Ukujikeleza kweesekethe phantsi komvuzo wokutya kunye nefuthe lokutya kwe-ghrelin: i-dopaminergic VTA-eqokelelelela uqikelelo lwempembelelo ye-ghrelin kumvuzo wokutya kodwa hayi ukutya (2013)

Neuropharmacology. I-2013 Oct; 73: 274-83. I-Doi: 10.1016 / j.neuropharm.2013.06.004. I-Epub 2013 Jun 14.

ISkibicka KP1, Shirazi RH, URabasa-Papio C, Alvarez-Crespo M, Neuber C, UVogel H, UDickson SL.

Abstract

Ukutyeba kakhulu kufikelele kububanzi bokubhubhane kwehlabathi kwaye kudala isidingo esingxamisekileyo sokuqonda iindlela ezisebenzisa kakhulu ukutya okungafunekiyo. I-Ghrelin, ekuphela kwehomoni e-orexigenic eyaziwayo, inokonyusa indlela yokuziphatha komvuzo. Ukujikeleza kwe-neurochemical okunxibelelanisa i-ghrelin kwinkqubo yemivuzo ye-mesolimbic kunye nokunyuka kokuziphatha komvuzo kuhlala kungacacanga. Apha sivavanya ukuba ingaba i-VTA-NAc dopaminergic signaling iyafuneka kwiziphumo ze-ghrelin kumvuzo wokutya kunye nokutya. Ukongeza, sijonga ukuba kunokwenzeka ukuba i-endrelas ghrelin isebenze kwi-VTA-NAc dopamine neurons. I-D1-efana okanye i-D2 receptor antagonist yafakwa kwi-NAc ngokudibana ne-ghrelin microinjection kwi-VTA ukuphanda ukuba ingaba le ndlela yokuvimba inemikhwa yokuvuyisa yokuziphatha ye-ghrelin. Inaliti ye-VTA ye-ghrelin ivelise ukonyuka okukhulu kokunyusa kokutya / indlela yokuziphatha, njengoko ilinganiselwe yi-sucrose-induction eqhubekekayo yokusebenza komgangatho wokusebenza, kunye nokutya kwe-chow. Ukucaphukisa nokuba une-D1-efana ne-D2 receptor antagonist kwi-NAc, uvaliwe ngokupheleleyo umphumo we-ghrelin, ushiya i-chow intake intact. Sifumanise ukuba le setyhula inokubaluleka kwimiphumela ye-ghrelin ekhutshwe ngokugqibeleleyo njengoko bobabini abachasi banciphise ukuzila (imeko yamanqanaba aphezulu esijikelezo se-ghrelin) indlela yokuziphatha ekhuthazwayo ye-sucrose kodwa hayi chower hyperphagia. Sithathiwe kunye nedatha yethu ichonga i-VTA ukuya kwi-NAc dopaminergic, kunye ne-D1-efana ne-D2 receptors kwi-NAc, njengezinto ezibalulekileyo kwimijikelezo ephendukayo yesiporho elawula indlela yokuziphatha komvuzo. Iziphumo ezinomdla zikwabonisa ukuba indlela yokufumana umvuzo wokutya kunye nokutya okulula kwe-chow kulawulwa kukujikeleza kweendlela ezahlukeneyo, apho i-NAc dopamine idlala indima ebalulekileyo kumvuzo wokutya kodwa kungabi kukutya.

Iimbalasane

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  • I-Intra-VTA ghrelin ifaka i-accumbal D1 kunye ne-D2 receptors.

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  • Ukuncitshiswa kokutya kuphakamisa indlela yokuziphatha yomvuzo nge-D1 kunye ne-D2 receptors.

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  • Ukutya ukutya akunakuthintelwa yi-accumbal D1 kunye ne-D2.

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  • Ukuziphatha komvuzo wokutya kunye nokutya okulula kwe-op kulawulwa zii-divergent circry.

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  • I-NAc dopamine idlala indima ebalulekileyo kumvuzo wokutya kodwa kungabi kukutya.

Abstract

Ukutyeba kakhulu kufikelele kububanzi bokubhubhane kwehlabathi kwaye kudala isidingo esingxamisekileyo sokuqonda iindlela ezisebenzisa kakhulu ukutya okungafunekiyo. I-Ghrelin, ekuphela kwehomoni e-orexigenic eyaziwayo, inokonyusa indlela yokuziphatha komvuzo. Ukujikeleza kwe-neurochemical okunxibelelanisa i-ghrelin kwinkqubo yemivuzo ye-mesolimbic kunye nokunyuka kokuziphatha komvuzo kuhlala kungacacanga.

Apha sivavanya ukuba ingaba i-VTA-NAc dopaminergic signaling iyafuneka kwiziphumo ze-ghrelin kumvuzo wokutya kunye nokutya. Ukongeza, sijonga ukuba kunokwenzeka ukuba i-endrelas ghrelin isebenze kwi-VTA-NAc dopamine neurons. I-D1-efana okanye i-D2 receptor antagonist yafakwa kwi-NAc ngokudibana ne-ghrelin microinjection kwi-VTA ukuphanda ukuba ingaba le ndlela yokuvimba inemikhwa yokuvuyisa yokuziphatha ye-ghrelin. Inaliti ye-VTA ye-ghrelin ivelise ukonyuka okukhulu kokunyusa kokutya / indlela yokuziphatha, njengoko ilinganiselwe yi-sucrose-induction eqhubekekayo yokusebenza komgangatho wokusebenza, kunye nokutya kwe-chow. Ukucaphukisa nokuba une-D1-efana ne-D2 receptor antagonist kwi-NAc, uvaliwe ngokupheleleyo umphumo we-ghrelin, ushiya i-chow intake intact. Sifumanise ukuba le setyhula inokubaluleka kwimiphumela ye-ghrelin ekhutshwe ngokugqibeleleyo njengoko bobabini abachasi banciphise ukuzila (imeko yamanqanaba aphezulu esijikelezo se-ghrelin) indlela yokuziphatha ekhuthazwayo ye-sucrose kodwa hayi chower hyperphagia.

Sithathiwe kunye nedatha yethu ichonga i-VTA ukuya kwi-NAc dopaminergic, kunye ne-D1-efana ne-D2 receptors kwi-NAc, njengezinto ezibalulekileyo kwimijikelezo ephendukayo yesiporho elawula indlela yokuziphatha komvuzo. Iziphumo ezinomdla zikwabonisa ukuba indlela yokufumana umvuzo wokutya kunye nokutya okulula kwe-chow kulawulwa kukujikeleza kweendlela ezahlukeneyo, apho i-NAc dopamine idlala indima ebalulekileyo kumvuzo wokutya kodwa kungabi kukutya.

Internet

  • Ghrelin;
  • Inkuthazo yokutya;
  • Ukutya;
  • Utyhefu;
  • Imeko yokusebenza;
  • Dopamine;
  • D1;
  • D2

1. intshayelelo

Umjikelezo wehomoni ojikelezayo kunye nemijikelezo ye-neural esebenza kuyo isebenza kakuhle iphandwe kwimeko yokukhuluphala kunye nolawulo lokutya (I-Skibicka kunye ne-Dickson, 2011), ekhuthazwe ngamathuba onyango kule ndawo yezifo (ICardona Cano et al., 2012). IGhrelin yahlukile phakathi kweeputheni ezijikelezayo zesisu kuba oko kukhulisa ukutya (UWren et al., 2000, Inui, 2001, UShintani et al., 2001 kwaye I-Kojima kunye ne-Kangawa, i-2002) isiphumo se-CNS esilinganiswa nee-receptors ezinikezelweyo, i-GHS-R1A (USalome et al., 2009 kwaye ISkibicka et al., 2011) ngokukodwa ezo zikwindawo ezinobuchopho ezibandakanyeka "kukondla ekhaya" (okt ukondla okunxulumene nokusilela kwamandla), i-hypothalamus kunye ne-brainstem (UMelis et al., 2002, IFaulconbridge et al., 2003 kwaye UOlszewski et al., 2003). Kutshanje, nangona kunjalo, indima ye-ghrelin ngaphandle kwale mimandla yekhaya iye yavela. I-GHS-R1A ikwakhona kwii-node eziphambili zenkqubo yembuyekezo ye-mesolimbic, kwiindawo ezinjenge-ventral tegmental ndawo (VTA) kunye ne-nucleus accumbens (NAc) (UZigman et al., 2006 kwaye ISkibicka et al., 2011), iindawo ezibandakanyekayo kukuziphatha okukhuthazayo okuye kwanxulunyaniswa "nokondla ngokwe-hedonic" (okt. ukutya okuphekwe kunye neepropathi zayo ezinomvuzo). IGhrelin iyakwazi ukuqhuba umthamo wokutya kuzo zombini ezi ndawo kwaye isiphumo sinokunxulunyaniswa nesenzo saso ukwandisa ukhuthazo kunye nexabiso lokukhuthaza umvuzo wokutya (UNaleid et al., 2005, UAbizaid et al., 2006 kwaye ISkibicka et al., 2011). Ke ngoko, kumagundwane okanye amagundwane azaliswe ngokupheleleyo, i-ghrelin isetyenziswa ngokungangqalanga okanye ngekhulu (kubandakanywa ngqo kwi-VTA) ikhokelela kukutya okwandisiweyo kokutya kunye nokuziphatha komvuzo wokutya (UNaleid et al., 2005, UPerello et al., 2010, ISkibicka et al., 2011 kwaye ISkibicka et al., 2012b) ibonakalisiwe, umzekelo, ngokunyusa ingcinezelo ye-lever yomvuzo weswekile kwishedyuli esebenzayo yomlinganiso. Esi senzo sibonisa indima evelayo ye-ghrelin ngaphakathi kwenkqubo yembuyekezo ye-mesolimbic yokuphucula indlela yokuziphatha njengomvuzo, kungekuphela kokutya kodwa nakwisiselo esinxilisayo kunye neziyobisi zokuxhaphaza (UDickson et al., 2011). Ngokubalulekileyo, le mpembelelo ye-ghrelin kukhuthazo lokutya olungaphaya kokuhamba ngemigca satiety, njengoko i-ghrelin ikhupha indlela yokuziphatha kumvuzo wezilwanyana ezivuthiweyo ukuya kwinqanaba elilinganayo nelifunyenwe kwiigundane ezikhuphe ukutya. Ngapha koko, isibakala sokuba ukuvalwa komqondiso we-ghrelin, kungekuko ngokwenkqubo kodwa nangokukhetha ngaphakathi kweVTA (ISkibicka et al., 2011), kukhokelela ekunyanzeliseni okunamandla kokuziphatha komvuzo kugxininisa ukubaluleka kunye nemfuneko yomqondiso we-ghrelin kumvuzo wokutya.

Isenzo se-Ghrelin kwinqanaba le-VTA yanele ukuqhuba ukutya kunye nokuziphatha okukhuthazayo, iziphumo ezibonakala zifuna ukusayinwa nge-GHS-R1A (UAbizaid et al., 2006 kwaye ISkibicka et al., 2011). Okumangalisayo kukuba, ukujikeleza okungaphantsi kwezenzo zokukhuthaza umvuzo kwi-VTA kuhlala kungasonjululwanga. Ngaphakathi kwi-VTA, i-ghrelin ibandakanya i-opioid, i-NPY kunye ne-GABAergic signaling (UAbizaid et al., 2006 kwaye ISkibicka et al., 2012a). Nangona kunjalo, i-VTA dopamine neurons, eboniswe ngaphambili ukubonisa i-ghrelin receptors (UAbizaid et al., 2006), isenokuba kukujolisa kokugqibela kweVTA kwiziphumo ze-ghrelin kumvuzo wokutya. Ukutya okunokuthenjwa / okunomvuzo kubandakanya i-VTA dopamine neurons kunye nomqondiso we-dopamine kwiindawo ezikhethiweyo ze-CNS ezinje nge-NAc, ngaloo ndlela kukhuthaza indlela yokuziphatha yomvuzo wokutya (UHernandez kunye noHoebel, 1988 kwaye UJoseph noHodges, 1990). Kufuneka kuqatshelwe, nangona kunjalo, ukuba ukukhutshwa kwe-dopamine kudityaniswe kakhulu nokuziphatha okuchukumisayo kukutya, kukwayimfuneko ukondla okusisiseko njengeempuku ezingakwaziyo ukudibanisa idopamine ibulawa yindlala (ICannon et al., 2004). Ikhonkco elisebenzayo phakathi kwe-ghrelin kunye ne-dopamine iphakanyiswa ziziphumo ze-ghrelin kwimisebenzi ye-VTA dopamine neuron kunye nenyani yokuba i-VTA dopaminergic neurons efunekayo kwiziphumo ze-ghrelin kumvuzo wokutya (UAbizaid et al., 2006 kwaye Weinberg et al., 2011). Nangona kunjalo, iprojekthi ye-VTA dopamine neurons yeprojekthi kwiindawo ezininzi kwaye ihlala ingafakwanga ngokupheleleyo ukuba ngaba ukubonwa kwe-dopamine kwi-NAc kuyafuneka kwimiphumo eqhutywa yiVTA ye-ghrelin kwindlela yokuziphatha ekhuthazwayo kukutya. Ngapha koko, i-ghrelin ibandakanyeka kulawulo lokuziphatha kwezinye izinto ngaphandle kokutya okanye ukunyanzelwa, oko kukuthi, ukufuna izinto ezintsha, ezikhutshiweyo nokukhululwa kwe-dopamine kwi-NAc (UBardo et al., 1996 kwaye UHansson et al., 2012).

Kwisifundo esikhoyo, sivavanye i-hypothesis ethi iziphumo ze-ghrelin kukuziphatha okukhuthazwayo kokutya kunye / okanye ukutya okuthe gqolo kwinqanaba le-VTA kufuna uphawu lokubonisa uphawu lwe-dopamine kwi-NAc. Ukuza kuthi ga ngoku, ukubakho kokutya kunye nokuziphatha okukhuthazwayo kukuqhutywa kweVTA ghrelin kuvavanyiwe kwinqanaba lokucinezelwa kwengcinezelo ye-sucrose paradigm kunye ne-NAc dopamine yokusayina ibhloko. Kwizifundo ezahlukileyo savavanya igalelo lomntu dopamine 1 (D1) njengee-receptors kunye ne-dopamine 2 receptors (D2). Ngapha koko, ukuze siphonononge igalelo le-endo native ghrelin kumqondiso we-NAc dopamine, sigqibe kwelokuba ngaba ezi recopept receptors zidlala indima ekuphuculweni kwendlala kwindlela yokuziphatha yomvuzo wokutya. Okokugqibela, ukuze sivavanye iziphumo zeemolekyuli zonyuka ephakamileyo kwi-NAc dopamine isayine, sagqiba isiphumo sendlala / ukungabikho kokutya ekubonakalisweni kwe-mRNA ye-NAc dopamine receptors kunye nee-enzymes.

2. Impahla nenkqubo

izilwanyana: Iigundane zabantu abadala i-Sprague-Dawley rats (200-250 g, Charles River, Germany) zagcinwa kumjikelo we-12-h wokukhanya / umjikelo omnyama (izibane nge-6 am) kunye ne-chow eqhelekileyo kunye namanzi afumanekayo ad adum emakhayeni abo. Zonke iinkqubo zezilwanyana beziqhutywa ngemvume yokuziphatha kunye nokuhambelana nezikhokelo zeKholeji yeGothenburg iZiko loKhathalelo lweZilwanyana kunye nezikhokelo zeKomiti.

UkuhlinzwaZonke iigundane kwizifundo zokuziphatha ziye zafakwa kwi-cannula yesikhokelo (i-26 gauge; Iplastikhi yokuqala, iRoanoke, VA), kugxilwe kwi-VTA kunye neqokobhe le-NAc kulandelayo. I-Ketamine anesthesia yayisetyenziswa. I-Cannulae yabekwa i-1.5 mm ngaphezulu kwendawo ekujoliswe kuyo, kwaye isitofu esandisa i-1.5 mm ukusuka kwisikhokelo se-cannulae sasetyenziselwa ii-microinjection. Ukujolisa kwi-VTA, la makhonkco alandelayo akhethwe kuwo Skibicka okqhubekayo. (2011): ± 0.75 ukusuka embindini, 5.7 mm ngasemva ukuya kwi-bregma, kunye ne-6.5 mm ye-ventral evela kumphezulu wokakayi, ngenaliti ejolise kwi-8.0 mm ye-ventral kwikakayi. Kwigobolondo le-NAc, ezi zilungelelaniso zilandelayo zisetyenzisiwe (ziguqulwe ukusuka UQuarta okqhubekayo. (2009): ± 0.75 ukusuka kumda ophakathi, i-1.7 mm ngaphambili ukuya kwi-bregma, kunye ne-6.0 mm ye-ventral kwikhakhayi, ene-injector ejolise kwi-7.5 mm ventral). ICannulae yayiqhotyoshelwe kukhakhayi ngesamente samazinyo kunye nezikere zejewler kwaye zavalwa nge-obturator, njengoko bekuchaziwe ngaphambili (ISkibicka et al., 2009). Kuzo zonke iigundane, indawo ye-microinjection yazo zombini i-VTA kunye ne-NAc yaqinisekiswa ngokufa komzimba, nge-microinjection ye-india-inki kwivolumu efanayo ye-microinjection (0.5 μl) esetyenziswe kufundo lonke. Izifundo kuphela ezibekwe ngokuchanekileyo (Umzobo 2) zifakiwe kuhlalutyo lwedatha.

  • Ubungakanani obugcweleyo (48 K)
  • Umzobo 1.  

    Imizobo emele uyilo olwahlukileyo lokuyisebenzisa luyasetyenziswa. Ishedyuli 1 isetyenziselwe ukufumana idatha eboniswe ngaphakathi Amakhiwane. 3 kwaye 4. Ishedyuli 2 isetyenziselwe ukufumana idatha eboniswe ngaphakathi Umzobo 5 kunye neshedyuli ye-3 yedatha eboniswe ngaphakathi Amakhiwane. 6 kwaye 7. Iibhokisi ezingwevu ezingqindilili zimela amaxesha xa kwakuqokelelwa imilinganiselo.

  • Ubungakanani obugcweleyo (77 K)
  • Umzobo 2.  

    Ummeli we-NAc (A) kunye ne-VTA (B) indawo yenaliti (iboniswe kwisangqa). Iphaneli yasekunene imele icandelo lobuchopho be-rat ye-coronal nge-india-inki encinci efakwe kwi-VTA okanye kwiqokobhe le-NAc (NAcS) kumthamo we-0.5 μl osetyenziswe kufundo. Iphaneli lasekhohlo libonisa icandelo leatlas yengqondo ehambelana nayo, i-2.16 mm ngaphambili kwi-bregma ye-NAc kunye ne-5.64 yangasemva kwi-bregma ye-VTA; Aq, ikhonkco; cc, corpus collosum; CPu, caudate kunye ne-putamen; I-LV, i-ventricle esecaleni; I-NAcC, isiseko se-NAc; SN, isanti enkulu.

2.1. Inkqubo yokujonga imeko yokusebenza

Uvavanyo lokujonga imeko lwenzekile kumagumbi okujonga imeko yeerati (30.5 × 24.1 × 21.0 cm; Med-Associates, Georgia, VT, USA). Inkqubo yoqeqesho esetyenziselwe imeko yokusebenza yahlengahlengiswa kwizifundo zangaphambili (I-la Fleur et al., 2007 kwaye UHansson et al., 2012). Ukuququzelela uqeqesho olusebenzayo lwe-sucrose, zonke iigundane zithotyelwe kuthintelo lokutya olungephi ngexesha apho ubunzima bomzimba wabo bokuqala bancitshiswa baba yi-90% kwithuba leveki enye. Phambi kokubekwa kwiibhokisi ezisebenzayo, iigundane zaziveliswa iipellets ze-sucrose (i-45 mg sucrose pellets; uvavanyo lokutya, iRichmond, IN, eU.SA) kwindawo yokuhlala ekhaya amaxesha amabini. Emva koko, iigundane zafunda ukuxinzelela i-sucrose pellets phantsi kwesilinganiselo esimiselweyo se-FR1, kunye neeseshoni ezi-2 / ngosuku. Kwi-FR1, umatshini omnye wokushicilela kwi-lever esebenzayo ukhokelele ekuhanjisweni kwepelethi enye ye-sucrose. Zonke iiseshoni ze-FR zigqibe i-30 min okanye de iigundane zafumana iipellets ze-50, nokuba yeyiphi eyenzeke kuqala. Uninzi lweempuku lufezekisile iipellets ezingama-50 kwisikhombisi seseshoni emva kweentsuku ezingama-5-7. Oomatshini bokushicilela abangasetyenziswanga baborekhodwa, kodwa babengenaziphumo zicwangcisiweyo. Iiseshoni zeeshedyuli ze-FR1 zilandelwe yi-FR3 kunye ne-FR5 (okt, u-3 no-5 koomatshini bokushicilela ngesisele ngasinye ngokulandelelana). Ishedyuli ye-FR5 yalandelwa sishedyuli yenkqubela phambili (PR) ngexesha apho iindleko zomvuzo zaye zonyuswa ngokuqhubekayo kumvuzo ngamnye olandelayo, ukuze kufunyaniswe isixa somsebenzi i-rat ekulungeleyo ukuyenza ekufumaneni umvuzo. Imfuno yempendulo inyukile ngokokulinganisa okulandelayo: umyinge wokuphendula = (5e (0.2 × inani lokumnika)) -5 ngothotho olulandelayo: 1, 2, 4, 9, 12, 15, 20, 25, 32, 40, 50 , 62, 77, 95, 118, 145, 178, 219, 268, 328. Iseshoni ye-PR yaphela xa i-rat isilele ukufumana umvuzo ngaphakathi kwe-60 min. Ukuphendula kwathathelwa ingqalelo kuzinzile xa inani leepellets zokutya ezifunyenwe kwiseshoni nganye azingafani ngaphezulu kwe-15% kwiiseshoni ezintathu zilandelelana. Kwiimeko ezininzi, ukuphendula kuzinzile kwiiseshoni ezi-5. Ezo mpuku zingakhange zifikelele kwiikhrayitheriya ezifunekayo kwelo xesha liqeqeshwe kwiiseshoni ezongezelelweyo. Uvavanyo lwe-PR lwenziwa kwiseshoni ye-1 / ngosuku. Iigundane emva koko zagqithiselwa kwiikati zazo zasekhaya nge-1 h chow yokuthatha imilinganiselo. Ukuphela koqeqesho naphambi kotyando kunye nokuvavanywa, iigundane zazinazo ad adum ukufikelela kwi-chow eqhelekileyo.

2.2. Zi yobisi

I-Acylated rat ghrelin (Tocris, Bristol, UK) yenziwa kwi-VTA ngedosi ye-1.0 μg ene-fluid ye-cerebrospinal fluid (aCSF) njengesithuthi (kunye nolawulo). Idosi ye-1.0 μg ye-ghrelin ibonakalisiwe ngaphambili ukuba inyuse ukuphendula kweswekile kunye nokwenza impendulo ye-orexigenic xa kusiwa kwi-VTA (UNaleid et al., 2005 kwaye ISkibicka et al., 2011). I-D1-efana ne-receptor antagonist, i-SCH-23390, yenziwa kwi-NAc ngedosi ye-0.3 μg (Tocris), ene-ACCS njengezithuthi (ulawulo). Kwisifundo sokuncitshiswa kokutya, idosi inyuswe yaya kwi-0.5 μg ngenxa yokusilela kwesiphumo sedosi yoqobo eyi-0.3 μg. I-SCH-23390 inamandla kwaye iyakhetha i-antagonist ye-D1-efana ne-dopamine receptors ene-1000-fold fold affinity ye-D1-efana ne-D2-efana ne-dopamine receptors (UBarnett et al., 1986). Inobuhlobo obufanayo kwi-D1 kunye ne-D5 receptors (UBarnett et al., 1992kungoko kulo lonke uphononongo siza kubhekisa kumandla alo okubamba ii-receptors ezinje nge-D1, igama eliquka zombini i-D1 kunye ne-D5 receptors. Idosi yokuqala ye-0.3 μg ye-SCH-23390 yakhethwa ngokusekwe (UGrimm et al., 2011). Idosi efakwe kwiqokobhe le-NAc ibonakalisiwe iyasebenza ekunciphiseni ukucinezela kwe-lever kwinto eyayifakwe ngambini kunikezelo lwesisombululo se-sucrose ngaphandle kokuchaphazela ukusebenza kwe-lever engasebenziyo. I-dopamine D2 receptor antagonist, eticlopride hydrochloride (Tocris), yenziwa kwi-NAc nge-aCSF njengezithuthi (ulawulo). Idosi yokuqala ye-eticlopride ekhethiweyo (1.0 μg) yayisekwe (I-Laviolette et al., 2008) kodwa yandiswa yaya kwi-1.5 μg kufundo lokuthintela ukutya. Onke amayeza ahanjiswa kumthamo we-0.5 μl we-aCSF.

2.3. Uyilo lo vavanyo

Zonke iigundane zifumene i-NAc kunye ne-VTA yayalelwa ngenaliti kwangoko kumjikelo wokukhanya, ngenaliti yesibini kwi-10 min ngaphambi kokuqala kovavanyo olusebenzayo. Zonke iimeko zahlulwe ngobuncinci be-48 h kwaye zibaleke ngendlela engqinelanayo, ukuze irati nganye ifumane zonke iimeko ezine: isithuthi sokuqala okanye i-dopamine receptor antagonist kwi-NAc emva koko, i-10 min kamva, isithuthi okanye i-ghrelin eya kwi-VTA. Kwinqanaba ngalinye i-VTA kunye ne-NAc yayijolise kuyo. Iinkcukacha zovavanyo ngalunye zikwaboniswa kwi Umzobo 1.

2.3.1. Iziphumo ze-D1-efana ne-receptor blockade kumvuzo wokutya osisidambisi kunye nokutya

Iimpendulo zavavanywa emva kokuba i-VTA ekugxilwe kuyo kunye ne-NAc (n = 12-14) ukuhanjiswa kweziyobisi emva kweemeko ezine ngolu hlobo lulandelayo: 1) imeko yolawulo (izisombululo zezithuthi kwi-NAc kunye neVTA), 2) imoto ye-NAc + i-VTA 1.0 μg ghrelin, 3) NAc 0.3 μg SCH-23390 + VTA isithuthi, 4 I-NAc 0.3 μg SCH-23390 + VTA 1.0 μg ghrelin. Uvavanyo lwenziwa kwimeko yokuhlutha (emva kwexesha lokutya elimnyama). Kwiintsuku zovavanyo iigundane zabuyiselwa ezindlini zazo emva kwe-120 min yovavanyo olusebenzayo kunye nokutya kwe-chow kwakulinganiswa ngexesha le-1 h kwimo yendlu yasekhaya (njengakwishedyuli 1, Umzobo 1). Eli nqaku lihambelana nelixa lesithathu emva kwenaliti yeVTA ghrelin, ekuya kulindeleka ukuba impendulo i-orexigenic iqhubeke, ngokusekwe kwizifundo zangaphambili zokuvavanya ixesha lesenzo se-ghrelin, esilawulwa ngophakathi okanye ngokungaphaya. UWren et al., 2000 kwaye IFaulconbridge et al., 2003) kunye nezifundo zethu zangaphambili ezisebenzise iseti yovavanyo olufanayo.

2.3.2. Iziphumo ze-D2 receptor blockade kwi-ghrelin-in induction yokutya kunye nokutya kwe-chow

Iimpendulo zavavanywa emva kokuba i-VTA ekugxilwe kuyo kunye ne-NAc (n = 7) ukuhanjiswa kweziyobisi kwiimeko ezine ngolu hlobo lulandelayo: 1) imeko yolawulo (izisombululo zezithuthi kwi-NAc kunye neVTA), 2) NAc isithuthi + VTA 1.0 μg ghrelin, 3) NAc 1 μg eticlopride hydrochloride + VTA isithuthi, 4) NAc 1 μg eticlopride hydrochloride + VTA 1.0 μg ghrelin. Uvavanyo lwenziwa kwimeko yokuhlutha (emva kwexesha lokutya elimnyama). Iigundane zibuyiselwe ezindlini zazo emva kwe-120 min yokuvavanywa kokusebenza kunye nokutya kwe-chow kwakulinganiswa ngexesha le-1 h kwimo yendlu yasekhaya (njengakwishedyuli 1 Umzobo 1) njengempembelelo ye-orexigenic ye-ghrelin-Mediated isekhona emva kokubambezeleka kokubekwa kwe-chow pellets (emva kwe-2 h).

2.3.3. Iziphumo ze-D1-efana kunye ne-D2 receptor blockade (eyahlukileyo okanye edibeneyo) kwi-ghrelin-indened chow intake yedwa

Ukuqinisekisa ukuba iziphumo ezifunyenwe kukutya kwe-chow kuvavanyo lwangaphambili khange ziphazanyiswe kukuvezwa kwangaphambili kwe-sucrose kwiparadigm esebenzayo okanye ukulibaziseka kwexesha le-2 h, kwisifundo esahlukileyo, sivavanye iziphumo zokuhanjiswa kwe-NAc. Ababini abachasi be-dopamine receptor bodwa okanye ngokudibeneyo kwi-VTA ghrelin-indased 2 kunye ne-3 h yokutya ukutya kwiigundane ezishushu (n = 10-11; ngokweshedyuli 2, Umzobo 1). Kule meko iigundane azibonakaliswanga kwimeko yokusebenza kweparadigm ngaphambi komlinganiso we-chow. Ke, ukutya ukutya kwakulinganiswa emva kokujoliswa kwe-VTA kunye ne-NAc yokuhambisa iziyobisi emva kweemeko ezine ngolu hlobo lulandelayo: 1) imeko yolawulo (izisombululo zezithuthi kwi-NAc nakwi-VTA), 2) Imoto ye-NAc + i-VTA 1.0 μg ghrelin, 3) NAc dopamine receptor antagonist + Isithuthi se-VTA, 4) NAc dopamine receptor antagonist + VTA 1.0 μg ghrelin. Kuqala sivavanye ii-dopamine receptor antagonists ngokwahlukeneyo kangangokuba, kwiimeko ze-3 kunye ne-4, elinye iqela leempuku lafumana i-0.3 μg SCH-23390 kwaye elinye iqela lafumana i-1 μg eticlopride hydrochloride. Emva kokululama kangangeentsuku ezi-3, malunga nesiqingatha seempuku kwiqela ngalinye baphinde babuyiswa, ngeli xesha ngokudityaniswa kwabachasi ababini kwiimeko ze-3 kunye ne-4. Kolu vavanyo ngalunye kwezi-3 uyilo olulinganisiweyo lwalusetyenziswa phakathi konyango, njengangaphambili (zonke Iigundane zifumene zonke iimeko kuvavanyo ngalunye ngaphakathi kokuthelekiswa kwesifundo). Isikhundla se-cannulae saqinisekiswa emva kokubhubha njengangaphambili. Idatha ebonisiweyo ibandakanya kuphela iigundane ngokubekwa kwenaliti okuqinisekisiweyo ukufikelela kwi-VTA kunye ne-NAc.

2.3.4. Iziphumo ze-D1-efana kunye ne-D2 i-receptor blockade kwisiphelo sokutya-okuphembelele ukutya kunye nokutya ukutya

I-dopamine receptor antagonists yavavanywa kwiimvavanyo ezahlukeneyo ze-2. Kwilingo lokuqala, iimpendulo zavavanywa emva kokujolisa kwi-NAc (n = 20) ukuhanjiswa kwesithuthi okanye i-D1-like receptor antagonist (0.5 μg SCH-23390). Uvavanyo lwenziwa kwimeko yokuzila (emva kokuba ukutya kuthintelwe ixesha lexesha elimnyama). Kwimpendulo yesibini yokuvavanywa kuvavanywa emva kokujoliswa kwe-NAc (n = 7) ukuhanjiswa kwesithuthi okanye i-1.5 μg NAc eticlopride hydrochloride. Uvavanyo lwenziwa kwimeko yokuzila (emva kokuba ukutya kuthintelwe ixesha lokujikeleza okumnyama; njengoko kubonisiwe kwishedyuli 3, Umzobo 1).

2.3.5. Ukutshintsha kokungafuneki kokutya ekubonakaliseni uhlobo lwentsholongwane ehambelana ne-dopamine kwi-NAc

Iinguqu eziqhutywa kukuncitshiswa kokutya kwi-gene expression of dopamine genes genes [dopamine receptors D1A, D2, D3, D5, catechol-O-methyltransferase (COMT), kunye ne-monoamine oxidase A (MAO)] zalinganiswa kwi-NAc.

2.3.6. Ukuzahlula i-RNA kunye nentetho ye-mRNA

Iibongo zisuswe ngokukhawuleza kwaye i-NAc yachithwa kusetyenziswa ubuchwephesha bengqondo, efriziwe kwi-nitrojeni engamanzi kwaye igcinwe kwi -80 ° C ukumisela kamva intetho ye-mRNA. Iisampulu zengqondo nganye ziye zahlanjululwa eQiazol (Qiagen, Hilden, Germany) zisebenzisa iTissue Lyser (Qiagen). Iyonke i-RNA yakhutshwa kusetyenziswa i-RNeasy Lipid Tissue Mini Kit (Qiagen) ngonyango olongezelelekileyo lwe-DNAse (Qiagen). Umgangatho we-RNA kunye nobungakanani bavavanywa ngemilinganiselo ye-spectrophotometric (iNanodrop 1000, iNanoDrop Technologies, e-USA). Ukusetyenziswa kwe-cDNA synthesis iScript cDNA Synthesis kit (BioRad) yayisetyenziswa. Ixesha le-RT PCR yenziwa kusetyenziswa iTaqMan® iprosesa kunye neeseti zokuqala zezinto ekujoliswe kuzo ezikhethwe kwikhathalogu eku-online (Applied Biosystems). Amaxabiso entetho yeGene abalwa ngokusekwe kwi Ct indlela ( Livak noSchmittgen, 2001), apho ad adum Iqela elondliweyo labizwa njengekhalbrator. I-Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) yasetyenziswa njengereferensi gene.

2.3.7. Uhlalutyo lwesatisatisti

Zonke iiparameter zokuziphatha zahlalutywa ngohlalutyo lwamanyathelo okuphindaphinda umahluko (ANOVA) kulandelwa iposi Uvavanyo lweTukey HSD njengoko kufanelekile okanye ngabafundi t kuvavanyo apho kuphela iimeko ezimbini zathelekiswa. Lonke uhlalutyo lweenkcukacha manani lwenziwa kusetyenziswa isoftware yeGraphPad. Umahluko uthathwe njengento ebalulekileyo p <0.05.

3. Iziphumo

3.1. Iziphumo ze-D1-efana ne-receptor blockade (NAc) kumvuzo wokutya ofakwe ngeVTA kunye ne-chow intake

Ukufumanisa ukuba ngaba imisebenzi efunyanwa kwi-receptors ye-D1 ifana ne-VTA ghrelin ebangelwa kukunyuka kwemivuzo yokutya ifuthe lokuxela kunye ne-D1-efana nomchasi (i-SCH-23390) kwi-ghrelin-indened ophethe i-ghrelin. Uvavanyo lwe-hoc Tukey olulandelayo ngendlela eyi-ANOVA (F(3,33) = 11.1, p <0.0005; F(3,33) = 3.7, p <0.01; F(3,39) = 3.6, p <0.05 yemivuzo, i-lever esebenzayo kunye ne-chow ngokwahlukeneyo) ityhile isiphumo esibonakalayo se-ghrelin yokunyusa inani lemivuzo efunyenwe (p <0.0005; Umzobo 3A), inani lamaphepha e-lever asebenzayo (p <0.05; Umzobo 3B), kunye nokutya i-chow.p <0.05; Umzobo 3C). Iiparamitha ezinxulumene nokuziphatha okunemivuzo, imivuzo efunyenwe kunye noomatshini bokushicilela be-lever, babevinjwe ngokucacileyo yi-SCH-23390 pretreatment ( Umzobo 3A, B). Umsebenzi kwi-lever engasebenziyo wawumncinci kwaye wawungafani ngokwahlukileyo phakathi kwamaqela ahlukeneyo onyango ( Umzobo 3B) ucebisa ukuba unyango aluvelisi utshintsho olungachazwanga olungenanjongo lomsebenzi. I-hyperphagia ye-Chow eqaphelelwe emva kokuba i-ghrelin icinywe kwi-VTA ayitshintshwanga yi-SCH-23390 pretreatment ( Umzobo 3C). Ezi datha zibonisa ukuba i-dopamine kunye ne-D1-efana ne-receptors kwiqokobhe le-NAc isezantsi kwe-ghrelin kwaye iyimfuneko kwi-VTA elawulwa yi-ghrelin ukuze ikhuphe iziphumo zayo ekuziphatheni komvuzo wokutya. Ayisiyo, nangona kunjalo, ibalulekile kumandla e-ghrelin okonyusa ukutya kwe-chow. Unyango lwe-NAc nge-SCH-23390 alunampembelelo ngomntu ngamnye nakuwuphi na umntu ophendulayo ophendula ngokutya okanye ukutya Umzobo 3).

  • Ubungakanani obugcweleyo (37 K)
  • Umzobo 3.  

    Iziphumo ze-intra-NAc iqokobhe le-D1 receptor blockade kwi-intra-VTA ghrelin-indased yokuziphatha komvuzo wokutya kunye ne-chow hyperphagia. Ukunyanga kwangaphambili kunye ne-D1-efana ne-receptor antagonist, i-SCH-23390, kuthintele ngokupheleleyo ukonyuka okunyanzelisiweyo kwimivuzo ye-sucrose efunyenwe (A), kunye nenani loomatshini bokushicilela abasebenzayo (imivalo emnyama) ngelixa umsebenzi we-lever engasebenziyo (imivalo engwevu) yayi aluchaphazelekanga nakuphi na unyango (B). I-Intra-VTA ghrelin hyperphagia khange ifakwe kwi-NAc iqokobhe lokukhetha i-D1 receptors (C). Amaxabiso aboniswa njengeendlela + SE. n = 12-14. *p <0.05, ***p <0.005.

3.2. Iziphumo ze-D2 blockade (NAc) kumvuzo wokutya owenziwe ngeVTA kunye ne-chow intake

Ukufumanisa ukuba ngaba imisebenzi kwi-D2s iyimfuneko yokubonakaliswa kwe-VTA ghrelin-intenised ephakanyisiweyo yokuziphatha komvuzo wokutya, ifuthe lokuqunjelwa kunye nomchasi we-D2 antagonist (eticlopride hydrochloride) kwi-ghrelin-indased in inductor yokusebenza kwe-sucrose. Enye indlela i-ANOVA ibonise impembelelo ebalulekileyo kunyango lweziyobisi (F(3,18) = 9.5, p <0.0005; F(3,18) = 8.1, p <0.001; F(3,39) = 3.8, p <0.05 yomvuzo, i-lever esebenzayo kunye ne-chow ngokwahlukeneyo). Uvavanyo lwe-hoc Tukey lubonise ukonyuka okubonakalayo kwimbuyekezo efunyenweyo (p <0.01; Umzobo 4A) kunye nomatshini wokushicilela osebenzayo (p <0.01; Umzobo 4B) emva konyango lwe-ghrelin olwavalwa nge-eticlopride exreatment. Umsebenzi kwi-lever engasebenziyo wawumncinci kwaye wawungafani ngokwahlukileyo phakathi kwamaqela ahlukeneyo onyango ( Umzobo 4B). Ngokuchasene nedatha yokuphendula yokusebenza, ukuvavanywa kwe-eticlopride akuzange kutshintshe ukunyuka okubangelwa yi-ghrelin okubangelwa kukunyuka kwe-chow int (p <0.05; Umzobo 4C). Kolu phononongo lwendibaniselwano unxibelelwano luqinisekisiwe ziindlela ezimbini ze-ANOVA phakathi kokunyanzelwa kwangaphambili x ghrelin kwimivuzo efunyenwe: F(1,24) = 4.8, p <0.05; oomatshini bokushicilela abasebenza ngokusebenzayo: F(1,24) = 4.7, p <0.05 kodwa hayi ukuthatha i-chow. Ke ii-receptors ze-D2 zinokusetyenziswa yi-ghrelin ukwenza utshintsho kwiindlela zokuziphatha ezinxulumene nomvuzo kodwa ingekuko ukusetyenziswa kwe-chow.

  • Ubungakanani obugcweleyo (39 K)
  • Umzobo 4.  

    Iziphumo ze-intra-NAc iqokobhe le-D2 receptor blockade kwi-intra-VTA ghrelin-indased yokuziphatha komvuzo wokutya kunye ne-chow hyperphagia. Ukunyanga kwangaphambili kunye ne-D2 receptor antagonist, i-eticlopride hydrochloride (i-ETC), iphelise ukunyuka okunyanzelisiweyo kwimivuzo ye-sucrose efunyenwe (A), kunye nenani loomatshini abasebenza ngokucinezela (imivalo emnyama) ngelixa umsebenzi we-lever ongasebenziyo (imivalo engwevu) wawungekho ezichaphazelekayo lulo naluphi na unyango (B). Ngokwahlukileyo i-intra-VTA ghrelin hyperphagia khange ifakwe kwi-NAc iqokobhe elikhethiweyo lokuvalwa kwee-receptors ze-D2 (C). Amaxabiso aboniswa njengeendlela + SE. n = 7. *p <0.05, **p <0.01.

3.3. Iziphumo ze-D1-efana kunye / okanye i-D2 receptor blockade (NAc) kwi-VTA ghrelin-indened chow intake

Ukufuna ukuqinisekiswa ngakumbi kokungabikho kwempembelelo ye-dopamine antagonists ekwenziweni kokondla, saphinda isifundo, ngeli xesha kwiigundane azikaze zichazwe kwimo yokusebenza yparadigm. Olu phononongo lokuqinisekisa lwandisiwe lubandakanya uvavanyo lwesithathu apho sajonga khona ukuhanjiswa ngokubambisana kwe-D1-efana ne-D2 receptor antagonists kwi-NAc kwi-VTA ghrelin eqhutywa kukutya. Ukutya i-Chow kunyuswe kakhulu yi-VTA ghrelin kwi-2 h emva kwenaliti (indlela enye ye-ANOVA: F(3,30) = 6.4, p <0.005 kunye F(3,27) = 9.0, p <0.0005 yesifundo se-D1 kunye ne-D2 receptor ngokulandelanayo) kwaye oku akuzange kuchaphazeleke kukunyanzelwa kwangaphambili kunye ne-D1-efana ( Umzobo 5A) okanye i-D2 receptor antagonist ( Umzobo 5B). Kuvavanyo lokugqibela, kuphononongwa isiphumo esidibeneyo se-dopamine receptor antagonists, asikwazanga ukubona isiphumo esibalulekileyo se-VTA ghrelin kude kube lixesha le-3 h, mhlawumbi kubonisa ifuthe lesitofu se-parenchymal inaliti esifunekayo kolu phononongo. Enye indlela i-ANOVA ibonakalise isiphumo esibalulekileyo kunyango (F(3,30) = 9.6, p <0.0005). Ukutya emva kokuhanjiswa kwe-VTA ghrelin kufikelele ekubalulekeni kwinqanaba lexesha le-3 h, nangona kunjalo, oku akuzange kuphinde kucinezelwe ngokudityaniswa kwesicelo se-dopamine receptor antagonists kwi-NAc ( Umzobo 5C). Qaphela ukuba ukusetyenziswa ngokudibeneyo kwezichaso zedopamine receptor ezichasene ne-NAc akunaziphumo ngomntu ngamnye ekutyeni ukutya.

  • Ubungakanani obugcweleyo (48 K)
  • Umzobo 5.  

    Iziphumo ze-intra-NAc iqokobhe le-dopamine receptor blockade kwi-intra-VTA ghrelin-induction chow hyperphagia kwiigundane ngaphandle koqeqesho olusebenzayo lwangaphambili okanye ukubonakaliswa kwe-sucrose. I-VTA ghrelin-induction hyperphagia elinganiselwe kwi-2 h post-injection ayizange icinezelwe yi-NAc ngaphambi konyango nokuba (A) i-D1-efana ne-receptor antagonist, i-SCH-23390 (SCH) okanye (B) i-D2 receptor antagonist, eticlopride hydrochloride ( Njl). Ku (C), chow hyperphagia ebangelwa yi-ghrelin elinganiswa ngexesha le-3 h ayizange icinezelwe kulawulo lwe-NAc yabo bobabini abachasi. Amaxabiso aboniswa njengeendlela + SE. n = 10-11. *p <0.05, **p <0.01.

3.4. Iziphumo ze-D1-efana kunye ne-D2 i-receptor blockade kwisiphelo sokutya-okuphembelele ukutya kunye nokutya ukutya

Ukuncitshiswa kokutya kuphakamisa ukuphendula okusebenzayo kunye ne-1 h chow; Iigundane zicinezele i-lever esebenzayo iphantse iphindwe kabini xa ilambile kwaye iphindwe kathathu ukuya kwesithandathu ngaphezulu kwe-chow kwindawo yokulinganisa ye-1 h (thelekisa imeko yemoto kwi Amakhiwane. 3 kwaye 4). I-blockade of D1-receptors-like receptors kwibhokisi ye-NAc iyinciphise kakhulu indlela yokuphazamiseka kokutya ekunyuseni kwindlela yokuziphatha kumvuzop <0.01; Umzobo 6A) kunye nokwehliswa kwengcinezelo esebenzayo ye-lever (p <0.01; Umzobo 6B). Olu nyango aluzange lube naziphumo zibucaphukisayo ukutya- Umzobo 6C). Ukufakwa komchasi we-D2 kwiqokobhe le-NAc kunciphise kakhulu ukunyanzeliswa kokutya okunyuselweyo kwindlela yokuziphatha yomvuzo wokutya xa kuvavanywa njengokuncitshiswa kwemivuzo yokutya efunyenweyo (p <0.01; Umzobo 7A). Nokuba wonke umlinganiso unciphise i-lever yakhe yokucinezela emva kwe-D2 blockade kwi-NAc isiphumo esikhokelela kumkhwa (p = 0.08; Umzobo 7B) ngokunokwenzeka ngenxa yokwahluka okuphezulu kwesiseko kuxinzelelo lwe-lever (impazamo esemgangathweni = i-86 yezithuthi kunye ne-41 yeemeko zeziyobisi, uluhlu lwe-lever esebenzayo ecinezela kwisithuthi ukusuka kuma-57 ukuya kuma-707 oomatshini). Ukususwa kweyona mpendulo iphezulu kwiziphumo zokusetwa kwedatha p = 0.001. Ngokubalaseleyo i-rat esusiweyo yabonisa oomatshini bokushicilela abangama-707 kwisithuthi kwaye ngama-303 kuphela kwichiza, yiyo loo nto ikwaxhasa nesiphelo. Nokuba i-dopamine receptor antagonist ayitshintshanga i-lever icinezela kwi-lever engasebenziyo. Ukutya i-Chow akuzange kutshintshwe yi-D2 blockade kwi-NAc ( Umzobo 7C).

  • Ubungakanani obugcweleyo (29 K)
  • Umzobo 6.  

    Iziphumo ze-intra-NAc iqokobhe le-D1 receptor blockade kukuncitshiswa kokutya-ukunyusa ukunyuka kokuziphatha komvuzo wokutya kunye ne-chow hyperphagia. Ukunyanga kwangaphambili kunye ne-D1 receptor antagonist, i-SCH-23390, kuthintelwe ukunyuka kokutya okunyanzelekileyo kwimivuzo ye-sucrose efunyenwe (A), kunye nenani loomatshini abasebenza ngokucinezela ngelixa umsebenzi we-lever ongasebenziyo ungakhange uchaphazeleke nakuphi na unyango (B) . I-Chow hyperphagia khange ifakwe kwi-NAc iqokobhe lokukhetha i-D1 receptors (C). Amaxabiso aboniswa njengeendlela + SE. n = 20. **p <0.01.

  • Ubungakanani obugcweleyo (30 K)
  • Umzobo 7.  

    Iziphumo ze-intra-NAc iqokobhe le-D2 receptor blockade kukuncitshiswa kokutya-ukunyusa ukunyuka kokuziphatha komvuzo wokutya kunye ne-chow hyperphagia. Ukunyanga kwangaphambili kunye ne-D2 receptor antagonist, eticlopride hydrochloride (ETC), kunciphise ukonyusa ukutya okunyanzeliswa kwimivuzo ye-sucrose efunyenwe (A), kwaye ithambekele ekunciphiseni inani loomatshini bokushicilela abasebenzayo (B). Umsebenzi okwenziwe kwilever engasebenziyo awuchaphazelekanga lulo naluphi na unyango (B). I-Chow hyperphagia khange ifakwe kwi-NAc iqokobhe lokukhetha i-D2 receptors (C). Amaxabiso aboniswa njengeendlela + SE. n = 7. **p <0.01.

3.5. Ukutshintsha kokungeniswa kokutya ekuguqukeni kwento ehambelana nedopamine ku-NAc

Ukuzila ukutya ebusuku kube nefuthe elibonakalayo ekubonakalisweni kwe-mRNA yeentlobo ezininzi ezihambelana ne-dopamine kwi-NAc. Ukubonakaliswa kwe-mRNA ye-dopamine receptor D2 yancitshiswa kakhulu ngelixa i-dopamine receptor D5 mRNA yaphakanyiswa. I-Dopamine receptor D1, D3, COMT kunye ne-MAO mRNAs azitshintshelwanga ngokuzila ukutya ebusuku (Umzobo 8). I-D1 kunye ne-D2 receptors zithathwa njengezona dopamine receptor zininzi kwingqondo ngelixa i-D3 kunye nokubakho kwe-D5 kwi-CNS kusikelwe umda ngakumbi. Sithe ke sithelekisa amanqanaba e-mRNA kwii-receptors ze-D5 kwi-D1 kwaye yafika kwi-2%; ubudlelwane obufanayo bafunyaniswa nge-D3 kunye ne-D2 (idatha ayiboniswanga). Ke apha siyaqinisekisa ukuba ngaphakathi kwe-NAc uninzi lwe-dopamine receptor mRNA lwenziwe nge-D1 kunye ne-D2 receptors ngelixa i-D3 kunye ne-D5 receptors zimele nje iqhezu elincinci le-dopamine receptor mRNA efunyenwe kwi-NAc.

  • Ubungakanani obugcweleyo (21 K)
  • Umzobo 8.  

    I-Nuklea eqokelela i-dopamine ehambelana nomqondiso ohambelana nomfuziselo ofunyenwe emva kokuthintelwa kokutya. Amaxabiso aboniswa njengeendlela + SE. *p <0.05.

4. Ingxoxo

Iziphumo eziphambili zophando lwangoku zibonisa ukuba uphawu lwe-dopamine kwigobolondo le-NAc luyimfuneko ekuhlaleni komlamli weziphumo ze-ghrelin kumvuzo wokutya. Iziphumo zibonisa ukuba i-D1-efana ne-D2 receptors kwigobolondo le-NAc zizinto eziphambili ze-ghrelin-activated circry kwaye zibalulekile kwi-VTA efakwe kwi-ghrelin ukuze ikhuphe iziphumo zayo ekuziphatheni komvuzo wokutya. I-D1-efana ne-D2 receptor signaling kwi-NAc (iqokobhe) ayisiyiyo, nangona kunjalo, ibalulekile kumandla e-ghrelin okwandisa ukutya kwe-chow. Ezi datha zicebisa ukwahluka kwiithagethi ze-neural ze-ghrelin ezilawula ukomeleza ukutya kunye nokutya. Okokugqibela iziphumo zethu zibonisa ukuba le sekethe ikwabandakanyeka yi-endo native ghrelin njengoko, kwimeko yendlala, xa ujikeleza amanqanaba e-ghrelin aphakanyisiwe, umqondiso we-dopamine kwi-NAc uyimfuneko ekunyuseni isimilo sokutya.

Kuyamangalisa, ngelixa kucacile ukuba i-ghrelin inefuthe kwinkqubo yedopaminergic (UAbizaid et al., 2006, UJerlhag et al., 2007, Kawahara et al., 2009 kwaye Weinberg et al., 2011), Olu luvavanyo lokuqala ukubonisa ukuba iimpembelelo ze-ghrelin kumvuzo wokutya zifuna i-NAc dopamine receptor signaling (kule meko, i-D1-like kunye ne-D2 signaling). Oku kuvele njengombuzo obalulekileyo njengezinye iihormone okanye ii-neuropeptides ezinxulunyaniswe nolawulo lwenkanuko kutshanje kubonisiwe ukuba zinobudlelwane obungalindelekanga kunye nenkqubo ye-mesolimbic dopamine. I-Leptin, umzekelo, njenge-ghrelin, inee-receptors kwii-dopamine neurons kwi-VTA; uninzi lwee-leptin ezibuthathaka zedopaminergic neurons, nangona kunjalo, aziqhubeki kwi-striatum kodwa endaweni yoko zenze i-amygdala (IHommel et al., 2006 kwaye ILeshan et al., 2010). I-Melanocortin, i-anorexigenic neuropeptide ene-receptor kwi-VTA, ngokuchasene noko kunokuqikelelwa kwi-arhente ye-anorexic, eneneni yandisa umsebenzi we-dopaminergic kunye nokukhutshwa kwe-dopamine kwi-striatum, ngelixa kunciphisa ngokucacileyo indlela yokuziphatha yokutya (I-Torre kunye neCelis, i-1988, ILindblom et al., 2001 kwaye Iseli, 2005). Olunye udaka lobunzima longezelelwa yidatha ebonisa ukuba isiphumo sokukhupha impompo ye-ghrelin ibonakala ixhomekeka kubukho bokutya: amanqanaba e-NAc e-dopamine afunyaniswe yintsholongwane akunyuswa kuphela yi-ghrelin esetyenziswa ngokungapheliyo kumagazi evunyelwe ukuba itye emva kolawulo lwe-ghrelin (Njengakwiimeko zovavanyo ezisetyenzisiweyo kwisifundo esikhoyo) kwaye bacinezelwa yi-ghrelin kwezo zaliwe ukuba zifumane ukutya (Kawahara et al., 2009), umphumo oboniswe kutshanje ubandakanya iindlela ezahlukeneyo zokubonisa umqondiso we-opioid kwi-VTA (Kawahara et al., 2013). Le mizekelo mibini igxininisa ukuntsonkotha kubudlelwane phakathi kokondla iipeptides, ukubakho kokutya kunye ne-dopamine kwaye kugxininise ukubaluleka kwezifundo eziphonononga ukusetyenziswa kweempembelelo ze-ghrelin kwinkqubo ye-dopamine kwindlela yokuziphatha yomvuzo wokutya.

Umba onomdla weziphumo ziziphumo ezihambelanayo ze-NAc dopamine receptor blockade kwishukumiso sokutya vs ukutya. Ngokukodwa, siqinisekisile ukungabikho kwesiphumo sokucinezelwa kwe-NAc dopamine kwityala lokutya i-VTA ghrelin-intenised kwizifundo ezizimeleyo ze-2: Kwiparigmm eyodwa yokutya ukutya kwenziwa kwangoko emva kovavanyo lokuphendula (apho ukutya imivuzo yeswekile kungatshintshwa kulandelayo Ukutya kakhulu) kwaye, kwelinye, kukutya kuphela okulinganiselwa kwizilwanyana ngaphandle kovavanyo lwangaphambili lomsebenzi. Ukongeza, kuvavanyo lwesibini sikwazile ukubonisa ukuba ukusebenziseka kwezixhobo ezichasene ne-dopamine receptor antagonists kwi-NAc akunampembelelo kwi-VTA ghrelin-indased yokutya kokutya, okwandisa inkxaso ye-hypothesis ukuba i-NAc dopamine isayina nge-D1-efana ne-D2 receptors ayimfuneko kwi-ghrelin hyperphagia. Uthathiwe kunye nenyaniso yokuba abachasi baphazamise ukutya okuqhutywa kukukhuthazeka kwe-VTA, ezi ziphumo zidibeneyo zicebisa ukuphambuka kwe-neuro-yesekethe esezantsi kwe-VTA ghrelin, elinye isebe elilawula ukutya kunye nolunye ukhuthazo lokutya / umvuzo. Kubonakala ngathi i-ghrelin isebenzisa i-dopamine ukutshintsha intshukumisa yokutya kodwa ingatyi. Ngaphambili, sibonisa ukuba iVARI ghrelin ifaka i-neuropeptide Y kwi-VTA ngokukhethekileyo ukulawula ukutya kunye ne-opioids ngendlela echaseneyo (ISkibicka et al., 2012a). Yiyo loo nto, sele kukho ulandulelo lokuphambuka kumjikelo wokusebenza ngotywala ngokutya nokutya okuchasene nokutya.

Ii-recumbal ze-D1-ezinje ngee-receptors zineendima ezime kakuhle kuzo zombini iziyobisi kunye nokuqiniswa kokutya okunobungqina obuninzi obubonisa ukuba ukumiliselwa kwe-intra-NAc D1-njenge-antagonist infusion kunciphisa indlela egxile ekujongeni kokutya. Inkqubo ye-D1 ye-receptor echasene ne-receptor antagonists iyakucutha ukuzilawula kwe-cocaine, i-heroin, i-nicotine kunye notywala [umzekelo (Weissenborn okqhubekayo., 1996, I-Liu kunye ne-Weiss, i-2002, IBossert et al., 2007 kwaye Liu et al., 2010)], eqaqambisa indima ephambili yezi receptors kwiinkqubo ezalisiweyo kumvuzo. Idatha yangoku ibonisa ukuba i-NAc D1-receptors njengento ebalulekileyo yomjikelezo owenziwe nge-VTA-ghostin ebambeleyo. Kwinkxaso, ukusetyenziswa komda wale mpikiswano ye-D1 ikwabonisiwe ukunciphisa ukuthotywa kwento eyaziwa ngokuba yi-ghrelin (UJacoby kunye noCurrie, 2011). Nangona kunjalo, xa ujonga ukuba isicelo se-peripheral sijolise kuyo yonke i-D1-i-expression ye-neuronal engqondweni kwaye ukuba abantu abangaphandle kwe-NAc (umzekelo, kwi-hippocampus) banokudlala indima enkulu ekufundeni nakwimemori, akucaci ukuba ngaba inani le-NAc lihlolile. Nika igalelo kwimemori ophuculo lwegremin.

Ii-receptors ze-D2 zihlala zisebenza kwikonsathi kunye ne-D1; ngenxa yoko izifundo ezininzi zibonisa indima ye-receptors ye-D2 kwimicimbi yokulungisa imbuyekezo kunye nokuziphatha okujolise kumvuzo. Nangona kunjalo, kuyaphawuleka ukuba i-D1 kunye ne-D2 receptors azihlali zenza ngendlela efanayo nomvuzo we-wrt. Kwi-amygdala, umzekelo, i-blockade ye-receptors ye-D1 ifumana ukuphinda kubuyiswe ekufuneni i-cueine ye-cueine, ngelixa abachasi be-D2 banokwenyusa le ndlela yokuziphatha (UBerglind et al., 2006). Oku kungahambi kakuhle kokusebenza kunokuba negalelo le-neuroanatomical, njengoko ii-receptors ze-D2 kwi-NAc zibonakala zisebenza umsebenzi ohlukileyo kwelinye kwabo bakwi-hypothalamus. Ngelixa ekukhuthazeni i-NAc kwii-receptors ze-D2 inokunyusa ukukhuthaza ukutya, yenza isilwanyana ngakumbi ukuba sizame ukuzama ukufumana ukutya, ekukhuthazeni i-hypothalamus receptors ye-D2 ngokucacileyo yi-anorexic (I-Leibowitz kunye neRossakis, 1979 kwaye Ngokuendend et al., 2001). Ukulandela ukuba kunokuba nzima ukutolika iziphumo emva kokusetyenziswa kokungapheliyo kweziyobisi ezichongiweyo ze-D2 apho abantu abajolise kuyo i-receptor badibana nomsebenzi ophikisayo. Esi isenokuba sesinye sezizathu ezichaza ukuba kutheni, kuphando oludlulileyo, inaliti yokuthanani nomchasi we-D2 ayinaziphumo ziphendulwa sisimo somphefumlo. Enye inkcazo enokwenzeka kukuba i-D2 yi-autoreceptor kwi-neurop evelisa i-dopamine kwi-substantia nigra kunye ne-VTA, apho kusebenze khona kunokukhokelela ekunyanzelweni komsebenzi we-dopaminergic (ULacey et al., 1987). Ke, xa i-inj injipherally, i-D2-ijolise kumachiza inokuthi ifumane ukufikelela kuluntu lwe-receptor, ngelixa kwisifundo sethu kuphela i-NAc shell D2 receptor yayijolise kuyo. Ngokucacileyo, isiphumo esipheleleyo senkqubo ecwangcisiweyo ye-D1-efana ne-receptor blockcode ivimbele ukuphendula isiselo se-sucrose kwiparadigm efanayo (I-Overduin et al., 2012). Ngapha koko, ulungelelwaniso, inaliti engalunganga ye-agonist ye-D1 ibonakala ikhulisa ukutya okuthandekayo ngelixa isitofu senkqubo ye-agonist ye-D2 siyinciphisa (UmSebenzi kunye neAl-Naser, 2006). Ke, kubonakala ngathi idatha yethu ibonisa isiphumo sokucinezela sabachasayo be-D1 kwi-ghrelin-indenti yokutya yokutya ihambelana nomnatha opheleleyo (wokucinezela) umphumo wokuvuselela ii-receptors ze-D1 ngomsebenzi womvuzo. Ngokwahlukileyo, isiphumo esili-receptor ye-D2 ye-receptor ilandela ngokusondeleyo kunye nento eyaziwayo malunga ne-hypothalamic D2 receptors, kunedatha eboniswe apha ye-NAc.

Kwisifundo esikhoyo zombini zombini i-D1-efana kunye ne-D2 antagonists bakwazi ukuvimba indlela yokusebenza yokusebenza kwe-sucrose emva kolawulo lwe-VTA ghrelin nasemva kokuphelelwa kukutya okucebisa ukuba isenzo sobambiswano kwii-receptors zombini kwi-NAc ziyafuneka ukuba i-ghrelin ikhuphe iziphumo zayo. Oku kuyavakala xa kuqwalaselwa imeko engapheliyo apho iVTA-isuselwe kwisiphelo sedopaminergic ikhupha i-dopamine kwibhokisi ye-NAc ngaxeshanye isebenze kuzo zonke ii-dopamine receptors ezifikelelekayo. Isidingo sokusebenza ngaxeshanye kokubini kwe-D1-efana kunye ne-D2 receptors sele ixeliwe kwezinye iindlela zokuziphatha kubandakanya ukuqiniswa (Ikemoto et al., 1997) nomsebenzi wengomaUPlaznik et al., 1989) kunye nokudubula kwe-neuronal (Mhlophe, 1987). Iziphumo zophononongo lwangoku zibonisa ukuba iblokheydi yesinye kwisibini sedopaminergic receptors yayanele ukunciphisa ezo ndlela zokuziphatha kanye njengokuba enye ibhlokosho yenye yezo receptors yayanele ukunciphisa indlela yokusebenza yomntu osebenzayo. Indlela elapha emva kokusebenzisana ayicacanga. Ezinye i-neurons kwi-NAc coexpress zombini i-D1 kunye ne-D2 receptors. Inye yezinto ezinokubangela ukubandakanyeka kwee-heterodimers ziyafuneka kwimpendulo yomvuzo, ukwakhiwa kweeheterodimers yi-D1 kunye ne-D2 receptors kuye kwachazwa kutshanje kwaye oku kudityaniswa kwaboniswa ukuba negalelo kukuziphatha okufana nokudakumba (UPei et al., 2010). Nangona kunjalo, iziphumo zethu zibonisa ukuba i-D1 kunye ne-D2 isibonakaliso kwi-NAc ayibalulekanga, kwaye i-receptor nganye iyafuneka ukwenzela ukuhambisa isiphumo se-ghrelin kumvuzo wokutya kuba ibhloko nganye yayisebenza kakuhle ekufumaneni impendulo yomvuzo. Ukongeza, kuba i-blockade yomntu ngamnye yayingasebenzi kwi-ghrelin hyperphagia, siye savavanya ngokwahlukeneyo kunokwenzeka ukuba ingaba uphawu lwe-D1 kunye ne-D2 lwalungafuneki kwakhona ngenxa yokuthathwa, ok. Kwangaxeshanye ibhloko yesibini inokufuneka ukuphelisa impendulo. Oku, nangona kunjalo, kwakungekho njengoko i-ghrelin hyperphagia ingachaphazwanga yi-blockade efanayo ye-D1 kunye ne-D2 receptors kwi-NAc. Yiyo loo nto kuphela okanye ukudityaniswa kweqokobhe le-NAc i-D1 kunye ne-D2 isayineli receptor ayisetyenziswanga yi-ghrelin ukwandisa ukubonwa.

Apha, sajongisa i-D1-efana kunye ne-D2 receptors kwibhombu ye-NAc. Umsebenzi weqokobhe kunye nengcambu ye-NAc ubonakala ungahambelani kwinqanaba elithile ngakumbi kunye nenguqu ephambili yotshintsho kulawulo lweziyobisi olunxulunyaniswa nentambo kunye neqokobhe elinempembelelo ngakumbi kwimeko yokuxhomekeka kolawulo lweziyobisi (IBossert et al., 2007). Oku kusebenza ngokungafaniyo kuxhaswa lunxibelelwano lwe-neuroanatomical, apho isiseko sifumana igalelo elingaphezulu kwi-amygdala kwaye iqokobhe libekiwe ngaphezulu kakhulu kwi-hippocampus (UGroenewegen et al., 1999 kwaye UFloresco et al., 2001). Iigundane ziya kuzilawula ngokwazo ukudityaniswa kwe-D1 kunye ne-D2 receptor agonists kuphela kwigobolondo le-NAc hayi kumbindi (Ikemoto et al., 1997), ebonisa ukuba isenzo sabo sokusebenzisana kumvuzo sinxulunyaniswa ikakhulu nomda weqokobhe elijolise apha.

Kwisifundo esikhoyo, siphonononge ngokuthe ngqo, impembelelo yokucinezelwa kwe-NAc dopamine ukubonakaliswa kokutya kunye nokutya okuqhutywa kukuziphatha okuqhutywa yi-ghrelin efakwe kwi-VTA. Kufuneka iqatshelwe, nangona kunjalo, ukuba i-ghrelin inokuqhuba nokuziphatha kokusebenza ngokuvula iindlela ezihambelanayo kwi-VTA. Umzekelo, i-ghrelin iboniswe ukuba iphucula indlela yokuziphatha eqiniswe kukutya ngokuthi isebenze nge-orexin neurons kwi-lateroth hypothalamus (UPerello et al., 2010), iqela leseli ye-orexinergic elenza iiprojekthi kwi-VTA kunye nokukhuthaza ukukhutshwa kwe-dopamine (UNarita et al., 2006). Ngelixa isifundo sethu sisebenzisa i-neuroanatomy kunye ne-neuropharmacology siyisasaza ngqo indlela ye-VTA-NAc, kwimeko yesiporho esikhutshiweyo esijikelezayo kungenzeka ukuba ivuselele i-VTA kunye nezinye iingqondo zengqondo ezibonisa i-ghrelin receptor nge projektha esebenzayo kwi-VTA. Ke, kwimeko yomzimba, ifuthe le-ghrelin lisasazwa kwiindawo ezininzi zobuchopho ezinokuthi zenze ikonsathi. Ingcinga yehormon okanye neuropeptide esebenza kwiindawo ezininzi ezisasazwe kwingqondo apho inokufumana isiphumo esifanayo, umzekelo, utshintsho olwenzeka ekutyeni, ayisiyoveli kwaye sele icetyisiwe kwaye ivavanywa i-leptin kunye ne-melanocortin (I-Grill, i-2006, ILeinninger et al., 2009, I-Skibicka kunye ne-Grill, 2009 kwaye I-Faulconbridge kunye neHayes, 2011).

Ukuncitshiswa kokutya kunxulunyaniswa nenqanaba eliphezulu le-ghrelin ejikelezayo. Kwiimeko zokuncitshiswa kokutya ukutya kuphakamisa ukukhutshwa kwe-dopamine kwi-NAc (Kawahara et al., 2013). Ukulandela loo nto yesondlo, kunganefuthe kwi-dopamine signature kwi-NAc, impembelelo yokupheliswa kokutya kwi-mRNA expression of dopamine receptors (D1-like receptors (D1, D5) and D2-like receptors (D2, D3) and dopamine Ii-enzymes (i-MAO, i-COMT) ezivavanywe kwisifundo esikhoyo. Ngelixa ukupheliswa kokutya kungazange kutshintshe ukuvakaliswa kwe-mRNA yayo nayiphi na i-enzymes eyonakalisayo ye-dopamine ekulinganiselweyo, sabona umgaqo owahlukileyo we-D5 vs D2 receptors. Ukuchazwa kwe-receptors ye-D5 kunyuswe phantse nge-30% ngelixa i-D2 receptor mRNA yancitshiswa malunga ne-20%. Iyahambelana nolu tshintsho, ukusetyenziswa kwangaxeshanye kwe-D1-efana ne-D2 receptor agonists ibikhe yaboniswa ngaphambili ukuyilawula ii-receptors ze-D2 kodwa ukwenyusa ii-receptors ze-D1 kwi-nanti ye-substantia (kunye nendlela efanayo kwi-NAc) (ISramramaniam et al., 1992). Into enomdla kukuba, iimpembelelo zokuncitshiswa kokutya kwi-NAc dopamine receptor expression converter kunye nedatha yethu ebonisa indima ye-D1-efana (ebandakanya i-D5) kunye ne-D2 receptors ekukhuthazeni okushukumisayo kokutya.

Olunye ucango lwesifundo sethu kukuba ukungabikho kokutya kunyusa amanqanaba e-ghrelin ajikelezayo ukuze abanye abantu abasebenza nge-ghrelin receptors ngaphandle kweVTA banakho ukusebenza. Ke ngoko, ngelixa ukuncitshiswa kokutya kuyindlela endo Natural kunye neyona nto iphambili ngokwasemzimbeni yokwandisa i-ghrelin, ayivumeli ukukhethwa kweVTA ekhethiweyo. Asinako ke ukuphelisa ukubakho kokutshintsha kwe-dopamine receptor efunyenwe kwi-NAc sisiphumo sokwenza umsebenzi we-ghrelin kwiindawo ezingaphandle kweVTA nefuthe elingathanga ngqo kwi-NAc. Okokugqibela, kufuneka kuqatshelwe ukuba idatha yethu ikhonkco lokuzila ngokukhawuleza kwiinguqu kwi-NAc dopamine receptor expression kodwa uvavanyo olongezelelekileyo luya kufuneka lubonise ukulamla (kwe-ghrelin-kuvuselelwe) i-VTA-NAc dopaminergic projektha kwesi siphumo kwaye, inene, ukuphonononga indima yezinye iindlela kunye neenkqubo zokuhambisa kwesi siphumo, njenge-hypothalamus yecala (njengoko kuxoxwe ngentla).

Kuba uninzi lweeseli zemithambo-luvo ziqhelekile kokubini ukuba likhoboka leziyobisi kunye nokutya okusasazekileyo, kunokwenzeka ukuba iziphumo zangoku zibonakalisa indima ye-D1-efana kunye ne-D2 receptors kwiziyobisi nakwiziphumo zokuqinisa utywala kwi-ghrelin (UDickson et al., 2011). Zombini ukutya kunye nomvuzo wecocaine kukhokelela ekukhutshweni kwe-dopamine kwi-NAc (UHernandez kunye noHoebel, 1988). I-blockade ye-D1 okanye i-D2 receptors inciphisa ukuvuza kokuziphatha kweziyobisi zokuxhatshazwa, utywala kunye ne-nicotine. Ukusukela nje igalelo elinokuqwalaselwa le-ghrelin ekuthambeni okanye ekufumaneni indlela yokuziphatha kwezi zinto zixeliweyo ngaphambili, kusenokwenzeka ukuba i-ghrelin-VTA-dopamine-NAc ukujikeleza okuchazwe apha kufanelekile kuludwe lweendlela zokuziphatha hayi ngokukodwa ekutyeni. Inkxaso yokuqala yale mbono inokutsalwa kwidatha ebonisa ukuba ukukhutshwa kokutya kunokubuyisela i-heroin yokufuna evaliweyo ngumqobo we-D1-receptorsUTobin et al., 2009).

Idatha yethu ibonelela ngolwazi olutsha malunga nokudityaniswa kweendlela ezimbini eziphambili zokutya ezinxulumene nomvuzo: iisekethe eziqhutywa yi-VTA eziphendulayo kwihomoni ye-orexigenic, ghrelin, nakwi-NAc dopamine ephendula imijikelezo. Ngokukodwa sibonisa ukuba iziphumo ze-ghrelin ezibhalwe kakuhle ezinxulumene neVTA kukuziphatha okukhuthaza ukutya kufuna i-D1 kunye ne-D2 ukusayina kwi-NAc. Idatha yethu ikwabonisa ukuba i-VTA eqhutywa (i-D1 / D2-exhomekeke) kwiziphumo ze-ghrelin kumvuzo wokutya zibandakanya ukujikeleza okungafaniyo kwezi zibalulekileyo ekutyeni ukutya, njengoko kungachaswanga nokuchaphazeleka kokutya okunyanzelekileyo xa kusiwa kwi-NAc. Okokugqibela, izifundo zokulamba (ngokuzila ukutya ubusuku bonke kwaye yiyo loo nto, i-hyperghrelinemic) iigundane zibeka uphawu lwe-NAc D1 / D2 kwiziphumo ze-endo native ghrelin kwindlela yokuziphatha ekhuthazwa kukutya. Ke, iindlela kunye nonyango oluphazamisa ukubonakaliswa kwe-dopamine kwi-NAc kubonakala ngathi lunokubaluleka kweziphumo ze-ghrelin-Mediated kwinkqubo yomvuzo, kubandakanya nezo zinxulunyaniswe nolawulo lokondla yiyo loo nto ukutyeba kakhulu kunye nonyango lwayo.

Ingxelo yokuchaza

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Imibulelo

Umsebenzi ubuxhaswe yi Ibhunga loPhando laseSweden kwiNyango (I-2011-3054 ukuya kwi-KPS kunye ne-2012-1758 ukuya kwi-SLD), Yekhomishini yaseYurophu Yenqanaba lesixhenxe izibonelelo (FP7-KBBE-2010-4-266408, Full4Health; FP7-HEALTH-2009-241592; EurOCHIP; FP7-KBBE-2009-3-245009, NeuroFAST), I-Forskning och Utvecklingsarbete / Avtal om Läkarutkuva i-Forskning Göteborg (ALFGBG-138741), the Isiseko saseSweden soPhando lweSicwangciso iZiko leSahlgrenska loPhando lweNtliziyo kunye neMetabolic (A305-188), kunye I-NovoNordisk Fonden. Abaxhasi babengenandima kuyilo lokufunda, ukuqokelelwa kwedatha kunye nohlalutyo, isigqibo sokupapasha, okanye sokulungiselela ukubhalwa.

Ucaphulo

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  • Umbhali ohambelanayo. ISebe le-Endocrinology, iZiko leNeuroscience kunye nePhysology, iSahlgrenska Academy kwiDyunivesithi yaseGothenburg, Medicinaregatan 11, PO Box 434, SE-405 30 Gothenburg, Sweden. Ifowuni: +46 31 786 3818 (eofisini); ifeksi: +46 31 786 3512.

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