Ukubaluleka kweklinikhi ye-neuroplasticity kumanethiwekhi omhlaba we-corticostriatal ngexesha lokufunda ngokusebenzayo (2013)

I-Neurosci Biobehav Rev. Umbhali-mbhalo wesandla; ifumaneka kwi-PMC 2014 Nov 1.

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PMCID: PMC3830626

I-NIHMSID: I-NIHMS464960

Inguqulelo yokugqibela yomhleli yeli nqaku iyafumaneka apha Neurosci Biobehav Rev

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Abstract

I-Dopamine kunye ne-glutamate zenza imisebenzi ebalulekileyo kwi-neural plasticity, ukufunda kunye nenkumbulo, kunye nokulutha. Iithiyori zangoku zibanga ukuba ezi zimbini, iinkqubo ze-neurotransmitter ezisasazwa ngokubanzi zidlala indima edibeneyo ekuqhubeni ulwazi olukhuthazayo kunye nolunxulumano. Ukubonakaliswa okudibeneyo kwezi nkqubo, ngakumbi nge-dopamine (DA) D1 kunye ne-glutamate (Glu) i-N-methyl-D-aspartate receptors (NMDAR), ibangela i-cascades ebalulekileyo ye-intracellular signaling ekhokelela kutshintsho kwisakhiwo se-chromatin, i-gene expression, i-synaptic plasticity, kwaye ekugqibeleni ukuziphatha. Iziyobisi ezikhobokisayo ziphinda ziphembelele i-neuroadaptations yexesha elide kumanqanaba emolekyuli kunye ne-genomic abangela utshintsho lwesakhiwo oluguqula unxibelelwano olusisiseko. Ewe, ubungqina bokuba iziyobisi zokuxhatshazwa zibandakanya i-D1- kunye ne-NMDA-mediated neuronal cascades ekwabelwana ngayo ngokufunda okuqhelekileyo komvuzo kubonelela ngowona mbono ubalulekileyo kwizifundo zangoku kwi-neurobiology yokulutha. I-neuroadaptations enje ngeziyobisi inokuba negalelo ekusetyenzweni kolwazi kunye nokuziphatha, okukhokelela ekwenziweni kwezigqibo kakubi, ukuphulukana nolawulo, kunye nokunyanzeliswa okuphawula ukuba likhoboka. Ezo mpawu zikwaqhelekile kwezinye izifo ezininzi ze-neuropsychiatric. Iingxaki zokuziphatha, ezithathwa njengobunzima obunxulunyaniswa nokufunda okusebenzayo kunye nokuziphatha, zibonelela ngemingeni enyanzelisayo kunye namathuba awodwa onyango afuna ukufundwa ngakumbi. Uphononongo lwangoku lubalaselisa umsebenzi odibeneyo ka-Ann E. Kelley kunye noogxa, ebonisa indima ebalulekileyo kungekhona kuphela kwi-NMDAR, i-D1 receptors (D1R), kunye ne-cascades yazo ehambelana nayo, kodwa kunye nezinye i-Glu receptors kunye ne-protein synthesis ekufundeni okusebenzayo kulo lonke ixesha. inethiwekhi ye-cortico-striatal-limbic. Umsebenzi wakutsha nje uye wandisa impembelelo yokufunda enomdla kwiinkqubo ze-epigenetic. Ukuqonda okungcono kwezi nkqubo kuya kunceda ekufumaneni unyango ukubandakanya iinkqubo ezinxulumene ne-neural plasticity kunye nokukhuthaza uhlengahlengiso lokuziphatha olusebenzayo.

Ukufunda ngokusebenza yenye yezona ndlela zisisiseko zokuziqhelanisa nokuziphatha (Rescorla, ngo-1994). Ngokutshintshana nendawo yaso, isilwanyana siyakwazi ukufunda ngeziphumo zezenzo zaso, kwaye ngaloo ndlela siguqule imeko yangoku ngokuziphatha okutsha ukuvelisa iimeko ezilunge ngakumbi (Isikhumba, i-1953). Utshintsho oluyisiphumo kwindlela yokuziphatha luyamangalisa kwaye luhlala ixesha elide. Abanye abaphengululi baye baphikisa ukuba ukufunda okusebenzayo sisiseko "solwazi" (Schnaitter, ngo-1987), inokugxininisa “ubuchule bokuyila” (UPryor et al., ngo-1969), sisiseko sokwenziwa kwezigqibo, kwaye inegalelo kubume obunganyangekiyo bokukhotyokiswa ziziyobisi. Njengoko ukuziphatha kwento ephilayo kuguqulwa ziimeko ezingalindelekanga zempendulo, iindlela zefiziyoloji ziyasebenza eziqinisekisa ukuba olu tshintsho luphantse lube sisigxina; "Zigximfizwa," njengoko uThorndike ecinga (I-Thorndike, 1911). No-Skinner uye wabonisa ukuba iingxaki zempendulo ziyasitshintsha: “Abantu basebenza ehlabathini, baliguqule, kwaye utshintshile nabo ngemiphumo yesenzo sabo.” (Isikhumba, i-1957, iphe. 1).

Ngenxa yobuninzi bobudlelwane bokuziphatha okusebenzayo kubomi bethu bengqondo, i-neurobiology yokufunda okusebenzayo (oko kukuthi, ukufumana impendulo yokuqala) ifumene ingqwalasela encinci ngokumangalisayo xa ithelekiswa nezinye iinkqubo zokufunda ezisisiseko ezifana nokufunda indawo (umz., uMorris). I-Maze yamanzi) okanye i-Pavlovian ukwesaba imeko. Nangona kunjalo, ubudlelwane obusebenzayo bucingelwa ukuba busebenza phantse ngalo lonke ixesha lobomi bethu kunye neemeko ezininzi ezibalaseleyo ze-neuropsychiatric: ukusetyenziswa kakubi kweziyobisi, i-autism, kunye nezinye iingxaki ezinzima zokuziphatha. Kolu hlaziyo, sigxininisa amashumi amabini eminyaka ophando lomsebenzi ka-Ann Kelley, xa wayefuna ukuqonda ngakumbi i-neurobiology yokufunda okusebenzayo ngethemba lokuba i-molecular, cellular, kunye ne-genomic constituents zokufunda okusebenzayo, eziqiniswe kwiinethiwekhi ezisasazwayo, ziya kuba. yazisa iindlela ezingcono zonyango.

Iingxaki ezixabisa kakhulu zokuziphatha kunye nokuziphatha komsebenzi

Ukusetyenziswa kakubi kweziyobisi yenye yezona ngxaki ziyingozi kakhulu, ezilahlayo kunye neendleko zempilo yezempilo e-US, kwaye ngokwenene, ihlabathi. Ukusetyenziswa kakubi kweziyobisi kweli lizwe kuphela kudla imali eqikelelwa kwiibhiliyoni ezingama-484 zeerandi ngonyaka kwiingxaki ezinxulumene nempilo, iingozi, ukuphelelwa ngumsebenzi nokuhlawula imali yeinshorensi.Umgaqo-nkqubo, 2001). Kukwaqikelelwa ukuba abantu abangama-540,000 bafa nyaka ngamnye ngenxa yezifo ezinxulumene neziyobisi. Olu qikelelo alubandakanyi iindleko ezingezizo ezemali okanye ezingathanga ngqo ezihlawulwe ngabazali1, amaqabane, abantakwabo, abahlobo, kunye noluntu lwethu ngokubanzi. Kusenokwenzeka ukuba wonke ummi kwesi sizwe uchatshazelwe kakubi kukusetyenziswa gwenxa kweziyobisi kunye nokukhotyokiswa ngandlela ithile (umzekelo, njengexhoba lezenzo zolwaphulo-mthetho, ingozi yemoto, okanye ngezenzo zelungu losapho). Ukukhotyokiswa ziziyobisi kujongwa ngakumbi ngokwemigaqo yotshintsho olusisiseko kwiindlela zokuqonda kunye nokuziphatha, kugxininiswa ekunxibelelaniseni isinyanzelo sokukhobokisa kutshintsho lwe-pathological kwizigqibo kunye neekhowudi zonxibelelwano lweemvakalelo (Everitt et al., 2001). Ke, ukuqonda ngcono iinkqubo zokufunda ezisebenzayo kunokuphucula ukuqonda kwethu nge-neural causation yokulutha.

Ngokutsho kwamaZiko oLawulo lweSifo (CDC), i-1 kubantwana be-88 baye bachongwa njenge-autism (Ulawulo, ngo-2012). Iziphazamiso ze-Autism spectrum (ASDs) zichaphazela abantu abavela kuzo zonke iintlanga kunye namanqanaba entlalo-qoqosho. Ii-ASD zinokubonakala zisenza buthathaka kwaye zifuna ukhathalelo lobomi bonke ngeendleko ezinkulu kuluntu (>$3,000,000 umntu ngamnye)Ganz, 2007). Kutshanje, uhlalutyo lokuziphatha olusetyenzisiweyo (ABA) kunye nezinto ezithile eziphuma kuyo (umzekelo, iDenver Start Model), egxininisa ukuguquguquka nokuguquguquka kwezemfundo, intlalontle, kunye nokuziphatha konxibelelwano, ibonise ukuba ukuzuza okumangalisayo kunokwenzeka ngonyango lwakwangoko, olunamandla.ISallows kunye neGraupner, ngo-2005, UDawson et al., 2010, Warren et al., 2011). Ezi modeli zibe nempumelelo kangangokuba abantwana abaninzi abafunyaniswa beno-ASD bathi kamva babizwe ngokuba “ababonakali” kwiintanga zabo. Abanye baqikelela ukuba i-40-50% yabantwana abafunyaniswa benoluphazamiseko banokulungiseka ngokupheleleyo.McEachin et al., 1993). Ukongeza, impumelelo eyothusayo yonyango lwe-ABA kunyango lwe-autism ikhokelele kumbono oqhelekileyo wokuba ihambelana nonyango lwe-autism.UDillenburger noKeenan, ngo-2009), kakhulu ukungathandeki kwabasebenzi, ukubiza ezimbalwa, zokulawulwa kokuziphatha kombutho (OBM), uhlalutyo lokuziphatha kweklinikhi, kunye nokuqeqeshwa kwezilwanyana; ubuchwephesha obusebenzisa uhlalutyo lokuziphatha olusetyenziswa kwiimeko hayi okubandakanya uphazamiseko. Okubangela umdla apha kukuba uninzi lwemigaqo ye-ABA isekwe kwithiyori yangoku yokusebenza kunye nohlalutyo lovavanyo lokuziphatha: ukuvavanya indlela yokusebenza enokwenzeka, ukuchonga imisebenzi elandela isimilo esingafanelekanga, ukomeleza isimilo esihle, ukohlwaya ukuziphatha okungafunwayo, kunye nokuvavanya obu budlelwane ngendlela engafanelekanga. imeko enkulu yentlalo-qoqosho (umzekelo, uqoqosho lokuziphatha). Kwisiqwenga sabo se-seminal kwi-ABA, i-Baer, ​​i-Wolf kunye no-Risley (i-1968) ibeka ubudlelwane obucacileyo phakathi kwethiyori yokusebenza kunye ne-"conceptual systems" umlinganiselo we-ABA, nangona uphononongo olupheleleyo lwelo phepha lungaphaya kolu hlaziyo lwangoku. Ke, ngenxa yokuba i-etiology yee-ASDs ubukhulu becala ijongwa njenge-neuro-genetic, kwaye ngenxa yendima ebalulekileyo yokuziphatha edlalwayo ekufundeni kunye nonyango lwe-ASDs, ukuqonda ngakumbi kwe-neurobiology yokuziphatha okusebenzayo kunokunceda ukucinga kwethu. Ii-ASDs.

Ibinzana elithi “ukuziphatha ngengxaki enkulu” liquka imiba eyahlukahlukeneyo ukususela ekungcungcuthekisweni esikolweni ukusa ekuzenzakalisani ngokugqithiseleyo. Iingxaki ezinzima zokuziphatha zinokuboniswa ngabantwana abakhula ngokuqhelekileyo, kodwa zixhaphake kakhulu kubantwana abakhubazekeyo kunye/okanye ngokwasengqondweni. Iingxaki zokuziphatha ezimandundu zidala imiqobo enkulu kwezentlalo nezemfundo kubantu ngabanye ngenxa yobunzulu babo kunye nokubonakala bengenakuqikelelwa. Unyango lusenokubandakanya ukunqunyanyiswa esikolweni, ukubekwa kwiindawo ezizodwa, ukusebenzisana nenkqubo yobulungisa kulwaphulo-mthetho, ukuvalelwa entolongweni okanye ukufakwa kweziko. Kunokuba zithathelwe ingqalelo ezi patheni njenge "maladaptive" okanye "engafanelekanga," izazi ngengqondo kunye nabafundisi ngoku bajonga uninzi lwezi ngxaki zokuziphatha njengezinto ezisebenzayo. Ngamanye amazwi, xa kujongwa njengokuziphatha okusebenzayo, iimeko zokuqinisa ezikhuthaza ezi ngxaki zinzima zokuziphatha zinokumiselwa, zivavanywe, kwaye zitshintshwe. Ngenxa yobungozi bezi ngxaki kunye nokungenwa kwemiba ye-neurophysiological enokubakho, nangona kunjalo, abantu abaninzi bangena kwiimeko ezinzima okanye ezinganyamezelekiyo zokuphila okanye iimeko zokunqongophala konyango. Ithuba lokuba ezi ngxaki zinzima zivele ngendibaniselwano yemfuzo-esingqongileyo kuphela ngoku kuqwalaselwa nzulu. Ukuqonda ngcono i-neurobiology yokuziphatha okusebenzayo kunokuphucula iindlela zonyango.

Iinkqubo zeplastiki ye-neural ekutshintsheni ukuziphatha okuhlala ixesha elide

Ngoku yamkelwe kakuhle ukuba uhlengahlengiso oluhlala ixesha elide lokuziphatha ngokweemeko ezisebenzayo zisisiphumo sotshintsho olubalulekileyo kwingqondo: ukomelezwa konxibelelwano lwe-synaptic, ukuphinda kuqwalaselwe ii-neural ensembles, ukuhlanganiswa kweeproteni ezintsha, ukunyuswa kokuchazwa kofuzo, kunye nokuguqulwa kwe-epigenetic. . Ixesha elide elinokwenzeka (LTP) lisebenze njengenye yeenkqubo eziye zabuzwa rhoqo zeplastiki ezinxulumene ne-data kunye nedatha ichaphazela ngamandla ukusebenza kwe-NMDAR njengesiganeko esibalulekileyo sokuqala. Oko kukuthi, iipateni eziphezulu zokuphindaphinda kwe-synaptic stimulation zivula i-NMDAR ekhokelela ekungeneni kweCa.2+, ngokuvula iindlela ezininzi zokubonisa iimpawu, ezininzi zazo zidibanisa kwi-ERK (i-Extracellular Receptor signaling Kinase). I-ERK icingelwa ukuba ilawule izinto ezahlukeneyo zokubhala ezilungelelanisa ukubunjwa kunye nokuzinzisa iinkumbulo zexesha elide (Levenson et al., 2004). Kukho iinkcukacha ezibalulekileyo eziqinisekisa indima ye-NMDAR-Ca2+-I-ERK i-cascade ekutshintsheni ukuziphatha okuhlala ixesha elide kunye nokwakhiwa kwememori kwimeko yokwesaba kunye nokufunda kweMorris Water Maze (Atkins et al., 1998, I-Blum et al., 1999, Schafe et al., 2000); Ingxelo yamva nje ibandakanya le cascade kwimeko yokuvuzwa kokutya, ngokunjalo, nangona kwimodeli ye-invertebrate (URibeiro et al., 2005). I-NMDAR-induced neural plasticity, ngokusebenzisa imimiselo yokubhaliweyo ngendlela ye-ERK, ngoko ke, ibonelela ngokubonakaliswa kwe-neural ye-operating conditioning kunye nomzekelo omhle wokufunda utshintsho oluhlala ixesha elide lokuziphatha.

Ekwandiseni ngokuthe ngqo le modeli, uKelley kunye noogxa (Kelley et al., 1997) okokuqala kuphonononge indima ye-NMDAR yokwenziwa kusebenze ekufundeni okusebenzayo ngaphakathi kwe-nucleus accumbens, indawo ecingelwa ukuba idlale indima enkulu ekudityanisweni okuntsonkothileyo kweemvakalelo, umvuzo kunye nolwazi lwemoto. Ukulandela ukuhlala kumagumbi asebenzayo omgangatho osebenzayo kunye noqeqesho lwamaphephancwadi, iinaliti zomchasi we-NMDAR (+/-) -2-amino-5-phosphonopentanoic acid (AP-5) zenziwe ngokuthe ngqo kwi-nucleus accumbens core (NAc) yokutya okuthintelweyo. iigundane ngokukhawuleza phambi kwezine zokuqala, i-15-minute-long, i-operating conditioning sessions. Nge-lever ngoku efakwe kwigumbi, ii-presses zomelezwa nge-sucrose pellets2. Kuzo zonke iiseshoni zoqeqesho zokuqala ze-4, iigundane eziphathwe nge-AP-5 zenze ii-lever-presses ezimbalwa kakhulu, ngokungafaniyo neegundane eziphathwa ngesithuthi. Zonke iigundane zishiywe zingaphathwanga kwiiseshoni ze-5 ezilandelayo kwaye amaqela omabini afikelela ngokukhawuleza kumanqanaba asymptotic e-lever-pressing. Okubalulekileyo, i-microinjection ye-AP-5 kwi-NAc ngaphambi kwe-10th Iseshoni ayizange ibe neziphumo ezibonakalayo. Uvavanyo olwahlukileyo alufumananga siphumo se-AP-5 ekutyeni okuzenzekelayo, okungenamiqathango kunye nokuziphatha kwemoto ekuphathweni ngokufanayo (umzekelo, utyando, ukuvinjwa, njl.) iimpuku. Ke ngoko, xa kuthelekiswa ne-saline-infusions, i-AP-5 infusions/i-NMDAR blockade kwi-NAC yonakalise ukufunda okusebenzayo kokuqala, kodwa ingenasiphumo ekusebenzeni okulandelayo, kwaye ibhlokhi ye-NMDAR ayizange ichaphazele inkuthazo ye-sucrose okanye ukuziphatha okuzenzekelayo kwemoto. Ke, ezi datha zibonakala zihambelana nemvumelwano ngokubanzi yokuba ukusebenza kwe-NMDAR kubalulekile ekufundeni ngendima yayo kwi-neural plasticity.

Ezi zifundo, ziqhutywe kwilabhoratri ka-Ann Kelley, zezokuqala ezibonisa indima yezamkeli ze-NMDA ekufundeni okusebenzayo ngaphakathi kwendawo engundoqo yothungelwano lwe-cortico-limbic-striatal. UHernandez et al (Hernandez et al., 2005) iphindaphinde ngokuthe ngqo le mpembelelo, kwaye, ngokuphawulekayo, ibonise indima yexesha elilinganiselweyo lomxholo wokusebenza kwe-NMDAR ekufundeni okusebenzayo kwi-post-seshini i-AP-5 infusions ayinayo impembelelo ekufundeni. Ngamanye amazwi, ukusetyenziswa kwe-NMDAR ngexesha lokuvezwa kwigumbi kunye neemeko ezingalindelekanga ezisebenzayo zazifuneka ukuze kufundwe kodwa akuyomfuneko emva kweseshoni. Oku kufunyaniswayo kuyachasana neziphumo zeziyobisi zasemva kweseshoni kwamanye amalungiselelo okuziphatha, anje ngemeko yoloyiko (Castellano et al., 1993). Kelley et al. (Kelley et al., 1997) Kwakhona kwabonisa ukuba ukunyanzeliswa kwe-AP-5 kwi-nucleus accumbens shell (NAS) ibe nefuthe elincinci kakhulu ekufundeni okusebenzayo, ebonisa ukuba ukulungiswa kwe-operating kubandakanya utshintsho lweplastiki kwinethiwekhi ecacileyo kunokuba i-neural action ye-NMDAR. Ukucaciswa okuchane ngakumbi kolu nxibelelwano kunokuba luncedo kwiimeko ezininzi ze-neuropsychiatric ezibandakanya ukufunda okanye iintsilelo ezinxulumene ne-plastiki ngokunceda i-neurobiologists ukuchonga i-nuclei ecacileyo ebalulekileyo ekuqhubeni ukuziphatha ngelixa ngaxeshanye zichonga ulamlo oluthile lwe-receptor yokuziphatha okuthethiweyo.

Ukwandisa kwezi ziphumo, u-Baldwin et al. (2000) yafumanisa ukuba i-AP-5 infusions kwi-basolateral amygdala (BLA) kunye ne-medial prefrontal cortex (mPFC) nayo iphazamise ukufunda okusebenzayo, kodwa i-AP-5 yayingenayo impembelelo ekufundeni okusebenzayo xa ifakwe kwi-dorsal (dSUB) okanye i-ventral ( vSUB) subiculum. Ngaphaya koko, ezi ziphumo ziphinde zakhawulelwa kwisigaba sokuqala semeko njengoko uthintelo lwe-NMDAR lungenampembelelo ekusebenzeni okusebenzayo okulandelayo, ukuziphatha okuzenzekelayo kwemoto okanye ukondla okuzenzekelayo. McKee et al. (McKee et al., 2010) yandisa indima yokuvula i-NMDAR ekufundeni okusebenzayo kwi-dorsal medial striatum (DMS) kunye ne-anterior cingulate cortex (ACC), kodwa ayizange ifumane indima ye-orbito-frontal cortex (OFC) ekufundeni okusebenzayo. Uphononongo lolawulo alufumananga bungqina benkuthazo okanye ukusilela kwemoto. Andrzejewski et al. (Andrzejewski et al., 2004) iphinde ihlolisise indima ye-NMDAR kwi-nucleus ephakathi ye-amygdala (CeA) kunye ne-2 enye i-striatal subnuclei. Ngelixa iintsilelo zokufunda zabonwa emva kokungeniswa kwe-AP-5 kwi-CeA kunye ne-posterior lateral striatum (PLS), kodwa hayi i-dorso lateral striatum (DLS), bekukho neziphumo ezinzulu kwimotor ezenzekelayo kunye nokuziphatha kokutyisa nge-AP-5 infusions kwi-CeA. kunye ne-PLS. Ezi ziphumo zibonisa ukuba ukufunda okusebenzayo kuxhomekeke ekusebenziseni i-NMDAR ngaphakathi kothungelwano olusasaziweyo, nganye inokuba negalelo elahlukileyo leemvakalelo, inkuthazo, imotor, kunye nokufunda. Ngokuqinisekileyo, izifundo ezizayo ziyafuneka ukuvavanya imida yenethiwekhi "yomsebenzi".

Ngokudibeneyo, olu phando lokuqala lubonisa ukuba i-NAC, i-BLA, i-mPFC, i-DMS kunye ne-ACC ziindawo ezibalulekileyo kuthungelwano lwe-cortico-limbic striatal elawula ukufunda okusebenzayo okungafunekiyo ekusebenzeni kamva. Nangona umsebenzi owongezelelekileyo unokucacisa le nethiwekhi kwaye mhlawumbi iindima ezithe ngqo zommandla ngamnye, uthungelwano olunjalo lubonakala ngathi lusisiseko sokufunda ngokuziphatha okukhobokisayo okanye okungalunganga okunokulawulwa ngakumbi xa sele kusekiwe.

Ukubandakanyeka kweDopamine ekusebenzeni komvuzo kunye neplastiki

Ukusetyenzwa okusekwe ekomelezeni kuxhomekeke kakhulu kwiinkqubo ze-mesocorticolimbic ze-DA, ezibandakanya i-neurons ye-DA kwindawo ye-ventral tegmental (VTA) kunye noqikelelo lwabo kwi-nucleus accumbens (NAc), i-amygdala, i-prefrontal cortex (PFC), kunye neminye imimandla ye-forebrain, kodwa indalo kanye yendima yeDA ekuqhubeni imivuzo isengumthombo wengxabano. Enye ithiyori yangaphambili yacebisa ukuba i-DA-yalamla ulonwabo lomvuzo kuba imivuzo emininzi yendalo kunye neziyobisi ivuselela iinkqubo ze-mesocorticolimbic kwaye ibhlokhi yabo iyonakalisa indlela yokuziphatha yabaninzi abaqinisayo.Ubulumko kunye no-Bozarth, 1985). I-hypothesis yesibini ithi i-mesocorticolimbic DA neurons ifunda kwaye iqikelele ukuhanjiswa komvuzo, kuba itshisa kwi-stimuli-conditioned stimuli, kodwa hayi kwi-stimuli engenamiqathango (okanye kwimivuzo ngokwayo) (Schultz, 1998, 2002). Okwesithathu, i-hypothesis enempembelelo kakhulu, ithi iinkqubo ze-DA ze-mesocorticolimbic zifakela iipropathi zenkuthazo ezibangelwa kukubonakaliswa kwe-neural ye-stimuli kunye nemivuzo. Ewe, i-DA ayilamleli impembelelo ye-hedonic yemivuzo emnandi, kodwa iyafuneka kwindlela yokuziphatha ejolise kwimivuzo efanayo (EBerridge noRobinson, i-1998). Okwesine, abanye baye baxoxa ukuba iinkqubo ze-DA ze-mesocorticolimbic zigcina imisebenzi enxulumene nomzamo ochaphazela ukuziphatha okomeleziweyo ngenxa yokuba ukuchithwa kwe-DA kunempembelelo encinci ekuphenduleni komsebenzi xa kuqiniswa kwishedyuli "elula" (i-FR-5, umzekelo), kodwa zibe neziphumo ezimangalisayo kwiishedyuli ezisebenzayo (Salamone et al., 1994, Salamone et al., 2001). Nangona kunjalo, ngelixa indima ye-DA ekuziphatheni okusebenzayo ingaguquguqukiyo, imo kanye neenkcukacha zendima yayo kusenokwenzeka ukuba zihlala zingumsebenzi wolungiselelo olusetyenzisiweyo kunye nokuqhelaniswa nethiyori yomlingi.

Siye savavanya indima ye-DA ekufundeni okusebenzayo sisebenzisa umsebenzi we-D1R kuninzi lwezakhiwo ezichazwe ngasentla. Baldwin et al. (UBaldwin et al., 2002b) ibonise ukuba i-D1R blockade kwi-PFC iphazamise ukufunda okusebenzayo kodwa ayinayo impembelelo ekusebenzeni. Ukuvalwa kwe-D1R kwi-BLA nakwi-CeA nako kuphazamise ukufunda okusebenzayo (Andrzejewski et al., 2005), ngendlela exhomekeke kwithamo. Nangona kunjalo, indima ye-D1R kwezinye izakhiwo kube nzima ukuhlukana nezinye iziphumo ze-D1R-mediated drug. Umzekelo, uHernandez et al (Hernandez et al., 2005) ibonise impembelelo enzulu ekuziphatheni okusebenzayo kulandela i-blockade yangaphambili ye-D1R kwi-NAc; nangona kunjalo, ukugqobhoza impumlo kwitreyi yokutya (ehlala ijongwa njengempendulo yePavlovian appetitively conditioned) nayo yancitshiswa kakhulu. Andrzejewski et al (Andrzejewski et al., 2006) yafumanisa ukuba i-D1R blockade kwi-vSUB, kodwa kungekhona i-dSUB, ukukhubazeka kokufunda okusebenzayo, kodwa kwakhona, iintsilelo zenkuthazo zifunyenwe. Ngelixa kubonakala ngathi ukusebenza kwe-DA kwe-D1R kubalulekile ekwalathiseni iplastiki ehambelana nokufunda okusebenzayo, indima echanekileyo ihlala inqabile. Ubungqina obuvelayo, nangona kunjalo, buye bakhokelela ekubeni sibeke indima ebalulekileyo ye-NMDAR kunye ne-D1R ekufundeni okusebenzayo.

I-intracellular convergence ye-NMDAR kunye ne-DA D1R activation: i-conscious detectors

Ukusuka kobu bungqina, saqala ukwenza ithiyori yokuba ii-NMDARs ngokubambisana ne-DA D1Rs, kwaye ngakumbi ukufunyanwa ngengozi kweempawu ezingenayo, zidlala indima ebalulekileyo ekuqulunqweni kolungelelwaniso lwe-synaptic, kunye nee-neural ensembles ezinokuthi ziqhubele phambili ekufundeni.UJay et al., ngo-2004). Ii-NDMAR kunye nee-DA D1Rs zisebenzisana ngeendlela eziguqukayo. Umzekelo, i-LTP exhomekeke kwi-NMDA kwizilayi ze-striatal ivaliwe yi-D1 kodwa hayi abachasi be-D2 (Weiss et al., 2000). In vivo ubungqina bentsebenziswano ye-NMDA-D1 kwizinto ezinxulumene neplastiki zibonisa ukuba i-LTP yenzeke kwiisekethe ezininzi kunye nezakhiwo. Ngokomzekelo, i-LTP kwi-hippocampal-prefrontal cortex synapses ixhomekeke ekusebenziseni ngokubambisana kwe-NMDA kunye ne-D1 receptors, kunye ne-intracellular cascades ebandakanya i-PKA.UJay et al., ngo-2004). Kuzo zombini i-striatum kunye ne-prefrontal cortex, ukusebenza kwe-D1 kunokubangela iimpendulo ze-NMDA-receptor-mediated (Cepeda et al., 1993, Seamans et al., 2001, Wang kunye no-O'Donnell, ngo-2001). Ukwenziwa komsebenzi we-hippocampal-evoked spiking of accumbens neurons kufuna intsebenziswano ye-D1 kunye ne-NMDA receptors, ngelixa i-synergism efanayo ibonwa kwindlela ye-amygdalo-accumbens.Floresco et al., 2001b, a). Izifundo zemolekyuli ziyancedisana nezi ziphumo, zibonisa ukuxhomekeka kwe-NMDA-receptor ye-D1-mediated phosphorylation ye-CREB (iprotein ye-cAMP ebophezelayo) (Das et al., 1997, ICarlezon kunye neKonradi, ngo-2004), into ebhaliweyo ecingelwa ukuba yimodyuli egcinwe ngokuguquguqukayo yeenkqubo zememori kunye neprotheyini ephambili kwiindlela zeselula ezichatshazelwa ziziyobisi eziluthayo (I-Silva et al., 1998, Nestler, 2001). Inkxaso eyomeleleyo yengxabano yokwenziwa kusebenze ngengozi ivela kumboniso wokwandiswa kwexesha elide lamandla e-synaptic xa i-corticostriatal excitation kunye nokusebenza kwe-dopaminergic kulungelelaniswa okwethutyana (Wickens et al., 1996). Ezinye iinkcukacha zibonisa ukuba imiqondiso ye-glutamate kunye ne-dopamine, ngokusebenzisa i-NMDA kunye ne-D1 activation, iguqulela ukwenza i-ERK isebenze kwi-hippocampus kunye ne-striatum, ngaloo ndlela kuhlengahlengiswa uthungelwano olubandakanyekayo ekufundeni nasekusebenziseni iziyobisi.Valjent et al., 2005, Kaphzan et al., 2006). Ke, xa kunikwa iimfuno eziyimfuneko zokufunda, kuyamangalisa ukuqikelela ukuba ukufika okulungelelanisiweyo kwe-dopaminergic kunye ne-glutamatergic signals, kunye neziphumo zayo ze-neuromolecular, zisebenza njengesixhobo sokujonga okwenzekayo esiqala utshintsho olubhaliweyo olukhokelela ekunyamezeleni ukuguqulwa kwe-synaptic. Kubalulekile ukuqaphela ukuba ezi cascades zizo ezicetywayo ukuba zitshintshwe kwinkqubo yokulutha (UHyman kunye noMalenka, ngo-2001).

Kuvavanyo oluthe ngqo lwale ngcamango, u-Baldwin et al. (UBaldwin et al., 2002b) bafumana iidosi ze-AP-5 kunye ne-R (+) -7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH-23390) (umchasi we-D1R) kwi-PFC eyayingenayo impembelelo ebonakalayo ekufundeni okusebenzayo. Nangona kunjalo, xa idityanisiwe kwaye ifakwe kwi-PFC yeegundane ze-naïve, ukufunda okusebenzayo kwakuphazamisekile kakhulu, kubonisa ukusebenzisana okuqinileyo phakathi kwee-receptors ezimbini. Oko kukuthi, iplastiki ehambelana nokuziphatha okusebenzayo kunokwenzeka kunye nenani elincinci le-NMDAR okanye i-D1R blockade, kodwa kungekhona zombini. Nangona siye sabona iziphumo ezixhomekeke kwithamo, siye sazibuza ukuba ingaba ukufunda okusebenzayo yinto "yonke okanye akukho nto", njengokufunda ingqiqo (Osler kunye noTrautman, ngo-1961). Kumava ethu, kubonakala ngathi iimpuku zethu ziqale zachitha ixesha lazo kwigumbi lokuphonononga, ukugqogqa impumlo, ukufutha, ukuzilungisa, ukukhulisa, njl. Emva kweeseshini ezimbalwa, iigundane zokulawula "ziyifumene" kwaye zaqhubela phambili ngokucinezela i-lever rhoqo, kwaye zakhulisa, zahlola, zafunxa, zaqeqeshwa, njl. kunye no-Simmelhag babonise kwilinge labo le-seminal yokuziphatha kweenkolelo (Staddon kunye noSimmelhag, ngo-1971). Ke ngoko, ukufunda okusebenzayo kokuqala kunokubandakanya "inqaku lokuchwetheza" okanye inkqubo efana nomqobo, ngokuchaseneyo nokutshintsha kancinci kancinci. Umzobo 1 ibonisa iimpendulo ezongezelekayo zeempuku ezimbini ezine-cannulae ezijolise kwi-NAc. Enye ifakwe kwisithuthi ngaphambi kweeseshoni zokuqala ezintlanu ngelixa okwesibini kufakwe kwi-AP-5. Ukufana kwemisebenzi kuyamangalisa kwaye kubonakala kuhambelana nombono wethu: kukho ukunyuka okucothayo kunye nokucothayo ekuphenduleni, ukuguqulwa, ngokukhawuleza, ukuya kwinqanaba eliphezulu, kunye nezinzile, izinga lokuphendula. Qaphela ukuba i-AP-5-treatment rat ilibazisekile kolu tshintsho, iphakamisa ukuba le "tipping point" ilibazisekile yi-NMDAR blockade.

Umzobo 1 

Uxinzelelo lwe-lever eyongezelelweyo kwiiseshini. Ukuziphatha kweegundane ezimele ezimbini, enye isithuthi esiphathwayo kunye ne-AP-5-iphathwe, ngokulandela i-infusions kwi-nucleus accumbens core (NAc) ngaphambi kwe-5 yokuqala, iiseshini ezide zemizuzu eyi-15. I-infusions yaphela emva koko ...

Ngelixa ezi datha zokuziphatha kunye nolunye uqwalaselo lunokuthi luveze ingxabano eqinisekileyo malunga nale "ndawo yokucofa" ingqikelelo, bekuya kuba yinto ebaluleke kakhulu ukuba i-neurobiology ilandele ngokufanelekileyo, kuba oku kuya kuthetha "ixesha elibalulekileyo" lokufunda ngokusebenzayo kwaye licebise ngeethagethi zongenelelo. ifashoni exhomekeke kwixesha. Kancinci, kubonakala ngathi ukufunda okusebenzayo kuhambelana neemeko eziphezulu ze-vis-a-vis temporal, ezendalo kunye nobudlelwane be-neurophysiological.

Imodeli ye-intracellular signaling yokufunda okusebenzayo

I-intracellular molecular constituents of learning (ngokubanzi, kungekhona ukufunda okusebenzayo), njengoko kuphawuliwe ngaphambili, ifumene umdla omkhulu. Ezethu iziphumo eziphathelele kwindima yokuvula i-NMDAR zaziswe ngokugqibeleleyo zezi ziphumo malunga ne-LTP. Nangona kunjalo, i-intracellular signaling cascades ejongene ne-LTP ngoku icaciswe kakuhle. Ngaba ziyi-cascades ezifanayo ezinoxanduva lokuqwalasela kwakhona iindlela ze-synaptic ngexesha lokufunda okusebenzayo? Baldwin et al (UBaldwin et al., 2002a) umsebenzi we-protein kinase evinjiweyo, izinto ezibalulekileyo ze-intracellular signaling eziyimfuneko kwi-LTP, kwi-NAc yeegundane ngaphambi kweeseshoni zokufunda ezisebenzayo kunye ne-compound 1-(5-isoquinolinesulfonyl) -2-methylpiperazine dihydrochloride (H-7). Kwiqela elihlukeneyo leegundane, umsebenzi we-protein kinase (PKA) oxhomekeke kwi-cAMP wawunqatshelwe yiyeza i-Rp-adenosine 3′,5′-cyclic monophosphothioate triethlyamine (Rp-cAMPS) ngokukhawuleza ngaphambi kweeseshoni zokufunda ezisebenzayo. Kuzo zombini ezi meko, ukufunda kwakuphazamisekile kucetyiswa ukuba iprotein kinase isayine ngokubanzi, kunye nomsebenzi we-PKA ngokukodwa, wawuyimfuneko ekufundeni okusebenzayo. Ke, uninzi lwamacandelo aphambili e-intracellular ye-neural plasticity ehambelana nokufunda okusebenzayo achongiwe.

I-PKA, i-PKC kunye neminye imisebenzi yeprotein kinase idibanisa ngaphakathi kwe-intracellularly, ngokweemodeli ezininzi ezibalaseleyo, kwi-ERK (Valjent et al., 2005, Kaphzan et al., 2006). I-ERK ye-Phosphorylated (pERK) itshintshela kwi-nucleus ye-neurons, apho imodareyitha umsebenzi we-CREB, ebanjwe ngokubanzi njengomlamli ogcinwe ngokuguquguqukayo we-neural plasticity yexesha elide. Okumangalisayo kukuba, sifumene indima encinci ye-ERK ekufundeni okusebenzayo. Okokuqala, i-U0126 (i-perK inhibitor) ifakwe kwi-NAc phambi kweeseshoni zokufunda ezisebenzayo ayizange ivelise umphumo obonakalayo (Umzobo 2, iphaneli A). Sisebenzise iiparadigms ezifanayo kunye namalungiselelo njengeengxelo zangaphambili, nangona kunjalo, ngenxa yokungabi namava kwethu ngeli chiza, kunokwenzeka ukuba esi siphumo esibi sasisiphumo sengxaki yobugcisa engaziwayo. Okwesibini, sihlolisise i-ERK phosphorylation emva kokufunda okusebenzayo kusetyenziswa ama-blots aseNtshona kunye nama-antibodies akhoyo ngokurhweba. Amaqela amabini eegundane ze-6 aqhutywe: i-1) uqeqesho oluqhelekileyo olusebenzayo (FR-1 / VR-2) kunye ne-2) ulawulo lwejoka (lufumene inani elifanayo le-reinforcers kodwa aluzange lube ne-lever-press ukuvelisa). Iingqondo zaqokelelwa kwimizuzu emihlanu ye-5th iseshoni kwaye iqhutywe yi-Western blot. Akukho mahluko kwi-ERK, i-perK okanye i-perK / ERK ratio yaphawulwa kuyo nayiphi na indawo ye-12 efundwayo, kubandakanywa ne-NAc (Umzobo 2, iphaneli B). Kubekho isiphumo esincinci, kodwa esibalulekileyo ngokwezibalo, kwi-perK kwi-vSUB nakwi-PFC, ebandakanya ukonyuka kwe-20% ngokunxulumene nolawulo olufakwe edyokhweni. Nangona isiphumo besibalulekile ngokweenkcukacha-manani, ibithozamile kwaye inokwenzeka impazamo yoHlobo loku-1 ngokunikwa inani lothelekiso esilwenzileyo. Okwesithathu, sizame ukujonga, kwaye ngethemba, isiqingatha sobungakanani be-perK kuyo yonke ingqondo emva kokufunda okusebenzayo ngokusebenzisa iindlela eziqhelekileyo ze-immunohistochemical kumacandelo obuchopho adadayo simahla. Ezi mpuku zaphathwa ngokufanayo kuvavanyo lwe-blot yaseNtshona, nangona kunjalo emva kokuqokelelwa kwengqondo, ubuchopho buphela banqunyulwa kwaye izilwa-buhlungu ze-perK zasetyenziselwa ukwenza i-perK.

Umzobo 2 

Indima ye-ERK ekufundeni okusebenzayo. Iphaneli A ibonisa ukuba i-U0126 ifakwe kwi-NAc ngaphambi kweeseshoni zokufunda ayinayo impembelelo xa ithelekiswa nolawulo olufakwe kwisithuthi. Iphaneli B ayibonisi i-ERK-1 okanye i-ERK-2 phosphorylation yonyuka kwiimpuku ezifunda umsebenzi ...

Kwakhona, ngelixa kwakukho ukungcola okubalulekileyo kwe-perK kwi-PFC kunye ne-vSUB, kwakukho encinane kakhulu kwi-NAc (Umzobo 2, iphaneli C). Ezi datha zihambelana ngokusondeleyo neziphumo zaseNtshona kwaye zicebisa indima encinci ye-ERK ekufundeni okusebenzayo, ngokungafaniyo nezifundo ezininzi ezibonisa indima ebalulekileyo kule kinase kwezinye iindlela zokufunda (Levenson et al., 2004, Chwang et al., 2006, Kaphzan et al., 2006). Nangona kunjalo, ukusetyenziswa kwe-NMDAR / D1R ngengozi kunokukhangela iindlela zokubonisa i-ERK ezizimeleyo kwi-nucleus.

Indima ye-CREB kwi-neural plasticity

Ukumodareyitha kwe-pCREB kwe-perK kubaluleke kakhulu ngexesha lokufunda kuba i-CREB yinto ekhutshelweyo enyusa okanye ethulisa ukubonakaliswa kofuzo oluthile. Ezi zofuzo kucingelwa ukuba ngabalawuli bokwenziwa kweeproteni ezithile ezenza iibhloko zokwakha ii-receptors, ii-membrane, kunye nezinye izakhiwo ezibalulekileyo kwi-neural plasticity. Ewe, siye sabonisa ukuba iprotein synthesis kwi-NAc ibalulekile ngexesha lokufunda okusebenzayo (Hernandez et al., 2002). Sisebenzisa iprotein synthesis inhibitor, i-anisomycin, sibonise ukuba ukufakwa kwangoko emva kweseshoni kwi-NAc kuthintele ukufunda okusebenzayo okulandelayo, kubandakanya izinto ezikhutshelweyo kunye de novo protein synthesis. Kuyathakazelisa ukuba i-infusions 2 okanye iiyure ze-4 emva kweseshoni ayinayo impembelelo; I-anisomycin nayo yayingenasiphumo ngexesha lovavanyo lokusebenza okanye uvavanyo lokutyisa. Kwakhona, kubonakala ngathi siye safumanisa iimpawu eziphambili zokulawulwa ngokuqinileyo, okwethutyana kunye nomxholo, inkqubo yokufunda ebandakanya izakhiwo ezininzi, ii-receptors, iindlela zokubonisa, kwaye ngoku, iprotheni synthesis.

Ukufunyaniswa kokuxhomekeka kwiprotein synthesis yokufunda okusebenzayo ngokungathandabuzekiyo yenye yezona zinto zibaluleke kakhulu kwilabhoratri yethu, kodwa oko kubuze umbuzo omkhulu ovulekileyo malunga neenkcukacha zale proteni synthesis. Ke ngoko siye saqhuba imifuniselo emininzi yokuchonga ukuba yeyiphi imfuza enokuthi yenziwe/ilungelelaniswe ngexesha lokufunda okusebenzayo. Ukusebenzisa umgangatho in situ iindlela zokuxutywa kweempuku eziphathwe kakhulu njengezo zisetyenziselwa izifundo ze-PERK zaseNtshona, sifumanise ukuba iijini zangoko zangoko (IEGs) I-Homer1a kwaye umz1 (zif-268) zaye zalawulwa, xa kuthelekiswa neempuku zokulawula, ngokukhawuleza emva kwe-3rd iseshoni yoqeqesho olusebenzayo ngaphakathi kwee-cortico-limbic-striatal nodes. Ukubonakaliswa kweGene kwaphakanyiswa ngokubanzi kwi-cortex kunye ne-striatum, kwaye kwezinye iimeko, i-hippocampus, kodwa ngokumangalisayo, kungekhona kwi-ventral striatum (okt, NAc). Ngokuchaseneyo “neqela lokufunda lakwangoko”, iqela lesibini leempuku lafumana iiseshini zokufunda ezisebenzayo ezingama-23. Ukanti I-Homer1a kwaye umz1 Ukuchazwa ngoku kwancitshiswa xa kuthelekiswa neqela lokufunda lokuqala, phantse kuzo zonke iinuclei ezifundisiweyo, ezibonisa ukuba ezi zakhi zofuzo zibandakanyeka kwimisebenzi enxulumene neplastiki ngexesha lokuvezwa kwangethuba, kodwa kungekuko ukuvezwa kwangethuba, kwiimeko ezisebenzayo. I-exception eyodwa yayiyi-ventrolateral striatum (VLS), ebonakala ihleli, ngokuthetha ngokwemfuza, "kwi-intanethi" nangexesha lokuvezwa okongeziweyo kokusebenza. Nangona abaphengululi abaninzi baye babiza uqeqesho olude olusebenzayo ngokuthi "ukwenza umkhwa" ezi mpendulo zihlala ziguquguquka kwaye zibhetyebhetye (qwalasela isiphumo "sexeshana" sokuqiniswa okanye ukunciphisa umntu angabona xa iimeko ezinokuthi zisuswe okanye zicinywe): inika umdla ukuqikelela ukuba i-VLS ingawugcina lo msebenzi wokubeka iliso.

Ezinye ii-receptors ze-glutamate zikwancedisa kwiplastiki ehambelana nokufunda okusebenzayo

I-Homer1a kucatshangelwa ukulawula kunye neqela le-traffic 1 i-metabotrophic glutamate receptors (mGluR1 kunye ne-mGluR5). ii-mGluR5s zenza umsebenzi wee-NMDAR ngokutshintsha ukungeneka kwazo kwi-Ca2+ (UPisani et al., 2001), ukuphakamisa ithuba elinomdla lokuba enye indlela ye-NMDAR-induced plasticity inokuxhomekeka kakhulu kumsebenzi we-mGluR5. Kungekudala, sivavanye ngokuthe ngqo indima yomsebenzi we-mGluR5 ekufundeni okusebenzayo ngokuthintela umsebenzi wabo kunye neyeza 3-((2-Methyl-4-thiazolyl) ethynyl)pyridine (MTEP). Iziphumo zethu zokuqala zibonisa ukuba ukuvinjelwa komsebenzi we-mGluR5 kwi-DMS kuphazamisa ukufunda okusebenzayo, nangona iimvavanyo ezilandelwayo kule nto ifunyenweyo iyaqhubeka.

Ukusebenza kwe-AMPA receptor kunye nokufunda okusebenzayo kuye kwaphononongwa kwilabhoratri yethu. Hernandez et al. (2002) ubonise indima elinganiselweyo yexesha lokusebenza kwe-AMPAR kwi-NAc ngexesha lokufunda okusebenzayo. Isiphumo, nangona kunjalo, sinyamezele iiseshini ezininzi kwaye sinokuba sisiphumo sommiselo ophantsi okanye ixesha elide lokungena ngaphakathi kwe-glutamate receptors. Ngelixa le ngxabano idinga inkxaso eyongezelelweyo yobungqina, safumanisa ukuba i-blockade yangaphambi kweseshoni ye-AMPAR iya kuvelisa umphumo wexesha elide malunga nokuvalwa kwe-post-seshini, engazange ivelise utshintsho ekufundeni okusebenzayo.

Utshintsho lwe-epigenetic ngexesha lokufunda okusebenzayo

Ukongeza kwimiba yoshicilelo olusebenzayo, umsebenzi we-NMDAR kunye ne-D1R uphinda ukhuthaze ukuguqulwa, okufana ne-histone acetylation, kwi-chromatin, iprotheni eququzelela kwaye idibanise i-genomic DNA. Olu hlengahlengiso lubonelela ngemiqondiso yokugaya ebandakanyekayo kushicilelo lwemfuza/ukuthula kwaye luphembelele ukufikelela kwi-DNA ngoomatshini bokukhutshelwa. Ukusebenza kwe-NMDAR kunye ne-intracellular signaling cascades ehambelana nayo, kubandakanywa ne-histone 3 (H3) i-acetylation, ilawula ukuguquka kwexesha elide lokuziphatha, i-Pavlovian ukwesaba imeko kunye ne-instrumental ye-Morris Water Maze yokufunda (Atkins et al., 1998, I-Blum et al., 1999, Schafe et al., 2000). Kutshanje siqale ukuphonononga ukuba ingaba ukufunda okusebenzayo kuyayiguqula na ichromatin. Ewe, inkcazo ye-acetylation ye-Histone H3 yonyuka kwizakhiwo ezithile ngexesha lokusebenza kokuziphatha okusebenzayo, ngokuchasene nolawulo lwe-sucrose feed. Kolu vavanyo, i-lever yeempuku ecinezela i-RI-30 "ishedyuli yabingelelwa imizuzu engama-30 emva kweseshoni. Ubuchopho buqokelelwe, bucutshungulwe kwaye bufakwe kwi-anti-acetyl-Histone H3 (i-Lysine 14) usebenzisa iiprotocol eziqhelekileyo.

Okubangel 'umdla kukuba, ngokumalunga nokulawulwa kwedyokhwe, sabona i-histone H3 acetylation ephakamileyo kwi-DMS, isakhiwo esithathwa ngokubanzi njengegalelo eliphambili ekufundeni okusebenzayo. Ezi zezinye zedatha yokuqala esiyaziyo yokubonisa ukuguqulwa kwe-histone ngexesha lokufunda okusebenzayo. Nangona kunjalo, ukunyuka kwinqanaba lehlabathi le-histone i-acetylation ye-histone inokuba ngumphumo wokuguqulwa kwabakhuthazi bezakhi zofuzo ngaphandle kwe-IEGs kwaye, ngokubhekele phaya, iigundane ezisetyenziswe kolu vavanyo zazinoqeqesho olubanzi. Ngaloo ndlela, ulwazi olongezelelweyo kwi-locus ye-acetylation ngexesha lokufunda okusebenzayo luyimfuneko. Nangona kunjalo, ezi datha, ngokubambisana nezinye iingxelo ezininzi, zibonisa ngokucacileyo ukuba iinkqubo ze-epigenetic zibandakanyeka ngexesha lokufunda okusebenzayo. Uhlengahlengiso oluhlala ixesha elide, olufana ne-histone acetylation, lunokusinceda siqonde uhlobo oluhlala luhleli lokuziphatha okusebenzayo, ukuxhathisa kwayo ukuguquka, kunye nokungakhathali kwezifo ezithile kunyango.

Iinkqubo ze-Epigenetic nazo zibonakala ziguqulwa ngexesha lokulawulwa kweziyobisi kunye nokufunda. Ngexesha lokuzilawula kwe-cocaine, iparadigm yesixhobo esixhomekeke kwi-D1R, uhlengahlengiso lwe-chromatin luyenziwa kwimimandla ethile ye-striatum kubakhuthazi bemfuza enxulumene neplastiki, njenge. Cbp, NR2B, Pd95, yaye GluR2. Cbp ibaluleke kakhulu ekuvuseleleni-i-CREB kwaye inomsebenzi we-histone acetyltranferase (HAT) wangaphakathi (UShaywitz noGreenberg, ngo-1999). Iimpuku eziguquguqukayo ezivakalisa uhlobo oluncitshisiweyo lwe Cbp banentsilelo ezininzi zokufunda (U-Wood et al., 2005). NR2B, i-subunit ye-NMDAR complex, iqulethe indawo yokubopha i-glutamate kwaye iyimfuneko kwi-LTP, ngelixa i-subunit NR2A akunjalo (Foster et al., Ukunyanzelwa et al., 2010). I NR2B i-subunit iphosphorylated yi-CaMKII, i-dephosphorylated yi-PP1, kwaye idibanisa i-NMDAR ngaphakathi (URoche et al., 2001). Pd-95 inhibits NR2BUkufakwa ngaphakathi ngaphakathi kwe-NMDAR (URoche et al., 2001) kwaye ilawula i-synaptic localization kunye nokuzinziswa kwe-NMDARs (Li et al., 2003). GluR2 yinxalenye ye-AMPAR kwaye iqulethe indawo ebalulekileyo ye-phosphorylation ekwamodareyithwa yi-intracellular protein kinase kunye nomsebenzi weprotein phosphatase. Phosphorylation ye GluR2 ngokuyinxenye ilawula i-AMPARs ukufikeleleka kwi-calcium kunye nezinye ii-cations. Okubangela umdla kukuba, ukuvuselela i-mGluR5 kwi-rat dorsal striatum induces. GluR2 iphosphorylation, isiphumo esithintelwe yi-NMDAR antagonism (UAhn noChoe, ngo-2009).

Imodeli ye-Intra-cellular convergence yokufunda okusebenzayo

Ngokuchasene nale mvelaphi yomsebenzi oguqukayo nonomdla, senze imodeli ye-NMDAR-DA D1R convergence enokukhuthaza ukuqonda ngakumbi kwe-neural plasticity ebandakanyeka ekufundeni okusebenzayo. Umzobo 4 ibonisa i-hypothesis ekhoyo yokuba i-glutamate-coded sensory / imiqondiso yokucubungula ulwazi isebenze i-NMDAR, kunye ne-AMPAR, ekhokelela kwi-Ca.2+ ukungena kwiseli. Ukusebenza kwe-DA kwe-D1Rs kusebenze i-adenyl cyclase (AC, echongwe ngotolo olumnyama), kwaye ngokulandelayo, i-camp. Iindlela ezimbini zokubonisa zinxibelelana kwiindawo ezininzi, umzekelo, njengoko i-CaM, ibangelwa kukusebenza kwe-NMDAR, ichaphazela i-AC (nangona oku kukubonakaliswa okugqithisileyo). I-PKA yenza i-MEK isebenze, kodwa ikwanqanda i-Ras/Raf (echongwe ngomgca webar-headed), icebisa ukuba hayi kuphela iindlela ezidibanayo, kodwa zinokukhuphisana kulawulo lomqondiso.

Umzobo 4 

Imodeli ye-intracellular signaling ye-operant leatning. Utshintsho olusebenzayo kunye nolwakhiwo olubandakanyekayo kwi-neural plasticity lubandakanya ukulungelelaniswa kwe-NMDAR kunye nokusebenza kwe-DA D1R kuyo yonke inethiwekhi ye-cortical-striatal-limbic. Lo mfanekiso ushwankathela okukhoyo ...

Amanqaku aliqela okudibana okunokwenzeka abonisiwe, ngakumbi ukwenziwa kusebenze kwe-CREB, MEK kunye ne-ERK. Iziphumo ezibalulekileyo ezinxulumene neplastiki nazo zibonisiwe, njengoshicilelo oluxhomekeke kwi-CREB yee-IEGs. Arc, iHomer1a, kwaye umz1. IHomer1a iTrafikhi i-mGluR5 receptors (emelwe lutolo olungwevu), oluthi emva koko lube neCa2+ ukungena nge-Gαq-protein edityaniswe ne-phospholipase C (PLC) umsebenzi (obu buchule bumelwe ngotolo olutyheli kunye neebholiti zokukhanyisa); Umsebenzi we-mGluR5 uphinda wenze i-DA isebenze i-D1R. Arc ithuthwa isiwe kwi-synapses esandula kuvuselelwa, mhlawumbi yenza uhlobo lwendima "yokuphawula". Kutshanje, idatha evelayo icebisa indima ebalulekileyo Arc kunye ne-ERK ekufakweni kwe-AMPAR-subunit kunye nokulawulwa kohlobo lwe-L-voltage gated channels calcium. I-DARPP-32, eyenziwa ngumsebenzi we-PKA, iqokelela kwi-nucleus, inhibiting protein phosphatase 1 (PP1) umsebenzi, obandakanyeka ngokuthe ngqo kulungiso lwe-chromatin ngomsebenzi we-intrinsic dephosphorylation (efanekiselwa lutolo olunesiqingatha-entloko-entloko "ukubamba" iqela le-phosphate. ). Iintshukumo ze-Histone deactylease (HDACs) zimelwe ngomgca wentolo eguqulelwe phantsi "ukubamba" amaqela e-acetyl ukusuka ku-Histone 3 (H3). Olu tshintsho lwe-histone luphumla okanye ludibanise i-chromatin ngokwenza oko lwenza okanye lucinezele ushicilelo lwemfuza (ulungiso oluthile olubonakaliswe kumzobo alubonisi uhlengahlengiso olululo olufunekayo kubakhuthazi bee-IEG zokukhutshelwa) (Umzobo 4 isekelwe kwi (Sweatt, ngo-2001, IKelley kunye neBerridge, 2002, UHaberny kunye noCarr, ngo-2005, I-Ostlund kunye neBalleine, 2005, Valjent et al., 2005). Ke ngoko, ukudibana kwe-neuromolecular yolwazi oluvela kwi-cortico-striatal-limbic NMDAR kunye ne-DA D1R ibonelela ngesiseko esinokwenzeka seplastiki kwimfundo esekwe kumvuzo. Iinuclei zobuchopho ezithile kunye ne-neuron ezimelwe kule modeli ngoku ziza kugxininiso, kodwa mhlawumbi zibandakanya iindawo eziphambili zokubethelwa, i-limbic, kunye ne-cortical. Isikrokro sethu esinamandla kukuba i-spiny neurons ephakathi, kwi-striatum ngokukodwa, inokuthi ifanelekele imisebenzi enxulumene neplastiki ngenxa yoxinano oluphezulu ngokungaqhelekanga lweendlela ze-ion ezixhomekeke kumbane ezivelisa iinguqu ezikhethekileyo zikarhulumente (Houk noWise, ngo-1995) ngokudityaniswa nokudityaniswa kwe-cortical, i-glutamate-coded afferents, kunye ne-thalamic afferents, kunye negalelo le-monoaminergic ukusuka kwi-midbrain.

UKelley kunye noogxa bakhe (Kelley et al., 1997) ekuqaleni yachaza indima ebalulekileyo ye-NAc kwi-neural plasticity kunye nokufunda okusebenzayo. Ngokwenene, ilabhoratri yethu iphonononge indima ye-nucleus accumbens kwiindlela ezahlukeneyo zokuziphatha kusetyenziswa indlela yoluleko ecwangciswe ngobuchwephesha (umzekelo, uhlalutyo lovavanyo lokuziphatha, i-neuroscience yokuziphatha, i-molecular and cell neuroscience, njl.). UDkt Kelley wayengomnye weengcali kwisakhiwo, i-physiology, ukudibanisa kunye nomsebenzi we-nucleus accumbens. Nangona kunjalo, uninzi lweemvavanyo zethu zibonakala ziphikisana nesibhengezo sokuqala sikaGqr. Kelley. Ukungabikho okukholisayo kokubandakanyeka kwe-MEK / ERK kwi-NAc ngexesha lokufunda okusebenzayo kunye nokunqongophala kwe-gene expression isebenza njengemiba emibini enesibindi kwingxabano yokuba iplastiki kwi-NAc ibalulekile ekufundeni okusebenzayo. Okokuqala, kusenokwenzeka ukuba i-MEK/ERK ayibandakanyekanga ekufundeni okusebenzayo naphi na engqondweni. Izifundo zethu kwezinye iisayithi ezili-12 zivelise umahluko omncinci kakhulu phakathi kokufunda okusebenzayo kunye nolawulo olubotshiweyo. Mhlawumbi, indlela ye-MEK/ERK ibandakanyeka ngexesha "lexesha elibalulekileyo" okanye "indawo yokucofa" xa iigundane zibonakala ngathi "ziyifumene" kwaye izifundo zethu azizange zibe nesisombululo sexeshana sokubona esi siphumo, ngakumbi njengoko ukusebenza kwe-ERK kunamandla kwaye isiganeko esikhawulezayo. Mhlawumbi iidosi zethu ze-U0126 zaziphantsi kakhulu ukuthintela ukusebenza kwe-ERK. Nangona kunjalo, i-hypothesis enokwenzeka ngokulinganayo kukuba i-CREB-mediated transcription of genes ebandakanyekayo kwi-neural plasticity yenziwe yasebenza ngokuthe ngqo ngezinye iindlela zokubonisa, ezifana ne-PKAc okanye i-CAM (bona Umzobo 4), igqitha indlela yeMEK/ERK. Kwaye mhlawumbi, asikhange sichonge uhlobo olubalulekileyo olunxulumene neplastikhi okanye inkitha yokuguqulwa kwe-epigenetic kwi-NAc neurons evumela kwaye iqinisekise indlela yokusebenza. Siyathemba ukuba siza kuphendula le mibuzo ngokungqongqo nangenzondelelo efanayo naleyo wayenayo uAnn.

Iziphumo zonyango

Ingqikelelo ekhoyo yolu hlaziyo kukuba imodeli eboniswe kuyo Umzobo 4 inokwazisa unyango lweengxaki ezininzi zeklinikhi. Eyona nto ibalulekileyo kukuba likhoboka leziyobisi, kuba ukusetyenziswa kakubi kweziyobisi kuchaphazela kakhulu iinkqubo ezifanayo zemolekyuli ezibandakanya ukufunda ngokusebenza. Kwiminyaka yakutshanje, ezinye zezona ziphumo zimangalisayo kuphando malunga nokulutha zezo zibonisa ukudityaniswa okubalulekileyo kweendlela zokulamla ukuba likhoboka leziyobisi kunye nokufunda okuqhelekileyo okunxulumene nomvuzo (UHyman kunye noMalenka, ngo-2001, Nestler, 2001, Wang et al., 2009). Siqinisekile ukuba uninzi lophononongo kolu hlelo lukhethekileyo luqaqambise ngobuchule ubudlelwane phakathi kokukhotyokiswa ziziyobisi kunye nokufunda okuqhelekileyo okunxulumene nomvuzo. Kuyavunywa, olu lwalamano lubonakalise ukuba lubalulekile ekuqondeni kwethu umlutha, nangona kunjalo, singathanda ukukhankanya amakhonkco amatsha abalulekileyo phakathi komsebenzi kaGqr Kelley ekufundeni okusebenzayo kunye nedatha evelayo kunye neziphumo kwezinye iingxaki zeklinikhi. Ezo ziphumo ziwela kwimixholo emibini jikelele: 1) iingxaki zeklinikhi kunye nokuphazamiseka kokufunda okuhambelanayo okunokwenziwa ngokuqondwa ngcono kwendlela yokusebenza. nokufunda iqhubeka ngeendlela ze-neuromolecular zeplastiki kunye ne-2) iingxaki zeklinikhi ezinxulumene nokuqhubekayo, sele efundile, kwaye mhlawumbi ixhathise kakhulu, ukuziphatha okusebenzayo kunye nezakhi ze-neuromolecular. Le meko yokugqibela ithatha ingxaki yokulutha, sicinga, njengoko ijongwa ngokufanelekileyo njengokuziphatha okuqhubekayo okuneziphumo ezibi kakhulu nezihlala ixesha elide.

Njengoko kuphawuliwe kwintshayelelo, ukuphazamiseka kwe-autism spectrum ngoku kucingelwa ukuba kuchaphazela umntwana omnye kwabangama-1. Iintsilelo zonxibelelwano, iingxaki zonxibelelwano lwentlalo kunye neepatheni zokuziphatha ezisoloko zihleli ziphawulwa ngoluphazamiseko, nangona izakhono zonxibelelwano zinokubonakala kubantwana abaneAsperger. Unyango lwakwangoko lokuziphatha olunzulu (EIBT), olusekwe kwimigaqo esebenzayo, lwakha umqolo werejimeni zonyango olubanzi olunika iziphumo ezimangalisayo. Olu nyango lwakwangoko, olulungiselelwe umntu ngamnye kakhulu kwaye lube nomxholo, lubandakanya ubuncinci iiyure ezingama-88 zonyango lomntu omnye ngeveki, rhoqo iminyaka emininzi. Idatha ibonisa ukuba kwangethuba ungenelelo luqala, kokukhona lingcono izinga lempumelelo. Kuninzi lwezi meko (olunye uqikelelo luphakathi kwama-40-40%), ukufakwa ngokupheleleyo kumagumbi okufundela aqhelekileyo kunokwenzeka ngaphandle kwenkxaso eyongeziweyo okanye eyongezelelweyo (incinci okanye akukho nkxaso yongeziweyo).Lovaas, ngo-1987, ISallows kunye neGraupner, ngo-2005, LeBlanc kunye neFagiolini, ngo-2011). Ezi ziphumo zeplastiki ye-neural esondeleneyo njengenxalenye yokuqhuba kwimpumelelo ye-EIBT. Abaphandi kuluntu lonyango lwe-autism baqikelela ngokubanzi malunga "namaxesha amanqam" ophuhliso ahambelana nokuphakama kweplastiki ye-neural (LeBlanc kunye neFagiolini, ngo-2011). Ke, uphando lwethu malunga nokufunda okusebenzayo lunokuba neziphumo ezimbini ezinokubakho: 1) kunokwenzeka ukuba i-autistic "ingqondo" inokuthi inciphise amandla eplastiki, kwaye kuphela ngokusebenza okunzulu kunye nonyango apho oku kuncitshiswa koyiswa kwaye 2) kunokwenzeka, kunye ukuqonda okupheleleyo kokufunda okusebenzayo, ukukhuthaza amaxesha eplastiki ukuze abantwana abadala baxhamle kunyango.

Ngelixa ingxabano eqikelelwayo kukuba ukufunda okusebenzayo, i-EIBT, kunye ne-neural plasticity yabelana nge-ASDs, kukho imithombo emininzi yokuguqula ubungqina obuxhasayo. Ukuqala, oyena nobangela uphambili we-ASDs yiFragile X syndrome (FXS), i-gene trinucleotide iphinda ingxaki nge-FMR1 gene. I-FXS inxulunyaniswa nokukhubazeka kokufunda, iintsilelo zokuziphatha kwentlalo kunye nokunye okungaqhelekanga komzimba (ikakhulu ebusweni). I-FMR1 gene ifaka iprotheni ye-Fragile X ye-mental retardation protein (FMRP), efunekayo kuphuhliso oluqhelekileyo lwe-neural (UCrawford et al., 2001, Antar et al., 2004). Ukongezelela, i-FMRP imodareyitha kakhulu iqela le-1 mGluR umsebenzi, kunye nokungabikho komsebenzi we-FMRP kuphazamisa i-NMDAR LTP (Antar et al., 2004). Umsebenzi wethu wakutshanje kunye ne-mGluR5 inhibitor MTEP iphakamisa indima ekufundeni okusebenzayo kule receptor phantsi kweemeko "eziqhelekileyo". I-Pharmacotherapies esekelwe ekumodareyitheni umsebenzi we-mGluR5 ngoku iyaphandwa ukuze isetyenziswe kubantu abane-FXS.UHagerman et al., ngo-2012).

Olunye uhlobo lwe-autism, olubizwa ngokuba "luphazamiseko lwe-regressive autism" kuba abantwana abanale fomu bakhula ngokwesiqhelo kangangexesha elithile baze baphulukane nonxibelelwano "oluqhelekileyo" kunye nezakhono zentlalo, kutshanje inxulunyaniswe nokuncipha komsebenzi we-PKA kunye ne-catalytic subunit ye-PKA, eyile. i-c-isoform. Xa kuthelekiswa ne-post-mortem kunye nolawulo lwe-autistic olungaguqukiyo, i-autism yangaphambili i-cortices yangaphambili ibonise ukunciphisa umsebenzi kunye nokubonakaliswa kwe-PKA.Ji et al., 2011). Akukho mahluko waphawulwa kweminye imimandla ye-cortical, kwaye kwakungekho mahluko phakathi kwe-autism engaguqukiyo kunye nolawulo olungelulo lwe-autistic. Ke ngoko, i-autism ebuyileyo inokudityaniswa ne-PKA-mediated phosphorylation yeeprotheyini kunye nokubonakaliswa kwe-intracellular engaqhelekanga. Kwakhona, umsebenzi wethu ubonise indima ebalulekileyo ye-PKA ekufundeni okusebenzayo, ukudibanisa kakuhle nalo msebenzi wakutsha nje we-regressive autism.

I-Rubenstein-Taybi syndrome (RTS) yi-autosomal dominant disorder ebangelwa ukuguqulwa kofuzo lwe-CREB yokubopha iprotheni (CREBBP). Ubude obufutshane, oobhontsi ababanzi, iimpawu zobuso ezahlukileyo, kunye nobunzima bokufunda obuphakathi ukuya kobunzima bubonakalisa iRTS (Bartsch et al., 2010). Eyona nto ibalulekileyo yokungenisa apha likhonkco elicacileyo phakathi kokufunda okusebenzayo, umsebenzi weCREB, kunye ne-RTS. Mhlawumbi abantwana abane-RTS banokuzuza kwi-EIBT okanye kunyango oluthile lwekhemesti oluvumela, ezongezelelekileyo, okanye endaweni ye-CREB yokumodareyithwa koshicilelo lwemfuza. I-CREB phosphorylation ibonakala ilawula umsebenzi we-IEG kunye nokuhlanganiswa kweeprotheni ezintsha, kwaye mhlawumbi ilawula iplastiki ye-neural ehambelana nokufunda okusebenzayo.

Ekugqibeleni, idatha yethu kunye nemodeli ye-intracellular ibandakanya iinkqubo ze-epigenetic njengexanduva lokunyamezela ukuziphatha okusebenzayo. Uqwalaselo lwethu oluqhelekileyo lokuziphatha okusebenzayo njengokuthi "ukwenza umkhwa", imiboniso ephindaphindiweyo yokubuyisela ngokukhawuleza, kunye nexesha elibonakala lingenasiphelo lokukhumbula elinxulumene neerepertoires ezisebenzayo linegalelo elinamandla kule ngcamango. Ngokwenyani, uninzi lweengxaki zokuziphatha ezinzima zibonakalise ukungakhathali kunyango, nto leyo ekhokelela kumathuba athintelweyo asekuhlaleni, uthintelo lwekhemikhali, ukulaliswa esibhedlele kunye nokufakwa kwiziko. Nangona kunjalo, udidi olubanzi lwezixhobo zokuxilonga, ezihlala zibizwa ngokuba "luhlalutyo olusebenzayo lokuziphatha kwengxaki" okanye "uvavanyo lokuziphatha olusebenzayo (FBA)", ziye zaphuhliswa ukuchonga ubudlelwane obulawulayo kwezi ziphatha zinzima. Ngokubanzi, ezi klasi zokuziphatha zijongwa njengezisebenzayo, zomelezwe yingqalelo, ukufikelela kwizinto ezikhethwayo/imisebenzi, okanye ukubaleka/ukuphepha iimeko ezingafunwayo (ULerman no-Iwata, ngo-1993). Ngolu lwazi lusesandleni, unyango lunokulawulwa ngendlela efana nokubonelela ngeminye imithombo yokuqinisa okanye abanye abasebenzi abafanelekileyo abavelisa ezo meko zifunwayo, mhlawumbi nasemva kwexesha elide emva kokufunda kwasekuqaleni kokuziphatha okungafanelekanga. Ngaba kunokwenzeka ukuba ukuqonda okungaphezulu kokufunda okusebenzayo kunokubonelela ngeethagethi ze-pharmacotherapeutic, njenge-histone acetylation, ephucula ukuphela kokusebenza kunye / okanye ukukhuthaza ukufunda okusebenzayo okutsha?

Ngelixa uninzi lwale ngcamango luqikeleleka kakhulu, umsebenzi kaGqr Ann Kelley kunye noogxa bakhe kwindawo yokufunda okusebenzayo kunokwenzeka ukuba bazise, ​​ubuncinci, ubume kunye nekhosi yokulutha kweziyobisi. Singathanda kwakhona ukwandisa ithiyori yethu kunye neziphumo zokunceda ukuqonda iintsilelo zokufunda ezinxulumene nee-ASDs, i-FXS kunye ne-RTS, kunye nobunzima obunxulunyaniswa namandla athile anengxaki enzima yokuphindaphinda.

​ 

Umzobo 3 

Ubuninzi be-acetylated histone H3 ngexesha lokusebenza buphakanyisiwe kwi-DMS ngokumalunga nokulawulwa kwedyokhwe, kodwa kungekhona kwi-NAc, PFC, okanye i-ACC. I-pictomicrographs emele amacandelo e-DMS anebala aboniswe ngasekunene.

Iimbalasane

Ukufunda ngokusebenza yinkqubo esisiseko yokuziphatha

Ukufunda ngokusebenza kufuna ulungelelwaniso lwe-NMDAR kunye ne-D1R receptors

I-Intracellular signaling cascades ichaphazeleka ngamandla ngexesha lokufunda okusebenzayo

Iithagethi ezinokubakho zonyango zokulutha, i-autism, kunye nokuziphatha okuyingxaki enkulu

Imihlathi

1Cinga ngeyona nto yokwenene, kodwa ekunzima ukuyiqikelela, ixabiso “lokungalali ebusuku” okanye ukwanda koxinezeleko kwimpilo nakwintlalo-ntle yabazali babantwana abaneengxaki zokuziphatha kweziyobisi.

2Le nkqubo yokuqala isebenzise iilever ezimbini, ezineshedyuli yeVR-2 ecwangciswe kwenye yazo, ilungelelaniswe kuzo zonke iimpuku. Okwesibini, i-lever "engalunganga" yayikhona ekuqaleni ukulinganisa ukufuduka okunokwenzeka okanye ukuziphatha okungacalulwanga. Sayifumanisa ingafanelekanga kwaye intsonkothile, endaweni yokucacisa, ukutolika okulandelayo. Ke ngoko, siye sayiphelisa le lever yesibini kwizifundo zamva. Ukongezelela, sitshintshe ishedyuli yokuqiniswa kokuqala kwi-FR-1, ngelixa sifudukela ngokukhawuleza kwi-VR-2 ngexesha le-5, endaweni ye-4, iiseshoni zokuqala. Olu tshintsho luncinci lwenkqubo alubonakali lunempembelelo kuzo naziphi na iziphumo ezinikwe inani lokuphindaphinda.

Iphepha elichazayo ukuba awusenanto oyifunayo: Le fayili yeFayile yombhalo wesandla ongabhalwanga owamkelwe ukushicilelwa. Njengenkonzo kumakhasimende ethu sinika le ngcaciso yokuqala kwincwadi yesandla. Umbhalo wesandla uza kufumana ukukopishwa, ukufakela, nokuphonononga ubungqina obunokubakho ngaphambi kokuba kukhutshwe kwifomu yayo yokugqibela. Nceda uqaphele ukuba ngexesha lokuveliswa kweeprogram ezinokuthi zifumaneke ezinokuthi ziphazamise umxholo, kunye nazo zonke izisemthethweni ezichasayo ezisetyenziswa kwiphephancwadi.

Ucaphulo

  1. Ahn SM, Choe ES. Utshintsho kwi-GluR2 AMPA receptor phosphorylation kwi-serine 880 ilandela iqela le-metabotropic glutamate receptor stimulation kwi-rat dorsal striatum. J Neurosci Res 2009 [PubMed]
  2. Andrzejewski ME, Sadeghian K, Kelley A. Central amygdalar kunye ne-dorsal striatal NMDA-receptor inxaxheba ekufundeni izixhobo kunye nokuziphatha okuzenzekelayo. I-neuroscience yokuziphatha. 2004;118 [Inkcazelo yamahhala ye-PMC] [PubMed]
  3. Andrzejewski ME, Spencer RC, Kelley AE. Ukufunda ngezixhobo, kodwa hayi ukusebenza, kufuna i-dopamine D1-receptor activation kwi-amygdala. Inzululwazi yemithambo-luvo. 2005;135:335–345. [Inkcazelo yamahhala ye-PMC] [PubMed]
  4. Andrzejewski ME, Spencer RC, Kelley AE. I-Dissociating Ventral kunye ne-Dorsal Subicular Dopamine D-sub-1 i-Receptor yokubandakanyeka kwi-Instrumental Learning, i-Spontaneous Motor Behavior, kunye ne-Motivation. I-neuroscience yokuziphatha. 2006;120:542–553. [Inkcazelo yamahhala ye-PMC] [PubMed]
  5. Antar LN, Afroz R, Dictenberg JB, Carroll RC, Bassell GJ. I-Metabotropic glutamate receptor activation ilawula i-fragile × iprotheni yokukhubazeka kwengqondo kunye ne-FMR1 mRNA yendawo ngokwahlukileyo kwi-dendrites nakwii-synapses. Ijenali yeNeuroscience: ijenali esemthethweni yoMbutho weNeuroscience. 2004;24:2648–2655. [PubMed]
  6. Atkins CM, Selcher JC, Petraitis JJ, Trzaskos JM, Sweatt JD. I-MAPK cascade iyafuneka kwi-mammalian associative learning. Inzululwazi ngendalo. 1998;1:602–609. [PubMed]
  7. Baldwin AE, Sadeghian K, Holahan MR, Kelley AE. Ukufunda ngezixhobo ezikhangayo konakaliswa kukuthintelwa kweprotein kinase exhomekeke kwi-cAMP ngaphakathi kwe-nucleus accumbens. I-Neurobiology yokufunda kunye nenkumbulo. 2002a;77:44–62. [PubMed]
  8. Baldwin AE, Sadeghian K, Kelley AE. Ukufunda ngesixhobo esinomdla kufuna ukuba kusebenze ngengozi ye-NMDA kunye ne-dopamine D1 receptors ngaphakathi kwe-medial prefrontal cortex. Ijenali yeNeuroscience: ijenali esemthethweni yoMbutho weNeuroscience. 2002b;22:1063–1071. [PubMed]
  9. UBartsch O, uKress W, uKempf O, uLechno S, uHaaf T, uZechner U. Ilifa kunye nokubonakaliswa okuguquguqukayo kwi-Rubinstein-Taybi syndrome. Ijenali yaseMelika yofuzo lwezonyango Icandelo A. 2010;152A:2254-2261. [PubMed]
  10. IBerridge KC, Robinson TE. Yintoni indima yedopamine emvuzweni: ifuthe le-hedon, ukufunda ngomvuzo, okanye ukukhuthala? I-Brain Res Brain Res Rev 1998; 28: 309-369. [PubMed]
  11. Blum S, Moore AN, Adams F, Dash PK. Iprotein kinase ye-mitogen-activated cascade kwi-CA1/CA2 subfield ye-dorsal hippocampus ibalulekile kwimemori yexesha elide. Ijenali yeNeuroscience: ijenali esemthethweni yoMbutho weNeuroscience. 1999;19:3535–3544. [PubMed]
  12. Carlezon WA, Jr, Konradi C. Ukuqonda imiphumo ye-neurobiological yokuvezwa kwangaphambili kwiziyobisi zengqondo: ukudibanisa ukuziphatha kunye neemolekyuli. I-Neuropharmacology. 2004;47(1):47–60. [Inkcazelo yamahhala ye-PMC] [PubMed]
  13. UCastellano C, u-Introini-Collison IB, uMcGaugh JL. Ukusebenzisana kwe-beta-endorphin kunye neziyobisi ze-GABAergic kulawulo lokugcina imemori. Ibhayoloji yokuziphatha kunye ne-neural. 1993;60:123–128. [PubMed]
  14. Cepeda C, Buchwald NA, Levine MS. Izenzo ze-Neuromodulatory ze-dopamine kwi-neostriatum zixhomekeke kwi-excitatory amino acid receptor subtypes esebenzayo. Iinkqubo zeZiko leSizwe leSayensi lase-United States of America. 1993;90:9576–9580. [Inkcazelo yamahhala ye-PMC] [PubMed]
  15. Chwang WB, O'Riordan KJ, Levenson JM, Sweatt JD. I-ERK/MAPK ilawula i-hippocampal histone phosphorylation ilandela imeko yoloyiko lomxholo. Funda uMem. 2006;13:322–328. [Inkcazelo yamahhala ye-PMC] [PubMed]
  16. Lawula CfD. I-Autism Spectrum Disorders. Amaziko oLawulo lweZifo; 2012.
  17. Crawford DC, Acuna JM, Sherman SL. I-FMR1 kunye ne-X syndrome ebuthathaka: uphononongo lwe-genome ye-epidemiology yabantu. I-Genetics kwezamayeza: ijenali esemthethweni yeKholeji yaseMelika yezoNyango lwezoNyango. 2001;3:359–371. [PubMed]
  18. Das S, Grunert M, Williams L, Vincent SR. I-NMDA kunye ne-D1 receptors zilawula i-phosphorylation ye-CREB kunye nokungeniswa kwe-c-fos kwi-striatal neurons kwinkcubeko yokuqala. I-Synapse. 1997;25:227–233. [PubMed]
  19. UDawson G, uRogers S, uMunson J, uSmith M, uWinter J, uGreenson J, uDonaldson A, uVarley J. Randomized, ulingo olulawulwayo lokungenelela kwabantwana abancinci abane-autism: i-Early Start Denver Model. Unyango lwabantwana. 2010;125:e17–23. [PubMed]
  20. Dillenburger K, Keenan M. Akukho nanye kwi-Aba emele i-autism: ukukhupha iintsomi. Ijenali yokukhubazeka kwengqondo nophuhliso. 2009;34:193–195. [PubMed]
  21. I-everitt BJ, iDickinson A, iRobbins TW. Isiseko se-neuropsychological yokuziphatha komlutha. I-Brain Res Brain Res Rev 2001; 36: 129-138. [PubMed]
  22. Floresco SB, Blaha CD, Yang CR, Phillips AG. I-Dopamine D1 kunye ne-NMDA i-receptors idibanisa amandla e-basolateral amygdala-evoked ukudubula kwe-nucleus accumbens neurons. Ijenali yeNeuroscience: ijenali esemthethweni yoMbutho weNeuroscience. 2001a;21:6370–6376. [PubMed]
  23. Floresco SB, Blaha CD, Yang CR, Phillips AG. Ukumodareyithwa kwe-hippocampal kunye nomsebenzi okhutshwe yi-amygdalar we-nucleus accumbens neurons nge-dopamine: iindlela zeselula zokukhetha igalelo. Ijenali yeNeuroscience: ijenali esemthethweni yoMbutho weNeuroscience. 2001b;21:2851–2860. [PubMed]
  24. Foster KA, McLaughlin N, Edbauer D, Phillips M, Bolton A, Constantine-Paton M, uSheng M. Iindima ezicacileyo ze-NR2A kunye ne-NR2B ye-Cytoplasmic Tails kwi-Potentiation yeXesha elide. J Neurosci. 30:2676–2685. [Inkcazelo yamahhala ye-PMC] [PubMed]
  25. Foster KA, McLaughlin N, Edbauer D, Phillips M, Bolton A, Constantine-Paton M, uSheng M. Iindima ezicacileyo ze-NR2A kunye ne-NR2B ye-cytoplasmic tails kwi-potentiation yexesha elide. Ijenali yeNeuroscience: ijenali esemthethweni yoMbutho weNeuroscience. 2010;30:2676–2685. [Inkcazelo yamahhala ye-PMC] [PubMed]
  26. Ganz ML. Ukusasazwa kobomi bonke kweendleko ezongezelelweyo zoluntu lwe-autism. Oovimba bezonyango zabantwana & namayeza olutsha. 2007;161:343–349. [PubMed]
  27. Haberny SL, Carr KD. Isithintelo sokutya sonyusa i-NMDA receptor-mediated calcium-calmodulin kinase II kunye ne-NMDA receptor/extracellular signal-regulated kinase 1/2-mediated cyclic amp response element-binding protein phosphorylation in nucleus accumbens on D-1 dopamine receptor stimulation in rats. Inzululwazi yemithambo-luvo. 2005;132:1035–1043. [PubMed]
  28. Hagerman R, Lauterborn J, Au J, Berry-Kravis E. Fragile X syndrome kunye nezilingo zonyango ezijoliswe kuzo. Iziphumo kunye neengxaki kulwahlulo lweeseli. 2012;54:297–335. [Inkcazelo yamahhala ye-PMC] [PubMed]
  29. Hernandez PJ, Andrzejewski ME, Sadeghian K, Panksepp JB, Kelley AE. I-AMPA / kainate, i-NMDA, kunye ne-dopamine D1 receptor umsebenzi kwi-nucleus accumbens core: indima elinganiselweyo nomxholo kwi-encoding kunye nokudityaniswa kwememori yesixhobo. Funda uMem. 2005;12:285–295. [Inkcazelo yamahhala ye-PMC] [PubMed]
  30. Hernandez PJ, Sadeghian K, Kelley AE. Ukudityaniswa kwangoko kwezixhobo zokufunda kufuna iprotein synthesis kwi-nucleus accumbens. Inzululwazi ngendalo. 2002;5:1327–1331. [PubMed]
  31. Houk JC, Wise SP. Ukuhanjiswa kwezakhiwo zeemodyuli ezidibanisa i-basal ganglia, i-cerebellum, kunye ne-cerebral cortex: indima yabo ekucwangciseni nasekulawuleni isenzo. Cereb Cortex. 1995;5:95–110. [PubMed]
  32. UHyman SE, uMalenka RC. Umlutha kunye nengqondo: i-neurobiology yokunyanzeliswa kunye nokuzingisa kwayo. Nat Rev Neurosci. 2001;2:695–703. [PubMed]
  33. Jay TM, Rocher C, Hotte M, Naudon L, Gurden H, Spedding M. Iplastiki kwi-hippocampal ukuya kwi-prefrontal cortex synapses iphazamiseka ngenxa yokulahlekelwa yi-dopamine kunye noxinzelelo: ukubaluleka kwezifo zengqondo. Uphando lwe-Neurotoxicity. 2004;6:233–244. [PubMed]
  34. UJi L, u-Chauhan V, uFlory MJ, u-Chauhan A. Ukunciphisa ummandla we-Brain-specific in the activity and expression of protein kinase A in the frontal cortex of regressive autism. PloS enye. 2011;6:e23751. [Inkcazelo yamahhala ye-PMC] [PubMed]
  35. I-Kaphzan H, i-O'Riordan KJ, i-Mangan KP, i-Levenson JM, i-Rosenblum K. NMDA kunye ne-dopamine ziyadibana kwi-NMDA-receptor ukuphembelela ukusebenza kwe-ERK kunye nokudakumba kwe-synaptic kwi-hippocampus evuthiweyo. PloS enye. 2006;1:e138. [Inkcazelo yamahhala ye-PMC] [PubMed]
  36. Kelley AE, Berridge KC. I-neuroscience yemivuzo yendalo: ukubaluleka kwiziyobisi ezikhobokisayo. Ijenali yeNeuroscience: ijenali esemthethweni yoMbutho weNeuroscience. 2002;22:3306–3311. [PubMed]
  37. Kelley AE, Smith-Roe SL, Holahan MR. Ukufundwa kwempendulo-yokuqinisa kuxhomekeke kwi-N-methyl-D-aspartate receptor activation kwi-nucleus accumbens core. Iinkqubo zeZiko leSizwe leSayensi lase-United States of America. 1997;94:12174–12179. [Inkcazelo yamahhala ye-PMC] [PubMed]
  38. LeBlanc JJ, Fagiolini M. Autism: "ixesha elibalulekileyo" ukuphazamiseka? Iplastiki yeNeural. 2011;2011:921680. [Inkcazelo yamahhala ye-PMC] [PubMed]
  39. Lerman DC, Iwata BA. Uhlalutyo oluchazayo kunye novavanyo lwezinto ezahlukeneyo ezigcina ukuziphatha ngokuzenzakalisa. Ijenali yohlalutyo lokuziphatha olusetyenzisiweyo. 1993;26:293–319. [Inkcazelo yamahhala ye-PMC] [PubMed]
  40. Levenson JM, O'Riordan KJ, Brown KD, Trinh MA, Molfese DL, Sweatt JD. Ukulawulwa kwe-histone acetylation ngexesha lokwenziwa kwememori kwi-hippocampus. Ijenali yekhemikhali yebhayoloji. 2004;279:40545–40559. [PubMed]
  41. Li B, Otsu Y, Murphy TH, Raymond LA. Ukuncipha kophuhliso kwi-NMDA receptor deensitization ehambelana nokutshintsha kwi-synapse kunye nokusebenzisana ne-postsynaptic density-95. Ijenali yeNeuroscience: ijenali esemthethweni yoMbutho weNeuroscience. 2003;23:11244–11254. [PubMed]
  42. Lovaas OI. Unyango lokuziphatha kunye nokusebenza okuqhelekileyo kwezemfundo kunye nengqondo kubantwana abancinci be-autistic. Ijenali yokubonisana kunye nesayikholoji yeklinikhi. 1987;55:3–9. [PubMed]
  43. McEachin JJ, Smith T, Lovaas OI. Isiphumo sexesha elide kubantwana abane-autism abafumene unyango olunzulu lokuziphatha kwangoko. Ijenali yaseMelika yokudodobala kwengqondo: AJMR. 1993;97:359–372. ingxoxo 373-391. [PubMed]
  44. McKee BL, Kelley AE, Moser HR, Andrzejewski ME. Ukufunda okusebenzayo kufuna kusebenze i-NMDA-receptor kwi-anterior cingulate cortex kunye ne-dorsomedial striatum, kodwa hayi kwi-orbitofrontal cortex. I-neuroscience yokuziphatha. 2010;124:500–509. [PubMed]
  45. Nestler EJ. Isiseko se-molekyuli yexesha elide ukuxhomekeka kweziyobisi. Nat Rev Neurosci. I-2001; 2: 119-128. [PubMed]
  46. Osler SF, Trautman GE. Ukufezekiswa kombono: II. Isiphumo sokuntsokotha kovuselelo ekufikeleleni kwingcinga kumanqanaba amabini obulumko. Ijenali yesayikholoji yovavanyo. 1961;62:9–13. [PubMed]
  47. Ostlund SB, Balleine BW. Izilonda ze-medial prefrontal cortex ziphazamisa ukufunyanwa kodwa kungekhona ukubonakaliswa kokufunda okujoliswe kuko. Ijenali yeNeuroscience: ijenali esemthethweni yoMbutho weNeuroscience. 2005;25:7763–7770. [PubMed]
  48. I-Pisani A, i-Gubellini P, i-Bonsi P, i-Conquet F, i-Picconi B, i-Centonze D, i-Bernardi G, i-Calabresi P. I-Metabotropic glutamate receptor 5 idibanisa amandla okuphendula kwe-N-methyl-D-aspartate kwi-neurons ephakathi kwe-spiny striatal. Inzululwazi yemithambo-luvo. 2001;106:579–587. [PubMed]
  49. Umgaqo-nkqubo OoNDC. Iindleko zezoQoqosho zokuSetyenziswa gwenxa kweziyobisi eMelika. 2001:1992–1998.
  50. Pryor KW, Haag R, O'Reilly J. I-porpoise yokuyila: uqeqesho lokuziphatha kwenoveli. J Exp Anal Behav. 1969;12:653–661. [Inkcazelo yamahhala ye-PMC] [PubMed]
  51. Rescorla RA. Inqaku lokudakumba kokuphendula kwesixhobo emva kovavanyo olunye lokuthotywa kwesiphumo. QJ Exp Psychol B. 1994;47:27–37. [PubMed]
  52. Ribeiro MJ, Schofield MG, Kemenes I, O'Shea M, Kemenes G, Benjamin PR. Ukuqaliswa kwe-MAPK kuyimfuneko ekudityanisweni kwememori yexesha elide emva kokulungiswa komvuzo wokutya. Funda uMem. 2005;12:538–545. [Inkcazelo yamahhala ye-PMC] [PubMed]
  53. Roche KW, Standley S, McCallum J, Dune Ly C, Ehlers MD, Wenthold RJ. Iimpawu zemolekyuli ze-NMDA receptor internalization. Inzululwazi ngendalo. 2001;4:794–802. [PubMed]
  54. USalamone JD, Abazala MS, McCullough LD, Carriero DL, Berkowitz RJ. I-Nucleus accumbens ukukhutshwa kwe-dopamine yonyuka ngexesha lokucinezela i-lever yokutya kodwa kungasetyenziswa ukutya simahla. I-Pharmacology, i-biochemistry, kunye nokuziphatha. 1994;49:25–31. [PubMed]
  55. I-Salamone JD, i-Wisniecki A, i-Carlson BB, i-Correa M. I-Nucleus iqokelela i-dopamine depletions yenza izilwanyana zibe novelwano kakhulu kwiimfuno zomlinganiselo ophezulu omiselweyo kodwa angonakalisi ukomeleza ukutya okusisiseko. Inzululwazi yemithambo-luvo. 2001;105:863–870. [PubMed]
  56. Sallows GO, Graupner TD. Unyango olunzulu lokuziphatha kubantwana abane-autism: iziphumo zeminyaka emine kunye nabaqikeleli. Ijenali yaseMelika yokudodobala kwengqondo: AJMR. 2005;110:417–438. [PubMed]
  57. Schafe GE, Atkins CM, Swank MW, Bauer EP, Sweatt JD, LeDoux JE. Ukusetyenziswa kwe-ERK / MAP kinase kwi-amygdala iyadingeka ukuze kuhlanganiswe imemori ye-pavlovian uloyiko lwemeko. Ijenali yeNeuroscience: ijenali esemthethweni yoMbutho weNeuroscience. 2000;20:8177–8187. [PubMed]
  58. Schnaitter R. Ulwazi njengesenzo: I-epistemology ye-radical behaviourism. Ku: Modgil S, Modgil C, abahleli. BF Skinner: Imvumelwano kunye neengxabano. ENew York: I-Routledge; 1987. iphepha 57–68.
  59. Schultz W. Umqondiso womvuzo oqikelelweyo we-dopamine neurons. Ijenali ye-neurophysiology. 1998;80:1–27. [PubMed]
  60. I-Schultz W. Ukufumana ngokusesikweni nge-dopamine kunye nomvuzo. Neuron. I-2002; 36: 241-263. [PubMed]
  61. Seamans JK, Durstewitz D, Christie BR, Stevens CF, Sejnowski TJ. I-Dopamine D1 / D5 i-receptor modulation ye-excitatory synaptic inputs to layer V prefrontal cortex neurons. Iinkqubo zeZiko leSizwe leSayensi lase-United States of America. 2001;98:301–306. [Inkcazelo yamahhala ye-PMC] [PubMed]
  62. Shaywitz AJ, Greenberg ME. I-CREB: i-stimulus-induced transcription factor eyenziwa luluhlu olwahlukeneyo lweempawu ze-extracellular. UAnnu uMfundisi Biochem. 1999;68:821–861. [PubMed]
  63. USilva AJ, uKogan JH, uFrankland PW, uKida S. CREB kunye nememori. U-Annu uMfundisi Neurosci. 1998;21:127–148. [PubMed]
  64. Skinner BF. Inzululwazi kunye nokuziphatha kwabantu. ENew York: Inkampani yeMacMillan; 1953.
  65. Skinner BF. Ukuziphatha ngomlomo. ENew York: Appleton-Century-Crofts; 1957.
  66. Staddon JER, Simmelhag VL. Umfuniselo “weenkolelo”: ukuphononongwa kwakhona kweziphumo zawo kwimigaqo yokuziphatha okuguquguqukayo. Uphononongo lwezeNgqondo. 1971;78:3–43.
  67. Sweat JD. I-neuronal MAP kinase cascade: inkqubo yokudibanisa umqondiso we-biochemical egcina iplastiki ye-synaptic kunye nememori. J Neurochem. 2001;76:1–10. [PubMed]
  68. Thorndike E. Ubukrelekrele bezilwanyana. ENew York: eMacmillan; 1911.
  69. Valjent E, Pascoli V, Svenningsson P, Paul S, Enslen H, Corvol JC, Stipanovich A, Caboche J, Lombroso PJ, Nairn AC, Greengard P, Herve D, Girault JA. Ukulawulwa kweprotein phosphatase cascade ivumela i-dopamine eguqukayo kunye nemiqondiso ye-glutamate ukuba isebenze i-ERK kwi-striatum. Iinkqubo zeZiko leSizwe leSayensi lase-United States of America. 2005;102:491–496. [Inkcazelo yamahhala ye-PMC] [PubMed]
  70. Wang J, O'Donnell P. D (1) i-dopamine receptors potentiate i-nmda-mediated excitability yonyuka kwinqanaba le-V prefrontal cortical pyramidal neurons. Cereb Cortex. 2001;11:452–462. [PubMed]
  71. Wang L, Lv Z, Hu Z, Sheng J, Hui B, Sun J, Ma L. Chronic Cocaine-Induced H3 Acetylation and Transcriptional Activation of CaMKIIalpha kwi-Nucleus Accumbens ibalulekile kwiNkuthazo yokuQinisekiswa kweziyobisi. Neuropsychopharmacology 2009 [Inkcazelo yamahhala ye-PMC] [PubMed]
  72. Warren Z, McPheeters ML, Sathe N, Foss-Feig JH, Glasser A, Veenstra-Vanderweele J. Uphononongo olucwangcisiweyo lokungenelela kwangaphambili okunzulu kwi-autism spectrum disorders. Unyango lwabantwana. 2011;127:e1303–1311. [PubMed]
  73. Weiss F, Maldonado-Vlaar CS, Parsons LH, Kerr TM, Smith DL, Ben-Shahar O. Ukulawulwa kokuziphatha kokufuna i-cocaine nge-stimuli ehambelana neziyobisi kwiigundane: iimpembelelo ekufumaneni kwakhona amanqanaba okuphendula okucinyiweyo kunye ne-extracellular dopamine kwi-amygdala. kunye ne-nucleus accumbens. Iinkqubo zeZiko leSizwe leSayensi lase-United States of America. 2000;97:4321–4326. [Inkcazelo yamahhala ye-PMC] [PubMed]
  74. Wickens JR, Begg AJ, Arbuthnott GW. I-Dopamine ibuyisela umva ukudakumba kwe-rat corticostriatal synapses edla ngokulandela uvuselelo lwe-high-frequency ye-cortex in vitro. Inzululwazi yemithambo-luvo. 1996;70:1–5. [PubMed]
  75. Ubulumko RA, Bozarth MA. Iindlela zobuchopho zomvuzo weziyobisi kunye nolonwabo. Psychiatr Med. 1985;3:445–460. [PubMed]
  76. I-Wood MA, i-Kaplan MP, i-Park A, i-Blanchard EJ, i-Oliveira AM, i-Lombardi TL, i-Abel T. Iigundane zeTransgenic ezivakalisa ifom ye-CREB-binding protein (CBP) ibonisa ukusilela kwi-hippocampal synaptic plasticity kunye nokugcinwa kwememori. Funda uMem. 2005;12:111–119. [Inkcazelo yamahhala ye-PMC] [PubMed]