungidzira tichienderera mberi kuti sekukwirira kwakanyanya kwekusimudzira kwepfungwa kunokonzeresa ΔFosB mune nucleus accumbens neurons, kushanda kweeuron kunochinjwa kuitira kuti vawedzere kunetseka kune zvinokomborera zvinokurudzira. Nenzira iyi, kuburitswa kweAFosB kwaizosimudzira-zvine chekuita nemubairo (kureva kushushikana) ndangariro kuburikidza neakasiyana mapurojekiti enucleus accumbens. Pasi pemamiriro ezvinhu akajairika, kuburitswa kwemwero wakaringana weAFosB nekupa mubairo kana kudzoreredza zvinokonzeresa nekusimudzira kugadzirisa kwemhuka kumatambudziko ezvakatipoteredza. Zvisinei, kuwedzera kwakanyanya kweAFosB kunoonekwa pasi pemamiriro ekurwara (semuenzaniso, kugara uchiratidzwa nemushonga wekushungurudzwa) kunotungamira mukukurudzira zvakanyanya kweiyo nucleus inounganidza kutenderera uye pakupedzisira inokonzeresa maitiro ekuzvibata (semuenzaniso kumanikidza kutsvaga zvinodhaka nekutora) zvine chekuita nekupindwa muropa nezvinodhaka. OsBFosB induction mune dzimwe nzvimbo dzehuropi ingangodaro inokonzeresa kune akasarudzika mativi eiyo inodhakwa nyika, sezvakataurwa nezvakawanikwa zvichangoburwa zveAFosB chiito mu orbitofrontal cortex.

Kana iyi fungidziro iri yechokwadi, inomutsa mukana unonakidza wekuti mazinga eAFosB mu nucleus accumbens kana zvimwe dzimwe nzvimbo dzehuropi dzinogona kushandiswa sechiomarker kuongorora mamiriro ekumisikidza kwemubairo wedunhu wedunhu, pamwe nedanho rekuti munhu i'akapindwa muropa ', zvese panguva yekuvandudza kwekupindwa muropa uye zvishoma nezvishoma zvichipera panguva yekuregedza kurapwa kana kurapwa. Iko kushandiswa kweAFosB sechiratidzo chenyika yekupindwa muropa kwakaratidzirwa mumhando dzemhuka. Mhuka dzechiri kuyaruka dzinoratidzira zvakanyanya kukura kweAFosB yakaenzaniswa nemhuka dzakwegura, zvichienderana nekunetseka kwavo kukuru kwekutsamwa (Ehrlich et al. 2002). Mukuwedzera, kucherechedza migumisiro inobatsira yeikicinine neGABA_B receptor positive allosteric modulator inobatanidza nekudzivirirwa kweikicinine induction yeAFosB mu nucleus accumbens (Mombereau et al. 2007). Kunyange zvazvo zvakanyanya kufungidzira, zvinogona kufungidzirwa kuti duku duku rePET ligand, rine hukama hwepamusoro neAFosB, rinogona kushandiswa kubatsira kubatsira kuongorora zvirwere zvinodhaka uye pamwe nekucherechedza kufambira mberi panguva yekurapa.

Chekupedzisira, ΔFosB pachayo kana chero yemageneti mazhinji ayo yaanogadzirisa - anoonekwa kuburikidza neDNA expression arrays kana ChIP pane chip assays - inomiririra zvingangotarisirwa zvekusimudzira kweakanyanya marapirwo ehurongwa hwekushandisa zvinodhaka. Isu tinotenda kuti zvakakosha kuti titarise zvinopfuura zvetsika zvinodhaka zvinangwa (semuenzaniso maurotransmitter receptors uye vatakuri) kune vangangorapa vamiririri vekupindwa muropa. Mamepu-akapamhama ekunyora zvinyorwa anokwanisa ehunyanzvi hwetekinoroji yanhasi anopa anovimbisa sosi yezvinangwa zveinovel mukuedza kwedu kurapa zvirinani uye pakupedzisira kurapa kusagadzikana kwekupindwa muropa.

Kutenda

Kuzivisa. Munyori anotaura kuti hapana kupesana kwekufarira mukugadzirira kuongorora uku.

Mashoko Omuzasi

· Mumwe mupiro we17 kuhurukuro yemusangano wekukurukurirana 'Iyo neurobiology yekupindwa muropa: vistas nyowani'.

© © The Royal Society

References

1.    ↵

1. Alibhai IN,

2. Girini TA,

3. Potashkin JA,

4. Nestler EJ

2007 Mutemo we fosB uye ΔfosB mRNA kutaura: mu vivo uye in vitro zvidzidzo. Ubongo Res. 1143, 22-33. doi: 10.1016 / j.brainres.2007.01.069.

CrossRefMedlinedandemutande yeScience

2.    ↵

1. Ang E,

2. Chen J,

3. Zagouras P,

4. Magna H,

5. Holland J,

6. Schaeffer E,

7. Nestler EJ

2001 Induction yeNFKB mu nucleus accumbens neyakagadzirwa cocaine administration. J. Neurochem. 79, 221-224. doi: 10.1046 / j.1471-4159.2001.00563.x.

CrossRefMedlinedandemutande yeScience

3.    ↵

1. Asanuma M,

2. Kadheti JL

1998 Methamphetamine-yakakonzera kuwedzera mukutura NFκB DNA-kusunga basa inodzivirirwa mu superoxide dismutase transgenic mice. Mol. Ubongo Res. 60, 305-309. doi:10.1016/S0169-328X(98)00188-0.

Medline

4.    ↵

1. Berton O,

2. et al.

2007 Induction yeAFosB mumaperaqueductal grey nekunyanya kunetseka kunokurudzira kushingaira kupindura mhinduro. Neuron. 55, 289-300. doi: 10.1016 / j.neuron.2007.06.033.

CrossRefMedlinedandemutande yeScience

5.    ↵

1. Bibb JA,

2. et al.

2001 Migumisiro yekugara kwenguva refu necocaine inotungamirirwa neprotonine neuronal Cdk5. Nature. 410, 376-380. doi: 10.1038 / 35066591.

CrossRefMedline

6.    ↵

1. Shiri A

2007 Pfungwa dze epigenetics. Nature. 447, 396-398. doi: 10.1038 / nature05913.

CrossRefMedline

7.    ↵

1. Carle TL,

2. Ohnishi YN,

3. Ohnishi YH,

4. Alibhai IN,

5. Wilkinson MB,

6. Kumar A,

7. Nestler EJ

2007 Kushaikwa kwakachengetedzwa kweC-terminal degron dome kunobatsira kuFosB yakasarudzika kugadzikana. Eur. J. Neurosci. 25, 3009-3019. doi: 10.1111 / j.1460-9568.2007.05575.x.

CrossRefMedlinedandemutande yeScience

8.    ↵

1. Carlezon WA, Jr,

2. Duman RS,

3. Nestler EJ

2005 Zviso zvakawanda zve CREB. Trends Neurosci. 28, 436-445. doi: 10.1016 / j.tins.2005.06.005.

CrossRefMedlineWebhu yeSayenzi

9.    ↵

1. Cenci MA

2002 Zvinyorwa zvinyorwa zvine chekuita nepathogenesis ye-l-DOPA-inosimudzira dyskinesia mune rat rat yechirwere chePasinson. Amino Acids. 23, 105-109.

CrossRefMedlineWebhu yeSayenzi

10. ↵

1. Chen JS,

2. Nye IYE,

3. Kelz MB,

4. Hiroi N,

5. Nakabeppu Y,

6. Tariro BT,

7. Nestler EJ

1995 Mutemo weAFosB uye FosB-semaprotinete nemagetsi anokonzerwa nemagetsi (ECS) uye mishonga yekhocaine. Mol. Pharmacol. 48, 880-889.

ngovepo

11. ↵

1. Chen J,

2. Kelz MB,

3. Tariro BT,

4. Nakabeppu Y,

5. Nestler EJ

1997 Mazuva EFS: zvipembenene zvakasimba zveAFosB zvakakonzerwa muuropi nemishonga isingaperi. J. Neurosci. 17, 4933-4941.

Abstract / FREE Full Text

12. ↵

1. Chen JS,

2. Zhang YJ,

3. Kelz MB,

4. Steffen C,

5. Ang ES,

6. Zeng L,

7. Nestler EJ

2000 Induction ye cyclin-dependent kinase 5 mu hippocampus nekusingaperi kwemagetsi anogunun'una: basa reAFosB. J. Neurosci. 20, 8965-8971.

Abstract / FREE Full Text

13. ↵

1. Chen J,

2. Newton SS,

3. Zeng L,

4. Adams DH,

5. Dow AL,

6. Madsen TM,

7.Nestler EJ,

8. Duman RS

2003 Downregulation ye CCAAT-enhancer inosunga protein beta muAFosB inoshandiswa mutsva uye nemagetsi anogunun'una. Neuropsychopharmacology. 29, 23-31. doi: 10.1038 / sj.npp.1300289.

CrossRefdandemutande yeScience

14. ↵

1. Colby CR,

2. Whisler K,

3. Steffen C,

4.Nestler EJ,

5. Kuzvipira DW

2003 ΔFosB inowedzera kukurudzira kwekodineine. J. Neurosci. 23, 2488-2493.

Abstract / FREE Full Text

15. ↵

1. Deroche-Gamonet V,

2. et al.

2003 Chirwere cheglucocorticoid sechinhu chinogona kudiwa kuti kuderedze kushandiswa kwekodineine. J. Neurosci. 23, 4785-4790.

Abstract / FREE Full Text

16. ↵

1. Dobrazanski P,

2. Noguchi T,

3. Kovary K,

4. Rizzo CA,

5. Lazo PS,

6. Bravo R

1991 Zvigadzirwa zvose zve fosB gene, FosB uye fomu yayo shoma, FosB / SF, inoshandisa shanduro mu fibroblasts. Mol. Cell Biol. 11, 5470-5478.

Abstract / FREE Full Text

17. ↵

1. Ehrlich INI,

2. Sommer J,

3. Canas E,

4. Unterwald EM

2002 Periadolescent mice zviratidzo zvinokurudzirwa ΔFosB kuregererwa mukupindura kwekodineine uye amphetamine. J. Neurosci. 22, 9155-9159.

Abstract / FREE Full Text

18. ↵

1. Greybiel AM,

2. Moratalla R,

3. Robertson HA

1990 Amphetamine uye cocaine inoshandisa zvinodhaka-zvinoshandiswa zvinoshandiswa zvechi-c-fos geni mumatambudziko anoshamisa-matrix uye zvidimbu zvezvikwata zve striatum. Proc. Natl Acad. Sci. USA. 87, 6912-6916. doi: 10.1073 / pnas.87.17.6912.

Abstract / FREE Full Text

19. ↵

1. Girini TA,

2. Alibhai IN,

3. Hommel JD,

4. DiLeone RJ,

5. Kumar A,

6.Theobald DE,

7.Neve RL,

8. Nestler EJ

2006 Induction yeCIER inzwi mumusasa inogadziriswa nekudzvinyirira kana amphetamine inowedzera maitiro ekuzvibata kune zvinokonzera mupfungwa. J. Neurosci. 26, 8235-8242.

Abstract / FREE Full Text

20. ↵

1. Girini TA,

2. Alibhai IN,

3. Unterberg S,

4.Neve RL,

5. Ghose S,

6. Tamminga CA,

7. Nestler EJ

2008 Induction yekuita zvinhu zvinyorwa zvepamusoro (ATFs) ATF2, ATF3, uye ATF4 mumusana wekuunganidza pamwe nekugadzirisa kwekuita maitiro. J. Neurosci. 28, 2025-2032. doi: 10.1523 / JNEUROSCI.5273-07.2008.

Abstract / FREE Full Text

21. ↵

1. Hiroi N,

2. Brown J,

3. Haile C,

4. Iwe H,

5. Greenberg INI,

6. Nestler EJ

1997 FosB mutant mice: kurasikirwa kwekusingaperi kwecocaine induction yemapuroteni anoenderana neFos uye kuwedzera kunzwisisika kune cocaine's psychomotor uye nemhedzisiro. Proc. Natl Acad. Sci. USA. 94, 10 397-10. doi: 10.1073 / pnas.94.19.10397.

22. ↵

1. Hiroi N,

2. Brown J,

3. Iwe H,

4. Saudou F,

5. Vaidya VA,

6. Duman RS,

7. Greenberg INI,

8. Nestler EJ

1998 Inokosha basa re fosB gene mumagadziriramu emaseroti, masero, uye maitiro ekutsvaira kwema electroconvulsive. J. Neurosci. 18, 6952-6962.

Abstract / FREE Full Text

23. ↵

1. Tariro B,

2. Kosofsky B,

3.Hyman SE,

4. Nestler EJ

1992 Mutemo weIEG kutaura uye AP-1 inosungirirwa nekodekine isingagumi muroti nucleus accumbens. Proc. Natl Acad. Sci. USA. 89, 5764-5768. doi: 10.1073 / pnas.89.13.5764.

Abstract / FREE Full Text

24. ↵

1. Tariro BT,

2. Nye IYE,

3. Kelz MB,

4. Kuzvipira DW,

5. Iadarola MJ,

6. Nakabeppu Y,

7. Duman RS,

8. Nestler EJ

1994 Induction yedhina yakareba refu-AP-1 yakaumbwa nemaprotinasi eFos-akaita muuropi nehupenyu husingaperi hwechicaine nezvimwe zvirwere zvisingaperi. Neuron. 13, 1235-1244. doi:10.1016/0896-6273(94)90061-2.

CrossRefMedlinedandemutande yeScience

25. ↵

1. Jorissen H,

2. Ulery P,

3. Henry L,

4. Gourneni S,

5.Nestler EJ,

6. Rudenko G

2007 Dimerization uye DNA-kusunga zvinhu zvechinyorwa chinokonzera ΔFosB. Biochemistry. 46, 8360-8372. doi: 10.1021 / bi700494v.

CrossRefMedlinedandemutande yeScience

26. ↵

1. Kalivas PW,

2. Volkow ND

2005 Mutsara wekutsvaga muropa: chirwere chekukurudzira uye chisarudzo. Am. J. Psychiatry. 162, 1403-1413. doi: 10.1176 / appi.ajp.162.8.1403.

Abstract / FREE Full Text

27. ↵

1. Kauer JA,

2. Malenka RC

2007 Synaptic plasticity uye zvinodhaka. Nat. Rev. Neurosci. 8, 844-858. doi: 10.1038 / nrn2234.

CrossRefMedlinedandemutande yeScience

28. ↵

1. Kelz MB,

2. et al.

1999 Tsanangudzo yezvinyorwa zvinyorwa ΔFosB muuropi inodzora kunzwisisika kwekodineine. Nature. 401, 272-276. doi: 10.1038 / 45790.

CrossRefMedline

29. ↵

1. Kumar A,

2. et al.

2005 Chromatin remodeling ndiyo chinhu chinonyanya kushandiswa chinonzi cocaine-induced plasticity mu striatum. Neuron. 48, 303-314. doi: 10.1016 / j.neuron.2005.09.023.

CrossRefMedlinedandemutande yeScience

30. ↵

1. Lee KW,

2. Kim Y,

3. Kim AM,

4. Helmin K,

5. Nairn AC,

6. Greengard P

2006 Cocaine-induced dendritic mushure mutsva muD1 uye D2 dopamine receptor-ine midzi inonzi spiny neurons inopinza inucleus accumbens. Proc. Natl Acad. Sci. USA. 103, 3399-3404. doi: 10.1073 / pnas.0511244103.

Abstract / FREE Full Text

31. ↵

1. Revhi A,

2. Guan Z,

3. Barco A,

4. Xu S,

5. Kandel E,

6. Schwartz J

2005 CREB-kusunga mapuroteni ekudzivirira kugadziriswa kwecocaine ne acetylating histones pa fosB kukurudzira mumushonga striatum. Proc. Natl Acad. Sci. USA. 102, 19 186-19 191. doi: 10.1073 / pnas.0509735102.

32. ↵

1. Liu HF,

2. Zhou WH,

3. Zhu HQ,

4. Lai MJ,

5. Chen WS

2007 Microinjection yeM (5) muscarinic receptor antisense oligonucleotide muVTA inhibits kutaura kweFosB muNac uye hippocampus ye heroin inokurudzira rats. Neurosci. Bull. 23, 1-8. doi:10.1007/s12264-007-0001-6.

CrossRefMedline

33. ↵

1. Mackler SA,

2. Korutla L,

3. Cha XY,

4. Koebbe MJ,

5. Fournier KM,

6. Bowers MS,

7. Kalivas PW

2000 NAC-1 iropi POZ / BTB protein inogona kudzivirira cocaine-induced sensitization muikati. J. Neurosci. 20, 6210-6217.

Abstract / FREE Full Text

34. ↵

1. McClung CA,

2. Nestler EJ

2003 Mutemo wejena kutaura uye cocaine mubayiro neC CREB uye ΔFosB. Nat. Neurosci. 11, 1208-1215. doi: 10.1038 / nn1143.

35. ↵

1. McClung CA,

2. Ulery PG,

3. Perrotti LI,

4. Zachariou V,

5. Berton O,

6. Nestler EJ

2004 ΔFosB: inoshandura ma molecule kwekugara kwenguva refu muuropi. Mol. Ubongo Res. 132, 146-154. doi: 10.1016 / j.molbrainres.2004.05.014.

Medline

36. ↵

1. McDaid J,

2. Dallimore JE,

3. Mackie AR,

4. Napier TC

Kuchinja kwezvakawanda uye pallidal pCREB uye ΔFosB mumakonzo e-morphine-anokurudzirwa: kuwirirana ne-receptor-yakavhiringidzwa nemagetsi emagetsi mu ventral pallidum. Neuropsychopharmacology. 31, 2006a 1212-1226.

MedlineWebhu yeSayenzi

37. ↵

1. McDaid J,

2. Graham MP,

3. Napier TC

Methamphetamine-inokonzera kushungurudzika zvakasiyana-siyana inoshandura pCREB uye ΔFosB munzvimbo yose yezvikwata zvemakumbo emammalian. Mol. Pharmacol. 70, 2006b 2064-2074. doi: 10.1124 / mol.106.023051.

Abstract / FREE Full Text

38. ↵

1. Mombereau C,

2. Lhuillier L,

3. Kaupmann K,

4. Cryan JF

2007 GABAB rector-positive modulation-induced blockade yemigumisiro yeikicin inobatanidza nekuderedza kweruzius accumbens ΔFosB kuunganidza. J. Pharmacol. Exp. Therapy. 321, 172-177. doi: 10.1124 / jpet.106.116228.

CrossRef

39. ↵

1. Moratalla R,

2. Elibol R,

3. Vallejo M,

4. Greybiel AM

1996 Network-level inoshandiswa mukutaura kwezvinyorwa zvisinganzwisisi Fos-Jun mapuroteni mu striatum munguva isingaperi ya cocaine kurapwa uye kubviswa. Neuron. 17, 147-156. doi:10.1016/S0896-6273(00)80288-3.

CrossRefMedlinedandemutande yeScience

40. ↵

1. Morgan JI,

2. Curran T

1995 Nenguva isipi-kutanga majeni: makore ane gumi pamusoro. Trends Neurosci. 18, 66-67. doi:10.1016/0166-2236(95)93874-W.

CrossRefMedlinedandemutande yeScience

41. ↵

1. Muller DL,

2. Unterwald EM

2005 D1 dopamine receptors modulate ΔFosB induction in rat striatum mushure mokutenda kwe morphine administration. J. Pharmacol. Exp. Therapy. 314, 148-155. doi: 10.1124 / jpet.105.083410.

CrossRef

42. ↵

1. Nakabeppu Y,

2. Nathans D

1991 Chimiro chechimiro cheFosB chinowanzoita kuti inosvibisa Fos / Jun transcriptional basa. Cell. 64, 751-759. doi:10.1016/0092-8674(91)90504-R.

CrossRefMedlinedandemutande yeScience

43. ↵

1. Nestler EJ

2001 Mazwi echiremera chenguva refu inonzi plastiki inokonzera kusvuta. Nat. Rev. Neurosci. 2, 119-128. doi: 10.1038 / 35053570.

CrossRefMedlinedandemutande yeScience

44. ↵

1.Nestler EJ,

2. Barrot M,

3. Kuzvipira DW

2001 ΔFosB: iyo yakasungirirwa yemasomendi inoshandiswa pakuita zvinodhaka. Proc. Natl Acad. Sci. USA. 98, 11 042-11 046. doi: 10.1073 / pnas.191352698.

45. ↵

1. Norrholm SD,

2. Bibb JA,

3.Nestler EJ,

4. Ouimet CC,

5. Taylor JR,

6. Greengard P

2003 Kuwanda kwekodineine-induced proliferation ye dendritic spines mu nucleus accumbens inobva pane basa re cyclin-dependent kinase-5. Neuroscience. 116, 19-22. doi:10.1016/S0306-4522(02)00560-2.

CrossRefMedlinedandemutande yeScience

46. ↵

1. Nye IYE,

2. Nestler EJ

1996 Induction yezvisingagumi Fras (ma-antigens anokonzerwa neFos) muhuropi hwepuro nekugara kusingaperi morphine administration. Mol. Pharmacol. 49, 636-645.

ngovepo

47. ↵

1. Nye H,

2. Tariro BT,

3. Kelz M,

4. Iadarola M,

5. Nestler EJ

1995 Zvidzidzo zvepamutemo zvekugadziriswa nekodhaine yekusingaperi Fra (Fos-related antigen) kuiswa mu striatum uye nucleus accumbens. J. Pharmacol. Exp. Therapy. 275, 1671-1680.

48. ↵

1. O'Donovan KJ,

2. Tourtellotte WG,

3. Millbrandt J,

4. Bharabhani JM

1999 Mhuri yeEGR yezvinyorwa-kutonga zvinhu: kufambira mberi pahutano hwema molecular uye zvirongwa zveurouroscience. Trends Neurosci. 22, 167-173. doi:10.1016/S0166-2236(98)01343-5.

CrossRefMedlinedandemutande yeScience

49. ↵

1. Olausson P,

2. Jentsch JD,

3. Tronson N,

4. Neve R,

5.Nestler EJ,

6. Taylor JR

2006 ΔFosB munharaus accumcums inodzora kudya-kusimbiswa kwakagadzirirwa maitiro uye zvinokurudzira. J. Neurosci. 26, 9196-9204. doi: 10.1523 / JNEUROSCI.1124-06.2006.

Abstract / FREE Full Text

50. ↵

1. Peakman M.-C,

2. et al.

2003 Inducible, rutivi rwehutano humwe ruzivo rwechimwe chinhu chisina kunaka chemuviri weC-Jun mumagetsi anokanganisa kunoderedza kushushikana kwekodhaine. Ubongo Res. 970, 73-86. doi:10.1016/S0006-8993(03)02230-3.

CrossRefMedlinedandemutande yeScience

51. ↵

1. Perez-Otano I,

2. Mandelzys A,

3. Morgan JI

1998 MPTP-Parkinsonism inofambidzana nekurondedzera kuratidza kweprotein yeA-FosB yakafanana nenzira ye dopaminergic. Mol. Ubongo Res. 53, 41-52. doi:10.1016/S0169-328X(97)00269-6.

Medline

52. ↵

1. Perrotti LI,

2. Hadeishi Y,

3. Ulery P,

4. Barrot M,

5. Monteggia L,

6. Duman RS,

7. Nestler EJ

2004 Induction yeAFosB muhuropi hunobatanidza mubairo shure kwekusagadzikana kwenguva refu. J. Neurosci. 24, 10 594-10 602. doi: 10.1523 / JNEUROSCI.2542-04.2004.

53. ↵

1. Perrotti LI,

2. et al.

2005 ΔFosB inounganidza mumusero weGABAergic mumushure wepamusoro wemhepo inotora chirwere chepfungwa pashure pepfungwa inokonzera kurapwa. Eur. J. Neurosci. 21, 2817-2824. doi: 10.1111 / j.1460-9568.2005.04110.x.

CrossRefMedlinedandemutande yeScience

54. ↵

1. Perrotti LI,

2. et al.

2008 Kusiyanisa maitiro eAFosB kuiswa muuropi nemishonga yekushandisa zvisina kunaka. Synapse. 62, 358-369. doi: 10.1002 / syn.20500.

CrossRefMedlinedandemutande yeScience

55. ↵

Picetti, R., Toulemonde, F., Nestler, EJ, Roberts, AJ & Koob, GF 2001 Ethanol mhedzisiro muAFosB transgenic mice. Soc. Neurosci. Abs. 745.16.

56. ↵

1. Pich EM,

2. Pagliusi SR,

3. Tessari M,

4. Talabot-Ayer D,

5. hooft van Huijsduijnen R,

6. Chiamulera C

1997 Zvose zvinoshandiswa neveural substrates zvekudhakwa kwekicinine uye cocaine. Sayenzi. 275, 83-86. doi: 10.1126 / science.275.5296.83.

Abstract / FREE Full Text

57. ↵

1. Renthal W,

2. et al.

2007 Histone deacetylase 5 inotarisana nehutano hunoenderana nemafungiro ekugadzirisa kusingaperi. Neuron. 56, 517-529. doi: 10.1016 / j.neuron.2007.09.032.

CrossRefMedlinedandemutande yeScience

58. ↵

Renthal, W., Carle, TL, Maze, I., Covington III, HE, Truong, H.-T., Alibhai, I., Kumar, A., Olson, EN & Nestler, EJ Mukudhinda. OsBFosB inopindirana epigenetic deensitization yeiyo c-fos geni mushure mekugara amphetamine J. Neurosci.

59. ↵

1. Robinson TE,

2. Kolb B

2004 Structural plastiki inobatanidza nekutsvaga kune zvinodhaka zvekushungurudzwa. Neuropharmacology. 47, S33-S46. doi: 10.1016 / j.neuropharm.2004.06.025.

CrossRef

60. ↵

Russo, SJ et al. 2007 NFKB chiratidzo chokuratidza cocaine-induced behavioral uye cellular plasticity. Soc. Neurosci. Abs., 611.5.

61. ↵

1. Shaffer HJ,

2. Eber GB

2002 Kufambira mberi kwekufamba kwenguva kwekodineine kuzviratidza kwezviratidzo muU.S. National Comorbidity Survey. Addiction. 97, 543-554. doi: 10.1046 / j.1360-0443.2002.00114.x.

CrossRefMedlinedandemutande yeScience

62. ↵

1. Shippenberg TS,

2. Rea W

1997 Sensitization kune zvinokonzera zvinokonzera cocaine: kushandiswa kwemazwi ne dynorphin uye kappa-opioid receptor agonists. Pharmacol. Biochem. Behav. 57, 449-455. doi:10.1016/S0091-3057(96)00450-9.

CrossRefMedlinedandemutande yeScience

63. ↵

1. Taylor JR,

2. Lynch WJ,

3. Sanchez H,

4. Olausson P,

5.Nestler EJ,

6. Bibb JA

2007 Inhibition yeCdk5 mu nucleus accumbens inosimudzira locomotor inobatsira uye inokurudzira zvinokonzera zvinokonzera cocaine. Proc. Natl Acad. Sci. USA. 104, 4147-4152. doi: 10.1073 / pnas.0610288104.

Abstract / FREE Full Text

64. ↵

1. Teegarden SL,

2. Bale TL

2007 Inoderera muzvokudya zvinoshandiswa zvinowedzera kuwedzera mafungiro uye njodzi yekudya zvakare. Biori. Psychiatry. 61, 1021-1029. doi: 10.1016 / j.biopsych.2006.09.032.

CrossRefMedlinedandemutande yeScience

65. ↵

Teegarden, SL, Nestler, EJ & Bale, TL Mune dzvanya. OsBFosB-yakagadziriswa shanduko mukuratidzira dopamine yakajairirwa neinonaka mafuta kudya. Biol. Psychiatry.

66. ↵

1. Tsankova N,

2. Renthal W,

3. Kumar A,

4. Nestler EJ

2007 epigenetic mutemo mune zvinetso zvepfungwa. Nat. Rev. Neurosci. 8, 355-367. doi: 10.1038 / nrn2132.

CrossRefMedlinedandemutande yeScience

67. ↵

1. Ulery PG,

2. Rudenko G,

3. Nestler EJ

2006 Mutemo weAFosB kusimbiswa nephosphorylation. J. Neurosci. 26, 5131-5142. doi: 10.1523 / JNEUROSCI.4970-05.2006.

Abstract / FREE Full Text

68. ↵

Vialou, VF, Steiner, MA, Krishnan, V., Berton, O. & Nestler, EJ 2007 Basa reAFosB mune iyo nucleus accumbens mukusingaperi kwevanhu kukundwa. Soc. Neurosci. Abs., 98.3.

69. ↵

Wallace, D., Rios, L., Carle-Florence, TL, Chakravarty, S., Kumar, A., Graham, DL, Perrotti, LI, Bolaños, CA & Nestler, EJ 2007 Simba reAFosB mune iyo nucleus accumbens. pane yakasikwa mibairo maitiro Soc. Neurosci. Abs., 310.19.

70. ↵

1. Werme M,

2.Messer C,

3. Olson L,

4. Gilden L,

5. Thorén P,

6.Nestler EJ,

7. Brené S

2002 ΔFosB inotungamirira magetsi. J. Neurosci. 22, 8133-8138.

Abstract / FREE Full Text

71. ↵

1. Winstanley CA,

2. et al.

2007 ΔFosB induction in orbitofrontal cortex inobatsira kutsungirira kucocaine-inokonzerwa nekuziva kusagadzikana. J. Neurosci. 27, 10 497-10 507. doi: 10.1523 / JNEUROSCI.2566-07.2007.

72. ↵

1. Yen J,

2.Uchenjeri RM,

3. Tratner Ini,

4. Verma IM

1991 Imwe nzira yakasiyana-siyana yakatsanangurwa yeFosB inoratidzikisa mitemo yekushandura kwechinyorwa uye kushandurwa nemaFos protini. Proc. Natl Acad. Sci. USA. 88, 5077-5081. doi: 10.1073 / pnas.88.12.5077.

Abstract / FREE Full Text

73. ↵

1. Mudiki ST,

2. Porrino LJ,

3. Iadarola MJ

1991 Cocaine inokonzera kusununguka c-fos-immunoreactive mapuroteni kuburikidza nedopaminergic D1 receptors. Proc. Natl Acad. Sci. USA. 88, 1291-1295. doi: 10.1073 / pnas.88.4.1291.

Abstract / FREE Full Text

74. ↵

1. Zachariou V,

2. et al.

2006 Chikamu chinokosha cheAFosB munharaus inowanikwa mu morphine action. Nat. Neurosci. 9, 205-211. doi: 10.1038 / nn1636.

CrossRefMedlinedandemutande yeScience

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