Nako e telele ea Fat Diet e fokotsa Dopamine Reuptake ntle le ho fetola maikutlo a DAT ea lefats'e (2013)

  • Jackson J. Cone,
  • Elena H. Chartoff,
  • David N. Potter,
  • Stephanie R. Ebner,
  • Mitchell F. Roitman

inahaneloang

Nts'etsopele ea botenya bo khothalletsoang ke ho ja (DIO) e ka fetola likarolo tse ngata tsa lets'oao la dopamine, ho kenyelletsa polelo ea dopamine transporter (DAT) le dopamine reuptake. Leha ho le joalo, nako ea nako ea phetoho e khothalletsoang ke lijo le tšebeliso ea li-DAT le hore na liphetoho tse joalo li its'etleha holima nts'etsopele ea DIO e lula e sa rarolloe. Mona, re fepa likhoto tse nang le phepo e phahameng (HFD) kapa e tlase (LFD) bakeng sa libeke tsa 2 kapa 6. Kamora ho pepesehela lijo, likhoto li ne li sa anngoe ka mosebetsi oa urethane le oa striatal DAT li ile tsa hlahlojoa ka motlakase tse matlafatsang 'mele ea lisele tsa dopamine sebakeng sa ventral tegmental (VTA) le ho rekota liphetoho tse tlisoang ke khatello ea dopamine ka hare ho terral striatum e sebelisang li-cyclic voltammetry tse potlakileng. Re boetse re hlalositse phello ea HFD ho li-membrane tse amanang le DAT ho likaroloana tsa sele tse tsoang sehlopheng se arotsoeng sa likhoto kamora ho pepesetsoa protocol e tšoanang. Haholo, ha ho sehlopha sa rona sa kalafo se fapaneng ka boima ba 'mele. Re fumane bofokoli ka tekanyo ea phumano ea dopamine ho likhoto tsa HFD tse amanang le likhoto tsa LFD kamora 6 empa eseng libekeng tsa 2 libekeng tsa tlhahiso ea lijo. Ntle le moo, keketseho ea dopamine e ileng ea tsoa ka mor'a phephetso ea meriana ea cocaine e ile ea totobala haholo ho HFD e amanang le likhoto tsa LFD. Tlhahlobo ea blot ea Bophirimela e senotse hore ha ho na phello ea lijo ka protheine e felletseng ea DAT. Leha ho le joalo, libeke tsa 6 tsa ho pepesetsoa ha HFD li fokotsehile haholo isNormX ea 50 kDa DAT ka karoloana e amanang le membrane e kopaneng, empa eseng ka karohano e amanang le endosomes endyomes. Lintlha tsa rona li fana ka bopaki bo eketsehileng ba liphetoho tse susumetsoang ke lijo ho dopamine reuptake tse ikemetseng tsa liphetoho tlhahisong ea DAT mme li bontša hore liphetoho tse joalo li ka hlaha ntle le nts'etsopele ea DIO. 

Tlhaloso: Cone JJ, Chartoff EH, Potter DN, Ebner SR, Roitman MF (2013) Proponged High Fat Diet Fokotsa Dopamine Reuptake ntle le ho Fetolela Tlhatlhobo ea DAT Gene. PloS ONE 8 (3): e58251. Doi: 10.1371 / journal.pone.0058251

mohlophisi: Sidney Arthur Simon, Setsi sa Bongaka sa Duke University, United States of America

Re amohetse: October 26, 2012; E amohetse: February 5, 2013; E phatlalalitsoe: March 13, 2013

Copyright: © 2013 Cone et al. Ena ke sengolo se bulehileng se fihletsoeng tlasa tumellano ea Lichelete ea Tlhahiso ea Creative Commons Attribution, e lumellang tšebeliso e sa thibeloang, phetiso, le tlhahiso hape ka mofuta o mong le o mong, ha feela moqapi oa mantlha le mohloli ba ngoliloe.

Lithuso: Morero o hlalositsoeng o tšehelitsoe ke lithuso tsa naha tsa National Institutes of Health (NIH) le DA025634 (MFR) le T32-MH067631 ho tsoa ho Biomedical Neuroscience Training Program (JJC). Ts'ehetso e eketsehileng e fanoe ke Setsi sa Naha sa Tlhahisoleseling ea Setsi sa Sechaba le Setsi sa Naha sa Tsoelo-pele ea Thutong ea Sechaba, NIH, ka thuso ea UL1RR029877 (JJC) le ke Chicago Biomedical Consortium ka tšehetso e tsoang licheleteng tsa Searle ho The Chicago Community Trust (JJC). Litaba ke feela boikarabello ba bangoli mme ha ho hlile ha li emetse maikutlo a semmuso a NIH kapa Chicago Biomedical Consortium. Bafani ba lichelete ba ne ba sena karolo morerong oa ho ithuta, ho bokella data le ho hlahlobisisa, qeto ea ho phatlalatsa, kapa ho hlophisa sengoloa.

Lithahasello tse tsitsitseng: Bangoli ba boletse hore ho na le lithahasello tsa tlhōlisano tse teng.

Selelekela

Ho nona ho feta tekano ebile ho nona haholo ke karolo e kholo ea lipalo tsa batho ba United States le ba lefats'e [1], [2]. Le ha ho na le mekhoa e mengata ea ho nona haholo, mohlomong e 'ngoe ea litšokelo tse kholo ho boima ba' mele bo phetseng hantle ke phepo le ts'ebeliso ea lijo tse matlafatsang haholo tse matla. [3]. Ho joalo, matla a khoheli (kcal / g) ea lijo a ka thusa ho nona haholo le botenya ho batho ba baholo [4], [5]. Lijo tse fumanehang habonolo li etsa hore ho lokolloe dopamine ka har'a li-striatum tsa batho le liphoofolo tseo e seng batho [6], [7], [8], [9] le litekanyetso tse ikhethileng tsa mafura lijong li hokahanngoa hantle le matla a likarabo tsa neural ho "ventral striatum" [10]. Ka hona, dopamine le striatum li bonahala li kenya letsoho lithahasellong tsa lijo tse matla haholo. Haufinyane, ho ile ha bontšoa hore liphapang tsa ho ja li ka baka liphetoho tse tšoanang nakong ea ho potoloha le ho tsamaisoa ke lijo [11]. Leha ho le joalo, mohlomong ha e ananeloe haholo ke bopaki bo ntseng bo eketseha ba hore phapang ea lijo tse kenyellelitsoeng, haholo-holo mabapi le mafura, e ka fana ka maikutlo mabapi le ho fetola dopamine ho saena.

Striatal dopamine signaling e laoloa ke lintlha tse 'maloa ho kenyelletsa tlhahiso ea dopamine ke enzyme tyrosine hydroxylase, pre- and postynaptic dopamine receptors, le li-presynaptic dopamine shipping (DATs), tseo kaofela li hlahisitsoeng ke botenya. [12], [13]. Liphetoho tsa palo ea tšebetso ea DAT kapa ts'ebetso li ka fetola karolo ea ts'usumetso ea dopamine e lokollotsoeng mme ka lebaka leo ts'ebetso ea striatal [14], [15]. Insulin, e lokollotsoeng ka lebaka la lijo tse entsoeng, e bontšitsoe hore e susumetsa ts'ebetso ea DAT [16], [17]. Kahoo, DAT ke e mong oa batho ba ka bang likhetho bakeng sa litlamorao tsa lijo.

Haufinyane, likhokahano lipakeng tsa botenya le ho fumaneha ha DAT hammoho le liphetoho tse hlahisitsoeng ke ho ja tsa ts'ebetso ea DAT li fumanoe. Index ea boima ba 'mele (BMI) e hokahane hampe le ho fumaneha ha DAT ho striatum ea motho [18]. Ho tlangoa ha DAT, ka hona, ho fumaneha, ho fokotsehile ho li-jaine tse nang le mafura a mangata (HFD) [19]. HFD -indied obesity (DIO) e amahanngoa le sekhahla se fokotsitsoeng sa ho khutlisoa ha dopamine ke DAT ka likhoto [20]. Ha li kopantsoe hammoho, liphuputso tsena li fana ka maikutlo a hore botenya bo thehiloeng ke ts'ebeliso ea HFD bo ka ba le tšusumetso e matla ho li-regynaptic regators tsa dopamine ho saena - haholo-holo DAT. Leha ho le joalo, nako ea liphetoho tse khothalletsoang ke ho ja lijong tsa dopamine le hore na ntshetsopele ea DIO e hlokahala bakeng sa liphetoho e lokela ho lula e sa tsejoe. Re ile ra leka ts'ebetso ea DAT ka ho etsa hore ho lokolloe dopamine ka har'a terri striatum le ho lekanya sekhahla sa ho khutlisa litekong re sebelisa li-volcammry tse potlakileng tsa scan. Ho fumana hore na ho fokotseha ha dopamine ho fokotsoe ho hlahisitsoe ke mofuta oa "gene" e fokotsitsoeng, re lekantsoe ka DAT mRNA sebakeng sa ventral tegmental le substantia nigra re sebelisa qRT-PCR ea nako ea nnete. Ntle le moo, re sebelisitse mokhoa oa karohano ea biochemical le tlhahlobo ea blot ea Bophirima ho ts'oara maemo a mokhoa oa ho ngola ka li-membrane tsa craptosomal le endosomal. Likhoto li ne li na le libeke tsa 2 kapa 6 tsa lijo tse nang le mafura a mangata kapa a tlase, empa litekanyo tsohle li entsoe ka ho se be teng ha DIO. Liphetho tsa rona li fana ka maikutlo a hore tšebeliso ea nako e telele ea HFD, e ikemetseng ho DIO, e fokotsa sekhahla sa ho khutlisetsa dopamine ka har'a ventral striatum ntle le ho fokotsa polelo ea DAT.

Lisebelisoa le mekhoa

Boitšoaro ba Melao

Boithuto bona bo ile ba etsoa ho latela likeletso tse tataisong ea Tataiso ea Tlhokomelo le Ts'ebeliso ea Liphoofolo tsa Laboraro tsa Setsi sa Naha sa Bophelo. Protocol e amohetsoe ke Komiti ea Tlhokomelo ea Liphoofolo Univesithing ea Illinois, Chicago. Ho buoa hohle ho ile ha etsoa ka tlasa anthhesia ea urethane, 'me boiteko bohle bo entsoe ho fokotsa mahlomola.

Lihlooho

Ho ile ha sebelisoa likhoto tse tloaelehileng tsa banna Sprague-Dawley (n = 67), tse ka bang likhoeli tse 2 le boima ba 225-275 g ha li fihla. Liphoofolo li ne li bolokiloe ka kotloloho mekotleng ea polasetiki (26.5 × 50 × 20 cm) mochesong oa mocheso- (22 ° C) le mongobo- (30%) tikoloho e laoloang sebakeng sa khanya ea 12∶12 h: potoloho e lefifi (mabone ho 07∶00 h). Lits'oants'o li ile tsa tumisoa setsing sa beke e le ngoe le ad libitum phihlello ea li-lab chow tse tloaelehileng le metsi.

Ho Lekanya Lijo le Mealo ea 'Mele oa' mele

Kamora ho honotha, likhoto li ile tsa imeloa mme tsa abeloa ka mokhoa o sa reroang ho 1 ea lihlopha tsa 4 tse neng li hanyetsoa bakeng sa boima ba 'mele ba pele. Lihlopha tse peli li ile tsa bolokoa lijong tse tlase tsa mafura (LFD; Dijo tsa Lipatlisiso, New Brunswick, NJ; D12450B; 10% kilocalories ho tsoa mafura (3.85 kcal / g). Lihlopha tse ling tsa 2 li ne li bolokiloe ho HFD (Lipatlisiso tsa Lijo; D12492; 60% kilocalories ho tloha mafura (5.24 kcal / g). Bakeng sa sejo se seng le se seng, likhoto li ne li bolokoa bakeng sa libeke tsa 2 kapa 6 (wks). Kahoo, lihlopha tsa 4 e ne e le: LFD-2 wk (n = 18), HFD-2 wk (n = 16), LFD-6 wk (n = 16) le HFD-6 wk (n = 17). Lihlopheng tsohle li ne li ad libitum phihlello ea metsi. Tekanyo ea lijo le litekanyo tsa boima ba 'mele li ile tsa etsoa makhetlo a mararo / wk mme data e tlalehoa ka thoko bakeng sa likhoto tse ntseng li rekisoa voltammetric kapa tlhahlobo ea protheine ea DAT / molaetsa.

Mekhoa ea Ts'ebetso le Litekanyo tsa Dopamine

Kamora ho pepesetsoa lijo, seteishene sa likhoto se neng se sa tšoane ka boima ba 'mele se ne se lokiselitsoe ho rekota voltammetric (LFD-2 wk (n = 8), HFD-2 wk (n = 6), LFD-6 wk (n = 6) , le HFD-6 wk (n = 7)) tlasa urethane (1.5 g / kg) anesthesia [joalo ka ho 9,21]. Cannula ea tataiso (Bioanalytical Systems, West Lafayette, IL) e ne e behiloe kaholimo ho ventral striatum (1.3 mm anterior, 1.5 mm lateral ho tloha bregma), elektrode ea litšepe ea silifera e nang le chlorine (Ag / AgCl) e kentsoe ka har'a cortex ea bobeli mme ka bobeli e sirelelitsoe lehateng ka lisepa tsa tšepe e sa hloekang le samente ea meno. Micromanipulator e nang le carbon-fiber electrode (CFE) e kentsoe ka har'a cannula ea tataiso mme eleketrode e theoleloa ka har'a ventral striatum. CFE le electrode ea litšupiso e ne e hokahantsoe le hlooho ea hlooho mme bokhoni ba CFE bo ile ba hlahlojoa ho tloha ho -0.4 ho ea ho +1.3 V (vs. Ag / AgCl) le morao (400 V / s; 10 Hz). Electrode e hlasimollang bipolar (Plastics One, Roanoke, VA) e ile ea theoleloa butle-butle sebakeng sa ventral tegmental / substantia nigra pars compacta (VTA / SNpc; 5.2 mm posterior, 1.0 mm lateral mme qalong 7.0 mm ventral ho tloha bregma) ka li-increment tsa 0.2 mm . Khatisong e ngoe le e ngoe, ho ile ha tsamaisoa terene ea li-pulses tsa morao-rao (60 pulses, 4 ms per pulse, 60 Hz, 400 µA). Ha eleketrode e hlasimollang e le VTA / SNpc mme CFE e le ho striatum, ts'usumetso e ts'epahala e tsosa ho lokolloa ha dopamine - e nkiloeng ho data ea voltammetric ho sebelisoa tlhahlobo ea mantlha ea likarolo [9], [22]; 'me ea fetoloa hore e be khatello ka mor'a CFE ka' ngoe e lekantsoeng tsamaisong ea ente ea flow flow kamora teko e ngoe le e ngoe [23]. Boemo ba li-electrode tse hlasimollang bo ile ba ntlafatsoa bakeng sa tokollo e phahameng. CFE ka nako eo e ile ea lumelloa ho lekana bakeng sa metsotso ea 10 pele e qala teko. Ho lokolloa ha Dopamine ho ile ha tsosoa ke ho hlohlelletsoa ha motlakase oa VTA / SNpc (matšoao a tšoanang le a kaholimo), 'me liphetoho tsa sephetho sa dopamine li ile tsa baloa ho tloha −5 s ho 10 s ho amana. Hang-hang ka mor'a ho hlohlelletsoa, ​​likhoto li ile tsa kenngoa ka koae ea cocaine hydrochloride e qhibilihileng ho saline ea 0.9% (10 mg / kg ip) mme, 10 min hamorao, ts'usumetso e ile ea phetoa. Lisebelisoa tse sebelisitsoeng, ho fumaneha ha data le tlhaiso li entsoe ka software e ngotsoeng ho LITLHAKISO (Lisebelisoa tsa Naha, Austin, TX, USA) [22].

Dopamine Reuptake

Dopamine reuptake e entsoe modemone ho sebelisa Software ea Demon Voltammetry Analysis (24; Wake Forest University, Winston-Salem NC). Mona re tlaleha ho bola ho tau khafetsa joalo ka tekanyo ea tekanyo ea dopamine reuptake. Tau e tsoa holima curve e lekanang boholo ba serethe sa dopamine clearance mme e hokahane haholo (r = .9899) e nang le Km, tumellano e totobetseng ea dopamine bakeng sa DAT [24]. Ho tseba phello ea koae ka ho hlaphoheloa ha litheko tsa dopamine re bapisitse boleng bo fumanoeng pele le ka mora ts'ebetso (phetoho ea%).

Histology

Kamora ho rekota ka seng, electrode ea tšepe e se nang tšepe (AM Systems #571500, Sequim, WA) e ile ea theoleloa botebong bo lekanang le CFE le lesion (10 µA, 4 s) ho tšoaea sebaka sa ho rekota. Li-brains li ile tsa tlosoa 'me tsa bolokoa ho 10% formalin. Microscopy e bobebe e ne e sebelisetsoa ho supa sebaka sa lesion ka likarolo tsa coronal (50 µm) ka striatum. Lirekoto tsohle tse tlalehiloeng mona li entsoe ka har'a ventral striatum [25].

Subcellular Fractionation ea Striatal Tissue

Likhoto (LFD-2 wk, HFD-2 wk, LFD-6 wk, le HFD-6 wk; n = 10 / sehlopha; ha ho na phapang ea boima ba 'mele) ba bolailoe ke ho bola. Karolo ea biochemical e ile ea etsoa ho sebelisoa protocol e hlalositsoeng ho [26], le liphetoho tse nyane. Li-brains li ile tsa tlosoa ka potlako, tsa hoamisoa ke isopentane 'me tsa siloa ho cryostat (HM505E, Microm, Walldorf, Jeremane, −20 ° C) ho fihlela e fihla striatum. Bilateral 1-mm3 punches ka har'a ventral striatum (boima ba lithane tse tloaelehileng: 15.2 mg) li ile tsa homogenized bakeng sa 20 s ho 0.8 ml ice-cold TEVP (10 mM Tris base, 5 mM NaF, 1 mM Na3VO4, 1 mM EDTA, 1 mM EGTA, pH 7.4) + 320 mM sucrose buffer. 100 µl aliquot ea homogenate eohle (H) e bolokiloe. Karolo e setseng ea H e ne e le centrifuged ho 800 × g bakeng sa 10 min ho 4 ° C. Pellet (P1, nuclei le maloanlahla a maholo) e ile ea sebelisoa hape ka 0.2 ml TEVP buffer mme ea bolokoa. Supernatant (S1) e ile ea tlosoa 'me ea kenngoa ka har'a thapo e hloekileng leqhoeng. S1 e ne e le centrifuged ho 9200 × g bakeng sa 15 min ho 4 ° C ho hlahisa pellet (P2, crude synaptosomal membranes) le supernatant (S2). P2 e hapuoe hanngoe ho TEVP + 35.6 mM sucrose buffer e ntan'o ts'oaroa ka 0.25 ml ea TEVP + 35.6 mM sucrose buffer, vortexed ka bonolo bakeng sa 3 s le hypo-osmotically lysed ka ho boloka sampole leqhoa bakeng sa 30 min. Supernatant (S2) e ile ea bokelloa mme ea hasoa ho 165,000 × g bakeng sa 2 h ho hlahisa pellet (P3, leseli le khanyang, li-endosomes tsa ho hlakola) tse ileng tsa qalisoa hape ho TEVP (0.1 ml) mme ea bolokoa. Mehlala eohle e ne e bolokiloe ho −80 ° C ho fihlela polyacrylamide gel electrophoresis.

Gel Electrophoresis le Western Blotting

Likahare tsa protheine li entsoe ka ts'ebeliso ea kit ea Bio-Rad DC Protein Assay kit (Hercules, CA), mme mohopolo oa sampole ka 'ngoe o fetotsoe ho protheine ea 0.3 mg / ml NuPAGE LDS (lithium dodecyl sulphate) sesampara (Invitrogen, Carlsbad, CA) le 50 mM dithiothreitol li kentsoe sampoleng ka ngoe pele ho futhumatsa ho 70 ° C bakeng sa 10 min. Ho kenya palo e lekanang ea protheine bakeng sa sekhechana ka seng, 3 µg ea sampole ka 'ngoe e ile ea kenngoa ho NuPAGE Novex 4-12% Bis-Tris gel (Invitrogen) bakeng sa karohano ka gel electrophoresis. Liprotheine li ile tsa fetisetsoa ho polyvinylidene fluoride membrane (PVDF) (PerkinElmer Life Science, Boston, MA). Libaka tse tlamang tse sa amaneng le letho li ne li koetsoe bakeng sa hr ea 2 ka mocheso oa kamore ho thibela buffer (5% lebese le omileng la nonfat ho PBS le 0.02% Tween 20 [PBS-T]). Li-blots li ile tsa kenella ka anti-antibody ea mantlha (1∶3000 mouse monoclonal anti-NR2B [# 05-920, Millipore], 1∶5000 mmutla o khahlanong le DAT [# AB2231, Millipore], le 1∶1000 mouse monoclonal anti-transferrin receptor ( TfR) [# 13-6800, Invitrogen]. Matheba a ile a khaoloa likarolo tse 3: e phahameng (> 97 kDa), e mahareng (46-97 kDa), le litekanyo tse tlase (<46 kDa) 'me karolo ka' ngoe e hlahlojoa ka lesole la mmele le amohelang Boima ba limolek'hule tse hlahang bakeng sa lithibela-mafu tse sebelisitsoeng ke: NR2B, 180 kDa; DAT, 75, 64, le 50 kDa; TrfR, 95 kDa. ka ho hula buffer (62.5 mM Tris, 2% SDS, 100 mM β-mercaptoethanol, pH 6.8) bakeng sa 15 min ho 50 ° C. Li-blots li ile tsa boela tsa koaloa hape tsa batloa ka anti-TfR. SeeBlue Plus 2 (Invitrogen) pre- litekanyetso li ne li sebelisoa bakeng sa tekanyetso ea limolek'hule.

Li-immunoblots tsa liprotheine li ile tsa hlahlojoa li sebelisoa ke Ts'ebetso ea Maqhubu a Tsamaiso ea Lisele tsa Meroalo 5.0 Botebo ba matla (kakaretso ea lipikselse kahare ho sehlopha sa lithahasello kamora kakaretso ea lipikselse tsa ka morao) e ne e reretsoe sehlopha se seng le se seng. Ho lumella ho bapisoa lipakeng tsa blots, lintlha li ne li thathamisitsoe ho li-LFD ho 2 le 6 wks. Lintlha li hlahisoa e le mokhoa o kenyelletsoang oa foldara ha o bapisoa le LFD ± SEM.

Bohlokoa Rea Reaction Transcriptase Polymerase Chain Reaction (qRT-PCR) ea bohlokoa

Kamora ho bokelloa ha litebele tsa litoro bakeng sa tlhahlobo ea blot bophirima, likelello tsa leqhoa li ile tsa aroloa ka sebopeho sa microtome ho fihlela li fihla VTA / SN. Bilateral 1-mm3 li-punches tsa VTA le SN tis (boima ba 'mele oa tishu = 15.0 mg) li entsoe mme RNA e ntšoa ka PureLink RNA Mini Kit (Invitrogen). Boleng le boleng ba RNA bo ile ba hlahlojoa ho sebelisoa RNA 6000 Nano Chip (Agilent, Santa Clara, CA) ho Agilent Bioanalyzer 2100. Nomoro ea botšepehi ba RNA (RIN) e feta 7 bakeng sa disampole tsohle, e bonts'a boleng bo holimo. VirNA e le 'ngoe ea RNA eohle e sebelisitsoe ho kopanya cDNA e sebelisa iScript cDNA Synthesis Kit (BioRad) ho ThermoHybaid iCyste (Thermo Science). Primers itseng bakeng sa lams (Slc6a3; Pele selelekela: GGAAGCTGGTCAGCCCCTGCTT, kgutlisetsa morao selelekela: GAATTGGCGCACCTCCCCTCTG), β-actin (NBA; Pele selelekela: AGGGAAATCGTGCGTGACAT; etsolla selelekela: AAGGAAGGCTGGAAGAGAGC), le Tata lebokose tlamang protheine (Tbp; Pele selelekela: ACCTAAAGACCATTGCACTTCGTGCC; etsolla selelekela : Mefuta ea GCTCCTGTGCACACCATTTTCC) (Linomoro tsa phumano ea Genbank NM_012694, NM_031144, le NM_001004198) li entsoe ka NCBI Primer-BLAST (http://www.ncbi.nlm.nih.gov/tools/primer-blast/) mme e rekoe ho tsoa ho Integrated DNA Technologies (Coralville, Iowa). Tlhahlobo ea molora oa curve le polyacrylamide gel electrophoresis li netefalitse bohlokoa ba li-primers. Li-DAT, β-actin, le li-amplicons tsa Tbp ke 266, 182, le li-pair tsa 136 tsa bolelele ka tatellano, ka ho latellana.

Setsi sa Q-PCR (iQ SybrGreen Supermix, BioRad) se ile sa sebelisoa. Karabelo e ile ea etsoa ka MyiQ single color Real-Time PCR Detection System (BioRad) ka bophahamo ba 20 µl, 2 µL ea 3 µM ​​e ea pele le ea morao ea li-primers le 4 µL cDNA sampuli e hlapolotsoe 1∶10. Maemo a libaesekele a PCR e ne e le 95 ° C bakeng sa 5 min; Lipotoloho tsa 40 ho 94 ° C bakeng sa 15 s, 60 ° bakeng sa 15 s, 72 ° C bakeng sa 15 s. Lintlha li ile tsa bokelloa ka mocheso o baliloeng oa 84 ° C bakeng sa 15 s ho latela mocheso oa amplicon o qhibilihang. Li-curve tse tloaelehileng tsa dilution li ile tsa hlahisoa bakeng sa primer e 'ngoe le e' ngoe e behiloeng ka ho hlapolloha ka bo-ralitaba (1.00, 0.2, 0.04, le 0.008-fold) setoko sa master cDNA se nang le motsoako o lekanang oa cDNA ho tsoa lihlopheng tsohle tsa kalafo. Lefu10 ea boleng ba dilution e reriloe khahlanong le litekanyetso tsa potoloho ea likotlo bakeng sa li-curve tse tloaelehileng. MyiQ Optical System Software (BioRad) e sebelisitsoe ho hlahlobisisa lintlha. Mehlala e senang template ea cDNA le mehlala ea karabelo ea cDNA e se nang transcriptase e ile ea tsamaisoa e le taolo bakeng sa tšilafalo le ho holisoa ha genomic DNA. Lintlha tse tlalehiloeng li ne li thathamisitsoe ho maemo a tloaelehileng a litekanyetso tse ka hare ß-actin le Tbp bakeng sa sampole ka 'ngoe. Lintlha li hlahisoa e le litekanyetso tse mpe tsa DAT / litekanyetso tsa kahare mRNA ± SEM.

Lipatlisiso tsa Statistical

Polelo ea DAT e fetoha haholo nakong ea bophelo ba batho ka bobeli [27] le likhoto [28], [29]. Ntle le moo, karabelo ea dopamine le boits'oaro ho cocaine le eona e fetoha ha likhoto li sa holile [30]. Kahoo, litekanyo tsa DAT li ka fapana hammoho le lilemo le ho thibela ho bapisoa ho nang le moeli pakeng tsa 2 wk le lihlopha tsa 6 wk. Ka hona, sehlopha se bolela ho ja lijo, boima ba 'mele, khatello ea tlhoro ea dopamine, tau, phetoho ea%, le polelo ea gene e lekantsoeng ka thoko bakeng sa lihlopha tsa 2 le 6 wk tse sebelisang tlhahlobo ea tP e sa lefelloeng. Bakeng sa litlhahlobo tsa blot bophirima, phapang ea lihlopha maemong a tloaelehileng a sehlopha sa DAT li ne li bapisoa ka thoko bakeng sa lihlopha tsa 2 le 6 wk li sebelisa mekhoa e 'meli e phetoang ANOVA (dietXfraction). Litlhahlobo tsohle tsa lipalo li ile tsa etsoa ho Graph Pad 5 (Prism Inc.).

Results

HFD e khothalletsa ho eketsa tšebeliso ea mafura

Pele ho qaleho ea ho pepesetsoa ho ja ho ne ho se na phapang ho boima ba 'mele ba mantlha ho 2 wk (LFD: 275.22 +/− 4.1 g; HFD: 280.87 +/− 4.8 g; p = 0.37), kapa wk tse 6 (LFD: 287.31 +/- 4.9 g; HFD: 289.44 +/- 5.1 g; 6 wk p = 0.97) lihlopha. Leha re ja lijo tse fapaneng haholo, ha rea ​​fumana phapang pakeng tsa boima ba 'mele lipakeng tsa lihlopha tsa lijo tse latelang 2 kapa 6 wks (Feiga. 1a-b; bobeli ka bobeli). Hape ha ho na phapang ho li-kcals tse jeoang lipakeng tsa lihlopha tse latelang 2 le li-6 wks tsa tlhahiso ea lijo (Feiga. 1c-d; ns). Leha ho le joalo, likhoto tsa HFD li jele kcals haholo ho tsoa mafura (Feiga. 1e-f; 2 wks: t (32) = 25.59; 6 wks: t (31) = 27.54; p<0.0001 bakeng sa nako tse peli tsa lijo).

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Setšoantšo sa 1. Karolelano ea lijo le litekanyo tsa boima ba 'mele.

Ho ne ho se na phapang lipakeng tsa HFD le LFD ka boima ba 'mele ba ho qetela (a-b) kapa li-kilocalories tse felletsengc-d) kamora libeke tsa 2 kapa 6 tsa ho pepesetsoa lijo. (e f) Likhoto tsa HFD li jele lik'hilojule tse ngata haholo ho feta mafura ho feta likhoto tsa LFD maemong a beke a 2 le maemong a beke a 6 (***p

http://dx.doi.org/10.1371/journal.pone.0058251.g001

HFD ea nako e telele e fokotsa Rate ea DA Reuptake

Lirekoto tsa voltammetric li entsoe ka har'a ventral striatum (Setšoantšo sa 2). Setšoantšo sa 3 e bonts'a moemeli a fetotseng liphetoho tsa motlakase ka tlhahisong ea dopamine e fumanoeng litatsong tse latelang 6 wks ea lijo. Ha e le hantle, boholo ba dopamine e soetsoeng bo ne bo sa fapana lipakeng tsa lihlopha tsa lijo le nakong ea lijo.Feiga. 4a-b, ns ka bobeli). Leha ho le joalo, tlhahlobo ea mehlala ka bomong e bonts'itse tekanyo ea ho bola ho latela tlhaselo ea dopamine e pharalletseng lipakeng tsa lihlopha tsa lijo ka mor'a ho hlahella ha 6 wksSetšoantšo sa 3 a-b ka mehlala). Sekhahla sa ho bola se bakoa haholo ke ho fufuleloa ha dopamine ke DAT [31], eo re e fetotseng e le mohopolo o le mong feela oa ho khetholla tau. Ho ne ho se na phapang lipakeng tsa lihlopha tsa lijo tse latelang 2 wks of exposure ea lijo (Feiga. 4c). Leha ho le joalo, kamora ho pepeseha ha 6 wks, tau e ne e le kholo haholo ho HFD-6 wk rats amanang le LFD-6 wk (Feiga. 4d; t (11) = 2.668; p<0.05). Kahoo, li-wks tsa 6 tsa HFD li fokotsa sekhahla sa tumello ea dopamine ho ventral striatum ha e bapisoa le liphoofolo tse jang LFD.

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Setšoantšo sa 2. Netefatso ea nalane ea libaka tsa ho rekota bakeng sa tlhahlobo e ncha.

Lirosa tsa rekoto bakeng sa likhoto tse fepeloang ke LFD li entsoe ka likonopo tse bohlooho le bakeng sa likhoto tsa HFD ke mekoloko e metšo. Lipalo li bonts'a sebaka se kahare ho mm ka kantle ho Bregma. Setšoantšo se fetotsoeng ho tloha Paxinos le Watson 2006.

http://dx.doi.org/10.1371/journal.pone.0058251.g002

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Setšoantšo sa 3. Matla a motlakase a VTA / SNc a tsosa spike ea phasic mahlorisong ea dopamine.

Mehlala ea baemeli ba data e fumanoeng kamora libeke tsa 6 tsa ho pepesetsoa lijo. a) Morero oa 'mala o khutliselitsoeng ka morao o bonts'a liphetoho tsa hona joale ka mefuta e fapaneng ea li-electrode pele (−5 ho 0 s e amanang le ho qala) le kamora (0.1 ho 10 s amanang le ho qala) tsusumetso ea motlakase (STIM) ea VTA / SNc. Nako ke bosesane, menyetla ea electrode ke eona e fetotsoeng, 'me liphetoho tsa hona joale li entsoe ka' mala oa leshano. Dopamine [e khethollotsoe ke oxidation ea eona (+ 0.6 V; botala) le phokotso (likarolo tsa −0.2 V; bolou) li eketseha ka nako le nako ha li arabela ts'usumetso ho sena LFD-6 wk rat. b) Hoa tšoana le ho a), ntle le ho tsoa ho HFD-6 wk rat. c) Dopamine mahloriso e le ts'ebetso ea nako e nts'oa moralo oa mebala ho) mme tau e khetholloa ka mokokotlo oa curve. Matheba a mabeli a bofubelu a tšoaea tlhako ea tlhalo le dopamine ka nako eo tau e fihletsoeng. Tau e bontšoa ka ho le letona. d) Hoa tšoana le ho c) empa data e ntšoa ho b).

http://dx.doi.org/10.1371/journal.pone.0058251.g003

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Setšoantšo sa 4. Libeke tse tšeletseng tsa lijo tse nang le mafura a mangata li fokotsa litekanyetso tsa dopamine hape li fihlela karabelo ea dopamine ho koae.

Karolelano ea tlhoro ea dopamine e hlahisoang ke VTA / SNpc e latela 2 (a) kapa libeke tsa 6 (b) ea ho pepesehela lijo pele ho entoa ea koae. c-dKarolelano ea Tau e latelang 2 (cWks kapa 6 wks (d) ho pepesetsoa lijo. Tau e ne e le kholo haholo ho HFD-6 wk rats amanang le LFD-6 wk rats (*p e f) Phetoho ea liperesente tse phahameng ea tlhoro ea dopamine ka mor'a hore ente ea cocaine ea 2 (e) le 6 (f) libeke tsa ho pepesetsoa lijo. Phetoho ea liperesente e ne e le nyane haholo ho HFD-6 wk e amanang le likhoto tsa LFD-6 wk (**p

http://dx.doi.org/10.1371/journal.pone.0058251.g004

HFD ea nako e telele e fokotsa karabelo ea DA ho Cocaine

Ho ntšetsa pele lipatlisiso tsa liphetoho tse susumetsoang ke ho ja ka selemo sa DAT, re kentse likhoto ka cocaine ea DAT blocker. Peak dopamine mahloriso kamora ho hlohlelletsa motlakase ho bakoa ke ho lokolloa ha dopamine empa e boetse e fokotsoe ke ho tlosoa ka nako e le 'ngoe ea dopamine ke DAT [21]. Re tšoaea phello ea koae ka ho fetisoa ha dopamine ka ho bala phetoho ea boholo ba evopamine e amanang le dopamine ho litekanyetso tsa pele ho lithethefatsi (phetoho ea%). Li-wks tse peli tsa HFD ha lia ka tsa ama phetoho% e amanang le LFD (Feiga. 4e; ns). Leha ho le joalo, kamora ho bonts'a lijo tsa 6, phetoho ea% e ile ea putlama haholo ho HFD e amanang le LFD (Feiga. 4f; t (10) = 4.014; p<0.01). Liphetho tsa rona li fana ka maikutlo a hore 6, empa eseng 2 wks, ea HFD exposure e fokotsa karabelo ea dopamine ho cocaine.

Phatlalatso ea HFD ea nako e telele e fokotsa Tlhahiso ea Liprotheine ea Synaptosomal Membranes

Ho fumana hore na litlamorao tsa HFD ea nako e telele li ne li bakoa ke liphetoho tsa palo ea DAT, tekanyetso ea protheine ea DAT e ile ea hlakoloa ka botlalo ho tishu homogenates (H karolo), likarolo tsa synaptosomal (karolo ea P2) le li-endosomes tsa intracellular recycling endosomes (karolo ea P3). DAT ke an N-Linked glycoprotein e nang le boima ba molek'hule bo pakeng tsa 50 le 80 kDa ka lebaka la maemo a ntseng a eketseha a glycosylation ha protein e ntse e hola [32]. Fractionation e tiisitsoe ke polelo e ntlafalitsoeng ea NR2B subunit ea NMDA receptor ka karoloana ea membaptane ea membrane ea synaptosomal le receptor ka karolo ea endosomal (ka mohlala blot bona Feiga. 5b). Ha rea ​​fumana phapang liprotheine tse felletseng tsa DAT kamora 2 le 6 wks ea tlhahiso ea lijo (data e sa bonts'itsoeng). Ho hlahloba liphapang tse ikhethang tsa protheine ea DAT, re sebelisitse mehato e 'meli e pheta-phetoang ANOVA (dietXfraction). Tumellanong le liteko tsa voltammetry, 2 wks of exposition ea lijo e ne e sa lekana ho fetola maemo a efe kapa efe ea li-isoforms tsa DAT ho likarolo tsa P2 kapa P3 (Feie. 5. c, e, g; tsohle ns). Leha ho le joalo, kamora ho 6 li-wks tsa tlhahiso ea lijo, ho bile le ts'ebelisano ea bohlokoa ea phepelo ea lijo (F(1,18) = 8.361, p<0.01); Feiga. 5d) bakeng sa 50 kD isoform ea DAT. Ka hona, HFD ea nako e telele e fokolitse haholo tekanyetso ea 50 kD ea halofo ea P2 mme ea baka mokhoa o lebisang keketseho ea karolo ea P3. Ha rea ​​fumana phello ea lijo kapa karoloana ho 64 kD (Feiga. 5f; ns) kapa 70 kD (Feiga. 5h; ns) DAT isoforms.

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Setšoantšo sa 5. Ts'ebeliso ea lijo tse nang le mafura a mangata e fokotseha "protheine" e amanang le DAT ho "ventral striatum".

a) Setšoantšo sa moemeli se bonts'ang (2) 1 × 1 mm lithaelese tse nkiloeng ho tsoa ho ventral striatum tse kopaneng bakeng sa tlhahlobo ea protheine ea DAT. VStr = Ventral Striatum; DStr = Dorsal Striatum; cc = Corpus callosum; ac = selallo sa ka ntle. b) Moemeli ea ka bophirimela melaetsa e hlahisitsoeng ka c-h. L = LFD; H = HFD; TfR = phetisetso ea phetisetso; NR2B = NR2B subunit ea NMDA receptor. c) Ho ne ho se na phapang liprotheine tsa 50 kD DAT bakeng sa likotlo tsa P2 kapa P3 kamora libeke tsa 2 tsa ho pepesetsoa lijo. d) Protheine ea 50 kD DAT e fokotsehile haholo ho P2 (* = p<.05), empa eseng karoloana ea P3 ea lisele tsa 'mele tse tsoang pele ho HFD-6 wk mabapi le likhoto tsa LFD-6 wk. Ho ne ho se na liphapang liprotheineng tsa 64 kD DAT tse latelang tse 2 (e) kapa libeke tsa 6 (f) ho pepesetsoa lijo. Ha ho na liphapang liprotheine tsa 70 kD DAT tse latelang 2 (g) kapa libeke tsa 6 (h) ho pepesetsoa lijo.

http://dx.doi.org/10.1371/journal.pone.0058251.g005

Ho fumana hore na maemo a theohileng a protheine ea DAT karolong ea P2 e ne e bakiloe, ka karolo e 'ngoe, phokotsong ea sengoloa sa DAT, litekanyetso tsa VTA / SNc DAT mRNA li lekantsoe ka likhoto tse tšoanang le tse kaholimo (Setšoantšo sa 6a ka mohlala). Ha rea ​​bona liphapang lipakeng tsa lihlopha tsa lijo ho midbrain DAT mRNA kamora hore 2 kapa 6 wks exposalFeiga. 6b-c; bobeli ka bobeli). Kahoo, phapang ea litekanyetso tsa liprotheine tsa DAT kahare ho striatum ea ventral ha e na monyetla oa ho ba teng ka lebaka la khaello ea tlhahiso ea DAT.

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Setšoantšo sa 6. Ts'ebeliso e phahameng ea mafura ha e fetole maemo a DAT mRNA. a)

Setšoantšo sa moemeli se bonts'a li-punches tsa 1 × 1 mm mm tse nkiloeng ho VTA / SN mme li kopantsoe tlhahlobo ea DAT mRNA. cp = penduncle ea motsoako; pc = kamohelo ea ka morao; Mm = mammaryary nucleus ea methapo. Ho ne ho se na liphapang maemong a amanang le mRNA a DAT a latelang ka mor'a libeke tsa 2 (b) kapa libeke tsa 6 tsa ho pepesetsoa lijo (c).

http://dx.doi.org/10.1371/journal.pone.0058251.g006

Puisano

Ho sebelisa HFD nako e telele ho ka lebisa ho DIO le polasetiki kahare ho tsamaiso ea methapo e kholo. Dopamine neurons le striatal dopamine receptors ho bonahala e le karolo e le 'ngoe ea lipheo tsa CNS tse anngoeng ke HFD le bathong ba batenya haholo. [11], [13], [33]. Mona re tlaleha hore HFD e fokotsitse sekhahla sa ho khutlisa dopamine ka har'a ventral striatum mme phello ena e ne e ipapisitse le nako ea ho pepesetsoa. Habohlokoa le ho feta, litlamorao tsa HFD ts'ebetsong ea DAT li etsahetse ho ba sieo ha DIO. Leha re sa ka ra lekanya matšoao a ho tsebahala ha 'mele phuputsong ena, liphoofolo li nkuoe ka tloaelo e le DIO kapa tse thibelang ho ja lijo tse thehiloeng ho boima ba' mele kamora ho pepesetsoa HFD [34]. HFD ea nako e telele e bonts'itse bokhoni ba koae, e kenang le DAT, ho hlahisa boholo ba tokollo ea dopamine. Re hlalositse maemo a liprotheine tsa DAT maemong a potral striatum re sebelisa tlhahlobo ea Bophirimela - ho khetholla lipakeng tsa DAT tse fumanehang kahara likarolo tse katlasetso tse ntlafalitsoeng tsa membrane ea plasma kapa li-recoscling endosomes. Re fumane phokotso ea bohlokoa ho isoform ea bongoana ea DAT e amanang le membrane ea plasma. Kahoo, HFD ea nako e telele e bonahala e fokotsa sekhahla sa dopamine reuptake ka mokhoa oa DAT ka ho kena-kenana le ho ts'oaroa ha DAT kapa mohlomong ho feto-fetoha ha mmele empa eseng ka ho fokotsa polelo ea mofuta oa DAT kapa botsitso ba DAT mRNA. Ho feta moo, nako e pakeng tsa libeke tse peli ho isa ho tse tšeletseng tsa ho pepesetsoa HFD e bonahala e le eona ntlha ea pele ea ho khothaletsa polasetiki e kentsoeng phepong mabapi le DAT.

Ho nona ho kopantsoe le likarolo tse ngata tsa ho saena matšoao a dopamine, ho kenyeletsa le ho fumaneha ha DAT ho batho ka bobeli [18] le litoeba [19]. Leha ho le joalo, haufinyane tjena ho bontšitsoe feela hore nts'etsopele ea DIO e fetola sekhahla sa dopamine reuptake ho litoeba [20]. Le ha thuto ena e bonts'itse ho senyeha ha dopamine ho latela ts'ebetso ea dopamine ka botlalo kamora libeke tsa 4 feela tsa HFD, liphoofolo tse neng li bolokiloe ho HFD li ile tsa khethoa ho ipapisitse le boima ba pele mme ka hona li ka emela bongata bo ikhethang. Ho latela pono ena, liphoofolo tsa HFD li ile tsa tsoela pele ho ja lik'hilojule tse ngata le ho fumana boima bo eketsehileng ha bo bapisoa le taolo ea LFD. Phuputso e 'ngoe ea morao-rao e tlalehile ho ts'oaroa ha dopamine ho khutlisa kamora libeke tsa 12 tsa HFD likotong tse tsoang kantle [35]. Leha ho le joalo, ho bile le phapano ea bohlokoa bo boima ba 'mele lipakeng tsa liphoofolo tse fepang HFD le lijo tse tloaelehileng ha li etsoa. Ka hona, ho ne ho lula ho sa hlake hore na liphokotso ho dopamine reuptake li hlaha e le sephetho se tobileng sa, kapa ho etella pele nts'etsopele ea DIO. Ho fapana le litlaleho tsena tsa morao-rao, ha rea ​​fumana karohano ea boima ba 'mele kapa tšebeliso ea kcal e felletseng lipakeng tsa lihlopha tsa rona tsa lijo ha ho etsoa litekanyo tse ncha. Hore re fumane liphapang tsa ho pheta-pheta ha dopamine kamora 6, empa eseng 2, libeke tsa HFD e fana ka maikutlo a hore liphetoho tse tlisoang ke phepo ho dopamine reuptake ke karabelo mehatong e sa foleng, empa eseng e mpe haholo. Ntle le moo, liphetho tsa rona li fana ka maikutlo a hore sebakeng sa ho ba sesosa sa botenya, liphetoho tse khothalletsoang ke ho ja li ka hlahisa karolo ho holiseng lefu lena. Boithuto ba nako e tlang bo tla hloka ho sebetsana le hore na liphoofotsoana tsa liphoofolo li na le monyetla oa ho khetholoha DIO kapa che [34] ho ba le phapang e atamelaneng ho polelo ea / ho sebetsa kapa e ka qhekelloa ka mokhoa o fapaneng le liphetoho tse tlisoang ke ho ja.

Ho tsebo ea rona, ena ke thuto ea pele e bonts'ang hore HFD e fokotsa karabelo ea dopamine ho koae. Ka lebaka la karolo ea dopamine moputsong oa lithethefatsi, liphetho tsa rona li lumellana le mosebetsi o fetileng o bonts'a hore likhoto tse fepelitsoeng HFD bakeng sa libeke tse ka bang 6 li lieha ho fumana taolo ea koae ho feta liphoofolo tse fuoeng lijo tse laoloang [36]. Habohlokoa, phello ena e ne e boetse e sa ikemetse ho nts'etsopele ea DIO. Ntle le moo, likhoto li reretsoe hore li be monyetleng oa ho bonts'a sebaka sa cocaine se fokotsehileng, se fana ka maikutlo a hore thepa ea moputso ea koae e koetsoe liphoofolo tsena. [37]. Karabelo e fokotsehileng ea cocaine eo re e boneng ho HFD-6 wk rats e kanna ea ba teng ka lebaka la phokotso ea striatal DAT. Le ha ho le joalo, cocaine e boetse e eketsa matšoao a dopamine ka ho sebelisa mekhoa e sa its'epaheng ea DAT. Ka ho khetheha, HFD e kanna ea sitisa cocaine e khothalletsang ts'usumetso ea ho boloka li-dicamine vesicles [38]. Cocaine e boetse e beha phetiso ea GABA ho li-dopamine neurons ka har'a VTA [39] le ho tsosa oscillations tekong ea ho thunya ea 'mele ea dopamine cell [40]. Ts'ebetso efe kapa efe kapa e meng kaofela e kanna ea angoa ke HFD. Patlisiso ea nako e tlang e tla hloka ho rarolla mekhoa e hlalosang kamoo HFD e fetolang likarolo tse khotsofatsang tsa koae le / kapa monyetla oa ho tloaela mekhoa ea tlhaho e amanang le lithethefatsi [18]. Tšebeliso ea HFD e bonts'a bobeli boits'oaro [41] le karabelo ea dopamine [20], [42] ho amphetamine, e boetse e kena-kenana le DAT. Habohlokoa, likhoto tseo ho ja ha HFD li neng li kopantsoe haholo le likhoto tse feptjoang taolo ea taolo ha li hlahise DIO empa li ntse li hloleha ho etsa khetho ea sebaka sa amphetamine [41]. Hammoho le data e hlahisitsoeng mona, ho bonahala eka tšebeliso ea HFD e hlakisa karabelo ho li-psychostimulants. Lithethefatsi tsohle tsa tlhekefetso li susumetsa sisteme ea dopamine, 'me ho eketsoa hoa lithethefatsi ka tšebeliso ea dopamine ho nahanoa hore ho bohlokoa bakeng sa nts'etsopele ea bokhoba ba tahi. [43]. Ka hona, karabelo e fokotsehileng ea koae ka likhotsong tsa HFD e lumellana le litlaleho tsa hore batho ba batenya ba na le menyetla ea bophelo e tlase haholo ea ho ba le bothata ba tlhekefetso ea lithethefatsi. [44]. Mosebetsi oa nako e tlang o tla hloka ho sebetsana le hore na litekanyetso tsa moputso oa koae li fapana hakae ho batho ba batenya ha ba bapisoa le taolo e tloaelehileng ea boima.

Tlhahlobo ea rona ea bophirima ea bophirima e fana ka maikutlo a hore tšebeliso ea nako e telele ea HFD ha e ame protheine e felletseng ea DAT, empa ho e-na le hoo e fokotsa ho hokahanngoa ha li-iscorm tsa non-glycosylated 50 kDa DAT ka li-membrane tsa synaptosomal. Le ha glycosylation ea DAT e ntlafatsa sekhahla sa lipalangoang tsa dopamine mme e eketsa botsitso ba sebopeho sa membrane [45], [46], [47], DAT e senang glycosylated e tsoang ho batho [45], [46] hammoho le likhoto [47] o tsamaisa dopamine habonolo. Ntle le moo, liteko tsa immunolabeling li senola hore litekanyetso tsa li-non-glycosylated tsa DAT li phahame kahare ho bapisoa le dorsal striatum ka bobeli litšoene le batho [47]. Ha li kopantsoe hammoho, liphuputso tsena li fana ka maikutlo a hore lipalo tsa "membrane tse fokotsang" tsa 50 kDa DAT li ka kenya letsoho ho khutliseng bofokoli boo re bo boneng ho 6 wk HFD rats. Lintlha tsa rona li lumellana le phuputso e fetileng e bonts'ang tšebeliso ea HFD e fokotsa ho fumaneha ha DAT ho litoeba tse tsoang hare tsa litoeba [19]. Leha ho le joalo, thuto ena ha ea ka ea lekanya ho ba teng ha tikoloho ea DAT ka likarolo tse fapaneng tsa intracellular. Ho feta moo, seo re se fumaneng se lumellana le phuputso e bonts'ang liphokotso molemong oa lisele tsa DAT maemong a litoeba tsa DIO [20]. Phuputso ena e boetse e tlaleha hore maemo ohle a liprotheine tsa DAT a ne a sa angoe ke lijo ka mofuta oa DIO. Re holisa tšebetso ea rona ho bonts'a hore protheine e felletseng ea DAT ha e amoheloe ke HFD ho likhakanyo tse kantle. Ka hona, tšebeliso ea nako e telele ea HFD ha e fetole polelo ea DAT, empa e ka kena-kenana le ho ts'oaroa ha DAT kapa ho fetoha ha mmele.

Ho haella ha liphapang maemong a VTA / SNpc DAT mRNA kamora hore 2 kapa 6 wks ea tlhahiso ea HFD e tšehetse maikutlo a hore litekanyetso tsa DAT ka kakaretso li ne li sa angoe ke mananeo a rona a ho ja. Sephetho sena se fapana le tlaleho ea pejana e bonts'ang MRNA ea DAT e fokolitsoeng ho panya ea VTA kamora libeke tsa 17 tsa tšebeliso ea HFD [12]. Leha ho le joalo, thutong ena litekanyetso tsa DAT mRNA li ile tsa lekanngoa kamora hore lihlopha tsa lijo li fapane ka boima ba 'mele bakeng sa libeke tsa 12. Kahoo, litholoana tsa bona li kanna tsa emela tloaelo ea morao-rao molemong oa DIO. Ka kakaretso, datha ea rona e fana ka bopaki bo matla ba hore ho pepesetsoa HFD ho lebisa ho liphetoho tse sebetsang mesebetsing ea dopamine dopamine reuptake ka ho fokotsa matsatsi a amanang le li-membrane ntle le ho fetola polelo ea kakaretso ea DAT. Habohlokoa le ho feta, re tlaleha hore litšitiso tse bakiloeng ke ho ja lijong tsa DAT li ka etsahala pele ho ho qaleha ha DIO, re fana ka maikutlo a hore liphetoho tsena li ka kenya letsoho kholisong ea botena.

Lintlha tsa rona li kenyelletsa lingoliloeng tse ntseng li eketseha tse amanang le phepo ea taolo ea dopamine, 'me li fana ka bopaki bo bong ba hore lijo li hlahisoa ke polelo ea DAT li tlisa liphetoho tse hlokahalang ho dopamine ho supa. Liphetoho tse bakoang ke ho ja lijo ka har'a matla a dopamine e bonts'ang ka nako ea DAT li kanna tsa ba le litlamorao bakeng sa boitšoaro ba ho fepa. Liphetoho tse amanang le lijo li etsa hore keketseho ea phasic e eketsehe ka har'a dopamine [9], [48], [49], tse ka eketsang le ho matlafatsa liketso tse tataisoang ke lijo [50]. Mona re bontša hore libeke tsa 6 tsa tšebeliso ea HFD li eketsa nako ea tokollo ea phasic dopamine ka ho fokotseha ha li-membrane tse amanang le li-DAT sebakeng sa striatum moo ts'ebetso ea dopamine e bohlokoa bakeng sa ts'ebeliso ea lijo. [51]. Liphetoho tse itšetlehileng ka mokhoa oa ho ja lijong tsa DAT li ka khothaletsa mokhoa oa ho iphepa oo ka nako e telele matšoao a dopamine a ts'oaroang ke ts'usumetso ea lijo e eketsang ts'ebetso ea li-receptor tse tlase tsa striatal dopamine D1, tse bohlokoa bakeng sa boits'oaro ba mekhoa [52], [53], [54]. Kamora nako, ho phahama ha nako e telele ho dopamine ho ka phahamisa liphetoho, joalo ka ho fokotsoa ha dopamine D2 receptors (D2R), e bonts'itsoeng mefuteng ea batho ba botona le botšehali. [11], [33]. Boithuto ba rona bo fana ka maikutlo a hore nts'etsopele ea botona ha se lebaka la ho fetola ho khutlisa dopamine. Kahoo, ho fokotseha ho amanang le ho ja ho fokotseha ka membrane DAT ho ka tlisa pele le ho kenya letsoho ho qaleheng ha D2R downregulation, botenya, le boits'oaro bo phehellang ba ho ja bo ntseng bo tsoela pele nakong ea ts'ebeliso ea HFD [11].

lumela hore baa fokola

Re lakatsa ho leboha Drs. Jamie D. Roitman le James E. McCutcheon bakeng sa litlhaloso tse thusang lithutong tsa pejana tsa buka e ngotsoeng ka letsoho. Litaba tsa pampiri ena ke boikarabello ba bangoli feela ha se hore li emela maikutlo a semmuso a NIH kapa Chicago Biomedical Consortium.

Menehelo ea Mongoli

Rea tseba le ho hlophisa liteko: JJC EHC MFR. O entse liteko: JJC DNP SRE. Ho hlahlobisisa lintlha: JJC EHC SRE MFR. Ngola pampiri: JJC EHC MFR.

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