Cov kev kuaj mob ntawm qhov chaw ntawm cov keeb kwm corticostriatal thaum lub sijhawm kawm ua haujlwm (2013)

Neurosci Biobehav Rev. Sau ntawv sau; muaj nyob rau hauv PMC 2014 Nov 1.

Luam tawm rau hauv daim ntawv kho tiav kawg nkaus li:

PMCID: PMC3830626

NIHMSID: NIHMS464960

Tus tshaj tawm cov lus hloov kho kawg ntawm tsab xov xwm no muaj nyob rau ntawm Neurosci Biobehav Rev

Mus rau:

Abstract

Dopamine thiab glutamate ua cov haujlwm tseem ceeb hauv neural plasticity, kev kawm thiab nco, thiab quav. Cov kev kawm thev naus laus zis sib cav hais tias ob qho no, nthuav dav cov tshuab xa xov xwm neurotransmitter ua lub luag haujlwm tseem ceeb hauv kev ua kom cov ntaub ntawv zoo thiab koom nrog. Cov paib ua ke ntawm cov kab ke no, tshwj xeeb los ntawm dopamine (DA) D1 thiab glutamate (Glu) N-methyl-D-aspartate receptors (NMDAR), ua rau cov teeb meem tseem ceeb ntawm cov teeb meem uas ua rau muaj kev hloov pauv hauv chromatin qauv, kev qhia txog gene, synaptic plasticity, thiab thaum kawg tus cwj pwm. Cov tshuaj muaj yees kuj tseem tsim cov tshuaj neuroadaptations mus sij hawm ntev tom cov qib molecular thiab genomic ua rau cov kev hloov pauv hloov uas hloov kev sib txuas. Tseeb, cov ntaub ntawv pov thawj hais tias cov tshuaj ntawm kev tsim txom txuam D1- thiab NMDA-mediated neuronal cascades sib koom nrog cov txiaj ntsig ntawm kev kawm paub muab ib qho tseem ceeb tshaj plaws los ntawm kev tshawb nrhiav kawm txog neurobiology ntawm kev quav. Xws li cov tshuaj neuroadaptations tuaj yeem ua rau cov ntaub ntawv tsis zoo thiab kev coj ua, uas ua rau kev txiav txim siab tsis zoo, poob ntawm kev tswj hwm, thiab yuam kev uas ua rau kev quav yeeb tshuaj. Cov yam ntxwv zoo li no feem ntau tseem muaj rau ntau lwm cov kev mob neuropsychiatric. Teeb meem coj cwj pwm, suav tias yog teeb meem cuam tshuam nrog kev kawm thiab kev coj ua, qhia txog cov kev cov nyom thiab cov hau kev tshwj xeeb rau lawv txoj kev kho uas yuav tsum tau kawm ntxiv. Kev tshuaj xyuas tam sim no hais txog kev ua haujlwm ua ke ntawm Ann E. Kelley thiab cov npoj yaig, ua lub luag haujlwm tseem ceeb tsis yog rau NMDAR, D1 receptors (D1R), thiab lawv cov kev sib txuas ntawm cov phiajcim, tab sis kuj rau lwm Glu receptors thiab protein synthesis hauv kev kawm thoob plaws ib cortico-striatal-limbic network. Cov hauj lwm tsis ntev los no tau txuas ntxiv qhov cuam tshuam ntawm qhov pib kawm rau cov txheej txheem epigenetic. Kev nkag siab zoo dua ntawm cov txheej txheem no yuav tuaj yeem pab tshawb nrhiav kev kho kom koom nrog neural plasticity-txog cov txheej txheem thiab txhawb kev ua haujlwm ntawm kev coj tus cwj pwm.

Kev kawm ua haujlwm yog ib qho ntawm feem thawj kev coj ntawm kev coj cwj pwm (Rescorla, 1994)). Los ntawm kev sib pauv nrog nws ib puag ncig, tus tsiaj muaj peev xwm paub txog qhov tshwm sim ntawm nws cov yeeb yam, thiab yog li hloov kho thaj chaw tam sim no los ntawm tus cwj pwm tshiab los tsim cov kab mob uas zoo dua (Skinner, 1953)). Qhov tshwm sim hloov pauv tus cwj pwm yog qhov txaus ntshai thiab kav ntev. Qee cov kws tshawb fawb tau sib cav hais tias kev kawm ua haujlwm yog lub hauv paus ntawm "kev paub" (Schnaitter, 1987), nkag mus rau cov “muaj tswv yim” (Pryor li al., 1969), yog lub hauv paus ntawm kev txiav txim siab, thiab muaj feem xyuam rau qhov xwm txheej ntawm kev quav yeeb tshuaj. Raws li kev coj tus cwj pwm ntawm kev hloov pauv hloov los ntawm cov lus teb-cov txiaj ntsig sib txuas, lub cev kev tawm dag zog tau ua haujlwm kom ntseeg tau tias cov kev hloov pauv no yuav luag tas mus li; lawv raug "ntawv ntuas hauv," zoo li Thorndike tau xav (Thorndike, 1911)). Txawm tias Skinner ntshai hais tias cov lus teb tshwm sim los hloov peb: “Cov txiv neej ua raws li lub ntiaj teb, thiab hloov nws, thiab yog hloov nyob rau hauv lem los ntawm lub txim ntawm lawv kev txiav txim. "(Skinner, 1957, p. 1).

In the light of the ubiquity of operant behaviour Relations Relations in our psychotherapy, lub neurobiology ntawm kev kawm kev ua haujlwm (piv txwv li, kev pib ntawm kev teb cov lus teb) tau txais kev xav tsis txaus ntseeg thaum piv rau lwm cov txheej txheem kev kawm xws li kev kawm paub sib nrug (piv txwv, Morris Dej Txhaum) lossis Pavlovian ntshai qhov txias. Txawm li cas los xij, kev sib raug zoo ua haujlwm tau xav tias yuav tau ua haujlwm nyob ze rau txhua lub sijhawm ntawm peb lub neej thiab hauv ntau qhov teebmeem ntawm neuropsychiatric: kev quav yeeb tshuaj, tsis meej pem, thiab lwm yam teebmeem loj ntawm tus cwj pwm. Hauv qhov kev tshuaj xyuas no, peb hais txog ob lub xyoo kawg ntawm Ann Kelley kev tshawb fawb txog kev ua haujlwm, thaum nws ua raws li kev nkag siab ntau dua ntawm cov neurobiology ntawm kev kawm ua haujlwm nrog kev cia siab tias molecular, ntawm tes, thiab cov qauv ntawm cov haujlwm ntawm cov kev kawm ua haujlwm, nrawm hauv kev faib tawm tes hauj lwm, yuav qhia kev kho mob zoo dua.

Tus nqi coj cwj pwm-kev noj qab haus huv thiab Kev Ua Haujlwm Zoo

Kev quav yeeb tshuaj yog ib qho ua rau muaj kev phom sij, rov ua haujlwm dua thiab raug nqi kev coj cwj pwm-kev noj qab haus huv hauv Teb Chaws Asmeskas, thiab yog tseeb, thoob ntiaj teb. Kev quav yeeb tshuaj hauv lub teb chaws no ib leeg raug nqi kwv yees $ 484 billion txhua xyoo hauv cov teeb meem kev noj qab haus huv, kev raug mob, kev ua haujlwm ploj, thiab kev tuav pov hwm (Txoj Cai, 2001)). Nws kuj tseem kwv yees tias cov neeg 540,000 tuag txhua xyoo los ntawm kev muaj mob rau tshuaj. Cov nyiaj kwv yees no tsis suav nrog cov nqi them nyiaj tsis yog nyiaj txiag lossis tsis ncaj rau cov nqi them los ntawm niam txiv1, cov txij nkawm, cov nkauj muam nraug nus, cov phooj ywg, thiab peb lub zej zog feem ntau. Nws yog qhov zoo tias txhua tus pej xeem hauv lub tebchaws no tau txais kev ua phem los ntawm kev quav yeeb tshuaj thiab quav tshuaj hauv qee txoj kev (piv txwv, xws li tus neeg raug tsim txom los ntawm tus cwj pwm kev ua txhaum, tsheb sib tsoo, lossis los ntawm kev coj ua ntawm tsev neeg). Kev quav yeeb tshuaj yeeb tshuaj tau raug pom ntau zuj zus txog qhov hloov pauv ntawm kev txawj ntse thiab kev coj tus cwj pwm, nrog kev hais txog kev txiav txim siab sib txawv ntawm kev quav yeeb quav tshuaj mus rau kev hloov pauv pathological hauv kev txiav txim siab- thiab kev xav kev xav hauv zej zog (Everitt li al., 2001)). Yog li, kev nkag siab zoo dua ntawm cov kev kawm ua haujlwm yuav ua rau peb nkag siab txog ntawm cov neural causation ntawm cov quav.

Raws li Cov Chaw Rau Lub Chaw Tswj Xyuas Kabmob (CDC), 1 hauv 88 cov menyuam yaus tau pom tias muaj tus kabmob autism (Tswj, 2012)). Autism spectrum cuam tshuam (ASDs) cuam tshuam rau cov tib neeg los ntawm txhua haiv neeg thiab qib kev sib raug zoo. ASDs tuaj yeem ua pov thawj tau zoo thiab yuav xav tau kev saib xyuas lub neej ntev uas tau them nyiaj ntau rau zej zog (> $ 3,000,000 rau ib tus neeg) (Ganz, 2007)). Tsis ntev los no, siv tshuaj ntsuam xyuas tus cwj pwm (ABA) thiab qee yam kev hloov pauv (piv txwv, Denver Pib Qauv), uas hais txog qhov hloov kho thiab kawm yooj yim, kev sib raug zoo, thiab kev coj tus cwj pwm sib txuas lus tau pom tias muaj txiaj ntsig tsis txaus ntseeg tau nrog kev kho thaum ntxov,Sallows thiab Graupner, 2005, Dawson li al., 2010, Warren li al., 2011)). Cov qauv no tau ua tiav tau zoo tias ntau tus menyuam yaus kuaj mob ASDs tom qab hu ua "cais tsis tau" los ntawm lawv cov phooj ywg. Qee qhov kwv yees tias 40-50% ntawm cov menyuam yaus tau kuaj pom tias muaj tus kabmob muaj autism tuaj yeem kho tau tag nrho (McEachin li al., 1993)). Ib qho ntxiv, kev vam meej dhau heev ntawm txoj kev kho ABA hauv kev kho tus cwj pwm tsis zoo tau ua rau lub tswv yim dav dav uas nws pom zoo nrog kev kho autism (Dillenburger thiab Keenan, 2009), ntau rau cov kev tsis txaus siab ntawm cov kws qhia, rau npe qee tus, ntawm kev tswj hwm kev coj tus cwj pwm (OBM), kev soj ntsuam xyuas tus cwj pwm, thiab kev cob qhia tsiaj; cov haujlwm uas siv kev tshawb xyuas tus cwj pwm siv rau cov xwm txheej tsis uas muaj autism. Ntawm kev txaus siab ntawm no yog qhov tseeb tias feem ntau ABA cov ntsiab lus yog ua raws li kev paub txog kev ua haujlwm tam sim no thiab kev tshuaj ntsuam xyuas kev coj ua: kev txheeb xyuas qhov tsim nyog tau ua haujlwm, txheeb xyuas qhov ua haujlwm tau txais txiaj ntsig ntawm kev coj cwj pwm tsis zoo, ntxiv dag zog tus cwj pwm zoo, kev rau txim txhaum tus cwj pwm tsis raug cai, thiab ntsuas kev sib raug zoo hauv ntau dua kev txheeb ze ntawm kev lag luam (piv txwv li, kev lag luam tus cwj pwm). Hauv lawv cov seminal ntu ntawm ABA, Baer, ​​Hma thiab Risley (1968) nteg tawm kev sib raug zoo ntawm kev ua haujlwm ntawm kev ua haujlwm thiab "kev xav tswv yim" qhov loj me ntawm ABA, txawm hais tias kev soj ntsuam tag nrho ntawm daim ntawv ntawd dhau ntawm kev saib xyuas ntawm qhov kev tshuaj xyuas tam sim no. Yog li, vim hais tias cov etiology ntawm ASD feem ntau pom tias yog neuro-caj, thiab vim hais tias lub luag haujlwm tseem ceeb hauv kev coj cwj pwm ua haujlwm hauv kev kawm thiab kev kho vis-vis-vis ASDs, kev nkag siab ntau dua ntawm neurobiology ntawm kev coj tus cwj pwm yuav pab peb kev xav txog ASDs.

Lo lus “tus cwj pwm muaj teeb meem loj” muaj ntau yam teeb meem txij li kev thab plaub ntawm tsev kawm ntawv mus rau qhov raug mob rau tus kheej. Cov cwj pwm muaj teeb meem loj tuaj yeem tshwm sim los ntawm cov menyuam yaus-kev loj hlob, tab sis ntau dua rau cov menyuam yaus uas muaj kev txhim kho thiab / lossis xiam oob khab. Kev coj tus cwj pwm ua teeb meem loj ua rau muaj kev sib raug zoo thiab kawm tsis tau zoo rau cov tib neeg vim lawv siv thiab zoo li tsis muaj kev cia siab. Kev kho mob yuav suav nrog kev ncua hauv tsev kawm ntawv, kev tso kawm hauv ib puag ncig tshwj xeeb, koom nrog kev ua txhaum kev cai lij choj, kaw hauv tsev lossis chaw haujlwm. Ntau dua li xaiv cov qauv no ua "hloov tsis raug" lossis "tsis tsim nyog", cov kws npliag siab thiab kws qhia ntawv tam sim no pom ntau tus cwj pwm muaj teeb meem no ua haujlwm. Hauv lwm lo lus, thaum pom tau tias yog kev coj tus cwj pwm ua haujlwm, lub zog txhawb ntxiv kev txhawb nqa cov teeb meem cwj pwm phem no tuaj yeem txiav txim siab, ntsuas tau, thiab hloov. Vim tias qhov xwm txheej txaus ntshai ntawm cov teeb meem no thiab kev nkag los ntawm cov teeb meem neurophysiological, txawm li cas los xij, ntau tus neeg muab kauv mus rau kev ua neej nyob nyuaj lossis tsis paub tab lossis muaj xwm txheej nrog kev kho tsis tau. Qhov tau hais tias cov teeb meem loj no tshwm sim los ntawm kev sib txuam ntawm caj ces-ib puag ncig tsuas yog tam sim no raug txiav txim siab tiag. Kev nkag siab zoo dua ntawm cov neurobiology ntawm kev coj tus cwj pwm ua haujlwm yuav txhim kho lwm txoj hauv kev kho.

Cov txheej txheem ntawm cov neural plasticity nyob rau hauv ntev ntev hloov pauv tus cwj pwm

Tam sim no zoo txais tias kev ua lub siab ntev txog kev hloov kho los ntawm kev ua haujlwm sib raug zoo yog qhov txiaj ntsig ntawm qhov kev hloov pauv tseem ceeb hauv lub hlwb: kev ntxiv dag zog ntawm kev sib txuas ntawm synaptic, rov txhim kho ntawm cov neural ensembles, synthesis ntawm cov protein tshiab, upregulation ntawm noob qhia, thiab kev hloov kho epigenetic. Cov. Lub sijhawm ntev ntawm qhov muaj zog (LTP) tau ua haujlwm ua ib qho ntawm feem ntau cov neeg cuam tshuam txog cov khoom siv ntsig txog kev siv yas thiab cov ntaub ntawv cuam tshuam rau NMDAR kev ua kom zoo raws li lub ntsiab lus tseem ceeb. Ntawd yog, ntau zaus qauv ntawm synaptic stimulation qhib NMDAR uas ua rau muaj kev cuam tshuam ntawm Ca2+, nyeg ua kom muaj ntau cov kev taw qhia, ob peb ntawm kev sib sau ua ke ntawm ERK (Kev Tso Tseg Kev Tso Tseg Kev Tso Taw hluav taws xob Kinase). ERK xav tias yuav tswj cov ntau yam hloov pauv ntawm cov txheej txheem uas ua kom muaj kev sib koom ua ke thiab tsim kho kev nco qab ntev (Levenson li al., 2004)). Muaj cov ntaub ntawv tseem ceeb tau lees tias lub luag haujlwm ntawm NMDAR-Ca2+-ERK ua qhov ntev hauv kev coj tus cwj pwm ntev ntev hloov thiab cim xeeb tsim nyob hauv qhov chaw ntshai tsam ntshai thiab Morris Dej Kev Ntxuam Dej (Atkins li al., 1998, Blum li al., 1999, Schafe li al., 2000); ib daim ntawv qhia ntxiv tsis ntev los no cuam tshuam qhov no cas hauv cov khoom noj khoom haus zoo rau khoom noj khoom haus, zoo li, txawm tias nyob hauv tus qauv invertebrate (Ribeiro li al., 2005)). NMDAR-induced neural plasticity, los ntawm transcriptional cov kev cai ntawm ERK txoj kev, yog li ntawd, muab cov neural sawv cev ntawm kev ua haujlwm txias thiab tus qauv zoo nkauj rau kev kawm ntev txog kev hloov pauv tus cwj pwm.

Hauv kev ncaj qha ntawm cov qauv no, Kelley thiab cov npoj yaig (Kelley li al., 1997) ua ntej tshawb txog lub luag haujlwm ntawm NMDAR kev ua kom tau zoo nyob rau hauv kev kawm ua haujlwm nyob rau hauv lub nucleus accumbens, lub vev xaib ua lub luag haujlwm tseem ceeb hauv txoj kev sib koom ua ke ntawm cov hnov, cov nqi zog thiab cov ntaub ntawv lub cev muaj zog. Ua raws li kev cai tswj hwm cov chav ua haujlwm thiab cov kev tshaj tawm xov xwm, kev txhaj tshuaj ntawm NMDAR antagonist (+/-) - 2-amino-5-phosphonopentanoic acid (AP-5) tau ncaj qha mus rau hauv nucleus accumbens core (NAc) ntawm cov zaub mov noj-txwv nas tam sim ntawd ua ntej thawj plaub, 15-feeb ntev, cov sijhawm ua haujlwm cov sijhawm ua haujlwm. Nrog tus kav mus ntxig tam sim no tso rau hauv chav, cov nias tau ntxiv dag zog nrog sucrose pellets2Cov. Thoob plaws thawj ntu 4 kev cob qhia, nas kho nrog AP-5 ua rau ob peb qib siab nias, tsis zoo li cov nas uas kho cov tsheb. Txhua tus nas tau tawm ntawm qhov tsis tau kho rau 5 kev sib ntsib tom ntej thiab ob pawg tau mus txog sai kawg ntawm qib qhov qog nias. Qhov tseem ceeb, microinjection ntawm AP-5 rau hauv NAc ua ntej 10th kev sib kho tsis muaj qhov pom txawv. Cov kev sim cais sib txawv pom tsis muaj qhov tshwm sim ntawm AP-5 ntawm kev tshwm sim rau qhov tsis xws luag, tsis noj zaub mov noj thiab lub cev muaj zog tus cwj pwm hauv kev txheeb xyuas tus kheej (piv txwv, phais, tsis pub, thiab lwm yam) nas. Yog li no, thaum piv rau saline-infusions, AP-5 infusions / NMDAR blockade nyob rau hauv NAC cuam tshuam kev kawm ua ntej, tab sis tsis muaj kev cuam tshuam los ntawm kev ua tau zoo tom ntej, thiab tsis NMDAR blockade cuam tshuam txog kev mob siab rau sucrose lossis spontaneous lub cev muaj zog tus cwj pwm. Yog li, cov ntaub ntawv no tshwm sim raws li kev pom zoo dav dav uas NMDAR kev ua haujlwm yog qhov tseem ceeb rau kev kawm los ntawm nws lub luag haujlwm hauv neural plasticity.

Cov kev tshawb fawb no, ua hauv Ann Kelley chav kuaj, yog thawj qhov qauv qhia txog NMDA cov neeg txais nyob rau hauv cov kev kawm ua haujlwm tsis pub dhau lub cortico-limbic-striatal network. Hernandez li al (Hernandez li al., 2005) rov hais dua qhov cuam tshuam no ncaj qha, thiab, tshwj xeeb, qhia pom lub sijhawm ua lub luag haujlwm rau NMDAR kev ua haujlwm hauv kev kawm ua haujlwm rau cov ntu tom qab AP-5 tsis muaj kev cuam tshuam kev kawm. Hauv lwm lo lus, NMDAR kev ua kom lub zog thaum raug rau hauv chav thiab cov neeg ua haujlwm ua haujlwm tau raug tseev kom ua rau kev kawm tshwm sim tab sis tsis tsim nyog tom qab kev sib kho. Qhov kev tshawb pom no cuam tshuam nrog kev hloov tshuaj yeeb tshuaj rau lwm cov kev coj cwj pwm, xws li ntshai tsam txias (Castellano li al., 1993)). Kelley li al. (Kelley li al., 1997) kuj tau qhia tias kev ua txhaum ntawm AP-5 mus rau lub plhaub nucleus accumbens (NAS) muaj qhov cuam tshuam zoo ntawm kev kawm ua haujlwm, qhia tias kev tswj hwm kev ua haujlwm nkag mus rau cov kev hloov pauv yas hauv lub network tsis zoo es muaj kev ua ub no neural ntawm NMDARs. Kev paub tseeb ntawm cov koom tes hauv lub network no tuaj yeem muaj txiaj ntsig ntau tus mob neuropsychiatric uas cuam tshuam txog kev kawm lossis plasticity-cuam tshuam tsis zoo los ntawm kev pab neurobiologist nrhiav pom qhov tsis zoo uas tseem ceeb rau kev coj tus cwj pwm thaum ib txhij paub meej txog kev haum xeeb ntawm kev coj tus cwj pwm.

Txhawm rau nthuav ntawm cov txiaj ntsig no, Baldwin li al. (2000) pom tias AP-5 infusions nyob rau hauv basolateral amygdala (BLA) thiab qhov nruab nrab prefrontal cortex (mPFC) kuj tsis muaj kev kawm ua haujlwm, tab sis AP-5 tsis muaj qhov cuam tshuam rau kev kawm ua haujlwm thaum infused nyob rau hauv dorsal (dSUB) lossis ventral ( vSUB) subiculum. Ntxiv mus, cov teebmeem no tau raug txwv dua rau thawj ntu kev tiv thaiv thaum NMDAR blockade tsis muaj kev cuam tshuam rau kev ua haujlwm txuas mus ntxiv tom ntej, tshwm sim lub cev muaj zog lossis kev pub mis. McKee li al. (McKee li al., 2010) txuas ntxiv lub luag haujlwm ntawm NMDAR kev ua haujlwm hauv kev ua haujlwm kom paub txog dorsal medial striatum (DMS) thiab anterior cingulate cortex (ACC), tab sis pom tsis muaj lub luag haujlwm rau orbito-frontal Cortex (OFC) hauv kev kawm ua haujlwm. Cov kev tshawb fawb tshawb pom tsis muaj pov thawj rau qhov ua kom lub zog lossis lub cev tsis txaus. Andrzejewski li al. (Andrzejewski li al., 2004) tseem tshawb nrhiav lub luag haujlwm ntawm NMDAR nyob rau hauv lub hauv paus loj ntawm lub amygdala (CeA) thiab 2 lwm striatal subnuclei. Thaum kev kawm tsis raug pom tau pom tom qab AP-5 cov kev tsis sib haum xeeb rau hauv CeA thiab posterior lateral striatum (PLS), tab sis tsis yog dorso lateral striatum (DLS), kuj tseem muaj cov txiaj ntsig zoo ntawm kev muaj lub cev muaj zog thiab kev coj noj coj ua nrog AP-5 infusions hauv CeA thiab PLS. Cov qhabnias no qhia tias cov kev kawm ua haujlwm nyob ntawm NMDAR kev ua haujlwm nyob rau hauv cov chaw sib faib tawm, txhua qhov ua tau zoo sib txawv, txhawb zog, lub cev muaj zog, thiab kev kawm ua haujlwm. Muaj tseeb, kev kawm yav tom ntej xav tau los ntsuas cov kev txwv ntawm cov "koom tes" network.

Ua ke, cov kev tshawb fawb xub thawj no qhia tias NAC, BLA, mPFC, DMS thiab ACC yog thaj chaw tseem ceeb hauv cortico-limbic striatal network tswj kev kawm ua haujlwm uas tsis xav tau rau kev ua haujlwm tom qab. Txawm hais tias kev ua haujlwm txuas ntxiv yuav qhia ntxiv cov network no thiab kab tias ntau lub luag haujlwm ntawm txhua cheeb tsam, xws li lub network zoo sib xws rau qhov kev kawm ntawm kev muaj yees lossis kev coj tsis zoo uas yuav ua tau ntau dua kev cai ib zaug tsim.

Dopamine kev koom tes hauv kev ua nqi zog thiab yas

Reinforcement-based processing tseem nyob ntawm lub zog loj ntawm mesocorticolimbic DA, suav nrog DA cov neurons hauv thaj chaw ventral tegmental thaj chaw (VTA) thiab lawv cov phiaj xwm mus rau nucleus accumbens (NAc), amygdala, prefrontal cortex (PFC), thiab lwm thaj chaw forebrain, tab sis qhov tseeb ntawm lub luag haujlwm ntawm DA hauv kev ua cov khoom plig tseem yog ib qho kev sib cav sib ceg. Ib qho kev tshawb pom thaum ntxov tau qhia tias DA-kho kom haum rau kev lom zem ntawm cov khoom plig vim tias muaj ntau yam khoom plig thiab tshuaj yeeb yaj kiab ua kom muaj zog cov kab mob mesocorticolimbic thiab lawv cov kev cuam tshuam uas cuam tshuam rau kev coj tus cwj pwm zoo ntawm cov feem ntau txhawb (Wise thiab Bozarth, 1985)). Thib ob qhov kev xav tau hais tias mesocorticolimbic DA neurons kawm thiab twv kev xa khoom plig, vim tias lawv tua hluav taws mus rau qhov kev xav tsis zoo, tab sis tsis ua rau qhov tsis muaj zog (lossis rau tus nqi zog lawv tus kheej) (Schultz, 1998, 2002)). Ib feem peb, cov kev xav muaj lub siab xav, hais tias mesocorticolimbic DA systems encode incentive properties los ntawm cov neural sawv cev ntawm stimuli thiab khoom plig. Qhov tseeb tiag, DA tsis koom nrog tus neeg lub siab nyiam ntawm cov khoom plig qab zib, tab sis yog qhov yuav tsum tau ua rau kev coj ua ntawm tib qhov khoom plig (Berridge thiab Robinson, 1998)). Thib plaub, qee tus tau sib cav hais tias mesocorticolimbic DA systems tso dag zog-cuam tshuam cov haujlwm uas cuam tshuam txhawb kev coj tus cwj pwm vim tias DA depletions muaj kev cuam tshuam me ntsis rau cov neeg ua haujlwm teb thaum rov ua haujlwm ntawm "yooj yim" (ib qho FR-5, piv txwv), tab sis muaj txoj kev cuam tshuam rau ntau lub sijhawm (Salamone li al., 1994, Salamone li al., 2001)). Txawm li cas los xij, thaum DA lub luag haujlwm hauv kev ua haujlwm ntawm kev coj ua yog tsis sib xws, qhov tseeb thiab cov ntsiab lus ntawm nws lub luag haujlwm tseem yuav yog txoj haujlwm ntawm kev npaj siv thiab theoretical orientation ntawm tus sim.

Peb tau sim ua lub luag haujlwm ntawm DA ntawm kev kawm ua haujlwm los ntawm D1R kev ua haujlwm hauv ntau yam ntawm cov qauv qub uas tau sau tseg saum toj no. Baldwin li al. (Baldwin li al., 2002b) pom tias D1R thaiv nyob rau hauv PFC kawm tsis tau zoo tab sis tsis muaj kev cuam tshuam ntawm kev ua tau zoo. D1R thaiv nyob rau hauv BLA thiab CeA kuj tseem tsis muaj kev ua haujlwm zoo (Andrzejewski li al., 2005)), raws li cov koob tshuaj koob. Txawm li cas los xij, lub luag haujlwm ntawm D1R hauv lwm cov qauv tau nyuaj rau kev sib cais los ntawm D1R-mediated cov tshuaj muaj yees. Piv txwv, Hernandez et al (Hernandez li al., 2005) tau ua rau muaj txiaj ntsig zoo rau kev coj ua raws li kev coj ua tom qab kev tiv thaiv ua ntej D1R blockade hauv NAc; txawm li cas los xij, lub qhov ncauj-ntxig rau hauv lub tais zaub mov (feem ntau suav hais tias yog Pavlovian cov lus teb muaj txiaj ntsig zoo) kuj yog qhov txo qis. Andrzejewski li al (Andrzejewski li al., 2006) pom tias D1R thaiv nyob rau hauv vSUB, tab sis tsis yog lub dSUB, kawm tsis kawm txoj kev kawm, tab sis ntxiv, kev cuam tshuam kev mob siab tau pom. Thaum nws pom zoo tias DA D1R kev ua haujlwm yog qhov tseem ceeb rau kev coj ncaj qha cov yas ua ke nrog kev kawm kev ua haujlwm, lub luag hauj lwm npliag tseem tshuav qee qhov nyuaj. Cov ntaub ntawv pov thawj tshwm sim, txawm li cas los xij, tau coj peb mus rau ib qho kev sib tham sib cuam tshuam tseem ceeb ntawm NMDAR thiab D1R hauv kev kawm ua haujlwm.

Intracellular convergence ntawm NMDAR thiab DA D1R kev ua kom nrov: cov khoom sib xws

Los ntawm cov ntaub ntawv pov thawj no, peb tau pib los theorize tias NMDARs ua ke nrog DA D1Rs, thiab tshwj xeeb hauv kev tshawb nrhiav qhov tsis sib xws ntawm cov lus taw qhia, ua lub luag haujlwm tseem ceeb hauv kev hloov kho cov kev teeb tsa, thiab yuav muaj kev cuam tshuam neural, uas yog qhov kev kawm paub tswj hwm (Jay et al., 2004)). NDMARs thiab DA D1Rs sib cuam tshuam nyob rau hauv ntau txoj hauv kev. Piv txwv, NMDA-dependant LTP hauv striatal slices raug thaiv los ntawm D1 tab sis tsis yog D2 cov thaiv kev ua haujlwm (Weiss li al., 2000). Nyob rau hauv vivo cov pov thawj rau NMDA-D1 kev sib cuam tshuam hauv cov xwm txheej yas txog kev qhia txog kev tiv thaiv kab mob pom tias LTP muaj nyob rau ntau qhov chaw thiab cov qauv. Piv txwv li, LTP nyob rau hauv hippocampal-prefrontal cortex synapses yog nyob ntawm kev sib koom tes ntawm NMDA thiab D1 receptors, ntxiv rau cov dej khov ua haujlwm nrog koom nrog PKA (Jay et al., 2004)). Hauv ob qho striatum thiab prefrontal cortex, D1 ua kom potentiates NMDA-receptor-mediated cov lus teb (Cepeda li al., 1993, Seamans li al., 2001, Wang thiab O'Donnell, 2001)). Lub hwj chim ntawm hippocampal-evoked spiking kev ua si ntawm accumbens neurons yuav tsum muaj kev sib koom tes ntawm ob qho D1 thiab NMDA receptors, thaum muaj qhov sib luag zoo sib xws rau cov amygdalo-accumbens pathway (Floresco li al., 2001b, a)). Cov kev tshawb fawb molecular ua tiav cov kev tshawb pom no, qhia NMDA-receptor dependence ntawm D1-mediated phosphorylation ntawm CREB (cAMP teb keeb los khi cov protein) (Das li al., 1997, Carlezon thiab Konradi, 2004), qhov kev hloov pauv ntawm kev xav tau hais tias yog kev hloov zuj zus los ntawm kev nco txog cov txheej txheem thiab cov protein tseem ceeb hauv xov tooj ntawm tes txoj kev cuam tshuam los ntawm kev siv yeeb tshuaj (Silva li al., 1998, Nestler, 2001)). Kev txhawb nqa hnyav kom muaj kev sib cav sib ceg ntawm kev ua kom sib luag tau los ntawm kev ua kom pom kev ua kom muaj lub zog ntev ntev ntawm kev ua tau zoo ntawm synaptic thaum corticostriatal excitation thiab dopaminergic activation yog ntu ua kom sib haum (Wickens li al., 1996)). Lwm cov ntaub ntawv qhia tias glutamate thiab dopamine teeb liab, dhau ntawm NMDA thiab D1 kev ua haujlwm, hloov mus ua kom muaj kev cuam tshuam ERK kev ua haujlwm hauv hippocampus thiab striatum, yog li rov tsim kho cov koom tes nrog kev kawm thiab siv tshuaj yeeb (Valjent li al., 2005, Kaphzan li al., 2006)). Yog li, muab cov tseev kom muaj rau txoj kev kawm, nws yog kev xav paub txog los ntawm kev sib koom tes ntawm dopaminergic thiab glutamatergic cov cim, thiab nws cov txiaj ntsig ntawm neuromolecular, ua cov xwm txheej ntes uas pib hloov cov kev hloov pauv uas ua rau muaj kev cuam tshuam cov kev hloov dua siab tshiab. Nws yog ib qho tseem ceeb kom nco ntsoov tias cov cascades heev yog qhov uas tau thov kom raug kho hauv qhov txheej txheem ntxiv (Hyman thiab Malenka, 2001).

Hauv kev sim ncaj qha ntawm qhov kev xav no, Baldwin li al. (Baldwin li al., 2002b) pom cov koob tshuaj ntawm AP-5 thiab R (+) - 7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH-23390) (a D1R antagonist) hauv PFC uas tsis muaj qhov cuam tshuam txog kev kawm kev ua haujlwm. Txawm li cas los xij, thaum ua ke thiab infused rau hauv PFC ntawm naïve nas, cov kev kawm ua haujlwm tau raug mob tsis txaus ntseeg, qhia tias muaj zog sib luag ntawm ob lub receptors. Ntawd yog, plasticity cuam tshuam nrog kev ua haujlwm kev coj ua tau nrog qhov me me ntawm NMDAR lossis D1R blockade, tab sis tsis yog ob qho tib si. Txawm hais tias peb tau pom qee qhov cuam tshuam los ntawm koob tshuaj, peb tau xav tsis thoob yog tias kev kawm ua haujlwm yog kev tshwm sim "txhua yam lossis tsis muaj dab tsi", zoo li kev kawm paub lub tswv yim (Osler thiab Trautman, 1961)). Hauv peb qhov kev paub, nws tau tshwm sim, tias peb cov nas ua ntej siv sijhawm nyob hauv chav tshawb nrhiav, txhaws ntswg, hnia, ntxhoo, tu, thiab lwm yam, thaum tsuas yog qee zaum qias-nias. Tom qab sib tham ob peb zaug, tswj cov nas "tau txais nws" thiab pib sib zog nias ntau ntau, thiab saib xyuas, tshawb nrhiav, hnia, tu cev, thiab lwm yam, tsawg dua (piv txwv li, cov lus teb rau qhov uas tsis muaj cov txheej txheem tshwm sim), ib yam li Staddon thiab Simmelhag qhia txog nyob rau hauv lawv cov kev sim qhia txog kev coj tus kheej txawv txawv (Staddon thiab Simmelhag, 1971)). Yog li ntawd, kev pib kawm paub yuav koom nrog "kev qhia taw tes" lossis qhov pib zoo li txoj hauv kev, nyob rau qhov sib txawv ntawm qhov hloov zuj zus thiab hloov pauv. Daim duab 1 qhia qhov nruam teb ntawm ob nas nrog cannulae tsom NAc. Ib qho yog infuse nrog lub tsheb ua ntej thawj tsib ntu thaum tus thib ob yog infused nrog AP-5. Qhov zoo sib xws hauv kev khiav dej num yog qhov txawv txav thiab zoo li ua tau raws li peb qhov kev xav: muaj qhov hloov maj mam thiab maj mam los ntawm kev teb, hloov, feem ntau sai sai, mus rau qhov siab, thiab khov kho ntawm tus lej teb. Nco ntsoov tias AP-5-kho cov nas tsuag qeeb hauv qhov kev hloov pauv no, hais tias qhov no "taw tes" raug ncua los ntawm NMDAR kev cuam tshuam.

Daim duab 1 

Cov tuam haujlwm loj zog nias thoob plaws ntu sijhawm. Cov cwj pwm ntawm ob tus neeg sawv cev nas, ib lub tsheb kho thiab ib qho AP-5-kho, ua raws li cov lus qhia hauv lub nucleus accumbens core (NAc) ua ntej thawj 5, 15-feeb ntev ntu. Infusions ceased tom qab ...

Thaum cov ntaub ntawv qhia txog tus cwj pwm no thiab lwm qhov kev soj ntsuam yuav nthuav tawm kev ntseeg txog qhov no "kev qhia taw tes" kev xav, nws yuav yog qhov tseem ceeb yog tias cov neurobiology ua raws,, rau qhov no yuav cuam tshuam "lub sijhawm tseem ceeb" rau cov kev kawm ua haujlwm thiab qhia cov hom phiaj rau kev cuam tshuam hauv lub sij hawm tos zam. Qhov tsawg kawg, nws pom tias cov kev kawm ua haujlwm tau muab coj los nthuav qhia ntsig txog vis-a-vis sab, ib puag ncig thiab neurophysiological kev sib raug zoo.

Tus qauv intracellular tseg ntawm kev kawm kev ua haujlwm

Cov tswv yim ntawm cov qauv molecular ntawm cov kev kawm (hais txog dav dav, tsis tas yuav kawm paub), raws li tau sau tseg ua ntej, tau txais ntau heev ntawm kev txaus siab. Peb tus kheej qhov kev tshawb pom hais txog lub luag haujlwm ntawm NMDAR kev ua haujlwm tau qhia kom meej meej los ntawm cov kev tshawb pom txog LTP. Txawm li cas los xij, cov teeb meem sib txuas hauv tsev kaw-tsev muaj lub luag haujlwm rau LTP yog tam sim no pom zoo. Lawv puas yog tib cov tub ceev xwm lub luag hauj lwm los kho dua txoj hauv kev rau txoj kev kawm thaum lub caij kawm? Baldwin li al (Baldwin li al., 2002a) inhibited protein kinase kev ua haujlwm, qhov tseem ceeb uas yuav tsum tau ua ntawm LP, nyob rau hauv NAc ntawm cov nas ua ntej kev kawm ua haujlwm nrog cov sib txuas nrog 1- (5-isoquinolinesulfonyl) -2-methylpiperazine dihydrochloride (H-7). Hauv kev sib cais ntawm cov nas, cAMP-dependant protein kinase (PKA) kev ua ub no tau raug cuam tshuam los ntawm cov tshuaj Rp-adenosine 3 ′, 5′-cyclic monophosphothioate triethlyamine (Rp-cAMPS) tam sim ntawd ua ntej kev kawm ua haujlwm. Hauv ob qho xwm txheej no, kev kawm tsis hnov ​​lus pom zoo hais tias cov kinase muaj protein feem ntau taw qhia, thiab PKA cov haujlwm tshwj xeeb, tsim nyog rau kev kawm ua haujlwm. Yog li, ob peb qhov tseem ceeb ntawm intracellular ntawm neural yas nrog txuam nrog kev kawm paub tau txheeb pom.

PKA, PKC thiab lwm cov dej num kinase protein sib tov sib zog, raws li ob peb tug qauv tseem ceeb, ntawm ERK (Valjent li al., 2005, Kaphzan li al., 2006)). Phosphorylated ERK (pERK) hloov mus rau ntawm lub hlwb ntawm neurons, qhov twg nws yog qhov hloov kho cov haujlwm ntawm CREB, dav pom tias yog qhov kev hloov kho tshwj xeeb ntawm kev sib kho ntawm neural plasticity ntev. Kuj ceeb tias, peb pom muaj lub luag haujlwm me ntsis rau ERK hauv kev kawm ua haujlwm. Ua ntej, U0126 (pERK inhibitor) tau muab tso rau hauv NAc ua ntej kev ua haujlwm ntawm kev kawm paub uas ua rau tsis muaj kev pom zoo (Daim duab 2, vaj huam sib luag A). Peb tau siv cov ntsiab lus zoo ib yam thiab kev npaj zoo ib yam li cov lus ceeb toom dhau los, txawm li cas los xij, muab peb qhov tsis muaj kev paub nrog cov tshuaj no, nws yog qhov ua tau hais tias qhov kev cuam tshuam tsis zoo no tshwm sim los ntawm cov teeb meem kev tsis paub. Thib ob, peb tshawb nrhiav ERK phosphorylation tom qab kev kawm ua haujlwm siv cov qauv Western blots thiab siv tshuaj ua lag luam. Ob pawg ntawm 6 nas tau khiav: 1) kev cob qhia ua haujlwm tshwj xeeb (FR-1 / VR-2) thiab 2) yoked tswj (tau txais tib cov xov tooj ntawm cov tsis muaj zog tab sis tsis tas yuav siv zog nias kom tsim lawv). Cov paj hlwb tau sau nyob rau hauv tsib feeb ntawm 5th kev sib kho thiab ua tiav los ntawm Western blot. Tsis muaj qhov sib txawv hauv ERK, pERK lossis pERK / ERK piv tau muab sau tseg hauv txhua qhov ntawm 12 cov chaw kawm, suav nrog NAc (Daim duab 2, vaj huam sib luag B). Muaj me ntsis, tab sis qhov xwm txheej, qhov cuam tshuam hauv pERK hauv vSUB thiab PFC, constituting ntxhib ib feem 20% nce piv rau cov tswj yoked. Txawm hais tias cov txiaj ntsig tau tshwm sim hauv keeb kwm, nws yog qhov tsawg heev thiab qhov ua tau yog hom 1 yuam kev muab cov lej ntawm kev sib piv peb tau ua. Thib peb, peb tau sim ua kom pom qhov tseeb, thiab cia siab tias, ib nrab-ntau yam pERK thoob plaws lub hlwb tom qab kev kawm ua haujlwm los ntawm kev siv cov txheej txheem txhaj tshuaj tiv thaiv kab mob ntawm cov paj hlwb dawb-ntab. Cov nas no tau coj los soj ntsuam rau Western blot thwmsim, txawm li cas los xij tom qab khaws hlwb, tag nrho cov paj hlwb raug hlais thiab cov tshuaj tua kab mob PERK tau siv los ua kom thaj chaw pERK.

Daim duab 2 

Lub luag haujlwm ntawm ERK hauv kev kawm txoj haujlwm. Vaj Huam Sib Luam A qhia tau hais tias U0126 ua txhaum rau NAc ua ntej kev kawm tsis muaj kev cuam tshuam thaum piv rau kev tswj hwm lub tsheb. Lub vaj huam sib luag B qhia tsis yog ERK-1 tsis yog ERK-2 phosphorylation tau nce ntawm cov nas kawm kev ua haujlwm ...

Ib zaug ntxiv, thaum muaj qhov tseem ceeb PERK staining hauv PFC thiab vSUB, muaj tsawg heev hauv NAc (Daim duab 2, vaj huam sib luag C). Cov ntaub ntawv no tau ua raws nraim nrog cov txiaj ntsig ntawm Westerns thiab qhia txog lub luag haujlwm tsawg rau ERK hauv kev ua haujlwm kev kawm, hauv kev sib piv ntawm lub ntau ntawm cov kev tshawb fawb pom txog lub luag haujlwm tseem ceeb rau kinase no hauv lwm hom kev kawm (Levenson li al., 2004, Chwang li al., 2006, Kaphzan li al., 2006)). Txawm li cas los xij, sib txig NMDAR / D1R kev ua kom rov tuaj yeem tuaj yeem nrhiav ERK-tus kheej cov paib qhia kev rau lub nucleus.

CREB lub luag haujlwm hauv neural plasticity

pERK qhov kev hloov kho ntawm pCREB yog qhov tseem ceeb thaum kawm vim tias CREB yog qhov kev hloov pauv zuj zus lossis txo qhov hais tawm ntawm qee cov noob. Cov noob no tau xav tias yog tus tswj hwm ntawm kev coj los ua ke ntawm cov roj ntsha tshwj xeeb uas ua cov tsev tsim ntawm cov khoom txais, qog thiab lwm yam kev teeb tsa tseem ceeb rau lub plawv neural. Qhov tseeb tiag, peb tau pom tias cov synthesis protein hauv NAc yog qhov tseem ceeb thaum kawm kev ua haujlwm (Hernandez li al., 2002)). Siv cov protein synthesis inhibitor, anisomycin, peb pom tias tam sim ntawd kev sib txuas lus tom qab kawg rau hauv NAc thaiv kev kawm tom qab txuas ntxiv, cuam tshuam txog kev hloov pauv ntawm thiab tsib novo protein ua kom sib haum. Qhov zoo siab, infusions 2 lossis 4 teev tom qab kev sib kho tsis muaj cov nyhuv; anisomycin kuj tsis muaj qhov cuam tshuam thaum sim ntsuas kev ntsuas los yog kev ntsuas kev pub mis. Ib zaug ntxiv, nws pom tau tias peb tau pom cov yam ntxwv tseem ceeb ntawm kev tswj nruj, ntu thiab ib puag ncig, cov qauv kev kawm uas muaj ntau cov qauv, receptors, cov paib tawm suab, thiab tam sim no, synthesis protein.

Qhov pom ntawm protein synthesis dependency ntawm kev kawm ua haujlwm yog ib qho tseem ceeb tshaj plaws hauv peb qhov chaw kuaj, nws tau muab lo lus nug qhib loj txog qhov tshwj xeeb ntawm cov synthesis protein no. Vim li no peb thiaj li ua ntau qhov kev sim rau txheeb xyuas kom pom cov noob twg uas yuav muab tso ua ke / upregulated thaum kawm paub. Siv tus qauv hauv situ cov kev sib xyaw ua ke nrog cov nas kho tau zoo ib yam nkaus li cov uas siv rau kev tshawb fawb PERK Western, peb pom tias cov caj ces ntxov sai (IEGs) Homer1a thiab egr1 (zif-268) tau tshaj tawm, piv rau cov tswj hwm nas, tam sim ntawd tom qab 3rd kev kawm ua haujlwm nyob rau hauv kev txiav txim siab sib txawv cortico-limbic-striatal nodes. Kev hais tawm noob tau tsa kom dav thoob plaws lub cortex thiab striatum, thiab qee kis, tus kabmob hippocampus, tab sis kuj ceeb tias, tsis yog nyob hauv ventral striatum (piv txwv li, NAc). Hauv kev sib piv rau "pab pawg kawm thaum ntxov", pawg thib ob ntawm cov nas uas tau ntsib 23 kev kawm ua ntu zus. Tsis tau Homer1a thiab egr1 kev hais tawm tam sim no raug txo piv rau pab pawg kawm thaum ntxov, nyob rau hauv tag nrho cov nuclei kawm, qhia tias cov noob no koom nrog plasticity-cuam tshuam lub luag haujlwm thaum ntxov, tab sis tsis tau tom qab kis, mus rau cov haujlwm ua haujlwm. Muaj ib qho kev zam tsuas yog lub tshuab ua pa (ventilateral striatum) (VLS), uas zoo li tseem nyob rau, hais lus txhob kaw, "ntawm txoj kab" txawm tias lub sijhawm ua haujlwm ntev. Txawm hais tias ntau tus kws tshawb fawb tau hu ua kev ua haujlwm ntev li "kev tsim tus cwj pwm" cov lus teb no tseem yoog raws thiab yoog raws (xav txog "kev ua tau ib ntus" ntawm kev txhawb nqa lossis txo qhov uas yuav pom thaum cov kev sib txuas lus tshem tawm lossis tshem tawm): nws yog qhov nthuav xav los xav tias tus VLS yuav suav ua ke txoj kev soj ntsuam no.

Lwm cov glutamate receptors kuj pab hauv plasticity cuam tshuam nrog kev kawm kev ua haujlwm

Homer1a yog xav kom muaj kev tswj hwm thiab tsheb pab pawg 1 metabotrophic glutamate receptors (mGluR1 thiab mGluR5). mGluR5s muaj zog ua haujlwm ntawm NMDARs los ntawm kev hloov pauv lawv cov permeability rau Ca2+ (Pisani li al., 2001), nce qhov kev xav tau nthuav dav uas ib lub tshuab ntawm NMDAR-induced plasticity yuav vam khom ntau mGluR5 kev ua haujlwm. Tsis ntev los no, peb tau sim ncaj qha rau lub luag haujlwm ntawm mGluR5 kev ua haujlwm ntawm kev kawm ua haujlwm los ntawm kev thaiv lawv cov kev ua nrog cov tshuaj 3 - ((2-Methyl-4-thiazolyl) ethynyl) pyridine (MTEP). Peb cov txiaj ntsig ua ntej pom tau tias thaiv ntawm mGluR5 kev ua haujlwm hauv DMS cuam tshuam kev kawm, txawm hais tias rov qab soj ntsuam ntawm qhov kev tshawb pom no tseem niaj hnub ua.

Peb tau tshawb txog AMPA kev ua kom lub zog thiab cov haujlwm ua haujlwm tau zoo. Hernandez li al. (2002) qhia lub sijhawm-sijhawm ua haujlwm rau AMPAR ua rau hauv NAc thaum kawm kev ua haujlwm. Cov nyhuv, txawm li cas los xij, thev rau ntau qhov kev sib tham thiab tej zaum yog qhov tshwm sim ntawm qee qhov down-regulation lossis kev ua haujlwm ntev ntev ntawm cov glutamate receptors. Txawm tias qhov kev sib cav no xav tau kev txhawb nqa ntxiv, peb pom nws xav tsis thoob tias kev tiv thaiv ua ntej ntawm kev tiv thaiv ntawm AMPAR yuav ua rau muaj kev cuam tshuam ntev ntev uas cuam tshuam nrog kev tiv thaiv tom qab kev tiv thaiv, uas ua rau tsis muaj kev hloov pauv hauv kev kawm.

Epigenetic hloov thaum lub sijhawm kawm

Ntxiv rau kev ua kom muaj kev hloov pauv, NMDAR thiab D1R kev ua haujlwm kuj tseem ua rau muaj kev hloov kho, xws li histone acetylation, rau chromatin, cov protein uas npaj thiab ua rau zam DNA genomic. Cov kev hloov kho no muab cov kev lees txais neeg tuaj koom nrog rau kev hloov pauv ntawm gene / silencing thiab cuam tshuam rau kev nkag mus rau DNA los ntawm lub tshuab hloov tsheb. NMDAR kev ua kom zoo thiab muaj kev cuam tshuam rau cov paib, xws li histone 3 (H3) acetylation, tswj hwm kev coj tus cwj pwm ntev mus ntev, Pavlovian ntshai kev tswj hwm thiab pab Morris Dej Tshawb kev kawm (Atkins li al., 1998, Blum li al., 1999, Schafe li al., 2000)). Peb nyuam qhuav pib tshawb xyuas seb puas muaj kev kawm ua haujlwm rau kev hloov kho chromatin. Tseeb, Keeb Kwm H3 acetylation qhia tau nce ntxiv hauv qee cov qauv thaum ua haujlwm ntawm kev coj tus cwj pwm, piv rau sucrose pub tswj. Hauv qhov kev sim no, cov qaij nas nias ntawm RI-30 "cov sijhawm tau muab xaum 30 feeb tom qab kev sib tham. Hlwb raug sau, ua tiav thiab tsim tawm nrog anti-acetyl-Histone H3 (Lysine 14) siv cov qauv kev cai.

Qhov zoo siab, txheeb ze rau kev tswj hwm yoked, peb pom kom txhawb siab histone H3 acetylation hauv DMS, tus qauv dav dav suav hais tias yog qhov tseem ceeb txhawb rau kev kawm ua haujlwm. Cov no yog qee yam ntawm cov ntaub ntawv thawj zaug uas peb paub txog kev qhia keeb kwm hloov kho thaum kawm kev ua haujlwm. Txawm li cas los xij, nce qib hauv ntiaj teb qib siab ntawm histone H3 acetylation tuaj yeem yog qhov txiaj ntsig ntawm kev hloov kho ntawm cov txhawb ntawm cov noob dua li IEGs thiab, ntxiv mus, cov nas uas siv hauv qhov kev sim no muaj cov kev kawm dav dav. Yog li, cov ntaub ntawv ntxiv ntawm cov chaw ntawm cov acetylation thaum kawm kev ua haujlwm yog qhov tsim nyog. Txawm li cas los xij, cov ntaub ntawv no, txuas nrog ntau lwm cov ntawv tshaj tawm, pom zoo hais tias cov txheej txheem epigenetic tau koom thaum kawm kev ua haujlwm. Cov kev hloov pauv ntev ntev, zoo li histone acetylation, tuaj yeem pab peb nkag siab qhov xwm txheej ntawm kev coj ua, nws qhov kev hloov pauv, thiab rov ua kom rov zoo li qee qhov mob tsis txaus rau kev kho.

Cov txheej txheem Epigenetic kuj pom tau hloov kho thaum kev tswj hwm tshuaj thiab kev kawm. Thaum lub sijhawm cocaine tswj hwm tus kheej, ib qho D1R-dependant paradigm, chromatin kev hloov kho tau tshwm sim hauv qee thaj tsam ntawm striatum ntawm cov txhawb nqa ntawm ntau cov yas-hais txog cov noob, xws li Cbp, NR2B, Psd95, Thiab GluR2. Cbp yog qhov tseem ceeb rau kev ua kom lub zog ntawm CREB thiab muaj kev ua keeb kwm acetone acetyltranferase (HAT) kev ua haujlwm (Shaywitz thiab Greenberg, 1999)). Transgenic nas qhia ib daim foos ntawm tsis siv Cbp muaj ob peb qhov kev kawm tsis txaus (Wood et al., 2005)). NR2B, subunit ntawm NMDAR complex, muaj qhov glutamate binding site thiab yog qhov tseem ceeb rau LTP, thaum lub subunit NR2A tsis yog (Foster li al., Foster et al., 2010). Cov NR2B subunit yog phosphorylated los ntawm CaMKII, dephosphorylated los ntawm PP1, thiab mediates NMDAR sab hauv (Roche li al., 2001). Psd-95 inhibits NR2B-tus neeg nruab nrog cev hauv NMDAR (Roche li al., 2001) thiab tswj hwm kev ua kom nrov nrov hauv zej zog thiab kev ua kom ruaj khov ntawm NMDARs (Li li al., 2003). GluR2 yog subunit ntawm AMPAR thiab muaj qhov tseem ceeb phosphorylation site kuj tau hloov los ntawm intracellular protein kinase thiab protein phosphatase kev ua ub no. Phosphorylation ntawm GluR2 qee tswj hwm AMPARs permeability rau calcium thiab lwm yam kev suav. Qhov zoo siab, mGluR5 kev txhawb nqa hauv cov nas dorsal striatum induces GluR2 phosphorylation, qhov cuam tshuam los ntawm NMDAR kev thaiv kev ua haujlwm (Ahn thiab Choe, 2009).

Ib qho qauv ntawm sab nruab nrab ntawm tes ntawm kev kawm kev ua haujlwm

Tawm tsam no cov thim rov qab ntawm kev ua haujlwm zoo thiab nthuav dav, peb tsim tus qauv ntawm NMDAR-DA D1R kev sib xyaw ua ke uas tuaj yeem txhawb kev nkag siab ntau ntxiv ntawm neural plasticity koom nrog kev kawm ua haujlwm. Daim duab 4 qhia txog qhov kev xav ntawm qhov tsis tseem ceeb uas glutamate-coded piav thoob hlo / cov ntaub ntawv ua cov paib NMDAR, thiab AMPAR, ua rau Ca2+ influx rau hauv lub cell. DA kev ua haujlwm ntawm D1Rs ua kom adenyl cyclase (AC, tsim muaj tus taw dub), thiab nyeg, cAMP. Ob txoj kev taw qhia cov kab kev sib tham hauv ntau qhov chaw, piv txwv li CaM, ntxias los ntawm NMDAR kev ua kom lub zog, cuam tshuam AC (txawm hais tias qhov no yog qee qhov sawv cev me ntsis dhau los). PKA ua kom MEK siv, tab sis kuj txwv tsis pub Ras / Raf (raug xaiv nrog txoj kab tuav kab), tawm tswv yim tias tsis tsuas yog ua cov kab kev sib tshuam, tab sis kuj tseem tuaj yeem sib tw rau cov phiaj xwm kev ua haujlwm.

Daim duab 4 

Qhov tso qauv ntawm sab hauv uas qhib kev ua haujlwm leatning. Kev ua haujlwm thiab kev hloov pauv koom nrog neural plasticity cuam tshuam ua haujlwm NMDAR thiab DA D1R kev ua haujlwm thoob plaws hauv cortical-striatal-limbic networks. Daim duab no nthuav qhia qhov tseem ntsiab ...

Ob peb lub ntsiab lus ntawm qhov sib xyaw ua ke tau qhia tau, feem ntau tshwj xeeb tshaj yog ua kom CREB, MEK thiab ERK. Kev cuam tshuam los cuam tshuam txog kev muaj txiaj ntsig ntsig txog plasticity kuj tseem ua rau pom kev, zoo li CREB-depend transmissions ntawm IEGs Arc, Homer1a, thiab egr1. Homer1a cov neeg lag luam mGluR5 receptors (sawv cev los ntawm ib tus cim grey), uas tom qab ntawd muaj zog Ca2+ influx ntawm Gαq-protein txuas ntxiv phospholipase C (PLC) kev ua ub no (qhov kev ua yeeb yam no sawv cev nrog lub xub daj thiab ua kom lub teeb pom kev zoo); mGluR5 kev ua haujlwm kuj potentiates DA D1R ua kom. Arc thauj mus rau cov synapses tsis ntev los no, yuav ua tau ib qho “tagging” lub luag hauj lwm. Tsis ntev los no, cov ntaub ntawv tawm tswv yim qhia lub luag haujlwm tseem ceeb rau Arc thiab ERK hauv AMPAR-subunit tso nkag thiab cov kev cai ntawm L-hom voltage gated calcium channel. DARPP-32, ua haujlwm los ntawm PKA kev ua haujlwm, tsub zuj zuj hauv lub nucleus, txwv tsis pub cov protein phosphatase 1 (PP1) kev ua haujlwm, uas yog ncaj qha rau hauv kev hloov kho chromatin los ntawm kev ua haujlwm ntawm qhov ua kom zoo dua (cim los ntawm ib nrab ntawm lub voj voos-taw qhia xub "kev loj hlob" ib pawg phosphate. )). Cov kev hla dhau los (HDACs) cov yeeb yam yog sawv cev nrog cov kab rov tav "taub" pawg ntawm cov keeb kwm 3 (H3). Cov histone kev hloov kho so los yog ua kom cov kua roj chromatin thiaj li ua kom zoo lossis tsim kev tiv thaiv cov ntawv sau (cov kev hloov pauv tshwj xeeb hauv daim duab tsis tas sawv cev rau qhov hloov kho tiag tiag ntawm qhov kev txhawb nqa ntawm IEGs rau kev hloov ntaub ntawv) (Daim duab 4 yog raws (Sweatt, 2001, Kelley thiab Berridge, 2002, Haberny thiab Carr, 2005, Ostlund thiab Balleine, 2005, Valjent li al., 2005)). Yog li ntawd, txoj kev sib txuas ntawm neuromolecular ntawm cov ntaub ntawv los ntawm cortico-striatal-limbic NMDAR thiab DA D1R muab cov khoom zoo tuaj yeem ua tiav rau cov khoom yas nyob rau hauv kev kawm tau txais txiaj ntsig. Qhov tshwj xeeb lub hlwb nuclei thiab cov neurons sawv cev hauv cov qauv no tsuas yog tam sim no los ua kom pom tseeb, tab sis yuav muaj kev cuam tshuam tseem ceeb striatal, limbic, thiab chaw cortical. Peb qhov kev ntseeg tsis txaus ntseeg yog tias nruab nrab ntawm cov neurons nruab nrab, hauv striatum tshwj xeeb, tej zaum yuav ua tau zoo rau cov haujlwm yas-vim muaj lawv qhov tsis xws luag ntawm qhov hluav taws xob uas muaj hluav taws xob tsis muaj teeb meem uas ua rau muaj kev hloov pauv hauv xeev (Houk thiab Wise, 1995) nyob rau hauv kev sib xyaw nrog kev sib txuam ntawm cov thoob plaws, glutamate-coded cortical, limbic, thiab thalamic afferents, nrog rau cov ntsiab lus monoaminergic los ntawm midbrain.

Kelley thiab cov npoj yaig (Kelley li al., 1997) xub pib hais lub luag haujlwm tseem ceeb rau NAc hauv neural plasticity thiab kawm kev ua haujlwm. Tseeb, peb lub chaw sim tau tshawb txog lub luag haujlwm ntawm nucleus accumbens nyob rau ntau qhov kev coj tus cwj pwm uas siv cov txheej txheem ntau txoj kev qhia (xws li, kev tshuaj ntsuam xyuas kev coj tus cwj pwm, kev coj tus yam ntxwv, molecular thiab cellular neuroscience, thiab lwm yam). Dr. Kelley yog ib tug ntawm cov kws tshaj lij rau cov qauv, physiology, sib txuas thiab ua haujlwm ntawm nucleus accumbens. Txawm li cas los xij, qee qhov ntawm peb tus kheej kev sim tshwm sim cuam tshuam nrog Dr. Kelley cov lus tshaj tawm thawj zaug. Kev ntseeg qhov tsis txaus ntseeg MEK / ERK koom nrog NAc thaum lub sijhawm kawm kev kawm thiab tsis muaj lub cev tawm tau ua ob qho kev zam rau qhov kev sib cav tias kev ua kom cov yas hauv NAc yog qhov tseem ceeb rau kev kawm ua haujlwm. Ua ntej, nws yuav yog tias MEK / ERK tsis koom nrog kev kawm kev kawm txhua qhov chaw hauv lub hlwb. Peb qhov kev tshawb fawb ntawm 12 lwm qhov chaw tau txais qhov sib txawv ntawm kev kawm thiab kev tswj hwm yoked. Tej zaum, MEK / ERK txoj hauv kev muaj feem cuam tshuam thaum "lub sijhawm tseem ceeb" lossis "tipping taw tes" thaum cov nas zoo li "tau" thiab peb cov kev tshawb fawb tsis muaj kev daws teeb meem hauv ntiaj teb los tshawb pom cov nyhuv no, tshwj xeeb yog kev ua kom ERK yog qhov hloov pauv thiab cov kev tshwm sim sai. Tej zaum peb cov koob tshuaj ntawm U0126 tau qis dhau los txwv qhov ua kom ERK. Txawm li cas los xij, ib qho kev xav yuav tau sib txig sib luag yog tias CREB-mediated cov kev hloov pauv ntawm cov noob koom nrog hauv neural plasticity yog ua kom ncaj qha los ntawm lwm cov kev taw qhia, xws li PKAc lossis CAM (saib. Daim duab 4), kev hla txoj MEK / ERK pathway. Thiab tej zaum, peb tsis tau txheeb xyuas qhov tseem ceeb tshaj plaws-plasticity ntsig txog cov noob los yog myriad ntawm cov kev hloov pauv epigenetic rau NAc neurons uas muaj peev xwm ua tau thiab muaj kev ua haujlwm sai. Peb cia siab tias yuav koom nrog cov lus nug no zoo tib yam thiab zoo siab uas Ann tau ua.

Clinical qhov cuam tshuam

Cov kev xav ntawm qhov kev soj ntsuam no yog cov qauv uas tau hais hauv Daim duab 4 tuaj yeem qhia kev kho mob ntawm ntau cov teeb meem kuaj mob. Ntawm qhov pom tseeb yog kev quav yeeb tshuaj, rau kev quav yeeb tshuaj muaj kev cuam tshuam rau ntau yam ntawm tib cov txheej txheem molecular koom nrog los ntawm kev kawm kev ua haujlwm. Nyob rau xyoo tas los no, qee qhov kev pom zoo tshaj plaws hauv kev tshawb fawb txog kev quav tshuaj yeeb yog qhov qhia pom qhov sib tshooj ntawm cov txheej txheem kev kho mob rau kev quav yeeb tshuaj thiab kev muaj feem cuam tshuam nrog kev kawm (Hyman thiab Malenka, 2001, Nestler, 2001, Wang et al., 2009)). Peb paub tseeb tias ntau qhov kev tshuaj xyuas nyob rau hauv tsab ntawv tshaj tawm no tau qhia meej txog kev sib raug zoo ntawm kev quav yeeb tshuaj thiab kev kawm hais txog khoom plig. Kev lees paub, qhov kev sib raug zoo no tau ua pov thawj rau qhov tseem ceeb ntawm peb txoj kev nkag siab txog kev quav, txawm li cas los xij, peb xav hais txog qee qhov txuas tshiab tseem ceeb ntawm Dr. Kelley kev ua haujlwm ntawm kev kawm ua haujlwm nrog cov ntaub ntawv tshiab thiab tshawb pom ntawm lwm qhov teeb meem hauv chaw kho mob. Cov kev cuam tshuam ntawd yuav ua ob qhov laj thawj: 1) cov teeb meem hauv tsev kho mob uas cuam tshuam nrog kev kawm tsis taus uas tuaj yeem tau txais txiaj ntsig zoo los ntawm kev nkag siab zoo dua txog kev ua haujlwm li cas. kev kawm tau nyaij los ntawm cov txheej txheem neuromolecular ntawm plasticity thiab 2) cov teeb meem kuaj mob cuam tshuam nrog txuas ntxiv mus, twb kawm, thiab tejzaum nws tiv taus, tus cwjpwm kev ua haujlwm thiab nws cov qauv ntawm neuromolecular. Cov xwm txheej tom kawg no suav qhov teeb meem ntawm kev quav, peb xav tias, vim tias nws raug saib xyuas raws li kev coj ua ua ntu zus nrog kev puas tsuaj thiab ua kom ntev ntev ntawm qhov tshwm sim.

Raws li tau sau tseg hauv cov lus qhia, qhov tsis meej pem pom kev xav tau tam sim no xav tias yuav cuam tshuam 1 ntawm 88 tus menyuam. Kev sib txuas lus tsis sib xws, teeb meem kev sib raug zoo thiab kev coj cwj pwm ua qauv zoo li tus cwj pwm tsis meej, txawm hais tias kev sib txuas lus tuaj yeem yog ib txwm muaj rau cov menyuam yaus nrog Asperger. Ntxov muab kev pab kho tus cwj pwm ntxov ntxov (EIBT), raws li cov qauv tswj hwm, ua cov caj qaum ntawm cov kev kho mob uas tau txais txiaj ntsig zoo kawg. Qhov kev kho thaum ntxov no, uas yog tus kheej muaj txiaj ntsig thiab cov ntsiab lus teb, ib txwm muaj tsawg kawg 40 xuaj moos ntawm kev kho ib zaug hauv ib lub lis piam, feem ntau tau ntau xyoo. Cov ntaub ntawv taw qhia tias cov kev cuam tshuam ntxov ua ntej pib, qhov ua tau zoo dua ntawm kev ua tiav. Hauv ntau qhov xwm txheej no (qee qhov kev kwv yees nyob nruab nrab ntawm 40-50%), ua kom tiav kev nkag mus rau hauv chav kawm ib txwm muaj peev xwm nrog tsawg kawg lossis tsis muaj kev txhawb nqa ntxiv (Lovaas, 1987, Sallows thiab Graupner, 2005, LeBlanc thiab Fagiolini, 2011)). Cov kev tshawb pom no txheeb ze neural plasticity raws li kev tsav tsheb hauv kev ua tiav ntawm EIBT. Cov kws tshawb nrhiav hauv zej zog kev kho qhov mob ua dab tsi yog dav kwv yees txog "ntu tseem ceeb" ntawm txoj kev txhim kho uas sib haum nrog kev siab neural plasticity (LeBlanc thiab Fagiolini, 2011)). Yog li, peb qhov kev tshawb fawb ntawm cov kev kawm ua haujlwm yuav muaj ob qhov cuam tshuam tau: 1) nws yog qhov ua tau ntawm lub hlwb "hlwb" yuav txo tau cov yas phom, thiab tsuas yog los ntawm kev ua haujlwm zoo thiab kev kho mob yog cov kev txo tau kov yeej thiab 2) nws yuav ua tau, nrog kev nkag siab ntxiv ntawm kev kawm ua haujlwm, txhawm rau ua kom lub sijhawm ntev ntawm cov khoom yas kom cov menyuam yaus laus muaj peev xwm tau txais txiaj ntsig los ntawm kev kho.

Txawm tias nws yog qhov kev sib cav sib cav heev uas ua txoj kev kawm ua haujlwm, EIBT, thiab neural plasticity qhia underlie ASDs, muaj ntau yam kev sib hloov ntawm kev txhawb nqa cov pov thawj. Txhawm rau pib, tus thawj coj ua kom muaj mob ntawm ASDs yog Fragile X syndrome (FXS), tib lub qe trinucleotide rov ua teeb meem nrog FMR1 gene. FXS cuam tshuam nrog kev kawm tsis taus, kev coj tus cwj pwm tsis zoo nrog rau qee yam kev qoj ib ce (feem ntau ntawm lub ntsej muag). Lub FMR1 gene encodes Fragile X hlwb ruamqauj protein (FMRP), uas yuav tsum muaj rau kev txhim kho neural (Crawford li al., 2001, Antar li al., 2004)). Ntxiv rau, FMRP xav hloov kho cov pab pawg 1 mGluR kev ua si, thiab tsis muaj FMRP kev ua haujlwm ua rau tsis ua hauj lwm NMDAR LTP (Antar li al., 2004)). Peb cov kev ua haujlwm tsis ntev los no nrog mGluR5 inhibitor MTEP qhia txoj haujlwm tseem ceeb hauv kev kawm rau cov txais no nyob rau hauv "li qub". Cov chaw muag tshuaj raws li kev hloov kho mGluR5 kev soj ntsuam tam sim no raug tshawb fawb txog kev siv hauv tib neeg nrog FXS (Hagerman li al., 2012).

Lwm qhov kev muaj autism, hu ua "regressive autism" vim tias cov menyuam yaus uas muaj daim ntawv no loj hlob ib ntu thiab tom qab ntawd "plam kev sib txuas lus" thiab kev txawj sib raug zoo, tsis ntev los no tau cuam tshuam rau kev ua tsis zoo ntawm PKA thiab catalytic subunit ntawm PKA, uas yog c-isoform. Thaum muab piv rau tom qab lub tsev tuag mus rau cov kev tswj tsis tau autistic, regressive tsi txawj has lug frontal cortices pom qhov tsawg kev ua ub no thiab kev qhia ntawm PKA (Ji li al., 2011)). Tsis muaj qhov sib txawv tau sau tseg hauv lwm cov cheeb tsam cortical, thiab tsis muaj qhov sib txawv ntawm qhov uas tsis muaj qhov txawv txav thiab qhov uas tsis yog autistic. Yog li, kev tsim kab mob autism tuaj yeem txuas rau PKA-mediated phosphorylation ntawm cov protein thiab cov ncauj lus tsis tuaj yeem tiv thaiv. Ib zaug ntxiv, peb txoj haujlwm tau ua lub luag haujlwm tseem ceeb rau PKA hauv kev kawm paub txog kev ua haujlwm, hloov mus ua haujlwm zoo nrog rau kev ua haujlwm tsis ntev los no ntawm cov kab mob autism.

Rubenstein-Taybi syndrome (RTS) yog ib qho kev hloov pauv tshwj xeeb uas tshwm sim los ntawm kev hloov ntawm CREB khi cov protein (CREBBP) noob. Luv luv, lub thim dav, lub ntsej muag txawv, thiab qhov nyuaj mus rau qhov tsis yooj yim kawm tau paub tus cwj pwm RTS (Bartsch li al., 2010)). Ntawm qhov tseem ceeb ntshuam ntawm no yog qhov pom tseeb ntawm kev kawm kev ua haujlwm, kev ua haujlwm CREB, thiab RTS. Tej zaum cov menyuam yaus nrog RTS tuaj yeem tau txais txiaj ntsig los ntawm EIBT lossis qee cov kev kho mob tshuaj uas pab txhawb, ntxiv, lossis cov khoom siv CREB kev hloov kho ntawm cov ntawv sau cov noob. CREB phosphorylation zoo li tswj IEG lub luag haujlwm thiab cov synthesis ntawm cov protein tshiab, thiab yuav tswj kev neural plasticity cuam tshuam nrog kev kawm kev ua haujlwm.

Thaum kawg, peb cov ntaub ntawv thiab intracellular qauv cuam tshuam cov txheej txheem epigenetic raws li lub luag haujlwm rau lub caij ntev ntawm kev coj ua tus cwj pwm. Peb qhov kev xam pom ntawm tus cwj pwm ua raws li "kev tsim tus cwj pwm", rov ua qauv qhia txog qhov tshwm sim rov tshwm sim, thiab lub sijhawm tsis tshua nco qab lub sijhawm cuam tshuam nrog kev ua haujlwm rov ua haujlwm pab txhawb lub tswv yim no. Qhov tseeb tiag, ntau tus cwj pwm muaj teeb meem loj tau ua pov thawj ntau dua rau kev kho mob, yog li ua rau muaj kev txwv tsis pub muaj kev sib raug zoo, tswj kev siv tshuaj lom neeg, pw hauv tsev kho mob thiab chaw haujlwm. Txawm li cas los xij, cov kev qhia dav dav ntawm cov cuab yeej kev kuaj mob, feem ntau hu ua "kev soj ntsuam cov teeb meem kev coj cwj pwm" lossis "kev ntsuam xyuas tus cwj pwm coj ua haujlwm" (FBA), tau tsim los nrhiav kev tswj hwm kev sib raug zoo rau cov kev coj tus cwj pwm phem no. Feem ntau, cov kev coj cwj pwm no yog saib raws li kev khiav dej num, ntxiv dag zog los ntawm kev saib xyuas, nkag mus rau cov khoom nyiam / cov haujlwm, lossis khiav tawm / zam dhau ntawm qhov tsis xav tau (Lerman thiab Iwata, 1993)). Nrog cov ntaub ntawv no hauv tes, txoj kev kho tuaj yeem qhia ncaj qha xws li muab lwm qhov los ntawm kev txhawb nqa lossis lwm cov neeg ua haujlwm sib raug zoo uas tsim cov xwm txheej xav tau, muaj peev xwm ntev ntev tom qab pib kev ua haujlwm los ntawm kev coj tus cwj pwm tsis tsim. Puas yog tias muaj kev nkag siab ntau ntxiv ntawm kev ua haujlwm ntawm kev kawm ua haujlwm tuaj yeem muab cov tshuaj kho mob rau lub hom phiaj, zoo li histone acetylation, uas txhim kho cov neeg ua haujlwm tu ncua thiab / lossis txhawb kev kawm rau kev ua haujlwm tshiab?

Thaum muaj ntau cov kev xav no yog cov neeg xav tau heev, kev ua haujlwm ntawm Dr. Ann Kelley thiab cov npoj yaig hauv thaj tsam ntawm kev kawm ua haujlwm yog qhov yuav ceeb toom, tsawg kawg, qhov thiab chav kawm ntawm kev quav yeeb tshuaj. Peb kuj tseem xav ntxiv peb txoj kev xav thiab kev tshawb pom los pab kom nkag siab txog kev kawm tsis raug cuam tshuam nrog ASDs, FXS thiab RTS, nrog rau qhov cuam tshuam nrog kev muaj zog ntawm qee qhov kev ua txhaum loj rau cov haujlwm.

​ 

Daim duab 3 

Acetylated histone H3 ceev thaum lub sijhawm ua haujlwm ua haujlwm tau nce siab hauv DMS ntu txheeb ze rau kev tswj hwm yoke, tab sis tsis nyob hauv NAc, PFC, lossis ACC. Tus sawv cev pictomicrographs ntawm ntu DMS uas tsuas nyob rau hauv sab xis.

highlights

Kev kawm ua haujlwm yog lub hauv paus coj tus cwj pwm

Kev kawm paub yuav tsum muaj kev ua haujlwm ntawm NMDAR thiab D1R receptors

Cov khoom sib tsoo sab hauv sab nraub qaum yog qhov cuam tshuam rau lub sijhawm kawm kev ua haujlwm

Cov tshuaj yuav kho lub hom phiaj rau kev quav yeeb tshuaj, tsi txawj has lug, thiab coj tus cwj pwm teeb meem loj

Tshooj ntawv

1Xav txog qhov tiag, tab sis tsis yooj yim kwv yees, nqi "pw tsis tsaug zog" los yog siab ntxhov siab rau kev noj qab haus huv thiab kev nyab xeeb ntawm cov niam txiv ntawm cov menyuam muaj teeb meem txog kev siv yeeb tshuaj.

2Thawj qhov txheej txheem no tau ua haujlwm rau ob lub pas dej, nrog VR-2 lub sijhawm tau ua haujlwm ntawm ib ntawm lawv, tiv thaiv kev sib txuam nrog nas. Thib ob, lub zog "tsis muaj tseeb" tau pib thaum xub thawj los ntsuas qhov hloov chaw lossis kev coj tus cwj pwm tsis sib xws. Peb pom nws ua superfluous thiab nyuaj, ntau dua qhia ntxiv, kev txhais lus tom ntej. Yog li, peb tau tshem tawm txoj haujlwm thib ob hauv kev kawm tom qab. Ntxiv rau, peb tau hloov lub sijhawm pib pabcuam rau FR-1, thaum maj mam khiav mus rau VR-2 thaum 5, hloov 4, pib ntu. Cov kev hloov pauv me me no tsis tshwm sim cuam tshuam ib qho twg ntawm peb qhov kev tshawb pom pom tias muaj ntau qhov kev hloov ntawd.

Publisher's Disclaimer: Qhov no yog ib phau ntawv PDF ntawm daim ntawv sau cia uas tau txais los rau ntawv tshaj tawm. Raws li kev pabcuam rau peb cov neeg siv khoom peb tau muab cov ntaub ntawv ntxov no ntawm phau ntawv sau. Cov ntawv sau npe yuav muab luam tawm, sau ntawv, thiab rov soj ntsuam cov pov thawj uas tau tshwm sim ua ntej nws luam tawm hauv nws daim ntawv kawg. Thov nco ntsoov tias thaum lub sijhawm cov txheej txheem ua txhaum yuav raug tshawb tau uas yuav cuam tshuam cov ntsiab lus, thiab tag nrho cov kev cai lij choj uas tsis txaus siab uas siv rau phau ntawv sau txog.

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