Nat Neurosci. 2010 June; 13(6): 745-752. E phatlalalitsoe inthaneteng 2010 May 16. doi: 10.1038 / nn.2551
Vincent Vialou,1 Alfred J. Robison,1, * Quincey C. LaPlant,1, * Herb E. Covington, III,1 David M. Dietz,1 Yoshinori N. Ohnishi,1 Ezekiell Mouzon,1 Augustus J. Rush, III,2 Emily L. Watts,1 Deanna L. Wallace,2, § Sergio D. Iniguez,3 Yoko H. Ohnishi,1 Michel A. Steiner,4 Brandon Warren,3 Vaishnav Krishnan,2 Rachael L. Neve,5 Subroto Ghose,2 Olivier Berton,2, § Carol A. Tamminga,2 'me Eric J. Nestler1
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inahaneloang
Ho fapana le lingoliloeng tse ngata tse mabapi le khatello ea kelello bokong, ha ho tsejoe hakaalo ka mehato ea limolek'hule ea matla a ho mamella, bokhoni ba batho ba bang ba ho phonyoha litlamorao tse bakang khatello ea maikutlo. Hpele re bonts'a hore karolo ea transcript, ΔFosB, e hokahanya mochini oa bohlokoa oa phepo ho litoeba. Ho hlahisoa ha ΔFosB bokong ba bohlokoa ba boko, ho arabela likhatellong tse sa feleng tsa khatello ea sechaba ho bohlokoa ebile ho lekane bakeng sa ho tiisetsa. Induction ea ΔFosB e boetse e hlokahala bakeng sa bokhoni ba antidepressant e tloaelehileng, fluoxetine, ho khutlisa mekhoa ea boitšoaro e hlahisoang ke ho hloloa hoa sechaba. ΔFosB e hlahisa litla-morao tsena ka ho kenngoa ha GluR2 AMPA glutamate receptor subunit, e fokotsang karabelo ea li-neuron tsa li-nucleus tsa li-glus ho glutamate, le ka liprotheine tse ling tsa synaptic. Ka bobeli, liphuputso tsena li theha tsela ea limolek'hule e tataisang ho mamella le ho loants'a khatello ea maikutlo.
SELELEKELA
Batho ba tlangoa ke khatello ea maikutlo e matla ba bonts'a likarabo tse fapaneng haholo, ba bang ba khona ho hlola mathata ha ba bang ba ba le psychopathology e matla joalo ka khatello ea maikutlo kapa khatello ea maikutlo (post-traumatic stress disorder (PTSD)). Bokhoni ba ho sebetsana ka katleho le maemo a sithabetsang, ke ho re, ho tiisetsa, ho ipapisitse le nts'etsopele ea mekhoa e metle ea boitsoaro le ea kelello ho imeloa kelellong1,2. Mekhatlo ea kelello e khothalletsang ho phomola e kenyelletsa boitlamo, mamello, ts'epo, le boitšepo, le bokhoni ba ho feto-fetola maikutlo le ho ntlafatsa boits'oaro bo botle ba sechaba. Litšoaneleho tsena li etsa hore boko bo sebetse meputso, e shebahalang e le sesupo sa bohlokoa bakeng sa tlhaiso ea methapo ea methapo e amanang le methapo.3,4. Li-amanang tsa Neurobiological tsa ho hlaseloa kapa ho hanyetsa khatello ea maikutlo li na le 2 e fumanoe bathong, empa hore na lisosa kapa sephetho sa ho ts'oaroa ha se tsejoe joang5.
Har'a mefuta e teng hona joale ea khatello ea maikutlo le PTSD, khatello ea maikutlo e sa feleng ea khatello ea kelello sechabeng ke mokhoa o sebetsang oa boitšoaro, o fanang ka phetoho ea nako e telele ea 'mele.6-8 le boits'oaro9-11 Liphetoho, ho kenyelletsa thibelo ea kahisano, anhedonia, le matšoao a kang a ho tšoenyeha, ho kenyelletsa ts'ebetso ea lipotoloho tse 'maloa tsa neural le lits'ebetso tsa methapo ea kutlo12-15. Tloaelo e tloaelehileng ea thibelo ea kahisano ke kalafo e sa foleng, empa e seng e matla, e loants'ang maikutlo e e etsa mohlala oa bohlokoa oa ho hlahloba likarolo tsa khatello ea maikutlo le PTSD bathong11,16. Karolo ea bohlokoa (~ 30%) ea litoeba tse sa hlotsoeng ho qoba litekanyetso tse mpe tsa boits'oaro10, ka tsela eo re lumella lipatlisiso tsa liteko tsa boits'oaro. Ha kenyelletso ea liprotheine tse 'maloa ka har'a nucleus accumbens (NAc), e leng sebaka sa bohlokoa sa moputso oa boko, e bontšitsoe e le bohlokoa bakeng sa tlhahiso ea boits'oaro bo joalo ka mor'a ho hloloa10,11,17,18, ha ho tsejoe haholo ka motheo oa molek'hule o bohareng ba sebaka sena sa boko. Mona, re arabetse potso ena ka ho shebisisa ΔFosB, karolo ea phetisetso ea lelapa la Fos e qobelloang ke NAc ka lithethefatsi tsa tlhekefetso, meputso ea tlhaho le mefuta e fapaneng ea khatello19-21.
LIPOTSO
ΔFosB ea NAc e khothaletsa ho tiisetsa khatello ea maikutlo sechabeng
C57BL / 6J litoeba tse tona li ile tsa beoa matsatsi a leshome a li-comsecutives tsa ho hloloa sechabeng10,11, 'me ba arotsoe ka bongata ba batho ba ka qhekelloang le ho ikemela ka ho ipapisa le maemo a itseng a thibelo ea sechaba (Setšoantšo sa 1a)10. Re fumane keketseho ea ΔFosB, e lekantsoeng ke immunohistochemistry, ho NAc kamora ho hloloa ho sa feleng sechabeng (Feiga. 1b, c), ka litoeba tse tiileng tse bonts'a ho kenella ho ho feta tsa ΔFosB ka bobeli subcions tsa mantlha le tsa shell (Feiga. 1b, c). Ho feta moo, re bone khokahano e matla (p <0.01) lipakeng tsa maemo a ΔFosB le tšebelisano-'moho ea sechaba (r = 0.80, NAc shell; r = 0.85, konokono ea NAc; r = 0.86, NAc kaofela), ho fana ka maikutlo a hore tekanyo ea ΔFosB NAc e kanna ea ba sesupo sa bohlokoa sa hore na phoofolo e bonts'a ts'oaetso e khahlano le phenotype. Tlhatlhobo ea blot Bophirimela ea likhaohano tsa NAc tse nang le likaroloana tsa mantlha le likhetla e netefalitse ΔFosB ho kenella litoeba tse tiileng feela (bona Tlhahiso e eketsehileng Fig. 1).
UctionFosB e kenyelletsa NAc ka ho hloloa ha balekane sechabeng
Ho lekola litlamorao tse sebetsang tsa ΔFosB, re sebelisitse litoeba tsa bitransgenic tse sa sebetseng hantle ΔFosB ka kotloloho ho NAc e kholo le ho dorsal striatum22. Litoeba tsena li bontsitse tekanyo e fokotsehileng ea ho nts'etsapele ho qoba sechaba ka mor'a matsatsi a mane kapa a leshome a ho hlotsoa sechabeng (Feiga. 1d), ka hona ho fana ka maikutlo a hore ΔFosB e fana ka ts'ebetso ea ts'ireletso khahlano le khatello ea sechaba. Ka lehlakoreng le leng, re sebelisitse litoeba tsa bitransgenic tse sa koaheleng ka mokhoa o phetheselang ΔcJun, sekhoba se sa sebetseng se hatisitsoeng sa cJun phetoho e hananang le ts'ebetso ea ΔFosB23,24. Ho fapana le litoeba tse fetelletseng tsa litoeba ΔFosB, litla-morao tsa icecJun li kotsing ea ho hlola tlholisano ea setjhaba ho fapana le ho laola batho ba bang mme li bonts'a boits'oaro bo botle ba ho latela matsatsi a 4 a ho hloloa (Feiga. 1e). Lesapo la ΔcJun le boetse le bonts'itse ho se sebetse hantle ha teko ea letsatsi le le leng e qobelloang ho sesa, hammoho le boikhethelo bo fokotsoang, ka bobeli bo hlalositsoeng e le boits'oaro bo eketsehileng bo kang ba khatello ea maikutlo (Tlatsetso ea feiga. 2a, b). Leha ho le joalo, ΔFosB kapa ΔcJun overexpression ha e fetole mehato e 'maloa ea motheo ea ts'ebetso ea phenomotor kapa boits'oaro bo ts'oanang le ho tšoenyeha (Mofuta oa tlatsetso oa feiga. 2c-f). Ka bobeli, liphuputso tsena li fana ka maikutlo a hore ts'ebetso ea ΔFosB e fokotseng NAc le dorsal striatum e fokotsa likarabo tse nepahetseng, tse lumellanang, tse hlahisitsoeng e le "ho sebetsana le maemo7”, Ho imeloa kelellong.
ΔFosB e fokotsehileng ho NAc e ntlafatsa khatello ea khatello ea maikutlo
Ho fumana leseli le eketsehileng mabapi le boits'oaro ba ΔFosB kamora khatello ea maikutlo, re sebelisitse nako e telele ea ho itšehla thajana nakong ea ho ba motho e moholo, e bakang khatello ea maikutlo joalo ka litlolo tsa litoeba ho litoeba.25 hape ke sesosa se seholo sa khatello ea maikutlo tleliniking. Re hlokometse hore maemo a ΔFosB a fokotsehile ho NAc ea litoeba tse ikhethileng sechabeng (Feiga. 2a, b). Re fumane hape hore ho itšehla thajana ho etsa hore litoeba li be kotsing e kholo ea ho hlaseloa sechabeng, le hore tlokotsi ena e bakiloeng ke ho khetholoha e khutlisitsoe ka botlalo ke ΔFosB e khethollang ho khetholoha ho NAc (Feiga. 2c). Ka lehlakoreng le leng, thibelo ea ts'ebetso ea ΔFosB ho NAc, ke botenya bo feteletseng ba ΔJunD, litokollong tsa sehlopha se laoloang ke sehlopha li khothalelitse monyetla oa ho hloloa hoa sechaba (Feiga. 2c). ΔJunD, joalo ka ΔcJun, ke phetoho e tsoang ho N-terminal e sebetsang e le mohanyetsi ea matla oa negativeFosB (Tlhahiso e eketsehileng Fig. 3)23. Liphumano tsena li hlahisa maemo a mantlha a alFosB ho NAc maemong a sithabetsang.
Kameho ea ho itšehla thajana ho ΔFosB le ho kotsing ea ho hloloa sechabeng
Ho ithuta bohlokoa ba bongaka ba liphumano tsena, maemo a ΔFosB a ile a lekanngoa ho li-sampuli tsa motho tsa postmortem tse fumanoang ho bakuli ba tepelletseng le taolo e tsamaeang hantle. Re fumane ho fokotseha ha ~ 50% maemong a ΔFosB ho bakuli ba sithabetseng (Feiga. 2d), ho tšehetsa karolo ea ΔFosB khatellong ea maikutlo ea batho. Batho ba tepelletseng maikutlo ba hlahlobiloeng ba kenyelletsa batho ka bomong ba tsoang kapa ba koala lingoloa tsa khatello ka nako ea bona ea lefu (Letlapa le tlatsetsang 1), 'me ha rea fumana khokahano lipakeng tsa boemo ba ΔFosB le tlhaiso-leseling ea antidepressant. Ka lebaka la tlhokomeliso ea rona ea hore kalafo ea antidepressant e phahamisa maemo a ΔFosB ho mouse NAc (bona ka tlase), liphumano tsena li fana ka maikutlo a hore ho hloleha ho susumetsa ΔFosB ho NAc e kanna ea ba qeto e bohlokoa bakeng sa khaello ea likarabo tsa antidepressant ho batho.
ΔFosB ho NAc e nka bohato ba ho rarolla mathata
Phekolo e sa feleng ea kalafo e fokotsa khatello ea maikutlo e hlohlellelitsoeng ho sechaba e bonoang ke litoeba tse ka bang teng11. Ka hona re ile ra hlahloba hore na ho kenella ka indFosB ho NAc e ka ba mochine eseng feela oa ho matlafatsa empa hape le oa bohato ba ho loants'oa khatello ea maikutlo. Litoeba tse laoloang tse sa hlotsoeng tse tšoaroang ke fluoxetine bakeng sa matsatsi a 20 ha li senole liphetoho lipakeng tsa boitšoaro ba sechaba, empa li bontšitse ho bokelloa ha ΔFosB ka polokelong ea NAc (Feiga. 3a, b) le mokokotlo (Tlhahiso e eketsehileng Fig. 4). Phekolo ea Fluoxetine ea litoeba tse qhekellang e ile ea khutlisa mokhoa oa bona oa ho qoba (Setšoantšo sa 3a), joalo ka ha ho tlalehiloe pejana, le maemo a ntlafatsang a ΔFosB ho NAc (Feiga. 3b, Tlhahiso e eketsehileng Fig. 4).
Ho kenella ha indFosB ho NAc ho kenyelletsa phello ea meriana e thibelang mafu
Ho leka ka kotloloho ho kenella ha ΔFosB ho kenella litlamorao tsa boitšoaro ba fluoxetine, ka botona re qoelisoa ΔJunD kapa GFP re le bang (joalo ka taolo) ho NAc ea litoeba tse fetileng tse hlotsoeng. Halofo ea litoeba sehlopheng ka seng li ile tsa phekoloa libeke tse tharo tse eketsehileng ka fluoxetine kapa koloi. Joalo ka ha ho lebeletsoe, kalafo ea fluoxetine ea litoeba tse feteletseng ho MF ho NAc e bonts'itse phetoho ea ts'ireletso ea sechaba e hlohlellelitsoeng ke tlhaselo e sa feleng ea sechaba. Ka lehlakoreng le leng, overexpression ea ΔJunD e thibetse phello ea kalafo ea fluoxetine (Feiga. 3c), e ts'ehetsang boikaketsi ba hore ΔFosB induction ho NAc e hlokahala bakeng sa ts'ebetso ea antidepressant. Ntle le moo, bongata bo feteletseng ba ΔFosB ea viral ho ratoa NAc e hlahisitse phello e matla joalo ka ha e lekantsoe ke nako e fokotsehileng ea ho se sebetse ka letsatsi la 2 ea tlhahlobo e qobelloang ea ho sesa (Tlatsetso ea feiga. 5a). Tlhahlobo e ngoe ea boitšoaro nakong ea tlhahlobo ena e bonts'itse keketseho ea ΔFosB ea ho sesa le ho nyoloha (Mofuta oa tlatsetso oa feiga. 5b-d), likarolo tse amanang le liphetoho tsa mekhoa ea serotonergic le noradrenergic26. Ho khahlisang, litoeba tse feteletseng tsa ΔFosB ho NAc li bontsitse nako e fokotsehileng ea ho se sebetse ka letsatsi la pele la tlhahlobo, hape e hlalosoa e le tšusumetso e matla ho bona (bona Mekhoa ea Inthaneteng 'me Tlatsetso ea tlatsetso. 5e – h).
Molao oa li-receptor tsa AMPA ho NAc Mediates resilience
ΔFosB e laola phetiso ea liphatsa tsa lefutso tse ngata ho NAc24,27. Mofuta o le mong oa sepheo se tsejoang ke AMPA glutamate receptor subunit GluR2: li-ovexpressing tsa mice ho NAc li na le maemo a phahameng a GluR2, ha li na litlamorao ho li-subeptits tse ling tsa glutamate receptor22. Phallo ena e khethiloeng ea GluR2 ho NAc e hokahane le ntlafatso ea moputso oa lithethefatsi le tlhaho22,28. Ho sebetsana le menyetla ea hore modulation ea GluR2 e kenya letsoho molemong oa boikhathatso ba ΔFosB hape, re ithutile polelo ea GluR2 ho NAc kamora ho hloloa ho sa feleng sechabeng. Litoeba tse sa bonahaleng li bontšitse ho fokotseha ho hoholo hoa maemo a GluR2 sebakeng sena sa boko ha ho bapisoa le taolo, ha litoeba tse mamellang li bonts'a litekanyetso tsa GluR2 tse ntseng li eketseha (Setšoantšo sa 4a). Ha mochini o hatelletsang polelo ea GluR2 ho litoeba tse amehang o lula o sa tsejoe, ho kenella ha GluR2 ho bonoang ho litoeba tse tsitsitseng ho bonahala ho bonts'a phello e tobileng ea ΔFosB ho mofuta oa GluR2, hobane re fumane tlamo e eketsehileng ea ΔFosB ho GluR2 ea morekisi chromatin immunoprecipitation (ChIP) (Feiga. 4b), mme PCR e bongata (qPCR) e senoletse ho kenella hoa maemo a GluR2 mRNA ho NAc ea litoeba tse sebetsang (Feiga. 4c), e tsamaisanang le kenyelletso e tsitsitseng ea ΔFosB. Ho khahlisang, GluR1 e ne e laoloa ka mokhoa o hanyetsanang kamora ho hloloa hoa sechaba: re bone polelo e eketsehang ho litoeba tse ka qhekelloang le polelo e fokotsehileng ho litoeba tse mamellang (Setšoantšo sa 4a). Leha ho le joalo, ha ho liphetoho tse tsamaellanang tse ileng tsa bonoa polelo ea GluR1 mRNA, ho fana ka tlhahiso ea mekhoa ea ho fetolela. Ntle le moo, kalafo ea fluoxetine e sa foleng ea litoeba tse sa hlotsoeng e ile ea eketsa maemo a GluR2 ho NAc (Feiga. 4d), le ho sekasekwa ha manonyeletso a batho a postmortem NAc ho tsoa ho bakuli ba tepelletseng ho senotse ho theoha ha maemo a GluR2 ha ho bapisoa le taolo (Feiga. 4e). Ha ho liphetoho tse fumanoeng maemong a GluR1 (Feiga. 4e).
Pro-Resilience, antidepressant joalo ka GluR2 ho NAc
Ho ba teng ha GluR2 ho na le litlamorao tse matla ho li-receptor tsa AMPA: Li-receptor tse se nang matla tsa AMPA tsa GluR22+E kenelletse, 'me e bontša boits'oaro bo boholo ba receptor bo tsamaeang ka matla le maqhubu a matla a khathollang kahare, a bapisoa le li-receptor tsa GluR229. Ho tlatselletsa liphetho tsa rona tsa biochemical, ka hona re ile ra etsa lirekoto tsa methapo ea methapo e meholo ea li-cell spiny neuron ho NAc ea litoeba tse sa hlotsoeng le ka mor'a ho hloloa sechabeng liphoofolong tse mamellang le tse kotsing. Likamano tsa hona joale tsa motlakase oa liqhubu tsa "melaetsa" ea AMPA-mediated evoked excitatory postsynaptic currents (EPSCs) li senole haholo phokotso ea kahare ho litoeba tse sa bonahaleng (Feiga. 5a-c) ha e bapisoa le taolo, e lumellanang le keketseho ea GluR1: GluR2 e bonoa tlasa maemo ana. Leha tekanyo ea ntlafatso liseleng tse rekotiloeng ho tsoa ho litoeba tse sa bonahaleng e ne e fetoha, re hlokometse phetoho e kholo haholo tokisetsong ea tokiso ha e bapisoa le lihlopha tse laolang le tse ikemiselitseng. Ho feto-fetoha ha se fumanoeng hona ho bontšoa ke 'nete ea hore tekanyo ea ntlafatso ea lisele tsohle ho litoeba tse senyehang e feta boleng ba boleng bo bonoang bakeng sa lisele tse laolang. Ntle le moo, re fumane hore boemo ba ntlafatso bo ne bo amana ka kotlolloho le phemelo ea kahisano (Feiga. 5d), ho fana ka tlhahiso ea hore liphetoho ho GluR1: Lenane la GluR2 ka karolo e 'ngoe e ka tsamaisa boitšoaro bona. Ho netefatsa ho ata hoa li-receptor tse haelloang ke GluR2 ho litoeba tse senyehang, re kentse linoko ho tsoa taolong le litšoeneng tse etsahalang ka 1-naphtylacetylsperimine (NASPM), blocker e khethang li-receptors tsa GluR2 tse sa hlokeng letho. Li-EPSC tse koetsoeng ka li-neurons tse tlalehiloeng ho tsoa ho litoeba tse kenang habonolo (Feiga. 5e-f) li fokotsoe haholo ke NASPM, ho bonts'a hore li-receptor tse se nang motlakase tsa AMPA tsa GluR2 li kenya letsoho haholo ho fetiseng lefu la glutamatergic ho litoeba tse amehang ho feta taolo. Ho hlakile hore phello ea NASPM ho litoeba tse senyehang e ne e le tlase ho feta kamoo ho neng ho boletsoe ka ho nahana ka phetoho e kholo e bonoeng tokollong. Leha ho le joalo, phapang ena ha e e-ba teng pele30 hape e ka hlaha ka lebaka la liphetoho tsa morao-rao tsa phetolelo kapa lipuisano tsa protheine tse amanang le GluR2 (bona Puisano), kapa boholo ba phello ea NASPM. Keketseho e bakiloeng ke khatello ea phetisetso ea kahare e fumanoeng litoebeng tse amehang habonolo e ne e le sieo litoebeng tse mamellang (Feiga. 5a-d), e tsamaellanang le ho fokotseha ho hlokometsoeng ha GluR1 le keketseho ea GluR2 tlasa maemo ana. Leha ho le joalo, ha rea bona ho fokotseha ha tokiso ea kahare ho litoeba tse iphelisang ha li bapisoa le taolo (bona Puisano).
Sebopeho sa li-receptor tsa AMPA se laoloa ka mokhoa o fapaneng ho litoeba tse ka qhekelloang le tse hlokang matla
Litholoana tse kang li-antidepressant-like tsa AMPA receptor blockade ho NAc
Lintlha tsena li fana ka maikutlo a hore ts'ebetso ea receptor ea AMPA e eketsehang (keketseho ea GluR1: karolelano ea li-GluR2) ho NAc ea litoeba tse amehang e khothaletsa tšireletso ea sechaba, athe ts'ebetso ea AMPA e fokotsehile (GluR1: ratio ea GluR2) e thusa ho tsitsisa. Ho etsa tlhahlobo-kholo ena, re kentse NPA ea receptor antagonist NBQX ka kotloloho ho NAc ea litoeba tse hlotsoeng hang-hang pele ho tlhahlobo ea thibelo ea sechaba. NBQX e ile ea eketsa nako ea tšebelisano ea sechaba (Feiga. 4f), ho bonts'a motsoako oo oa phetoho e potlakileng ea NAc o hanana le polelo ea phello ena e mpe ea khatello ea maikutlo ea sechaba. NBQX ha e fetole mesebetsi ea kakaretso ea locomotor (Tlhahiso e eketsehileng Fig. 6). Ntle le moo, phello e kang ea antidepressant e kang ea ts'oaetso e le 'ngoe ea NBQX mabapi le ho qoba maemo a bophelo e bile ea nako e telele ha litšoene li boetse li lekoa beke e' ngoe hamorao li bonts'a ntlafatso ea tšebelisano ea sechaba.
Re latela GimaR2 ka botšehali ho khetha NAE ea litoeba tse ka qhekelloang. Polelo ea GluR2 e khutlisitse ka mokhoa o felletseng qobellong ea sechaba e hlahisoang ke ho hloloa ho sa feleng sechabeng (Feiga. 4g), e ts'ehetsang maikutlo a hore GluR2 upregulation ho NAc ke mokhoa oa bohlokoa oa ho sebetsa ka thata. Ho khahlisang, phello ea GluR2 overexpression e ile ea phehella bonyane matsatsi a 10 kamora ho buuoa (Feiga. 4g) ha polelo ea "GluR2-virated-mediated" e felisitsoe ka botlalo. Ka lehlakoreng le leng, lithutong tse mamellehang, ho fetella hoa mofuta o sa lebelloang oa GluR2, GluR2Q, e tšoanang le GluR1 lithutong tse sebetsang, e file litoeba tse kotsing ea ho hloloa sechabeng (Mofuta oa 4g), e ts'ehetsang pono e eketsang tšebetso ea li-receptor tsa AMPA ho NAc e etsa hore ho be bonolo.
SC1, sepheo se seng sa ΔFosB, le eona ke mokena-lipakeng oa ho mamella
Ho supa mefuta e meng ea sepheo sa ΔFosB e tlatselletsang ho matlafala, re bapisitse lethathamo la lethathamo la li-gene tse fumanoeng ho NAc ea li-mice tsa bitransgenic overexpressing ΔFosB le ho tloha C57Bl / 6J litoeba tsa 48 kamora ho hloloa ho sa feleng sechabeng ho bonts'itseng sepheo sa ho ts'oaroa ka mokhoa o ts'oanelang.10,24. Setšoantšo sa 6a e bonts'a ho kopana ho hoholo (> 75%) lipakeng tsa liphatsa tsa lefutso tse hlohlellelitsoeng ho NAc ka bobeli ke ΔFosB le ka mamello. Har'a liphatsa tsa lefutso tsena (tse thathamisitsoeng ho Letlapa le tlatsetsang 2), re khethile tlhahlobo e ngoe ea SC1, e ipapisitse le boholo ba eona e kenelletseng kahare ho bokhoni ba eona le ho ΔFosB overexpression. SC1, e tsejoang hape e le Sparc (proteni e bolokiloeng, acidic, e nang le cysteine)-joalo ka 1 kapa hevin, ke molek'hule oa matrix o hanyetsanang o hlahisoa haholo bokong ba motho e moholo, moo a fumanehang ho boholo ba posynaptic mme a kenella ho synaptic polasetiki31. Ho hlahloba ka kotloloho karolo e ka bang teng ea SC1 boitlamong, ka botona re tšoaetsa SC1 ho NAc ea litoeba tse kotsing. SC1 e khutlisitse haholo ts'ireletso ea boiketlo e hlahisitsoeng ke ho hloloa ho sa feleng sechabeng (Feiga. 6b). SC1 overexpression e boetse e hlahisitse phello e kang ea antidepressant ka letsatsi 2 ea tlhahlobo e qobelloang ea ho sesa (Feiga. 6c 'me Mofuta oa tlatsetso oa feiga. 7a-c), empa ha e na phello mosebetsing oa basal locomotor le boits'oaro bo amanang le ho tšoenyeha (Mofuta oa tlatsetso oa feiga. 7d-g). Ntle le moo, re fumane tšekamelo e matla ea litekanyetso tsa SC1 tse fokotsehileng litekeng tsa motho tsa postmortem NAc ho tsoa ho bakuli ba tepelletseng maikutlo (Feiga. 6d).
Pro-Resilience, litlamorao tse kang li-antidepressant joalo ka SC1 ho NAc
TŠOHLOA
Liphetho tsa boithuto ba hona joale li fana ka bopaki ba pele ba liphetoho tsa limolek'hule tse etsahalang lipakeng tsa li-spiny neurons tsa NAc tse arabang ka mokhoa o hlakileng khatello ea khatello ea maikutlo le tse tlatsetsang liphellong tsa kalafo tse sa feleng tsa kalafo ea kalafo. Re bontša hore maemo a tlase a ofFosB ho NAc a supa ho ba kotsing ea motho ea ho imeloa kelellong, le hore tekanyo ea ΔFosB ha e sebetsana le khatello ea maikutlo e sa fetoheng e fana ka karabelo e tsitsitseng ea ho hanyetsa khatello eo. Re bontša hape hore phetoho e atlehileng ea tlhekefetso ea boits'oaro e kenelletseng liphoofolong tse ts'oaroang ke tsamaiso e sa foleng ea fluoxetine e hloka hore ho kenngoe lithethefatsi tsa ΔFosB sebakeng sena sa boko. Liphumano tsena li bonts'a hore ho kenngoa ha ΔFosB ho NAc ke mokhoa oa ho sebetsana le ho raroloha mathata ka mokhoa o hlakileng. Ho fumaneha ha maemo a tlase a ΔFosB ho NAc ea batho ba tepelletseng maikutlo ho tšehetsa bohlokoa ba lipatlisiso tsena tsa mehlala ea mouse ho tepella maikutlo. ΔFosB e laola ts'ebetso ea NAc ka ho qobella kapa ho hatella mefuta e mengata ea sepheo24,27. Re tšoaea mefuta e 'meli ea sepheo sa eona, AMPA receptor subunit GluR2 le SC1, protheine ea extracellular matrix,' me re e kenya ka kotloloho ho hanyetsanang khatello ea khatello ea sechaba.
Karolo e joalo ea ho matlafatsa boiketlo ba ΔFosB maemong a khatello ea maikutlo e sa feleng e ea khahlisa molemong oa ho kenya letsoho ha inFosB ho laola likarabo tsa lithethefatsi tsa tlhekefetso le meputso ea tlhaho joalo ka lijo, thobalano le boikoetliso19. ΔFosB e qobelloa ho NAc ka meputso ea lithethefatsi le ea tlholeho, mme e eketsa likarabo tse khotsofatsang liphoofolong tsena. Ka hona e susumetsoa joalo ka mokena-lipakeng oa likarolo tse ling tsa bokhoba ba lithethefatsi. Se fumanoeng hona joale mehatong ea khatello se fana ka leseli le lecha ka karolo ea protheine ena taolong ea boitšoaro bo rarahaneng ba maikutlo. Tlas'a maemo a tloaelehileng, ΔFosB e hlahisoa ka maemo a holimo ho NAc ha e bapisoa le libaka tsohle tse ling tsa boko19. Re kholoa hore litekanyetso tsa ΔFosB ho NAc li bapala karolo ea bohlokoa ho theha boemo ba motho ba ho susumetsa le ho tataisa boits'oaro bo susumetsang bo lebisang molemong oa moputso o tsebahalang. Ho tlosoa ha ts'usumetso ea tikoloho nakong ea ho arohana nako e telele ho fokotsa maemo a ΔFosB ho leihlo la NAc, ho matlafatsa sepheo sa bona le ho eketsa tlokotsi ea bona khatellong e sa feleng ea sechaba, joalo ka ha re bonts'a mona. Phokotseho e hlokometsoeng ea maemo a ΔFosB ho postmortem NAc ea bakuli ba tepelletseng maikutlo e tsamaisana le khopolo ena, mme e fana ka maikutlo a karolo ea ΔFosB ka ts'usumetso e mpe le moputso o bonoang ho batho ba bangata ba nang le khatello ea maikutlo. Ka lehlakoreng le leng, bokhoni ba ho susumetsa ΔFosB ho NAc ho sebetsana le khatello ea maikutlo bo sa foleng bo thusa motho ho ntlafatsa khothatso le moputso oa tlhaho le ha khatello ea maikutlo e ntse e le teng, mohopolo o lumellanang le maikutlo a teng a ho tiea ho batho1,2. Re pheta hape taba ea hore ho kenya ΔFosB ho NAc ka ho pepesehela lithethefatsi tsa tlhekefetso, e kholo haholo ho feta e boneng ka khatello ea maikutlo kapa meputso ea tlhaho19, e hlahisa boemo ba methapo ea tšusumetso e ntlafalitsoeng ka mokhoa o senyang potoloho ea meputso e lebisang kholisong e matla ea lithethefatsii.
Ho hlakile hore lintlha tse ikhethileng tsa khopolo ena li hloka hore ho etsoe lipatlisiso tse ling. Ho kenyelletsoa ha ΔFosB ho NAc ka khatello ea maikutlo kapa ka fluoxetine ho ka lebelloa ho eketsa moputso oa lithethefatsi. Ho joalo ka hona, ho hlonama ho tlisoang ke khatello ea maikutlo le bokhoba ba tahi ho thehiloe bathong, 'me maikutlo a lipakeng tsa lithethefatsi tsa tlhekefetso le khatello ea maikutlo a bontšitsoe litoeba32-34. Ka lehlakoreng le leng, khatello ea maikutlo le ts'ebeliso ea lithethefatsi li matla haholo, li-syndromes tsa khale mme batho ba bangata ba nang le khatello ea maikutlo ha ba na temallo le ka ho fapanyetsana. Ho feta moo, fluoxetine ha e na litlamorao tse hlakileng mabapi le karabo ea lithethefatsi ho liphoofolo, hape ha se kalafo e sebetsang ea bokhoba ba lithethefatsi le bona ba sa sithabetseng maikutlo. Tumellanong le ho rarahana hona, re fumane hore litoeba tse ka qhekelloang eseng litoeba tse matla, ho paradigm ea tlhaselo ea sechaba e bonts'a likarabo tse ntlafalitsoeng litabeng tsa lithethefatsi tsa tlhekefetso10. Sena se ka fana ka tlhahiso ea hore kotsi e ntlafalitsoeng ea litoeba tse hlasetsoeng ke lithethefatsi tsa tlhekefetso e tsamaisoa ka ho sebelisa mekhoa e meng e mengata e kenyellelitsoeng ho NAc le libakeng tse ling, e le mohlala o le mong, BDNF, e kenyellelitsoeng mokhoeng oa ho se sebetse, eseng ho tiisetsa, litoeba ho NAc le ho ntlafatsa mekhoa ea meputso ea lithethefatsi.sheba 10.
Tlhaloso eo ΔFosB e khothalletsang likarolo tsa bokhoba, ha e ntse e khothaletsa khatello ea maikutlo, ha e makatse ha ho na le likamano tse rarahaneng tse bonts'itsoeng pakeng tsa karolo ea protheine e fanoeng NAc metsong ea khatello ea maikutlo. Liprotheine tse ling (mohlala, BDNF) li khothaletsa karabo ho lithethefatsi tsa tlhekefetso le khatello ea maikutlo, ha liprotheine tse ling li hlahisa litlamorao tse tlasa maemo ana a mabeli: mohlala, CREB ho NAc e hlahisa mofuta oa pro-khatello ea maikutlo, leha ho le joalo e etsa karabelo ho lithethefatsi tsa tlhekefetso. sheba 4,10.
Liphumano tsena li totobatsa tlhokeho ea lipatlisiso tse ling hape tsa ho nyakurela kameho ea molek'hule ea boitšoaro bo rarahaneng ba maikutlo, le bohlokoa ba ho sebelisa tlhahlobo e batsi ea boits'oaro lipatlisisong tse joalo. Liphetho li boetse li bonts'a hore, joalo ka ha ho ka lebelloa, ΔFosB feela e ke ke ea hlalosa liketsahalo tse felletseng tsa khatello ea maikutlo le bokhoba, ho fapana le moo, ke molaoli oa bohlokoa oa mekhoa ea moputso e ts'episitsoeng ke NAc mme ka hona e bohlokoa ho hokahanya likarolo tse ling tsa maemo ana ka bobeli.
Leha ho le joalo, sesosa se ka sehloohong sa puisano ena ke mefuta e fapaneng ea sele ho NAc moo ΔFosB e kenyellelitsoeng maemong a khatello le litumelo. Lithethefatsi tsa tlhekefetso le meputso ea tlhaho li susumetsa ΔFosB haholo-holo ho subclass ea li-spiny neurons tse mahareng tsa NAc tse hlalosang D1 dopamine li-receptors19,22, ha khatello ea maikutlo e etsa hore ΔFosB e lekane ka ho lekana ka har'a D1 le D2 li-neuron tse nang le metso e lipakeng tsa "receptor"20. Tlhahiso ena e khethollang e ka ba le litlamorao tse ntle tsa ts'ebetso, hobane bokhoni ba ΔFosB ba ho ntlafatsa moputso bo bontšitsoe bakeng sa D1 sehlopha sa methapo ea kutlo feela19.
Ho tsebahatsoa ha GluR2 e le mofuta oa sepheo se amehang ho sebeliseng matla a ts'ebetso ea'sFosB e fana ka leseli mabapi le lintlha tsena. Re bontša hore bofokoli ba litoeba, le khatello ea maikutlo ea batho, li hokahana le keketseho ea GluR1: Karolelano ea GluR2 ho NAc, e bonts'ang ho eketseha ha thabo ea "spiny neuron" ho arabela glutamate.
NAc e fumana litlatsetso tsa glutamatergic tse tsoang libakeng tse 'maloa tsa boko, haholo, cortex ea pele, amygdala, le hippocampus35. Ho kenella ka mokhoa o joalo oa glutamatergic ho hlophisa botle le bohahlauli ba meputso e khahlisang le e nyarosang 'me ka hona e laole boitšoaro bo susumetsoang36-38. Boithuto ba morao-rao bo tsamaisana le mohopolo oa rona oa ntlafatso oa NAc o ka ntlafatsang ho ba le khatello ea maikutlo. Matšoenyeho a qobelloang a ho sesa a eketsa matla a synaptic le tšebetso ea AMPA receptor ho NAc39, ha ho kenngoa ha glutamate ho NAc ho fokotsa boitšoaro ba ho sesa tekong e qobelloang ea ho sesa, phello e kang ea khatello ea maikutlo40. Ka kakaretso, ho eketsa ho fofa ha libaka tsa NAc ho hlasela libaka tse fapaneng tse fapaneng mefuteng ea liphoofolo41. Liphetoho mosebetsing oa NAc li hlokometsoe ho bakuli ba nang le khatello ea maikutlo e kholo42 'me mabothong a ikhethileng, masole a khethiloe pele le ho koetlisetsoa ho phela ka thata ha a le tsietsing e kholo43. Ka mokhoa o ts'oanang, ts'usumetso e matla ea bokong ea cgenex ea cgenex kapa ea NAc (sepheo se ka sehloohong sa cortex cgenex), khopolo ea ho kenella e thusa ho fokotsa thabo ea karolo e matla ea boko, e fokotsa matšoao a nyahamisang ho bakuli ba hanyetsang kalafo3,44.
Joalo ka mefuta ea khatello ea maikutlo, karabelo e eketsehang ea glutamatergic ho NAc le eona e kentse letsoho ts'ebelisong ea lithethefatsi30,45-47. Sena se kenyelletsa keketseho ea li-receptor tsa AMPA tse haelloang ke GluR2 sebakeng sena sa boko30,47, e ts'oanang le eo re e tlalehang mona bakeng sa khatello ea maikutlo. Ka kopanelo, liphuputso tsena li hlahisa monyetla o khahlisang oa hore phetisetso ea glutamatergic e ntlafalitsoeng ho NAc e etsa hore ho be bonolo ho lemalla le ho tepella maikutlo. Phetoho e fapaneng, ke hore, karolelano ea GluR1: GluR2 karolelano, e bontšitsoeng ho NAc ea litoeba tse ikemiselitseng, e fana ka maikutlo a hore ts'ebetso ea glutamatergic e fokolitsoeng e kanna ea itšireletsa khahlano le litlamorao tse tlisoang ke khatello ea maikutlo e sa foleng. Sena se lumellana le lipono tse ileng tsa eketsa ts'ebetso ea GluR2, kapa ea fokotsa mosebetsi oa GluR1, ho NAc e eketsa moputso le khothatso.28,37,48. Bokhoni ba fluoxetine ba ho susumetsa polelo ea GluR2 ka mokhoa o tšoanang ho NAc e phahamisa monyetla oa hore ho fokotsoe ho bolokoa ha glutamate sebakeng sena sa boko ho ka ba le tlatsetso ho likarabo tsa antidepressant. Ho joalo, re bonts'a mona hore thibelo ea ts'ebetso ea AMPA receptor ka hara NAc e hlahisa karabelo e matla joalo ka nako e telele ea ho loants'oa khatello ea maikutlo.
Ha liphetoho tse re li supang ho polelo ea AMPA ea receptor ho NAc ea litoeba tse amehang li lumellana le maikutlo a rona a maikutlo, liphetoho tse bonts'ang boikemisetso li rarahane ho feta. Ha rea ka ra fumana bopaki ba electrophysiological bakeng sa li-receptors tse fokotsang GluR2-AMPA tse fumanehang ho NAc ea litoeba tse tiisitsoeng ha li bapisoa le taolo. Re kholoa hore ΔFosB-Mediated induction of GluR2 in resilience e mpa e le e 'ngoe ea liphetoho tse ngata tse etsahallang NAc tse amang phetisetso ea glutamatergic le hore, ha ts'ebetso ena e lekane ho khutlisa ts'ebetso e kholo ea AMPA ea receptor e bonoang ka tsietsing. lehlakoreng le fapaneng. Ehlile, data ea rona e senola taolo e rarahaneng ea phetisetso ea glutamatergic ho NAc kamora khatello e sa feleng ea khatello ea maikutlo sechabeng. Liphetoho tse fapaneng le polelo ea GluR1 sebakeng sena sa boko maemong a ts'ebetso ea ts'oaetso ha li bonoe ho boemo ba mRNA, leha e le hore maemo a fokotsehileng a GluR2 maemong a pherekano a bonoa maemong a mRNA. Sena se tsamaisana le liphetoho tsa morao-rao tsa phetolelo, ho kenyelletsoa le liphetoho tsa khoebo ea li-receptor tsa AMPA le tsona li bapala karolo ea bohlokoa, joalo ka ha ho bonoa mehlaleng ea tlhekefetso ea lithethefatsi30,47.
Tekanyetso e rarahaneng ea phetisetso ea glutamatergic ho NAc ka khatello ea maikutlo e sa feleng e totobatsoa ke ho sibolla ha rona ha SC1 e le mofuta o mong oa sepheo sa ΔFosB, oo, joalo ka induction ea GluR2, mediates resiliency. SC1 e tsejoa ho laola polasetiki ea synaptic31. Ka lebaka la thepa ea eona e khahlano le ho khomarela, ho kenngoa ha SC1 ho NAc ho ka baka tikoloho e lumellehang bakeng sa liphetoho tsa sebopeho tse tsamaeang le polasetiki ho li-glapsamatergic synapses tse shebahalang li le bohlokoa bakeng sa ho tiisetsa. Mohlala, bopaki ba morao-rao bo bonts'a hore ho tlosoa hoa matrix a tsoang kantle ho nako ho lumella phapang ea li-receptor tsa AMPA ebe ka tsela eo e phahamisa polasetiki ea synaptic49.
Ka kakaretso, sephetho sa rona se ts'ehetsa morero oo ka oona ΔFosB ea NAc e sebelisang matla a ho sebetsana le khatello ea maikutlo ka nako e telele ka ho kenya mofuta oa polokeho ea testaptic e sebetsanang le thuto e mpe e kopaneng ea ho ithuta e etsahalang ho litoeba tse ka bang teng. Mohlala, keketseho ea li-receptor tsa AMPA tse sa hlokeng letho tsa NAPA ho NAc, tseo re li bonang ho litoeba tse ka qhekelloang, li bonts'itsoe ho phahamisa likarabo ho lithahasello tse amanang le koae tse khothalletsang ho lakatsa le ho khutlela mekhoeng ea ho lemalla.30,47. Ho fapana le moo, ho fokotseha ha molumo oa glutamatergic ho litoeba tse mamellehang, ka ntlafatso ea GluR2 mohlomong le ho kenella ha SC1, ho ka fana ka tšusumetso e kholo, joalo ka panya ea lenane ho paradigm ea sechaba, mme ha e khone ho kenya ts'ebetsong li-neurc tsa Nec, 'me ka tsela eo e thusa sepheo Boitšoaro bo tsamaisitsoeng ho tsoela pele ho sa na le khatello ea maikutlo. Mefuta ea rona ea gene e fana ka maikutlo a ho nka karolo ha lipheo tse ling tsa ΔFosB tse kenyang letsoho ho matlafatsong. Karolo e kholo e bapaloang ke ΔFosB le sepheo sa eona ho bokhoni ba motho ba ho ikamahanya le khatello ea maikutlo e sa feleng e hlahisa mekhoa e mecha bakeng sa nts'etsopele ea litlhare tse thibelang khatello ea maikutlo.
METHODA
Mekhoa le litšupiso tse amanang le eona li fumaneha ka har'a mofuta oa pampiri ea inthaneteng ho http://www.nature.com/natureneuroscience/.
Boitsebiso bo Eketsehileng
Suppl
Tobetsa mona ho sheba.(1024K, doc)
Tobetsa mona ho sheba.(136K, pdf)
lumela hore baa fokola
Mosebetsi ona o tšehelitsoe ke lithuso tse tsoang Setsing sa Naha sa Bophelo ba Kelello le ka tumellano ea lipatlisiso le AstraZeneca. Re leboha Drs. P. McKinnon le H. Russell bakeng sa mpho e mosa ea SC1 cDNA. Re boetse rea leboha. Maze, Drs. R. Oosting, S. Gautron le D. Vialou bakeng sa puisano e ntle le litlhaloso mabapi le buka e ngotsoeng ka letsoho.
Mongolo o botlaaseng ba leqephe
Menehelo ea Mongoli VV le EJN ba ne ba ikarabella ho moralo oa ho ithuta ka kakaretso. QL le VV e qapile, ea tsamaisoa le ho hlahlobisisa liteko tsa RNA le ChIP. AJ Robison o qapile, a khanna, a ba a lekola lithuto tsa electrophysiological. HEC le VV li thehile le ho etsa liteko tsa meriana ea NBQX. QL, DMD, ELW, le VV ba ile ba etsa liopereishene tsa methapo. YNO e ile ea kopanya SC1 cDNA ho sethala sa HSV. YHO e entse assX APUMNUMX luciferase assay. QL, DMD, DW, le VV li thehile le ho etsa liteko tsa tlhahlobo ea sechaba. VV, ELW, le AJ Rush ba ile ba etsa liteko tsa ho hloloa sechabeng le boitekanyetso ba immunohistochemical. SI, QL, BW, le VV ba entse opereishene ea ratoa le ho hlahlobisisa liteko tsa ho sesa. EM le RN li fane ka livaerase tsa vaerase bakeng sa vaerase-transgenesis. MAS, VK, le OB ba koetlisitse VV ho hloleheng sechabeng le tlhahlobisong ea biochemical mme e fane ka taolo ea boleng holim'a datha ea ho hloleha sechabeng. SG le CAT li fane ka lisele tsa boko tsa motho kamora lefu. VV le EJN ba ngotse pampiri eo ka thuso ea bangoli ba bang.
Boitsebiso ba Mongoli Tlhahisoleseling ea lintlha le mangolo e fumaneha ho www.nature.com/reprints.
eketsehileng Boitsebiso bo Eketsehileng e hokahane le mofuta oa pampiri ea inthanete ho www.nature.com/natureneuroscience/.
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