Ukulinganisa okutshatyalaliswayo ngokushushumbisa iziyobisi: iindima ezihlukileyo zendlela echanekileyo neyiyo ngqo ye-spiny neurons (2011)

intshayelelo

Iziyobisi zokuxhatshazwa zenza iinguqu ezenzeka kwiimolekyuli kunye neeselula kuzo zombini isistri dorsal striatum (dStr) kunye ne-ventral striatum (nucleus accumbens, NAc), kwaye uninzi lwezi nguqu zenzeka kwii-spiny neurons eziphakathi (MSNs), ii-neurons eziphambili zeprojekti kwi-dStr ne-NAc, iakhawunti ye-90-95% yazo zonke ii-neuron kwezi ndawo. Nangona kunjalo, abaphandi ukuza kuthi ga ngoku abanakukwazi ukuchaza ngokucacileyo indima eyahlukileyo yecandelwana leMMSN ezimbini ezinxulumene nomlutha. Ii-subtypes ezimbini ze-MSN zahlulwe ngokutyebisa kwabo i-dopamine receptor 1 (D₁) okanye i-dopamine receptor 2 (D₂) kunye nezinye iintlobo zofuzo (UGerfen kunye noMncinci, 1988; UGerfen et al., 1990; Le Moine et al., 1990, 1991; UBernard et al., 1992; Ince et al., 1997; Lobo et al., 2006, 2007; Heiman et al., 2008; gensat.org) nangokuqikelela kwabo ngendlela eya kumgaqo we-cortico-basal ganglia (indlela ethe ngqo kwindlela engathanga ngqo; Gerfen, 1984, 1992). Umsebenzi wakuqala waphakamisa ukuba iziyobisi zokuxhatshazwa zinamandla kakhulu kwi-D₁Ii-MSNs, kusetyenziswa ii-agopist ze-dopamine receptor agonists kunye neqela elichasene nokubonelela ngolwazi oluchanekileyo kwindima yokusebenza kunye ne-molecule ye-MSN nganye kwiindlela zokuziphatha ezivuzayo.I-self, i-2010). Nangona kunjalo, iindlela zangoku zohlobo oluthile lweseli, kubandakanya neempuku zefluorescent ezibonisa GFP phantsi kweD₁ okanye iD₂ ii-chromosomes ezinobacteria (BACs; Gong et al., 2003; Valjent et al., 2009; gensat.org), iimodeli zemouse ezinemeko ethile njengokusetyenziswa kweempuku ze-tetracycline-ezilawulwa ngokungekho mthethweni ze-transgenic (Chen et al., 1998; UKelz et al., 1999), kunye neempuku ze-transgenic ezibonisa i-Cre-recombinase kusetyenziswa i-D₁ okanye iD₂ Ii-BACs, i-chromosomes yokufaka iigwele (i-YACs), okanye iimpuku zokunkqonkqoza (Gong et al., 2007; Lemberger et al., 2007; UHeusner et al., 2008; I-Parkitna et al., 2009; Valjent et al., 2009; Bateup et al., 2010; Lobo et al., 2010; gensat.org) kunye nokudluliselwa kuhlobo lweseli oluchaziweyo oluhambelana nentsholongwaneUCardin et al., 2010; IHikida et al., 2010; Lobo et al., 2010; Ferguson et al., 2011), banike ukuqonda okutsha kokungangqinelani kokuchaneka kwe-molekyuli yecandelwana ngalinye le-MSN kunye nommiselo wabo ngamachiza okuphatha gadalala (Itheyibhile 1).

1 Table. Iziphumo zoxinzelelo lohlobo oluthile lweseli kwi-D₁+ kunye no-D₂Ii-MSN kwiimodeli zokusetyenziswa kweziyobisi.

Iziphumo ezifunyenweyo kutshanje zixhasa ukugqitywa kwendima ephambili ye-D₁Ii-MSNs ekuveliseni ukuqiniswa kunye nokubonakalisa ukusebenza kweziyobisi zokuxhatshazwa, luninzi lweenguqu eziguqukayo zeemolekyuli ezenzeka kwezi MSN. Umzekelo, ukubonakaliswa kakhulu kwii-psychostimulants kunokubangela iimolekyuli ezininzi ezibandakanya i-FosB, i-ERK, i-c-Fos, kunye ne-Zif268 kwi-D.₁+ Ii-MSN, ngelixa i-cocaine iphindaphindwe kuqala ikhetha i-ΔFosB kunye nokutshintsha kwe-GABA receptor kunye nezinye iziteshi ze-ion ezizisa kolu hlobo lweeseli ngokunjalo (URobertson et al., 1991; Young et al., 1991; UBerretta et al., 1992; UCenci et al., 1992; Moratalla et al., 1992; Hope et al., 1994; Bertran-Gonzalez et al., 2008; Heiman et al., 2008). Ngapha koko, ukuphazamisa okanye ukuchaza ngaphezulu iimolekyuli ezithile, ezinje nge-ΔFosB, DARPP-32, okanye Nr3c1 (glucocorticoid receptor), kwi-D.₁IiMSNs ziqhele ukulinganisa indlela ezinxulumene neziyobisi eziqwalaselwayo xa olu tshintsho lwenziwe ngendlela engeyiyo eyolulo uhlobo, ngelixa luphazamisa uhlobo lwento kuD₂IiMSNs zihlala zibangela impendulo ephikisayo (Fienberg et al., 1998; UKelz et al., 1999; UDeroche-Gamonet et al., 2003; Zachariou et al., 2006; Ambroggi et al., 2009; Bateup et al., 2010). Nangona kunjalo, asinakukwazi ukubiza igalelo elibalulekileyo le-D₂Ii-MSNs kulungelelwaniso kumachiza okuphathwa gadalala, ngenxa yokuba ukubhencwa kwecocaine kubonakalisa ukucaciswa kofuzo kuzo zombini iziqendu zeMSN (Heiman et al., 2008) kunye no-D₂-i-arceptor agonists kunye neqela elichasayo linika iimpembelelo ezinamandla kwizenzo zokuziphatha (I-self, i-2010). Ewe, iziphumo zakutshanje zibonisa ukuba iimolekyuli zibonisa uhlengahlengiso ku-D₂Ii-MSNs ngokulula ziguqula indlela yokuziphatha kwesilwanyana kumachiza okuphathwa gadalala (Lobo et al., 2010). Iziphumo zokugqibela zibonise ukuba ilahleko yeTrkB (isamkeli se-BDNF) ku-D₂Ii-MSNs ziphumela kwiindlela ezifanayo zokuphendula kwi-cocaine njenge-TrkB yokunkqonkqozwa ngokupheleleyo kwi-NAc, ibonisa okokuqala indima ekhethekileyo kwindlela yimolekyuli kwi-D.₂Ii-MSNs ekulamleni iziphumo zeziyobisi zokuxhatshazwa.

Okokugqibela, uncwadi lwakutsha nje lutyhila ukuba iiMPNs ezimbini zineziphumo ezichasene nokuziphatha okunxulumene neziyobisi, apho kusebenze khona i-D.₁+ Ii-MSN okanye ukuthintelwa kwe-D₂+ Ii-MSN zenza ukuba izilwanyana zikwazi ukuziva uchaphazela isiyobisi.IHikida et al., 2010; Lobo et al., 2010; Ferguson et al., 2011). Ezi zinto zifunyanisiweyo ziyahambelana nendima echaseneyo ye-MSNs ezimbini kunye neendlela zazo ezingqalileyo kwi-basal ganglia kwiindlela zokuziphatha zeemoto (UAlexander et al., 1986; Albin et al., 1989; IGreybiel, i2000; Kravitz et al., 2010). Olu ncwadi lwakutshanje luhambelana nombono jikelele wokuba i-dopaminergic neurotransication, esebenza ngawo onke amachiza okuphatha gadalala, yenza ukuba kusebenze ukufakwa kwe-glutamatergic₁Ii-MSNs ngelixa zithintela ukwenziwa kwe glutamatergic ye-D₂+ Ii-MSN ngezenzo zayo kwi-D₁ vs. D₂ Ii-dopamine receptors (umzobo 1). Kolu hlaziyo, sithetha ngolwazi lwangoku lokubonakalisa imolekyuli eyahlukileyo eboniswe zezi ziqendu zimbini ze-MSN ngokunxulumene nendima yabo yokusebenza kunye nokuphendula kumachiza okuphatha gadalala.

Umzobo 1. Zonke iziyobisi zokuphathwa gadalala zonyusa uphawu lwe-dopamine kwi-striatum, enokuguqula ngokungafaniyo imisebenzi ye-glutamatergic kwezi zimbini zangaphantsi ze-MSN. Ngokukodwa, i-cocaine ibopha kwi-dopamine transporter ukunqanda ukuphindaphinda kwakhona kwe-dopamine kwii-terminals ze-VTA dopamine neurons. Ukusebenza kwe-G_s/_olf kunye D₁ Ii-receptors ziphucula umsebenzi we-PKA kunye nezinye ezitshintsha iiCa²⁺ K⁺ Ukuqhuba ukuphucula i-glutamate mediated "up-state" kwezi MSNs. Ngokwahlukileyo, ukwenziwa kukaG_i/G_o D₂-izamkeli zinciphisa umsebenzi we-PKA kunye notshintsho lweCa²⁺, N / A⁺, no K⁺ Ukuziphatha ukunciphisa i-glutamate "

I-Dopamine Receptor Signaling ku-D₁ vs. D₂ Ii-MSN

Njengoko sele kuphawuliwe, onke amachiza okuphathwa gadalala enza ukuba i-dopaminergic ingeniswe kwi-NAc kunye nemimandla yobuchopho obuhambelana nobuchopho (Volkow et al., 2004; Ubulumko, 2004; Nestler, 2005). Umzekelo, ii-psychostimulants ezinjenge-cocaine okanye i-amphetamine yenza ngokuthe ngqo kwindlela yomvuzo dopaminergic ngokungenelela kwisithuthuthu sedopamine: icocaine ivala umthuthi kwaye amphetamine irhoxisa into yokuhambisa, zombini isenzo esikhokelela ekwakhiweni kwe-dopamine kwi-synapse enokusebenzisa ukuhla kwe-dopamine. ii-receptors kwii-neurons ekujoliswe kuzo (Umzobo 1). Ii-MSNs ezimbini zahlulwe ngokwahlukileyo ngokucebisa kwabo ngo-D₁ vs. D₂-izamkeli nangona i-single-cell RT-PCR izifundo zibonisa ukuba D₁+ Ii-MSN zibonisa amanqanaba asezantsi eD₂-Yamkela i-receptor, D₃ kunye noD₂+ Ii-MSN zibonisa amanqanaba asezantsi eD₁-Yamkela i-receptor, D₅ (Surmeier et al., 1996). Ii-MSN ezimbini zifuna indawo yokuhlala ene-glutamatergic ukuqhuba umsebenzi we-neural; dopamine ngokuchaseneyo imodareyitha ezi mpendulo zisebenza ngokuvuselela izinto ezingafaniyo zedopamine receptor: ngokwenza imodeli ngokuqinisekileyo yokufaka igutamatergic yegalelo ngo-D.₁ receptor isayina nge-G_s okanye G_olf, ekhuthaza i-adenylyl cyclase ekhokelela ekunyukeni kwemisebenzi ye-PKA, ngelixa i-dopamine ngokungalunganga imodareyitha oku kugalelo ngo-D₂-receptor isayinela uG_i kunye G_o ethintela i-adenylyl cyclase ebangela ukunciphisa umsebenzi we-PKA (Surmeier et al., 2007; UGerfen noSurmeier, 2011). Ngokwenyani, i-receptor nganye inikezela iziphumo ezintsokothileyo kwiindlela ezininzi ezongezelelweyo ezibonisa ukuhla kweendlela. Ukuphumla, ii-subtypes ezimbini ze-MSN zithintelwe ngokubanzi, zikwimeko yokuba abaphandi babize i-low-state. Umsebenzi obekekileyo we-glutamatergic synaptic unokuthi ukhuphe ii-MSNs kule meko iphantsi kwaye uziguqulele kwilizwe elinoburhalarhume ngakumbi (up-state). I-Dopamine ngokuchaseneyo imodareyitha i-glutamatergic yotshintsho kwi-state-up. D₁ ukusebenza kwe-PKA kuphucula i-Cav1 L-uhlobo lweCa²⁺ Umsebenzi wesiteshi, uyancipha ngokwe-K⁺ umsebenzi wesiteshi, kunye nokuthoba i-Cav2 Ca²⁺ iitshaneli zokulawula ukusebenza kweCa²⁺ ukuxhomekeka, ukuqhuba okuncinci K⁺ (SK) amajelo, kukhokelela kukonyuka kwe spiking kwezi MSN (Surmeier et al., 2007; UGerfen noSurmeier, 2011). Ngokwahlukileyo, D₂ Ukubonakalisa uthintela uguquko-lukarhulumente, ngaloo ndlela kuthintelwa ukunyuka kwe-spiking, ngokunciphisa i-Cav1 L-uhlobo lwe-Ca²⁺ umsebenzi wesiteshi kunye Nav1 Na⁺ Umsebenzi wesiteshi ngelixa usandisa uK⁺ imisinga yejelo (Surmeier et al., 2007; UGerfen noSurmeier, 2011; Umzobo 1). Utshintsho oluchasene noko kwii-Microsoft ezimbini zicebisa ukuba ukonyusa uphawu lwe-dopamine kuphakanyiswe ngamachiza okuphathwa gadalala kufuneka kukhuthaze ukwenziwa kwe-glutamatergic kwe-D.₁+ Ii-MSNs kunye nokucutha ukusebenza kwe-glutamatergic ye-D₂+ Ii-MSN. Ngokwenyani, iimpendulo ezinjalo zinokwahluka kakhulu kwaye zintsokothile ngenxa yezizathu ezingasiqondakali kakuhle. Esi sihloko siza kuqwalaselwa apha ngezantsi.

Indima ye-dopamine receptors ekusebenziseni iziyobisi inzima kwaye idla ngokuxakeka (I-self, i-2010). Kukho intabalala yoluncwadi ngendima ka D₁ kunye noD₂-receptor agonists kunye nabachasi ekuguquleni iipropathi ezinomvuzo kunye nokuzilawula kweziyobisi zokuxhatshazwa, nangona kunjalo, iziphumo ziyahluka kuxhomekeka kuhlobo lwe-agonist / antagonist esetyenzisiweyo, uhlobo lokuhambisa (systemic vs. kwingingqi yengqondo echaziweyo), kunye nexesha UnyangoI-self, i-2010). Iziphumo ezinjalo ziphinde zangcoliswe ziziphumo ezithile ezingezozamayeza, ezifana negalelo le-pre-synaptic D₂-izamkeli ezivela kwiVTA okanye ubukho be-D₁ Ii-receptors kweminye imimandla emininzi yeengalo, kunye nokungabikho kokungangqinelani kwama-agonists / abachasi abasetyenzisiweyo kunye nenkcazo ye-D.₁-ngathi kwaye-D₂Ii-receptors-ezinje kuzo zombini ii-subtypes ze-MSN njengoko kuchaziwe ngaphambili. Ngokubanzi, kucingelwa ukuba ngu-D₁ Ii-receptors zidlala eyona ndima iphambili kwizibonelelo eziphambili zokwenza iziyobisi zokuxhatshazwa, kanti u-D₂Abathathi-nxaxheba banenxaxheba kwiindlela zokufumana iziyobisi (I-et et al., 1996; I-self, i-2010). Izifundo kunye no-D₁ receptor kunye D₂Iimpuku ze-recceptor zokunkqonkqoza zibonelela ngokuqonda kwindima yezi receptors kwii-MSNs ezimbini. D₁ Iimpuku zokunkqonkqoza zibonisa ungeniso olungalunganga lohlobo lwangoko (i-IEGs) c-Fos kunye neZif268 ekuphenduleni i-cocaine, impendulo enciphile kumsebenzi we-locomotor owenziwe nge-psychostimulant kodwa ngaphandle kotshintsho kukhetho lwendawo ene-cocaine (CPP) - indlela engathanga ngqo umvuzo wamachiza, kunye nokunciphisa ukuzilawula kwe-cocaine kunye nokusetyenziswa kwe-ethanol (Umncinci et al., 1995; UDrago et al., 1996; UCrawford et al., 1997; El-Ghundi et al., 1998; I-Caine et al., 2007). D₂ Ukuphuma kweempuku kuboniswa kunciphise iziphumo ezinomvuzo kwi-opiates kunye necocaine kunye nokuncipha kokusetyenziswa kwe ethanol kodwa akukho kuncitshiswa kokuthatha icocaine (Maldonado et al., 1997; Cunningham et al., 2000; Ukuvuselela i-et al., 2000; I-Caine et al., 2002; I-Chausmer et al., 2002; Elmer et al., 2002; I-Welter et al., 2007). Ezo datha zixhasa iindima ezibalulekileyo ze-D₁ kunye noD₂-e-receptors kwii-MSNs ezimbini kwiinkalo ezininzi zokusetyenziswa gwenxa kweziyobisi, nangona kunjalo, ukungqongqo akunakucaciswa ngokuthe ngqo kwaye kwenzeka ngokukhawuleza kuphuhliso, ke ngenxa yoko umntu akanakuyalela eminye imimandla yobuchopho kunye nohlobo lweeseli kunye nezinto ezibangela ukukhula ekuchaseni ezi ndlela zokuziphatha. Ekugqibeleni, ukunciphisa amanqanaba e-D₂/D₃ ii-receptors kwi-striatum, njengoko kubonwe kukucinga kwengqondo, iye yangumphawu oqhelekileyo wokulutha kwizigulana zabantu ngakumbi ngexesha lokurhoxa (Volkow et al., 2009). Iirongo ezifumana udluliselo lwentsholongwane oluhambelana nentsholongwane kaD₂-izamkeli kumboniso we-NAc obonisiweyo wolawulo lwecocaine kunye nokusetyenziswa kwe ethanolThanos et al., 2004, 2008). Olu phononongo alwenzelwanga ngohlobo-lweseli-luhlobo oluthile, ngoko ke asinakufikelela kwisiphumo seD₂Ugqithiso lwempembelelo ku-D₁+ Ii-MSN. Ukuqokelelwa kweenkcukacha kugxininisa isidingo sokufudukela kwindlela ekhethiweyo ngakumbi, kubandakanya uhlobo lweeseli-ekhethekileyo, engqamene nomda othile, kunye nexesha elichaziweyo lobuchwephesha be-dopamine receptors ukucacisa ngakumbi iindima zabo zokusebenza kwiindawo ezingaphantsi ezimbini ze-MSN iziyobisi.

Okokugqibela, kuye kwaxelwa ukuba ngu-D₂-GFP homozygote BAC transgenic mbezi ibonisa ukunyuka kwamanqanaba entetho ye-D₂Isincoko esikwi-striatum kunye nokuphucula uvakalelo lokuziphatha kunye dopamine isibonakaliso ku-D₂ i-agonists. Ngaphezu koko, zombini i-homozygotes kunye ne-hemizygotes zibonisa iimpendulo ezichaseneyo zokuziphatha kwi-cocaine (Kramer et al., 2011). Olu phononongo lubalaselisa imfuneko yokwenza uphawu oluchanekileyo lwe-D₁ kunye noD₂ intatheli ye-fluorescent kunye nemigca yomqhubi weCre. Nangona kunjalo, uninzi lwedatha eqokelelwe kolu phando lusebenzise iihomozygotes, olungeyona olona vavanyo luhlobo lovavanyo kuba i-5-10% yokudityaniswa kwe-transgene ikhokelela kuguquko olufakelweyo.Umlingisi, 1992); Ke ngoko, i-hemizygote genotype yeyona genotype ithembekileyo yokuhlola. Ukongeza, olu phononongo aluzange lisebenzise i-littermate wiltypepe yolawulo kodwa basebenzise ulawulo kwimvelaphi efanayo (Swiss Webster) efunyenwe kwiTaconic, ngelixa imigca yabo ye-transgenic ifunyenwe kwi-GENSAT kunye neMMRRC. Okokugqibela, elinye iqela libonise iimpendulo eziqhelekileyo zecocaine locomotor kwi-D₂-GFP hemizygotes (UKim et al., 2011). Ke ngoko, izifundo ezizayo zisebenzisa ulawulo oluchanekileyo kunye ne-genotypes efanelekileyo kufuneka yenziwe ukuba ibonakalise ngokupheleleyo imigca eyahlukeneyo yeselfini ekhethekileyo ekhoyo.

I-glutamate kunye ne-GABA Signaling ku-D₁ vs. D₂ Ii-MSN

I-neurons ye-spiny ephakathi ifumana igalelo le-glutamatergic ukusuka kwimimandla emininzi yobuchopho kubandakanya i-cortex yangaphambili, i-amygdala, kunye ne-hippocampus, kunye negalelo le-GABAergic ukusuka kwi-interneurons yendawo kwaye mhlawumbi nokufakelwa kokungahambelani kwezinye iiMMSN. Isincoko somnatha kunye nolawulo lwe-inhibitory ye-MSNs ngokuqinisekileyo ayibalulekanga kulawulo lwekhobisi elineziyobisi, kwaye ngoku kukho uncwadi olukhulayo ngeendlela ezinobunzima apho iziyobisi zokusebenzisa gwenxa i-alter glutamatergic neurotransmission ngokukodwa kwi-NAc (UPierce et al., 1996; Thomas et al., 2001; I-Beurrier neMalenka, 2002; UKourrich et al., 2007; I-Bachtell kunye ne-Self, i-2008; Bachtell et al., 2008; UConrad et al., 2008; Kalivas, 2009; Wolf, 2010). Nangona ii-MSN kucingelwa ukuba zibekho kwimeko-engaphantsi ethintelweyo phantsi kweemeko ezisisiseko ezinomsebenzi wokuqhutywa kwe glutamate zontlobo-ntlobo zentsholongwane, kusekho ulwazi olunomda ngokubhekisele kulawulo olwahlukileyo oluzenzekelayo e-D.₁ vs. D₂ Ii-MSN.

Δ I-osFosB oxpxpression ku-D₁+ Ii-MSNs (jonga ngezantsi malunga neenkcukacha ezithe kratya) zonyusa iziphumo ezinomvuzo zecocaine kunye nokunyusa amanqanaba eCa²⁺-unomdla we-glutamate receptor subunit, GluR2, kwi-NAc. Ngapha koko, ukugqithiselwa kohlobo oluhambelana nentsholongwane yeGluR2 kwi-NAc ngokufanayo kuphucula iziphumo ezinomvuzo zecocaine (UKelz et al., 1999). Nangona kunjalo, ayaziwa ukuba induction yeGluR2 ibonwe ekuphenduleni ΔFosB overexpression kwi-D₁I-+MSN ikwabhekiswa kwezi Neurons, kwaye i-overexpression ye-GluR2 ayichazwanga ngohlobo oluthile lweselfowuni, ke ngenxa yoko asinakukwenza izigqibo ezizezona ngqo malunga nokusebenza kweGluR2 kwezi zinto zimbini zeMSN kumvuzo wamachiza. I-Heusner kunye nePalmiter (2005) Ivavanye indima yokuziphatha kwe-NMDA glutamatergic ekuziphatheni kwe-cocaine ngokuchaza isuntswana le-NR1, equlethe inguquko kwisilonda esinciphisa i-calcium flux, ngokukhetha ku-D₁+ Ii-MSN. Eli qela libonise ukuba ukusilela kokuqhuba kwe-NMDA ku-D₁+ Ii-MSN zithintela i-cP ye-cocaine ye-cocaine kunye ne-cocaine locomotor sensitization, eqaqambisa imfuneko yokusayinwa kwe-NMDA ku-D.₁Ii-MSNs zokufumana umvuzo kunye nethamsanqa wecocaine (I-Heusner kunye nePalmiter, 2005). Ngapha koko, kutsha nje kufumaniseke ukuba ukukhupha i-NR1 subunit ku-D₁+ Ii-MSN zifumana ukuxhotyiswa kwe-amphetamine kwaye le phenotype yahlangulwa ngokuseta ngokutsha i-NR1 subunit kwi-D.₁Ii-MSNs ngokukodwa kwi-NAc (UBeutler et al., 2011). Okokugqibela, ukunqonqozwa kwe-mGluR5 subunit, usebenzisa ukuphazamiseka kwe-RNA, ku-D₁+ Ii-MSN azinampembelelo kwimpahla yokuqala evuzayo ye-cocaine kodwa iyanciphisa ukubuyiselwa kwe-cueine ebangelwa kukufuna i-cocaine (I-Novak et al., 2010). Ngelixa le datha ibonisa iindima ezinyanzelekileyo zokusayinela i-glutamatergic kwi-D₁+ Ii-MSNs, umsebenzi wexesha elizayo uyadingeka ukuze ufunde i-glutamatergic system kwi-D₂+ Ii-MSN. Uphando lwexesha elizayo kufuneka luphinde luvavanye indlela yokuguqulwa kwezi ziqwengana ze-glutamate receptor kwimizila emibini yee-MSN ezichaphazela ngayo utshintsho olwenziwe ngokubonakalayo kwi-NAc emva kweziyobisi zokuphathwa gadalala (I-Dietz et al., 2009; Russo et al., 2010), ngakumbi izilungiso eziguqulweyo eziqwalaselweyo emva kokubhenca icocaine ngokukhethekileyo kwi-D₁Ii-MSNs (ULee et al., 2006; UKim et al., 2011) ezinokuthi zinxulunyaniswe nokunyuka kwemijikelezo encinci yovuyo lwepostynaptic egcinwe ku-D₁Ii-MSNs (UKim et al., 2011). Okubangela umdla, ΔFosB induction in D₁+ Ii-MSN zidibene ngokuthe ngqo nolungelelaniso olunjalo lokuchwechwa emva kwecocaine engapheliyo (Maze et al., 2010).

Ngokuchasene ne-glutamate, kukho ukusilela kophando malunga nomsebenzi we-GABA kwiiMPs ezimbini kwiimodeli zokulutha, okumangazayo ukuthathela ingqalelo i-ethanol kunye ne-benzodiazepines kuphucula iimpembelelo ze-GABA kwaye ii-MSNs ezimbini zifumana igalelo elinamandla leGABAergic njengoko kuchaziwe apha ngasentla. Kukho ubungqina obucacisayo obukhombisa inhibition ephuculweyo kwi-NAc ubuncinci emva kokuvezwa kwe-cocaine (I-White et al., 1995; Abantu et al., 1998; Zhang et al., 1998; Thomas et al., 2001; I-Beurrier neMalenka, 2002). UHeiman et al. (2008) kwenziwe uvavanyo oluphezulu lwento yemvelo kwiMDNs ezimbini emva kokubhenceka kwe-cocaine kwaye, okubangela umdla, yeyona nkqubo itshintshileyo yendalo kwi-D.₁+ I-MSNs yayisisibonakaliso se-GABA. Ngokukodwa, bekukho nokunyanziswa kwamandla e-GABA_A i-receptor ihambisa iGabra1 kunye neGabra4 kunye neGABA_B I-receptor subunit Gabrb3, kwaye eli qela lafumanisa ukuba i-cocaine enganyangekiyo yonyusa isantya samaza amancinci endawo ye-GABAergic mini inhibitory postynaptic currents (mIPSCs) in D₁Ii-MSNs (Heiman et al., 2008). Kwelinye icala, elinye iqela elisandula ukubonakalisa ukuba i-cocaine engapheliyo ikhokelela kwimpendulo echaseneyo ngokuncipha kwamaza kunye nokuchithwa kwe-MIPSCs kwi-D1 + MSNs (UKim et al., 2011). Nangona kunjalo, iqela lokugqibela libonise ukuncipha kochulumanco lwe-membrane kwi-D₁Ii -MSNs emva kwe-cocaine engapheliyo, enokuthi ibonakalise ithoni ye-GABA eyandisiweyo kwaye iyahambelana novavanyo lwentsimi lwe-inhibition eyandisiweyo kwi-NAc emva kokubhengeza i-cocaine engapheliyo. Ngaphaya koko, umahluko phakathi kwala maqela mabini unokubangelwa lixesha lokuvezwa kwecocaine kunye nokurhoxa. Ngokubanzi, kukho isidingo sokufunda ukusebenza kwe-glutamatergic kunye ne-GABAergic kwii-MSNs ezimbini ukuphendula iziyobisi zokuxhatshazwa kwaye intsimi ngoku ixhotywe ngezixhobo ezenza uhlobo olunjalo lweseli- kunye nommandla okhethekileyo nongingqi.

Olunye uphawu lokuYamkela kwi-D₁ vs. D₂ Iziqwengana zeMMSN

Zombini ii-MSN zicebise ngokwahlukeneyo kwezinye ii-receptors ezidityaniswe nge-G-protein ukongeza ii-dopamine receptors. D₁+ Ii-MSN ziveza amanqanaba aphezulu e-acetylcholine muscarinic receptor 4 (M₄; UBernard et al., 1992; Ince et al., 1997) kunye no-D₂+ Ii-MSN zidityanisiwe kuzo zombini i-adenosine receptor 2A (A_2A; Schiffmann et al., 1991; I-Schiffmann kunye neVanderhaeghen, 1993) kunye ne-G-protein-edityanisiweyo ye-receptor 6 (Gpr6; Lobo et al., 2007; gensat.org). M₄ idityaniswe no-G_{mna / o}, eya kuthi ivelise impendulo echaseneyo, xa kuthelekiswa no-D₁ ii-receptors, ku-D₁+ Ii-MSNs ngokuthintela umsebenzi we-CAMP / PKA. Ewe, a₁+ I-MSN ekhethiweyo M₄ Ukunkqonkqoza kubonisiwe kokuziphatha okuphuculweyo kwi-cocaine kunye ne-amphetamine (UJeon et al., 2010). Ngaphaya koko, uphononongo lwakutsha nje usebenzisa i-receptor yoyilo eyenzelwe kuphela ichiza elenziweyo (DREADDs) lubonise ukuba kusebenze kwe-DREADD Gi / o-edibeneyo yomntu M₄ i-receptor (hM₄D) kwi-D₁+ Ii-MSNs zinciphise imvakalelo yokuziphatha yokuziphatha ukuba i-amphetamine, kunye nokuphendula okuchaseneyo kubonwe ku-D₂Ii-MSNs (Ferguson et al., 2011). Ezo datha zibonisa indima ye-M₄ Ii-receptors kwi-D₁Ii-MSNs ekusebenziseni iziyobisi gwenxa. Kananjalo, okoko hM₄I-receptor inokuthi ithintele ezi MSNs, idatha ibonelela ngengqondo malunga nefuthe lomsebenzi otshintshiweyo walezi zimbini zeSMN ekusebenziseni iziyobisi, eziya kuthi zixoxwe ngakumbi apha ngezantsi.

Zombini A_2A kunye neGpr6 zidityaniswe kakuhle kwi-G_s/G_olf iiproteni, zibonisa indima yazo ekuchaseni i-D₂Umamkeli kwi-D₂+ Ii-MSN. Ewe, ukuvuselela kuka-A_2A Ii-receptors zibonisiwe ukunciphisa zombini uphuhliso kunye nokubonisa kwe-cocaine sensitization (UFilip et al., 2006), thintela ukuqaliswa kwe-cocaine-self-managementI-Knapp et al., 2001), kunye nokuxhathisa ukubuyiselwa kwe-cocaine efuna ukuphakanyiswa yi-cocaine, D₂Ukuvuselela okungasasebenziyo, okanye imikhondo yemeko yecocaine (I-Bachtell kunye ne-Self, i-2009). Njengoko i-Gpr6 ikwaphuhliswa nayo kwi-D₂Ii-MSNs (Lobo et al., 2007), indima yayo kwimisebenzi yokuziphatha kwestriatum kufuneka ivavanywe. Ukuza kuthi ga ngoku, ibonakalisiwe ukuba nefuthe ekufundeni kwesixhobo (Lobo et al., 2007) kodwa indima yayo kwiimodeli zokusetyenziswa gwenxa kweziyobisi ayikaziwa.

I-cannabinoid receptor 1 (CB1) ibonakaliswa ubiquitously kuyo yonke inkqubo ye-nerve ephakathi (IMackie, 2008), ngenxa yoko kunzima ukwala indima eyiyo yeengingqi ezithile zobuchopho kunye neentlobo zeseli ekulamleni isiyobisi se-Δ9-tetrahydrocannabinol (THC). Kutshanje, ukucinywa kwe-CB1 kwi-D₁+ Ii-MSN zafunyanwa ukuba zichaphazele ngokuthobeka iimpendulo zokuziphatha kwi-THC, kubandakanya iziphumo ezingalunganga kwi-hypolocomotion ye-THC, i-hypothermia, kunye ne-analgesia (I-Monory et al., 2007). Kuya kuba ngumdla ukuvavanya i-cannabinoid receptor function in D₂+ Ii-MSNs ngenxa yokuba ezi MSN ziveza uxinzelelo lwe-endocannabinoid-Medium yexesha elide (eCB-LTD), efuna dopamine D₂-usebenzayoIKreitzer neMalenka, 2007).

I-glucocorticoid receptor, Nr3c1, ikwaboniswa ngokubanzi kwi-CNS kunye nomda. Ukukhuseleka okucinezelwe yi-glucocorticoid secretion kunokubangela isimilo esingalunganga kubandakanya nokulutha kweziyobisi (UFrank et al., 2011). Ngokukodwa, ukuphazamisa ukungena kweglucocorticoid ku-D₁+ Ii-MSN ngokususa i-Nr3c1 zinciphise isishukumiso sokuboniswa kweempuku kukuzenzela i-cocaine, kwaye oku kuyahambelana nedatha yangaphambili apho iNr3c1 icinywe kuyo yonke ingqondo (Ambroggi et al., 2009). Ezi datha ziyahambelana nezinye iziphumo ezifunyenwe kolu hlolo, zibonisa indima ephambili ye-D₁Ii-MSNs ekulamleni ezininzi zeziphumo zeziyobisi zokuphathwa gadalala.

Okokugqibela, siphazamise ukusayina kwe-BDNF kwii-MSNs ezimbini ngokucima i-receptor yayo ye-TrkB ngokukhethekileyo kwi-subtype nganye ye-MSN. Siqwalasele iziphumo ezichaseneyo zokuziphatha okuphantsi kwe-cocaine: umsebenzi we-cocaine-owenziweyo we-cocaine kunye nokungeniswa kweCPocaine yeCoca iphuculwe emva kokucinywa kweTrkB ku-D.₁+ Ii-MSNs, kodwa zamiswa emva kokuba kucinyiwe ku-D₂Ii-MSNs (Lobo et al., 2010). Into ebangela umdla kukuba kucinywe iTrBB ku-D₂Ii-MSNs zilingisa iziphumo zokucinywa ngokupheleleyo kweTrBB kwi-NAc kunye nokuphazamiseka kokubhalwa kwegama BDNF kwiVTA (Horger et al., 1999; Graham et al., 2007, 2009; UBahi et al., 2008; UCrooks et al., 2010). Ezi zinto zifunyanisiweyo zibonakalisa okwesiqendu sokuqala indima ephambili yomqondiso we-Cascade kwi-D₂Ii-MSNs ekulamleni iziphumo zetyala lokuphathwa gadalala. Indima ephambili ye-D₂Ii-MSNs ekulameni iziphumo ze-BDNF kwi-cocaine-elicited behaviours ayimangalisi xa kuthathelwa ingqalelo zombini iTrkB mRNA kunye neeprotein kutyetyiswe ku-D.₂Ii-MSNs (Lobo et al., 2010; Baydyuk et al., 2011). Utshintsho kwindlela yokuziphatha ebonwe kwezi mbethi zihamba kunye nomsebenzi ophuculweyo we-neuronal kwi-D₂+ Ii-MSN kwisikhuselo esikhethiweyo seTrB. Ezi ziphumo zisishukumisele ukuba sisebenzise itekhnoloji ye-optogenetic ukukhetha ngokunyanzela imisebenzi ye-MSN kumvuzo wecocaine (jonga ngezantsi).

Izinto zokukhuphela kuD₁ vs. D₂ Ii-MSN

Obona bungqina bunyanzelekileyo kwendima eyomeleleyo ye-D₁IiMSNs ekusetyenzisweni gwenxa kweziyobisi zivela kuncwadi oluvavanya ungeniso lweemolekyuli zangaphakathi. Njengoko kuchaziwe apha ngasentla, iidosi ezinamandla zee-psychostimulants zenza ibinzana le-IEG, kubandakanya i-c-Fos, iZif268 (Egr1), kunye ne-FosB ngokuyintloko ku-D.₁Ii-MSNs kwi-NAc nakwi-dStr (URobertson et al., 1991; Young et al., 1991; UBerretta et al., 1992; UCenci et al., 1992; Moratalla et al., 1992; Bertran-Gonzalez et al., 2008). Olu fakelo lufuna ukwenziwa ku-D₁ Ii-receptors, kunye nohlobo lweeseli lwe-IEG yokungenisa impendulo kwi-cocaine ye-acute esandula ukuqinisekiswa kusetyenziswa i-D.₁-GFP kunye ne-D₂-GFP intatheli (Bertran-Gonzalez et al., 2008). Into enomdla kukuba ukuqinisekiswa kokungeniswa kwe-cocaine ye-c-Fos ngokuyintloko ku-D₁-GFP kuyo yonke i-striatum ngeniso oluncinci kwi-D₂Ii-MSNs ze-GFP kuphela kwi-dStr zaqinisekiswa kusetyenziswa iparadigm exhomekeke kwimeko (iigundane zifakwe kwindawo yenoveli ngaphandle kwekhaya labo). Ngapha koko, isifundo sangaphambili sisebenzisa in situ ukwenziwa kwe-hybrid kumagundane kubonise ukwenziwa kwe-c-Fos ku-D₁+ kunye no-D₂+ Ii-MSNs kwi-dStr, nangona kolu luhlu lubonisa igrafu ebonisa inani elikhulu le-D₁I-c-Fos elungileyo i-neurons (Ferguson et al., 2006). Into enomdla kukuba, olu phando lutyhila kakhulu ukuphuculwa kwe-c-Fos ku-D₂Ii-MSNs kwi-dStr emva kokuphulukana ne-ERK1, ehambelana nezinto esizifumeneyo zokungeniswa kwe-c-Fos ku-D₂Ii-MSNs ngokukodwa kwiqokobhe le-NAc emva kokuphazanyiswa kokusayinwa kweBDNF eyaziwa ngokuba yinxalenye yomsebenzi we-ERK (Lobo et al., 2010). Nangona kunjalo, iimpendulo ezichaseneyo zokuziphatha kwe-cocaine zaqwalaselwa kwisifundo ngasinye, ezinokubonisa ukwenziwa kwe-c-Fos ku-D.₂+ Ii-MSN kwii-dStr vs NAc igobolondo. Okokugqibela, uncwadi lwangaphambili usebenzisa in situ I-hybridization / i-immunohistochemistry kwiigundane ibonise ukuba ii-psychostimulants zisesisifo zinokubangela i-c-Fos ngokulinganayo kuzo zombini ii-MSN xa ichiza linikezelwa kwindawo yenoveli (Badiani et al., 1999; Uslaner et al., 2001a,b; UFerguson kunye noRobinson, 2004) kunye nolawulo olungapheliyo lwe-amphetamine kuxelwa ukuba kukhetheke i-c-Fos ku-D₂Ii-MSNs (UMattson et al., 2007). Ezi ziphumo zahlukeneyo zinokubonakalisa iinkqubo zokuvavanya ezisetyenzisiweyo (in situ hybridization vs. GFP intatheli yeempuku) okanye nokuba kungenxa yesilwanyana esisetyenzisiweyo njengophando lokugqibela olusebenzise iigundane.

Kutshanje, abaphandi basebenza ngenkqubo ye-cocaine-exhomekeke, i-c-Fos isebenze kwiigundane kusetyenziswa i-immunolabeled fluorescence activation cell Planning (FACS) kwaye yabonisa ukuba ii-neuron ze-c-Fos + zityetyiswe ku-D.₁+ Uhlobo lwe-MSN, prodynorphin (Pdyn), kodwa banamanqanaba asezantsi eD₂ kunye A_2Abobabini₂+ I-genN genes (Guez-Barber et al., 2011), ucebisa ukuba ii-neurons ze-c-Fos + ezivuselelweyo zibandakanya ikakhulu i-D₁+ Ii-MSN. Ngapha koko, eli qela ngaphambili labonisa ukuba i-c-Fos echaza i-MSNs ibalulekile koluvo lokuxhomekeka kwimeko yesiqhelo, njengoko ukufakwa kwezi mitha kuphelisa le ndlela yokuziphatha yokuziphatha (UKoya et al., 2009). Nangona idatha yangaphambili ibonise ukuba umxholo we-cocaine oxhomekeke kwi-c-Fos uyenzeka kuzo zombini₁+ kunye no-D₂+ Ii-MSN kwiirati, iziphumo zamva nje ziyahambelana nokufunyenwe apho kucinywe i-c-Fos ekhethiweyo kwi-D₁+ I-MSN i blunts cocaine-inased locomotor sensitization kwiimpuku (Zhang et al., 2006). Ngapha koko, eli qela lafumanisa ukuba ukucinywa kwe-c-Fos ku-D₁Ii-MSNs zenza amabala atshintshileyo eguqulwe ngesiqhelo yi-cocaine kwi-NAc, ebonisa indima ye-c-Fos ekulamleni olu tshintsho lweplastiki ye-synaptic. Okokugqibela, iqela alibonanga tshintsho lwenziwayo kwi-cocaine ye-cocaine, kodwa lafumanisa ukuba ilahleko ye-c-Fos ku-D₁Ii-MSN zithintele ukupheliswa kwe-CPP ye-cocaine. Idatha enjalo ibonisa indima eguqukayo yokungeniswa kwe-c-Fos ku-D₁+ Ii-MSN, nangona kunjalo, umntu akanakukhupha isiphumo sokungafani kwinqanaba lokuziphatha njengokulawulwa kwayo nayiphi na enye imimandla eliqela yobuchopho obunamandla echaza i-D.₁ i-receptor.

Enye i-IEG ethe yafundwa ngokubanzi kwii-subtypes ezimbini ze-MSN yiFosB. Ukuboniswa kakhulu kwecocaine ye-cocaine ye-FosB ku-D₁Ii-MSNs (UBerretta et al., 1992), ngelixa ukubonakaliswa okungapheliyo kuzisa i-ΔFosB, imveliso ezinzileyo yohlobo lwe-FosB oluveliswe kukuphindaphinda (Hope et al., 1994; Nestler et al., 2001; Nestler, 2008), kwi-D₁Ii-MSNs (Nye et al., 1995; Moratalla et al., 1996; ULee et al., 2006). Iziphumo ezifanayo ziyajongwa kunye nezinye iziyobisi ezininzi zokuxhatshazwa kunye nemivuzo yendalo njengokutya, isondo, kunye nokuhamba ngevili. Umzekelo, ivili elingapheliyo liyasebenza, ngumvuzo wendalo (Iversen, 1993; Belke, 1997; Lett et al., 2000), induces ΔFosB kwi-D₁+ Ii-MSNs kodwa hayi ii-D₂Ii-MSNs (Werme et al., 2002). Ukufumana ulwazi olusebenzayo kwindima ye-ΔFosB kwii-MSN ezimbini, iqela lethu lavelisa imigca ye-NSE-tTa, ebizwa ngokuba yi-11A kunye ne-11B, ebeka ngqo intetho yotshintsho kuyo nokuba kukwa-D.₁+ okanye D₂+ Ii-MSNs, ngokwahlukeneyo (Chen et al., 1998; UKelz et al., 1999; Werme et al., 2002). Iimpuku zomgca 11A ziwele umgca we-Tet-Op ΔFosB zibonisa iimpendulo kwimbuyekezo kunye neziphumo ze-cocaine yecocaine (UKelz et al., 1999), ehambelana ne-ΔFosB yokungeniswa kwi-D₁Ii-MSNs (Nye et al., 1995; Moratalla et al., 1996). Ngapha koko, ezi mpuku zibonakalisa ukwanda komvuzo we-morphine (uhlolwe yi-CPP) kunye nokuhla kwe-morphine analgesia kunye nokuphuculwa kokunyamezelwa morphine, ngelixa 11B Tet-Op ΔFosB iimpuku zibonisa akukho tshintsho kumvuzo we-morphine. Uxinzelelo olukhulu oluchasayo olubi lwe-ΔFosB luvelisa iziphumo ezichasene nezo zibonwe nge-ΔFosB, nangona imodeli ye mouse ingahlukanisi D₁ vs. D₂ Ii-MSN (Peakman et al., 2003). Ngokudibeneyo, le datha iyaxhasa ngakumbi indima yokungeniswa kwe-ΔFosB ku-D₁+ Ii-MSNs njengomdlali obalulekileyo weemolekyuli kwiipropati ezinomvuzo zeziyobisi zokuxhatshazwa (Zachariou et al., 2006). Le nto iphinda ibonwe kwezinye ihambo ezinemivuzo, ngakumbi, ivili eliqhutywa: I-11A Tet-Op ΔFosB iimpuku zibonisa ukunyuka kweendlela zokuqhuba, ngelixa i-11B Tet-Op ΔFosB iimpuku zibonisa ukwehla kwevili lokuqhuba (Werme et al., 2002). Ukufumanisa ukuba yi-ΔFosB induction ku-D₁ Ii-MSN zikhuthaza umvuzo uhambelana nezinto ezifunyaniswe kutshanje zokuba uhlobo lwezinto ezikhethiweyo zeeselfini zikhuthaza iimpendulo zokomelela koxinzelelo olukhulu (Vialou et al., 2010). Okokugqibela, ukumiliselwa kwe-cocaine engapheliyo kwe-ΔFosB ku-D₁Ii-MSNs zaboniswa ukuba zihamba kunye nokunyuka okuhlala ixesha elide kwindawo ezixineneyo (dendritic spine densities)ULee et al., 2006) kwaye kutsha nje ΔFosB kwi-NAc ibonakalisiwe ukuba iyimfuneko kwaye yanele ekuthetheleleni uxinizelelo olonyukayo lwamazinga okunyanga kulo mmandla wengqondo (Maze et al., 2010). Ezo datha zixhasa indima ye-ΔFosB ku-D₁Ii-MSNs ekulamleni iinkalo ezinomvuzo zamachiza okuphathwa gadalala kunye nemivuzo yendalo kunye notshintsho oluhamba nolwakhiwo lweplastiki. Idatha ikwacebisa ukuba ukwenziwa kwe-ΔFosB ku-D₂IiMSNs zinika iziphumo ezingalunganga kwisikhuthazo esinomvuzo. Ukusukela ΔFosB induction kuD₂+ Ii-MSN zibonwa ekuphenduleni ngoxinzelelo olungapheliyo kunye nokuvezwa kweziyobisi ze-antipsychotic (UHiroi noGreybiel, i-1996; Perrotti et al., 2004), Izifundo ezongeziweyo zezenzo zokugqibela ziyafuneka.

Ezinye iiMolekyuli zophawu lwangaphakathi kwi-D₁ vs. D₂ Ii-MSN

Imolekyuli enye ebonakalisa ukuba ifundwe kakuhle kwii-MSNs ezimbini kwimeko yokusetyenziswa gwenxa kweziyobisi yi-kinase ye-protein, i-ERK (i-kinase yangaphandle enxulumene nomqondiso). Ukuvezwa okungalunganga okanye okungapheliyo kwe-cocaine induces phosphorylated ERK (pERK), ifom ye-proteni, kwi-NAc nakwi-DStr ku-D.₁+ Ii-MSNs zisebenzisa i-D₁-GFP kunye ne-D₂-GFP BAC intatheli yentatheli yegengen (Bertran-Gonzalez et al., 2008) kwaye lempendulo iphakathi kwi-D₁ receptors (Valjent et al., 2000; Lu et al., 2006). Eli qela likwabonisa ukuba i-pMSK-1 (phospho-MAP kunye noxinzelelo lwe-kinase-1) kunye ne-histone H3, zombini iinjongo zomqondiso we-PERK, zibethelelwa ngamandla kwi-PERK equkethe u-D.₁Ii-MSNs emva kokuvezwa kwe-cocaine yecute kwaye kwandiswe ngokuthozamileyo emva kwe-cocaine engapheliyo (Bertran-Gonzalez et al., 2008). I-PERK ikwabangelwa kukuphendula kwi-morphine engapheliyo, ngakumbi, igama elithi PERK liqhutywa ngamandla ku-D.₁+ Ii-MSNs kwaye zangeniswa ngokuthozama kuD₂+ Ii-MSN kwiqokobhe le-NAc emva kokurhoxiswa ekuphenduleni kubudlelwane obuthile be-morphine (I-Borgkvist et al., 2008). Umsebenzi ofanelekileyo we-pERK kwikhoboka leziyobisi uhlala umisiwe. Unyango lwe-Pharmacological kunye ne-ERK inhibitors lubonakalisiwe ukunciphisa umvuzo we-cocaine, nangona kunjalo, ukungqongqo komvuzo we-ERK1 onokubambisa i-cocaine, iphakamisa ukuba i-ERK inhibitors inokuthi ichaphazele i-ERK2. Kutshanje, sibonisa ukuba ukusebenza kwe-optogenetic ye-D₁+ Ii-MSN kwi-NAc, eyonyusa iimpendulo ezinomvuzo wesilwanyana kwi-cocaine, ngokunokwenzeka inciphisa zombini i-pERK1 kunye ne-PERK2. Izifundo ezizayo zenzakalisa intetho ye-ERK ngendlela yodidi lweseli ziyafuneka ukujongana ngokupheleleyo nomsebenzi we-ERK wokusayina kwii-MSN ezimbini ekusebenziseni iziyobisi.

I-DARPP-32 yenye imolekyuli ebonisa ukuba ifundwe kakhulu ekuphenduleni iziyobisi zokuxhatshazwa. Kuyaziwa ukuba i-psychostimulants ebukhali ikhokelela kwi-PKA phosphorylation ye-DARPP-32 kwi-threonine 34 (T34), ibangela ukuba ibe yi-inhibitor enamandla e-protein phosphatase 1 (PP-1), elawula imeko ye-phosphorylation. Izinto ezikhutshelweyo, ii-ionotropic receptors, kunye neendlela ze-ion (Greengard et al., 1999). Nangona kunjalo, kude kube kutshanje, bekungacacanga ukuba yeyiphi i-subNpe subtype eguqula olu tshintsho lwe-biochemical. U-Greengard et al. (1999) Imodeli ye-BAC yokuhambisa ye-transgenic eyenza ukuba uvavanyo lwe-phosphorylation ye-DARPP-32 i-D₁+ okanye D₂+ Ii-MSN ngokubonisa iinguqulelo ezimakiweyo ze-DARPP-32 kusetyenziswa i-D₁ okanye iD₂ Ii-BACs ezivumela ukhuselo lwe-DARPP-32 kwindawo nganye ye-MSN. Ezi zifundo zibonise ukuba unyango lwecocaine yecocaine yonyusa phosphorylation ye-T34 kwi-D₁+ Ii-MSN kunye ne-induces phationphation ye-threonine 75 (T75) yi-Cdk5, ethintela ukusayinwa kwe-PKA, ngokukhetha kwi-D₂Ii-MSNs (Bateup et al., 2008). Ekugqibeleni eli qela labonisa ukuba kucinywe i-DARPP-32 kwindawo nganye ye-MSN isebenzisa i-D₁-Cre kunye D₂-Cre BAC transgenic mbezi ziphumela kummiselo ochasene nemisebenzi ye-cocaine eyenziwe nge-cocaineBateup et al., 2010). Ukuphulukana kwe-DARPP-32 ukusuka kwi-D₁Ii-MSNs zinciphise iziphumo ze-locomotor ze-cocaine, ezilingisa idatha yangaphambili yokuvavanya i-DARPP-32 yokunkqonkqozwa (Fienberg et al., 1998), ngelixa ilahleko ye-DARPP-32 isuka kwi-D₂Ii-MSNs ziphucula iimpendulo ze-cocaine locomotor. Idatha enjalo ibonelela ubungqina obuqinisekileyo bendima eyahlukileyo ye-DARPP-32 kwii-MSN ezimbini ekuphenduleni iziyobisi zokuxhatshazwa kwaye zibonisa ukubaluleka kweendlela zodidi lweseli ukuqonda ngokupheleleyo igalelo lezi ntlobo zimbini ze-neuronal kwikhoboka leziyobisi.

Umsebenzi wokuModareyitha we-D₁ okanye iD₂ Ii-MSN

Ukukhokela ngokuthe ngqo imisebenzi yeziqendu ezibini ze-MSN kutsha nje kunike ulwazi lwenoveli kwindima yemolekyuli kunye nokusebenza kweD.₁ kunye noD₂ IiMSNs zikhobokisa. Sisebenzise izixhobo ze-optogenetic zidityaniswa ne-veena ehambelana nemeko ethile (okt, ukuxhomekeka kwindalo) kwi-adeno ehambelana ne-adeno (AAV) echaza ishaneli ye-cation ye-activation eluhlaza, isiteshi se-Channelrhodopsin-2 (ChR2). Sisifakele injektha, okanye ulawulo, kwi-NAc ye-D₁-Cre okanye D₂-Cre BAC transgenic mbezi emva koko zivuselela indawo enalayishwe ngokukhanya okuluhlaza ukukhetha ngokunyanzelekileyo D₁+ vs. D₂Ii-MSNs kwimeko yeCocaine yeCocaine. Sifumene ukuba kusebenze kwe-D₁Ii-MSNs zinika amandla ukwenziwa kwe-cocaine ye-cocaine, ngelixa kusebenze i-D₂Ii-MSNs zithintela le nto (Lobo et al., 2010). Njengoko bekutshiwo ngaphambili, sabona iziphumo zokuziphatha ezifanayo xa iTrkB yayicocwa ngokukhethekileyo kwezi ziqwengana ze-MSN: inkqubo ye-cocaine ye-cocaine kunye nomsebenzi we-locomotor emva kokucinywa kweTrB ku-D.₁+ Ii-MSNs, kunye nokucutha i-CPP ye-cocaine kunye nomsebenzi we-locomotor emva kokuba kucinywe iTrBB ku-D₂+ Ii-MSN. Esona senzo siqhelekileyo seTrkB sokunkqonkqoza kunye nokukhuthaza optogenetic ku-D₂+ Ii-MSN ngumsebenzi wazo owandisiweyo, ukususwa kwe-TrkB kwezi seli kukhulisa ukugcwala kombane. Njengoko bekutshiwo ngaphambili, sikwafumanise ukwehliswa ngamandla kwe-pERK emva kokuba kucinywe iTrBB ku-D₁+ Ii-MSN. I-PERK yeyona nto ijolise kuyo iphantsi ye-BDNF isibonakaliso, ngenxa yoko, indlela yokuziphatha ebonakalisiweyo emva kokucinywa kwe-TrkB ku-D.₁+ Ii-MSNs kunye nokuvula ukusebenza kwe-optogenetic kwezi seli zingenxa yokuguqula iziphumo zomsebenzi we-PERK. Nangona kunjalo, umsebenzi wexesha elizayo uyadingeka ukumisela ukuchaneka, ukwabiwa kwe-molekyuli engaphantsi kolawulo lweendlela zokuziphatha ezibonakalayo emva kokuphazamiseka kokusayinwa kwe-BDNF kunye nolawulo lwe-optogenetic yezi subtypes ezimbini ze-neuronal.

Amanye amaqela asebenzise izixhobo ezahlukeneyo ukumodareyitha imisebenzi yee-MSN ezimbini kwiimodeli zokusetyenziswa gwenxa kweziyobisi. Hikida et al. (2010) Usebenzise i-vea ye-AAV ukubonisa into ebhaliweyo yokuprakthiza (tTa) usebenzisa into P (a D₁+ MSN gene) okanye enkephalin (a D₂+ I-MSN gene) inyhweba. Ezi veins zafakwa kwi-NAc yeempuku, apho i-tetanus toxin chain light (TN) - ityhefu yebhaktiriya esusa iproteni enxulumene ne-synaptic vesicle, i-VAMP2 - yayilawulwa yinto ehambelana ne-tetracycline-to-transimentically, to aberate the transaptic transaptic in nganye. I-MSN subtype. Ngokuhambelana nendlela yethu ye-optogenetic, ezi datha zibonise indima ka-D₁+ Umsebenzi weMSN ekonyuseni i-cocaine ye-cocaine kunye nomsebenzi we-cocaine owenziwe nge-cocaine, oko kuphelisa ukuthunyelwa kwe-synaptic ku-D.₁+ Ii-MSNs zinciphise iziphumo zokuziphatha zombini. Ngokuchasene nezifundo ze-optogenetic, ababhali abafumananga zinguqu kwi-CPP ye-cocaine emva kokuphelisa ukuhanjiswa kwe-synaptic ku-D.₂+ Ii-MSNs, kodwa ziye zajonga ukunciphisa umsebenzi we-cocaine ovuselelweyo we-cocaine ukuphendula kwimiboniso emibini yokuqala ye-cocaine. Okubangela umdla kukuba, eli qela libonise ukuba ukwenziwa kwe-D₂Ii-MSN zidlale indima ebaluleke kakhulu ekuchaseni isimilo sokuziphatha gwenxa.

Njengoko kuchaziwe ngaphambili, UFerguson et al. (2011) Usebenzise i-herpes simplex virus (HSV) ukuveza i-GPCR enobunjineli (a G_{mna / o}-umxube we-muscarinic yoluntu M₄ i-receptor yoyilo eyenzelwa kuphela ichiza lokuyila, hM₄D) eyenziwa ngenye indlela yonyango engenza ikhemisi isebenzisa inkephalin kunye nabanyuseli be-dynorphin ukuba bakhethe ukuthula D₁+ okanye D₂+ Ii-MSN kwi-dStr. Ababhali babonisa ukuba okwethutyana ukuphazamisa u-D₂+ Umsebenzi weMSN kwi-dStr iququzelela uvakalelo lwe-amphetamine, ngelixa kuncitshiswa okukhulu kwe-D₁+ Ii-MSN ziphazamise ukunyanzeliswa kwamandla e-amphetamine. Okokugqibela, ukutshitshisa D₂+ Ii-MSN kwi-NAc kubudala obudala kusetyenziswa i-diptheria toxin receptor yongeza isiphumo esonwabisayo se-amphetamine (UDurieux et al., 2009). Idatha enjalo ihambelana neziphumo zethu ze-optogenetic, kunye kunye nendima echaseneyo ye-D₁+ vs. D₂+ Ii-MSNs iziyobisi, kunye no-D₁Ii-MSNs zikhuthaza umvuzo kunye nokufumana iimpendulo kwii-psychostimulants kunye ne-D₂+ Ii-MSN zidodobalisa ezi ndlela zokuziphatha.

Izikhokelo zexesha elizayo

Ibanga lenze inkqubela phambili enkulu ekuqondeni indima ekhethiweyo ye-D₁+ kunye no-D₂+ I-Microsoft subtypes kwi-NAc kunye ne-dStr ekulamleni iziphumo zeziyobisi zokuxhatshazwa. Ngokukodwa izixhobo ezisandula ukwenziwa ezinika amandla ekukhetheni ezi ntlobo zeeseli zidlale indima ephambili ekufumaneni uninzi lolu lwazi. Ngawaphi la manyathelo alandelayo? Ukusukela apha uguquko olusisiseko lwesimolekyuli kwiimodeli zokulutha iziyobisi alusosigxina, kodwa unamandla amakhulu, kubalulekile ukuba kuphuhliswe amandla okunyanzela ukukhohlisa iisystemi ezinomdla ku-D.₁+ vs. D₂+ Ii-MSN ngendlela echanekileyo yexeshana. Ii-DREADD kunye nezixhobo ze-optogenetic zinokukunceda ngeli xesha lokudalwa kwezixhobo. I-ligrets ye-DREADD inokulawulwa ngexesha lezifundo ezahlukeneyo ngexesha lokuziphatha kweziyobisi ukubethelela indima ekhethiweyo yokutywina ii-receptors kwii-MSNs ezimbini kwiimodeli zamachiza. Izixhobo ze-Optogenetic ngokukodwa zibonelela ngeendlela ezinamandla kakhulu zokulawula okwethutyana umsebenzi we-neuronal kodwa i-G-protein-coupled coupept signaling usebenzisa i-OptoXRs (I-Airan et al., 2009), Isibonakaliso se glutamatergic (Volgraf et al., 2006; INumano et al., 2009), Ukubonisa isiginali ye-GABAergic, kunye neeseli ezithile zommqondiso we-intracellular (Wu et al., 2009; IHahn kunye noKuhlman, i-2010). Ekugqibeleni, kunokwenzeka ukwandisa obu buchule kummiselo we-optogenetic womsebenzi wokukhuphela. Ngokukwanjalo, izixhobo ze-optogenetic zenza ukuba ithuba lokuqala lokufunda ifuthe lamagalelo athile afakwe kwis striatum kunye nokufumanisa ukuba ingaba loo magalelo angenelela kusini na ngeendlela zokukhetha kwi-D.₁+ vs. D₂Ii-MSNs (U-Higley kunye noSabatini, 2010). Isakhono sokulawula iipropathi zokutyikitya kunye nezimolekyulu ezinesisombululo esikhulu sokwexeshana ziya kuvumela amanyathelo amakhulu ukuba enziwe ekuqondeni okugcwele ngakumbi kwee-subtypes ezimbini ze-MSN, kunye nezinye izinto ezingaphantsi kweseli kwi-NAc kunye ne-dStr, ekulameni ixesha lekhosi kunye nezigaba ezahlukeneyo zamachiza. iziyobisi.

Ukuxabana kweNkcazo yeNzala

Ababhali bavakalisa ukuba uphando lwenziwe ngokungabikho naluphi na ulwalamano lwezorhwebo okanye lwezezimali olubhekiswa njengengxabano yenzuzo.

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