DeltaFosB: Molek'hule e tsitsitseng ea ho lemala (2001)

LITLHAHISO: Joalokaha lithuto tsa morao-rao li tla senola DeltaFosB ke phetoho e tloaelehileng ea limolek'hule tsa lithethefatsi le boits'oaro. Ke ntho ea phetolelo e bolelang hore e ama hore na liphatsa tsa lefutso li buletsoe kapa ho tima. Joalokaha ho boletsoe libakeng tse ling, lithethefatsi tse lemalloang li koetela mekhoa e tloaelehileng. Ke ka hona e leng bothoto ho fana ka maikutlo a hore mekhoa ea boitšoaro e ke ke ea ba teng.

 THUTO E TLAHANG

Proc Natl Acad Sci US A. 2001 September 25; 98 (20): 11042-11046.

Doi: 10.1073 / pnas.191352698.

Eric J. Nestler *, Michel Barrot, le David W. Self

Lefapha la Psychiatry le Setsi sa Neuroscience ea Motheo, Univesithi ea Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070

inahaneloang

Nako e telele ea boits'oaro bo bong bo amanang le bokhoba ba lithethefatsi e bontšitse hore taolo ea polelo ea tlhaho ea neural e ka ameha ts'ebetsong eo lithethefatsi tsa tlhekefetso li bakang boemo ba tlhekefetso. IBopaki bo hlalosang bo fana ka maikutlo a hore transFosB e hatisang e emela mochine o le mong moo lithethefatsi tsa tlhekefetso li hlahisang liphetoho tse tsitsitseng bokong tse tlatsetsang tlatsong ea ho lemalla. ΔFosB, setho sa lelapa la Fos la lintlha tse hatisoang, se bokellana ka har'a sethala se bokellaneng sa methapo ea kutlo le li-dorsal striatum (likarolo tsa boko tse bohlokoa bakeng sa bokhoba ba taolo) kamora taolo e pheta-phetoang ea mefuta e mengata ea lithethefatsi tsa tlhekefetso. Ho bokelloa ho ts'oanang ha ΔFosB ho etsahala kamora ho sebetsa ka thata, ho fanang ka maikutlo a hore ΔFosB e ka bokellana ho arabela mefuta e mengata ea boits'oaro bo qobelloang. Habohlokoa, ΔFosB e phehella ho li-neuron nako e telele haholo ka lebaka la botsitso ba eona bo sa tloaelehang. Ka hona, ΔFosB e emela molek'hule o ka qalang le ho boloka liphetoho liphatlalatsong tsa lefutso tse tsoelang pele nako e telele kamora ho pepesetsoa lithethefatsi li khaolang. Boithuto ho litoeba tse sa sebetseng tsa "transgenic" tse fetisang ΔFosB kapa "inhibitor" e mpe ea protheine e fana ka bopaki bo hlakileng ba hore ΔFosB e baka kutloelo-bohloko e mabapi le litlamorao tsa boits'oaro ba lithethefatsi tsa tlhekefetso, mme mohlomong, e eketsa boits'oaro ba lithethefatsi. Mosebetsi ona o ts'ehetsa pono ea hore ΔFosB e sebetsa e le mofuta oa "molek'hule e ts'oaroang" eo butle-butle e fetolang likarabo tsa lithethefatsi tse matla hore li fetohe maemong a tsitsitseng a tlatselletsang molemong oa nako e telele oa neural le boits'oaro bo tlatselletsang tlatsong.

Patlisiso ea bokhoba ba tai e shebane le ho utloisisa mekhoa e rarahaneng eo lithethefatsi tsa tlhekefetso e fetolang boko ho etsa lits'oants'o tse mpe tse bonts'ang bokhoba. E 'ngoe ea liqholotso tse boima masimong ke ho supa liphetoho tse tsitsitseng tse tlisoang ke lithethefatsi bokong hore li ikarabelle bakeng sa boits'oaro bo bobe bo sa pheleng nako e telele. Mohlala, motho ea lemaletseng joala a ka ba kotsing e kholo ea ho khutlela bothateng esita le ka mor'a ho tlohela lilemo tse ngata.

Ho tiea ha litlolo tsena tsa boitšoaro ho lebisitse ho tlhahiso ea hore li ka kopanngoa, bonyane ka karolo, ka liphetoho lipuong tsa mofuta oa gene (1-3). Ho ea ka pono ena, ho pepesehela lithethefatsi tsa tlhekefetso khafetsa ho fetisoa hoa phetisetso ho li-synaps tse itseng bokong bo shebileng sethethefatsi. Boitšisinyo bo joalo bo qetella bo supa ka melaetsa e kenang ka hare ho ntho e kenang mokokotlong, moo e qalang teng ebe e boloka liphetoho ponong ea liphatsa tse itseng tsa lefutso. Mokhoa o ka sehloohong oo ka oona liphatsa tsa lefutso li susumetsang polelo ea liphatsa tsa lefutso ke taolo ea lintlha tse tsoang liprotheong, liprotheine tse tsamaeang le likarolo tsa mola le liphatsa tsa tsona.

Morero o mong oa lipatlisiso tsa bokhoba ba tahi ke ho bona lintlha tse fetotsoeng libakeng tsa boko tse amanang le tšebeliso ea lithethefatsi ka tlhekefetso. Ho fumanoe lintlha tse 'maloa tsa sengoloang lilemong tse leshome tse fetileng (1-6). Sepheo sa tlhahlobo ena se holim'a ntlha e le 'ngoe ea mongolo e bitsoang ΔFosB.

Tlhahiso ea ΔFosB ka Lithethefatsi tsa Tlhekefetso

ΔFosB, e kenyelelitsoeng ke mofuta oa fosB, ke setho sa lelapa la Fos la lintlha tse ngotsoeng, le ho kenyelletsa c-Fos, FosB, Fra1, le Fra2 (7). Liprotheine tsena tsa malapa tsa Fos heterodimerize le liprotheine tsa lelapa tsa Jun (c-Jun, JunB, kapa JunD) ho etsa likarolo tse sebetsang tsa phetisetso ea AP-1 (activator protein-1) e lumellanang le libaka tsa AP-1 (tatellano ea tumellano: TGAC / GTCA) e fumanehang ka har'a bahlahisi ba liphatsa tsa lefutso tse itseng ba lokela ho laola sengoloa sa bona.

Liprotheine tsena tsa malapa tsa Fos li kenella ka potlako le ka nako e telele libakeng tse itseng tsa boko kamora ho tsamaisoa ka matla hoa lithethefatsi tse ngata tsa tlhekefetso (sa feiga. 1) (8-11). Libaka tse hlahelletseng ke li-bokellase tsa li-nucleus le dorsal striatum, tseo e leng babuelli ba bohlokoa ba likarabo tsa boitšoaro ho lithethefatsi, haholo-holo, litlamorao tsa bona tse atlehang le tse sebetsang tsa XPUMX (12, 13). Liprotheine tsena li khutlela maemong a basal ka mor'a lihora tse ngata tsa tsamaiso ea lithethefatsi.

 

 

Setšoantšo sa 1

Morero o bonts'a ho bokella butle-butle ha ΔFosB ha ho bapisoa le ho itšireletsa ka potlako le ka nakoana ha liprotheine tse ling tsa lelapa la Fos ho arabela lithethefatsi tsa tlhekefetso. (A) Autoradiogram e bontša ho kenella ka mokhoa o fapaneng oa liprotheine tsena tse fapa-fapaneng ka ho hlohlelletsa ho hoholo (1-2 hr kamora ho pepesetsoa ke lithethefatsi tse le ngoe) khahlanong le ho hlohlelletsa ho sa feleng (letsatsi la 1 kamora ho pepesetsoa lithethefatsi khafetsa). (B) Maqhubu a mangata a liprotheine tse kang Fos [e nang le li-c-Fos (52- ho 58-kDa isoforms), FosB (46- ho 50-kDa isoforms), ΔFosB (33-kDa isoform), le Fra1 (Fra2 kapa Fra40 (Fra35 kapa Fra37) XNUMX kDa)] li qaptjoa ho li-nucleus accumbens le dorsal striatal neurons ka tsamaiso e matla ea lithethefatsi tsa tlhekefetso. Ho boetse ho susumetsoa ke li-isoforms tse fetotsoeng biochemically tsa ΔFosB (XNUMX-XNUMX kDa); le bona, ba ts'oaroa (le ha e le maemong a tlase) kamora taolo ea lithethefatsi tse matla, empa ba phehella ka nako e telele ka lebaka la botsitso ba bona. (C) Ka tsamaiso ea lithethefatsi tse pheta-phetoang (mohlala, habeli ka letsatsi), ts'usumetso e 'ngoe le e' ngoe ea sethoathoa e hlohlelletsa maemo a tlase a li-isoforms tse tsitsitseng, tse bonts'itsoeng ke sete e tlase ea mela e fetang e bonts'ang indicateFosB e susumetsoang ke ts'usumetso e 'ngoe le e' ngoe e mpe. Sephetho ke keketseho ea butle-butle ea maemo ohle a ΔFosB a susumetsoang khafetsa nakong ea kalafo e sa foleng, e bontšitsoeng ke mola o ntseng o eketseha oa graph.

Likarabo tse fapaneng haholo li bonoa kamora taolo e sa feleng ea lithethefatsi tsa tlhekefetso (feiga. 1). Li-isoforms tse ntlafalitsoeng ka biochemically of ΔFosB (molek'hule ea 35-37 kDa) li bokellana kahare ho likarolo tse tšoanang tsa boko kamora ho pepesetsoa lithethefatsi khafetsa, athe litho tse ling tsa lelapa la Fos li bonts'a mamello (ke hore, tlhahiso e fokolang e bapisoang le tlhahiso ea pele ea lithethefatsi). Ho bokelloa ho joalo ha ΔFosB ho hlokometsoe cocaine, morphine, amphetamine, joala, nicotine le phencyclidine (11, 14-18). Ho na le bopaki bo bong ba hore ts'ebetso ena e khetha mofuta oa dynorphin / ntho P e nang le "subset" ea "kati" ea "spiny" e fumanehang libakeng tsena tsa boko (15, 17), leha ho hlokahala mosebetsi o mongata ho netefatsa sena. The 35- to 37-kDa isoforms of dimFosB dimerize haholo le JunD ho theha mofuta o sebetsang oa nako e telele oa AP-1 kahara libaka tsena tsa boko (19, 20). Li-isoforms tsena tsa ΔFosB lia bokellana ka ho pepesetsoa lithethefatsi ka nako e telele ka lebaka la ho phela ha bona ka nako e telele halofo ea bophelo (21), mme ka hona li phehella ho li-neurons bonyane libeke tse 'maloa ka mor'a ho tlohela taolo ea lithethefatsi. Hoa thahasellisa ho hlokomela hore li-isoforms tsa ΔFosB ke lihlahisoa tse tsitsitseng tsa mofuta oa pele (genos) oa pele. Kholiseho ea li-isoforms tsa ΔFosB e fana ka mochine o mocha oa molek'hule o ka fetolang le ha nako e teletsana e le ho tlohela lithethefatsi.

Le ha li-nucleus accumbens li bapala karolo ea bohlokoa ho litlamorao tse khotsofatsang tsa lithethefatsi tsa tlhekefetso, ho lumeloa hore li sebetsa ka mokhoa o tloaelehileng ka ho laola likarabo ho litlatsetso tsa tlholeho, joalo ka lijo, lino, thobalano le litšebelisano tsa sechaba (12, 13). Ka lebaka leo, ho na le tjantjello e kholo ea karolo e ka bang teng ea sebaka sena sa boko mekhoeng e meng e qobelloang (mohlala, ho ja ho feta tekano, papali ea chelete, boikoetliso, jj.). Ka lebaka lena, re ile ra hlahloba hore na ΔFosB e laoloa ka sebopeho sa phoofolo se sebetsang. Ka sebele, li-isoforms tsa 35 tse tsitsitseng - ho 37-kDa li entsoe ka mokhoa o ikhethileng kahare ho li-nucleus accumbens ka likhoto tse bonts'ang boitšoaro bo qobellehang ba ho sebetsa. †

Boitsebiso ba Biochemical of Stable ΔFosB Isoforms

Joalokaha ho boletsoe kaholimo, li-isoforms tsa ΔFosB tse bokellanang kamora ts'ebetso ea ts'ebetso ea ts'ebeliso e mpe ea lithethefatsi kapa tlhekefetso e bonts'a boima ba 35-37 kDa. Li ka khetholloa ho 33-kDa isoform ea ΔFosB e kenyelletsoang ka potlako empa butle-butle ka mor'a ho pepeseha ha lithethefatsi (Fig. 1) (14, 19, 22). Bopaki ba hajoale bo fana ka maikutlo a hore 33-kDa isoform ke mofuta oa protheine ea tlhaho, e fetotsoeng ho etsa lihlahisoa tse tsitsitseng tsa 35- ho 37-kDa (19, 21). Leha ho le joalo, mofuta oa phetoho ea biochemical e fetolang isoform e sa tsitsang ea 33-kDa isoforms e tsitsitseng ea 35- ho 37-kDa isoforms e ntse e le sephiri. Ho nahanoa hore phosphorylation e kanna ea ikarabella (11). Mohlala, ho kenyelletsoa ha ΔFosB ho ipapisitsoe le litoeba tse haelloang ke DARPP-32, protheine e ntlafalitsoeng (23, 24). Hobane DARPP-32 e laola ts'ebetso ea bohlokoa ea protheine phosphatase-1 le protheine kinase A (25, 26), tlhoko ea protheine ena bakeng sa ho bokella ka mokhoa o tloaelehileng oa li-isoforms tsa ΔFosB e bonts'a karolo e ka etsahalang phosphorylation molokong oa lihlahisoa tsena tse tsitsitseng.

Karolo ea ΔFosB ho Behahlangual Plasticity ho Lithethefatsi Tse Sebelisang Tlhekefetso

Tlhahiso ea karolo ea ΔFosB ts'ebetsong ea lithethefatsi tsa lithethefatsi e tsoa haholo ho tsoa thutong ea litoeba tsa transgenic moo ΔFosB e ka kenelloang ka mokhoa o ikhethileng ka har'a li-nucleus tsa li-nucleus le libaka tse ling tsa liphoofolo tsa baholo (27, 28). Bohlokoa ke hore litoeba tsena li sebetsa hantle haholo ho "dynorphin" kapa "P-" e nang le li-spiny neurons tse bohareng, moo ho lumeloang hore lithethefatsi li kenya protheine. Mokhoa oa boits'oaro oa litoeba tsa BFosB-overexpressing, tseo ka litsela tse ngata li ts'oanang le liphoofolo kamora ho pepeseha ha lithethefatsi tse sa feleng, li akaretsoa ho Tafole 1. Lintšu li bontša likarabo tsa locomotor tsa cocaine kamora ts'ebetso ea taolo e mpe le e sa foleng (28). E boetse e bonts'a kutloisiso e ntlafalitsoeng ea litlamorao tse khahlisang tsa koae le morphine litselaneng tsa maemo a bophelo (11, 28) mme li tla ipeha tekanyetso e tlase ea cocaine ho feta litterlings tse sa oxpxpress ΔFosB. Ho fapana le hoo, liphoofolo tsena li bonts'a sebaka se tloaelehileng sa boemo bo phahameng. sensitization ho koae le ho ithuta ka mokhoa o tloaelehileng sepakapakeng ho Morris water maze (28). TLintlha tsa hese li bonts'a hore ΔFosB e eketsa kutloisiso ea phoofolo k'hok'heine 'me mohlomong le lithethefatsi tse ling tsa tlhekefetso mme e kanna ea emela mochini oa ho matlafatsa lithethefatsi nako e telele.

Lethathamo 1
Plastiki ea boitšoaro e tataisoang ke ΔFosB ho li-nucleus accumbens-dorsalstriatum

 

Ho eketsa ts'ebetso ea locomotor ho arabela taolong ea koae e mpe le e pheta-phetoang.
Ho eketsa likarabo tse khotsofatsang ho koae ka cocaine le morphine lithutong tsa maemo a sebaka.
Eketsa tsamaiso ea litekanyetso tse tlase tsa cocaine.
Khothatso e eketsehileng ea koaeine ka tekanyo e tsoelang pele ea karolelano ea nako.
Likarabo tse eketsehang tsa karabelo ea joala.
Ho eketsa boitšoaro bo qobelloang.

E ipapisitse le data ho li-Ref. 28 'me 29.† ‡ §¶

 

Plastiki ea boitšoaro e kopantsoeng le ΔFosB ho li-nucleus accumbens-dorsal striatum

INtle le moo, ho na le bopaki ba pejana ba hore litlamorao tsa ΔFosB li ka fetela ka nqane ho melao ea kutloisiso ea lithethefatsi ka litloaelo tse thata tse amanang le ts'ebetso ea bokhoba. Ho fana ka maikutlo a ΔFosB e sebetsa ka thata ho ipeha k'hok'heine ka nako ea boiketsetso ea ho itaola,Ho tsilatsila hore ΔFosB e ka etsa hore liphoofolo li latoe ke matla a susumetsang a koae, ka ho etsa joalo, 'me ea lebisa ho boeleng bocha kamora ho tloheloa ke lithethefatsil. m ΔFosB e buoang ke motho hape e bonts'a litlamorao tse matlafatsang tsa joala, mofuta oa "phenotype" o amanang le tšebeliso e mpe ea joala ho batho. Ka kopanelo, liphumano tsena tsa pejana li khothaletsa hore ΔFosB, ho ekelletsa ho matlafatseng a kutloisiso ea lithethefatsi tsa tlhekefetso, e hlahisa liphetoho tse lokelang boits'oaro bo khothalletsang boits'oaro ba ho batla lithethefatsi. Kahoo, ΔFosB e ka sebetsa e le "phetoho ea limolek'hule" e thusang ho qala le ho boloka likarolo tsa bohlokoa tsa mmuso o lemaletseng. Potso ea bohlokoa tlasa lipatlisiso tsa hajoale ke hore na ho bokelloa ha ΔFosB nakong ea ts'ebetso ea lithethefatsi ho nts'etsapele mekhoa ea ho batla lithethefatsi kamora nako e teletsana ea ho tlohela, le kamora hore maemo a ΔFosB a se a lekantsoe (bona ka tlase).

batho ba baholo litoeba tse tlatselletsang ΔFosB ka mokhoa o ikhethileng ka har'a li-nucleus tse bokelletsoeng le li-dorsal striatum li boetse li bonts'a ho qobelloa ho hoholo ha ho bapisoa le lithollo tsa taolo. † Litlhahlobo tsena li hlahisa monyetla o makatsang oa hore ho bokellana ha ΔFosB ka har'a methapo ena ea kutlo ho phetha karolo e akaretsang ho bopeng le ho boloka mehopolo ea tloaelo le ho e qobella boits'oaro, mohlomong ka ho tiisa ts'ebetso ea li-circuits tsa neural moo li-neuron tsena li sebetsang ho tsona.

ΔFosB e bokellana libakeng tse ling tsa bokantle ba khubung ea nucleus le dorsal striatum kamora ho pepesetsoa koae ka nako e telele. E tsebahala har'a tsena libaka ke amygdala le medial prefrontal cortex (15). Morero o moholo oa lipatlisiso tsa morao-rao ke ho utloisisa liphallelo tsa ΔFosB ho kenya likarolo libakeng tsena ho ts'ebeliso ea tlholeho.

Mosebetsi oa pejana oa litoeba tsa ho kokota tsa fosB o senotse hore liphoofolo tsena li hloleha ho hlahisa ts'usumetso ho litlamorao tsa koae, tse lumellanang le se fumanoeng ke litoeba tsa osBFosB-overexpressing tse boletsoeng kaholimo (22). Leha ho le joalo, liphetoho tsa fosB li bontšitse kutloisiso e matlafalitsoeng ke litlamorao tse bohloko tsa cocaine, tse sa lumellaneng le liphetho tse ling. Tlhaloso ea se fumanoeng ka liphetoho tsa fosB, leha ho le joalo, e thatafalloa ke hore liphoofolo tsena ha li na feela osBFosB, empa le FosB e bolelele bo felletseng. Ho feta moo, liphetoho tse fetotsoeng li haelloa ke liprotheine ho pholletsa le boko le ho tloha methating ea pele ea kholo. Ha e le hantle, mosebetsi oa morao-rao o tšehetsa liqeto tse tsoang ho litoeba tsa osBFosB tse fetelletseng: khatello e fetelletseng ea seqhoqhoane sa c-Jun, se sebetsang joalo ka mohanyetsi ea matla oa ΔFosB, ka khethollo ea li-nucleus accumbens le dorsal striatum e bonts'a kutloisiso e fokotsang litlamorao tse khahlisang tsa cocaine Liphuputso tsena li hatisa tlhokomeliso e lokelang ho sebelisoa ho toloka liphetho tse tsoang ho litoeba tse nang le liphetoho tse teng 'me e bonts'a bohlokoa ba litoeba tse nang le liphetoho tse sa sebetseng le tsa mofuta oa sele ho lithuto tsa polasetiki bokong ba motho e moholo.

Target genese ea ΔFosB

Hobane ΔFosB ke ntho e hatisang, mohlomong protheine e baka boits'oaro phetohong ha ho hlahisoa mefuta e meng. ΔFosB e hlahisoa ke mofuta o mong oa mofuta oa fosB ebile e haelloa ke karolo ea C-terminal transactivation domain e teng ka bolelele bo felletseng ba FosB. Ka lebaka leo, qalong ho ile ha etsoa tlhahiso ea hore ΔFosB e sebetse e le khatello ea likhatiso (29). Leha ho le joalo, ts'ebetso moetlong oa sele e bontšitse ka ho hlaka hore ΔFosB e ka susumetsa kapa ea hatella Transcript ea AP-1-Mediated ho latela sebaka se itseng sa AP-1 se sebelisitsoeng (21, 29-31). FosB ea bolelele bo felletseng e na le litlamorao tse tšoanang le ΔFosB likhechaneng tse ling tsa khothaletso, empa litlamorao tse fapaneng ho ba bang. Ho hlokahala mosebetsi o eketsehileng ho utloisisa mekhoa e tlisitseng liketso tsena tse fapaneng tsa ΔFosB le FosB.

Sehlopha sa rona se sebelisitse mekhoa e 'meli ea ho khetholla liphatsa tsa lefutso tsa ΔFosB. E 'ngoe ke mokhoa oa liphatsa tsa lefutso. Qalong re ne re nahana ka α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors joalo ka liphofu tsa putative, e fuoeng karolo ea bohlokoa ea phetiso ea glutamatergic ho li-nucleus accumbens. Mosebetsi ho fihlela joale o bontšitse hore karolo e le 'ngoe ea AMPA glutamate receptor, GluR2, e kanna ea ba sepheo sa' nete sa ΔFosB (Setšoantšo sa 2). Polelo ea GluR2, empa eseng polelo ea li-subunits tse ling tsa AMPA receptor, e eketsehile ka li-nucleus accumbens (empa eseng dorsal striatum) ka lebaka la tlhatlhobo e fetelletseng ea ΔFosB (28), le polelo ea semousine e mpe e matlafatsang bokhoni ba cocaine ho susumetsa protheine. Ntle le moo, mohanyetsi oa mofuta oa GluR2 o na le sebaka sa tumellano sa AP-1 se tlamang ΔFosB (28). Ho hatella haholo ha GluR2 ka har'a li-nucleus accumbens, ka ts'ebeliso ea phetisetso ea liphatsa tsa lefutso, ho eketsa kutloisiso ea phoofolo liphellong tse putsang tsa cocaine, ka ho etsisa karolo ea phenotype e bonoang litoeba tsa ΔFosB (28). Ho qhekelloa ha GluR2 ho ka ikarabella bakeng sa phokotso ea kutlo ea motlakase ea li-nucleus accumbens neurons ho li-AMPA receptor agonists kamora tsamaiso e sa foleng ea cocaine (32), hobane li-receptor tsa AMPA tse nang le GluR2 li bonts'a ho fokotsa boits'oaro ka kakaretso le ho fokotsa matla a Ca2 +. Ho fokotsa ho arabela ha li-neuron ho lisebelisoa tsa thabo ho ka ntlafatsa likarabo tsa sethethefatsi sa tlhekefetso. Leha ho le joalo, litsela tseo ka tsona lipontšo tsa dopaminergic le glutamatergic tse bokellaneng ba taolo ea boitšoaro bo lemalloang li sa tsejoeng; sena se tla hloka boemo ba kutloisiso ba potoloho ea methapo ea kutlo, bo so fumaneheng.

 Setšoantšo sa 2

Kopano ea AMPA glutamate receptor subunit, GluR2, ke sepheo sa ho beha bakeng sa ΔFosB. Ho bonts'itsoe ka moo ΔFosB-mediated induction ea GluR2 e ka fetolang karabelo ea mmele ea nucleus accumbens neurons mme ea lebisa likarabong tse matlafatsang ho lithethefatsi tsa tlhekefetso. Ho ea ka morero ona, lithethefatsi tsa tlhekefetso li hlahisa litlamorao tse matla tsa ho matlafatsa ka ho thibela li-nucleus accumbens neurons. Ka ho pepeseha khafetsa, lithethefatsi li baka ΔFosB, e laolang liphatsa tsa lefutso tse ngata, ho kenyeletsoa le GluR2. Sena se eketsa karolo ea li-receptor tsa AMPA (AMPA-R) ho li-nucleus tse bokellanang li-neuron tse nang le subluit ea GluR2, e bakang ho fokotsoa ha kakaretso ea AMPA le ho fokotsa ha Ca2 + hona joale. Ts'ebetso ena e fokotsang thabo e ka etsa hore methapo ea kutlo e amehe haholo ke litlamorao tse mpe tsa lithethefatsi 'me ka hona e matlafatse litlamorao tsa lithethefatsi..

Morero o mong o khathollang oa ΔFosB ke dynorphin ea gene. Joalokaha ho boletsoe pejana, dynorphin e hlahisoa ka har'a methapo ea kutlo e bokellanang ea methapo e bonts'a ho kenella ha ΔFosB. Dynorphin e bonahala e sebetsa sebakeng se arabelang ka tsela e fapaneng: ho tsoa ha eona ho thibela li-neuron tsa dopaminergic tse kahare tsa methapo ea methapo e bohareng, ka li-receptor tsa vera opioid tse teng litsing tsa methapo ea methapo ea methapo bohareng ba methapo ea methapo le methapo ea sele le dendrites sebakeng se potolohileng kahare. (Feiga. 3) (33-35). Mohopolo ona o lumellana le bokhoni ba setsebi sa kelello sa "lic receptor agonist", ho tsamaiso ho e 'ngoe ea libaka tsena tse peli tsa boko, ho fokotsa ho khutla ha lithethefatsid (35).

Rmosebetsi oa ecent o bonts'itse hore ΔFosB e fokotsa tlhahiso ea dynorphin, ‖ e ka kenyang ntlafatso ea mekhoa ea meputso e bonoang ka ts'ebetso ea ΔFosB. Ho khahlisang, ntlha e 'ngoe e laoloang ke lithethefatsi, CREB (cAMP Karolo e tlamang protheine) (2, 3), e fana ka phello e fapaneng: e etsa hore polelo ea dynorphin e bokellaneng e sebetse le ho fokotsa thepa e ruisang ea koae le koae. (4). **

Bsesosa sa ts'usumetso ea ts'ebeliso ea lithethefatsi ea CREB e fela kapele kamora ts'ebetso ea lithethefatsi, taolo e joalo ea phetisetso ea dynorphin ke CREB le ΔFosB e ka hlalosa liphetoho tse amanang le boitšoaro tse etsahalang nakong ea methati ea pele le morao ea ho tlohela, ka matšoao a mabe a maikutlo le ho fokotsa kutloisiso ea lithethefatsi nakong ea methati ea pele. ea ho ikhula, le ho ts'oarella ho litlamorao le tse khothatsang tsa litlamorao tsa lithethefatsi nakong e tlang.

 

 

Setšoantšo sa 3

 Dynorphin ke sepheo se behang bakeng sa ΔFosB. E bonts'oa ke sebaka sa "ventral tegmental area" (VTA) dopamine (DA) se kenellang sehlopheng sa li-neuron tsa li-nucleus accumbens (NAc) Gabaergic projeke ea neurion e hlalosang dynorphin (DYN). Dynorphin e sebetsa mochine oa ho fana ka likarabo potolohong ena: dynorphin, e lokollotsoeng lits'oants'o tsa methapo ea methapo ea methapo ea kutlo, e sebetsa ho li-receptor tsa κ opioid tse fumanehang litsing tsa methapo le methapo ea sele ea li-neurons tsa DA ho thibela tšebetso ea tsona. ΔFosB, ka ho thibela polelo ea dynorphin, e kanna ea theola molaong ona oa ho fana ka litlatsetso le ho ntlafatsa thepa e ruisang ea lithethefatsi tsa tlhekefetso. Ha ho bontšoe phello ea boipheliso ea CREB ts'ebetsong ena: CREB e ntlafatsa polelo ea dynorphin ebe ka tsela ena e fumana thepa e ruisang lithethefatsi tsa tlhekefetso (4). GABA, γ-aminobutyric acid; DR, recopor ea dopamine; KAPA, receptor ea opioid.

Mokhoa oa bobeli o sebelisitsoeng ho khetholla liphatsa tsa lefutso tsa ΔFosB o kenyelletsa tlhahlobo ea DNA microarray. Tlhaloso e fetelletseng ea ΔFosB e eketsa kapa e fokotsa polelo ea liphatsa tsa lefutso tse ngata ka har'a li-nucleus accumbens (36). Le ha ho se ho hlokahala mosebetsi o mongata ho netefatsa mofuta o mong le o mong oa liphatsa tsa lefutso joalo ka sepheo sa 'mele sa ΔFosB le ho utloisisa tlatsetso ea bona ho phenotype ea lithethefatsi, sepheo se seng sa bohlokoa se bonahala e le Cdk5 (kinase-5 e itšetlehileng ka cyclin). Kahoo, Cdk5 qalong e ile ea tsejoa e le ΔFosB e laoloang ke ts'ebeliso ea li-microarrays, mme hamorao ea bonts'oa hore e kentsoe ka har'a li-nucleus accumbens le dorsal striatum kamora tsamaiso e sa foleng ea cocaine (37). OsBFosB e kenya tšebetsong lefutso la cdk5 ka sebaka sa AP-1 se teng ka har'a 'mampuli oa lefutso (36). Hammoho, lintlha tsena li tšehetsa leano leo k'hok'heine e kenyang polelo ea Cdk5 libakeng tsena tsa boko ka ΔFosB. Ho qhekelloa ha Cdk5 ho bonahala ho fetola lets'oao la dopaminergic bonyane ka karolo e eketsehileng ka phosphorylation e eketsehileng ea DARPP-32 (37), e fetotsoeng ho tloha inhibitor ea protein phosphatase-1 ho ea ho inhibitor ea protein kinase A holima phosphorylation ea eona ea Cdk5 (26).

Karolo ea ΔFosB ea ho nka karolo polokelong ea "ho sa feleng" ts'ebelisong ea lithethefatsi hampe

Leha lets'oao la ΔFosB le phela nako e telele, ha le tšoarelle. ΔFosB e nyenyefatsa butle-butle mme ha e sa khona ho fumanoa kelellong kamora likhoeli tsa 1-2 tsa ho tlohela lithethefatsi, leha litloaelo tse ling tsa boits'oaro li tsoela pele nako e telele. Ka hona, ΔFosB ka sekhechana e ne e ke ke ea bonahala e khona ho kopanya litlolo tsena tsa boits'oaro ba semipermanent. Boemo bo thata ba ho fumana liphetoho tse amanang le limolek'hule tse tsamaisang liphetoho tse tsitsitseng tsa boitšoaro bo amanang le bokhoba ke li ananele mathata a tobaneng le ona lebaleng la ho ithuta le ho hopola. Leha ho na le mefuta e metle ea lisele le ea limolek'hule ea ho ithuta le ea memori, ha e so fihle ho fihlela hona joale ho khetholla liphetoho tsa limolek'hule le tsa cellular tse bileng teng nako e telele ho lekana bakeng sa mehopolo e tsitsitseng e tsitsitseng. Ho joalo, osBFosB ke phetoho e telele ka ho fetesisa e tsejoang hore e ka etsahala bokong ba batho ba baholo, eseng feela ka lebaka la lithethefatsi tsa tlhekefetso, empa le pherekano efe kapa efe (e sa amaneng le liso). Litlhahiso tse peli li fetohile, maemong a bokhoba le ho ithuta le ho hopola, ho ikarabella bakeng sa phapang ena.

Monyetla o mong ke oa hore liphetoho tse liehang ho feta tsa polelo ea tlhaho, joalo ka tse hlalosoang ka ΔFosB kapa lintlha tse ling tsa ho ngola (mohlala, CREB), e ka 'na ea kopanya liphetoho tse bileng teng ka nako e telele ho morphology ea neuronal le sebopeho sa synaptic. Ka mohlala, keketseho ea methapo ea methapo ea methapo ea dendritic (haholo-holo keketseho ea methapo ea lihlooho tse peli) e tsamaisana le katleho e eketsehileng ea li-synapses tsa glutamatergic ho hippocampal pyramidal neurons nakong ea bokhoni ba nako e telele (38-40), 'me e tsamaellana le matla a ntlafalitsoeng a kutloisiso ea cocaine e arolelanoang maemong a li-neuron tsa "spiny" tsa "kati" tsa "kati" tsa "methapo" ea methapo ea methapo ea methapo (41). Ha ho tsejoe hore na liphetoho tse joalo tsa sebopeho li phela halelele ka ho lekana hore li ikarabelle bakeng sa liphetoho tse tsitsitseng boits'oarong, leha e le hore tsa morao li phehella bonyane khoeli ea 1 ea ho tlohela lithethefatsi. Bopaki ba morao-rao bo hlahisa monyetla oa hore ΔFosB, le ho kenella ha Cdk5, ke mokena-lipakeng oa liphetoho tse hlahisitsoeng ke lithethefatsi ka sebopeho sa synaptic ho li-nucleus accumbens (Fig. 4) .‡‡ Kahoo, ho kenngoa ha inhibitor ea Cdk5 ho bokellase ea nucleus ho thibela " bokhoni ba ho pepesetsoa koae khafetsa ho eketsa letsoalo la mokokotlo oa dendritic sebakeng sena. Sena se lumellana le maikutlo a hore Cdk5, e ntlafalitsoeng bokong, e laola sebopeho sa neural le kholo (bona li-Ref. 36 le 37). Hoa etsahala, leha e se ho netefatsoang, hore liphetoho tse joalo ho "neuronal morphology" li ka mpefatsa lets'oao la ΔFosB ka boyona.

 Setšoantšo sa 4

Taolo ea sebopeho sa dendritic ke lithethefatsi tsa tlhekefetso. Ho bontšitsoe ke katoloso ea sefate sa "dendritic" sa "neuron" kamora ho pepesehela sethethefatsi sa tlhekefetso khafetsa, joalo ka ha ho bonoe ka k'hok'heine ka har'a li-nucleus accumbens le prefrontal cortex (41). Libaka tsa ho holisa li bonts'a keketseho ea methapo ea kutlo, e reretsoeng hore e etsahale hammoho le li-terminals tsa methapo. Keketseho ena ea mokokotlo oa mokokotlo oa mokokotlo oa mokokotlo e ka buelloa ka ΔFosB le ho kenella ha Cdk5 (bona mongolo). Liphetoho tse joalo ka sebopeho sa dendritic, tse ts'oanang le tse bonoang mefuteng e meng ea ho ithuta (mohlala, bokhoni ba nako e telele), li ka arabela likarabo tse matlafalitsoeng tsa nako e telele lithethefatsing tsa tlhekefetso kapa ka mekhoa ea tikoloho. [E hlahisitsoe hape ka tumello ho tsoa ho Ref. 3 (Copyright 2001, Macmillian Magazines Ltd.)].

Monyetla o mong ke hore tlhahiso ea nakoana ea ntho e ngotsoeng (mohlala, ΔFosB, CREB) e lebisa ho liphetoho tse sa feleng ponong ea gene ka ho fetoloa ha chromatin. Lintlha tsena le tse ling tse ngata tsa mongolo ho lumeloa hore li kenya ts'ebetso kapa li hatella ho hatisoa ha mofuta oa sepheo ka ho nts'etsapele acetylation kapa deacetylation, ka tatellano, ea li-histones tse haufi le gene (42). Le ha acetylation le deacetylation ea li-histone li ka hlaha ka potlako haholo, ho ka etsahala hore ΔFosB kapa CREB li hlahise liphetoho tse tšoarellang mochineng oa enzymatic o laolang histone acetylation. ΔFosB kapa CREB e kanna ea khothaletsa liphetoho tsa nako e telele ho polelo ea gene ka ho hlophisa liphetoho tse ling tsa chromatin (mohlala, DNA kapa histone methylation) tse kentsoeng phetohong e sa feleng ea bongaka ba gene bo hlahang nakong ea ntlafatso (bona li-Ref. 42 le 43) . Leha menyetla ena e lula e nahanisisa, e ka fana ka mokhoa oo ka tloaelo tloaelo ea ho tloaela lithethefatsi tsa tlhekefetso (kapa tšohanyetso) e bang le litlamorao tsa bophelo ba nako e telele.

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