DeltaFosB e phelisana le maikutlo a epigenetic deensitization ea liphatsa tsa lefutso tsa c-fos ka mor'a ho pepeseha ha amphetamine e sa foleng (2008)

William Renthal,¹ Tiffany L. Carle,¹ Ian Maze,¹ Herbert E. Covington, III,¹ Hoang-Trang Truong,¹ Imran Alibhai,¹ Arvind Kumar,¹ Rusty L. Montgomery,² Eric N. Olson,² 'me Eric J. Nestler^1,*

Lits'ebetso tsa limolek'hule tse fetolang ts'ebeliso ea lithethefatsi ho ea ho boithabiso ho fihlela ho lemalla ho ts'oara joala ho sa feleng li lula li sa utloisisehe. Molek'hule e le 'ngoe e kentsoeng ts'ebetsong ena ke ΔFosB, ntho ea ho ngola e bokellanang ka har'a striatum kamora ho pepesetsoa lithethefatsi khafetsa ebe e hanana le karabelo ea boits'oaro ho li-psychostimulants le lithethefatsi tse ling tsa tlhekefetso. Mekhoa e tlase ea ho ngola e sebelisang "ΔFosB" e sebelisang boitšoaro bo susumetsoang ke lithethefatsi e utloisisoa ka mokhoa o phethahetseng. Re ne re tlalehetse mekhoa ea ntlafatso ea chromatin eo ΔFosB e sebelisang tlhahiso ea liphatsa tse ling tsa lefutso, leha ho le joalo, hore na khatello ea mofuta oa mediFosB-mediated e ntse e sa tsejoe joang. Mona, re supa c-fos, mofuta o potlakileng oa tlhaho o kentseng ts'ebetso ea ts'ebetso ka mor'a ho pepeseha ha psychostimulant, joalo ka sepheo sa ho theoha sa sepheo se hatisitsoeng ke ΔFosB. Re bontša hore ho bokelloa ha ΔFosB ka striatum kamora kalafo ea amphetamine e sa foleng c-fos ho kenyelletsa mRNA ho lethal dose le latelang la lithethefatsi. OsFosB e hlonepha c-fos polelo ka ho hira histone deacetylase 1 (HDAC1) ho c-fos morekisi oa liphatsa tsa lefutso, o fetolang nalane ea lipalesa tse potileng le ho fihlela tšebetso ea mofuta oa hau. Ka hona, ho kokota hoa tikoloho ea HDAC1 ho striatum ho felisa amphetamine-induction desensitization ea c-fos mofuta. K'honthineng, amphetamine e sa foleng e eketsa histone H3 methylation ho c-fos papatso, phetoho ea chromatin e tsejoang hape ho hatella ts'ebetso ea gene, hammoho le maemo a polelo a H3 histone methyltransferase, KMT1A / SUV39H1. Boithuto bona bo senola tsela e 'ngoe ea epigenetic eo ho eona ΔFosB e sebelisanang le mananeo a ikhethileng a ho ngola,' me qetellong e le boits'oaro bo botle ba ho pepeseha ha amphetamine.

Ho ikarola ho RNA le ho ahloloa

Lithane tsa boko tse emisitsoeng li ile tsa qhekelloa ho TriZol (Invitrogen, Carlsbad, CA) mme ea sebetsoa ho latela protocol ea moetsi. RNA e ile ea hloekisoa ka likholomo tsa RNAesy Micro (Qiagen, Valencia, CA). Kakaretso ea RNA e ne e ngotsoe ka sepheo sa ho sebelisa Superscript III (Attitrogen). PCR ea nako ea nnete e ile ea tsamaisoa ka SYBR Green (ABI, Foster City, CA) 'me ea hlalosoa e sebelisa mokhoa oa ΔΔCt. Bona Lethathamo la tlatsetso bakeng sa lenane le felletseng la li-primers.

Chromatin immunoprecipitation (ChIP)

Chromatin e ile ea qaptjoa 'me ea ntšoa ka morao ho moo (bona Mekhoa ea Tlatsetso) sebelisa li-antibodies tsa histone tsa acetylated (Millipore, Billerica, MA), anti-HDAC1, kapa anti-H3K9me2 ho Abcam (Cambridge, UK), anti-FosB (C-terminus) (Kumar et al., 2005), anti-FosB (N-terminus) (Santa Cruz Biotechnology, Santa Cruz, CA, State), kapa taolo ea IgG ea taolo (Millipore). IP e ile ea bokelloa ho sebelisoa li-protein tsa Protein A tse tsoang Millipore. Kamora ho hlatsoa, ​​chromatin e ile ea nkuoa ho tloha liaparong 'me ea khutlisoa e khubung moo ho nang le proteinase K. DNA e ile ea hloekisoa le ho hlakoloa ka ho sebelisa PCR ea nako ea nnete.

Ho itšireletsa mafung

Lisele tsa PC12 li ile tsa fetisetsoa ka V5-tagged HDAC1 (Montgomery et al., 2007), FosB, kapa ΔFosB joalo ka ha ho hlalositsoe pele (Carle et al., 2007). Li-lysates tsa sele li ile tsa aroloa tsa ba tsa kenngoa ka li-antibodies tse se nang 'mele tsa IgG (Sigma) kapa anti-FosB (sc-48, Santa Cruz) bosiu ho 4 ° C. Immunoprecipitation e entsoe ka lieta tsa Protein G (Sigma). Liprotheine tse immunoprecipended li ne li tsamaisoa le SDS-PAGE mme li hlahlobisisoa ke ho thibeloa ha Bophirimela ho sebelisa antibody ea polyclonal ea anti-FosB (N-terminus)Carle et al., 2007) le anti-V5 antibody (Abcam). Ho fumana hore na HDAC1 le ΔFosB ke balekane ba tlamang Ka vivo, re sebelisitse ho ts'oaroa hoa motlakase ka makhetlo a mangata ho hula liprotheine tse phahameng tsa ΔFosB (Hope et al., 1994). Litonki tsa cortical li ile tsa qhaloa ho tsoa ho likhoto tse sa foleng tsa (7 letsatsi le letsatsi) kapa litoeba tse tšoaroang ke sham, lysed, le immunoprecipended joalo ka ha ho hlalositsoe kaholimo ka li-antibodies tsa anti-HDAC1 (Abcam).

Laser thunngoa microdis Assembly

U sebelisa ts'ebetso ea bongaka ea stereotactic, litla-morao tsa litoeba li ile tsa ts'oaetsoa ke vaerase e amanang le adeno (AAV) e hlalosang gene kapa GFP e bonts'itsoeng mahlakoreng a fapaneng a boko. Kamora kalafo ea amphetamine, methapo ea leqhoa e ile ea sebetsoa likarolo tsa "coron" tsa 8 -m mme tsa kenngoa li-slide tsa membrane (Lieca, Wetzlar, Jeremane). Likarolo tse nang le tšoaetso ea AAV li ile tsa hlaseloa ka laser-dissected (Leica) ho qolla lisele tse se nang tšoaetso mme tsa sebetsoa ka PicoPure RNA kit (MDS, Sunnyvale, CA). RNA e ile ea holisoa ka RiboAmp HS kit (MDS) mme ea boela ea hatisoa joalo ka ha ho hlalositsoe kaholimo. Bona Mekhoa ea Tlatsetso bakeng sa lintlha tse felletseng.

OsFosB e hlonepha c-fos ho kenella ka mRNA ka har'a striatum ka mor'a ho pepeseha ho sa feleng ha amphetamine

Ho fumana hore na takatso ea c-fos Polelo ea mRNA ke selefouno e laoloang ke ΔFosB, re ile ra tšoara likhoto ka letsoai kapa ka amphetamine e mpe kapa e sa foleng 'me ra ba tlohela hore ba tlohele lapeng la bona bakeng sa 1 ho ea matsatsing a 10. Liraka li ile tsa hlahlojoa ha 1 hr kamora lethal e le phephetso ea saline kapa amphetamine. Joalokaha ho bontšitsoe pejana (bona Selelekela), c-fos mRNA e kentsoe 4-fold in striatum ke tsamaiso e matla ea amphetamine. Ho litoeba tse neng li pepesitsoe ke amphetamine e sa foleng, leha ho le joalo, polelo ea c-fos ho arabela phephetsong ea lithethefatsi ho ile ha amoheloa ka mokhoa o hlakileng bakeng sa matsatsi a 5 a ho khaotsa lithethefatsi (Setšoantšo sa 1A), ntlha eo ΔFosB e lulang e phahame sebakeng sena sa boko (Hope et al., 1994). Ntle le moo, ho litoeba tse neng li tlositsoe ho amphetamine ea nako e telele bakeng sa matsatsi a 5, re fumane basal c-fos Polelo ea mRNA e fokotsoe ka tlase ho litekanyetso tse fumanoang ka har'a li-control tse tšoaroang ka saline (Setšoantšo sa 1A). Bohlokoa, boholo ba c-fos ho kenella phephetsong ea amphetamine ho ile ha tsebahala haholo ka letsatsi 1 ea ho khaotsa ho bapisoa le liphoofolo tse tšoaroang letsoai. Ka bobeli, lipatlisiso tsena li bonts'a phello ea amphetamine e sa foleng ho basal le ho susumetsang c-fos maemo a mRNA, leha e le litlamorao tse peli tse etsahalang ka nako e rarahaneng ea nako.

  

Setšoantšo sa 1

OsFosB e hlonepha c-fos ho kenella ka mRNA ka har'a striatum ka mor'a ho pepeseha ho sa feleng ha amphetamine

Ho fumana hore na ho bokellana ha ΔFosB ka mora amphetamine e sa foleng ho kenya letsoho ka kotlolloho ho hloloheloeng ha c-fos polelo, re qalile re etsa ChIP ea ΔFosB ka c-fos papatso ea gene ho striatum. Joalokaha ho bontšitsoe Setšoantšo sa 1B, e c-fos morekisi o na le ΔFosB e tlamang haholo kamora ho pepesetsoa ha amphetamine, phello e bonoang bonyane matsatsi a 5 a ho tlosoa hoa lithethefatsi. Lintlha tsena li lokisa "osFosB" ho lula ho c-fos papatso le kinetics ea e fokotsehile c-fos mosebetsi oa mofuta. E latelang, ho hlahlobisisa ka kotloloho hore na lisosa tsa ΔFosB li fokotsehile c-fos ho itlhahisa ho araba phephetso ea amphetamine, re sebelisitse vector ea AAV ho tlatselletsa ΔFosB, kapa GFP e le taolo, litekong. Ka mor'a moo, re ile ra qolla tšoaetso e tšoaelitsoeng ke laser microdis Assembly (Setšoantšo sa 1Cmme e sebetsa qRT-PCR ea c-fos mRNA. Ha re bone tse fokolang c-fos mRNA e kentsoe kamora hore ho be le kokoana-hloko e mpe ea amphetamine ka hara thipa ea methapo e tšoaelitsoeng ke AAV-ΔFosB ha e bapisoa le lehlakore la konteraka le tšoaelitsoeng ke AAV-GFP β-tubulin mRNA e lula e sa fetoha (Setšoantšo sa 1D). Lintlha tsena li fana ka maikutlo a hore c-fos desensitization e kopantsoe le ho bokelloa ha ΔFosB ho morekisi oa eona kamora ho pepeseha ho sa tsitsitseng amphetamine.

ΔFosB e hira HDAC1 ho c-fos morekisi ho buella c-fos khatello ea mofuta

Ho fuputsa mekhoa eo ΔFosB e ikamahanyang le eona c-fos ho nyahama, re ile ra shebana le nako eo ka eona c-fos e hatelitsoe haholo: Matsatsi a 5 a ho tlohela ho tsoa ho amphetamine e sa foleng. Mochine oa bohlokoa o amehang ho c-fos ts'ebetso ho araba mefuta e fapaneng ea ts'usumetso, ho kenyelletsa le koae (Kumar et al., 2005), ke histone acetylation. Ka hona re ne re thahasella ho tseba hore na histone acetylation ho c-fos morekisi oa liphatsa tsa lefutso le eena o ile a susumetsoa ke acute amphetamine le hore na ho hlahisa lithethefatsi khafetsa ho ile ha hlahisa karabelo. Ehlile, amphetamine ea hlobaetsang e matlafalitse histone H4 acetylation ho c-fos morekisi, 'me, kamora kalafo e matla ea amphetamine, tlhahiso ena e ne e se e sa bonoe (Setšoantšo sa 2A). Acetylation ea H4 e ne e ikhethile, kaha ha ho na phello e hlokometsoeng bakeng sa H3 (ha e bontšoe). Lintlha tsena li fana ka maikutlo a hore histone acetylation e theotsoeng, e amanang le sebopeho se sebetsang sa "chromatin" se sebetsang hantle.Kouzarides, 2007), e kenya letsoho hore takatso ea c-fos gene kamora ho pepeseha hoa amphetamine e sa foleng. Ho etsa tlhahlobo ena ka kotloloho, re ile ra tšoara litoeba ka amphetamine e sa feleng, mme kamora matsatsi a 5 a ho tlosa, ra tsamaisa HDAC inhibitor, sodium butyrate kapa koloi ea eona. Re fumane hore sodium butyrate e khutlisa khatello ea amphetamine e susumetsoang ke c-fos polelo (Setšoantšo sa 2B), e tšehetsa ka kotloloho mohopolo oa hore hypoacetylation ho c-fos Promoter ke mochini o ka sehloohong o khethollang mofuta oa mofuta.

  

Setšoantšo sa 2

Ho amoheloa ha mediactivs ea HDAC1 ΔFosB on c-fos

Ho utloisisa kamoo ΔFosB e thibelang histone acetylation ho c-fos morekisi, re fuputse hore na ΔFosB e sebelisana le enzymes tse fokotsang histone acetylation, e leng, li-HDAC. Re qalile ho hlahloba HDAC1 le HDAC2 hobane li-enzyme tsena li rarahane ka lintlha tse fapaneng tsa mongolo ho hatella polelo ea mofuta oa gene (Grozinger le Schreiber, 2002). Kaha lithuto tsa pele tsa ChIP li ile tsa supa tšebetso ea bohlokoa ea HDAC1 ho c-fos papatso (bona ka tlase), empa ha ho na HDAC2 e sa bonoeng (e sa bonts'ang), re ile ra etsa liteko tsa co-immunoprecipation ho bona hore na ΔFosB e sebelisana le HDAC1 na. Ehlile re fumane hore immunoprecipitation of ΔFosB e boetse e theotse HDAC1 liseleng tsa PC12 (Setšoantšo sa 2D). Taba ea bohlokoa ke hore ts'ebelisano ena e sebetsa ka kotloloho bakeng sa ΔFosB, joalo ka bolelele bo felletseng bo sa bokelleng ka mora ts'ebetso ea psychostimulant e sa felengHope et al., 1994), ha e sebelisane le HDAC1. Re entse liteko tse fapaneng Ka vivo ka ho qobella palo e kholo ea ΔFosB ka ho ts'oaroa hoa motlakase. E lumellana le datha ea rona ea setso sa sele, ho itšireletsa mafung le antibody khahlanong le HDAC1 e theotsoe ΔFosB ho tsoa liseleng tsa boko (Setšoantšo sa 2E).

Ho ipapisitsoe le lintho tsena tse fumanoeng tse ΔFosB le HDAC1 li sebelisana 'moho a vitro 'me Ka vivo, re khothalelitse hore, kamora ho ba le mamello e sa foleng, ΔFosB e hira HDAC1 ho c-fos papatso ea gene. Ehlile, ChIP ea lysate tse tiisitsoeng e fumanoe e le maemong a phahameng haholo a HDAC1 ho c-fos papatso ka mor'a ho pepesetsoa nako e telele ea amphetamine (Setšoantšo sa 2C), athe amphetamine ha ea ka ea fetola HDAC1 e tlamang β-Actin papatso ea gene. Ho tseba ka kotloloho hore na HDAC1 e ne e lekane ho amohela c-fos induction, re fetisitse lisele tsa HEK293T ka HDAC1 kapa GFP mme ra li susumetsa ka serum ea 5% (bona Mekhoa ea Tlatsetso). Re fumane serum e hlohlellelitsoe c-fos polelo e ile ea hlaseloa haholo liseleng tse nang le khatello e fetisisang ea HDAC1 (Setšoantšo sa 2F). Lithuto tsena li ile tsa eketsoa Ka vivo ka ho sebelisa litoeba tsa HDAC1 tse tšoaelitsoeng ke AAV-GFP ka lehlakoreng le leng la bona le AAV-CreGFP hdac1 gene ho contralateral striatum. AAV-CreGFP e fokotsehile Hdac1 Tlhaloso ea mRNA meleng e nang le ts'oaetso (e arotsoe ke laser microdissection) ka> 75% ha e bapisoa le taolo ea AAV-GFP ha Hdac2 polelo e lutse e sa fetohe (Setšoantšo sa 2G). Litoeba li ile tsa phekoloa ka nako e telele le amphetamine e lateloang ke ho tlosoa hoa lithethefatsi bakeng sa matsatsi a 5. Litoeba li ile tsa hlahlojoa metsotso ea 30 kamora phephetso ea amphetamine mme libaka tse nang le tšoaetso li tšoaetsoe microdissect. Re fumane hore amphetamine e hlohlelletsa haholo c-fos mRNA liseleng tsa striatal tse tšoaelitsoeng ke AAV-CreGFP ha li bapisoa le AAV-GFP (Setšoantšo sa 2G), ho bontša hore HDAC1 ea hlokahala bakeng sa khatello e matla ea amphetamine e tsitsitseng ea c-fos polelo. Lintlha tsena li fana ka maikutlo a hore ho bokelleloa ha ΔFosB ka likhoto kamora kalafo e sa foleng ea amphetamine ho fella ka ΔFosB e tlamang ho c-fos papatso, ho hira HDAC1, histone acetylation e fokolang, 'me qetellong ke mosebetsi o fokolang oa gene.

Histyl methylation e phahame ho c-fos papatso ka mor'a ho pepeseha ha amphetamine e sa foleng

Phetoho ea ts'ebetso ea gene hangata e kenyelletsa liphetoho tse 'maloa tsa epigenetic tse etsahalang ka tsela e tšoanang (Kouzarides, 2007; Tsankova et al., 2007). E 'ngoe ea liphetoho tse hlakileng tsa histone tse amanang le ts'ebetso ea gene e fokotsehileng ke methylation ea histone H3 ho lysine 9 (H3K9). Phetoho ena ea histone, ha e fumanoa libakeng tse ntlafatsang, e amahanngoa le khatello ea ho ngola ka ho thaepa bahatisi ba kang HP1 (heterochromatin protein 1) (Kouzarides, 2007). Ka hona re ile ra sekaseka hore na hypoacetylation ea c-fos gene, e bonoang kamora tsamaiso ea amphetamine e sa foleng, e boetse e amahanngoa le liphetoho ho H3K9 methylation. Tumellanong le khopolo-taba ena, ChIP e entsoeng ka lisele tsa litšoelesa tse tsoang ho likhoto tse tšoaroang ke amphetamine ea nako e telele e senotse hore di-methylated H3K9 (H3K9me2) e ile ea eketseha haholo ka mokokotlong. c-fos morekisi (Setšoantšo sa 3A), phello e sa bonoang ho β-Actin papatso ea gene. E 'ngoe ea li-enzyme tsa bohlokoa tse sebelisang methapo ea methapo ea H3K9 ke KMT1A / SUV39H1, e ileng ea tsosa potso ea hore na polelo ea enzyme ena e laoloa ke tlhahiso ea amphetamine e sa foleng. Re sebelitse qRT-PCR kahar'a litoeba tse tšoaroang ke amphetamine e sa feleng mme re bone ho nyolisoa ho hoholo hoa Kmt1a / Suv39h1 MRNA, ha chromatin e ikhethileng e hlophisa enzyme Hdac5, o lula a sa angoe (Setšoantšo sa 3B). Ho fapana le HDAC1, leha ho le joalo, liteko tsa Co-immunoprecipation ha li a ka tsa senola tšebelisano efe kapa efe e hlakileng pakeng tsa ΔFosB le KMT1A / SUV39H1, leha e le hore re ne re sa tsebe ho fumana ntlafatso e kholo ea methyltransferase ho c-fos papatso ke ChIP (ha e bontšoe). Ho sa tsotelehe, liphuputso tsena li fana ka maikutlo a hore ho eketseha ha KMT1A / SUV39H1 ho ka ba le hypermethylate H3 ho c-fos hape kenya letsoho ho fokotsa mekhoa c-fos ketsahalo ea gene ka mor'a ho pepeseha ha amphetamine e sa foleng.

  

Setšoantšo sa 3

Histyl methylation ka mor'a ho pepesetsoa ha nako e telele ea amphetamine

Supp1

Mosebetsi ona o ne o tšehelitsoe ke lithuso tse tsoang NIDA

• Bibb JA, Chen J, Taylor JR, Svenningsson P, Nishi A, Snyder GL, Yan Z, Sagawa ZK, Ouimet CC, Ronaldn AC, Nestler EJ, Greengard P. Liphello tsa ho pepeseha ha cocaine e sa laoleheng li laoloa ke protheine ea neuronal Cdk5. Tlhaho. 2001; 410: 376-380. [E fetotsoe]
• Karolina TL, Karolina KN, Karolina KS, Karolina KS IN, Karolina KS Karolina, Karolina K, Karolina KS. Ts'ebeliso ea li-proteasome le -e leng mekhoa e fokolang ea FosB ho felisa ts'ebetso: ho tsebahatsa libaka tsa FosB tsa maemo a meholo le liphello tsa botsitso ba DeltaFosB. Eur J Neurosci. 2007; 25: 3009-3019. [E fetotsoe]
• Colby CR, Whisler K, Steffen C, Nestler EJ, Boiketsetso ba DW. Tlhahlobo e hlakileng ea sele ea striatal mofuta oa DeltaFosB e eketsa khothatso ea cocaine. J Neurosci. 2003; 23: 2488-2493. [E fetotsoe]
• Grozinger CM, Schreiber SL. Li-enzymes tsa Deacetylase: Ts'ebetso ea likokoana-hloko le tšebeliso ea li-inhibitors tse nyane tsa limolek'hule. Chem Biol. 2002; 9: 3-16. [E fetotsoe]
• Tšepo B, Kosofsky B, Hyman SE, Nestler EJ. Taolo ea polelo ea pele ea liphatsa tsa lefutso le AP-1 e tlamang lenaneong la litekanyetso ke cocaine e sa foleng. Proc Natl Acad Sci US A. 1992; 89: 5764-5768. [Tlhahiso ea mahala ea PMC] [E fetotsoe]
• Tšepo BT, Nye HE, Kelz MB, Self DW, Iadarola MJ, Nakabeppu Y, Duman RS, Nestler EJ. Tlhahiso ea motsoako oa AP-1 oa nako e telele o qapiloeng ke liprotheine tse kang Fos ka bokong ka cocaine e sa feleng le kalafo tse ling tse sa foleng. Neuron. 1994; 13: 1235-1244. [E fetotsoe]
• Hyman SE, Malenka RC, Nestler EJ. Mekgwa ya Neural ea bokhoba: karolo ea thuto e amanang le moputso le memori. Annu Rev Neurosci. 2006; 29: 565-598. [E fetotsoe]
• Kell MB, Chen J, Karl J, Karl K Wheller, Kelli Keller, Kelli MB, Karl Keller, Nestler EJ. Tlhaloso ea motsoako oa deltaFosB oa khatiso boko bo laola ho utloahala ha cocaine. Tlhaho. 1999; 401: 272-276. [E fetotsoe]
• Liphetoho tsa Kouzarides T. Chromatin le ts'ebetso ea tsona. Sele. 2007; 128: 693-705. [E fetotsoe]
• Kumar A, Choi KH, Renthal W, Tsankova NM, Theobald DE, Truong HT, Russo SJ, Laplant Q, Sasaki TS, Whistler KN, Neve RL, Self DW, Nestler EJ. Chodatin remodeling ke mochine oa bohlokoa o hlahisang polasetiki e entsoeng ka koae ho striatum. Neuron. 2005; 48: 303-314. [E fetotsoe]
• McClung CA, Nestler EJ. Tlhophiso ea liphatsa tsa lefutso le moputso oa cocaine ke CREB le DeltaFosB. Nat Neurosci. 2003; 6: 1208-1215. [E fetotsoe]
• McClung CA, Ulery PG, Perrotti LI, Zachariou V, Berton O, Nestler EJ. DeltaFosB: molek'hule oa limolek'hule bakeng sa ho fetola nako e telele bokong. Brain Res Mol Brain Res. 2004; 132: 146-154. [E fetotsoe]
• Montgomery RL, Davis CA, Potthoff MJ, Haberland M, Fielitz J, Qi X, Hill JA, Richardson JA, Olson EN. Histori deacetylases 1 le 2 li hlophisa ka nepo melao ea pelo ea morphoasemisis, kholo, le contractility. Dev Dy. 2007; 21: 1790-1802. [Tlhahiso ea mahala ea PMC] [E fetotsoe]
• Morgan JI, Curran T. Stimulus-transiling coupling in neurons: karolo ea liphatsa tsa lefutso tsa kapele-pele. Mekhoa ea Neurosci. 1989; 12: 459-462. [E fetotsoe]
• Nye HE, Hope BT, Kelz MB, Iadarola M, Nestler EJ. Liphuputso tsa litsebi tsa thuto ea lefapha la tlhophiso ea tlhahiso ea antigen e sa foleng e amanang le li-FOS ke k'hok'heinine ea striatum le nucleus accumbens. J Pharmacol Exp Ther. 1995; 275: 1671-1680. [E fetotsoe]
• Persico AM, Schindler CW, O'Hara BF, Brannock MT, Uhl GR. Polelo ea polelo ea bongoli: litlamorao tsa khatello e matla le e sa foleng ea amphetamine le khatello ea ente. Boko Res Mol Boko Res. 1993; 20: 91-100. [E fetotsoe]
• Renthal W, Maze I, Krishnan V, Covington HE, 3rd, Xiao G, Kumar A, Russo SJ, Graham A, Tsankova N, Kippin TE, Kerstetter KA, Neve RL, Haggarty SJ, McKinsey TA, Bassel-Duby R, Olson EN, Nestler EJ. Histori deacetylase 5 epigenetically e laola litloaelo tsa boits'oaro ho susumetsa maikutlo a sa foleng. Neuron. 2007; 56: 517-529. [E fetotsoe]
• Steiner H, Gerfen CR. Cocaine e susumetsoang ke c-fos messenger RNA e amana hofeta le polelo ea dynorphin ho striatum. J Neurosci. 1993; 13: 5066-5081. [E fetotsoe]
• Tsankova N, Renthal W, Kumar A, Nestler EJ. Taolo ea Epigenetic mathateng a kelello. Nat Rev Neurosci. 2007; 8: 355-367. [E fetotsoe]
• Zachariou V, Bolanos CA, Selley DE, Theobald D, Cassidy MP, Kelz MB, Shaw-Lutchman T, Berton O, Sim-Selley LJ, Dileone RJ, Kumar A, Nestler EJ. Karolo ea bohlokoa bakeng sa DeltaFosB nucleus accumbens morphine khato. Nat Neurosci. 2006; 9: 205-211. [E fetotsoe]
• Zhang J, Zhang L, Jiao H, Zhang Q, Zhang D, Lou D, Katz JL, Xu M. c-Fos e thusa ho fumana le ho felisoa ha liphetoho tse phehellang tsa koae. J Neurosci. 2006; 26: 13287-13296. [E fetotsoe]