- ISIHLOKO ESIFUNDWAYO
- ebabaza incazelo - Nge-Stress Resiliance, ngiyabonga iDeltaFosB
Nat Neurosci. I-2010 Juni; 13(6): 745-752. Ishicilelwe online 2010 May 16. doi: 10.1038 / nn.2551
Vincent Vialou,1 U-Alfred J. Robison,I-1, * U-Quincey C. LaPlant,I-1, * Herb E. Covington, III,1 UDavid M. Dietz,1 Yoshinori N. Ohnishi,1 UHezekell Mouzon,1 U-Augustus J. Rush, III,2 Emily L. Watts,1 UDeanna L. Wallace,I-2, § USergio D. Iniguez,3 U-Yoko H. Ohnishi,1 UMichel A. Steiner,4 Brandon Warren,3 I-Vaishnav Krishnan,2 URachael L. Neve,5 I-Subroto Ghose,2 U-Olivier Berton,I-2, § UCarol A. Tamminga,2 futhi U-Eric J. Nestler1
Ulwazi lomlobi ► Ulwazi lobunikazi nelayisense ►
Uhlobo lokugcina oluhleliwe lomshicileli luyatholakala at Nat Neurosci
Bona ezinye izihloko ku-PMC ukuthi ubalula isihloko esishicilelwe.
abstract
Ngokuphikisana nezincwadi eziningi zemiphumela yokucindezela ebuchosheni, akukho okuncane okwaziwayo ngamasu wamandla okuqina, ikhono labanye abantu lokuphunyuka emiphumeleni yokuxineka kwengcindezi. HNgaphambi kokuthi sikhombise ukuthi isakhi sokubhaliwe, i-ΔFosB, sidingida inqubo ebalulekile yokuqina kokuqina kumagundane. Ukungeniswa kwe-ΔFosB ku-nucleus accumbens, isiza somvuzo wobuchopho obalulekile, ekuphenduleni kwengcindezi yokuhluleka ukunqotshwa komphakathi kubalulekile futhi kwanele ukubekezelela. Ukungeniswa kwe-ΔFosB kuyadingeka futhi nekhono le-antidepressant esejwayelekile, i-fluoxetine, ukuguqula indlela yokuziphatha ebangelwa ukuhlulwa komphakathi. I-ΔFosB ikhiqiza le miphumela ngokungeniswa kwe-GluR2 AMPA glutamate receptor subunit, enciphisa ukuphendula kwama-nucleus accumbens neurons kuya ku-glutamate, nangamanye amaprotheni e-synaptic. Ngokubambisana, lokhu okutholakele kusungula indlela entsha yamangqamuzana engaphansi kokuqina nokulwa nesinyathelo sokulwa nokucindezela.
ISINGENISO
Abantu bafakwa ngaphansi kwengcindezi enkulu bakhombisa izimpendulo ezihluke kakhulu, abanye bekwazi ukunqoba ubunzima ngenkathi abanye beba nokukhubazeka kwengqondo okuqinile okufana nokudangala noma i-post-traumatic stress disorder (PTSD). Amandla okubhekana nezimo ezicindezelayo, ie, ukuqina, kuncike ekuthuthukisweni kokuzivumelanisa okwanele kokuziphatha nokwengqondo kwengqondo ekucindezelekeni okungapheli1,2. Ukuqanjwa ngokwengqondo okuthuthukisa ukuzinza kufaka phakathi ukuzibophezela, ukubekezela, ukuba nethemba, nokuzithemba, kanye namandla okulinganisa imizwa nokuthuthukisa ukusebenza ngokuzibandakanya kwezenhlalo. Lezi zici zenza umjikelezo womvuzo wobuchopho ubonakale njengosichaza ngokubucayi bokuvela kwe-phenological vs. resilient phenotypes3,4. Ukuxhumeka kwe-Neurobiological yokuba sengozini noma ukumelana nokucindezelwa kuveziwe i-2 kubantu, kodwa ukuthi bangezimbangela noma umphumela wokungabikhona kwengozi kangakanani5.
Phakathi kwamamodeli wamanje wokuxineka kanye ne-PTSD, ukucindezelwa okungapheli kokuhlaliswa komphakathi kuyindlela evumayo yokuziphatha, ebamba impilo ende yesikhathi eside6-8 nokuziphatha9-11 ukushintshwa12-15. Ukujwayezwa kokugwemeka komphakathi ngokungalapheki, kodwa hhayi okunamandla, okubulala izinhlungu kwenza kube yimodeli ebalulekile yokuhlola izici zokudangala ne-PTSD kubantu11,16. Ingxenye ebalulekile (~ 30%) yamagundane ahluleke kakhulu igwema iningi lokuziphatha okungafanele kokuhlulwa10, ngalokho kuvumela ukuphenywa kokuhlolwa kokuqina. Ngenkathi ukutholwa kwamaprotheni ambalwa ngaphakathi kwe-nucleus accumbens (NAc), isiza somklomelo wobuchopho obalulekile, kuboniswe njengokubalulekile ekubonakaliseni kokuziphatha okucindezelayo ngemuva kokwehlulwa10,11,17,18, kuncane kakhulu okwaziwayo ngesisekelo samaseli sokuqina okulamulwa yilesi sikhathi sobuchopho. Lapha, sabheka lo mbuzo ngokugxila ku-ΔFosB, into eqoshwe emndenini wakwa-Fos eqhutshwa yi-NAc ngezidakamizwa zokuhlukumeza, imivuzo yemvelo, kanye nezinhlobo eziningana zokucindezelwa19-21.
IZIPHUMA
I-ΔFosB ku-NAc ikhuthaza ukuqinisela ekucindezelekeni kwenhlalo yomphakathi
Amagundane abesilisa e-C57BL / 6J atholwe ngaphansi kwezinsuku eziyishumi zomhlangano wokuhlulwa komphakathi10,11, bese ihlukaniswa ibe yingxenye yokutholwa kalula futhi okunamandla okususelwa kusilinganiso esithile sokugwemeka emphakathini (I-Fig. 1a), exhumanisa nezinye izindlela zokuziphatha ezicindezelayo ezinjengokucindezela10. Sithole ukwanda kwe-ΔFosB, kukalwa nge-immunohistochemistry, ku-NAc ngemuva kokuhlulwa okungapheli kwezenhlalo (I-Fig. 1b, c), ngamagundane avumelanayo abonisa lokungeniswa okukhulu kwe-ΔFosB kuzo zombili izikhombisi ezingumgogodla nogobolondo we-NAc (I-Fig. 1b, c). Ngaphezu kwalokho, sabona ukuhlangana okuqinile (p <0.01) phakathi kwamazinga we-ΔFosB nokuxhumana komphakathi (r = 0.80, igobolondo le-NAc; r = 0.85, umongo we-NAc; r = 0.86, i-NAc yonke), okuphakamisa ukuthi izinga lokungeniswa kwe-osBFosB I-NAc ingaba yisinqumo esibucayi sokuthi isilwane sikhombisa i-phenotype ethintekayo noma enamandla. Ukuhlaziywa kwe-Western blot kokuchithwa kwe-NAc okuqukethe izizinda eziyinhloko nezingamagobolondo kuqinisekisile ukufakwa kwe-ΔFosB kumagundane aqinile kuphela (bona Fig Supplementary 1).
Ukungeniswa kwe-ΔFosB e-NAc ngokunqotshwa komphakathi kube nokuqiniswa
Ukuhlola imiphumela esebenzayo yokungeniswa kwe-ΔFosB, sisebenzise amagundane we-bitransgenic angenza i-vereFosB ngokungenhloso ku-NAc yabantu abadala ne-dorsal striatum22. Lawa amagundane akhombisa ubukhulu bokunciphisa ukugwemeka emphakathini ngemuva kwezinsuku ezine noma eziyishumi zokuhlulwa komphakathi (Umdwebo. 1d), ngaleyo ndlela kusikisela ukuthi i-ΔFosB yenza isenzo sokuvikela ekucindezelweni komphakathi. Ngakolunye uhlangothi, sisebenzise amagundane e-bitransgenic aphethe ngokweqile i-ΔcJun, isenzo esingasebenzi sombhalo we-cJun esisebenzayo esiphikisa umsebenzi we-ΔFosB23,24. Ngokungafani nama-oFosB amagundane, ukuhlaselwa ngokweqile kwamagundane kusengozini enkulu yokunqotshwa komphakathi okungapheli kunokulawula abanye futhi kukhombise ukuzivikela okuphezulu okulandela izinsuku ze-4 zokunqotshwa (Umdwebo. 1e). Amagundane e-ΔcJun abuye abonise ukungasebenzi kahle kokuvivinywa kokubhukuda okwenziwa ngosuku olulodwa, kanye nokuncipha kokuncipha kwe-sucrose, zombili ezihunyushwa njengokuziphatha okukhulayo okufana nokudangala (I-Supplementary Fig. 2a, b). Kodwa-ke, i-ΔFosB noma i-ΔcJun overexpression ayishintshanga izindlela eziyisisekelo zomsebenzi we-locomotor noma isimilo esifana nokuxakeka (Umdwebo owengeziwe. 2c-f). Ngokubambisana, lokhu okutholakele kusikisela ukuthi umsebenzi we-ΔFosB oncishisiwe kwi-NAc naku-dorsal striatum wehlisa izimpendulo ezinhle, eziguqukayo, ezenziwe ngokuthi "ukubhekana7", Ekucindezelekeni okungapheli.
Ukuncipha kwe-ΔFosB ku-NAc kukhuthaza ukucindezelwa kokucindezela
Ukuthola ukuqonda okwengeziwe ngezenzo zokuziphatha ze-ΔFosB ngemuva kwengcindezi engapheli, sisebenzise isikhathi eside sokuhlukaniswa komphakathi lapho sesikhulile, okubangela ukudana okufana nokungahambi kahle emgundwini25 futhi iyisici esikhulu sengozi yokudangala kliniki. Sibone ukwehla kwamazinga we-ΔFosB ku-NAc yezimpuku ezihlukaniswe nomphakathi (Umdwebo. 2a, b). Siphinde sathola ukuthi ukuzihlukanisa kwenza ukuthi amagundane abe sengozini enkulu yokwehlulwa ngumphakathi, nokuthi lokhu kubekeka engcupheni yokuzihlukanisa kuguqulwe ngokuphelele ngokuhlaselwa ngokweqile kwe-allyFosB ngokukhetha ku-NAc (I-Fig. 2c). Ngakolunye uhlangothi, ukuvimba kokusebenza kwe-ΔFosB ku-NAc, ngokweqile kwe-viral ye-unJunD, kumagundane okulawulwa ngamaqembu kugqugquzele usizi lokunqotshwa komphakathi (I-Fig. 2c). I-ΔJunD, efana ne-ΔcJun, iyisakhi esiguqukayo se-N-termine esisebenza njengomphikisi omkhulu we-ΔFosB (Fig Supplementary 3)23. Lokhu okutholakele kugcizelela ngokuqondile amazinga asisekelo we-ΔFosB ku-NAc ekucindezelekeni kwengcindezi.
Umphumela wokuhlukaniswa komphakathi ku-ΔFosB kanye nasengcupheni yokunqotshwa komphakathi
Ukutadisha ukuhambisana kwemitholampilo kwalokhu okutholakele, amazinga we-ΔFosB alinganiswa kumasampula we-NAc wesintu atholakala ezigulini ezicindezelekile kanye nezilawuli ezihambelana kakhulu. Sithole ukwehla kwe-~ 50% kumazinga we-ΔFosB ezigulini ezicindezelekile (Umdwebo. 2d), ukusekela iqhaza le-ΔFosB ekucindezelekeni kwabantu. Abantu abacindezelekile abahlaziye bafaka phakathi noma kwabakhipha imishanguzo ngesikhathi sokufa kwabo (Ithebula Lokungezelela 1), futhi asitholanga ukuhlangana phakathi kwamazinga we-ΔFosB nokuchayeka kwe-antidepressant. Ngokubona kwethu ukuthi ukwelashwa okubhebhethekisa ukukhulisa amazinga we-ΔFosB ku-NAc yegundane (bheka ngezansi), lokhu okutholakele kusikisela ukuthi ukwehluleka ukunxenxa i-ΔFosB ku-NAc kungaba yisichasiselo esibalulekile sokuntuleka kwezimpendulo zokulwa nezinkinga kubantu.
I-ΔFosB ku-NAc ilawula isenzo sokulwa nokucindezela
Ukwelashwa okungapheli kokuqeda amandla kuphindisela emuva ekugwemeni ukunqotshwa komphakathi okunqobayo okubonwa kumagundane angenzeka11. Ngakho-ke sihlolisise ukuthi i-ΔFosB lokungeniswa e-NAc kungenzeka ukuthi ingumsebenzi hhayi wokuqina kuphela kepha nesenzo sokulwa nokucindezela. Amagundane okulawula angahlulwa aphathwe nge-fluoxetine yezinsuku ze-20 aveze ukuthi akukho zinguquko ekuziphatheni komphakathi, kodwa abonise ukunqwabelana kwe-ΔFosB ngegobolondo le-NAc (Umdwebo. 3a, b) nomongo (Fig Supplementary 4). Ukwelashwa kwe-Fluoxetine kwamagundane atholakalayo kuguqule ukugwema kwabo zenhlalo (I-Fig. 3a), njengoba kubikwe phambilini, futhi kubuye kuthuthukiswe amazinga we-ΔFosB ku-NAc (I-Fig. 3b, Fig Supplementary 4).
Ukungeniswa kwe-ΔFosB ku-NAc kuxhumanisa umphumela we-antidepressant we-fluoxetine
Ukuhlola ngokuqondile ukubandakanyeka kwe-ΔFosB lokungeniswa okunjalo emiphumeleni yokuziphatha ye-fluoxetine, thina ngokweqile ΔJunD noma i-GFP sisodwa (njengendlela yokulawula) ku-NAc yamigundane eyanqotshwa ngaphambili. Ingxenye yamagundane eqenjini ngalinye yabe iselashwa amanye amasonto amathathu nge-fluoxetine noma imoto. Njengoba bekulindelekile, ukwelashwa kwe-fluoxetine kwe-GFP yamagundane ku-NAc kukhombisa ukuguqukela ekugwemeni komphakathi okubangelwa ukwehlulwa okungapheli komphakathi. Ngokuphambene, i-overexpression ye-ΔJunD ivimbele lo mphumela wokwelapha we-fluoxetine (I-Fig. 3c), kusekelwa i-hypothesis ethi i-ΔFosB yokungeniswa ku-NAc iyadingeka ezenzweni zokulwa nezinyathelo. Ngaphezu kwalokho, i-overexpression-Mediated Medium ye-ΔFosB ku-rat NAc ikhiqize umphumela obalulekile we-antidepressant njengoba ulinganiswe yisikhathi esinciphile sokungakwazi ukusebenza ngosuku lwe-2 lokuhlolwa kokubhukuda okuphoqelekile (Umdwebo owengeziwe. 5a). Ukuhlaziywa okwengeziwe kokuziphatha ngalesi sivivinyo kuveze ukwanda okwenziwe yi-ΔFosB kokubhukuda nokukhwela (Umdwebo owengeziwe. 5b-d), izici ezihlobene nezinguquko ku-serotonergic and Noradrenergic mechanisms26. Kuyathakazelisa ukuthi amagundane agxile kakhulu kwi-ΔFosB ku-NAc akhombise ukunciphisa isikhathi sokungasebenzi ngosuku lokuqala lokuhlolwa, ahumushe njengomphumela we-pro-motivational activation (bona Izindlela ze-Inthanethi futhi Umdwebo owengeziwe. 5e-h).
Umthethonqubo we-AMPA receptor ku-NAc mediates resilience
I-ΔFosB ilawula okubhaliwe kwezinhlobo eziningi zezimpawu ku-NAc24,27. Uhlobo oluthile lokuhlosiwe olusunguliwe i-AMPA glutamate receptor subunit GluR2: amagundane we-over ye-vereFosB e-NAc abe namazinga aphezulu we-GluR2, ngaphandle kwemiphumela kwezinye izihambisi ze-glutamate receptor22. Lokhu kubhalwa kabusha okukhethiwe kwe-GluR2 ku-NAc kuxhumene nokwenyusa umvuzo wezidakamizwa nowemvelo22,28. Ukubhekana nokuthi kungenzeka ukuthi ukuguqulwa kwe-GluR2 kuhlanganyele ku-ΔFosB isenzo sokuqinisa amandla futhi, safunda inkulumo ye-GluR2 ku-NAc ngemuva kokwehlulwa okungapheli kwezenhlalo. Amagundane aqabukelayo abonise ukwehla okukhulu kwamazinga we-GluR2 esifundeni sobuchopho uma kuqhathaniswa nezilawuli, ngenkathi amagundane abekezelayo akhombisa ukukhuphuka kwamazinga we-GluR2 (I-Fig. 4a). Ngenkathi indlela esetshenziselwa ukunyanzelwa kwegama le-GluR2 kumagundane atholakalayo isahlala ingaziwa, ukutholwa kwe-GluR2 kubonwe emgundwini wokuqina kubonakala kukhombisa umphumela oqondile we-ΔFosB ku-GluR2 gene, ngoba sithole ukubopha okuningi kwe-ΔFosB kusetshenziswa kwe-GluR2 yokuphromotha chromatin immunoprecipitation (ChIP) (I-Fig. 4b), kanye ne-PCR ye-quantitative (qPCR) iveze ukutholwa okuqhubekayo kwamazinga we-GluR2 mRNA ku-NAc yamagundane avumelekile (I-Fig. 4c), ehambelana nokungeniswa okuqhubekayo kwe-ΔFosB. Kuyathakazelisa ukuthi i-GluR1 ilawulwa ngokungemthetho ngemuva kokwehlulwa komphakathi: sabona ukwanda kokuzwakala kumagundane athambekele futhi sinciphise ukubonakaliswa kumagundane avumayo (I-Fig. 4a). Kodwa-ke, azikho izinguquko ezihambisanayo ezibonakala ku-GluR1 mRNA expression, eziphakamisa izindlela ezisebenza ngemuva kokuhumusha. Ngaphezu kwalokho, ukwelashwa okungamahlalakhona kwe-fluoxetine yezintwala ezinganqotshwanga kwenyusa amazinga we-GluR2 ku-NAc (Umdwebo. 4d), kanye nokuhlaziywa kwezicubu zabantu ze-postmortem NAc kusuka ezigulini ezicindezelekile ziveze ukuthi kwehle amazinga we-GluR2 uma kuqhathaniswa nezilawuli (Umdwebo. 4e). Akukho zinguquko emazingeni we-GluR1 atholakele (Umdwebo. 4e).
Ukuqina kokuqina, Umphumela we-antidepressant-of GluR2 ku-NAc
Ukuba khona kweGluR2 kunethonya elikhulu kuma-receptors e-AMPA: I-GluR2-entulekayo ye-AMPA receptors yiCa2+-Ipermeable, futhi ikhombisa ukusebenza kwe-receptor enkudlwana futhi nemijikelezo yokulungisa eqinile yangaphakathi, kuqhathaniswa nama-receptors we-GluR229. Ukufeza imiphumela yethu ye-biochemical, ngakho-ke saqopha ama-cell cell cell clamp aqukethe ama-medium spiny neurons ku-NAc yezimpuku ezingazange zehlulwe nangemva kokuhlulwa komphakathi kuzo zombili izilwane ezinamandla nezisengozini. Ubudlelwano bamanje bamandla we-AMPA-Mediated mediated evusa amadlingozi we-postsynaptic currents (EPSCs) kuveze ukulungiswa kwangaphakathi okukhulu kakhulu kumagundane avele (I-Fig. 5a-c) kuqhathaniswa nezilawuli, ezihambisana nesilinganiso esandayo se-GluR1: I-GluR2 ibonwa ngaphansi kwale mibandela. Yize izinga lokuphinda lilinganiswe kumaseli aqoshwe kusuka kumagundane athambekele ekushintsheni, sabona ushintsho olubaluleke kakhulu ekubuyiseleni kabusha ngokuqhathaniswa namaqembu okulawula nawokuqina. Ukuvumelana kwalokhu okutholakele kuboniswa yiqiniso lokuthi izinga lokuphinda lenziwe kabusha kwawo wonke amaseli kusuka kumagundane angabonakala lingaphezu kwenani elibonakalayo lamaseli alawulayo. Ngaphezu kwalokho, sithole ukuthi izinga lokuphinda lilungiswe ngokungaqondile ngokuvikelwa komphakathi (Umdwebo. 5d), kuphakamisa ukuthi ushintsho kusilinganiso se-GluR1: Isilinganiso se-GluR2 kungenzeka ukuthi kuqhube lokhu kuziphatha. Ukuqinisekisa ukwanda okukhulu kwama-receptors angenayo i-GluR2 kumagundane atholakalayo, sifake izingcezu zezilawuli kusuka kokulawulwayo nokulimazeka kwe-1-naphtylacetylsperimine (NASPM), blocker ekhethiweyo ye-GluR2-receptors AMER receptors. I-EPSC evuswe kuma-neurons aqoshiwe kusuka kumagundane atholakalayo (Fig. 5e-f) ancishiswe kakhulu yi-NASPM, okukhombisa ukuthi ama-AMPL receptors angenayo i-GluR2 abamba iqhaza elikhulu ekudluliseleni kwe-glutamatergic ezimpondweni ezisengozini kunokulawulwa. Impela, imiphumela ye-NASPM kumagundane atholakalayo yayingaphansi kokuqagelwa ngokubheka ushintsho olukhulu olubonwe kulungiswa kabusha. Lokhu kwehluka, nokho, akuyona into engakaze ibonwe30 futhi kungahle kube nokuvela kokuguqulwa kokuguqulwa kokuguqulela noma ukusebenzisana kwamaprotheni okubandakanya i-GluR2 (bheka Ingxoxo), noma nje ubukhulu bokudalulwa kwe-NASPM. Ukwanda okubangelwa ukucindezelwa kokulungiswa kwangaphakathi okubonwe emgundweni osengozini bekungekho ezimpundwini ezivuselelayo (U-Fig. 5a-d), iyahambisana nokwehla okubonakalayo kwe-GluR1 kanye nokwenyuka kwe-GluR2 ngaphansi kwale mibandela. Kodwa-ke, asibonanga ukwehla kokulungiswa kwangaphakathi kumagundane aqinisayo uma kuqhathaniswa nezilawuli (bona iNgxoxo).
Ukwakheka kwe-receptor ye-AMPA kulawulwa ngokuhlukile emgundwini ongabonakali futhi oqinile
Imiphumela elwa ne-antidepressant efana ne-AMPA receptor blockade ku-NAc
Le mininingwane iphakamisa ukuthi kukhuphuke ukusebenza kwe-AMPA receptor (ukukhuphuka kwe-GluR1: isilinganiso se-GluR2) ku-NAc yemilomo engabonakali kungenzeka kuthuthukisa ukugwema kwezenhlalo, kuyilapho ukuncipha komsebenzi we-AMPA (kwehle i-GluR1: ratio ye-GluR2) kunomthelela ekuqineni. Ukuhlola le mqondo, sangena ngqo kwi-AMPA receptor antagonist NBQX ngqo kwi-NAc yemigundane ehluliwe ngokushesha ngaphambi kokuhlolwa kokugwema umphakathi. I-NBQX inyuse isikhathi sokusebenzisana komphakathi (Umdwebo. 4f), okubonisa ukuthi ukuvimba kokufaka okusheshayo okujabulisayo ku-NAc kuphikisana nokuvezwa kwalomphumela wokususa kwengcindezi engapheli yezenhlalo. I-NBQX ayishintshanga umsebenzi we-locomotor jikelele (Fig Supplementary 6). Ngaphezu kwalokho, umphumela wokuqhathaniswa ne-infidepressant of infusion eyodwa ye-NBQX ekugwemeni kwezenhlalo uhlala isikhathi eside njengoba amagundane ahlolwe kabusha ngesonto elilodwa kamuva abonisa ukuthuthuka kokuxhumana komphakathi.
Silandela ngokuzithandela i-GluR2 ngokungakhethi ku-NAc yemagundane atholakalayo. Isichasiso se-GluR2 siguqule ngokuphelele ukugwemeka komphakathi okubangelwa ukuhlulwa komphakathi okungapheli (Umdwebo. 4g), kusekela umbono wokuthi ukukhiqizwa kwe-GluR2 ku-NAc kuyindlela ebalulekile yokuqina. Ngokuthakazelisayo, umphumela we-GluR2 overexpression uphikelele okungenani ezinsukwini ze-10 ngemuva kokuhlinzwa (Umdwebo. 4g) lapho i-GluR2 ye-viral -amu-Mediated isichithile ngokuphelele. Ngakolunye uhlangothi, kumagundane avumayo, ukweqisa kwe-unedited ye-GluR2, GluR2Q, efana ne-GluR1 ezifundweni ezisebenzayo, inikeze amagundane ingozi yokunqotshwa umphakathi (I-Fig 4g),, esekela ukubuka okungezelela ukusebenza kwe-AMPA receptor ku-NAc kunomthelela ekuqaphelekeni.
I-SC1, elinye ilitshe le-ΔFosB, futhi ingumlamuli wokuqina
Ukuthola izinhlobo ezengeziwe zokuhlwaya ze-ΔFosB ezifake isandla ekuqineni amandla, siqhathanise imininingo egciniwe yezinhlobo zamalungu atholakala ku-NAc ye-bitransgenic amagundane overexpressing ΔFosB kanye namahora we-C57Bl / 6J amagundane we-48 ngemuva kokunqotshwa okungapheli kwezenhlalo okukhombise ukuqhathaniswa okuphikisayo nokuqhathaniswa nokwenzeka ngokuthile.10,24. I-Fig. 6a kukhombisa ukuhlangana okukhulu (> 75%) phakathi kofuzo olwenziwe ku-NAc zombili yi-ΔFosB nangokuqina. Phakathi kwalezi zofuzo (ezibalwe ku- Ithebula Lokungezelela 2), sikhethe ukuhlaziya okuthe xaxa kwe-SC1, kususelwa kubukhulu bokufakwa kwayo kokuqina nokwe-ΔFosB overexpression. I-SC1, eyaziwa nangokuthi yi-Sparc (iprotheni esetshenzisiwe, i-acidic, ecebile nge-cysteine)-enjenge-1 noma i-hevin, iyi-molecule ye-matrix ephikisayo eboniswa kakhulu ebuchosheni obudala, lapho ifinyelela khona kule ndawo ye-postynaptic density futhi ifakwe ku-synaptic ipulasitiki31. Ukuhlola ngqo iqhaza elingaba khona le-SC1 ekuqineni amandla, sibona ngokweqile i-SC1 ku-NAc yemagundane atholakalayo. I-SC1 iguqule kakhulu ukugwemeka komphakathi okubangelwa ukuhlulwa komphakathi okungapheli (I-Fig. 6b). I-SC1 i-overexpression ibuye ibe nomphumela ofana nse wokulwa nokucindezela ngosuku 2 wesilinganiso sokuhlolwa kokubhukuda okwenziwe nge-rat (I-Fig. 6c futhi Umdwebo owengeziwe. 7a – c), kepha akunamphumela emsebenzini we-basal locomotor nokuziphatha okuhlobene nokukhathazeka (Umdwebo owengeziwe. 7d-g). Ngaphezu kwalokho, sithole inkambiso eqinile yamazinga we-SC1 anciphile kumathishu abantu we-postmortem NAc ezigulini ezicindezelekile (Umdwebo. 6d).
Ukuqina kokuqina, imiphumela elwa nama-antidepressant efana ne-SC1 ku-NAc
UKUKHULUMA
Imiphumela yocwaningo lwamanje inikela ubufakazi bokuqala bokuguqulwa kwamangqamuzana okwenzeka kuma-spiny neurons aphakathi we-NAc okuphendula okucashile kokucindezelwa okungapheli futhi okunomthelela emiphumeleni yokwelashwa yokwelashwa okungalapheki kwama-antidepressant. Sibonisa ukuthi amazinga asisekelo we-ΔFosB ku-NAc anquma ukubekeka engcupheni kokuqala kokucindezelwa kokunqoba komphakathi, nokuthi izinga lokungeniswa le-ΔFosB ekuphatheni ukucindezelwa okungapheli linquma izimpendulo ezibuthakathaka eziqhathaniswa nalezo zingcindezi. Sibonisa futhi ukuthi ukubuyela emuva okuphumelelayo kokulimazeka kokuziphatha okufakwa ezilwaneni ezisengozini ngokuphathwa kwe-fluoxetine engapheli kudinga ukwenziwa lokungenisa isidakamizwa kwe-ΔFosB kule ndawo yobuchopho. Lokhu okutholakele kukhombisa ukuthi i-ΔFosB yokungeniswa e-NAc iyindlela eyanele futhi eyanele yokuqina nokuphendula ngezimpikiswano. Ukutholwa kwamazinga aphansi we-ΔFosB ku-NAc wabantu abacindezelekile kusekela ukuhambisana kwalokhu okuqashelwe kumamodeli wegundane ekucindezelekeni komtholampilo. I-ΔFosB ilawula umsebenzi we-NAc ngokunxenxa noma ukucindezela izinhlobo eziningi zokuhlonza24,27. Sikhomba izinhlobo zayo ezimbili ezihlosiwe, i-AMPA receptor subunit GluR2 kanye ne-SC1, iprotheni ye-matrix engaphandle, futhi siyifaka ngokuqondile ekuvumelaneni nokuqinisela ekucindezelekeni kokwehlulwa ngumphakathi.
Indima enjalo yokuqina kokuqina kwe-ΔFosB ngokwesimo sokucindezela okungamahlalakhona iyathakazelisa ngenxa yengcebo eningi yobufakazi bokuzibandakanya kwe-ΔFosB ekulawuleni izimpendulo kuzidakamizwa zokuhlukumeza nemivuzo yemvelo njengokudla, ucansi nokuzivocavoca19. I-ΔFosB idonswa yi-NAc ngemivuzo yezidakamizwa nemvelo, futhi yandisa izimpendulo ezinomvuzo kulezi zivuseleli. Ngakho-ke kuthakwa njengomlamuleli wezinto ezithile zokulutha kwezidakamizwa. Ukutholwa kwamanje kumamodeli wokucindezela kunikeza ukuqonda okusha ngokuyisisekelo ngeqhaza leproteyini ekuphathweni kokuziphatha okuyinkimbinkimbi kwemizwelo. Ngaphansi kwezimo ezijwayelekile, i-ΔFosB ivezwa emazingeni aphezulu ku-NAc ngokuqhathaniswa nazo zonke ezinye izifunda zobuchopho19. Sibonisa ukuthi amazinga we-ΔFosB e-NAc abamba iqhaza elikhulu ekubekeni izinga lokugqugquzelwa komuntu siqu nasekuqondiseni izimilo zokuziphatha ezishukumisela ekubuseni okuhle okuzuzayo. Ukususwa kokukhuthazeka kwemvelo ngesikhathi sokuhlukaniswa isikhathi eside kunciphisa amazinga asisekelo we-ΔFosB ku-NAc yegundane, ukufaka isisusa sazo futhi kwandise ubungozi bawo ekucindezelekeni okungapheli komphakathi, njengoba sibonisa lapha. Ukwehla okubonakalayo kwamazinga we-ΔFosB ku-postmortem NAc yeziguli ezihlukumezekile kuhambisana nale mqondo, futhi kuphakamisa iqhaza le-ΔFosB ekushukumiseni okungenampilo nomvuzo obonwa kubantu abaningi abanokucindezeleka. Ngakolunye uhlangothi, amandla okufaka i-ΔFosB ku-NAc ekuphenduleni kwengcindezi engapheli yenza umuntu akwazi ukuqinisa inkuthazo nomvuzo wemvelo naphezu kwengcindezi eqhubekayo, isizatho esivumelana nemicabango esivumelana nemibono yamanje yokuqina kokukhuthala kubantu1,2. Siphinda sigqamisa ukuthi ukwenziwa kwe-ΔFosB ku-NAc ngokuchayeka njalo kwezidakamizwa zokuhlukunyezwa, okukukhulu kakhulu ngobukhulu kunalokho okubonwe ngengcindezi noma nemivuzo engokwemvelo19, kuphumela ezingeni lobunzima besisusa esithuthukisiwe ngendlela eyonakalisa ukujikeleza komvuzo ekunyuseni isidakamizwa esinamandlai.
Ngokusobala, izici ezithile zale hypothesis zidinga ukuphenywa okwengeziwe. Ukufakwa kwe-ΔFosB ku-NAc ngokucindezelwa okungapheli noma nge-fluoxetine kungalindeleka ukuthi kwandise umvuzo wezidakamizwa. Ngempela, ukuqina kokudangala nokulutha kumiswe kahle kubantu, futhi ukuzwakala phakathi kwezidakamizwa zokuhlukunyezwa nengcindezelo kubonisiwe kumagundane32-34. Ngakolunye uhlangothi, ukudana nokulutha kuyinkimbinkimbi kakhulu, ama-syndromes asezingeni eliphakeme futhi abantu abaningi abanokudangala abanawo umlutha futhi ngendlela efanayo. Ngaphezu kwalokho, i-fluoxetine ayinikezi imiphumela ebonakalayo ekuphenduleni kwezidakamizwa ezilwaneni, futhi akuyona indlela ephumelelayo yokuluthwa umlutha kwabayimilutha futhi abangacindezelekile. Ngokuhambisana nale nkimbinkimbi, sithole ukuthi amagundane atholakalayo, hhayi amagundane aqine, ekuphambukeni komphakathi ekuboniseni izimpendulo ezithuthukisiwe ezidakamizweni zokuhlukunyezwa10. Lokhu kungaphakamisa ukuthi ubungozi obuthuthukisiwe bezimpuku ezihlaselwayo ezidakamizweni zokuhlukunyezwa buqondiswa ngokusebenzisa ezinye izinto eziningi ezifakwe kwi-NAc nakwezinye izindawo, njengesibonelo esisodwa, i-BDNF, efakwa ekuthambekeni, hhayi ekuqineni, amagundane ku-NAc futhi ithuthukisa izindlela zokuvuza ngemithibheka 10.
Ukuhunyushwa ukuthi i-ΔFosB kugqugquzela izici zokulutha, ngenkathi kukhuthaza ukuqina kokucindezelwa, akumangazi ngokunikezwa ubudlelwane obuyinkimbinkimbi obukhona phakathi kwendima yeprotheni enikezwe kwi-NAc ezimelweni zokulutha nezokucindezela. Amanye amaprotheni (isib, i-BDNF) akhuthaza izimpendulo kwizidakamizwa zokuhlukumeza futhi acindezele, ngenkathi amanye amaprotheni amaningi enza imiphumela emibi ngaphansi kwalezi zimo ezimbili: isib, i-CREB e-NAc ikhiqiza i-proot-pro phenotype, kepha ilufaka izimpendulo kwizidakamizwa zokuhlukumeza bheka 4,10.
Lokhu okutholakele kugcizelela isidingo sokuqhubeka nokucwaninga ekwakhekeni kwesisekelo semikhuba yokuziphatha kwemizwelo eyinkimbinkimbi, kanye nokubaluleka kokusebenzisa uhla lokuhlola lokuziphatha oluphelele olwenzekayo. Imiphumela ibuye ikhombise ukuthi, njengoba bekulindelekile, i-ΔFos iyodwa ayinakuchaza konke okugcwele kokudangala nokulutha, kunalokho, ingumlawuli oyisihluthulelo wezinqubo zokuvuza ezithembele ku-NAc futhi ngalokho kubalulekile ekulameni izici ezithile zalezi zimo zombili.
Kodwa-ke, umgodi omkhulu wale ngxoxo izinhlobo ezahlukahlukene zamaseli e-NAc lapho i-ΔFosB ifakwa khona ekucindezelweni nasekumamelweni okulutha. Izidakamizwa zokuhlukunyezwa kanye nemivuzo yemvelo iheha i-ΔFosB ngokuyinhloko ekuqothulweni kwama-medium spiny neurons ku-NAc eveza u-D1 ama-dopamine receptors19,22, ngenkathi ukucindezelwa kukwenza ΔFosB cishe ngokulinganayo ngaphakathi kwe-D1 kanye no-D2 ama-receptor aqukethe i-medium spiny neurons20. Lokhu kungeniswa okungafani kungaba nemiphumela yokusebenza okuhle, ngoba ikhono le-ΔFosB lokukhombisa umvuzo libonisiwe ku-D1 i-class neurons kuphela19.
Ukuchazwa kwe-GluR2 njengohlobo lokuhlosiwe oluhilelekile ekulameni amandla qobo we-ΔFosB kusinika ukukhanya kulokhu kucatshangelwa. Sibonisa ukuthi ukushuba kwezimpuku, nokucindezelwa kwabantu, kuhlotshaniswa nokwanda kwe-GluR1: Ukulinganiselwa kwe-GluR2 ku-NAc, okuphakamisa ukuthi ukunyuka kwe-neuron ephakathi nendawo kukhuphuka ngokuphendula ubudlova.
I-NAc ithola okokufaka kwe-glutamatergic kusuka ezifundeni eziningana zobuchopho, ikakhulukazi i-cortex yangaphambili, i-amygdala ne-hippocampus35. Ukufakwa okunjalo kwe-glutamatergic kulungisa ubuhle nobungqabavu bokukhuthazeka okuvusa amadlingozi futhi ngaleyo ndlela kulawula isimilo esiqhutshwa36-38. Izifundo zakamuva ziyahambisana ne-hypothesis yethu ethuthukisiwe ye-NAc kungakhuthaza ubungozi bokucindezelwa. Ukucindezelwa kokubhukuda okuphoqelekile kwandisa amandla e-synaptic nomsebenzi we-AMPA receptor ku-NAc39, ngenkathi ukumfaka kwe-glutamate kwi-NAc kunciphisa ukusebenza kokubhukuda ekuvivinyweni kokubhukuda okuphoqelelwe, umphumela ofana noka-pro40. Ngokuvamile, ukwanda kokudubula okubandayo kwe-NAc kufinyelela izifunda eziphikisayo ezinhlotsheni eziningana zezilwane41. Izinguquko emsebenzini we-NAc ziye zabonwa ezigulini ezinokudangala okukhulu42 futhi embuthweni okhethekile amasosha akhethwe ngaphambilini futhi aqeqeshelwa ukomelela lapho ebhekene nobunzima obukhulu43. Ngokufanayo, ukuvusa ubuchopho okujulile kwe-cgenex cortex ye -gengenual noma i-NAc (okuhlosiwe okukhulu kwe-cingex cortex), ukucabanga kokungenelela ukunciphisa ukwehla kwesimo sobuchopho esishukumisayo, kunciphisa izimpawu ezixakayo ezigulini ezivuselela ukwelashwa3,44.
Njengamamodeli wokucindezela, ukwanda kokuphendula kwe-glutamatergic ku-NAc nakho kube nomthelela ekuluthweni kwezidakamizwa30,45-47. Lokhu kufaka phakathi ukwanda kwe-GluR2-entulekayo ye-AMPA receptors esifundeni sobuchopho30,47, kufana nalokhu esikubika lapha ukuze kube lula ukucindezelwa. Ngokubambisana, lokhu kubukwa kuphakamisa amathuba athakazisayo athuthukisa ukudluliswa kwe-glutamatergic ku-NAc kukhuthaza ubungozi ekuluthweni nasekucindezelekeni. Ushintsho oluphambene, okungukuthi, isilinganiso se-GluR1 esinciphile: Isilinganiso se-GluR2, esikhonjiswe lapha ku-NAc yezimpuku ezomelele, siphakamisa ukuthi ukusebenza kwe-glutamatergic okuncishisiwe kungahle kuvikeleke emiphumeleni eyisusa yokuxineka okungapheli. Lokhu kuyahambisana nokubonwa okwandise umsebenzi we-GluR2, noma ukunciphisa umsebenzi we-GluR1, ku-NAc kuthuthukisa umvuzo kanye nogqozi28,37,48. Amandla we-fluoxetine afune ngokufana ukubiza i-GluR2 expression ku-NAc kuphakamisa ukuthi kungenzeka ukuthi kuncishiswe ukugcinwa kwe-glutamate yalesi sifunda sobuchopho futhi kungaba nomthelela ekuphenduleni okukucindezelayo. Impela, sibonisa lapha ukuthi ukuvimbela umsebenzi we-AMPA receptor ngaphakathi kwe-NAc kukhiqiza impendulo enamandla nehlala isikhathi eside yokulwa nokulwa nezinkinga.
Ngenkathi ushintsho esalukhombisa ku-AMPA receptor expression ku-NAc yemigundane engabonakali kungenzeka luhambisana nokubonwa kwethu kwe-elekthronikhi, ushintsho olubonwa ekuqineni kobunzima luyinkimbinkimbi kakhulu. Asitholanga bufakazi be-electrophysiological bokwehla kwe-GluR2-receptors kwe-AMPA kwe-NAc yemagundane avumayo uma kuqhathaniswa nezilawuli. Sifakazela ukuthi i-ΔFosB-Mediated induction ye-GluR2 ekuqineni kokunye kungenye yezimo eziningi ezenzeka kwi-NAc ezithinta ukudluliswa kwe-glutamatergic nokuthi, ngenkathi lokhu kuvumelana kwanele ukuhlehlisa umsebenzi we-AMPA receptor ngokweqile obonakale kusengozini. ngaphesheya. Ngempela, idatha yethu iveza ukulawulwa okuyinkimbinkimbi kokudluliselwa kwe-glutamatergic ku-NAc ngemuva kwengcindezi yokunqotshwa komphakathi okungapheli. Izinguquko eziphikisanayo ekukhulumeni kwe-GluR1 kulesi sifunda sobuchopho ekuqothulweni kwe-inclceptibility vs. azibonwa ezingeni le-mRNA, futhi futhi amazinga ancishisiwe we-GluR2 ekuthambekeni kokubonakala kweleveli ye-mRNA. Lokhu kuyahambisana nokulungiswa ngemuva kokuhumusha, kufaka phakathi izinguquko ekushushumbisweni kwe-AMPA receptor, futhi kudlala indima enkulu, njengoba kuye kwabonwa kumodeli yokusebenzisa kabi izidakamizwa30,47.
Ukulawulwa okuyinkimbinkimbi kokudluliswa kwe-glutamatergic ku-NAc ngokucindezelwa okungapheli kuqokonyiswa ukutholwa kwethu kwe-SC1 njengenye uhlobo lwenkomba ye-ΔFosB, okuthi, njengokufakwa kweGluR2, kube nokuqina kokuqina. I-SC1 iyaziwa ukulawula i-synaptic plasticity31. Njengomphumela wezakhiwo zayo ezilwa nokunamathela, ukufakwa kwe-SC1 ku-NAc kungahle kube nemvelo evumayo yezinguquko ezihlelekile ezihambisana nokubumbana kwe-glutamatergic synapses ebonakala ibalulekile ekuqineni. Isibonelo, ubufakazi bamuva nje bukhombisa ukuthi ukususwa kwe-matrix engaphandle kuvumela ukufakwa kwe-AMPA receptors futhi ngaleyo ndlela kuthuthukisa i-synaptic plasticity49.
Ngamafuphi, imiphumela yethu isekela uhlelo lapho i-ΔFosB ku-NAc isebenzisa ukuqina lapho ibhekene nengcindezi engapheli ngokwengamela uhlobo lwe-synaptic plasticity oluphathelene nokufunda okungahambisani nokuhlangana okwenzeka emgundweni ongatheni. Isibonelo, ukwanda kwe-GluR2-receptors ye-AMPA engekho ku-NAc, esiyibona kumagundane angenzeka, kuboniswe ukuthi kukhulisa izimpendulo ezinhlotsheni ezihlobene ne-cocaine ezikhuthaza ukunxanela nokubuyela emuva ezimodeli zokulutha.30,47. Ngokuphambene nalokho, ukuncipha kwephimbo le-glutamatergic kumagundane aqinayo, ngokuthuthuka kwe-GluR2 futhi mhlawumbe nokungeniswa kwe-SC1, kunganikeza isikhuthazo esisezingeni eliphakeme, njengegundane elinoveli kupharadesi yokuhlulwa komphakathi, lingakwazi ukwenza kusebenze i-NAc neurons, futhi ngaleyo ndlela inikwe amandla inhloso Ukuziphatha okuqondisiwe ukuqhubeka naphezu kwengcindezi. Ukuhlelwa kwethu kofuzo kuveza ukubandakanyeka okungenzeka kwamaphutha amaningi angeziwe we-ΔFosB anikela ekuqineni futhi. Indima ebaluleke kakhulu edlalwa yi-ΔFosB nezinjongo zayo emandleni womuntu ukuzivumelanisa kahle nokucindezelwa okungapheli kuphakamisa izindlela ezintsha zokuthuthuka kwezindlela zemithi zokwelapha ezinqabayo.
IZINDLELA
Izindlela nezinkomba ezihambisanayo ziyatholakala kunguqulo ye-inthanethi yephepha ku- http://www.nature.com/natureneuroscience/.
Izinto ezengeziwe
Suppl
Chofoza lapha ukuze ubuke.(I-1024K, i-doc)
Chofoza lapha ukuze ubuke.(136K, pdf)
Ukuvuma
Lo msebenzi wesekwa izibonelelo ezivela ku-National Institute of Mental Health kanye nobumbano locwaningo ne-AstraZeneca. Siyabonga Drs. U-P. McKinnon noH. Russell ngesipho esivulekile se-SC1 cDNA. Siyabonga futhi. Maze, Drs. R. Oosting, S. Gautron noD. Vialou ngengxoxo elusizo namazwana ngombhalo wesandla.
Imibhalo yaphansi
Iminikelo Yomlobi I-VV ne-EJN zazibhekele ukwakhiwa okuphelele kokufunda. I-QL ne-VV yakhelwe, yaqhutshwa, futhi yahlaziywa ucwaningo lwe-RNA ne-ChIP. U-AJ Robison waklama, waqhuba, futhi wahlaziya izifundo ze-elekthronikhi. I-HEC ne-VV yaklama futhi yaqhuba izivivinyo zamakhemikhali ze-NBQX. I-QL, i-DMD, i-ELW, ne-VV bahlinza abahlinzayo nge-stereotaxic. I-YNO ibambe i-SC1 cDNA kwi-VS ye-HSV. I-YHO yenze i-AP1 luciferase assay. I-QL, i-DMD, i-DW, ne-VV yaklama futhi yaqhuba izivivinyo zokuhlukaniswa nomphakathi. I-VV, i-ELW, ne-AJ Rush benze izivivinyo zokuhlulwa komphakathi kanye ne-immunohistochemical quanifying. I-SI, QL, BW, neVV basebenza futhi bahlaziya ukuhlinzwa kwe-rat nokuhlolwa okuphoqelelwe kokubhukuda. I-EM ne-RN bahlinzeka ngemithambo ye-viral ye-viral trans transis. I-MAS, VK, ne-OB yaqeqesha i-VV ekunqotshweni komphakathi nasekuhlaziyeni ngamakhemikhali futhi yanikeza ukulawulwa kwekhwalithi kwedatha yokuhlulwa komphakathi. I-SG ne-CAT bahlinzeka ngezicubu zomuntu zangemva kwesidumbu. IVV ne-EJN babhale iphepha ngosizo lwabanye ababhali.
Ulwazi Lomlobi Imininingwane yokuphrinta nemvume iyatholakala ku- www.nature.com/reprints.
Imininingwane engeziwe Ulwazi Olwengeziwe ixhunyaniswe nenguqulo ye-inthanethi yephepha ku- www.nature.com/natureneuroscience/.
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