Kugwiritsa ntchito ovomerezeka a Dopamine mu Nucleus Accumbens Kumalimbikitsa Chikhalidwe cha Sucrose-Cholimbikitsidwa ndi Njira Yotsamba (2016)

nyama

Long-Evans wamwamuna asanu ndi atatu omwe anayeza 275-300 g anagulidwa kuchokera ku Harlan ndipo amaimba pa 12 kuwala / mdima. Zonse zoyesera zinachitidwa pang'onopang'ono. Kusamalira nyama kunali kofananako ndi nkhani zofalitsidwa kale (Nicola, 2010; du Hoffmann et al., 2011; McGinty et al., 2013; du Hoffmann ndi Nicola, 2014; Morrison ndi Nicola, 2014). Atafika, makoswe anapatsidwa mlungu wa 1 wa mpumulo ndipo kenako anazoloŵera kuti azitsatiridwa ndi experimenter. Pambuyo pa chizoloŵezi, nyama zinkakhala zowonjezera kwa ~ 90% ya kulemera kwa thupi kwaulere musanayambe magawo oyambirira a maphunziro. Pambuyo pa maphunziro oyambirira, nyama zinapatsidwa mwayi womvera ma laboratory chow mu nyumba yawo. Zotsatira za zinyama zonse zinali zogwirizana ndi US National Institutes of Health Zitsogolere za Kusamalira ndi Kugwiritsa Ntchito Zanyama Zanyama ndipo anavomerezedwa ndi Komiti ya Institutional Animal Care ndi Komiti Yogwiritsira ntchito ku Albert Einstein College of Medicine.

Zipinda zogwira ntchito

Maphunziro a chikhalidwe adachitika m'zipinda zogwiritsira ntchito (30 × 25 masentimita) omwe anagulidwa kuchokera ku Med Associates. Zofufuza zinkapangidwa mu makina ochepetsera bwino okhala ndi nyali za buluu. Phokoso loyera nthawi zonse (65 dB) linali kusewera m'chipinda kuti athetse zosokoneza phokoso lakunja. Zipinda zogwiritsira ntchito zinali ndi mphoto yokhala pa khoma limodzi. Chithunzi cha photobeam chomwe chili kutsogolo kwa cholandiracho chinayesa kulowa ndi nthawi zochoka. Pampu ya syringe, yomwe ili kunja kwa chipinda, idagwiritsidwa ntchito popereka mphotho ya sucrose mu mphoto yolandirira. Zisampha za nthawi za makhalidwe zidalembedwa ndi chisankho cha 1 ms.

Ntchito yopanga ntchito ya 2CS

Nyama zinali zoletsedwa chakudya panthawi yoyamba yophunzitsira. Gawo loyamba la maphunziro limafuna kuti nyamazo zilowe muzakudya, zomwe zidapangitsa kuti 10% yamadzi sucrose. Pambuyo pakuchedwa kwa 10 kulola kuti mugwiritse ntchito mphotho, nyama zimayenera kusiya cholowetsamo ndikulowanso kuti zikapeze mphotho yowonjezera. M'magawo ophunzirira otsatira, kuchedwa kwa 20 s kenako 30 s kunayambitsidwa pakati pakupezeka kwa mphotho. Magwiridwe adayikidwa pamalipiro 100 omwe adalandira 1 h. Ntchito zogwirira ntchito zitakhazikitsidwa ndikuchedwa kwa 30 pakati pa kupezeka kwa mphotho, njira ziwiri zowunikira zidayambitsidwa zomwe zimaneneratu za mphotho yaying'ono kapena yayikulu (150 kapena 250 μl ya 10% yankho la sucrose m'madzi). Zolemba zake zinali ndi mawu a siren (omwe amayenda pafupipafupi kuchokera ku 4 mpaka 8 kHz kupitilira 400 ms) ndi mawu apakatikati (6 kHz kamvekedwe ka 40 ms, kutali kwa 50 ms); Malangizo amapatsidwa mphotho yayikulu ndi yaying'ono mwachisawawa pa makoswe aliwonse ndipo ubale wamalipiro opitilira muyeso umakhalabe wopitilira maphunziro ndi zoyeserera za makoswe. Kupereka mphotho kunadalira kuti makoswe amalowa mchilandiliro cha mphotho panthawi yomwe awonetsere, pomwe cue idathetsedwa. Zotsatira zinali mpaka 5 s. Nthawi yoyeserera idasankhidwa mosasamala kuchokera pagawidwe lotsogola laling'ono ndi tanthauzo la 30 s. Nyama zikayankha> 80% yazinthuzo, nyama zimadyetsedwa ad libitum m'nyumba zawo zosungira kuyambira nthawi imeneyo mpaka mapeto a kuyesera. Pambuyo pa ntchito yogwirira ntchito, sucrose ndondomeko ya madzi mphoto idachepetsedwa kuchokera ku 10% mpaka 3%; mabukuwo sanasinthe. Makhalidwe anali kuyang'aniridwa tsiku ndi tsiku mpaka ntchito ya asymptotic ikwaniritsidwe.

Opaleshoni

Pambuyo pa kuyendetsa bwino kwa makhalidwe, ndondomeko ya maynulae yomwe inagwirizanitsa nthenda ya NAC inalembedwa mobwerezabwereza (monga Nicola, 2010; Lardeux et al., 2015). Mwachidule, nyama zinkakondweretsedwa ndi isofluorane ndipo zimayikidwa mu stereotaxic chimango ndi mutu wapansi. Mabowo ang'onoang'ono anaphwanyidwa pang'onopang'ono mumagazi a 1.4 mm anterior ndi ± 1.5 mm pambuyo pa Bregma. Dzanja la stereotaxic linagwiritsidwa ntchito poika malo a cannulae m'mabowo awa ndi kuwachepetsera mu ubongo kuti apite kumapeto kwa 6 mm kuchokera pamwamba pa chigaza (2 mm pamwamba pa NAc). Cannulae ankagwiritsidwa ntchito m'malo ndi mafupa a pakhosi ndi simenti. Mizere iwiri yosakanizika inaikidwa pamtunda pagawo ndipo imakhala mu simenti yamazinyo. Zithunzizi zimagwirizanitsidwa ndi zikuluzikulu kumutu wa mutu womwe uli ndi ma LED awiri, omwe amalola kutsatila mavidiyo pamayesero. Nyama zinalandira ma antibiotic enrofloxacin musanakhale tsiku la opaleshoni yotsatira ya 1. Pambuyo pa opaleshoni, makoswe anapatsidwa 1 sabata kuti adziwetse nthawi yochepa yobwerera pambuyo pa opaleshoni pa ntchito ya 2CS inayamba.

mankhwala

Mankhwala adagulidwa kuchokera ku Sigma ndipo amasungunuka mu 0.9% wosabala saline tsiku limene adagwiritsidwa ntchito. Mankhwala osokoneza bongo pambali anali: "D1 agonist low," 0.1 μg SKF81297; "D1 agonist mkulu," 0.4 μg SKF81297; "Wotsutsa D1," 1.1 μg Kutaya 23390; "D2 agonist low," 1 μg quinpirole; "D2 agonist mkulu," 10 μg quinpirole; "Wotsutsa D2," 2.2 μg raclopride.

Njira ya microinjection

Monga tafotokozera kale (Nicola, 2010; Lardeux et al., 2015), makoswe anali oleredwa ndi thaulo pamene 33 ga injection anali atalowetsedwa mu guide guide cannulae kotero kuti jekeseni inapititsa patsogolo 2 mm kuchokera pansi pa chitsogozo, kufika pakatikati pa NAC. Pambuyo pa 1 min, 0.5 μL ya mankhwala yothetsera mankhwala inayikidwa mu 2 min ndi pompeni yeniyeni yoyenera. Mankhwalawa anapatsidwa 1 min kuti apitirire, kenako ziwetozo zinayikidwa pakhomo. Ndondomeko ya jekeseni ya mankhwala inali yopangidwira pa makoswe. Majekesiti ankachitidwa kawiri pa sabata (Lachiwiri ndi Lachinayi kapena Lachisanu), ndi gawo lopanda kukanika lomwe limayambira tsiku lomwe lisanayambe jekeseni kuti zitsimikizire kuti khalidwe lanu latuluka kuchokera mu jekeseni yapitayo.

Kuwonera kanema

Patsiku loyesa, makoswe adalemba pogwiritsa ntchito kamera yapamtunda (mafelemu 30 / s) ndi makina owonera (mwina Plexon Cineplex kapena Noldus Ethovision). Njirayi idasanthula ma x ndi y ma LED ofiira ndi obiriwira omwe ali pamutu pa khoswe. Monga tafotokozera kale (Nicola, 2010; McGinty et al., 2013; du Hoffmann ndi Nicola, 2014; Morrison ndi Nicola, 2014), Kuti tidziwe malo amphaka m'chipinda chogwiritsira ntchito tidawerengera centroid (malo apakati) pakati pama LED pamafayilo aliwonse. Malo osowa mpaka mafelemu 10 motsatizana adalumikizidwa; ngati> mafelemu 10 otsatizana omwe anali kusowa zatayidwako. Pa chimango chilichonse, kenako tinawerengera SD ya kutalika kwa malo okhala ndi centroid pazenera lazakanthawi la 200 ms. Chipika chikasinthidwa, mfundo za SDzi zidagawidwa mofananamo, pomwe nsonga yotsika imayimira nthawi zosayenda komanso mayendedwe apamwamba. Tidakwaniritsa magwiridwe awiri aku Gaussian kumagawidwewa ndipo gawo loyenda lidatsimikiziridwa kuti ndilo gawo lomwe magawidwe apamwamba ndi apansi adakwanira ochepa. Kusuntha kumatanthauzidwa ngati mafelemu 8 motsatizana pamwamba pa malowa.

Kusanthula deta

Nkhumba imodzi inalephera kubwezeretsanso machitidwe opangira opaleshoni pambuyo pa kuikidwa kwachitsulo ndipo motere sichidavomerezedwe ndi microinjections. The cannulae kuchokera pirata yachiwiri inatsekedwa ndipo chifukwa chake microinjections sanachitidwe. Kotero, deta inapezedwa kuchokera ku 7 microinjections kwa mayesero ena ndi 6 kwa ena. Zomwe zimakhazikitsidwa nthawi komanso zida zosakanizidwa zojambulazo zinkatumizidwa ndi kusanthula zomwe zinkachitidwa ndi miyambo yowonongeka (R Core Team, 2013).

Muziwerengero 1B-E, tinayesa chiwerengero cha mayankho pogawa chiwerengero cha zizindikiro zomwe zinayankhidwa ndi 15 min kapena 1 hins ndipo zinawakonza monga njira zowonongeka. Pofufuza ntchito zosiyanasiyana zomwe zimakhudza ntchito mu mankhwala ena, tinagwiritsa ntchito njira zowonjezera ANOVA ndi chiwerengero choyankhidwa monga kusintha kwadalira pazifukwa ziwiri, nthawi yam'mbuyo (1 ndi 2 h) ndi mtundu wa cue (zazikulu ndi zazing'ono). Kutumiza awiri-tailed paired t-kuyesa kunkagwiritsidwa ntchito mkati mwa vuto lililonse la mankhwala kuti muwone ngati nthawi yamagawo ndi mtundu wa cue (yayikulu ndi yaying'ono) idakhudza kwambiri kuchuluka kwa mayankho. Welch ya miyendo iwiri t-zinali zogwiritsidwa ntchito kuyerekeza kuyanjana kwa mayankho kwa mankhwala alionse kuti amchere. Ma P a Pambuyo pake-zinthu zinawongosoledwa pogwiritsira ntchito mafananidwe a Sidak ambiri omwe amatha kuwongolera. Chofunika kwambiri pamayeso onse owerengetsera adayikidwa p <0.05. Zotsatira zamayesero onse owerengeka zitha kupezeka mu Gome Table11.

  

Chithunzi 1

D1 ndi D2 amalandirira anthu omwe amatsutsana ndi anthu omwe amatsutsana nawo.. (A) Zolinga za ntchito ya 2CS +. Nthawi sikuti iwonongeke. (B, C) Chiwerengero chokhazikika chosankhidwa choyankhidwa (% ya cues atayankhidwa) mu 15 minimenti yamphindi ya nthawi kuti amvetse izo ...

  

Gulu 1

Zotsatira zazotsatira.

Muziwerengero 2F, G, zomwe zimayankhidwa popanda kuyankhidwa poyamba, ndipo "kupuma" kunatanthauzidwa ngati ≥2 mayesero otsatizana opanda yankho. Kutalika kwa pause kunatanthauzidwa ngati nthawi ya pakati pa cues ndi mayankho. Nthawi yowonjezera yomwe amathera panthawi yopuma imakonzedweratu potsatira nambala yopuma (mapepala akumanzere), ndipo nthawi yowonjezera yomwe imagwiritsidwa ntchito poyimitsa pamapeto pa gawoli ikuwonetsedwa muzenera zamatabwa (zolumikiza zamanja). Njira imodzi Yomwe ali ndi mankhwala osokoneza bongo monga chinthu anagwiritsidwa ntchito kuti aone ngati chiwerengero cha mapulaneti kapena nthawi yowonjezera yosagwiritsidwa ntchito pakati pa mankhwala. Kutumiza awiri a mchira wa Sidak-wokonza Welch t-zinthu zinkagwiritsidwa ntchito kuyerekezera nambala yonse ya pause ndi nthawi yonse yomwe amagwiritsidwa ntchito poima pa mankhwala ndi saline.

  

Chithunzi 2

Odwala D1 ndi D2 amalandira malire amachepetsa nthawi yomwe sakukhala. (A-E) Omasula amasonyeza magawo asanu a chitsanzo, imodzi ya mankhwala (mankhwala ochepa okha). Mzere uliwonse ukuimira nthawi yomwe chidziwitso chimatchula mphoto yaikulu (yakuda) kapena yaing'ono (lalanje) ...

In Zizindikiro 4A, C, F, H, yesero lililonse t Ankalembedwanso ngati kuyambitsa yankho (R +) kapena kulephera kuyankha (R-). Kenaka tinkawerengera mwakuya zowoneka za R + kapena R- at t+ 1. Ndondomekoyi imabweretsa zochitika za 4, zomwe zimagwirizanitsidwa ndi njira yapadera yoyankhira ndipo palibe yankho pa mayesero awiri otsatizana, t ndi t+ 1: P_{(R + R +)}, P_{(R + R-)}, P_(R-R-), P_{(R-R +)}. Pamene zowonjezerazi zikukonzekera kuti gulu lililonse liyambike ndi mtundu wofanana (R + kapena R-) liri pamzere umodzi wa 2 × 2 matrix, mzere uliwonse umakhala umodzi; mwachitsanzo, matrix ali bwino stochastic. Mu Zizindikiro 4A, C, F, H, tinalinganiza (mosiyana ndi mankhwala ena) ndizomwe zimatanthawuza kuti zikhale zofunikira pa chigawo chilichonse ndi miyeso ya masiteti omwewo pamtundu womwewo. Mwachitsanzo, P_{(R + R +)}, P_{(R + R-)} ali pamzere wokhoma chifukwa mbali iliyonse imayamba ndi R +. Chifukwa mzere uliwonse wa chiwerengero cha matrix umaphatikizapo chimodzi, ziwerengero zamakono zimakhala zabwino, ndipo makoswe amatha kusintha mosavuta kuchokera kumbali (R +) kumalo osamvera (R-), ndipo mosiyana, stochastic matrix akhoza kufotokoza Markov chingwe chimene chokhazikitsira chithunzi chowoneka π chikhoza kuwerengedwa. Zizindikiro zoterezi ndizoyesa zotsatila za kupeza makoswe pamtundu wosamvera komanso wosamvera pazitsulo zolimba za Markov (Chithunzi (Figure3) .3). Kuti tiwerenge zigawo za π, tinasintha matrix, tinapeza zilembo zotsalira za matrices omwe tinasintha ndikugawa miyezo imeneyi ndi ndalama zawo (zomwe zimatsimikizira kuti zigawo za π zonse ndi 1). Zomwe zikutanthawuza zogwiritsidwa ntchito pa gulu lililonse la mankhwala zikukonzedwa muzinthu 4B, D, G, I. Choncho, tili ndi njira ziwiri zofotokozera khalidwe: ndi stochastic matrix, yomwe imasonyeza kusinthika mosavuta, komanso ndi vector of probability, zomwe zimapereka chiwerengero cha mwinamwake kuti katsulo ali mwina akumvetsera kapena osamvera boma. Poyerekeza ndi odwala omwe ali ndi mankhwala osokoneza bongo komanso nthawi, timachotsa zigawo ziwiri za π, njira yomwe imasungira chidziwitso chokhudza momwe zingakhazikitsire. Muziwerengero 4E, J, tinakonza zokambirana zosiyana siyana pakati pa mankhwala onse pa gawo lililonse. Kuti mudziwe kuti mankhwalawa ndi osiyana bwanji ngati odwalawa anali osiyana pakati pa oyamba ndi ola limodzi la magawowa, ife tinkafanizira kusiyana kwawo ndi mayesero olembedwa awiriwa. Kenaka, tinachita Wilcoxon osagwirizanitsa mayesero (saline vs. mankhwala) mkati mwa hr ndi kukonza ma 6 p (imodzi mwa mankhwala ndi saline) ndi kukonzedwa kwa Sidak.

  

Chithunzi 3

Kukonzekera kwa chitsanzo cha Markov chachiwiri. Pa mayesero omwe apatsidwa, makoswe amatha kukhalabe kumbali (kumbuyo ndi kuzungulira mtsinje) kapena malo osamvera (mzere wozungulira ndi kuvomereza mtsinje) kapena kusintha kumalo ena (mivi pakati pa mabwalo). Aliyense ...

  

Chithunzi 4

Odwala D1 ndi a D2 omwe amalandira ziphuphu amachititsa kuti anthu asamvetsetse zomwe zimachitika. (A, C, F, H). Ma grafu awa amasonyeza kusinthika komwe kumagwirizanitsidwa kwa onse a 4 omwe angayankhe / awiriwa osayankha, owerengedwa ndi equation yoperekedwa mu ...

Muziwerengero 5A, B, zomwe nyamazo zinayankha zinali zoyambirira. Mu Chithunzi Chithunzi5A, 5A, ziwalo za nyama zimayamba kusunthira kupita kumalo otsekemera (kumalo omanzere) ndi kukafika kulandirira malipiro (zolumikiza zoyenera) zinawerengedweratu ndipo zimakonzedweratu ngati gawolo likutanthawuza. Mu Chithunzi Chithunzi5B, 5B, tidawerengera, pamayeso aliwonse, kutalika kwa njira (mu cm) yomwe nyama idapita nayo cholowetsera kuchokera pomwe idayamba. Tidawerengetsa kuchuluka kwamitengo iwiri: (A) mtunda wolunjika pakati pa mbewa poyambira ndi cholandirira, ndi (B) kutalika kwa njira yeniyeni yomwe idatengedwa kuti ifike pacholowa. Izi A: B magawanidwe amatchedwa "njira yabwino"; amachokera ku 0 mpaka 1, okhala ndi mfundo zoyandikira ku 1 zosonyeza njira zosavuta (zochepa zoyenda). Mphamvu zadongosolo zidakonzedwa monga njira zophunzitsira za mtundu uliwonse wamankhwala. Kuti tiwone ngati mulingo uliwonse wa latency kapena njira yoyendetsera njira ndiyosiyana pakati pa mankhwala, tidachita njira imodzi ya ANOVAs ndi mankhwala. Chithunzi Chithunzi5C, 5C, pa yesero lirilonse ndi kulowa kolowera zopindulitsa tinayesa chiwerengero cha zolembera 5 zomwe zisanachitike ndi 5 s pambuyo pake. Izi ziwerengero zinasinthidwa kukhala ziwerengero (zolembedwera pa s) poziwerengera pa mayesero onse opindula mu gawoli ndikugawaniza phindu limeneli ndi mayesero opindula omwe amachulukitsidwa ndi 5 s (kutalika kotalika kwa mayeso). Gawoli likutanthawuza mitengo ya mankhwala aliwonse omwe amasonyezedwa muzenera zojambulajambula Chithunzi5C.5C. Poyerekeza mitengo iwiriyi, pa mankhwala aliwonse, tinagwiritsa ntchito njira za ANOVA mobwerezabwereza ndi nthawi (pre and post cue intervals) monga kusiyanasiyana. Poyerekeza kuyerekezera kolowera pakati pa mchere ndi mankhwala mkati mwa nthawi iliyonse, tidachita ma Welch omwe adakonzedwa ndi Sidak t-tsitsi. Mu Chithunzi Chithunzi5D, 5D, tinayesa mayesero ndi kutalika kwa nthawi yayitali (ITI) ndipo tinagwiritsa ntchito zidazi muzinthu za 10. Tinawerengetsera mawerengedwe a mayankho kwa mayesero omwe ali ndi ITI omwe adalowa mkati mwa binki iliyonse ndipo amawerengera tanthauzo la gawoli pamtundu uliwonse. Tinagwiritsa ntchito chiwerengero cha ITI monga chiwerengero cha zochitika mobwerezabwereza ANOVA kuti tione ngati, mu mankhwala alionse, zowonjezera zowonjezera zimadutsa pa nthawi yonse ya ITI. Mu Chithunzi Chithunzi5E, 5E, pa yesero lirilonse tinkawerengera kutalika kwa mtunda wautali (masentimita) pa chiyambi cha ITI chisanachitike. Kenaka tinkawerengera kutalika kwa gawoli kutanthauza mtunda womwe unkayenda mu IZI zomwe zisanachitike zomwe mbuziyo inayankha, komanso mofanana ndi zomwe nyamayo sinachite. Kuwona ngati kuchuluka kwa mtunda woyendayenda kunasiyana pakati pa mayesero osayankhidwa, ndipo mkati mwa mankhwala omwe tinagwiritsira ntchito mobwerezabwereza ANOVA ndi mtundu wovomera ngati chinthu. Kenako, tinachita posachedwa Adakonza a Welch's t-kuyerekezera kutalika kwa njira zamtunduwu zomwe zimayendera mtundu uliwonse wa mayankho (mankhwala ndi saline).

  

Chithunzi 5

Dopamine agonists amachulukitsa kukwera, koma kuwonjezereka koyankhidwa sikukukhudzidwa ndi kuwonjezeka kwa chiwombankhanga. (A) Gulu lamanzere lamanzere limasonyeza zotsatira za jekeseni wa saline, D1 ndi agonists a D2 pazomwe zikutanthauza kuti ayambe kuyenda pambuyo ...

Histology

Nyama zinkasokonezeka kwambiri ndi Euthasol ndipo zinasintha ndi guillotine. Ubongo unachotsedwa mwamsanga ku gazi ndikukhazikika mu formalin. Asanayambe kupopera ndi cryostat, ubongo sunatetezedwe mwa kumizidwa mu 30% sucrose masiku angapo. Zigawo (50 μm) zinadetsedwa chifukwa cha mankhwala a Nissl kuti awonetsere chingwe ndi injini. Chiwerengero cha jekeseni malo pa chinyama chilichonse chikuwonetsedwa mu Chithunzi Chithunzi66.

  

Chithunzi 6

Kubwezeretsedwa kwake kwa malo opangira jekeseni. Chithunzi chikuwonetsera zigawo ziwiri zamakono a ubongo zomwe zimaphatikizapo mbali zambiri zamkati za NAc (0.8-2.8 mm anterior kuchokera ku Bregma). Madontho akuda amaimira zowonjezera za malo ...

Zomwe zingayankhe

Tinaphunzitsanso makoswe a 8 kuti tiyankhe mapepala osiyana siyana omwe adanenedwa kuti ndi mphoto yaying'ono kapena yaikulu (Figure (Figure1A) .1A). Ngakhale kuti nyama sizinali zakudya zokha, zimayankha pafupifupi pafupifupi cue predictive ya 10% liquid sucrose (Zizindikiro 1B, C, mizere yakuda) pamene sichikusiyanitsa pakati pa zikuluzikulu (Chithunzi (Chithunzi1B) 1B) ndi zochepa (Chithunzi (Chithunzi1C) 1C) kupezeka kwapindula. Mosiyana, kuyambira tsiku loyamba lomwe sucrose mphoto ndondomeko inachepetsedwa kuchokera ku 10% mpaka 3%, kutchulidwa kothamanga kwa mayankho a mchere kunkawonetsedwa ku 2 h ya kuyesedwa (Zizindikiro 1B, C, mizere imvi). Pali zifukwa zosachepera ziwiri zomwe zingatheke. Choyamba, chikhoza kukhala chifukwa cha chikhalidwe chokhalira ngati nyama zowonjezera zakudya zowonjezera ndi mayankho otsatizana. Komabe, izi sizingatheke chifukwa mchere umakula mofulumira ndi 10% kuposa 3% imapatsa mphotho ya mpukutu womwewo, komabe kuthamanga kunakhala kotchuka kwambiri ndi 3% sucrose. Njira yachiwiri, yomwe timavomereza, ndi yakuti pamene 10% sucrose ikuwongolera mokwanira kuti apitirize kuyankha mu gawoli, ma volume ofanana a 3% sucrose sali. Zirizonse zomwe zimayambitsa vutoli, zimatithandiza kudziwa ngati kupuma kwa dopamine pogwiritsa ntchito agonist wodabwitsa kumawonjezera chiwerengero cha mayankho. Funso limeneli silingayankhidwe pogwiritsira ntchito 10% kuchepetsa mphotho kapena zinyama zoperewera chakudya chifukwa mchitidwe woyankhidwa uli pafupi ndi 100% muzochitikazo ndipo kotero sungapitirire.

Panthawi yomwe ntchitoyi imakhazikika, masiku a 4 atasintha kwa 3% amachotsa mphotho, kusiyana kwakukulu pamayeso akuluakulu ndi aang'ono kunkaonekera kumayambiriro kwa gawoli. Chithunzi1B1B ndi Chithunzi Figure1C); 1C); Kusiyana kumeneku kunachepetsedwa pamene gawoli linapitiliza ndikuyankhidwa pa mitundu yonse ya cue yomwe inachepa. Kusiyanitsa kwakukulu pakati pa mayankho akuluakulu ndi ang'onoang'ono akuwonetsetsanso kuwirikiza kwa chiwerengero cha ola limodzi pa ola loyamba la gawoli pambuyo pa saline (kuyendetsa galimoto) jekeseni mu NAC: mitu idavomerezedwa ku 54 ± 5% ya zilembo zazikulu zothandizira mphoto ndi 33 ± 3% yazinthu zochepa zothandizira mphoto (zizindikiro 1D, E, anasiya mabwalo akuda). Mpata wa kuyankha kwa onse awiriwa unali wotsika mu ora lachiwiri; Kuwonjezera apo, chiwerengero cha mayankho a zikuluzikulu ndi zing'onozing'ono sizinadziwikiratu panthawiyi (zizindikiro 1D, E, zoyenera zakuzungulira; onani Table Table11 kwa zotsatira za chiwerengero). Choncho, zinyama zinayankha zowonjezereka zomwe zimalosera zazikulu kuposa mphotho yaying'ono pokhapokha theka la gawoli.

Kuti tiyese ndondomeko yamakono ya kuyankha mwatsatanetsatane, tinapanga ziwembu zomwe zimasonyeza nthawi ya chidziwitso chilichonse komanso ngati chinyama chinayankha (top raster, Figure Figure2A) 2A) kapena ayi (pansi pa raster). Monga momwe zasonyezedwera mu gawo loyambirira musanayambe kulandira saline, mayankho onse ndi zolephera kuyankha zimapezeka mumagulu angapo otsatizana (Chithunzi (Figure2A) .2A). Izi zikusonyeza kuti pali mayiko awiri omwe amachititsa kuti anthu athe kuyankhapo: akumvetsera komanso osamvera. Komanso, pamene gawoli likupita patsogolo, kuchepetsa kuchitapo kanthu poyankhidwa kunali chifukwa cha nthawi yochuluka yomwe simunayankhe (Chithunzi (Chithunzi2A, 2A, top raster). Poyerekeza kusintha kwa anthu osamvera, tinakonzekera, pa gawo lililonse, nthawi yowonjezera yomwe imakhala nthawi yosayima (osayankha). Muzitsulo zonse zopangira saline, mizereyi inayamba kumapeto kwa gawolo, posonyeza kuti munthu amene sanamvere akukhala motalika pamene magawo apitirira (Zizindikiro 2F, G, mizere yakuda).

Pofuna kuwona zopereka za NAC core dopamine ku chisankho choyenera kuyankha, timagwiritsa ntchito mankhwala osokoneza bongo kapena kuchepa kwa D1 kapena D2 dopamine receptor powonetsera microinjecting D1 receptor agonist SKF 81297 kapena wotsutsa SCH 23390, kapena D2 receptor agonist quinpirole kapena wotsutsa raclopride. Tapeza kuti onse a D1 ndi a D2 agonist akuwonjezeka kuyankha ku cues (Chithunzi (Chithunzi1D, 1D, malo ofiira owala; Chithunzi Chithunzi1E, 1E, malo obiriwira a buluu); makamaka, mlingo wochepa wa agonist aliyense wawonjezeka kuyankha mu ora lachiwiri, pamene mlingo waukulu ukuwonjezeka kuyankha pa gawo lonseli (Chithunzi (Chithunzi1D, 1D, malo ofiira otseguka; Chithunzi Chithunzi1E, 1E, malo obiriwira a buluu). Kawirikawiri, kulabadira ndalama zazikulu ndi zazing'ono zowonjezera zinawonjezeredwa kufika madigiri ofanana, ndipo izi zinali zowonjezera kwa D1 ndi D2 receptor agonists (Zizindikiro 1D, E ndi Table Table11).

Kuwonjezeka uku mu chiwerengero cha kuyankhidwa kunkaphatikizidwa ndi njira yosiyana yochitira poyerekeza ndi nyama zothandizidwa ndi saline (Zizindikiro 2B, C). Mosiyana ndi chikhalidwe cholamulira, komwe nthawi yomwe idaperekedwa kudziko lomwe silingayankhe pamene gawoli likupita patsogolo, mayankho a zinyama zokhudzana ndi agonist zinasungidwa panthawi yonseyi, ndi kusintha kochepa koma kawirikawiri kumalo osamvera (Chithunzi (Chithunzi2F, 2F, D1 agonist, mizere yofiira; Chithunzi Chithunzi2G, 2G, D2 agonist, mizere yakuda buluu). Onse odwala matendawa amachepetsera nthawi yochulukirapo yomwe imakhala yosasintha ndipo nthawi zambiri imalepheretsa kuwonjezeka kwakukulu pa nthawi yowerengeka yomwe inachitika mu ola lachiwiri la zokambirana za nyama zamchere.

Zotsutsana kwa ma D1 ndi D2 receptors zinali ndi zotsatira zosiyana za agonists. Otsutsawo adachepetsedwa kwambiri poyankha ku gawo loyamba la gawoli, pamene kusiya kusiyanitsa kwa theka lachiwiri kusasinthika (mwina chifukwa cha zotsatira zake) (Chithunzi (Chithunzi1D), 1D), katatu wakuda wofiira; (Chithunzi (Chithunzi1E, 1E, katatu a buluu wakuda). Otsutsa onsewa adatambasula nthawi yochulukirapo yomwe yakhala ikuchitika muzosavomerezeka (zizindikiro 2D, E, F, G).

Kusintha kwazochitika

Kuwonjezeka kwa mayankho omwe anachitidwa chifukwa cha a D1 ndi a D2 agonists, komanso nthawi yambiri yomwe amamvetsera kusiyana ndi zomwe sizimvera, zikhoza kufotokozedwa ndi mwayi wochulukirapo wosintha kuchokera ku anthu omwe sali omvera kudziko lakumvera, kapena kuti, kuchepa kwa mwayi wosintha kuchokera kumbali ya anthu osamvera (kapena onse). Kuti mudziwe kuti ndi yani yomwe takhala tikugwiritsira ntchito njira yachidule ya Markov (Chithunzi (Figure3) 3) powerenga kusintha kwa masinthidwe omwe amatha kusinthika kwa 4 zochitika ziwiri zofanana ndizo: Zotsatira ziwiri zotsatizana (R + R +), yankho lachitsulo lotsatiridwa ndi osayankhidwa ku chidziwitso chotsatira (R + R-), osati -response ikutsatiridwa ndi yankho (R-R +), ndipo osati yankho lotsatiridwa ndi osakhala yankho (R-R-). Dziwani kuti R + R + ndi R-R-zimagwirizana ndi kukhalabe m'magulu omvera komanso osamvera, motsatira; komanso kuti R + R- ndi R-R + zimasintha kuchoka ku dziko lina kupita ku lina. Mpata uliwonse wa zotsatira ziwiriziwiri unkawerengedwa ndi kugawa chiwerengero cha nthawi yomwe awiriwa adachitika muwindo la nthawi (mwachitsanzo, ola loyamba la gawo) ndi chiwerengero cha nthawi yoyamba yomwe mzakeyo adafika (mwachitsanzo, P_{(R + R-)} = N_{(R + R-)} / N_{(R +)}; onani Njira Zamagulu Zomwe mukufufuza). Dziwani kuti mwayi wochoka mu boma ndichifukwa chake 1 ilibe mwayi wokhala mu boma (mwachitsanzo, P_{(R + R-)} = 1 - P_{(R + R +)}). Choncho, muzinthu 4A, C, F, H, deta yomwe ili pamzere wotsalirawo imasonyeza pafupifupi (pambali pa makoswe) mwayi wokhala kapena kusinthira kunja kwa dzikoli, pamene deta yomwe ili pamzere wosakanikirana ikuwonetsa mwayi wosunga kapena kusinthika kwa anthu osamvera .

Mu ola loyamba la kuyezetsa khalidwe, amphaka ochiritsira amchere amatha kufotokozera zomwe akuyankha: ngati atayankha pamodzi, mwayi wotsatira yankho lotsatira unali wamkulu kuposa wosayankha (P_{(R + R +)} > P_{(R + R-)}; Chithunzi Chithunzi4A, 4A, ozungulira ofunikira); Komanso, ngati iwo sanayankhepo kanthu, kuthekera kwa kusakhala yankho ku chidziwitso chotsatira chinali chachikulu kuposa cha yankho (P_(R-R-) > P_{(R-R +)}; Chithunzi Chithunzi4A, 4A, osakanikirana). Chithandizo ndi D1 kapena D2 agonist sichinasinthe kwambiri mwayi wotsalira mu dziko lovomerezeka (R + R +) [kapena, mofananamo, mwayi wopita kudziko losamvera (R + R-)] poyerekeza ndi saline jekeseni (Chithunzi (Chithunzi4A, 4A, ozungulira ofunikira). Komabe, nyama zogwidwa ndi agonist zinasinthidwa mobwerezabwereza kuchokera kwa anthu omwe sali omvera ku dziko lovomerezeka (ndipo, mofananamo, adakhalabe mmalo osamvera nthawi zambiri; Chithunzi4A, 4A, osakanikirana).

Mu ola lachiwiri la zokambirana, makoswe ochiritsira amchere amasonyeza kuchepa kwakukulu kuti angasinthike kuchokera kwa osayankha kudziko lovomerezeka poyerekeza ndi ola loyamba (Chithunzi (Chithunzi4C4C vs. Fanizo Chithunzi4A, 4A, osakanikirana). Kuwonjezera pamenepo, iwo amatha kusintha kuchokera kumbali ya osamvera kanthu mu ola lachiwiri kuposa loyambirira (Chithunzi (Chithunzi4C4C vs. Fanizo Chithunzi4A, 4A, ozungulira ofunikira). Choncho, pamene gawoli likupita patsogolo, kulamulira kumakhala kuchepa poyankha (Ziwerengero 1B, D) ndi chifukwa cha mautali awiri omwe sali omvera komanso maulamuliro omwe amamvetsera mwachidule. Chithandizo ndi a D1 kapena agonists a D2 anasintha malingaliro awo mu ola lachiwiri pamodzi ndi nkhwangwa zonse (Chithunzi (Chithunzi4C) .4C). Choncho, mu ola loyamba agonists adawonjezera mwayi wochoka kunja kwa anthu omwe sanamvere koma osakhudzidwa ndi kusintha kwa dziko, mu ola lachiwiri, agonist onsewa adawonjezeka kusintha kuchokera kuzinthu zomwe sizimvera komanso kuchepetsa kusintha Kuchokera kudziko lovomerezeka-kutanthawuza kuti agonists onse adawonjezereka kutalika kwa mauthenga omwe akumvera ndipo adachepetsa kutalika kwa mawu osamvera. Zowoneka kuti zotsatirazi za agonist zinachititsa kuti kusintha kwa maola oyamba kukhale ofanana ndi omwe ali ola loyambirira. Izi zikutanthauza kuti agonist sanathe kuchepetsa kuyankha mu ola lachiwiri poletsa kusintha kwachizoloŵezi kuti zikhale zosavuta kuti zikhale zovomerezeka.

Onse a D1 ndi adani a D2 adasintha poyankha mu ora loyamba limodzi ndi zida zonse, zomwe zikusonyeza kuti analimbikitsa kusintha kwa dziko lomwe silinayankhe komanso kulepheretsa kusintha kwa dzikoli. (Chithunzi4F) .4F). Chodabwitsa, mu ola lachiwiri, kusintha kwachidziwitso kwa otsutsana ndi saline kunali pafupifupi (Chithunzi (Chithunzi4H), 4H), ndipo zowonongeka kusintha kwa nyama zomwe zinkamenyana ndi adani zinali zosiyana kwambiri pa oyamba ndi ora lachiwiri (Chithunzi (Chithunzi4F4F vs. Fanizo Chithunzi4H) .4H). Zotsatira izi zimasonyeza kuti otsutsa a D1 ndi D2 amachititsa kuti, mu ola loyamba, pakhale kusintha kofanana komwe kumakhala kofanana ndi zomwe zimachitika mu gawo lachiwiri la gawoli muzolamulira, zomwe zikugwirizana ndi nthawi yayitali yopanda kumvera .

Pofuna kufotokoza mofanana ndi kusintha kumeneku mu mankhwala ndi saline, tinathetsa matrix kuti akhale ovuta; kutanthauza kuti, kuchokera ku matrices osinthika, mwayi uliwonse wa makoswe pamtundu uliwonse umakhala womvera komanso wosamvera pazitsulo zolimba za Markov (onani Njira, Gawo la Deta, ndi Chithunzi Figure3) .3). Muziwerengero 4B, D, zikuonekeratu kuti mu mkhalidwe wolamulira (saline), magawo omwe angakhale okhudzidwa ndi osamvera omwe amasintha amakhala osasintha mu ola lachiwiri. Mosiyana ndi zimenezi, izi zimakhala zolimba mu agonist onse kupatula gawo lonse. Wotsutsa (zizindikiro 4G, I), kufalikira kwa zotsatila za boma lirilonse lamasunthira kwambiri kumbali yomwe siimvetsedwe muzomwe zonsezi ndipo izi zikhoza kukhala zofanananso ndi omwe ali ora lachiwiri mu nyama zamchere zamchere. Muziwerengero 4E, J ife timachotsapo, pa gawo lililonse hr ndi mankhwala onse, zigawo zikuluzikulu za mawonekedwe omwe amawonetsedwa muzinthu 4B, D, G, I. Choncho, chiyero pamwamba ndi pansi pa zero chimasonyeza mwayi waukulu wokhala mu chisamaliro ndi chosamva kanthu, motsatira. Pa ola loyamba mu saline, pamakhala mwayi wofanana wokhala nawo muzoyankha komanso osamva. Mu ola lachiwiri, kufalitsa kumeneku kwa boma kumakhala kovuta kwambiri kudziko lomwe silili lolandira (Chithunzi (Chithunzi4E, 4E, asiya madontho wakuda motsutsana ndi madontho akuda). Pa mlingo waukulu wa agonist, pangakhale kuwonjezeka kwakukulu kwa kukhala mukumvetsera kwa ola loyambirira poyerekeza ndi saline (Chithunzi (Chithunzi4E, 4E, otsalira) ndipo izi zinasungidwa mu ora lachiwiri la gawoli (Chithunzi (Chithunzi4E, 4E, madontho abwino). Choncho, kukhazikitsa mphamvu za dopamine receptors ndikwanira kulimbikitsa ndi kusunga dziko lovomerezeka pansi pa zikhalidwe za normative satiety. Otsutsa anali ndi zotsatira zosiyana; iwo mwamphamvu kwambiri ndipo anasintha kwambiri zigawo za boma zotheka kupezeka kwa anthu omwe sali omvera m'gawo lachiwiri ndi lachiwiri ola limodzi. Kuwonjezera apo, panalibe kusiyana kwa chiwerengero pakati pa magawo a boma omwe angakhale nawo otsutsa komanso saline panthawi yachiwiri. Choncho, kutseka dopamine receptor activation kumapangitsa kuti anthu asamvetsere ndi mphamvu zomwezo monga ntchito yowonjezereka m'nthaŵi yolamulira. Kuwonjezera apo, kutsegulira kwa mapulogalamu omwewo kumalimbikitsa kwambiri kusintha kwa malo omwe amavomereza kuti adzalandire mphotho ya chakudya ngakhale pokhapokha ngati palibe chosowa cha caloric.

Mtsuko ndi kuphulika kwapadera

N'zotheka kuti zotsatira za agonist zimachokera kuzinthu zowonjezera zomwe sizinawatsogoleredwe chifukwa cha kuwonjezeka kosavuta kwa chiwonongeko kusiyana ndi kuwonjezeka kwa mayankho otsogolera otsogolera. Poyerekeza ndi malingaliro awa, tinagwiritsa ntchito deta yolondola pa data kuti tifufuze magawo omwe amayendetsa pamayesero komwe nyamayo inayankha. Panalibe kusiyana kwakukulu pakati pa ulamuliro ndi agonist zochitika pa latency kuti ayambe kuyendetsa masewerawa (Chithunzi (Chithunzi5A, 5A, kuchoka pamapiringidzo) kapena latency kufika pa cholandira (Chithunzi (Chithunzi5A, 5A, mipiringidzo yolondola). Kuonjezerapo, njira yoyendetsera kayendedwe ka chikopa (chiŵerengero cha kutalika kwa mzere wolunjika pakati pa nyama ndi cholumikizira mpaka kutalika kwa njira yomwe chinyama chinatsatira kwenikweni) sichinasinthidwe ndi mankhwala a agonist (Chithunzi (Figure5B) .5B). Chifukwa chakuti kusuntha kosagwiritsidwe ntchito, kosasunthika komwe kumalowetsa polojekiti kungakhale kochepa kwambiri (ndipo motero sizowona bwino) ndi / kapena kuchitika patali yaitali, izi zikuwonetsa kuti nyama zogwidwa ndi agonist zinkatsogoleredwa kupita kumalo otengera mphoto Zomwe zimayambira mofanana ndi njira zawo zoyendetsera mchere mu saline.

Tinaonanso ngati kuwonjezeka kwa agonist kuwonjezeka muzitsulo zingakhale chifukwa cha kuwonjezeka kwapadera. Kuyesa mayesero okha ndi mayankhidwe, ife tinayimira kuchuluka kwa zolowera zolembera mu 5 s zomwe zisanafike poyambira pa mlingo wa 5 s pambuyo pake. A agonist sanawonjezere kuchuluka kwa msinkhu wa zolembera kapena zokopa (Chithunzi (Chithunzi5C) 5C) zomwe zikutanthauza kuti cholowa chotsalira chimakhalabe pansi pa ulamuliro wa agonist. Pamodzi, zotsatira zimakhala zowerengera 5A-C Onetsani kuti kuwonjezereka kwa njira yophika chifukwa cha agonist sikumayenderana ndi zinthu zomwe sizinapangidwe monga kuwonjezeka kwa kutayidwa kosaloledwa kapena kuthamanga kwa zolembedwera.

Kudzikonda pa nthawi ya ITI

Ngakhale kuti kuwonjezeka kwa agonist kuwonjezeka mu makotedwe ophika sikunagwirizane ndi kuwonjezeka kwa kutayidwa kosagwiritsidwa ntchito, izi sizikutanthauza kuti zikhoza kutheka kuti agonists zinapangitsa kuwonjezereka kochulukana kwa kuphulika kumene sikupita ku cholandirira. Kuti tipeze kuyendayenda pakati pa ITI, ife tinayamba kufunsa ngati kuthekera kwa yankho lachidziwitso kunasiyana monga ntchito ya kutalika kwa ITI. Monga tawonetsera mu Chithunzi Chithunzi5D, 5D, chiwerengero cha mayankhidwe (chinagwa pazipinda zazikulu ndi zing'onozing'ono) chinali chosasunthika pamtunda wonse wa ITI kutalika kwa agonist ndi saline. Kenaka, tinkawerengera kutalika kwa mtunda wautali wa ITI kwa gulu lililonse la mankhwala, ndipo poyerekeza ndi kuchuluka kwa chiwonongeko pamayesero kumene makoswe amavomereza ndipo sanayankhe pa chidziwitso chomwechi. Chochititsa chidwi, mu chikhalidwe cha (saline), chinali kuwonongeka kwakukulu pa nthawi ya ITIs potsatira njira yopezera chophika (Chithunzi (Chithunzi5E, 5E, chotsatira chakuda chakuda) kuposa pamene nyamazo zinalephera kupanga njira yowonjezera yophika (Chithunzi (Chithunzi5E, 5E, wasiya wakuda wakuda). Zotsatira izi zimasonyeza kuti kuphulika kumeneku kumachitika mobwerezabwereza pamene chinyama chili mu dziko lakumvera.

Kuti mudziwe ngati ntchitoyi ikuphatikizapo dopamine receptor activation mu NAc, tinayang'ana zotsatira za dopamine agonists pa kuphulika pa ITI. D1 agonist yowonjezereka kuwonongeka kwa nthawi ya ITI zonse komanso popanda kuyankha; Mofananamo, D2 agonist inachititsa kuti kuwonjezeka kwakukulu (ayi-mayesero) kapena kuti kuwonjezereka (mayesero oyankha) (Chithunzi (Chithunzi5E) .XUMUMU). Choncho, dopamine agonists inachititsa kuti pakhale kuwonjezeka kwa chiwonongeko pa nthawi ya ITIs. Pamaso pa agonists, kuphulika kumeneku kunayambira pamtunda wofanana ngati nyamayo inayankha kapena ayi, ponena kuti ITI locomotion ndi yovuta kwambiri ku dopamine receptor activation kusiyana ndi chiyeso kuyankha. Mwachidule, zotsatira zomwe zasonyezedwa mu Chithunzi Chithunzi55 amasonyeza kuti, kudzera mu njira mkati mwa NAc, dopamine receptor activation imasokoneza zinyama zonse pazowonjezereka zowonjezera chiwerengero ndi mitengo yapamwamba ya kutuluka kwadzidzidzi, ndipo ngakhale kuti dopamine ali ndi zotsatirapo zonsezi, njira yowonjezera yowonjezera yotengedwa ndi dopamine si zotsatira zachinyengo zazitali zazengereza zokha.

Nac dopamine ndi yofunika komanso yokwanira njira yothetsera msonkho

Njira yodziwika bwino imadalira kwambiri masolimbic dopamine kuchokera ku VTA kupita ku NAc mwachindunji. Anthu omwe akuyankha amakhala ndi "njira zowonongeka" (Nicola, 2010) [kumatchedwanso "matsenga" (Petrosini et al., 1996) kapena "chitsogozo" (O'keefe ndi Nadel, 1978) njira; mawu oti "njira yoopsa" agwiritsidwa ntchito pano]. Njira yoledzeretsa imatanthawuza kukokoloka komwe kumalondoleredwa ku chinthu chowoneka kuchokera kumalo omwe amasiyana nthawi yoyandikira. Chofunikira, njira yoopsa imafunikira ubongo kuti ugwiritse ntchito njira yatsopano yoyendera pazochitika zilizonse [mosiyana ndi "praxic," "oriency," kapena "inflexible", yomwe imachitika pomwe malo oyambira ndi kutha amakhala nthawi zonse zochitika (O'keefe ndi Nadel, 1978; Petrosini et al., 1996; Nicola, 2010)]. Kafukufuku wamakono amatsimikizira kuti NAC dopamine imafunikila kuwonetsa msonkho m'njira zinayi. Choyamba, pamene kudalira kwa njira ya misonkho pa mesolimbic dopamine poyamba kunakhazikitsidwa ntchito yogwira ntchito (DS) yomwe inkafuna kuti nyamayo ipite ku operandum (chiwindi kapena mphuno) pofuna kupeza mphotho ya sucrose yopitidwa kumalo ozungulira (Yun et al. , 2004a,b; Ambroggi et al., 2008; Nicola, 2010), pantchito yapano, nyama zimayenera kungoyandikira cholandirira chokha. Monga momwe DS imagwirira ntchito, zikhalidwe zimaperekedwa kwakanthawi komanso kosiyanasiyana, zomwe zimabweretsa madera osiyanasiyana poyambira chifukwa cha kuyenda kwa nyama pafupi ndi chipinda nthawi yopingasa (osawonetsedwa) - mikhalidwe yomwe machitidwe ake amakhala oopsa. Kuzindikira kwathu kuti D1 ndi D2 dopamine receptor antagonist jekeseni mu NAc maziko adachepetsa kuchuluka kwa zomwe nyama idayankha zikufanana ndikuwonanso koyambirira ndi DS task (Yun et al., 2004a,b; Ambroggi et al., 2008; Nicola, 2010). Mofanana ndi zomwe zapeza kale ndi ntchito yochedwa kuchepetsa ntchito (Wakabayashi et al., 2004), zotsatira zathu zimatsimikizira, mu ntchito yovuta kwambiri, kuti kuphatikiza kwa wogwira ntchito mwachindunji pamalo osiyana ndi mapepala operekera malipiro si chinthu chofunikira kwambiri chomwe chimapangitsa kuti khalidwe lausichite likudalira pa NAC dopamine.

Chachiwiri, pamene maphunziro oyambirira ankachitidwa pa zinyama zopanda zakudya, ntchitoyi ikuwonetsa kuti njira ya msonkho imalephera ndi jekeseni wa NAC dopamine wotsutsa ngakhale nyama zomwe zapatsidwa ad libitum kufikira chow. Kudalira kwa njira yoopsa pa mesolimbic dopamine sikuti kumangokhala vuto la michere kapena njala ya mutuwo. Zowonadi, zotsatirazi zikuthandizira gawo la mesolimbic dopamine popititsa patsogolo njira zopezera chakudya cha ma calorie ambiri ngakhale kulibe chosowa chokhala ndi chakudya chambiri, kuchirikiza lingaliro loti madera awa amathandizira kudya kwambiri ndi kunenepa kwambiri (Berridge et al., 2010; Kenny, 2011; Stice et al., 2013; Meye ndi Adan, 2014).

Chachitatu, pamene kafukufuku wakale anagwiritsa ntchito antchito a dopamine kusonyeza kuti NAC dopamine ndi yofunikira kuti ayambe kutsogolera misonkho, mu ntchito yomwe tikuwonetsa kuti kuwonjezeka kwa NAc D1 kapena D2 dopamine receptor activation ndi kulandira kwa agonist mu mapulogalamu ameneŵa ndikwanira kuwonjezera mwayi chidziwitso chidzapangitsa njira yothetsera. Kuyeseraku sikungatheke m'maphunziro ambiri apitalo chifukwa makoswe oletsedwa chakudya amadya pafupi ndi 100% ya mankhwala omwe amanena mosakayika zakudya, kuyika denga pa zotsatira zowonongeka. Komabe, pamene chithunzithunzi chanenedwa sichinali chodalirika mu "ntchito yowonjezera" (PS) yomwe PS inaneneratu kuti 10% imapereka mphotho pa 15% chabe ya mayesero, mwinamwake zowonjezera zowonjezera zinali zochepa, ndipo kutsekedwa kwa mankhwala a dopamine reuptake kunachulukitsa mwayi uwu (Nicola et al., 2005). Mu phunziro lino, makoswe anadyetsedwa chow ad libitum ndipo mphotho yothandizira yankho linali 3% mmalo mwa 10% sucrose. Pansi pazifukwazi, ngakhale kuti zizindikirozo zinatsimikiziridwa mosadalirika, mphothozo zimayankhidwa pamagazi ang'onoang'ono kusiyana ndi chakudya chokhazikika kapena 10% sucrose conditions, kuthetsa zotsatira za padenga ndi kutithandiza kuti tione zotsatira za agonist pa njira ya msonkho. Mogwirizana ndi zotsatira zochokera ku ntchito ya PS, dopamine agonist jekeseni mu NAC core inapanga kuwonjezeka kwakukulu mu cue yankho. Zotsatira zomwe zilipo tsopano zimatsimikizira kuti NAC core dopamine receptor activation ndi yofunikira komanso yokwanira kulimbikitsa njira yothetsera misonkho, kutsimikizira ndondomeko yathu yakale yakuti mesolimbic dopamine ndi gawo la njira yothetsera msonkho (du Hoffmann ndi Nicola, 2014).

Chachinayi, zomwe timawona kuti agonist a D1 ndi D2 ali ndi zovuta zofananira zomwe zimatsutsana ndi zomwe otsutsana ndi D1 ndi D2 ali ndi tanthauzo lofunikira pomvetsetsa zakudziwika kwa zotsatira za mankhwalawa. M'maphunziro ambiri am'mbuyomu, ma microinjected D1 ndi D2 antagonists anali ndi machitidwe ofanana (Hiroi ndi White, 1991; Ozer et al., 1997; Koch et al., 2000; Yun et al., 2004b; Eiler et al., 2006; Pezze et al., 2007; Lex ndi Hauber, 2008; Liao, 2008; Nicola, 2010; Shin et al., 2010; Haghparast et al., 2012; Steinberg ndi al., 2014) ndi electrophysiological (du Hoffmann ndi Nicola, 2014) zotsatira. Chifukwa chakuti anthu omwe amatsutsa omwe amamwa mankhwalawa amawoneka bwino kwambiri kuposa momwe zimagwiritsira ntchito mankhwalawa pamagulu awo, zolinga za D1 ndi D2 zimayambitsa zovuta zawo: ndizotheka kuti mankhwalawa amamanga mofanana dopamine receptor, kapena ku gulu lachitatu la alendo omwe si dopamine receptor nkomwe. Kalelo, kuyambitsa chimodzi mwa zovomerezeka sikuyenera kubweretsa khalidwe; Pachifukwa chotsatira, kuyambitsa kapena kulandira mankhwala sikuyenera kubweretsa khalidwe. Komabe, ife tikupeza kuti agulu a D1 ndi a D2 onse amabala zotsatira za khalidwe, ndi kuti zotsatira zake ziri zofanana kwa wina ndi mzake ndi ndendende mosiyana ndi za otsutsa. Zidzakhala zodabwitsa ngati 4 mankhwala osokoneza bongo amatha kuchita chimodzimodzi. Choncho, chochitika chachikulu ndi chakuti mankhwala onsewa amachita makamaka pazolandila zawo zolinga.

Zotsatira za dopamine agonist sizinachoke chifukwa cha kuwonjezeka kwa chilengedwe

Zingakhale zovuta ndi kutanthauzira kuti dopamine agonists amachititsa kuti anthu athe kuyankhapo ndikuti zotsatira zake zikhoza kukhala chifukwa cha kuwonjezereka kwakukulu kwa chiwonongeko, zomwe zimapangitsa kuti zikhale zovuta zowonjezera zomwe zikanachitika kaya zidachitika kapena ayi. Inde, mu chikhalidwe choyendetsa, deta yolondola ma data omwe anapezeka patsikuli adawonetsa kuti chiwerengero cha phokosolo panthawi yamagwirizano chinagwirizanitsidwa pamayesero ndi mayesero ndi mwayi wolowera polojekiti pakadutsa zochitikazo. Kuwonjezera apo, agonist anawonjezereka kukwera kwapakati pa nthawi yoyesayesa komanso kuyang'ana mwakuya. Njira imodzi yothetsera mphamvu ya generalized motor isagwiritsidwe ntchito mopanda malipiro okhudzidwa (NS) kusonyeza kuti kuyankha kwa NS presentation siwonjezeredwa ndi agonists. Sitinaphatikizepo NS m'chilengedwe chathu. Timaganiza kuti tikadatero, tikanawona kuwonjezeka kwa chiwombankhanga nthawi ya NS (monga momwe zinachitikira panthawi yamadzulo) koma osati kuwonjezeka kwa zolembera. Lingaliro limeneli limachokera pa zochitika zingapo zomwe zikusonyeza kuti mwayi wowonjezera wowonjezera pambuyo poti chiwonetsero chazomwe sichinali chifukwa cha kuwonjezeka kwa chilengedwe chonse. Choyamba, kuwonjezeka kwa chiwombankhanga pa nthawi yoyesayesa yomwe inayambitsidwa ndi agonists inadulidwa kuchokera kuwonjezeka kwa chidziwitso choyankhidwa, zikuchitika ngakhale pakapita nthawi zomwe zatsatiridwa ndi osayankhidwa ku chidule (Chithunzi (Chithunzi5E) .XUMUMU). Chachiwiri, mwayi wolowetsa cholowa mkati mwa ITI sunadulidwe ndi agonists (Chithunzi (Chithunzi5C) .5C). Potsirizira pake, poyerekeza ndi zolembedweramo, zolowera chifukwa cha kuwonjezeka kwa chiwombankhanga ziyenera kuchitika patapita nthawi yaitali, ndipo chiweto chiyenera kuyendanso njira yochulukirapo kuchokera kumalo ake omwe akuyambira kumalo ololedwa; Komabe, agonist sichikuwonjezekanso pang'onopang'ono (entry) (Chithunzi5A) 5A) kapena kuchepetsa kayendetsedwe ka kayendetsedwe ka kayendetsedwe ka kayendetsedwe ka kayendedwe kake (Chithunzi (Figure5B) .5B). Zonsezi, zotsatirazi zikuwonetsa kuti kuwonjezeka kwa zolembera zophika chifukwa cha agonist si chifukwa cha kuwonjezeka kwamtunda. Zowonjezereka ndizoti zochitika zina zodzikongoletsera zokhazokha zinali zokhudzana ndi zinthu zamkati mwa chipinda, ndipo mwinamwake njira zoterezi zinawonjezeredwa ndi agonist monga momwe kuthekera kwa njira zamatisi kumayankhidwa ndi zolemba zathu zodziwika bwino zawonjezeka.

Kupanda kusiyana kotchulidwa poyankha kuzinena zoganizira za mphotho yayikulu ndi yaing'ono

Kusiyanitsa kwina pakati pa ntchito yamakono ndi maphunziro athu akale pogwiritsa ntchito ntchito za DS ndi PS ndikuti tinapereka ndondomeko ziwiri zowonetsera mphoto, zomwe zinaneneratu ma volumes akulu ndi ang'onoang'ono a sucrose, m'malo modzidzimutsa mphoto imodzi ndi imodzi yopanda malipiro ( NS). Tinaphatikizapo njira ziwiri zomwe timagwiritsa ntchito pokonzekera ntchito kuti tiwone ngati zochitika za NAc dopamine zotengera zimakhudza khalidwe zomwe zimayambitsa zomwe zimapangitsa kuti zikhale zosiyana siyana. Komabe, sitingachite kafukufuku wotero chifukwa zinyamazo sizinasiyanitse pakati pazinthu ziwirizi. Pamene mphothoyo inali 10% sucrose, panalibe kusiyana kwakukulu mu kuyanjana kwa chiwerengero pakati pa zikuluzikulu zazikulu ndi zazing'ono; ndipo pamene mphotho inali 3% sucrose, kusiyana kochepa (~ 20%) kunangowoneka mu ola loyamba la gawoli (Chithunzi (Figure1) .1). Zowunikirazi zikusiyana ndi machitidwe amtundu wa DS ogwiritsa ntchito chimodzimodzi, momwe nyama zimayankhira> 80% ya ziwonetsero za DS ndi <10% ya ziwonetsero za NS (Nicola, 2010). Posachedwa, tapeza kuti pantchito yofananira ndi yomweyi, kugwiritsa ntchito zoyeserera ziwiri zomwezo koma ndikulosera kumodzi kwa mphotho yomwe ikulowa pakulandila ndi NS imodzi, kuyankha NS kunali kwakukulu (> 20%; osawonetsedwa ). Kuyankha kwakukulu kumeneku (poyerekeza ndi kuchuluka kwa mayankho a NS mu ntchito za DS ndizofunikira zogwira ntchito) mwina chifukwa cha kufalikira kwakanthawi pakati pazomwe zimanenedweratu komanso zosaneneratu, komanso kusowa kwa mayankho ogwira ntchito. Kupezeka kwadzidzidzi koteroko kumatanthauza kuti kuyankha poyankha sikumakhala kovuta ndipo kumafunikira kuyesayesa kochepa poyerekeza ndi kuyankha pantchito ya DS, zomwe zingafotokozere kusiyana komwe kuyankha kwa NS. Ngati> 20% mayankho a NS afala, ndiye kuti ayenera kukhala okulirapo kwambiri pomwe chidziwitso chimaneneratu za mphotho zochepa, monga momwe tawonera mu kafukufuku wapano.

Kuchepa pakuyankha pa nthawi kungakhale kutayika-ngati zotsatira

Mbali yochititsa chidwi ya khalidwe lowonedwa mwaife ad libitum Zinyama zodyedwa zinali zochepa muyeso wokhoza kuyankhidwa pa mndandanda wa 2, womwe umatchulidwa kwambiri pamene mphoto inali 3% sucrose kusiyana ndi pamene 10% sucrose. Mphungu zopatsidwa ufulu wa sucrose zimasonyeza kuchepa komweko kwa mlingo wa chiwombankhanga kuyambira pachiyambi cha gawoli, zomwe zimayesedwa ndi kusamalidwa: zotsatira zowonongeka kwa njira ya ubongo yowonjezera ubongo, 2001). Komabe, satiation silingathe kuyankha chifukwa cha kuchepa kwachitsulo chomwe chachitidwa pano chifukwa chakuti zakudya zowonjezera zowonjezera zowonjezera pamene 10% sucrose inali mphotho yomwe iyenera kuti iwonongeke mofulumira poyankha kusiyana ndi pamene 3% sucrose inaperekedwa, komabe chosiyana chinachitika (Chithunzi (Figure1) .1). Chinthu china chotheka ndi chakuti kuchepa ndiko kutha kwapadera-monga zotsatira zomwe zimabwera chifukwa cha kubwezeredwa kwa othandizira ena omwe alibe okwanira kuti azikhalabe akutsatira zomwe zikuchitika pa mayesero otsatila. Ngakhale kuti tilibe umboni weniweni wakuti izi ndizochitika, kungosiya sucrose kumathandizanso kuchepetsa (osati kusonyeza). Ngakhale kuti izi zowonongeka mofulumira kuposa zomwe zatchulidwa pano, kutuluka kwa nthawi yochepa pakali pano kungatheke chifukwa pang'ono cha sucrose inaperekedwa. Komanso, pamene mchere wambiri wa sucrose (10%) unaperekedwa, sichidawonongeke, potsutsana ndi lingaliro lakuti 3% sucrose reinforcers analibe okwanira kwakukulu kuti ayambe kuyankha.

Zomwe 3% zimadya sizitsitsimutsa kuposa 10% sizodabwitsa, kupatsidwa osati kuti 3% sucrose sichisankhika pa madzi kuposa 10% (Sclafani, 1987), komanso kuti 10% sucrose ingakhale yowonjezereka kwambiri yowonjezera njira zowonjezeramo zomwe zimazindikira kuti zakudya zowonjezera, zomwe zingathandizire kulimbitsa ngakhale popanda kukoma (de Araujo et al., 2012; Sclafani ndi Ackroff, 2012; Sclafani, 2013; de Araujo, 2016). Njirazi zimalimbikitsa dopamine kufotokozera ndipo kwenikweni zimawoneka kuti ndizowathandiza kukhala ndi thanzi la sucrose olimbitsa thupi kuti apitirizebe kuchuluka kwa ntchito zomwe zimagwira ntchito kwambiri kuposa zowonjezera zopanda thanzi (Beeler et al., 2012). Ndipotu, cues predictive sucrose amachititsa kuti dopamine amasulidwe mu NAC kusiyana ndi zomwe zimachitika zowonongeka kwa osakondweretsa (McCutcheon et al., 2012) ndipo, pansi pa zochitika zina, sucrose ngokhayo imapangitsa kuti dopamine amasulidwe kuposa wokoma (Beeler et al., 2012). Zotsatira izi zimasonyeza kuti chizindikiro cha dopamine chosadulidwa panthawi ya 3% sucrose sessions (vs. 10%) chikhoza kukhala ndi udindo wokhudzidwa-ngati kuchepa poyankha pamene mankhwala ochepa a sucrose agwiritsidwa ntchito.

Mogwirizana ndi lingaliro limeneli, kutsegulira ndi kutetezedwa kwa dopamine receptors zimagwirizanitsidwa ndi kutayika-ngati zotsatira. D1 kapena D2 dopamine receptor jekeseni ya agonist yonse inapanga kuchuluka koyamba (ora loyamba) kuyankha ndikuchepetsa kuchepa kwachizoloŵezi chokhazikika poyankha kuyambira oyamba kufika pa ora limodzi poyerekeza ndi chikhalidwe cholamulira (Zizindikiro 1D, E), makamaka kuteteza kutayika-ngati zotsatira. Mosiyana ndi zimenezi, jekeseni wa D1 kapena D2 wotsutsa umachepetsera kuyankha kwa ola limodzi loyamba la gawoli kuti likhale losadziwika bwino lomwe likupezeka mu ola lachiwiri, makamaka kutsanzira ndi / kapena kuthamangira kutha. N'kutheka kuti NAC yaikulu dopamine ndi imodzi mwa njira zothandizira kutayika. Lingaliro limeneli likugwirizana ndi gawo lofunsidwa la dopamine ngati chizindikiro cholakwika cholosera za mphotho, chomwe chimaganiziridwa kuti ndicho maziko a ophunzira omwe amasintha mu maimidwe a neural a mtengo wotchulidwa ndi zolimbikitsa (Montague et al., 1996; Schultz et al., 1997; Schultz, 1998). Zimagwirizananso ndi gawo la dopamine mu "kubwezeretsanso" mawonekedwe ofunika kwambiri (Berridge, 2012). Komabe, dopamine agonists ayenera kuyembekezera kupanga dopamine receptors, motero kumatsanzira chomwe chimatchedwa "tonic" dopamine; ngakhale kuti agonists angagwiritse ntchito dopamine receptors panthawi yomwe mphoto imaperekedwa, iyenso amachititsa ovomerezeka kuti afike pa digiri yofanana nthawi zina. N'zovuta kulingalira momwe chizindikiro chokhazikikacho chingatanthauzidwe ngati cholakwika cholosera kapena ngati chizindikiro cha "reboosting" chomwe chimasonyeza kuti chinthu chowongolera chatsopano chachitika.

Njira ina ndiyokuti mankhwala ophera dopamine sanalepheretse kulimbikitsa, koma ndi njira yokhala ndi neural yomwe imayambitsa njira zoyenera kuchita. Phunziroli likugwirizana ndi maphunziro athu akale omwe amasonyeza kuti ambiri (pafupifupi theka) a NAc neurons amasangalala ndi ntchito ya DS (Ambroggi et al., 2008; McGinty et al., 2013; du Hoffmann ndi Nicola, 2014; Morrison ndi Nicola, 2014); Kuwonjezera apo, mumalo ophika mchere wothandizira ntchito yofanana ndi yomwe imagwiritsidwa ntchito pano (mwachitsanzo, popanda kuchitapo kanthu mofulumira), mofanana ndi NAc neurons amasangalala (Caref ndi Nicola, 2014). Pogwiritsa ntchito mavidiyo, tawonetsa kuti izi zimayambitsa kuyambika kwa kayendedwe ka kayendedwe kake ndikudziwiratu kuti zidzachitika bwanji (McGinty et al., 2013; du Hoffmann ndi Nicola, 2014; Morrison ndi Nicola, 2014). Kuwonjezera apo, jekeseni wa otsutsa a dopamine mu NAC inachepetsa kukula kwa zosangalatsa izi pamene zikusowetsa mphamvu yakuyambitsa njira yophika (du Hoffmann ndi Nicola, 2014). Zotsatira izi zimasonyeza kuti dopamine imatsogolera mwachindunji chisangalalo chokhudzidwa ndi ziwalo za NAc zomwe zimayendetsa njira, mwina mwa kuwapangitsa kukhala okondweretsa kwambiri chifukwa cha kulumikizana kwa glutamatergic (Nicola et al., 2000, 2004; Hopf et al., 2003). Choncho, mankhwala a NAc neurons ndi odwala a dopamine omwe amatha kupweteka kwambiri amatha kuwonjezera mwayi wotsalira njira yophika poyesa kutsanzira njira yodzikongoletsera ya dopamine yodalirika ndipo motero kuwonjezereka kwakukulu kokhala ndi zokopa zomwe zimachotsedwa.

Ndondomeko yowonjezera yogwira ntchito ingakhale chifukwa cha kusintha kwa ma tonic dopamine

China chomwe nyama imagwira ntchito ndikuti mayankho ndi osayankha mayankho sizinagawidwe mwachisawawa, koma zimawoneka kuti zidaphatikizidwa ndimayankho angapo motsatizana kapena osayankha. Mukuwongolera (jekeseni wamagalimoto kapena jekeseni wamagalimoto), masango oyankha anali ataliatali komanso pafupipafupi kumayambiriro kwa gawoli, amakhala ocheperako komanso osafupika kumapeto kwa gawo; makamaka mosinthanitsa ndi masango osayankha. Izi zikuwonetsa kuti pali mayiko awiri, omvera komanso osayankha (Chithunzi (Figure3), 3), yomwe imasinthasintha ndi mphindi zochepa, ndi kusintha komwe kumakhala koyambirira kumbali yotsatila mkhalidwe wotsutsana ndi anthu omwe sali omvera. Dopamine jekeseni wa agonist inalimbikitsa kuti anthu azikhala omvera chifukwa cha kuchepetsa mwayi wopita ku zinthu zomwe sizinayankhe (kumapeto kwa magulu a mayankho) komanso kuonjezera mwayi wopita kumalo omvera (kuchepetseratu magulu osagwira ntchito), pamene otsutsa anali ndi zotsatira zosiyana. Zotsatira zomvetsa chisoni kwambiri za agonist zotsatira zachitika mu ora lachiwiri la gawoli, pamene mankhwalawa akuwoneka kuti alepheretsa chizoloŵezi chowonjezeka chowonjezeka ku dziko losamvera: ora lachiwiri kusintha kosakayika kunapitiriza kufanana ndi awo ola loyamba m'malo Kusunthira kumbali ya dziko lomwe silili lolandira. Mosiyana ndi zimenezi, otsutsanawo adakhudzidwa kwambiri ndi ola loyambirira, pamene iwo amachititsa kuti kusinthaku kukhale kovomerezeka ndi anthu omwe sali omvera, mofanana ndi kusintha kwachidziwitso kawirikawiri kumachitika ora lachiwiri.

Zotsatira za a dopamine agonists ndi otsutsa pa kusintha kosakayika zimagwirizana ndi lingaliro lakuti mayankho akugwira ntchito ya dopamine receptor ntchito. Choncho, pamene nthenda ya NAc dopamine imadutsa ndikudutsa pamtunda, chiweto chiri mu dziko lovomerezeka; pansi pa chigawo ichi, chinyama chili muzosavomerezeka. Kuyesera lingaliro limeneli kungafunike kuchuluka kwa ma tonic dopamine ngati nyama zikuchita izi kapena ntchito yofanana; chiphunzitsochi chimaneneratu kuti magulu a dopamine ayenera kukhala apamwamba pamagulu osankhidwa kusiyana ndi magulu osagwira ntchito. Ngakhale kuti zomwe taphunzira kale zakale za microdialysis sizinawone ngati kusinthasintha kwa dopamine kumagwirizana ndi njira yopezera msonkho mwinamwake, kafukufuku wapitawo anapeza kuti NAc dopamine mazinga anali apamwamba pamene zakudya zowonjezera zidaponyedwa m'zinthu za 45 kapena 4 mphindi (zonsezi kufunikira njira yowonongeka kuti apeze chakudya pa mayesero aliwonse) kusiyana ndi pamene chakudya chinali kupezeka momasuka (zochepetsera kufunika kwa njira zamatauni) (McCullough ndi Salamone, 1992). Zofukufuku zomwe zakhala zikuyendera pazifukwa zomwe zimakhala zovuta zokhudzana ndi kuyankhidwa zimapangitsa zotsatira zotsutsana, ndi ena akuwona mgwirizano wabwino pakati pa mlingo woyenera kuyankha ndi dopamine level (McCullough et al., 1993; Sokolowski et al., 1998; Cousins ​​et al., 1999) ndi ena omwe amapeza zosiyana ndi chiyanjanochi (Salamone et al., 1994; Azibale ake ndi Salamone, 1996; Ahn ndi Phillips, 2007; Ostlund et al., 2011). Zomwe zikhoza kufotokozera kusagwirizana kumeneku ndikuti ntchito zosiyana zimagwirizana ndi kufunika kwa njira zamatauni ku madigiri osiyanasiyana (Nicola, 2010); Kugwirizana ndi mlingo wa dopamine kungakhale kolimba kwambiri kwa njira yothetsera msonkho kusiyana ndi kuchuluka kwa mayankho omvera.

Cholinga chogwirizana ndi chakuti ma tonic dopamine amachititsa kuti asamangoyenda mofulumira (kapena mwinamwake wamkulu kwambiri wa njira zamatisi), komanso kuti ma dopamine amadziwika ndi kuchuluka kwa mphamvu (Niv et al., 2005, 2007), lingaliro limene lakhala likuchirikizidwa posachedwapa (Hamid et al., 2016). Choncho, ma dopamine m'zinyama zogwiritsa ntchito zowonjezera zakudya zowonjezera ziyenera kukhala zochepa ad libitum-posa kuposa nyama zanjala [monga momwe zilili (Ostlund et al., 2011)], ndipo pansi pamene reinforcer ndi 3% sucrose kusiyana ndi momwe zilili zofanana ndi 10% sucrose. Zomwe zimakakamizika kuti zikhale ndi dopamine mu 3% sucrose zingayambitse mchitidwe wambiri, ndi otsika kwambiri dopamine omwe amachititsa kuti pakhale mwayi wochepa kuchitapo kanthu; Kulephera kuchitapo kanthu kumabweretsa ndalama zowonjezera ndipo motero nambala ya dopamine imakhala yocheperapo, ndipo motero kuchitapo kanthu pachithunzi chotsatirachi kumakhalanso kochepa. Zotsatira zake zikanakhala kuchepetsa kupititsa patsogolo kwa chiwerengero choyankhidwa chofanana ndi chomwe chikuwonedwa apa.

Zomwe mwapeza: Kuphika mchitidwe wamakhalidwe ndi chitsanzo cha kufufuza za kayendedwe ka masolambic dopamine ndi mavitamini

Kutha kovomerezeka kotsika kwambiri kwa dopamine ad libitum-fed nyama zomwe zawonedwa pano zikugwirizana ndi kafukufuku waposachedwa wamalamulo a dopamine neurons ndi amithenga, monga cholecystokinin, orexin, ghrelin, leptin, insulin ndi peputide 1 wofanana ndi glucagon, zomwe zimafotokoza za michere ya thupi yomwe imapezeka kudzera munjira zosiyanasiyana. Mwambiri, zikwangwani zomwe zimafotokoza kuchepa kwa michere kumachulukitsa ntchito ya dopamine neuronal, pomwe ma sign omwe amafotokoza kukhuta kapena kuperewera kwa michere kumachepetsa (Ladurelle et al., 1997; Helm et al., 2003; Krügel et al., 2003; Abizaid et al., 2006; Fulton et al., 2006; Hommel et al., 2006; Narita et al., 2006; Kawahara et al., 2009; Leinninger et al., 2009; Quarta et al., 2009, 2011; Jerlhag et al., 2010; Perry et al., 2010; Domingos et al., 2011; España et al., 2011; Skibicka et al., 2011, 2012a,b, 2013; Davis et al., 2011a,b; Mebel et al., 2012; Patyal et al., 2012; Egecioglu et al., 2013; Cone et al., 2014, 2015; Mietlicki-Baase et al., 2014). Zokongola kwambiri za mesolimbic dopamine zosonyeza kuti zakudya zowonjezera zimakhala zogwirizana ndi malingaliro akuti mwayi wa mesolimbic dopamine-wodalira khalidwe ungasinthe pomwepo chifukwa cha mtengo wake, wokhudzana ndi zakudya za mchere, wa reinforcer (Berridge, 2012). Timaona kuti phindu loperewera kwa nyama zowonongeka limapangitsa kuti kusintha kwabwino kukhale kovuta kwambiri. Izi zowonjezera, kuphatikizapo kusintha kochititsa chidwi ndi kusintha kwabwino komwe kumapangidwa ndi jekeseni wa agonist ndi amatsutso ku NAC, akusonyeza kuti, malinga ndi momwe zinthu ziliri, muyezo wathu wa dopamine umagwira pansi pamtunda ndi njira zowonongeka. Kulamulira kwa ma dopamine ndi magawo ena ndi ena (monga posinthidwa posachedwapa) kungabweretse ma dopamine omwe amasinthasintha mozungulira pakhomo kuti apangitse yankho, kuchititsa mayankho komanso mayankho omwe sapezeka mumagulu. Makhalidwe apamwamba omwe timagwiritsa ntchito pano-masolimbic dopamine-amadalira njira yowonjezera yophika katrose ad libitumzinyama-ndizoyenera kuti apitirize kufufuzira kafukufuku wa dopamine mphamvu ndi mavitamini, kuchulukitsitsa kwa mlingo, ndi zigawo zina, ndi momwe njirazi zimakhudzira makhalidwe a NAC dopamine-odalira.

Kusamvana kwa mawu achidwi

Olembawo akunena kuti kufufuza kunkachitika popanda mgwirizano uliwonse wa zamalonda kapena zachuma zomwe zingatengedwe kuti zingatheke kukangana.

Ntchitoyi inathandizidwa ndi mabungwe ochokera ku NIH (DA019473, DA038412, DA041725), Klarman Family Foundation, ndi NARSAD ku SN.

1. Abizaid A., Liu ZW, Andrews ZB, Shanabrough M., Borok E., Elsworth JD, et al. . (2006). Ghrelin amachititsa kuti ntchito ndi syaptic zowonongeka za bungwe la midbrain dopamine neurons zikhazikitsidwe pamene zikulimbikitsa kudya. J. Clin. Sungani ndalama. 116, 3229-3239. 10.1172 / JCI29867 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
2. Ahn S., Phillips AG (2007). Dopamine efflux mkatikatikatikatikatikatikatikatikatikatikatikatikatikatikatikatikatikatikati, kumadalira, ndi chizoloŵezi chokhazikitsidwa ndi chizolowezi chokhalira chakudya. Psychopharmacology (Berl) 191, 641-651. 10.1007 / s00213-006-0526-9 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
3. Ambroggi F., Ishikawa A., Fields HL, Nicola SM (2008). Basolateral amygdala neurons amachititsa khalidwe lofunafuna mphoto mwachisangalalo cha nucleus accumbens neurons. Neuron 59, 648-661. 10.1016 / j.neuron.2008.07.004 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
4. Beeler JA, Mccutcheon JE, Cao ZF, Murakami M., Alexander E., Roitman MF, et al. . (2012). Kulakwitsa kwa zakudya zopanda thanzi kumalephera kulimbikitsanso chakudya. EUR. J. Neurosci. 36, 2533-2546. 10.1111 / j.1460-9568.2012.08167.x [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
5. Berridge KC (2012). Kuchokera kuchinyengo cholosera cholimbikitsana: mesolimbic chiwerengero cha mphoto zolimbikitsa. EUR. J. Neurosci. 35, 1124-1143. 10.1111 / j.1460-9568.2012.07990.x [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
6. Berridge KC, Ho CY, Richard JM, Difeliceantonio AG (2010). Ubongo woyesedwa umadya: zosangalatsa ndi maulendo okhumba mu kunenepa kwambiri ndi matenda odwala. Resin ya ubongo. 1350, 43-64. 10.1016 / j.brainres.2010.04.003 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
7. Boulos R., Vikre EK, Oppenheimer S., Chang H., Kanarek RB (2012). ObesiTV: momwe TV ikukhudzira mliri wa kunenepa kwambiri. Physiol. Behav. 107, 146-153. 10.1016 / j.physbeh.2012.05.022 [Adasankhidwa] [Cross Ref]
8. Boyland EJ, Halford JC (2013). Kuwonetsera TV ndi kuika chizindikiro. Zotsatira za khalidwe la kudya ndi zakudya zomwe amakonda ana. Kufuna 62, 236-241. 10.1016 / j.appet.2012.01.032 [Adasankhidwa] [Cross Ref]
9. Nthambi SY, Goertz RB, Sharpe AL, Pierce J., Roy S., Ko D., et al. . (2013). Kuletsedwa kwa zakudya kumapangitsanso kupopera kwa mphutsi ya dopamine neurons. J. Neurosci. 33, 13861-13872. 10.1523 / JNEUROSCI.5099-12.2013 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
10. Caref K., Nicola SM (2014). Nucleus accumbens opioids amayendetsa njira yopita ku calorie yapamwamba mphoto pokhapokha ngati palibe homeostatic drive, Msonkhano Wapachaka wa Society for Neuroscience (Washington, DC:).
11. Yoyamba JJ, Mccutcheon JE, Roitman MF (2014). Ghrelin amagwiritsa ntchito mawonekedwe pakati pa chikhalidwe cha thupi ndi chizindikiro cha dopamine. J. Neurosci. 34, 4905-4913. 10.1523 / JNEUROSCI.4404-13.2014 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
12. Mmodzi JJ, Roitman JD, Roitman MF (2015). Ghrelin imayambitsa phasic dopamine ndi nucleus accumbens kusonyeza kutayidwa ndi zakudya zowononga chakudya. J. Neurochem. 133, 844-856. 10.1111 / jnc.13080 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
13. Msuwani MS, Salamone JD (1996). Kuphatikizidwa kwazomwe zimayambitsa dopamine poyambitsa kayendedwe ndi kupha: microdialysis ndi kufufuza zamakhalidwe. Neuroscience 70, 849-859. 10.1016 / 0306-4522 (95) 00407-6 [Adasankhidwa] [Cross Ref]
14. Msuwani MS, Trevitt J., Atherton A., Salamone JD (1999). Ntchito zosiyana za khalidwe la dopamine mu nucleus accumbens ndi ventrolateral striatum: microdialysis ndi kufufuza zamakhalidwe. Neuroscience 91, 925-934. 10.1016 / S0306-4522 (98) 00617-4 [Adasankhidwa] [Cross Ref]
15. Davis JF, Choi DL, Schurdak JD, Fitzgerald MF, Clegg DJ, Lipton JW, et al. . (2011a). Leptin imayendetsa mphamvu zowonjezera mphamvu ndi zolimbikitsa pogwiritsa ntchito maulendo osiyana siyana. Ubweya. Psychiatry 69, 668-674. 10.1016 / j.biopsych.2010.08.028 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
16. Davis JF, Choi DL, Shurdak JD, Krause EG, Fitzgerald MF, Lipton JW, et al. . (2011b). Central melanocortins amachititsa mchitidwe wogwira ntchito komanso chakudya chofunafuna pakompyuta. Physiol. Behav. 102, 491-495. 10.1016 / j.physbeh.2010.12.017 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
17. de Araujo IE (2016). Dongosolo la pulaneti la shuga lolimbikitsa. Physiol. Behav. [Epub patsogolo pa kusindikiza]. 10.1016 / j.physbeh.2016.04.041 [Adasankhidwa] [Cross Ref]
18. de Araujo IE, Ferreira JG, Tellez LA, Ren X., Yeckel CW (2012). Mitsempha-ubongo dopamine axis: dongosolo lolamulira la kudya kwa caloric. Physiol. Behav. 106, 394-399. 10.1016 / j.physbeh.2012.02.026 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
19. Domingos AI, Vaynshteyn J., Voss HU, Ren X., Gradinaru V., Zang F., ndi al. . (2011). Leptin imayendetsa mtengo wapatali wa zakudya. Nat. Neurosci. 14, 1562-1568. 10.1038 / nn.2977 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
20. Du Hoffmann J., Kim JJ, Nicola SM (2011). Mtengo wotsika mtengo wosakanizidwa wothandizira makina ojambulidwa palimodzi pokhapokha kutsekedwa kwa mankhwala ndi mankhwala osokoneza bongo mumtima umodzi womwewo wa khalidwe la makoswe. J. Neurophysiol. 106, 1054-1064. 10.1152 / jn.00349.2011 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
21. Du Hoffmann J., Nicola SM (2014). Dopamine imapatsa mphoto kufunafuna mwa kulimbikitsa chisangalalo chomwe chimachotsedwa mu nucleus accumbens. J. Neurosci. 34, 14349-14364. 10.1523 / JNEUROSCI.3492-14.2014 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
22. Egecioglu E., Engel JA, Jr. E. (2013). Glucagon-ngati peptide 1 analogue Exendin-4 imachepetsa kukopa kwa kansalu komwe kumapangitsa kuti anthu azikhala ndi chidwi chofuna kukopa, kumangokhalira kutulutsa dopamine, malo okonzedweratu omwe amadziwika bwino komanso malingaliro amtundu wa makina. PLoS ONE 8: e77284. 10.1371 / journal.pone.0077284 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
23. Eiler WJ II, Masters, J., Mckay PF, Hardy L., III, Goergen J., Mensah-Zoe B., et al. . (2006). Amphetamine imachepetsa mphotho ya ubongo (BSR) m'malo mwa mowa-kusankha (P) ndi -kumasulira (NP) makoswe: malamulo a D-sub-1 ndi D-sub-2 amalandila mu nucleus accumbens. Exp. Kliniki. Psychopharmacol. 14, 361-376. 10.1037 / 1064-1297.14.3.361 [Adasankhidwa] [Cross Ref]
24. España RA, Melchior JR, Roberts DC, Jones SR (2011). Hypocretin 1 / orexin A mu ventral tegmental dera limapangitsa mayankho a dopamine kuti ayambe kukonda cocaine ndipo amalimbikitsa cocaine kudzilamulira. Psychopharmacology (Berl) 214, 415-426. 10.1007 / s00213-010-2048-8 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
25. Fulton S., Pissios P., Manchon RP, Stiles L., Frank L., Pothos EN, et al. . (2006). Leptin lamulo la masoaccumbens dopamine njira. Neuron 51, 811-822. 10.1016 / j.neuron.2006.09.006 [Adasankhidwa] [Cross Ref]
26. Haghparast A., Ghalandari-Shamami M., Hassanpour-Ezatti M. (2012). Kuwonongedwa kwa D1 / D2 receptors mkati mwa nucleus accumbens anatsimikizira zotsatira za antinociceptive ya cannabinoid receptor agonist mu basolateral amygdala. Resin ya ubongo. 1471, 23-32. 10.1016 / j.brainres.2012.06.023 [Adasankhidwa] [Cross Ref]
27. Hamid AA, Pettibone JR, Mabrouk OS, Hetrick VL, Schmidt R., Vander Weele CM, et al. . (2016). Mesolimbic dopamine imasonyeza kufunika kwa ntchito. Nat. Neurosci. 19, 117-126. 10.1038 / nn.4173 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
28. Helm KA, Rada P., Hoebel BG (2003). Cholecystokinin pamodzi ndi serotonin mu malire a hypothalamus amapezetsa dopamine kumasulidwa pamene akuwonjezera acetylcholine: njira yothetsera vutoli. Resin ya ubongo. 963, 290-297. 10.1016 / S0006-8993 (02) 04051-9 [Adasankhidwa] [Cross Ref]
29. Hiroi N., White NM (1991). Amphetamine inkaika malo okonda malo: kutengeka kwa dopamine receptor subtypes ndi malo awiri otetezera dopaminergic. Resin ya ubongo. 552, 141-152. 10.1016 / 0006-8993 (91) 90672-I [Adasankhidwa] [Cross Ref]
30. Hommel JD, Trinko R., Sears RM, Georgescu D., Liu ZW, Gao XB, et al. . (2006). Leptin receptor signaling pakatikati ya dopamine neurons imayang'anira kudya. Neuron 51, 801-810. 10.1016 / j.neuron.2006.08.023 [Adasankhidwa] [Cross Ref]
31. Chiyembekezo FW, Cascini MG, Gordon AS, Diamond I., Bonci A. (2003). Kugwirizanitsa ntchito za dopamine D1 ndi D2 receptors kumawonjezera kuwombera kwachitsulo kokhala ndi nthenda yokhala ndi neurons kudzera mu mapuloteni a G-βγ subunits. J. Neurosci. 23, 5079-5087. Ipezeka pa intaneti pa: http://www.jneurosci.org/content/23/12/5079.long [Adasankhidwa]
32. Mayi E., Egecioglu E., Dickson SL, Engel JA (2010). Kutsutsana kwa Ghrelin kulandira mankhwala a cocaine- ndi amphetamine-omwe amachititsa chidwi chokongoletsera, kutuluka kwa dopamine kumasulidwa, ndi malo okonda malo. Psychopharmacology (Berl) 211, 415-422. 10.1007 / s00213-010-1907-7 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
33. Kawahara Y., Kawahara H., Kaneko F., Yamada M., Nishi Y., Tanaka E., et al. . (2009). Momwemo amachitira ghrelin amachititsa zotsatira za bimodal pa disolimbic dopamine dongosolo malinga ndi zida za chakudya. Neuroscience 161, 855-864. 10.1016 / j.neuroscience.2009.03.086 [Adasankhidwa] [Cross Ref]
34. Kenny PJ (2011). Zopereka mphotho za kunenepa kwambiri: zidziwitso zatsopano ndi kutsogolo kwa mtsogolo. Neuron 69, 664-679. 10.1016 / j.neuron.2011.02.016 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
35. Koch M., Schmid A., Schnitzler HU (2000). Udindo wa minofu umasonkhanitsa dopamine D1 ndi D2 receptors mu chothandizira ndi Pavlovian paradigms ya malipiro mphoto. Psychopharmacology (Berl) 152, 67-73. 10.1007 / s002130000505 [Adasankhidwa] [Cross Ref]
36. Krügel U., Schraft T., Kittner H., Kiess W., Illes P. (2003). Dothi ndi kudyetsedwa kwa dopamine kutuluka mu khola la nkhono accumcums ndilopweteka ndi leptin. EUR. J. Pharmacol. 482, 185-187. 10.1016 / j.ejphar.2003.09.047 [Adasankhidwa] [Cross Ref]
37. Ladurelle N., Keller G., Blommaert A., Roques BP, Daugé V. (1997). Bungwe la CCK-B agonist, BC264, limawonjezera dopamine mu nucleus accumbens ndipo limapangitsa chidwi ndi chidwi pambuyo pa jekeseni la intraperitoneal mu makoswe. EUR. J. Neurosci. 9, 1804-1814. 10.1111 / j.1460-9568.1997.tb00747.x [Adasankhidwa] [Cross Ref]
38. Lardeux S., Kim JJ, Nicola SM (2015). Kutsekemera kwapakati pa mafuta okoma kwambiri sikutanthauza opioid kapena dopamine receptors mu nucleus accumbens. Behav. Resin ya ubongo. 292, 194-208. 10.1016 / j.bbr.2015.06.015 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
39. Leinninger GM, Jo YH, Leshan RL, Louis GW, Yang H., Barrera JG, et al. . (2009). Leptin amagwiritsa ntchito leptin receptor-expressing lateral hypothalamic neurons kuti asamalire malimbic dopamine dongosolo ndi kupondereza chakudya. Ma Metab Cell. 10, 89-98. 10.1016 / j.cmet.2009.06.011 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
40. Lex A., Hauber W. (2008). Dopamine D1 ndi D2 receptors mu nucleus accumbens pachimake ndi chipolopolo pakati Pavlovian-instrumental kutumiza. Phunzirani. Mem. 15, 483-491. 10.1101 / lm.978708 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
41. Liao RM (2008). Kupititsa patsogolo malo okonzedweratu omwe amachititsidwa ndi intra-accumbens kulowetsedwa kwa amphetamine kumatetezedwa ndi kulowetsedwa kwa dopamine D1 ndi D2 omwe amamenyana nawo. Pharmacol. Chilengedwe. Behav. 89, 367-373. 10.1016 / j.pbb.2008.01.009 [Adasankhidwa] [Cross Ref]
42. McCullough LD, Msuweni MS, Salamone JD (1993). Udindo wa nucleus accumbens dopamine poyankha pulogalamu yowonjezera yogwiritsira ntchito: maphunziro okhudza ubongo ndi maphunziro. Pharmacol. Chilengedwe. Behav. 46, 581-586. 10.1016 / 0091-3057 (93) 90547-7 [Adasankhidwa] [Cross Ref]
43. McCullough LD, Salamone JD (1992). Kuphatikizidwa kwa nucleus accumcums dopamine mu zoyendetsa galimoto zomwe zimaperekedwa ndi nthawi ya chakudya: microdialysis ndi kuphunzira khalidwe. Resin ya ubongo. 592, 29-36. 10.1016 / 0006-8993 (92) 91654-W [Adasankhidwa] [Cross Ref]
44. McCutcheon JE, Beeler JA, Roitman MF (2012). Zotsatira zowonjezera zowonjezera zimapangitsa kuti kutuluka kwa dopamine kutuluke kuposa saccharin-predictive cues. Yosinthasintha 66, 346-351. 10.1002 / syn.21519 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
45. McGinty VB, Lardeux S., Taha SA, Kim JJ, Nicola SM (2013). Kukonzekera kwa kufunafuna mphotho ndi chidziwitso ndi kuyandikira kokodola mu nucleus accumbens. Neuron 78, 910-922. 10.1016 / j.neuron.2013.04.010 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
46. Mebel DM, Wong JC, Dong YJ, Borgland SL (2012). Insulin mu ventral tegmental m'deralo imachepetsa kudya kwa hedonic ndi kupondereza dopamine ndondomeko mwa kuchulukanso kwa reuptake. EUR. J. Neurosci. 36, 2336-2346. 10.1111 / j.1460-9568.2012.08168.x [Adasankhidwa] [Cross Ref]
47. Meye FJ, Adan RA (2014). Maganizo okhudzana ndi chakudya: malo amodzi omwe amawathandiza kupeza chakudya komanso kupatsa maganizo. Miyambo ya Pharmacol. Sci. 35, 31-40. 10.1016 / j.tips.2013.11.003 [Adasankhidwa] [Cross Ref]
48. Mietlicki-Baase EG, Reiner DJ, Cone JJ, Olivos DR, Mcgrath LE, Zimmer DJ, et al. . (2014). Amylin amachititsa kuti masolimbic dopamine athetse mphamvu. Neuropsychopharmacology 40, 372-385. 10.1038 / npp.2014.18 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
49. Montague PR, Dayan P., Sejnowski TJ (1996). Cholinga cha machitidwe a mesophaine a dopamine okhudzana ndi maphunziro oyamba a Ahebri. J. Neurosci. 16, 1936-1947. [Adasankhidwa]
50. Morrison SE, Nicola SM (2014). Neurons mu nucleus accumbens amalimbikitsa kukondera kwa zinthu zoyandikana. J. Neurosci. 34, 14147-14162. 10.1523 / JNEUROSCI.2197-14.2014 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
51. Narita M., Nagumo Y., Hashimoto S., Narita M., Khotib J., Miyatake M., et al. . (2006). Kugwira ntchito mwachindunji ka machitidwe orexinergic poyambitsa maisolimbic dopamine njira ndi makhalidwe okhudzana ndi morphine. J. Neurosci. 26, 398-405. 10.1523 / JNEUROSCI.2761-05.2006 [Adasankhidwa] [Cross Ref]
52. Nicola SM (2010). Njira yokhazikika yokhulupirira: kugwirizana kwa kuyesayesa ndi kuganizira mozama zomwe zimachitika kuti pakhale mbali ya mtima wophatikizira dopamine poyambitsa khalidwe lofunafuna mphotho. J. Neurosci. 30, 16585-16600. 10.1523 / JNEUROSCI.3958-10.2010 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
53. Nicola SM, Hopf FW, Hjelmstad GO (2004). Kupititsa patsogolo kwapadera: chikhalidwe cha thupi cha kubala dopamine? Maselo a Cell Cell. 318, 93-106. 10.1007 / s00441-004-0929-z [Adasankhidwa] [Cross Ref]
54. Nicola SM, Surmeier J., Malenka RC (2000). Dopaminergic modulation of neuronal excitability mu striatum ndi nucleus accumbens. Annu. Rev. Neurosci. 23, 185-215. 10.1146 / annurev.neuro.23.1.185 [Adasankhidwa] [Cross Ref]
55. Nicola SM, Taha SA, Kim SW, Fields HL (2005). Nucleus accumbens dopamine kumasulidwa ndi kofunika ndipo ndikwanira kulimbikitsa khalidwe loyankhidwa pazinthu zowonongeka. Neuroscience 135, 1025-1033. 10.1016 / j.neuroscience.2005.06.088 [Adasankhidwa] [Cross Ref]
56. Niv Y., Daw N., Dayan P. (2005). Kufulumira kugwira ntchito: kuyankha mwamphamvu, kulimbikitsana ndi dopamine ya tonic, mu Neural Information Processing Systems 18, eds Weiss Y., Scholkopf B., Platt J., olemba. (Cambridge, MA: MIT Press;), 1019-1026.
57. Niv Y., Daw N., Joel D., Dayan P. (2007). Tonic dopamine: ndalama zowonjezera komanso kuyang'anira mphamvu yowonongeka. Psychopharmacology 191, 507-520. 10.1007 / s00213-006-0502-4 [Adasankhidwa] [Cross Ref]
58. O'keefe J., Nadel L. (1978). Hippocampus ngati Mapu Ozindikira. Oxford: Clarendon.
59. Ostlund SB, Wassum KM, Murphy NP, Balleine BW, Maidment NT (2011). Maselo a extracellular dopamine m'madera omwe akuwombera akuyendetsa kayendetsedwe ka mtengo wolimbikitsa ndi kuyanjanitsa panthawi yogwiritsa ntchito mankhwala. J. Neurosci. 31, 200-207. 10.1523 / JNEUROSCI.4759-10.2011 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
60. Ozer H., Ekinci AC, Starr MS (1997). Dopamine D1- ndi D2 wodalirika wodalirika mu khola amafunika kugwira ntchito zothandizira NMDA mu corpus striatum, nucleus accumbens ndi substantia nigra parsticata. Resin ya ubongo. 777, 51-59. 10.1016 / S0006-8993 (97) 00706-3 [Adasankhidwa] [Cross Ref]
61. Patyal R., Woo EY, Borgland SL (2012). Local hypocretin-1 imagwiritsa ntchito dopamine ndondomeko mu nucleus accumbens shell. Kutsogolo. Behav. Neurosci. 6: 82. 10.3389 / fnbeh.2012.00082 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
62. Perry ML, Leinninger GM, Chen R., Luderman KD, Yang H., Gnegy ME, et al. . (2010). Leptin imalimbikitsa dopamine transporter ndi tyrosine hydroxylase ntchito mu nkhono yomwe imakhala ndi makoswe a Sprague-Dawley. J. Neurochem. 114, 666-674. 10.1111 / j.1471-4159.2010.06757.x [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
63. Petrosini L., Molinari M., Dell'anna ME (1996). Cerebellar yothandizira pakukonzekera zochitika zapakati: morris madzi maze ndi T-maze. EUR. J. Neurosci. 8, 1882-1896. Onetsani: 10.1111 / j.1460-9568.1996.tb01332.x [Adasankhidwa] [Cross Ref]
64. Pezze MA, Dalley JW, Robbins TW (2007). Ntchito zosiyana za dopamine D1 ndi D2 receptors mu nucleus accumbens mu ntchito mwakhama pa chisanu kusankha chisankho nthawi ntchito. Neuropsychopharmacology 32, 273-283. 10.1038 / sj.npp.1301073 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
65. Quarta D., Di Francesco C., Melotto S., Mangiarini L., Heidbreder C., Hedou G. (2009). Kukonzekera mwachidwi kwa ghrelin kumawonjezera danga la extracellular mu chipolopolo koma osati kugawidwa kwakukulu kwa nucleus accumbens. Neurochem. Int. 54, 89-94. 10.1016 / j.neuint.2008.12.006 [Adasankhidwa] [Cross Ref]
66. Quarta D., Leslie CP, Carletti R., Valerio E., Caberlotto L. (2011). Kulamulira kwapakati pa NPY kapena NPY-Y5 yowonjezera agonist kuwonjezeka mu vivo Maselo a monoamine owonjezera a monoamine m'madera omwe amagwiritsa ntchito masewera olimbitsa thupi. Neuropharmacology 60, 328-335. 10.1016 / j.neuropharm.2010.09.016 [Adasankhidwa] [Cross Ref]
67. R Gulu lalikulu (2013). R: A Chilankhulo ndi Chilengedwe kwa Masalimo Achidule. Maziko a Compatimenti Yachibalo. Ipezeka pa intaneti pa: http://www.R-project.org/ (Kupezeka 2016).
68. Jalam Salamone, Msuwani MS, McCullough LD, Carriero DL, Berkowitz RJ (1994). Nucleus accumbens dopamine kumasulidwa kumawonjezeka panthawi ya chiwombankhanga chowongolera chakudya koma osati kudya. Pharmacol. Chilengedwe. Behav. 49, 25-31. 10.1016 / 0091-3057 (94) 90452-9 [Adasankhidwa] [Cross Ref]
69. Schultz W. (1998). Ndalama zowonetsera mphoto za dopamine neurons. J. Neurophysiol. 80, 1-27. [Adasankhidwa]
70. Schultz W., Dayan P., Montague PR (1997). A neural gawo la kuneneratu ndi mphotho. Sayansi 275, 1593-1599. 10.1126 / sayansi.275.5306.1593 [Adasankhidwa] [Cross Ref]
71. Sclafani A. (1987). Zakudya za m'magazi, kulawa, ndi kunenepa kwambiri: mwachidule. Neurosci. Biobehav. Mtsutso 11, 131-153. 10.1016 / S0149-7634 (87) 80019-2 [Adasankhidwa] [Cross Ref]
72. Sclafani A. (2013). Kutsegula kwa ubongo wa ubongo. Kuchita nawo masewero ndi kusaganizira. Kufuna 71, 454-458. 10.1016 / j.appet.2012.05.024 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
73. Sclafani A., Ackroff K. (2012). Udindo wa m'matumbo umamveketsa kuwonetsa chilakolako chofuna kudya ndi chikhalidwe cha zakudya. Am. J. Physiol. Regul. Kugwirizana. Kuphatikiza. Physiol. 302, R1119-R1133. 10.1152 / ajpregu.00038.2012 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
74. Shin R., Cao J., Webb SM, Ikemoto S. (2010). Maofesi a Amphetamine mu ventral striatum amachititsa kuti anthu azigwirizana ndi zizindikiro zosaoneka bwino m'makoswe. PLoS ONE 5: e8741. 10.1371 / journal.pone.0008741 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
75. Skibicka KP, Hansson C., Alvarez-Crespo M., Friberg PA, Dickson SL (2011). Ghrelin imalowera mwachindunji malo omwe amachititsa kuti anthu azikhala ndi chakudya. Neuroscience 180, 129-137. 10.1016 / j.neuroscience.2011.02.016 [Adasankhidwa] [Cross Ref]
76. Skibicka KP, Hansson C., Egecioglu E., Dickson SL (2012a). Udindo wa ghrelin mu chakudya mphotho: zotsatira za ghrelin pa sucrose kudziyang'anira bwino ndi mesolimbic dopamine ndi acetylcholine phwando jini maonekedwe. Kusokoneza. Ubweya. 17, 95-107. 10.1111 / j.1369-1600.2010.00294.x [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
77. Skibicka KP, Shirazi RH, Hansson C., Dickson SL (2012b). Ghrelin imagwirizana ndi neuropeptide Y Y1 ndi mapulogalamu opioid opititsa patsogolo chakudya. Endocrinology 153, 1194-1205. 10.1210 / en.2011-1606 [Adasankhidwa] [Cross Ref]
78. Skibicka KP, Shirazi RH, Rabasa-Papio C., Alvarez-Crespo M., Neuber C., Vogel H., ndi al. . (2013). Zosintha zamagetsi zomwe zimapereka mphotho ya chakudya komanso zotsatira za ghrelin: dopaminergic VTA-accumbens projection imathandizira mphamvu ya ghrelin pamalipiro a chakudya koma osadya. Neuropharmacology 73, 274-283. Onetsani: 10.1016 / j.neuropharm.2013.06.004 [Adasankhidwa] [Cross Ref]
79. Smith GP (2001). John Davis ndi matanthauzo a kunyoza. Kufuna 36, 84-92. 10.1006 / appe.2000.0371 [Adasankhidwa] [Cross Ref]
80. Sokolowski JD, Conlan AN, Salamone JD (1998). Phunziro la microdialysis la nucleus accumbens pachimake ndi chipolopolo cha dopamine panthawi yogwira ntchito pamphati. Neuroscience 86, 1001-1009. 10.1016 / S0306-4522 (98) 00066-9 [Adasankhidwa] [Cross Ref]
81. Steinberg EE, Boivin JR, Saunders BT, Witten IB, Deisseroth K., Janak PH (2014). Kulimbikitsidwa kovomerezeka ndi midbrain dopamine neurons kumafuna D1 ndi D2 kulandira cholowa mu nucleus accumbens. PLoS ONE 9: e94771. 10.1371 / journal.pone.0094771 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
82. Stice E., Figlewicz DP, Gosnell BA, Levine AS, Pratt WE (2013). Chopereka cha ubongo mphoto madera kwa kunenepa mliri. Neurosci. Biobehav. Mtsutso 37, 2047-2058. 10.1016 / j.neubiorev.2012.12.001 [Nkhani yaulere ya PMC] [Adasankhidwa] [Cross Ref]
83. Wakabayashi KT, Fields HL, Nicola SM (2004). Kusiyanitsa kwa gawo la nucleus accumbens dopamine poyankha mphotho-zowonongeka ndi kuyembekezera mphotho. Behav. Resin ya ubongo. 154, 19-30. 10.1016 / j.bbr.2004.01.013 [Adasankhidwa] [Cross Ref]
84. Yun IA, Nicola SM, Masamba HL (2004a). Zotsatira zosiyana za jekeseni wa dopamine ndi glutamate wotsutsana ndi nkhonya mu nucleus accumbens amasonyeza njira ya neural yomwe imayesedwa ndi cholinga choyendetsa cholinga. EUR. J. Neurosci. 20, 249-263. 10.1111 / j.1460-9568.2004.03476.x [Adasankhidwa] [Cross Ref]
85. Yun IA, Wakabayashi KT, Fields HL, Nicola SM (2004b). Malo amtundu woyenera amafunika kuti khalidwe ndi nkhono zikhale ndi mayankho omwe amawombera. J. Neurosci. 24, 2923-2933. 10.1523 / JNEUROSCI.5282-03.2004 [Adasankhidwa] [Cross Ref]