DeltaFosB Induction i Striatal Medium Spiny Neuron Subtypes in Response to Chrono Pharmacological, Emotional, and Optogenetic Stimuli (2013)

J Neurosci. 2013 Nov 20; 33 (47):18381-95. doi: 10.1523/JNEUROSCI.1875-13.2013.

Lobo MK, Zaman S, Damez-Werno DM, Koo JW, Bagot RC, Dinieri JA, Tagata A, Finkel E, Chaudhury D, Chandra R, Riberio E, Rabkin J, Mouzon E, Cachope R, Cheer JF, Han MH, Dietz DM, Manatu DW, Hurd YL, Vialou V, Nestler EJ.

puna

Matagaluega o le Anatomy ma Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, Departments of Psychiatry and Pharmacology and Systems Fomaʻi, Icahn School of Medicine i le Mauga o Sinai, New York, Niu Ioka 10029, Matagaluega o Fomaʻi, University of Texas Southwestern Medical Centre, Dallas, Texas 75390, Matagaluega o Pharmacology ma Toxicology ma le Institute Research on Addictions, University of New York i le Buffalo, Niu Ioka, New York 14214, ma le Institut National de la Santé et de la Recherche Médicale, U952, National Scientific Research Center, Unity Mixte de Recherche 7224, UPMC, Paris, 75005, Farani.

lē faʻatino

O le faʻaliliuga o le transcription, ΔFosB, e malosi ma faʻaauau pea ona faʻaauau i le tele o meaola faʻapitoa, e pei o fualaau faasaina, togafitiga antipsychotic, taui faalenatura, ma le atuatuvale. Ae ui i lea, e itiiti lava ni suʻesuʻega na suʻesuʻeina ai le tikeri o le ΔFosB induction i vaega laiti e lua o le numera (spiny neuron) (MSN). Matou te faʻaaogaina le tusitala faʻamalosi o le BAC transiceic souris e iloilo ai le induction o le ΔFosB i le dopamine receptor 1 (D1) faʻamalosia ma le dopamine receptor 2 (D2) faʻamalosia MSNs i le striatum ventral, shell shell accumbens (NAc) ma le pito i tua, ma i le ogatotonu (dStr ) pe a uma ona faʻaalia i le tele o vailaʻau faʻasaina e aofia ai le kokeni, ethanol, Δ (9) -tetrahydrocannabinol, ma le 'opiates; le antipsychotic fualaau faasaina, haloperidol; faʻamalosia tamaiti; soona inu; calorie restriction; o le serotonin filifilia le inhibitor reuptake antidepressant, fluoxetine; ma le faʻaleagaina faʻaletonu o faʻafitauli. O a matou sailiga e faʻaalia ai o le masani ona faʻaalia i le tele o fua ninii e mafua ai le ΔFosB i se mamanu filifilia o MSN-subtype i vaega uma e tolu. I le suʻesuʻeina o le faʻataʻitaʻiina o le Ava o le Ava i le striatum, matou te faʻaaogaina optogenetics e faʻaleleia ai le gaioiga i vaega o le faiʻai o le limu e auina atu ai meafaigaluega synaptic i le NAc; o nei itulagi e aofia ai le faʻalauteleina o le faʻaleleia o le gataifale ma le tele o vaega o loʻo i luga o le vailaʻau faʻataʻitaʻi: medial frontfront cortex, amygdala, ma hippocampus faʻalauiloa. O nei tulaga o le optogenetic e oʻo atu ai i mamanu iloga o le atinaʻe o le ΔFosB i subtypes MSN i totonu o le NAc ma le atigi. Faʻatasi, o nei suʻesuʻega e faʻatulagaina ai ni mamanu filifilia o le ΔFosB induction i lalo o le MSN subtypes e tali atu i faʻasolosolo masani ma tuʻuina atu ni malamalamaga faʻalauiloa i le faʻavaeina o auala o le ΔFosB induction i striatum.

faʻatomuaga

O faʻasolosolo taimi faʻafuaseʻi, e aofia ai fualaau faasaina, faʻaaogaina o fualaau oona, faʻamaʻi, ma taui faʻaleaganuʻu, mafua ai le faʻaleleia o le tamaoaiga o le ΔFosB, o se oloa tuʻufaʻatasi o le FosB gene, in striatum (eg, Faamoemoe ma al., 1994; Hiroi ma Kamalaele, 1996; Hiroi et al., 1997; Moratalla et al., 1996; Perrotti et al., 2004, 2008; Muller ma Unterwald, 2005; McDaid et al., 2006; Teegarden ma Bale, 2007; Wallace et al., 2008; Solinas et al., 2009; Vialou et al., 2010, 2011; Kaplan et al., 2011). O lenei faaputuga e taʻitaʻia ai le tulafono faatonutonu o le tele o genes e le ΔFosB i lenei vaʻa faiva (McClung ma Nestler, 2003; Renthal et al., 2008, 2009; Vialou et al., 2010; Robison ma Nestler, 2011). O le vaega autu e aofia ai (~95%) o le GABAergic spiny neurons (MSNs), ua vaevaeina i ni vaega se lua e faavae i luga o le faʻamalosia o le tele o genes, e aofia ai le 1 (D1) le receptor 2 (D2)Gerfen, 1992; Kiliata, 2000; Lobo et al., 2006; Heiman et al., 2008) ma a latou gaioiga faʻavae eseese i fausaga vavaevaega manino (Albin et al., 1989; Gerfen, 1992; Kalivas et al., 1993; Kiliata, 2000; Nicola, 2007; Smith et al., 2013). Talu ai nei, ua tele naua ripoti o loʻo faʻaalia ai le manino o le molécula ma le faʻatinoga o nei subtypes MSN i le ventral striatum (nucleus accumbens [NAc]) ma le dorsal striatum (dStr) i le faʻasalalau o faʻaosofiaga ma amioga faʻaletino (Lobo ma Nestler, 2011; Gittis ma Kreitzer, 2012).

O suʻesuʻega talu ai na faʻaalia ai o le ΔFOSB o loʻo faʻateleina i le D1-MSN e ala i togafitiga masani ma le cocaine poʻo le uila faʻasolosolo, o se ituaiga o taui masani (Moratalla et al., 1996; Werme et al., 2002; Lee et al., 2006), ae o le faʻasologa masani o le faʻamalosia o le faʻalavelave e aʻafia ai le ΔFosB i both subtypes MSN (Perrotti et al., 2004). E le gata i lea, o faʻamaoniga faʻamaonia mai le ituaiga masini faʻapitoa poʻo le vailaʻau faʻafefeteina e faʻaalia ai le faʻailogaina o le ΔFosB i le D1-MSN e faʻapupulaina ai le gaioiga o le amio ma le gaosiga i le koko, tali amio i le morphine, o le uili o le uila, taui o meaʻai, popolega, ae o le ΔFosB induction i D2-MSN e faʻasalaina ai amioga faʻasalaga i le uila o tamomoʻe (Kelz et al., 1999; Werme et al., 2002; Colby et al., 2003; Olausson et al., 2006; Zachariou et al., 2006; Vialou et al., 2010; Grueter et al., 2013; Robison et al., 2013).

Talu ai ona o le taua tele o le ΔFosB i le faʻatonutonuina o nei faʻasolosolo faʻasolosolo, faʻatasi ai ma aʻafiaga i le D1-MSNs ma le D2-MSN, tatou te faia iinei se suʻesuʻega atoa i mamanu o le induction o le ΔFosB i subtypes MSN e ala i le tele o faʻasolosolo masani, e aʻafia ai le faʻagaʻi masani i fualaau o le faʻaleagaina, togafitiga faʻasolosolo i fualaau faʻasaina, faʻasalaga faifaipea i suiga fesuiaiga o le siosiomaga ma mea faʻaleleia, faʻasolosolo le faʻaleagaina o le agavaʻa, ma le togafitiga masani i se faʻamaʻi pipisi. Ina ia malamalama i auala femalagaaʻi e puleaina ai le ΔFosB i totonu o le lotoa e le tele o itu o le faiʻai, ole faʻaaogaina o tekonolosi e faʻaauau ai ona faʻaosoosoina tino i totonu o le dopaminergic poʻo le glutamatergic itulagi o le mafaufau, ma suʻesuʻe le iʻuga o le ΔFosB induction i subtypes MSN. O a matou taunuʻuga e maua ai se malamalamaʻaga fou i le faʻavaeina o le ΔFosB i D1-MSNs ma D2-MSN e ala i faʻamalosi masani, ma, mo le taimi muamua, faʻaalia ai le faʻapipiʻiina o le ΔFosB i striatum ma i totonu ole subtypes MSN filifilia.

Mea ma Metotia

Meaola.

D1-GFP or D2-GFP kusi mimiti (Gong et al., 2003) i luga o le C57BL / 6 pito i tua sa tausia i luga o le lio o le 12 H mafiafia ad libitum meaai ma vai. O suʻesuʻega uma na faʻatinoina e tusa ai ma taʻiala na faʻatonuina e le Komiti Faʻafoeina o Manu ma Faʻaaoga i le Iunivesite o Maryland School of Medicine ma le Icahn School of Medicine i le Mauga Sinai. Masini tama (tausaga 8) na faʻaaogaina mo suʻega uma. O mio uma na faʻafefeteina, ma na faʻaputuina mafaufauga i le aoauli o le taamilosaga. Hemizygote D1-GFP ma D2-GFP mice i luga o le C57BL / 6 poʻo le FVB / N o le ata ua faʻaalia e tutusa lelei ma maunu-ituaiga e tusa ai ma amio, physiology o D1-MSN ma D2-MSN, ma le atinaʻeina o MSN (Lobo et al., 2006; Chan et al., 2012; Nelson et al., 2012). E le gata i lea, o le aotelega o mamanu o le ΔFosB induction o loʻo vaaia i lenei suʻesuʻega e faʻatusatusa i latou o loʻo vaaia i manu feʻai faʻatasi ma ni mea e leai ni ituaiga-meafaigaluega filifilia (eg, Perrotti et al., 2004, 2008).

Laʻau faʻamaʻi.

D1-GFP (n = 4 i togafitiga) ma D2-GFP (n = 4 i togafitiga) o mice na maua 7 i aso uma o incaua o le cocaine (20 mg / kg) poʻo le 0.9% saline i le fale ole fale. Mo 1 poʻo 3 cocaine (20 mg / kg) inisiua, na maua ai e mice le 6 poʻo le 4 d o 0.9% inisite saline sosoo ai ma le 1 poʻo le 3 d o cocaine injections, i le faasologa. O munu uma na faʻaaogaina le 24 h i le maea ai o le tui mulimuli. O lenei fualaau o cocaine na filifilia e faavae i luga o suʻesuʻega talu ai (eg, Maze et al., 2010).

Haloperidol togafitiga.

D1-GFP (n = 3 poo 4 i togafitiga) ma D2-GFP (n = 4 mo togafitiga) o mice na maua le haloperidol (2 mg / kg) i le vai inu, pH 6.0 (Narayan et al., 2007), poo vaiinu masani, pH 6.0, mo 3 vaiaso (21 d). O manogi sa faʻafefeteina i le aso 22.

Togafitiga Morphine.

D2-GFP mumu (n = 4 po o le 5 i togafitiga) na faʻataunuʻuina faʻapitoa i le isoflurane ma maua ai ni mea faʻapitoa o morphine (25 mg) poʻo paʻu palapala i le aso 1 ma le aso 3 e pei ona faʻamatalaina muamua (Mazei-Robison et al., 2011). O manogi sa faʻafefeteina i le aso 5.

Ethanol togafitiga.

D2-GFP mumu (n = 4 poʻo 5 i togafitiga) na faʻaalia i le 10% ethanol (EtOH), o se fualaau na faʻaalia e le C57BL / 6 e inu ai (Yoneyama et al., 2008). Na tuʻuina atu i ni masini se suʻega e lua mo filifiliga a le 10% EtOH (fagu A) ma le vai (fagu B), ae D2-GFP pulea na maua vai i fagu uma e lua (fagu A ma le B) mo 10 d. O musi uma na maua ia EtOH sa faʻailoa mai se mea e sili ona lelei mo EtOH e pei ona fuafuaina e (100 × kalama A volume / [fagu A volume + o le B b)]. O mice na maua le 10% EtOH o le afi na faʻaaogaina atili le EtOH i le vai, ao mice na maua vai i totonu o fagu e lua e leai se eseesega i le faʻaaogaina o le vai. I le afiafi o le aso 10, o fuamoa na tuʻuina atu i ai le vai inu masani ma faʻafefe i le aso 11.

Δ (9) -tetrahydrocannabinol (Δ (9) -THC) togafitiga.

D2-GFP (n = 3 mo togafitiga) o mice na maua ni iniseti initua o le Δ (9) -THC (10 mg / kg) poo le taavale (0.9% saline ma le 0.3% Tween) faalua i le aso mo 7 d (Perrotti et al., 2008). Sa faʻauluina masini 24 h i le maea ai o le tui mulimuli.

Cocaine self-administration.

D2-GFP mumu (n = 4 poo le 5 i togafitiga) na muamua aoaoina ina ia faapipiiina mo le 20 mg pellets i luga o le fua faatusatusa o le 1 (FR1) seia oʻo ina ausia se fuataga o le 30 sugase pellets mo 3 aso mulimuli e tusa ai ma tulaga masani (Larson et al., 2010). O masini na aʻoaʻoina e taʻavale le lomitusi na faʻapipiʻiina i se taotoga ma se mea e sili ona afaina ai le gaʻo ina ia mafai ai ona maua le puleaina o le cocaine mulimuli ane. I le tasi le vaiaso talu ona taʻalo, na faʻafeiloaʻi ai maso i le faʻafoega o le tagata lava ia i le 2 h i aso uma i luga o le FR1 faʻatulagaga o le faʻamalosia. Na faʻapipiʻiina le masini faʻafoega (Med Associates) ina ia mafai ai ona tali atu i luga o le levela malosi (faʻaaogaina le 2.5 s) o le cocaine (0.5 mg / kg / infusion i luga o le leve press press), ae o se tali i le le galue malosi leai se polokalama na afifiina. Mice pulea e le tagata ia cocaine i se faasologa FR1 i aso uma 2 h sessions, 5 d i le vaiaso, mo 3 vaiaso. D2-GFP munu na maua 0.9% injections o saline i luga o le taimi tutusa tutusa na faʻaaogaina e fai ma pule. O manogi na faʻaaogaina le 24 h i le maeʻa ai o le cocaine mulimuli po o le puleaina o le saline.

Heroin self-administration.

Aʻo lei avea heroin ma ia lava, D2-GFP mumu (n = 4 mo togafitiga) na aʻoaʻoina e faʻasili ai le masini loka (BioServ, Dustless Prequision Pellets) i le fitu 1 h i aso uma. O masini na aʻoaʻoina e taʻavale le lomitusi na faʻapipiʻiina i se taotoga i se mea e sili ona afaina ai le gaʻo ina ia mafai ai ona mulimuli atu i le pule a le heroin. I le tasi vaiaso talu ona taotoga, na faʻafeiloaʻi ai maso i le faʻafoega o le tagata lava ia i le 3 i aso taʻitasi i luga o le FR1 faʻatulagaina o le faʻamalosi e tusa ai ma faiga faʻavae (Navarro et al., 2001). Na faʻapipiʻiina le masini faʻafoega (Med Associates) ina ia mafai ona tali atu i luga o le levela malosi (auina atu le 5 s) o le heroin (30 μg / kg / injection, NIDA Drug Supply Program), ae o se tali i le le toaga le leve sa leai se poloketi o taunuuga. Na tuʻuina atu i manu le avanoa i le heroin mo le faʻatinoina o ia lava mo 14 d. D2-GFP munu na maua 0.9% injections o saline i luga o le taimi tutusa tutusa na faʻaaogaina e fai ma pule. O masini na faʻaaogaina le 24 h i le maeʻa ai o le heroin mulimuli poʻo le pulega o saline.

Faʻaolaina o le siʻosiʻomaga o tagata.

D2-GFP (n = 4 i le tasi vaega) o niumu na gaoia i totonu o se 'oloa faʻamafanafana poʻo tulaga masani fale i le aso postnatal 21 (P21) faʻaaogaina ai se ata na faʻaaogaina mai le maile (Green et al., 2010). O le faʻamafanafanaina o le siosiomaga na i ai se fale tele hamster ma faʻamalosia-o-cob moega (Andersons Laboratory bedding) faʻatumu i mea faʻapitoa e aofia ai paipa, paipa ma uili, taʻalo polo, fale e taʻalo ai (Bio Serv), ma isi meataalo. Sa nonofo pea masini i totonu o le fale mo 4 vaiaso seia oo i le P50 ona faʻamalo ai lea.

Sucrose togafitiga.

D2-GFP mumu (n = 4 po o le 5 i togafitiga) na tuʻuina atu i ai se suʻega faʻaiuga e lua mo le 10% sucrose e tutusa ma suʻesuʻega muamua (Wallace et al., 2008). Na tuʻuina atu i le masini 10% sucrose (fagu A) ma le vai (fagu B), ae D2-GFP puleaina o vai i pusa uma e lua mo le 10 d. O musi uma na maua pusa suamalie na faʻaalia ai se mea e sili ona lelei mo le sucrose e pei ona fuafuaina e (100 × kalama O le voluma / fagu O le voluma + le fagu B). O mice na maua le 10% sucrose oona na faʻaaogaina le sili atu o le sosolo pe a faatusatusa i le vai, ao le maile na maua vai i totonu o fagu e lua e leai se eseesega i le faʻaaogaina o le vai. I le afiafi o le aso 10, o fuamoa na tuʻuina atu i ai le vai inu masani ma faʻafefe i le aso 11.

Faʻatapulaʻa o kalori.

D2-GFP mumu (n = 4 i faʻasologa faʻasolo) na faʻaogaina se faʻatautaia o kalori restriction, lea na latou maua 60% o ad libitum calories i aso uma (Vialou et al., 2011) mo 10 d. D2-GFP le pulea o laulei na mauaina le avanoa atoa i le aufaipese. I le afiafi o le aso 10, o mio uma na maua le avanoa atoa i le paʻu ma na faʻafefeteina i le aso 11.

Faʻasalaga manuia faʻaletino.

D2-GFP mumu (n = 4 po o le 5 mo le vaega) na faia le 10 d o le faʻaleagaina o faʻafitauli faʻaleagafesa e pei ona faʻamatalaina muamua (Berton et al., 2006; Krishnan et al., 2007). O tamaʻitaʻi na faʻaalia i le faʻamalosi o le CD1 faʻamalosi litaea mo 5 min i se fale tele hamster. Ona nonofo ai lea o masini mo le 24 H i le fale e tasi i le isi itu o se tufatufa vavae e faatumauina fesootaiga faʻapitoa. O le aso na sosoo ai na faʻaalia ai ni mailei i se CD1 fou i lalo o tulaga tutusa ma fale. Na toe faia lenei mea mo 10 d ma CD1 fou i aso taʻitasi. O mice pulea na tuʻuina i lalo o tulaga talitutusa e aunoa ma le faʻaleagaina o faʻafitauli. O suʻe na tofotofoina mo fegalegaleaiga faʻaagafesootai i le aso 11. Na muamua suʻeina masini mo le taimi e faʻaoga ai ma se potu tusi i totonu o le pusa avanoa e aunoa ma se isi kulupu o loʻo i ai (leai se faʻataʻitaʻiga) ma mulimuli ane tofotofoina mo le taimi na faʻafegalegaleai ai ma CD1 mouse (target) na i tua o le potu (Berton et al., 2006; Krishnan et al., 2007). Na vavaeʻesea mailei i totonu o vaega e ono mafai ona faʻaaogaina pe faʻavaeina e faʻavae i luga o faʻataʻitaʻiga na faʻamatalaina muamua (Krishnan et al., 2007). E aofia ai le taimi atoa e faʻaalu i le kiore ma le fefaʻatauaʻiga: (taimi faʻaalu ma le tau / taimi faʻaalu e aunoa ma se taumatau) × 100. O lenei fuataga ua faʻaalia e faʻalagolago ai le faʻaalia o kulupu faigofie ma faʻafouina ma e matua faʻamalosia lelei ma isi eseesega amio (Krishnan et al., 2007). O munu uma na faʻaaogaina le 24 h i le maea ai o le suʻega faʻasalalauga lautele (48 h i le maea ai o le faʻasologa mulimuli faʻaleagaina faʻaleagafesootai).

Fluoxetine togafitiga.

D2-GFP mumu (n = 3 po o le 4 i le vaega) na maua 14 i aso taitasi o injections o le fluoxetine (20 mg / kg) poʻo le taavale (0.9% saline ma le 10% cyclodextrin) (Berton et al., 2006). Sa faʻauluina masini 24 h i le maea ai o le tui mulimuli.

Toto tipitipi.

D2-GFP O mice na faʻaaogaina i le ketamine (100 mg / kg) / xylazine (10 mg / kg), ma tuʻuina i totonu o se meafaigaluega laiti-manu, ma o latou ulupulu o loʻo faʻaalia. O le tolu sefulu tolu suāuʻu tuilaina na faʻaaogaina e faʻaaogaina ai le 0.5-1 μl, i le fua faatatau o le 0.1 μl i le minute, o le vevela i totonu o le vaega faʻalauteleina (VTA), cortex muamua (mPFC), amygdala, poʻo le hippocampus ventral ( vHippo). AAV [siama adeno-virus] -hSyn-ChR2 [channelrhodopsin 2] -EYFP poʻo le AAV-hSyn-EYFP sa faʻaaogaina i le VTA o D2-GFP mumu (n = 5 i le vaega) i faʻamaumauga faʻasolosolo (pito i luma, -3.3 mm; lautele-medial, 0.5 mm, faʻasalalauga, -4.4 mm, 0 ° angle). O lenei na mulimuli mai ai le luanulani (26-gauge), faʻatasi ai ma le umi o le 3.9 mm, faʻapipiʻiina o le VTA (pito i tua, -3.3 mm, lautele-medial, 0.5 mm; dorsal-ventral, -3.7 mm) (Koo et al., 2012; Chaudhury et al., 2013). AAV-CaMKII-ChR2-mCherry poʻo le AAV-CaMKII-mCherry na tui i le mPFC (n = 4 po o le 5 ile vaega), amygdala (n = 3 po o le 4 ile vaega), poʻo le vHppo (n = 3 po o le 4 ile vaega) o D2-GFP maunu na sosoo ai ma le faʻaaogaina o filo o le eletise ole 105 μm (Sparta et al., 2011). O loʻo faʻapipiʻiina nei: MPFC (o le infralimbic, o loʻo faʻamoemoeina, ae na matou vaʻaia le vevela o le siama i vaega ole lalata: pito i tua, 1.7 mm; lautele, medal, 0.75 mm, faʻavaʻa-vents, -2.5 mm, 15 ° angle) ma le fiber optic (taʻavale, -2.1 mm); amygdala (amygdala amatalia (target) amygdala (amolate) amygdala, but we observed the spread of virus into the central center of amygdala, front-posterior, -1.6 mm, lateral-medial, 3.1 mm, dorsal-ventral, -4.9 mm, 0 ° angle) and optic fiva (faʻavao-ventral, -4.9 mm); vHippo (faʻavae vaʻaia na faʻatulagaina, ae na matou matauina le vevela o le siama i isi itulagi o le hippocampus ventral, pito i luma, -3.9 mm, lalata-medial, 3.0 mm, leʻo-ventral, -5.0 mm, 0 ° angle) ma le fiber optic (taʻavale, -4.6 mm).

Optogenetic conditions.

mo i vivo O le faʻaaogaina o le VTA neuronal firing, na faʻafouina ai le 200 μm mo le faʻapipiʻiina o le fila i le canlaula. Ina ua maua le fiva i le taifau, o le pito i luga o le filo na faalauteleina atu i le itulagi e sili atu i le (0.5 mm)Lobo et al., 2010; Chaudhury et al., 2013). Aua i vivo o le mPFC, amygdala, ma le vHoppo neuronal firing, o le 62.5 μm vavae paʻu fiva ua faʻapipiʻiina i luga ole laupepa ulu (Sparta et al., 2011). O filo filo na faʻapipiʻiina i le PC / PC i le laser diode laser 473 (Crystal Lasers, BCL-473-050-M), ma o masini elemene na maua mai i stimulator (Agilent, 33220A). Mo VTA, malamalama lanumoana (473 nm) faʻasologa o meaola, 20 Hz mo 40 ms (Chaudhury et al., 2013), na tuʻuina atu mo 10 min i le aso ile 5 d. Mo mPFC, amygdala, ma vHppo, malamalama lanumoana (473 nm), 20 Hz mo 30 s, na tuʻuina atu mo 10 min i le aso mo 5 d. O le moliina o le malamalama na tupu i totonu o le fale o le fale, ma na faʻapipiʻi uma maile i le 24 h i le maeʻa ai o le faʻamalosia o le moli mulimuli.

In vitro patch-clamp electrophysiology.

O lipine uma lava na mauaina mai VTA dopamine neurons poʻo mPFC glutamatical neurons i ni mafaufauga o le mafaufau tele mai le mailei na tuiina i siama na taʻua i luga. O lipine na pueina i luga o moa ae leai i vivo faaosofia, ae faʻatasi ai ma le 1 d o le faʻafiafiaina o le paina (1 d) poʻo le 4 d o i vivo faaosofia ma le 1 d o le faʻamalosia o le paina (5 d). Ina ia faʻaitiitia le faʻamaʻi ma ia maua ni fasi soifua maloloina, na vave ona faʻaogaina mice i le taimi lava na tuʻuina atu ai i le vaega o le electrophysiology ma faʻauluina ai le 40-60 s aCSF, lea e aofia ai 128 mm NaCl, 3 mm KCl, 1.25 mm NaH2PO4, 10 mm d-glucose, 24 mm NaHCO3, 2 mm CaCl2, ma 2 mm MgCl2 (faʻamaʻiina i le 95% O2 ma 5% CO2, pH 7.4, 295-305 mOsm). O fasi pepa faiʻai o loʻo i ai mPFC poʻo le VTA na tipiina ma faʻaaogaina le microslicer (Ted Pella) i le malulu-aCSF, lea na mafua mai i le suitulaga atoa o le NaCl ma le 254 mm sucrose ma faʻatumu e 95% O2 ma 5% CO2. O fasi keke na tausia i totonu o se potu malolo ma seCSF mo 1 h i le 37 ° C. Patch pipettes (3-5 MΩ), mo le atoatoa o le gaʻo, na tumu i vaifofo i totonu e aofia ai: 115 mm potassium gluconate, 20 mm KCl, 1.5 mm MgCl2, 10 mm phosphocreatine, 10 mm HEPES, 2 mm magnesium ATP, ma le 0.5 mm GTP (pH 7.2, 285 mOsm). O lipine faʻapitoa na faia i le faʻaaogaina o le ACSF i le 34 ° C (fua faʻatatau = 2.5 ml / min). O taʻavale malamalama moli (20 Hz mo mPFC poʻo le 20 Hz, 40 ms mo VTA) na fatuina e se stimulator e fesoʻotaʻi atu i le FC / PC adapter i le 473 nm blue laser diode (OEM) ma tuʻuina atu i mPFC ma VTA slices via a 200 μm filo filo. O faʻamatalaga faʻapipiʻi nei na faʻaaogaina e faʻaaoga ai le Multiclamp 700B amplifier, ma na maua le faʻamaumauga i le pClamp 10 (Molecular Devices). Sa maitauina le faʻafeteina o laina i le taimi o suʻesuʻega, ma o paʻu o le membrane ma voltages na faʻamamaina i le 3 kHz (Bessel filter).

Immunohistochemistry.

O mice na faʻaaogaina i le chloral hydrate ma faʻaalu i 0.1 m PBS mulimuli ai le 4% paraformaldehyde i le PBS. O paʻu na tuʻuina i le 4% paraformaldehyde i le po ona faʻasolosolo ai lea i le 30% sucrose. Na faʻapipiʻiina paʻu i luga o se cryostat (Leica) i le 35 μm i le PBS ma le 0.1% sodium azide. Mo le immunohistochemistry, na poloka ai vaega i le 3% faʻatasi ma le 0.01% Triton-X i le PBS mo le 1 h luga o le shaker i le potu vevela. Ona faʻaaogaina ai lea o vaega i fomaʻi muamua i le poloka i le po i luga o le tagata vevela i le vevela o le potu. O meaola na faʻaaogaina e pei o nei: rabbit anti-FosB (1: 2000, catalog # sc-48, Santa Cruz Biotechnology), anti-NeuN souris (1: 1000, catalog #MAB377, Millipore), anti-GFP chicken (1: 5000 , nusipepa # 10-20, Aves), ma le anti-CREB (o le tali tali a le CAMP o loʻo fusifusia le protein; 1: 1000, kopi # 06-863, Millipore). O le aso na sosoo ai, na fufulu ai vaega i le PBS sosoo ai ma le 1 h incubation i fomaʻi lona lua: Cy3 lapisi lapisi, Cy5 kione, ma le moa moa DyLight-488 poʻo le Alexa-488 (Jackson ImmunoResearch Laboratories). Mo mCherry ma tyrosine hydroxylase immunohistochemistry, na faia ai suʻesuʻega e pei ona faʻamatalaina muamua (Lobo et al., 2010; Mazei-Robison et al., 2011). O vaega na faʻamamaina i le PBS, faʻapipiʻi i luga o palama, ma ufiufi.

Faʻataʻitaʻiga ma le faitauina o le cell.

Na faʻataʻitaʻiina le faʻamaonia i le Zeiss Axioscope poʻo le Olympus Bx61 microscope confocal. O le siakiina o le siaki na faia i le software i le ImageJ. O ata sampling bregma 1.42-1.1 o le NAc (autu ma le atigi) ma le ogatotonu na ave mai i le 2 poʻo le 3 brain sections / animal (see Mati. 1A). Ole numera 400-500 atoa na faitauina i le va o le faiʻai i le mole e faʻaaoga ai 250 μm × 250 μm ata. Sa faʻaaogaina Cells i le faʻaaogaina o le software i le ImageJ e pei o se suʻesuʻega talu ai (Lobo et al., 2010). E tusa ma le 400-500 o fuainumera uma o le NeuN na faitauina i le va o le faiʻai i le mouse, ona sosoo ai lea ma le numera o le GFP+, GFP+: ΔFosB+, GFP-, ma le GFP-: ΔFosB+ sela sa faitauina i itulagi taʻitasi. Na faʻamaonia faʻamaumauga e pei ona taʻua i lalo: (GFP+: ΔFosB+ neurons × 100%) / (aofaiga GFP+ neurons) ma (GFP-: ΔFosB+ neurons × 100%) / (aofaiga GFP- neurons). Na faia suʻega faʻamaumauga i le faʻaaogaina o le polokalama GraphPad Prism. E toʻalua auala o le ANOVA na sosoo ai ma le suʻega o le post a Bonferroni na faʻaaogaina mo suʻesuʻega uma o fuainumera.

Ata 1.  

O le cocaine faʻapitoa e faʻaaogaina ai le ΔFosB i le D1-MSN i vaega tetele. A, O vaega tetele mai le bregma + 1.42 i le 1.10 na faʻaaogaina mo le faitauina o le cell. Ata o a D2-GFP vaega taʻitasi o loʻo faʻaalia ai vaega e tolu o loʻo suʻesuʻeina: NAc core, ...

i'uga

ΔFOSB e ese le faʻaaogaina i le D1-MSN ma le D2-MSN ina ua maeʻa ona faʻaalia i le cocaine ma le haloperidol

Na matou suʻesuʻeina muamua le ΔFosB induction i subtypes MSN D1-GFP ma D2-GFP maunu e faʻaaogaina cocaine masani na muai faaalia e sili ona faatosina le protein o le ΔFosB i D1-MSN (Moratalla et al., 1996). D1-GFP ma D2-GFP BAC faʻagasolo mice, lea e faʻaalia ai le faʻalauteleina o le protein i le fulafula i lalo o le generator generator D1 poʻo D2 (Mati. 1A), na maua inisua o le cocaine (intraperitoneal injections) (20 mg / kg) poʻo le saline mo le 7 d, ma o le mafaufau na aoina le 24 h i le maea ai o le tui mulimuli (Mati. 1B). Ona matou faia lea o le immunohistochemistry i vaega o le faiai e faaaoga ai auupega e faasaga i le NeuN, GFP, poo le FosB ma atagia ma faitauina fua i NAc core, NAc shell, ma dStr (Mati. 1A,C). E ui o le antibody FosB antibody recognizes FosB atoa ma le ΔFosB, o le tele o suʻesuʻega e faʻaaoga ai le Western Western blotting poʻo le immunohistochemistry ua faʻamaonia ai o le ΔFosB o le ituaiga o meaola e mafai ona iloa i le 24 h taimi o le taimi e taofia ai (eg, Perrotti et al., 2008). O le mea lea matou te faʻaaoga ai le 24 h po o le umi taimi taimi e aoina ai le mafaufau i le maea ai o tuʻutuʻuga i lenei suʻesuʻega ina ia mautinoa o loʻo matou mauaina le ΔFosB. Talu ai ona o MSN o loʻo i ai le ~95% o laina uma i le striatum, matou te faʻaaogaina le immunolabeling NeuN e faailoa ai le GFP- neurons, lea o loʻo faʻamaoaigaina i le faʻafeagai o le subtype MSN (ie, D2-MSN i le D1-GFP munu ma D1-MSN i le D2-GFP moa). Na ma mauaina lena mea D1-GFP munu na togafitia ma le faʻamaina o le cocaine o se faʻaaogaina tele o le ΔFosB i le GFP+/ NeuN+ neurons (D1-MSN) i le NAc core, NAc shell, ma le dStr, ao GFP-/ NeuN+ sel (D2-MSNs) e leʻi faʻaalia ai le amataina o le ΔFosB i vaega uma o itulagi (Mati. 1D): auala e lua ANOVA, NAc autu: vailaʻau vailaʻau vailaʻau F(1,12) = 16.41, p <0.05, Bonferroni post test: p <0.01; Atigi NAc: vailaʻau × sela ituaiga F(1,12) = 12.41, p <0.05, Bonferroni post test: p <0.001; dStr: vailaʻau × sela ituaiga F(1,12) = 12.07, p <0.05, Bonferroni post test: p <0.01. E tusa ai ma nei sailiiliga, na matou maitauina i D2-GFP munu e leai se taua tele o le faʻaaogaina o le ΔFosB ile GFP+/ NeuN+ neurons (D2-MNs) ae o se faʻavae taua o le ΔFosB ile GFP-/ NeuN+ (D1-MSNs) i itu uma o le itulagi pe a maeʻa togafitiga o le koko (Mati. 1D): auala e lua ANOVA, NAc autu: vailaʻau vailaʻau vailaʻau F(1,12) = 15.76, p <0.01, Bonferroni post test: p <0.0001; Atigi NAc: vailaʻau × sela ituaiga: F(1,12) = 20.33, p <0.05, Bonferroni post test: p <0.01; dStr: vailaʻau × sela ituaiga: F(1,12) = 35.96, p <0.01, Bonferroni post test: p <0.001. Na matou suʻesuʻeina i vailaʻau o le ΔFosB faʻasolosolo i MSNs ina ua maeʻa 1, 3, poʻo le 7 d o cocaine (20 mg / kg, ip) tui. Na matou maitauina le taua o le ΔFosB i le D1-MSNs ma le 3 poʻo le 7 d o togafitiga o le cocaine pe a faʻatusatusa i le saline togafitiga i itulagi uma.Mati. 1F): sui o kalafi mai le dStr; lua-way ANOVA, ituaiga cell × le aso F(2,13) = 17.87, p <0.01, Bonferroni post test: p <0.01, p <0.001. E o gatasi ma le taimi kosi o le ΔFosB faʻaputuputuga i striatum vaaia muamua e Sisifo blotting (Faamoemoe ma al., 1994) ma faʻamaonia le filifilia o le ΔFosB i totonu o D1-MSN i le gasologa o le faʻaaogaina o cocaine.

Na matou suesueina mulimuli ane le ΔFosB induction e immunohistochemistry i subtypes MSN ina ua maeʻa ona faʻaalia i haloperidol (Mati. 2). O le galuega muamua na fautua mai e le tuusaʻo e mafai e le halopaleidol masani ona faʻaaogaina le ΔFosB i le D2-MSN (preferentially in DXNUMX-MSNs)Hiroi ma Kamalaele, 1996; Atkins et al., 1999), e ui lava o lenei mea e lei faʻatalanoaina saʻo. D1-GFP ma D2-GFP mice na maua le haloperidol (2 mg / kg) i le vai inu, pH 6.0, ae D1-GFP ma D2-GFP pulea o fuamalie na maua i taimi uma vai inu, pH 6.0, mo 21 d (3 vaiaso) ma le mafaufau na aoina i le aso 22 (Mati. 2A). E pei o le cocaine, matou te iloa o le FosB-pei o le puipuiga mai le tino i lenei taimi o le sui lea o le ΔFosB, ae le o le FosB atoa atoa (Atkins et al., 1999). Na ma mauaina lena mea D1-GFP munu na maua le haloperidol e leʻi faʻaalia ai se faʻaaogaina tele o le ΔFosB ile GFP+/ NeuN+ neurons (D1-MSN) i le NAc core, NAc shell, or dStr; ae peitai, o se siitaga taua o le ΔFosB sa matauina i le GFP-/ NeuN+ neurons (D2-MSN) i itu uma o itu (Mati. 2B,C): auala e lua ANOVA, NAc autu: vailaʻau vailaʻau vailaʻau: F(1,10) = 23.29, p <0.05, Bonferroni post test: p <0.01; Atigi NAc: vailaʻau: fualaʻau × sela ituaiga: F(1,10) = 30.14, p <0.05, Bonferroni post test: p <0.01; dStr: vailaʻau × sela ituaiga: F(1,10) = 37.63, p <0.001, Bonferroni post test: p <0.0001. Na faʻamaonia lea ile suʻesuʻega o D2-GFP maunu: sa ma matauina le taua o le amataina o le ΔFosB i le GFP+/ NeuN+ neurons (D2-MSNs) i vaega uma e tolu, ae leai se suiga taua i le ΔFosB ile GFP-/ NeuN+ (D1-MNs) pe'ā uma le togafitiga o haloperidol (Mati. 2B,C): auala e lua ANOVA, NAc autu: vailaʻau vailaʻau vailaʻau: F(1,12) = 24.30, p <0.05, Bonferroni post test: p <0.05; Atigi NAc: vailaʻau × sela ituaiga: F(1,12) = 26.07, p <0.01, Bonferroni post test: p <0.001; dStr: vailaʻau × sela ituaiga: F(1,12) = 21.36, p <0.01, Bonferroni post test: p <0.01. Talu ai na matou maitauina le tutusa mamanu o le ΔFosB induction i D1-MSNs e ala i le faʻaauau ona maua o cocaine i mea uma e lua D1-GFP (GFP+/ NeuN+) ma D2-GFP (GFP-/ NeuN+) maso, ma le toe faapalepale haloidol i D2-MSN i totonu D1-GFP (GFP-/ NeuN+) ma D2-GFP (GFP+/ NeuN+) muse, o totoe na matou faʻaaogaina D2-GFP munu e suʻesuʻe le ΔFosB induction i D1-MSN (GFP-/ NeuN+) ma le D2-MSN (GFP+/ NeuN+) i le mavae ai o isi faʻasolosolo masani.

Ata 2.  

O le halopaleidol taimi faʻapitoa e aʻafia ai le ΔFosB i D2-MSN i vaega tetele. A, Taimi o le 21 o togafitiga o haloperidol (2 mg / kg, i totonu o vaiinu) poʻo vai. B, Immunohistochemistry o le NAc shell o D1-GFP ma D2-GFP isumu pe a uma le haloperidol ...

I le avea ai o se taʻaloga, matou te suʻesuʻeina vaega o le CREB faʻaaliga i le cocaine ma haloperidol tulaga e fuafua ai pe mafai ona faʻasalalau a matou sailiga i isi tusitusiga (Mati. 3). Matou te leʻi maitauina se eseʻesega tele i le tautalaga a le CREB i le va o le puleaina ma fualaau faasaina. E le gata i lea, matou te leʻiloa se eseesega i le CREB i le va o D2-MSN ma D1-MSN (Mati. 3B,C).

Ata 3.  

O le cocaine po o le haloperidol e le faatosinaina ai le CREB i lalo o le MSN. A, Faʻamaonia mo le CREB ma le GFP i le tele o D2-GFP musi pe a maeʻa le cocaine masani poʻo le halopaleidol masani (Mati. 1 ma Ma22 taleni mo togafitiga fualaau faasaina). Laina sikuea, 50 μm. ...

O mamanu maʻoti o le ΔFosB induction i subtypes MSN i fualaau faasaina

Ona o suʻesuʻega talu ai na faʻaalia ai o isi vailaʻau o le faʻaleagaina e ono mafai ona faatosinaina ai le ΔFosB i lalo o tulafono laiti (Perrotti et al., 2008), na matou suʻeina le ΔFosB i lalo ifo o le MSN ina ua maeʻa ona faʻaalia i opiates, EtOH, poo le Δ (9) -THC. Na matou suʻesuʻeina muamua pe faʻafefea e le chronic morphine le faatosinaina o le ΔFosB i ni vaega laiti MSN i itu uma o le itu. D2-GFP o munu na maua ai ni meaola se lua o le paʻu poo le morphine (25 mg) pellet i aso 1 ma le 3, ma na maua ai mafaufau i aso 5 (Mati. 4A) pe a faʻaosoina le ΔFosB, ae le o le FosB (Zachariou et al., 2006). I se eseesega iloga i le cocaine, o vaega laiti uma o le MSN ua faaalia ai le taua (ma le tutusa) i le ΔFosB i le NAc core, NAc shell, ma le dStr i le vaega o le morphine pe a faatusatusa i le pulea o le sham, e aunoa ma se isi ituaiga intype induction o le ΔFosB ua vaaia i vaega uma itulagi (Mati. 4A): auala e lua o le ANOVA; NAc autu: fualaau faasaina F(1,14) = 75.01, p <0.0001, Bonferroni post test: p <0.01 (D2-MSN), p <0.001 (D1-MSN); Atigi NAc: fualaʻau F(1,14) = 62.87, p <0.0001, Bonferroni post test: p <0.01 (D2-MSN), p <0.05 (D1-MSN); dStr: fualaʻau F(1,14) = 60.11, p <0.001, Bonferroni post test: p <0.01 (D2-MSN), p <0.05 (D1-MSN).

Ata 4.  

O vailaʻau o le sauaina e faatosina ai ΔFosB i lalo ifo o MSN i vaega tetele. A, Togafitiga o le timeline (25 mg pellets i aso 1 ma 3) i totonu D2-GFP mice e maua ai le taua tele o le ΔFosB i both subtypes MSN i le NAc core, NAc shell, ma dStr ...

Na matou suʻesuʻeina mulimuli ane le mamanu o le faʻaaogaina o le ΔFosB i subtypes MSN ina ua maeʻa ona faʻaalia i EtOH. D2-GFP E iai ni suʻega na tuʻuina atu i le 10% EtOH (fagu A) ma le vai (fagu B) D2-GFP pulea na maua vai i fagu uma e lua (fagu A ma le B), mo le 10 d ma le mafaufau na aoina i le aso 11 (Mati. 4B). O mice na maua le 10% EtOH o le kulini na faʻaaogaina atili le EtOH i le vai, ao mice na maua vai i totonu o fagu e lua e leai se eseesega i le faʻaaogaina o le vai (Mati. 4B): fiafia i le fagu O le vai vaega: 50.00 ± 4.551%, EtOH kulupu: 84.44 ± 8.511%; Tamaiti aʻoga t suega, p <0.05. Faʻataʻitaʻi EtOH pulega faʻaiʻuina i le taua induction o ΔFosB filifili i D1-MSNs i NAc autu, NAc atigi, ma dStr, ma leai se suiga i D2-MSNs (Mati. 4B): auala e lua ANOVA, NAc autu: vailaʻau vailaʻau vailaʻau: F(1,14) = 24.58, p <0.05, Bonferroni post test: p <0.05; Atigi NAc: vailaʻau × sela ituaiga: F(1,14) = 36.51, p <0.01, Bonferroni post test: p <0.01; dStr: vailaʻau × sela ituaiga: F(1,14) = 29.03, p <0.01, Bonferroni post test: p <0.01.

D2-GFP sa togafitiina foi maunu i le Δ (9) -THC (10 mg / kg, ip) faalua i le aso mo le 7 d, ma o le mafaufau na aoina 24 h i le maea ai o le tui mulimuli. E tutusa lelei ma le cocaine ma le EtOH, na matou matauina le faateleina o le alualu i luma o le ΔFosB i le D1-MSN i itu uma o laufanua e maua mai ai le Δ (9) -THC masani (Mati. 3E): auala e lua ANOVA, NAc autu: vailaʻau vailaʻau vailaʻau F(1,8) = 26.37, p <0.01, Bonferroni post test: p <0.01; Atigi NAc: vailaʻau × sela ituaiga: F(1,8) = 44.49, p <0.05, Bonferroni post test: p <0.001; dStr: vailaʻau × sela ituaiga F(1,8) = 29.30, p <0.05, Bonferroni post test: p <0.01.

Na matou suʻesuʻeina pe o le mamanu o le ΔFosB i totonu ole subtypes MSN e faia e le suʻega sailiili o cocaine poʻo opiates e tupu mai i ni mea e faʻaogaina ai le mea e faʻaaogaina ai e mio le fualaau faasaina. Tulaga tasi, D2-GFP o fualaau sa aoaoina i le cocaine (0.5 mg / kg / infusion) i se fua faatatau FR1 mo le 2 ha i aso mo 3 vaiaso ma na maua ai le mafaufau i le 24 h i le maea ai o le faʻasalaga mulimuli (Mati. 4D), pe a lauiloa le ΔFosB, ae le o le FosB,Larson et al., 2010). E sili atu le tele o le taimi na faʻaaluina ai e le masini le faʻamalosi o le gaioiga gaioiga ma le vaivai (Mati. 4D; Tamaiti aʻoga t suega, p <0.01). O le averesi fualaʻau o le cocaine i le aso o le 19.1 mg / kg i totonu (Mati. 4D), e talitutusa ma le 20 mg / kg dose faʻapitoa o le intraperitoneal faʻaaoga i luga (Mati. 1). E faʻapei ona faʻaalia mai ai le cocaine (Mati. 1), na matou iloa o le cocaine self-administration na mafua ai le amataina o le ΔFosB i na o D1-MSN i itu uma o itu e faʻatusatusa i le faʻafefe o le saline (Mati. 4D): auala e lua ANOVA, NAc autu: vailaʻau vailaʻau vailaʻau F(1,14) = 21.75, p <0.05, Bonferroni post test: p <0.01; Atigi NAc: vailaʻau × sela ituaiga: F(1,14) = 26.52, p <0.01, Bonferroni post test: p <0.01; dStr: vailaʻau × sela ituaiga F(1,14) = 33.68, p <0.001, Bonferroni post test: p <0.001. Faʻapena foi, tutusa ma noncontingent opiate (morphine) faʻaalia (Mati. 4A), na matou mauaina lena mea D2-GFP Iuniti na pulea e le tagata lava ia heroin (30 μg / kg i infusion), i luga o le aso FR1 3 aso mo 2 vaiaso na suesueina 24 h i le maea ai o le faʻamaʻi faʻamaʻi mulimuli, faʻaalia le initaneti ΔFosB i D2-MSN ma D1-MSN uma itulagi (Mati. 4E): auala e lua ANOVA, NAc autu: fualaau faasaina F(1,12) = 68.88, p <0.001, Bonferroni post test: p <0.01 (D2-MSN), p <0.05 (D1-MSN); Atigi NAc: fualaʻau F(1,12) = 80.08, p <0.0001, Bonferroni post test: p <0.01 (D2-MSN), p <0.001 (D1-MSN); dStr: fualaʻau F(1,12) = 63.36, p <0.001, Bonferroni post test: p < 0.05 (D2-MSN), p <0.05 (D1-MSN). O le averesi fualaʻau i aso taʻitasi mo le heroin o le 0.459 mg / kg, ma isumu faʻaalu taimi sili atu teleomiina o le toaaga faʻagaioʻoga lever (Tamaiti aʻoga t suega, p <0.05) (Mati. 4E).

Faʻaolaina o le siʻomaga ma mea faʻapitoa e faʻaosofia ai ΔFosB i D1-MSN ma D2-MSN

Talu ai o suʻesuʻega talu ai na faʻaalia ai o taui masani e faʻaaogaina ai le ΔFosB i vaega tetele (Werme et al., 2002; Teegarden ma Bale, 2007; Wallace et al., 2008; Solinas et al., 2009; Vialou et al., 2011), faʻatasi ai ma le faʻaaogaina e le uili o loʻo filifili e filifili mo D1-MSN (Werme et al., 2002), na matou suʻeina pe na faʻaaogaina e isi taui faʻanatura na faʻaalia ai le telefoni feaveaʻi. Na matou muai faʻaaogaina se faʻataʻitaʻiga faʻatamaoaigaina o tamaiti D2-GFP sa i ai ni manoa i totonu o se lalolagi faʻamalosia mai le susu (3 vaiaso) mo se vaitaimi o le 4 (Mati. 5A). O lenei faiga na muai faaalia e faatosina ai le ΔFosB i le kiota NAc ma le dStr (Solinas et al., 2009; Lehmann ma Herkenham, 2011). Pe a faatusatusa i tulaga masani o fale, o le tamaoaiga o le siosiomaga na faateleina ai le ΔFosB i itu uma o itu, ae le faia i se ituaiga tele-ituaiga, faatasi ai ma le induction vaaia i D1-MSN ma D2-MSN (Mati. 5A): auala e lua ANOVA, NAc autu: siosiomaga F(1,12) = 89.13, p <0.0001, Bonferroni post test: p <0.0001 (D2-MSN), p <0.0001 (D1-MSN); Atigi NAc: siosiomaga F(1,12) = 80.50, p <0.0001, Bonferroni post test: p <0.001 (D2-MSN), p <0.001 (D1-MSN); dStr: siosiomaga F(1,12) = 56.42, p <0.01, Bonferroni post test: p <0.05 (D2-MSN), p <0.05 (D1-MSN).

Ata 5.  

O le faʻaleleia o le siosiomaga ma faʻamalosi tino e faatosina ai ΔFosB i subtypes uma MSN. A, D2-GFP munu sa i totonu o se siosiomaga faʻamalosia e amata i le P21 mo 4 vaiaso faʻaalia le induction o le ΔFosB i subtypes MSN uma i vaega uma ...

Na matou toe suʻesuʻeina le ΔFosB expression i subtypes MSN pe a maeʻa ona faʻaosoosoina le malosi. Na matou muai tofotofoina aafiaga o le gasegase tumau o le ava malosi, lea na muai faaalia e faatosina ai le ΔFosB i le rat NAc (Wallace et al., 2008). D2-GFP o mice na tuʻuina atu i ai se suʻega e lua faʻaiuga mo le 10% sucrose (fagu A) ma le vai (fagu B), ae D2-GFP pulea na maua vai i fagu uma e lua (fagu A ma le B) mo le 10 d ma le mafaufau na aoina i le aso 11 (Mati. 5B). O mice na mauaina le 10% sucrose na faʻaaogaina le sili atu o le sosolo, ae o mice na maua vai i totonu o fagu uma e lua e leai se eseesega i le faʻaaogaina o le vai (Mati. 5B): fiafia i le fagu A, vai: 50.00 ± 4.749%, sukarosa: 89.66 ± 4.473%; Tamaiti aʻoga t suega, p <0.001. Na matou mauaina le faʻaaogaina o le sucrose i le cFosB i le NAc core, NAc shell, ma le dStr ma o lenei mea na tupu i vaega uma e lua o le MSN (Mati. 5B): auala e lua ANOVA, NAc autu: togafitiga F(1,12) = 76.15 p <0.0001, Bonferroni post test: p <0.01 (D2-MSN), p <0.01 (D1-MSN); Atigi NAc: togafitiga F(1,12) = 63.35, p <0.001, Bonferroni post test: p <0.05 (D2-MSN), p <0.01 (D1-MSN); dStr: togafitiga F(1,12) = 63.36, p <0.001, Bonferroni post test: p <0.01 (D2-MSN), p <0.05 (D1-MSN).

Mulimuli ane, na matou suʻesuʻeina le faʻamaoniga o le ΔFosB i subtypes MSN ina ua maeʻa le calorie ona o lenei tulaga, lea na faʻaleleia ai le locomotor activity ma le tulaga faʻaosofia, na muamua faʻaalia e faʻaleleia ai le maualuga o le ΔFosB i le kiota NAc (Vialou et al., 2011). D2-GFP mice na pasia se calorie-tapulaa faasaina, lea na latou mauaina 60% o ad libitum calories i aso uma mo le 10 d ma le mafaufau na aoina i le aso 11 (Mati. 5C). O faʻatapulaʻa o kalori na faʻaititia le maualuga o le ΔFosB i le NAc core ma le NAc shell e pei ona faʻaalia muamua (Vialou et al., 2011) ma faʻateleina foi le maualuga o le ΔFosB i le dStr. Ae ui i lea, matou te leʻi vaʻaia se inisiua eseese i D1-MSN ma D2-MSN (Mati. 5C): auala e lua ANOVA, NAc autu: togafitiga F(1,12) = 67.94 p <0.0001, Bonferroni post test: p <0.01 (D2-MSN), p <0.01 (D1-MSN); Atigi NAc: togafitiga F(1,12) = 67.84, p <0.0001, Bonferroni post test: p <0.001 (D2-MSN), p <0.01 (D1-MSN); dStr: togafitiga F(1,12) = 82.70, p <0.0001, Bonferroni post test: p <0.001 (D2-MSN), p <0.001 (D1-MSN).

Faʻasalaga faʻasolosolo faʻafitauli faʻaleagaga ma togafitiga faʻamalosia e mafua ai le faʻavaeina o le ΔFosB i lalo o le MSN

Matou te faʻamuamua na faʻaalia le ΔFOSB i le NAc o miole ina ua mavae le faʻasolosolo masani o le faʻaleagaina o le faʻaleagaga (Vialou et al., 2010). E ui lava na matauina lenei gaioiga i mice uma e ono mafai ona faʻaaogaina (o mea ia e faʻaalia ai le matuia o le atuatuvalega) faʻapea foi ma mailei e mafai ona faʻaaogaina (o mea na e sola ese mai le tele o nei aʻafiaga), na sili atu le atinaʻe o le ΔFosB i le vaega faʻafouina ma na faʻaalia saʻo e faʻatalanoa se tulaga o le maufetuunaʻi. I le suʻesuʻega nei, na matou maua ai le tele o le telefoni feaveaʻi mo le atinaʻe o le ΔFosB i nei vaega lua o le phenotypic. D2-GFP o manuʻa na tuʻuina atu i le 10 d o le faʻapalepalega faʻaleagafesoʻotaʻi ma vavaeʻesea i ni tagata maʻaleʻale ma toe faʻaleleia e faavae i luga o se fua o fegalegaleaiga faʻaagafesootai (Mati. 6A), lea e matua faʻamaeʻaina ma isi faʻasologa o amioga (Krishnan et al., 2007). O masini na atiaʻe amioga le lelei ina ua mavae le faʻaleagaina o agavaʻa faʻaleagaga na faʻaalia ai le taua tele o le ΔFosB i le D2-MSN i le NAc core, NAc shell, ma le dStr pe a faʻatusatusa i le pulea ma le mausali o muse, e aunoa ma se inisiua i D1-MSN. I se eseesega iloga, o mumumu mautu na faaalia ai le taua tele o le ΔFosB i D1-MSN i itu eseese uma pe a faʻatusatusa atu i manulele e mafai ona gafatia ma pulea, e aunoa ma se faʻaaliga manino i le D2-MSN (Mati. 6A; auala e lua ANOVA, NAc autu: vaega × ituaiga masini F(1,20) = 20.11, p <0.05, Bonferroni post test: D2-MSN / faigofie p <0.05, D1-MSN / faʻaalia p <0.05; Atigi NAc: kulupu × sela ituaiga F(1,20) = 27.79, p <0.01, Bonferroni post test: D2-MSN / faigofie p <0.001, D1-MSN / faʻaalia p <0.01; dStr: kulupu × sela ituaiga F(1,20) = 19.76, p <0.01, Bonferroni post test: D2-MSN / faigofie p <0.05, D1-MSN / faʻaalia p <0.01).

Ata 6.  

Faʻasalaga faʻasolosolo faʻaleagaina le atuatuvale ma le mafuaʻaga o le fluoxetine mafuaʻaga ΔFosB induction in distinct MST subtypes i striatum. A, D2-GFP e ono aʻafia i le 10 d o le faʻaleagaina faʻaleagafesootai faʻalavelave faʻalavelave ΔFosB induction i D2-MSN i itu uma ...

O togafitiga faʻasolosolo ma le SSRI antidepressant, fluoxetine, faʻafesoʻotaʻi amioga faʻaleagatu-e pei ona faʻaalia e moli vaivai ina ua maeʻa le faʻavaivaia faʻaletonu o agavaʻa (Berton et al., 2006). E le gata i lea, o ia togafitiga e faʻaosofia ai le ΔFosB i le NAc o loʻo faigofie ona maua faʻapea foi ma isumu faʻatonutonu, ma ua matou faʻaalia foʻi, e manaʻomia le faʻatonutonu mo aafiaga o amioga lelei a le fluoxetine (Vialou et al., 2010). O lea na matou suesueina ai le tulaga faapitoa o le cellular o le ΔFosB induction ina ua uma le pulega masani o le fluoxetine. D2-GFP munu na maua le fluoxetine (20 mg / kg, ip) mo le 14 d, ma na maua ai mafaufau i aso 15 (Mati. 6B). Na ma matauina le taua tele o le ΔFosB i D1-MSN, ae le o le D2-MSN, i mumua e togafitia i le fluoxetine pe a faatusatusa i le ave taavale (Mati. 6B; auala e lua ANOVA, NAc autu: vailaʻau vailaʻau vailaʻau F(1,10) = 14.59, p <0.05, Bonferroni post test: p <0.01; Atigi NAc: vailaʻau × sela ituaiga: F(1,10) = 26.14, p <0.05, Bonferroni post test: p <0.01; dStr: vailaʻau × sela ituaiga F(1,10) = 8.19, p <0.05, Bonferroni post test: p <0.001).

O togafitiga i le vivo optogenetic o le NAc afferent brain brains e mafua ai ni mamanu eseese o le atinaʻe o le ΔFosB i vaega tuusao ma subtypes MSN

Avanoa o le dopaminergic ma le glutamatergic faʻafefe o meafaigaluega i le NAc e mafai ona faafaigofieina ai le taui ma sui amioga faʻalavelave (Tsai et al., 2009; Covington et al., 2010; Adamantidis et al., 2011; Witten et al., 2011; Britt et al., 2012; Lammel et al., 2012; Stuber et al., 2012; Chaudhury et al., 2013; Kumar et al., 2013; Tye et al., 2013), na matou suʻesuʻeina le amataina o le ΔFosB i vaega laiti MSN i le maeʻa ai o le faʻamalosiina o gaoioiga a le tele o itu taua o le faiʻai. Na matou viliina le ChR2 i totonu o le tele o itulagi ma faʻaaogaina i le lanumoana (473 nm) e pei ona faʻamatalaina muamua (Gradinaru et al., 2010; Yizhar et al., 2011). Talu ai o se suʻesuʻega talu ai nei na faʻaalia ai le faʻamalosia o le lanu lanumoana, ina ua maeʻa le faʻavasegaina o le ChR2 i le VTA, na mafua ai le faʻasologa o le amio faʻapitoa e pei o le ChR2 phasic faaosofia o le VTA dopamine neurons (Chaudhury et al., 2013), matou faʻaalia ChR2 faʻaoga AAV-hsyn-ChR2-EYFP i le VTA o D2-GFP mio; o le pulea o le maile na tuiina i le AAV-hsyn-EYFP. VTA vaega na faʻatauina faʻatasi ma tyrosine hydroxylase ma le GFP e faʻafofoga i le faʻaaliga o le ChR2-EYFP (Mati. 7C). D2-GFP mice na faʻaalia le ChR2-EFYP poʻo le EYFP naʻo le VTA na mauaina le 5 d o 10 min o le lanu lanumoana faʻamalosia o le VTA pei ona faʻamatalaina muamua (Koo et al., 2012; Chaudhury et al., 2013) (Mati. 7A), ma o mafaufauga sa aoina 24 h i le maea ai o le faʻamalosi mulimuli. E leai se faʻaaogaina o le gafatia o le ChR2 e faʻaalia ai le VTA dopamine neurons i le 5 d o le faʻamalosi (Mati. 7B). Na matou iloa o le faʻateleina o le faʻaosofiaina o neu VTA e faʻaalia ai le ChR2-EYFP ua faʻatupulaia le ΔFosB i subispes MSN i le NAc, ae naʻo le D1-MSN i le NAc shell (Mati. 7C; auala e lua ANOVA, NAc ogaoga: fualaau o le optogenetic F(1,16) = 51.97, p <0.0001, Bonferroni post test: p <0.001; (uma MSN subtypes) NAc atigi: optogenetic stimulus × sela ituaiga: F(1,16) = 13.82, p <0.05, Bonferroni post test: p <0.01). Na matou maitauina le faʻauluina o le ΔFosB i le dStr ina ua maeʻa le lanumoana malamalama phasic stimulate i le VTA-faʻaalia ChR2-EYFP faʻatusatusa i pulega EYFP. O nei taunuʻuga e tatau ona faʻamatalaina ma le faʻaeteete, talu ai matou te leʻi vaʻaia VTA dopamine neu mo le faʻaosofiaina o mata, ma talu ai nei suʻesuʻega na faʻaalia ai le nondopaminergic projection neurons i le VTA faʻapea foi ma le tele o le feteʻenaʻi o le VTA, lea e mafai ona mafua ai le feʻeseʻeseaʻi o amioga faʻalagolago i le fanaina. tapulaʻa ma subpopulation o neurons aʻafia (Tsai et al., 2009; Lammel et al., 2011, 2012; Witten et al., 2011; Kim et al., 2012, 2013; Tan et al., 2012; van Zessen et al., 2012; Stamatakis ma Stuber, 2012; Chaudhury et al., 2013; Tye et al., 2013).

Ata 7.  

O le faʻamalosia o le ogatotonu o le faiʻai ole atunuʻu lea na nofoia ai le NAc e mafua ai le mamanu o le atinaʻe o le ΔFosB i subtypes MSN ma vaega tetele. A, O le optogenetic e faʻaosofia ai foliga faʻapitoa mo tulaga uma. Na seleseleina Brains 24 i le 5 d o le optogenetic ...

Matou te faʻaaogaina le AAV-CaMKII-ChR2-mCherry ma le AAV-CaMKII-mCherry vectors e faʻaali ai le ChR2-mCherry, poʻo le mCherry na o oe e pulea, i le mPFC, amygdala, poo le vHppo D2-GFP mumu (Mati. 7D-F). ChR2 ma mCherry faʻamatalaga na faʻapipiʻiina e le CaMKII-ChR2 virus ua faʻataʻitaʻiina muamua e faʻaaogaina ai faʻamatalaga CaMKII, o le igoa sili ona taua o le faʻaaogaina o fua ninii (glutamatical neurons)Gradinaru et al., 2009; Warden et al., 2012). Matou te faʻaaogaina siamupini e faʻaalia ai ChR2 i nei eria ma le 20 Hz lanumoana lanumoana mo le 10 min i le aso mo le 5 d, ma o le mafaufau na aoina 24 h i le maea ai o le faʻamalosi mulimuli (Mati. 7A). O lenei mamanu faʻaosofia na mafua ai le faʻaaogaina o leXXUMX-27 Hz, e mafua ona o le matauina o le faaluaina o le sipili. Leai se faʻaaliga manino o ChR33 na tupu i le 2 d o le faʻamalosi; ae ui i lea, na matou matauina se laʻititi laʻititi i le paina mai le 5 i le 1 d (5-32 Hz) o le faʻamalosi. Na matou iloa o le faʻamalosia o le mPFC i le optogenetic na mafua ai le initua o le ΔFosB i le D33-MSN i le NAc, ae o le ΔFosB induction na tupu i totonu o both subtypes MSN i le NAc shell (Mati. 7D; auala e lua ANOVA, NAc ogaoga: fualaau o le optogenetic × ituaiga masini F(1,14) = 10.31, p <0.05, Bonferroni post test: p <0.01; NAc atigi: optogenetic stimulus F(1,14) = 57.17, p <0.001, Bonferroni post test: p <0.05 (D2-MSN), p <0.01 (D1-MSN)). Leai se suiga ile ΔFosB maualuga na maitauina ile dStr pe a maeʻa le faʻatagaina ole mPFC. I se faʻatusatusaga, o le optogenetic activation o amygdala neurons na faʻaosoina le ΔFosB i itu uma e lua o le MSN i le NAc core, ma le filifilia i le D1-MSN i le NAc shell, e aunoa ma se suiga na tupu i le dStr (Mati. 7E; auala e lua ANOVA, NAc ogaoga: fualaau o le optogenetic F(1,10) = 78.92, p <0.0001, Bonferroni post test: p <0.001 (D2-MSN), p <0.0001 (D1-MSN); NAc atigi: optogenetic stimuli × sela ituaiga: F(1,10) = 30.31, p <0.0001, Bonferroni post test: p <0.0001). I le mea mulimuli, o le optogenetic activation o vHippo neurons na mafua ai le taua ΔFosB faʻatosina naʻo D1-MSN i uma NAc autu ma NAc atigi, ma toe leai se suiga matauina i dStr (Mati. 7F; auala e lua ANOVA, NAc ogaoga: fualaau o le optogenetic × ituaiga masini F(1,10) = 18.30, p <0.05, Bonferroni post test: p <0.01; Atigi NAc: optogenetic stimuli × sela ituaiga: F(1,10) = 22.69, p <0.05, Bonferroni post test: p <0.01).

Talanoaga

O le suʻesuʻega nei o loʻo suʻesuʻeina le ΔFosB induction i D1-MSN ma D2-MSN i itulagi tetele i le maeʻa ai o faʻasolosolo masani (Laulau 1). Tatou muai faavaeina le aoga o le faʻaaogaina D1-GFP ma D2-GFP laina o faʻasalalauga e faʻaalia ai le filifilia o le ΔFosB i le D1-MSN i le maeʻa o cocaine masani ma i le D2-MSN i le maeʻa o halobaridol. O suʻesuʻega cocaine e ogatusa ma suʻesuʻega muamua (Moratalla et al., 1996; Lee et al., 2006) ma le faʻatulagaina o le matafaioi mo le ΔFosB i D1-MSN i le faʻaleleia o le tau o le koko (Kelz et al., 1999; Colby et al., 2003; Grueter et al., 2013). Na matou faailoa muamua o lena tagata sailiili-ma cocaine e pulea e le tagata lava ia, e faatosina ai le ΔFosB i se tutusa tutusa i le NAc (Winstanley et al., 2007; Perrotti et al., 2008), ma o le mea taua tatou te faʻaalia iinei o faʻaaogaina uma o vailaʻau o le koko e faatosina faʻamalosi ai ΔFosB i le D1-MSN i vaega uma e tolu. O a matou sailiga e ogatasi ma suʻesuʻega talu ai o loʻo faʻaalia ai na maua e le cocaine tele vave isi genes muamua ma le phosphorylation o le tele o faʻamalologa o faʻamaʻi intracellular na o D1-MSN (Bateup et al., 2008; Bertran-Gonzalez et al., 2008). E faʻapea foʻi, o le faʻafeagai o le ΔFosB induction ina ua maeʻa le haloaraidol chronic e tutusa ma le poloka o lenei faʻaliliuga e le D2 pei ole agonists (Atkins et al., 1999), faʻatasi ai ma le tigaina o le haloperidol's filifiliga filifilia o vave vavega o kenera ma le phosphorylation o le tele o polotini faʻailo i D2-MSNs (Bateup et al., 2008; Bertran-Gonzalez et al., 2008).

Laulau 1.  

ΔFosB induction i le MSN subtrapes meli pe a maeʻa faʻasolosolo faʻasolosolo faʻamalosi, lagona, ma optogenetica

E pei o le cocaine, na matou iloa ai e masani ona faʻaalia i le isi lua vailaʻau o le faʻaleagaina, EtOH ma le Δ (9) -THC, faʻapipiʻi ai le ΔFosB ma le filifilia i D1-MSN i itu eseese uma. Na matou muai faailoaina le faaosofia e le EtOHA o le ΔFosB i le NAc core, NAc shell, ma le dStr, ae o le Δ (9) -THC ua faʻapitoaina ai le ΔFosB i le NAc, faatasi ai ma se tulaga vaaia i isi itulagi (Perrotti et al., 2008). Matou te maitauina foi iinei le sili atu Δ (9) -THC induction o le ΔFosB i le NAc core i D1-MSN; o lo tatou gafatia e faʻaalia ai le faʻaaogaina i isi vaega eria e ono mafua mai ona o le faʻamalamalamaina o le tino-faʻapitoa. O le mea e malie ai, o le chronic morphine ma le heroin self-administration, e le pei o isi vailaʻau faʻaleagaina, na faʻaosoina ai le ΔFosB i lalo uma o le MSN i se tulaga faʻatusatusa i itu uma o vaega. O se suʻesuʻega talu ai nei na faaalia ai o le morphine mataga na mafua ai le C-F i D1-MSN, ae o le naloxone-na vavae ese mai le maeʻa o le chronic morphine e mafua ai le C-F i D2-MSN (Enoksson et al., 2012). E ui lava tatou te leʻi matauina faailoga o le vaʻaia o le opiate i totonu oa tatou suʻesuʻega, e mafai ona iloa e sili atu le faʻaaogaina o le morphine poʻo le heroin i le taimi e suʻesuʻe ai, e nafa ma le atinaʻe ΔFosB i D2-MSN o loʻo vaaia iinei. Na matou faailoa muamua atu o le ΔFosB i D1-MSN, ae le o le D2-MSN, e faʻaopoopoina ai tali lelei i le morphine (Zachariou et al., 2006). O le a sili nei le manaia le tofotofoina le ono mafai e le ΔFosB induction i D2-MSN ona fesoasoani i aafiaga faʻaleagaga o le aveeseina o le opiate. E faʻapea foʻi, o le saofaga talafeagai o le faʻamaʻiina o fualaau faasaina ma le naunau i le ΔFosB induction vaaia i vailaʻau uma e tatau ona suʻesuʻeina.

O suʻesuʻega muamua e faʻaalia ai le faʻamaoaigaina o le siosiomaga i le taimi o atinaʻe atinaʻe ΔFosB i NAc ma dStr (Solinas et al., 2009; Lehmann ma Herkenham, 2011). O a matou faʻamaumauga o loʻo faʻaalia ai o lenei faaputuga e tupu tutusa i le D1-MSN ma le D2-MSN i itu eseese uma. O le faʻalautelega o faʻataʻitaʻiga na faʻaalia i le taimi muamua e faʻanoanoa ai le tauia ma le tali atu o le locomotor i cocaine (Solinas et al., 2009); peitaʻi, o lenei faʻasologa o amioga e foliga mai e le o se taunuuga o le faatupulaia o le ΔFOSB ona o le ΔFosB induction i D1-MSN naʻo ia na o le faʻaleleia ai tali o amioga i le cocaine, ae o le induction i D2-MSN e leai se faʻamatalaga iloga (Kelz et al., 1999; Colby et al., 2003; Grueter et al., 2013). O le taimi muamua o le taumafataga na muaʻi faaalia e siitia ai le ΔFosB i le NAc, ma le faʻaalia o le ΔFosB, pe na o le D1-MSN na o ia poʻo i lalo ifo foi, i le NAc e faʻaleleia ai le faʻasolosolo solo (Olausson et al., 2006; Wallace et al., 2008). O iinei, matou te maitauina ai le faatusatusaina o le ΔFosB i inumaga uma MSN i le NAc ma le dStr ina ua uma le inu ava malosi. Mulimuli ane, na matou faʻaalia i le taimi muamua, o le faʻavaeina o le ΔFosB i le NAc e faʻasalalau nisi tali talafeagai i le faʻatapulaʻa o le kalori e ala i le faʻaleleia atili o le faʻatinoina o meaʻai maualuluga ma faʻaititia ai tupe faʻaalu (Vialou et al., 2011). I le aotelega, o nei taunuuga e faaalia ai o le faaputuputuina o le ΔFosB i le NAc ma le dStr e tupu i le D1-MSN ma le D2-MSN i le tali atu i nisi taui faalenatura. O lenei sailiga o se mea e ofo ai ona o le matauina o le ΔFosB faʻapupula i le D1-MSN pe a uma le isi taui masani, o le uila faifai pea, ma o le faʻamalosagaina o le ΔFosB i le D1-MSNs o loʻo faʻaauau le uila ae o le ΔFosB overexpression i D2-MSN na faʻaitiitia ai le uila (Werme et al., 2002). Ae ui i lea, o le uili o le uila e mafai ona faʻagaoioia ni auala maʻoti vaʻaia, ia e nafa ma ona mamanu eseese ole atinaʻe o le ΔFosB. I soʻo se mea, o taunuʻuga ma isi taui masani e taʻu mai ai latou te pulea le eseʻese o le ΔFosB i le paʻu pe a faatusatusa i taui sili atu ona malosi, e pei o cocaine, EtOH, ma le Δ (9) -THC. ΔFosB induction i subispes MSN i lalo o nei tulaga masani tauia e ogatasi ma suʻesuʻega talu ai nei o loʻo faʻaalia ai lena faʻataʻitaʻiga mo se taui o mea taumafa ua faʻagaoioia uma subtypes MSN (Cui et al., 2013).

Faʻasalaga faʻasolosolo le faʻalavelave faʻaosoosoina le ΔFosB i le NAc shell o muse vaivai ma mafai ona faʻaaogaina ae na o le NAc na o ni mice e faʻaaogaina (Vialou et al., 2010). E le gata i lea, o le ΔFosB o le faʻamatalaga i D1-MSN e faʻaleleia ai le maufetuunaʻi pe a maeʻa ona faʻavaivaia faʻasalalau faʻaleaga tagata. O togafitiga masani i le fluoxetine e mafua ai foi le faaputuputuina o le ΔFosB i le NAc o le maaleale o le moa ma le gasegase vaivai ina ua mavae le faavaivaia o agavaʻa, ma le faaalia o le ΔFosB o le vavalalata i tali o amioga i lalo o tulaga mulimuli (Vialou et al., 2010). Mulimuli ane, o se suʻesuʻega talu ai na faʻaalia ai le ΔFosB induction i lalo ifo o le masini MSN ina ua maeʻa le faʻasaʻoga masani (Perrotti et al., 2004). Iʻuga o le suʻesuʻega o loʻo i ai nei, o loʻo tatou faʻaali atu ai le ΔFosB induction filifilia i le D1-MSN i mice ma le fluoxetine, ma filifili i le D2-MSN i mice faatosina, tuʻuina atu se malamalama taua i nei suʻesuʻega muamua ma lagolagoina le manatu o le ΔFosB i le D1- MSNs resilience and antidepressant action, ae o ΔFosB i D2-MSN e mafai ona faʻatalanoa le ono mafai. O isi galuega e manaʻomia nei e suʻe ai lenei manatu.

Galuega lata mai e faʻaaoga ai optogenetics o loʻo faʻaalia ai le malosi o le dopaminergic male glutamatergic afferents i le NAc i le faʻafetaui o taui ma faʻafitauli tali (tali iʻuga). Matou te faʻaogaina nei meafaigaluega e faʻataʻitaʻi ai le atinaʻe o le ΔFosB i le D1-MSN ma le D2-MSN ina ua uma ona toe faʻafouina le NAc afferent rohe. Na matou iloa o le faaosofia o le faaosofia o le VTA, poʻo le faʻamalosia o le tele o le kulutamatical neurons i amygdala, faʻaosoina ai le ΔFosB i D1-MSN i le NAc shell ma i both subtypes MSN i le NAc core. I le eseesega, o le faʻafouina o neo mPFC e maua ai le faʻafeagai o le atinaʻe o le ΔFosB, faʻatasi ai ma le maualuga o tulaga i le D1-MSN i totonu o le NAc matua, ae o le induction i subispes MSN uma ile motu o le NAc. Ma le mea mulimuli, o le faʻamalosia o le vailaau o le vHippo e mafua ai le faʻapitoa o le ΔFosB i D1-MSN i le NAc ma le atigi. O faʻamaoniga o mea o loʻo ogatasi ma suʻesuʻega talu ai nei na faʻaalia ai na fesoasoani i le hippocampal e sili atu le vaivai ile D2-MSN pe a faʻatusatusa i le D1-MSN (MacAskill et al., 2012) ma o nei mea e faʻaaogaina ai le siakiina o le cocaine-faʻaosoina (locomotion)Britt et al., 2012). E le gata i lea, o la tatou faʻamaoniga o le faʻaaogaina o le ΔFosB i le D1-MSN ma mea uma e ogatusa ma suʻesuʻega ua mavae e faʻaalia ai o le ΔFosB i D1-MSNs e faʻaleleia ai tali tali i fualaau faʻaleagaina faʻapea foi suʻesuʻega o le optogenetic stimulation of VTA dopamine neurons or of mPFC, amygdala, poʻo sui sui o le malo i le NAc faʻaleleia le taui (Kelz et al., 1999; Zachariou et al., 2006; Tsai et al., 2009; Witten et al., 2011; Britt et al., 2012; Grueter et al., 2013).

Ma le mea mulimuli, e foliga mai o loʻo i ai ni aʻoaʻoga faʻapitoa filifilia i totonu o nei subtypes e lua MSN e eseese le faʻaaogaina e ala i ni aʻafiaga lelei pe le lelei. O lenei mea e mafai ona faʻamatalaina mo le maitauina o le atinaʻe o le ΔFosB i le D2-MSN i nisi o faʻamanuiaga (faʻapipiʻi ma taui faʻapitoa) faʻatasi ai ma tulaga faʻaleagaina. O le Striatum e matua ese lava i tala atu o subtypes MSN, e aofia ai pusa ma matrix compartments i le pito i tua ma le alatele (Gerfen, 1992; Watabe-Uchida et al., 2012). E le gata i lea, o suʻesuʻega talu ai na faʻaalia ai le faʻaleleia o se laʻititi laʻititi o pasene o aʻoaʻoga o le neuroronal e psychostimulants, faʻatasi ai ma le faʻaleleia atili o le FosB gaʻo i totonu o nei gaʻo galue (Guez-Barber et al., 2011; Liu et al., 2013), e ui lava e le o iloa pe o nei gaioiga faʻaalia o D1-MSN poʻo D2-MSNs. O le faʻatinoga o le ΔFosB i le autu ma le atigi i le faʻasalalau o amioga faʻamalieina ma le faʻaleagaina e le o iloa foi. ΔFosB faʻamatalaga faʻaalia i D1-MSN na faʻateleina synapses lemu i totonu o le fatu ma le atigi, ae o le faʻaaliga i D2-MSN na faʻaititia ai le lemu filemu i totonu o le atigi (Grueter et al., 2013). E le gata i lea, o le ΔFosB induction i totonu ma le atigi e foliga mai o le aufaasālalau e auala atu i auala eseese, aʻo matou mauaina le cocaine-mediated CaMKIIa faamautuina o le ΔFosB i le atigi ae le o le autu e tau atu i le faateleina o le ΔFosB accumulation in shell (Robison et al., 2013). O suʻesuʻega i le lumanaʻi e faʻamoemoeina le faʻatulagaina o subtypes MSN i le autu ma le atigi, faʻaaogaina o faʻataʻitaʻiga, poʻo le patch i vaega matrix o le a fesoasoani e faʻamalamalamaina le matafaioi a le ΔFosB i totonu o nei itulagi eseese.

I le aotelega, o nei ituaiga masini faataamilosaga-o filifiliga filifilia o le ΔFosB i le NAc ua fautua mai ai o fuamalie tauleleia ma le malosi o le malosi e ese mai le vavaeeseina o NAc afferents ina ia inosia ai uiga faapitoa o nei fualaau. O a tatou taunuuga e le gata ina maua ai se malamalamaaga loloto i le amataina o le ΔFosB i vaega laiti o le MSN e mafua mai i mea masani ae o loo faaalia ai foi le aoga i le faaaogaina o le ΔFosB e avea ma faailoga sikola ina ia malamalama ai i le tumau o aafiaga o neural circuits faapitoa i le faatosinaina o le galuega NAc.

Faamatalaga Faʻamatalaga

O tusitala e leai se tauvaga tautupe tauva.

mau faasino

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