Tlhaloso e fapaneng ea liprotheine le Lintho tse ka 'nang tsa etsahala tsa liphatsa tsa lefutso ka Khetho ea libaka tsa bokhoba le ho tepella maikutlo bakuli (2016)

Paula A. Gajewski,
Gustavo Turecki,
Alfred J. Robison

E phatlalalitsoe: Phato ea August 5, 2016

http://dx.doi.org/10.1371/journal.pone.0160355

inahaneloang

Ho pepesehela khatello ea maikutlo kapa lithethefatsi hampe ho hokahane le polelo e fetotsoeng ea 'mele,' me ho nahanoa hore liphetoho lipuong tsa lefutso likarolong tse sa bonahaleng tsa kelello li baka mafu a mangata a kelello, ho kenyeletsa pherekano e kholo le khatello ea lithethefatsi. Mehlala ea 'nete ea mathata ana e fane ka bopaki ba mekhoa ea polelo ena e fetotsoeng, ho kenyelletsa lintlha tse ngotsoeng, empa bopaki bo tšehetsang karolo ea lintlha tsena ho bakuli ba motho bo liehile ho hlaha. Taba ea trans transidence ΔFosB e kentsoe ka pele ho cortex (PFC) le hippocampus (HPC) ea litoeba ho arabela khatello ea maikutlo kapa cocaine, 'me polelo ea eona libakeng tsena e nahanoa hore e laola taolo ea bona ea "top down" ea li-circry tsa meputso, ho kenyelletsa le khubu accumbens (NAc). Mona, re sebelisa biochemistry ho hlahloba polelo ea FosB Lelapa la lintlha tse amanang le ho ngoloa le sepheo sa bona sa liphatsa tsa lefutso ho PFC le li-sampuli tsa postmortem tsa HPC tse tsoang ho bakuli ba tepelletseng maikutlo le bokhoba ba koae. Re bonts'a hore ΔFosB le li-isoform tse ling tsa FosB li theotsoe ka tlase ho HPC empa eseng PFC ka kelellong ea batho ba tepelletseng maikutlo le ba lemaletseng. Ho feta moo, re bonts'a liphofu tse ka bang teng tsa ΔFosB tsa ho ngola, ho kenyeletsoa GluA2, le tsona li theotsoe ka tlase ho HPC empa eseng PFC ea batho ba lemaletseng koae. Kahoo, re fana ka bopaki ba pele ba FosB polelo ea mofuta oa HPC ea motho le PFC mathateng ana a mafu a kelello, hape ka leseli la liphumano tsa morao-rao tse bonts'ang karolo ea bohlokoa ea HPC BFosB mehlaleng e hlokolosi ea ho ithuta le ho hopola, lintlha tsena li fana ka maikutlo a hore reducedFosB ho HPC e ka baka bofokoli bo hlakileng bo tsamaeang le ts'ebeliso e mpe ea koae kapa khatello ea maikutlo.

Tlhaloso: Gajewski PA, Turecki G, Robison AJ (2016) Tlhaloso e Ikhethileng ea Liprotheine tsa FosB le Tlhaho e ka Behiloeng ea Target ho Select Brain Regions le Bakuli ba Tepelletseng Maikutlong. PloS ONE 11 (8): e0160355. Doi: 10.1371 / journal.pone.0160355

mohlophisi: Ryan K. Bachtell, Univesithi ea Colorado Boulder, UNITED STATES

Re amohetse: February 29, 2016; E amohetse: July 18, 2016; E phatlalalitsoe: August 5, 2016

Copyright: © 2016 Gajewski et al. Ena ke sengolo se bulehileng sa phihlello se tsamaisitsoeng tlasa maemo a License ea Boikarabelo ba Creative Commons, e lumellang hore ho sebelisoe, ho abeloa, le ho beleha ho sa sebelisetsoe, ho fana ka moqapi le mohloli oa pele.

Ho fumaneha ha Data: Lintlha tsohle tse amehang li ka har'a pampiri.

Lithuso: Sengoli PAG se fumane tšehetso e itseng ea moputso ho tsoa kamohelong ho mongoli AJR ho tsoa Whitehall Foundation. Bafani ba lichelete ba ne ba sena karolo morerong oa ho ithuta, ho bokella data le ho hlahlobisisa, qeto ea ho phatlalatsa, kapa ho hlophisa sengoloa.

Lithahasello tse tsitsitseng: Bangoli ba boletse hore ho na le lithahasello tsa tlhōlisano tse teng.

Selelekela

Mekhoa ea limolek'hule le ea potoloho ea mafu a mafu a kelello joalo ka khatello ea maikutlo le bokhoba ha li utloisisehe ka botlalo, 'me tsebo ena e bohlokoa bakeng sa nts'etsopele ea liphekolo tse ncha le tse ntle. Liphetoho tse mabapi le mofuta oa gene ho li-nucleus accumbens (NAc) le libaka tsa boko tse fanang ka taolo e holim 'a ts'ebetso ea NAc, joalo ka pele ho cortex (PFC) le hippocampus (HPC) li bile le tšusumetso ho pathogeneis ea ho lemalla le khatello ea maikutlo ke lithuto tse ngata. mefuteng ea bobeli ea lintho tse phelang le bokong ba motho ba ka mor'a lefu1-5]. Mekhoa e mengata ea kalafo ea hona joale ea khatello ea maikutlo e sebetsa ka ntlafatso e sa feleng ea ho saena ha serotonergic le / kapa dopaminergic, mme hoo e batlang e le lithethefatsi tsohle tsa tlhekefetso li ama ho saena ha dopamine ho NAc. Ho feta moo, bokhoba ba khatello ea maikutlo le khatello ea maikutlo bo monate haholo, hoo e ka bang karolo ea boraro ea bakuli ba nang le khatello e kholo ea khatello ea maikutlo le ba nang le mathata a ts'ebeliso ea lithethefatsi le ho songoa ke kotsi e phahameng ea ho ipolaea le ho senyeha ho hoholo sechabeng le bathong [6, 7]. Ha re li nka hammoho, li-data tsena li fana ka maikutlo a hore ho ba le mathata a sa foleng ho mesolimbic dopamine pot le likarolo tse hokahaneng li ka tlatsetsa bohlorisong le khatello ea maikutlo, le hore liphetoho lipuong tsa gene li ka bapala karolo ea bohlokoa lithutong tsena tse mpe.

Ha khatello ea maikutlo le bokhoba bo ntse bo eketseha ha nako e ntse e ea 'me li ka hokahanngoa le ho pepesetsoa nako e telele ho khatello ea maikutlo le / kapa lithethefatsi tsa tlhekefetso [8, 9], hape hobane li-antidepressant tse tloaelehileng tse lebisang serotonergic le dopaminergic signaling li hloka libeke tsa kalafo ho sebetsa [10], ho bonahala ho ka etsahala hore ebe pathogenesis ea maloetse ana le mekhoa ea kalafo ea bona e ka hokahana le nako e telele liphetoho lipuong tsa mofuta oa gene. Liphetoho tse joalo li ka bakoa ke liphetoho tsa epigenetic tsa sebopeho sa gene, 'me bonneteng bopaki bo ntse bo eketseha bakeng sa karolo ea bohlokoa bakeng sa liphetoho tsa methapo ea methapo ea methapo ea methapo le tšibollo ea maikutlo [11-14]. Leha ho le joalo, sena ha se fane ka karolo e ka ba teng bakeng sa lintlha tsa mongolo lits'ebetsong tsena, haholo-holo lintlha tse tsitsitseng tsa mongolo tse hlahisoang ke ts'ebetso e sa foleng ea neuronal. E 'ngoe ea lintlha tse joalo tse ngotsoeng ke ΔFosB [1, 15, 16], splice variant hlahisoa ho tloha FosB mofuta. Ho fapana le protheine ea FosB e bolelele bo felletseng, ΔFosB e tsitsitse ka mokhoa o tsotehang ha e bapisoa le lihlahisoa tse ling tsa pele tsa gene (halofo ea bophelo ba matsatsi a 8 bokong [17]), haholo-holo ka lebaka la ts'isinyeho ea libaka tse peli tse senyehileng ho c-terminus [18], hammoho le phosphorylation e tsitsitseng ho Ser27 [19, 20]. ΔFosB e kentsoe bokong bohle ba methapo, ho kenyeletsa le NAc le likarolo tse amanang le eona, ka khatello ea maikutlo [21-23], lingoloa tsa khatello ea maikutlo [22], le lithethefatsi tsa tlhekefetso [24]. Ntle le moo, meetso ea litoeba e hlahisa polelo ea ΔFosB ho NAc litlamong ka bobeli [20, 25] le khatello ea maikutlo [26, 27], mme liphuputso tsa morao-rao li hlahisa karolo ea ΔFosB ho maloetse ana ho PFC [21] le HPC [28]. Ho NAc, polelo ea "ΔFosB e khothalletsa ho phahamisa maikutlo le ho putsa ho tsoa ho li-psychostimulants ka litoeba [20, 25]. NAc ΔFosB e sebetsa hape e le sesosa sa ho fokotsa khatello ea maikutlo ea khatello ea maikutlo ea panya, mme polelo ea eona e ea hlokahala bakeng sa ts'ebetso ea ho fokotsa khatello ea maikutlo [26]. Ho fapana le moo, polelo ea "osFosB ho PFC e phahamisa menyetla ea khatello ea taolo ea setjhaba litlamong [21], ho fana ka maikutlo a hore ΔFosB e bapala likarolo tse fapaneng haholo potolohong ea moputso le likarolo tsa bokong tse e hlalosang. Kamora nako, ΔFosB e kenyellelitsoe ho panya ea dorsal HPC ka ho ithuta mme ts'ebetso ea eona ho hlokahala bakeng sa kaho ea memori e tloaelehileng ea sepakapaka [28], ho fana ka mokhoa o ka khonehang bakeng sa bofokoli ba kelello bo atisang ho tsamaellana le ho pepeseha hoa lithethefatsi tse sa feleng le / kapa khatello ea maikutlo [29-31].

Joalo ka ha ΔFosB e le tšibollo ea litaba, hangata ho nahanoa hore e fana ka litlamorao tsa eona ea tlhaho ka ho feto-fetoha ha polelo ea mefuta e khethiloeng ea sepheo, 'me boholo ba mefuta eo ea sepheo e kentsoe pherekanong le bokhobeng. ΔFosB e laola polelo ea litlatsetso tse ngata tsa α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) - le N-methyl-D-aspartate (NMDA) -type receptors [25, 26, 32], 'me li-receptor tsena li kentsoe ka ho toba tlhagisong [33, 34], khatello ea maikutlo [35, 36], le tšebetso ea antidepressant [36, 37]. ΔFosB e boetse e laola tlhahiso ea limolek'hule tse tšoaeang, joalo ka calcium / proteinodulin-based protein proteinasease (CaMKIIcy), e amanang le mathata a mangata a kelello [38], mme re bonts'itse hore molaoana ona oa polelo ea CaMKII ho litoeba o khannela sensorization ea psychomotor ho cocaine [20] le ts'ebetso ea ho fokotsa khatello ea maikutlo [27]. Ntle le moo, ΔFosB e laola polelo ea cyclin-based kinase 5 (cdk5) [39], e khothalletsoang ke striatum ka ho pepeseha hoa psychostimulant le khatello ea maikutlo [40-42] hape e laola likarabo tsa psychomotor le likarabelo tse susumetsang tsa koae [43]. Kahoo, ho na le bopaki bo matla mehlaleng ea methapo ea hore ho kenella ha ΔFosB libakeng tse ngata tsa boko ka khatello ea maikutlo, litlhare tsa khatello ea maikutlo, le lithethefatsi tsa tlhekefetso li ka laola boits'oaro bo amanang le khatello ea maikutlo le ho lemalla ka ho fetolela polelo ea mefuta ea sepheo e khethiloeng libakeng tse bohlale tsa boko.

Le ha mefuta ea litlatsetso le khatello ea maikutlo li bile le litholoana tse ngata, ho bohlokoa ho ts'ehetsa liphumano tse fumanoang mehlaleng ea liphoofolo ka bopaki bo tsoang lithutong tsa batho haeba re lebelletse ho fetolela mekhoa e ka ntlafatsang ea limolek'hule molemong oa likhetho tsa nalane. Re kile ra bonts'a hore ΔFosB e ngolisitsoe ho NAc ea batho ba lemaletseng koae.20] mme ea fokotseha ho NAc ea batho ba tepeletseng maikutlo [26]. Leha ho le joalo, molao oa FosB polelo ea sehlahisoa sa mofuta oa HPC le PFC, batsamaisi ba bohlokoa ba ts'ebetso ea methapo ea methapo ea methapo ea methapo, ha e so ithutoe bokong ba motho, leha e le hore taolo ea "genos" ea mofuta oa "geno" e ka hlahang. Ka hona re ile ra hlahloba polelo ea FosB Lihlahisoa tsa liphatsa tsa lefutso, hammoho le polelo ea mefuta ea sepheo ea targetFosB e ka etsahalang, ho PFC le HPC ea bakuli ba nang le bothata bo boholo ba khatello ea maikutlo kapa bokhoba ba koae.

Lisebelisoa le mekhoa

Mehlala ea Batho

Lisele tsa boko ba motho ea ka mor'a lefu li fumanoe ho Douglas Bell-Canada Brain Bank (Douglas Mental Health University Institute, Montreal, Quebec, Canada). Tlhahisoleseling ea tšebeliso ea lithethefatsi mabapi le bokhoba ba batho ba lithethefatsi tsa koae, batho ba nang le khatello ea maikutlo le taolo e tšoanang e ka fumaneha ho Lethathamo 1. Pholoso ea linama e tsoetse-pele joalo ka ha ho hlalositsoe [44]. Ka bokhutšoanyane, hang ha e ntšoa, kelello e beoa leqhoeng le metsi ka lebokoseng la Styrofoam ebe e potlakisetsoa litsing tsa banka ea Douglas Bell-Canada Brain Bank. Metsoako e arohanngoa hang-hang ke sekhechana se khutsitsoeng bohareng ba bokong, bokong ba boko, le "cerebellum". Lisebelisoa tsa mali, gase ea phaeneal, choroid plexus, halofo ea "cerebellum" le "halofo" ea "boko" hangata li aroloa ho tloha hemisphere e ka lehlakoreng le leng ebe e khaoloa ho ba likonopo tsa 1 cm ka bophara pele e kenella. Karolo e 'ngoe ea "cerebellum" ea hoqetela e khaoloa ka mokhoa o fapaneng ka ho ba likhechana tsa 1cm tse teteaneng. Lithane li batetsoe ke serame nakong ea 2-methylbutane ho -40 ° C bakeng sa ~ 60 sec. Li-tishu tsohle tse leqhoa li bolokoa ka thoko mekotleng ea polasetiki ho -80 ° C bakeng sa polokelo ea nako e telele. Libaka tse ikhethileng tsa boko li qheletsoe ka thoko ho leqhoa le bosootho bo bonojoana ka leqhoa le omileng hohle ho laola mocheso oa tikoloho. Mehlala ea PFC e tsoa sebakeng sa Brodmann 8 / 9, mme li-sampuli tsa HPC li nkuoa ho tloha bohareng ba sebopeho sa hippocampal (Setšoantšo sa 1).

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Mofuta oa 1. Setšoantšo sa libaka tse arohaneng tsa sampole ea boko ba motho.

Litšoantšo li emela likarolo tse ka ntle tsa (A) le tsa morao-rao (B) tsa boko ba motho tse sebelisoang bakeng sa ho lahla sampole ea PFC, le (C) sampuli ea HPC. Mabokose a bofubelu a totobatsa libaka tsa ho arohana. SFG: gyrus e ka pele; MFG: gyrus e ka pele e bohareng; IG: gyrus e kenang; FuG: fusiform gyrus.

http://dx.doi.org/10.1371/journal.pone.0160355.g001

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Tafole 1. Ho itšetleha ka lithethefatsi, tahi, le ts'ebeliso ea meriana ea litlhare ho lithethefatsi tsa koae, batho ba nang le khatello ea maikutlo le lihlopha tse laoloang.

http://dx.doi.org/10.1371/journal.pone.0160355.t001

Mehlala ea Mouse

Boithuto bo ile ba latela tataiso e hlalositsoeng ho Tataiso bakeng sa tlhokomelo le tšebeliso ea liphoofolo tsa liphoofolo, khatiso ea borobeli (Sesebelisoa sa Lisebelisoa tsa Liphoofolo tsa Laboraro, 2011). Pele ho tlhahlobo efe kapa efe, lits'ebetso tsohle tsa liteko li ile tsa amoheloa ke Komiti ea Tlhokomelo ea Liphoofolo le Ts'ebeliso ea Univesithi ea Michigan State. Haeba phoofolo efe kapa efe e bonts'a ho hloka boikoetliso, ts'oaetso, ho theola boima ba 'mele kapa ho se khone ho etsa joalo, phoofolo e khothalelitsoe. Ha ho liphoofolo tse neng li hlokauthollo e joalo pele ho liteko tsa tlhahlobo thutong ea hona joale. Kamora ho fihla setsing, litoeba tsa banna tsa 7 tsa beke ea X57BL / 6 (The Jackson Laboratory, Bar Harbor, ME, USA) li ne li arotsoe ka sehlopha sa 4 ka kofing e ka kamoreng ea kolone e behiloeng ka mocheso o sa feleng (23 ° C) bonyane Matsatsi a 3 pele ho liteko ho 12 h light / potoloho e lefifi le ad libidum lijo le metsi. Lice li ile tsa fuoa matsatsi a sa ts'oaneng (7 matsatsi) kapa cuteine ea sethoathoa (15 mg / kg) kapa saline e sa hlapolloang (0.9% saline) ka ente ea intraperitoneal (ip), 'me ea nyeheloa ka ho hlapolloa ka sefuba ka hora e le ngoe kamora ho entoa ea ho qetela. Lithane li ile tsa kotuloa hanghang (Setšoantšo sa 2) kapa ka linako tse fapaneng ka mor'a sehlabelo (Setšoantšo sa 3).

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Mofuta oa 2. Ho bapisoa ha liprotheine tsa FosB tsa motho le mouse.

(A) Bothata ba liprotheine tsa hippocampal tse nang le antios ea FosB li senola lihlopha tse ling tse ngata tsa sampole tse lemalloang ke koae HPC ha li bapisoa le mofuta oa "cocaine" (15 mg / kg bakeng sa matsatsi a 7). Li-band tsa Novel li bonahala ho 20 kDa, 23 kDa (motsu o mosoeu), le 30 kDa (motsu o motšo). (B) Litla-morao tsa 'mele le karolo ea methapo ea polelo ea protheine bakeng sa sehlopha ka seng ka har'a sampole ea motho ka nako ea postmortem (nako pakeng tsa lefu le leqhoa la kelello) molemong oa motho e mong le e mong. Mehala e nang le matšoao e emela 95% nako ea kholiseho; ha ho na moeli o pharalletseng oa "regression" o fapaneng hantle le 0.

http://dx.doi.org/10.1371/journal.pone.0160355.g002

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Mofuta oa 3. Pontšo ea liprotheine tsa FosB ho HPC ea mouse kamora linako tse telele tsa postmortem.

Boea ba litoeba bo fuoeng ente e matla ea koae (15 mg / kg ip) e ne e setse in situ bakeng sa 0, 1, kapa 8 hrs kamora ho etsa sehlabelo pele ho kotuloa HPC. Botlaela ba Bophirimela bo senola ho hahoa ha sehlopha sa 23 kDa ho liphoofolo tsa 8 hr, empa ha e bonts'e lihlopha tse ling tse fumanoang mehlaleng ea HPC ea motho.

http://dx.doi.org/10.1371/journal.pone.0160355.g003

Bophirimela ba Blotting

Mekokotlo ea mouse e ne e ntšoa ka potlako leqhoeng ebe e kenngoa likarolo tsa 1 mm, ebe dorsal hippocampus e tlosoa ka punch ea 12 'me hang-hang ea hoama leqhoa le omileng. Mehlala ea batho le ea panyae e ile ea homogenized ka khanya ea sonication ho RIPA buffer (10 mM Tris chloride, 150 mM sodium chloride, 1 mM EDTA, 0.1% sodium dodecyl sulfate, 1% Triton X-100, 1% sodium deoxXo. proteinase le phosphatase inhibitors [Sigma Aldrich]. Khokahano e lekantsoe ho sebelisoa liprotheine tsa DC Protein Assay (BioRad) le sampole tsa li-gel li etselitsoe maemo a tloaelehileng bakeng sa protheine e felletseng. Liprotheine li ile tsa aroloa ho 7.4-4% polyacrylamaide gradient gels (Criterion System, BioRad), le blotting Western e entsoe ka chemiluminescence (SuperSignal West Dura, Thermo Science). Protheine e felletseng e anngoe ka tšebeliso ke Swift Membrane Stain (G Bioscience) mme liprotheine li ile tsa qaptjoa ho sebelisoa software ea ImageJ (NIH). Li-antibodies tsa mantlha li ne li sebelisetsoa ho bona FosB isoforms (15G5; 4: 1; Cell signaling, 500), GluA2251 / 2 (3: 1; Millipore, 1,000-07), CaMKIIcy (598NNXNNNNXLNNXNNXNNXNNXNNXLNXNNXNNXNXLNXNNXL (1: 1,000; Santa cruz, sc-05), GAPDH (532: 5; Cell Signaling, 1).

Lipalo-palo li

Litlhahlobo tsohle tsa lipalo li ile tsa etsoa ho sebelisoa sephutheloana sa software sa Prism 6 (GraphPad). Ts'ebetso ea "regression regression" e sebelisitsoe ho bona hore na polelo ea FosB lihlahisoa tsa gene li ne li hokahanngoa le nako ea postmortem. Ho thellisoa ha mohala o mong le o mong oa mehala ho ile ha lekoa bakeng sa phapang ea bohlokoa ho tloha ho zero. Liteko tsa moithuti li sebelisitsoe bakeng sa papiso eohle e bohlale e pakeng tsa taolo le batho ba lemaletseng koae (ho bontšitsoe ho litholoana moo boleng ba boleng bo fanoang). Li-ANOVA tsa tsela e le 'ngoe li ile tsa sebelisoa bakeng sa lipapiso tsohle tse fapaneng lipakeng tsa taolo, batho ba tepelletseng maikutlo ba nang le li-antidepressant tse ka sekepeng, kapa batho ba sithabetseng ba se nang li-antidepressants (tse bontšitsoeng ho Liphetho moo boleng ba F bo fanoang). Li-ANOVA tsa tsela e le 'ngoe li ile tsa lateloa ke Tukey post hoc teko. P <0.05 e ne e nkuoa e le bohlokoa.

Results

Boithuto ba rona ba morao-rao bo bonts'a hore lihlahisoa tse tharo tse kholo tsa FosB gene bokong, bolelele bo felletseng ba FosB (~ 50 kDa), ΔFosB (~ 35-37 kDa), le Δ2ΔFosB (~ 25 kDa), li kenyelitsoe ka mokhoa o fapaneng likarolong tse amanang le moputso oa boko ho arabela khatello le kalafo ea kalafo ea kalafo [22], le li-antigen tse ling tse amanang le Fos tse ka hlahisoang ke FosB gene e boetse e bonoe bokong ba mouse [45-47]. Ka hona, re ile ra qala ho batla ho tseba hore na boko ba motho bo bontša mofuta oa FosB Lihlahisoa tsa gene tse tšoanang le tse fumanoang bokong ba mouse. Re bapisa mohlala o tloaelehileng oa HPC ho motho ea lemaletseng koae.Lethathamo 2) ho HPC ho tloha ho panya e fuoeng cocaine e sa foleng (15 mg / kg, ip bakeng sa matsatsi a 7). Ka boraro ba tsona tse kholo FosB lihlahisoa tsa mofuta oa liphatsa tsa lefutso li fumanoe ka har'a linama tsa mouse le tsa bokong ba motho, empa lihlopha tse ling li ile tsa bonoa sampoleng ea motho ha li bapisoa le panya (Setšoantšo sa 2A). Haholo-holo, lihlopha ho ~ 30 kDa, ~ 23 kDa, le ~ 20 kDa li hlahile ka har'a disampole tsa batho empa li sa ka tsa bonoa ho mehlala ea panya. Re hatisitse hore lihlopha tsena li ka emela lihlahisoa tsa proteinolytic tse hlahisoang ke ho senyeha ha FosB kapa ΔFosB ka lebaka la nako e telele ea postmortem (PMI) mehlaleng ea rona ea batho (Lethathamo 2). Leha ho le joalo, ha ho kamano pakeng tsa matla a lihlopha tsena tsa lipale le PMI (Setšoantšo sa 2B), kapa lipakeng tsa PMI le lihlahisoa tse kholo tsa lefutso, FosB, ΔFosB, le Δ2ΔFosB (Setšoantšo sa 2B), ke hore, ha ho le e 'ngoe ea mela ea regression e neng e na le phallo e fapaneng haholo le zero. Kahoo, lihlopha tsena tsa lipale ha li na ho ba lihlahisoa tsa ho senyeha tsa protheine ka lebaka la nako e telele lipakeng tsa lefu le ho tsitsipana hoa tishu.

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Tafole 2. Palo ea batho ba lemaletseng koae, batho ba nang le khatello ea maikutlo le lihlopha tse laoloang.

http://dx.doi.org/10.1371/journal.pone.0160355.t002

Ho etsa lipatlisiso tse ling hape, re ile ra fa litoeba ente e le 'ngoe ea koae (15 mg / kg, ip) kapa saline' me ra li etsa sehlabelo ka ho hlohlona ka sefuba ka hora e le ngoe hamorao. Joale likelello li ile tsa siuoa in situ bakeng sa zero, e le 'ngoe, kapa lihora tse robeli pele sampole e nkuoa. Re hlokometse lihlahisoa tse ling tsa ho nyenyefatsa (Setšoantšo sa 3), e hlahelletseng ka ho fetisisa ke ~ 23 kDa, empa sebopeho se hlahisitsoeng ha sea ka sa etsisa se etsahalang mehlaleng ea HPC ea motho. Ha li kopantsoe hammoho, lintlha tsena li bonts'a hore ho na le li-antigen tse amanang le Fos bokong ba motho tse ka emang rialo FosB Lihlahisoa tsa gene mme ha li na monyetla oa ho ba sephetho sa protheine ea FosB kapa ΔFosB.

Ka mor'a moo re ile ra batla ho fumana hore na ho ts'epa koae, ho tepella maikutlong ho sa phekoloe kapa khatello ea maikutlo e tsamaeang le ho pepesetsoa litlhare tsa meriana e thibelang khatello ea maikutlo e amana le liphetoho tse teng. FosB Lihlahisoa tsa gene ho HPC ea motho kapa PFC. Bakuli le lithuto tsa taolo ba ile ba khethoa ka mokhoa oo ho neng ho se na phapang e kholo ka karolelano ea lilemo, bong, pH ea bongo, kapa PMI (Lethathamo 1). Moo sampole e tsoang ho bakuli ba ts'ehetsang koae, motho ea tsoang Bophirimela o sa senola phapang lipuisanong la mofuta ofe kapa ofe oa FosB ho PFC ha o bapisoa le taolo (Setšoantšo sa 4A le 4B). Leha ho le joalo, re bone ho fokotseha ho hoholo ho HPC ea batho ba itšetlehileng ka koae ka botlalo ba FosBt(35) = 2.67, p = 0.012), ΔFosB (t(31) = 2.81, p = 0.009), hammoho le lihlopha tsohle tse tharo tsa lipale, 30 kDa (t(34) = 2.71, p = 0.011), 23 kDa (t(15) = 2.7, p = 0.016), le 20 kDa (t(13) = 2.43, p = 0.031), le mokhoa o lebisang ho fokotseha ha Δ2ΔFosB (t(29) = 2.03, p = 0.052). Ka mokhoa o ts'oanang, ka disampole tse tsoang ho bakuli ba nang le khatello ea maikutlo, ho ne ho se na phapang pontšong ea mofuta ofe kapa ofe oa FosB ho PFC, ha HPC e bontsitse e fokotseha ka bolelele bo felletseng ba FosB (F (2,35) = 1.98, p = 0.048) le ΔFosB ( F (2,30) = 1.38, p = 0.027), hammoho le sehlopheng sa 23 kDa band (F (2,21) = 2.05, p = 0.022) le 20 kDa band (F (2,18) = 0.97, p = 0.028) (Fig 4C le 4D). Lintlha tsena li fana ka maikutlo a hore FosB polelo ea mofuta oa HPC e fokotseha maemong a mangata a kelello ha polelo ea PFC e sa angoe.

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Mofuta oa 4. Pontšo ea liprotheine tsa FosB ho HPC le PFC ea batho ba lemaletseng koae le koae.

(A) Thibelo ea Bophirimela ea liprotheine tsa FosB tse tsoang ho HPC le PFC ea batho ba lemaletseng k'hok'heine (Coc) le litsamaiso (Con). (B) Palo e senola ho fokotseha ho itšetlehileng ka k'hok'heine liprotheine tse ngata tsa FosB ho HPC empa eseng PFC (*: p <0.05, #: p = 0.05). (C) Phokotso ea Bophirimela ea liprotheine tsa FosB tse tsoang ho HPC le PFC ea bakuli ba khatello ea maikutlo (Dep) kapa ho li-anti-depressing (Dep + AD) le litsamaiso (Con). (D) Palo e senola ho fokotseha ho itšetlehileng ka khatello ea maikutlo liprotheine tse ling tsa FosB ho HPC empa eseng PFC (*: p <0.05). Mekoallo ea liphoso e bontša ho bolela +/- SEM.

http://dx.doi.org/10.1371/journal.pone.0160355.g004

Bopaki bo tobileng ba lipheo tsa mofuta oa phetisetso ea ΔFosB ho HPC ha bo na letho, ha feela sepheo sa protheine se itšetlehileng ka cyclin-kinase 5 (cdk5) se behiloe pakane ka mor'a ho susumetsoa ke motlakase ka litoeba [39]. Le ha ho le joalo, mefuta e meng e mengata e tsejoa ka sepheo sa ho fetisa molaetsa oa ΔFosB libakeng tse ling tsa boko, haholo-holo ho NAc. Tsena li kenyelletsa mefuta e mengata ea bohlokoa bakeng sa ts'ebetso ea sele ea hippocampal le polasetiki ea synaptic, joalo ka GluA2 [48] le CaMKII [20]. Ka hona, re sebelisitse blot Bophirimela ho hlahloba maemo a lipehelo tsa lefutso tsa ΔFosB ho HPC le PFC ea bakuli ba ts'ebelisang koae le ba tepelletseng maikutlo. Ha rea fumana phapang e kholo litekanyetsong tsa liprotheine tsa mofuta oa ba khethiloeng ho PFC ea batho ba itšetlehileng ka koae, ha HPC e bontšitse ho fokotseha ho hoholo ho GluA2 (t (34) = 2.31, p = 0.027) le mokhoa o matla oa ho fokotseha Maemo a CaMKII (t (35) = 1.99, p = 0.053) polelo, ha cdk5 e ntse e sa fetohe (Setšoantšo sa 5A le 5B). Ho PFC le HPC ea bakuli ba tepelletseng maikutlo ho ne ho se na liphetoho mabapi le mefuta ea sepheo sa ΔFosB (Fig 5C le 5D). Lintlha tsena li fana ka maikutlo a hore ΔFosB e kanna ea laola tlhahiso ea mefuta e ka hlahang ho HPC ea motho, mme molao ona e ka ba sebaka sa boko le lefu le itseng.

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Mofuta oa 5. Tlhaloso ea liprotheine tsa mofuta oa targetFosB tse hlahang ho HPC le PFC tsa batho ba lemaletseng koae le koae.

(A) Thibelo ea Bophirimela ea liprotheine tse ka hlahisoang ke liphatsa tsa lefutso tsa ΔFosB tse tsoang ho HPC le PFC ea batho ba hlekefetsang batho ka li-cocaine (Coc) le litsamaiso (Con). (B) Palo e senola ho fokotseha ho itšetlehileng ka cocaine ho GluA2 le CaMKII ho HPC empa eseng PFC (*: p <0.05, #: p = 0.05). (C) Thibelo ea Bophirimela ea liprotheine tse ka hlahisoang ke liphatsa tsa lefutso tsa ΔFosB tse tsoang ho HPC le PFC ea bakuli ba khatello ea maikutlo (Dep) kapa ho li-anti-depressing (Dep + AD) le litsamaiso (Con). (D) Palo ea palo ha e senole liphetoho tse itšetlehileng ka khatello ea maikutlo. Mekoallo ea liphoso e bontša ho bolela +/- SEM.

http://dx.doi.org/10.1371/journal.pone.0160355.g005

Puisano

Mona, re hlahisa tlhahiso ea pele ea FosB sehlahisoa sa mofuta oa gene le tlhahlobo ea protheine ea ΔFosB-target ho hippocampus le preortalal cortex ea lithethefatsi tsa koae le bakuli ba tepelletseng maikutlo. Libaka tsena tsa boko li tsejoa li bapala karolo ea bohlokoa ho pathophysiology ea maloetse ana, 'me ts'ebeliso ea mehlala ea motho ka mor'a lefu e re lumella ho: 1) ho etsa qeto ea hore na liphetoho tse fumanoang mefuteng ea methapo ea mafu ana li boetse li phetoa ho batho ; 2) tseba litsela tse fumanehang tsa ho ithuta ka mefuta ea litoeba bakeng sa ho ka kenella kalafong. Bohlahlobisisi ba rona bo shebane haholo le polelo ea FosB Lihlahisoa tsa gene, joalo ka ha polelo ea bona libakeng tsena e khothalelitsoe ho bapala karolo ea khatello ea maikutlo mme e khothalletsoa ke ho pepesetsoa ha koae mefuteng ea litoeba [21, 22, 24]. Ha re qala ho hlahloba maemo a protheine ea FosB mehlaleng ea rona ea batho, ho ne ho hlakile hore antiox ea rona ea FosB e lemohile lihlopha tse ngata ho feta tse kileng tsa tlaleheloa ho mehlala ea boko ba sehlopha sa rona le ba bang ba bangata [1, 22]. Hobane kelello ea motho e hoamme lihora tse ngata kamora lefu ha li-sampuli tsa mouse li tlositsoe 'me li hoamme kamora metsotso e' meli ea sehlabelo, re tlohetse likelello tsa mouse in situ kamora ho etsa sehlabelo lihora tse robeli ho bona hore na lihlopha tse tšoanang li ka hlaha. Leha ho le joalo, hobane ha re ka ra sheba sebopeho se tšoanang sa liprotheine tsa FosB tse fumanoeng mehatong ea batho, hape hobane re boetse re sa fumana khokahano lipakeng tsa bolelele ba PMI le litsi tsa lihlopha tse fapaneng limeleng tsa batho, re ile ra fihlela qeto ea hore lihlopha tse ngata li disampole tsa boko ba motho ha li na monyetla oa ho ba sephetho sa ho senyeha hoa liprotheine tsa li-isoforms tse kholo tsa FosB. Leha re ke ke ra khona ho khaola liphapang mochineng oa liprotheole o pakeng tsa mefuta ea liphoofolo, re ka fana ka maikutlo a hore lihlopha tse ling tsa batho li ka hlaha ka lebaka la karohano ea FosB mRNA, 'me lithuto tsa nako e tlang sehlopheng sa rona li tla araba potso ena.

Liphetho tsa nakong e fetileng tse tsoang lithutong tsa litoeba li fumane keketseho ea li-isoforms tsa FosB ho HPC le PFC kamora cocaine e sa foleng [24]. Leha ho le joalo, ho tsoa ho sehlopha sa rona sa batho ba itšetlehileng ka koae re fumane ho fokotseha hoa li-isoforms tsohle tsa FosB ho HPC, ha ho na phetoho ho PFC ha e bapisoa le batho ba laoloang. Re lumela hore sena se ka etsahala ka lebaka la liphapang tse teng lipakeng tsa lithuto tsa lefutso le maemo a bokhoba ba batho. Boithuto ba bokhoba ba koae bo lula feela karolo e nyane ea bophelo ba rodent, 'me ha ho lithuto tsa induction tsa ΔFosB ho fihlela joale li fetile matsatsi a 14 a ho pepesetsoa ha koae [1, 20]. Basebelisi ba koae ea batho ba ka lemalla nako e teletsana, e leng se ka bakang litlamorao tsa lapeng FosB gene e tla hatelloa ho HPC. Ho feta moo, liphuputso tse ngata li bonts'itse hore ts'ebetso ea nako e telele ho li-psychostimulants e tsamaea le ts'ebetso ea kelello e fokotsehileng [9, 49]. Mosebetsi oa rona oa morao-rao o bonts'a hore HPC ΔFosB e bapala karolo ea bohlokoa ho ithuteng [28], mme ka hona ho fokotseha ha HPC FosB polelo ea mofuta oa lithethefatsi tsa koae e bonts'itsoeng mona e ka emela mokhoa oa ho theoha ha kelello ho lemaletseng lithethefatsi tsa psychostimulant. Ka polelo e fokotsehileng ea FosB gene ho HPC, hape re hlokometse ho fokotseha ha lipalo tsa liprotheine tsa mofuta oa sepheo sa candidateFosB GluA2 le CaMKII, mme limolek'hule tsena ka bobeli le tsona li bohlokoa bakeng sa ts'ebetso ea HPC le ho ithuta [50] hape li kile tsa hokahanngoa le bokhoba ba tahi [38, 51].

Ka HPC ea bakuli ba tepelletseng maikutlo, re hlokometse ho fokotseha ha liprotheine tse ngata tsa FosB, ho latela hore na bakuli ba nka li-antidepressants. Sena se ka bonts'a hore litlhare tsa litlatsetso li na le litlamorao tse fapaneng ho boteng kapa botsikeng ba FosB Lihlahisoa tsa liphatsa tsa lefutso, leha lithuto tsa rona tse fetileng lipolaong li sa hlahise liphapang tse joalo [22]. Leha ho le joalo, ho ne ho se na phapang pontšong ea mefuta e ka bang teng ea sepheo ho HPC kapa PFC ea bakuli bana. Le ha khatello ea maikutlo e kholo hangata e tsamaisana le mathata a kelello [52], ho ka etsahala hore HPC ΔFosB ha se eona feela ntho e fetotsoeng ho araba khatello ea maikutlo. Le ha batho ba lemaletseng koae ba bontšitse liphetoho ho HPC ΔFosB le polelong ea mofuta oa sepheo, khatello ea maikutlo e kanna ea lebisa mekhoeng e fapaneng ea matšeliso e thibelang phokotso ea polelo ea GluA2 kapa CaMKII. Kahoo, lithuto tsa nakong e tlang li tla hlakisa hore na ho na le liphetoho tse tlisoang ke mofuta oa HPC molemong oa khatello ea maikutlo le bokhoba ba lithethefatsi.

Ho bohlokoa ho hlokomela hore palo ea batho ba sebelisitsoeng phuputsong ena ha ba na litsoantso tsa mofuta oa litoeba kapa litso tsa mehleng ea khale. Mohlala, bakuli ba bahlano ba nang le khatello ea maikutlo ba ne ba le lekhoba la tahi, 'me ba babeli ba ne ba e-na le opiate ka sekepeng nakong ea lefu. Ka mokhoa o ts'oanang, batho ba tšeletseng ba batho ba neng ba ts'epa koae ba ne ba sebelisitse meriana e loantšang likhathatso likhoeling tse tharo pele ho lefu. Le ha hona ha ho makatse, hobane khatello ea maikutlo le bokhoba ba maikutlo bo na le boemo bo phahameng ba comorbidity [6, 7], e fana ka phetolelo e boima ea sephetho. Ha re bone phapang ea bohlokoa mefuteng efe kapa efe ea likamano tsa rona tsa biochemical lipakeng tsa lithuto tse itšetlehileng ka koae tse neng li e-na le li-antidepressants tse ka sekepeng le tse sa kang tsa bona, hape ha re bone phapang lipakeng tsa bakuli ba tepelletseng maikutlo ba neng ba e-na le ts'ebeliso ea lithethefatsi le ba neng ba sa e bone. ). Le ha ho le joalo, sena ha se lumellane le litlamorao tsa tlhabollo ea maikutlo le bokhoba ba maikutlo le ho lemalla mehato ea rona. Ho fapana le hoo, ha re ntse re bona ho fokotseha ho tšoanang ho HPC FosB isoform expression ka khatello ea maikutlo le bokhoba, ho ka etsahala hore phokotso ea HPC FosB mofuta oa polelo ke mokhoa o tloaelehileng lipakeng tsa maemo ana a mabeli mme o ka kenya letsoho ho qabola. Ho etsa patlisiso ena ho tla hloka sehlopha se seholo sa lithuto tsa batho le lithuto tse ling tsa preclinical.

Qetellong, re fumana tse ngata FosB Lihlahisoa tsa gene li nyenyefalitsoe HPC, empa eseng PFC, ea batho ba nang le khatello ea maikutlo le khatello ea maikutlo. Le ha re sa khone ho hokahanya kamano ea lefu lena le lefu lena, ho ka etsahala hore ebe ho fokotseha ho HPC ΔFosB le / kapa li-isoforms tse ling tsa FosB ka karolo e ka tlasa bofokoli ba kelello bo amanang le khatello ea maikutlo le bokhoba, kapa ho kenya letsoho ho hlasimolohileng ha mafu ana a kelello. mathata.

lumela hore baa fokola

Bangoli ba ka thabela ho leboha Kenneth Moon ka thuso e ntle ea theknoloji.

Menehelo ea Mongoli

O ithutile le ho hlophisa liteko: LEQEPHE AJR.
O entse liteko: LEQEPHE AJR GT.
Hlahloba lintlha LEQEPHE AJR.
Li-reagents tse kentsoeng / lisebelisoa / lisebelisoa tsa tlhahlobo: GT.
Ngola pampiri: LEQEPHE AJR.

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