Ho fokotsa ho se sebetse ha dopamine tsamaiso ea lijo tse phahameng haholo (2013)

. Sengoloa se ngotsoeng; e fumaneha ho PMC 2014 Jun 1.

E hatisitsoe ka mokhoa o qetelle o hlophisitsoeng e le:

Botenya: 2013 Dec; 21 (12): 2513-2521.

E hatisitsoe Inthaneteng 2013 May 29. doi:  10.1002 / oby.20374

PMCID: PMC3700634

NIHMSID: NIHMS435903

inahaneloang

sepheo

Ho lekola hore na lijo tse nang le mafura a mangata (HFD) li fokotseha na molumo oa dopaminergic libakeng tsa boko le ho lekola hore na liphetoho tse joalo lia khutla kamora ho tlosoa ha HFD.

Moralo le Mekhoa

Limpisi tsa banna le tsa basali li fepelitsoe 60% HFD bakeng sa libeke tsa 12. Sehlopha se eketsehileng se ile sa hlahlojoa libeke tsa 4 kamora ho tlosoa ha HFD. Lihlopha tsena li ne li bapisoa le taolo e fepetsoeng, e tsamaeang le lilemo. Likhetho tsa Sucrose le saccharin li ile tsa lekanngoa hammoho le polelo ea mRNA ea liphatsa tsa lefutso tse amanang le dopamine ke RT-qPCR. Dopamine le DOPAC li ne li lekantsoe li sebelisa chloratography e phahameng e sebetsang. DNA methylation ea promoter ea DAT e lekantsoe ke methylated DNA immmunoprecipitation le RT-qPCR.

Results

Kamora HFD e sa foleng, khetho ea sucrose e ile ea fokotseha, 'me ea beoa maemong a tloaelehileng ka mor'a ho tlosoa ha HFD. Polelo e theohileng ea liphatsa tsa lefutso tsa dopamine, litaba tse fokotsehileng tsa dopamine le liphetoho lipakeng tsa methapo ea li-DAT li ile tsa bonoa. Habohlokoa le ho feta, karabelo ho HFD le ho phehella ha liphetoho ho ipapisitse le tikoloho ea thobalano le bokong.

Nahanisisa

Lintlha tsena li khetholla molumo oa "dopamine" oa morao-rao ka nako ea HFD ea bongoaneng. Liphetoho tsa CNS tse sa kang tsa khutla ka mor'a ho tlohela HFD li ka kenya letsoho ho thatafatseng ho boloka boima ba 'mele ka mor'a ho kenella phepelong ea lijo.

Keywords: Dopamine, Lijo tse nang le mafura a mangata, DAT, phapang ea botona le botšehali, botenya, ho khaotsa, methapo ea methapo ea kutlo

Selelekela

Ho nona ho feta tekano ea lijo tse fumanehang habonolo, tse nang le mafura a mangata haholo ho nkoa e le sesosa se ka sehloohong se bakang litheko tse phahameng tsa botena ba Amerika (). Hobane lijo tse natefeloang hangata li jeoa kamora litlhoko tsa matla, litšebeletso tse khothatsang tsa lijo tse matlafatso li ka fetisa matšoao a satiety a homeostatic. Li-neurotransmitters tse ngata li bapala karolo ea boitšoaro ba ho fepa (mohlala, li-opioid, dopamine, GABA, serotonin) hammoho le ho kopanngoa ha lipontšo tsa phepo ea phepo (mohlala, leptin, insulin, ghrelin). Dopamine signaling ke mokena-lipakeng oa bohlokoa ho moputso oa lijo le boits'oaro ba ho batla moputso, kaha dopamine sebakeng sa mesolimbic / mesocortical e amahanngoa le thepa ea moputso ea lijo, thobalano le lithethefatsi tsa lithethefatsi (). Ha e le hantle, lijo tse fumanehang hantle li baka tšibollo ea dopamine tsamaisong e kholo ea moputso (,). Ka tšebeliso e sa feleng ea lijo tse nang le moputso, ho eketseha ha dopamine ka nako ho ka lebisa ho liphetoho tse amanang le moputso oa hypo-function.

Ho na le lintlha tse 'maloa tse tšehetsang tšebetso ea dopamine e fetotseng botenya. Liphuputso tsa batho tsa ho nahana ka batho li senotse ts'ebetso e atlehileng libakeng tsa moputso oa bakuli ba batenya haholo ha ba ntse ba e-noa tharollo e bonolo haholo (milkshake) (). Karabelo ea moputso o phoso e ne e amahanngoa le phihlello e fokolang ea dopamine receptor D2. Ebile, liphetoho tse hlahisang motho dopamine D2 receptor li hokahane le botena le bokhoba ba tahi (). Likahare tsa dopamine ka har'a synapse li laoloa haholo ke phetoho ea dopamine transporter (DAT). Maemo a transporter a Dopamine a kopantsoe hampe le index ea boima ba 'mele le mefuta ea liphatsa tsa lefutso ea DAT le tsona li amana le botenya (,). Mefuta ea liphoofolo ea botenya e bontsitse ho fokotseha ha basal extracellular dopamine le ho fokotsa dopamine neurotransuction sebakeng sa nucleus accumbens le ventral tegmental sebakeng (,,). Phokotso ea liphatsa tsa lefutso tse amanang le dopamine kamora ho ja haholo mafura a mangata (HF) e fokotsehile ho supa ho saena hoa lipalo libakeng tsa moputso (, ,,). Ho fokotseha hona ha tšebetso ea dopamine ka mor'a ho ja lijo tse nang le mafura a mangata ho ka fokotsa maikutlo a meputso ea tlhaho le ho nolofalletsa ho tsitsa ho feteletseng le ho eketsa boima ba 'mele.

Bophelo ba bongoaneng ke nako e mahlonoko ho nts'etsopele ea boko, 'me tikoloho ea phepo e nepahetseng e ka susumetsa litsela tsa boko tse laolang ho ja lijo le metabolism ea matla. Ho pepesetsoa litoeba ho ja lijo tse phahameng tsa mafura bakeng sa beke e le 'ngoe ho fetotsoeng lijo tsa caloric tsa batho ba baholo le polelo ea limolek'hule tse amanang le dopamine (). Ho feta moo, phepelo ea morao-rao ea phepo ea phepo ho litoeba, e tsamaisoang ke palo e nyane ea litšila hohle, e rera esale pele hore ngoana e tla ba motho e moholo oa ho ba botenya ka ho fetola kholo ea hypothalamic (). Le ha ho hlakile hore phepo e ntle ea bophelo ba pele e ka ama nts'etsopele ea kelello le kotsi ea botenya, ha ho tsejoe ka ho sa feleng ha liphetoho tsena ho latela bophelo bohle. Ho feta moo, lithuto tsa pejana li entsoe liphoofolong tse tona empa tse tšehali ha li sa ithutoa molemong ona. Ka mabaka ana, litoeba tsa banna le tsa basali li ile tsa ithutoa bakeng sa liphetoho liphatlalatsong tsa lefutso le metabolism ea dopamine ka mor'a hore ba nkoe ba le batenya bophelong ba pele ba nako ka tšebeliso e sa feleng ea lijo tsa HF ho tloha ka nako ea libeke tsa 8. Sisteme ea dopamine e ile ea boela ea hlahlojoa libeke tsa 4 kamora ho tlosoa ha phepo ea HF, ho hlahloba hore na liphetoho li ile tsa phehella kapa tsa khutla.

Mekhoa le Mekhoa ea Ts'ebetso

Liphoofolo le mohlala oa liteko

Li-C57BL / 6J tse tšehali li ne li fuoe le banna ba DBA / 2J (The Jackson Laboratory, Bar Harbor, ME). Matamo ohle a ne a filoe li-control control tse tloaelehileng (#5755; 18.5% protein, 12% mafura, 69.5% carbohydrate) ho fihlela parturition ha halofo ea matamo / litter e beoa lijong tse phahameng tsa mafura (Test Diet, Richmond, IN #58G9; 18% protein, 60% mafura, le 20.5% carbohydrate). Bana ba seotsoa ba ile ba khoesoa nakong ea libeke tsa 3 'me ba lula ba le lijong tsa taolo kapa lijong tse phahameng tsa mafura ho fihlela libeke tsa 12 li le lilemo. Boima ba 'mele bo ne bo tlalehiloe beke le beke,' me ho ne ho sebelisoa litoeba tse tona (n = 5-10) le tsa basali (n = 5-10). Komiti ea Tlhokomelo ea Liphoofolo le Ts'ebeliso (Institutional Animal Care and Use Use Committee (IACUC)) ea Univesithi ea Pennsylvania e amohetse mekhoa eohle.

Khetho ea Sucrose le Saccharin

Litekong tse fapaneng, litoeba li ne li bolokiloe ka bomong (n = 8-10 / group) ka har'a mekotla e tloaelehileng ea matsatsi a 3 ka botlolo e le 'ngoe ea 200 ml ea tharollo ea liteko (4% sucrose kapa 1% saccharin tharollo (w / v) le e' ngoe botlolo e nang le 200 ml ea metsi a pompo. House chow e ne e fumaneha ad libitum. Sucrose (ml), metsi (ml), le tšebeliso ea lijo (g), li ile tsa lekanngoa mme ho beoa ha libotlolo ho ne ho khutlisoa letsatsi le letsatsi. Khetho e ile ea baloa ho sebelisoa kakaretso ea litekanyetso ho tloha matsatsing a 2 a hoqetela ka tsela e latelang: preference% = [(tšebeliso ea sucrose / sucrose + tšebeliso ea metsi) × 100].

DNA ea genomic le karohano e felletseng ea RNA ho tloha bokong

Liphoofolo (n = 5 / sehlopha) li ne li khothallelitsoe ka khase e ngata ea khabone, e lateloe ke ho phatloha ka sefuba; mokhoa o khothalelitsoeng ke Panel on Euthanasia of American Veterinary Medical Association. Li-brains li ile tsa tlosoa kapele mme tsa beoa RNAlater (Ambion, Austin, TX) bakeng sa lihora tsa 4-6 pele ho ho arohana. Li-dissections tsa brain ho khetholla cortex ea pele, li-bokellase tsa nucleus le sebaka sa likarolo tsa pente li ile tsa hlophisoa esale pele joalokaha ho hlalositsoe pele (,, ). DNA ea genomic le RNA ka kakaretso e ile ea aroloa ka nako e le 'ngoe ba sebelisa AllPrep DNA / RNA Mini Kit (Qiagen).

Tlhahlobo ea polelo ea Gene ka ho lekanya PC-Nako ea 'nete

Bakeng sa sampole e 'ngoe le e' ngoe, 500ng ea RNA e felletseng e sebelisitsoe ho hatisa sengoloa ka ho sebelisa High Capacity Reverse Transcript Kit (ABI, Foster City, CA). Pontšo ea mefuta ea sepheo e ne e khethiloe ke lipalo tsa RT-PCR tse ngata tse sebelisang mofuta o ikhethang oa Taqman o nang le polelo ea Taqman gene Master Mix (ABI) ho ABI7900HT Real-Nako PCR Cyste. Litekanyetso tsa boloi li thathamisitsoe ho lisebelisoa tse tlatsetsang. Palo e lekanang ea sengolo se seng le se seng e ne e beoa ho sebelisoa boleng ba "delta" ba "" joalokaha ho hlalositsoe ho (). Liphetoho puong ea gene li ile tsa balelloa khahlano le maemo a sa fetoheng a GAPDH.

Ex vivo Dopamine le Dopamine Metabolites

High performance liquid chromatography (HPLC) e ne e sebelisetsoa ho lekanya litaba tsa dopamine le metabolites ea eona libakeng tsa moputso oa mesolimbic bokong (n = 8-12), joalo ka ha ho hlalositsoe pele (,). Mabali a ne a bokelloa ho tsoa liphoofolong ebe a li phunyeletsoa ka letsohong le letšehali le ka ho le letšehali. NAc le PFC li ile tsa qhaloa 'me tsa hoamisoa ka potlako ke leqhoa le omileng' me tsa bolokoa ho −80 ° C. Letata le ne le hlophisitsoe hore le ka hlahlojoa ka homogenization ho 0.1 N perchloric acid, centrifuged ho 15,000 rpm bakeng sa 15 min ho 2-8 ° C, le ea phahameng e hlohliloeng. Mehlala e ile ea hlahlojoa ke Bioanalytical Systems HPLC (West Lafayette, IN, USA) e sebelisa LC-4C detector electrochemical detector. Sampole (12 ul) e ile ea kenngoa mokokotlong oa "reverse phase microbore" ka lebelo la phallo ea 0.6 ml / min le electrodetection e behiloeng ho + 0.6 V. Khethollo ea dopamine le dopamine metabolites e phethiloe ke karolo ea mohala e nang le 90-mM sodium acetate, 35-mM citric acid, 0.34-mM ethylenediamine tetraacetic acid, 1.2-mM sodium octyl sulfate, le 15% methanol v / v ho pH ea 4.2. Bolelele bo phahameng ba sampole bo ile ba lekanngoa mme ba bapisoa le litekanyetso tsa dopamine le metabolite ea eona 3,4-dihydroxyphenylacetic acid (DOPAC).

Methylated DNA Immunoprecipitation (MeDIP) Assay

Mehato ea MeDIP e ntlafalitsoe ho sebelisa MagMeDIP kit (Diagenode, Denville, NJ). DNA ea Methylated e ile ea enteloa ka ho sebelisoa li-0.15ul tsa lieta tsa makenete tse koahetsoeng ka anti-5methylcytidine antibody (Diagenode) kapa serum ea pre-immune. Ntlafatso ea karoloana ea MeDIP e ile ea khethoa ke bongata ba RT-PCR e sebelisang ChIP-qPCR Assay Master Mix (SuperArray) ho ABI7900HT Real-Time Cyulin. Bakeng sa liphatsa tsa lefutso tsohle tse hlahlobiloeng, li-primers li fumanoe ho SuperArray (ChIP-qPCR Assays (−01) kb, SuperArray) bakeng sa ntlafatso ea libaka tsa genomic tse qalang libaka tsa CpG tse fumanehang haufi le libaka tsa 300-500 bp tse holimo mohloling oa libaka tsa ho qala tsa mongolo. Liphetho tsa MeDIP li hlahisitsoe e le mohloli o ntlafalitsoeng oa li-immunoprecipended DNA sebakeng se seng le se seng. Ho lekanya phetoho e fapaneng ea ho lula ha kh'olo (% enforment), boleng ba MeDIP DNA likarolo tsa CT li ne li thathamisitsoe ho boleng ba karolo ea lipentšele tsa DNA.

Lipalo-palo li

Tlhatlhobo ea polelo ea Gene e entsoe ka ho sebelisa teko ea Moithuti T ho bapisa lits'oants'o tse tsofetseng tsa sehlopha sa HF le HF + lihlopha tsa ho hlaphoheloa. Boemo ba alpha bo ile ba fetoloa bakeng sa likarolo tse ngata tsa boko tse hlahlojoe. Bohlokoa ba mofuta o sebelisitsoeng sebakeng se le seng sa boko e ne e le p = .05; bakeng sa libaka tse peli, p = 0.025, bakeng sa libaka tsa boko tsa 3 p = .016. Likhetho tsa Sucrose, likhetho tsa saccharin, HPLC le MEDIP, litekanyo tsa mmele le tlhahlobo ea corticosterone e hlahlojoa ho sebelisoa ANOVA e le 'ngoe ho bapisa taolo, HF le HF + lihlopha tsa ho hlaphoheloa. Liteko tsa ho bapisa tsa Post-hoc Bonferonni li ne li sebelisoa ho bapisa liphapang tse bohlale pakeng tsa lihlopha. Bohlokoa ba liteko tsena bo behiloe maemong a alpha a p = .05.

Results

Litoeba li na le phihlello e tsoelang pele ea taolo ea phepo (taolo) kapa 60% ea phepo e phahameng ea mafura (HFD) ho fihlela libeke tse 12. Ha li le libeke tse 12, halofo ea liphoofolo tse fepehileng ke HF li ile tsa beoa ka ntlo ea ntlo bakeng sa libeke tse 4 (HF + recovery). Ho banna le basali, liphoofolo tsa HFD (selikalikoe) li ne li le boima ho feta taolo ho qala ka libeke tse 9 tsa lilemo (p <.05) mme li lula li le boima ho feta taolo nakong eohle ea phomolo (Setšoantšo se tlatsetsang 1).

Liteko tse ratoang tsa Sucrose le saccharin li ile tsa fanoa ho lekola karabelo ea liphoofolo molemong oa moputso oa tlhaho le o seng monate. Khetho ea Sucrose empa e se khetho ea saccharin e fetotsoe kamora ho pepesetsoa lijo tsa HF mme e khutlele maemong a tloaelehileng kamora ho hlaphoheloa ha HFD ho banna le basali. Tsela e le 'ngoe ANOVA e senotse khetho ea sucrose e fokotsehile haholo ho banna (Setšoantšo sa 1A) le tloaelo ea ho fokotseha ha basali (Setšoantšo sa 1B) kamora ho pepesetsoa HFD (F (2,16) = 4.82, p <.05; F (2,16) = 5.41, p <.06, ka ho latellana). Kamora ho tlosoa ha HFD, boitšoaro bona bo tloaelehileng le khetho ea sucrose ha bo sa fapana le taolo. Khetho ea Saccharin ha ea ka ea fetoloa ho banna ba bangSetšoantšo sa 1C) kapa tse tšehali (Setšoantšo sa 1D) ka lebaka la ho pepesoa ha HFD.

Setšoantšo sa 1 

Khetho ea Sucrose empa e se khetho ea saccharin e fetoloa kamora ho pepesetsoa mafura a mangata (HFD) ebe e khutlela maemong a taolo kamora ho hlaphoheloa ha HFD ho banna le basali.

Hobane dopamine ke molaoli oa bohlokoa oa boitšoaro ba moputso, polelo ea liphatsa tsa lefutso e amanang le dopamine e ile ea hlahlojoa ka har'a potoloho ea moputso oa sehlopha se ikemetseng sa banna le basali ka mor'a libeke tsa 12 ho HFD, le sehlopheng se eketsehileng, kamora libeke tsa 4 ho hlaphoheloa ho tsoa ho HFD. Lethathamo 1 e akaretsa kakaretso ea lipontšo tsa mofuta oa gene le tlhahlobo ea lipalo ho VTA, PFC le NAc. Ho VTA, liphatsa tsa lefutso tse tharo tsa bohlokoa ho laola maemo a dopamine litsing tsa synaptic li ile tsa lekanngoa: catecholamine methyl transferase (COMT) e kenyang letsoho ho inactivation ea catecholamine neurotransmitters; dopamine transporter (DAT), pompan e pudang ea membrane e tlotsang dopamine ho tloha synapse, le tyrosine hydroxylase (TH), enzyme e fokotsang sekhahla bakeng sa dopamine synthesis. Melao ea liphetoho tse 'maloa bakeng sa sehlopha ka seng e ne e ikemiselitse ho sebelisa li-control matched older (mohlala, linako tse laoloang li behiloe ho 1,' me ka ho hlaka feela taolo ea HFD e bontšoa ho graph). T-liteko tsa moithuti (n = 5 / sehlopha) li senoletse VTA e tona hore COMT, DAT, le TH mRNA li fokotsehile haholo ke ho pepesetsoa hoa HFD (Setšoantšo sa 2A) mme e khutlele ho kapa ho fetisa maemo a taolo kamora nako ea ho hlaphoheloa mosebetsing (ho hlaphoheloa ha HF +).

Setšoantšo sa 2 

Lijo tse matla tse sa feleng tse nang le mafura a mangata (HFD) le ho hlaphoheloa ha mmele ka mor'a HFD alter dopamine polelo e amanang le lefutso ho banna le basali
Lethathamo 1 

Kakaretso ea Phatlalatso ea Gene le Lipalopalo ho Banana

Ho PFC le NAC, liphatsa tsa lefutso tsa bohlokoa bakeng sa ho saena ka dopamine le tlhahiso ea dopamine li ile tsa hlahlojoa (n = 5 / sehlopha): COMT; protheine ea phosphatase 1 subunit e tsamaisang 1B (DARPP-32), protheine e tlase e bonts'ang liprotheine tse laoloang ke ts'usumetso ea li-receptor; dopamine receptor D1 (DRD1), protynaptic G-protein e kopantsoeng le "receptor" e khothalletsang cymbase ea adenylyl; le dopamine receptor D2 (DRD2), protynaptic G-protein e kopantsoeng le "receptor" e thibelang cymbase ea adenylyl. Ho PFC e tona (Setšoantšo sa 2B), DARPP-32 e ile ea eketsoa, ​​ha DRD1, le DRD2 e ile ea fokotseha kamora ho pepesoa ha HFD, mme liphetoho tsena li ile tsa phehella kamora ho tlosoa hoa HFD (leha keketseho ea DARPP-32 mRNA e ne e sa ts'epahala). Ho NAC ea banna (Setšoantšo sa 2C), COMT, DRD1, le DRD2 li ile tsa fokotsoa ke ho pepesetsoa ha HFD, 'me tsa lula maemong a taolo kamora ho tlosoa hoa HFD. Maemo a DARPP-32 a ile a eketsoa ke HFD, empa a fokotseha haholo ho tsoa taolong kamora libeke tsa 4 ho tloha HFD.

Libaka tse tšoanang tsa boko le liphatsa tsa lefutso li ile tsa hlahlojoa ho litoeba tsa basali (n = 5 / sehlopha). Joalokaha ho bontšitsoe Lethathamo 2, ho bile le phapang e kholo e hlokometsoeng sebopeho sa polelo ea liphatsa tsa lefutso ho arabela HFD, hammoho le ho fola. Hoa tšoana le ho banna, ho VTA, maemo a mRNA a COMT, le TH a fokotsehile haholo kamora ho pepesoa ha HFD (Setšoantšo sa 2D). Leha ho le joalo, ho fapana le banna, liphetoho tsena li ile tsa phehella kamora ho tlosoa ha HFD. Ho feta moo, khahlano le 'moho ka kotloloho e bonoang ho banna, ho pepesetsoa hoa HFD ho ekelitse polelo ea DAT MRNA ho VTA ho basali,' me kamora ho tlosoa ha maemo a HFD e ne e le tlase le ho feta litekanyetso tsa lilemo. Ho PFC, ke DARPP-32 feela e ileng ea angoa ke HFD e sa foleng, ka keketseho e kholo ea maemo a mRNA kamora beke ea 12 beke ea HFD, le ho khutlela maemong a taolo kamora ho tlosoa hoa HFD. Ka bobeli COMT le D1R mRNA li ile tsa fokotseha haholo kamora libeke tsa 4 ho tloha HFD. Ho NAC ea basali, COMT, DRD1, le DRD2 kaofela li ile tsa fokotseha kamora ho pepesetsoa hoa HFD (Setšoantšo sa 2F). DRD1 le DRD2 li hlaphoheloe ho laola maemo kamora ho tlosoa ha lijo, ha maemo a COMT a lula a fokotsehile haholo kamora ho hlaphoheloa ha 4wk

Lethathamo 2 

Kakaretso ea Phatlalatso ea Gene le Lipalopalo ho Basali

Ka lebaka la ho fokotseha ho sa lekanyetsoang ha polelo ea mofuta oa dopamine e laolang liphatsa tsa lefutso ho VTA, li-dopamine le dopamine metabolites li ile tsa hlakoloa libakeng tse fuoang likhakanyo ho tsoa ho VTA, PFC le NAC. Setšoantšo sa 3 e bonts'a dopamine (DA) le dopamine metabolite (DOPAC) ho tsoa ho PFC le NAC ho banna (Feiga. 3A, 3Cle tse tšehali (Feiga. 3B, 3D). Ho banna, ho pepesetsoa HFD ho hlahisitse ho theoha ha maemo a dopamine ho PFC (Setšoantšo sa 3A) le NAC (Setšoantšo sa 3C) (F (2,13) ​​= 3.95; F (2,18) = 3.536, p <.05), e ileng ea fola kamora ho tlosoa ha HFD feela ho NAC. Phetoho ea Dopamine (DOPAC: DA ratio) e eketsehile ho banna PFC (F (2,12) = 3.85, p <.05) le NAC (F (2,17) = 4.69, p <.05). Ka lehlakoreng le leng, phello ea HFD ho DA le DOPAC ho basali e ne e fapane ho latela maemo a banna. Ho PFC, HFD ha ea ka ea ama maemo a DA kapa DOPAC. Ho NAc, maemo a DA a fokotsehile liphoofolong tse fepehileng ke HFD mme a lula a fokotseha le kamora ho tlosoa ha HFD (Setšoantšo sa 3D(F (2,23) = 4.79, le <.05). Maemo a DOPAC a ne a sa fetohe ho NAc ea basali, e leng ho ileng ha baka keketseho ea phaello ea DA (DOPAC: DA ratio) (F (2,23) = 7.00, p <.01).

Setšoantšo sa 3 

Phokotso ea maemo a Dopamine ho PFC le NAC kamora HFD ho tsoaloeng le pholiso e tsoakaneng kamora ho tlosoa hoa HFD

Ka lebaka la hore ho ngolisoa ha DAT ho ka laoloa ke phapang e fapaneng ea methapo ea DNA le ho shebella phapang e totobetseng ea thobalano pontšong ea DAT ho VTA, ho hlahlojoa ha methapo ea methapo ea methapo ea tikoloho ho phatlalatso ea DAT ho ile ha hlahlojoa. Ho Setšoantšo sa 4A, 4C Polelo ea mofuta oa DAT ho VTA e hlahisoa hape bakeng sa ho hlaka (ho nkiloe ho Fig 2A le 2D). DAT promoter methylation e ile ea eketseha haholo ho banna (Setšoantšo sa 4Bkamora HFD mme e khutletse maemong a taolo ho banna ba hlaphoheloang ba HFD + (F (2,11) = 23.64, p <.01). Ho basali, khothaletso ea methylation ea DAT e shebaneng le ho fokotseha ha liphoofolo tsa HFD (D) mme e fokotsehile haholo ho basali ba hlaphoheloang ba HFD (Fig 5D, F (2,12) = 5.70, p <.05).

Setšoantšo sa 4 

Liphetoho maemong a methapo ea methapo ea methapo ea liphetoho tsa tsoelo-pele ea DAT e amanang le mofuta oa gene ho VTA

Ho lekola haeba ho tlosoa hoa HFD nakong ea ho hlaphoheloa e ne e le khatello ea maikutlo, maemo a mantlha a corticosterone (ug / dl) a nkuoe a le taolong, HFD e pepesitsoe (libeke tsa 12), HFD + 1wk hlaphoheloa le lihlopha tsa ho hlaphoheloa tsa HFD + 4wk (n = 5 / sehlopha, Tlatsetso ea feiga. 2). ANOVA e nang le tsela e le 'ngoe ha ea ka ea senola liphapang tsa bohlokoa pakeng tsa lihlopha tsa liphoofolo tse tona (F (3,16) = 3.21, ns).

Puisano

Tšebeliso e sa feleng ea phepo e phahameng ea mafura (HFD) ho tloha bonyenyaneng e ne e sebelisetsoa ho theha botenya bo khothalletsoang ke litheko ho litoeba. Tsena e bontšitsoeng e fokotsehile khetho ea sucrose le bopaki ba molumo o fokotsehileng oa dopaminergic libakeng tsa boko. Kamora libeke tsa 4 ho tloha HFD, khetho ea sucrose e tloaelehileng ho banna le basali, leha ho le joalo, liphetoho tse ling tsa mofuta oa dopamine li ile tsa phehella. Liteko tsena li fana ka datha ea bohlokoa e hlalosang phello ea HFD e sa feleng tsamaisong ea moputso oa boko, e totobatsa bokhoni ba ho hlaphoheloa le liphapang tsa bohlokoa tsa thobalano lipakeng tsa litoeba tsa banna le basali.

Ho liphoofolo tse feptjoang tsa HFD, ho ile ha bonoa khetho e fokotsang ea sucrose, e ileng ea khutla kamora nako ea ho hlaphoheloa. Liphumano tsena li atolosa tlaleho ea rona ea nakong e fetileng ea ho hloka ts'ebetso ea HFD mokhoa o fokotsoang oa ho khetha () ka ho bonts'a hore sena se ka etsahala ka nako e khuts'oane ea ho pepesetsoa hoa HFD (libeke tsa 12 le libeke tsa 22), mme ho bohlokoa, ke hore karabelo e ea khutla ntle le HFD. Malinyane a basali a bontšitse mokhoa o tšoanang o tšoanang le oa banna. Liphumano tsena li lumellana hantle le tse ling ho lingoliloeng tse bonts'itseng ka ho kenyelletsa sehlopha se fephileng se nang le phepo e sa foleng ea HFD, mme eseng botenya ka bongata, se hlahisa karabelo ea ho ikemela mosebetsing o sebetsang.). Ka mokhoa o ts'oanang, lithutong tsa hona joale, likhetho tsa sucrose li hlaphoheloa kamora libeke tsa 4 li tlohile HFD, ha boima ba 'mele bo lula bo phahamisitsoe haholo, ho ts'ehetsa qeto ea hore ho fokotsa khetho ea sucrose ho khannoa ke ho pepeseha ha HFD eseng phaello e tsamaeang le' mele. Ho ne ho khahlisa ka ho khethehileng hore ha ho na phetoho ho khetho ea saccharin. Sena se ka supa hore HFD e sa foleng e ama karabelo ho meputso e monate le e seng caloric. Liphello tsa ho kenella ka morao ho bophelo li bontšitsoe ho susumetsa khetho e ikemetseng ea ho tsebahala, kaha ho jeletsoe ka mokhoa oa sucrose ho kenyelletsa ho lokolloa ha dopamine ka litoeba tsa "blind-blind" tse amohelang "), boleng ba phepo bo hlokahala bakeng sa moputso le matlafatso () le tsela tse ikemetseng tsa metabolism tse khahlisang metabolic li hlalositsoe ho drosophila (). Saccharin e monate haholo ho feta sucrose, kahoo ho ile ha etsoa boiteko ba ho fumana ho tšoana ho monate (hangata 4-10x e phahameng ea mahloriso a sucrose ()) leha ho le joalo khetho ea kakaretso ea saccharin e ne e le tlase ho feta ea ho batla ho sesa liphoofolong tsena. Ka hona, tlhaloso e 'ngoe e kanna ea ba hore HFD e amme ka mokhoa o fapaneng khetho ea sucrose hobane e ne e le moputso o fetang oa saccharin (moputso o phahameng oa boleng bo tlase), leha liphoofolo li ntse li netefatsa khetho e matla bakeng sa saccharin (~ 75-80% to ~ 85-90% preference for sucrose).

Ka kakaretso, mofuta oa liphatsa tsa lefutso tsa dopaminergic ka har'a VTA, NAc le PFC li fokotsehile ho litoeba tse tona kamora HFD e sa foleng. Liphumano tsena li lumellana le liphuputso tse ling tse boneng li fokotseha ho liphatsa tsa lefutso tse amanang le dopamine ho arabela HFD (,,). Ho theoha ha polelo ea dopamine D2 receptor le ts'ebetso ho hlokometsoe lithutong tsa ho nahana ka batho (, ) le mefuta ea botenya, ). Ho theoha ha dopamine ho theola ho fokotsa maikutlo a meputso ea tlhaho kahoo ho ka nolofalletsa ts'ebeliso e fetelletseng ea lijo tse matlafatsoang le phaello e eketsehileng ea boima (,). Ho ea pele, tšitiso ea dopamine homeostasis e khannoang ke ho fokotseha ha polelo ea selemo ea DAT e tsejoa ho khanna ho eketsa takatso ea lijo tse phahameng tsa mafura (). Phapang ea mokhoa ona e bonoe le DARPP-32, phophoprotein e laoloang ke dopamine- le cyclic, e ileng ea eketseha kamora HFD ho NAc le PFC. DARPP-32 e bapala karolo ea bohlokoa ho kopanya likarabo tse fapaneng tsa biochemical le boitšoaro bo laoloang ke dopamine. E kanna ea ba hore DARPP-32 upregulation e ne e le compenshene ha e arabela taolong e tlase ea D1R. Ka mohlala o tšoanang (12 wk HFD ka litoeba), ho bontšitsoe hore D1R tlase regulation e ne e bapisoa le keketseho ea phosphorylation ea DARPP-32 ho NAc ().

Ke liphuputso tse fokolang tse ileng tsa lekola bokhoni ba ho khutlisa liphetoho tsena kamora ho tlosoa ha HFD. Leha ho le joalo, litlalehong tse peli tsa morao-rao, liphetoho tsa polelo ea tlhaho le liphoso tsa tsamaiso ea moputso li ile tsa phehella kamora nako e khutšoane ea ho tlohela (14-18d) (, ). Ho fapana le hoo, liphuputso ho bakuli ba batenya haholo pele le ka mor'a ho buuoa ka mpeng li bontšitse phetoho ea phetoho ea dopaminergic kamora nako e telele ea ho theola boima ba 'mele (). Ho banna, mokhoa oa ho hlaphoheloa o fapana ka karolo ea boko. Ka VTA, lits'ebetso tse boneng li fokotseha ho COMT, DAT, le TH kaofela li ile tsa tloaeleha ha ho tlosoa HFD. Ho fapana le hoo, liphetoho tsohle tsa polelo ea tlhaho tse bonoang ho NAc le PFC ha lia ka tsa tloaela. Thutong ea hona joale, HFD e sa foleng e lebisitse ho nona e kholo 'me ka mor'a libeke tsa 4 ho ja lijo, liphoofolo li ne li ntse li le boima haholo ho feta taolo. Ka hona, liphetoho tse latelang tsa metabolic le lihormone tse tsamaeang le botenya (mohlala, leptin e eketsehileng, li-adipokines tse phahameng) li kanna tsa ba li le teng libekeng tsa 4 lijong. Ka hona, liphetoho tsa mofuta oa gene tse tloaetseng (mohlala, ho VTA) li kanna tsa tsamaisoa haholo ke HFD, athe tse neng li bolokiloe (ho NAc le PFC) li kanna tsa kopanngoa le botenya haholo. Tlhokomelo ea ho fokotsa boima ba 'mele ka ho ja lijo tse tlaase e na le tšobotsi e tlase (ka 67% () ho 80% () ea bakuli ba fumanang boima bo lahlehileng). Ho phehella hona ha liphetoho tsa mofuta oa liphatsa tsa lefutso libakeng tsa moputso ho ka ba bohlokoa molemong oa ho hlalosa ketsahalo ena e tloaelehileng. Ho bohlokoa hape ho hlokomela hore liphetoho tse bonts'itsoeng tsa boitšoaro le mofuta oa liphatsa tsa lefutso li kanna tsa se be teng ka lebaka la khatello ea maikutlo e amanang le phetoho ea lijo, hobane ho ne ho sena liphetoho tse kholo maemong a basal plasma corticosterone ho HFD kapa kamora ho hlaphoheloa ha 1wk kapa 4wk.

Ho ile ha senoloa liphapang tse khahlisang tsa thobalano, ka bobeli karabelo ea HFD e sa foleng, hammoho le karabelo ea ho tlosoa hoa lijo. Basali ba ne ba tšoana le ba batona ho bonts'a ho fokotseha ka botlalo hoa liphatsa tsa lefutso tse amanang le dopamine tse ka bolelang ho fokotseha hoa ts'ebetso ea DA, haholoholo ho VTA le NAc. Phapang e 'ngoe e hlokomelehang ea thobalano e bile keketseho ea polelo ea DAT mRNA ho VTA ea basali ka mor'a HFD. Phapang ena ponahalong ea liphatsa tsa lefutso, hammoho le ho fokotseha ho tšoanang ha polelo ea TH bathong ka bobeli, e ka supa phapang e kholo ho dopamine neurotransmission kahare ho NAc, ka bobeli qetellong ea tlhahiso ea HFD le kamora nako ea ho hlaphoheloa. Kananelo e kholo bakeng sa bohlokoa bo sebetsang ba liphapang tsena ke sepheo sa bohlokoa sa lipatlisiso tsa nako e tlang.

Ntle le moo, ha COMT le TH li fokotseha li fumaneloa ho VTA e tona, litheko tsena li ile tsa phehella ho basali ka mor'a 4-beke ho tsoa HFD. Ho sa ntse ho tlameha ho tsejoa hore na liphapang tsena li tla khutla ka mor'a nako e telele li sa jele paate, leha ho le joalo, e tšehetsa qeto ea hore basali, bonyane ba lieha ho fola, haeba ba fola ho hang. Ho feta moo, liphetoho tsa polelo ea mofuta oa D1R le D2R ho NAc le PFC li ne li fapane haholo lipakeng tsa banna le basali. Ho banna, ho ne ho fokotsehile ka kakaretso polelo ea liphatsa tsa lefutso libakeng tseo ka bobeli tse phehellang haholo kamora ho tlosoa hoa lijo. Ho basali, D1R le D2R li ile tsa fokotseha ho NAc tsa ba tsa hlaphoheloa, empa ha ho na phello ea HFD ho li-dopamine receptors ho PFC. Lithutong tsa hona joale, liphoofolo tse tšehali li ne li etsoa sehlabelo ntle le ho ikarabella bakeng sa sethala sa estrus. Le ha tse ling tsa lintlha tsa ho qetela tse bonoang li tsejoa ka ho fapana ka potoloho ea li-estrus, liphoofolo tse tšehali thutong ena ha li a ka tsa bontša phapang e kholo ho pheletso, haholo ha ho bapisoa le phello ea phetoho e nepahetseng.

Ho tlatsana le liphetho tsa mofuta oa gene, dopamine e ile ea lekanngoa libakeng tsa mantlha tsa projeke ea VTA, e leng PFC le NAc. Maemo a Dopamine a ipapisitse le liphetoho tse tšoanang tse bonoang ho TH mRNA ho VTA. Ka NAc ea ba batona le ba batšehali, maemo a DA a fokotsehile ka lebaka la lijo tsa HFD; Karabelo e ileng ea fuma ho banna, empa eseng basali. Ho PFC, maemo a dopamine a ne a boetse a fokotsehile ke HFD, leha ho le joalo, ho ne ho se na ho hlaphoheloa ho tloha phepong ho PFC. Ho feta moo, tse tšehali li ne li e-na le dopamine e tlaase ka ho fetisisa ea "dopamine" pele ho "cortex" ho feta banna. Phapang pakeng tsa thobalano mabapi le polelo ea DAT le ts'ebetso ea eona li tsebahala ka har'a lingoliloeng, tse tšehali li bonts'a polelo e eketsehang ea DAT () le tšebetso (), mme phapang ena e ka kenya letsoho maemong a fapaneng a mantlha a dopamine lipakeng tsa ba batona le ba batšehali. Ho hlahlojoa ha DOPAC: Boemo ba DA le bona bo na le tsebo. Keketseho ea keketseho ena e kanna ea bonts'a karabelo ea matšeliso e tsamaisoang ke litheko ho DA. Bohlokoa bo sebetsang ba nako e telele ba liphetoho tsena ho metabolite ea dopamine li ne li tla khantšoa ke ho lekanya liphetoho tse tlisoang ke ho lokolloa ha dopamine ho sebelisoa Ka vivo microsalysis.

Ntle le moo, datha tsena li supa taolo e matla ea methapo ea DNA ka har'a morekisi oa mofuta oa DAT, haholo-holo ho banna. Haufinyane, re bonts'itse hore polelo ea DAT e ka laoloa ka matla ke phapang ea methapo ea methapo ea lefutso ho arabela HFD (), mme seo se nyolla tloaelo ea ho hlohlelletsoa ha methapo ea DAT ka ho fokotseha ha polelo ea mofuta. Mona re supa boteng ba karabelo ena, joalo ka ha methapo ea methapo ea DNA (le kutloisiso e fokotsehileng ea mRNA) e bonoa ho banna ba tlisoang ke ho tlosoa ha HFD. Melao ea liphatsa tsa lefutso ea Epigenetic, mohlala ka phetoho ea methapo ea DNA, e hlahisa tsela eo ka eona lintho tse phelang li ka ikamahanyang le liqholotso tsa tikoloho. Matšoao a Epigenetic a ka bolokoa ho pholletsa le sebaka sa bophelo (), le liseleng tsa semolao tsa "embryonic stem" tse fetotsoeng ka bobeli, tse feto-fetohang le tse phehellang tsa methapo ea DNA e fapaneng li ile tsa shejoa ho arabela maemo a fetohileng a tikoloho (). Lintlha tsena ke tsa pele ho bonts'a Ka vivo sebopeho se matla sa methylation se fetohang ho ba teng kapa ho ba sieo ha phephetso ea tikoloho. Ho ne ho hlokomelehile hore mokhoa ona o ne o sa bonoe ho basali. Ha karabelo ea pele ho HFD e ne e le joalo ka ha ho boletsoe esale pele (e fokotse ts'ebetso ea methapo ea methapo ea DNA), mokhoa ona ha oa ka oa bolokoa nako eohle ea ho hlaphoheloa. Sena se fana ka maikutlo a hore methapo ea methapo ea kutlo le mofuta oa liphatsa tsa lefutso li ka senyeha nakong ea libeke tse 'ne tse tlohang HFD kapa ho ka fana ka tlhahiso ea hore DAT mRNA e laoloa ka mekhoa e meng ho basali.

Ho banna, khetho ea sucrose, polelo ea liphatsa tsa lefutso tse amanang le DA ho VTA, le dopamine ho NAc latela mokhoa o ts'oanang, oa khatello ka karabelo ho HFD e sa foleng e fumanang kamora ho tlosetsoa lijo. Ho khahlisang ke hore, leha likarabo tsa boits'oaro ho sucrose li ts'oana le tse tšehali, mekhoa ea polelo ea liphatsa tsa lefutso le maemo a NAc dopamine li bontša ho haelloa ke pheko ha ho tlosoa HFD. Boitšoaro bo amanang le moputso bo susumetsoa ka mokhoa o hlakileng ke lits'ebetso tse ling tsa li-neurotransmitter tse kang li-opioid, mme mohlomong ho basali, karabelo ea boitšoaro ho sucrose e amana haholo le liphetoho tsa li-opioids. Ka kakaretso, tlhaiso-leseling e teng hona joale e fana ka maikutlo a hore phapang ea thobalano ho karabelo ea pele ho HFD, le ho hlaphoheloa kamora ho tlosoa hoa HFD, mabapi le polelo e amanang le dopamine e emela tataiso ea bohlokoa bakeng sa lipatlisiso tsa nako e tlang tse lebisitsoeng ho tšebeliso e sa feleng ea ts'ebeliso HFD e ama tsamaiso ea moputso oa boko. Haholo-holo, datha tsena li supa bohlokoa ba polasetiki karabong ea dopaminergic ho HFD, li fana ka maikutlo a hore le ha litlamorao tsa tšebeliso e mpe ea HFD le / kapa botena li bohlokoa, monyetla oa ho hlaphoheloa o teng.

Ho se ho tsebahala ka taba ena

  • Dopamine receptor expression le tšebetso e fokotsehile ho bakuli ba batenya
  • Ho pepesehela lijo tse nang le mafura a mangata ho baka liphetoho mekhoeng e amanang le dopamine le boitšoaro ba moputso
  • Dopamine neurotransication e fetoloa ka litoeba tse ngata.

Seo buka ena e ngotsoeng ka letsoho e se buang e bua ka taba ena

  • Khethollo ea phapang ea thobalano karabong ea CNS ho ja lijo tse mafura a mangata.
  • Teko ea polasetiki ea dopaminergic liphetoho ha ho tlosoa phepelo e phahameng ea mafura.
  • Khethollo ea liphetoho tsa methapo ea methapo ea DNA ha u arabela lijong tse phahameng tsa mafura

Boitsebiso bo Eketsehileng

lumela hore baa fokola

Mosebetsi ona o tšehelitsoe ke lithuso tse latelang: MH087978 (TMR), MH86599 (IL), le T32 GM008076 (JLC).

Mongolo o botlaaseng ba leqephe

 

Likhohlano tsa Polelo ea Thahasello

Bangoli ha ba na likhohlano ho senola.

 

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