Usoro ntinye akwụkwọ nke ịṅụ ọgwụ ọjọọ: ọrụ nke ΔFosB (2008)

IHE: Eric Nestler na-enye nkọwa dị ukwuu banyere DeltaFosB na ahụ riri ahụ. (Enweela ihe ọzọ.) N'ikwu ya n'ụzọ dị mfe, DeltaFosB na-ebili na ụgwọ ọrụ ụgwọ maka ị toụ ọgwụ ọjọọ na-adịghị ala ala na ụfọdụ ụgwọ ọrụ nkịtị. Ebumnuche nke evolushọn bụ ka ị nweta ya mgbe ị na-enweta ihe dị mma (nri na mmekọahụ) - ya bụ, lezie anya ụgwọ ọrụ ụgwọ ọrụ. Agbanyeghị, nsụgharị nke ụgwọ ọrụ nkịtị nwere ike ibute oke oriri na mkpokọta DeltaFosB… na mgbanwe ụbụrụ nke na-eme ka agụụ na ụfụ na-agụkwu. N'ụzọ na-akpali mmasị, ndị nọ n'afọ iri na ụma na-emepụta DeltaFosB karịa ndị okenye, nke bụ otu ihe mere ha ji enwe ike ị toụ ọgwụ ọjọọ.

AKWỤKWỌ NDỊ KWURU

Eric J Nestler*

10.1098 / rstb.2008.0067 Phil. Trans. Akwukwo nso. B 12 October 2008 vol. 363 ọ dịghị. 1507 3245-3255

+ Njikọ ndị edemede Ngalaba Neuroscience, Ugwu Saịnaị nke Ọgwụ

New York, NY 10029, USA

nkịtị

A na-ewere iwu nke mkpụrụ ndụ ihe nketa dị ka usoro dị mma nke ị addictionụ ọgwụ ọjọọ, n'ihi nkwụsi ike nke ọdịiche omume na-akọwa ọnọdụ riri ahụ. N'etiti ọtụtụ ihe ederede nke a maara na ọ na-emetụta usoro ahụ riri ahụ, otu n'ime ihe kachasị mma bụ ΔFosB, nke a na-ebute n'ime mpaghara ụgwọ ọrụ ụbụrụ site na ikpughe na-adịghị ala ala na ọgwụ ọjọọ niile na-eme mkpesa ma na-emegharị azịza nke ị toụ ọgwụ ọjọọ. Ebe ọ bụ na ΔFosB bụ protein siri ike, ọ na - anọchite anya usoro nke ọgwụ ndị na - emepụta mgbanwe na - adịgide adịgide n'ọmụmụ okwu ogologo oge mgbe ịkwụsị ọgwụ. Nnyocha na-aga n'ihu iji nyochaa usoro ihe omimi nke omuma nke nke ΔFosB na-achịkwa mkpụrụ ndụ ihe nketa ma na-emepụta mmetụta ya. Anyị na-abịarute ajụjụ a site na iji nkọwa nke DNA tinyere nyocha nke nchịkọta nke chromatin-mgbanwe na mgbanwe mgbanwe nke akụkọ ihe mere eme na ndị na-emepụta ọgwụ na-achịkwa ọgwụ-iji chọpụta mkpụrụ ndụ nke ọgwụ ọjọọ na-achịkwa site na ịmalite ΔFosB na inweta nghọta n'ime usoro ihe omumu di omimi. Ihe ndị anyị chọpụtara mere ka chromatin weghachite dị ka usoro dị mkpa nke usoro iwu nke na-etinye ọgwụ plastic, na nkwa iji kpughere nghọta ọhụrụ banyere otú ΔFosB si eme ka ụbụrụ na-achịkwa okwu nke mkpụrụ ndụ gọọmenti a kapịrị ọnụ na ụbụrụ.

1. Okwu Mmalite

Ọmụmụ nke usoro ederede nke riri ahụ dabeere n'echiche bụ na ụkpụrụ nke okwu mkpụrụ ndụ bụ otu ụzọ dị mkpa nke na-egosi na ịṅụ ọgwụ ọjọọ na-eme ka ụbụrụ na-adịte aka n'oge ụbụrụ, bụ nke na-ebute ọdịiche dị na omume nke na-akọwa ọnọdụ nke riri ahụ (Nestler 2001). Nkọwa nke nkwupụta a bụ na mgbanwe ndị ọgwụ ọjọọ na-etinye na ntinye nke dopaminergic na glutamatergic na nchịkwa nke ụfọdụ sel neuronal cell na ụbụrụ, nke ejikọtara ya na ọnọdụ ahụ riri ahụ, na-agbakwụnye akụkụ ụfọdụ site na mgbanwe n'ọhụụ okwu.

Ọrụ a na-arụ n'ime afọ 15 gara aga enyewo ihe akaebe na-arịwanye elu maka ọrụ nke ịkọwapụta mkpụrụ ọgwụ na ị addictionụ ọgwụ ọjọọ, dị ka ọtụtụ ihe ederede - protein ndị na-ejikọta ihe nzaghachi kpọmkwem na mpaghara nkwalite nke mkpụrụ ndụ ihe nketa na-achịkwa okwu mkpụrụ ndụ ihe ndị ahụ ọgwụ ọjọọ. Ihe atụ ndị na-atụ aro gụnyere ΔFosB (protein Fos family), protein CAMP-response-protein (CREB), repamorti mbụ (ICER) nke na-emepụta ihe, ọrụ mmepụta ihe (ATFs), protein ndị na-ebute ngwa ngwa (EGRs), 1 (NAC1) ), ihe nuklia kbb (NFBB) na glucocorticoid onye nata (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). Nyocha a na-elekwasị anya na ΔFosB, nke yiri ka ọ na-arụ ọrụ pụrụ iche na usoro ahụ riri ahụ, dị ka ụzọ isi gosipụta ụdị nnwale nke nnwale nke ejiworo mee ihe iji nyochaa usoro mmegharị ahụ.

2. Mmetụta nke ΔFosB na oghere na-ebuwanye ibu site na iji ọgwụ ọjọọ eme ihe

ΔFosB bu nke fosba geneọgụgụ 1) na ikwekọrịta homology na ihe ndị ọzọ Fos family transcription factors, nke gụnyere C-Fos, FosB, Fra1 na Fra2 (Morgan & Curran 1995). Ndị a na-edozi protein ezinụlọ bụ heterodimerize na protein ndị ezinụlọ ezinụlọ (c-Jun, JunB ma ọ bụ JunD) iji mepụta ihe ndị na-emepụta ihe na-emetụta 1 (usoro nkwekọrịta: TGAC / GTCA). ndị na-akwado ụfọdụ mkpụrụ ndụ ihe nketa iji mezie ha. A na - ebute ndị na - edozi protein ezinụlọ ndị a ọsọsọ ọsọ ọsọ na mpaghara ụbụrụ dị iche iche mgbe nnukwu nlekọta nke ọtụtụ ịṅụ ọgwụ ọjọọ (ọgụgụ 2; Graybiel et al. 1990; Young et al. 1991; Olileanya na al. 1992). A na-ahụ nzaghachi ndị a dịka ihe kachasị anya na ngwongwo ndị na-emepụta ihe na ndị na-arụ ọrụ, bụ ndị dị mkpa maka ndị ọrụ mgbasaozi na-akwụ ụgwọ ma na-eme ụgwọ ọrụ nke ọgwụ. Ndị a nile na-echebe protein Fos, Otú ọ dị, na-enweghị ike ịdaghasị ma laghachi n'ọkwa dị ala n'ime awa nchịkọta ọgwụ.

Nyocha 1

Ihe ndabere nke biochemical nke ntọala uniqueFosB pụrụ iche: (a) FosB (338 aa, M_r ihe dika. 38 kD) na (b) ΔFosB (237 aa, M_r ihe ruru. 26 kD) bu nkpuru fosB gbanyere ya. A na - eme ΔFosB site na ntinye ọzọ ma enweghị C-terminal amino acid 101 dị na FosB. A maara usoro abụọ na akaụntụ maka nkwụsi ike ΔFosB. Nke mbu, ΔFosB enweghi uzo abuo abuo di na C-terminus nke FosB zuru oke (ma achota ndi ozo di na Fos). Otu n'ime ngalaba degron a na-elekwasị anya FosB maka ịba ụba na mbibi na proteasome. Ngalaba degron nke ọzọ na-eleba anya na nbibi FosB site na usoro nnwere onwe ubiquitin- na proteasome. Nke abụọ, ΔFosB bụ phosphorylated by casein kinase 2 (CK2) na ikekwe site na protein kinases ndị ọzọ (?) Na N-terminus, nke na-eme ka protein ahụ kwụsie ike. 

Nyocha 2

Usoro nke na-egosi nchịkọta mpịakọta nke ΔFosB gbasara ntinye ngwa ngwa na nke na-agafeghị agafe nke ndị ọzọ na-edozi protein Fos maka mmeghachi omume nke iji ọgwụ ọjọọ eme ihe. (a) Ihe osise ahụ na-egosi ntinye dị iche iche nke protein protein Fos na oghere ahụ site na mkpali dị ukwuu (1-2 awa mgbe ọhụụ cocaine na-ekpo ọkụ) na mgbatị na-adịgide adịgide (ụbọchị 1 mgbe ọhụụ cocaine ugboro ugboro). (b) (i) Ọtụtụ ebili mmiri nke protein protein Fos (gụnyere c-Fos, FosB, ΔFosB (33 kDformform), na ikekwe (?) Fra1, Fra2) na-ebugharị na ngwongwo na ihe ndị na - ọgwụ ọjọọ. Ejikwa ya na-edozi ΔFosB (35-37 kD); ha na-eduga ha n'obere ala site na nnukwu nlekọta ọgwụ, ma nọgide na ụbụrụ ruo ogologo oge n'ihi nkwụsi ike ha. (ii) Na ugboro ugboro (dịka ugboro abụọ kwa ụbọchị) nchịkwa ọgwụ, ihe mmetụ ọ bụla na-ebute ọkwa dị ala nke nrụpụta ΔFosB. E gosipụtara nke a site na ntinye dị ala nke ederede na-egosi ΔFosB emetụta site na mkpali ọ bụla. Ihe si na ya pụta bụ mmụba na-arịwanye elu na ọkwa niile nke ΔFosB na nrụpụta ugboro ugboro n'oge usoro ọgwụgwọ na-adịghị ala ala. E gosipụtara nke a site na nrịba arịgoro arịgoro na eserese.

A na - ahụ azịza dị iche iche mgbe a na -ọgụgụ 2). Mgbanwe edozi nke ΔFosB (M_r 35-37 kD) na-agbakọta n'ime otu ụbụrụ mgbe ọ na-ekpughe ọgwụ ọjọọ ugboro ugboro, ebe ndị ọzọ ezinụlọ Fos gosipụtara ndidi (ya bụ, belata ntinye iji tụnyere nkwupụta ọgwụ mbụ; Chen et al. 1995, 1997; Hiroi et al. 1997). Ahụwo ụdị ΔFosB ahụ maka ihe fọrọ nke nta ka ọ bụrụ ọgwụ ọjọọ nile (table 1; Olileanya na al. 1994; Nye et al. 1995; Moratalla et al. 1996; Nye & Nestler 1996; Pich et al. 1997; Muller & Unterwald 2005; McDaid et al. 2006b), ọ bụ ezie na ọgwụ dịgasị iche iche dịgasị iche iche na ogo nke mmepụta nke a hụrụ n'ime oghere ahụ na -Perrotti et al. 2008). Dịkarịa ala maka ụfọdụ iji ọgwụ ọjọọ eme ihe, ntinye nke ΔFosB na-egosi ịhọrọ maka ntinye nke dinorphin nke nwere ọkpụkpụ spiny nke dị na mpaghara ụbụrụ ndị a (Nye et al. 1995; Moratalla et al. 1996; Muller & Unterwald 2005; Lee et al. 2006), ọ bụ ezie na ọ dị mkpa ka a rụkwuo ọrụ iji kwado nke a n'eziokwu. Ụdị 35-37 kD nke ΔFosB na-ejikọta na JunD ka ọ bụrụ ihe mgbagwoju anya na-adịgide adịgide AP-1 dị n'ime mpaghara ụbụrụ ndị a (Chen et al. 1997; Hiroi et al. 1998; Pérez-Otao et al. 1998). Ntinye ọgwụ nke ΔFosB na ngwangwa acumbens yiri ka ọ bụ nzaghachi na ọgwụ ndị na-eji ọgwụ ọjọọ eme ihe ma ọ bụghị na ịṅụ ọgwụ ọjọọ, ebe ọ bụ na ụmụ anụmanụ ndị na-ahụ maka cocaine ma ọ bụ na-enweta ọgwụ mgbochi ọgwụ na-ekpughe otu mmepụta nke ihe a transcript na ụbụrụ a mpaghara (Perrotti et al. 2008).

Isiokwu 1

A ghaghị iji ọgwụ ọjọọ eme ihe na-eme ka ΔFosB bụrụ ihe na-eme ka ọ bụrụ ihe na-adịghị mma.

·       ↵a na-akọ banyere Ntuzi maka ọgwụ nchịkwa onwe ya na mgbakwunye na ọgwụ na-eme nchọpụta. E gosipụtara ịṅụ ọgwụ ọjọọ nke ΔFosB na oke ma ụmụ oke, ma e wezụga ihe ndị a: nro naanị, cannabinoids; oke nanị, methamphetamine, phencyclidine.

T35-37 kD ΔFosB nhazi na-ejikọta ya na ọgwụ na-adịghị ala ala n'ihi na ha dị ogologo ndụ (Chen et al. 1997; Alibhai et al. 2007). N'ụzọ dị iche, ọ dịghị ihe àmà na-egosi na nhazi nke ΔFosB ma ọ bụ nkwụsi ike nke mRNA na-achịkwa site na nchịkwa ọgwụ. N'ihi nkwụsi ike ya, ya mere, protein ΔFosB na-anọgide na ọkpụkpụ ma ọ dịkarịa ala izu ole na ole mgbe ịkwụsị ọgwụ. Anyị maara ugbu a na nkwụsi ike a bụ n'ihi ihe abụọ na-esonụ (ọgụgụ 1): (i) enweghi ngalaba degron abụọ na ΔFosB, bụ ndị nọ na C-terminus nke FosB zuru oke na ndị ọzọ protein protein Fos ma lelee ndị ahụ na-edozi ahụ ka ọ dị ngwa ngwa na (ii) phosphorylation nke ΔFosB na ya N-ngwụ site na 2 casin kinase na ikekwe protein kinases ọzọ (Ulery et al. 2006; Carle et al. 2007). Tọ kwụsiri ike na nhazi nke ΔFosB na-enye usoro ihe omuma nke ohuru site na ngbanwe nke ọgwụ na -eme okwu n'ahịrị nwere ike ịnọgide na-agbanyeghị n'agbanyeghị ogologo oge ịṅụ ọgwụ ọjọọ. Ya mere, anyị nwere ike ime ka ọrụ ΔFosB dị ka 'mgbanwe' nke na-enyere aka ịmalite ma nọgide na -Nestler et al. 2001; McClung et al. 2004).

3. Ọrụ nke ΔFosB na oghere na-eme ka ọ ghara ịmalite ịhazi azịza omume banyere ọgwụ ọjọọ

Ịghọta ọrụ nke ΔFosB na ịṅụ ọgwụ ọjọọ sitere na nyocha nke ụmụ irighiri bitransgenic nke nwere ike ịmepụta ΔFosB n'ụzọ dị irè n'ime oghere ahụ na-eme ka anụ ọhịa na-eto eto (Kelz et al. 1999). N'ụzọ dị oke mkpa, ụmụ oke ndị a nke kachasị njọ ΔFosB n'ụzọ na-adị na dynorphin-nwere ọkpụkpụ spiny neurons, ebe a na-ekwenye ọgwụ ndị ahụ iji mee ka protein ahụ dị. Ụdị phenotype nke ụmụ oke ΔFosB-overexpressing, nke n'ụzọ ụfọdụ dị ka ụmụ anụmanụ mgbe ọ na-apụtaghị ọgwụ ọjọọ, na-achikota na table 2. Ụmụ oke ahụ na-egosi mmelite locomotor buru ibu na-azaghachi na cocaine mgbe nnukwu nlekọta na-adịghị ala ala (Kelz et al. 1999). Ha na-egosiputa mmetụta dịkwuo mma na mmetụta na-akwụghachi ụgwọ nke cocaine na morphine nọ n'ọnọdụ-atụle ọnọdụ (Kelz et al. 1999; Zachariou et al. 2006), na ime onwe onye ka ọ na-eme ka cocaine dị ala karịa ndị na-ede akwụkwọ na-adịghị overexpress ΔFosB (Colby et al. 2003). Nakwa, ΔFosB overexpression na nucleus accumbens na-ekwupụta mmepe nke ịdabere na ụbụrụ na-akwado ya ma na-akwalite ịdị na-eme ka a na -Zachariou et al. 2006). N'ụzọ dị iche, ΔFosB-na-egosipụta ụmụ oke bụ ndị nkịtị na mpaghara ndị ọzọ gbasara omume, gụnyere agụmakwụkwọ gbasara ọdịiche dị ka a na-enyocha na mmiri nke Morris (Kelz et al. 1999).

Usoro ntinye akwụkwọ nke ịṅụ ọgwụ ọjọọ: ọrụ nke ΔFosB

Isiokwu 2

Ụdị phenotype na mbịpụta ΔFosB na dynorphin + neurons nke nucleus accumbens na dorsal striatum^a.

·       ↵a A na-emepụta ihe ndị a kọwara na tebụl a na-ekwu okwu banyere ΔFosB na ụmụ irighiri bitransgenic ebe okwu ΔFosB na-atụkwasị anya na dynorphin + neurons nke nucleus accumbens na dorsal striatum; A na-ahụ ọtụtụ mkpụrụ akụkụ dị iche iche nke ΔFosB na hippocampus na frontte cortex. N'ọtụtụ ọnọdụ, phenotype ejikọtawo kpọmkwem na okwu ΔFosB na ngwangwa accumbens kwa otu site na iji nnyefe nyefe mkpụrụ ndụ nje.

Ihe ezubere iche nke ΔFosB overexpression na isi ihe na-ebuwanye ibu, site na iji nnyefe nke mbufe mgbasa ozi, bu ihe n 'Zachariou et al. 2006), nke na-egosi na mpaghara ụbụrụ a nwere ike ịkọ maka phenotype a hụrụ na ụmụ irighiri bitransgenic, ebe a na - egosikwa ΔFosB na storseti dorsal nakwa n'ókè dị nta na mpaghara ụbụrụ ndị ọzọ. Ọzọkwa, na-elekwasị anya na enkephalin nke nwere ọkpụkpụ spiny neurons na ngọngọ accumbens na ụbụrụ dorsal dị iche iche nke ụmụ irighiri ihe dị iche iche nke na-adịghị egosiputa ọtụtụ n'ime ụdị phenotypes ndị a, na-emetụta kpọmkwem dynorphin + nucleus na-eme ka ihe ndị a na-emetụta.

N'adịghị ka ikwu okwu nke ΔFosB, overexpression nke protein mutant Jun (ΔcJun ma ọ bụ ΔJunD) - ọrụ ndị dịka onye na-adịghị mma na-adịghị mma nke ihe ndekọ nke AP-1-site na iji ụmụ bitransgenic ma ọ bụ nnyefe ntanetị nke mgbasa ozi gwọọ kpatara mmetụta omume (Peakman et al. 2003; Zachariou et al. 2006). Tihe omuma a na-egosi na ntinye nke ΔFosB na dynorphin-nke nwere ihe omimi nke ihe omimi nke ihe ndi ozo na-eme ka obi umu anu na cocaine na ogwu ndi ozo na-eme ihe, ma nwee ike ichoputa usoro nke ime ka ndi mmadu nwee mmuta.

Mmetụta nke ΔFosB nwere ike ịgbatị nke ọma karịa iwu nke ịmara ọgwụ ọjọọ n'ihi na ọ na-eme ka àgwà ndị dị mgbagwoju anya metụtara usoro ahụ riri ahụ. Ndị na-arụ ọrụ na-egbuke egbuke ΔFosB na-arụsi ọrụ ike iji gwọọ cocaine na-enwe usoro nchịkọta onwe onye, ​​na-atụ aro na ΔFosB nwere ike ime ka ụmụ anụmanụ mara ihe mkpali na-akpali akpali nke cocaine ma si otú ahụ duga nkwụghachi azụ mgbe ịṅụ ọgwụ ọjọọ (Colby et al. 2003). Achịkwa ΔFosB-egosipụ na-egosipụtakwa mmetụta nke nchegbu nke mmanya na-aba n'anya (Picetti et al. 2001), a phenotype nke ejikọtara ya na mmụba mmanya na ụmụ mmadụ. Otu n'ime nchọpụta mbụ a na-egosi na ΔFosB, na mgbakwunye na ịmalite ịmalite iji ọgwụ ọjọọ eme ihe, na-eme mgbanwe mgbanwe nke omume na-akwalite àgwà ịchọ ọgwụ ọjọọ, ma kwado echiche ahụ, nke e kwuru n'elu, na ΔFosB na-arụ ọrụ dịka mgbagwoju anya maka ahụike ahụ. ala. Otu ajụjụ dị mkpa n'okpuru nyocha ugbu a bụ ma mmelite ΔFOSB n'oge ọgwụ ọjọọ na-akwalite omume ịchọ ọgwụ ọjọọ mgbe oge nkwụsịtụ dị, ọbụna mgbe ọkwa ΔFosB bichara (lee n'okpuru).

4. Akwụsị nke ΔFosB na oghere na-esiwanye ike site n'inye ụgwọ ọrụ

A na-ekwenye na nsogbu ahụ na-arụ ọrụ site na ịchịkwa nzaghachi maka ụgwọ ọrụ nkịtị, dịka nri, ihe ọṅụṅụ, mmekọahụ na mmekọrịta mmekọrịta mmadụ na ibe ya. N'ihi nke a, enwere mmasị na mpaghara nke ụbụrụ a nke a na-akpọ ọgwụ ọjọọ (dịka ịṅụbiga mmanya ókè, ịgba chaa chaa, mmega ahụ, wdg). Ụdị anụmanụ nke ọnọdụ dị otú ahụ dị oke; Otú o sina dị, anyị na ndị ọzọ achọpụtala na nnukwu ihe oriri nke ọtụtụ ụdị ụgwọ ọrụ nkịtị na-eduga ná nchịkọta nke 35-37 kDformforms nke ΔFosB na nucleus accumbens. A hụla nke a mgbe nnukwu ọkwa ụkwụ na-agba ọsọ (Werme et al. 2002) nakwa dị ka mgbe na-eri nri shuga nke sucrose, nri ma ọ bụ mmekọahụ (Teegarden & Bale 2007; Wallace et al. 2007; Teegarden et al. na pịa). N'ọnọdụ ụfọdụ, ntinye a na-ahọrọ maka ntinye nke dynorphin + nke ọkpụkpụ spiny (Werme et al. 2002). Nnyocha nke inducible, ụmụ anụ bitransgenic na nke nnyefe mkpụrụ ndụ nke gwọọ ọrịa egosipụtawo na ikwubiga okwu ókè nke ΔFosB na ngwongwo na-eme ka ụgbọala na oriri dịkwuo uru maka ụgwọ ọrụ ndị a, mgbe nkwupụta nke protein protein kachasị mma na-eme ọpụpụ effect (table 2; Werme et al. 2002; Olausson et al. 2006; Wallace et al. 2007). Ihe ndị a chọpụtara na ΔFosB na ụbụrụ ụbụrụ a na-enwe mmetụta maka ụmụ anụmanụ ọ bụghị naanị n'ihi ụgwọ ọgwụ kama maka ụgwọ ọrụ nke ọma, ma nwee ike itinye aka na nkwupụta ụbụrụ.

5. Mmetụta nke ΔFosB na oghere na-ebuwanye ibu site na nrụgide na-adịghị ala ala

N'ibu ihe akaebe na-egosi na ΔFosB na-ebute ya n'ime oghere ahụ site na-ekpughe ya na ọgwụ ọjọọ, ọ na-adọrọ mmasị ịhụ na a na-ebute ΔFosB na mpaghara ụbụrụ a mgbe ọtụtụ ụdị nrụgide na-adịghị ala ala, gụnyere nrụgide nchịkwa, mmeri nke mmadụ (Perrotti et al. 2004; Vialou et al. 2007). N'adịghị ka ọgwụ ọjọọ na ụgwọ ọrụ nkịtị, Otú ọ dị, a na-ahụkarị mmeghe a na mpaghara ụbụrụ a n'ihi na a na-ahụ ya n'ụzọ dị ịrịba ama na dynorphin + na enkephalin + ụda nke ọkpụkpụ spiny neurons. Ihe omuma nke mbu na-egosi na ntinye nke ΔFosB nwere ike nnochite anya nzaghachi nke oma, nke na enyere mmadu aka ime ka nsogbu di. Nkwupụta a kwadoro site na nchoputa mbụ nke ikwu okwu nke ΔFosB na ngwongwo, site n'iji mpempe akwụkwọ, ọnyá bitransgenic ma ọ bụ nnyefe mkpụrụ ndụ mgbasa ozi, nke na-eme nzaghachi dịka nke antidepressant dị iche iche (dịka mmeri ndị mmadụ, ugwo mmiri egwu), mgbe Okwu ΔcJun na-akpata mmetụta pro-depression-mmetụta (Vialou et al. 2007). Ọzọkwa, nchịkwa na-adịghị ala ala nke ọgwụ ndị na-agwọ ọrịa antidepressant na-enwe mmetụta dịka nchekasị na inducing ΔFosB na mpaghara ụbụrụ a. Ọ bụ ezie na ọ dị mkpa ịrụkwu ọrụ iji mee ka nchọpụta ndị a pụta ìhè, ọrụ dị otú ahụ ga-adabere na nkwupụta ndị ahụ ΔFosB na - eme ka ụbụrụ nke ụbụrụ na - akwụ ụgwọ ụgwọ ọrụ ma nwee ike inyere ụmụ anụmanụ aka ịnagide nsogbu nrụgide. N'ụzọ na-adọrọ mmasị, ọrụ a nke a na-eche maka ΔFosB na nucleus accumbens yiri nke ahụ egosipụtara na nso nso a maka agba ntụ nke periaqueductal ebe ihe edemede ahụ na-ebutekwa site na nrụgide na -Berton et al. 2007).

6. Mkpụrụ ebumnuche maka ΔFosB na ngwangwa accumbens

Ebe ọ bụ na ΔFosB bụ ihe na-ederede, ọ nwere ike ịmepụta ụdị phenotype a na-adọrọ adọrọ n'ime oghere site na ịmepụta ma ọ bụ na-emegharị okwu nke mkpụrụ ndụ ndị ọzọ. Dị ka egosiri na ọgụgụ 1, ΔFosB bụ ngwaahịa na-enweghị atụ nke fosB gene nke na-enweghị ihe ka ukwuu n'ime ngalaba transactivation C-na-eweta n'ogo FosB n'ogologo ma na-ejigide ebe nchekwa na DNA. ΔFosB jikọtara ndị òtù ezinụlọ nke Jun na ihe na-eme ka dimer jikọtara saịtị AP-1 na DNA. Ụfọdụ nnyocha na-akọwa na vitio na-egosi na ebe ọ bụ na ΔFosB enweghị ọtụtụ n'ime azụmahịa transactivation ya, ọ na-arụ ọrụ dị ka onye na-adịghị mma nke ọrụ AP-1, ebe ọtụtụ ndị ọzọ na-egosi na ΔFosB nwere ike rụọ ọrụ transcript na saịtị AP-1 (Dobrazanski et al. 1991; Nakabeppu & Nathans 1991; Yen et al. 1991; Chen et al. 1997).

Iji mice anyị nwere ike imebi, bitransgenic nke na-eme ka ΔFosB ma ọ bụ njedebe ya kachasị njọ ΔcJun, na nyochaa okwu mkpụrụ okwu na ibe ibe Affymetrix, anyị gosipụtara na, na nucleus accumbens in vivo, Ọrụ ΔFosB bụ isi dị ka transcriptal activator, ebe ọ na-eje ozi dị ka nrụpụ maka obere mkpụrụ nke mkpụrụ ndụ ihe nketa (McClung & Nestler 2003). MN'ụzọ dị mma, ọrụ a dị iche iche nke ΔFosB bụ ọrụ nke oge na ogo nke okwu ΔFosB, na mkpirikpi oge, ọkwa dị ala na-eduga ná nrụgide ndị ọzọ na ogologo oge, ọkwa dị elu na-eduga n'ịmalite ọrụ. Nke a kwekọrọ na ịchọpụta na okwu dị mkpirikpi na ogologo oge ΔFosB na-eduga na mmetụta ndị ọzọ na omume: okwu ΔFOSB oge dị mkpirikpi, dịka okwu nke ΔcJun, na-ebelata mmasị cocaine, ebe ogologo okwu ΔFosB okwu na-eme ka mmasị cocaine (McClung & Nestler 2003). A na-enyocha usoro a maka nhazi a; otu akwukwo akwukwo ozo, nke na-adighi ndu, bu na ΔFosB, n'ogo di elu, nwere ike iguzo ndi mmadu na-eme ka akwukwo AP-1 (Jorissen et al. 2007).

A na-eguzobe ọtụtụ mkpụrụ ndụ nke ΔFosB site na iji usoro n 'table 3). Otu onye na-etinye aka na ya bụ GluR2, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) onye na-enweta glutamate subunit (Kelz et al. 1999). ΔFosB overexpression n'ime ụmụ irighiri bitransgenic na - eme ka okwu GluR2 na - eme ka o doo anya na enweghi ike igosi ya, na enweghi ihe a na - achoputa na otutu ntinye ihe ntinye aka ndi natara AMPA glutamate, ebe okwu ΔcJun na-egbochi ike cocaine iji dozie GluR2 (Peakman et al. 2003). Ihe gbasara AP-1 gụnyere ΔFosB (ma yikarịrị JunD) na-ejikọta AP-1 saịtị dị na promuler GluR2. Ọzọkwa, GluR2 overexpression site na nnyefe mkpụrụ ndụ nke gwọọ ọrịa na-eme ka ọ dịkwuo utịp nke cocaine, dị ka ogologo oge ΔFosB overexpression (Kelz et al. 1999). Ebe GluR2-nwere ọdụ AMPA nwere mmekorita ọ bụla na-ejikọta na channel AMPA nke na-enweghị akụkụ a, cocaine- na ΔFosB na-eme ka a gbanwee nke GluR2 na accumbens nwere ike ịdekọ, ma ọ dịkarịa ala, maka nzaghachi glutamatergic dị ntakịrị hụrụ na ndị a na-emepụta mgbe ọ na -Kauer & Malenka 2007; table 3).

Ihe nlele nke edere aha maka ΔFosB na ogidi na-ebuwanye ibu^a.

·       ↵a Ọ bụ ezie na ΔFosB na-achịkwa ngosipụta nke ọtụtụ mkpụrụ ndụ ihe nketa na ụbụrụ (dịka McClung & Nestler 2003), okpokoro na-edepụta naanị mkpụrụ ndụ ihe nketa ndị na-ezute ma ọ dịkarịa ala atọ n'ime usoro ndị a: (i) ụba (↑) ma ọ bụ belata (↓) okwu na ΔFosB Nkwupụta okwu, (ii) mmeghachi omume ma ọ bụ usoro nha anya site na ΔcJun, onye mmegide na-adịghị mma nke ntụgharị ederede AP-1, (iii) ΔFosB nwere ngwugwu AP-1 jikọtara na saịtị AP-1 na mpaghara nkwalite nke mkpụrụ ndụ, na ( iv) ΔFosB na-akpata mmetụta yiri nke ahụ na ọrụ nkwalite mkpụrụ ndụ na vitro dị ka a hụrụ na vivo.

·       ↵b N'agbanyeghị ihe àmà na-egosi na ΔFosB na-edegharị mkpụrụ ndụ dynorphin n'ime ụdị ọgwụ ọjọọ (Zachariou et al. 2006), e nwere ihe ndị ọzọ na-egosi na ọ nwere ike ime ihe n'ịmepụta mkpụrụ ndụ n'okpuru ọnọdụ dị iche iche (lee Cenci 2002).

Isiokwu 3

Ihe nlereanya nke emeziri emezi maka ΔFosB na ngwangwa accumbensa.

Onye ọzọ na-etinye aka na ΔFosB site na ΔFosB na ngwangwa accumbens bụ opioid peptide, dynorphin. Cheta na ΔFosB na-egosi na mmegide nke ọgwụ ọjọọ na-ebute ya kpọmkwem na mkpụrụ ndụ nke na-arụ ọrụ na mpaghara ụbụrụ a. Iji ọgwụ ọjọọ eme ihe na-enwe mmetụta dị mgbagwoju anya n'okwu mmechi, na-abawanye ma ọ bụ na-ebelata anya dabere na ọnọdụ ọgwụgwọ ejiri. Gini nke dynorphin nwere saịtị AP-1, nke nwere ike ijikọ ΔFosB-nke nwere AP-1. Ọzọkwa, anyị egosila na ntinye nke ΔFosB na-egosipụta okwu mkpụrụ ndụ nke dynorphin na nucleus accumbens (Zachariou et al. 2006). A na-eche na Dynorphin na-eme ka ndị ntinye aka-opioid rụọ ọrụ na VTA dopamine neurons ma na-egbochi dopaminergic nnyefe ma si otú a debe usoro nkwụghachi ụgwọ (Shippenberg & Rea 1997). Hn'eziokwu, ngbanwe ΔFosB nke okwu dynorphin nwere ike inye aka na mmelite nke usoro ụgwọ ọrụ nke ihe ederede a na-ekwu. E nwere ihe akaebe doro anya ugbu a na-akwado nsonye nke nchịkwa dynorphin na ụdị omume omume ΔFosB (Zachariou et al. 2006).

Ihe akaebe a egosila na ΔFosB na-edegharịkwa ọnụọgụ c-fos nke na-enyere aka ịmepụta mgbagwoju anya - site na ntinye ọtụtụ protein protein Fos na-adịte aka mgbe nnukwu ọgwụ na-apụta na nnukwu ΔFosB mgbe ịṅụ ọgwụ ọjọọ-Buru na mbụ (Renthal et al. na pịa). Usoro nke maka ΔFosB mmeghari okwu nke c-fos expression bụ mgbagwoju ma kpuchie n'okpuru.

Ụzọ ọzọ a na-eme iji chọpụta mkpụrụ ndụ nke mkpụrụ ndụ nke ΔFosB ejirila atụpụta okwu mkpụrụ ndụ nke mgbanwe nke na-adabere na ikwu okwu nke ΔFosB (ma ọ bụ ΔcJun) n'ime oghere na-eme ka iji okwu nkọwa DNA, dị ka akọwapụtara na mbụ. Ụzọ a emeela ka njirimara nke ọtụtụ mkpụrụ ndụ nke okwu ΔFosB mepụtara na mpaghara ụbụrụ a (Chen et al. 2000, 2003; Ang et al. 2001; McClung & Nestler 2003). Tmkpụrụ ndụ ihe nketa nke na-egosi na a ga-ebute site na omume osFosB dị ka onye na-eme ihe ntụgharị ederede bụ kinase-5 (Cdk5) na onye na-arụ ọrụ na P35 (Bibb et al. 2001; McClung & Nestler 2003). Cdk5 na-ebutekwa ya site na cocaine na-adịghị ala ala n'ime nsogbu ahụ, na-egbochi mmetụta nke okwu ΔcJun, na ΔFosB na-ejikọta ma na-eme ka usoro Cdk5 site na saịtị AP-1 na onye na-akwado ya (Chen et al. 2000; Peakman et al. 2003). Cdk5 bụ ihe dị mkpa nke ΔFosB ebe ọ bụ na okwu ya na njikọ nke ọnọdụ phosphorylation nke ọtụtụ protein na synaptic tinyere glutamate subunits (Bibb et al. 2001), nakwa dị ka mmụba na njupụta spine dendritic (Norrholm et al. 2003; Lee et al. 2006), n'ime nsogbu ndị ahụ, bụ ndị ejikọtara na nlekọta cocaine na-adịghị ala ala (Robinson & Kolb 2004). N'oge na-adịbeghị anya, iwu nke ọrụ Cdk5 dị na ngọngọ na-ejikọta ya na mgbanwe ndị a na-eme na cocaine (omume behavioral)Taylor et al. 2007).

Ntụle ΔFOSB ọzọ a chọpụtara site na iji microarys bụ NFκB. A na - ebute ihe edemede a na - ebute site na ΔFosB overexpression na cocaine na - adịghị ala ala, okwu nke ΔcJun gbochiri ya (Ang et al. 2001; Peakman et al. 2003). Ihe akaebe egosiputara na ntinye nke NFκB nwekwara ike inye aka na cocaine nwere ike ime ka ọkpụkpụ dendritic dị na mkpụrụ ndụ (Russo et al. 2007). Tụkwasị na nke ahụ, NFBB anọwo na-emetụta ụfọdụ n'ime nsogbu nsị nke methamphetamine na mpaghara mpaghara (Asanuma & Cadet 1998). Nchoputa na NFBB bụ mkpụrụ ndụ ebumpụta ụwa maka ΔFosB na-emesi ịdị mgbagwoju anya nke usoro nke ΔFosB na-eji kọwaa mmetụta nke cocaine na okwu mkpụrụ ndụ. Ya mere, na mgbakwunye na mkpụrụ ndụ nke ΔFosB na-enye site na AP-1 saịtị na ndị na-emepụta mkpụrụ ndụ, A ga-atụle ΔFosB ọtụtụ mkpụrụ ndụ ndị ọzọ site na ngbanwe NFBB na ihe ndị ọzọ na-emepụta proteins.

Nkọwa nke DNA na-enye ndepụta bara ọgaranya nke ọtụtụ mkpụrụ ndụ ndị ọzọ nke nwere ike itinye na ya, kpọmkwem ma ọ bụ n'ụzọ ntụgharị, site na ΔFosB. N'ime mkpụrụ ndụ ndị a bụ ndị ntinye aka na ntanetransmitter, ndị na-edozi ahụ na-arụ ọrụ na mbụ na postsynaptic, ọtụtụ ụdị ọnụọgụ ion na ọgwụ protein intracellular, yana ndị na-edozi ahụ nke na-achịkwa cytoskeleton na-eto eto na uto (McClung & Nestler 2003). A ghaghị ịrụ ọrụ ndị ọzọ iji gosi na onye ọ bụla n'ime ndị a na-edozi protein dị ka ihe dị iche iche nke cocaine na-eme site na ΔFosB na iji gosipụta ọrụ dị mkpa nke protein nke ọ bụla na-arụ n'ịgbasa usoro mmechi nke omume cocaine. N'ikpeazụ, n'ezie, ọ ga-abụ ihe dị mkpa iji gbanwee nyocha nke mkpụrụ ndụ ihe mgbaru ọsọ ọ bụla na usoro nke ụdị nke mkpụrụ ndụ ihe nketa nke iwu ya nwere ike ịchọrọ iji kwado ọnọdụ ahụike ahụ.

7. Mmetụta nke ΔFosB na mpaghara ụbụrụ ndị ọzọ

Mkparịta ụka a ruo ugbu a na-elekwasị anya nanị na ihe dị njọ. Ọ bụ ezie na nke a bụ ụbụrụ ụbụrụ ụgwọ ọrụ mpaghara ma dị mkpa maka mmegbu nke cocaine na ọgwụ ọjọọ ndị ọzọ, ọtụtụ ụbụrụ ụbụrụ ndị ọzọ dị oke mkpa na mmepe na nlekota nke ụbụrụ. Ajụjụ dị mkpa bụ, ma ΔFosB na-eme ihe na ụbụrụ ụbụrụ ndị ọzọ karịa ụbụrụ ahụ nwere ike imetụta ọgwụ ọjọọ. Mndi mmadu nwere ugbua, ugbua enwere ugbua na-egosi na mmegbu nke na-akpali akpali ma na-egbu egbu na-amanye ΔFosB n'ọtụtụ ụbụrụ dị iche iche na-emetụta n'akụkụ dịgasị iche iche nke ịṅụ ọgwụ ọjọọn (Nye et al. 1995; Perrotti et al. 2005, 2008; McDaid et al. 2006a,b; Liu et al. 2007).

Nnyocha e mere n'oge na-adịbeghị anya jiri nlezianya tụnyere ntinye nke ΔFosB na mpaghara ụbụrụ dị iche iche dị iche iche nke ọgwụ ọjọọ dị iche iche dị iche iche: cocaine; ụfụ; cannabinoids; na ethanol (table 4; Perrotti et al. 2008). Ngwurugwu anọ a na - eme ka ihe odide ahụ dịgasị iche iche dị iche iche na ngwongwo dị iche iche na ụbụrụ na-eme ka ọkpụkpụ dị na ya, amygdala, hippocampus, oghere ụbụrụ nke stria terminalis na akụkụ interstitial nke akụkụ ikpeazụ nke nsụgharị ihu. Cocaine na ethanol na-eme ka ΔFosB dị na mpụta septum, ọgwụ niile ma e wezụga maka cannabinoids na-eme ka ΔFosB dị na awọ ntụpọ periaqueductal, cocaine dị iche iche na-eduzi ΔFosB na mkpụrụ ndụ nke gamma-aminobutyric acid (GABA) n'ime ọnụọgụ akụkụ nke etiti mpaghara (Perrotti et al. 2005, 2008). Ke adianade do, e gosipụtara morphine iji mee ΔFosB na ventral pallidum (McDaid et al. 2006a). Na nke ọ bụla n'ime mpaghara ndị a, ọ bụ 35-37 kDformforms nke ΔFosB nke na-ejikọta ya na ọgwụ na-adịghị ala ala ma nọgide na-adịru ogologo oge mgbe ị na-apụ.

Isiokwu 4

N'iji tụnyere ụbụrụ ụbụrụ nke na-egosi mmịnye ΔFosB mgbe ọ na-apụtaghị na ndị ọgwụ nnọchiteanya nke mmegbu^a.

·       ↵a Tebụl anaghị egosi ụdị mmịba nke ΔFosB site na ọgwụ dị iche iche. Lee Perrotti et al. (2008) maka ozi a.

·       ↵Enwetaghị cocaine, ethanol na cannabinoids na ntinye nke ΔFosB na ventral pallidum ka a mụtabeghị, ma a hụla mmepụta dịka nzaghachi methamphetamine (McDaid et al. 2006b).

·       ↵A hụrụ ΔFosB ntinye n'ọtụtụ mpaghara mpaghara nke ụbụrụ mbụ, gụnyere infralimbic (medial prefrontal) na orbitofrontal cortex.

Ihe mgbaru ọsọ gbara ọkpụrụkpụ maka nchọpụta n'ọdịnihu bụ ịme ihe ọmụmụ, dị ka ihe ndị a kọwara n'elu maka nsogbu dị iche iche, iji kọwaa ihe ngosi ntanetị na omume nke ΔFosB nyere maka mpaghara nke ụbụrụ ndị a. Nke a bụ nnukwu ọrụ, ma ọ dị oké mkpa maka ịghọta mmetụta zuru ụwa ọnụ nke ΔFosB na usoro ahụ riri ahụ.

Anyị emeela ihe dị mkpa na nso nso a site na iji nnyefe mkpụrụ ndụ nke gwakọtara ọbara na-eme ka a mara omume nke ΔFosB na subregion nke corpox mbụ, ya bụ, orbitofrontal cortex. Nke a na-esi ike na-eri ihe, karịsịa, na-enye aka na impulsivity na compulsivity nke na -Kalivas & Volkow 2005). N'ụzọ na-adọrọ mmasị, n'adịghị ka oghere ahụ na-ebuwanye ibu ebe njide onwe onye na cocaine na-ejikọta aka na-eme ka ogo ΔFosB dị ka anyị kwuru na mbụ, anyị hụrụ na nchịkwa nke cocaine na-eme ka ọtụtụ ndị na-ebupụta ΔFosB na orbitofrontal cortex, na-atụ aro na nzaghachi a nwere ike ịbụ ihe metụtara akụkụ dị iche iche nke nchịkwa ọgwụ. (Winstanley et al. 2007). Mgbe ahụ, anyị na-eji nyocha nke nyocha nke nlezianya na ime mkpebi (dịka oge ntinye uche nke oge ise na nyocha oge ịkwụsị) iji chọpụta ma ΔFosB n'ime cortex orbitofrontal na-etinye aka na mgbanwe nke ọgwụ na cognition. Achọpụtara na ọgwụgwọ cocaine na-adịghị ala ala na-eme ka mmadụ nwee ike ịnagide nsogbu nke cocaine. Nnukwu okwuputa nke ΔFosB n'ime mpaghara a ka mimicked mmetụta nke cocaine na-adịghị ala ala, ebe nkwupụta nke onye iro na-adịghị mma, ΔJunD, na-egbochi mmezi omume a. Ihe nyocha DNA nke nyocha microarray mere ka a mara ọtụtụ ihe nwere ike ime ka a gbanwee omume a, gụnyere mgbanwe cocaine na nke ΔFosB na ntụgharị nke mpempe akwụkwọ glutamate metabotrophic mGluR5 na GABA_A onye na-anabata ihe yana ihe P (Winstanley et al. 2007). Mmetụta nke ndị a na ọtụtụ ihe ndị ọzọ na-etinye azịza ΔFosB chọrọ nyocha ọzọ.

Nchoputa ndị a na-egosi na ΔFosB na-enyere aka na-egbochi imegide nsogbu nke cocaine. Ndị na-ahụ maka nhụjuanya nke mmetụta cocaine nwere ike ịdaba na cocaine, ma ndị na-achọta ọgwụ ndị ọzọ na-akpata ọgba aghara na-arụ ọrụ ma ọ bụ ụlọ akwụkwọ enweghi ike ịghọ ndị na-eri ahụ (Shaffer & Eber 2002). Ịnagide ntachi anya nke mkparịta ụka cocaine nwere na cocaine-ndị nwere ahụmahụ nwere ike ịkwado mmezi ahụ. N'ụzọ dị otú a, mmịnye ΔFosB na cortex orbitofrontal nwere ike ịkwalite ọnọdụ ahụ riri ahụ, dịka omume ya na oghere ahụ ebe ΔFosB na-akwalite mmerụ ahụ site n'ịdị na-eme ka ọgwụ na-akpali akpali ma na-akpali akpali.

8. Usoro nke Epigenetic nke ΔFosB eme

Ruo n'oge na-adịbeghị anya, ọmụmụ ihe niile gbasara usoro ntụgharị ederede na ụbụrụ dabere na nha nke ọkwa mRNA dịgide. Dịka ọmụmaatụ, ọchụchọ maka mkpụrụ ndụ ihe nketa nke ΔFosB gụnyere ịchọpụta mRNA nke dị elu ma ọ bụ nke edepụtara na ΔFosB ma ọ bụ JcJun, dịka e kwuru na mbụ. Ntụle nyocha a bara uru nke ukwuu n'ịchọpụta ebumnuche ntinye maka ΔFosB; otu o sila di, o ghaghi igbochi ya ime ka a mata ihe ndi di n’ime ya. Kama nke ahụ, ihe ọmụmụ niile nke usoro dabere na usoro in vitro dịka ΔFosB na-agbaso usoro nkwalite nke mkpụrụ ndụ na usoro mgbanwe gel ma ọ bụ iwu ΔFosB nke ọrụ nkwado nke mkpụrụ ndụ na sel. Nke a adịghị enye afọ ojuju n'ihi na usoro nke usoro ntụgharị na-egosi ọdịiche dị egwu site na ụdị sel na ụdị sel, na-ahapụ ya ihe ọ bụla amachaghị otu ọgwụ ọjọọ, ma ọ bụ ΔFosB, na-achịkwa mkpụrụ ndụ ihe nketa ya n'ụbụrụ na vivo.

Nnyocha nke epigenetic mechanisms na-eme ka o kwe omume, na nke mbụ ya, ịkwanye envelopu otu nzọụkwụ ọzọ na-enyocha iwu ederede na ntụrụndụ nke ụmụ anụmanụ na-eme omume (Tsankova et al. 2007). Kemgbe ụwa, okwu ahụ bụ epigenetics na-akọwa usoro nke nwere ike iji keta àgwà mmadụ na-enweghị mgbanwe na usoro DNA. Anyị na-eji okwu ahụ karia nke ọma iji 'gbanwee mmezi nke mpaghara chromosomal ka ị debanye aha, ama ma ọ bụ na-eme ka ọrụ a gbanwere agbanwe' (Bird 2007). Ya mere, anyị maara ugbu a na ọrụ mkpụrụ ndụ ihe nketa na-achịkwa mgbanwe nke covalent (dịka acetylation, methylation) nke akụkọ ihe mere eme na gburugburu mkpụrụ ndụ ihe nketa na mbanye nke ụdị dị iche iche nke coactivators ma ọ bụ ndị isi na-edegharị ederede. Chromatin immunoprecipitation (ChIP) na-eme ka o kwe omume iji ihe omuma a na-eto eto banyere ihe ọmụmụ nke chromatin iji chọpụta ọnọdụ ọrụ nke mkpụrụ ndụ ihe nketa na mpaghara ụbụrụ nke anụmanụ nke ejiri ọgwụ eme ihe.

Ihe atụ nke otú ọmụmụ banyere ụkpụrụ chromatin nwere ike isi nyere anyị aka ịghọta usoro ihe omimi nke cocaine na ΔFosB na ọgụgụ 3. Dịka e kwuru n'elu, ΔFosB nwere ike ịrụ ọrụ dị ka onye na-arụ ọrụ ma ọ bụ onye nrụgharịrị ederede dabere na ọnụọgụ nke sitere na ya. Iji ghọtakwuo omume ndị a, anyị nyochara ọnọdụ chromatin nke nyocha elele anya nke abụọ maka ΔFosB, cdk5 nke ΔFosB na c-fos na-emegharị bụ nke a na-emegharị na ngwongwo. Usoro ọmụmụ nke immunoprecipitation chromatin gosipụtara na cocaine na-eme ka usoro cdk5 na ụbụrụ ụbụrụ a site na ihe ndị na-esonụ: ΔFosB na-ejikọta na cdk5 gene na recrues histone acetyltransferases (HAT, nke acetylate dị nso na akụkọ ihe mere eme) na SWI-SNF ihe; omume abụọ ahụ na-akwalite nsụgharị mkpụrụ ndụ (Kumar et al. 2005; Levine et al. 2005). Cocaine dị ala na-eme ka ụbụrụ na-emepụta ihe omimi site na phosphorylation na mgbochi nke histone deacetylases (HDAC; Renthal et al. 2007). N'aka nke ọzọ, cocaine na-abanye mkpụrụ ndụ c-fos: mgbe ΔFosB jikọtara na mkpụrụ ndụ a ọ na-achọpụta HDAC na ikekwe histone methyltransferases (HMT; nke methylate dị nso na akụkọ ihe mere eme) ma si otú ahụ mechie transcript c-fos (ọgụgụ 3; Renthal et al. na pịa). Ajụjụ bụ isi bụ: gịnị na-ekpebi ma ΔFosB na-arụ ọrụ ma ọ bụ na-egbochi mkpụrụ ndụ mgbe ọ jikọtara na onye nkwalite mkpụrụ ndụ?

Nyocha 3

Usoro nke Epigenetic nke ΔFosB eme. Ọnụ ọgụgụ ahụ na-egosi ihe dị iche iche na-akpata mgbe ΔFosB jikọtara na mkpụrụ ndụ ọ na-arụ ọrụ (dịka cdk5) na-edegharị (dika c-fos). (a) Na promoter cdk5, ihe ndị a na-akpọ ΔFosB recat HAT na SWI-SNF, nke na-akwalite nhazi ọrụ. Enwerekwa ihe akaebe maka iwepu HDACs (lee ederede). (b) N'ụzọ dị iche, na promoter c-fos, ndị a na-akpọ ΔFosB HDAC1 nakwa ma eleghị anya HMTs nke na-eme ka okwu nchịkwa dị. A, P na M na-egosipụta ihe omimi nke histone, phosphorylation na methylation, n'otu n'otu.

Usoro omumu omumu nke usoro epigenetic nke riri ogwu na adi nma n'ihi na ha kwere nkwa ikpughere ihe omuma banyere ihe omuma di iche iche nke ndi ozo ji eme ihe n'emebi okwu nke okwu ozo n'onu acumbens na mpaghara ndi ozo. Ijikọta okwu DNA nke a na-akpọ ChIP maka mgbagha mgbagwoju anya (ebe ngbanwe na nchịkọta chromatin ma ọ bụ ihe odide nke nwere ike nyochaa genome n'obosara) ga - eduga na njirimara mkpụrụ ndụ mkpụrụ ndụ ọgwụ na ΔFosB nwere nnukwu obi ike na izuzu. Tụkwasị na nke ahụ, usoro epigenetic bụ ndị na-achọ ịma mma na-adọrọ mmasị ka ha nwee ike ịkọwa ọnọdụ dị ogologo oge dị ogologo na ọnọdụ nke ịba ahụ. N'ụzọ dị otú a, ọgwụ ọjọọ na ΔFosB na-agbanwe agbanwe na akụkọ ihe mere eme na ihe ndị metụtara epigenetic alterations na-enye usoro ndị nwere ike ịme ka mgbanwe mgbanwe ederede na-adịgide ogologo oge mgbe ọgwụ ọjọọ kwụsị na ikekwe ọbụna mgbe ΔFosB mebiri na ọkwa nkịtị.

9. Mkpebi

Ofkpụrụ nke ntinye nke ΔFosB na oghere na-eme ka ọ ghara ịmalite site na ikpughe ụgwọ ọrụ na-adịghị ala ala, nrụgide ma ọ bụ ọgwụ ọjọọ na-eweta echiche na-adọrọ mmasị banyere arụmọrụ nkịtị nke protein na mpaghara ụbụrụ a. Dị ka e sere na ọgụgụ 2, enwere ọkwa dị mma nke ΔFosB na ntọala na-abanye n'okpuru ọnọdụ nkịtị. Nke a pụrụ iche na mpaghara dị iche iche, ebe ọ bụ na BFosB fọrọ nke nta ka ọ bụrụ na enweghị ike ịchọta ebe ọzọ na ụbụrụ na ntọala. Anyị na-eche na ọkwa nke ΔFosB na ngwongwo na-anọchi anya ịgụpụta ihe mmadụ na-ekpughe na mmetụta uche, ma nke ọma ma nke na-adịghị mma, jikọtara ogologo oge dị ogologo nke enyere ikike nke protein. Achọpụtaghị ọdịiche dị iche iche na mkpụrụ ndụ nke mkpụrụ ndụ ΔFosB site na ịkwụghachi ụgwọ na nsogbu ntụgharị, ọ dịkwa mkpa ịrụ ọrụ ọzọ iji kọwaa nsonaazụ arụmọrụ nke ọdịiche ndị a. Anyị na-echekwu na ka ọkwa dị elu nke mkpali nke mmetụta uche na-eme ka ΔFosB nwee ike ime ka ọrụ ghara ịmalite, a na-agbanwe ọrụ ndị ahụ ka ha wee nwee ike ịmatakwu ihe ndị na-akwụghachi ụgwọ. N'ụzọ dị otú a, ntinye nke ΔFosB ga-akwalite ncheta metụtara ụgwọ ọrụ (ntụgharị uche) site na ọrụ dị iche iche nke ihe na-eme ka ọ pụta ìhè. N'okpuru ọnọdụ nkịtị, ntinye nke ọkwa dị oke ala nke moderateFosB site na ịkwụghachi ụgwọ ma ọ bụ ịgbagha ihe ga-agbanwe site na imezi mgbanwe anụmanụ maka nsogbu gburugburu ebe obibi. Otú ọ dị, oke ịbata ΔFosB nke a hụrụ n'okpuru ọnọdụ ahụike (dịka ikpughe na ọgwụ na-adịghị ala ala) ga-eduga n'ịghọta oke oke nke ihe na-eme ka ihe na-eme ka ọ ghara ịmalite ị andụ ọgwụ ọjọọ. Ntinye ΔFosB na mpaghara ụbụrụ ndị ọzọ nwere ike itinye aka na akụkụ dị iche iche nke obodo riri ahụ, dị ka atụpụtara site na nchọpụta recentFosB na nso nso a na orbitofrontal cortex.

Ọ bụrụ na echiche a ziri ezi, ọ na-eme ka o kwe omume na ọkwa nke ΔFosB na ngwongwo ma ọ bụ ikekwe mpaghara ụbụrụ ndị ọzọ nwere ike iji dị ka onye na-emepụta ihe iji chọpụta ọnọdụ nke ịmalite ọrụ ụgwọ ọrụ nke onye ọ bụla, yana ogo nke mmadụ 'riri ahụ', ma n'oge mmepe nke ahụ riri ahụ na nwayọọ nwayọọ na-ebelata ya n'oge ọpụpụ ma ọ bụ ọgwụgwọ. E gosipụtara ofFosB dị ka ihe nrịba ama nke ọnọdụ riri ahụ na ụdị anụmanụ. Ụmụ anụmanụ na-eto eto na-egosi oke ntinye nke ΔFosB iji tụnyere ụmụ anụmanụ ndị okenye, na-adabere na nhụsianya dị ukwuu ha nwere maka ahụ riri ahụ (Ehrlich et al. 2002). Tụkwasị na nke ahụ, nkwụsị nke mmetụta nkwụkọ nke nicotine na GABA_B onye na-anabata ezigbo allosteric modulator na-ejikọta nchikota nke nicotine induction nke ΔFosB na nucleus accumbens (Mombereau et al. 2007). Ọ bụ ezie na ọ dị oke ụbụrụ, ọ bụ ihe a pụrụ ichepụta na a pụrụ iji obere oghere PET ligand, nke dị elu maka ΔFosB, iji nyere aka chọpụta nsogbu ọrịa na-eri ahụ nakwa nyochaa ọganihu n'oge ọgwụgwọ.

N'ikpeazụ, ΔFosB n'onwe ya ma ọ bụ nke ọ bụla n'ime ọtụtụ mkpụrụ ndụ ihe nketa ọ na-achịkwa-nke a chọpụtara site na usoro okwu DNA ma ọ bụ ChIP na mgbawa mgbawa-na-anọchite anya ebumnuche ndị nwere ike maka mmepe nke usoro ọgwụgwọ ọhụụ maka ị addictionụ ọgwụ ọjọọ. Anyị kwenyere na ọ dị mkpa ileba anya karịa ọgwụ ọgwụ ọjọọ (dịka ndị na-anabata neurotransmitter na ndị na-ebugharị) maka ndị ọrụ ọgwụgwọ nwere ike ị addictionụ ọgwụ ọjọọ. Ihe ngosi ederede nke genome-wide nke nwere ike inweta teknụzụ dị elu nke oge a na-enye isi iyi dị mma nke ụdị ọhụụ a na mbọ anyị na-eme ka ọgwụgwọ na-agwọ ọrịa na-eri ahụ.

Nkweta

Ngosipụta. Onye edemede ahụ ekwughị na ọ dịghị esemokwu ọ bụla gbasara ịkwadebe nyocha a.

Ihe odide ala

· Otu onyinye nke 17 na Nzukọ Mkparịta ụka Issue 'Ihe nhụjuanya nke ị addictionụ ọgwụ ọjọọ: ọhụụ ọhụrụ'.

· © 2008 Royal Society

References

1.    ↵

1. Alibhai IN,

2. Green TA,

3. Potashkin JA,

Nestler EJ

2007 Iwu nke fosB na ΔfosB mRNA okwu: ọmụmụ ihe na vivo na in vitro. Nkwụsị Brain. 1143, 22-33. a: 10.1016 / j.brainres.2007.01.069.

CrossRefMedlineweb nke Sayensị

2.    ↵

1. Ang E,

2. Chen J,

3. Zagouras P,

4. Magna H,

5. Holland J,

6. Schaeffer E,

Nestler EJ

2001 Induction nke NFBB n'ime oghere na-ebuwanye ibu site n'ọchịchị cocaine na-adịghị ala ala. J. Neurochem. 79, 221-224. ma ọ bụ: 10.1046 / j.1471-4159.2001.00563.x.

CrossRefMedlineweb nke Sayensị

3.    ↵

1. Asanuma M,

2. Cadet JL

1998 Methamphetamine na-ebuli elu na NFBB DNA-arụ ọrụ na-atọrọ na superoxide dismutase transiceic ụmụ oke. Mol. Nkwụsị Brain. 60, 305-309. doi:10.1016/S0169-328X(98)00188-0.

Medline

4.    ↵

1. Berton O,

2. et al.

Ngosipụta 2007 nke ΔFosB na periaqueductal gray by stress na-akwalite mmeghachi omume na-arụ ọrụ. Neuron. 55, 289-300. ma ọ bụ: 10.1016 / j.neuron.2007.06.033.

CrossRefMedlineweb nke Sayensị

5.    ↵

1. Bibb JA,

2. et al.

2001 mmetụta nke na-adịghị ala ala na-ekpuchi cocaine bụ protein Cuban protein Cdk5. Nature. 410, 376-380. a: 10.1038 / 35066591.

CrossRefMedline

6.    ↵

1. Nnụnụ A

Echiche 2007 nke epigenetics. Nature. 447, 396-398. ma ọ bụ: 10.1038 / nature05913.

CrossRefMedline

7.    ↵

1. Ihe Car TL,

2. Ohnishi YN,

3. Ohnishi YH,

4. Alibhai IN,

5. Wilkinson MB,

6. Kumar A,

Nestler EJ

Ọnụnọ nke nchekwa C-terminal degron ngalaba na-enyere aka na nkwụsi ike pụrụ iche ΔFosB. Eur. J. Neurosci. 2007, 25–3009. ma ọ bụ: 10.1111 / j.1460-9568.2007.05575.x.

CrossRefMedlineweb nke Sayensị

8.    ↵

1. Carlezon WA, Jr,

2. Duman RS,

Nestler EJ

2005 Ọtụtụ ihu nke CREB. Ụdị Neurosci. 28, 436-445. a: 10.1016 / j.tins.2005.06.005.

CrossRefMedlineWeb Science

9.    ↵

1. Cenci MA

Ihe ndi edeputara na 2002 ihe banyere oria ojoo nke dyskinesia l-DOPA kpatara na oria oke nke oria Parkinson. Amino Acids. 23, 105–109.

CrossRefMedlineWeb Science

10. ↵

1. Uchechi JS,

2. Nye O,

3. Kelz MB,

4. Hiroi N,

5. Nakabeppu Y,

6. Olileanya BT,

Nestler EJ

Iwu 1995 nke ΔFosB na ndị na-edozi FosB dịka nchịkwa electroconvulsive (ECS) na ọgwụgwọ cocaine. Mol. Pharmacol. 48, 880-889.

nkịtị

11. ↵

1. Chen J,

2. Kelz MB,

3. Olileanya BT,

4. Nakabeppu Y,

Nestler EJ

1997 Na-emeghị Ihe Ọhụụ: Ụdị dịgasị iche iche nke ΔFosB nke ụbụrụ na-adịghị agwọ ọrịa na ụbụrụ. J. Neurosci. 17, 4933-4941.

Abstract / FREE Full Text

12. ↵

1. Uchechi JS,

2. Chidinma JJ

3. Kelz MB,

4. Steffen C,

5. Ang ES,

6. Zeng L,

Nestler EJ

2000 Induction nke 5 kinase-cyclin-dependence na hippocampus site na nchịkwa electroconvulsive na-adịghị ala: ọrụ nke ΔFosB. 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 Ndabere nke CCAAT-enhancer na-ejikọta protein beta na ΔFosB transiceic ụmụ oke na site na mwepụ electroconvulsive. Neuropsychopharmacology. 29, 23-31. dị: 10.1038 / sj.npp.1300289.

CrossRefweb nke Sayensị

14. ↵

1. Colby CR, Nkem

2. hisgagharị,

3. Steffen C,

4. Nestler EJ,

5. Onwe DW

2003 ΔFosB na-akwalite mmetuta maka cocaine. J. Neurosci. 23, 2488-2493.

Abstract / FREE Full Text

15. ↵

1. Deroche-Gamonet V,

2. et al.

2003 Onye na-enweta glucocorticoid dị ka ihe ga-enyere gị aka iji belata ịṅụ ọgwụ cocaine. 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 Ngwa abụọ nke fosba FosB, FosB na ụdị ya dị mkpirikpi, FosB / SF, bụ ndị na-emepụta ihe na fibroblasts. Mol. Cell Cell. 11, 5470-5478.

Abstract / FREE Full Text

17. ↵

1. Ehrlich ME,

2. Sommer J,

3. Canas E,

4. Unterwald EM

Mice 2002 nke ndị na-adịghị edozi ahụ na-egosi mmelite nke ΔFosB dịkwuo mma na nzaghachi nye cocaine na amphetamine. J. Neurosci. 22, 9155-9159.

Abstract / FREE Full Text

18. ↵

1. Graybiel AM,

2. Moratalla R,

3. Robertson HA

1990 Amphetamine na cocaine na-eme ka mmezi ọgwụ kpọmkwem nke c-fos gene dị iche iche na matrix akụkụ na akụkụ ntụpọ nke striatum. Proc. Natl Acad. Sci. USA. 87, 6912-6916. dị: 10.1073 / pnas.87.17.6912.

Abstract / FREE Full Text

19. ↵

1. Green TA,

2. Alibhai IN,

3. Hommel JD,

4. DiLeone RJ,

5. Kumar A,

6. Theobald DE,

7. Neve RL,

Nestler EJ

Nkọwa nke 2006 nke okwu ICER na nsogbu nke nrụgide ma ọ bụ amphetamine na-eme ka mmeghachi omume na-eme ka mmeghachi omume mmetụta uche. J. Neurosci. 26, 8235-8242.

Abstract / FREE Full Text

20. ↵

1. Green TA,

2. Alibhai IN,

3. Unterberg S,

4. Neve RL,

5. Ghose S,

6.mimi CA,

Nestler EJ

Ihe ntinye 2008 nke ihe mmeghari ihe (ATFs) ATF2, ATF3, na ATF4 n'ime ihe omuma na ihe ha na-eme banyere omume uche. J. Neurosci. 28, 2025-2032. dị: 10.1523 / JNEUROSCI.5273-07.2008.

Abstract / FREE Full Text

21. ↵

1. Hiroi N,

2. Brown J,

3. Haile C,

4. Unu H,

5. Greenberg ME,

Nestler EJ

Mice 1997 FosB mutant: ọnwụ nke cocaine na-adịghị ala ala nke protein na-emetụta Fos ma mee ka uche cocaine si psychomotor na-akwụghachi ụgwọ. Proc. Ihe natal Acad. Sci. USA. 94, 10 397–10. dị: 10.1073 / pnas.94.19.10397.

22. ↵

1. Hiroi N,

2. Brown J,

3. Unu H,

4. Saudou F,

5. Vaidya VA,

6. Duman RS,

7. Greenberg ME,

Nestler EJ

1998 Ọrụ dị mkpa nke ụbụrụ fosba dị na mkpụrụ ndụlịl, cellular, na omume omume nke ihe mgbochi electroconvulsive. J. Neurosci. 18, 6952-6962.

Abstract / FREE Full Text

23. ↵

1. Olileanya B,

2. Kosofsky B,

3. Hyman SE,

Nestler EJ

Iwu 1992 nke okwu IEG na AP-1 nke na-ejide cocaine na-adịghị ala ala na nkịta rat. Proc. Natl Acad. Sci. USA. 89, 5764-5768. dị: 10.1073 / pnas.89.13.5764.

Abstract / FREE Full Text

24. ↵

1. Olileanya BT,

2. Nye O,

3. Kelz MB,

4. Onwe DW,

5. Iadarola MJ,

6. Nakabeppu Y,

7. Duman RS,

Nestler EJ

Ntupụta 1994 nke AP-1 na-adịgide adịgide bụ nke nwere protein dịka Fos dịka ụbụrụ site na cocaine na-adịghị ala ala na ọgwụgwọ ndị ọzọ na-adịghị ala ala. Neuron. 13, 1235-1244. doi:10.1016/0896-6273(94)90061-2.

CrossRefMedlineweb nke Sayensị

25. ↵

1.Jorissen H, bụ J

2. Ulery P,

3. Henry L,

4. Gourneni S,

5. Nestler EJ,

6. Rudenko G

2007 Dimerization na DNA-ejide ihe nke ihe odide ΔFosB. Mmiri nyocha. 46, 8360-8372. dị: 10.1021 / bi700494v.

CrossRefMedlineweb nke Sayensị

26. ↵

1. Kalivas PW,

2. Volkow ND

2005 Ụdị nkwụsị nke njiriji: usoro ọgwụgwọ nke mkpali na nhọrọ. M. J. Ọchịachukwu. 162, 1403-1413. dị: 10.1176 / appi.ajp.162.8.1403.

Abstract / FREE Full Text

27. ↵

1. Kauer JA,

2. Malenka RC

2007 Synaptic plasticity na riri ahụ. Nat. Mkpu. Neurosci. 8, 844-858. ma ọ bụ: 10.1038 / nrn2234.

CrossRefMedlineweb nke Sayensị

28. ↵

1. Kelz MB,

2. et al.

1999 Nkwupụta nke ihe odide transcript ΔFosB na ụbụrụ na-ejikwa nlezianya mee ka cocaine. Nature. 401, 272-276. a: 10.1038 / 45790.

CrossRefMedline

29. ↵

1. Kumar A,

2. et al.

Ngwongwo nke Chromatin 2005 bụ usoro bụ isi nke cocaine nwere ike ime ka plasticity dị na striatum. Neuron. 48, 303-314. ma ọ bụ: 10.1016 / j.neuron.2005.09.023.

CrossRefMedlineweb nke Sayensị

30. ↵

1. Lee KW,

2. Kim Y,

3. Kim AM,

4. Helmin K,

5. Nairn AC,

6. Greengard P

2006 Cocaine na-emepụta ihe nkedo azụ dendritic na D1 na D2 dopamine receptor-nwere ọkpụkpụ spiny neurons na ngwakọta accumbens. Proc. Natl Acad. Sci. USA. 103, 3399-3404. dị: 10.1073 / pnas.0511244103.

Abstract / FREE Full Text

31. ↵

1. Levine A,

2. Guan Z,

3. Barco A,

4. Xu S,

5. Kandel E,

6. Schwartz J

Ngwunye 2005 CREB na-ejide onwe ya na-emeghachi omume na cocaine site na acetylating histones na promoser fosB na snoetum òké. Proc. Natl Acad. Sci. USA. 102, 19 186-19 191. dị: 10.1073 / pnas.0509735102.

32. ↵

1. Liu HF,

2. Zhou WH,

3. Zhu HQ,

4. Lai MJ,

5. Chen WS

2007 Microinjection of M (5) onye na-anabata muscarinic antisense oligonucleotide n'ime VTA na-egbochi okwu FosB na NAc na hippocampus nke heroin na-achọpụta oke. Neurosci. Ncha. 23, 1-8. doi:10.1007/s12264-007-0001-6.

CrossRefMedline

33. ↵

1. Udechukwu M,

2. Korutla L,

3. Cha XY,

4. Koebbe MJ,

5. Ugboro anọ KM,

6. Bowers MS,

7. Kalivas PW

2000 NAC-1 bụ ụbụrụ POZ / BTB ụbụrụ nke nwere ike igbochi nkwụnye nke cocaine n'ihe banyere oke. J. Neurosci. 20, 6210-6217.

Abstract / FREE Full Text

34. ↵

1. McClung CA,

Nestler EJ

2003 Iwu nke mkpụrụ okwu na okwu cocaine site n'aka CREB na ΔFosB. Nat. Neurosci. 11, 1208-1215. dị: 10.1038 / nn1143.

35. ↵

1. McClung CA,

2. Ulery PG,

3. Perrotti Li,

4. Zachariou nke V,

5. Berton O,

Nestler EJ

2004 ΔFosB: mgbaghari nke ihe omimi nke imeghari oge na ụbụrụ. Mol. Nkwụsị Brain. 132, 146-154. a: 10.1016 / j.molbrainres.2004.05.014.

Medline

36. ↵

1. McDaid J,

2. Dallimore JE,

3. Mackie AR,

4. Napier TC

Mgbanwe na mgbidi na pallidal pCREB na ΔFosB na eriri morphine-ndị a na-echebara echiche: mmekọrịta ya na onye na-anabata ya-electrophysiological evokes na ventral pallidum. Neuropsychopharmacology. 31, 2006a 1212-1226.

MedlineWeb Science

37. ↵

1. McDaid J,

2. Graham MP,

3. Napier TC

Mmetụta nke methamphetamine na-emetụta ihe dị iche iche na pCREB na ΔFosB n'oche dum nke ụbụrụ anụ ahụ. Mol. Pharmacol. 70, 2006b 2064-2074. dị: 10.1124 / mol.106.023051.

Abstract / FREE Full Text

38. ↵

1. Mombereau C,

2. Onyekwere L,

3. Kaupmann K,

4. Cryan JF

Ejikọtara 2007 GABAB receptor-positive modulation-induced blockade of the rewarding properties of nicotine na mbelata na ngwangwa accumens ΔFosB accumulation. J. Pharmacol. Gwa. Ọgwụ. 321, 172-177. dị: 10.1124 / jpet.106.116228.

CrossRef

39. ↵

1. Moratalla R,

2. Elibol R,

3. Vallejo M,

4. Graybiel AM

Ngbanwe 1996 mgbanwe nke netwọk na ngosipụta nke protein protein Fos-Jun na-adịghị emetụta na striatum n'oge ọgwụgwọ cocaine na-adịghị ala ala na nkwụsị. Neuron. 17, 147-156. doi:10.1016/S0896-6273(00)80288-3.

CrossRefMedlineweb nke Sayensị

40. ↵

1. Morgan JI,

2. Curran T

1995 Ụdị mkpụrụ ndụ oge mbụ: afọ iri na. Ụdị Neurosci. 18, 66-67. doi:10.1016/0166-2236(95)93874-W.

CrossRefMedlineweb nke Sayensị

41. ↵

1. Muller DL,

2. Unterwald EM

Ndị ntinye aka nke 2005 D1 na-edozi ΔFosB induction na rat striatum mgbe usoro nchịkwa morphine. J. Pharmacol. Gwa. Ọgwụ. 314, 148-155. dị: 10.1124 / jpet.105.083410.

CrossRef

42. ↵

1. Nakabeppu Y,

2. Nathans D

1991 Ụdị FosB a na-ahụkarị nke na-emekarị nke na-egbochi ọrụ Fos / Jun. Cell. 64, 751-759. doi:10.1016/0092-8674(91)90504-R.

CrossRefMedlineweb nke Sayensị

43. ↵

Nestler EJ

2001 Mkpụrụ ndụ bụ ihe ndabere nke ịṅụ ọgwụ ọjọọ na-adịgide adịgide. Nat. Mkpu. Neurosci. 2, 119-128. a: 10.1038 / 35053570.

CrossRefMedlineweb nke Sayensị

44. ↵

1. Nestler EJ,

2.Ogba M,

3. Onwe DW

2001 ΔFosB: nkwụsị nke mgbagwoju anya maka ọgwụ ọjọọ. Proc. Natl Acad. Sci. USA. 98, 11 042-11 046. dị: 10.1073 / pnas.191352698.

45. ↵

1. Norrholm SD,

2. Bibb JA,

3. Nestler EJ,

4. Ouimet CC,

5. Taylor JR,

6. Greengard P

Nkọwa nke 2003 Cocaine na-ebuwanye ibu nke mkpụrụ osisi dendritic na ngwangwa accumbens dabere na ọrụ nke kincy-kin-5. Neuroscience. 116, 19-22. doi:10.1016/S0306-4522(02)00560-2.

CrossRefMedlineweb nke Sayensị

46. ↵

1. Nye O,

Nestler EJ

1996 Induction nke ụbụrụ na-adịghị ala ala (antigens metụtara n'ụbụrụ) na ụbụrụ ụbụrụ site n'ọchịchị na-adịghị ala ala. Mol. Pharmacol. 49, 636-645.

nkịtị

47. ↵

1. Nye H,

2. Olileanya BT,

3. Kelz M,

4. Iadarola M,

Nestler EJ

1995 Ọmụmụ ihe banyere ọgwụ ndị ọkachamara banyere usoro iwu site na cocaine nke Fra na-adịghị ala ala na-emepụta ihe n'ime striatum na isi ojii. J. Pharmacol. Gwa. Ọgwụ. 275, 1671-1680.

48. ↵

1. O'Donovan KJ,

2. Tourtellotte WG, nke

3. Millbrandt J,

4. Baraban JM

1999 Ezinụlọ EGR nke transcript-usoro iwu: ọganihu na interface nke molecular na usoro neuroscience. Ụdị Neurosci. 22, 167-173. doi:10.1016/S0166-2236(98)01343-5.

CrossRefMedlineweb nke Sayensị

49. ↵

1. Olausson P,

2. Ikechukwu JD,

3. Tronson N,

4. Neve R,

5. Nestler EJ,

6. Taylor JR

2006 ΔFosB na isi ihe dị iche iche na-achịkwa àgwà na mkpali na-akwalite nri. J. Neurosci. 26, 9196-9204. dị: 10.1523 / JNEUROSCI.1124-06.2006.

Abstract / FREE Full Text

50. ↵

1. Peakman M.-C,

2. et al.

2003 Inducible, ụbụrụ ụbụrụ nke na-ekwu okwu ọjọọ nke c-Jun na ụmụ oke transgenic na-ebelata ntụgharị uche na cocaine. Nkwụsị Brain. 970, 73-86. doi:10.1016/S0006-8993(03)02230-3.

CrossRefMedlineweb nke Sayensị

51. ↵

1. Pérez-Otano I,

2. Mandelzys A,

3. Morgan JI

1998 MPTP-Parkinsonism na-esonyere site n'igosi okwu protein nke Δ-FosB dị na ụzọ dopaminergic. Mol. Nkwụsị Brain. 53, 41-52. doi:10.1016/S0169-328X(97)00269-6.

Medline

52. ↵

1. Perrotti Li,

2. Hadeishi Y,

3. Ulery P,

4.Ogba M,

5. Monteggia L,

6. Duman RS,

Nestler EJ

2004 Induction nke ΔFosB na mpaghara ụbụrụ na-akwụ ụgwọ ụgwọ mgbe nrụgide siri ike. J. Neurosci. 24, 10 594-10 602. dị: 10.1523 / JNEUROSCI.2542-04.2004.

53. ↵

1. Perrotti Li,

2. et al.

2005 ΔFosB na - agbakọta n'ime mkpụrụ ndụ GABAergic na ọdụdụ nke azụ nke akụkụ ahụ ventral mgbe ọgwụgwọ psychostimulant gasịrị. Eur. J. Neurosci. 21, 2817-2824. ma ọ bụ: 10.1111 / j.1460-9568.2005.04110.x.

CrossRefMedlineweb nke Sayensị

54. ↵

1. Perrotti Li,

2. et al.

2008 Ebumnuche dị iche iche nke ΔFosB ntinye ụbụrụ site na iji ọgwụ ọjọọ eme ihe. Synapse. 62, 358-369. dị: 10.1002 / syn.20500.

CrossRefMedlineweb nke Sayensị

55. ↵

Picetti, R., Toulemonde, F., Nestler, EJ, Roberts, AJ & Koob, GF 2001 Ethanol utịp ke ΔFosB ụmụ oke nje. Soc. Neurosci. Nna 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 Ihe ntanetị ndị na-emekarị maka ihe ndị na-eri ahụ bụ nicotine na cocaine. Sayensị. 275, 83-86. ma ọ bụ: 10.1126 / science.275.5296.83.

Abstract / FREE Full Text

57. ↵

1. Ezumike W,

2. et al.

2007 Histone deacetylase 5 na-achịkwa nhazi nke omume iji mee ka mmetụta uche na-adịghị ala ala. Neuron. 56, 517-529. ma ọ bụ: 10.1016 / j.neuron.2007.09.032.

CrossRefMedlineweb nke Sayensị

58. ↵

Renthal, W., Carle, TL, Maze, I., Covington III, HE, Truong, H.-T., Alibhai, I., Kumar, A., Olson, EN & Nestler, EJ Na pịa. ΔFosB na-agbakwunye epigenetic desensitization nke c-fos site na amphetamine na-adịghị ala ala. J. Neurosci.

59. ↵

1. Robinson TE,

2. Kolb B

2004 Ngwunye plastic na-ejikọta na iji ọgwụ ọjọọ eme ihe. Neuropharmacology. 47, S33-S46. a: 10.1016 / j.neuropharm.2004.06.025.

CrossRef

60. ↵

Russo, SJ et al. Nkọwa 2007 NFBB na-achịkwa àgwà cocaine na-akpa àgwà na plasticity. Ya mere. Neurosci. Abs., 611.5.

61. ↵

1. Shaffer HJ,

2. Eber GB

Ọnụ ọgụgụ 2002 Temporal na-aga n'ihu na ngosipụta nke nkwado cocaine na Nchịkọta National Comorbidity US. Ịṅụ ọgwụ ọjọọ. 97, 543-554. ma ọ bụ: 10.1046 / j.1360-0443.2002.00114.x.

CrossRefMedlineweb nke Sayensị

62. ↵

1. Shippenberg TS,

2. Rea W

Nyocha nke 1997 na mmetụta nke cocaine: mmụba site na dynorphin na kappa-opioid agonists na-anabata. Pharmacol. Mmiri mmiri. Behav. 57, 449-455. doi:10.1016/S0091-3057(96)00450-9.

CrossRefMedlineweb nke Sayensị

63. ↵

1. Taylor JR,

2.Lynch WJ,

3. Sanchez H,

4. Olausson P,

5. Nestler EJ,

6. Bibb JA

2007 Mgbochi nke Cdk5 na ngwangwa accumbens na-eme ka ọrụ melite na ume mkpali nke cocaine. Proc. Natl Acad. Sci. USA. 104, 4147-4152. dị: 10.1073 / pnas.0610288104.

Abstract / FREE Full Text

64. ↵

1. Teegarden SL,

2. Bale TL

2007 Mbelata na nhọrọ iri nri na-eme ka enwekwu mmetụta uche na ihe ize ndụ maka nlọghachi ihe oriri. Biol. Ọrịa. 61, 1021-1029. ma ọ bụ: 10.1016 / j.biopsych.2006.09.032.

CrossRefMedlineweb nke Sayensị

65. ↵

Teegarden, SL, Nestler, EJ & Bale, TL Na pịa. Mgbanwe mgbanwe nke ΔFosB na akara ngosi dopamine bụ nke a na-edozi site na nri dị oke abụba. Biol. Ọrịa.

66. ↵

1. Tsankova N,

2. Ezumike W,

3. Kumar A,

Nestler EJ

Nchịkọta Epigenetic 2007 na ọrịa uche. Nat. Mkpu. Neurosci. 8, 355-367. ma ọ bụ: 10.1038 / nrn2132.

CrossRefMedlineweb nke Sayensị

67. ↵

1. Ulery PG,

2. Rudenko G,

Nestler EJ

Iwu 2006 nke ΔFosB kwụsie ike site na phosphorylation. J. Neurosci. 26, 5131-5142. dị: 10.1523 / JNEUROSCI.4970-05.2006.

Abstract / FREE Full Text

68. ↵

Vialou, VF, Steiner, MA, Krishnan, V., Berton, O. & Nestler, EJ 2007 Ọrụ nke ΔFosB na ntọala ahụ na-abanye na mmeri na-adịghị ala ala. Soc. Neurosci. Ezigbo., 98.3.

69. ↵

Wallace, D., Rios, L n'omume ugwo olu. Soc. Neurosci. Ezigbo., 2007.

70. ↵

1. Werme M,

2. Nwee C,

3. Olson L,

4. Gilden L, bụ

5. Thorén P,

6. Nestler EJ,

7. Brené S

2002 ΔFosB na-achịkwa ụkwụ na-agba ọsọ. J. Neurosci. 22, 8133-8138.

Abstract / FREE Full Text

71. ↵

1. Uchechukwu CA,

2. et al.

Ntinye 2007 ΔFosB na orbitofrontal cortex na-egbochi imegide cocaine na-eme ka a ghara inwe mmerụ. J. Neurosci. 27, 10 497-10 507. dị: 10.1523 / JNEUROSCI.2566-07.2007.

72. ↵

1. Nke J,

2. Amamihe RM,

3. Tratner nke m,

4. Verma IM

1991 Ụdị FosB ọzọ a gbanyere mkpọrọgwụ bụ ihe na-adịghị mma nke ntinye ederede na mgbanwe site na Fos proteins. Proc. Natl Acad. Sci. USA. 88, 5077-5081. dị: 10.1073 / pnas.88.12.5077.

Abstract / FREE Full Text

73. ↵

1. Na-eto eto ST,

2. Porrino LJ,

3. Iadarola MJ

1991 Cocaine na-ebute protein ndị na-edozi ahụ na c-fos-immunoreactive site na ndị nzaghachi D1 dopaminergic. Proc. Natl Acad. Sci. USA. 88, 1291-1295. dị: 10.1073 / pnas.88.4.1291.

Abstract / FREE Full Text

74. ↵

1. Zachariou nke V,

2. et al.

2006 Otu ọrụ dị mkpa maka ΔFosB n'ime oghere ahụ na-ebuwanye ibu na mmemme morphine. Nat. Neurosci. 9, 205-211. dị: 10.1038 / nn1636.

CrossRefMedlineweb nke Sayensị

·       CiteULike

·       Kọmputa

·       Connotea

·       Del.icio.us

·       Digg

·       Facebook

·       Twitter

Kedu ihe bụ nke a?

Isiokwu na-edeba isiokwu a

o EW Klee,

o JO Ebbert,

o H. Schneider,

o RD merụrụ ahụ,

o na SC Ekker

Azụ Zebra maka ọmụmụ ihe banyere Nchọpụta Ọdịdị nke NicotineNicotine Tob Res May 1, 2011 13: 301-312

o   nkịtị

o   Ederede zuru ezu

o   Full Text (PDF)

O LA Briand,

FM Nkechi,

o RC Pierce,

o RJ Valentino,

o na JA Blendy

Ndị Nne Na - ahụ Maka Nne Na - ahụ Maka Mkpa na Nrụpụta Mgbochi: Nrụ ọrụ nke Mmeghachi Ndị Na - akpata Mmekọrịta CAMP. Neurosci. December 1, 2010 30: 16149-16159

o   nkịtị

o   Ederede zuru ezu

o   Full Text (PDF)

o V. Vialou,

o I. Maze,

o W. Renthal,

o QC LaPlant,

o EL Watts,

o E. Mouzon,

O S. Ghose,

CA CA Tamminga,

o na EJ Nestler

Onye na-eme ka ihe na-eme ka ahụ sie ike na-eme ka ahụ ghara ịdị na-akpata nsogbu site na ntinye nke FNBJ. Neurosci. October 27, 2010 30: 14585-14592

o   nkịtị

o   Ederede zuru ezu

o   Full Text (PDF)

o F. Kasanetz,

o V. Deroche-Gamonet,

o N. Berson,

o E. Balado,

o M. Lafourcade,

o O. Manzoni,

o na PV Piazza

A na - ejikọta nsogbu na - eri ihe na Synaptic PlasticityScience June 25, 2010 328: 1709-1712

o   nkịtị

o   Ederede zuru ezu

o   Full Text (PDF)

o Y. Liu,

o BJ Aragona,

o KA Na-eto Eto,

O Dietz,

o M. Kabbaj,

M. Mazei-Robison,

o EJ Nestler,

o na Z. Wang

Ihe ojoo na-eme ka dopamine na-eme ka amphetamine mebie mmekorita nke mmekorita nke ndi mmadu na ndi otu osisi. Natl. Aka. Sci. USA January 19, 2010 107: 1217-1222

o   nkịtị

o   Ederede zuru ezu

o   Full Text (PDF)

o I. Maze,

O Ọ Covington,

O Dietz,

O Q. LaPlant,

o W. Renthal,

o SJ Russo,

M. M. Igwe,

o E. Mouzon,

o RL Neve,

o SJ Haggarty,

Nke Y. Ren,

o SC Sampath,

YL Hurd,

o P. Greengard,

o A. Tarakhovsky,

o A. Schaefer,

o na EJ Nestler

Ọrụ Dị Oké Mkpa nke Akụkọ MXDNUMXa nke Methyltransferase na Cocaine-Induced PlasticityScience January 9, 8 2010: 327-213

o   nkịtị

o   Ederede zuru ezu

o   Full Text (PDF)

o SJ Russo,

O MB Wilkinson,

MS Mazei-Robison,

O Dietz,

o I. Maze,

o V. Krishnan,

o W. Renthal,

o A. Graham,

o SG Birnbaum,

TA TA Green,

O B. Robison,

o A. Lesselyong,

o LI Perrotti,

ọ CA ​​Bolanos,

o A. Kumar,

MS Clark,

o JF Neumaier,

o RL Neve,

O AL Bhakar,

PA PA Barker,

o na EJ Nestler

Ihe nkedo nuchoputa (kappa) B Signaling Regulates Neuronal Morphology and Cocaine RewardJ. Neurosci. March 18, 2009 29: 3529-3537

o   nkịtị

o   Ederede zuru ezu

o   Full Text (PDF)

o Y. Kim,

ma MA Teylan,

M. Baron,

A. A. Sands,

o AC Nairn,

o na P. Greengard

Methylphenidate na-emepụta ihe nkedo nke dendritic na {Delta} okwu FosB na accumbensProc. Natl. Aka. Sci. USA February 24, 2009 106: 2915-2920

o   nkịtị

o   Ederede zuru ezu

o   Full Text (PDF)

RK Chandler,

o BW Fletcher,

o na ND Volkow

Na-emeso Mgbochi Ọgwụ na Ịṅụ Egwu na Usoro Ikpe Ikpe Mmehie: Ịdịwanye Mma na Ahụike Ọha na SafetyJAMA January 14, 2009 301: 183-190

o   nkịtị

o   Ederede zuru ezu

o   Full Text (PDF)

o D. L Wallace,

o V. Vialou,

o L. Rios,

o TL Carle-Florence,

S. Chakravarty,

o A. Kumar,

DL Graham,

TA TA Green,

A. A. Kirk,

o SD Ikegwu,

o LI Perrotti,

o M. Barrot,

RJ DiLeone,

o EJ Nestler,

o na CA Bolanos-Guzman

Mmetụta nke {Delta} FosB na Nzuzo Na-ebuwanye Ụba na Egwuregwu Na-arụ Ọrụ Na-akpata. Neurosci. October 8, 2008 28: 10272-10277

o   nkịtị

o   Ederede zuru ezu

o   Full Text (PDF)