Neuroanat i luma. 2011;5:41. doi: 10.3389/fnana.2011.00041. Epub 2011 Iulai 18.
puna
Fishberg Matagaluega o Neuroscience, Friedman Brain Institute, Mount Sinai School of Medicine Niu Ioka, NY, ISA.
lē faʻatino
O le striatum e faia se sao taua i le faʻatalanoaina o aʻafiaga ogaoga ma le tumau o vailaʻau faʻamaʻi, faʻatasi ai ma vailaʻau o le faʻaleagaina e mafua ai suiga mole mole ma feaveaʻi umi i le pito i tua ma nuʻu accumbens (ventral striatum). E ui lava i le tamaoaiga o suʻesuʻega i gaioiga faʻale-aganuʻu o vailaʻau faʻaleagaina i le striatum, e oʻo mai talu ai nei, o matafaioi maʻoti a le striatum's subtypes tetele e lua o medium spiny neurons (MSNs) i vaisu o fualaau faasaina na tumau pea le le mautonu. O le alualu i luma lata mai i tekinolosi faʻapitoa faʻapitoa, e aofia ai isumu fai lipoti felafolafoaʻi, transgenic, poʻo isumu tuʻituʻi, ma viral-mediated gene transfer, ua faʻalauteleina ai le fanua i se malamalamaga sili atu i le lua MSN subtypes i gaioiga umi o fualaau faasaina. o sauaga. O iinei tatou te toe iloiloina ai le alualu i luma i le faʻamalamalamaina o sao mole mole ma galuega a le MSN subtypes e lua i le faʻatalanoaina o vaisu.
faʻatomuaga
O vailaʻau o le faʻaleagaina e faʻaaogaina ai suiga malolosi mole mole ma feaveaʻi i le pito i tua (dStr) ma le ventral striatum (nucleus accumbens, NAc), ma o le tele o nei suiga e tupu i neu vavalo (MSNs), o neu mataʻitū autu i le dStr ma NAc, lea. e tusa ma le 90-95% o neu uma i nei itulagi. Ae ui i lea, o tagata suʻesuʻe e oʻo mai talu ai nei e leʻi mafai ona faʻamalamalama manino le tulaga eseʻesega o vaega laiti MSN e lua i mea faʻapitoa e fesoʻotaʻi ma vaisu. O vaega laiti MSN e lua e faʻavasegaina e ala i lo latou faʻatamaoaigaina o le dopamine receptor 1 (D1) poʻo le tali atu o le dopamine 2 (D2) fa'apea fo'i ma isi kenera (Gerfen ma Young, 1988; Gerfen et al., 1990; Le Moine et al., 1990, 1991; Bernard et al., 1992; Ince et al., 1997; Lobo et al., 2006, 2007; Heiman et al., 2008; gensat.org) ma e ala i a latou va'aiga ma'oti e ala i le auala cortico-basal ganglia (le auala tuusa'o ma le le tuusao; Gerfen, 1984, 1992). O suʻesuʻega muamua na fautua mai ai o vailaʻau o le faʻaleagaina e sili atu ona aʻafia i le D1+ MSNs, faʻatasi ai ma le faʻaaogaina o le tele o le dopamine receptor agonists ma antagonists e maua ai se malamalamaaga taua i le gaioiga ma le mole mole matafaioi a MSN taʻitasi i amioga tau fualaau (Tagata, 2010). Ae ui i lea, o loʻo i ai nei auala faʻapitoa-ituaiga-faʻapitoa, e aofia ai isumu fai lipoti fluorescent e faʻaalia le GFP i lalo ole D.1 poʻo le D2 chromosomes fa'a siama (BACs; Gong et al., 2003; Valjent et al., 2009; gensat.org), fa'ata'ita'iga o isumu fa'apitoa e pei o le fa'aogaina o isumu transgenic e fa'atulafonoina e tetracycline (Chen et al., 1998; Kelz et al., 1999), ma isumu transgenic faʻaalia Cre-recombinase faʻaaoga D1 poʻo le D2 BACs, chromosomes fa'afefete fa'afefete (YACs), po'o isumu tu'itu'i (Gong et al., 2007; Lemberger et al., 2007; Heusner et al., 2008; Parkitna et al., 2009; Valjent et al., 2009; Bateup et al., 2010; Lobo et al., 2010; gensat.org) faʻapea foʻi ma le faʻaliliuina o kenera faʻamaʻi-faʻasalalau faʻapitoa i le cell-type (Cardin et al., 2010; Hikida et al., 2010; Lobo et al., 2010; Ferguson et al., 2011), ua tu'uina mai ai se fa'amatalaga fou loloto i le sa'o mole mole fa'avae o ta'iala MSN ta'itasi ma a latou fa'atonuga e ala i vaila'au fa'aleagaina (Laulau). 1).
O suʻesuʻega talu ai nei e lagolagoina ai le faʻaiʻuga o se matafaioi sili atu mo D1+ MSNs i le gaosia o le faʻamalosia ma le faʻalauiloaina o aʻafiaga o vailaʻau o le faʻaleagaina, ma le tele o suiga mole mole malolosi o loʻo tutupu i nei MSNs. Mo se faʻataʻitaʻiga, o le faʻaalia tele i psychostimulants e mafai ona faʻaosofia ai le tele o mole faʻailoga e aofia ai FosB, ERK, c-Fos, ma Zif268 i le D.1+ MSNs, a o le cocaine toe faʻaaogaina e sili ona faʻaosofia ai le ΔFosB ma suia le GABA receptor ma isi vaega o le ion channel i totonu o lenei cell-type foi (Robertson et al., 1991; Young et al., 1991; Berretta et al., 1992; Cenci et al., 1992; Moratalla et al., 1992; Faamoemoe ma al., 1994; Bertran-Gonzalez et al., 2008; Heiman et al., 2008). E le gata i lea, o le faʻalavelaveina poʻo le sili atu o le faʻaalia o meaola faʻapitoa, e pei ole ΔFosB, DARPP-32, poʻo le Nr3c1 (le glucocorticoid receptor), ile D.1+ MSNs e masani lava ona faʻataʻitaʻiina amioga faʻatatau i fualaau faʻasaina o loʻo matauina pe a faia nei suiga i se auala e le o se cell-type-faʻapitoa, aʻo faʻalavelaveina ia kenera i le D2+ MSN e masani ona mafua ai se tali faafeagai (Fienberg et al., 1998; Kelz et al., 1999; Deroche-Gamonet et al., 2003; Zachariou et al., 2006; Ambroggi et al., 2009; Bateup et al., 2010). Ae ui i lea, e le mafai ona tatou taofiofia se sao taua a le D2+ MSNs i fetuutuunaiga i fualaau faasaina o le faatautala, ona o le faʻaalia o le cocaine e suia ai faʻamatalaga o kenera i vaega laiti e lua o le MSN (Heiman et al., 2008) ma le D2-Agonists ma tagata fa'afeagai e fa'atino a'afiaga malosi i su'esu'ega o amioga (Tagata, 2010). O le mea moni, o suʻesuʻega talu ai nei o loʻo faʻaalia ai le faʻaogaina o faʻailoga mole i D2+ MSNs e mafai ona suia le tali atu a se manu i fualaau faasaina (Lobo et al., 2010). O suʻesuʻega mulimuli na faʻaalia ai le leiloa o le TrkB (le talitali mo le BDNF) ile D2+ MSNs e maua ai tali tutusa i le cocaine e pei o le aofaʻi o le TrkB knockout mai le NAc, faʻaalia mo le taimi muamua se matafaioi faʻapitoa filifilia mo se auala mole mole i D.2+ MSNs i le faatalanoaina o aafiaga o fualaau faasaina.
Ma le mea mulimuli, o tusitusiga talu ai nei o loʻo faʻaalia ai o MSN e lua o loʻo faʻaalia aʻafiaga faʻafefe i amioga faʻatau fualaau faasaina, pe a faʻagaoioia le D.1+ MSNs poʻo le faʻasaina o D2+ MSN e faʻaleleia ai le lagona o se manu i se vailaʻau faʻaleagaina (Hikida et al., 2010; Lobo et al., 2010; Ferguson et al., 2011). O nei suʻesuʻega o loʻo ogatasi ma matafaioi faʻafeagai a MSN e lua ma a latou auala tuusaʻo vs.Alexander et al., 1986; Albin et al., 1989; Kiliata, 2000; Kravitz et al., 2010). O nei tusitusiga talu ai nei o loʻo ogatasi ma le manatu lautele o le dopaminergic neurotransmission, lea e faʻagaoioia e vailaʻau uma o le faʻaleagaina, faʻafaigofie le glutamatergic activation o D.1+ MSN aʻo taofia le faʻagaioiina o le glutamatergic D2+ MSNs e ala i ana gaioiga ile D1 vs. D2 dopamine receptors (Ata 1). I lenei iloiloga, matou te faʻamatalaina le malamalama o loʻo i ai nei i le faʻailoga mole mole faʻaalia e nei MSN subtypes e lua e faʻatatau i a latou matafaioi faʻatino ma tali i vailaʻau o le faʻaleagaina.
Dopamine Receptor Signaling i D1 vs. D2 MSNs
E pei ona taʻua muamua, o vailaʻau uma o le faʻaleagaina e faʻagaoioia ai le dopaminergic i totonu ole NAc ma vaega ole faiʻai limbic (Volkow et al., 2004; Poto, 2004; Nestler, 2005). Mo se faʻataʻitaʻiga, o le psychostimulants e pei o le cocaine poʻo le amphetamine e galue tuusaʻo i luga o le auala taui dopaminergic e ala i le faʻalavelaveina o le dopamine transporter: cocaine poloka le felauaiga ma le amphetamine e fesuiaʻi le felauaiga, o gaioiga uma e mafua ai le fausiaina o le dopamine i le synapse lea e mafai ona faʻagaoioia le dopamine i lalo. tali i luga o neu taulaʻi (Ata 1). O MSN e lua e sili ona iloga le eseesega i lo latou faʻatamaoaigaina o D1 vs. D2-receptors e ui lava o suʻesuʻega a le RT-PCR e tasi e faʻaalia ai D1+ O loʻo faʻaalia e MSN tulaga maualalo o le D2-pei o le tali atu, D3 ma le D2+ O loʻo faʻaalia e MSN tulaga maualalo o le D1-pei o le tali atu, D5 (Surmeier et al., 1996). O MSN e lua e manaʻomia le faʻaogaina o le glutamatergic e faʻaosoina ai le neural; dopamine fa'afeagai fa'afeagai le fa'aogaina o nei tali fa'atino e ala i le fa'aosofiaina o fa'ailoga fa'apitoa o le su'eina o le dopamine: e ala i le fa'aogaina lelei o le fa'aogaina o le glutamatergic fa'afiafia e ala i le D.1 faʻailoga faʻailoga e ala ile Gs poʻo le Golf, lea e faʻaosofia ai le adenylyl cyclase e taʻitaʻia ai le faʻateleina o le PKA, ae o le dopamine e le lelei le faʻaogaina o lenei mea e ala i le D.2- faʻailoga faʻailoga e ala ile Gi ma le Go lea e taofia ai le adenylyl cyclase e mafua ai le faʻaitiitia o le gaioiga PKA (Surmeier et al., 2007; Gerfen ma Surmeier, 2011). O le mea moni lava, e fa'atino e tali ta'itasi a'afiaga lavelave i le tele o ala fa'ailoga fa'aopoopo i lalo. I le malologa, o le MSN subtypes e lua e masani ona faʻasaina, o loʻo i ai i le mea na taʻua e le au suʻesuʻe o le lalo-setete. Excitatory glutamatergic synaptic activity e mafai ona faʻasaʻolotoina MSNs mai lenei lalo-setete ma faʻafeiloaʻi i latou i se tulaga e sili atu le faʻaleagaina (le tulaga maualuga). O le Dopamine e fa'afeagai ma fa'afeagai le suiga o le glutamatergic fa'afiafia i le tulaga maualuga. D1 fa'agaoioia o PKA fa'aleleia Cav1 L-ituaiga Ca2+ gaioiga ala, faʻaititia somatic K+ gaioiga ala, ma fa'aititia le Cav2 Ca2+ auala e pulea le faʻagaoioia o Ca2+ fa'alagolago, la'ititi le amio K+ (SK), e mafua ai le faʻateleina o le faʻafefe i nei MSNs (Surmeier et al., 2007; Gerfen ma Surmeier, 2011). I le eseesega, D2 fa'ailoga e taofia ai le suiga i luga o le setete, ma taofia ai le fa'ateleina o le spiking, e ala i le fa'aitiitia o Cav1 L-ituaiga Ca.2+ fa'agaioiga alalaupapa ma le Nav1 Na+ alaala gaioioiga ao faateleina le K+ alavai (Surmeier et al., 2007; Gerfen ma Surmeier, 2011; Ata 1). O ia suiga faʻafeagai i MSN e lua o loʻo fautua mai ai o le faʻateleina o faʻailoga o le dopamine e mafua mai i vailaʻau o le faʻaleagaina e tatau ona faʻaleleia le faʻagaioiina o le glutamatergic o D.1+ MSNs ma faʻaitiitia le faʻamalosia o le glutamatergic o D2+ MSNs. O le mea moni, o ia tali e sili atu ona eseese ma lavelave mo mafuaaga e tumau pea le le malamalama. O lenei mataupu o le a talanoaina atili i lalo.
O le matafaioi a le dopamine receptors i le faʻaaogaina o fualaau faasaina e lavelave ma e masani ona faigata (Tagata, 2010). O loʻo i ai le tele o tusitusiga i le matafaioi a D1 ma le D2-receptor agonists ma antagonists i le modulating tauia meatotino ma le pulea e le tagata lava ia o fualaau faasaina o le sauaina, ae peitai, o taunuuga e eseese e faalagolago i le ituaiga o agonist / antagonist faʻaaogaina, le ituaiga o tuʻuina atu (systemic vs. brain region-specific), ma le taimi. o togafitiga (Tagata, 2010). O ia faʻaiʻuga e atili faʻafememeaʻi i aʻafiaga faʻapitoa e le o ni faʻalavelave, e pei o le sao o le pre-synaptic D.2-Receptors mai le VTA poʻo le i ai o D1 faʻalogo i le tele o isi vaega limbic, ma le leai o se faʻapitoa o agonists / antagonists faʻaaogaina faʻapea foʻi ma le faʻaaliga o le D.1-o pei o le D2-pei o tali atu i vaega laiti MSN e lua e pei ona taʻua muamua. I se tulaga lautele, e manatu o D1 talitaliga e sili atu lona sao i meatotino tauia muamua o fualaau faasaina, ae o D2-o fa'auluuluga e iai sona sao i faiga su'esu'e fualaau (Tagata ma al., 1996; Tagata, 2010). Suesuega ma D1 talitali ma D2-receptor knockout isumu e maua ai se malamalamaaga i le matafaioi a nei tali i totonu o MSN e lua. D1 O isumu knockout o loʻo faʻaalia ai le faʻaogaina o le vave vave (IEGs) c-Fos ma le Zif268 i le tali atu i cocaine, o le faʻaitiitia o le tali atu i le psychostimulant-induced locomotor activity ae leai se suiga i le cocaine-conditioned place preferred (CPP) - o se fua faʻatatau o taui o fualaau faasaina, ma faaitiitia le pulea e le tagata lava ia cocaine ma le taumafaina o le ethanol (Miner et al., 1995; Drago et al., 1996; Crawford et al., 1997; El-Ghundi et al., 1998; Caine et al., 2007). D2 O isumu tu'itu'i fa'aalia le fa'aitiitia o a'afiaga tauia i opiates ma cocaine fa'apea fo'i ma le fa'aitiitia o le taumafaina o le ethanol ae leai se fa'aitiitiga o le fa'aaogaina o cocaine (Maldonado et al., 1997; Cunningham et al., 2000; Risinger et al., 2000; Caine et al., 2002; Chausmer et al., 2002; Elmer et al., 2002; Welter et al., 2007). O ia fa'amaumauga e lagolagoina ai matafaioi taua mo D1 ma le D2-receptors i le MSNs e lua i le tele o itu o le faʻaaogaina o fualaau faasaina, ae ui i lea, o le tuʻituʻi e leai ni faʻamatalaga faʻapitoa ma e tupu vave i le atinaʻe, o lea e le mafai ai e se tasi ona faʻasalaina isi vaega o le faiʻai ma ituaiga cell ma mea tau atinaʻe i le faʻatalanoaina o nei amioga. Mulimuli ane, faʻaititia le maualuga o le D2/D3 talitali i striatum, e pei ona vaaia e le faiʻai ata, ua avea ma faailoga masani o vaisu i tagata gasegase aemaise lava i taimi o le toesea (Volkow et al., 2009). O rodents o loʻo maua e viral-mediated gene transfer of D2-Receptors i le NAc faʻaalia le faʻaogaina o le cocaine ma le faʻaaogaina o le ethanol (Thanos et al., 2004, 2008). O nei suʻesuʻega e leʻi faia i se cell-type-specific auala, o lea e le mafai ai ona tatou faʻamaonia le aʻafiaga o le D.2-ova faʻamatalaga faʻamatalaga e aʻafia ai D1+ MSNs. O lenei aoina o faʻamaumauga o loʻo faʻamamafaina ai le manaʻoga e siitia atu i auala sili atu ona filifilia, e aofia ai le cell-type-specific, region-specific, ma e oʻo lava i faʻalavelave faʻapitoa faʻapitoa o le dopamine receptors e faʻamalamalama atili ai a latou matafaioi galue i le lua MSN subtypes i vaisu fualaau.
Mulimuli ane, ua lipotia talu ai nei o D2-GFP homozygote BAC transgenic isumu faʻaalia le maualuga o faʻaaliga o le D2-receptor i striatum ma faʻaleleia le faʻaogaina o amioga ma le dopamine faʻailoga ile D2 agonists. E le gata i lea, o le homozygotes ma le hemizygotes o loʻo faʻaalia tali faʻafefe i le cocaine (Kramer et al., 2011). O lenei suʻesuʻega o loʻo faʻamaonia ai le manaʻoga e faia faʻamatalaga maeʻaeʻa o D1 ma le D2 fai lipoti felanulanua'i ma laina avetaavale Cre. Ae ui i lea, o le tele o faʻamaumauga na aoina i lenei suʻesuʻega na faʻaaogaina homozygotes, e le o se faʻataʻitaʻiga faʻataʻitaʻiga sili ona lelei talu mai le 5-10% o fesoʻotaʻiga transgene e mafua ai suiga faʻapipiʻi (Meisler, 1992); o le mea lea, o le genotype hemizygote o le genotype faʻataʻitaʻiga sili atu ona faʻatuatuaina. E le gata i lea, o lenei suʻesuʻega e leʻi faʻaogaina ai le littermate wildtype controls ae faʻaogaina faʻatonuga i luga o se talaaga tutusa (Swiss Webster) maua mai Taconic, ae o latou laina transgenic na maua mai GENSAT ma MMRRC. Mulimuli ane, o le isi vaega na faʻaalia tali masani a le cocaine locomotor i D2-GFP hemizygotes (Kim et al., 2011). O le mea lea, o suʻesuʻega i le lumanaʻi e faʻaogaina ai faʻatonuga talafeagai ma genotypes saʻo e tatau ona faia e faʻamaonia atoatoa ai laina eseese transgenic faʻapitoa e maua.
Glutamate ma le GABA Signaling i le D1 vs. D2 MSNs
Medium spiny neurons maua glutamatergic input mai le tele o faiʻai itulagi e aofia ai prefrontal cortex, amygdala, ma hippocampus, ma GABAergic faʻaoga mai interneurons i le lotoifale ma masalo faʻapipiʻi faʻapipiʻi mai isi MSNs. Net excitatory ma faʻagata tulafono faatonutonu a MSNs e le masalomia le taua i le faatonutonuina o le tulaga o fualaau faasaina, ma o loʻo i ai nei le faʻatupulaia o tusitusiga i luga o auala lavelave lea e suia ai e fualaau faʻaleagaina le neurotransmission glutamatergic aemaise i le NAc (Pierce et al., 1996; Thomas et al., 2001; Beurrier ma Malenka, 2002; Kourrich et al., 2007; Bachtell ma Self, 2008; Bachtell et al., 2008; Conrad et al., 2008; Kalivas, 2009; Wolf, 2010). E ui lava o MSNs e manatu o loʻo i ai i totonu o se faʻalavelave lalo-setete i lalo o tulaga faʻatasi ma le glutamate taʻavale gaioiga o ituaiga uma e lua, o loʻo i ai pea le faʻatapulaʻaina o faʻamatalaga e faʻatatau i tulafono faatonutonu maʻoti o loʻo tupu i le D.1 vs. D2 MSNs.
ΔFosB overexpression i le D1+ MSNs (silasila i lalo mo nisi faʻamatalaga) faʻaleleia le tauia o aʻafiaga o cocaine ma faʻateleina le maualuga o le Ca2+-impermeable glutamate receptor subunit, GluR2, i le NAc. E le gata i lea, o le viral-mediated gene transfer of GluR2 i le NAc e faʻapena foi ona faʻaleleia ai aʻafiaga tauia o cocaine (Kelz et al., 1999). Ae ui i lea, e le o iloa pe o le induction o GluR2 na vaaia i le tali atu i le ΔFosB overexpression i D.1+ MSNs e patino foi i nei neurons, ma o le viral overexpression o GluR2 e le o se ituaiga-faʻapitoa, o le mea lea e le mafai ai ona tatou faia ni faaiuga tuusaʻo e uiga i le galuega a GluR2 i nei MSN e lua i le taui o fualaau faasaina. Heusner ma Palmiter (2005) suʻesuʻeina le matafaioi a le NMDA glutamatergic conductance i amioga cocaine e ala i le faʻaalia o le NR1 subunit, lea e aofia ai se suiga i le pore e faʻaitiitia ai le calcium flux, filifilia i le D.1+ MSNs. O lenei vaega na faʻaalia ai le le lava o le NMDA i le D1+ MSNs e taofia ai le CPP ma le cocaine locomotor sensitization, faʻamaonia le manaʻomia o le NMDA faʻailoga i le D1+ MSNs mo le tauia ma le maaleale o aafiaga o cocaine (Heusner ma Palmiter, 2005). E le gata i lea, talu ai nei na maua ai o le tuʻituʻi i fafo o le NR1 subunit i D1+ MSNs e faʻaitiitia le faʻalogoina o le amphetamine ma o lenei phenotype na laveaʻiina e ala i le toe tuʻuina atu o le NR1 subunit i le D1+ MSNs faapitoa i le NAc (Beutler et al., 2011). Mulimuli ane, tu'itu'i lalo ole mGluR5 subunit, fa'aaoga RNA fa'alavelave, ile D1+ MSNs e leai se aafiaga i luga o meatotino tauia muamua o cocaine ae faʻaitiitia ai le faʻaogaina o le toe faʻaleleia o le suʻeina o cocaine (Novak et al., 2010). E ui o nei faʻamatalaga o loʻo faʻaalia ai matafaioi faʻamalosi mo faʻailoga glutamatergic i D1+ MSNs, e manaʻomia galuega i le lumanaʻi e suʻesuʻe ai le glutamatergic system i D2+ MSNs. O suʻesuʻega i le lumanaʻi e tatau foi ona iloilo pe faʻafefea ona aʻafia le suiga o nei glutamate receptor subunits i le lua MSN subtypes suiga faʻatulagaina o le synaptic na matauina i le NAc pe a maeʻa fualaau faʻaleagaina (Dietz et al., 2009; Russo et al., 2010), aemaise lava suiga o le dendritic na matauina pe a uma ona faʻaalia le cocaine i le D1+ MSNs (Lee et al., 2006; Kim et al., 2011) lea e mafai ona fesoʻotaʻi ma le faʻateleina o galu postsynaptic laʻititi o loʻo matauina i le D1+ MSNs (Kim et al., 2011). O le mea e malie ai, ΔFosB induction i D1+ MSNs ua fesoʻotaʻi tuusaʻo i ia faʻasologa o le dendritic pe a uma le cocaine masani (Maze et al., 2010).
I le faʻatusatusa i le glutamate, o loʻo i ai le leai o se suʻesuʻega i luga o le GABA galuega i MSN e lua i faʻataʻitaʻiga o mea ua fai ma vaisu, o se mea e ofo ai pe a mafaufau i le ethanol ma le benzodiazepines e faʻaleleia ai aʻafiaga o le GABA ma o MSN e lua e maua ni mea faʻaoga GABAergic e pei ona taʻua i luga. O loʻo iai foʻi faʻamaoniga tele e faʻasino i le faʻaleleia atili o le faʻasaina i le NAc a itiiti mai pe a uma le faʻaalia o le cocaine masani (White et al., 1995; Tagata ma al., 1998; Zhang et al., 1998; Thomas et al., 2001; Beurrier ma Malenka, 2002). Heiman et al. (2008) faia suʻesuʻega faʻasolosolo maualuga i MSN e lua ina ua maeʻa le faʻaalia o le cocaine ma, e manaia, o le sili ona suia le faagasologa o meaola i le D.1+ MSNs o GABA faailoilo. Aemaise lava, o loʻo i ai le faʻamalosia malosi o le GABAA su'esu'ega subunits Gabra1 ma Gabra4 fa'apea fo'i ma le GABAB receptor subunit Gabrb3, ma o lenei vaega na maua ai o le cocaine tumau e faʻateleina le tele o taimi ole GABAergic mini inhibitory postsynaptic currents (mIPSCs) ile D.1+ MSNs (Heiman et al., 2008). I le isi itu, o se isi vaega talu ai nei na faʻaalia ai o le cocaine tumau e maua ai se tali faʻafeagai ma le faʻaitiitia o taimi ma le tele o mIPSC i le D1 + MSNs (Kim et al., 2011). Ae ui i lea, o le vaega mulimuli na faʻaalia le faʻaitiitia o le fiafia o le membrane i le D1+ MSNs pe a maeʻa cocaine masani, lea e mafai ona avea ma ata o le faʻaleleia o le GABA ma e ogatasi ma le iloiloga a le fanua o le faʻaleleia atili o le faʻasaina i le NAc pe a uma ona faʻaalia i le cocaine masani. E le gata i lea, o ia eseesega i le va o vaega e lua e mafai ona mafua ona o le taimi o le faʻaalia o le cocaine ma le toesea. I se tulaga lautele, o loʻo i ai se manaʻoga e suʻesuʻe le glutamatergic ma le GABAergic galuega i MSN e lua e tali atu ai i vailaʻau o le faʻaleagaina ma o le fanua ua faʻapipiʻiina nei ma punaoa e mafai ai se suʻesuʻega faʻapitoa ma le itulagi.
Isi Receptor Signaling i D1 vs. D2 MSN Subtypes
O MSN e lua o loʻo faʻatamaoaigaina faʻatamaoaigaina i isi G-protein-coupled receptors faʻaopoopo i le dopamine receptors. D1+ MSNs o loʻo faʻaalia le maualuga maualuga o le acetylcholine muscarinic receptor 4 (M4; Bernard et al., 1992; Ince et al., 1997) ma le D2+ MSNs ua faʻatamaoaigaina i le adenosine receptor 2A (A2A; Schiffmann et al., 1991; Schiffmann ma Vanderhaeghen, 1993) ma le G-protein-coupled receptor 6 (Gpr6; Lobo et al., 2007; gensat.org). M4 faʻatasi ma Gi / o, lea o le a maua ai se tali faʻafeagai, faʻatusatusa i le D1 talitali, i le D1+ MSNs e ala i le taofia o le cAMP/PKA gaoioiga. O le mea moni, o se D1+ MSN filifilia M4 tu'itu'i fa'aalia le fa'aleleia atili o amioga i cocaine ma amphetamine (Jeon et al., 2010). E le gata i lea, o suʻesuʻega talu ai nei e faʻaaogaina ai se faʻailoga faʻailoga faʻapitoa e faʻaaogaina e se vailaʻau faʻapipiʻi (DREADDs) na faʻaalia ai le faʻagaoioia o le DREADD Gi / o-coupled human M.4 talitali (hM4D) i le D1+ Ua faaitiitia e le MSN le lagona o le amio i le amphetamine, faatasi ai ma le tali faafeagai o loo vaaia i le D.2+ MSNs (Ferguson et al., 2011). O ia faʻamaumauga o loʻo faʻaalia ai le tulaga faʻafefe a M4 talitali i le D1+ MSNs i fualaau faasaina. E le gata i lea, talu mai le hM4O le talipupuni e mafai ona taofia nei MSNs, o faʻamaumauga e maua ai le malamalama i le aafiaga o suiga o gaioiga a nei MSN e lua i le faʻaaogaina o fualaau faasaina, lea o le a talanoaina atili i lalo.
O A2A ma Gpr6 o loʻo tuʻufaʻatasia lelei ma Gs/Golf polotini, e aofia ai la latou matafaioi i le tetee atu i le D2-Receptor i D2+ MSNs. O le mea moni, o le faʻamalosia o A2A ua faʻaalia tali e faʻaitiitia ai le atinaʻeina ma le faʻaalia o le faʻaogaina o cocaine (Filip et al., 2006), fa'aleagaina le amataina o le pule a le tagata lava ia cocaine (Knapp et al., 2001), ma tetee i le toe faʻafoʻiina o le suʻega cocaine e mafua mai i le cocaine, D2-fa'aoso fa'aoso, po'o fa'ailoga e fa'atatau i cocaine (Bachtell ma Self, 2009). E pei ona faʻatamaoaigaina Gpr6 i le D2+ MSNs (Lobo et al., 2007), e tatau ona iloiloina lona sao i galuega tau amio a le striatum. E oʻo mai i le taimi nei, ua faʻaalia e aʻafia ai aʻoaʻoga meafaigaluega (Lobo et al., 2007) ae o lona sao i faʻataʻitaʻiga o le faʻaaogaina o fualaau faasaina e le o iloa.
O le cannabinoid receptor 1 (CB1) o loʻo faʻaalia i soo se mea i le ogatotonu o le tino (Meki, 2008), o le mea lea e faigata ai ona faʻavasega le sao saʻo o vaega o faiʻai ma ituaiga o sela i le faʻatalanoaina o vaisu Δ9-tetrahydrocannabinol (THC). Talu ai nei, o le tapeina o le CB1 mai le D1+ MSNs na maua e tauagafau aʻafia ai tali atu i le THC, e aofia ai aʻafiaga faʻafefe i le THC-induced hypolocomotion, hypothermia, ma analgesia (Monory et al., 2007). O le a manaia le iloiloina o le gaioiga o le faʻaogaina o le cannabinoid i le D2+ MSNs talu mai nei MSN o loʻo faʻaalia le endocannabinoid-mediated long-term depression (eCB-LTD), lea e manaʻomia ai le dopamine D2-faagaioiina o mea e tali atu (Kreitzer ma Malenka, 2007).
O le glucocorticoid receptor, Nr3c1, o loʻo faʻaalia lautele foi i le CNS ma le pito. O le fa'aosoina o le glucocorticoid e fa'aosoina le fa'apopoleina e mafai ona fa'amalosia ai amioga fa'aletonu e aofia ai le tagofia o fualaau fa'asaina (Frank et al., 2011). Aemaise lava, faʻalavelaveina faʻailoga glucocorticoid i D1+ MSNs e ala i le tapeina o le Nr3c1 na faʻaitiitia ai le faʻaosofia o nei isumu e faʻaalia e le tagata lava ia cocaine, ma o loʻo ogatasi ma faʻamaumauga muamua lea na tape ai le Nr3c1 mai le faiʻai atoa (Ambroggi et al., 2009). O nei faʻamaumauga e ogatasi ma isi suʻesuʻega o loʻo faʻamatalaina i lenei iloiloga, o loʻo faʻaalia ai se matafaioi sili mo D1+ MSNs i le faatalanoaina o le tele o aafiaga o fualaau faasaina.
Mulimuli ane, talu ai nei na matou faʻalavelaveina le BDNF faʻailoga i MSN e lua e ala i le tapeina o lona TrkB faʻafeiloaʻi filifilia mai MSN subtype taʻitasi. Na matou matauina aʻafiaga faʻafeagai i luga o le cocaine-elicited behavior: cocaine-induced locomotor activity and induction of cocaine CPP na faʻaleleia ina ua maeʻa le tapeina o le TrkB mai le D.1+ MSNs, ae faʻaitiitia pe a uma ona tapeina mai le D2+ MSNs (Lobo et al., 2010). O le mea e malie ai, o le tapeina o le TrkB mai le D2+ MSNs faʻataʻitaʻiina aʻafiaga o le tape atoa o le TrkB mai le NAc faʻapea foʻi ma le faʻalavelaveina o le BDNF faailo mai le VTA (Horger et al., 1999; Graham et al., 2007, 2009; Bahi et al., 2008; Crooks et al., 2010). O nei suʻesuʻega o loʻo faʻaalia ai mo le taimi muamua se matafaioi sili o se faʻailoga faʻailoga i D2+ MSNs i le faatalanoaina o aafiaga o se fualaau faasaina o le faatautala. O le matafaioi sili a D2+ MSNs i le faʻatalanoaina o aʻafiaga a le BDNF i luga o amioga faʻaosoina cocaine e le o se mea e ofo ai ona o le TrkB mRNA ma le protein e faʻatamaoaigaina i le D.2+ MSNs (Lobo et al., 2010; Baydyuk et al., 2011). O suiga o amioga na matauina i nei isumu na faʻatasi ma le faʻaleleia atili o gaioiga i le D2+ MSN i luga o se tu'itu'i filifilia o TrkB. O nei suʻesuʻega na faʻaosofia ai i matou e faʻaoga tekinolosi optogenetic e faʻaogaina ai le MSN i le taui cocaine (silasila i lalo).
Fa'amatalaga Fa'aliliuga ile D1 vs. D2 MSNs
O faʻamaoniga sili ona faʻamalosia mo le sili atu le malosi o le matafaioi a D1+ MSNs i le faʻaaogaina o fualaau faʻasaina e sau mai tusitusiga e iloilo ai le faʻaogaina o mole mole faʻailoga intracellular. E pei ona taʻua i luga, o tui ogaoga o psychostimulants e faʻaosofia ai le faʻaaliga IEG, e aofia ai le c-Fos, Zif268 (Egr1), ma le FosB muamua ile D.1+ MSNs i le NAc ma le dStr (Robertson et al., 1991; Young et al., 1991; Berretta et al., 1992; Cenci et al., 1992; Moratalla et al., 1992; Bertran-Gonzalez et al., 2008). O lenei induction e manaʻomia ai le faʻagaoioia o D1 receptors, ma le cell-type-specificity o le IEG induction i le tali atu i cocaine mataʻutia na faʻamaonia talu ai nei e faʻaaoga ai le D.1-GFP ma D2-GFP tusitala isumu (Bertran-Gonzalez et al., 2008). O le mea e malie ai, o le faʻamaoniga o le faʻaogaina o le cocaine o le c-Fos faʻapitoa ile D1-GFP i le striatum atoa ma se faʻauluina laʻititi i le D2-GFP MSNs na'o le dStr na fa'amaonia i le fa'aogaina o se fa'ata'ita'iga fa'atatau (na tui isumu i se si'osi'omaga fou i fafo atu o lo latou fale). E le gata i lea, o se suʻesuʻega muamua na faʻaaogaina i totonu O le faʻafefiloi i isumu na faʻaalia ai foi le faʻaogaina o c-Fos i le D1+ ma le D2+ MSNs i le dStr, e ui lava i lenei suʻesuʻega o faʻataʻitaʻiga o kalafi pa o loʻo faʻaalia ai le numera tele o D1+ c-Fos lelei neu (Ferguson et al., 2006). O le mea e malie ai, o lenei suʻesuʻega e faʻaalia ai le faʻaleleia atili o le c-Fos induction i D2+ MSNs i le dStr pe a maeʻa le leiloa o le ERK1, lea e tutusa ma a matou sailiga o le faʻaleleia o le c-Fos induction i le D2+ MSNs faʻapitoa i le atigi NAc pe a maeʻa le faʻalavelaveina o le faailo BDNF lea e iloa e faʻaleleia ai le gaioiga ERK (Lobo et al., 2010). Ae ui i lea, o tali faʻafeagai o amioga i cocaine na matauina i suʻesuʻega taʻitasi, lea e ono atagia mai ai le faʻaogaina o le c-Fos i D.2+ MSN i le dStr vs. NAc atigi. Mulimuli ane, faʻaaogaina tusitusiga muamua i totonu hybridization/immunohistochemistry i isumu ua faʻaalia ai le malosi o le psychostimulants e mafai ona faʻaosoina tutusa le c-Fos i MSN uma pe a tuʻuina atu le vailaʻau i se siosiomaga fou (Badiani et al., 1999; Uslaner et al., 2001a,b; Ferguson ma Robinson, 2004) ma le faʻaaogaina masani o le amphetamine ua lipotia mai e faʻaosofia ai le c-Fos i le D2+ MSNs (Mattson et al., 2007). O nei fa'ai'uga 'ese'ese e mafai ona avea ma ata o faiga fa'ata'ita'iga na fa'aaogaina (i totonu hybridization vs. GFP reporter isumu) po'o le mafua mai fo'i i ituaiga manu na fa'aaogaina e pei o su'ega mulimuli na fa'aogaina ai isumu.
Talu ai nei, na faʻaalia ai e le au suʻesuʻe le faʻaogaina o le cocaine, c-Fos activated neurons i isumu e faʻaogaina ai le immunolabeled fluorescence activated cell sorting (FACS) ma faʻaalia ai o le c-Fos + neurons e faʻatamaoaigaina i se D.1+ MSN gene, prodynorphin (Pdyn), ae e maualalo le maualuga o D2 ma A2A, uma D2+ MSN genes (Guez-Barber et al., 2011), o loʻo fautua mai ai o le c-Fos + activated neurons e aofia ai le D1+ MSNs. E le gata i lea, o lenei vaega na faʻaalia muamua o le c-Fos o loʻo faʻaalia MSNs e taua tele mo lenei faʻamatalaga-faʻalagolago, ona o le faʻaaogaina o nei neu e faʻaumatia ai lenei uiga faʻaalia (Koya et al., 2009). E ui o faʻamatalaga muamua na faʻaalia ai o le cocaine-faʻalagolago i le faʻaogaina o le c-Fos e tupu i le D1+ ma le D2+ MSNs i isumu, o faʻaiʻuga sili ona lata mai e fetaui ma suʻesuʻega o le tapeina o c-Fos filifilia mai le D1+ MSNs e faʻafefe ai le faʻaogaina o le locomotor e faʻaosoina i le koko i isumu (Zhang et al., 2006). E le gata i lea, na maua e lenei vaega o le tapeina o c-Fos i le D1+ MSNs blunts le dendritic spine suiga e masani ona faʻaosoina e cocaine i le NAc, e faʻaalia ai se matafaioi mo c-Fos i le faʻatalanoaina o nei suiga palasitika synaptic. Mulimuli ane, na matauina e le vaega le leai o se suiga i le induction o le cocaine CPP, ae na maua le leiloa o c-Fos i le D.1+ MSNs na taofia le faʻaumatia o cocaine CPP. O ia faʻamatalaga o loʻo faʻaalia ai se matafaioi malosi mo le induction c-Fos i le D1+ Ae ui i lea, MSNs, e le mafai e se tasi ona taofiofia le eseesega o aʻafiaga i le tulaga o amioga e pei ona faʻatalanoaina e soʻo se isi vaega o le faiʻai limbic e faʻaalia le D.1 talini.
O le isi IEG sa su'esu'eina tele i vaega laiti MSN e lua o le FosB. O le faʻaalia tele i cocaine e faʻaosofia ai le FosB i le D1+ MSNs (Berretta et al., 1992), ae o le faʻalavelave faʻafuaseʻi e faʻaosofia ai le ΔFosB, o se oloa mautu o le FosB gene faʻatupuina e ala i isi faʻapipiʻi (Faamoemoe ma al., 1994; Nestler et al., 2001; Nestler, 2008), i le D1+ MSNs (Gagana et al., 1995; Moratalla et al., 1996; Lee et al., 2006). O su'esu'ega tutusa o lo'o matauina i le tele o isi vaila'au o le fa'aleagaina fa'apea fo'i ma taui fa'anatura e pei o mea'ai, feusua'iga, ma le ta'avale uili. Mo se faʻataʻitaʻiga, taʻavale masani uili, o se taui masani (Iversen, 1993; Pele, 1997; Lett et al., 2000), faʻaosofia le ΔFosB i le D1+ MSNs ae le o D2+ MSNs (Werme et al., 2002). Ina ia maua se malamalamaga aoga i le matafaioi a le ΔFosB i MSNs e lua, o la matou vaega na gaosia laina NSE-tTa, e taʻua o le 11A ma le 11B, lea e tuusaʻo ai le transgene faʻamatalaga i le D.1+ po o le D2+ MSNs, faasologa (Chen et al., 1998; Kelz et al., 1999; Werme et al., 2002). Laina 11A isumu na sopoia ma le Tet-Op ΔFosB laina o loʻo faʻaalia ai le tele o tali i le tauia ma le locomotor aafiaga o cocaine (Kelz et al., 1999), lea e ogatasi ma le ΔFosB induction i D1+ MSNs (Gagana et al., 1995; Moratalla et al., 1996). E le gata i lea, o nei lava isumu e faʻaalia le faʻateleina o le taui o le morphine (faʻavasegaina e le CPP) faʻapea foʻi ma le faʻaitiitia o le morphine analgesia ma le faʻaleleia o le faʻapalepale o le morphine, ae o le 11B Tet-Op ΔFosB mice e leai se suiga i le taui o le morphine. O le faʻaalia o se faʻalavelave le lelei o le ΔFosB e faʻaalia ai aʻafiaga e faʻafeagai ma mea na vaʻaia i le ΔFosB, e ui o lenei faʻataʻitaʻiga o le isumu e leʻo iloa D.1 vs. D2 MSNs (Peakman et al., 2003). Faʻatasi, o nei faʻamaumauga e lagolagoina atili le matafaioi a le ΔFosB induction i D1+ MSNs o se tagata taʻalo mole mole taua i meatotino tauia o vailaʻau faʻaleagaina (Zachariou et al., 2006). O lenei mea mataʻutia o loʻo matauina foi i isi amioga tau taui, aemaise lava, uili taʻavale: 11A Tet-Op ΔFosB mice faʻaalia le faʻateleina o le amio taʻavale uili, ae o le 11B Tet-Op ΔFosB mice faʻaalia le faʻaitiitia o uili taʻavale (Werme et al., 2002). O le mauaina o le ΔFosB induction i D1 O loʻo faʻamalosia e le MSN le taui e ogatasi ma suʻesuʻega talu ai nei e faʻapea o sea ituaiga-selective induction e faʻamalosia ai foi le faʻaleleia o tali i le faʻalavelave masani (Vialou et al., 2010). Mulimuli ane, o le faʻaaogaina o cocaine masani o le ΔFosB i le D1+ MSNs na faʻaalia o loʻo faʻatasi ma le faʻatupuina umi umi o le dendritic spine densities (Lee et al., 2006) ma talu ai nei o le ΔFosB i le NAc na faʻaalia uma e manaʻomia ma lava i le faʻatalanoaina o le faʻateleina o le tele o tui o le dendritic i lenei vaega faiʻai (Maze et al., 2010). O ia faʻamaumauga e lagolagoina se matafaioi mo le ΔFosB i D1+ MSNs i le faʻatalanoaina o vaega tauia o vailaʻau o le faʻaleagaina ma taui masani faʻapea foʻi ma suiga faʻapipiʻi faʻapipiʻi. O faʻamaumauga foi o loʻo fautua mai ai o le faʻaogaina o le ΔFosB i D2+ MSNs e tuʻuina atu aʻafiaga leaga i faʻaosofia tauia. Talu ai ona o le ΔFosB induction i D2+ MSNs o loʻo vaʻaia i le tali atu i le faʻalavelave masani ma le faʻaalia o fualaau faʻasaina (antipsychotic).Hiroi ma Kamalaele, 1996; Perrotti et al., 2004), e manaʻomia nisi suʻesuʻega o gaioiga mulimuli.
Isi Intracellular Signaling Molecules i D1 vs. D2 MSNs
O se tasi mole mole faʻailoga na suʻesuʻeina lelei i MSN e lua i le tulaga o le faʻaaogaina o fualaau faasaina o le protein kinase, ERK (extracellular signal related kinase). O le faʻalavelave faʻafuaseʻi poʻo le faʻaalia i le cocaine e faʻaosofia ai le ERK (pERK), le faʻaogaina o le porotini, i le NAc ma le dStr i le D.1+ MSNs faʻaaogaina D1-GFP ma D2-GFP BAC transgenic reporter isumu (Bertran-Gonzalez et al., 2008) ma o lenei tali e faʻasalalau e ala i le D1 talini (Valjent et al., 2000; Lu et al., 2006). O lenei vaega na faʻaalia foi o le pMSK-1 (phospho-MAP ma le faʻamalosia o le kinase-1) ma le histone H3, o sini uma e lua o le pERK faailo, o loʻo faʻamalosia malosi i le pERK o loʻo i ai D.1+ MSNs ina ua maeʻa le faʻaalia o le cocaine ma faʻateleina le faʻatupulaia pe a uma le cocaine masani (Bertran-Gonzalez et al., 2008). O le pERK o loʻo faʻaosoina foi o le tali atu i le morphine masani, aemaise lava, o le pERK o loʻo faʻamalosia malosi i le D.1+ MSNs ma faatosina tauagafau i D2+ MSNs i le atigi NAc pe a uma ona faaui i tua e tali atu i le fesoʻotaʻiga faʻapitoa ma le morphine (Borgkvist et al., 2008). Ole matafaioi tonu ole pERK ile vaisu o fualaau oona o lo'o tumau pea ona fuafuaina. O togafitiga faʻamaʻi faʻatasi ma ERK inhibitors ua faʻaalia e faʻaitiitia ai le taui o le cocaine, ae ui i lea, o le tuʻituʻi o le ERK1 e faʻamalosia ai le taui o le cocaine, e faʻapea o le ERK inhibitors atonu e sili ona aʻafia ai le ERK2. Talu ai nei, na matou faʻaalia ai o le optogenetic activation o D1+ MSNs i le NAc, lea e faʻateleina ai le faʻamalieina o tali a se manu ile cocaine, faʻaitiitia ai le pERK1 ma le pERK2. O suʻesuʻega i le lumanaʻi e faʻaogaina ai le faʻaaliga ERK i se faʻaoga-ituaiga faʻapitoa e manaʻomia e faʻatautaia atoatoa ai le matafaioi faʻatino a le ERK faʻailoga i MSN e lua i le faʻaaogaina o fualaau faasaina.
O le DARPP-32 o le isi mole faʻailoga ua maeʻa suʻesuʻeina i le tali atu i vailaʻau o le faʻaleagaina. O loʻo lauiloa o le psychostimulants ogaoga e taʻitaʻia ai le PKA phosphorylation o le DARPP-32 i le threonine 34 (T34), ma mafua ai ona avea ma se faʻalavelave malosi o le protein phosphatase 1 (PP-1), lea e faʻatonutonuina ai le tulaga o le phosphorylation o le tele o polotini effector, e aofia ai. fa'aupuga fa'aliliuga, tali ionotropic, ma alavai ion (Greengard et al., 1999). Peita'i, se'ia o'o mai talu ai nei, e le'o manino po'o le fea MSN subtype e fa'atalanoaina lenei suiga fa'aola. Greengard et al. (1999) faia BAC transgenic faʻataʻitaʻiga kiore e mafai ai le iloiloga o le DARPP-32 phosphorylation i D1+ po o le D2+ MSNs e ala i le faʻaalia o faʻailoga o le DARPP-32 faʻaaoga D1 poʻo le D2 BACs fa'atagaina mo le immunoprecipitation o le DARPP-32 mai ta'itasi MSN subtype. O suʻesuʻega nei na faʻaalia ai o le togafitiga o le cocaine e faʻateleina ai le T34 phosphorylation i D1+ MSNs ma faʻaosofia le phosphorylation o le threonine 75 (T75) e le Cdk5, lea e faʻalavelaveina ai le faʻailoga PKA, filifilia i le D.2+ MSNs (Bateup et al., 2008). Mulimuli ane na faʻaalia e lenei vaega le tapeina o le DARPP-32 mai taʻitasi MSN subtype faʻaaoga D1-Cre ma D2-Cre BAC transgenic isumu e maua i le faʻafeagai o tulafono faatonutonu o gaioiga faʻaosoina o cocaine (Bateup et al., 2010). Le maua o le DARPP-32 mai le D1+ MSNs na faʻaititia le locomotor aʻafiaga o cocaine, lea e faʻataʻitaʻiina ai faʻamatalaga muamua e iloilo ai le aofaʻi o le DARPP-32 knockout (Fienberg et al., 1998), ae o le leiloa o le DARPP-32 mai le D2+ MSNs faʻaleleia le cocaine locomotor tali. O ia faʻamaumauga e tuʻuina atu ai faʻamaoniga faʻamaonia mo le eseesega o matafaioi a le DARPP-32 i MSN e lua e tali atu ai i fualaau oona ma faʻaalia le taua o auala faʻapitoa-ituaiga e malamalama atoatoa ai i le sao o nei ituaiga neuronal e lua i vaisu fualaau.
Gaoioiga Fa'atulagaina o D1 poʻo le D2 MSNs
O le fa'avasegaina sa'o o le gaioiga a vaega laiti MSN e lua ua maua talu ai nei se fa'amatalaga fou i le mole mole ma galuega a le D.1 ma le D2 MSN i vaisu. Na matou faʻaogaina meafaigaluega faʻapitoa faʻatasi ma se faʻaupuga (ie, Cre-dependent) adeno-associated viral (AAV) vector e faʻaalia ai le alalaupapa cation faʻamalosi moli lanumoana, channelrhodopsin-2 (ChR2). Na matou tui le vector, poʻo se pule, i totonu o le NAc o le D1-Cre poʻo D2-Cre BAC transgenic isumu ona faʻaosofia ai lea o le itulagi tui ma le moli lanumoana e filifili faʻagaoioia D1+ vs. D2+ MSNs i le tulaga o cocaine CPP. Na matou mauaina o le faʻagaoioia o D1+ MSNs e faʻamalosia le faʻaogaina o le cocaine CPP, ae o le faʻagaoioia o D2+ MSNs e taofia lenei induction (Lobo et al., 2010). E pei ona taʻua muamua, na matou matauina le tutusa o aʻafiaga o amioga pe a tape le TrkB filifilia mai nei MSN subtypes: faʻaleleia le cocaine CPP ma le gaioiga o le locomotor pe a uma le tapeina o le TrkB mai le D.1+ MSNs, ma faʻaitiitia le cocaine CPP ma le gaioiga o locomotor pe a maeʻa le tapeina o le TrkB mai le D2+ MSNs. Ole gaioiga masani ole TrkB knockout ma optogenetic stimulation ile D2+ MSNs o la latou gaioiga faʻateleina, talu ai o le tapeina o le TrkB mai nei sela e faʻateleina ai lo latou eletise eletise. E pei ona taʻua muamua, na matou maua foi se faʻaitiitiga malosi o le pERK ina ua maeʻa le tapeina o le TrkB mai le D1+ MSNs. O le pERK o se faʻailoga lauiloa i lalo ole faʻailoga BDNF, o le mea lea, o aʻafiaga o amioga faʻasoa na matauina pe a uma le tapeina o le TrkB mai le D.1+ MSNs ma mai le optogenetic activation o nei sela e mafai ona mafua ona o le feliuliuaʻi o aʻafiaga i le pERK gaioiga. Ae ui i lea, o galuega i le lumanaʻi e manaʻomia e fuafua ai le saʻo, fefaʻasoaaʻi faʻavae mole e pulea ai aʻafiaga o amioga na vaʻaia pe a maeʻa le faʻalavelaveina o le BDNF faʻailoga ma le optogenetic pulea o nei lua neuronal subtypes.
O isi vaega ua fa'aogaina meafaigaluega eseese e fa'afetaui ai le gaioiga a MSN e lua i fa'ata'ita'iga o le fa'aaogaina o fualaau fa'asaina. Hikida et al. (2010) na fa'aogaina ve'a AAV e fa'aalia ai le tetracycline-repressive transcription factor (tTa) e fa'aaoga ai le vaila'au P (a D.1+ MSN gene) poʻo le enkephalin (se D2+ MSN gene) faʻalauiloa. O nei vesi na tui i totonu o le NAc o isumu, lea o le tetanus toxin light chain (TN) - o se siama siama e tipi le synaptic vesicle-fesoʻotaʻi porotini, VAMP2 - na pulea e le tetracycline-responsive elemene, e filifili faʻaumatia synaptic transmission i taʻitasi. MSN subtype. E ogatasi ma la tatou auala optogenetic, o nei faʻamatalaga na faʻaalia ai se matafaioi a D1+ MSN gaioiga i le faʻaleleia o le cocaine CPP faʻapea foʻi ma le cocaine-induced locomotor activity, talu mai le soloia o le synaptic transmission i le D1+ MSNs na faʻaititia uma aʻafiaga o amioga. I le faʻatusatusa i suʻesuʻega optogenetic, e leʻi maua e le au tusitala ni suiga i le cocaine CPP ina ua uma ona faʻaumatia le faʻasalalauga i le D.2+ MSNs, ae na maitauina le faʻaitiitia o le gaioiga o le cocaine i le tali atu i faʻaaliga muamua e lua. O le mea e malie ai, o lenei vaega na faʻaalia o le le faʻaaogaina o le D2+ MSNs na faia se sao sili atu ona loloto i le faʻatalanoaina o amioga faʻafefe.
E pei ona taʻua muamua, Ferguson et al. (2011) fa'aaoga le herpes simplex virus (HSV) e fa'aalia ai se GPCR (se Gi / o-o le tagata muscarinic M4 fa'ailoga fa'ailoga fa'apitoa e fa'agaoioia e se vaila'au fa'apitoa, hM4D) o lo'o fa'agaoioia e se ligand fa'afoma'i fa'afoma'i e fa'aaoga ai le enkephalin ma le dynorphin fa'alauiloa e fa'agugu fa'agogo D.1+ po o le D2+ MSN i le dStr. Na faʻaalia e tusitala o le faʻalavelave faʻafuaseʻi D2+ O gaoioiga a le MSN i le dStr na faafaigofieina le lagona o le amphetamine, ae o le faaitiitia o le fiafia o D1+ MSNs na faʻaleagaina le faʻaauau pea o le faʻaogaina o le amphetamine. Mulimuli ane, faʻaumatia D2+ MSNs i le NAc i tausaga matutua e faʻaaoga ai le diptheria toxin receptor e faʻaleleia ai le tauia o le amphetamine (Durieux et al., 2009). O ia faʻamatalaga e tusa ai ma a tatou suʻesuʻega optogenetic, ma faʻatasi faʻatasi ai ma faʻafeagai matafaioi a D.1+ vs. D2+ MSN i vaisu o fualaau faasaina, faatasi ai ma le D1+ MSNs o loʻo faʻalauiloaina uma taui ma tali faʻapitoa i psychostimulants ma D2+ MSNs e faʻavaivaia nei amioga.
Taʻiala i le Lumanaʻi
Ua tele le alualu i luma o le fanua i le malamalama i le filifiliga filifilia a le D1+ ma le D2+ MSN subtypes i le NAc ma le dStr i le faʻatalanoaina o aʻafiaga o vailaʻau o le faʻaleagaina. Aemaise lava, o mea faigaluega talu ai nei na fausia e mafai ai ona faʻaogaina le filifilia o nei sela-ituaiga ua faia se sao taua i le mauaina o le tele o nei faʻamatalaga. O ā laasaga e sosoo ai? Talu ai o suiga faʻavae mole mole i faʻataʻitaʻiga o mea ua fai ma vaisu e le tumau, ae sili ona malosi, e taua tele le atinaʻeina o le gafatia e filifili ai le faʻaogaina o mole mole o le fiafia ile D.1+ vs. D2+ MSNs i se auala saʻo faaletino. DREADDs ma meafaigaluega optogenetic e mafai ona fesoasoani i lenei faʻaogaina fua o le taimi. DREADD ligands e mafai ona faʻatinoina i taimi eseese kosi i faʻataʻitaʻiga faʻataʻitaʻiga o vailaʻau e faʻavasega ai le filifiliga filifilia o faʻailoga faʻailoga i MSN e lua i faʻataʻitaʻiga fualaau. O mea faigaluega faʻapitoa faʻapitoa e maua ai se auala sili ona mamana e faʻatonutonu ai faʻaletino e le gata o gaioiga o le neuronal ae o le G-protein-coupled receptor signaling e faʻaaoga ai OptoXRs (Airan et al., 2009), fa'ailoga glutamatergic(Volgraf et al., 2006; Numano et al., 2009), faʻailoga GABAergic, ma e oʻo lava i nisi molelaula faʻailoga intracellular (Wu et al., 2009; Hahn ma Kuhlman, 2010). Mulimuli ane, atonu e mafai ona faʻalauteleina nei agavaʻa i le optogenetic regulation o le transcriptional activity. E faʻapea foʻi, o meafaigaluega faʻapitoa e mafai ai mo le taimi muamua ona suʻesuʻeina le aʻafiaga o mea faʻapitoa i le striatum ma fuafua pe faʻafefea ia mea i auala filifilia ile D.1+ vs. D2+ MSNs (Higley ma Sabatini, 2010). O le mafai ona pulea ia faʻailoga ma mea mole mole faʻatasi ma le tele o faʻafitauli faaletino o le a mafai ai ona faia ni laasaga tetele agai i se malamalama sili atu o le lua MSN subtypes, ma isi cell subtypes i le NAc ma le dStr, i le faʻatalanoaina o le taimi ma vaega eseese o vailaʻau. vaisu.
Feteʻenaʻiga o Tupulaga e Tetee ai
Fai mai tusitala o le suʻesuʻega sa faia i le leai o soʻo se fefaʻatauaʻiga faʻapisinisi pe tau tupe e mafai ona avea o se feteenaʻiga e ono aʻafia ai.
mau faasino
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uputatala: neu tui vavalo, vaisu, nucleus accumbens, cell-type-specific, D1+ MSNs, D2+ MSNs, cocaine, dopamine
Fuaiupu: Lobo MK ma Nestler EJ (2011) O le faʻatulagaina o le paleni o gaioiga i vaisu o vailaʻau: tulaga maʻoti o le auala tuusaʻo ma le le tuusaʻo ala faʻafefe. I luma. Neuroanat. 5:41. doi: 10.3389/fnana.2011.00041
Maua: 12 Me 2011; Pepa fa'atali lomia fa'asalalau: 31 Me 2011;
Talia: 05 Iulai 2011; Lomia i luga o le initaneti 18 Iulai 2011.
Faatonutonu e:
Emmanuel Valjent, Iunivesite Montpellier 1 & 2, Farani
Toe iloiloina e:
Bruce Thomas Faamoemoe, National Institute on Drug Abuse, ISA
Ioane Neumaier, Iunivesite o Uosigitone, ISA
Puletaofia: © 2011 Lobo ma Nestler. O se tala e tatala avanoa i lalo o se laisene e le faʻapitoa i le va o tusitala ma Frontiers Media SA, lea e faʻatagaina ai le faʻaogaina, tufatufaina ma le toe gaosia i isi faʻasalalauga, pe a faʻapea o tusitala muamua ma punaoa o loʻo faʻamaonia ma isi aiaiga Frontiers e tausisia.
* Tusitusi: Eric J. Nestler, Matagaluega o Neuroscience, Friedman Brain Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1065, Niu Ioka, NY 10029-6574, ISA. imeli: [imeli puipuia]