Mphatso Zachilengedwe ndi Zamankhwala Zochita pa Common Neural Plasticity Njira ndi DFF monga Mkhalapakati Wofunika (2013)

Kafukufukuyu anafufuza zotsatira za mphotho ya kugonana pa DeltaFosB ndi zotsatira za DeltaFosB pa chiwerewere ndi mphotho. Kusintha kwa ma molekyulu komwe kumadziwika kuti kumachitika ndikumwa mankhwala osokoneza bongo kumapezeka kuti kumafanana ndi komwe kumachitika ndi kugonana. Mwa kuyankhula kwina, DeltaFosB inasintha chifukwa cha zofuna zogonana, komabe mankhwala osokoneza bongo amachitanso chimodzimodzi. Izi zimamaliza mkangano wokhudza momwe kugwiritsa ntchito mankhwala osokoneza bongo kumasiyana ndi zizolowezi zamakhalidwe, komanso momwe zizolowezi zamakhalidwe zimangokhala zokakamiza (zilizonse zomwe zikutanthauza). Maseketi omwewo, njira zomwezo, kusintha kwama cell komweko, machitidwe omwewo ogwirizana - ndimasiyana pang'ono.

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

PHUNZIRO LONSE

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

gwero

Dipatimenti ya Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario N6A 3K7, Canada, department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, Fishberg department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York 10029, ndi Madipatimenti a Neurobiology ndi Anatomical Sayansi ndi Physiology ndi Biophysics, University of Mississippi Medical Center, Jackson, Mississippi 39216.

Kudalirika

Mankhwala osokoneza bongo amachititsa kuti munthu asagwiritsidwe ntchito mopitirira muyeso mu njira ya malipiro, makamaka nucleus accumbens (NAc). Umboni waposachedwapa umasonyeza kuti madalitso achilengedwe angayambitse kusintha kwa NAC, ponena kuti mankhwala akhoza kuyambitsa njira zopangira mapulasitiki zomwe zimapindula ndi madalitso achilengedwe, komanso kulola kusagwirizana pakati pa mphotho ndi mankhwala osokoneza bongo.

Mu phunziroli, timasonyeza kuti kugonana kwa abambo amphongo pakutsatiridwa ndifupipafupi kapena nthawi yayitali yoperewera kugonana kumayambitsa mphotho ya amphetamine, yomwe imasonyezedwa ndi malo opatsirana amodzi (0.5 mg / kg) amphetamine. Komanso, kuyambira, koma osati nthawi yayitali, yowonjezera mphoto ya amphetamine inali yogwirizana ndi kuwonjezeka kwapadera kwa mitsempha ya dendritic ku NAc. Pambuyo pake, gawo lofunika kwambiri pa cholembera ΔFosB mu zochitika zogonana zowonjezera mphotho ya amphetamine komanso kuwonjezeka komwe kumagwiritsidwa ntchito m'mitsempha ya dellritic pa NAc neurons inakhazikitsidwa pogwiritsira ntchito tizilombo toyambitsa matenda kuchokera kwa wodwalayo. Komanso, zinasonyezedwa kuti mphotho yothandizira kugonana, ΔFosB, ndi spinogenesis zimadalira kugwiritsira ntchito dopamine D1 kulandirira ku NAC. Kusamalidwa kwa mankhwala kwa D1 receptor, koma osati D2 receptor, mu NAc panthawi ya chiwerewere anatsutsa ΔFosB kulowetsedwa ndikuletsa kuwonjezeka kwa spinogenesis ndi kulimbikitsa mphoto ya amphetamine.

TZomwe zikupezekazi zikuwonetsa kuti mankhwala osokoneza bongo ndi machitidwe a malipiro amachitidwe pamagulu a maselo ndi mapulogalamu a pulasitiki omwe amachititsa kuti chiopsezo cha mankhwala osokoneza bongo chikhale chovuta, ndipo kuti kuwonjezeka kwa chiopsezochi ndikulumikizana ndi ΔFosB ndi zolembera zomwe zili pansi pake.

Introduction

Makhalidwe a mphotho ndi madokotala amaphatikizapo njira yodziwika bwino ya neural pathway, masolimbic dopamine (DA) dongosolo, momwe khunyu accumcums (NAc) ili ndi gawo lalikulu (Kelley, 2004). Mankhwala osokoneza bongo amachititsa kuti tizilombo toyambitsa matenda tizilombo toyambitsa matenda tizilombo toyambitsa matenda,Hyman et al., 2006; Kauer ndi Malenka, 2007; Kalivas, 2009; Chen et al., 2010; Koob ndi Volkow, 2010; Wolf, 2010a; Mameli ndi Luscher, 2011). Zikugodometsedwa kuti mankhwala osokoneza bongo ndi madalitso a chilengedwe sagwiritsa ntchito neurons yomweyi m'masolambic system, ndipo motero mankhwalawa amachititsa kusintha ndikusintha dera ili (Cameron ndi Carelli, 2012). Komabe, zakhala zikuonekeratu kuti madalitso achilengedwe ndi mankhwala omwe amagwiritsidwa ntchito ndi mankhwala amachititsa masolimbic dongosolo m'njira zofanana ndi zosiyana zomwe zimaloleza kuyanjana pakati pa mphotho zachilengedwe, mphotho yapadera ya kugonana, ndi zotsatira za mankhwala osokoneza bongo (Frohmader et al., 2010a; Pitchers et al., 2010a; Olsen, 2011).

Chiwerewere chimapindulitsa kwambiri (Tenk et al., 2009),

Zofukufukuzi zikusonyeza kuti zochitika zapachilengedwe ndi zakumwa mankhwala zimagwirizanitsa njira zofala za pulasitiki za neural, zomwe zimakhudza chiopsezo cha kugwiritsa ntchito mankhwala osokoneza bongo.

Cholinga cha kafukufuku wamakono chinali kudziwa njira zamagulu zogwirizanitsa kugonana kwapadera komwe kunayambitsa kugonana, komwe kumapangitsa kuti pakhale mphotho ya mankhwala. Mwachindunji, udindo wa cholembedwerako ΔFosB inkafufuzidwa chifukwa imakhudzidwa ndi zotsatira za mphotho zonse zakuthupi ndi mankhwala (Nestler et al., 2001; Werme et al., 2002; Olausson et al., 2006; Wallace et al., 2008; Hedges et al., 2009; Pitchers et al., 2010b). Kuonjezera apo, ntchito ya dopamine D1 receptors (D1R) yothandizira kugonana ndi neural plastiki inayesedwa chifukwa NAC ΔFosB induction ndi kuchulukitsa msinkhu wa msinkhu pambuyo psychostimulant administration akufotokozedwa mu D1R munali neurons (Lee ndi al., 2006; Kim et al., 2009) ndipo amadalira pa activation D1R (Zhang et al., 2002).

Pano, tinagwiritsa ntchito mavotolo ogwirizana ndi mavairasi a DFB, diOlistic ma labeling, ndi machitidwe apamtima kuti ayesere kuganiza kuti zotsatira zowonongeka za kugonana zotsatiridwa ndi mphotho yolepheretsa kupititsa patsogolo Amph kupindula ndizogwirizana ndi Kudalitsidwa kwa D1R kwa ΔFosB mu NAc ndi kuwonjezereka kwina kwa msana wa NAc. Zonsezi, zomwe zapeza zimapereka umboni wakuti madalitso a chilengedwe ndi mankhwala amagawana njira zofala za pulasitiki ya neural, ndi ΔFosB monga mkhalapakati wovuta.

Zida ndi njira

Nyama.

Amuna akuluakulu (225-250 g pofika) ndi akazi (210-220 g) Kupopera makoswe a Dawley (Charles River Laboratories) ankalowetsamo ku Plexiglas osagwiritsidwa ntchito pamagulu amodzimodzi pazomwe akuyesera, pansi pa kutentha ndi kutentha komanso pa 12 / 12 h Kuwala / mdima ndi chakudya ndi madzi momasuka. Amayi omwe amawathandiza kuti azitha kukambirana nawo amatha kukhala osakanikirana ndipo amalandira implants omwe ali ndi 5% estradiol benzoate (Sigma-Aldrich) ndi jekeseni wa 500 μg wa progesterone (mu 0.1 ml ya mafuta a sesame; Sigma-Aldrich) 4 h asayesedwe. Ndondomeko zonse zinavomerezedwa ndi Komiti Yogwiritsira Ntchito Zanyama Zogwiritsira Ntchito Zilombo za Yunivesite ya Western Ontario ndi Yunivesite ya Michigan ndikugwirizana ndi Canada Council on Animal Care ndi malangizo a National Institutes of Health okhudza zinyama zofufuza.

Chiwerewere.

Zokambirana zachitika nthawi yamdima (pakati pa 2 ndi 6 h pambuyo pa nthawi ya mdima) poyerekeza kofiira, muzitsulo zoyera (60 × 45 × 50 masentimita). Amphaka amatsatiridwa kuti azisakanizika pa nthawi ya 4 kapena 5 masewera olimbitsa thupi tsiku ndi tsiku. Masankho asanu adasankhidwa chifukwa takhala tikuwonetsa kuti pulogalamuyi imayambitsa kutsogolera kwa nthawi yayitali khalidwe la kugonana (Pitchers et al., 2010b), kukudziwitsidwa pamtunda kwa ntchito ya Amph wogwira ntchito (Pitchers et al., 2010a), ndi mphoto (Pitchers et al., 2010a). Kusankhidwa kunasankhidwa ngati mapeto a gawo lililonse lakutetezera chifukwa tinaliwonetsa kuti ndilofunikira kuti zotsatira za kugonana zitheke pa chidziwitso cha Amph chodziwitsira (Pitchers et al., 2010a), zomwe sizinachitike pamene nyama zinkaloledwa kukwatirana ndi akazi popanda kusindikizidwa. Zotsatira za khalidwe la kugonana (mwachitsanzo, latency ku mount yoyamba, kuthamangitsidwa ndi kuthamangitsidwa, ndi chiwerengero cha mapulaneti ndi kutuluka mkati) zinalembedwa monga momwe tafotokozera poyamba (Pitchers et al., 2010b). Pazoyesa zonse, magulu odziwa za kugonana anafananirana ndi khalidwe la chiwerewere (chiwerengero cha ejaculations ndi latency kwa ejaculation pa nthawi iliyonse yobwereza). Pambuyo pachisanu chakumapeto kwa masewera, amuna adakakhala ndi abwenzi omwe amagonana nawo ndipo samaloledwa kukwatirana pa nthawi ya kugonana kwa 1, 7, kapena 28 d. Nyama zomwe zidali zachiwerewere zinkasamalidwa ndipo zimakhala m'zipinda zomwezo monga amuna amodzi. Kuphatikiza apo, maulamuliro osadziwika anaikidwa muzitsulo zoyesera zoyerekeza kwa ola limodzi pa tsiku la 5 motsatizana, popanda kupeza mkazi wolandira.

FosB expression.

Nyama zinali zosavomerezeka kwambiri (sodium pentobarbital; 390 mg / kg; ip) ndipo zimagwiritsidwa ntchito mosagwirizana ndi 50 ml wa 0.9% saline, zotsatiridwa ndi 500 ml wa 4% paraformaldehyde (Sigma-Aldrich) mu 0.1 m phosphate buffer (PB) kwa nthawiyo mfundo ndi zotsutsa za DR. Ubongo unachotsedwanso ndi 1 h panthawi ya firiji yofanana, kenako amasungidwa ku 4 ° C mu 20% sucrose ndi 0.01% sodium azide mu 0.1 m PB. Kwa zitsulo za DR zotsutsa, ubongo unachotsedwa ndipo ndi theka pambali pa sagittal axis. Theka linawasungidwa mu PB ndipo amagwiritsidwa ntchito kwa DiOlistics, ndipo ina inakonzedwa kuti ΔFosB. Zigawo za Coronal (35 μm) zinadulidwa ndi michere yozizira kwambiri (Microm H400R), yomwe inasonkhanitsidwa muzitsulo zinayi zofanana mu cryoprotectant solution (30% sucrose ndi 30% ethylene glycol mu 0.1 m PB) ndi kusungidwa ku -20 ° C. Zigawo zosasuntha zidatsukidwa kwambiri ndi 0.1 m PBS, pH 7.35, pakati pa kuika makina, ndipo mapazi onse anali kutentha kutentha. Zigawo zinawonetsedwa ku 1% H2O2 (10 min) ndi njira yotsitsimula (1 h; PBS yomwe ili ndi 0.1% BSA, Fisher; ndi 0.4% Triton X-100, Sigma-Aldrich). Zigawozo zimagwiritsidwa ntchito usiku umodzi m'thupi la pan-FosB la rabbit polyclonal (1: 5K; sc-48 Santa Cruz Biotechnology), yomwe idatsimikiziridwa kale (Perrotti et al., 2004, 2008; Pitchers et al., 2010b). Woteteza pan-FosB adaleredwa motsutsana ndi dera lamkati logawidwa ndi FosB ndi ΔFosB, ndipo amadziwika kale kuti amawonetsa bwino maselo a ΔFosB panthawi yomwe adagwiritsa ntchito phunziroli (> 1 d pambuyo pa kukondoweza) (Perrotti et al., 2004, 2008; Pitchers et al., 2010b). Pambuyo pake, zigawo zinayambika mu biotin-conjugated mbuzi yotsutsana ndi kalulu IgG (1 h; 1: 500 mu PBS +; Vector Laboratories), pidyidase (avidin-biotin-horseradish peroxidase (1 h; ABC elite; 1: 1000 mu PBS; Vector Laboratories) , ndi 0.02% 3,3'-diaminobenzidine tetrahydrochloride (10 min; Sigma-Aldrich) ndi 0.02% nickel sulfate mu 0.1 m PB ndi hydrogen peroxide (0.015%). Zigawozo zinapangidwira pazithunzi za Superfrost (Fisher) komanso zophimbidwa ndi dibutyl phthalate xylene.

Mawerengero a ΔFosB-IR maselo anawerengedwa mu chipolopolo cha NAc ndi maziko mkati mwa malo ofunikira (400 × 600 μm) monga momwe tafotokozera kale (Pitchers et al., 2010b). Zigawo ziwiri zinkawerengedwa pa NAC, m'madera osiyanasiyana. Panthawi yoyesera nthawi, mayina a DFF-IR maselo amawonetsedwa ngati kusintha kwa gulu la anthu osadziŵa nthawi pa nthawi yoyenera ndikuyerekeza pakati pa magulu odziwa bwino komanso osadziwika pa gawo lililonse pa nthawi iliyonse yogwiritsira ntchito opanda ntchito t mayesero okhala ndi chiwerengero chofunikira p <0.05. Pazoyeserera zotsutsana ndi ΔJunD-AAV ndi DR, njira ziwiri kapena njira imodzi ANOVA, motsatana, ndi njira ya Holm-Sidak idagwiritsidwa ntchito. Kuphatikiza apo, ΔFosB-IR maselo amawerengedwa mu dorsal striatum (malo owunikira: 200 × 600 μm), nthawi yomweyo kutsata kwa NAc komanso moyandikana ndi ventricle yotsatira, munyama zonse zoyeserera zotsutsana ndi DR. Njira imodzi ANOVA ndi t mayesero amagwiritsidwa ntchito poyerekeza pakati pa magulu.

Diolistics.

Kwa nthawi komanso nthawi yowonongeka kwa tizilombo toyambitsa matenda, makoswe ankasokonezeka kwambiri ndi 50 ml saline (0.9%), motsogozedwa ndi 500 ml wa 2% paraformaldehyde mu 0.1 m PB. Ubongo unagawidwa (100 μm coronal) pogwiritsa ntchito vibratome (Microm) ndi zigawo zosungidwa mu 0.1 m PB ndi 0.01% sodium azide pa 4 ° C. Kuphimba kwa tungsten particles (1.3 μm m'mimba mwake, Bio-Rad) ndi lipophilic carbocyanine dye DiI (1,1'-dioctadecyl-3,3,3'3'-tetramethylindocarbocyanine yozungulira; Invitrogen) inachitika monga momwe tafotokozera kale (Forlano ndi Woolley, 2010). Pulogalamu ya tungsten yophikidwa ndi dii inaperekedwa m'kati mwa 160-180 psi pogwiritsira ntchito Helios Gene Gun dongosolo (Bio-Rad) pogwiritsa ntchito fyuluta ndi 3.0 μm kukula kwa pore (BD Biosciences) ndipo amaloledwa kufalikira kudzera m'magulu a neuronal mu 0.1 m PB 24 h pamene itetezedwa bwino pa 4 ° C. Pambuyo pake, magawo anali atasindikizidwa mu 4% paraformaldehyde mu PB ya 3 h kutentha, kusambitsidwa mu PB, ndi kukwera muzipinda zowindikizidwa (Bio-Rad) ndi gelvatol yomwe ili ndi 1,4-diazabicyclo (2,2) octane (anti-fading) 50 mg / ml, Sigma-Aldrich) (Lennette, 1978).

Mapuloteni olembedwa ndi DiI anali kujambulidwa pogwiritsa ntchito Zeiss LSM 510 m chipangizo chamakono (Carl Zeiss) ndi helium / neon 543 nm laser. Pa nyama iliyonse, 2-5 neurons m'kati mwa NAc, kapena mu chipolopolo (kuchokera kumalo okhudzana ndi zizindikiro, kuphatikizapo chitukuko chotsatira ndi kutuluka kwa anterior) muyeso la ADJunD-AAV ndi DR, adagwiritsa ntchito kufufuza dera la chidwi pa tsamba lachiwiri la dendrite chifukwa cha msana. Kwa neuron iliyonse, 2-4 dendrites anayesedwa kuti awerengetse kutalika kwa dendritic kutalika kwa 40-100 μm. Zigawo zowonongeka zinagwidwa pogwiritsa ntchito 40 × cholinga chodzizira madzi pamtunda wa 0.25 μm motsatira z-axis, ndi chithunzi cha 3D chinamangidwanso (Zeiss) ndipo adasinthika (Autoquant X, Media Cybernetics) pogwiritsira ntchito kusintha (osasamala) ndi zolemba za PSF zomwe zikugwirizana ndi mapulogalamu. Kuchulukanso kwapakati kunkapezeka podutsitsa pulogalamu ya Imaris software (version 7.0, Bitplane). Mndandanda wa misomali ya dendritic inafotokozedwa pa 10 μm, yowerengedwa pa neuroni iliyonse ndiyeno kwa chinyama chilichonse. Kusiyana kwa chiwerengero kunatsimikiziridwa pogwiritsa ntchito ANOVAs m'njira ziwiri zomwe zimayesedwa panthawi yomwe zimakhalapo pakati pa zogonana ndi achiwerewere nthawi iliyonse (mfundo: chidziwitso chogonana ndi chiwerengero cha NAC) ndi muyeso WONSE (zifukwa: chidziwitso chogonana ndi vector virusi), ndi imodzi -kuyenda kwa ANOVA mu kuyesera kwa mdani wa DR. Kuyerekeza kwa magulu kunapangidwa ndi njira ya Holm-Sidak ndi chiwerengero chofunikira p <0.05.

Malo okonda malo.

Kupanga kuyesera kwa CPP kunali chimodzimodzi monga momwe tafotokozera kale (Pitchers et al., 2010a), pogwiritsa ntchito zipangizo zamagulu atatu (Med Associates), komanso mapangidwe osakondera, ndi mayesero amodzi a d-Amph sulphate (Amph; Sigma-Aldrich; 0.5 mg / ml / kg sc yowerengedwa chifukwa cha ufulu waulere) mu chipinda chosakanikirana ndi saline mu chipinda chopanda chithandizo m'masiku ena osakwanira, ndipo anachitapo gawo limodzi loyamba la kuwala. Kuteteza nyama kumalandira saline m'zipinda ziwiri.

Zolemba za CPP zinkawerengedwa pa chinyama chilichonse monga nthawi yomwe inagwiritsidwa ntchito (pamphindi) mu chipinda choyendetsa panthawi yopitilira mayesero osapitirira. Njira zina za ANOVA ndi njira ya Holm-Sidak amagwiritsidwa ntchito poyerekeza magulu a nthawi yomwe ayesedwa. Osasamala t mayesero ndi kufunikira kuikidwa p <0.05 idagwiritsidwa ntchito kuyerekezera Naive-Sal ndi Naive Amph munthawi iliyonse yoyeserera, komanso mkati mwa chithandizo chilichonse cha ma virus mu kuyesa kwa unJunD. Poyesa nthawiyo, ANOVA za njira imodzi ndi njira ya Holm-Sidak adagwiritsidwa ntchito kuyerekezera magulu odziwa zachiwerewere (Exp-Sal, 7 d Exp Amph ndi 28 d Exp Amph), komanso osakonzedwa t Kuyesedwa kunagwiritsidwa ntchito poyerekeza magulu a 2 osadziwika. Njira ziwiri za ANOVA ndi njira ya Holm-Sidak zinagwiritsidwa ntchito poyerekeza magulu onse mu kuyesera kwa mdani wa DR. Zilibechapa t mayeso amagwiritsidwa ntchito kufanizitsa Naive-Sal ndi Amphawi Amph magulu ndi matenda amtundu uliwonse wa mavairasi (GFP kapena ADJunD), monga deta inali yosasunthika m'magulu APA kuti alolere kusanthula ANOVA. Magulu onse ofunika adayikidwa p <0.05.

Zowonongeka za virale.

Mankhwala amphongo amatsitsimadziwa ndi ketamine (87 mg / ml / kg; ip) ndi xylazine (13 mg / ml / kg ip), amaikidwa mu zida za stereotaxic (Kopf Instruments), ndipo amalandira microinjections zamtundu wina wa kachilombo koyambitsa matenda a virusi. GFP yokha (puloteni wobiriwira wa piritsisenti), kapena Wothandizira (Wopambana-wosayanjana naye mnzake wa ΔFosB) ndi GFP, kulowa mu NAc (makonzedwe: AP + 1.5, ML ± 1.2 kuchokera ku bregma; DV -7.6 ku fupa), mu volume la 1.5 μl / hemisphere pa 7 min pogwiritsa ntchito siringi ya Hamilton (Harvard Apparatus). ZOYENERA kuchepetsa ΔFosB-kulembedwa pamasom'pamaso ndi mpikisano wokhudzana ndi mpikisano ndi ΔFosB ndipo motero kuletsa kukakamizidwa kwa ΔFosB kumadera AP-1 mkati mwa zigawo zotsitsimula za majeremusi (Winstanley et al., 2007; Pitchers et al., 2010b). Ngakhale kuti INDA imagwirizanitsa kwambiri ndi DFF, ndizotheka kuti zina mwa zotsatira zowonjezera zikhoza kukhala zotsutsana ndi mapuloteni ena AP-1. Komabe, zikuwoneka kuti ΔFosB ndilopuloteni yaikulu ya AP-1 yomwe imayesedwa pansi pa zovuta (Pitchers et al., 2010b). Pakati pa masabata a 3 ndi a 4, nyama zinkakhala zogonana pa nthawi ya 4 motsatizana ndikutsatirana kapena kukhalabe osayenerera kupanga magulu a 4: GFP zokhudzana ndi kugonana, kugonana ndi ma GFP, kugonana ndi amuna osagonana, osadziwa zachiwerewere ZOYENERA. Chidziwitso cha kugonana chinali ndi 4 yolimbitsa thupi tsiku lililonse. Nyama zinayesedwa kwa CPP ndi diOlistics. Kutsimikizira kwa malo ojambulidwa kunayendetsedwa monga momwe tafotokozera poyamba (Pitchers et al., 2010b). Nac zigawo (coronal; 100 μm) zinkatetezedwa ku GFP (1: 20,000; kalulu anti-GFP antibody; Invitrogen). Kufalikira kwa kachilombo kunali kokha ku gawo la shell ya NAc, ndipo zina zinapitirira kufalikira.

Otsutsa a D1R / D2R.

Mankhwalawa amatsitsidwa ndi injection ya intraperitoneal (0.1 ml / kg) ya ketamine (87 mg / ml) ndi xylazine (13 mg / ml), ndipo amaikidwa mu zipangizo za stereotaxic (Kopf Instruments). Zokambirana za 21-gauge guide cannulas (Plastics One) zatsikira ku NAc pa AP + 1.7, ML ± 1.2 kuchokera ku bregma; -6.4 DV kuchokera ku fupa ndipo imatetezedwa ndi mano akhungu, omangirizidwa ku zikopa zitatu zomwe zimayikidwa mu chigaza. Nyama zinkagwiritsidwa ntchito tsiku ndi tsiku kuti zizolowezi zowonongeka panthawi ya kuchipatala kwa 2. Mphindi khumi ndi zisanu ndi zitatu (1) za tsiku ndi tsiku (1) Zisudzo za tsiku ndi tsiku (1) za tsiku ndi tsiku (1) (1) (1) Mphindi khumi ndi zisanu ndi zitatu (1) -) eticlopride hydrochloride (Sigma-Aldrich) inasungunuka mu stine wosabala (4%; iliyonse pa 1 μg mu 23390 μl pa chilengedwe; itasungunuka mu 2% saline), kapena saline (2 μl pa chilengedwe), pamtunda wa 0.9 μl / min pamtunda wa 10 wamphindi wotsatira ndi 1 min ndi kanjini yoyamwa yomwe yasiyidwa m'malo mwa kusokonezeka kwa mankhwala. Vuto la jekeseni limeneli lidzapangitsa onse kukhala pachimake ndi chipolopolo, monga infusions a 0.9 μl amangokhala chigoba kapena zigawo zofunikira (Laviolette et al., 2008). Mlingoyo unakhazikitsidwa pa kafukufuku wakale wosonyeza kuti izi kapena kuchepa kwa mlingo zakhudzana ndi mankhwala kapena chikhalidwe cha mphotho (Laviolette et al., 2008; Roberts ndi al., 2012). Amuna amodzi adakhalabe ndi chilakolako chogonana koma adalandira intra-NAc saline asanalowetsedwe mu khola lopanda kanthu, pa nthawi ya 4 tsiku lililonse. Mlungu umodzi mutatha kumaliza kukambirana kapena kukambirana, amuna adayesedwa kwa Amph CPP, ndi msana ndi kusanthula ΔFosB. Kugwiritsa ntchito magawo anai, m'malo mwa magawo asanu monga momwe ena anayesera, anasankhidwa kuthetsa kuwonongeka koopsa kwa NAC chifukwa cha mobwerezabwereza infusions ndipo motero amalola msana ndi ΔFosB kufufuza. Zoonadi, kuwonongeka sikunali koonekeratu, ndipo msinkhu wothandizira ndi DFBB ku NAC wa nyama zomwe zimalowetsa saline zinkawonetsera dera lofanana ndi magulu omwe sanaphatikizedwe m'mayesero ambuyomu. Njira ziwiri za ANOVA ndi Holm-Sidak ndizofunika kwambiri p <0.05 idagwiritsidwa ntchito kuti izindikiritse zomwe zimapangitsa kuti anthu azigonana.

Results

Kugonana kwa ΔFosB komwe kumachitika chifukwa cha kugonana kumakhala kosatha

Choyamba, mgwirizano wa nthawi pakati pa kugonana unachititsa kusintha kwa mafotokozedwe a ΔFosB, mitsempha ya dtritic mu NAC, ndi Amph-CPP, makamaka pambuyo pafupipafupi komanso nthawi yaitali kuti asamapereke mphoto (7 kapena 28 d). Poyamba, zinasonyezedwa kuti kugonana kwa 5 tsiku ndi tsiku kumasewera magawo kunachititsa kuwonjezeka kwa ΔFosB kudutsa dongosolo la masolimbic, makamaka mu NAC (Wallace et al., 2008; Pitchers et al., 2010b). M'maphunziro akale, ma DFBB anayesedwa mkati mwa 1 d pambuyo pa khalidwe la kugonana, ndipo sizinadziwike ngati ΔFosB yokhalapo inapitirizabe kupuma kwa nthawi yaitali. Amuna ogonana ndi amuna omwe anali ndi chiwerewere anapangidwanso 1, 7, kapena 28 d pambuyo pamapeto omaliza a 5 tsiku ndi tsiku, pamene amunawo ankamenyana. Kugonana kwauchiwerewere kunagwiritsidwa ntchito mopweteka panthawi imodzimodziyo pamapeto omaliza maphunziro a 5 tsiku ndi tsiku. Mawerengero a ΔFosB-IR maselo mu chipolopolo cha NAc ndi pachimake zinali zazikulu kwambiri kusiyana ndi machitidwe achiwerewere achiwerewere nthawi zonse (Chith. 1A, chipolopolo; 1 d, p = 0.022; 7 d, p = 0.015; Chith. 1B: pachimake; 1 d, p = 0.024; 7 d, p <0.001; 28 tsiku, p <0.001), kupatula mu chipolopolo cha NAc pambuyo pa 28 d kudziletsa (p = 0.280). Choncho, kufotokozera kwaFFB kumapitirizabe kudziletsa pambuyo pa chidziwitso cha kugonana kwa nthawi yosachepera 28 d.

Chithunzi 1.      

Chithunzi 1.      

Chidziwitso cha kugonana chinayambitsa kuwonjezeka kwatsopano ndi kosalekeza kwa chiwerengero cha ΔFosB-IR maselo. Kusintha kwa nambala ya maselo ΔFosB-IR mu shell ya NAc (A) ndi pakati (B) mu zinyama (zakuda) zogonana pogonana poyerekeza ndi machitidwe achiwerewere (azungu)n = 4 gulu lirilonse). Deta ndi gulu lotanthauza ± SEM. *p <0.05, kusiyana kwakukulu poyerekeza ndi kuwongolera zopanda nzeru. Woimira zithunzi za Naive 1 d (C), Exp 1 d (D), Exp 7 d (E), ndi Exp 28 d (F). ac, Anterior ayambe. Mzere wamtengo, 100 μm.

Kugonana kwapangidwe kowonongeka kwa dendritic spines ndikumalizira

Pitchers ndi al. (2010a) kale anagwiritsa ntchito kugwiritsa ntchito njira za kugwiritsira ntchito Goggi zomwe zokhudzana ndi kugonana zotsatiridwa ndi 7 d, koma osati 1 d, kudziletsa kwapadera kunayambitsa kwambiri kuwonjezeka kwa udzu wambiri ndi kuchuluka kwa misomali ya dellritic pa NAc shell ndi core neurons (Pitchers et al., 2010a). Pano, spinogenesis mwa amuna opatsirana pogonana komanso amuna odziwa bwino zachiwerewere anayesedwa kaya 7 d kapena 28 d mutatha kumaliza kusamvana. Zotsatira zamakono pogwiritsa ntchito njira yolemba ma dililistiki zinatsimikizira kuti chiwerewere chotsatira ndi nthawi ya kudziletsa kwa kugonana kwa 7 chinawonjezeka chiwerengero cha mankhwala osokoneza bongo (dendritic spines)F(1,8) = 9.616, p = 0.015; Chith. 2A-C). Mwachindunji, chiwerengero cha mankhwala otchedwa dendritic spines chinawonjezeka kwambiri mu NAc shell ndi pakati (Chith. 2A: chipolopolo, p = 0.011; pachimake, p = 0.044). Komabe, izi zidachulukitsidwa ndi msinkhu wamtunduwu zinali zowonongeka ndipo sizinapezenso pambuyo pa nthawi yosiya kugonana nthawi yayitali ya 28 d iliyonse NAc subregion (Chith. 2B).

Chithunzi 2.      

Chithunzi 2.     

Chidziwitso cha kugonana chinachulukitsa kuchuluka kwa mitsempha ya dendritic mu NAC ndipo amathandizira Amph kupereka. A, B, Chiwerengero cha misomali ya dellritic mu chipolopolo cha NAc ndi phokoso la 7 d (A) kapena 28 d (DB ya nyama zakuda [zoyera] ndi zodziwa; n = 4 kapena 5). Deta ndi gulu lotanthauza ± SEM. #p <0.05, kusiyana kwakukulu poyerekeza ndi kuwongolera zopanda nzeru. C, Zigawo zoimira dendritic kuchokera ku Naive 7 d ndi Exp 7 a magulu omwe amagwiritsidwa ntchito poyeza msinkhu. Mzere wamtengo, 3 μm. D, Nthawi imene amatha kupitilira (amph kapena saline) panthawi yoyezetsa magazi kupatulapo chiwerengero cha pretest (CPP) kwa ziwalo zogonana (zoyera) kapena zodziwa (nyama zakuda) zomwe zimayesedwa ngati 7 d kapena 28 d mutatha kukwanitsa komaliza kapena Gawoli: Naive-Sal (7 d pambuyo pakugwira ntchito; n = 8), Amph Naive (7 d pambuyo pakugwira ntchito; n = 9), Exp-sal (gulu limodzi la zinyama zayesedwa ngati 7 d kapena 28 d pambuyo pa kukwatira; n = 7), 7 d Exp Amph (7 d pambuyo kukwanitsa; n = 9), ndi 28 d Exp Amph (28 d pambuyo pa kukwanitsa; n = 11). Magulu a Sal alandire Sal akuphatikizana ndi zipinda zonse ziwiri. *p <0.05, kusiyana kwakukulu poyerekeza ndi zowongolera zamchere zogonana.

Kugonana komwe kumakhudzidwa kwambiri ndi Amph kulipira kumakhala kwamuyaya

Poyamba tasonyeza kuti kugonana komwe kunatsatiridwa ndi 7-10 ya kudziletsa kunabweretsa Amph kupititsa patsogolo (Pitchers et al., 2010a). Makamaka, nyama zogonana zimapanga malo okonda kwambiri a Amph (0.5 kapena 1.0 mg / kg) zomwe sizinapangitse CPP kuti ikhale yoyenera kugonana. Kafukufuku wamakono adatsimikizira ndikuwonjezera zotsatirazi powonetsa Amph kupindulitsa kwa zinyama zokhudzana ndi kugonana pambuyo pa 7 d komanso nthawi ya kudziletsa kugonana kwa 28 (Chith. 2D; F(2,24) = 4.971, p = 0.016). Makamaka, nyama zogonana zogonana ndi 7 kapena 28 d nthawi yosiya kudziletsa zinathera nthawi yochuluka kwambiri mu chipinda cha Amph-paired pamapeto pa mayesero poyerekeza ndi machitidwe osokoneza kugonana omwe adalandira saline m'zipinda zonse ziwiri (Chith. 2D: Exp-Sal vs 7 d Exp AMPH, p = 0.032; vs 28 d Exp AMPH, p = 0.021). Kutsimikizira zochitika zapitazo, nyama zogonana zogonana sizinathe nthawi yambiri mu chipinda cha Amph-paired panthawi yoyezetsa magazi ndipo sizinasiyana mosiyana ndi gulu loletsa kugonana lachiwerewere (Chith. 2D) (Pitchers et al., 2010a).

Ntchito yaFosB ndi yofunika kwambiri pa zochitika za kugonana zomwe zimapangitsa kuti Amph apindule

Zotsatira pakali pano zikuwonetsa kuti chiwerewere chomwe chinayambitsa kuwonjezereka kosatha kwa ΔFosB mu NAc neurons yogwirizana ndi kupititsa patsogolo Amph mphoto. Kuti mudziwe ngati kuwonjezeka kwa ntchito ya FosB ndi yofunika kwambiri kuti Amph athandizidwe, WONSE, wokondedwa womangirira kwambiri wa ΔFosB amene amaletsa kufotokozera kwa ΔFosB.Winstanley et al., 2007), ankadandaula kwambiri pogwiritsa ntchito mavairasi omwe amatsutsana nawo ku NAC (Chith. 3A,B). Zotsatira za machitidwe a Amph CPP zasonyeza kuti kuchepetsa ntchito ya ΔFosB pofotokozera kuti ZOCHITIKA mu NAC zinkateteza zotsatira za kugonana ndi mphoto ya 7 yogonana chifukwa cha kudzichepetsa kwa Amph kupindula. Zilombo zogonana ZINTHU zosaoneka sizinapangitse CPP yayikulu ya Amph ndipo sizinasiyana ndi anthu osagonana ndi ziweto ZINYAMATA zinyama (Chith. 3B). Mosiyana ndi zimenezi, nyama zogonana za GFP zogonana zinapanga CPP kwa Amph monga momwe ziwonetsedwera ndi chiwerengero chachikulu cha CPP poyerekeza ndi maulamuliro a GFP okhudzana ndi kugonana (Chith. 3B, p = 0.018).

Chithunzi 3.     

Chithunzi 3.     

Kusamalitsa ΔFosB ntchito mu NAC yotsekedwa imalimbikitsa mphoto ya AMPH ndikuwonjezeka mu ziwerengero za NAc zinyama zogonana. A, Zithunzi zoimira GFP kuzilombo zitatu zomwe zimalandira jekeseni wa kachilombo koyambitsa matenda a adeno -Indondomeko yomwe imayendetsedwa pamtengowo, poyerekeza ndi malo ocheperako (kumanzere), pakati, ndi pakati (kumanja). ac, anterior chitetezo; LV, ventralle yotsatira. Mzere wamtengo, 250 μm. B, Chizindikiro chokhazikitsidwa cha malo otchuka kwambiri komanso momwe zimafalitsira kachilombo ka HIV. Pa zinyama zonse, GFP inkapezeka mu chipolopolo, koma kufalikira kumtima kunali kusinthika. C, Nthawi yochuluka mu chipinda cha Amph-paired panthawi yopitiliza kuyesa kupatulapo chiwerengero cha pretest (CPP) kwa ziwalo zogonana (zoyera) ndi zodziwa (nyama zakuda) zomwe zimalandira jekeseni wa GFP control vector (Naive, n = 9; Exp, n = 10) kapena WONSE wodabwitsa (Wopanda, n = 9; Exp, n = 9). D, Zithunzi zoimira zigawo za dendritic kuchokera ku GFP zokhudzana ndi kugonana ndi ΔIYunD imagwiritsidwa ntchito poyeza kuchuluka kwa msana. Mzere wamtengo, 3 μm. E, Chiwerengero cha mankhwala opatsirana pogonana mu NAC a ziwalo zogonana (azungu) komanso nyama zodziwa (zakuda) zomwe zimalandira jekeseni wa vutolo la GFP kapena ZINTHU zosaoneka. Deta ndi gulu lotanthauza ± SEM. *p <0.05, kusiyana kwakukulu poyerekeza ndi kuwongolera zopanda nzeru. #p <0.05, kusiyana kwakukulu kuchokera ku maulamuliro a GFP.

Zowonongeka za kusadandaula kwakukulu sikunali chifukwa cha kusokonezeka kwa chiwerewere panthawi yogonana. Kulongosola kwa ZOCHITIKA ku NAC zakhala zikuwonetsedwa kuti zisalepheretsedwe kogonana kachitidwe ka chiwerewere (Pitchers et al., 2010b). Inde, izi zatsimikiziridwa mu kuyesedwa kwamakono. Ziweto zolamulira za GFP zimasonyeza kuchepa kwafupipafupi kuti zitha kukwera, kuthamanga, ndi kuthamangitsidwa, ndi kuchepa kwa mapiritsi ndi kutulutsa zochepa pa tsiku lachinayi lachiwiri lokhalitsa, poyerekeza ndi tsiku loyamba la kukwatira (Gulu 1). Mosiyana ndi zinyama, nyama zosadetsedwa sizinawonetseke kuti zimakhala zochepa kwambiri kuti zitha kusuntha kapena kutsika pang'ono pa tsiku lachinayi la kusamba poyerekeza ndi zoyamba. Choncho, osadandaula ku NAC anathetsa zotsatira za kugonana. Komabe, panalibe kusiyana kwakukulu pakati pa magwiridwe osiyana pakati pa GFP ndi magulu omwe analowetsedwa m'magulu pa nthawi iliyonse yowonongeka, zomwe zimasonyeza kuti zotsatira za kusokonezeka kwa kugonana pazochitika zogonana -zimene zimapangitsa kuti Amph CPP iwonongeke sizomwe zimayambitsa kusiyana chidziwitso chokwanira paokha (Gulu 1).

Onani gome ili:      

Gulu 1.     

Zomwe zimachitika pa chiwerewere pakupeza zochitika za kugonana m'magulu omwe analandira NAC infusions a GFP- kapena ΔJunD-expressing vectors vectorsa

ΔFosB ndi yofunikira kwambiri kuwonjezeka kwa chiwerewere kuwonjezeka kwa NAc dendritic spines

Ntchito yaFosB inkafunikanso kuwonjezeka kwa msinkhu wa msana wa NAC neurons pambuyo pa chiwerewere ndi kugonana kwa 7 d kugonana (Chith. 3C,D). Pofufuza msana mu NAC ya nyama zomwe zafotokozedwa pamwambapa kwa CPP, njira ziwiri za ANOVA zinasonyeza zotsatira zazikulu zokhudzana ndi kugonana (F(1,34) = 31.768, p <0.001) ndi mankhwala a vector vector (F(1,34) = 14.969, p = 0.001), komanso kugwirizana (F(1,34) = 10.651, p = 0.005). Mwachidziwitso, nyama zogonana za GFP zokhudzana ndi kugonana zinali ndi ziphuphu zambiri za NAC poyerekeza ndi maulamuliro a GFP okhudzana ndi kugonana (Chith. 3D: p <0.001), kutsimikizira zomwe tidapeza m'mbuyomu (Pitchers et al., 2010a). Mosiyana ndi izi, nyama zogonana zogonana sizinali zosiyana kwambiri ndi magulu a anthu osagonana ndi magulu ankhanza, ndipo anali ochepa kwambiri poyerekeza ndi nyama zogonana za GFP zogonana (Chith. 3D: p <0.001). Chifukwa chake, MAFotokozedwe a NAc mu NAc adatseka zovuta zakugonana ndikupereka mphotho yodziletsa pa NAc spinogenesis.

Wotsutsa wa D1R amalepheretsa chizoloŵezi cha kugonana-chinapangitsa kuti ΔFosB zisamangidwe

Kuti mudziwe ngati D1R kapena D2R yothandizira ku NAc panthawi yopikisanitsa imafunika kugonana kwa ΔFosB ndikukakamizidwa ndi Amph CPP, zinyama zimalandira zowonongeka za D1R kapena D2R (kapena saline) ku NAC 15 min chisanafike 4 masewera olimbitsa thupi tsiku ndi tsiku. Chofunika kwambiri, ngakhalenso D1R kapena D2R satsutsana ndi chiyambi cha NAC choyambitsa kapena chiwonetsero cha khalidwe la chiwerewere panthawi iliyonse yotsatila (Chith. 4D-F). Mofananamo, Kutsutsana kwa D1R kapena D2R sikulepheretsa zotsatira zokhudzana ndi kugonana pazokhalitsa, monga magulu onse adasonyezera kutsogolera kwa chiwerewere, zikuwonetsedwa ndi kuchepa kwafupipafupi pa tsiku 4 poyerekeza ndi tsiku 1 (Chith. 4F) (F(1,40) = 37.113, p <0.001; Sal, p = 0.004; D1R Ant, p = 0.007; D2R Ant, p <0.001).

Chithunzi 4.     

Chithunzi 4.     

Otsutsa a Dopamine omwe amalowerera mu NAC sanakhudze kugonana. Coronal NAc zigawo (A, + 2.2; B, + 1.7; C, + 1.2 kuchokera ku bregma) posonyeza malo a intra-NAc malo a nyama zonse. Mankhwalawa ankagwiritsidwa ntchito pokhapokha koma amaimira unilaterally kuti athe kufotokozera zinyama zonse (Naive-Sal, zoyera, n = 7; Chithandizo; mdima wakuda, n = 9; Exp D1R Ant, yofiira, n = 9; Exp D2R Ant, wakuda, n = 8). ac, anterior chitetezo; LV, ventricle yotsatira; Chuma, caudate-putamen. Phiri latency (D), kuthamangitsidwa kosavuta (E), ndi kuthamanga kwajambulidwa (F) kwa magulu onse ogonana (Saline, woyera; D1R Ant, imvi; D2R Ant, wakuda). Deta ikuyimira imatanthauza ± SEM. *p <0.05, kusiyana kwakukulu pakati pa tsiku 1 ndi tsiku 4 mkati mwa chithandizo.

Kufufuza kwa chiwerengero cha ΔFosB-IR maselo mu NAC 7 d pambuyo pa kutaya kwa NAc kotsiriza ndi kukambirana mmagulu kapena kuwonetserana bwino kunawonetsa kusiyana kwakukulu pakati pa magulu onse a NAc shell (F(3,29) = 18.070, p <0.001) ndi pachimake (F(3,29) = 10.017, p <0.001). Choyamba, chidziwitso cha kugonana mu saline-infused controls chinachititsa kuti ΔFosB iwonongeke poyerekeza ndi machitidwe achiwerewere (Chith. 5A, chipolopolo p <0.001; Chith. 5B: core, p <0.001), kutsimikizira zotsatira pamwambapa. Kutsutsana kwa D1R, koma osati D2R, kulepheretsa kapena kuchepetsa kusokonekera kwa ΔFosB. Mu chipolopolo cha NAc, wotsutsana ndi D1R yemwe amathandizira amuna ogonana sanasonyeze kuwonjezeka kwa ma cell a osBFosB-IR poyerekeza ndi kuwongolera zachiwerewere (Chith. 5A: p = 0.110), ndipo kufotokoza kwaFosB kunali kochepa kwambiri poyerekeza ndi amuna amchere amchere (Chith. 5A: p = 0.002). M'katikati mwa NAC, kutsutsana kwa D1R kunali ndi zotsatira zochepa: ΔFosB yowonjezereka kwambiri mu amuna omwe amachitira nkhanza D1R poyerekeza ndi machitidwe amchere amchere (Chith. 5B: p = 0.031), koma kuphulika kumeneku kunali kochepa kwambiri poyerekeza ndi amuna ochizira amchere (Chith. 5B: p = 0.012). Mankhwala otsutsana ndi D2R sanakhudze ΔFosB kudulidwa monga amuna omwe anali ndi chiwerewere omwe analandira mdani wa D2R anali ndi chiwerengero chachikulu cha maselo a FosB-IR poyerekeza ndi machitidwe a saline amchere (Chith. 5A: chipolopolo, p <0.001; Chith. 5B: core, p <0.001) ndi amuna omwe amathandizidwa ndi D1R ()Chith. 5A: chipolopolo, p <0.001; Chith. 5B: core, p = 0.013), ndipo sanali kusiyana ndi amuna amchere odziwa zachiwerewere.

Chithunzi 5.      

Chithunzi 5.      

Kuletsa D1R ku NAc kumatsutsa kuwonjezeka kwa chiwerengero cha ΔFosB-IR maselo mu NAC ya nyama zogonana. Kusintha kwa nambala ya maselo ΔFosB-IR mu shell ya NAc (A) ndi pakati (B) mu nyama zogonana (zakuda) poyerekeza ndi zolaula (zoyera) zakugonana (Naive-Sal, n = 6; Exp-Saline, n = 7; Exp D1R Ant, n = 9; Exp D2R Ant, n = 8). Deta ndi gulu lotanthauza ± SEM. *p <0.05, kusiyana kwakukulu poyerekeza ndi kuwongolera zopanda nzeru. #p <0.05, kusiyana kwakukulu poyerekeza ndi saline ndi D2R Ant nyama zodziwika bwino. Woimira zithunzi za Naive Sal (C), Exp Sal ​​(D), Exp D1R Ant (E), ndi Exp D2R Ant (F). ac, Anterior ayambe. Mzere wamtengo, 100 μm.

Pofuna kuthetsa kufalikira kwa adani a D1R kapena a D2R kupita ku dorsa striatum, kufotokoza kwaFosB kunasanthuledwa kudera lomwe nthawi yomweyo limathamangira ku NAc ndi pafupi ndi mitsempha yowonongeka, monga momwe kudula kwa ΔFosB mu dorsal striatum ndi psychostimulants ndi opiates zimadalira D1R ntchito (Zhang et al., 2002; Muller ndi Unterwald, 2005). Zochitika zokhudzana ndi kugonana zinachulukitsa chiwerengero cha ΔFosB-ir maselo ophatikizira m'matumbo aamuna amodzi (Naive-Sal: 35.6 ± 4.8 vs Exp-Sal: 82.9 ± 5.1; p <0.001), kutsimikizira lipoti lathu lakale (Pitchers et al., 2010b). Komanso, palibe D1R kapena D2R amene amatsutsana nawo ku NAC zomwe zakhudzana ndi kugonana-zinayambitsa ΔFosB mu dorsal striatum (Exp-D1R: 82.75 ± 2.64 ir maselo; Exp-D2R: 83.9 ± 4.4 maselo; p <0.001 poyerekeza ndi Naive-Sal zowongolera). Zotsatira izi zikuwonetsa kuti kufalikira kwa infusions kwa omwe akutsutsana kumangokhala ku NAc kokha.

Wotsutsa D1R ku NAc amalepheretsa Amph kupereka mphotho

D1R ikusungidwa mu NAc panthawi yomwe ikugonjetseranso kugonana komwe kunachititsa kuti Amph athandizidwe, athandizidwe, atayesedwa 7 d pambuyo pa kutaya kwa NAC kotsiriza ndi kuyesedwa kwa mating (F(3,29) = 2.956, p = 0.049). Zinyama zokhudzana ndi kugonana zomwe zinalandira saline ku NAc panthawi ya kukambirana zimathera nthawi yochuluka kwambiri mu chipinda cha Amph-paired poyerekeza ndi amuna achiwerewere (Chith. 6A, p = 0.025), kutsimikizira zotsatira pamwambapa. Mosiyana ndi izi, nyama zokhudzana ndi kugonana zomwe zinkalandira mdani wa intra-NAc D1R pa nthawi ya kukwatira sizinapange CPP kwa Amph. Iwo sanali osiyana ndi maulamuliro okhudzana ndi chiwerewere, ndipo anakhala nthawi yochepa mu chipinda cha Amph-paired poyerekeza ndi saline (Chith. 6A: p = 0.049) kapena wotsutsa D2R (Chith. 6A: p = 0.038) amachititsa amuna omwe amadziwika ndi kugonana. D2R otsutsana ndi matendawa sanagwirizane ndi Amph omwe amathandizidwa kuti adzalandire mphoto monga zinyama zogonana ndi NAC D2R omwe amatsutsana ndi matendawa.Chith. 6A: p = 0.040) ndi D1R amene amatsutsa zinyama (Chith. 6A: p = 0.038), ndipo sanali kusiyana ndi amuna amchere odziwa zachiwerewere.

Chithunzi 6.      

Chithunzi 6.      

Kuletsa ma D1 receptors ku NAc kumathetsa mphamvu za Amph kupindula ndikuwonjezereka mankhwala opatsirana pogwiritsa ntchito ziweto zogonana. A, Nthawi yochuluka mu chipinda chotchedwa Amph-paired Room pamapeto pa mayesero kupatula chiwerengero cha pretest (CPP, masekondi) kwa anthu opatsirana pogonana (oyera, n = 6) ndi nyama zodziwa (zakuda) zomwe zinalandira saline (n = 7), wotsutsa D1R (n = 9), kapena wotsutsa D2R (n = 8). Deta ndi gulu lotanthauza ± SEM. *p <0.05, kusiyana kwakukulu poyerekeza ndi zowongolera zamchere zamchere. #p <0.05, kusiyana kwakukulu kuchokera ku nyama zodziwika bwino za D1R Ant. B, Chiwerengero cha mankhwala osokoneza bongo (pa 10 μm) kwa anthu opatsirana pogonana (oyera, n = 7) ndi nyama zodziwa (zakuda) zomwe zinalandira saline (n = 8), wotsutsa D1R (n = 8), kapena wotsutsa D2R (n = 8). Deta ndi gulu lotanthauza ± SEM. *p <0.05, kusiyana kwakukulu poyerekeza ndi zowongolera zamchere zamchere. #p <0.05, kusiyana kwakukulu ndi kuwongolera mchere wambiri.

Mankhwala otsutsana a D1R amachititsa kuti kugonana kugwire ntchito - kunapangitsa NAc spinogenesis

Kufufuza kwa msinkhu wa msana m'kati mwa NAc ya nyama zomwezo zimasonyeza kuti D1R kulumikiza panthawi yomwe imatetezera anafunika kuwonjezera kuchulukitsa kwa msana wa NAc pambuyo pa zochitika zogonana ndi 7 d za kugonana kwapadera (Chith. 6B; F(3,26) = 41.558, p <0.001). Makamaka, zowongolera zamchere zamchere komanso nyama zotsutsana ndi D2R zinali ndi mitsempha yochulukirapo poyerekeza ndi zowononga zamchere zamchere (Chith. 6B: p <0.001) kutsimikizira zomwe tidapeza m'mbuyomu (Pitchers et al., 2010a) ndi zomwe zili ndi GFP zowononga tizilombo toyambitsa matenda tafotokozedwa pamwambapa. Mosiyana ndi zimenezi, D1R wotsutsana ndi chiwerewere-ankalowetsa nyama zomwe zinali zosiyana ndi saline yachisembwere (kugonana)Chith. 6B). Panali ndi zotsatira zochepa za kulowetsedwa kwa D2R kutsutsana monga D2R inalowetsa zinyama zikuwonetsa kuchepa kwa msana kuposa momwe zimakhalira ndi mchere (Chith. 6B: p = 0.02), koma nambala yochulukirapo ya spines poyerekeza ndi machitidwe olimbitsa thupi amchere ndi azimayi omwe amadziwika ndi D1R (p <0.001; Chith. 6B). Choncho, D1R yoletsedwa ku NAC nthawi yolepheretsa zotsatira zokhudzana ndi kugonana komanso kuletsa kudziletsa pa NAc spinogenesis.

Kukambirana

Phunziroli, tawonetsa kuponderezana pakati pa malipiro a chilengedwe ndi mankhwala, pamene malipiro a chilengedwe amatsatidwa ndi nthawi yodziletsa. Mwachindunji, ife tawonetsa chidziwitso cha khalidwe la chiwerewere, titatsatiridwa ndi 7 kapena 28 d kudziletsa, zimayambitsa Amph kupititsa patsogolo. Zotsatirazi zili ndi zofanana ndi ntchito yofunika kwambiri yodziletsa nthawi yachisokonezo kuchokera ku mankhwala osokoneza bongo pokhapokha ngati mukugwiritsira ntchito mankhwala osokoneza bongo (Lu et al., 2005; Thomas et al., 2008; Wolf, 2010b, 2012; Xue et al., 2012). Kuwonjezera apo, DFFB yomwe imayambitsa mphoto ku NAC ndi yofunika kwambiri kuti zitha kuwonetsa mphotho zowonongeka pa psychostimulant mphotho, zomwe zingathe kupyolera pa spinogenesis mu NAC panthawi yopuma. Tinawonetsa kuti ΔFosB yasonkhanitsa ku NAC pambuyo pa chidziwitso cha kugonana ndi yokhalitsa ndi kudalira ntchito ya NAc D1R panthawi yokwatira. Pomwepo, kulembedwa kwa D1R kwa ΔFosB kulembedwa kwa NAc kunasonyezedwa kukhala kovuta kuti phindu la Amph liwonjezereke ndi kuwonjezeka kwa msinkhu wambiri mu NAC, ngakhale kuti zotsatirazi zokhudzana ndi kugonana zimadalira nthawi yosiya kugonana (Pitchers et al., 2010a). Pomalizira, tinasonyeza kuti NAc spinogenesis ikhoza kuthandizira kufotokozera mwachidule mafupipafupi Amph kupatsa mphotho koma sizowonjezereka kuti apitirize kuwonetsa mphotho yowonjezereka ya mankhwala, chifukwa kuchulukitsidwa kwa msana ku NAC kunali kochepa komanso kwatha pambuyo pa 7 d, koma osati 28 d, nthawi ya kudziletsa.

Kwadziwika kale kuti dopamine imatulutsidwa mu NAC pazochitika zachilengedwe, kuphatikizapo chiwerewere. Pambuyo poyambira mkazi wothandizira, extracellular dopamine mu NAc yowonjezera ndipo imakhala ikukweza pa nthawi ya kukwatira (Fiorino et al., 1997). Kafukufuku wamakono akuwonetsa kuti kulowetsa antchito a dopamine receptor ku NAc panthawi yopikisana sikunakhudze pa kuyambitsa kapena kugwira ntchito za kugonana, zomwe zikugwirizana ndi lingaliro lakuti dopamine sichikuphatikizidwa mu kufotokoza kwa mphotho pazokha, koma kuti apereke chidziwitso cholimbikitsana cha nkhani zogonana (Berridge ndi Robinson, 1998). Zoonadi, kuganizira zokhudzana ndi kugonana kumapangitsa kuti mitsempha yothandizira mitsempha ya dopamine ipangidwe, kuphatikizapo maselo a dopaminergic omwe ali m'dera la ventral tekali ndi cholinga chawo, NAC (Balfour et al., 2004). Chizolowezi chogonana chobwerezabwereza chimapangitsa ΔFosB ku NAC, yomwe imayanjanitsa zomwe zinachititsa kuti anthu azigonana (Pitchers et al., 2010b). Zotsatira zamakono zikuwonetsa kuti kuperewera kwa ΔFosB kusakanikirana ndikutengera, kumadalira kuchitidwa kwa D1R ku NAc panthawi yokwatira. Kupeza uku kukugwirizana ndi kafukufuku wammbuyo omwe akuwonetsa kuti nthawi zambiri mauthenga a psychostimulant akupitiriza kuwonjezeka ΔFosB mu NAC yomwe imayankhula ndi D1R (Lee ndi al., 2006; Kim et al., 2009) komanso kuti kufooka kwa DFFB kumadalira kuchitidwa kwa D1R (Zhang et al., 2002). Kuonjezera apo, mayankho ogwira ntchito, omwe amawoneka ndi mankhwala osokoneza bongo, amatha kupangidwanso popanda kugwiritsira ntchito mankhwala osokoneza bongo chifukwa cha kudandaula kwakukulu kwa DFBB mu D1R yomwe imatulutsa neurons mu statum (Kelz et al., 1999). TMwamuna ndi mkazi, zonse zowonjezera zachilengedwe ndi za mankhwala zimapangitsa ΔFosB ku NAC kudzera njira zothandizira D1R kuti ziwathandize kukhala ndi mphotho.

Komanso, zomwe zapeza tsopano zikusonyeza kuti ΔFosB ndi mkhalapakati wofunika kwambiri pakati pa chidziwitso pakati pa chilengedwe ndi mphotho ya psychostimulant. Monga taonera, ntchito ya FosB ku NAC yakhala ikukhudzidwa ndi mayankho a mankhwala, monga momwe ΔFosB yodziwira momveka bwino mu NAC imathandizira kuti anthu azigwiritsa ntchito mankhwalawa kuti ayambe kumwa mankhwalawa.Kelz et al., 1999), kumawonjezera mphamvu ya cocaine ndi morphine CPP (Kelz et al., 1999; Zachariou et al., 2006), ndipo amachititsa kudziyendetsa bwino kwa mankhwala ochepa a cocaine (Colby et al., 2003). Kafukufuku wamakono akuwonetsa kuti kubwezeretsedwa kwa D1R kapena ntchito ya FFB ku NAC pamene akugonjetseratu kuthetsa kugonana komwe kunapangitsa kuti Amph apindule.

Kafukufuku wamakono akuwonetsa kuti nthawi yodziletsa kuchokera ku mphotho ya kugonana ikufunika kuti chidziwitso cha Amph chipindule ndi NAc spinogenesis. Timaganiza kuti ΔFosB panthawi imeneyi yodziletsa imakhudza ntchito ya neuronal potembenuza mazira a mafupa kuti ayambe spinogenesis ndikusintha mphamvu ya synaptic. Ndipotu, kuletsa kutsekedwa kwa ΔFosB mu NAc nthawi ya kusamalidwa kunalephereka kuwonjezeka kwa msinkhu wambiri m'kati mwa NAc atazindikiranso pambuyo pa mphoto. Kuwonjezera apo, kulowetsedwa kwa mdani wa D1R ku NAC musanayambe kusonkhana kumathandiza kuti kuwonjezeka kwa kugonana kwapangitsa kuti ΔFosB iwonjezeke komanso zotsatira zake zowonjezereka.

ΔFosB ndi chinthu cholembera kuti chikhale ngati choyimitsa cholembera kapena chopondereza kuti chikhudze mafotokozedwe a zowonongeka za majeremusi zomwe zingasokoneze mphamvu ndi mphamvu ya synaptic mu NAC (Nestler, 2008). Makamaka, ΔFosB imayambitsa cyclic-dependent kinase-5 (Bibb et al., 2001; Kumar et al., 2005), chinthu cha nyukiliya κ B (NF-κB) (Russo et al., 2009b), ndi GluA2 subunit ya glutamate AMPA receptor (Vialou et al., 2010) ndi rimafotokoza zolembera za jekeseni wam'mbuyo oyambirira (Pitchers et al., 2010b) ndi histone methyltreferase G9 (Maze et al., 2010). Cxc-dependent kinase-5 imayambitsa mapuloteni a cytoskeletal ndi kutuluka kwa neurite (Taylor ndi al., 2007). Kuwonjezera apo, kuyambitsa NF-κB kumawonjezera chiwerengero cha mitsempha ya dendritic mu NAC, pamene kukanizidwa kwa NF-κB kunachepetsanso mitsempha ya dendritic yowonjezera ndipo imapangitsa kuwonjezeka kwa cocaine kuwonjezeka pamphepete (Russo et al., 2009b). Chifukwa chake, mphotho ya kugonana imachulukitsa ΔFosB mu NAC, yomwe ingasinthe Nc kuperewera kwazambiri mwachitsanzo (ie, cyclic-dependent kinase-5, NF-κB) ndi kuti zotsatira zake zonse ndi mphotho ya mankhwala, monga momwe Russo et al. (2009a) chifukwa cha zochita za mobwerezabwereza cocaine.

Chidziwitso chosayembekezereka mwa kafukufuku wamakono chinali chakuti kuwonjezeka kwa msinkhu wa msana mu NAC kunali kochepa, ndipo sikunapezenso ku 28 d pambuyo pa chidziwitso cha kugonana. Motero, kuchuluka kwa msinkhu wa msana kunagwirizanitsidwa ndi kuyamba kwa Amph kupindula ndipo kungapangitse chitukuko choyamba kapena kufotokoza kwafupipafupi kwa mayankho a Amph. Komabe, kuwonjezeka kwa msinkhu wa msana sikunali kofunika kuti pitirizani kulimbitsa Amph mphotho pambuyo pa nthawi yodziletsa nthawi yaitali. Tinawonetsa kale kuti chiopsezo cha kugonana chimayambitsa kanthawi kochepa (7, koma osati 28, masiku apambuyo omaliza omaliza) kuwonjezeka kwa NMDA gawo lachipatala cha NR-1 ku NAc, yomwe idabwerera ku miyeso yoyambira pambuyo pa nthawi yochuluka yosiya kudziletsa (Pitchers et al., 2012). Izi zowonjezera kuyankhulana kwa NMDA kulandira chiwonetsero kukhala chiwonetsero cha kugonana kosasokonezeka komweko (Huang et al., 2009; Brown ndi al., 2011; Pitchers et al., 2012), ndikuwonetseratu kuti kuthekera kwa kugonana-kumayambitsa kukula kwa msana kumadalira ntchito yowonjezera ya NMDA yomwe imalandira (Hamilton et al., 2012).

Pomalizira, kafukufuku wamakono akuwonetseratu kuwonetsetsa kwapakati pa mphotho ya mankhwala chifukwa cha mphotho (kugonana) ndi kudalira kwake pa nthawi yopuma. Komanso, mapulasitikiwa amatsutsana ndi ΔFosB pogwiritsa ntchito D1R kukhazikitsa ku NAC. Choncho, deta imasonyeza kuti kutaya kwa mphotho zapadera pambuyo pothandizira mphotho kungapangitse anthu kukhala osatetezeka ku chitukuko cha mankhwala osokoneza bongo komanso kuti mkhalapakati mmodzi wa chiopsezo ichi ndi ΔFosB ndi zolembera zake zolembera pansi.

Mawu a M'munsi

  • Adalandira October 16, 2012.
  • Kukonzanso kunalandira December 12, 2012.
  • Adalandira December 23, 2012.

  • Ntchitoyi inathandizidwa ndi Institute of Health Research (LMC) ku Canada, National Institute of Mental Health (EJN), ndi Natural Sciences ndi Engineering Research Council of Canada (KKP ndi LMC). Tikuthokoza Dr. Catherine Woolley (University of Northwestern University) kuti athandizidwe ndi njira zolemba ma dilisti.

  • Olembawo salengeza kuti palibe mpikisano wa ndalama.

  • Mndandanda wa zolembera uyenera kuuzidwa kwa Dr. Lique M. Coolen, Dipatimenti ya Physiology ndi Biophysics, Medical Center ya University of Mississippi, 2500 North State Street, Jackson, MS 39216. [imelo ndiotetezedwa]

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