I-Synapse ye-Addicted: Iinkqubo ze-Synaptic kunye ne-Structural Plasticity kwi-Nucleus Accumbens (2010)

Iimpawu zeNeurosci. Umbhalo-ngqangi wombhali; ifumaneka kwi-PMC 2011 Juni 1.Ipapashwe kwifomu yokugqibela ehleliweyo ngolu hlobo:

Iintlobo zeeurosci. 2010 Juni; 33(6): 267-276.

Ipapashwe kwi-intanethi ye-2010 ngo-Matshi 5. ikhonkco: 10.1016 / j.tins.2010.02.002

UScot J. Russo,^1,^* UDavid M. Dietz,¹ UDani Dumitrium,¹ Robert C. Malenka,² kwaye Eric J. Nestler¹

Bona amanye amanqaku ku-PMC Wisdom nqaku epapashwe.

Abstract

Iziyobisi ezikhobokisayo zibangela uhlengahlengiso oluzingileyo lweentlobo ezininzi zeeseli ze-neuronal kwimimandla yobuchopho ekucingelwa ukuba inoxanduva lokuziphatha ixesha elide kwiplastikhi yokuqhuba umlutha. Nangona olu tshintsho lwesakhiwo lubhalwe kakuhle kwi-nucleus accumbens medium spiny neurons, kuncinci okwaziwayo malunga neendlela ezisisiseko zemolekyuli. Ukongeza, akukacaci ukuba iplastiki yolwakhiwo kunye ne-synaptic ehambelana nayo iqhuba indlela yokuziphatha ekhobokisayo, okanye ingaba ibonisa imbuyekezo ye-homeostatic kwichiza elinganxulumananga nokukhotyokiswa ngokwesibini. Apha, sixoxa ngedatha ye-paradoxical yamva nje, enokuthi ixhase okanye ichase i-hypothesis yokuba utshintsho olwenziwe ngamachiza kwi-dendritic spines luqhuba isimilo somlutha. Sichaza iindawo apho uphando lwexesha elizayo lunokubonelela ngomfanekiso othe chatha wokuhlengahlengiswa kwe-synaptic eyenziwe ngamachiza, kubandakanywa i-ultrastructural, i-electrophysiological, kunye nezifundo zokuziphatha.

Internet: i-dendritic spines, umlutha weziyobisi, ukuphinda ubuyele, inkqubo ye-mesolimbic dopamine, amandla exesha elide (LTP), ukudakumba kwexesha elide (LTD), i-medium spiny neuron (MSN), i-α-amino-3-hydroxyl-5-methyl-4-isoxazole -propionate (AMPA), i-N-methyl D-aspartate (i-NMDA), i-ΔFosB, i-cyclic AMP impendulo ye-protein ebophezelayo (CREB), i-nuclear factor kappaB (NFκB), kunye ne-myocyte-enhancing factor 2 (MEF-2)

intshayelelo

Ukukhotyokiswa ziziyobisi kuphawulwa ngotshintsho oluhlala luhleli kwindlela yokuziphatha, njengokunqwenela nokubuyela emva. Okunxulunyaniswa nolu kuziphatha luzinzile luzinzile kuhlengahlengiso oluzingileyo lweentlobo ezininzi zeeseli ze-neuronal kwimimandla ye-limbic yobuchopho. Iindidi ezimbini eziqhelekileyo zeplastiki yesakhiwo ziye zabonwa: utshintsho kubungakanani bemizimba yeeseli [1] kunye notshintsho kwi-dendritic arborizations okanye i-spine morphology [2]. Ngokubhekiselele kokokugqibela, kuxhomekeke kudidi lweziyobisi, ubume beparadigm yolawulo lweziyobisi (umzekelo, umfuniselo ngokuchasene nokuzilawula), kunye nohlobo lweeseli ze-neuronal ezivavanyiweyo, iziyobisi zokusetyenziswa kakubi zinokutshintsha ubunzima be-dendritic branching, kunye inani kunye nobukhulu be-dendritic spines kwi-neurons kwiindawo ezininzi zobuchopho (1 Table). Ubungqina obunxibeleleneyo bucebisa ukuba utshintsho oluthile lwe-morphological ngabalamli ababalulekileyo bokuziphatha okukhobokisayo. Umzekelo, i-morphine kunye ne-cocaine ziguqula ukuxinana kwe-dendritic spines kwi-medium spiny neurons (MSNs) kwi-nucleus accumbens (NAc), indawo engundoqo yomvuzo wobuchopho, ukuya kuthi ga kwizilwanyana ezizilawula ngokwazo ichiza, xa kuthelekiswa nezilwanyana ezinikwe ichiza. umphandi, ecebisa ukuba ukuzikhethela kunokubaluleka kwimiba ephambili yeplastiki (ihlaziywe kwi- [3]). Ukongeza, utshintsho olwenziwe yi-cocaine kwisakhiwo se-NAc dendritic sinxibelelene ngokuqinileyo kunye nokungeniswa kokuziphatha [4]: iidosi kunye neeparadigms zolawulo lweziyobisi ezikhuthaza ukwazisa ngokuthembekileyo ukwandisa i-dendritic spines kunye ne-branching. Nangona obu bungqina, nangona kunjalo, ukufaneleka kokuziphatha kweplastiki yesakhiwo akukaqinisekwa. Izifundo ezininzi zakutsha nje zisebenzisa ukuhanjiswa kofuzo oluphakathi kwentsholongwane kunye nezinye iindlela zokuqonda ngcono ukubaluleka kokuziphatha kunye nesiseko semolekyuli yotshintsho olwenziwe yi-cocaine kwisakhiwo se-dendritic se-MSNs zivelise iziphumo eziphikisanayo, kunye nemibhalo-ngqangi emibini exhasa i-hypothesis yokuba ukonyuka kwe-cocaine-induced ku-dendritic spine. ukuxinana kolamlo wokuziphatha kunye nabanye ababini abayichasayo ngokuphandle [5-8]. Kolu hlaziyo, sixoxa ngedatha yovavanyo ekhoyo ngoku kwaye siqulunqa iindawo zophando lwexesha elizayo. Sichaza imixholo ephambili, siqala ngeentlobo zeplastikhi ye-synaptic ebangelwa ziziyobisi zokusetyenziswa kakubi kunye neendlela zokubonisa iindlela ezilamla iplastikhi yesakhiwo esenziwe ngamachiza, kunye nokuqhubela phambili kwiingxoxo ezineenkcukacha zomnqonqo we-morphometry kunye nendima esebenzayo yohlengahlengiso lwe-actin kubukhoboka.

Utshintsho olubangelwa ngamachiza kwi-neuronal morphology

Iplastiki yesakhiwo ebangelwa yi-opiate kunye neziyobisi ezikhuthazayo zokuxhatshazwa

I-Plasitiki ye-Drug-induced structural structural of dendrites yachazwa okokuqala kwi-1997 (ihlaziywe kwi- [3, 9, 10]). Ukusukela ngoko, iilabhoratri ezininzi zibonise ukuba ulawulo olungapheliyo phantse lonke ichiza lokusetyenziswa kakubi lubangela iplastiki yesakhiwo kumvuzo wokujikeleza kwengqondo. Ezi zifundo zikwanxibelelanisene notshintsho lwesakhiwo ngaphakathi kwemimandla ethile yobuchopho kwiiphenotypes zokuziphatha ezinxulumene nokulutha. Ukusukela kwiingxelo zokuqala zikaRobinson kunye noogxa (zihlaziywe kwi [3]), abaphandi abaninzi bongeze kolu ncwadi lukhulayo kwaye baye bafumanisa iziphumo ezifihlakeleyo kunye neklasi yeziyobisi kwi-neuronal morphology. Ngokomzekelo, ii-opiates kunye nezivuseleli zilawula iplastiki yesakhiwo kwicala elichaseneyo. I-opiates inciphisa inani kunye nobunzima be-dendritic spines kwi-NAc MSNs, i-medial prefrontal cortex (mPFC) kunye ne-hippocampus pyramidal neurons, kwaye inciphisa ubungakanani be-soma yendawo ye-ventral tegmental (VTA) i-dopaminergic neurons [1, 3, 11, 12]. Ukuza kuthi ga ngoku, kukho into eyahlukileyo kwezi zinto zifunyanisiweyo: imorphine engapheliyo yonyusa inani lomnqonqo kwi-orbitofrontal cortex (oPFC) i-pyramidal neurons [13]. Ngokuchaseneyo neeopiates, izivuseleli ezinje ngecocaine, amphetamine, kunye nemethylphenidate zihlala zonyusa ukuntsonkotha kwe-dendritic kunye noxinzelelo lomqolo we-NAc MSNs, i-VTA dopaminergic neurons, kunye ne-mPFC pyramidal neurons [2, 8, 14-17]. Ukusuka kumbono wokuziphatha, i-morphine iyanciphisa ukuxinana komnqonqo kunye nobunzima be-dendritic kungakhathaliseki ukuba ilawulwa ngokuqhubekayo ukuvelisa ukunyamezela kunye nokuxhomekeka, okanye ngokukhawuleza ukunyusa ukwazisa, ngelixa i-paradigms evuselelayo eyandisa ukuxinwa komqolo kunye nobunzima bonke basebenzise kanye ukuya kumaxesha amaninzi imihla ngemihla. iyeza lokuphembelela uvakalelo lwechiza [3, 9].

Utshintsho oluchaseneyo lwe-morphological oluye lwenziwa kwimimandla yomvuzo wobuchopho ngama-opiates ngokuchasene nezivuseleli ziyaxaka kuba la machiza mabini abangela i-phenotypes yokuziphatha efanayo. Ii-opiates kunye nezivuseleli zombini zikhuthaza ukusebenza kwe-locomotor ngokukhawuleza kunye ne-locomotor kunye nokuvuselela okungapheliyo [9]. Bobabini baphembelela iipatheni ezifanayo zokunyuka kokuzilawula kweziyobisi kunye nesimo sengqondo esibi (dysphoria) ngexesha lokurhoxa [18]. Ke ngoko, ukuba utshintsho oluchaseneyo lwe-morphological olubangelwa yi-opiates kunye nezivuseleli zingabalamli ababalulekileyo bomlutha, nokuba kufuneka babe neempawu ze-bidirectional, apho utshintsho olusuka kwisiseko kumacala omabini luvelisa i-phenotype yokuziphatha efanayo, okanye kukho iziqwenga eziphambili zolwazi malunga nomsebenzi we-synaptic. azibanjwa ngokulinganisa utshintsho olubi kakhulu kuxinano lomqolo we-dendritic njengoko oku kunokubuyekezwa ngotshintsho kumandla e-synaptic ukugcina igalelo le-synaptic lilonke kwi-neuron engaguqukiyo [19]. Umzekelo, utywala bunciphisa ukuntsonkotha kwe-neuronal kunye noxinaniso ngelixa udibanisa i-synapses esele ikhona [20], kwaye kusenokwenzeka ukuba i-opiates kunye nezivuseleli zivelisa iziphumo ezifanayo kubungakanani be-postsynaptic density (PSD) ekhokelela kutshintsho olufanayo kwi-synaptic efficacy. Akukacaci nokuba ukuvezwa okungapheliyo kwii-opiates okanye izivuseleli kukhokelela kutshintsho olufanayo lwe-electrophysiological kwi-NAc synapses, njengoko kunokulindelwa ukuba kunikwe iimpawu ekwabelwana ngazo zephenotype. Okokugqibela, kufuneka sithathele ingqalelo ukuba utshintsho oluye lwenziwa ngamachiza kwinombolo ye-synaptic kunye nokusebenza kwindawo enye yobuchopho kunokukhokelela ekomelezeni okanye ekwehleni unxibelelwano nezinye iindawo zobuchopho, kwaye kunokuqhuba imiba eyahlukileyo yokuziphatha okukhobokisayo [21-23].

Ukufaneleka kwe-Neurophysiological yeplastiki yesakhiwo esenziwe ngamachiza

Uphando olusisiseko malunga nokubaluleka kweenguqu ze-dendritic spine kwi-hippocampus kunye ne-cerebral cortex ibonisa ukuba ubungakanani kunye nokuma kwe-spines nganye kuhambelana neendlela ze-synaptic plasticity ezifana ne-long-term potentiation (LTP) kunye nokudakumba kwexesha elide (LTD) [24, 25]. Kukholelwa ukuba ukuzinziswa komgudu odlulayo, ongakhulanga ube ngumqolo osisigxina, osebenzayo wenziwa ngendlela exhomekeke kumsebenzi (uhlaziywe kwi [26]). Iiprothokholi zokuvuselela ezenza i-LTD idityaniswe nokushwabana okanye ukurhoxa kwemiqolo [27-29], ngelixa ukuqaliswa kwe-LTP kuhambelana nokusekwa kwemigca emitsha kunye nokwandiswa kwemisipha ekhoyo [27, 28, 30]. Kwinqanaba le-molecular, kukholelwa ukuba i-LTP kunye ne-LTD ziqala utshintsho kwiindlela zokubonisa iimpawu, kunye nokudibanisa kunye nokwakhiwa kweeprotheni ze-cytoskeletal, eziguqula i-polymerization ye-actin ukuchaphazela ukuvuthwa komgudu kunye nokuzinza kunye nokuba yiyiphi i-anchor okanye i-internalize α-amino-3 -hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) i-glutamate receptors ukuvelisa umqolo osebenzayo (LTP) okanye ukurhoxiswa komqolo okhoyo (LTD) [24, 26]. Emva kokuzinziswa, i-spines iba yi-mushroom-shape, ibe noxinzelelo olukhulu lwe-postsynaptic [31], bonisa ukwanda kokubonakaliswa komphezulu we-AMPA receptors, kwaye ziqhubeke iinyanga [29, 32]. Olu tshintsho lubonisa isiganeko esizinzile kakhulu seselula esinokuba yinkcazo evakalayo kwiinguqu ezithile zokuziphatha zexesha elide ezinxulumene nokulutha.

Umsebenzi wamva nje kwiimodeli zokulutha ngokwenene ubonise utshintsho olusebenzayo kwii-NAc MSNs ezixhomekeke kakhulu kwixesha kunye nolwelo ngexesha lenkqubo yokulutha.Umzobo 1). Ngexesha lokuqala emva kokuvezwa kokugqibela kwe-cocaine, kukho ukonyuka kwe-spines (iplastiki ephezulu kakhulu) kunye noxinzelelo lwe-synaptic [33, 34], enokumela iqula elandisiweyo lee-synapses ezithuleyo [35, 36]. I-synapses ethuleyo iqulethe i-N-methyl-D-aspartate (NMDA) i-glutamate receptors kodwa imbalwa okanye ayikho i-AMPA receptors, ivakalisa i-NMDA receptor-mediated excitatory currents ye-postsynaptic currents, kwaye ziyi-substrates ezifanelekileyo ze-LTP [36, 37]. Kungekudala emva konyango lwe-cocaine, ii-synapses ezithe cwaka kwi-NAc zibonakala zibonisa ulwandiso olwandisiweyo lwe-NR2B equlathe ii-NMDA receptors [35], ukufunyaniswa okuhambelana nezi synapses zintsha kwaye zingekavuthwa [38, 39]. Ngexesha lokurhoxa kwe-cocaine, ezi spines zisandula ukuvela zibonakala ngathi zidlula kakhulu kwaye zinokuhlehla okanye zidibanise kwimizobo emile okwekhowa [33], isiganeko esikhatshwa kukwanda kokubonakaliswa komphezulu we-GluR2-eswele i-AMPA receptors kunye nokuba nokwenzeka kwezi synapses ze-glutamatergic [40-42]. (I-GluR2-eswele i-AMPA receptors ibonisa i-Ca²⁺ kunye nokuziphatha ngokubanzi xa kuthelekiswa ne-GluR2-equlethe i-AMPA receptors.) Ngokuziphatha, ukufukanyelwa kwenkanuko ye-cocaine kubonakala ngexesha lokurhoxa kwi-cocaine self-administration; oku kuphawulwa ngokunyuka okuthe ngcembe kunye nokuqhubekayo kokufuna i-cocaine kunye nokuba sengozini yokuphinda ibuyele, nto leyo enokufuna olu tshintsho kwi-stoichiometry ye-synaptic AMPA receptors [42, 43]. Nangona kunjalo, izifundo zokuziphatha zisebenzisa i-viral-mediated gene transfers zibonisa ukuba overexpression ye-AMPA GluR1 subunit kunciphisa ngokumangalisayo uvakalelo lokuziphatha kwi-cocaine, igxininisa imfuneko yophando oluqhubekayo kule ndawo [44]. Ubungqina obongezelelweyo bubonisa ukuba ukuvezwa kwakhona kwi-cocaine emva kwe-14 okanye i-30 yeentsuku zokurhoxa kubangela ukunciphisa ububanzi bentloko yomgogodla [33], ukubonakaliswa komhlaba okwehlisiwe kwezamkeli ze-AMPA [40], nokudandatheka komelela kwezi synapses [45]. Ngethuba lolu tshintsho lwexeshana kwisakhiwo se-synapse kunye nokubunjwa, kukho utshintsho oluphawulekayo kumsebenzi we-RhoGTPase yokubonisa iiprotheni ezifunekayo kwi-actin polymerization, umphumo onokuba noxanduva lokuhlengahlengiswa komqolo [46]. Ezi datha zikhomba kwintsebenziswano entsonkothileyo phakathi kwesakhiwo sentloko yomqolo, iipropathi ze-electrophysiological ze-NAc MSNs, kunye nokuziphatha okunxulumene nokulutha. Ngenxa yokuba ezininzi iiprotheyini ze-synaptic ziyakwazi ukulawula ezi ziganeko, kuya kubaluleka ukuchonga uthungelwano oluchanekileyo lwee-molecular ezibandakanyekayo kulawulo lwabo.

Imodeli ye-synaptic enxulumene nokulutha kunye nolwakhiwo lweplastiki

Iinkqubo ze-opiate- kunye ne-stimulant-induced structural plasticity

Ukufaneleka kokusebenza kolwakhiwo lweplastikhi kwiimodeli zokulutha lunzima, njengoko kuphawuliwe ngaphambili, yinto yokuba imorphine kunye necocaine zineziphumo ezichaseneyo kuxinzelelo lomqolo we-MSN. Ngaphezu koko, kukho uhlolo oluncinci oluthe ngqo lwezenzo zeziyobisi ezisezantsi ukucacisa le dichotomy kwiplastiki yesakhiwo. Ngelixa kukho izifundo ezininzi ezinkulu ze-microarray ezivavanya utshintsho kwimbonakalo yemfuza emva kolawulo lwe-psychostimulant, kukho ukunqongophala kolwazi olukhoyo kwiiopiates. Ngaphaya koko, izifundo zoguqulo lwembonakalo yemfuza ekuphenduleni imorphine okanye icocaine zisebenzise amaxesha ahlukeneyo ahlukeneyo, iirejimeni, kunye needosi, zisenza uthelekiso oluthe ngqo lungenzeki. Ngaphandle kwezi zilumkiso, kucacile ukuba i-opiate kunye neziyobisi ezikhuthazayo zokusetyenziswa kakubi zilawula ufuzo oluninzi olufaka iiproteni zokulawula i-cytoskeleton. Ngokomzekelo, kwi-NAc, i-morphine iyancipha i-Homer 1 kunye ne-PSD95 [47], iiprotheni ze-scaffolding ezinxulumene ne-postsynaptic cytoskeleton. Okubangela umdla kukuba, i-cocaine ngokufanayo inciphisa ezi proteni kwi-NAc [48-51]. Ukongezelela, i-morphine iyancipha i-RhoA, i-Rac1, kunye ne-Cdc42, ii-GTPases ezincinci ezilawula i-actin cytoskeleton (jonga ngezantsi) [47]. Umsebenzi wezi GTPases kunye neethagethi zazo ezisezantsi zicuthwa yicocaine ngokunjalo [52]. Ezi zifundo bezingenzelwanga ukuthelekisa ngokuthe ngqo i-morphine kunye nolawulo lwe-cocaine yemfuza enxulumene nolwakhiwo, ukanti omabini amachiza afunyaniswa ukuba enze utshintsho oluninzi olufanayo ngaphandle kommiselo ochaseneyo we-dendritic spines ye-NAc MSNs. Oku kuphakamisa ukuba ukulawulwa kwale ndlela kunokusebenza njengomqalisi weplastiki; nangona kunjalo, ayichazi i-dichotomy phakathi kwe-opiate- kunye ne-stimulant-induced structural plasticity.

Inyani yokuba ii-opiates kunye nezivuseleli ngokufanayo ziphembelela iijini ezininzi zolawulo lwe-cytoskeleton zinokubalelwa ekusebenzeni kwazo kwabalawuli abafanayo bokubhaliweyo, kubandakanywa nezinto ezikhutshelweyo, i-ΔFosB kunye ne-cyclic AMP yokuphendula into ebopha iprotein (CREB), kwi-NAc [53-56] (Umzobo 2). I-ΔFosB yenziwe kwi-NAc phantse zonke iindidi zeziyobisi zokusetyenziswa kakubi [57] kwaye iphucula iziphumo ezinomvuzo wazo zombini imorphine kunye necocaine [58, 59]. I-ΔFosB ibonakala iphendula malunga ne-25% yazo zonke iintlobo zofuzo ezilawulwa kwi-NAc yi-cocaine engapheliyo, kubandakanya iintlobo ezininzi ezinxulumene ne-synaptic plasticity efana ne-cofilin, iprotheni enxulumene ne-actin-4 (ARP4), kunye neprotein ye-cytoskeletal elawulwa ngumsebenzi (Arc) [58, 60]. Ngaphaya koko, i-ΔFosB iyimfuneko kwaye yanele kutshintsho oluye lwenziwa yi-cocaine kuxinaniso lomqolo we-dendritic [7]. Nangona kunjalo, ukuba zombini i-morphine kunye ne-cocaine zenza i-ΔFosB, kunye ne-ΔFosB ngumlamli ophambili we-spinogenesis ephuculweyo, kutheni i-morphine engapheliyo inciphisa uxinano lomqolo we-NAc MSN? Enye into enokwenzeka kukuba i-ΔFosB ilawula iiseti zofuzo ezithile kumxholo we-morphine ngokuchasene nolawulo lwe-cocaine, kuxhomekeke kolunye utshintsho olubhaliweyo olubandakanyekayo, okanye ukuba i-morphine idala olunye uhlengahlengiso kwii-neuron ze-NAc ezingaphezulu kophawu lwe-ΔFosB, ekuphela kwayo evuselela i-spinogenesis. Uphononongo olongezelelweyo luyafuneka ukulungisa ezi kunye nezinye iingcaciso.

Umqondiso weendlela ezibandakanyekayo ekuhlengahlengisweni kwe-cytoskeleton enxulumene nokulutha

Ngokuchaseneyo ne-ΔFosB, indima ye-CREB kulwakhiwo lweplastiki eyenziwe ngamachiza luqikelelo ngakumbi. Ngaphandle kobungqina bokuba ukungeniswa kwe-CREB kwi-NAc kulamla ukunyamezela kunye nokuxhomekeka kwi-morphine kunye nomvuzo we-cocaine (uhlaziywe kwi- [61]), kukho idatha embalwa evavanya ukuba i-CREB ilamla utshintsho lwesakhiwo emva kokuvezwa kwiziyobisi zokuxhatshazwa. Kwezinye iindawo ezininzi zobuchopho, iCREB yenza i-spinogenesis [37, 62, 63[]5, 64, 65]. I-CREB inokuphinda idibanise iplastiki ngokungeniswa kwe-microRNA, i-mir132, esandul 'ukuboniswa ukuba ibangele ukuphuma kwe-neurite ye-hippocampal neurons kwinkcubeko, ngokuyinxenye, ngokunciphisa amanqanaba e-GTPase p250GAP [66]. Ukunikezelwa kobungqina obuninzi obuchaphazela indima ye-CREB kulwakhiwo lweplastikhi kwezinye iisekethe ze-neural, uphando oluthe ngqo lwendima ye-CREB kulamlo lweplastiki yesakhiwo esenziwe ngamachiza kwi-NAc yeyona nto iphambili kuphando lwexesha elizayo. Apha, nangona kunjalo, kukho i-paradox yokuba i-opiates kunye nezivuseleli zombini zibangela umsebenzi we-CREB kwi-NAc ngelixa zisenza iziphumo ezichaseneyo kwisakhiwo se-dendritic.

Iindlela zemolekyuli zokulamla i-cocaine-induced iplastiki yesakhiwo

1. Iindlela zokubonisa i-RhoGTPase zilawula iplastiki yesakhiwo

Utshintsho lwesakhiwo kwi-actin cytoskeleton luyinxalenye enkulu elawulwa yintsapho encinci ye-GTPases, oko kukuthi, i-Rho, i-cell division cycle 42 (Cdc42), i-Ras, kunye ne-Rac (bona Umzobo 2). Ezi GTPases zincinci zisebenza yi-guanine nucleotide exchange factor (GEFs), njenge-Ras-guanine nucleotide releasing factor (RasGRF1 / 2), i-VAV, i-Kalirin 7, kunye ne-Tiam1, yonke into eyenza ukutshintshiselwa kwe-GDP ye-GTP [67-71]. Ii-GEFs zona ngokwazo zenziwe zisebenze ngemiqondiso emininzi engaphandle kweseli, kubandakanywa ubuchopho obuphuma kwi-neurotrophic factor (BDNF) ngokusebenzisa indlela ye-tyrosine receptor kinase (TRKB), i-tumor growth factor-B (TGF-B), i-cell adhesion proteins (integrins), kunye ne-NMDA glutamate receptors ngokusebenzisa ukwanda kweCa²⁺ kunye nokusebenza kweCa²⁺/i-calmodulin exhomekeke kwiprotheni kinase-II (CAMKII) [71-74]. Ukubophelela kwe-GTP kuvula ezi GTPase, nto leyo ekhokelela ekubeni kusebenze izilawuli ezisezantsi ze actin cytoskeleton, kuquka i-lim domain kinase (LIMK), Wiskott-Aldrich Syndrome proteins (WASPs), ARP, kunye ne-WASP-family verprolin homologues (WAVEs) [75-77]. Nangona kunjalo, amanyathelo acacileyo eemolekyuli apho ezi proteni zahlukeneyo zilawulwa yimiqondiso ye-extracellular, kwaye emva koko iindlela zokulawula isizukulwana, ukuhlehliswa, okanye ukulungiswa kwakhona kwe-dendritic spines, zihlala zingaqondwa kakuhle.

Kutshanje, ezi GTPase zincinci kunye nezivuseleli zazo zeGEF ziye zaphandwa ngendima yazo kwiplastikhi yesakhiwo eyenziwe ngamachiza. Iimpuku eziswele i-GEF i-Ras-GRF1 zibonisa ubuntununtunu obunciphileyo kwi-cocaine, ngelixa ukubonakaliswa okugqithisileyo kuyo yonke ingqondo kwandisa uvakalelo lweziyobisi kunye nomvuzo [78]. Ngaphaya koko, iRas-GRF1 ibonakala ngathi ilamla intetho ye-ΔFosB [78], njengoko kuphawuliwe ngaphambili ikhuthaza i-spinogenesis kwi-NAc MSNs [6, 7Okubangel 'umdla kukuba, i-cocaine engapheliyo isandul 'ukuboniswa ukunciphisa amanqanaba e-GTP-bound RhoA, ekucingelwa ukuba ikhokelele ekunciphiseni i-actin yokuqhawula iimolekyuli ezifana ne-LIMK kunye ne-cofilin [52].

Ifomu esebenzayo yee-GTPases ezincinci zipheliswa yi-GTPase-activating proteins (GAPs), ephucula i-GTP hydrolysis kwaye ngaloo ndlela isebenze njengabalawuli abangalunganga be-RhoGTPases. Nangona kuncinci kakhulu okwaziwayo malunga nendima yee-GAPs kumlutha, olunye uphononongo lubonise ukuba utshintsho kwi-RhoGAP18B ludlulisela ubuntununtunu obutshintshileyo be-ethanol, inikotini, kunye ne-cocaine. Drosophila [79]. Ezi ziphumo ziqaqambisa imfuneko yophando oluninzi lwexesha elizayo lokuchaza ukulawulwa kwe-RhoGTPases kunye neeproteni zabo ezilawulayo xa besesichengeni se-cocaine okanye ezinye iziyobisi.

2. Izilawuli ezibhaliweyo zeplastiki yolwakhiwo

Nangona amanyathelo achanekileyo emolekyuli apho i-ΔFosB ilamla i-cocaine-induced spine density change kwi-NAc MSNs ihlala ingaziwa, izifundo ezininzi zamva nje ziye zabonisa abaviwa imfuza emazantsi e-ΔFosB ekunokwenzeka ukuba babandakanyeke kuhlengahlengiso lwe-synaptic (bona. Umzobo 2). Isebenzisa uhlalutyo lwe-genome-wide-wide, i-ΔFosB ibonakaliswe ukulawula iintlobo ezininzi zemfuza ezaziwa ngokulamla i-spinogenesis [58]. Enye into ekujoliswe kuyo yi-cyclin dependent kinase 5 (Cdk5), eyenziwa yi-cocaine kwi-NAc nge-ΔFosB [80] kwaye kwaziwa kwezinye iinkqubo zokulawula iRhoGTPases. Ukuvinjwa kwendawo ye-Cdk5 kuthintela ukwanda komnqonqo we-cocaine kwi-NAc [8]. Ithagethi enye ye-Cdk5 yi-MEF2: ukungeniswa kwe-Cdk5 phosphorylates kwaye inqanda i-MEF2, eyandisa i-dendritic spines kwi-NAc MSNs [5]. Ukunyanzeliswa komsebenzi we-MEF2 ekuphenduleni i-cocaine kunokuvumela ukushicilelwa kwejene ehambelana ne-cytoskeleton, i-N-WASP kunye ne-WAVEs, eneendawo zokubopha i-MEF kwiindawo zabo ezikhuthazayo. Kukho ubungqina obubonisa ukuba iprotheni ethile ye-WAVE, i-WAVE1, ilawula i-spine morphogenesis ngendlela exhomekeke kwi-Cdk5.81, 82]. Ke ngoko, ukwenziwa kwe-Cdk5 nge-cocaine engapheliyo nge-ΔFosB, kunokukhokelela kulawulo lomsebenzi we-WAVE, ngelixa i-MEF2 inokulawula inqanaba lokuthetha ukulamla utshintsho lwexesha elide olubandakanyekayo kumlutha. Ukusuka kwimbono esebenzayo, inhibition ye-Cdk5, okanye ukusebenza kwe-MEF2, zombini ezo zichasene neziphumo ze-cocaine kwi-NAc dendritic spines, ngokumangalisayo. phucula iimpendulo zokuziphatha kwi-cocaine [5, 83, 84]. Ezi ziphumo bezingalindelekanga zibonisa ukuba utshintsho olubi kakhulu kuxinzelelo lomnqonqo lulonke lusenokungakhokelela kwiimpendulo zeziyobisi ngokwesehlo, kodwa kunokuba sisiphumo "sokulungelelaniswa kwe-homeostatic" ukuhlawulela ezinye iinguqu ezibangelwa kukuvezwa okungapheliyo kwe-cocaine, njengokuncitshiswa kovuselelo lwe-glutamatergic. ii-MSNs ngamacandelo angaphambili ecortical [34, 85].

Kuphononongo olulandelayo, sihlolisise enye into ebhaliweyo, i-nuclear factor κB (NFκB). Sifumene ukuba i-cocaine yenza umsebenzi we-NFκB kwi-NAc kwaye umphumo we-NFκB uyimfuneko kwi-cocaine-induced dendritic spine formation kwi-MSNs [6]. Njengakwindlela ye-Cdk5-MEF2, i-ΔFosB iyafuneka ekufakweni kwe-cocaine ye-NFκB subunits, ebonisa ukuba i-ΔFosB ilawula inkqubo enkulu ye-genesis eguquliweyo ekhokelela ekugqibeleni kwi-spinogenesis ye-NAc MSNs. Okubangela umdla kukuba, siye safumanisa ukuba ukuvinjwa kwendlela ye-NFκB kuthintele iimpendulo zokuziphatha kwi-cocaine, ngokuhambelana ne-hypothesis ekhoyo ebaleni yokuba ukonyuka okubangelwa yi-cocaine kwi-spine density mediate sensitization yokuziphatha [6].

Umahluko omangalisayo phakathi kweziphumo zokuziphatha ze-Cdk5-MEF2 vs. iziphumo ze-NFκB, ngaphandle kwento yokuba ukungeniswa kwazo zombini iindlela kulamlwa nge-ΔFosB kwaye kwandisa ukuxinana komqolo we-dendritic, kuqaqambise ukuntsonkotha kwezi ndlela ze-intracellular kunye nokubaluleka kophando lwexesha elizayo. I-hypothesis yethu yeyokuba isiphumo se-cocaine kukukhuthaza, nge-ΔFosB, i-NAc yoxinaniso lomqolo ngokusebenzisa iithagethi ezininzi ezisezantsi (umzekelo, i-NFκB, i-Cdk5-MEF2, abanye abaninzi) kwaye isiphumo sothungelwano kukuphendulwa kweempendulo zokuziphatha kwi-cocaine. Kwangaxeshanye, nangona kunjalo, indlela ekujoliswe kuyo yomntu efana ne-Cdk5-MEF2 inokuthi ibe yodwa ivelise iziphumo zokuziphatha ezahlukeneyo ngeziphumo zayo ezahlukeneyo zemolekyuli. Ke ngoko, kubalulekile ukuba izifundo zexesha elizayo zibe sezantsi kwiindlela zeemolekyuli kwiithagethi ezininzi ze-cocaine kunye ne-ΔFosB zokufumana ukuqonda kwigalelo elithile lendlela nganye ye-cocaine-induced spinogenesis kunye neempendulo ezitshintshileyo zokuziphatha kwi-cocaine. Ezi ziphumo zingangqinelaniyo zinokuchazwa ngokubhideka okunxulunyaniswa neempuku eziguquguqukayo kunye ne-knockout okanye iinkqubo zentsholongwane egqithisileyo. Ezi modeli, ezibaluleke kakhulu ekufundeni iindlela zemolekyuli ezibandakanyekayo kwiplastiki yesakhiwo, zinokuvelisa iziphumo zemfuza ekujoliswe kuzo kwaye zenze iimveliso zemfuza kumanqanaba angaphaya kwalawo abonwa emva kokuvezwa kweziyobisi. Ekugqibeleni, simele siqonde ukuba, ngokulinganisa inani elipheleleyo le-dendritic spine kuphela, silahlekelwa ulwazi olubalulekileyo malunga nokuba ezi zihlunu zenza i-synapses esebenzayo kwaye ngaloo ndlela iguqule ukuhamba kolwazi kwisiphaluka. Ngale miqolomba engqondweni, izifundo zexesha elizayo ziyafuneka ukujonga utshintsho oluthe kratya kubume bomqolo kunye nokwakheka kunye negalelo labo le-presynaptic (Ibhokisi 1) kunye neziphumo ze-electrophysiological zolu tshintsho lweemolekyuli kumxholo womqolo owenziwe ngamachiza kunye neplastiki ye-synaptic (Ibhokisi 2).

Ibhokisi ye-1 Iindlela zokulinganisa iplastiki yesakhiwo kwi-NAc MSNs

(A) I-morphology kunye nokuxinana kwee-dendritic spines ziye zaphononongwa ngeendlela ezininzi, nganye inamandla kunye nobuthathaka. Amabala eGolgi awabizi kwaye kulula ukwenza. Ukubonakaliswa kwe-Viral-mediated yeeprotheyini ze-fluorescent ezifana ne-GFP ivumela ukukwazi ukuphanda iindlela ze-molecular intrinsic ezilawula iplastiki yesakhiwo. Nangona kunjalo, iGolgi okanye usulelo lwentsholongwane aluvumeli uhlalutyo oluneenkcukacha lwe-3-dimensional (3D) yobume bomqolo okanye inombolo. Iindlela ezintsha ze-diolistics (ukuhanjiswa kompu wemfuza - okuqhelekileyo - idayi ye-carbocyanide ye-DiI) kunye ne-microinjection yeemolekyuli ze-fluorescent ezifana nedayi ye-Alexa Fluor kunye ne-Lucifer Yellow, ngokudityaniswa ne-3D ye-confocal imaging ye-10D ephezulu, inika umbono ongazange ubonwe kwi-morphology. imisipha ye-dendritic. (B) Umzekelo we-microinjection (okanye i-cell loading) ye-NAc neurons kunye no-Lucifer Yellow umfanekiso kwi-40X (iphaneli ephantsi), i-100X (iphaneli ephezulu), kunye ne-2X (iphaneli yasekunene). (C) Ngokusebenzisa iigundane ze-transgenic ezivakalisa i-GFP ngokukhethiweyo kwi-Drd1- okanye i-Drd3-ebonisa i-neurons (iphaneli yasekhohlo), sinokujolisa kwi-diolistics okanye idayi ye-microinjections ukufunda utshintsho oluthile lweseli kwi-morphology. (D) Enye inzuzo ye-microinjection kukuba iqinisekisiwe ukuba isetyenziswe kunye ne-NeuronStudio, inkqubo yokwenza uhlalutyo lwe-XNUMXD oluzenzekelayo lwe-spine density kunye ne-morphology, kunye nokuhlelwa okungakhethiyo kwe-spines ibe yincinci, i-mushroom, i-stubby kunye nezinye ii-subtypes.http://www.mssm.edu/cnic/tools-ns.html). Iinkqubo ezifanayo zikhona ukuze zisetyenziswe kunye nedayi ebotshelelwe kwinwebu efana neDiI [33]. (E) Zonke iindlela ezisekelwe kwi-microscope yokukhanya zinobuthathaka obukhulu xa kuthelekiswa ne-electron microscopy (EM). I-EM, umgangatho wegolide wokujonga i-synapses, isebenzisa uphawu olulodwa lwe-synapse: i-postsynaptic densities (PSDs) i-electron-dense kwaye inokubonwa ngokulula. Ukongezelela, iimpawu ezithile ze-synaptic ezifana ne-synaptic boutons ezininzi (i-yellow bow) kunye ne-perforated synapses (ibhokisi ye-orenji) inokubonwa kuphela yi-EM. Ubungakanani be-PSD bubonelela ngomlinganiselo wamandla e-synapse kuba ubukhulu be-PSD buhambelana nomsebenzi we-synaptic kunye neplastiki [91]. Eli nqanaba lolwazi linokubaluleka kwiimodeli zokulutha. Ngokomzekelo, kunokwenzeka ukuba iyeza lokuxhatshazwa litshintsha ukuxinana komqolo ngaphandle kokuguqula ukusebenza kweseli, mhlawumbi ngokudibanisa i-synapses ekhoyo ibe yincinci kodwa enamandla, okanye ngokudala i-synapses entsha kodwa ethule. Ngokwahlukileyo, utshintsho olubangelwa ngamachiza kwisayizi yomqolo okanye ukumila - kwaye ngoko ke umsebenzi - unokwenzeka ngokungabikho kwenguqu kwinani elipheleleyo lomqolo. Ukujongana nale mibuzo kwizifundo ezizayo, kuya kufuneka sithelekise ngokuthe ngqo i-opiate- kunye ne-stimulant-induced structural plasticity ye-NAc kunye nezinye ii-neurons zisebenzisa ukukhanya kunye ne-electron microscopy, kunye nohlalutyo lwe-3D lwe-morphometric yohlobo lomqolo, kunye nokulinganisa i-electrophysiological correlates ye-synaptic state. . Ukongeza, iimvavanyo zisebenzisa i-multi-photon microscopy edityaniswe ne-uncaging yendawo ye-caged glutamate, okanye uvuselelo lwee-terminal ze-presynaptic nerve terminals ezine-rhodopsins zesiteshi, ziyafuneka ukuvavanya ngokuthe ngqo umsebenzi kunye nokusebenza kwespines emitsha. 'Yabona Ibhokisi 2 ukufumana inkcazo ebanzi yezi zifundo zisebenzayo. Ibha yokulinganisa: 5 μm ku (A), 1 μm ku (E). Kwi-(D) eluhlaza okwesibhakabhaka, obomvu, oluhlaza kubonakalisa ubhityile, ikhowa, i-stubby type spines ngokulandelelanayo. Kwi-(E) i-blue shading ibonisa i-axon, i-pink shading ibonisa umqolo, iintolo zikhomba kwi-PSDs.

Ibhokisi yesi-2 Ukulinganisa amandla e-synaptic kwiisynapses ze-MSN nganye: kutheni oku kuyimfuneko?

Eyona nto ibalulekileyo kuphando lokusetyenziswa kakubi kweziyobisi kukulinganisa ngokuthe ngqo amandla e-synaptic kwi-synapses yomgogodla ngamnye ukwenzela ukuba uxhulumaniso lwe-causal phakathi kweenguqu ze-structural spine kunye neenguqu zokusebenza kwi-synaptic transmission zingenziwa. Okwangoku, oku kunokufezekiswa ngcono ngokudibanisa i-microscope ye-photon ye-laser yokuskena imikroskopu ukwenza umfanekiso wespina nganye ene-multi-photon laser uncaging ye-caged glutamate ukuze kusebenze i-spines efanayo.92, 93]. Ukuqhubela phambili okubalulekileyo kobugcisa kuya kuba kukukwazi ukuchonga amagalelo athile ahlukeneyo okwenza i-synapses kwi-spines nganye, kuba ukuguqulwa okwenziwe ngamachiza kwisakhiwo se-synaptic kunye nomsebenzi unokwahluka ngokuxhomekeke kwigalelo (umzekelo, i-hippocampal xa ithelekiswa ne-amygdala ngokuchasene negalelo le-cortical kwi-NAc MSNs. indlela echulumancisayo kodwa engumceli mngeni yokuphumeza oku kukuvakalisa amajelo avuleke ukukhanya, afana netshaneli irhodopsins, kwiitheminali zesynaptic zamagalelo athile ahlukeneyo. Ii-synapses zenziwe ukuba zirekhode iimpendulo zazo zomntu ngamnye kwi-glutamate ekhutshwe nge-synaptic.Ekugqibeleni, njengoko kugxininisiwe kwisicatshulwa, uhlobo oluthile lweseli ye-NAc kufuneka ichongwe, kuba uguqulo lwe-synaptic olubangelwa ngamachiza lunokwahluka phakathi kwe- Drd1- kunye ne- Drd2-ebonisa i-MSNs. kunye neentlobo ezahlukeneyo ze-interneurons kwi-NAc.

3. Ubume bohlobo lweseli lweplastiki yesakhiwo

Ii-MSNs ze-NAc zikhona kwii-subtypes ezimbini eziphambili, ubukhulu becala ziqulethe i-Drd1 okanye i-Drd2 dopamine receptors. Iindlela ze-intracellular ezisezantsi kwee-receptors zihluke kakhulu, kwaye ngoko ke iindlela ze-molecular ezilawula isakhiwo se-neuronal zingahluka ngokufanelekileyo. Nangona ukufakwa kwe-dendritic spines emva kokunyangwa ngokuphindaphindiweyo kunye ne-psychostimulants kwenzeka kuzo zombini i-Drd1- kunye ne-Drd2-ebonisa i-MSNs, ukuzinza kwexesha elide lee-spines ezintsha kubonakala kukhulu kwi-neurons ye-Drd1. Olu qwalaselo luxhasa uluvo lokuba i-intracellular signaling pathways ezantsi kwe-Drd1 inokudibanisa ukuzinziswa kwexesha elide kune-Drd2 neurons [17, 86]. Ewe, ukuzingisa kokunyuka kwe-dendritic spines kwi-Drd1-equlethe i-MSNs inxibelelana kakhulu nokungeniswa okuzingisileyo kwe-ΔFosB kwi-Drd1 MSNs kunye nempendulo yokuziphatha evuselelayo ekuvezweni kweziyobisi okungapheliyo [87, 88]. Ke, kunokwenzeka ukuba i-morphine kunye ne-cocaine zilawule i-intracellular cascades kwi-Drd1 kunye ne-Drd2 MSNs. Umbuzo ophambili ke ngoko kukuba ingaba iziyobisi ezahlukeneyo zokusetyenziswa kakubi zilawula ngokwahlukileyo ubume be-neuronal ngolawulo olukhethiweyo lokubonakaliswa kofuzo kwezi zahlukileyo ze-NAc MSNs. Olu luqwalaselo olubalulekileyo njengoko aba bantu babini bebandakanyiwe kwiinkalo ezahlukileyo zomsebenzi we-NAc, zisachazwa ngokungaphelelanga, kubandakanya iminikelo eyahlukeneyo kwiziphumo zokuziphatha zecocaine. Umzekelo, ukukhetha okukhethiweyo kwe-dopamine kunye ne-cAMP-elawulwa yi-phosphoprotein ye-32 kDa (DARPP-32) evela kwi-Drd1 ngokuchasene neeseli ze-Drd2 zenza iziphumo ezichaseneyo kwi-locomotion ye-cocaine [89]. Ngaphaya koko, ukunkqonkqozwa okukhethiweyo kwe-glucocorticoid receptor evela kwi-Drd1 neurons kunciphise inkuthazo ye-cocaine kunye nokutya okucinezelweyo kunye noluhlu olubanzi lweedosi [90]. Ukukwazi ukusebenzisa iindlela ezithe kratya zokujonga utshintsho kwimolekyuli kwi- Drd1 kunye ne Drd2 MSNs (Ibhokisi 1) iya kusinceda ukuba siqonde ukuba utshintsho lwemolekyuli olwenzeka kwezi ntlobo zeeseli ze-neuronal lunokukhokelela kutshintsho olwahlukileyo kulwakhiwo lwe-neuronal ekuphenduleni kwiindidi ezahlukeneyo zeziyobisi zokusetyenziswa kakubi, kunye nokuba olu tshintsho luyichaphazela njani indlela yokuziphatha ekhobokisayo.

izigqibo

Iplastiki yolwakhiwo lweziyobisi lolunye lolona tshintsho lunokuphinda-phinda kunye noluhlala luhleli olunxulunyaniswa neemodeli zokulutha. Izifundo ezininzi ezinxibeleleneyo, kunye nezifundo ezimbalwa ezisebenzayo, zibonelela ngobungqina obubambekayo bokuba ezi neuroadaptations zibalulekile ekulaleni uvakalelo lokuziphatha kwicocaine. Nangona kunjalo, kukho neengxelo ezininzi ezisebenzayo eziphikisa ukuba i-plasticity-induced spine plasticity yi-epi-phenomenon engahambelani novakalelo. Kuyacaca ukuba umsebenzi omninzi uyimfuneko ukuze uqonde ngokupheleleyo ukubandakanyeka kwe-synaptic kunye ne-plasticity yesakhiwo ekuziphatheni okukhobokisayo. Kweli nqanaba, kuphambi kwexesha ukuxoxa ngokuqinisekileyo kulo naliphi na icala, njengoko uninzi lwezifundo ezipapashiweyo zixhomekeke kwimilinganiselo yobuninzi be-dendritic spine density, ukungahoywa kwezinto ezininzi zeplastiki yomqolo (bona Ibhokisi 1). Kulo lonke olu phononongo, siye sachaza iinkalo eziphambili zophando lwexesha elizayo, olushwankathelweyo 2 Table, ezifunekayo ukucacisa idatha yovavanyo lwe-paradoxical kunye nokunceda ukuchaza indima ye-dendritic spine plasticity kwi-addiction. Izifundo zexesha elizayo zisebenzisa i-multi-photon kunye ne-electron microscopy ziya kufuneka ukuthelekisa iziphumo ze-opiate kunye neziyobisi ezivuselelayo zokuxhatshazwa kwiipropathi ezineenkcukacha zesakhiwo se-synapses evuselelayo, njengenani le-docked kunye ne-reserve pool presynaptic vesicles, i-PSD kunye nobude bendawo esebenzayo, kunye nomqolo. ukuxinana kwentloko kunye nomthamo. Oku kuya kunceda ukuphendula umbuzo wokuba ingaba iyantlukwano edidayo ebonwe kubuninzi be-dendritic spine emva kwe-morphine kunye ne-cocaine ngokwenene ibonisa umahluko kwinani le-synapse kunye namandla. Ukongeza, ngenxa yokwexeshana kotshintsho oluninzi lwe-electrophysiological, sifuna ulwazi oluthe kratya lwexesha le-dendritic plasticity, ye-LTD/LTP, kunye nokufakwa okanye ukufakwa ngaphakathi kwee-receptors ze-glutamate ezibangelwa yi-opiates kunye nezivuseleli ezinokubonisa iimpawu ezithile zokuziphatha. umlutha. Ukuseka i-causality, emva koko kuya kufuneka sijonge ukuba nganye kwezi zinguqu zisebenzayo kunye nolwakhiwo ziyichaphazela njani indlela yokuziphatha efana nomlutha. Le ngongoma yokugqibela ibaluleke kakhulu kwaye iya kufuna ukuhlanganiswa kweendlela ezininzi. Okokuqala, indlela yeemolekyuli ichongiwe njengelawulwa ngamachiza okuxhatshazwa kunye nejene ekujoliswe kuyo esezantsi echazwe kuyo nayiphi na imfuza enxulumene nolwakhiwo lweplastiki. Emva koko, ngokusebenzisa i-viral-mediated gene transfer translate, i-expression of shRNAs, okanye i-inducible genetic mutant iigundane ukuze zilawule ezi ndlela zeemolekyuli, kuya kuba nako ukumisela iindima zabo ezithile kwi-electrophysiological, i-structural, kunye neenguqu zokuziphatha ezilandela ulawulo lweziyobisi ezingapheliyo. Okokugqibela, zonke ezi zifundo kufuneka zithathelwe ingqalelo kuhlobo lweeseli kunye nesiseko sobuchopho esikhethekileyo sokuqonda okunentsingiselo kweendlela ezichanekileyo ze-pathology yobuchopho ekukhobokeni.

Imibuzo ebalaseleyo

Imibulelo

Ukulungiswa kolu hlaziyo kuxhaswe zizibonelelo ezivela kwiZiko leSizwe lokuSetyenziswa gwenxa kweZiyobisi

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Iirejimeni zonyango ezivuselelayo: Oku kuquka umfuniselo-okanye ozilawulayo i-cocaine amphetamine, okanye inikotini kwidosi enikiweyo kunye nokuphindaphinda kangangexesha elithile. Izilwanyana ziye zihlalutywe ngamaxesha ahlukeneyo emva kwedosi yokugqibela yechiza
Iiparadigms zonyango lwe-opiate: Oku kuquka umfuniselo- okanye ukuzilawula ngokwakho imorphine, i-heroin, okanye amanye amachiza e-opiate okuxhatshazwa ngedosi enikiweyo kunye nokuphindaphindwa kwexesha elinikiweyo. Izilwanyana ziye zihlalutywe ngamaxesha ahlukeneyo emva kwedosi yokugqibela yechiza
Imimandla yomvuzo wobuchopho: Oku kubandakanya i-midbrain dopaminergic neurons kwindawo ye-ventral tegmental, kunye nemimandla ye-limbic apho le projekthi ye-neurons, kubandakanya i-nucleus accumbens (ventral striatum) i-amygdala, i-hippocampus, kunye nemimandla emininzi ye-prefrontal cortex (umz., i-medial, i-orbitofrontal, njl.
Glutamate receptors: Ii-receptors ezinkulu ze-ionotropic glutamate ebuchosheni zibizwa ngokuba zii-agonists ezithile, i-α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) kunye ne-N-methyl-D-aspartate (NMDA)
I-dopamine receptor: Iintlobo ezimbini eziphambili ze-dopamine receptors zibonakaliswa kwi-nucleus accumbens, equlethe nokuba yi-Drd1 okanye i-Drd2 receptors, eyahlukileyo kwiindlela zabo zokubonisa i-post-receptor. I-Drd1 i-receptors i-Gs-dityanisiwe kwaye ivuselela i-adenylyl cyclase, ngelixa i-Drd2 i-receptors i-Gi/o-coupled kwaye inhibisa i-adenylyl cyclase, ivula ukulungiswa kwangaphakathi kwe-K.⁺ imijelo, kwaye inqanda i-voltage-gated Ca²⁺ imijelo. Zombini ii-receptors zinokulawula i-extracellular signal regulated kinase (ERK) cascades
RhoGTPases: Ezi zincinci ze-G proteins zidlala indima ephambili ekulawuleni i-actin cytoskelelton, ekucingelwa ukuba ibalulekile ekukhuleni nasekuhoxisweni kwe-dendritic spines. Ziye zisebenze yi-guanine nucleotide exchange factor (GEFs) kwaye zithintelwe yi-GTPase-activating proteins (GAPs)
Imiba yokukhutshelwa: Ezi ziiprotheyini ezibophelela kulandelelwano oluthile lwe-DNA (ebizwa ngokuba yi-reaction elements) ngaphakathi kwejini esabelayo kwaye ngaloo ndlela yandise okanye yehlise ireyithi apho ezo mfuza zibhalwa khona. Imizekelo yezinto ezikhutshelweyo ezilawula i-dendritic spines zezi: ΔFosB (iprotein yosapho lwe-Fos), i-cyclic AMP response element binding element (CREB), i-nuclear factor κB (NFκB), kunye ne-myocyte-enhancing factor-2 (MEF2)
Iiprotheni kinases: Uninzi lweprotein kinases, i-enzymes ephosphorylate ezinye iiprotheni ukulawula umsebenzi wazo, ziye zabandakanyeka kulawulo lwe-dendritic spine formation, kuquka i-Ca.²⁺/ iprotein kinase-II exhomekeke kwi-calmodulin (CaMKII), i-cyclin-dependent kinase-5 (Cdk5), i-p21-activated kinase (PAK1), kunye ne-lim domain kinase (LIMK), phakathi kwezinye ezininzi
Iiprotheni ezinxulumene ne-Actin: I-actin cytoskeleton ilawulwa yinani elikhulu leeprotheni, nangona kunjalo, indima ecacileyo nganye ekugqibeleni ikhule okanye ihoxise umqolo, okanye ukuguqula ubungakanani bomqolo kunye nokuma, ihlala ingaqondwanga ngokupheleleyo. Imizekelo ibandakanya iiproteni ezinxulumene ne-actin (ARPs), Wiskott-Aldrich Syndrome proteins (WASPs), WASP-family verprolin homologues (WAVEs), kunye necofilin, phakathi kwezinye ezininzi.

Imihlathi

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.

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