Mitemo yemasikirwo emitemo uye yemishonga Mutemo we Common Common Neural Plasticity Maitiro neAFosB seMurevereri Mukuru (2013)

Ichi chidzidzo chakaongorora mhedzisiro yemubairo wepabonde paDeltaFosB uye mhedzisiro yeDeltaFosB pane zvebonde uye mubairo. Iyo yakajairwa mamorekuru shanduko inozivikanwa kuti inoitika nekupindwa muropa nezvinodhaka yakawanikwa yakafanana nekuitika nebonde. Mune mamwe mazwi, DeltaFosB yakashanduka nekuda kwepabonde, asi zvinodhaka zvinotora nzira imwechete iyi. Izvi zvinogumisa gakava rekuti madhiragi emadhiragi akasiyana sei neanopindwa muropa nehunhu, uye kuti kupindwa muropa nehunhu kungori kumanikidzwa (chero zvoreva). Maseketi mamwe chete, mashandiro akafanana, shanduko dzakafanana dzemuma cell, maitiro akafanana anofambidzana- nemisiyano midiki

J Neurosci. 2013 Feb 20;33(8):3434-3442.

DZIDZIDZO YOSE

Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM.

mabviro

Dhipatimendi reAnatomy & Cell Biology, Schulich Chikoro cheMishonga uye Dentistry, Yunivhesiti yeWestern Ontario, London, Ontario N6A 3K7, Canada, Dhipatimendi reMolekyuli & Rakabatanidza Physiology, Yunivhesiti yeMichigan, Ann Arbor, Michigan 48109, Fishberg Dhipatimendi reNeuroscience uye Friedman Brain Institute, Mount Sinai Chikoro cheMishonga, New York, New York 10029, uye Madhipatimendi eNeurobiology uye Anatomical Sayenzi uye Physiology uye Biophysics, University of Mississippi Medical Center, Jackson, Mississippi 39216.

ngovepo

Zvinodhaka zvekushungurudza zvinoita kuti neuroplasticity mumugwagwa wemupiro wepanyama, kunyanya nucleus accumbens (NAc), zvichidaro zvinokonzera kukura uye kutaura kwekuita zvekuita zvekuita. Uchapupu huchangobva kupa hunoratidza kuti zvipo zvepanyama zvingaita kuti kuchinja kwakadaro kuNac, kureva kuti mishonga inogona kushandisa nzira dzepurasitiki dzakagoverwa nemaropafadzo ezvokwadi, uye kubvumira kushamwaridzana kwakasiyana pakati pemaropafadzo evanhu nemishonga.

Muchidzidzo ichi, tinoratidza kuti hutano hwepabonde mumakumbo evarume kana kuteverwa nenguva shoma kana kwenguva refu yekurasikirwa kwepabonde kunokonzera kukurudzira amphetamine mubairo, unoratidzwa nenzvimbo yakagadziriswa nzvimbo inofanirwa nehuwandu-dose (0.5 mg / kg) amphetamine. Uyezve, kutanga, asi kwete kwenguva refu, kuratidzira amphetamine mubairo kwakabatana nekuwedzera kwemazuva emadzinza emuDaint. Zvadaro, chikamu chakakosha chechinyorwa chechirwere ΔFosB muhutano hwepabonde-yakaita kuti amphetamine mupiro wemubairo uye kuwedzerwa kwakasanganiswa mumadzinza eDendritic pa NAc neurons yakagadzirirwa kushandisa hutachiona hwemajeni ekutengeserana wehutungamiri-husina kusunga musikana ΔJunD. Zvakare, zvakaratidzwa kuti ruzivo rwepabonde-rwakakonzerwa nemishonga yemishonga, ΔFosB, uye spinogenesis inobva mukubatana-induced dopamine D1 receptor activation mu NAc. Kuvharwa kwemapurisa kweD1 receptor, asi kwete D2 receptor, muAc panguva yekuita zvepabonde akaregererwa ΔFosB kutengesa uye kudzivirirwa kuwedzerwa spinogenesis uye kukurudzira amphetamine mubairo.

Tezvo, izvi zvinowanikwa zvinoratidza kuti zvinodhaka zvekushungurudzwa uye maitiro emararamiro emararamiro anobata pane maitiro evanhu mashoma nemasero epurasitiki anochengetedza kusagadzikana kudhakwa kwezvinodhaka, uye kuti kuwedzerwa kunetseka kunopindirana neAFosB uye zvinowanikwa pasi pezvinyorwa.

ziviso

Makomborero emhando yemararamiro uye mishonga yemishonga inoshandura pane imwe nzira inowanikwa neural neway, the mesolimbic dopamine (DA) system, iyo iyo nucleus accumbens (NAc) inonyanya kuita basa (Kelley, 2004). Zvinodhaka zvekushungurudza zvinokonzera neuroplasticity mumasolimbic system, iyo inobata basa rinoisa mukutendeuka kubva kushandiswa kwezvinodhaka kushandiswa kwezvinodhaka (Hyman et al., 2006; Kauer naMalenka, 2007; Kalivas, 2009; Chen et al., 2010; Koob uye Volkow, 2010; Wolf, 2010a; Mameli naLuscher, 2011). Yakave yakanyatsofungidzirwa kuti mishonga uye mibairo yezvisikwa haibvumiri neuroni imwechete mumasolimbic system, uye naizvozvo mishonga iyi inoshandura zvakasiyana uye inoshandura dunhu iri (Cameron uye Carelli, 2012). Zvisinei, zvave zvichinyatsojeka kuti zvikomborero zvepanyama nemishonga zvinokonzera mesolimbic system mune zvose zvakafanana uye nenzira dzakasiyana dzinobvumira kuwirirana pakati pemubairo wepanyama, kunyanya zvepabonde mubayiro, uye migumisiro yemishonga yekutsvaga (Frohmader et al., 2010a; Pitchers et al., 2010a; Olsen, 2011).

Kuita zvepabonde kunobatsira zvikuru (Tenk et al., 2009),

Izvi zvitsva zvinoratidza kuti zviitiko zvehupenyu uye zvemishonga zvinowanzogovana nzira dzinowanzoenderana neural neural plasticity, izvo zvinozoita kuti zvive nyore kukuvadza kushandisa zvinodhaka.

Chinangwa chekudzidza ikozvino chaiva chekutarisa nzira dzemagetsi dzinopindirana nehutano-huchiita hupurasitiki, iyo iyo inokonzera kukonzera mishonga yemubairo. Kunyanya, basa rezvinyorwa zvinyorwa ΔFosB yakatsvakurudzwa nekuti inobatanidzwa mumigumisiro yezvipo zvepanyama uye zvemishonga (Nestler et al., 2001; Werme et al., 2002; Olausson et al., 2006; Wallace et al., 2008; Hedges et al., 2009; Pitchers et al., 2010b). Mukuwedzera, basa reDopamine D1 receptors (D1R) nokuda kwehutano hwepabonde-yakaitwa neural plasticity yakaongororwa nokuti NAc ΔFosB induction uye yakawedzera musana wechipfuva pashure pokunge psychostimulant administration inoratidzwa muD1R-ine neurons (Lee et al., 2006; Kim et al., 2009) uye vanovimba neD1R kushandiswa (Zhang et al., 2002).

Pano, takashandisa viral vector-mediated kutaura wemunhu ane simba-asingasungiriri musungo weAFosB, diOlistic mazita, uye kushandiswa kwemasvomisitiri kuti aongorore pfungwa yokuti kuora mwoyo kunokonzera kusangana kwepabonde kunoteverwa nemubairo wekusagadzikana kweAmph kupa mubayiro kunopindirana ne D1R-inotenderera inductions yeAFosB muAc uye kuwedzera kwakatevera kweAc spine density. Pamwe chete, zvakawanikwa zvinopa uchapupu hwekuti zvipo zvepanyama uye zvemishonga zvinowanzogovana nzira dzinowanikwa neural neural plasticity, neAFosB semurevereri mukuru.

Zvinhu uye Nzira

Animals.

Mukuru wevarume (225-250 g paanosvika) uye mukadzi (210-220 g) Kuputika Dawley rats (Charles River Laboratories) vakagara munzvimbo dzePlexiglas muzvikamu zvakafanana zvepabonde pakati pezviongorori, pasi pekushisa uye mutemo wehutano uye pane 12 / 12 h chiedza / rima nerima uye zvokudya nemvura zvinowanikwa pachena. Madzimai echikadzi ekugadzirisa matanho aiva ovariectomized uye akagamuchira subcutaneous implants ane 5% estradiol benzoate (Sigma-Aldrich) uye injections ye500 μg yeprogesterone (mu 0.1 ml yeesameamu; Sigma-Aldrich) 4 h asati aedza. Mitemo yose yakagamuchirwa neImhuka yekuchengetedza uye Kushandisa Komiti dzeYunivhesiti yeWestern Ontario neYunivhesiti yeMichigan uye yakaenzanirana neCanada Council pamusoro pePil Care nekuNational Institutes of Health mirayiridzo inosanganisira mhuka dzakagadziriswa mukutsvakurudza.

Kuita zvepabonde.

Zvirongwa zvekuenzanisa zvakaitika munguva yekutanga kwemafu (pakati pe2 ne 6 h mushure mekutanga kwemazuva masikati) pasi pechiedza chiedza tsvuku, muzvidzidzo zvakachena zvekuongorora (60 × 45 × 50 cm). Nhave dzomukati dzakasungirirwa kuchinjwa panguva ye 4 kana 5 zuva nezuva. Zvikamu zvishanu zvakasarudzwa nokuti takamboratidza kuti iyi paradigm inokonzera kushandiswa kwenguva refu kwehupombwe (Pitchers et al., 2010b), kudarika-kukurudzira kuAmph kukwanisa kuita basa (Pitchers et al., 2010a), uye mubayiro (Pitchers et al., 2010a). Ejaculation yakasarudzwa semugumo wepurogiramu imwe yekugadzirisa nokuti isu takambozviratidza kuti inokosha kuti zvive nemigumisiro yehutano hwehupombwe paAmph kukwanisa kukurudzirwa (Pitchers et al., 2010a), izvo hazvina kuitika apo mhuka dzaibvumidzwa kuti dzibatane nevakadzi pasina kuratidzwa kwekudzivirira. Kuita zvepabonde zvipimo (kureva, latency kusvika pagomo rekutanga, intromission uye ejaculation, uye nhamba yezvikwata uye zvinyorwa) zvakanyorwa sezvakatsanangurwa kare (Pitchers et al., 2010b). Pamusana pekuedza kwose, mapoka evanhu vanoita zvepabonde akafananidzwa nenzira yekuita zvepabonde (nhamba yese ye ejaculations uye latency kusvika kune imwe nguva panguva yekugadzirisa chidzidzo chega). Mushure mechikamu chechishanu chekugadzirira, varume vakaramba vachigara pamwe chete nevarume vanoita zvepabonde uye havana kubvumirwa kuroorana panguva yekuita zvepabonde kwenguva 1, 7, kana 28 d. Mhuka dzakaramba dzisina zvepabonde dzakagadziriswa uye dzakagara mumakamuri akafanana nevanhurume vane zvepabonde. Mukuwedzera, kutonga kwevanhu vasina kuisa kwakaiswa munzvimbo dzakachena dzekuvhara kweawa imwe panguva ye 5 mazuva akatevera, pasina ruzivo rwevakadzi vanogamuchira.

ΔFosB kutaura.

Mhuka dzakanga dzakanyanyisa anesthetized (sodium pentobarbital; 390 mg / kg; ip) uye yakashandiswa zvisina kumira ne 50 ml ye 0.9% saline, yakatevera 500 ml ye 4% paraformaldehyde (Sigma-Aldrich) mu 0.1 m phosphate buffer (PB) yenguva chirevo uye DR inopikisa zvidzidzo. Ubongo hwakabviswa uye hwakasvibiswa nokuda kwe 1 h muchitsiko chemukati mune imwe yakagadzirisa, ndokuchengetwa pa 4 ° C mu 20% sucrose uye 0.01% sodium azide mu 0.1 m PB. Nokuda kwezvakaitwa neD DR zvinoshandiswa, ubongo hwakabviswa uye hukaita sagittal axis. Imwe hafu yakachengetwa muPB uye yakashandiswa kuDiOlistics, uye imwe yakashandurwa kuti ΔFosB. Zvikamu zveCoronal (35 μm) zvakagurwa nemhepo inotonhora (Microm H400R), inounganidzwa mune zvinyorwa zvina zvakafanana mu cryoprotectant solution (30% sucrose uye 30% ethylene glycol mu 0.1 m PB) uye yakachengetwa pa -20 ° C. Zvikamu zvisingasviki-zvakadzika zvakashambidzwa zvikuru ne 0.1 m PBS, pH 7.35, pakati pekudzivirirwa, uye matanho ose akanga ari kutonhorera. Zvikamu zvakaiswa kune 1% H2O2 (10 min) uye kuputira mhinduro (1 h; PBS ine 0.1% BSA, Fisher; uye 0.4% Triton X-100, Sigma-Aldrich). Zvimwe zvikamu zvakange zvichinyorwa usiku humwe pan-FosB rabbit polyclonal antibody (1: 5K; sc-48 Santa Cruz Biotechnology), yakambomirirwa (Perrotti et al., 2004, 2008; Pitchers et al., 2010b). Iyo pan-FosB antibody yakakwidziridzwa ichipesana nenzvimbo yemukati yakagovaniswa neFosB uye ΔFosB, uye yakambozivikanwa kuti inonyatso kuona ΔFosB maseru panguva dzeapo nguva dzakashandiswa muchidzidzo chino (> 1 d mushure mekukurudzira) (Perrotti et al., 2004, 2008; Pitchers et al., 2010b). Zvadaro, zvikamu zvakange zvakabatanidzwa mu biotin-conjugated goat anti-rabbit IgG (1 h; 1: 500 muPBS +; Vector Laboratories), avidin-biotin-horseradish peroxidase (1 h; ABC elite; 1: 1000 muPBS; Vector Laboratories) , uye 0.02% 3,3'-diaminobenzidine tetrahydrochloride (10 min; Sigma-Aldrich) ne 0.02% nickel sulfate mu 0.1 m PB ne hydrogen peroxide (0.015%). Zvikamu zvakaiswa paSuperfrost pamwe nemirasirasi egirasi (Fisher) uye yakavharwa ne dibutyl phthalate xylene.

Nhamba dzeAFosB-IR masero akaverengwa muAc shell uye nhengo mukati memamiriro ezvinhu akaenzana ekuongorora (400 × 600 μm) sezvakafanotaurwa kare (Pitchers et al., 2010b). Zvikamu zviviri zvakaverengwa neAc subregion, yakaenzana nemhuka. Mune nguva yekutsvaga kuongorora, nhamba dzeDFBB-IR masero dzakaratidzwa sechinyorwa chekuchinja kweboka rekutonga kwevanhu vasina nguva panguva yakakodzera yakatarwa uye kuenzaniswa pakati pevanhu vane ruzivo uye vasina maonero kune imwe nharaunda panguva imwe neimwe nguva nguva isina kushandisa t miedzo ine kukosha kwehuwandu hwe p <0.05. Mune ΔJunD-AAV uye DR antagonist kuyedza, nzira mbiri kana imwe-nzira ANOVA, zvichiteerana, uye nzira yeHolm-Sidak yakashandiswa. Uye zvakare, ΔFosB-IR maseru akaverengerwa mudorsal striatum (nzvimbo yekuongorora: 200 × 600 μm), nekukasira kune NAc uye padhuze neiyo lateral ventricle, mune mhuka dzese muDR anopikisa kuyedza. Imwe-nzira ANOVA uye t miedzo yakashandiswa kuenzanisa pakati pemapoka.

DiOlistics.

Nokuda kwenguva yechiratidzo uye ΔJunD viral vector kuongorora, rats dzakasvibiswa zvisina kuvhiringidzwa ne 50 ml saline (0.9%), inoteverwa ne 500 ml ye 2% paraformaldehyde mu 0.1 m PB. Ubongo hwakaparadzaniswa (100 μm kuronga) kushandisa vibratome (Microm) uye zvikamu zvakachengetwa mu 0.1 m PB ne 0.01% sodium azide pa 4 ° C. Kupfeka tungsten particles (1.3 μm mamita, Bio-Rad) ne lipophilic carbocyanine dye DiI (1,1'-dioctadecyl-3,3,3'3'-tetramethylindocarbocyanine perchlorate; Invitrogen) yakaitwa sezvakafanotaurwa (Forlano uye Woolley, 2010). DiI-akabatanidzwa tungsten particles akaiswa mumucheka pa 160-180 psi achishandisa Helios Gene Gun system (Bio-Rad) kuburikidza nefaira ne 3.0 μm pore size (BD Biosciences) uye yakabvumirwa kupararira kuburikidza neuronal membranes mu 0.1 m PB 24 h panguva yakadzivirirwa pa 4 ° C. Zvadaro, zvimedu zvakasimbiswa mu 4% paraformaldehyde muPB ye 3 h muchitonho chekupisa, yakashambidzwa muPB, uye yakaiswa mumakamuri akavharidzirwa (Bio-Rad) ne gelvatol ine anti-fading agent 1,4-diazabicyclo (2,2) octane ( 50 mg / ml, Sigma-Aldrich) (Lennette, 1978).

Dhii-akanyorwa neuroni aifungidzirwa achishandisa Zeiss LSM 510 m confocal microscope (Carl Zeiss) uye helium / neon 543 nm laser. Kune mhuka imwe neimwe, 2-5 neurons mune imwe NAC imwe neimwe, kana muhomwe (yakatarwa nenzvimbo maererano nemiganhu yepamusoro, kusanganisira inonzi lateral ventricle uye anterior commissure) muAJJD-AAV uye DR dzinopikisa zvidzidzo, dzakashandiswa kuwana nzvimbo ye kufarira pane yechipiri dendrite yepine quantification. Pamusoro peeuron imwe neimwe, 2-4 dendrites yakaongororwa kuti ienzanise dendritic yakareba urefu hwe40-100 μm. Zvikamu zveDendritic zvakatorwa uchishandiswa 40 × chinangwa chokudiridza mvura pa 0.25 μm nguva pfupi z-axis, uye mufananidzo we3D wakavakwazve (Zeiss) uye yakave yakagadziriswa (Autoquant X, Media Cybernetics) vachishandura (mapofu) uye zvinyorwa zvinonzi PSF zvakarongwa ne software. Utachiona hwepamusoro hwaive hunoshandiswa uchishandisa Filament module ye Imaris software package (version 7.0, Bitplane). Nhamba dzependritic spines dzakaratidzwa ne10 μm, yakaenzana neuroni imwe neimwe uye ipapo yemhuka imwe neimwe. Kusiyana kwezvakaitika kwakagadzirirwa kushandisa nzira mbiri dzeAOVAs munguva yekuongororwa kwedzidzo pakati pepabonde nevechizivo pane imwe nguva pfungwa (zvinhu: ruzivo rwepabonde uye NAc subregion) uye muAJunD kuedza (zvikonzero: ruzivo rwepabonde uye viral vector), uye imwe -kubva kune ANOVA munyaya yeD DR. Kutevedzera kweboka kwakaitwa nemutemo weHolm-Sidak ane chirevo chekukosha kwe p <0.05.

Nzvimbo yakagadzirirwa nzvimbo.

Icho chirongwa cheCPP chekuenzanisa chakanga chakafanana sezvakafanotaurwa kare (Pitchers et al., 2010a), achishandura makamuri matatu emagetsi (Med Associates), uye maitiro asina kukodzera, nekutarisana kwemajeri mamiriro ekuedzwa kwe d-Amph sulfate (Amph; Sigma-Aldrich; 0.5 mg / ml / kg sc inotarwa zvichienderana neshoko risina kubhadhara) mumakamuri maviri uye saline muimba isina kubhadharwa mumazuva akasiyana, uye akaitwa mukati mehafu yekutanga yechiedza chechiedza. Kudzora mhuka kwakagamuchirwa saline mumakamuri maviri.

Nhamba dzePPP dzakaverengwa pamhuka imwe neimwe seyo nguva yakashandiswa (mumaminitsi mashoma) muimba yepamhanho panguva yechipupuriro mushure mokufungidzira. Imwe nzira iyo ANOVAs uye nzira yeHolm-Sidak yakashandiswa kuenzanisa mapoka mumazuva ekutenda kuongororwa. Unpaired t kuedza nekukosha kunowanikwa p <0.05 yakashandiswa kuenzanisa Naive-Sal uye Naive Amph mukati meimwe nguva poindi panguva yekuyedza, uye mukati mega yega hutachiona vector kurapwa mune ΔJunD kuyedza. Munguva yekuyedza, imwe-nzira ANOVAs uye nzira yeHolm-Sidak yakashandiswa kuenzanisa mapoka ane ruzivo rwepabonde (Exp-Sal, 7 d Exp Amph uye 28 d Exp Amph), uye isina kubhadharwa t muedzo wakashandiswa kuenzanisa mapoka e2 neveive. Nzira mbiri yeAOVA uye nzira yeHolm-Sidak yakashandiswa kuenzanisa mapoka ese muDD inopikisa. Vaviri vasina kubhadhara t muedzo wakashandiswa kuenzanisa Naive-Sal neNaive Amph mapoka nehutachiona hwehutachiona hwehutachiona hwega (GFP kana ΔJunD), sezvo deta yaive yakasiyana-siyana mumapoka eAJU kuti abvumira ANOVA kuongororwa. Zvose zvinorehwa mazinga zvakagadzirirwa p <0.05.

Viral vector miedzo.

Male rats akanga anesheti ne ketamine (87 mg / ml / kg; ip) uye xylazine (13 mg / ml / kg ip), akaiswa mune zvigadzirwa zve stereotaxic (Kopf Instruments), uye akagamuchira michina inokonzerwa nemakemikari adeno-anokonzerwa neviral vectors encoding GFP chete (green fluorescent protein), kana kuti DNA (inonyanya-kusunga musikana weAFosB) neGFP, kupinda mu NAc (mazano: AP + 1.5, ML ± 1.2 kubva ku bregma; DV -7.6 kubva padhehenya), mubhuku re1.5 μl / hemisphere pamusoro pe7 min kushandisa siramende yeHamilton (Harvard Apparatus). DHDD inoderedza ΔFosB-kupindirana kwepakati nekukwikwidzana hterodizeri neAFosB saka nekudzivirira kusunga kweAFosB kune AP-1 munharaunda mukati mekusimudzira zvikamu zvezvinangwa zvemajeni (Winstanley et al., 2007; Pitchers et al., 2010b). Kunyange zvazvo IJUN inosunga nehukama hwepamusoro neAFosB, zvinokwanisika kuti zvimwe zvezviitiko zvinocherechedza zveAJUN zvinogona kupindirana nekudzivirira dzimwe AP-1 mapuroteni. Zvisinei, zvinoratidzika kuti ΔFosB ndiyo inonyanya kushandisa pro-1 protein inoratidzwa pasi pemamiriro ezvinhu akaedzwa (Pitchers et al., 2010b). Pakati pe3 nevhiki ye4 gare gare, mhuka dzakagamuchira ruzivo rwepabonde panguva ye 4 inokwidziridzana maitiro kana kuti yakaramba isina ruzivo kuumba mapoka e4: GFP yepabonde, zvekuita zvepabonde GFP, zvekuita zvepabonde DHD, uye vane ruzivo rwepabonde ΔJunD. Chiitiko chepabonde chakakonzerwa neC4 inopesana zuva rega rekusangana. Mhuka dzakaedzwa kuCPP uye diOlistics. Kuongorora kwejeri nzvimbo kwakaitwa sezvakatsanangurwa kare (Pitchers et al., 2010b). Nac zvikamu (coronal; 100 μm) zvakasarudzwa-maitiro eGFP (1: 20,000; rabbit anti-GFP antibody; Invitrogen). Kupararira kwehutachiona kwaive kwakanyanya kune chikamu chikamu cheNac, uye kuwedzerwa kupararira kusvika pamusoro.

D1R / D2R vanopikisa.

Makuve evanhu akange anestitizedeki neine intraperitoneal injection (0.1 ml / kg) yeketamine (87 mg / ml) uye xylazine (13 mg / ml), ndokuiswa mune zvigadzirwa zve stereotaxic (Kopf Instruments). Bilateral 21-gauge guide cannulas (Plastics One) yakaderedzwa kuenda kuNac pa AP + 1.7, ML ± 1.2 kubva bregma; -6.4 DV kubva padhehenya uye yakachengetedzwa nemazino acrylic, akabatanidzwa kune zvidzidzo zvitatu zvakaiswa muhenya. Mhuka dzakashandiswa zuva rega rega kuti dzigadziriswe pakugadzirisa zvirongwa munguva ye2 yevhiki yekudzikinura. Maminitsi gumi nemashanu asati atanga imwe neimwe yeZ4 zuva nezuva yekugadzirisa zvirongwa nekuisa mukadzi anogamuchira, mhove dzomukati dzakagamuchira michina ye microikections yeD1R mutsigiri R (+) SCH-23390 hydrochloride (Sigma-Aldrich), D2 receptor (D2R) mutsigiri S- ( -) eticlopride hydrochloride (Sigma-Aldrich) yakanyungudzwa muhuori husina kuchena (0.9%; imwe neimwe pa 10 μg mu 1 μl pa hemisphere; yakaparadzwa mu 0.9% saline), kana saline (1.0 μl per hemisphere), pakuyerera kwe1.0 μl / min pamusoro pe1 min interval yakatevera ne 1 min ne cannula yerojoya yakasiyiwa panzvimbo yekuparadzirwa kwezvinodhaka. Nhamba yejoyi iyi inobatanidza zvose zviri mukati nehombodo, sezvo infusions ye0.5 μl inongorongedzwa kugobvu kana kumativi akadzika (Laviolette et al., 2008). Dhawiti dzaive dzakavakirwa pane zvidzidzo zvekare zvakaratidza kuti idzi kana kuti madhesi mashoma akabatana nemishonga kana mararamiro emararamiro emhuka (Laviolette et al., 2008; Roberts et al., 2012). Kudzora varume vakaramba vachiita zvepabonde asi vakagamuchira intra-NAc saline vasati vagoiswa muchitoro chisina maturo, panguva ye 4 zuva nezuva. Imwe vhiki mushure mekusangana kwekupedzisira kana kugadzirisa chirongwa, varume vakayerwa Amph CPP, uye musana uye ΔFosB kuongororwa. Kushandiswa kwezvikamu zvina, panzvimbo yezvidzidzo zvishanu sezvimwe mune zvimwe zviitiko, zvakasarudzwa kuti zvibvise kukanganisa kwakawandisa kuAc inokonzerwa nekudzokidzwa kwechirwere uye nekudaro kubvumira musana uye ΔFosB kuongorora. Zvechokwadi, kukanganisa kwakanga kusingaoneki, uye kuongorora kwepemusoro uye ΔFosB mu NAC yemhuka yakakonzerwa nesarine yakaratidza zvimwe zvakafanana nedzimwe dzisina kukanganisa mumapoka ekutsvaga kwekare. Nzira mbiri yeAnOVA neHolm-Sidak nzira ine kukosha yakatemwa p <0.05 yaishandiswa kuona chiitiko chebonde-chakakonzera kufambisa maitiro epabonde.

Results

Zvepabonde zvakagadziriswa -AFosB kuregererwa kunogara kwenguva refu

Chokutanga, kuwirirana kwepakati pakati pepabonde kuonekwa-kunokonzerwa kushandiswa kweAFosB kutaura, dendritic spines mu NAc, uye Amph-CPP dzakagadziriswa, kunyanya pashure penguva pfupi uye kwenguva refu yokurega zvepabonde (7 kana 28 d). Pakupedzisira, zvakaratidzwa kuti ruzivo rwepabonde rweZ5 zuva nezuva kuenzanisa zviitiko zvakakonzera kuunganidza ΔFosB mukati mezisolimbic system, kunyanya mu NAc (Wallace et al., 2008; Pitchers et al., 2010b). Mune zvidzidzo izvi zvakapfuura, DFFB dzakaenzana mukati me1 d mushure mekuita zvepabonde, uye yakanga isingazivikanwe kana ΔFosB kuunganidza yakaenderera mberi mushure mekunge kwenguva yakareba yemubairo wekusagadzikana. Vanhurume vanoita zvepabonde vakashandurwa 1, 7, kana 28 d mushure mekupedzisira kwemasangano ekugadzirisa kwezuva rimwe nerimwe e5, panguva iyo varume vakatevedzera kune rimwechete. Kuita zvepabonde kusina maturo kwakakonzerwa panguva imwechete paya mushure mekupedzisira kwe5 zuva nezuva. Nhamba dzeAFosB-IR masero muAc shell uye nheyo dzaive dzakakwirira kudarika kutonga zvepabonde pasina nguva dzose panguva dzese (Fig. 1A, shell; 1 d, p = 0.022; 7 d, p = 0.015; Fig. 1B: core; 1 d, p = 0.024; 7 d, p <0.001; 28 d, p <0.001), kunze kweiyo NAc shell mushure me28 d kurega (p = 0.280). Nokudaro, DFFB inotenderera inopfuurira panguva yekusara shure kwehutano hwepabonde kwenguva inenge ye28 d.

Mufananidzo 1.      

Tarisa chikwata chikuru:      

Mufananidzo 1.      

Chiitiko chepabonde chakakonzera kuwedzera nokukurumidza kwehuwandu hweAFosB-IR masero. Fold shanduko yenhamba yeAFosB-IR masero muA NA shell (A) uye nheyo (B) muzviitiko zvepabonde (madema) mhuka zvichienzaniswa nevepabonde (white) controls (n = 4 boka rimwe nerimwe). Dhiyabhorosi ndiro boka rinoreva ± SEM. *p <0.05, musiyano wakakura uchienzaniswa neasina simba kutonga. Mumiriri wemifananidzo yeNaive 1 d (C), Exp Exp 1 d (D), Exp Exp 7 d (E), uye exp 28 d (F). ac, anterior commissure. Nhamba yezinga, 100 μm.

Kuita zvepabonde kunowanikwa-kuwedzeswa kwekuwedzera mu dendritic spines kunopera

Pitchers et al. (2010a) yaimbove ichishandiswa ichishandisa Goggi michina yekusagadzirisa kuti hutano hwepabonde hwakatungamirirwa ne 7 d, asi kwete 1 d, yekuregererwa kwemubairo kwakakonzerwa zvikuru kuwedzerwa dendritic branching uye nhamba yezinonzi dendritic spines pa NAc shell uye core neurons (Pitchers et al., 2010a). Pano, spinogenesis mune zvepabonde uye vakadzi vane ruzivo vakaongororwa kana 7 d kana 28 d mushure mokunge mushure mokugadzirisa. Izvo zvitsva zvinowanikwa uchishandisa diOlistics nzira yekucherechedza yakatsigira kuti ruzivo rwepabonde rwakazotevera nehuwandu hwepabonde hwepabonde hwe 7 hwakawedzera huwandu hwezvinyorwa zve dendritic (F(1,8) = 9.616, p = 0.015; Fig. 2A-C). Kunyanya, nhamba ye dendritic spines yakanyanya kuwedzera mu NAc shell uye nheyo (Fig. 2A: shell, p = 0.011; core, p = 0.044). Zvisinei, izvi zvakawedzera kuwedzera kwepfungwa zvakaderera uye hazvisati zvaonekwa mushure mokunge kwenguva refu nguva yekuita zvepabonde nguva ye28 d mune NAC subregion (Fig. 2B).

Mufananidzo 2.      

Tarisa chikwata chikuru:      

Mufananidzo 2.     

Chiitiko chepabonde chakakonzera kuwedzera kwenhamba ye dendritic spines mu NAC uye kukurudzira Amph kupa. A, B, Nhamba ye dendritic spines mu NAc shell uye nhengo ye 7 d (A) kana 28 d (DB yevanhu vanoita zvepabonde [vachena] uye vane ruzivo [mhuka] yakasviba; n = 4 kana 5). Dhiyabhorosi ndiro boka rinoreva ± SEM. #p <0.05, musiyano wakakura uchienzaniswa neasina simba kutonga. C, Representative dendritic segments kubva kuNaive 7 d uye Exp 7 d mapoka akashandiswa kuenzana nemafungiro emagetsi. Nhamba yezinga, 3 μm. D, Nguva yakawanda inopedzerwa muimba yepamhizha (Amph kana saline) panguva yechipupuriro kunze kwechikwata chekutanga (CPP score) yepabonde (chichena) kana ruzivo (rusiya) mhuka dzakaedzwa kana 7 d kana 28 d mushure mekusangana kwekupedzisira kana Kugadzirisa chidzidzo: Naive-Sal (7 d mushure mekubata; n = 8), Naive Amph (7 d mushure mekubata; n = 9), Exp-Sal (mapoka akabatanidzwa emhuka akaedzwa kana 7 d kana 28 d mushure mekusangana; n = 7), 7 d Exp Amph (7 d mushure mekusangana; n = 9), uye 28 d Exp Amph (28 d mushure mekusangana; n = 11). Mapoka eSar akagamuchira Sal akabatana nemakamuri maviri. *p <0.05, musiyano wakakura uchienzaniswa neanodzorwa zvine saline pabonde.

Zvepabonde dzakagadziriswa-dzinokonzerwa kukurudzirwa Amph mubayiro inogara kwenguva refu

Takave tatiratidza kuti ruzivo rwepabonde rwakatungamirirwa ne 7-10 d yekuzvidzivirira rwakaita kuti Amph yawedzere kubhadharwa (Pitchers et al., 2010a). Kunyanya, mhuka dzakagadzirisa zvepabonde dzakagadzira nzvimbo yakanyanya kufanirwa nzvimbo (CPP) yezvikamu zvakaderera zveAmph (0.5 kana 1.0 mg / kg) izvo hazvina kuita kuti CPP iite zvekutengesa zvepabonde. Izvo zvidzidzo zvemazuva ano zvakasimbisa uye zvakarongedza zviitiko izvi zvekare kuburikidza kuratidza kuti Amph yakasimbiswa inobhadharwa mumhuka dzinotarisana nepabonde mushure mokunge 7 d uyewo 28 d zvekudzivirira nguva dzepabonde (Fig. 2D; F(2,24) = 4.971, p = 0.016). Kunyanya, mhuka dzine ruzivo rwepabonde dzine 7 kana 28 d kudzivirira nguva dzakapedza nguva yakareba zvikuru muImba yeAmph-paired panguva yekuedzwa kunoenzaniswa nekutarisana nehutano hwepabonde hwakagamuchira saline mumakamuri acho maviri (Fig. 2D: Exp-Sal vs 7 d Exp AMPH, p = 0.032; vs 28 d Exp AMPH, p = 0.021). Kusimbisa kutsvaga kwekare, mhuka dzepabonde dzisina kumbodha dzisina kupedza nguva yakawanda muimba yeAmph-paired panguva yekuongorora uye haina kusiyanisa pane yakasarudzwa neboka revanhu vasina zvepabonde rinokonzerwa neshure (Fig. 2D) (Pitchers et al., 2010a).

DFFB basa rinokosha pamusana pepabonde-huwandu hunoita kuti Amph awane mubayiro

Zvigumisiro ikozvino zvinoratidza kuti chiitiko chepabonde chakakonzera kugara kwenguva refu kweAFosB mu NAc neurons yakabatana neAmph yakawedzera. Kuti uone kana kuwedzerwa ΔFosB basa rinokosha kuti Amph awedzere kubhadhara, ΔJunD, musikana anonyanya kuisa musungo weAFosB uyo anonyadzisa ΔFosB-Winstanley et al., 2007), yakanyanyisa kunzwisiswa neviral vector-mediated gene kuendesa mu NAc (Fig. 3A,B). Mhinduro dzeAmph CPP miedzo dzakaratidza kuti kuvharwa kwechiitiko cheFΔB nekuratidza kuti ZVINHU muA NAc zvakadzivirira migumisiro yehutano hwepabonde uye 7 d zvepabonde rekudzivirira kubvisa paAmph anovandudzwa. Kuziva zvepabonde Mhuka dzisina kujairika dzisina kuumba hukuru hweCPP yeAmf uye dzakanga dzisina kusiyana nevarume vasina zvepabonde Mhuka dzeJUND (Fig. 3B). Kusiyana neizvi, mhuka dzekudzivirira dzeGFP dzepabonde dzakagadzira CPP yeAmph sezvinoratidzwa nepamusoro zvikuru yePP score iyo yakaenzaniswa nehutachiona hweGFP hwekuita zvepabonde (Fig. 3B, p = 0.018).

Mufananidzo 3.     

Mufananidzo 3.     

Kuchengetedza ΔFosB basa muNac rakabviswa richikurudzira AMPH mubairo uye kuwedzerwa muhuwandu hweAc spines mumhuka dzine ruzivo rwepabonde. A, Mumiririri wemifananidzo yeGFP kutaura mumhuka mitatu inogamuchira jekiseni reinclinant adeno-inokonzerwa nehutachiona -AJunD inotungamirirwa nucleus accumbens, kuratidza zviduku (kuruboshwe), mukati-kati (mukati), uye huru (kurudyi) injection sites. ac, anterior commissure; LV, lateral ventricle. Nhamba yezinga, 250 μm. B, Schematic mufananidzo wenzvimbo dzakakurumbira nzvimbo uye maitiro ekupararira kwetachiona. Mune mhuka dzose, GFP yakaonekwa muhombodo, asi yakapararira kusvika kune imwechete yakanga yakasiyana. C, Nguva yakawanda yakashandiswa muImba yeAmph-paired panguva yekuongorora-kupimwa kunze kwepakutanga (CPP chikwata) zvepabonde (chichena) uye vane ruzivo (madema) mhuka iyo yakagamuchira mujenya weGFP control vector (Naive, n = 9; Exp, n = 10) kana ΔJunD vector (Naive, n = 9; Exp, n = 9). D, Mumiririri mifananidzo yezvikwata zve dendritic kubva paGFP yezvepabonde uye ΔJunD inoshandiswa kuenzanisa kuwanda kwemhepo. Nhamba yezinga, 3 μm. E, Nhamba ye dendritic spines muNac yepabonde nevevei (nyeupe) uye vane ruzivo (madema) mhuka iyo yakagamuchira jekisi yeGFP control vector kana IJUND vector. Dhiyabhorosi ndiro boka rinoreva ± SEM. *p <0.05, musiyano wakakura uchienzaniswa neasina simba kutonga. #p <0.05, musiyano wakakura kubva kuGFP yakawana kutonga.

Kukanganisa kuipa kweAJUD kuwedzera kutsvaga kwakanga kusiri chikonzero chekuvhiringidzwa kwehutano hwepabonde munguva yekuwana chiitiko chepabonde. Kutsanangurwa kweZVIRI muAcc zvakambove zvichiratidzwa kuti dzidzivise kuve nekufambisa kwehupombwe mushure mekuita zvepabonde (Pitchers et al., 2010b). Zvechokwadi, izvi zvakasimbiswa mune chiitiko chazvino. GFP mhuka dzekutarisa dzinoratidzika shorter latencies kuti dzikwire, dzisinganzwisisiki, uye kuvharidzira, uye zvishoma zvishoma uye kutapira mukati mezuva rechina rinopfurikidza rekuedza kusangana, richienzaniswa nezuva rokutanga rokusangana (Tafura 1). Kusiyana neizvi, mhuka dzeJIND-dzakatarwa dzakanga dzisingaratidziki zvishoma shotter latencies kuti dzikwire kana kuti dzisina kumira kana nhamba shomanana dzekusimudza mukati rezuva rechina rokubata kufanana nekutanga. Nokudaro, KUNYORWA kunokwidza muAc kukanganisa migumisiro yehutano hwepabonde. Zvisinei, kwakanga kusina kusiyana kwakasiyana mune imwe yenharaunda yekutarisana pakati peGFP yekudzivirira uye maAJJD-akabatanidzwa mapoka panguva ipi zvayo yekuongorora kwekugadzirisa, zvichiratidza kuti migumisiro yeAJUND kushungurudzika mune zvepabonde-yakakonzera kukurudzira kweAmph CPP haisi iyo mhedzisiro yekusiyana ruzivo rwekukwirirana kwega (Tafura 1).

Ona tafura iyi:      

Tafura 1.     

Zviratidzo zvekuita zvepabonde panguva yekuwana ruzivo rwepabonde mumapoka akawana NAc infusions yeGFP- kana ΔJunD-kuratidza vector vectorsa

DFFB inonyanya kukosha mune zvepabonde-kuwedzerwa kuwedzera mu NAc dendritic spines

Basa reFFB raitarisirwawo kuti kuwedzerwa kwepine simba reNac neurons mushure mekuita zvepabonde uye 7 d zvepabonde mubhadharo kubvisa (Fig. 3C,D). Nokuda kwepasipera muA NAc yemhuka yakarondedzerwa pamusoro apa yeCPP, nzira mbiri ANOVA yakaratidza zvikwereti zvezvose zvepabonde (F(1,34) = 31.768, p <0.001) uye hutachiona vector kurapwa (F(1,34) = 14.969, p = 0.001), pamwe chete nekubatana (F(1,34) = 10.651, p = 0.005). Kunyanya, mhuka dzekudzivirira dzeGFP dzepabonde dzakange dzine nhamba yakawanda yeAc spines kana ichienzaniswa nehutachiona hweGFP hwepabonde (Fig. 3D: p <0.001), ichisimbisa kuwanikwa kwedu kwekare (Pitchers et al., 2010a). Kusiyana neizvi, zviitiko zvepabonde Mhuka dzisina kujairika dzakanga dzisinganyatsosiyana nekuita zvepabonde nemapoka eAJUN, uye akanga akadzika zvakaderera achifananidzwa nemhuka dzekudzivirira GFP dzepabonde (Fig. 3D: p <0.001). Nekudaro, KUSANGANA kutaura mu NAC kwakadzivirira mhedzisiro yehutano hwepabonde uye mubairo wekurega paNac spinogenesis.

D1R anorwisana anovhara chiitiko chepabonde-akaita kuti ΔFosB kuregererwa

Kuti uone kana D1R kana D2R kushandiswa muNac panguva yekugadzirisa inotarisirwa kuti uite zvepabonde-inokonzerwa ΔFosB kuregererwa uye kunzwisiswa Amph CPP, mhuka dzakagamuchirwa neveD1R kana D2R (kana kuti saline) mu NAc 15 min mushure meumwe we4 zuva nezuva kutevera mating sessions. Zvinonyanya kukosha, kana D1R kana D2R kupikisa kunopindira muAcc yakanganisa kutanga kana kutaura kwehupombwe panguva ipi zvayo yekugadzirisa (Fig. 4D-F). Saizvozvowo, D1R kana kuti D2R kupikisa hakuna kudzivisa kubatsira kwekuita zvepabonde pakubatana, sezvo mapoka ose akaratidza kuve nekuita zvekuita zvepabonde, inoratidzwa ne shorter ejaculation latencies pazuva 4 yakaenzaniswa nezuva 1 (Fig. 4F) (F(1,40) = 37.113, p <0.001; Sal, p = 0.004; D1R Ant, p = 0.007; D2R Ant, p <0.001).

Mufananidzo 4.     

Mufananidzo 4.     

Dopamine receptor vatsoropodzi vakapindirwa muAc haina kuchinja maitiro epabonde. Coronal NAc sections (A, + 2.2; B, + 1.7; C, + 1.2 kubva kuBregma) inoratidza intra-NAc injection sites nokuda kwezvipfuwo zvose. Cannulas yakanga iri pamwe chete asi inomiririrwa unilaterally kuitira nyore kutaura kwezvipfuwo zvose (Naive-Sal, chena, n = 7; Exp-Saline; rima guru, n = 9; Exp D1R Ant, chiedza chakachena, n = 9; Exp D2R Ant, dema, n = 8). ac, anterior commissure; LV, yakagadziriswa mhepo; CPU, caudate-putamen. Gomo latency (D), intromission latency (E), uye ejaculation latency (F) kumapoka ose ane ruzivo rwepabonde (Saline, chena; D1R Ant, grey; D2R Ant, yakasviba). Data inomirira zvinoreva ± SEM. *p <0.05, musiyano wakakura pakati pezuva 1 nezuva 4 mukati mekurapwa.

Kuongororwa kwenhamba yeAFosB-IR masero mu NAC 7 d mushure mekupedzisira kubudiswa kweN NA nekugadzirisa kana kusangana chirongwa chekugadzirisa zvakaratidza kusiyana kukuru pakati pemapoka muA NAc shell (F(3,29) = 18.070, p <0.001) uye musimboti (F(3,29) = 10.017, p <0.001). Kutanga, ruzivo rwepabonde mu saline-yakadzora kutonga kwakakonzera kukwirisa kwakanyanya kweAFosB kana ichienzaniswa nehurongwa hwekuita bonde.Fig. 5A, shell p <0.001; Fig. 5B: core, p <0.001), ichisimbisa mhedzisiro pamusoro. Kupokana kweD1R, asi kwete D2R, inodzivirirwa kana kudzikisira kukwidziridzwa kweAFosB. MuNac shell, D1R anopikisa akabata varume vane ruzivo rwepabonde haana kuratidza kuwedzera kweAFosB-IR maseru achienzaniswa neanodzora bonde.Fig. 5A: p = 0.110), uye ΔFosB kutaura kwakanyanya kuderera kana ichienzaniswa nevarume vane ruzivo rwepabonde (Fig. 5A: p = 0.002). MuAc core, D1R kupikisa kwaive nemagumisiro ezvishoma: ΔFosB yakanyanya kuwedzera muvarume vanopikisa D1R vachienzaniswa neineive saline controls (Fig. 5B: p = 0.031), asi kuregererwa uku kwaive kwakanyanya kuderera kana kuchienzaniswa nevarume vane ruzivo rwezvepabonde vanobatwa nevarume (Fig. 5B: p = 0.012). D2R kupikisa kusagadzikana hazvina kukanganisa ΔFosB kushandiswa kwevarume sezvakaita varume vane zvepabonde vakagamuchira varwi veD2R vaiva nenhamba yakawanda zvikuru yeAFosB-IR masero akaenzana newaive saline controls (Fig. 5A: shell, p <0.001; Fig. 5B: core, p <0.001) uye D1R vanopikisana nevarume vanobatwa (Fig. 5A: shell, p <0.001; Fig. 5B: core, p = 0.013), uye yakanga isiri yakasiyana nevarume vane ruzivo rwepabonde vanoita zvepabonde.

Mufananidzo 5.      

Tarisa chikwata chikuru:      

Mufananidzo 5.      

Kudzivirira D1R muNac kunomesa kuwedzera kwenhamba yeFFB-IR masero muNac yemhuka dzine ruzivo rwepabonde. Fold shanduko yenhamba yeAFosB-IR masero muA NA shell (A) uye nheyo (B) muzviitiko zvepabonde (madema) mhuka zvichienzaniswa nevepabonde (white) control (Naive-Sal, n = 6; Exp-Saline, n = 7; Exp D1R Ant, n = 9; Exp D2R Ant, n = 8). Dhiyabhorosi ndiro boka rinoreva ± SEM. *p <0.05, musiyano wakakura uchienzaniswa neasina simba kutonga. #p <0.05, musiyano wakakura uchienzaniswa nesaline uye D2R Ant mhuka dzine ruzivo. Mumiriri wemifananidzo yeNaive Sal (C), Exp Sal ​​(D), Exp D1R Ant (E), uye Exp D2R Ant (F). ac, anterior commissure. Nhamba yezinga, 100 μm.

Kuti uchengetedze kuti zvinogona kuparadzirwa kweD1R kana kuti D2R vanopikisa kupinda dorsal striatum, kutaura kweDFBB kwakaongororwa munharaunda yakangoerekana yanyura kune NAC uye yakatarisana ne-lateral ventricle, sezvo kubudiswa kweAFosB mune dorsal striatum ne-psychostimulants uye opiates inobva pane D1R basa (Zhang et al., 2002; Muller uye Unterwald, 2005). Chiitiko chepabonde chakawedzera huwandu hweAFosB-ir masero mu-dorsal striatum muvarume vane chirwere chesaini (Naive-Sal: 35.6 ± 4.8 vs Exp-Sal: 82.9 ± 5.1; p <0.001), ichisimbisa yedu yapfuura mushumo (Pitchers et al., 2010b). Uyezve, hakuna D1R kana D2R anorwisana neAcc inobata chiitiko chepabonde-yakaita ΔFosB mune dorsal striatum (Exp-D1R: 82.75 ± 2.64 ir cells; Exp-D2R: 83.9 ± 4.4 ir masero; p <0.001 zvichienzaniswa neNaive-Sal zvinodzora). Izvi zvakawanikwa zvinoratidza kuti kupararira kweanopikisa infusions kwainyanya kuganhurirwa kuNac.

D1R anopikisa muNac anovharira Amph kukurudzira

D1R yakavharidzirwa muAc panguva yekubatana uye yakavharirwa zvepabonde chiitiko-chakaita kuti Amph yakasimbiswa, yakaedzwa 7 d mushure mekupedzisira kweAc infusion uye test mating (F(3,29) = 2.956, p = 0.049). Mhuka dzinotarisana nepabonde dzakagamuchira saline muNac panguva yekugadzirisa matambudziko yakashandisa nguva yakawanda kwazvo munguva yeAmph-paired chamber yakaenzaniswa nevarume vasina zvepabonde varume (Fig. 6A, p = 0.025), kusimbisa zvizere pamusoro. Kusiyana neizvi, mhuka dzine ruzivo rwepabonde dzakagamuchira intra-NAc D1R mhirizhonga panguva yekubatana haina kuita CPP yeAmph. Vakanga vasina kusiyana nekudzivirira zvepabonde, uye vakapedza nguva shomanana muimba yeAmph-paired yakaenzaniswa ne saline (Fig. 6A: p = 0.049) kana mutauriri weD2R (Fig. 6A: p = 0.038) inokonzera varume vanoziva zvepabonde. D2R vanopesana nehutachiona hahupi hunoita kuti Amph yawedzerwa kubhadharwa semhuka dzinotarisana nepabonde ne NAc D2R vanopikisana nevanopikisa vakaumba maAmph-CPP yakaenzana nekuenzaniswa neveive saline controls (Fig. 6A: p = 0.040) uye D1R anopikisa mhuka dzakaona (Fig. 6A: p = 0.038), uye yakanga isiri yakasiyana nevarume vane ruzivo rwepabonde vanoita zvepabonde.

Mufananidzo 6.      

Tarisa chikwata chikuru:      

Mufananidzo 6.      

Kudzivirira D1 receptors mu NAC inopedza kukurudzira Amph kupiwa uye kuwedzera dendritic spines mumhuka dzine ruzivo rwepabonde. A, Nguva yakawanda yakashandiswa muImba yeAmph-paired panguva yechipupuriro kunze kwechikwata chekutanga (CPP chikamu, masekondi) zvekuita zvepabonde (chichena, n = 6) uye nharaunda (dzvuku) mhuka dzakagamuchira saline (n = 7), D1R anorwisana (n = 9), kana kuti D2R anopikisa (n = 8). Dhiyabhorosi ndiro boka rinoreva ± SEM. *p <0.05, musiyano wakakura uchienzaniswa neasina simba saline kutonga. #p <0.05, musiyano wakakosha kubva kuD1R Ant mhuka dzine ruzivo. B, Nhamba ye dendritic spines (pamusana pe10 μm) yepabonde (white, n = 7) uye nharaunda (dzvuku) mhuka dzakagamuchira saline (n = 8), D1R anorwisana (n = 8), kana kuti D2R anopikisa (n = 8). Dhiyabhorosi ndiro boka rinoreva ± SEM. *p <0.05, musiyano wakakura uchienzaniswa neasina simba saline kutonga. #p <0.05, musiyano wakakura kubva kune ane ruzivo rwekudzora munyu.

D1R inopesana nekurapa inodzivirira hutano hwepabonde-yakaita NAc spinogenesis

Kuongororwa kwepine simba mukati meNac yemhuka imwechete yakaratidza kuti D1R kushandiswa panguva yekukwirirana kwaidiwa kuwedzerwa kwaNc musana wechipfuva mushure mekuita zvepabonde uye 7 d yekuita zvepabonde mubhadharo (Fig. 6B; F(3,26) = 41.558, p <0.001). Zvikurukuru, zvine ruzivo rwepabonde zvine ruzivo nezve saline uye mhuka dzinopikisa D2R dzaive nenhamba yakakura kwazvo yemiperesa kana ichienzaniswa neasina kudzora saline kutonga (Fig. 6B: p <0.001) ichisimbisa zviwanikwa zvedu zvekare (Pitchers et al., 2010a) uye zvinowanikwa neGFP kudzora vector vectors inotsanangurwa pamusoro apa. Kusiyana neizvi, mutsigiri weD1R wepabonde-wakakonzera mhuka haina kusiyanisa nehutano hwepabonde hwemhando dzepabonde-dzakakonzera kutonga (Fig. 6B). Paiva nemigumisiro yechirwere yeD2R inopesana nekuputika sezvo D2R inopindira mhuka dzakaratidza zvakanyanya kuderera kwepamusoro pepine kupfuura kurara kwehutano hwehutano (Fig. 6B: p = 0.02), asi huwandu hwepamusoro hwezvipembenene zvichienzaniswa nehutachiona husina urombo hwemakondomu uye varume vanorwara nevanonzi D1R (p <0.001; Fig. 6B). Nokudaro, D1R yakadzivirirwa muAc panguva yekugadzirisa yakavhara migumisiro yehutano hwepabonde uye mubayiro wokurega kuNac spinogenesis.

hurukuro

Muchidzidzo chemazvino, takaratidza kudarika-kukurudzira pakati pemararamiro emhuka uye emishonga, apo mubairo wekuzvarwa unoteverwa nenguva yekurega. Kunyanya, takaratidza chiitiko ichocho nemitemo yepabonde, yakateverwa ne7 kana 28 d yekurega, inokonzera Amph kukurudzira. Izvi zvinowanikwa zvakafanana neyoyo yakagadziriswa basa rekudzivisa nguva kubva kune zvinodhaka zvekushungurudzwa mune kuwedzera kwechido chemishonga (Lu et al., 2005; Thomas et al., 2008; Wolf, 2010b, 2012; Xue et al., 2012). Uyezve, mubairo wakakonzerwa naDFFB muAcc inokosha nekuda kwepakati-kukurudzira migumisiro yekuwana mubayiro wekuzvidzivirira pamagariro e-psychostimulant, zvichida kuburikidza ne spinogenesis mu NAC panguva yekupa mubayiro kubvisa. Takaratidza kuti ΔFosB inounganidza muNac mushure mekuita zvepabonde inogara kwenguva yakareba uye inotarisirwa neAc D1R basa panguva yekubatana. Nekudaro, iyi D1R-yakagadziriswa neAFosB kugadziriswa muA NAc yakaratidzwa kuva yakakosha pakuwedzerwa mubayiro weAmph uye kuwedzerwa kwepenenji yepamusoro mu NAC, kunyange zvazvo zviitiko izvi zvepabonde zvichitarisira nguva yekurega zvepabonde (Pitchers et al., 2010a). Pakupedzisira, takaratidza kuti NAc spinogenesis inogona kuita kuti kutanga kwekutsvaga kwenguva shomanana kwekukurudzirwa Amph kupa mubayiro asi haisi chinhu chakakosha kuti varambe vachiratidza kuwedzerwa kwemishonga yemishonga, sezvo kuwedzerwa kwepine simba mukati meNac kwaive kwechinguva uye kwakachengetwa mushure mokunge 7 d, asi kwete 28 d, nguva yekurega.

Yakagara ichizivikanwa kuti dopamine inosunungurwa mu NAC munguva yekuita maitiro emubairo, kusanganisira tsika dzepabonde. Pamusoro pekutsvaga kwevakadzi vanogamuchira, extracellular dopamine mu NAC inowedzera uye inoramba ichikwidziridza panguva yekubatanidzwa (Fiorino et al., 1997). Izvo zvidzidzo zvezvino zvairatidza kuti kuisa dopamine receptor vapikisi mu NAC panguva yekugadzirisa kwaisava nemigumisiro yekutanga kana kushanda kwekuita zvepabonde, iyo inopindirana nepfungwa yokuti dopamine haina kubatanidzwa mumashoko ekupa mubayiro maitiro ega, asi pane pamusana pekuita kwekukurudzira kwehukama hwepabonde (Berridge naRobinson, 1998). Zvechokwadi, inotaura nezvehupano hwekuita zvepabonde hunokonzera kushandiswa kweeuroni mukati me mesolimbic dopamine mubairo wehurongwa, kusanganisira dopaminergic masero mu ventral tegmental nzvimbo uye chinangwa chawo, NAC (Balfour et al., 2004). Kudzokorora kuita zvepabonde kunokonzera ΔFosB mune NAC, iyo inobatanidzawo zvakasangana-zvinoita kuti kusimbiswa kwepabonde (Pitchers et al., 2010b). Mhinduro dziripo zvino dzinoratidza kuti kufambisa-kuderedzwa kweAFosB kuregererwa, zvechokwadi, kunoenderana neD1R kushandiswa mu NAC panguva yekubatana. Izvi zvinowirirana neongororo dzakapfuura dzinoratidza kuti kudzokorora psychostimulant nekuenderera mberi kwakaramba kuchiwedzera ΔFosB mu NAc medium spiny neurons inotaura D1R (Lee et al., 2006; Kim et al., 2009) uye kuti ΔFosB kuregererwa kunoenderana neD1R kushandiswa (Zhang et al., 2002). Mukuwedzera, kupindurwa kwezvinodhaka zvezvinodhaka, zvinowanzoonekwa mumhuka ine ruzivo, zvinogona kubudiswa musipo kusati kwava kushandiswa kwezvinodhaka nekunyanya kufungidzirwa kweAFosB muD1R kuratidza neurons mu statum (Kelz et al., 1999). Tasi, zvose zvepanyama uye mishonga yemishonga inowedzera ΔFosB muAcc kuburikidza neD1R-inotarisira nzira yekukurudzira maitiro ekupa mubayiro.

Uyezve, zvitsva zvinowanikwa zvino zvinoratidza kuti ΔFosB inyanzvi inopindirana yepakati-kukurudzirwa pakati pezvipo zvekuwana mubayiro uye psychostimulant mubayiro. Sezvakataurwa, basa reDFBB muA NAc raimbove rakabatanidzwa mune zvinokuvadza zvinodhaka, sezvinonzi DFFB inonyanya kufanana mu NAC inosimudzira kushandiswa kwemaoko kunobata cocaine mushure mokutungamira kwepamusoro kana kuwedzerwa (Kelz et al., 1999), inowedzera kushuvira ku cocaine uye morphine CPP (Kelz et al., 1999; Zachariou et al., 2006), uye zvinokonzera kuzvitonga kweauto rezasi recocaine (Colby et al., 2003). Kuongorora kwemazuva ano kunoratidza kuti kudzivirirwa kweD1R kana yeAFosB basa muNac panguva yekugadzirisa kubviswa kwepabonde yekuita zvepabonde-kwakaita kuti kukurudzirwa kweAmph kupa.

Chidzidzo chezvino chakaratidza kuti nguva yekurega kubva pamubairo wepabonde inodiwa kuti kukurudzirwa kweAmph kupiwa uye NAc spinogenesis. Tinofungidzira kuti ΔFosB panguva iyi yekurega nguva inobata neuronal basa kuburikidza nekushandura pasi pemagumo ekutaura kuti atange spinogenesis uye kuchinja simba rekugadzirisa simba. Zvechokwadi, kudzivisa kuiswa kweAFosB mune NAC panguva yekugadziriswa kunodziviswa kuwedzera kuwedzera kwepenene muAcc yakaonekwa mushure mokupa mubayiro kubvisa. Uyezve, kuiswa kwemuvengi weD1R kupinda muAc mushure mega yega yekugadzirisa chikwata chakadzivirira kuitika kwepabonde-kwakakonzerwa kuwedzerwa kweAFosB uye yakatevera kuwedzerwa kwepfungwa.

ΔFosB ichinyorwa chinonyora chinogona kuita sechinyorwa chechinyorwa kana kuti kudzvinyirira kuti chive nemafungiro ezvakawanda zvezvinangwa zvemajeni izvo zvingaita kuti zvinyanye kuwedzera simba uye simba re-synaptic mu NAc (Nestler, 2008). Kunyanya, ΔFosB inoita cyclic-dependent kinase-5 (Bibb et al., 2001; Kumar et al., 2005), nyukireya chikonzero κ B (NF-κB) (Russo et al., 2009b), uye GluA2 subunit ye ​​glutamate AMPA receptor (Vialou et al., 2010) uye rinodzokorora kudhindwa kweiyo pfupi yekutanga geni c-fos (Pitchers et al., 2010b) uye histone methyltransferase G9 (Maze et al., 2010). Cyclic-dependent kinase-5 inoronga cytoskeletal proteins neurite outgrowth (Taylor et al., 2007). Uyezve, kushandura NF-κB kunowedzera nhamba yependritic spines mu NAc, asi kuvharidzirwa kweNF-κB kwakaderedza basal dendritic spines uye inovhara kuwedzera kwekodhaine mumhepo (Russo et al., 2009b). Nokudaro, mubairo wepabonde unowedzera ΔFosB muNac, iyo inogona kuchinja NAc spine density kuburikidza nezvinangwa zvakasiyana (kureva, cyclic-dependent kinase-5, NF-κB) uye kuti mugumisiro wose unogadziriswa mishonga yemishonga, sezvakakanganiswa Russo et al. (2009a) nokuda kwezviito zvekudzokorora cocaine.

Kushandurwa kusingatarisirwi mune zvidzidzo zvemazuva ano ndechokuti kuwedzerwa kwepine simba mukati meNac kwaive kwechinguva, uye hakuchina kuonekwa pa 28 d mushure mekuita zvepabonde. Nokudaro, kuwedzerwa kwepenenji yepamusoro kwakabatana nekutangira kweAmph kukurudzirwa nekupa uye kunogona kuita kuti kutanga kukurudzirwa kana kutaura kwenguva pfupi kwekukurudzira Amph kupindura. Kunyange zvakadaro, kuwedzerwa kwepenjeni yepamusoro kwakanga kusingadi kuti kutsungirira kweAmf kukurudzire kubhadhara pashure pokuramba kwenguva refu. Takave takaratidza kuti hutano hwepabonde hunokonzera nguva pfupi (7, asi kwete 28, mazuva mushure mekupedzisira kusangana) kuwedzerwa kweNMDA receptor subunit NR-1 mu NAc, iyo yakadzokera kumazinga ekutanga shure kwekuwedzerwa kwenguva yenguva yekurega kubvisa (Pitchers et al., 2012). Izvi zvakasimudza kutaura kweNMDA rekutsvaga kwaive kutengesa kuva chiratidzo chepabonde zvakagadziriswa-induced silent synapses (Huang et al., 2009; Brown et al., 2011; Pitchers et al., 2012), uye inofungidzira yehutano kuti chiitiko chepabonde-chakakonzera kukura kwepamusoro kunobva pakuwedzera basa reNMDA receptor (Hamilton et al., 2012).

Mukupedzisa, chidzidzo chezvino chinoratidzira kupesana-kunzwisiswa kwemishonga yemishonga nemubairo wepanyama (zvepabonde) uye kuvimba kwayo pamubairo wokurega nguva. Uyezve, iyi mapurisa epurasitiki aipindirana neAFosB neD1R kushandiswa mu NAC. Nokudaro, deta inoratidza kuti kurasikirwa kwemararamiro emagetsi mushure mekupa ruzivo ruzivo kunogona kuita kuti vanhu vatarise kukura kwezvinodhaka zvinodhaka uye kuti murevereri mumwe wekuwedzera kwekunetseka ndiye ΔFosB uye maitiro ayo ari pasi apa.

Mashoko Omuzasi

  • Yakagamuchira October 16, 2012.
  • Kuongorora kwakagamuchirwa muna December 12, 2012.
  • Yakagamuchira December 23, 2012.

  • Basa iri rakatsigirwa neCanada Institutes of Health Research (LMC), National Institute of Mental Health (EJN), uye Natural Sciences uye Engineering Research Council yeKanada (KKP neLMC). Tinotenda Dr. Catherine Woolley (Northwestern University) kuti abatsirwe neOlistic maitiro ekuraira.

  • Vanyori vanoti hakuna kupikisana mune zvemari.

  • Mharidzo inofanira kutaurirwa kuna Dr. Lique M. Coolen, Dhipatimendi rePhysiology uye Biophysics, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216. [email inodzivirirwa]

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Nyaya dzinotsanangura nyaya ino

  • Mipiro inokwanisika yenzira inoverengeka ye synaptic plasticity muAplysia kupa mubayiro, chirangaridzo, uye maitiro avo muuropi hwemammalian Kudzidza & Ndangariro, 18 Gunyana 2013, 20 (10): 580-591