DeltaFosB Induction nyob rau hauv Striatal Medium Spiny Neuron Subtypes nyob rau hauv Teb rau Chronic Pharmacological, Emotional, thiab Optogenetic Stimuli (2013)

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

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

Tau qhov twg los

Department of Anatomy thiab Neurobiology, University of Maryland Lub Tsev Kawm Ntawv Tshuaj, Baltimore, Maryland 21201, Fishberg Department of Neuroscience thiab Friedman Lub Hlwb Lub Tsev Kawm Ntawv, Icahn Tsev Kawm Ntawv ntawm Cov Tshuaj ntawm Mount Sinai, New York, New York 10029, Saib Xyuas Kev Txawj Ntse thiab Pharmacology thiab Systems Therapeutics, Icahn School of Medicine rau Mount Sinai, New York, New York 10029, Department of Psychiatry, University of Texas Sab Qab Teb Kho Mob Center, Dallas, Texas 75390, Department of Pharmacology thiab Toxicology thiab Tshawb Fawb Lub Koom Txoos ntawm Addictions, State University of New York ntawm New York, New York 14214, thiab Institut National de la Santé et de la Recherche Médicale, U952, Lub Chaw Teb Xov Tooj Tsav Xwm Txheej, Chav Tsev Ua Tau Txais 7224, UPMC, Paris, 75005, Fabkis.

Abstract

Qhov tseem ceeb tshaj plaws, ΔFosB, yog muaj zog thiab pheej thab plab hauv kev mob ntsws los ntawm ob peb lub yeeb tshuaj, xws li kev siv yeeb tshuaj, kev siv tshuaj tiv thaiv, kev ntshaw nyiaj txiag, thiab kev nyuab siab. Txawm li cas los xij, cov kev tshawb fawb tau tshawb xyuas qhov teeb meem ΔFosB pib nyob rau hauv ob qhov nruab nrab qis qis neuron (MSN) subtypes. Peb siv cov fluorescent reporter BAC transgenic nas mus ntsuam xyuas qhov ΔFosB nyob rau hauv dopamine receptor 1 (D1) enriched thiab dopamine receptor 2 (D2) enriched MSNs hauv ventral striatum, nucleus accumbens (NAc) plhaub thiab core, thiab hauv dorsal striatum (dStr ) tom qab ntev raug ntau yam tshuaj yeeb los ntawm kev tsim txom xws li cocaine, ethanol, Δ (9) -tetrahydrocannabinol, thiab opiates; qhov tshuaj tiv thaiv kev puas hlwb, haloperidol; kev loj hlob rau menyuam yaus; haus dej cawv; calorie txwv; lub serotonin selective reuptake inhibitor antidepressant, fluoxetine; thiab kev ntaus kev ntxhov siab. Peb cov kev tshawb pom qhia tau hais tias muaj kev raug mob rau ntau hom kev ua rau ΔFosB hauv MSN-subtype selective qauv nyob thoob plaws peb cheeb tsam. Txhawm rau tshawb nrhiav qhov ΔFosB hauv qhov nruab nrab, peb siv optogenetics los txhim kho kev ua si hauv thaj chaw nruab nrab ntawm lub hlwb uas xa cov kev nkag mus rau hauv NAc synaptic; cov cheeb tsam no muaj xws li ventral tegmental cheeb tsam thiab ntau thaj chaw glutamateric hais tias: medial prefrontal cortex, amygdala, thiab ventral hippocampus. Cov kev mob uas zoo no ua rau cov qauv ntawm ΔFosB induction hauv MSN subtypes hauv NAc core thiab plhaub. Ua ke, cov kev tshawb no tsim cov qauv zoo ntawm ΔFosB induction hauv kev sib txuas lus MSN subtypes teb rau qhov stimuli ntev thiab muab kev pom tshiab rau hauv cov tswv yim ntawm kev sib cog lus ntawm ΔFosB induction hauv kev txheeb ze.

Introduction

Kev hnov ​​mob, nrog rau kev siv yeeb tshuaj, kev siv tshuaj tiv thaiv, kev nyuab siab, thiab kev zoo siab, ua rau muaj kev ruaj khov ntawm ΔFosB, ib yam khoom ntawm lub FosB noob, hauv kev txheeb ze (xws li, Hope li al., 1994; Hiroi thiab Greybiel, 1996; Hiroi li al., 1997; Moratalla li al., 1996; Perrotti li al., 2004, 2008; Muller thiab Unterwald, 2005; McDaid thiab al., 2006; Teegarden thiab Bale, 2007; Wallace li al., 2008; Solinas li al., 2009; Vialou li al., 2010, 2011; Kaplan li al., 2011). Qhov no tsub zuj zus tuaj yeem ua rau cov cai ntawm ob lub qe los ntawm ΔFosB hauv cheeb tsam lub hlwb (bidirectional regulation)McClung thiab Nestler, 2003; Renthal li al., 2008, 2009; Vialou li al., 2010; Robison thiab Nestler, 2011). Cov kab mob no muaj xws li (~ 95%) ntawm GABAergic projection medium spiny neurons (MSNs), uas tau muab cais ua ob qho hauv subtypes raws li lawv kev txhawb cov noob, xws li dopamine receptor 1 (D1) lossis dopamine receptor 2 (D2) (Gerfen, 1992; Graybiel, 2000; Lobo li al., 2006; Heiman li al., 2008) thiab los ntawm lawv cov kev sib txawv ntawm cov khoom sib txawv los ntawm cov kev teeb tsa los ntawm cov tsiaj txhu (Albin li al., 1989; Gerfen, 1992; Kalivas li al., 1993; Graybiel, 2000; Nicola, 2007; Smith et al., 2013). Tsis ntev los no, muaj ntau cov lus ceeb toom qhia tau hais tias cov haujlwm hauv Mauv Nyoog thiab cov haujlwm ntawm cov MSN subtypes hauv ventral striatum (nucleus accumbens [NAc]) thiab dorsal striatum (dStr) hauv kev kho kom haum xeeb thiab kev tsav tsheb (Lobo thiab Nestler, 2011; Gittis thiab Kreitzer, 2012).

Cov kev tshawb fawb yav dhau los tau pom tau tias ΔFosB yog qhov ua rau feem ntau hauv D1-MSNs los ntawm kev kho mob nrog cov neeg tsav tsheb khiav los sis cov kauj voos uas muaj keeb kwm yav dhau los, ib daim ntawv so ntawm ib qho khoom plig (Moratalla li al., 1996; Werme thiab lwm tus, 2002; Lee et al., 2006), whereas muaj kev tswj fwm tsis zoo rau qhov ΔFosB nyob hauv MSN subtypes (Perrotti li al., 2004). Tsis tas li ntawd, cov pov thawj los ntawm hom cell-type transgenic lossis cov kab mob kis tau tus kab mob viral-mediated qhia tias ΔFosB induction hauv D1-MSNs tsub kom muaj kev coj cwj pwm thiab kev ua kom muaj cocaine, kev coj tus cwj pwm zoo rau morphine, khiav khiav, khoom noj khoom haus, kev nyuab siab, whereas ΔFosB induction hauv D2-MSNs negatively tswj cov cwj pwm teb rau cov log khiav (Kelz li al., 1999; Werme thiab lwm tus, 2002; Colby li al., 2003; Olausson li al., 2006; Zachariou li al., 2006; Vialou li al., 2010; Grueter li al., 2013; Robison li al., 2013).

Muab lub luag haujlwm tseem ceeb rau ΔFosB hauv kev tswj cov kev mob siab ntev no, nrog cov teebmeem hauv D1-MSNs tiv D2-MSNs, peb tau ua qhov no ntawm txoj kev tshawb fawb ntawm ΔFosB induction hauv MSN subtypes los ntawm ob peb yam kev ua kom ntev, xws li mob ntev ntawm kev tsim txom, kev kho mob nrog tshuaj antipsychotic, muaj kev raug mob hloov kho thiab kev ua kom muaj zog, muaj kev sib raug zoo nrog kev nyuaj siab, thiab kev kho mob nrog kev kho mob antidepressant. Yuav kom nkag siab txog qhov kev teeb tsa ΔFosB hauv qhov nruab nrab ntawm ntau lub suab paj nruag lub hlwb, peb siv optogenetic yees kom pheej yig qhib lub cev hauv dopaminergic los yog glutamatergic hais lus paj hlwb thiab kuaj qhov tshwm sim ΔFosB induction hauv MSN subtypes. Peb cov qhabnias tau muab cov kev qhia tshiab rau qhov induction ntawm ΔFosB hauv D1-MSNs thiab D2-MSNs los ntawm kev ua kom ntev ntev thiab, thawj zaug, qhia qhov kev sib txuam ntawm Circuit Court ntawm ΔFosB hauv kev txheeb ze thiab hauv kev xaiv MSN subtypes.

Ntaub ntawv thiab kev

Tsiaj txhu.

D1-GFP or D2-GFP hemisygote nas (Gong li al, 2003) ntawm C57BL / 6 keeb kwm yav dhau los tau tswj tseg rau ntawm 12 h lub teeb tsaus nti nrog ad libitum zaub mov thiab dej. Tag nrho cov kev tshawb nrhiav tau ua raws li cov txheej txheem tsim los ntawm Institutional Animal Care thiab Siv Committee ntawm University of Maryland lub Tsev Kawm Ntawv ntawm Tshuaj thiab Icahn Tsev Kawm Ntawv ntawm Tshuaj ntawm Mount Sinai. Txiv neej nas (lub hnub nyoog 8 lub lim tiam) tau siv rau tag nrho cov kev sim. Tag nrho cov nas tsuag muaj perfused, thiab paj hlwb tau sau thaum tav su ntawm lub voj voog. Hemizygote D1-GFP thiab D2-GFP mice ntawm C57BL / 6 lossis FVB / N keeb kwm tau pom tias sib npaug rau cov tsiaj qus hom tsom nrog rau kev coj cwj pwm, physiology ntawm D1-MSNs thiab D2-MSNs, thiab kev tsim kho ntawm MSNs (Lobo li al., 2006; Chan et al., 2012; Nelson li al., 2012). Tsis tas li ntawd, tag nrho cov qauv ntawm ΔFosB qhov pom tshwm hauv txoj kev tshawb no yog piv nrog cov neeg pom hauv cov tsiaj qus hom tsiaj uas tsis yog hom cell-selective instruments (xws li, Perrotti li al., 2004, 2008).

Cocaine kev kho mob.

D1-GFP (n = 4 kev kho mob) thiab D2-GFP (n = 4 rau kev kho mob) cov nas tsuag tau txais 7 txhua hnub hauv kev lam tshuaj (xNUMX mg / kg) los yog 20% saline hauv lub tsev tawb. Rau 0.9 los yog 1 d cocaine (3 mg / kg), cov nas tsuag tau txais 20 los 6 ntawm 4% ntsev los tom qab 0.9 los 1 ntawm cov tshuaj yeeb yaj kiab. Tag nrho cov nas nyob perfused 3 h tom qab kawg kev txhaj tshuaj. Cov tshuaj no yog xaiv los ntawm cov kev tshawb fawb yav dhau los (xws li, Maze li al., 2010).

Kev kho mob Haloperidol.

D1-GFP (n = 3 lossis 4 rau kev kho mob) thiab D2-GFP (n = 4 rau kev kho mob) cov nas tau txais haloperidol (2 mg / kg) hauv dej haus, pH 6.0 (Narayan li al., 2007), lossis dej haus tsis tu ncua, pH 6.0, rau 3 lub lis piam (21 d). Cov nas nyob ntawm lub hnub 22.

Morphine kho.

D2-GFP nas (n = 4 lossis 5 rau kev kho mob) yog luv luv tshuaj loog nrog isoflurane thiab tau txais cov kab mob hauv cov kab mob morphine (25 mg) los yog cov khoob khoob khoob rau hnub 1 thiab hnub 3 raws li yav tas los tau qhia (Mazei-Robison li al., 2011). Cov nas nyob ntawm lub hnub 5.

Ethanol kho.

D2-GFP nas (n = 4 lossis 5 rau kev kho mob) tau raug 10% ethanol (EtOH), ib koob tshuaj C57BL / 6 tau pom tias haus (Yoneyama li al., 2008). Mice tau muab ob lub raj mis xaiv rau 10% EtOH (lub raj mis A) thiab dej (lub raj mis B), whereas D2-GFP ntawm cov dej tau txais nyob hauv ob lub hwj (lub raj mis A thiab B) rau 10 d. Tag nrho cov nas txais cov fwj dej ntawm EtOH tau pom zoo rau EtOH raws li xam los ntawm (100 × lub raj mis / lub raj mis (lub raj ntim hauv lub hwj / lub raj mis dej). Cov nas uas tau txais qhov 10% EtOH lub raj mis noj ntau dua EtOH piv nrog dej, whereas cov nas txais dej hauv ob lub hwj tsuas pom tias tsis muaj qhov txawv hauv cov dej ua kua. Hmo ntuj hnub 10, txhua tus nas tau muab dej haus rau haus thiab tau ua haujlwm rau hnub 11.

Δ (9) -tetrahydrocannabinol (Δ (9) -THC) kev kho mob.

D2-GFP (n = 3 rau ib txoj kev kho) cov nas tau txais cov tshuaj intraperitoneal ntawm Δ (9) -THC (10 mg / kg) lossis tsheb (0.9% saline nrog 0.3% Tween) ob zaug ib hnub rau 7 d (Perrotti li al., 2008). Mice tau ua kom zoo dua 24 h tom qab kawg kev txhaj tshuaj.

Cocaine kev tswj hwm tus kheej.

D2-GFP nas (n = 4 los yog 5 rau kev kho mob) tau pib kawm qib xaum rau 20 mg sucrose pellets nyob rau ntawm daim ntawv txhim kho 1 (FR1) kom txog thaum lub sij hawm txais tau 30 sucrose pellets noj rau 3 sib law liag hnub ua tiav raws li cov txheej txheem (Larson li al., 2010). Cov nas uas tau kawm txog qib xovxwm muaj kev phais mob nrog lub hauv catheter intravenous catheter los tso cai rau cov neeg siv tshuaj tua kab tom ntej. Ib lub lis piam tom qab phais, cov nas tau nkag mus rau kev tswj hwm tus kheej thaum lub caij 2 h txhua txhua lub caij nyob rau ntawm FR1 lub sij hawm txhawb. Cov khoom siv ntawm kev tswj tus kheej (Med Associates) tau txais kev pab cuam xws li cov lus teb rau lub zog ua haujlwm hauv tus xa (dhau 2.5s) ntawm cov yeeb yaj kiab (0.5 mg / kg / infusion ib qhov tseeb qib lever xovxwm), yog qhov lus teb rau cov qib tsis sib npaug twb tsis muaj qhov kawm tau. Cov nas ntiag tug ntawm tus kheej ua rau cov neeg ua yeeb yam rau ntawm lub sijhawm Fr1 hauv 2 h zaug, 5 d ib as thiv, rau 3 lub lis piam. D2-GFP cov nas uas tau txais 0.9% saline injections dhau lub sij hawm sib npaug tau siv los ua kev tswj hwm. Mice tau zoo kawg nkaus 24 tom qab cov neeg ua hauj lwm zaum kawg los sis cov khoom noj haus.

Heroin tus kheej tswj hwm.

Ua ntej tus nees ej nws tus kheej, D2-GFP nas (n = 4 rau ib txoj kev kho mob) tau kawm rau qib xovxwm rau chocolate pellets (BioServ, Dustless Precision Pellets) hauv xya 1 h txhua hnub. Cov nas uas tau kawm txog qib xovxwm muaj kev phais mob nrog rau cov tub ntxhais hlua tub rau hauv kab yas tso cai rau kev tso cai rau heroin intravenous. Ib lub lis piam tom qab kev phais, cov nas tau nkag mus rau kev tswj hwm tus kheej thaum lub caij 3 h txhua hnub ntawm kev caij Fr1 kev txhawb zog raws li cov txheej txheem txheej txheem (Navarro li al., 2001). Cov khoom siv ntawm tus kheej (Med Associates) tau txais kev pab cuam xws li cov lus teb rau ntawm lub zog ua tus xaij (tshaj 5 s) ntawm tus heroin (30 μg / kg / injection; NIDA Drug Supply Program), yog qhov lus teb rau ntawm lub cev qib tau tsis tau qhov teeb meem programmed. Tsiaj txhu tau muab nkag rau tus npoj nws tus kheej rau tus txheej txheem rau 14 d. D2-GFP cov nas uas tau txais 0.9% saline injections dhau lub sij hawm sib npaug tau siv los ua kev tswj hwm. Mice tau ua kom zoo dua 24 h tom qab kawg tus heroin los yog saline coj.

Kev tsim kho kom zoo rau cov menyuam yaus.

D2-GFP (n = 4 ib pawg) cov nas tau muab tso rau hauv ib qho chaw kawm zoo lossis muaj vaj tse nyob rau tom qab hnub 21 (P21) uas siv cov lus qhia los ntawm cov nas (Ntsuab li al., 2010). Lub chaw kawm zoo tshaj plaws yog muaj lub pob zeb loj tshaj plaws nrog kev ua kom khov kho (Andersons Laboratory bedding) uas muaj cov kev ua kom zoo nkauj xws li nas lub pob zeb, dome thiab cov log, cov khoom tawg, huts (Bio Serv), thiab lwm yam khoom ua si. Mice tseem nyob hauv cov vaj tse nyob rau 4 lub lis piam mus txog P50 thiab tau ua kom zoo dua.

Sucrose kev kho mob.

D2-GFP nas (n = 4 los yog 5 rau ib qho kev kho mob) tau muab ob lub raj mis xaiv rau 10% sucrose zoo ib yam li ib txoj kev kawm yav dhau los (Wallace li al., 2008). Mice tau muab 10% sucrose (lub raj mis A) thiab dej (lub raj mis B), whereas D2-GFP ntawm cov dej tau txais cov dej hauv ob lub fwj rau 10 d. Tag nrho cov nas txais kas phos tau pom muaj kev nyiam rau kev ua raws li suav los ntawm (100 × lub raj mis / lub raj mis Ib lub raj ntim + lub raj mis B). Cov nas uas tau txais qhov 10% sucrose lub raj mis siv ntau dua sucrose piv nrog dej, whereas cov nas txais dej nyob hauv ob lub hwj tsuas pom tias tsis muaj qhov txawv hauv cov dej ua kua. Hmo ntuj hnub 10, txhua tus nas tau muab dej haus rau haus thiab tau ua haujlwm rau hnub 11.

Calorie txwv.

D2-GFP nas (n = 4 rau cov genotype) mus dhau ntawm ib qho kev txwv tu laij (calorie restriction protocol), uas lawv tau txais 60% ntawm ad libitum calorie ntau ntau txhua hnub (Vialou li al., 2011) rau 10 d. D2-GFP tswj cov nas tau txais kev nkag mus rau chow. Nyob rau yav tsaus ntuj ntawm hnub 10, tag nrho cov nas tau txais kev nkag mus rau chow thiab tau ua tiav rau hnub 11.

Kev kov yeej kev ntxhov siab.

D2-GFP nas (n = 4 lossis 5 ib pawg) hauv 10 d ntawm kev sib tw kev nyuab siab raws li tau piav qhia yav dhau los (Berton li al., 2006; Krishnan li al., 2007). Mice tau raug rau txhawj xeeb CD1 retireders rau 5 min nyob rau hauv lub pob zeb loj heev. Cov nas nyob tom qab ntawd tau xoob 24 nyob rau hauv tib lub tawb ntawm sab nraud ntawm ib qho kev cais sib cais kom muaj kev sib txuas lus. Hnub tom qab cov nas tsuag tau tawm ntawm CD1 mouse tshiab nyob rau hauv tib lub sijhawm thiab vaj tse. Qhov no raug rov qab ua dua rau 10 d nrog CD1 tshiab txhua hnub. Kev tswj cov nas muaj tsev nyob hauv cov neeg mob zoo li tsis muaj kev nyuab siab. Mice tau sim rau kev sib raug zoo rau hnub 11. Mice tau raug kuaj thawj zaug rau lub sij hawm siv kev sib tham nrog ib lub tsho tshiab rau hauv lub thawv qhib teb tsis muaj lwm tus nas tam sim no (tsis muaj hom phiaj) thiab tom qab ntawd sim rau lub sijhawm siv nrog CD1 tus nas tshiab (hom phiaj) uas muaj nyob tom qab lub chamber (Berton li al., 2006; Krishnan li al., 2007). Mice tau muab cais ua rau cov neeg mob nyav lossis muaj zog thaum muaj cov kev txwv yav dhau los (Krishnan li al., 2007). Qhov no muaj tag nrho cov sij hawm siv nrog tus nas tshiab thiab qhov sib xyaw ua ke: (lub sij hawm siv nrog phiaj / lub sij hawm siv nrog tsis muaj hom phiaj) × 100. Qhov kev ntsuas no tau pom tias muaj kev paub tseeb tias cov neeg raug mob thiab cov neeg tsis muaj zog thiab muaj feem xyuam nrog lwm tus cwj pwm txawv (Krishnan li al., 2007). Txhua tus nas tau ua kom zoo dua 24 tom qab kev sib tham nrog kev sib raug zoo (48 h tom qab kawg kev sib tw rov qab).

Kev kho Fluoxetine.

D2-GFP nas (n = 3 lossis 4 ib pawg) tau txais 14 txhua txhua hnub hauv cov tshuaj fluoxetine (20 mg / kg) lossis tsheb (0.9% saline nrog 10% cyclodextrin)Berton li al., 2006). Mice tau ua kom zoo dua 24 h tom qab kawg kev txhaj tshuaj.

Stereotaxic phais.

D2-GFP cov nas tsuag yog cov tshuaj lom nrog ketamine (100 mg / kg) / xylazine (10 mg / kg), muab tso rau hauv cov cuab yeej me me, thiab lawv cov pob txha taub hau yog raug. Pebcaug-peb koob ntsuas koob txhaj tshuaj tau siv rau lub cev tsis muaj tshuaj tiv thaiv 0.5-1 μl, ntawm tus nqi ntawm 0.1 μl ib feeb, ntawm cov kab mob hauv ventral tegmental (VTA), hlwb prefrontal cortex (mPFC), amygdala, lossis ventral hippocampus ( vHippo). AAV [adeno-infected virus] -hsyn-ChR2 [channelrhodopsin 2] -EYFP los yog AAV-hSyn-EYFP tau muab tso rau hauv VTA ntawm D2-GFP nas (n = 5 ib pawg) ntawm stereotaxic coordinates (anterior-posterior, -3.3 mm; lateral-medial, 0.5 mm; dorsal-ventral, -4.4 mm, 0 ° angle). Qhov no tau ua raws li kev sib haum ntawm ob sab sib dhos (26-gauge), nrog ntev ntawm 3.9 mm, implantation dhau VTA (anterior-posterior, -3.3 mm; lateral-medial, 0.5 mm; dorsal-ventral, -3.7 mm)Koo li al., 2012; Chaudhury li al., 2013). AAV-CaMKII-ChR2-mCherry lossis AAV-CaMKII-mCherry raug txhaj rau hauv mPFC (n = 4 lossis 5 ib pawg), amygdala (n = 3 lossis 4 ib pawg), lossis vHippo (n = 3 lossis 4 ib pawg) ntawm D2-GFP cov nas tom qab ntawm implantation ntawm 105 μm ntev implantable optic fibers (Sparta li al., 2011). Cov kev tswj hwm muaj raws li nram no: mPFC (infralimbic twb tau tsom, tiam sis peb pom spillover ntawm cov kab mob rau thaj tsam ua ntej: sab nrauv-posterior, 1.7 mm; lateral-medial, 0.75 mm; dorsal-ventral, 2.5 mm, 15 ° angle) thiab optic fiber (dorsal-ventral, -2.1 mm); amygdala (basolateral amygdala raug tsom, tab sis peb pom spillover ntawm tus kab mob mus rau hauv lub plawv nruab nrab ntawm amygdala; anterior-posterior, -1.6 hli; lateral-medial, 3.1 mm; dorsal-ventral, 4.9 mm, 0 ° angle) thiab optic fiber ntau (dorsal-ventral, -4.9 mm); vHippo (ventral subiculum raug tsom, tab sis peb pom spillover tus kab mob rau lwm thaj chaw ntawm ventral hippocampus; anterior-posterior, -3.9 mm; lateral-medial, 3.0 mm; dorsal-ventral, xNUMX mm, 5.0 ° angle) thiab optic fiber (dorsal-ventral, -0 mm).

Optogenetic puag.

rau nyob rau hauv vivo kho qhov muag ntawm VTA neuronal firing, ib 200 μm core optic fiber ntau lub nplhaib tau hloov rau kev xa mus rau lub cannula. Thaum lub fiber tau ruaj ntseg rau lub cannula, qhov ntxeev ntawm txoj hlua ntev ~ 0.5 hli dhau lub cannula (Lobo li al., 2010; Chaudhury li al., 2013). Rau nyob rau hauv vivo kho qhov muag ntawm mPFC, amygdala, thiab vHippo neuronal firing, ib 62.5 μm split fiber ntau thaj qaum rau txuas rau lub taub hau ntawm cov pob fais fab (Sparta li al., 2011). Optic fibers tau txuas los ntawm lub FC / PC adapter mus rau 473 nm xia xia laser diode (Crystal Lasers, BCL-473-050-M), thiab lub teeb pulses generated ntawm ib tug stimulator (Agilent, 33220A). Rau VTA, xiav lub teeb (473 nm) phasic pulses, 20 Hz rau 40 ms (Chaudhury li al., 2013), tau xa rau 10 ib hnub dhau hnub 5 d. Rau mPFC, amygdala, thiab vHippo, xiav teeb (473 nm) pulses, 20 Hz rau 30 s, tau xa rau 10 ib hnub rau 5 d. Lub teeb me me tshwm sim nyob rau hauv lub tsev tawb, thiab tag nrho cov nas twb perfused 24 h tom qab lub xeem lub teeb stimulation.

Hauv vitro thaj-clamp electrophysiology.

Whole-cell recordings tau txais los ntawm VTA dopamine neurons los yog mPFC glutamatergic neurons hauv mob hlwb ntsej muag los ntawm cov nas uas muaj viruses sau saum toj no. Daim ntawv teev cov ntawv tau ua rau cov nas tsuag tsis tau nyob rau hauv vivo stimulation, tab sis nrog 1 d ntawm daim stimulation (1 d) los yog 4 d ntawm nyob rau hauv vivo stimulation thiab 1 d ntawm txoj kev npliag (5 d). Los txo cov kev nyuab siab thiab kom tau txais cov kabmob zoo, cov nas tau tso tshuaj loog tom qab coj mus rau hauv thaj chaw hauv electrophysiology thiab perfused rau 40-60 s nrog dej khov-txias aCSF, uas muaj 128 mm NaCl, 3 mm KCl, 1.25 mm NaH2PO4, 10 mm d-glucose, 24 hli NaHCO3, 2 mm CaCl2, thiab 2 mm MgCl2 (oxygenated nrog 95% O2 thiab 5% CO2, pH 7.4, 295-305 mOsm). Mob hlwb ntsej muag uas muaj mPFC los yog VTA raug txiav uas siv lub microsiler (Ted Pella) hauv txias sucrose-aCSF, uas tau muab los ntawm siab hloov NaCl nrog 254 mm sucrose thiab ua los ntawm 95% O2 thiab 5% CO2. Slices raug khaws cia hauv ib chav tuav nrog aCSF rau 1 h tom 37 ° C. Patch pipettes (3-5 MΩ), rau tagnrho-cell tam sim no, tau muaj cov kua hauv nrog cov nram qab no: 115 mm potassium gluconate, 20 mm KCl, 1.5 mm MgCl2, 10 mm phosphocreatine, 10 mm HEPES, 2 mm magnesium ATP, thiab 0.5 mm GTP (pH 7.2, 285 mOsm). Tag nrho cov xov tooj ntawm tes tau ua tiav kev siv aCSF ntawm 34 ° C (ndlwg = 2.5 ml / min). Cov teeb ciav hlau xia (20 Hz rau mPFC los yog phasic 20 Hz, 40 ms rau VTA) tau tsim los ntawm ib qho kev txhawb nqa ntawm lub FC / PC adapter rau 473 nm xm xiav laser diode (OEM) thiab xa mus rau mPFC thiab VTA daim ntawm 200 μm fiber ntau fiber ntau. Tam sim no-clamp thwmsim tau siv lub Multiclamp 700B amplifier, thiab cov ntaub ntawv tshaaj tau ua hauv pClamp 10 (Molecular Devices). Series ua hauj tau raug saib xyuas thaum lub sij hawm sim, thiab membrane currents thiab voltages tau lim ntawm 3 kHz (Bessel lim).

Immunohistochemistry.

Cov nas muaj anesthetized nrog chloral hydrate thiab perfused nrog 0.1 m PBS raws li 4% paraformaldehyde hauv PBS. Lub hlwb raug tom qab 4% paraformaldehyde dhau ib hmo thiab tom qab ntawd cyropreserved hauv 30% sucrose. Lub hlwb tau muab faib rau ib qho cryostat (Leica) ntawm 35 μm rau PBS nrog 0.1% sodium azide. Rau kev tiv thaiv kabmob, qhov raug muab xauv rau hauv 3% xauv npo nrog 0.01% Triton-X hauv PBS rau 1 h rau ntawm shaker ntawm chav tsev kub. Tshaj ntawd tau muab cov kabmob hauv cov tshuaj tiv thaiv kabmob hauv lub sijhawm thaum tsaus ntuj ntawm tus dej nyob hauv chav tsev. Cov tshuaj tiv thaiv siv tau ua raws li nram qab no: luav tshuaj tiv thaiv los ntawm FosB (1: 2000, catalog # sc-48, Santa Cruz Biotechnology), nas anti-NeuN (1: 1000, catalog #MAB377, Millipore), qaib los tiv thaiv GFP (1: 5000 , Catalog # 10-20, Aves), thiab luav anti-CREB (cAMP response element binding protein; 1: 1000, catalog # 06-863, Millipore). Hnub tom qab, tshooj tau yaug hauv PBS tom qab 1 nyob rau hauv cov tshuaj tiv thaiv kab mob ntxiv: khawm luav tiv thaiv Cy3, tus muas tua tsiaj Cy5, thiab dais anti-nqaij qaib DyLight-488 los yog Alexa-488 (Jackson ImmunoResearch Laboratories). Rau mCherry thiab tyrosine hydroxylase immunohistochemistry, cov kev sim tau ua raws li yav tas los tau piav (Lobo li al., 2010; Mazei-Robison li al., 2011). Tshooj raug rinsed hauv PBS, ntsia mus rau slides, thiab coverlipped.

Kev ntsuam xyuas thiab xov tooj ntawm tes.

Immunofluorescence raug saib ntawm Zeiss Axioscope lossis Olympus Bx61 confocal microscope. Xov tooj ntawm tes tau ua nrog ImageJ software. Cov duab thaij duab 1.42-1.1 ntawm NAc (tub ntxhais thiab plhaub) thiab dorsal striatum raug coj los ntawm 2 lossis 3 lub hlwb tshooj / tsiaj (saib Daim duab. 1A). Ib qho tag nrho ntawm 400-500 hlwb raug suav txhua lub hlwb hauv cheeb tsam ib tus nas siv 250 μm × 250 μm dluab. Cov hlwb raug suav nrog siv ImageJ software zoo ib yam li ib txoj kev kawm yav dhau los (Lobo li al., 2010). Kwv yees 400-500 tag nrho NeuN hlwb raug suav txhua lub paj hlwb hauv cheeb tsam ib tus nas, thiab ces tus GFP+, GFP+: ΔFosB+, GFP-, thiab GFP-: ΔFosB+ cov hlwb raug suav rau hauv txhua cheeb tsam. Cov ntaub ntawv tau ntsuas raws li nram no: (GFP+: ΔFosB+ neurons × 100%) / (tag nrho GFP+ neurons) thiab (GFP-: ΔFosB+ neurons × 100%) / (tag nrho GFP- neurons). Kev ntsuam xyuas tshwm sim tau ua siv GraphPad Prism software. Ob txoj kev ANOVAs tom qab Bonferroni cov ntawv xeem tau siv rau txhua tus neeg suav cov xov tooj.

Daim duab 1.  

Tus kab mob chwv xaiv ua kom zoo dua li ΔFosB hauv D1-MSNs hauv cheeb tsam txhawm. A, Striatal seem ntawm bregma + 1.42 rau + 1.10 tau siv rau kev suav cell. Image ntawm a D2-GFP section ntu qhia txog peb cheeb tsam ntawm kev kawm uas tau kawm: NAc core, ...

tau

ΔFosB yog qhov sib txawv ntawm qhov D1-MSNs thiab D2-MSNs tom qab tau raug ntau dua rau cov yeeb yam tiv thaiv haloperidol

Peb ua ntej soj ntsuam ΔFosB induction hauv MSN subtypes hauv D1-GFP thiab D2-GFP nas siv cov mob uas muaj kab mob yav dhau los pom tau hais tias yog vim li cas thiaj li induce ΔFosB protein hauv D1-MSNs (Moratalla li al., 1996). D1-GFP thiab D2-GFP BAC transgenic nas, uas nthuav qhia muaj zog ntsuab fluorescent protein nyob hauv D1 los yog D2 receptor noob (Daim duab. 1A), tau txais cov tshuaj intraperitoneal ntawm xiav (20 mg / kg) los yog saline rau 7 d, thiab paj hlwb tau muab 24 h tom qab qhov kawg txhaj tshuaj (Daim duab. 1B). Peb mam li ua kev tiv thaiv kabmob ntawm lub hlwb siv rau kev tiv thaiv tawm tsam NeuN, GFP, los yog FosB thiab cov cim hauv NAc core, NAc plhaub, thiab dStr (Daim duab. 1A,C). Whereas anti-FosB antibody lees paub tas-FosB thiab ΔFosB, ntau cov kev tshawb fawb siv Western blotting los yog immunohistochemistry tau paub tseeb tias ΔFosB yog tib txoj kev kuaj pom tam sim no ntawm 24 h tshem tawm lub sij hawm (piv txwv li, Perrotti li al., 2008). Yog li peb thiaj li siv 24 h los yog ntev dua ntawm lub sij hawm los sau cov paj hlwb tom qab tag nrho cov kev mob hauv txoj kev tshawb no los xyuas kom meej tias peb tsuas yog nrhiav tau ΔFosB. Vim tias cov kev sib tw MSNs muaj li ~ 95% ntawm tag nrho cov paj hlwb, peb siv cov tshuaj tiv thaiv NeuN los txheeb cov GFP- neurons, uas yog cov yeeb yaj kiab hauv MSN subtype rov qab (piv txwv li, D2-MSNs hauv D1-GFP nas thiab D1-MSNs nyob rau hauv D2-GFP nas). Peb pom tias D1-GFP Cov nas tsuag kho nrog cov yeeb tshuaj pom ib qho tseem ceeb induction ntawm ΔFosB hauv GFP+/ NeuN+ neurons (D1-MSNs) hauv NAc core, NAc plhaub, thiab dStr, whereas GFP-/ NeuN+ hlwb (D2-MSNs) tsis pom qhov tseem ceeb ntawm ΔFosB hauv txhua thaj tsam (Daim duab. 1D): ob txoj kev ANOVA, NAc core: tshuaj × cell hom F(1,12) = 16.41, p <0.05, Bonferroni post kuaj: p <0.01; NAc plhaub: tshuaj × cell hom F(1,12) = 12.41, p <0.05, Bonferroni post kuaj: p <0.001; dStr: tshuaj × hom cell F(1,12) = 12.07, p <0.05, Bonferroni post kuaj: p <0.01. Raws li cov kev tshawb pom no, peb tau pom hauv D2-GFP cov nas tsuag tsis tseem ceeb induction ntawm ΔFosB hauv GFP+/ NeuN+ neurons (D2-MSNs) tiam sis tseem ceeb induction ntawm ΔFosB hauv GFP-/ NeuN+ (D1-MSNs) nyob hauv txhua thaj tsam ntawm kev kho mob tom qab kev kho yeeb tshuaj (Daim duab. 1D): ob txoj kev ANOVA, NAc core: tshuaj × cell hom F(1,12) = 15.76, p <0.01, Bonferroni post kuaj: p <0.0001; NAc plhaub: tshuaj × cell hom: F(1,12) = 20.33, p <0.05, Bonferroni post kuaj: p <0.01; dStr: tshuaj × cell hom: F(1,12) = 35.96, p <0.01, Bonferroni post kuaj: p <0.001. Peb tau tshuaj xyuas cov kinetics ntawm ΔFosB induction hauv MSNs tom qab 1, 3, lossis 7 d ntawm cocaine (20 mg / kg, ip) kev txhaj tshuaj. Peb tau pom qhov tseem ceeb ntawm ductionFosB hauv D1-MSNs nrog 3 lossis 7 d kev kho mob cocaine piv nrog kev kho mob saline hauv txhua thaj tsam striatal (Daim duab. 1F): tus sawv cev ntawm tus qauv dStr; ob-txoj kev ANOVA, hom xov tooj ntawm × × hnub F(2,13) = 17.87, p <0.01, Bonferroni post kuaj: p <0.01, p <0.001. Qhov no yog raws li lub sijhawm kawm ntawm accumFosB txuam nrog hauv striatum pom ua ntej dhau los ntawm Western blotting (Hope li al., 1994) thiab lees paub tias qhov kev xaiv ntawm ΔFosB tsuas yog xaiv rau hauv D1-MSNs thoob plaws hauv ib chav kawm ntawm kev kis tau tus kabmob.

Peb tom ntej kuaj ΔFosB induction los ntawm immunohistochemistry hauv MSN subtypes tom qab mob raug rau haloperidol (Daim duab. 2). Ua ntej ua hauj lwm tau pom zoo tias tus mob haloperidol yuav ua rau induce ΔFosB nyiam hauv D2-MSNs (Hiroi thiab Greybiel, 1996; Atkins li al., 1999), txawm hais tias qhov no nws tau ua tsis tiav ncaj qha. D1-GFP thiab D2-GFP cov nas tsuag tau txais haloperidol (2 mg / kg) hauv cov dej haus, pH 6.0, whereas D1-GFP thiab D2-GFP tswj cov nas tau txais dej haus tsis tu ncua, pH 6.0, rau 21 d (3 lub lis piam) thiab paj hlwb tau sau rau hnub 22 (Daim duab. 2A). Raws li nrog yeeb yaj kiab, peb paub tias tag nrho cov FosB zoo li immunoreactivity nyob hauv kev ntsuas ntawm qhov teeb meem tam sim no sawv cev rau ΔFosB, tsis tag nrho ntev FosB (Atkins li al., 1999). Peb pom tias D1-GFP cov nas uas tau txais haloperidol pom tsis muaj qhov tseem ceeb ntawm ΔFosB hauv GFP+/ NeuN+ neurons (D1-MSNs) hauv NAc core, NAc plhaub, lossis dStr; txawm li cas los xij, kev nce qib hauv ΔFosB tau raug pom zoo hauv GFP-/ NeuN+ neurons (D2-MSNs) nyob hauv txhua thaj tsam (Daim duab. 2B,C): ob txoj kev ANOVA, NAc core: tshuaj × cell hom: F(1,10) = 23.29, p <0.05, Bonferroni post kuaj: p <0.01; NAc plhaub: tshuaj: tshuaj × cell hom: F(1,10) = 30.14, p <0.05, Bonferroni post kuaj: p <0.01; dStr: tshuaj × cell hom: F(1,10) = 37.63, p <0.001, Bonferroni post kuaj: p <0.0001. Qhov no tau lees paub los ntawm kev xeem ntawm D2-GFP Piv txwv: peb pom tias tseem ceeb induction ntawm ΔFosB hauv GFP+/ NeuN+ neurons (D2-MSNs) nyob rau txhua qhov peb cheeb tsam, tab sis tsis muaj kev hloov hauv ΔFosB hauv GFP-/ NeuN+ (D1-MSNs) tom qab siv tshuaj kho mob haloperidol (Daim duab. 2B,C): ob txoj kev ANOVA, NAc core: tshuaj × cell hom: F(1,12) = 24.30, p <0.05, Bonferroni post kuaj: p <0.05; NAc plhaub: tshuaj × cell hom: F(1,12) = 26.07, p <0.01, Bonferroni post kuaj: p <0.001; dStr: tshuaj × cell hom: F(1,12) = 21.36, p <0.01, Bonferroni post kuaj: p <0.01. Muab hais tias peb tau pom tus qauv zoo ib yam li ntawm ΔFosB induction hauv D1-MSNs los ntawm kev quav yeeb nyob rau hauv ob qho D1-GFP (GFP+/ NeuN+) thiab D2-GFP (GFP-/ NeuN+) nas, thiab los ntawm ntau dua haloperidol nyob rau hauv D2-MSNs nyob rau hauv D1-GFP (GFP-/ NeuN+) thiab D2-GFP (GFP+/ NeuN+) nas, qhov seem ntawm peb cov kev sim siv D2-GFP nas mus ntsuam xyuas ΔFosB induction hauv D1-MSNs (GFP-/ NeuN+) thiab D2-MSNs (GFP+/ NeuN+) tom qab lwm cov kev mob nkeeg tom qab.

Daim duab 2.  

Chronic haloperidol selectively induces ΔFosB hauv D2-MSNs hauv cheeb tsam txhim kho. A, Lub sij hawm kawm ntawm 21 d kho ntawm haloperidol (2 mg / kg, hauv dej haus) lossis dej. B, Immunohistochemistry ntawm NAc plhaub ntawm D1-GFP thiab D2-GFP nas tom qab haloperidol ...

Ua tus tswj, peb tau soj ntsuam cov CREB cov kev qhia hauv cov yeeb-tshuaj thiab haloperidol los txiav txim siab tias seb peb cov kev tshawb pom puas muaj feem xyuam rau lwm cov ntawv sau tseg (Daim duab. 3). Peb pom tsis muaj qhov sib txawv hauv CREB kev qhia ntawm kev tswj hwm thiab tshuaj tua tshuaj. Tsis tas li ntawd, peb pom tsis muaj qhov sib txawv ntawm CREB qib ntawm D2-MSNs thiab D1-MSNs (Daim duab. 3B,C).

Daim duab 3.  

Mob cocaine los yog haloperidol tsis induce CREB hauv MSN subtypes. A, Immunostaining rau CREB thiab GFP hauv kev txheeb ntawm D2-GFP cov nas tsuag tom qab cov kabmob lossis cov nqaij mob haloperidol (Daim duab. 1 thiab Thiab 22 legends rau kev kho mob tshuaj). Nplai bar, 50 μm. ...

Distinct qauv ntawm ΔFosB induction hauv MSN subtypes los ntawm cov tshuaj ntawm kev tsim txom

Vim tias cov kev tshawb fawb yav dhau los tau pom hais tias lwm cov yeeb tshuaj ntawm kev tsim txom muaj peev xwm ntxias ua rau ΔFosB hauv qis qis dua (Perrotti li al., 2008), peb soj ntsuam ΔFosB hauv MSN subtypes tom qab mob raug opiates, EtOH, lossis Δ (9) -THC. Peb ua ntej kuaj seb tus mob morphine raug induces ΔFosB hauv MSN MSN subtypes nyob thoob plawg thaj tsam. D2-GFP cov nas tsuag tau txais ob daim tawv nqaij ntawm cov txaj los yog morphine (25 mg) pellet rau hnub 1 thiab 3, thiab cov paj hlwb tau sau rau hnub 5 (Daim duab. 4A) thaum ΔFosB, tiam sis tsis yog FosB, yog vim li cas (Zachariou li al., 2006). Nyob rau hauv kev sib txawv ntawm cov yeeb yaj kiab, cov MSN subtypes tau pom ib qho tseem ceeb (thiab kwv yees li sib piv) nce hauv ΔFosB hauv NAc core, NAc plhaub, thiab dStr nyob rau hauv cov pab pawg neeg hu ua morphine piv nrog cov kab mob sham, tsis muaj qhov sib txawv cell cell induction ntawm ΔFosB pom thoob tag nrho thaj chaw (Daim duab. 4A): ob-txoj kev ANOVA; NAc tub ntxhais: tshuaj F(1,14) = 75.01, p <0.0001, Bonferroni post kuaj: p <0.01 (D2-MSN), p <0.001 (D1-MSN); NAc plhaub: tshuaj F(1,14) = 62.87, p <0.0001, Bonferroni post kuaj: p <0.01 (D2-MSN), p <0.05 (D1-MSN); dStr: tshuaj yeeb F(1,14) = 60.11, p <0.001, Bonferroni post kuaj: p <0.01 (D2-MSN), p <0.05 (D1-MSN).

Daim duab 4.  

Tshuaj ntawm kev tsim txom induce ΔFosB hauv MSN subtypes nyob rau hauv thaj tsam striatal. A, Kev kho mob morphine (25 mg pellets rau hnub 1 thiab 3) nyob rau hauv D2-GFP cov nas nyob hauv qhov tseem ceeb induction ntawm ΔFosB hauv MSN subtypes hauv NAc core, NAc plhaub, thiab dStr ...

Peb tom ntej no tau soj ntsuam tus qauv ntawm kev tshem tawm ntawm ΔFosB hauv MSN subtypes tom qab mob raug rau EtOH. D2-GFP cov nas tsuag tau muab ob lub raj mis xaiv rau 10% EtOH (lub raj mis A) thiab dej (lub raj mis B), whereas D2-GFP ntawm cov kav dej tau txais nyob hauv ob lub hwj (fwj A thiab B), rau 10 d thiab paj hlwb tau sau rau hnub 11 (Daim duab. 4B). Cov nas uas tau txais qhov 10% EtOH lub raj mis noj ntau dua EtOH piv nrog dej, whereas cov nas txais dej nyob hauv ob lub hwj tsuas pom tias tsis muaj qhov txawv ntawm cov kua (Daim duab. 4B): kev nyiam rau lub raj mis Ib pawg dej: 50.00 ± 4.551%, EtOH pawg: 84.44 ± 8.511%; Tub ntxhais kawm ntawv t kev sim, p <0.05. Chronic EtOH kev tswj hwm ua rau muaj qhov tseem ceeb ntawm ductionFosB xaiv zoo hauv D1-MSNs hauv NAc core, NAc plhaub, thiab dStr, nrog rau tsis muaj kev hloov pauv hauv D2-MSNs (Daim duab. 4B): ob txoj kev ANOVA, NAc core: tshuaj × cell hom: F(1,14) = 24.58, p <0.05, Bonferroni post kuaj: p <0.05; NAc plhaub: tshuaj × cell hom: F(1,14) = 36.51, p <0.01, Bonferroni post kuaj: p <0.01; dStr: tshuaj × cell hom: F(1,14) = 29.03, p <0.01, Bonferroni post kuaj: p <0.01.

D2-GFP Cov nas tseem raug kho nrog Δ (9) -THC (10 mg / kg, ip) ib hnub ob zaug rau 7 d, thiab paj hlwb tau sau 24 tom qab txhaj tshuaj kawg. Zoo ib yam li cov neeg mob Eco thiab EtOH, peb tau pom tias muaj ntau yam ntxiv hauv ΔFosB xaiv hauv D1-MSNs hauv txhua thaj tsam uas nyob hauv cov nas uas tau txais cov mob ntev (9) -THC (Daim duab. 3E): ob txoj kev ANOVA, NAc core: tshuaj × cell hom F(1,8) = 26.37, p <0.01, Bonferroni post kuaj: p <0.01; NAc plhaub: tshuaj × cell hom: F(1,8) = 44.49, p <0.05, Bonferroni post kuaj: p <0.001; dStr: tshuaj × hom cell F(1,8) = 29.30, p <0.05, Bonferroni post kuaj: p <0.01.

Peb tom ntej kuaj xyuas seb qhov pom ntawm ΔFosB tshwm sim nyob rau hauv MSN subtypes los ntawm tus neeg tshawb xyuas saib xyuas ntawm cov tshuaj los yog opiates tshwm sim nyob rau hauv cov ntsiab lus ntawm cov kabmob sib txawv uas yog cov nas ntawn lawv tus kheej qhov kev siv tshuaj. Ua ntej, D2-GFP cov nas tsuag tau txais kev kawm rau tus kheej-tswj kev ua yeeb dawb (0.5 mg / kg / infusion) ntawm lub sijhawm Fr1 rau 2 ha hnub rau 3 lub limtiam thiab paj hlwb tau sau 24 tom qab lub sijhawm dhau los (Daim duab. 4D), thaum ΔFosB, tiam sis tsis yog FosB, paub tias yog vim li casLarson li al., 2010). Mice siv ho ntau lub sij hawm nias lub cev tiv tiag tsis voos (Daim duab. 4D; Tub ntxhais kawm ntawv t kev sim, p <0.01). Qhov nruab nrab ib hnub twg ntawm cov neeg muaj yeeb yog 19.1 mg / kg pluaj (Daim duab. 4D), zoo ib yam li 20 mg / kg intraperitoneal koob siv saum toj no (Daim duab. 1). Ua ke nrog cov neeg tsis tuaj yeem ua rau tib neeg (Daim duab. 1), peb pom hais tias cocaine self-administration los ua rau ΔFosB tseem ceeb ntawm D1-MSNs hauv txhua thaj tsam uas piv rau cov dej ntsaws kabmob (Daim duab. 4D): ob txoj kev ANOVA, NAc core: tshuaj × cell hom F(1,14) = 21.75, p <0.05, Bonferroni post kuaj: p <0.01; NAc plhaub: tshuaj × cell hom: F(1,14) = 26.52, p <0.01, Bonferroni post kuaj: p <0.01; dStr: tshuaj × hom cell F(1,14) = 33.68, p <0.001, Bonferroni post kuaj: p <0.001. Ib yam li ntawd, zoo ib yam li noncontingent opiate (morphine) kev cuam tshuam (Daim duab. 4A), peb pom tias D2-GFP (30 μg / kg per infusion), ntawm lub sijhawm Fr1 3 hnub rau 2 lub lis piam soj ntsuam 24 h tom qab zaum kawg tshuaj, qhia tau tias tseem ceeb ΔFosB induction hauv D2-MSNs thiab D1-MSNs hauv txhua qhov kev sib tw thaj chaw (Daim duab. 4E): two-way ANOVA, NAc core: tshuaj F(1,12) = 68.88, p <0.001, Bonferroni post kuaj: p <0.01 (D2-MSN), p <0.05 (D1-MSN); NAc plhaub: tshuaj F(1,12) = 80.08, p <0.0001, Bonferroni post kuaj: p <0.01 (D2-MSN), p <0.001 (D1-MSN); dStr: tshuaj yeeb F(1,12) = 63.36, p <0.001, Bonferroni post kuaj: p < 0.05 (D2-MSN), p <0.05 (D1-MSN). Qhov nruab nrab niaj hnub txhaj tshuaj rau tus txiv neej yog 0.459 mg / kg, thiab nas tau siv sijhawm ntau dua los nias lub nquag tiv thaiv kev dhia tsis tsaug zog (Me Nyuam Kawm Ntawv lub t kev sim, p <0.05) (Daim duab. 4E).

Environmental enrichment thiab appetitive stimuli induce ΔFosB hauv D1-MSNs thiab D2-MSNs

Vim yav dhau los cov kev tshawb fawb pom tau tias cov txiaj ntsim thaum ntuj tsim tawm ΔFosB hauv cov cheeb tsam txhim kho (Werme thiab lwm tus, 2002; Teegarden thiab Bale, 2007; Wallace li al., 2008; Solinas li al., 2009; Vialou li al., 2011), nrog induction los ntawm log khiav xaj rau D1-MSNs (Werme thiab lwm tus, 2002), peb tau soj ntsuam seb puas yuav ua kom pom los ntawm lwm cov txiaj ntsim ntawm sab ntsuj plig tau qhia tias yog cellular specificity. Peb tau siv thawj zaug rau cov menyuam kawm ntawv D2-GFP cov nas tsuag muaj nyob rau hauv ib qho chaw ntawm cov nqaij npuas los ntawm lub cev (3 lub lis piam) rau lub caij xaum 4 (Daim duab. 5A). Qhov no yog ze tau pom los induce ΔFosB hauv nas NAc thiab dStr (Solinas li al., 2009; Lehmann thiab Herkenham, 2011). Piv nrog rau ib qho chaw zoo li qub, qhov chaw kawm tau zoo zuj zus ΔFosB hauv txhua cheeb tsam tseem ceeb, tab sis tsis ua li ntawd rau hauv hom qee hom, nrog rau kev pom zoo hauv D1-MSNs thiab D2-MSNs (Daim duab. 5A): two-way ANOVA, NAc core: ib puag ncig F(1,12) = 89.13, p <0.0001, Bonferroni post kuaj: p <0.0001 (D2-MSN), p <0.0001 (D1-MSN); NAc plhaub: ib puag ncig F(1,12) = 80.50, p <0.0001, Bonferroni post kuaj: p <0.001 (D2-MSN), p <0.001 (D1-MSN); dStr: ib puag ncig F(1,12) = 56.42, p <0.01, Bonferroni post kuaj: p <0.05 (D2-MSN), p <0.05 (D1-MSN).

Daim duab 5.  

Environmental enrichment thiab appetitive stimuli induce ΔFosB hauv MSN subtypes. A, D2-GFP nas uas tau muaj tsev nyob rau hauv ib qho chaw kawm zoo pib ntawm P21 rau 4 lub lis piam tawm induction ntawm ΔFosB nyob rau hauv ob qho tib si MSN subtypes thoob plaws tag nrho striatal ...

Peb tom ntej kuaj ΔFosB qhia hauv MSN subtypes tom qab kev ua kom muaj zog appetitive. Peb tau sim ua ntej cov teebmeem kev haus dej haus cawv, uas yog yav tas los qhia rau induce ΔFosB hauv nas NAc (Wallace li al., 2008). D2-GFP cov nas tsuag tau muab ob lub raj mis xaiv rau 10% sucrose (lub raj mis A) thiab dej (lub raj mis B), whereas D2-GFP ntawm cov kwj dej tau txais cov dej hauv ob lub hwj (lub raj mis A thiab B) rau 10 d thiab paj hlwb tau sau rau hnub 11 (Daim duab. 5B). Cov nas uas tau txais 10% sucrose noj ntau dua sucrose, whereas cov nas txais dej hauv ob lub hwj tsuas pom tias tsis muaj qhov txawv ntawm cov kua (Daim duab. 5B): kev nyiam rau lub raj mis A, dej: 50.00 ± 4.749%, sucrose: 89.66 ± 4.473%; Tub ntxhais kawm ntawv t kev sim, p <0.001. Peb pom tias kev noj sucrose mus ntev ua rau ΔFosB hauv NAc core, NAc plhaub, thiab dStr thiab qhov no tau tshwm sim hauv ob qho MSN subtypes (Daim duab. 5B): ob txoj kev ANOVA, NAc core: kev kho mob F(1,12) = 76.15 p <0.0001, Bonferroni post kuaj: p <0.01 (D2-MSN), p <0.01 (D1-MSN); NAc plhaub: kev kho mob F(1,12) = 63.35, p <0.001, Bonferroni post kuaj: p <0.05 (D2-MSN), p <0.01 (D1-MSN); dStr: kev kho mob F(1,12) = 63.36, p <0.001, Bonferroni post kuaj: p <0.01 (D2-MSN), p <0.05 (D1-MSN).

Thaum kawg, peb kuaj ΔFosB kev qhia hauv MSN subtypes tom qab calorie txwv vim qhov mob no, uas ua rau muaj kev ua rau lub cev muaj zog thiab muaj lub luag haujlwm, tau pom yav tom ntej kom txhim kho ΔFosB qib hauv nas NAc (Vialou li al., 2011). D2-GFP cov nas tau dhau los ntawm ib qho kev txwv ntawm kev siv calorie, uas lawv tau txais 60% ntawm ad libitum calories txhua hnub rau 10 d thiab paj hlwb tau sau rau hnub 11 (Daim duab. 5C). Calorie txwv ntau ntxiv ΔFosB theem hauv NAc core thiab NAc plhaub li yav tas los pom (Vialou li al., 2011) thiab tseem nce ΔFosB theem hauv dStr. Txawm li cas los xij, peb pom tsis muaj qhov sib txawv ntawm D1-MSNs tiv D2-MSNs (Daim duab. 5C): ob txoj kev ANOVA, NAc core: kev kho mob F(1,12) = 67.94 p <0.0001, Bonferroni post kuaj: p <0.01 (D2-MSN), p <0.01 (D1-MSN); NAc plhaub: kev kho mob F(1,12) = 67.84, p <0.0001, Bonferroni post kuaj: p <0.001 (D2-MSN), p <0.01 (D1-MSN); dStr: kev kho mob F(1,12) = 82.70, p <0.0001, Bonferroni post kuaj: p <0.001 (D2-MSN), p <0.001 (D1-MSN).

Chronic kev kev nyuaj siab ntxhov siab thiab kev kho mob antidepressant ua rau indial sib txawv ntawm ΔFosB hauv MSN subtypes

Peb yav tas los qhia tias ΔFosB raug nce hauv NAc ntawm nas tsuag tom qab kev puas siab ntsws kev nyuab siab heev (Vialou li al., 2010). Txawm tias qhov induction tau pom nyob rau hauv ob lub suab uas raug (cov uas qhia tias kev sib tw ntawm kev nyuab siab) thiab raws li cov nas uas muaj zog (cov neeg uas khiav tawm feem ntau ntawm cov teebmeem no), ΔFosB induction tau ntau dua nyob rau hauv cov resilient subgroup thiab tau qhia ncaj qha kom kho kom haum xeeb rau lub xeev muaj kev tiv thaiv. Hauv txoj kev tshawb nrhiav tam sim no, peb pom cov cwj pwm cellular tshwj xeeb rau ΔFosB induction ntawm ob pawg phenotypic. D2-GFP nas tsuag tau raug 10 d ntawm kev sib tw kev ntxhov siab sib txawv thiab sib cais ua rau neeg raug mob thiab muaj zog heev raws li kev ntsuas kev sib raug zoo (Daim duab. 6A), uas muaj correlates heev nrog lwm cov cwj pwm coj tus cwj pwm (Krishnan li al., 2007). Cov nas uas tsim cov cwj pwm coj zoo tom qab kev sib tw kev ntxhov siab tshwm sim tom qab kev sib txig sib txig ntawm ΔFosB hauv D2-MSNs hauv NAc core, NAc plhaub, thiab dStr piv nrog kev tswj thiab cov av ci ntsa iab, tsis muaj kev pom tseeb hauv D1-MSNs. Hauv kev sib txawv ntawm cov sib txawv, cov moj khaum ntawm cov xim tuaj yeem pom tias tseem ceeb ΔFosB induction hauv D1-MSNs thoob cov cheeb tsam sab nraud piv nrog cov neeg raug mob thiab tswj cov nas, tsis muaj kev pom tseeb hauv D2-MSNs (Daim duab. 6A; ob txoj kev ANOVA, NAc core: pawg × cell hom F(1,20) = 20.11, p <0.05, Bonferroni post xeem: D2-MSN / raug tau p <0.05, D1-MSN / tawv p <0.05; NAc plhaub: pab pawg × hom cell F(1,20) = 27.79, p <0.01, Bonferroni post xeem: D2-MSN / raug tau p <0.001, D1-MSN / tawv p <0.01; dStr: pawg × hom xov tooj F(1,20) = 19.76, p <0.01, Bonferroni post xeem: D2-MSN / raug tau p <0.05, D1-MSN / tawv p <0.01).

Daim duab 6.  

Chronic siab kev nyuaj siab ntxhov plawv thiab mob fluoxetine ua rau ΔFosB induction hauv MSN subtypes txawv hauv kev mob. A, D2-GFP uas raug rau 10 d dais ntawm kev sib tw kev sib raug zoo hauv kev nthuav qhia ΔFosB induction hauv D2-MSNs hauv txhua qhov kev hloov ...

Kev kho mob ntev kho nrog SSRI antidepressant, fluoxetine, hloov cov kev coj cwj pwm xws li kev pom zoo ntawm cov nas tsuag tom qab mob kev nyuab siab (Berton li al., 2006)). Ntxiv mus, kev kho mob zoo li ntawd ΔFosB hauv NAc ntawm kev muaj feem raug tswj tau zoo li kev tswj hwm nas, thiab peb tau qhia tias qhov induction yuav tsum muaj rau fluoxetine cov txiaj ntsig kev coj tus cwj pwm (Vialou li al., 2010). Peb thiaj li xyuas cov cellular yam ntawm ΔFosB induction tom qab kev tswj hwm fluoxetine. D2-GFP cov nas tsuag tau txais fluoxetine (20 mg / kg, ip) rau 14 d, thiab paj hlwb tau sau rau hnub 15 (Daim duab. 6B). Peb pom ib qho tseem ceeb induction ntawm ΔFosB hauv D1-MSNs, tab sis tsis nyob hauv D2-MSNs, nyob rau hauv cov nas fluoxetine kho nrog rau cov tsheb tswj (Daim duab. 6B; ob txoj kev ANOVA, NAc core: tshuaj × cell hom F(1,10) = 14.59, p <0.05, Bonferroni post kuaj: p <0.01; NAc plhaub: tshuaj × cell hom: F(1,10) = 26.14, p <0.05, Bonferroni post kuaj: p <0.01; dStr: tshuaj × hom cell F(1,10) = 8.19, p <0.05, Bonferroni post kuaj: p <0.001).

Nyob rau hauv vivo optogenetic manipulation ntawm NAc plaub lub suab paj nruag regions ua rau cov qauv ntawm ΔFosB induction hauv cheeb tsam striatal thiab MSN subtypes

Vim tias dopaminergic thiab glutamatergic hais lus siv rau NAc tuaj yeem pab txhawb qhov kev nrhiav thiab sib pauv kev coj tus cwj pwm zoo xws li (Tsai li al., 2009; Covington li al., 2010; Adamantidis li al., 2011; Witten thiab lwm tus, 2011; Britt li al., 2012; Lammel li al., 2012; Stuber li al., 2012; Chaudhury li al., 2013; Kumar li al., 2013; Tye thiab lwm tus, 2013), peb soj ntsuam ΔFosB induction hauv striatal MSN subtypes tom qab manipulating kev ua si ntawm ntau lub ntsiab lus hais hauv lub hlwb. Peb virally expressed ChR2 nyob hauv txhua qhov chaw ntau thiab tau txais lawv nrog xiav lub teeb (473 nm) raws li tau piav yav tas los (Gradinaru li al., 2010; Yizhar li al., 2011). Vim tias txoj kev tshawb no tsis ntev dhau los pom tias phasic stimulation nrog xiav lub teeb, tom qab tsis yog-cell-selective qhia ntawm ChR2 hauv VTA, ua rau tib yam cwj pwm phenotype li Xaiv Chr2 phasic stimulation ntawm VTA dopamine neurons (Chaudhury li al., 2013), peb qhia ChR2 siv AAV-hsyn-ChR2-EYFP hauv VTA ntawm D2-GFP nas nas; tswj cov nas tau txhaj nrog AAV-hsyn-EYFP. VTA seem tau coimmunostained nrog tyrosine hydroxylase thiab GFP rau pom tau tus ChR2-EYFP kev qhia (Daim duab. 7C). D2-GFP nas uas hais txog ChR2-EFYP los yog EYFP ib leeg nyob hauv VTA tau txais 5 ntawm 10 min ntawm xiav teeb phasic stimulation ntawm VTA raws li tau piav yav tas los (Koo li al., 2012; Chaudhury li al., 2013) (Daim duab. 7A), thiab cov paj hlwb tau sau 24 h tom qab qhov kev tsim tawm zaum kawg. Muaj tsis desensitization ntawm lub peev xwm ntawm ChR2 mus qhib VTA dopamine neurons tom qab 5 ntawm stimulation (Daim duab. 7B). Peb pom tau hais tias qhov kev ua qee zaum ua rau cov VTA neurons tshaj tawm ChR2-EYFP tuaj yeem ΔFosB nyob hauv MSN subtypes hauv NAc core, tiam sis tsuas yog hauv D1-MSNs hauv NAc plhaub (Daim duab. 7C; ob-txoj kev ANOVA, NAc core: optogenetic stimuli F(1,16) = 51.97, p <0.0001, Bonferroni post kuaj: p <0.001; (ob qho tib si ntawm MSN subtypes) NAc plhaub: optogenetic stimuli × cell hom: F(1,16) = 13.82, p <0.05, Bonferroni post kuaj: p <0.01). Peb tau pom tsis muaj qhov induction ntawm ΔFosB hauv dStr tom qab lub teeb xiav phasic stimulation mus rau VTA-qhia ChR2-EYFP piv nrog EYFP tswj. Cov txiaj ntsig no yuav tsum tau txhais nrog ceev faj, vim tias peb tsis tau xaiv lub hom phiaj VTA dopamine neurons rau kev kho qhov muag, thiab cov kev tshawb fawb tsis ntev los no tau qhia nondopaminergic projection neurons nyob rau hauv VTA zoo li muaj kev hloov kho qhov tseem ceeb ntawm VTA, uas tuaj yeem ua rau cov kev coj cwj pwm sib txawv nyob ntawm kev tua phom tsis thiab subpopulations ntawm neurons cuam tshuam (Tsai li al., 2009; Lammel li al., 2011, 2012; Witten thiab lwm tus, 2011; Kim et al., 2012, 2013; Tan thiab al., 2012; van Zessen li al., 2012; Stamatakis thiab Stuber, 2012; Chaudhury li al., 2013; Tye thiab lwm tus, 2013).

Daim duab 7.  

Optogenetic qhib lub hlwb hauv cheeb tsam uas tau txais qhov NAc ua rau cov qauv ntawm ΔFosB induction hauv MSN subtypes thiab cov cheeb tsam puag. A, Optogenetic stimulation paradigm rau tag nrho cov neeg mob. Lub hlwb raug tua 24 tom qab 5 d ntawm optogenetic ...

Peb tom ntej siv AAV-CaMKII-ChR2-mCherry thiab AAV-CaMKII-mCherry vectors los nthuav qhia ChR2-mCherry, lossis mCherry ib leeg tswj hwm, hauv mPFC, amygdala, lossis vHippo ntawm D2-GFP nas (Daim duab. 7D-F). ChR2 thiab mCherry qhia hais kom sib haum los ntawm CaMKII-ChR2 tus kab mob tau yav tas los tau pom tias yuav muaj kev cem nrog CaMKII qhov kev qhia, uas feem ntau cov lus glutamatergic neurons (Gradinaru li al., 2009; Warden et al., 2012). Peb qhib lub hlwb tawm ntawm ChR2 hauv cov cheeb tsam no nrog 20 Hz xiav lub teeb rau 10 ib hnub rau 5 d, thiab paj hlwb tau sau 24 h tom qab qhov kev sib tw kawg (Daim duab. 7A). Qhov kev xav ntawm qhov stimulation elicited ~ 27-33 Hz firing, vim yog vim qhov kev sib xyaw doublet. Tsis pom meej desensitization ntawm ChR2 tshwm sim nrog 5 d ntawm stimulation; Txawm li cas los xij, peb tau pom ib qho me ntsis nce tawm ntawm 1 mus rau 5 d (32-33 Hz) ntawm stimulation. Peb pom tias optogenetic ua kom cov mPFC neurons ua rau ΔFosB induction hauv D1-MSNs hauv NAc core, whereas ΔFosB induction tshwm sim hauv MSN subtypes hauv NAc plhaub (Daim duab. 7D; ob-txoj kev ANOVA, NAc core: optogenetic stimuli × cell hom F(1,14) = 10.31, p <0.05, Bonferroni post kuaj: p <0.01; NAc plhaub: optogenetic stimuli F(1,14) = 57.17, p <0.001, Bonferroni post kuaj: p <0.05 (D2-MSN), p <0.01 (D1-MSN)). Tsis muaj pauv dab tsi hauv levelsFosB qib tau pom nyob rau hauv dStr tom qab mPFC ua kom. Hauv kev sib piv, kev ua kom zoo ntawm amygdala neurons ntxias ΔFosB hauv ob MSN subtypes hauv NAc core, thiab xaiv hauv D1-MSNs hauv NAc plhaub, nrog tsis muaj kev hloov pauv hauv dStr (Daim duab. 7E; ob-txoj kev ANOVA, NAc core: optogenetic stimuli F(1,10) = 78.92, p <0.0001, Bonferroni post kuaj: p <0.001 (D2-MSN), p <0.0001 (D1-MSN); NAc plhaub: optogenetic stimuli × cell hom: F(1,10) = 30.31, p <0.0001, Bonferroni post kuaj: p <0.0001). Thaum kawg, qhov ua kom zoo ntawm vHippo neurons ua rau muaj qhov tseem ceeb ΔFosB induction tsuas yog hauv D1-MSNs hauv ob qho tib si NAc thiab NAc plhaub, nrog dua tsis muaj qhov hloov pauv hauv dStr (Daim duab. 7F; ob-txoj kev ANOVA, NAc core: optogenetic stimuli × cell hom F(1,10) = 18.30, p <0.05, Bonferroni post kuaj: p <0.01; NAc plhaub: optogenetic stimuli × cell hom: F(1,10) = 22.69, p <0.05, Bonferroni post kuaj: p <0.01).

kev sib tham

Txoj kev tshawb xyuas tam sim no soj ntsuam ΔFosB induction hauv D1-MSNs thiab D2-MSNs hauv thaj tsam striat tom qab ntau stimuli ntev (rooj 1). Peb xub tsim kom muaj kev siv tau D1-GFP thiab D2-GFP cov kab ntawv qhia kom pom tau zoo ΔFosB induction hauv D1-MSNs tom qab cov yeeb-tshuaj thiab tom D2-MSNs tom qab tus mob haloperidol. Cov kev tshawb nrhiav tau muaj raws li cov kev tshawb fawb dhau los (Moratalla li al., 1996; Lee et al., 2006) thiab lub luag hauj lwm tsim rau ΔFosB hauv D1-MSNs hauv kev txhawb nqa kev ua yeeb yam (Kelz li al., 1999; Colby li al., 2003; Grueter li al., 2013). Peb yav tas los tau qhia tias tus neeg tshawb nrhiav- thiab nws tus kheej muab cov tshuaj yeeb dawb to Induces ΔFosB mus rau qhov sib npaug ntawm NAc (Winstanley li al., 2007; Perrotti li al., 2008), thiab qhov tseem ceeb peb qhia no tias ob qho tib si ntawm cocaine kom induce ΔFosB selectively nyob rau hauv D1-MSNs nyob rau hauv tag nrho peb cheeb tsam striatal. Peb cov kev tshawb pom raws li yav dhau los cov kev tshawb fawb pom tias cov neeg ua hauj lwm cocaine induces lwm cov noob thaum ntxov thiab phosphorylation ntawm ntau cov pob txha ua paj hlwb hauv D1-MSNs (Bateup li al., 2008; Bertran-Gonzalez li al., 2008). Ib yam li, qhov txawv cov qauv ntawm ΔFosB induction tom qab mob haloperidol yog ib yam li qhov blockade ntawm no induction los ntawm D2 zoo li receptor agonists (Atkins li al., 1999), thiab nrog cov muaj mob haloperidol xaiv qhov pib ntawm cov noob keeb kwm ntxov thiab phosphorylation ntawm ob peb lub teeb liab protein hauv D2-MSNs (Bateup li al., 2008; Bertran-Gonzalez li al., 2008).

Cov lus 1.  

ΔFosB induction nyob rau hauv striatal MSN subtypes tom qab cov tshuaj pharmacological, siab ntsws, thiab optogenetica

Ua ke nrog cov yeeb tshuaj, peb pom tau tias muaj mob lwm yam tshuaj lom neeg raug tsim txom, EtOH thiab Δ (9) -THC, induces ΔFosB selectively hauv D1-MSNs thoob thaj tsam txhua cheeb tsam. Peb yav tas los qhia tias EtOH induces ΔFosB hauv NAc core, NAc plhaub, thiab dStr, tiam sis qhov Δ (9) -THC significantly upgrulates ΔFosB hauv NAc core, nrog ib txoj kev pom hauv lwm thaj tsam (Perrotti li al., 2008). Peb zoo sib xws ntawm no yog qhov loj tshaj Δ (9) -THC induction ntawm ΔFosB hauv NAc core hauv D1-MSNs; peb lub peev xwm los ua kom pom qhov sib txawv ntawm lwm cov cheeb tsam uas tau txhawj xeeb yog qhov yuav tshwm sim vim yog txoj kev ntsuam xyuas ntawm tes siv. Interestingly, morphine thiab heroin self-administration, tsis zoo li lwm cov tshuaj ntawm kev tsim txom, vim ΔFosB nyob rau hauv ob MSN subtypes rau ib tug sib piv li thoob plaws txhua thaj tsam striat. Txoj kev tshawb no tsis ntev dhau los pom tias cov kab mob morphine induces c-Fos hauv D1-MSNs, whereas naloxone-precipitated tshem tawm tom qab mob morphine induces c-Fos hauv D2-MSNs (Enoksson li al., 2012). Txawm hais tias peb tsis pom cov cim qhia ntawm kev tshem tawm ntawm peb txoj kev tshawb, nws yog qhov tshwm sim uas ntau dua maj mam tshem tawm tshwm sim nrog morphine los yog tus tswj hwm heroin thaum lub sij hawm kawm kawm yog lub luag hauj lwm rau ΔFosB induction hauv D2-MSNs pom ntawm no. Peb pom ntxov tias ΔFosB hauv D1-MSNs, tab sis tsis yog D2-MSNs, ua rau muaj txiaj ntsim zoo rau morphine (Zachariou li al., 2006). Nws yuav tam sim no yuav nthuav mus ntsuam xyuas tseem tias ΔFosB induction hauv D2-MSNs contributes rau cov teebmeem aversive opiate thim. Ib yam li ntawd, qhov yuav muaj txiaj ntsig ntawm kev siv tshuaj yeeb thim thiab tawm tsam ΔFosB qhov muag pom tag nrho cov tshuaj yuav tsum raug tshawb xyuas.

Cov kev tshawb fawb yav dhau los qhia tau hais tias ib puag ncig kev loj hlob thaum lub sij hawm txoj kev loj hlob tsom rau ΔFosB hauv NAc thiab dStr (Solinas li al., 2009; Lehmann thiab Herkenham, 2011). Peb cov ntaub ntawv qhia tau hais tias qhov kev txuam nrog tshwm sim hauv D1-MSNs thiab D2-MSNs thoob plaws txhua cheeb tsam. Cov kev ua tau zoo tshaj plaws yog qhia txog qhov txiaj ntsim zoo siab thiab cov lus teb rau cov neeg ua haujlwm rau cov yeeb yaj kiab (cocaine)Solinas li al., 2009); Txawm li cas los, qhov phenotype coj cwj pwm no yuav tsis yog qhov tsim nyog ntawm ΔFosB txam vim tias ΔFosB induction nyob rau hauv D1-MSNs ib leeg pab txoj kev coj tus cwj pwm rau cov yeeb yaj kiab, whereas xws li induction hauv D2-MSNs tsis muaj cov nyhuv discernible (Kelz li al., 1999; Colby li al., 2003; Grueter li al., 2013). Kev mob plab hnyuv ntxwm tau pom yav dhau los kom pom tau tias ΔFosB hauv NAc, thiab overexpression ntawm ΔFosB, xws li hauv D1-MSNs ib leeg los yog hauv ob qhov subtypes, hauv NAc zoo siv sucrose (Olausson li al., 2006; Wallace li al., 2008). Ntawm no, peb pom comparable ΔFosB induction hauv MSN subtypes india NAc thiab dStr tom qab sucrose haus. Thaum kawg, peb pom tau tias qhov pib ntawm ΔFosB nyob rau hauv NAc sib kho kom haum cov lus teb rau cov kev txwv kom muaj calorie los ntawm kev txhawb zog siab rau cov zaub mov muaj roj thiab txo kev siv zog (Vialou li al., 2011). Zuag qhia tag nrho, cov ntsiab lus tshwm sim qhia tau tias ΔFosB txuam hauv NAc thiab dStr tshwm sim nyob rau hauv ob qho tib si D1-MSNs thiab D2-MSNs teb rau ntau qhov kev ua tau zoo. Qhov kev tshawb pom no yog ib qho kev ceeb toom tias qhov kev soj ntsuam ΔFosB nyob hauv D1-MSNs tsuas yog tom qab lwm qhov khoom plig, qhov ntev log khiav, thiab qhov kev sib txeeb ntawm ΔFosB hauv D1-MSNs zoo log khiav qhov chaw ΔFosB overexpression hauv D2-MSNs diminished log khiavWerme thiab lwm tus, 2002). Txawm li cas los xij, lub lauj kaub khiav yuav qhib tau cov kev sib tw tshwj xeeb, uas yog lub luag hauj lwm rau nws cov qauv txawv ntawm ΔFosB. Nyob rau txhua qhov kev tshwm sim, cov txiaj ntsim tau zoo nrog lwm cov txiaj ntsim tau hais tias lawv tswj hwm ΔFosB hauv kev txheeb ze nrog kev siv yeeb tshuaj ntau ntxiv, xws li yeeb dawb, EtOH, thiab Δ (9) -THC. ΔFosB induction nyob rau hauv ob qho tib si MSN subtypes nyob rau hauv cov natural tej yam kev mob nqi zog no raws li ib txoj kev tshawb no tsis ntev los no uas qhia tau hais tias qhov pib ua rau kev noj mov ua rau ob qho tib si MSN subtypes (Cui li al., 2013).

Chronic kev nyuaj siab ntxhov plawv induces ΔFosB nyob rau hauv NAc plhaub ntawm cov nas uas raug cov kab mob thiab cov tshuaj tua kab mob tab sis nyob rau hauv NAc core tsuas nyob rau hauv cov nas tsuag (Vialou li al., 2010). Tsis tas li ntawd, ΔFosB overexpression hauv D1-MSNs txhawb kev muaj peev xwm tom qab muaj kev cuam tshuam nrog kev sib raug zoo ntawm kev sib raug zoo. Kev kho mob nrog cov tshuaj fluoxetine kuj ua rau ΔFosB txos hauv NAc ntawm cov nas tsuag daj thiab hauv cov nqaij ntshiv uas muaj kev ntxhov siab tom qab muaj kev nyuaj siab ntawm kev sib raug zoo, thiab ΔFosB overexpression tau qhia txog kev kho tus cwj pwm xws li antidepressant-cwj pwm hauv cov xwm txheej tom qab (Vialou li al., 2010). Thaum kawg, qhov kev tshawb fawb yav dhau los qhia tau tias ΔFosB pib nyob rau hauv ob qho tib si MSN subtypes tom qab qhov muaj kev ntxhov siab (Perrotti li al., 2004). Cov ntsiab lus ntawm txoj kev tshawb xyuas tam sim no, uas peb qhia ΔFosB induction selectively hauv D1-MSNs cov nas uas muaj zog thiab fluoxetine kho, tab sis selectively nyob hauv D2-MSNs hauv cov nqaij ntshiv, muab tswv yim tseem ceeb rau cov kev tshawb fawb ua ntej thiab txhawb qhov hypothesis uas ΔFosB hauv D1- MSNs kho cov kev ua haujlwm thiab kev kho mob antidepressant, yog tias ΔFosB hauv D2-MSNs tej zaum muaj kev ywj pheej. Cov hauj lwm ntxiv yog tam sim no xav tau los sim qhov kev ntsuam xyuas no.

Kev ua hauj lwm tsis ntev los no uas siv cov kev xaiv ua kom pom tau tias ua tau zoo ntawm dopaminergic thiab glutamatergic cov lus hais rau NAc hauv kev hloov kho cov nqi zog thiab kev ntxhov siab (saib Cov Ntsiab Lus). Peb siv cov cuab yeej zoo no los ntsuam xyuas ΔFosB induction hauv D1-MSNs thiab D2-MSNs tom qab rov ua dua ntawm thaj tsam NAc dua. Peb pom tias phasic stimulation ntawm VTA neurons, los yog ua kom yog glutamatergic neurons hauv amygdala, induces ΔFosB hauv D1-MSNs hauv NAc plhaub thiab hauv ob lub thawv MSN subtypes hauv NAc core. Hauv kev sib piv, kev ua ntawm mPFC neurons tau tshwm sim hauv cov qauv txawv ntawm ΔFosB induction, nrog ntau ntau hauv D1-MSNs hauv NAc core tab sis induction hauv MSN subtypes hauv NAc plhaub. Thaum kawg, optogenetic qhib rau ntawm vHippo neurons ua rau ΔFosB txuam nrog hauv D1-MSNs hauv NAc core thiab plhaub. Cov kev tshawb nrhiav vHippo zoo ib yam li cov kev tshawb fawb tsis ntev los no uas qhia tias qhov hippocampal inputs muaj zog li cas rau D2-MSNs piv nrog D1-MSNs (MacAskill li al., 2012) thiab hais tias cov kev cai tswjfwm no yog tswj cov neeg ua haujlwm yuam kev (yuam kev)Britt li al., 2012). Ntxiv thiab, peb cov kev qhia ntawm ΔFosB induction feem ntau nyob rau hauv D1-MSNs nrog tag nrho cov inputs raws li cov kev tshawb fawb dhau los qhia raws li qhia tias ΔFosB hauv D1-MSNs ua cov txiaj ntsim zoo rau cov tshuaj ntawm kev tsim txom thiab cov kev tshawb fawb qhia tau tias optogenetic stimulation ntawm VTA dopamine neurons los yog ntawm mPFC, amygdala, los yog vHippo terminals hauv NAc txhawb zog (Kelz li al., 1999; Zachariou li al., 2006; Tsai li al., 2009; Witten thiab lwm tus, 2011; Britt li al., 2012; Grueter li al., 2013).

Thaum kawg, nws yuav hais tias muaj kev xaiv cov neuronal ensembles hauv no ob MSN subtypes uas yog sib txawv ua kom zoo los ntawm kev zoo los yog tsis zoo. Qhov no yuav suav rau peb kev soj ntsuam ntawm ΔFosB kev qis hauv D2-MSNs hauv tej yam kev mob nqi (opiates thiab natural rewards) thiab cov aversive (kev sib tw). Striatum heev heterogeneous tshaj li MSN subtypes, nrog rau thaj thiab thaj chaw hauv matrix ob leeg dorsal thiab ventral striatum (Gerfen, 1992; Watabe-Uchida li al., 2012). Tsis tas li ntawd, cov kev tshawb fawb yav dhau los ua piv txwv txog kev ua kom muaj tsawg feem pua ​​ntawm cov kev ua kom nruab nrab ntawm lub cev ntaj ntsug los ntawm psychostimulants, nrog kev kho kom zoo ntawm qhov FosB noob nyob rau hauv cov activated neurons (Guez-Barber li al., 2011; Liu li al., 2013), tab sis nws tsis paub tias seb cov activated neurons yog D1-MSNs los yog D2-MSNs. Kev ua haujlwm ntawm ΔFosB hauv qhov tseem ceeb ntawm lub plhaub hauv kev sib hais kom muaj txiaj ntsim zoo thiab kev coj cwj pwm zoo yog qhov tsis paub. ΔFosB overexpression nyob rau hauv D1-MSNs muaj suab seev synapses hauv cov tub ntxhais thiab lub plhaub, tab sis kev qhia hauv D2-MSNs tsis sib thooj synapses hauv plhaub xwb (Grueter li al., 2013). Tsis tas li ntawd, ΔFosB induction hauv tub ntxhais tiv thaiv plhaub kuj yuav kho tau los ntawm ntau lub tswv yim, raws li peb pom muaj CMAine-mediated CaMKIIa stabilization ntawm ΔFosB hauv plhaub, tab sis tsis yog tseem ceeb ua rau ΔFosB ntau dua nyob hauv plhaub (Robison li al., 2013). Yav tom ntej cov kev tshawb fawb uas xaiv lub hom phiaj MSN subtypes nyob rau hauv core core plhaub, activated neuronal ensembles, los yog patch tiv tiag matrix compartments yuav pab txhais lub luag hauj lwm cwj pwm ntawm ΔFosB hauv cov cheeb tsam heterogeneous.

Zuag qhia tag nrho, cov kev sib txuam ntawm hom mob cell-selective induction ntawm ΔFosB hauv NAc hais tias kev txhawb zog thiab kev nyuab siab muaj kev txawv txav txawv txav cov NAc cov lus hais los ua kom muaj cov nta tshwj xeeb ntawm cov stimuli. Peb lub ntsiab lus tsis tsuas yog qhia rau kev pom ntawm ΔFosB hauv kev ua kom induction ntawm ΔFosB nyob rau hauv kev sib raug zoo ntawm cov tub ntxhais kawm ntawv hauv MSN stimuli, tiam sis kuj qhia txog lub chaw siv ΔFosB ua ib lub cim rau cov ntsiab lus ntawm cov teeb meem ntawm cov neural hauv kev cuam tshuam NAc kev ua haujlwm.

Tshooj ntawv

Cov sau phau ntawv tshaj tawm tsis muaj kev sib tw nyiaj txiag.

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