Tlhoko ea kliniki ea methapo ea methapo ea methapo ea methapo ea corticostriatal nakong ea thuto e sebetsang (2013)

Neurosci Biobehav Rev. Mongoli o ngotsoeng ka letsoho; e fumanehang ho PMC 2014 Nov 1.

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Dopamine le glutamate sebeletsa mesebetsi ea bohlokoa ho neural polasetiki, ho ithuta le ho hopola, le ho lemalla. Likhopolo tsa sejoale-joale li hanana le hore li-system tsena tse peli, tse abeloang haholo li bapala karolo ea bohlokoa ts'ebetsong ea tlhahiso-leseling e susumetsang le e kopanyang. Pontšo e kopantsoeng ea lits'ebetso tsena, haholo-holo ka dopamine (DA) D1 le glutamate (Glu) N-methyl-D-aspartate receptors (NMDAR), e tsosa likhakanyo tsa bohlokoa tsa "intracellular signaling" tse lebisang phetohong ea sebopeho sa chromatin, polelo ea mofuta, polasetiki ea synaptic, mme qetellong boits'oaro. Lithethefatsi tse tlatsetsang li boetse li kenya li-neuroadaptations tsa nako e telele maemong a limolek'hule le genomic tse bakang liphetoho tse hlophisitsoeng tse fetolang khokahano ea mantlha. Ho joalo, bopaki ba hore lithethefatsi tsa tlhekefetso li kenyelletsa li-cascade tsa neuronal tsa D1- le NMDA-mediated tse arolelanoang le thuto e tloaelehileng ea moputso e fana ka leseli la bohlokoahali ho tsoa lithutong tsa mehleng ena ho neurobiology ea ho lemalla. Li-neuroadaptations tse joalo tse bakoang ke lithethefatsi li ka ba tsa tlatsetsa ts'ebetsong e sa tloaelehang ea tlhahisoleseling le boits'oaro, tsa fella ka ho etsa liqeto tse fosahetseng, tahlehelo ea taolo, le ho qobelloa ho tsebahalang ho lemalla. Likarolo tse joalo li boetse li tloaelehile ho mafu a mang a mangata a neuropsychiatric. Mathata a boitšoaro, a hlahisoa e le mathata a amanang le ho ithuta le boitšoaro ba mosebeletsi, a hlahisa liphephetso tse matla le menyetla e ikhethang ea kalafo e hlokang ho ithutoa hape. Tlhahlobo ea hajoale e totobatsa mosebetsi o kopantseng Ann Ann Kelley le basebetsi mmoho, ba bonts'a karolo e bohlokoa eseng feela bakeng sa NMDAR, D1 receptors (D1R), le li-Cascade tse amanang le tsona, empa hape le li-receptor tse ling tsa Glu le protheine ea mantlha ho ithuteng mosebeletsi ho pholletsa le cortico-striatal-limbic network. Mosebetsi oa morao-rao o atolositse phello ea ho ithuta ho khotsofatsang ho li-epigenetic process. Kutloisiso e ntlafalitsoeng ea lits'ebetso tsena e kanna ea thusa ho sibolla mekhoa ea kalafo ho kenya tšebetsong maano a amanang le neural le ho khothaletsa boits'oaro bo sebetsang.

Ho ithuta ka ts'ebetso ke e 'ngoe ea mekhoa ea mantlha ea boits'oaro.Rescorla, 1994). Ka ho feto-fetoha le tikoloho ea eona, phoofolo e khona ho ithuta ka litlamorao tsa liketso tsa eona, 'me ka hona e fetole tikoloho ea hona joale ka boits'oaro bo bocha ho hlahisa maemo a matle haholoanyane (Skinner, 1953). Phetoho e hlahisitsoeng ke boitšoaro e makatsa ebile e nka nako e telele. Litsebi tse ling li pheha khang ea hore ho ithuta ka mokhoa o sebetsang ke motheo oa "tsebo" (Schnaitter, 1987), e ka tlisoa ke "popo"Pryor et al., 1969), ke motheo oa ho nka liqeto, 'me e kenya letsoho molemong oa ho lemalla lithethefatsi. Ha boitšoaro ba setho bo fetoha ke maemo a phello ea karabelo, mekhoa ea 'mele e kengoa tšebetsong e netefatsang hore liphetoho tsena li batla li tšoarella; ba "patiloe ka har'a," joalo ka Thorndike hypothesized (Thorndike, 1911). Le Skinner o ratile hore maemo a sephetho sa karabelo a re fetola: "Batho ba sebetsa holim'a lefatše, 'me ba le fetola,' me ba fetohile ka lebaka la litholoana tsa ketso tsa bona. ”(Skinner, 1957, leq. 1).

Ka lebaka la boteng ba likamano tse sebetsang tsa boits'oaro bophelong ba rona ba kelello, methapo ea methapo ea thuto e sebetsang (ke hore, ho fumana karabelo ea pele) e fumane tlhokomelo e nyane ha ho bapisoa le lits'ebetso tse ling tsa mantlha tsa ho ithuta joalo ka ho ithuta ka sebaka (mohlala, Morris Maze ea Metsi) kapa boemo ba tšabo ba Pavlovia. Leha ho le joalo, likamano tsa basebetsi li nahanoa hore li sebetsa hoo e ka bang motsotso o mong le o mong oa bophelo ba rona le maemong a mangata a hlahelletseng a lefu la methapo: tšebeliso e mpe ea lithethefatsi, autism, le a mang mathata a mabe a boitšoaro. Tlhahlobisong ena, re totobatsa lilemo tse mashome a mabeli tse fetileng tsa mosebetsi oa lipatlisiso oa Ann Kelley, ha a ne a latela kutloisiso e kholo ea methapo ea kutlo ea thuto e sebetsang ka ts'epo ea hore limolek'hule, lisele le genomic tsa thuto e sebetsang, tse kentsoeng marang-rang a abuoang, li tla tsebisa mekhoa e meng e betere ea kalafo.

Mathata a boits'oaro a bophelo bo botle le boits'ebetso

Ts'ebeliso e mpe ea lithethefatsi ke e 'ngoe ea mathata a kotsi ka ho fetisisa a bophelo bo botle le a theko e boima haholo ho la Amerika, mme ka nnete le lefats'e. Ts'ebeliso e mpe ea lithethefatsi naheng ena feela e ja chelete e hakanyetsoang ea $ 484 bilione selemo le selemo ho mathata a amanang le bophelo bo botle, likotsi, mosebetsi o lahlehileng le litefiso tsa inshorense (Leano, 2001). Ho boetse ho hakanngoa hore selemo le selemo batho ba 540,000 ba shoa mafu a amanang le lithethefatsi. Likhakanyo tsena ha li kenyeletse litšenyehelo tsa kelello tse sa lefelloeng chelete kapa tse sa lefelloeng ke batsoali1, balekane, banab'eso, metsoalle, le sechaba sa rona ka kakaretso. Ho ka etsahala hore moahi e mong le e mong sechabeng sena a angoe hampe ke ts'ebeliso e mpe ea lithethefatsi le bokhoba ba hae ka tsela e itseng (mohlala, joalo ka lehlatsipa la boitšoaro ba botlokotsebe, kotsi ea koloi, kapa ka liketso tsa setho sa lelapa). Bokhoba ba lithethefatsi bo ntse bo shebeloa khafetsa mabapi le liphetoho tsa mantlha mekhoeng ea boitšoaro le boits'oaro, ka ho hatella ho amanang le tlolo ea tlhabollo ea liphetoho taolong ea methapo ea kutlo litabeng tsa liqeto le maikutlo-khokahano (Everitt et al., 2001). Kahoo, kutlwisiso e betere ea lits'ebetso tsa ho ithuta tse sebetsang li ka ntlafatsa kutloisiso ea rona ea neural causation ea ho lemalla.

Ho latela Centers for Disease Control (CDC), 1 ho bana ba 88 e fumanoe e le Autism (Taolo, 2012). Mathata a Autism (ASDs) a ama batho ba merabe eohle le maemo a moruo. Li-ASD li ka fokolisa haholo 'me mohlomong li hloka tlhokomelo ea bophelo bohle ka litšenyehelo tse kholo ho sechaba (> $ 3,000,000 ka motho ka mong) (Ganz, 2007). Haufinyane tjena, tlhahlobo ea boitšoaro e sebelisitsoeng (WA) le lintlha tse tsoang ho eona (mohlala, Mohlala oa Denver Start), e hatisang boits'oaro bo matla ba maemo a thuto, a sechaba le a puisano, a bontšitse hore meputso e makatsang e ka khonahala ka kalafo ea pele, e matla (Sallows le Graupner, 2005, Dawson et al., 2010, Warren et al., 2011). Mefuta ena e atlehile hoo bana ba bangata ba fumanoeng ba na le li-ASD hamorao ba bitsoang "ba sa tsebe letho" ho lithaka tsa bona. Ba bang ba hakanya hore 40-50% ea bana ba fumanoeng ba e-na le lefu la Autism ba na le bothata bo felletseng (McEachin et al., 1993). Ntle le moo, katleho e makatsang ea kalafo ea WA kalafong ea kalafo ea autism e lebisitse khopolong e akaretsang ea hore e amana le kalafo ea autism (Dillenburger le Keenan, 2009), haholo ho khopisa litsebi, ho bolela tse 'maloa, tsa taolo ea boitšoaro bo hlophisitsoeng (OBM), tlhahlobo ea boits'oaro ba kliniki, le koetliso ea liphoofolo; Litsebi tse sebelisang tlhahlobo ea boitšoaro li sebelisoa maemong eseng e amanang le Autism. Ho khahlisang mona ke taba ea hore melao-motheo e mengata ea WA e thehiloe khopolong ea tšebeliso ea sejoale-joale le tlhahlobo ea liteko ea boitšoaro: ho lekola ts'ebetso e ka etsahalang, ho supa mesebetsi ea bohlokoa ea boits'oaro bo fosahetseng, ho tiisa boitšoaro bo botle, ho otla boitšoaro bo sa batleheng, le ho lekola likamano tsena ka boemo bo boholo ba moruo le sechaba (mohlala, moruo oa boitšoaro). Karolong ea bona ea semina ka WA, Baer, ​​Wolf le Risley (1968) ba thehile kamano e hlakileng pakeng tsa mohopolo oa "trademtual system" ea WA, leha ho le joalo ka tlhahlobo e felletseng ea pampiri eo ho feta tekolo ea tlhahlobo ena ea hajoale. Kahoo, hobane thuto ea kelello ea li-ASD e shebiloe haholo joalo ka neuro-genetic, mme ka lebaka la karolo e totobetseng e sebetsang e bapala ho ithuta le kalafo ea vis-à-vis ASDs, kutlwisiso e kholo ea "neurobiology" ea ts'ebetso ea ts'ebetso e ka thusa ho nahana ha rona ka Li-ASD.

Poleloana e reng, "ho ba le mathata a tebileng" e akaretsa lintlha tse ngata tse fapaneng ho tloha ho bo-'mampoli ba bang sekolong ho ea ho intša kotsi haholo. Boitšoaro bo boholo ba boits'oaro bo ka bontšoa ke bana ba tloaetseng ho hola, empa bo atile haholo baneng ba nang le bokooa bo holang le / kapa ba kelello. Boitšoaro bo boholo ba boits'oaro bo baka litšitiso tse ngata sechabeng le thutong bakeng sa batho ka bomong ka lebaka la matla a bona le ho bonahala e le ntho e sa reroang. Phekolo e ka kenyelletsa ho emisoa ho tsoa sekolong, ho beoa libakeng tse ikhethang, ho kenya ts'ebetsong tsamaiso ea toka ea botlokotsebe, ho kenngoa chankaneng kapa ho kenngwa tšebetsong. Sebakeng sa ho nka lits'oants'o tsena e le "hampe" kapa "ho sa lokelang," litsebi tsa kelello le matichere joale ba nka boits'oaro bona ba mathata bo sebetsa. Ka mantsoe a mang, ha ho nkoa e le boitšoaro ba ts'ebetso, ts'ebetso e matlafatsang e khothalletsang mathata ana a boitšoaro bo matla e ka khethoa, ea hlahlojoa mme ea fetoloa. Ka lebaka la kotsi ea mathata ana le ho kenella ha mathata a amanang le ho ruruha, batho ba bangata ba ipeha maemong a thata kapa a sa sebetseng a bophelo kapa maemo a ho hloka kalafo. Monyetla oa hore mathata ana a tebileng a hlaha ka ho kopana ha tikoloho ea liphatsa tsa lefutso o se o ntse o nahanoa ka botebo. Kutloisiso e ntlafalitsoeng ea neurobiology ea ts'ebetso ea ts'ebetso e ka ntlafatsa mekhoa e meng ea kalafo.

Mekhoa ea polasetiki ea neural ka liphetoho tsa boitšoaro bo tšoarellang nako e telele

Hona joale ho amoheloe hantle hore liphetoho tse sa feleng tsa boits'oaro ka maemo a ts'ebetso ke lisosa tsa liphetoho tse kholo bokong: ho matlafatsoa ha likhokahano tsa synaptic, ho hlophisoa bocha ha li-enuralles, tlhahiso ea liprotheine tse ncha, ntlafatso ea polelo ea gene, le liphetoho tsa epigenetic. . Potentiation ea nako e telele (LTP) e sebelitse e le e 'ngoe ea li-systemity tse amanang khafetsa tse amanang le polasetiki le datha e kenyang ts'ebetso ea NMDAR ka matla e le ketsahalo ea bohlokoa ea ho qala. Ka mantsoe a mang, mekhoa e phahameng ea maqhubu ea matla a phetoho ea synaptic e hlahisang NMDAR e hlahisang tšubuhlellano ea Ca2+, le eona e kenya tšebetsong mekhoa e mengata ea ho saena, e 'maloa e tlohang ho ERK (extracellular Receptor signaling Kinase). ERK e nahanoa hore e laola lintlha tse fapaneng tsa mongolo tse tsamaisang sebopeho le botsitso tsa memori ea nako e telele (Levenson et al., 2004). Ho na le datha e kholo e netefatsang karolo ea NMDAR-Ca2+K'haonte -ERK papaling ea phetoho ea boits'oaro bo tšoarellang le sebopeho sa memori maemong a ts'abo le ho ithuta ha Morris Water Maze (Atkins et al., 1998, Blum et al., 1999, Schafe et al., 2000); Tlaleho ea morao-rao e beha papali ea bohlasoa maemong a putsa a lijo, le ha e le ka mokhoa oa ho hloka toka (Ribeiro et al., 2005). NMDAR e kentsoeng ka polasetiki ea NMDAR, ka melaoana e hatisitsoeng ka tsela ea ERK, ka hona, e fana ka pontšo ea neural ea boemo ba ts'ebetso le mohlala o motle oa ho ithuta phetoho ea boitšoaro bo tšoarellang.

Kaholo ea mofuta ona ka kotloloho, Kelley le basebetsi mmoho (Kelley et al., 1997) e qalile e lekola karolo ea ts'ebetso ea NMDAR ho ho ithuta ho sebetsang ka har'a likarolo tsa nucleus, sebaka se hokahantsoeng ho bapala karolo e kholo ho kopantseng litaba tse matla tsa moputso, moputso le koloi. Kamora ho lula ntlong e tloaelehileng ea likamore tse sebetsanang le lithupelo tsa limakasine, liente tsa NMDAR antagonist (+/-) - 2-amino-5-phosphonopentanoic acid (AP-5) li ile tsa etsoa ka kotlolloho ka har'a nucleus accumbens core (NAc) ea lijo tse thibetsoeng lijo. likhoto kapele pele ho likarolo tse 'ne tsa pele, metsotso ea 15 e telele, e sebetsang. Ka sehokelo se kentsoeng ka phapusing, likhatiso li ile tsa matlafatsoa ka lipentšele tsa sucrose2. Nako eohle lithupelong tsa 4 tsa pele, litoeba tse tšoaroang ka AP-5 li entse mechine e menyenyane ea lever, ho fapana le likhoto tse tsamaisoang ke koloi. Likhoto tsohle li ile tsa tloheloa li sa phekoloe bakeng sa likarolo tse latelang tsa 5 mme lihlopha ka bobeli li ile tsa fihla kapele maemong a asymptotic a lever-Press. Habohlokoa, microinjection ea AP-5 ho NAc pele ho 10th Seboka se ne se se na litlamorao. Liteko tse arohaneng ha lia ka tsa fumana phello ea AP-5 mabapi le ho itšunya-tšunya, ho ja ka mokhoa o se nang meeli le boits'oaro ba makoloi ho kalafo e ts'oanang (mohlala, ho buoa, ho hloka, joalo-joalo) likhoto. Ka hona, ha ho bapisoa le saline-infusions, infusions ea AP-5 / NMDAR ho thuto ea mathomo e sebetsitseng ea NAC e senyehile, empa ha e na ts'ebetso ho ts'ebetsong e ileng ea latela, kapa NMDAR blockade ha e ame tšusumetso ea boits'oaro ba sucrose kapa boits'oaro bo ikemetseng. Kahoo, datha tsena li bonahala li lumellana le tumellano e akaretsang ea hore ts'ebetso ea NMDAR e bohlokoa bakeng sa ho ithuta ka karolo ea eona ho li-neural plasticity.

Lithuto tsena, tse entsoeng laboratoring ea Ann Kelley, ke tsona tsa pele tse bonts'ang karolo bakeng sa li-receptor tsa NMDA ho ithuteng ka har'a ts'ebetso ea senotlolo sa marang-rang a cortico-limbic-striatal. Hernandez et al (Hernandez et al., 2005) ka ho pheta-pheta phello ena, 'me, ho fapana le hoo, e bonts'itse karolo e lekanyelitsoeng ea nako ea ts'ebetso ea NMDAR ho ithuteng mochini bakeng sa thuto ea morao-rao ea AP-5 ha e na phello ea ho ithuta. Ka mantsoe a mang, ts'ebetso ea NMDAR nakong ea ho pepesehela kamoreng le maemo a ts'ohanyetso a ts'ebetso e ne e hlokahala hore ho ithute ho etsahala empa ho sa hlokahale kamora thuto. Ho fumana hona ho fapana le litlamorao tsa lithethefatsi tsa kamora 'seboka litokisetsong tse ling tsa boitsoaro, joalo ka boemo ba tšabo (Castellano et al., 1993). Kelley et al. (Kelley et al., 1997) e boetse e bonts'itse hore infusions ea AP-5 ka har'a li-shell tsa "nucleus accumbens" (NAS) e bile le phello e fokolang haholo ho ho ithuta ho ts'ebetso, e fana ka maikutlo a hore maemo a sebetsang a kenyelletsa liphetoho tsa polasetiki netweke ea discrete ho fapana le ts'ebetso e hlakileng ea neural ea NMDARs. Tšobotsi e hlakileng haholoanyane ea marang-rang ena e ka una molemo maemong a mangata a amanang le ho ithuta kapa ho sebetsa ka polasetiki ka ho thusa litsebi tsa methapo ea kutlo hore li bone bohlokoa ba ts'ebetso nakong ea ha ka nako e ts'oanang li khetholla mokhoa o ikhethileng oa boits'oaro.

Ho holisa liphetho tsena, Baldwin et al. (2000) e fumane hore infusions ea AP-5 ho basolateral amygdala (BLA) le medial prefrontal cortex (mPFC) le eona e sitisitse ho ithuta ka ts'ebetso, empa AP-5 ha e na phello ea ho ithuta ho sebetsang ha ho kenngoa ka har'a dorsal (dSUB) kapa ventral ( vSUB) subiculum. Ho feta moo, litla-morao tsena li ne li boetse li lekantsoe molemong oa boemo ba pele ha NMDAR blockade e sena ts'ebetso ho ts'ebetsong e latelang ea ts'ebetso, boits'oaro ba koloi e ikemetseng kapa ho fepa ka mokhoa o ikemetseng. McKee et al. (McKee et al., 2010) e ekellelitse karolo ea ts'ebetso ea NMDAR ho ho ithuta ho sebetsang ho dorsal medial striatum (DMS) le anterior cingrate cortex (ACC), empa ha e a ka ea nka karolo ea orbito-frontal cortex (OFC) ho ithuteng mosebetsi. Lithuto tsa taolo ha li fumane bopaki ba bofokoli ba tšusumetso kapa ba koloi. Andrzejewski et al. (Andrzejewski et al., 2004) hape e fuputse karolo ea li-NMDARs khubung e bohareng ea amygdala (CeA) le 2 subnuclei e 'ngoe ea striatal. Ha bofokoli ba ho ithuta bo bonoa kamora ho ts'oaroa ha AP-5 ho CeA le posterior lateral striatum (PLS), empa eseng dorso lateral striatum (DLS), ho bile le litlamorao tse kholo boits'oarong ba koloi le boits'oaro ba ho ja ka infusions ea AP-5 ho CeA le PLS. Liphetho tsena li fana ka maikutlo a hore ho ithuta ka mohiruoa ho itšetleha ka ts'ebetso ea NMDAR ka har'a marang-rang a phatlalalitsoeng, e mong le e mong a ka fana ka maikutlo a susumetsang, ho susumetsa, ho khanna, le ts'ebetso ea ho ithuta. Ehlile, lithuto tsa nakong e tlang lia hlokahala ho lekola meeli ea "mosebeletsi" oa "sebetsa".

Mmoho, lithuto tsena tsa pele li bonts'a hore NAC, BLA, mPFC, DMS le ACC ke libaka tse bohlokoa ho cortico-limbic striatal network network controlist e sa hlokeheng bakeng sa ts'ebetso ea kamoso. Le ha mosebetsi o mong o ka hlakisa marang-rang ana mme mohlomong le likarolo tse ikhethang tsa sebaka ka seng, khokahano e joalo e bonahala e thefula thuto ea boits'oaro bo bobebe kapa bo bobe bo ka laoloang haholo hang ha bo thehiloe.

Ho kenya letsoho ho dopamine ts'ebetsong ea moputso le polasetiki

Ts'ebetso e matlafatsang e boetse e itšetleha haholo ka lits'ebetso tsa mesocorticolimbic DA, e nang le li-neurons tsa DA tikolohong ea li-ventral tegmental (VTA) le merero ea tsona ho li-nucleus accumbens (NAc), amygdala, preortalal cortex (PFC), le libaka tse ling tsa bokapele. Karolo eo karolo ea DA e sebetsanang le moputso e ntseng e baka likhang. Khopolo e 'ngoe ea pejana e khothalelitse hore DA-e kopanye le monate oa moputso hobane meputso e mengata ea tlhaho le ea lithethefatsi e etsa hore lits'ebetso tsa mesocorticolimbic le li-blockade tsa bona li sitise bokhoni ba boits'oaro ba bathusi ba bangata (Bohlale le Bozarth, 1985). Polelo ea bobeli e pheha khang ea hore li-neurocorticolimbic tsa li-neurons li ithuta le ho bolela ho tlisoa ha meputso, hobane li chesa sepheo se setle sa maemo, empa eseng molemong oa maemo (kapa meputso ka boyona) (Schultz, 1998, 2002). Tlhatlhobo ea boraro, e nang le tšusumetso haholo, e tiisa hore litsamaiso tsa mesocorticolimbic DA li kenyelletsa thepa e khothalletsoang ho hlahisoa ke neural ea mehopolo le meputso. Ehlile, DA ha e sebelisane le tšusumetso ea matla a meputso e monate, empa e hlokahala bakeng sa boits'oaro bo lebisitsoeng meputsong e tšoanangBerridge le Robinson, 1998). Khetlo la bone, ba bang ba pheha khang ea hore sisteme ea mesocorticolimbic DA e fana ka tšebetso e amanang le boiteko bo amang boitšoaro bo matlafatsoang hobane litsi tsa DA ha li na tšusumetso e kholo ho ts'ebeliso ea mosebeletsi ha e khothaletsoa lenaneong le "bonolo" (mohlala, FR-5), empa o ba le litlamorao tse matla lenaneong le sebetsang haholoanyane (Salamone et al., 1994, Salamone et al., 2001). Leha ho le joalo, leha karolo ea DA ho boits'oaro bo sebetsang e sa hlaka, sebopeho le lintlha tsa karolo ea sona li kanna tsa lula e le ts'ebetso ea boitokisetso bo sebelisitsoeng le mohopolo oa boithuto oa liteko.

Re lekile karolo ea DA ho ithuteng ho sebetsa ka mosebetsi oa D1R mehahong e mengata e boletsoeng ka holimo. Baldwin et al. (Baldwin et al., 2002b) e bonts'itse hore D1R blockade ho PFC e sitisitse ho ithuta empa ha e na phello ea ts'ebetso. D1R blockade ho BLA le CeA le eona e sitisa ho ithuta ho sebetsang (Andrzejewski et al., 2005), ka mokhoa o itšetlehileng ka tekanyetso. Leha ho le joalo, karolo ea D1R mehahong e meng e bile thata ho e khetholla ho litlamorao tse ling tsa lithethefatsi tsa D1R. Mohlala, Hernandez et al (Hernandez et al., 2005) e bonts'itse phello e matla boits'ebetsong ba ts'ebetso kamora ho etsa thulaganyo ea D1R blockade ho NAc; leha ho le joalo, nko e kenang ka sekirining sa lijo (hangata e nkoang e le karabelo e khotsofatsang ea boemo ba Pavlovian) le eona e ile ea fokotsoa haholo. Andrzejewski et al (Andrzejewski et al., 2006) e fumane hore D1R blockade ho vSUB, empa eseng dSUB, ho ithuta ho sa sebetseng hantle ka ts'ebetso, empa hape, bofokoli bo susumetsang bo fumanoe. Le ha ho bonahala eka ts'ebetso ea DA D1R e bohlokoa bakeng sa ho tsamaisa polasetiki e amanang le ho ithuta ka mosebetsi, karolo e tobileng e lula e sa tsitsa. Bopaki bo hlahang, leha ho le joalo, bo re lebisitse ho hatelleng karolo e mahlonoko ea ho ba le karolo ea NMDAR le D1R ho ithuteng mosebetsi.

Ho kenella ka hare ho litaba tsa NMDAR le DA D1R activation: Bahlahisi ba kopanetsoeng

Ho tsoa ho bopaki bona, re ile ra qala ho tiisa hore li-NMDAR li kopane le DA D1R, mme ka ho khetheha tlhahlobo e lumellanang ea matšoao a tlang, e bapala karolo ea bohlokoa ho fetoleng meralo ea synaptic, le mohlomong li-enuralles tse ka sehloohong, tse ithutoang haholo ke ho ithuta (Jay et al., 2004). Li-NDMAR le DA D1R li sebelisana ka litsela tse matla. Mohlala, LTP e itšetlehileng ka NMDA ka maqhetsoana a litheko e thibetsoe ke D1 empa eseng bahanyetsi ba D2 (Weiss et al., 2000). Ka vivo bopaki ba tšebelisano ea NMDA-D1 ho liketsahalo tse amanang le polasetiki li bontša hore LTP e etsahala makaleng a mangata le meaho. Mohlala, LTP ho hippocampal-prefrontal cortex synapses e itšetlehile ka ts'ebetso ea ts'ebelisano ea li-receptors tsa NMDA le D1, hammoho le li -ccade tsa Intracellular tse kenyelletsang PKA (Jay et al., 2004). Ka bobeli striatum le preortal ea cortex, D1 ts'ebetso e ka hlahisang likarabo tsa NMDA-receptor-mediated (Cepeda et al., 1993, Seamans et al., 2001, Wang le O'Donnell, 2001). Matla a ts'ebetso ea ts'ebetso ea spiking ea hippocampal-evoke ea neurons e hloka ts'ebetso ea tšebelisano ea li-receptor tsa D1 le NMDA, ha synergism e tšoanang e bonoa tseleng ea amygdalo-accumbens (Floresco et al., 2001b, a). Boithuto ba limolek'hule bo tlatsana le liphumano tsena, li bonts'a ho itšetleha ha NMDA-receptor ea phosphorylation ea D1-mediated phosphorylation ea CREB (cAMP reaction element binding protein) (Das et al., 1997, Carlezon le Konradi, 2004), ntho e ngotsoeng e nahanoang hore ke mochini o bolokiloeng oa tlhaho oa ts'ebetso ea ho hopola le liprotheine tsa bohlokoa litseleng tsa maqhubu tse amiloeng ke lithethefatsi tse lemalloang (Silva et al., 1998, Nestler, 2001). Ts'ehetso e matla bakeng sa khang ea ts'ebetso e kopanetsoeng e tsoa ponong ea matlafatso ea nako e telele ea matla a synaptic ha corticostriatal excation le dopaminergic activation li hokahane ka nakoana (Wickens et al., 1996). Lintlha tse ling li fana ka maikutlo a hore matšoao a glutamate le dopamine, ka ts'ebetso ea NMDA le D1, a ka fetohela ho kenya ts'ebetso ea ERK hippocampus le striatum, ka ho etsa joalo, a kopanya marang-rang a amanang le ho ithuta le tšebeliso ea lithethefatsi (Valjent et al., 2005, Kaphzan et al., 2006). Ka hona, ha ho fanoa ka litlhoko tse hlokahalang bakeng sa ho ithuta, hoa makatsa ho nahana hore ho fihla ka kopanelo ha matšoao a dopaminergic le glutamatergic, le litlamorao tsa eona tsa methapo, ho sebetsa e le lefapha la tšebelisano 'moho le qalang liphetoho tsa mongolo o lebisang ho phetoho ea liphetoho tsa synaptic. Ho bohlokoa ho hlokomela hore likhase tsena ke tsona tse hlahisitsoeng hore li fetoloe tšebetsong ea bokhoba (Hyman le Malenka, 2001).

Teko e tobileng ea tlhahiso ena ea maikutlo, Baldwin et al. (Baldwin et al., 2002bdosesa tsa AP-5 le R (+) - 7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH-23390) in a DXNist PFC e neng e sena tšusumetso e hlakileng lithutong tsa mosebetsi. Leha ho le joalo, ha e kopantsoe le ho kenngoa ho PFC ea likhoto tsa naïve, ho ithuta ka ts'ebetso ho ne ho senyehile haholo, ho fana ka maikutlo a kutloano e matla lipakeng tsa li-receptors tse peli. Ka mantsoe a mang, polasetiki e amanang le boits'oaro ba ts'ebetso e khonahala ka palo e nyane ea NMDAR kapa D1R blockade, empa eseng ka bobeli. Leha re bone litlamorao tse tlisoang ke lethalinyana, re ile ra ipotsa hore na ho ithuta ke "ntho feela kapa letho", joalo ka ho ithuta mohopolo (Osler le Trautman, 1961). Ka boiphihlelo ba rona, ho ile ha bonahala hore, likhoto tsa rona li qalile ho qeta nako ea bona ka phapusing ba ntse ba hlahloba, ba ts'oara nko, ba fofa, ba ikoetlisa, ba holisa, joalo-joalo, ha ka linako tse ling ba ne ba tobetsa feela. Kamora linako tse ngata, likhoto tsa taolo li ile tsa "e fumana" 'me ea hatella khafetsa,' me ea holisa, ea phenya, ea fafatsa, ho ikoetlisa, joalo-joalo, tlase (mohlala, likarabo tseo ho neng ho se na liphetho tse hlahisitsoeng), joalo ka Staddon mme Simmelhag a bonts'a boitekong ba bona ba semelo mabapi le boitšoaro bo lumelang ho litumela-khoela (Staddon le Simmelhag, 1971). Ka hona, ho ithuta ho qala ka "activist" ho ka kenyelletsa "ntlha ea ho phahamisa" kapa mokhoa o ts'oanang, ho fapana le o fetolelang butle butle ebile o fetoha hantle. Setšoantšo sa 1 e bonts'a likarabo tse ngata tsa makotlo a mabeli a nang le cannulae e lebileng ho NAc. E ngoe e ile ea kenngoa ka koloing pele ho liboka tse hlano tsa pele ha ea bobeli e ntse e ts'oaroa ka AP-5. Ho ts'oana hoa ts'ebetso hoa makatsa ebile ho bonahala ho lumellana le maikutlo a rona: ho na le keketseho e tsoelang pele le e liehang ea ho arabela, phetoho, kapele, ho isa tekanyong e phahameng, le e tsitsitseng, ea ho arabela. Hlokomela hore lenaka le phekotsoeng la AP-5 le lieha phetohong ena, le fana ka maikutlo a hore "ntlha ena ea ho pepa" e liehisoa ke NMDAR blockade.

Setšoantšo sa 1 

Cumulative lever e hatella ka linako tsohle. Boitšoaro ba likhoto tse peli tsa baemeli, e le 'ngoe e alafsitsoeng ke koloi le e' ngoe ea AP-5 e lateloang kamora ho kenella ka har'a infoshene ea bohlokoa ba mantlha (NAc) pele ho mananeo a malelele a 5, 15. Litlhaselo li felile kamora ...

Le ha datha tsena tsa boits'oaro le lintho tse ling tse hlokometsoeng li ka hlahisa taba e kholisang mabapi le khopolo ena ea "tipping", e ka ba thuso e ntle haholo haeba lefu la neurobiology le latela, hobane sena se ka bolela "nako e mahlonoko" bakeng sa ho ithuta ea sebetsang le ho fana ka maikutlo lipeanong tsa ho kenella feshene e itšetlehileng ka nako. Bonyane haholo, ho bonahala eka ho ithuta ke mosebetsi ho na le likamano tsa nakoana tsa pono ea tikoloho le tikoloho le tikoloho.

Moetso o khahlisang oa ho ithuta o sebetsang

Likarolo tse ikhethang tsa thuto ea limolek'hule tsa thuto (ka kakaretso, ha ho hlokahale hore e sebetse ho ithuta), joalo ka ha ho boletsoe pejana, li fumane phaello e kholo. Liphetho tsa rona mabapi le karolo ea ts'ebetso ea NMDAR li ile tsa tsebisoa hantle ke liphetho tsena mabapi le LTP. Leha ho le joalo, li-cascade tse sa tsotelleng tsa litaba tse ikarabellang bakeng sa LTP joale li bonahala hantle. Na ke tsona li-cascade tse ts'oanang tse ikarabellang ho ntlafatseng litsela tsa synaptic nakong ea ho ithuta ka mosebetsi? Baldwin et al (Baldwin et al., 2002a) ts'ebetso e thibelitsoeng ea protheine kinase, likarolo tsa bohlokoa tsa ho saena ka hloko ho hlokahalang bakeng sa PDP, ho NAc ea likhoto pele ho nako ea ho ithuta e sebetsang le ramatiki 1- (5-isoquinolinesulfonyl) -2-methylpiperazine dihydrochloride (H-7). Sehlopheng se ikemetseng sa likhoto, ts'ebetso ea cAMP-protein proteinasease (PKA) e ne e thibetsoe ke lithethefatsi Rp-adenosine 3 ′, 5'-cyclic monophosphothioate triethlyamine (Rp-cAMPS) kapele pele ho nako ea ho ithuta. Maemong ana ka bobeli, ho ithuta ho ne ho haella ho fana ka maikutlo a hore protheine kinase e supa ka kakaretso, le ts'ebetso ea PKA ka kotloloho e ne e hlokahala bakeng sa ho ithuta ho sebetsang. Ka hona, likarolo tse 'maloa tsa bohlokoa tsa intracellular ea neural plasticity e amanang le ho ithuta ka ts'ebetso e fumanoe.

PKA, PKC le mesebetsi e meng ea protheine kinase e kenella hare, ho latela mehlala e 'maloa e hlaheletseng, ho ERK (Valjent et al., 2005, Kaphzan et al., 2006). Phosphorylated ERK (pERK) e fetela ka nqane ea li-neuron, moo e fetolang tšebetso ea CREB, e tšoaroang haholo e le mokena-lipakeng oa polokeho ea tlhaho ea neural ea nako e telele. Ka mokhoa o makatsang, ha re fumane karolo e nyane bakeng sa ERK ho ithuteng ka mosebetsi oa matsoho. Taba ea pele, U0126 (pERK inhibitor) e kentsoe ho NAc pele ho nako ea ho ithuta e sa hlahise phello e bonoang (Setšoantšo sa 2, phanele A). Re sebelisitse li-paradigms tse tšoanang le litokisetso joalo ka litlaleho tse fetileng, leha ho le joalo, ka lebaka la ho hloka tsebo ea rona ka sethethefatsi sena, ho ka etsahala hore ebe phello ena e mpe e bile lebaka la bothata bo sa tsejoeng ba botekgeniki. Taba ea bobeli, re ile ra hlahloba phosphorylation ea ERK kamora ho ithuta ka ts'ebeliso re sebelisa litlolo tse tloaelehileng tsa Bophirimela le li-antibodies tse fumanehang khoebong. Lihlopha tse peli tsa likhoto tsa 6 li ne li tsamaisoa: 1) koetliso e sebetsang ea li-((CO-1 / VR-2) le 2) taolo ea taolo (ba amohetse palo e ts'oanang ea li -forcist empa ba sa tlameha ho hatella hore ba li hlahise). Li-brains li ile tsa bokelloa nakong ea metsotso e mehlano ea 5th Seboka le ho sebetsoa ke blot Western. Ha ho na phapang pakeng tsa ERK, pERK kapa karolelano ea PERK / ERK li ile tsa bonoa libakeng tsohle tsa 12 tse ithutileng, ho kenyelletsa le NAc (Setšoantšo sa 2, phanele B). Ho bile le phello e nyane, empa ea bohlokoa ka lipalo, ho pERK ho vSUB le PFC, e kenyelletsa keketseho ea 20% e amanang le taolo ea joko. Le ha phello e ne e le ea bohlokoa lipalo, e ne e le bonolo haholo ebile e le phoso ea mofuta oa 1 e fuoeng palo ea papiso eo re e tsamaisitseng. Taba ea boraro, re lekile ho bona ka leihlo le ts'epo, 'me ka ts'epo, re sa lekanye palo eohle ea boko kamora ho sebetsa ka ho ithuta ka ho sebelisa mekhoa e tloaelehileng ea immunohistochemical likarolong tse sa sebetseng tsa boko. Tsena li ile tsa tšoaroa ka mokhoa o ts'oanang ho liteko tsa blot tsa Bophirimela, leha ho le joalo ka mor'a ho bokelloa ha boko, likotoana kaofela li ile tsa thelisoa 'me li-antibodies tsa PERK li ile tsa sebelisoa ho tsebisa pERK.

Setšoantšo sa 2 

Karolo ea ERK ho ithuteng mosebetsi o mong. Panel A e bonts'a hore U0126 e kentsoe NAc pele ho linako tsa ho ithuta ha e na phello ha e bapisoa le taolo e kentsoeng ke koloi. Panel B ha e bonts'e phallo ea mantsoe ea ERK-1 kapa ERK-2 ...

Hape, ha ho ne ho na le lits'oants'o tse kholo tsa PERK ho PFC le vSUB, ho bile le tse nyane haholo ho NAc (Setšoantšo sa 2, phanele C). Lintlha tsena li lumellana haufi le sephetho sa batho ba Bophirimela mme li fana ka maikutlo a karolo e lekantsoeng bakeng sa ERK ho ithuteng mosebetsi, ho fapana le lithuto tse ngata tse bonts'a karolo ea bohlokoa ho kinase ena ka mefuta e meng ea ho ithuta (Levenson et al., 2004, Chwang et al., 2006, Kaphzan et al., 2006). Leha ho le joalo, ts'ebetso e kopanetsoeng ea NMDAR / D1R e ka hira mekhoa ea ho saena e ikemetseng ea ERK ho ea bokong.

Karolo ea CREB ho polasetiki ea methapo

Ho feto-fetoha ha molumo oa pCREB ho bohlokoa nakong ea ho ithuta hobane CREB ke sengoloa sa sengoloa se eketsang kapa se khutsisang polelo ea liphatsa tse ling tsa lefutso. Liphatsa tsa lefutso tsena ho nahanoa hore ke tsona li laolang ho qaptjoa ha liprotheine tse ikhethang tse etsang li-receptor, lera la mochini le likarolo tse ling tsa bohlokoa ho polasetiki ea methapo. Ho joalo, re bonts'itse hore protheine synthesis ho NAc e bohlokoa nakong ea ho ithuta ka ts'ebetso (Hernandez et al., 2002). Re sebelisa protheine synthet inhibitor, anisomycin, re bonts'itse hore litlatsetso tsa kamoso tsa morao-rao tsa NAc li thibetse ho ithuta tsa ts'ebetso tsa morao-rao, li hlahisa lintlha tsa mongolo le de novo protheine ea tlhaho. Ho khahlisang, infusions 2 kapa lihora tsa 4 ka mor'a hore seboka li se na phello; anisomycin hape ha e na phello nakong ea tlhahlobo ea ts'ebetso kapa tlhahlobo ea phepo. Hape, ho bonahala eka re buletse likarolo tsa bohlokoa tsa sistimi e laoloang ka thata, ka nakoana le ka maemo, le mekhoa ea ho ithuta e kenyelletsang meralo e mengata, li-receptors, li-signaching methane, 'me joale, synthetiki.

Ho fumaneha hoa ts'ebeliso ea protheine ea ts'ebetso ea ho ithuta ka "activant" e ne e le e 'ngoe ea bohlokoa ka ho fetisisa laboratoring ea rona, leha ho le joalo e ile ea botsa potso e kholo e bulehileng mabapi le bonnete ba polasetiki ena. Ka hona re entse liteko tse 'maloa ho khetholla hore na ke mefuta efe e ka raliloeng / ho ngolisoa nakong ea ho ithuta e sebetsang. Ho sebelisa maemo in situ Mekhoa e nyalisitsoeng ka likhoto e tšoeroe joalo ka e sebelisoang lithutong tsa Bophirimela tsa BOPHELO, re fumane hore liphatsa tsa pele tsa lefutso (IEGs) li haufi Homer1a 'me egr1 (zif-268) li ile tsa ts'oaroa hape, ha li bapisoa le likhoto tsa taolo, hang kamora 3rd Seboka sa boikoetliso se sebetsang kahare ho methapo ea pelo. Polelo ea Gene e ile ea phahamisoa haholo ho pholletsa le cortex le striatum, 'me maemong a mang, hippocampus, empa ka mokhoa o makatsang, eseng ho "ventral striatum" (ke hore, NAc). Ho fapana le "sehlopha sa pele sa ho ithuta", sehlopha sa bobeli sa likhoto se nang le linako tsa ho ithuta tsa 23 se ile sa ithuta. Leha ho le joalo Homer1a 'me egr1 polelo e ne e se e fokotsehile ha e bapisoa le sehlopha sa pele sa ho ithuta, hoo e batlang e le linthong tsohle tse ithutoang, tse fanang ka maikutlo a hore mefuta ena e kentse letsoho mesebetsing e amanang le polasetiki nakong ea ho pepeseha, empa eseng hamorao ho hlahella, ho lietsahala tse sebetsang. Mokhelo o le mong e ne e le "ventrolateral striatum" (VLS), e shebahalang eka e lula e le ka liphatsa tsa lefutso, "ka" esita le nakong ea ho pepesetsoa nako e telele. Leha litsebi tse ngata li re koetliso ea nako e telele e le "tloaelo ea ho tloaela" likarabo tsena li lula li fetoha le maemo (nahana ka "phello ea nakoana" ea ts'usumetso kapa phokotso eo motho a tla e bona ha likonteraka tsa basebetsi li felisoa kapa li tima): ho monate ho hakanya hore VLS e kanna ea tšehetsa mosebetsi ona oa ho beha leihlo.

Li-receptors tse ling tsa glutamate li boetse li thusa ho polasetiki e amanang le ho ithuta ho sebetsang

Homer1a ho nahanoa hore e laola le sehlopha sa sephethephethe sa 1 metabotrophic glutamate receptors (mGluR1 le mGluR5). mGluR5s li bonts'a tšebetso ea li-NMDARs ka ho fetoleha ha tsona tsa molao ho Ca2+ (Pisani et al., 2001), ho phahamisa monyetla o khahlisang oa hore mochine o le mong oa polasetiki e hlahisitsoeng ke NMDAR o ka itšetleha haholo ts'ebetsong ea mGluR5. Haufinyane tjena re lekile karolo ea tšebetso ea mGluR5 ho ithuteng ka tšebetso ka ho thibela tšebetso ea bona le lithethefatsi 3 - ((2-Methyl-4-thiazolyl) ethynyl) pyridine (MTEP). Liphetho tsa rona tsa pele li fana ka maikutlo a hore thibelo ea mosebetsi oa mGluR5 ho thuto ea ts'ebetso ea DMS e sitisa ho ithuta, leha liteko tsa ho fumana li ntse li tsoela pele.

AMPA receptor activation le ho ithuta ho sebetsang ho boetse ho fumanoe ka laboratoring ea rona. Hernandez et al. (2002) o bonts'itse karolo e sa lekanyetsoang ea ts'ebetso ea AMPAR ho NAc nakong ea ho ithuta ha mosebetsi. Tšusumetso, leha ho le joalo, e ile ea mamella bakeng sa linako tse ngata mme e kanna ea ba litholoana tsa taolo-tlase kapa taolo e telele ea li-receptors tsa glutamate. Le ha ngangisano ena e hloka tšehetso e eketsehileng ea matla, re fumane ho makatsa haholo hore prepital blockade ea AMPAR e tla hlahisa sephetho sa nako e telele se amanang le thuto ea kamora thupelo, e sa hlahiseng phetoho ho ithuteng mosebetsi.

Liphetoho tsa epigenetic nakong ea ho ithuta ha mosebetsi

Ntle le lintlha tse qalang tsa mosebetsi oa ho ngola, mosebetsi oa NMDAR le D1R o boetse o etsa liphetoho tse kang histone acetylation, ho chromatin, protheine e hlophisang le ho buella DNA ea genomic. Liphetoho tsena li fana ka matšoao a ho hira a kenyelletsang molemong oa ho ngola liphatsa tsa lefutso / ho khutsisa le ho susumetsa phihlello ea DNA ka mochini o hatisang. Ts'ebetso ea NMDAR le li-cascade tse amanang le intracellular tse tšoaeang, tse kenyeletsang histone 3 (H3) acetylation, e laola phetoho ea boits'oaro bo tšoarellang, boemo ba tšabo ba Pavlovian le ho ithuta ha Morris Water Maze (Atkins et al., 1998, Blum et al., 1999, Schafe et al., 2000). Re sa tsoa qala ho hlahloba hore na ho ithuta ho sebetsang ho ntlafatsa chromatin. Kannete, polelo ea acetylation ea Hole NHNNX e eketsehile mehahong e itseng nakong ea ts'ebetso ea ts'ebetso ea ts'ebetso, khahlanong le taolo ea lijo tsa sucrose. Boitekong bona, likhoto tse hatelang lenaneong la RI-3 ”li ile tsa etsoa mahlabelo metsotso ea 30 kamora thupelo. Li-brains li ile tsa bokelloa, tsa sebetsoa mme tsa kenngoa ka anti-acetyl-Histone H30 (Lysine 3) li sebelisa li-protocol tse tloaelehileng.

Ho khahlisang, ho latela taolo ea joko, re bone histone H3 acetylation ho DMS, sebopeho se nkoang e le karolo ea bohlokoa ho thuseng ho ithuta. Tsena ke tse ling tsa data ea pele eo re e tsebang ea ho bonts'a liphetoho tsa histone nakong ea ho ithuta ha mosebetsi. Leha ho le joalo, keketseho ea boemo ba lefats'e ea histone H3 acetylation e ka ba lebaka la liphetoho tse ntlafatsong ea liphatsa tsa lefutso ntle le li-IEG mme, ho feta moo, likhoto tse sebelisitsoeng tekong ena li bile le koetliso e pharalletseng. Kahoo, tlhaiso-leseling e tlatselletsang mabapi le locus ea acetylation nakong ea ho ithuta ea mosebetsi e hlokahala. Leha ho le joalo, datha tsena, hammoho le litlaleho tse ling tse ngata, li khothaletsa ka matla hore lits'ebetso tsa epigenetic li etsoa nakong ea ho ithuta ho sebetsang. Liphetoho tse tšoarellang halelele, joalo ka histone acetylation, li ka re thusa ho utloisisa sebopeho se tšoarellang sa ts'ebetso ea ts'ebetso, ho hanyetsa ha eona phetoho, le ho phelisoa ha mathata a itseng kalafong.

Ts'ebetso ea Epigenetic le eona e bonahala e fetoloa nakong ea tsamaiso ea lithethefatsi le ho ithuta. Nakong ea boikoetliso ba k'hok'heine, mofuta o sebetsang oa paraligm e itšetlehileng ka D1R, liphetoho tsa chromatin li kenngoa libakeng tse ling tsa striatum ho bapalami ba mefuta e mengata e amanang le polasetiki, joalo ka Cbp, NR2B, Psd95, 'me GluR2. Cbp e bohlokoa bakeng sa ts'usumetso e susumetsang ea CREB mme e na le ts'ebetso ea histone acetyltranferase (HAT) ea bohlokoa.Shaywitz le Greenberg, 1999). Litoeba tsa Transgenic tse bontšang mofuta oa truncated oa Cbp ho ba le likhaello tse 'maloa tsa ho ithuta (Wood et al., 2005). NR2B, subunit ea NMDAR tataiso, e na le setsi se tlamang sa glutamate mme e bohlokoa ho LTP, ha se seholo NR2A ha a (Foster et al., Hlahisa et al., 2010). The NR2B subunit e phosphorylated ke CaMKII, dephosphorylated ke PP1, mme mediates NMDAR Internization (Roche et al., 2001). Psd-95 inhibits NR2BSekhahla se hlophisitsoeng sa NMDAR (Roche et al., 2001) hape e laola ho fetoha hoa tikoloho le ntlafatso ea li-NMDAR (Li et al., 2003). GluR2 ke subunit ea AMPAR mme e na le sebaka sa bohlokoa sa phosphorylation hape se fetotsoeng ke intracellular protein kinase le ts'ebetso ea protheine ea phosphatase. Phosphorylation of GluR2 ka mokhoa o fapaneng o laola bosholu ba AMPAR ba calcium le cations tse ling. Ho khahlisang, mGluR5 e tsosa ho li-dorsal striatum induces GluR2 phosphorylation, phello e koetsoeng ke antagonism ea NMDAR (Ahn le Choe, 2009).

Moetso oa Intra-cellular convergence oa ho ithuta o sebetsang

Khahlano le karolo ena ea morao-rao ea mosebetsi o matla le o khahlisang, re thehile mohlala oa converter ea NMDAR-DA D1R e ka khothalletsang kutloisiso e kholo ea polasetiki ea neural e amehang ho ithuteng ho sebetsa. Setšoantšo sa 4 e bontša khopolo-taba e atileng ea hore li-signature tsa glutamate-coded sensory / tsa ts'ebetso ea tlhahisoleseling li kenya letsoho NMDAR, le AMPAR, e lebisang Ca2+ kenella ka seleng. DA activation of D1Rs activates adenyl cyclase (AC, e khethiloeng ka motsu o motšo), ka lehlakoreng le leng, cAMP. Litsela tse peli tse bontšang matšoao li sebelisana libakeng tse 'maloa, ho etsa mohlala, joalo ka CaM, e susumetsoang ke ts'ebetso ea NMDAR, e susumetsa AC (leha sena e le setšoantšo se bonts'itsoeng ho feta). PKA e kenya ts'ebetso MEK, empa hape e thibela Ras / Raf (e khethiloeng ka mola o nang le li-bar), e fana ka maikutlo a hore ha se litsela tse kopaneng feela, empa hape li ka qothisanang lehlokoa le matla.

Setšoantšo sa 4 

Moetso o tšoaeang liphiri oa motho ea sebetsang ea lemalloang. Liphetoho tse sebetsang le tsa sebopeho tse kentsoeng polasetiki ea neural li fana ka tšebetso e kopanetsoeng ea NMDAR le DA D1R ho pholletsa le li-network tsa cortical-striatal-limbic network. Palo ena e akaretsa se atileng ...

Ho bontšitsoe lintlha tse 'maloa tsa khokahano e sebetsang, haholo ts'ebetso ea CREB, MEK le ERK. Litlamorao tse tebileng tse amanang le polasetiki le tsona li bonts'oa, joalo ka phetisetso e itšetlehileng ka CREB ea li-IEG Arc, Homer1a, 'me egr1. Homer1a morekisi mGluR5 receptors (e emeloang ke motsu o moputsoa), eo hamorao e ileng ea baka Ca2+ tšusumetso ka har'a ts'ebetso ea Gíq-protein e kopantsoeng le phospholipase C (PLC) (ts'ebetso ena e emeloa ka motsu o moputsoa le li-bolts tsa mabone); ts'ebetso ea mGluR5 e boetse e khona ts'ebetso ea DA D1R. selikalikoe e fetisetsoa ho li-synapses tse sa tsoa etsoa, ​​tse batlang li etsa karolo ea "ho emisa". Haufinyane, data e hlahang e fana ka maikutlo a karolo ea bohlokoa bakeng sa selikalikoe le ERK ho kenngoeng le ho tsamaisoa ha AMPAR-subunit le l-channels tsa mofuta oa L-voltage gated calcium. DARPP-32, e hlahisitsoeng ke ts'ebetso ea PKA, e bokellana ka setsing sa bohlokoa, e thibelang protheine phosphatase 1 (PP1), e kenelletseng ka kotlolloho phetohong ea chromatin ka ts'ebetso ea intrinsic dephosphorylation (e bontšitsoeng ke motsu o chitja o nang le hloohoana ea "ho utloisisa" sehlopha sa phosphate ). Liketsahalo tsa histori tsa deactylease (HDACs) li hlahisoa ka mola o kahare o nang le "inaser" oa li-acetyl tse tsoang ho Histone 3 (H3). Litokiso tsena tsa histone lia khatholla kapa ho hatisa chromatin ka tsela eo e nolofalletsang kapa e hatisang ho hatisoa ha mofuta oa mofuta (liphetoho tse itseng tse boletsoeng setšoantšong ha se hlile li emela liphetoho tse hlokahalang ho baphatlalatsi ba li-IEG bakeng sa mongolo)Setšoantšo sa 4 e ipapisitse le (Sweatt, 2001, Kelley le Berridge, 2002, Haberny le Carr, 2005, Ostlund le Balleine, 2005, Valjent et al., 2005). Ka hona, ho feto-fetoha ha methapo ea methapo ea kutlo ho tsoa ho cortico-striatal-limbic NMDAR le DA D1R e fana ka sebaka se ka tlase sa polasetiki bakeng sa ho ithuta ka moputso. Boko le li-neuron tsa "brain" tse ikhethileng mohlaleng ona li se li qala ho sheboa feela, empa li ka kenyelletsa libaka tsa mantlha tsa striatal, limbic le cortical. Ho belaela ha rona ka matla ke hore li-neurons tse mahareng, tse maemong a mantlha, li ka ba hantle bakeng sa ts'ebetso e amanang le polasetiki ka lebaka la methati e meholo ea li-ion tse tsamaeang le motlakase tse hlahisang liphetoho tse ikhethileng tsa mmuso (Houk le Wise, 1995) hammoho le khokahano ea lipapatso tse pharalletseng, likharafu tsa cortical, limbic, le thalamic, le litlatsetso tsa monoaminergic tse tsoang bohareng ba mpa.

Kelley le basebetsi-'moho (Kelley et al., 1997Qalong o phatlalalitse karolo ea bohlokoa bakeng sa NAC ho polasetiki ea methapo le thuto e sebetsang. Ka sebele, laboratori ea rona e hlahlobile karolo ea li-nucleus tse bokellaneng mefuteng e fapaneng ea boits'oaro e sebelisa mokhoa o hlophisitsoeng hantle oa taeo (mohlala, tlhahlobo ea liteko tsa boits'oaro, boits'oaro ba boits'oaro, methapo ea kutlo ea limolek'hule le lisele tsa cellular, jj.). Dr. Kelley e ne e le e mong oa litsebi tsa sebopeho, fisioloji, khokahano le ts'ebetso ea li-nucleus accumbens. Leha ho le joalo, liteko tsa rona tse 'maloa li bonahala li hanyetsana le phatlalatso ea pele ea Dr. Kelley. Ho haella ho kholisang ha ho nka karolo ha MEK / ERK ho NAc nakong ea ho ithuta ka matla le ho haella ha polelo ea liphatsa tsa lefutso ho sebetsa joalo ka mabaka a mabeli a sebete ho phehisanong ea hore polasetiki ho NAc e bohlokoa molemong oa ho ithuta. Taba ea mantlha, ekaba hore MEK / ERK ha e kenelle ho ithuteng ka ts'ebetso kae kapa kae bokong. Boithuto ba rona ba libaka tse ling tsa 12 bo hlahisitse phapang e nyane haholo lipakeng tsa thuto e sebetsang le taolo ea joko. Mohlomong, tsela ea MEK / ERK e ea ameha nakong ea "nako e mahlonoko" kapa "ntlha e khuts'oane" ha likhoto li bonahala li "e fumana" mme lithuto tsa rona li ne li sena qeto ea nakoana ea ho lemoha phello ena, haholo hobane ts'ebetso ea ERK e matla ebile ketsahalo e potlakileng haholo. Mohlomong litekanyetso tsa rona tsa U0126 li ne li le tlase haholo ho thibela ts'ebetso ea ERK. Leha ho le joalo, khopolo-taba e ka bang ka mokhoa o ts'oanang ke hore sengoloa sa CREB se kopantsoeng sa liphatsa tsa lefutso se amehang polasetiki ea methapo se sebelisoa ka kotloloho ke litsela tse ling tse bontšang, joalo ka PKAc kapa CAM (bona Setšoantšo sa 4), ho feta tseleng ea MEK / ERK. Mme mohlomong, ha re so ka ra tseba mefuta ea bohlokoa e amanang le polasetiki kapa menahano e mengata ea liphetoho tse ka etsahalang ho epigenetic ho li-neuron tsa NAc tse thusang le ho tiisa ts'ebetso ea ts'ebetso ea ts'ebetso. Re tšepa hore re tla araba lipotso tsena ka matla le ka cheseho e tšoanang le eo Ann a ileng a e etsa.

Litlamorao tsa tleleniki

Khopolo-taba e hlahelletseng ea tlhahlobo ena ke hore mohlala o hlahisitsoeng Setšoantšo sa 4 e ka tsebisa kalafo ea mathata a mangata a kliniki. Taba e totobetseng ke bokhoba ba lithethefatsi, hobane tšebeliso e mpe ea lithethefatsi e ama haholo lits'ebetso tse tšoanang tsa limolek'hule tse sebetsanang le ho ithuta ke mosebetsi. Lilemong tsa morao tjena, tse ling tsa liphetho tse makatsang ka ho fetisisa lipatlisisong mabapi le bokhoba ba tahi ke tse bonts'a phapang e kholo ea mehato e sebelisang bokhoba ba lithethefatsi le ho ithuta ka mokhoa o tloaelehileng o amanang le moputso (Hyman le Malenka, 2001, Nestler, 2001, Wang et al., 2009). Re na le bonnete ba hore litlhahlobo tse ngata khatisong ena e khethehileng li totobalitse kamano e teng lipakeng tsa bokhoba ba lithethefatsi le thuto e tloaelehileng e amanang le moputso. Ke 'nete hore kamano ena e ipakile e le bohlokoa kutloisisong ea rona ea bokhoba ba tahi, leha ho le joalo, re ka rata ho qolla likhokahano tse ncha tsa bohlokoa lipakeng tsa mosebetsi oa Dr. Kelley oa ho ithuta ka ts'ebetso le tlhaiso-leseling e fumanoeng le mathata a mang a bongaka. Litlamorao tseo li oela ka har'a lihlooho tse peli tse akaretsang: 1) mathata a bongaka a nang le mathata a amanang le ho ithuta a ka fanoang ka kutloisiso e betere ea hore na e sebetsa joang ho ithuta e hlaha ka methapo ea methapo ea methapo ea methapo ea mokokotlo ea "plasticity" le "2". o se a ithutile, mme mohlomong e hanyetsa haholo, boitšoaro bo sebetsang le litho tsa eona tsa methapo. Nyeoe ena ea morao-rao e tšehetsa bothata ba bokhoba ba tahi, re nahana, joalo ka ha bo bonoa ka nepo e le boits'oaro bo sebetsang ba basebetsi bo nang le litlamorao tse mpe haholo le tsa nako e telele.

Joalokaha ho boletsoe selelekeleng, mathata a autism spectrum joale ho nahanoa hore a ama ngoana a le mong ho ba 1. Ho haelloa ke puisano, mathata a likamano tsa sechaba le mekhoa ea boits'oaro bo khethollang autism, leha tsebo ea puisano e ka ba tloaelo ho bana ba nang le Asperger. Phekolo ea pele ea boits'oaro bo matla (EIBT), e ipapisitse le melao-motheo e sebetsang, e etsa mokokotlo oa mekhoa ea kalafo e felletseng e hlahisang litholoana tse ntle. Kalafo ena ea pele, e ikhethileng ka mokhoa o ikhethileng le e nang le maemo, hangata e kenyelletsa bonyane lihora tse 88 tsa kalafo ea motho a le mong ka beke, hangata bakeng sa lilemo tse ngata. Lintlha li bonts'a hore ts'ebetso ea pele e qala, ho ba le sekhahla sa katleho. Boholo ba linyeoe tsena (likhakanyo tse ling li lipakeng tsa 40-40%), ho kenella ka ho phethahetseng ka litlelaseng tse tloaelehileng ho a khonahala ka litšehetso tse fokolang kapa tse se nang tsona (Lovaas, 1987, Sallows le Graupner, 2005, LeBlanc le Fagiolini, 2011). Liphumano tsena li fumanehang botebong ba pelo joaloka ntho e tsamaisang katleho ea katleho ea EIBT. Bafuputsi sechabeng sa kalafo ea autism ba nahana haholo ka "linako tse mahlonoko" tsa nts'etsopele tse tsamaellanang le polasetiki e phahameng ea neural (LeBlanc le Fagiolini, 2011). Kahoo, lipatlisiso tsa rona mabapi le ho ithuta tse sebetsang li ka ba le litlamorao tse peli: 1) ho ka etsahala hore "kelello" ea "autistic" e ka be e fokolitse bokhoni ba polasetiki, mme ke feela ka ts'ebetso e matla le kalafo tse fokotsang matla ana le 2) ho ka khonehang, ka kutlwisiso e felletseng ea ho ithuta ho sebetsang, ho hohela linako tsa polasetiki hore bana ba baholo ba ka rua molemo ho tsa bongaka.

Le ha e le khang e kholo ea hore motho ea ithutang, EIBT, le karolo ea polasetiki ea neural underlie ASDs, ho na le mehloli e mengata ea bopaki bo tšehetsang. Ho qala, sesosa se ka sehloohong sa li-ASD ke Fragile X syndrome (FXS), bothata bo pheta-phetang ba gene trinucleotide le mofuta oa FMR1. FXS e amahanngoa le mathata a ho ithuta, bofokoli ba boitšoaro ba sechaba hammoho le litlolo tse ling tsa 'mele (haholo-holo sefahleho). Mofuta oa FMR1 o kenyelletsa protheine ea kelello ea Fragile X retardation (FMRP) e hlokahalang bakeng sa nts'etsopele e tloaelehileng ea neural (Crawford et al., 2001, Antar et al., 2004). Ntle le moo, FMRP e hlophisa ka matla mosebetsi oa sehlopha sa 1 mGluR, le ho haella ha dysregulates tsa mosebetsi oa FMRP NMDAR LTP (Antar et al., 2004). Mosebetsi oa rona oa morao-rao le mGluR5 inhibitor MTEP o bonts'a karolo ea bohlokoa ho ithuteng mochini oa "receptor" tlasa maemo a "tloaelehileng". Li-pharmacotherapies tse thehiloeng ho modulating mGluR5 li se li ntse li hlahlojoa hore li sebelisoe bathong ba nang le FXS (Hagerman et al., 2012).

Mofuta o mong oa Autism, o bitsoang "regression autism" hobane bana ba nang le sebopeho sena ba hola ka nako e itseng ebe ba lahleheloa ke "ho tloaela" puisano le litsebo tsa ho ba le setsoalle, haufinyane li hokahane le mosebetsi o fokotsehang oa PKA le subunit e matla ea PKA, e leng c-isoform. Ha e bapisoa le setopo sa post-mortem le li-control tse se nang registry tsa autistic, li-cortices tsa "regism" tse ikhethileng li bonts'itse ts'ebetso le polelo ea PKA (Ji et al., 2011). Ha ho phapang e ileng ea bonoa libakeng tse ling tsa cortical, ebile ho ne ho se na phapang pakeng tsa autism e sa laoleheng le taolo eo e seng ea boithati. Ka hona, autism e khutsitseng e ka amahanngoa le phosphorylation ea lipakeng tsa PKA le lipontšo tse sa utloahaleng tsa intracellular. Hape, mosebetsi oa rona o bonts'itse karolo ea bohlokoa bakeng sa PKA ho ithuteng ts'ebetso, e fetolela hantle le mosebetsi ona oa morao-rao oa autism e utloisang bohloko.

Rubenstein-Taybi syndrome (RTS) ke bokuli bo atisang ho bakoa ke liphetoho tse hlahisoang ke liphetoho tse hlahisoang ke liphatsa tsa lefutso tsa CREB (CREBBP). Bolelele bo bokhutšoanyane, marang-rang a sephara, litšobotsi tsa sefahleho tse ikhethang, le mathata a ho ithuta a tebileng a tsebahala ka RTS (Bartsch et al., 2010). Ho bohlokoa ho tlatselletsang mona ke khokahano e hlakileng lipakeng tsa ho ithuta ho sebetsang, mosebetsi oa CREB, le RTS. Mohlomong bana ba nang le RTS ba ka rua molemo ho EIBT kapa kalafo e itseng ea meriana e thusang, litlatsetso, kapa tse fetisang CREB phetiso ea mofuta oa gene. CREB phosphorylation e bonahala e laola ts'ebetso ea IEG le ho hlophisoa ha liprotheine tse ncha, mme mohlomong li laola polasetiki ea neural e amanang le ho ithuta ho sebetsang.

Qetellong, mohlala oa rona oa "data" le "intracellular model" o kenya ts'ebetso ea epigenetic e le o ikarabellang bakeng sa tlhaho ea ts'ebetso ea ts'ebetso ea ts'ebetso. Khopolo ea rona e tloaelehileng ea boits'oaro ba "opereishene ea tloaelo", lipontšo tse pheta-phetoang tsa ho hlaphoheloa hang-hang, le nako e hopoloang e se na moeli e amanang le barekisi ba libuka e kenya letsoho molemong oa mohopolo ona. Ho joalo, boits'oaro bo bongata ba mathata bo ipakile bo le bohlokoa haholo kalafong, ka hona, bo lebisitse menyetleng ea lithibelo sechabeng, thibelo ea lik'hemik'hale, ho kena sepetlele le setheong. Leha ho le joalo, sehlopha se pharaletseng sa lisebelisoa tsa ho hlahloba lintho, tseo hangata ho thoeng ke "ts'ebetso ea ts'ebetso ea mekhoa ea mathata" kapa "ts'ebetso ea ts'ebetso ea boits'oaro (FBA)", e ntlafalitsoe ho khetholla likamano tse laoloang bakeng sa boits'oaro bona bo bobe. Ka kakaretso, litlelase tsena tsa boits'oaro li nkoa li sebetsa, li matlafatsoa ke tlhokomelo, phihlello ea lintho tse ratoang, kapa ho baleha / ho qoba maemo a sa batleheng (Lerman le Iwata, 1993). Ka tlhaiso-leseling ena ka letsoho, kalafo e ka lebisoa ka tsela e tla fana ka mehloli e meng ea matlafatso kapa basebetsi ba bang ba loketseng ba hlahisang maemo a batlang, ka nako e telele le ho feta ka mor'a thuto ea pele ea ts'ebetso ea boitšoaro bo sa lokang. Na ho na le monyetla oa hore kutloisiso e kholo ea ho ithuta ea opareitara e ka fana ka lipheo tsa pharmacotherapeutic, joalo ka histone acetylation, e ntlafatsang ts'ebetso le / kapa ho khothaletsa ho ithuta ho sebetsang?

Le ha mehopolo e mengata e nahanisisa haholo, mosebetsi oa Dr. Ann Kelley le basebetsi mmoho le thuto ea ts'ebetso ea ts'ebetso ba ka tsebisa, bonyane haholo tlhaho le mokhoa oa ho lemalla lithethefatsi. Re rata hape ho atolosa mohopolo oa rona le seo re se fumaneng ho thusa ho utloisisa mefokolo ea ho ithuta e amanang le li-ASD, FXS le RTS, hammoho le kamano e thata le matla a lipapatso tse ling tsa mathata a sebetsang.

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Setšoantšo sa 3 

Acetylated histone H3 density nakong ea ts'ebetso ea ts'ebetso e phahamisoa ho DMS e amanang le taolo e kopantsoeng, empa eseng ho NAc, PFC, kapa ACC. Li-pictomicrographs tse emelang likarolo tsa DMS tse nang le lits'oants'o tse bonts'itsoeng ka letsohong le letona.

Lintlha-khōlō Tsa

Ho ithuta ka ts'ebetso ke mokhoa oa motheo oa boitšoaro

Ho ithuta ka ts'ebetso ho hloka ts'ebetso e kopanetsoeng ea li-receptors tsa NMDAR le D1R

Li-Cascade tsa Intracellular tse tšoaeang maikutlo li ameha ka matla nakong ea ho ithuta ha mosebetsi

Lipheo tse ka ba teng tsa kalafo bakeng sa bokhoba ba lithethefatsi, bo-autism le boits'oaro bo thata ba mathata

Mongolo o botlaaseng ba leqephe

1Nahana ka tsa 'nete, empa ho le thata ho li lekanya, litšenyehelo tsa "ho robala bosiu" kapa ho eketsa khatello ea bophelo bo botle le boiketlo ba batsoali ba bana ba nang le mathata a boitšoaro ba lithethefatsi.

2Ts'ebetso ena ea pele e sebelisitse likhara tse peli, e nang le kemiso ea VR-2 ho e 'ngoe ea tsona, e loants'ang likhoto. Motho oa bobeli, ea neng a sa "nepahala" o ne a le teng ho lekanyetsa bokhoni ba ho fallisoa kapa ho khetholoha. Re e fumane e le majabajaba ebile e le thata, ho e-na le ho e hlalosa, le ho e fetolela, e latelang. Ka hona, re felisitse lever ena ea bobeli lithutong tsa morao. Ntle le moo, re fetotse kemiso ea ho qala ea matlafatsa ho ea FR-1, ha re ntse re fallela butle ho ea VR-2 nakong ea 5, sebakeng sa 4, linako tsa pele. Liphetoho tsena tse nyane tsa lits'ebetso ha li bonahale li ama liphetho tsa rona tse fuoeng karabelo tse 'maloa.

Boitlhotlhollo ba Mohoeletsi: Ena ke faele ea PDF ea mongolo o ngotsoeng ka letsoho o sa amoheloang o amoheletsoeng bakeng sa ho hatisoa. Joaloka tšebeletso ho bareki ba rona re fana ka phetolelo ena ea pele ea mongolo o ngotsoeng ka letsoho. Mongolo o ngotsoeng ka letsoho o tla ba le ho kopitsa, ho kenya lihlopha le ho hlahloba bopaki bo hlahang pele o hatisoa ka mokhoa oa oona oa ho qetela. Ka kopo hlokomela hore nakong ea mekhoa ea tlhahiso ea lihlahisoa e ka fumanoa e ka amang litaba, le litsebiso tsohle tsa molao tse sebetsang koranteng e amanang le eona.

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