Monehelo oa Moputso Hang-hang phetolelo ea Gene ea mathomo ka mathata a mohopolo (2017)

. 2017; 11: 77.

E hatisitsoe Inthaneteng 2017 Apr 28. doi:  10.3389 / fnbeh.2017.00077

PMCID: PMC5408019

inahaneloang

Lilemong tse mashome a mararo tse fetileng, ho ile ha hlaka hore ts'ebetso e fetelletseng ea marangrang a libaka tse amanang tsa boko tse ikarabellang bakeng sa ts'ebetso ea moputso le boits'oaro bo susumetsang bo baka mathata a fapaneng a maikutlo, ho kenyeletsa khatello ea maikutlo le matšoenyeho. Ho boetse ho hlakile hore liphetoho tse bakiloeng ke khatello mesebetsing ea marang-rang tsa moputso tse tsamaisang mokhoa o tloaelehileng le oa ts'ebetso ea methapo ea methapo le tsona li baka phetoho ho polelo ea mofuta. Mona, re leka ho hlalosa likarolo tsa meputso le ho hlahloba liphallelo tse tsejoang le tse ka bang teng mesebetsing ea liphatsa tsa lefutso ka har'a potoloho ena ho liphetoho tse tlisoang ke boitšoaro bo amanang le mathata a maikutlo, mme re bapisa tse ling tsa litlamorao le tse hlahisitsoeng ke ho pepeseha. ho lithethefatsi tsa tlhekefetso. Re tsepamisa maikutlo letotong la mefuta ea pele e laoloang ke khatello ea maikutlo lipakeng tsa khokahano ena le likhokahano tsa tsona, tse sibolotsoeng hantle le tse nyane haholo ho tsa potoloho le boits'oaro bo latelang bo amanang le moputso. Re phethela ka hore li-IEG li bapala karolo ea bohlokoa ho rarolleng khatello ea maikutlo ho li-circry tsa meputso, le hore li ka sebetsa e le lintho tse ka kenang molek'huleng oa methapo, liseleng le maemong a potoloho ea ho feto-fetoha ha maikutlo le maikutlo.

Keywords: khatello ea maikutlo, tsamaiso ea moputso, mofuta oa pele oa lefutso (IEG), FosB / ΔFosB, CREB, accumbens, hippocampus, khatello ea maikutlo

Selelekela

Neurocircuitry e bile teng ho putsa mekhoa e tlatsetsang ho matlafatseng ea ho iphetola ha lintho ka maikutlo a thabo, e susumetsang libopuoa ka bomong ho nka boleng, le ho pheta liketso tse eketsang monyetla oa ho jala lisebelisoa tsa bona tsa lefutso. Sena se ka kenyelletsa ho etsa thobalano, ho ja lijo tse itseng, ho hlokomela bana kapa ho etsa boithabiso. Leha ho le joalo, tikoloho ea motho ea sejoale-joale, e nang le lisebelisoa tse ngata le phihlello e khahlisang, e ka lumella tšebetso e eketsehileng ea meputso ho kenya litabatabelo tse mpe, joalo ka ho ja kapa ho lemalla lithethefatsi kapa thobalano (Berridge le Kringelbach, ). Ka lehlakoreng le leng, ho haella ha ts'ebetso ea moputso ho etsa hore ho be le matšoao a anhedonic a mathata a ho feto-fetoha ha maikutlo ho sa laoleheng (Nestler, ; Luking et al., ), 'me kalafo ea morao-rao le lipatlisiso tsa mathata a ho feto-fetoha le maikutlo li bua haholo ka moputso oa mantlha le mekhoa e ka kenyang letsoho ho etseng moputso o fosahetseng.

Boitšoaro bo nang le moputso oa amoheloa hobane bo matlafatsoa. Ts'ebetso ena e hloka hore: (1) e hlahise maikutlo a monate (monyaka), (2) ho ithuta ho ithutoang, le (3) ho hlahisa boitšoaro bo eketsang (ho ja, ho kopitsa, ho hokahana, joalo-joalo). Kahoo, potoloho ea moputso e tlameha ho kopanya leseli le tsoang metsong ea boko e tsamaisang maikutlo a thabo, ho theha le ho boloka mehopolo, le ho etsa liqeto le boitšoaro. E se e ntse e hlaka haholoanyane lilemong tse mashome a mabeli tse fetileng tse hore liphetoho tse fetisitsoeng ho liphatsa tsa lefutso ka har'a meputso ena ea moputso li kenya letsoho kholisong ea mathata a ho feto-fetoha ha maikutlo (Nestler, ). Liphetoho tsena tse amanang le bokuli li ka kenyelletsa mekhoa e fapaneng joaloka histone le phetoho ea DNA, polelo ea RNA eo eseng ea cod, le tlhahiso ea tlhahiso le ts'ebetso (Dalton et al., ; Geaghan le Cairns, ; Nestler, ). Polelo ea lintlha tse ngata tse ngotsoeng tse amehang lits'ebetsong tsena e laoloa ka thata ke ts'ebetso ea methapo, mme lintlha tse joalo tsa mongolo ke karolo ea sehlopha sa limolek'hule tse bitsoang li-gene tsa pele (IEGs). Li-IEG tsena li bontša mokhoa o ikhethileng bakeng sa maloetse a amanang le anhedonia, joalo ka ha ts'ebetso ea potoloho ea "neuronal" e fetoloa mefuteng e mengata ea khatello ea maikutlo (Russo le Nestler, ;; Lammel et al., ), mme ka hona polelo ea li-IEG tse ngata e sa sebetse mehlaleng e le 'ngoe (Reul, ; Nestler, ). Ka hona, ho otlolla ka botlalo boits'oaro ba mathata a maikutlo a batho, ho bohlokoa hore re utulle taolo ea li-IEG maemong a meputso tlasa maemo a basal le a mafu. Tlhahlobo ena e tla akaretsa tsoelo-pele ho khetholla lipehelo tsa taolo le liphula tsa li-IEG ka har'a likarolo tsa boko tse kenyelletsang meputso, le bopaki ba hona joale bo kopanyang li-IEG tsa moputso ho likarabelo tsa khatello ea maikutlo le khatello ea maikutlo.

Khokahano ea moputso oa cortico-basal ganglia

Karolo ea mantlha ea potoloho ea meputso ke ho lokolloa ha dopamine (DA) sebakeng sa "ventral tegmental sebakeng" (VTA) ho ea likarolong tsa boko tsa litho tse laolang ho bolela esale pele, pono, le ts'ebetso ea mehopolo e khotsofatsang. Li-neurons tsa VTA DA li na le lipakanyo tse kholo ho preortalal cortex (PFC; tsela ea mesocortical) le ho li-nucleus accumbens (NAc; tsela ea mesolimbic), empa hape le projeke ea hippocampus, amygdala, le libaka tse ling tsa 'mele tse ka pele. Ho nahanoa hore Mesocortical DA e ameha likarabo tsa maikutlo le taolo ea kelello (Nestler et al., ), le ha mesolimbic DA e amana le setso le boits'oaro bo susumetsang. Ho lokolloa ha Mesolimbic DA ho kenya tšebetsong dopamine receptors (DRs) ho NAc medium spiny neurons (MSNs), lisele tsa GABAergic tse nang le likarolo tse peli tse arohaneng haholo tse hlalosang boholo ba eona e ka ba D1 kapa D2 DRs (Surmeier et al., ; Lobo, ). D1 MSNs e na le "tsela" e otlolohileng, e qetellang e eketsang drive ea thalamocortical, ha D2 MSN e etsa tsela e sa "sa tsejeng", e lebisang ho fokotseng thalamocortical drive. Hobane D1 DRs e eketsa ho arabela ho monyelisong oa glutamatergic ha D2 DRs e theola thabo ena e nyonyehang, ho lokolloa ha VTA DA ho thusa tseleng e otlolohileng ha o ntse o beha brake tseleng e sa tobang, ka sephetho se kopaneng sa ho eketseha ha cortical drive.

Li-NAc MSN li fumana litlatsetso tsa glutamatergic tse tsoang mekhatlong e 'maloa ea cortical le limbic, ho kenyeletsoa karohano ea maikutlo le ea morao-rao ea PFC, ventral hippocampus (vHPC), basolateral amygdala (BLA), le medial thalamus (Sesack le Mohau, ; Floresco, ). Lits'ebetso tsa PFC ho NAc li laola boits'oaro bo lebisitsoeng ho sepheo, joalo ka ho batla le ho ja lintho / mesebetsi e amanang le moputso, ho kenyelletsa lijo, thobalano, lithethefatsi, le litšebelisano tsa sechaba (Kalivas et al., ; Gruber et al., ), ho fana ka "taolo e kholo" e hlokahalang bakeng sa ho rala le ho etsa liketso ho fumana meputso. Kenyelletso ea vHPC ho NAc e fana ka tlhaiso-leseling mabapi le libaka tse ntle tsa libaka le boiphihlelo bo fetileng bo hlahisitsoeng ke ho ithuta maikutlo. Hona ho sebetsa maemong a monate le a mabe a maikutlo, ke ho re, ho fumana moputso- le ho ithuta ho thehiloeng mananeong, ho kenyelletsa maemo a ts'abo a atamelaneng le maemo, boitšoaro ba ho fepa le likarabo tsa lithethefatsi tsa tlhekefetso (Vezina et al., ; Fanselow, ; Kanoski le Grill, ). Ha ts'ebetso ea BLA e akaretsang le litekanyetso tsa BLA libakeng tse ling tse ngata tsa boko li laola ho ithuta ho amanang le tšabo le boits'oaro, lipallo tsa glutamatergic tse tsoang ho BLA ho ea NAc MSNs li eketsa ho batla moputso le ho ts'ehetsa khothaletso e ntle (Ambroggi et al., ; Stuber et al., ; Janak le Tye, ).

Bongata ba libaka tsena tsa tlatsetso ea NAc glutamatergic le tsona lia rera, 'me li-NAc li-MSN li romella le ho amohela likhakanyo tsa GABAergic ho tsoa le VTA hape. Sena se hlahisa marang-rang a moputso oa "cortico-basal ganglia" (Sesack le Grace, ; Floresco, ), mofuta o nolofalitsoeng o hlahisitsoeng mona (Setšoantšo (Figure1A) .1A). Ts'ebetso ea mantlha ea marang-rang ena ke ho laola le ho kopanya matšoao a cortical / limbic glutamatergic a emelang taolo ea motsamaisi, mohopolo le maikutlo ka ts'ebetso ea moputso oa dopaminergic ho laola liphetho tsa thalamocortical tse tsamaisang boitšoaro. Ka bomalimabe, litereke tse ngata tse kenyang potoloho ena li fetoha ka nako e telele ho mofuta oa gene, le ts'ebetso ea lisele, hangata ka lebaka la ho pepesetsoa khatello ea maikutlo, e ka tsamaisang mathata a amanang le maikutlo, mme liphetoho tsena, ka karolo, ho tsoa ho polelo ea bohlasoa le ts'ebetso ea li-IEG. Sena se bonahala haholo liphetoho tse bakiloeng ke khatello ea maikutlo mokhoeng oa li-neurons tsa moputso.

Setšoantšo sa 1  

Cortico-basal ganglia moputso oa marang-rang. (A) The nucleus accumbens (NAc) e kenyelletsa ho kenella ha glutamatergic (khubelu) e laolang libaka tsa sepakapaka (ventral hippocampus, vHPC), maikutlo (basolateral amygdala, BLA), le molaoli (boitsoaro ba preortal cortex, PFC), le ...

Matšoenyeho a sa feleng a khatello ea sechaba, mohlala oa khatello ea maikutlo, o baka keketseho ea letsoalo la lesapo la mokokotlo ho NAc MSNs (Setšoantšo. (Figure1B) .1B). Meetso ea li-dendritic ea MSN ke mohokahanyo oa lipheo tsa ho kenella ha glutamatergic, 'me palo le sebopeho sa methapo e emetse palo le matla a keketso eo. Sekhahla se matla sa lesapo la mokokotlo se bonoang ho NAc kamora khatello e matla ea khatello ea sechaba (CSDS) se bakoa haholo ke keketseho ea palo ea makhapetla a fehloang, a sa ts'oaneng, mme ha ho na phetoho ea li-spines tse nang le sebopeho sa li-mushroom (Christoffel et al., ). Li-spines tsa Stubby li amahanngoa le likarabelo tse nyane tsa postynaptic densities (PSDs) le likarabo tse fokolang ho glutamate, empa ho eketseha ha khatello ea maikutlo kamora khatello ea maikutlo ho ka emela keketseho ea ho saena ha glutamatergic ho NAc, mme ehlile e tsamaisana le keketseho ea palo (empa eseng amplitude) ea lintho tse nang le bokhoni bo boholo ba litabatabelo tsa postynaptic (mEPSPs; Christoffel et al., ). Ntle le likhatello tsa khatello ea maikutlo tse kang CSDS, tsamaiso ea li-psychostimulants tse kang cocaine le eona e eketsa letsoalo la mokokotlo oa dendritic, haholoholo ka lebaka la keketseho ea palo ea methapo e tšesaane (Robinson le Kolb, ; Russo et al., ), sebopeho se boetse se nkuoa e le ngoana. Leha ho le joalo, ho fapana le khatello ea maikutlo, taolo ea lithethefatsi tse hlasimollang e eketsa ho rarahana ha lesapo la mokokotlo ho NAc MSNs, ka methapo e mengata e bonts'a lekala le lihlooho tse ngata (Robinson le Kolb, ;; Setšoantšo Figure1B) .1B). Keketseho ena ea ho rarahana e ka emela ho hlophisoa bocha le ho eketseha ha letšoao la synaptic, ho bontšang phetoho mosebetsing oa potoloho kamora boiphihlelo ba lithethefatsi. Lihlahisoa tse ngata tsa liphatsa tsa lefutso li ka kenya letsoho taolong ea li-dendritic spine literekeng tse hatelletsoeng le tse pepesitsoeng ke lithethefatsi, ho kenyelletsa le li-IEG tse ngata tse boletsoeng ka tlase (mohlala, ΔFosB, CREB; Maze et al., ; Russo et al., ). Kutloisiso e ntlafetseng ea lihokela pakeng tsa polelo ea IEG le polasetiki ea sebopeho sa moputso e bohlokoa haholo kholisong ea kutloisiso ea rona ea mekhoako le bokhoba ba taolo.

proteni e tlamang ea cAMP (CREB)

CREB ke ntho e hatisang e tlamang karolo ea canonical cAMP Karolo ea (CRE) ho DNA ha e arabela ts'ebetsong ea litsela tse saenneng tse amang CAMP, Ca2+/ calmodulin, kapa lintlha tse fapaneng tsa kholo le / kapa li-cytokine. CREB ts'ebetso ea phetisetso ea mofuta o lebisitsoeng (setšoantšo (Figure2) 2) e laoloa ke phosphorylation ho serine 133 ke protheine kinase A (PKA, moeling oa cAMP), Ca2+/ proteinodase e tsamaeang le protheine kinase IV (CaMKIV, moeling oa Ca2+), le / kapa MAP kinase e tšoaea (e theoha ea lintlha tsa kholo le cytokine; Kida le Serita, ). Phosphorylation ea Ser133 e khothalletsa ho sebelisana le protheine e tlamang CREB (CBP), mohato oa bohlokoa bakeng sa ts'ebetso ea ts'ebetso ea transactional (Chrivia et al., ). Boithuto ba pele le bo pharalletseng ka ho fetesisa ba karolo ea CREB ts'ebetsong ea methapo ea kutlo bo thehiloe taolong ea eona ea phetolelo ea liphatsa tsa lefutso e ka bang matla a nako e telele a li-synapses le sebopeho sa mohopolo. CREB e bohlokoa bakeng sa mohopolo le polasetiki ea synaptic ka har'a slug ea leoatle e sa sebetseng Aplysia (Dash et al., ; Kandel, ) le fofa ea litholoana (Yin et al., ), mme memori ea nako e telele e senyehile ho litoeba tsa tahlehelo ea CREB, empa e ntlafalitsoe ho litoeba tsa ho sebetsa tsa CREB, haholo-holo ka lebaka la karolo ea eona ho hippocampus (e akaretsoang Kida le Serita, ).

Setšoantšo sa 2  

Lits'oaetso tse bonts'ang li lebisa ts'ebetsong ea CREB. Lipontšo le liphetoho tse bang teng ka har'a li-membrane tse ka hlahisang li-receptor le liteishene tse kenyelletsang: G-protein receptors (GPCR), NMDA-mofuta oa li-glutamate receptors (NMDAR), voltage gated Ca2+ liteishene (VGCC), ...

CREB e susumetsoa ke NAc ka ho pepesetsoa khatello ea maikutlo e fapaneng, mme ts'ebetso ea eona ho NAc e hokahane le likarabo tse fapaneng tsa maikutlo, ka tumellano e akaretsang ea hore ts'ebetso e sa fetoheng ea CREB ho NAc e lebisa ho anhedonia ha e ntse e thibela mosebetsi oa CREB ho NAc e phahamisa moputso. (Barrot et al., ; Carlezon et al., ). Ho feta moo, ts'ebetso ea CREB e fokotsehileng ho NAc e bonahala e na le litlamorao tse tšoanang le tsa khatello maemong a mangata a khatello ea maikutlo (Pliakas et al., ; Conti et al., ; Newton et al., ; Covington et al., ), ho fana ka maikutlo a hore ts'ebetso ea CREB e bakang khatello ea maikutlo ho NAc e ka kenya letsoho ho etiology ea khatello ea maikutlo. Leha ho le joalo, se fapaneng se bonahala se le 'nete mabapi le boits'oaro bo tšoanang le ba ho tšoenyeha, ha ts'ebetso ea NAc CREB e hlaha e tšoenya ha ho ntse ho thibeloa NAc CREB ho phahamisa matšoenyeho (Barrot et al., , ; Wallace et al., ), e bonts'a ho qhekella hoa ts'ebetso ea NAc CREB e kanna ea se ke ea ba kalafi e bonolo bakeng sa kalafo ea mathata a maikutlo.

Ho fapana le ts'ebetso ea eona ho NAc, ts'ebetso ea CREB ho hippocampus e hlahisa phello ea antidepressant (Chen et al., ), mme e hlile e ts'oaroa hippocampus ka mekhoa e fapaneng ea kalafo ea antidepressant (Nibuya et al., ; Thome et al., ). E 'ngoe ea mefuta ea li-CREB tse boletsoeng esale pele ke mofuta oa neurotrophic factor (BDNF),' me BDNF e boetse e kentsoe hippocampus ke li-antidepressants (Nibuya et al., ) mme ke phetisetso ea mantlha ea litlamorao tsa litlamorao tsa khatello ea maikutlo (Björkholm le Monteggia, ). Tsela ena ea CREB-BDNF e kentsoe tšebetsong ea ho susumetsa hippocampal neurogeneis e le mohato oa bohlokoa oa bohato ba ho loants'a khatello ea maikutlo (Duman, ; Carlezon et al., ). Ka hona ho latela hore ho se sebetse ha CREB ho hippocampus ho ka baka khatello ea maikutlo le mathata a mang a kelello a amanang le khatello ea maikutlo eo hangata e tsamaisanang le khatello ea maikutlo (Bortolato et al., ). Ho bohlokoa hape ho hlokomela hore CREB e laola polelo ea li-IEG tse ling tse amanang le karabelo ea khatello ea maikutlo le khatello ea maikutlo, ho kenyelletsa FosB, c-fos, le Arc (bona ka tlase), ka hona e ka sebetsa e le molaoli ea hloahloa oa sengoloa se itšetlehileng ka ts'ebetso. karabelo ea khatello ea maikutlo maemong ohle a meputso.

Protheine ea AP-1 — c-fos, FosB / ΔFosB, Jun

Protheine ea activator 1 (AP1) ke motsoako o rarahaneng oa liprotheine tsa lelapa tsa Fos, liprotheine tsa lelapa tsa Jun, liprotheine tsa Jun, le / kapa li-protheine tsa transcript factor (ATF) tseo ha li bokane, li sebetse e le li-regator tse matla le tse ikhethang tsa phetisetso ea mofuta oa gene. Mochine o tloaelehileng oa AP1 o na le li-heterodimers tsa Fos-Jun tse sebelisang li-zip tsa leucine tse teng liproteineng ka bobeli bakeng sa dimerization le sebaka sa motheo se sebetsanang le DNA. Lelapa la Fos la lintlha tse hatisitsoeng le entsoe ka c-fos, FosB (le mefuta ea lona ea splice, ΔFosB le Δ2ΔFosB), Fra1, le Fra2, tseo kaofela li susumetsoang ke ts'ebetso ea methapo ea methapo. c-fos e kenella hanyane ka hanyane ebile e hlohlelletsoa, ​​bophelo bo bolelele ho tloha metsotso ho fihlela lihora tse 'maloa (Sheng le Greenberg, ; Kovács, ; Ferrara et al., ), 'me e sebelisoa e le ho batla mefuta e fapaneng e amanang le phapang ea lisele, nts'etsopele ea sele le kutloano, polasetiki ea synaptic, le ho ithuta (Alberini, ; Bophirima le Greenberg, ). Khokahano ea eona e hlakileng mesebetsing ea maqhubu e lebisitse ho ts'ebeliso ea eona e le sesupo sa ts'ebetso ea tikoloho ea boko maemong a fapaneng a boitšoaro le a 'mele, leha ho le joalo bopaki bo phethahetseng ba lipheo tsa gene tse ikhethang tsa c-fos ha bo so fanoe, mme karolo ea eona e tobileng ho li-neuronal ts'ebetso e lula e patehile. E kenelloa ho potoloha le moputso ka linako tsohle tse susumetsang maikutlo (Kovács, ; Cruz et al., ; Nestler, ), empa karolo ea eona ea ts'ebetso ea mathata a maikutlo le karabelo ea antidepressant ha e utloisisoe hantle.

FosB e kentsoe ke FosB gene mme e arolelana litšobotsi tse ngata le c-fos: FosB e na le polelo e tlase e tlase ebile e susumetsoa ke ts'ebetso ea nakoana le e matla ea ts'ebetso ea neuronal (Nestler et al., ), e nang le halofo e khuts'oane ea bophelo liseleng tse kang ea c-fos (Dobrazanski et al., ; Ferrara et al., ; Ulery et al., ). Splice phapang ea FosB Mefuta ea liphatsa tsa lefutso e hlahisa codon ea pele ho nako e bakang protheine ea "uncFosB" e fokolang, 'me e haelloa ke lits'ebetso tse peli tsa "c-terminal defon" e ileng ea eketsa botsitso (Carle et al., ). Li-IEG tse ngata li na le halofo ea bophelo ba lihora tse 'maloa, ha ΔFosB e phela bophelo bo bolelele bo sa tloaelehang, ho fihlela matsatsing a 7 Ka vivo (Tšepo et al., ; Andersson et al., ; Ulery-Reynolds et al., ), ho e etsa letšoao la e sa foleng ts'ebetso ea methapo. ΔFosB e ts'oaroa ho potoloha le moputso ka khatello ea maikutlo (Perrotti et al., ) le ponts'o e sa foleng ea antidepressant (Vialou et al., ), joalo ka CREB (e bohlokoa bakeng sa ho kenya ΔFosB, Vialou et al., ), litlamorao tsa boits'oaro ba polelo ea eona li fapana ka sebaka sa boko. Ho NAc, ΔFosB e susumetsoa ke khatello ea maikutlo ea khatello ea khatello ea sechaba, mme ho kenella ha eona ho hoholo ho liphoofolo tse ikemiselitseng litlamorao tsa khatello ea maikutlo ho feta ho tse atamelaneng le khatello ea maikutlo e kang phenotype (Vialou et al., ). Ho feta moo, ho kenella ha ΔFosB ho NAc ho phahamisa boikemelo ho khatello ea maikutlo e sa feleng mme ho hlokahala bakeng sa litlamorao tsa kalafo tsa li-SSRIs tse kang fluoxetine (Vialou et al., ), ka ho hlakileng ka ho feto-fetoha ha polelo ea AMPA receptor subunit le taolo ea epigenetic ea polelo ea CaMKIIcy (Vialou et al., ; Robison et al., ). Ho kenella ha eona ka khatello ea litoeba tse matlafatsang ho hlaha ka ho khetheha ho li-mofuta oa li-D1 tsa mofuta oa li-NAN, ha boemo bo tlase ba induction bo bonoa ho D2-mofuta MSNs ea litoeba tse hlasetsoeng (Lobo et al., ). Ka sebele, overexpression e khethehileng ea ΔFosB ho D1 MSNs e bonahala e na le litlamorao tsa khatello ea maikutlo (Vialou et al., ; Muschamp et al., ; Donahue et al., ), 'me e fetola sebopeho sa methapo ea kutlo ea glutamatergic ho li-neuron tsena tse khethehileng. ΔFosB e nts'etsapele polelo ea litlolo tse bobebe tse bobebe le tse nyonyehang, le keketseho e ts'oanang ea li-synapses tse khutsitseng, ho D1 empa eseng D2 MSNs (Grueter et al., ), e fana ka maikutlo a hore ka mokhoa o hlakileng o fetola litlatsetso tsa "glutamatergic" ho tsoa ho li-neuron tse kenang ka kotloloho tseleng, ka kotloloho e hlophise moputso.

Ho PFC ea moriana, ΔFosB e kenella ka mokhoa o khethiloeng ho litoeba tse kotsing ea khatello ea khatello ea kelello ea khatello ea kelello (Vialou et al., ). Ho feta moo, khahlanong le litlamorao tsa eona tsa NAc D1 MSNs, hibFosB inhibition in mPFC neurons e khothalletsa ho tsitsipana ha khatello ea kelello, ha ΔFosB overexpression e khanna ts'oaetso, bonyane karolo e 'ngoe ka ho kenyelletsa receptor ea cholecystokinin-B (Vialou et al., ). Phello e bonahala e kopantsoe ke polelo ea ΔFosB ho li-neuron tsa mPFC tse projeke ea NAc, e totobatsa mofuta oa bohlokoa oa polelo ea ts'ehetso ea liphatsa tsa lefutso ka har'a potoloho ea moputso. Re sa tsoa tlaleha hore polelo ea ΔFosB ka hippocampus e bohlokoa mefuteng e mengata ea ho ithuta (Eagle et al., ), empa karolo ea hippocampal ΔFosB mabapi le likarabo tsa khatello ea maikutlo le mathata a ho feto-fetoha ha maikutlo, hammoho le tsa projeke ea NAc kapa PFC, e ntse e sa tsejoe.

Ntho ea karabelo ea Serum (SRF)

SRF ke ntho e hatisang e kopanang ka kotloloho ho karolo ea karabelo ea serum e fumanehang ho bahlahisi ba li-IEG tse ling tse ngata le mefuta e 'maloa e tobileng ea pelo (Knöll le Nordheim, ). Bokong ba batho ba baholo, SRF e hlokahala bakeng sa polelo-e khothalletsoang ea mofuta oa gene le polasetiki ea synaptic empa eseng bakeng sa ho pholoha ha neuronal (Ramanan et al., ). Ka tšubuhlellano ea eona ea polelo le ts'ebetso ea liprotheine tse amanang le cytoskeletal, SRF e bonahala e thusa haholo ho fetoleng mosebetsi oa synaptic hore e be liphetoho tse amanang le polasetiki tse amanang le li-circonal tsa neuronal (Knöll le Nordheim, ), e e etsa sebapali se ka bang teng lenaneong le itšetlehileng ka ts'usumetso ea mofuta oa phetoho e bakang khatello lipakeng tsa meputso Kannete, SRF e kenyellelitsoe ho NAc ea litoeba tse tiileng kamora ho sithabetsoa ke khatello ea maikutlo ea sechaba, mme e tlamahanya le FosB nts'etsopele le ho phahamisa phetisetso ea mofuta oa mofuta (Vialou et al., ). Tlhahiso ea morao-rao ea khatello ea khatello ea SRF ea ΔFosB e bohlokoa ho phenotype e sa tsitsang, mme, ho fapana le ho kenngoa ka ts'ebeliso ea koae ea ocaFosB, e bonahala e sa sebetse liketsong tsa CREB ho FosB morekisi (Vialou et al., , ).

Karabelo ea kholo ea karabelo ea pejana-1 (Egr-1)

Egr-1, e tsejoang hape ka "proteni ea menoana ea zinki" 268, ke ntho e itšetlehileng ka ts'ebeliso ea methapo ea methapo e amanang le DNA e nang le likarolo tse tharo tse ikhethileng tsa menoana ea zinc. Ho bonahala e bapala karolo ea "neuronal plasticity" (Knapska le Kaczmarek, ), mohlomong ka taelo ea eona ea polelo ea synaptobrevin II (Petersohn le Thiel, ). Egr-1 e ts'oaroa ka hippocampus ke khatello ea maikutlo, joalo ka ho sututsoa ka likhoto, ka ts'ebetso ea ts'ebetso e rarahaneng ea "epigenetic" e tsoang ho hationocampal glucocorticoid receptor (GR) (e akaretsitsoeng ho Reul, ). MAPK e tšoaeang ho theoha hoa noka ea GRs e khanna tšebetso ea MSK1 le Elk-1, tsela e boetse e nyoloha ka CREB le c-fos induction. Sena se rata phosphorylation ea Ser10 le acyslation ea Lys14 ea morekisi oa mofuta oa Erg-3, e lebisang ho ts'ebelisanong ea chromatin, liphetoho liphatseng tsa methapo ea DNA, le polelo ea Erg-1 (Gutièrrez-Mecinas et al., ; Saunderson et al., ). Tšusumetso ena e lula matsatsi a bonyane bokong, 'me e kanna ea ikarabella bakeng sa likarabo tse fetotsoeng tsa ho sesa tse qobelloang, mohlomong tse bakang khatello ea maikutlo e telele ea nako e telele, letšoao la mathata a ho feto-fetoha ha maikutlo. Ka 'nete, polelo ea Egr-1 e fokotsehile ho bobeli hippocampus le PFC ka karohano ea sechaba (Ieraci et al., ), ho supa hore e ka kenya letsoho phetohong ea maikutlo a nako e telele ka lebaka la khatello ea maikutlo e telele. Nakong e tlang, ho tla ba bohlokoa ho tseba hore na litlamorao tsa polelo ea Egr-1 ho hippocampus li etsahala ka lebaka la phetoho ea lipalo tsa hippocampal ho ea kapa ho tsoa likarolong tse ling tsa moputso, tse kang NAc.

Egr-3, e ikopantseng le Egr-1 hape e hlohlellelitsoeng ka mokhoa o itšetlehileng ka ts'ebetso, e sa tsoa ameha ho mathata a mangata a maikutlo. Lipheo tse ngata tsa Egr-3 li kenyelletsa Arc (Li et al., ), e tšohliloeng ka tlase, hammoho le NMDA le GABA receptor subunits (Roberts et al., ; Kim et al., ), ho fana ka maikutlo a hore e ka kenya letsoho ho thabiseng / inhibitory balance in circry moputso. Lithuto tsa pele tse sebelisang SNPs ho mofuta oa Egr-3 li fumane setsoalle se ka amanang le lefu la ho feto-fetoha ha bana (Gallitano et al., ). Phuputso ea morao-rao e sebelisitse data e kholo ea li-microarray mme e fumane hore Erg-3 e ka bapala karolo ea bohlokoa ho hatseng ha marang-rang a likhatiso tsa PFC ho bakuli ba nang le khatello ea maikutlo ea phefumoloho (Pfaffenseller et al., ). Ho feta moo, lithuto tsa litoeba li bontša hore Egr-3 e ka ba le litla-morao tsa li-clozapine ho phekoleng matšoao a psychosis le a bipolar (Gallitano-Mendel et al., ; Williams et al., ), ho fana ka tlhahiso ea hore thuto e tsoelang pele ea Egr-3 e ka fana ka leseli la bohlokoa ho etiology ea merusu ea maikutlo.

NPAS4

Neuronal PAS domain protein 4, kapa NPAS4, ke karolo e ts'ehetsang ea ho ngola e hlahisoang feela ke li-neurons. Hoa hlokahala bakeng sa nts'etsopele e tloaelehileng ea li-interneurons tsa inhibitory hammoho le polasetiki ea neuronal ho arabela boiphihlelo (Lin et al., ; Ploski et al., ; Ramamoorthi et al., ; Sim et al., ). Kaha NPAS4 e kenngoa ka har'a li-neurons tsa thabo le tse thibelang mme e qala li-cascade tse ikhethang mofuteng o mong le o mong oa sele (Spiegel et al., ), ho nahanoa hore e laola tekano ea thabo le lithibelo kahare ho lipotoloho (Bloodgood et al., ). Lits'oaetso tse tlase tsa NPAS4 tse khethiloeng li kenyelletsa li-neurotrophic factor (BDNF) li-neurons tse hlasimollang, le FERM le PDZ domain e nang le protheine ea 3 (Frmpd3) ho li-neurons tsa inhibitory (Spiegel et al., ).

Ho HPC, tlhahiso ea NPAS4 ka liprothokhone ka bobeli tsa testaptic le pherekano e hloka litsela tsa MAPK le PI3K (Coba et al., ), ho fana ka tlhahiso ea khokahano ea ts'ebetso ea li-IEG tse ling, joalo ka CREB. Khatello ea kelello e kenella ka ho toba ts'ebetsong ea NPAS4, joalo ka ha agonist e tlameletsoeng glucocorticoid receptor e tlama ho morekisi oa NPAS4 ho theola polelo ea eona nakong ea khatello ea maikutlo (Furukawa-Hibi et al., ). Kamora khatello ea maikutlo e sa feleng, NPAS4 mRNA e fokotsehile haholo ho litoeba tsa hippocampus ea bana, mme bana ba banyenyane ba nang le bothata ba NPAS4 ba ile ba holisa bofokoli ba kelello ba ho ba motho e moholo (Ibi et al., ;; Yun et al., ; Coutellier et al., ). Liphetoho tsena tsa nako e telele li ka hlaha ka molao oa epigenetic, joalo ka ha morekisi oa NPAS4 a le lihlekehleke tse 'maloa tsa CpG,' me khatello ea maikutlo e eketsa methylation libakeng tsena (Furukawa-Hibi et al., ). Likokoana-hloko tse 'maloa tsa liphoofolo, ho kenyelletsa le likhoto tsa SERT tsa ho kokota le Flinders Sensitive Line, li bontšitse khokahano lipakeng tsa polelo e tlase ea NPAS4, boits'oaro bo nyenyefatsang, le ho hanyetsa khatello ea maikutlo (Guidotti et al., ; Bigio et al., ). Boholo ba mosebetsi ona o entsoe HPC, 'me ho hlokahala lithuto tse ling ho supa karolo ea NPAS4 ho NAc le libakeng tse ling tsa meputso maemong a mefuta e tšoanang ea khatello ea maikutlo. Ho feta moo, NPAS4 e ngolisitsoe ho NAc kamora ho pepesetsoa lithethefatsi tsa tlhekefetso (Guo et al., ), empa karolo ea likarabo tsa lithethefatsi kapa boits'oaro bo tlase e ntse e sa tsejoe.

Protheine e amanang le tšebetso ea cytoskeleton-Arc

Arc ke protheine e feto-fetohang, modular, multidomain e sebelisanang le balekane ba bangata (Myrum et al., ; Zhang et al., ). Ka litšebelisano tsena, Arc e sebeletsa ho boloka phosphorylation ea actin depolymerization factor cofilin, e boloka sebopeho sa eona se sa sebetseng, mme ka hona e rata polymerization ea actin (Messaoudi et al., ). Ka mokhoa ona, Arc e khothaletsa ho kenngoa ha methapo ea methapo e mosesaane, e sa sebetseng, mosebetsi o arolelanoang le ΔFosB (bona ka holimo). Habohlokoa, Arc e boetse e fumaneha tikolohong ea posynaptic density moo e phethang karolo ea bohlokoa ho tsebisa li-receptors tsa AMPA (Chowdhury et al., ) hape e khothaletsa sebopeho sa methapo e sa sebetseng ea dendritic (Peebles et al., ) le khatello ea maikutlo e telele (LTD; Bramham et al., ).

Bopaki ba morao-rao bo bonts'a hore polelo ea Arc le ts'ebetso e kanna ea khangoa le likarolo tse ngata tsa khatello ea maikutlo. Mefuteng e fapaneng ea litekanyo le lipanya, Arc e lula e ts'oaroa hohle cortex le hippocampus ka khatello e matla ea maikutlo, empa e kanna ea ba ea holimo kapa ea tlase-ea laoloa ke khatello ea maikutlo e sa foleng ho latela paradigm (Elizalde et al., ; Molteni et al., ; Boulle et al., ). Ntle le moo, boholo ba lithuto bo fana ka maikutlo a hore phekolo e sa foleng ea antidepressant e baka polelo ea Arc ho pholletsa le centex le hippocampus, le khatello ea maikutlo ea Arc likarolong tse ikhethang tsa boko e bonahala e bolela litlamorao tse tlang tsa khatello ea maikutlo mosebetsing o akaretsang (kakaretso ka Li et al. , ). Kahoo, ho bonahala ho ka etsahala hore khatello ea maikutlo kapa e hlohlontšang litsebe Arc e kanna ea ba bohlokoa bakeng sa ho nchafatsa lipapatso tsa potoloho ea meputso, mohlomong litlatsetsong tsa glutamatergic ho NAc kapa khokahano lipakeng tsa libaka tse ling tsa cortical le basal-ganglia, empa ho tla hlokahala lipatlisiso tse ling ho fumana hore na ehlile tlatsetso ea polelo ea Arc ho likarabo tsa khatello ea maikutlo le mathata a maikutlo.

Homer1a

Liprotheine tsa Homer1 li sebetsa ka ho khetheha e le li-scaffolds tse sebelisang ho sebetsana le liprotheine tse ling tsa neuronal, ho kenyelletsa le li-receptor tsa metabotropic glutamate (mohlala, mGluR1 le mGluR5), IP3 li-receptors, Shank le ba bang. Mefuta e mokhuts'oane ea splice ea Homer1, Homer1a, e susumetsoa ke ts'ebetso ea methapo 'me e sebetsa e le ntho e mpe haholo ho thibela ts'ebelisano ea nako e telele, e sebetsang ka bongata ea li-splice (Homer1b le Homer1c) ka ligands tsa bona tse tloaelehileng ka tlholisano bakeng sa libaka tsa binding tsa EVH1. Mohlala, Homer1a e bonts'itsoe ho li-receptors tsa mGluR tse sa hlabolohang ho tsoa ho lets'ollo le tlase (Tu et al., ) hammoho le ho baka ho fokotseha ha boholo le botenya ba methapo ea methapo (Sala et al., ) ka thibelo ea Shank e tobileng ho li-synapses. The Homer1 gene e na le tšusumetso ho pathogenesis ea khatello ea maikutlo e kholo ka setsoalle se akaretsang hammoho le lithuto tsa neuroimaging (Rietschel et al., ). Ka mokhoa o pheta-phetoang oa ho sutumetsa oa pompo ea khatello ea maikutlo, Homer1a e fokotseha ka cortex, mme sena se khutlisoa ke ho pepesetsoa ha antidepressant (Sun et al., ). Ho khahlisang, Homer1b le 1c li qobelloa ho HPC ke khatello ea khatello ea maemo a bophelo (Wagner et al., ), le ho eketsa maemo a bona ka tekanyo ea Homer1a ho ka sebetsa e le mochine oa ho inchafatsa. Lebaka ke hobane overexpression ea Homer1a ho HPC ea mouse e khothaletsa likhatello tsa khatello ea taolo ea sechaba, ka liphoofolo tse nang le khatello e matla li bonts'a ho eketseha ha boitšepo le boits'oaro bo sa sebetseng ba ho sebetsana le boemo bona (Wagner et al., ). Ho li-accumbens, Homer1a e susumetsoa ke li-antipsychotic tse sebetsang ho dopamine receptors (e hlahlojoe ho Iasevoli et al., ), empa karolo e 'ngoe le e' ngoe ea Homer1a ho likarabo tsa boitšoaro bo kopaneng ba khatello ea maikutlo le lithethefatsi tsa tlhekefetso e ntse e sa senoloe.

Lipotso tse ikhethang le mekhoa e tlang

Leha re na le bopaki bo bokelletsoeng ba ho kenella ha IEG ka har'a meputso ea potoloho ka mefuta ea litoeba le bakuli ba nang le mathata a maikutlo, re ntse re sa utloisise ka botlalo monehelo oa li-IEG ho putsa ts'ebetso ea potoloho le boits'oaro ba mafu. Mohato o boima oa ho latela ke ho lebisa li-IEG lipotolohong tse itseng tsa methapo. Mokhoa o joalo o bile thata ho sebelisoa mekhoa ea khale, empa tsoelo-pele ea morao-rao ea ho beha lisele le ho sebetsana le lisele le potoloho e fana ka menyetla e khahlisang ea ho araba lipotso tse bohlokoa tse hlahelletseng.

Na ho na le likarolo tse ikhethang tsa li-IEG ka li-subtypes tse ikhethang tsa neuronal?

Na li-IEG li etsa mesebetsi e tšoanang mefuteng eohle ea lisele tsa neuronal? Hobane li-IEG tse ling li qhekelletsoa hanyane hanyane ha li bapisoa le ba bang (mohlala, NPAS4), bohlokoa ba polelo ea IEG ho mathata a ho feto-fetoha ha maikutlo bo ka amana le tlhahiso ea bona maemong a ikhethang a sele. Lithane tsa "mouse" tsa "Transgenic" tse lumellang hore ho sebelisoe li-overexpression kapa li-IEG tse sebelisang li-neuron tse hlahisang li-neurotransmitters tse itseng (ke hore, DAT-Cre kapa GAD-Cre) kapa li-receptors tse ikhethang (ke hore, D1-Cre kapa D2-Cre) e tla ba sesebelisoa sa bohlokoa lithutong tsa kamoso. . Ntle le moo, ho kopanya mela ena le li-veine tsa vaerase tse itšetlehileng ka mofuta oa K'honthinente ho tla sebetsana le karolo ea li-IEG ho li-subtypes tsa motho ka mong tsa neuronal ka ho ikamahanya le maemo le sebaka sa nakoana.

Karolo ea li-IEG ke efe makaleng a ikhethang a boko?

Le ha li-IEG li ka etsoa ts'ebetsong libakeng tse ngata tsa boko ho arabela khatello ea maikutlo kapa lithethefatsi, ho tšoaneleha ha tsona makaleng a potolohileng bokhoba ba ho lemalla le ho tepella maikutlong ha ho utloisisehe ka botlalo. Ho lekola monehelo oa li-IEG tse kenelletseng kahare ho mesolimbic le cortical circry ho ts'ebetso ea lisele le boits'oarong ba liphoofolo, mekhoa ea li-veterback ea vaerase e tla ba bohlokoa haholo. Mohlala, ka ho kopanya vaerase ea morao-rao e hlalosang Kiri e kentsoeng sebakeng se lebelletsoeng joalo ka NAc e nang le vaerase e hlalosang ka mokhoa o fetisang IEG ea phaello ka mokhoa o ts'ehetsang oa Cre o kenngoe kahare ho HPC, motho a ka lekanya litlamorao tsa IEG ts'ebetsong ea li-neurons tsa HPC tse hlahelletseng ho NAc, le boitšoaro bo latelang ba phoofolo (Setšoantšo (Figure3A) .3A). Ntle le moo, ka ho kopanya polelo ea morao-rao ea enzyme ea Cas9 le polelo ea lehae ea tataiso RNA, CRISPR-mediated editing ea IEG e ka sebelisoa ho tseba karolo ea eona e ikhethang ea potoloho (Setšoantšo. (Figure3B), 3B), mokhoa o hajoale o lekiloeng ke sehlopha sa rona le ba bang. Ho joalo, mekhoa ena e ka kopantsoe le mela ea transgenic Cre e hlalositsoeng ka holimo ho lumella mofuta oa sele 'me mananeo a ikhethileng a potolohileng li-IEG, mehato ea bohlokoa bakeng sa kutloisiso ea rona ea karolo ea bona ho pathophysiology ea lefu la mafu a kelello.

Setšoantšo sa 3  

Mekhoa e ka khonehang ea ho hlongoa lipotso ka ho khetheha mabapi le ts'ebetso ea IEG. (A) Schematic e bonts'ang motsoako oa vaerase ea retrograde Cre (botala) e kentsoeng sebakeng se tšoailoeng joalo ka NAc e nang le vaerase ea lehae e bonts'a IEG ka mokhoa o ts'epahalang oa Cre ...

Lipheo tsa gene tsa li-IEG ka mefuta e ikhethang ea lisele le lipotoloho ke li fe?

Le ha ho le bohlokoa ho utloisisa likarolo tsa li-IEG ka mefuta e ikhethileng ea lisele, li-envirles tsa neuronal le li-circuits tse ikhethang, li-IEG tse ngata li etsa lipheo tse sa rateheng tsa kalafo bakeng sa kalafo ea mafu a mafu a kelello, kaha hangata li bapala likarolo tsa bohlokoa libakeng tse sa amanang le lefu la lisele le tse ling. lisele. Leha ho le joalo, ho senola liphofu tsa liphatsa tsa lefutso tsa IEG, joalo ka liprotheine tsa lelapa la Fos kapa NPAS4, ho ka senola babuelli ba liphatlalatso tse matla tsa pathophysiology tse sebetsang ka ho fetesisa ho tsa meriana. Khatelo-pele e ncha ho profeseng ea gene, joalo ka ho fetolela tlhoekiso ea tumellano ea ribosomal (TRAP; Heiman et al., ), li fetoha ka mokhoa o lekaneng 'me li matla haholo hore li sebelisoe ho mekhoa e ikhethileng ea ho phela ka sele le ka potoloho e hlalositsoeng kaholimo (Lobo, ; McCullough et al., ), hape e etelletsoe pele hore e sebelisoe ha ho buuoa ka mekhoa e ikhethileng ea mofuta oa Cre (Sakurai et al., ). Ho sebelisa mela ea litlaelese e itšetlehileng ka mohala oa "CFP" e amanang le li-virus tsa mofuta oa GFP, hammoho le li-virus tsa mofuta oa "re" (Figure3C) .3C). Ho kopanya mokhoa o joalo le litoeba tse koaelitsoeng bakeng sa IEG e itseng o tla lumella tlhahlobo ea tlhahiso ea IEG ho polelo ea gene e ikhethang maemong a khatello kapa lithethefatsi. Re bolela esale pele hore mekhoa e joalo e tla senola lihlahisoa tsa mofuta oa gene tse tlasa khatello ea maikutlo kapa tšebeliso ea lithethefatsi tse ka fihlellang liphekolo tsa meriana ka litlhare.

Nahanisisa

Ho hlakile hore ho pepeseha liketsahalong tse sithabetsang bophelong ho eketsa menyetla ea mathata a ho feto-fetoha ha maikutlo, 'me lithuto tse ngata tsa tlhaiso-leseling tsa morao-rao tse boletsoeng mona li fana ka maikutlo a hore sena se ka hlaha karolo e' ngoe ho tsoa ho ho nchafatsoa ke khatello ea moputso ho tsamaisoa ke polelo ea IEG. Bakeng sa tse ling tsa li-IEG tsena, joalo ka CREB, Homer1a, le ΔFosB, bopaki bo ata bakeng sa likarolo tsa bona maikutlong a khatello ea maikutlo, likarolo tse ngata tsa mathata a ho feto-fetoha ha maikutlo, tšebeliso ea lithethefatsi, esita le kalafo ea khatello ea maikutlo, 'me joale phephetso ke ho kopanya mesebetsi ea bona libakeng tsohle tsa boko. le mefuta ea lisele tse amehang le ho bonts'a liphofu tsa bona tse tlase-tlase molemong oa ho sibolla liphofu tse fumanehang tsa lithethefatsi. Bakeng sa li-IEG tse ling, joalo ka Egr-1, NPAS4, le Arc, ho kenella ha tsona ka khatello ho ba etsa li-molecule tsa thahasello lipatlisisong tsa maikutlo a feto-fetohang maikutlo, empa ho hokahana ha lebaka le boits'oaro bo amanang le khatello ea maikutlo ha ho so fumanoe, mme ba tsoela pele ho ithuta ka karolo ea bona ho moputso mosebetsi oa potoloho ea hlokahala. Maemong kaofela, ho hlakile hore ho fokotsa khatello ea maikutlo ka mokelikeli oa meputso, haholo litheko tsa NAC, ke karolo ea bohlokoa katolosong ea khatello ea maikutlo le litabatabelo tse amanang le bokhoba, le hore li-IEG li bapala karolo ea bohlokoa ho Ts'ebetso ena ebile e ka fana ka tsela ea methapo ea limolek'hule, sele, le potoloho ea methapo ea kutlo ea maikutlo le phekolo.

Menehelo ea Mongoli

CM, EW, le AR ba entseng lipatlisiso, ba ngola, 'me ba e hlophisa.

dithuso tsa ditjhelete

Mosebetsi ona o tšehelitsoe ka likhau ho tsoa ho National Institute of Mental Health (1R01MH111604-01) le Whitehall Foundation (2013-08-43).

Khohlano ea polelo ea thahasello

Bangoli ba bolela hore lipatlisiso li ne li etsoa ka ho se be le likamano leha e le life tsa khoebo kapa tsa lichelete tse ka nkoang e le khohlano e ka 'nang ea e-ba le thahasello.

Notes

Pampiri ena e ne e tšehelitsoe ke lithuso tse latelang:

Setsi sa Sechaba sa Bophelo ba kelello10.13039/100000025 1R01MH111604-01.
Whitehall Foundation10.13039/100001391 2013-08-43.

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