PLoS One. 2017 Aug 31; 12 (8): e0183685. I-doi: 10.1371 / journal.pone.0183685.
Pheka uJB1,2, Hendrickson LM1,3, Garwood GM3, Toungate KM3, Nania CV1, Morikawa H1,3.
Abstract
Ngokufana neziyobisi zokuxhatshazwa, ixabiso le-hedonic lokutya lixutywe, ubuncinci ngokuyinxalenye, yinkqubo ye-mesostriatal dopamine (DA). Ukutya ixesha elide nokuba kukutya okunekhalori ephezulu okanye iziyobisi zokusetyenziswa kakubi zombini zikhokelela ekubeni inkqubo yeDA ibe buthuntu. Uninzi lwezifundo zijolise kutshintsho lwe-DAergic kwi-striatum, kodwa kuncinci okwaziwayo malunga neziphumo zokutya kwekhalori ephezulu kwindawo ye-ventral tegmental (VTA) ye-DA neurons. Kuba ukutya okunekhalori ephezulu kuvelisa ulungelelwaniso olufana ne-DAergic, kunokwenzeka ukuba oku kutya kunokonyusa ukuba sengozini. Nangona kunjalo, ukutya okunekhalori ephezulu kuhlala kunciphisa ukuthathwa kwe-psychostimulant kunye nendawo ekhethwayo kwindawo yeempuku. Ngokwahlukileyo, ukutya okunekhalori ephezulu kunokunyusa okanye kunciphise ukusela kwe-ethanol, kodwa akwaziwa ukuba ukutya okungenamsoco (i-cafeteria diet) kukuchaphazela njani ukusela i-ethanol. Kuphononongo lwangoku, siye salawula ukutya okutyiwayo okubandakanya ibhekoni, iitshiphusi zetapile, ikeyiki yetshizi, iicookies, iicereals zakusasa, iimarshmallows, kunye neelekese zetshokolethi kwiimpuku zeWistar ezingamadoda kangangeveki ezi-3-4, zivelisa i-phenotype etyebileyo. Ukutya kwangaphambili kwi-cafeteria yokutya kunciphise ukusela i-ethanol yekhaya kwiiveki ezi-2 zovavanyo, kunye nokunciphisa okwethutyana i-sucrose kunye nokutya kwe-chow. Okubalulekileyo, ukutya kwe-cafeteria akuzange kube nefuthe kumlinganiselo we-ethanol metabolism okanye ukugxilwa kwe-ethanol yegazi emva kwe-2g / kg yolawulo lwe-ethanol. In izilayi ze-midbrain, sibonise ukuba ukutya kwe-cafeteria yokutya kwandisa i-DA D2 receptor (D2R) i-autoinhibition kwi-VTA DA neurons. Ezi ziphumo zibonisa ukuba ukutya okungenamsoco okubangelwa kukutyeba kunciphisa ukusela kwe-ethanol, kwaye iphakamisa ukuba ukunyuka kwe-D2R autoinhibition kwi-VTA kunokuba negalelo kwintsilelo kwi-DAergic signaling kunye nomvuzo we-hypofunction ebonwa ngokutyeba.
PMID: 28859110
DOI: 10.1371 / journal.pone.0183685
Ukutya okungenamsoco okubangelwa kukutyeba kwandisa i-D2 receptor autoinhibition kwindawo ye-ventral tegmental kunye nokunciphisa ukusela kwe-ethanol.
PLoS One. I-2017 Aug 31; 12 (8): e0183685. doi: 10.1371 / ijenali.pone.0183685. eCollection 2017.
Pheka uJB1,2, Hendrickson LM1,3, Garwood GM3, Toungate KM3, Nania CV1, Morikawa H1,3.
Abstract
Ngokufana neziyobisi zokuxhatshazwa, ixabiso le-hedonic lokutya lixutywe, ubuncinci ngokuyinxalenye, yinkqubo ye-mesostriatal dopamine (DA). Ukutya ixesha elide nokuba kukutya okunekhalori ephezulu okanye iziyobisi zokusetyenziswa kakubi zombini zikhokelela ekubeni inkqubo yeDA ibe buthuntu. Uninzi lwezifundo zijolise kutshintsho lwe-DAergic kwi-striatum, kodwa kuncinci okwaziwayo malunga neziphumo zokutya kwekhalori ephezulu kwindawo ye-ventral tegmental (VTA) ye-DA neurons. Kuba ukutya okunekhalori ephezulu kuvelisa ulungelelwaniso olufana ne-DAergic, kunokwenzeka ukuba oku kutya kunokonyusa ukuba sengozini. Nangona kunjalo, ukutya okunekhalori ephezulu kuhlala kunciphisa ukuthathwa kwe-psychostimulant kunye nendawo ekhethwayo kwindawo yeempuku. Ngokwahlukileyo, ukutya okunekhalori ephezulu kunokunyusa okanye kunciphise ukusela kwe-ethanol, kodwa akwaziwa ukuba ukutya okungenamsoco (i-cafeteria diet) kukuchaphazela njani ukusela i-ethanol. Kuphononongo lwangoku, siye salawula ukutya okutyiwayo okubandakanya ibhekoni, iitshiphusi zetapile, ikeyiki yetshizi, iicookies, iicereals zakusasa, iimarshmallows, kunye neelekese zetshokolethi kwiimpuku zeWistar ezingamadoda kangangeveki ezi-3-4, zivelisa i-phenotype etyebileyo. Ukutya kwangaphambili kwi-cafeteria yokutya kunciphise ukusela i-ethanol yekhaya kwiiveki ezi-2 zovavanyo, kunye nokunciphisa okwethutyana i-sucrose kunye nokutya kwe-chow. Okubalulekileyo, ukutya kwe-cafeteria akuzange kube nefuthe kumlinganiselo we-ethanol metabolism okanye ukugxilwa kwe-ethanol yegazi emva kwe-2g / kg yolawulo lwe-ethanol. Kwizilayi ze-midbrain, sibonise ukuba ukutya kokutya kwe-cafeteria kwandisa i-DA D2 receptor (D2R) i-autoinhibition kwi-VTA DA neurons. Ezi ziphumo zibonisa ukuba ukutya okungenamsoco okubangelwa kukutyeba kunciphisa ukusela kwe-ethanol, kwaye iphakamisa ukuba ukunyuka kwe-D2R autoinhibition kwi-VTA kunokuba negalelo kwintsilelo kwi-DAergic signaling kunye nomvuzo we-hypofunction ebonwa ngokutyeba.
PMID: 28859110
DOI: 10.1371 / journal.pone.0183685
Citation: Ukupheka i-JB, i-Hendrickson LM, i-Garwood GM, i-Toungate KM, i-Nania CV, i-Morikawa H (2017) Ukutya okungenamsoco okwenziwa kukutyeba kwandisa i-D2 receptor autoinhibition kwindawo ye-ventral tegmental kunye nokunciphisa ukusela kwe-ethanol. PLoS ONE 12(8): e0183685. https://doi.org/10.1371/journal.pone.0183685
umhleli: UJames Edgar McCutcheon, weDyunivesithi yaseLeicester, UMBUSO OBUNGULUNGILE
I funyenwe: Ngamana i-24, 2017; Zamkelwa: Agasti 9, 2017; Yashicilelwe: Agasti 31, 2017
Copyright: © 2017 Cook et al. Eli linqaku elivulekileyo lokufikelela lisasazwe phantsi kwemiqathango ye Ilayisenisi yeCreation Commons Licribution, evumela ukusetyenziswa, ukuhanjiswa, nokuvelisa okungahambisani naluphi na uhlobo, ukuba unobumba bokuqala kunye nomthombo baxelwe.
Ukufumaneka kwedatha: Yonke idatha efanelekileyo ingaphakathi ephepheni kunye neefayile zayo zoLwazi oluxhasayo.
Inkxaso: Lo msebenzi wawuxhaswa yi-RO1 AA015521 (HM), i-F32AA021640 (LMH), kunye ne-T32-AA007471 (iYunivesithi yaseTexas e-Austin, iCandelo le-Pharmacology kunye ne-Toxicology, iKholeji ye-Pharmacy). Ezi nkxaso-mali bezixhaswa okanye zixhaswa yiNational Institute on Alcohol Abuse and Alcoholism. https://www.niaaa.nih.gov/. Abaxhasi babengenandima kuyilo lokufunda, ukuqokelelwa kwedatha kunye nohlalutyo, isigqibo sokupapasha, okanye sokulungiselela ukubhalwa.
Injongo yokunyanzela: Ababhali baye bavakalisa ukuba akukho mfuno ekhuphisanayo.
intshayelelo
Iipropathi zokuqinisa iziyobisi ezikhobokisayo kunye nokutya okunencasa kulamlwa, ngokuyinxenye, yinkqubo ye-mesostriatal dopamine (DA) [1]. Ngapha koko, ukuvezwa okwandisiweyo kwiziyobisi zokusetyenziswa kakubi, kubandakanya i-ethanol, okanye ukutya okuxineneyo okunencasa kuvelisa i-neuroadaptations ye-DAergic efanayo. Ngokomzekelo, ukubonakaliswa okungapheliyo kwi-ethanol kunye nezinye iziyobisi zokuxhatshazwa kunciphisa i-D2 receptors (D2Rs) kunye namanqanaba e-basal DA kwi-striatum [2-4], ebonwa nangokutya okuxineneyo kwamandla [5-7]. Abantu abatyebe kakhulu baye banciphisa ukubonakaliswa kwe-D2R kwi-striatum [8] kunye nokunciphisa ukusebenza kwe-striatal ekuphenduleni ukutya okunencasa [9]. Ke ngoko, kuba ii-neuroadaptations ezilandela ukutya okuxineneyo kwamandla okanye ukuba sesichengeni seziyobisi ezingapheliyo ziyafana, ukusetyenziswa ngokugqithisileyo kokutya okuxineneyo kunokonyusa ukubakho kweziyobisi. Okubangel 'umdla kukuba, izifundo zeempuku zibonise ukuba ukusetyenziswa kwamafutha aphezulu okanye iswekile kunciphisa ukuthathwa kwe-psychostimulant kunye nendawo ekhethwayo [10-13]. Ngokwahlukileyo, ukusetyenziswa kwamafutha aphezulu okanye iswekile / icarbohydrate kunokunyuka [14, 15] okanye unciphise [16, 17] Ukusela i-ethanol kwiimpuku. Nangona kunjalo, akwaziwa ukuba ukusetyenziswa kokutya okungenamsoco okutyiwa rhoqo ngabantu kukuchaphazela njani ukusela i-ethanol.
EUnited States malunga ne-35% yabantu abadala kunye ne-17% yabantwana kunye nabafikisayo batyebe ngokugqithiseleyo [18]. Ukwanda kokuxhaphaka kokutyeba kakhulu kuye kwanxulunyaniswa nokufikeleleka okwandisiweyo “kukutya okungenamsoco” kunamafutha amaninzi, iswekile kunye nezinye iicarbohydrates [19], kwaye ukusetyenziswa kwezi zidlo zivelele ngakumbi ngexesha lokufikisa [20-22]. Kwiinzame zokulinganisa olu hlobo lokutya okuxineneyo okubangela ukutyeba, abaphandi banike iimpuku ukufikelela kwizinto ezityiwayo, ezibizwa ngokuba kukutya kwecafeteria [5, 6, 23]. Ukutya ukutya okutyiwa kwiCafeteria kubonakaliswe ukunciphisa i-D2Rs kunye namanqanaba e-basal e-DA kwi-striatum, ukunciphisa ubuntununtunu bomvuzo wokujikeleza usebenzisa ukuzivuselela kwe-intracranial, kunye nokuvelisa ukusetyenziswa kokutya okunyanzelekileyo [5, 6]. Nangona kunjalo, akwaziwa ukuba ukutya ukutya kwe-cafeteria kuguqula iipropathi ze-electrophysiological ze-DA neurons kwindawo ye-ventral tegmental (VTA) okanye kuphembelela ukusela kwe-ethanol.
Ukukhutshwa kwe-Somatodendritic DA kusebenze i-D2Rs kwi-somata kunye ne-dendrites ye-neuron ye-DA ekhokelela kwi-autoinhibition. kwi vivo [24, 25] kunye in vitro [26, 27] ngokwenza kusebenze i-G protein-gated internal rectifying potassium channels (GIRK) nge-Gmna / o umqondiso. Ke, ukusebenza kwe-D2R ye-GIRK kuphumela kwi-hyperpolarization kunye nokunciphisa ukonwaba kwe-neuronal [28]. Kwi-VTA DA neurons, ukulawulwa ngokuphindaphindiweyo kwe-ethanol okanye ulawulo lwe-cocaine olubukhali kwandisa i-D2R-mediated autoinhibition [29, 30]. Ngapha koko, emva kokulawulwa ngokuphindaphindiweyo kwe-ethanol kwiimpuku, ukonyuka kwe-D2R autoinhibition yayanyaniswa nokusela kwe-ethanol yasekhaya [29]. Nangona kucacile ukuba ukutya okunekhalori ephezulu kuvelisa ulungelelwaniso olufana ne-DAergic kwi-striatum, iziphumo zokutya okunekhalori ephezulu kwi-D2R autoinhibition kwi-VTA DA neurons ayikhange ibonakaliswe.
Kuphononongo lwangoku, siphande iziphumo zokutya kwe-cafeteria kwi-ethanol yasekhaya okanye ukusela i-sucrose, i-VTA DA neuron basal firing frequency, kunye ne-D2R-mediated autoinhibition ye-VTA DA neurons. I-Cafeteria yokutya ukutya ngexesha lokufikisa kubangele i-phenotype efana ne-obese-like phenotype kunye nokunciphisa ixesha elide lokusela i-ethanol usebenzisa i-2 hr yokusela ebumnyameni (DID) umboniso we-ethanol ovelisa i-ethanol ephakathi. Okubalulekileyo, ukutya kwe-cafeteria yokutya kwakungenayo impembelelo kwi-ethanol concentrations (BECs) okanye izinga le-ethanol metabolism elandela i-2 g / kg ye-intraperitoneal (ip) ye-ethanol injection. Ngaphaya koko, ukondla ukutya kwe-cafeteria kwandisa i-D2R-mediated autoinhibition ye-VTA DA neurons.
Iindlela kunye nezixhobo
Izihloko Iigundane zeWistar zamadoda zafunyanwa kwiilabhoratri zaseHarlan (Indianapolis, IN) kwiiveki ezi-3 ubudala. Iimpuku zazihlaliswa zodwa kwiikheji zePlexiglass, kwelinye icala lekheji zineqonga lePlexiglass elinomlinganiselo we-7” x 4” x 1.25” elikhuselwe emgangathweni ukuze kubekwe indawo yokutya. Zonke iimpuku zinechow eqhelekileyo yaselabhoratri ekhoyo ad adum kwaye amanzi ayefumaneka ngawo onke amaxesha ngaphandle kwangexesha leethanol okanye iiseshoni zokusela i-sucrose. I-vivarium yayigcinwe kwi-reverse 12 hr ukukhanya-mnyama umjikelezo (ukukhanya ukuqala kwi-0100 hr), ubushushu obuqhubekayo be-22 ± 2 ° C, kunye ne-65% yomswakama ohambelanayo. Ukhathalelo lwezilwanyana kunye neenkqubo zokuphatha zilandele iNational Institutes of Health Guidelines phantsi kweYunivesithi yaseTexas eAustin Institutional Animal Care kunye neKomiti yoSetyenziso yemigaqo evunyiweyo.
Indawo yokutyela yokutya
Kanye ngosuku (i-1 hr ukuya kumjikelo omnyama) i-cafeteria yokutya equkethe i-calorie ephezulu yokutya okungenamsoco kuquka i-cheesecake (i-Atlanta Cheesecake Inkampani, i-Kennesaw, i-GA), i-bacon (HEB, i-San Antonio, i-TX), i-cookies (i-Chips Ahoy / Oreo, I-Nabisco, i-East Hanover, i-NJ i-sugar wafer, i-Vista, i-Sheare's Foods, i-Massillon, i-OH), ii-chips zamazambane (i-Lays Classic / Ruffles, i-Frito Lay, i-Plano, i-TX) i-cereals ye-sugar breakfast ephezulu (i-CoCo Puff, i-General Mills, i-Minneapolis, i-MN; I-Froot Loops, i-Kellog, i-Battle Creek, i-MI), i-marshmallows (i-Kraft, i-Northfield, i-IL), okanye i-chocolate candies (M & M, MARS, McLean, VA) yanikezelwa kwiqela lokutya lokutya. Izinto ezine zokutya zokutya ezityiwayo zazilawulwa ngemini kwaye iintlobo ngeentlobo zokutya zagcinwa ngokutshintshana kokutya yonke imihla. Iqela le-chow kuphela lafumana i-chow yebhubhoratri kuphela (i-LabDiet, i-Prolab RMH 1800, iSt. Umxholo we-macronutrient (osekelwe kwiikhalori ezinikeziweyo) we-chow kuphela ukutya okubandakanya i-14% yamanqatha, i-65% ye-carbohydrate, kunye ne-21% yeprotheni, kwaye ngokomndilili wokutya kwe-cafeteria yayine-42% yamafutha, i-52% ye-carbohydrate, kunye ne-6% yeprotheni. Ukutya kweCafeteria kwalawulwa iiveki ezi-3 kwi-caloric intake kunye ne-D2R yangaphandle yovavanyo lwangoku (ukuqala malunga neeveki ezi-3-4 ubudala) kunye neeveki ezi-4 kuzo zonke ezinye iimvavanyo (ukuqala malunga neeveki ezi-5 ubudala). Ukulinganisa i-caloric intake, ukutya kwe-cafeteria kunye ne-chow kuphela ukutya kwakulinganiswa imihla ngemihla kwaye i-caloric intake ibalwe kusetyenziswa ulwazi lwe-macronutrient olunikezelwe kumenzi.
Ukusela i-ethanol yasekhaya okanye i-sucrose
Iveki enye emva kokuhlala, iigundane zanikwa i-2 hr / imini ukufikelela okulinganiselwe kwi-ethanol (10% v / v) okanye i-sucrose (5% w / v) isisombululo sokuvavanya ukusela okusisiseko. Ngexesha lazo zonke iiseshini zokusela i-ethanol okanye i-sucrose ibhotile yamanzi ye-homecage yatshintshwa ngebhotile ene-ethanol okanye isisombululo se-sucrose kwi-1 iyure kumjikelezo omnyama. Ukulandela isiseko se-ethanol okanye ukusela i-sucrose (iintsuku ze-7), iigundane zabelwa ngokungaqhelekanga kwisidlo sokutya okanye iqela le-chow kuphela. Emva koko, iimpuku zondliwa ukutya kwe-cafeteria okanye i-chow kuphela kwiiveki ze-4. Kwiiyure ezingamashumi amabini anesine emva kokulawulwa kokutya kokugqibela kwe-cafeteria, iimpuku zaqala imihla ngemihla i-ethanol okanye iiseshini zokusela i-sucrose.
Uxinzelelo lwe-ethanol yegazi (BEC)
Ukulandela iiveki ze-4 zokutya kwe-cafeteria okanye ukutya kwe-chow kuphela, iigundane zalawulwa i-ethanol (2g / kg, i-15% v / v kwi-saline, ip) i-24 hr emva kokulawulwa kokutya kwe-cafeteria yokugqibela. Iisampulu zegazi elipheleleyo (i-10 μL) zaqokelelwa ngokunqunyulwa komsila nge-30, 60, kunye ne-120 min elandela inaliti ye-ethanol kwaye yongezwa kwiglasi yegesi yechromatography (GC) yeengqayi ezine-90 μL ye-5M ye-sodium chloride. Isampuli ye-ethanol concentrations yahlalutywa ngosuku olufanayo kunye nokuqokelela kwegazi kunye ne-GC usebenzisa i-Bruker 430-GC (i-Bruker Corporation, i-Fremont, i-CA) exhotywe nge-flame ionization detector kunye ne-Combi PAL autosampler. Ngokufutshane, isampuli nganye yafudumala ukuya kwi-65 ° C kwi-3 min ngaphambi kokuba i-fiber-phase-fiber microextraction fiber (SPME; 75 μm CAR / PDMS, i-silica edibeneyo; i-Supelco) ithathe umphunga we-ethanol kwi-3 min. Ifayibha ye-SPME emva koko yaxutywa isampuli kwizibuko le-GC inaliti ye-1 min kwi-220 ° C. I-Helium (i-8.5 mL/min flow rate) isetyenziswe njengerhasi yokuthwala kunye nekholamu ye-HP Innowax ye-capillary (30 mx 0.53 mm x 1 μm ubukhulu befilimu; i-Agilent Technologies, i-Santa Clara, CA) isetyenziselwe ukwahlula. Imigangatho ye-ethanol yangaphandle (25, 50, 100, 200, 400, kunye ne-600 mg / dL) yahlaziywa ukubala ijika eliqhelekileyo. IiChromatograms zahlaziywa kusetyenziswa isoftware yeCompassCDS Workstation (iBruker Corporation, Fremont, CA), kunye nokuphakama okuphezulu kwe-ethanol (~ 2 min retention time) zisetyenziselwe ukwakha ijika eliqhelekileyo kunye ne-interpolate ye-ethanol concentrations.
I-Electrophysiology
Amagundane ayenziwe i-anesthetized nge-isoflurane kwaye ingqondo yasuswa kwaye yachithwa kwisisombululo sokusika esibandayo esiqulethe (kwi-mM) 205 sucrose, 2.5 KCl, 1.25 NaH2PO4, 7.5 MgCl2, 0.5 CaCl2, 10 glucose, kunye 25 NaHCO3, izaliswe yi-95% ye-O2, kunye ne-5% CO2 (~300mOsm/kg). Izilayi ze-Horizontal midbrain (200 μm) zahlulwe kwi-vibratome kwaye zavunyelwa ukuba ziphinde zibuyele kwi-1 hr ku-artificial cerebrospinal fluid (aCSF) kwi-34 ° C. Ukurekhoda kwenziwa kwi-VTA ye-lateral 50-150 μm ukusuka kumda we-medial ye-nucleus ye-terminal ye-accessory optic tract. Ngexesha lokurekhoda, iziqwenga zixutywe nge-oxygen, zifudumale (34 ° C) i-aCSF (kwi-mM) 126 NaCl, 2.5 KCl, 1.2 NaH2PO4, 1.2 MgCl2, 2.4 CaCl2, 11 iswekile, 21.4 NaHCO3. Ushicilelo oluqhotyoshelweyo lwe-cell-patch (~20 MΩ seal) lwenziwa ngeepipettes eziqulethe i-150mM NaCl. Ukurekhodwa kweeseli ezipheleleyo zenziwa ngeepipettes eziqulethe isisombululo se-intracellular esibandakanya (kwi-mM) 115 K-methylsulfate okanye i-K-gluconate, i-20 KCl, i-1.5 MgCl2, 10 HEPES, 0.025 EGTA, 2 Mg-ATP, 0.2 Na2-GTP, kunye 10 Na2-phosphocreatine (pH 7.2–7.3, ~285 mOsm kg-1). I-Pututive DA neurons ichongiwe ngokudubula kwazo okuzenzekelayo okuphantsi kwe-pacemaker (1-5 Hz) kunye nezenzo ezinokwenzeka ezibanzi (> 1.2 ms) kuqwalaselo oluncanyathiselwe kwiseli, kunye ne-I enkulu.h (>200 pA) ekuphenduleni inyathelo lombane we-1.5 sec ukusuka ku--62mV ukuya kwi--112 mV kwimowudi ye-voltage-clamp epheleleyo. Ushicilelo lwe-voltage-clamp lwenziwe kwisakhono sokubamba esingu -62mV, silungiselwe ukuhlangana kolwelo okunokubakho -7 mV. Ukurekhodwa kweeseli ezipheleleyo zalahlwa ukuba ukuchasana kochungechunge kunyuke ngaphezu kwe-20 MΩ okanye ukuchasana kwegalelo kwehla ngaphantsi kwe-200 MΩ. Idatha yahluzwa kwi-1-5 kHz kwaye yafakwa kwidijithali kwi-2-10 kHz.
Uhlalutyo lwedatha
Idatha ichazwa njengentsingiselo ±SEM. Ukubaluleka kwamanani kugqitywe luvavanyo lwe-t yoMfundi okanye i-ANOVA yeendlela ezimbini elandelwa luvavanyo lwe-Bonferroni post hoc.
iziphumo
Ukufikelela kwi-Cafeteria yokutya kubangela ukuba kubekho i-caloric ephezulu kunye ne-phenotype efana ne-obese-like
Ukutya okunekhalori kwisidlo sokutya kunye namaqela e-chow kuphela kunye nomthombo weekhalori zeqela lokutya lokutya ziye zavavanywa kwiiveki ezi-3. Iqela lokutya lokutya lidle iikhalori ezininzi kuneqela le-chow kuphela kwiiveki ezi-3 zokutya (unxibelelwano: F(2,62) = 22.43, p <0.0001; ukutya: F(1,62) = 17.41, p <0.001; ixesha F(2,62) = 254.7, p <0.0001; Umzobo 1A). Iqela lokutya lokutya litya kakhulu iikhalori ezisuka kwi-cafeteria yokutya ukutya kune-chow pellets kwiiveki ezi-3 zokutyisa (intsebenziswano: F(2,72) = 57.22, p <0.0001; ukutya: F(1,72) = 117.2, p <0.0001; ixesha F(2,72) = 110.5, p <0.0001; Umzobo 1B). Iikhalori ezithathwe kwi-chow pellets zazinkulu kakhulu kwiqela le-chow kuphela ngexesha lovavanyo lweeveki ezi-3 (intsebenziswano: F(2,62) = 28.80, p <0.0001; ukutya: F(1,62) = 196.3, p <0.0001; ixesha F(2,62) = 150.0, p <0.0001; Umzobo 1C). Ekugqibeleni, iqela lokutya lokutya libonise iqondo elikhulu lokuzuza ubunzima kwiiveki ezi-3 zokutyisa (intsebenziswano: F(2,62) = 8.188, p <0.001; ukutya: F(1,62) = 10.62, p <0.005; ixesha F(2,62) = 18.48, p <0.0001; Umzobo 1D). Iiveki ezine zokutya kwisidlo sokutya kubangele i-phenotype efana ne-obese-like phenotype enobunzima bomzimba obunzima kakhulu kuneqela le-chow kuphela (intsebenziswano: F(27,2376) = 44.48, p <0.0001; ukutya: F(1,2376) = 14.89, p <0.001; ixesha F(27,2376) = 2634, p <0.0001; Umzobo 1E). Ngaphaya koko, kwiqela elahlukileyo lezilwanyana sabonisa ukuba iqela lokutya lokutya litya i-chow encinci kakhulu kwiiveki ezi-4 zokutya kokutya xa kuthelekiswa nolawulo (intsebenziswano: F(27,486) = 3.039, p <0.0001; ukutya: F(1,486) = 601.7, p <0.0001; ixesha F(27,486) = 8.097, p <0.0001; Isazobe 1F). Ezi ziphumo zibonisa ukuba ukufikelela kwisidlo sokutya kukhokelele ekutyeni ngokugqithisileyo ukutya okunencasa okunencasa kakhulu kunye nelahleko elandelayo ye-homeostatic energy balance.
Ukutya kweekhalori kunye nomthombo weekhalori zavavanywa kwiiveki ze-3. (A) Iigundane ezinokufikelela kwimihla ngemihla kwi-cafeteria yokutya kudla ngokugqithisileyo iikhalori kwiiveki ze-3 zokutya kuneqela le-chow kuphela (n = 14-19 / iqela). (B) Iqela lokutya lokutya lisebenzise iikhalori ezininzi kakhulu kwi-cafeteria yokutya yokutya kune-chow pellets (n = 19). (C) Iqela le-chow kuphela lidla iikhalori ezingaphezulu kwi-chow pellets kuneqela le-cafeteria yokutya (n = 14-19 / iqela). (D) Ukufikelela kwi-Cafeteria yokutya kubangele ukwanda kwesisindo kwiiveki ze-3 zokutya (n = 14-19 / iqela). (E) Iiveki ezine ze-cafeteria yokutya ukutya okunyusa kakhulu ubunzima bomzimba, xa kuthelekiswa nokulawulwa kwe-chow kuphela (isiphumo esiphambili sokutya, p <0.001, i-ANOVA yeendlela ezimbini, n = 44-46 / iqela). (F) Kuzo zonke iiveki ze-4 zokufikelela kwi-cafeteria yokutya, iqela lokutya lokutya lidla kakhulu i-chow encinci kuneqela le-chow kuphela (impembelelo enkulu yokutya, p <0.0001, i-ANOVA yeendlela ezimbini, n = 10-11 / iqela). * p <0.05, ** p <0.01, *** p <0.001, uvavanyo lwe-post hoc lwe-Bonferroni.
https://doi.org/10.1371/journal.pone.0183685.g001
Ukutya kwangaphambili kokutya ukutya okuncitshisiweyo kwe-ethanol yasekhaya ngaphandle kwefuthe kwireyithi ye-ethanol metabolism okanye ii-BECs.
Ukufumanisa iziphumo zokutya kwangaphambili kwe-cafeteria yokutya ekuseleni i-ethanol sasebenzisa i-DID ye-2hr yokufikelela okulinganiselweyo kwe-ethanol yasekhaya (ibhotile enye, i-10% v / v) inkqubo yokusela evelisa amanqanaba aphakathi e-ethanol. Isiseko sokusela i-ethanol (g/kg) kumndilili weentsuku ezisi-7 phambi kokufikelela kwisidlo sokutya kwakufana phakathi kwamaqela (t(11) = 0.3295, p = 0.7480; Umzobo 2A). Nangona kunjalo, emva kweeveki ezi-4 zokutya kwisidlo sokutya, umthamo opheleleyo we-ethanol esetiweyo uye wancitshiswa kwiiveki ezi-2 zovavanyo (ukutya: F(1,143) = 5.635, p <0.05; ixesha F(13, 143) = 3.638, p <0.0001; Umzobo 2B). Ubungakanani bokuncitshiswa kokusela kwe-ethanol babumkhulu xa ukuthathwa kwe-ethanol kwacwangciswa nge-g/kg kuba ubunzima bomzimba bokutya kwe-cafeteria kunye namaqela e-chow kuphela ahluke ngokuphawulekayo. Ukuthathwa kwe-Ethanol kwi-g/kg ephakathi kwiiveki ezi-2 zovavanyo kwakuyi-0.67 ± 0.11 g/kg kwiqela le-chow kuphela kunye ne-0.25 ± 0.06 g/kg kwiqela le-cafeteria yokutya. Ukusetyenziswa kwamanzi kwiiveki ezi-2 zovavanyo akuzange kwahluke phakathi kwamaqela (ukutya: F(1,143) = 0.1280, p = 0.7273; Umzobo 2C).
(A) Kuthetha ukusela i-ethanol esisiseko (g / kg) kwiintsuku ze-7 ngaphambi kokutya kwe-cafeteria yokutya kwakufana phakathi kwamaqela (p = 0.7480, uvavanyo lwe-t-te yoMfundi, n = 6-7 / iqela). (B) Ngaphambi kokutya ukutya kwe-cafeteria (iiveki ze-4) kuncitshiswe umthamo opheleleyo we-ethanol (10%, v / v, 2hr / day) esetyenzisiweyo kwiiveki ze-2 zokuvavanya (umphumo oyintloko wokutya, p <0.05, indlela emibini ye-ANOVA , n = 6-7 / iqela), (C) ngaphandle kwempembelelo ekusetyenzisweni kwamanzi ngokupheleleyo (n = 6-7 / iqela). (D) Kwakungekho mmahluko kwimithambeka ye-BECs (i-30-120 min ilandela i-2g / kg yolawulo, ip) phakathi kwamaqela (p = 0.6535, ukuhla komgca, n = 4-5 / iqela). I-BECs yayifana phakathi kwamaqela kwi-30, i-60, kunye ne-120 min yolawulo lwe-post-ethanol. I-BEC, i-concentration ye-ethanol yegazi; ip, intraperitoneal.
https://doi.org/10.1371/journal.pone.0183685.g002
Ekubeni ukutya kwe-cafeteria kunokutshintsha iinkqubo zemetabolism, kuquka i-ethanol metabolism, silawula i-ethanol (2g/kg, ip) kwaye silinganisa ii-BECs kwi-30, i-60, kunye ne-120 imizuzu emva kokutofa ngokulandela ukutya kwe-cafeteria okanye i-chow kuphela. Ukusebenzisa i-linear regression ukuthelekisa i-BEC slopes (30-120 min post-injection) phakathi kwamaqela, ukutya kwe-cafeteria yokutya kwakungenayo impembelelo kwi-ethanol metabolism rate (p = 0.6535; Umzobo 2D). Ngaphaya koko, kwakungekho mahluko kwii-BECs phakathi kwamaqela (ukutya: F(1,14) = 2.056). Ke ngoko, utshintsho kwireyithi ye-ethanol yemetabolism okanye ukufunxwa kwe-ethanol egazini ayinakuchaza ukusela okuncitshisiweyo kwe-ethanol emva kokutyisa ukutya kokutya.
Ukutya kwangaphambili ukutya okutyiwayo kwe-cafeteria okutshintshileyo okwethutyana kwi-homecage sucrose kunye nokutya kwe-chow
Ukufumanisa ukuba ukutya kwe-cafeteria kuyakuguqula ukusetyenziswa kwezinye izisombululo zokuqinisa, siye savavanya iziphumo zokutya kwangaphambi kokutya kwi-homecage sucrose. Ukusebenzisa i-DID ye-2hr yokufikelela okulinganiselweyo kwi-sucrose (ibhotile enye, i-5% w / v) inkqubo yokusela, isiseko sokusela i-sucrose (mL/kg) yayifana phakathi kwamaqela (t(29) = 0.4600, p = 0.6489; Umzobo 3A). Ukutya kwangaphambili kwesidlo sokutya okwehliswa okwethutyana ukusela i-sucrose (ukutya x ixesha lokusebenzisana: F(13,377) = 2.520, p <0.005; Umzobo 3B). Nangona kwakukho ukutya okubalulekileyo x ukusebenzisana kwexesha, uhlalutyo lwe-post hoc aluzange lufikelele ukubaluleka naliphi na ixesha. Nangona kunjalo, ngokusekelwe kwidatha (Umzobo 3B), ukusebenzisana phakathi kweqela lokutya kunye nexesha kunokuchazwa ngokuncipha kwexeshana lokusela i-sucrose ngokulandela ukutya kokutya kwi-cafeteria. Ngeveki yesibini yovavanyo, nangona kunjalo, ukusela i-sucrose kwakufana neqela le-chow kuphela. Ukusetyenziswa kwamanzi kwiiveki ezi-2 zovavanyo akuzange kwahluke phakathi kwamaqela (ukutya: F(1,377) = 1.176, p = 0.2870; Umzobo 3C). Ifana nesifundo sangaphambili [31], ukutya okutyiwayo kwesidlo sokutya kuncitshiswe kancinci ukutya kwe-chow (ukudibana: F(6,110) = 12.46, p <0.0001; ukutya: F(1,110) = 15.46, p <0.005; ixesha F(6,110) = 10.97, p <0.0001; Umzobo 3D) kwiintsuku ezi-2 ezilandela ukutya kwe-cafeteria (uvavanyo lwe-posthoc lwe-Bonferroni, p <0.001; Umzobo 3D). Ke ngoko, ukubonakaliswa kokutya kwe-cafeteria kuvelisa ukuncitshiswa okuhlala ixesha elide ekuseleni kwe-ethanol kunye nokunciphisa okwethutyana ekuseleni i-sucrose kunye nokutya kwe-chow.
(A) Ukusela isiseko sokusela i-sucrose (mL / kg) ngaphezu kweentsuku ze-7 ngaphambi kokutya kwe-cafeteria yokutya kwakufana phakathi kwamaqela (p = 0.6489, uvavanyo lomfundi, n = 15-16 / iqela). (B) Ngaphambi kokutya ukutya kwe-cafeteria (iiveki ze-4) i-sucrose eguqulelwe ngokukhawuleza (5%, w / v, 2hr / ngosuku) ukusetyenziswa (ukutya x ukusebenzisana kwexesha, p <0.005, iindlela ezimbini ze-ANOVA, n = 15-16 / iqela) . (C) Kwakungekho mmahluko ekusetyenzisweni kwamanzi phakathi kwamaqela (n = 15-16 / iqela). (D) Ngaphambi kokutya ukutya kwe-cafeteria ngokukhawuleza kuncitshiswe ukutya kwe-chow (n = 10 / iqela). *** p <0.001, Bonferroni post hoc uvavanyo.
https://doi.org/10.1371/journal.pone.0183685.g003
Ukutya kweCafeteria kwandisa i-D2R autoinhibition kwi-VTA DA neurons
I-brain slice electrophysiology yasetyenziswa ukuphonononga iziphumo zokutya kwe-cafeteria kwi-basal firing frequency kunye ne-D2R-mediated autoinhibition ye-VTA DA neurons. I-Cafeteria yokutya yokutya ayizange ibe nefuthe kwi-basal tonic pacemaker yokudubula i-VTA DA neurons (t(72) = 0.7294, p = 0.4681; Umzobo 4A kunye 4B). Emva koko, siye savavanya imiphumo yokutya kwe-cafeteria kwi-D2R-mediated yangaphandle yangaphandle usebenzisa i-D2R agonist quinpirole. Ukutya okutyiwa kwiCafeteria kunyuse i-implitude eyincopho ye-quinpirole-mediated (100nM) inhibitory currents zangaphandle (t(39) = 3.167, p <0.005; Umzobo 5A) xa kuthelekiswa nolawulo. Ngapha koko, ukutya kwe-cafeteria kwandisa iziphumo zokuthintela ze-10nM quinpirole ekudubuleni i-VTA DA neurons ngexesha le-10 min yolawulo lwe-quinpirole (intsebenziswano: F(19,513) = 5.425, p <0.0001; ukutya: F(1,513) = 16.40, p <0.0005; ixesha F(19,513) = 39.24, p <0.0001; Umzobo 5B), kunye nepesenti inhibition ye-firing frequency eyenziwa yi-quinpirole (t(27) = 3.824, p <0.001; Umzobo 5C). Kwinqanaba eliphezulu le-quinpirole (30nM) kwakungekho mmahluko ekuthinteleni ukuphindaphinda kokudubula ngexesha le-10 min yolawulo lwe-quinpirole (ukutya: F(1,304) = 0.1049, p = 0.7502; Umzobo 5D) okanye uthintelo lwepesenti lokudubula phakathi kwamaqela (t(16) = 0.05265, p = 0.9587; Umzobo 5E). Ke ngoko, ukuvezwa kokutya kwe-cafeteria kwandisa i-quinpirole-mediated (100nM) imisinga yangaphandle kunye nokwandisa uvakalelo lwe-quinpirole-mediated inhibition of firing frequency.
(A) I-basal tonic firing frequency ye-VTA DA neurons yayifana phakathi kwamaqela (p = 0.4681, uvavanyo lwe-t-test yoMfundi, n = 36-38 / iqela). (B) Umkhondo omele i-VTA DA neuron ukudubula emva kweeveki ze-4 ze-chow kuphela (eluhlaza okwesibhakabhaka) okanye ukutya kwe-cafeteria (obomvu). I-DA, i-dopamine; I-VTA; indawo ye-ventral tegmental.
(A) Ukutya kwe-Cafeteria kwandisa i-implitude ye-peak amplitude ye-quinpirole-mediated (100 nM) inhibitory ngaphandle kwemisinga ye-GIRK xa kuthelekiswa nolawulo lwe-chow kuphela. I-Quinpirole yayisetyenziselwa ukuhlamba i-10 min kunye ne-sulpiride (1 μM) ngokukhawuleza iguqule i-quinpirole-mediated current. Imizekelo ye-quinpirole-mediated outward currents (Vh = -62 mV) ye-chow kuphela (eluhlaza okwesibhakabhaka) okanye i-cafeteria yokutya idliwe (obomvu) iigundane (n = 16-25 / iqela). (B) Ukutya ukutya kwe-Cafeteria kwandisa imiphumo yokuvimbela i-10 nM quinpirole kwi-VTA DA neuron yokudubula i-frequency ngaphezu kwe-10 min ye-quinpirole isicelo sokuhlambela (isiphumo esiphambili sokutya, p <0.0005, indlela emibini ye-ANOVA, n = 13-16 / iqela) kunye (C) i-quinpirole-mediated percent inhibition of firing frequency (p <0.001, t-test yoMfundi). Umkhondo omeleyo we-DA neuron yokudubula i-frequency ngexesha lesiseko okanye i-10 nM ye-quinpirole yesicelo elandela i-chow kuphela (eluhlaza okwesibhakabhaka) okanye ukutya kwe-cafeteria (obomvu). (DE) Ukuvinjelwa kwe-DA neuron yokudubula i-frequency nge-30 nM quinpirole yayifana phakathi kwamaqela (n = 9 / iqela). Ukulandela i-10 min ye-30 nM ye-quinpirole yesicelo sokuhlambela, i-sulpiride (1 μM) isetyenziswe kwibhafu ukuguqulwa ngokukhawuleza kwe-quinpirole-mediated inhibition of firing frequency. Umkhondo omele i-DA neuron yokudubula i-frequency ngexesha lesiseko okanye i-30 nM ye-quinpirole yesicelo elandela i-chow kuphela (eluhlaza okwesibhakabhaka) okanye ukutya kwe-cafeteria (obomvu). *** p <0.001, Uvavanyo lomfundi. I-DA, i-dopamine; I-D2R, i-dopamine D2 receptor; I-GIRK, i-G protein-gated yangaphakathi yokulungisa iziteshi ze-potassium; I-VTA; indawo ye-ventral tegmental.
https://doi.org/10.1371/journal.pone.0183685.g005
ingxoxo
Injongo yolu phononongo lwangoku yayikukuphonononga iziphumo zokutya kwe-cafeteria yokutya kwi-ethanol yasekhaya yokusela kunye ne-VTA DA neuron physiology. Ukutya kwangaphambili kwe-cafeteria yokutya kuncitshiswe ukusela kwe-ethanol kwiiveki ze-2 zokuvavanya, kodwa kwakungekho nefuthe kwi-ethanol metabolism rate okanye i-BECs elandela i-2g / kg (ip) yolawulo lwe-ethanol. Kubhalwe kakuhle ukuba ukutya okunekhalori ephezulu kunye nokutyeba okubangelwa kukutya okukhokelela ekubonakalisweni kwe-DAergic kwi-striatum, eye yathunyelwa ukuba ibe negalelo kwintsilelo kumvuzo [32-34]. Nangona kunjalo, iziphumo zokutyeba okubangelwa kukutya kwi-midbrain DA neurons azikabonakali. Apha, sibonisa ukuba ukufikelela okwandisiweyo kwi-cafeteria yokutya konyusa i-D2R autoinhibition kwi-VTA DA neurons, ngaphandle kwesiphumo kwi-basal tonic pacemaker yokudubula frequency kwisilayi. Akucaci ukuba ukonyuka kwe-D2R autoinhibition kulandela ukutya kwe-cafeteria kunegalelo ekunciphiseni ukusela kwe-ethanol, nangona kunjalo, ukonyuka kwe-DA neuron autoinhibition kunokufaka isandla ekuvuzweni kwe-hypofunction ebonwa ngokutyeba.
Iziphumo zesidlo sokutya ekuseleni i-ethanol
Ukutya kwangaphambili kwi-cafeteria yokutya kukhokelele ekunciphiseni ixesha elide lokusela i-ethanol yasekhaya. Umthamo opheleleyo we-ethanol osetyenzisiweyo wancitshiswa kwiiveki ezi-2 emva kokuvezwa kokutya kwe-cafeteria. Ngapha koko, ukutya okutyiwayo kwe-cafeteria akubanga nafuthe kwi-BECs okanye kwisantya se-ethanol metabolism emva kwe-2g/kg yolawulo lwe-ethanol. Ke ngoko, ukusela okuncitshisiweyo kwe-ethanol akunakuchazwa ngokutya okanye utshintsho olubangelwa ubunzima bomzimba kwisantya se-ethanol metabolism okanye ukufunxwa kwe-ethanol egazini. Ngokuchasene nokusela i-ethanol, ukusela i-sucrose kunye nokutya kwe-chow kwancitshiswa okwethutyana. Ekugqibeleni, ukuvezwa kokutya kwangaphambili kwi-cafeteria kuvelise ukucutha okuhlala ixesha elide kwi-ethanol, xa kuthelekiswa nokuvuzwa kwendalo.
Kuhlala kungacacanga ukuba ukwakheka kokutya kukuchaphazela njani ukusela i-ethanol kwiimpuku. Ke ngoko, kuphononongo lwangoku, iimpuku zondliwa ngokutya okubandakanya ukutya okungenamsoco okutyiwa rhoqo ngabantu. Iziphumo zangoku zivumelana nophononongo lwakutsha nje olubonisa ukuba ukutyeba okuphezulu okubangelwa kukutya okunamafutha aphezulu okanye ukutya okunamafutha aphezulu-okutya iimpuku ezingatyebileyo zibonisa ukhetho oluncitshisiweyo lwe-ethanol [16]. Kwakhona, ukutya okuneprotein ephezulu yecarbohydrates kubonakaliswe ukunciphisa ukusela kwe-ethanol kwiimpuku [17], nangona kunjalo, i-ethanol intake yalinganiswa ngexesha lokuvezwa kokutya. Ngoko ke, ukusela i-ethanol kunokuba kuncitshisiwe ngokusekelwe kwimfuno yekhalori endaweni yokunciphisa iipropati zokuqinisa i-ethanol. Ngokwahlukileyo, ukusetyenziswa kwangaphambili kwe-sucrose (iintsuku ezingama-21) okanye ukutya okunamafutha aphezulu (iintsuku ezi-7) kubonakaliswe ukwandisa ukusela kwe-ethanol yasekhaya.14, 15]. Zombini ezi zifundo zisebenzise i-12 hr inkcazo ye-4-5 yokwandisa i-ethanol (1,2,4,7, okanye i-9%) kwiintsuku ze-4 nganye, eyahluke kakhulu kwi-2 hr ukufikelela kwi-10% ye-ethanol esetyenziswa kwi-ethanol. ngoku isifundo. Ukungangqinelani kwimiphumo yokutya okunekhalori ephezulu ekuseleni i-ethanol kunokubangelwa kukungafani kumxholo wesondlo sokutya, ubude kunye nexesha lokuvezwa kokutya, i-ethanol yokusela i-paradigm esetyenzisiweyo, okanye uxinzelelo / iintlobo zeziphumo ezithile.
Iziphumo zesidlo sokutya kwi-D2R autoinhibition
Ukutya ukutya kweCafeteria kwandisa i-D2R autoinhibition, ekwabonwa emva kokulawulwa okuphindaphindiweyo kwe-ethanol. Ilebhu yethu ibonise ngaphambili ukuba ukulawulwa ngokuphindaphindiweyo kwe-ethanol kwiimpuku kwandisa amandla e-D2R-mediated currents ngaphandle kwi-VTA, kwaye kunciphisa i-Ca.2+ ukudakumba okuxhomekeke kule misinga [29]. Kweso sifundo, ukubonakaliswa kwe-ethanol ngokuphindaphindiweyo kwandisa imiphumo yokuvimbela i-quinpirole kwi-frequency yokudubula kuzo zombini i-10 nM kunye ne-30 nM. Nangona kunjalo, ukubonakaliswa kokutya kwe-cafeteria kwandisa umphumo wokuthintela we-quinpirole ekudubuleni rhoqo kuphela kwi-concentration ye-10 nM (Isazobe 5B kunye no-5C). Nangona asizange sinqume ukuba i-potency / ukuphumelela kwe-quinpirole kwaguqulwa ngokutya kwe-cafeteria, ezi ziphumo zibonisa ukuba ukutya kwe-cafeteria kwandisa uvakalelo lwe-quinpirole ukuvimbela ukudubula kwe-neuron ye-DA. Ulawulo lwe-cocaine olubukhali (20 mg/kg) lukwabonisiwe ukuba lonyusa imisinga yangaphandle ye-D2R kwi-substantia nigra pars compacta yeempuku [30]. Ngokwahlukileyo, i-methamphetamine yokuzilawula ngokwayo ibonakaliswe ukunciphisa i-D2R-mediated currents kwi-VTA, eyayikwayiCa.2+ oxhomekeke [35]. Ke ngoko, ngokungafaniyo nee-neuroadaptations kwi-striatum apho ukuvezwa kweziyobisi zokusetyenziswa kakubi okanye ukutya okunekhalori ephezulu kunciphisa ukubonakaliswa kwe-D2R, iziyobisi ezithile zokuxhatshazwa zineziphumo ezahlukileyo kwimisinga ye-D2R/GIRK-mediated. Kufuneka kuqatshelwe ukuba uthintelo lokutya lunyusa ukuthathwa kweziyobisi [36], kuquka i-ethanol [37], kwaye yehlisa i-D2R autoinhibition [38]. Ekubeni i-cafeteria ye-exposure yokutya ikwandisa i-D2R autoinhibition kwaye iyanciphisa i-ethanol, kuya kubaluleka ukumisela ubudlelwane phakathi kokutya, utshintsho kwi-D2R autoinhibition, kunye nokusela i-ethanol. Kulwazi lwethu, kukho olunye uphando oluvavanye iziphumo zokutyeba okubangelwa kukutya kwi-D2R autoinhibition. Kweso sifundo, ukutyeba okuphezulu okubangelwa kukutya okutyebileyo akuzange kutshintshe imiphumo yokuthintela idosi enye ye-quinpirole (3-100 nM) kwi-VTA DA isantya sokudubula neuron kwiigundane [39]. Nangona kunjalo, ukusetyenziswa kwe-quinpirole (3, 10, 30, kunye ne-100 nM) kubangele ukuthotywa kwemiphumo yokunciphisa i-quinpirole ekudubuleni, okukhokelela ababhali ukuba bacebise ukuba iigundane ezityebileyo zibonakaliswe ngokukhawuleza i-D2R deensitization xa kuthelekiswa nokulawula iimpuku ezibhityileyo. Akucaci ukuba yintoni ephantsi koku kungangqinelani kwimiphumo yokutya kwe-cafeteria kwi-rats ngokuchasene nokutya okunamafutha aphezulu kwiigundane kwi-D2R autoinhibition. Uphononongo olongezelelweyo luqinisekisiwe ukumisela iziphumo zokutya okuxineneyo kwamandla kunye nokutyeba okubangelwa kukutya kwi-VTA DA neurons kunye ne-D2R autoinhibition.
Akucaci ukuba ukusela kwe-ethanol kuncitshisiwe okanye iziphumo ze-electrophysiological zaphenjelelwa kukunyuka kobunzima bomzimba kuphononongo lwangoku. Nangona kunjalo, ukutya okunekhalori ephezulu kunokunciphisa inkqubo ye-DA [13] kunye nokunciphisa ukusela i-ethanol [16] ngokungabikho kokutyeba. Ukunyuka kwe-adiposity kuhambelana notshintsho kwi-leptin, i-insulin, kunye ne-ghrelin, yonke into enokulungelelanisa umsebenzi wenkqubo ye-DA [40-42]. Ngoko ke, asikwazi ukukhupha ukuba utshintsho kwiindlela zokutyisa i-homeostatic zinokuba nefuthe kwiziphumo. Kananjalo asinako ukukhupha ukuba kungenzeka ukuba ukutya kokutya kwi-cafeteria kutshintshe iipatheni ze-circadian zokuziphatha kokutya kuba i-ethanol kunye nokusela i-sucrose kwakulinganiswa kuphela ngexesha lokufikelela kwe-2 hr.
Uphononongo lwangoku lohlukile kwizifundo zangaphambili [5, 6] eziye zavavanya iziphumo zokutya kwe-cafeteria kwinkqubo ye-DA ngokubonelela ngesondlo sokutya kwi-cafeteria ngexesha lokufikisa endaweni yokuba ngumntu omdala. Ithatyathwe kunye, idatha icebisa ukuba ukutya kokutya okufikisayo kunye nabantu abadala kuvelisa ii-neuroadaptations ezithomalalisa inkqubo ye-DA kwaye zibe negalelo ekuvuzweni kwe-hypofunction. Nangona kungaziwa ukuba ukutya ukutya kwe-cafeteria ngexesha lokukhula kuchaphazela njani i-D2R autoinhibition, ukulawulwa kweziyobisi zokusetyenziswa kakubi kunokunyusa i-D2R autoinhibition xa ilawulwa ngexesha lokufikisa.29] okanye ngexesha lobudala [30].
Ukubaluleka kokunyuka kwe-D2R autoinhibition kunye nemeko ye-hypodopaminergic elandela ukutya kwe-cafeteria ekuseleni i-ethanol kunye nokuziphatha okugqibeleleyo
In vivo, ukwanda kwe-D2R autoinhibition kunokunciphisa i-basal DA neuron firing frequency, ngoko ke, kunciphisa inkqubo ye-DA kunye negalelo kwimeko ye-hypodopaminergic. Kuphononongo lwangoku kunye nophononongo lwangaphambili oluvela kwilebhu yethu [29], asizange sibone ithoni ye-basal ye-DAergic kwisilayi njengoko i-sulpiride isilela ukuguqula i-DA neuron yokudubula rhoqo. Nangona kunjalo, kwi vivo umsebenzi we-DA neurons uphenjelelwa ngokuqhubekayo yi-DA yendawo kunye ne-D2R autoinhibition. Ke ngoko, ukonyuka kwe-D2R autoinhibition elandela ukutya kwe-cafeteria kufuneka kukhokhelele ekunciphiseni izinga lokudubula kwe-DA neurons kwisilwanyana esiphilayo, kwaye negalelo kwimeko ye-hypodopaminergic ecinga ukuqhuba ukutya okugqithisileyo [19]. Ngokufanayo, ubungqina obuninzi obuvela kwizifundo zangaphambi kweklinikhi kunye nezifundo zabantu bukhokelele kwingqikelelo yokuba imeko ye-hypodopaminergic inegalelo ekuthatheni okunyanzelekileyo kwe-ethanol kunye nokubuyela kwakhona [43, 44]. Iziphumo zangoku zongeza kuncwadi olukhulayo olucebisa ukuba ukutya kokutya kuvelisa utshintsho olufana ne-DAergic oluhambelana nemeko ye-hypodopaminergic [5, 6]. Nangona imeko ye-hypodopaminergic kudala icingelwa ukuba ibe negalelo ekuseleni i-ethanol ngokugqithisileyo, i-cafeteria yokutya-i-hypodopaminergia ayiguquleli ekuseleni kwe-ethanol. Umsebenzi wangaphambili kwilebhu yethu ubonise ukuba ulawulo lwe-ethanol oluphindaphindiweyo lonyuse i-D2R autoinhibition, eyayanyaniswa nokusela kwe-ethanol yasekhaya kwiimpuku [29]. Kolu phononongo, sigqibe kwelokuba ukonyuka kwe-D2R autoinhibition kulandela ukulawulwa okuphindaphindiweyo kwe-ethanol kube negalelo kwimeko ye-hypodopaminergic eqhele ukubonwa ngokuvezwa okungapheliyo kwe-ethanol. Xa kuthatyathwe kunye, kubonakala ngathi kuyabonakala ukuba ukubonakaliswa kwemeko ye-hypodopaminergic eveliswa kukusetyenziswa okungapheliyo kokutya okuxineneyo kwamandla kukhokelela ekuziphatheni okugqithisileyo / okunyanzelekileyo okugxininisa ngokuthe ngqo. Ewe, ukusetyenziswa ngokugqithisileyo kokutya okuxineneyo akuguquleli ukusetyenziswa ngokugqithisileyo kweziyobisi zokusetyenziswa kakubi, kodwa endaweni yoko, kunciphisa ukusetyenziswa kweziyobisi. Ubungqina obudlulileyo kunye neziphumo zangoku ziyakuxhasa oku kuba ukufikelela okwandisiweyo kwisidlo sokutya kuvelisa ukutya okunyanzelekileyo okufana nokutya okunencasa [6], kodwa yehlisa ukusela i-ethanol kunye ne-sucrose njengoko sibonisa apha. Ngapha koko, ukutya kwe-chow kuye kwancitshiswa okwethutyana emva kokutya kokutya. Ngaphezu koko, ukutya okunamafutha aphezulu okanye ulawulo lweswekile kubonakaliswe ukunciphisa ukuthathwa kwe-psychostimulant kunye nemeko ekhethwayo kwindawo kwiimpuku [10-13]. Izifundo ezininzi ze-epidemiological zikwabonisa ukuba ukutyeba kwabantu ngokuqhelekileyo akunxulunyaniswa notywala okanye ukuphazamiseka kokusetyenziswa kweziyobisi [45-48]. Ngokwahlukileyo koko, kukho izifundo ezilinganiselweyo ezibonelela ngobungqina bokuba ukutya okunamafutha aphezulu kwangaphambili okanye ulawulo lwe-sucrose kwandisa ukusela kwe-ethanol kwiimpuku [14, 15] okanye ukutyeba kunxulunyaniswa nokuphazamiseka kokusetyenziswa kotywala ebantwini [49]. Ulawulo lwe-ethanol olungapheliyo lunokuvelisa iziphumo ezithile zokuqinisa ekusebenziseni iziyobisi. Ngokomzekelo, ukubonakaliswa kwangaphambili kwe-ethanol engapheliyo kwandisa i-ethanol self-administration [50], kodwa ayinasiphumo kulawulo lwe-cocaine [51], nangona ulawulo olungapheliyo lwe-ethanol okanye i-cocaine zombini zivelisa uhlengahlengiso olufanayo kwinkqubo ye-DA. Ngaphaya koko, ngokwendlela imeko ye-hypodopaminergic ekuchaphazela ngayo ukusela i-ethanol kunye nokuphinda ubuyele, uphononongo lwakutsha nje luvavanye utshintsho kwinkqubo ye-DA kuwo wonke umjikelo wokulutha kwiimpuku nakubantu, kwaye yabonisa ukuba ukuziyeka kubonakaliswa yi-hypodopaminergia yokuqala elandelwa yi-hyperdopaminergia ngexesha lokuyeka ixesha elide, zombini. enokuthi ifake isandla ekubuyeleni ekubeni sesichengeni [52]. Ke ngoko, ukutenxa ekubonakalisweni kwe-DAergic kunxulunyaniswa nokusetyenziswa kwe-ethanol kunye nokuphazamiseka kokusetyenziswa kotywala, kodwa ubudlelwane obuchanekileyo phakathi kokubonakaliswa kwe-DA kunye nokusela i-ethanol okanye ukuphinda kubuye kuhlale kungacaci.
Ukubaluleka kokunyuka kwe-D2R autoinhibition ekutyebeni okubangelwa kukutya
Ukonyuka kwe-D2R autoinhibition kunokuba negalelo kukusilela ekuhanjisweni kwe-DA yokubulawa kunye nomvuzo we-hypofunction ebonwa ngokutyeba okubangelwa kukutya. Ukutyeba kakhulu kunxulunyaniswa nokusilela kumvuzo kunye nokuphazamiseka kwempembelelo kunye nokuphazamiseka ngokweemvakalelo okuhlala kuchazwa ngokuyinxenye ekunciphiseni ukubonakaliswa kwe-DA kwi-striatum [32, 33, 53]. Ukutya ukutya kweCafeteria kuye kwaboniswa ukunciphisa amanqanaba e-DA ye-basal kunye namanqanaba e-DA metabolites i-3,4-dihydroxyphenylacetic acid (DOPAC) kunye ne-homovanillic acid (HVA) kwi-NAc [5]. Ngaphezu koko, olunye uphononongo lubonise ukuba iigundane ezityebileyo ezityebileyo zibonise i-50% ngaphantsi kwe-basal DA kwi-NAc xa kuthelekiswa nolawulo [54]. Ezi zifundo zimbini zibonelela ngobungqina bokuba ukutya okutyiwayo kokutya kunye nokutyeba kakhulu kunokusilela kwe-presynaptic ekukhutshweni kwe-DA kusetyenziswa i-coronal NAc isilayi samalungiselelo. Umzekelo, iigundane ezityebileyo ezityebileyo ziye zancitshiswa kwi-DA biosynthetic enzyme tyrosine hydroxylase kunye ne-vesicular monoamine transporter 2 (VMAT2) enokunciphisa i-DA synthesis kunye nokukhulula [54]. Nangona kunjalo, inkalo engahoywayo kwintsimi kukubandakanyeka kweenkqubo zomzimba kwi-VTA apho uninzi lwezi neurons ze-DA zivela khona. Iziphumo zangoku zibonisa ukuba ukunyuka kwe-D2R autoinhibition kunokufaka isandla kwiintsilelo ze-DAergic ezibonwa ngokutyeba okubangelwa kukutya. Ke ngoko, izifundo ezivavanya iindlela ze-presynaptic mesolimbic kwi-NAc kunye ne-VTA inokubonelela ngengqiqo kwiindlela ze-neurobiological ezinegalelo ekutyebeni.
izigqibo
Ukuhanjiswa okucuthiweyo kwe-DA kwi-striatum yabantu abatyebe kakhulu kunye neempuku kubhalwe kakuhle [6, 8, 19]. Uphononongo lwangoku lucebisa ukuba ukonyuka kwe-D2R autoinhibition kwi-VTA kunokuthi kube negalelo ekutyeni okubangelwa kukungaphumeleli kokubonisa i-DA kunye nomvuzo we-hypofunction obonwa ngokutyeba. Nangona ukutya okunekhalori ephezulu kunye neziyobisi zokuxhatshazwa zivelisa utshintsho olufanayo kwinkqubo ye-DA ye-mesolimbic, sibonisa ukuba ukutya kwe-cafeteria yokutya kunciphisa ukusela kwe-ethanol kwiigundane. Ngokubanzi, kubonakala ngathi utshintsho lokutya okubangelwa kukutya okukhokelela kumlutha kwinkqubo ye-DA inokuqhuba ngokuthe ngqo ukusetyenziswa kwesidlo sokutya [6], ngelixa ukurhoxa kwisidlo sokutya kubangela ukucinezelwa ixesha elide lokusela i-ethanol kunye nokucinezela okwethutyana ukusetyenziswa kwemivuzo yendalo (okt, sucrose kunye ne-chow pellets). Ezi ziphumo zongeza kuncwadi olukhulayo olubonisa ukuba ukutyeba okubangelwa kukutya kunye nokuba likhoboka leziyobisi kuvelisa i-neuroadaptations efanayo kumjikelezo womvuzo. Uphando olongezelelweyo kwi-midbrain midbrain DAergic adaptations emva kokutya okuxineneyo kwamandla okugqithisileyo okanye ukuthatha iziyobisi kunokukhokelela ekuqondeni okubalulekileyo kwiindlela ezinegalelo kwezi ngxaki zinkulu zempilo yoluntu.
Ulwazi oluxhasayo
1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 | 21 | 22 | 23 | 24 | 25 | 26 | 27 | 28 | 29 | 30 | 31 | 32 | 33 | 34 | 35 | 36 | 37 | 38 | 39 | 40 | 41 | 42 | 43 | 44 | 45 | 46 | 47 | 48 | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | ||||||||||||||||||||||||||||||||||||||||||||||||
2 | ||||||||||||||||||||||||||||||||||||||||||||||||
3 | Umfanekiso 1A. Iikhalori ngeveki | |||||||||||||||||||||||||||||||||||||||||||||||
4 | Chow kuphela (ID) | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | |||||||||||||||||||||||||||||||||
5 | Iveki 1 | 464 | 484 | 504 | 456 | 492 | 176 | 276 | 284 | 376.4445 | 463.5555 | 438.6667 | 392 | 283.1111 | 301.7778 | |||||||||||||||||||||||||||||||||
6 | Iveki 2 | 712 | 700 | 788 | 680 | 728 | 452 | 492 | 452 | 660.8 | 705.6 | 733.6 | 672 | 621.6 | 571.2 | |||||||||||||||||||||||||||||||||
7 | Iveki 3 | 662.6667 | 653.3333 | 802.6667 | 634.6667 | 630 | 512 | 484 | 488 | 700 | 728 | 777 | 452.6667 | 616 | 576.3333 | |||||||||||||||||||||||||||||||||
8 | ||||||||||||||||||||||||||||||||||||||||||||||||
9 | Isidlo sokutya (ID) | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | ||||||||||||||||||||||||||||
10 | Iveki 1 | 810.11 | 783.9116 | 813.6035 | 857.5615 | 705.5117 | 780.7995 | 354.83 | 414.8343 | 354.5233 | 515.7778 | 386.4445 | 393.1111 | 466.1111 | 489.3333 | 337.5555 | 466.4445 | 398.8889 | 440.5555 | 320.2222 | ||||||||||||||||||||||||||||
11 | Iveki 2 | 971.8041 | 1003.042 | 946.6136 | 1012.289 | 946.2327 | 926.5184 | 569.1601 | 530.6304 | 546.8109 | 788.8925 | 740.2822 | 916.6797 | 680.6889 | 857.7944 | 756.5599 | 805.8618 | 796.4995 | 834.9358 | 687.0909 | ||||||||||||||||||||||||||||
12 | Iveki 3 | 1258.863 | 1219.169 | 1219.993 | 1210.393 | 1121.678 | 1124.869 | 631.8867 | 656.8687 | 587.3893 | 897.3823 | 882.5435 | 936.5898 | 860.3552 | 1045.424 | 864.0526 | 990.0101 | 867.4072 | 941.0391 | 893.0363 | ||||||||||||||||||||||||||||
13 | ||||||||||||||||||||||||||||||||||||||||||||||||
14 | ||||||||||||||||||||||||||||||||||||||||||||||||
15 | Isazobe 1B. Umthombo weeCalories (Cafeteria diet group) | |||||||||||||||||||||||||||||||||||||||||||||||
16 | Chow iipellets | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | ||||||||||||||||||||||||||||
17 | Iveki 1 | 144 | 128 | 112 | 60 | 156 | 64 | 132 | 104 | 189.7778 | 96.44444 | 59.11111 | 199.1111 | 233.3333 | 15.55556 | 208.4444 | 80.88889 | 71.55556 | 34.22222 | 116 | ||||||||||||||||||||||||||||
18 | Iveki 2 | 320 | 268 | 292 | 224 | 284 | 148 | 76 | 188 | 243.6 | 207.2 | 243.6 | 201.6 | 366.8 | 221.2 | 324.8 | 212.8 | 182 | 201.6 | 312 | ||||||||||||||||||||||||||||
19 | Iveki 3 | 182 | 182 | 149.3333 | 102.6667 | 196 | 184 | 68 | 204 | 207.6667 | 144.6667 | 238 | 156.3333 | 284.6667 | 163.3333 | 245 | 221.6667 | 228.6667 | 142.3333 | 261.3333 | ||||||||||||||||||||||||||||
20 | ||||||||||||||||||||||||||||||||||||||||||||||||
21 | Isidlo sokutya | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | ||||||||||||||||||||||||||||
22 | Iveki 1 | 694.11 | 639.9116 | 685.6035 | 745.5615 | 645.5117 | 624.7995 | 290.83 | 282.8343 | 250.5233 | 326 | 290 | 334 | 267 | 256 | 322 | 258 | 318 | 369 | 286 | ||||||||||||||||||||||||||||
23 | Iveki 2 | 659.8041 | 683.0422 | 678.6136 | 720.2889 | 722.2327 | 642.5184 | 421.1601 | 454.6304 | 358.8108 | 545.2925 | 533.0823 | 673.0798 | 479.0889 | 490.9944 | 535.3599 | 481.0618 | 583.6995 | 652.9358 | 485.4909 | ||||||||||||||||||||||||||||
24 | Iveki 3 | 997.5293 | 1037.169 | 1037.993 | 1061.059 | 1019.012 | 928.8688 | 447.8867 | 588.8687 | 383.3893 | 689.7157 | 737.8768 | 698.5898 | 704.0219 | 760.7576 | 700.7192 | 745.0101 | 645.7406 | 712.3724 | 750.7029 | ||||||||||||||||||||||||||||
25 | ||||||||||||||||||||||||||||||||||||||||||||||||
26 | Umzobo 1C. Iikhalori ezivela kwiChow | |||||||||||||||||||||||||||||||||||||||||||||||
27 | Chow kuphela (ID) | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | |||||||||||||||||||||||||||||||||
28 | Iveki 1 | 464 | 484 | 504 | 456 | 492 | 176 | 276 | 284 | 376.4445 | 463.5555 | 438.6667 | 392 | 283.1111 | 301.7778 | |||||||||||||||||||||||||||||||||
29 | Iveki 2 | 712 | 700 | 788 | 680 | 728 | 452 | 492 | 452 | 660.8 | 705.6 | 733.6 | 672 | 621.6 | 571.2 | |||||||||||||||||||||||||||||||||
30 | Iveki 3 | 662.6667 | 653.3333 | 802.6667 | 634.6667 | 630 | 512 | 484 | 488 | 700 | 728 | 777 | 452.6667 | 616 | 576.3333 | |||||||||||||||||||||||||||||||||
31 | ||||||||||||||||||||||||||||||||||||||||||||||||
32 | Isidlo sokutya (ID) | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | ||||||||||||||||||||||||||||
33 | Iveki 1 | 144 | 128 | 112 | 60 | 156 | 64 | 132 | 104 | 189.7778 | 96.44444 | 59.11111 | 199.1111 | 233.3333 | 15.55556 | 208.4444 | 80.88889 | 71.55556 | 34.22222 | 116 | ||||||||||||||||||||||||||||
34 | Iveki 2 | 320 | 268 | 292 | 224 | 284 | 148 | 76 | 188 | 243.6 | 207.2 | 243.6 | 201.6 | 366.8 | 221.2 | 324.8 | 212.8 | 182 | 201.6 | 312 | ||||||||||||||||||||||||||||
35 | Iveki 3 | 182 | 182 | 149.3333 | 102.6667 | 196 | 184 | 68 | 204 | 207.6667 | 144.6667 | 238 | 156.3333 | 284.6667 | 163.3333 | 245 | 221.6667 | 228.6667 | 142.3333 | 261.3333 | ||||||||||||||||||||||||||||
36 | ||||||||||||||||||||||||||||||||||||||||||||||||
37 | Umfanekiso 1D. Ukunyuka kobunzima ngeVeki (g) | |||||||||||||||||||||||||||||||||||||||||||||||
38 | Chow kuphela (ID) | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | |||||||||||||||||||||||||||||||||
39 | Iveki 1 | 55 | 57 | 61 | 50 | 52 | 35 | 39 | 36 | 45.5 | 49.7 | 52.5 | 46.9 | 40.6 | 39.2 | |||||||||||||||||||||||||||||||||
40 | Iveki 2 | 64 | 58 | 63 | 52 | 67 | 52 | 51 | 48 | 48.5 | 51.3 | 54.25 | 51.35 | 44.9 | 42.3 | |||||||||||||||||||||||||||||||||
41 | Iveki 3 | 43 | 51 | 57 | 49 | 39 | 32 | 43 | 40 | 50.75 | 52.5 | 55.5625 | 54.6875 | 48.125 | 44.625 | |||||||||||||||||||||||||||||||||
42 | ||||||||||||||||||||||||||||||||||||||||||||||||
43 | Isidlo sokutya (ID) | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | ||||||||||||||||||||||||||||
44 | Iveki 1 | 61 | 63 | 62 | 70 | 60 | 58 | 33 | 37 | 37 | 51.8 | 42 | 53.2 | 42.7 | 55.3 | 49.7 | 47.6 | 48.3 | 49.7 | 46.2 | ||||||||||||||||||||||||||||
45 | Iveki 2 | 67 | 72 | 70 | 69 | 59 | 59 | 52 | 58 | 59 | 58.95 | 50 | 59.55 | 50.05 | 66.7 | 57.3 | 56.15 | 58.2 | 52.55 | 55.8 | ||||||||||||||||||||||||||||
46 | Iveki 3 | 68 | 63 | 66 | 66 | 61 | 59 | 43 | 54 | 47 | 64.3125 | 56 | 64.3125 | 55.5625 | 75.25 | 63 | 62.5625 | 65.625 | 54.6875 | 63 | ||||||||||||||||||||||||||||
47 | ||||||||||||||||||||||||||||||||||||||||||||||||
48 | Umzobo 1E. Ubunzima bomzimba (g) | |||||||||||||||||||||||||||||||||||||||||||||||
49 | Chow kuphela (ID) | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 | 21 | 22 | 23 | 24 | 25 | 26 | 27 | 28 | 29 | 30 | 31 | 32 | 33 | 34 | 35 | 36 | 37 | 38 | 39 | 40 | 41 | 42 | 43 | 44 | 45 | 46 | |
50 | ngosuku | 1 | 180 | 183 | 190 | 217 | 226 | 193 | 181 | 203 | 197 | 223 | 211 | 134 | 207 | 195 | 206 | 208 | 182 | 148 | 147 | 183 | 167 | 174 | 199 | 159 | 184 | 157 | 174 | 178 | 185 | 145 | 186 | 228 | 222 | 208 | 224 | 222 | 211 | 216 | 150 | 169 | 150 | 147 | 159 | 163 | 172 | 165 |
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Idatha ekrwada yeFig 1.
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Idatha ye-S1. Idatha ekrwada ye Umzobo 1.
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Idatha ye-S2. Idatha ekrwada ye Umzobo 2.
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Idatha ye-S3. Idatha ekrwada ye Umzobo 3.
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https://doi.org/10.1371/journal.pone.0183685.s005
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Imibulelo
Sithanda ukuvuma uJorge Tovar Diaz, uRegina Mangieri, uNhi Le, uJeremiah Ling, kunye noTrevor Hadley ngoncedo lwabo lobugcisa. Singathanda kwakhona ukubulela uMichela Marinelli ngeengxoxo zenzululwazi ezibalulekileyo kunye noChristopher Mazzone ngoncedo lokuhlela umbhalo wesandla.
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