Ho se sebetse ha Basal Ganglia ho tlatsetsa ho ho se sebetse ha 'mele ho botenya (2016)

E fumaneha Inthaneteng 29 December 2016

• Danielle M. Friend^{1, 9},
• Kavya Devarakonda^{1, 9},
• Timothy J. O'Neal^{1, 9},
• Miguel Skirzewski⁵,
• Ioannis Papazoglou¹,
• Alanna R. Kaplan²,
• Jeih-San Liow⁴,
• Juen Guo¹,
• Sushil G. Rane¹,
• Marcelo Rubinstein^{6, 7, 8},
• Veronica A. Alvarez²,
• Kevin D. Hall¹,
• Alexxai V. Kravitz^{1, 3, 10,,}

 Hlahisa ho feta

http://dx.doi.org/10.1016/j.cmet.2016.12.001

Lintlha-khōlō Tsa

• Botenya bo amana le ho se sebetse

• Litoeba tse nang le li-D2R li tlama haholo, tse ka 'nang tsa hlalosa hore ha li sebetse

• Ho tsosolosa G_i ho bonts'a li-iMSN ho pholosa litebelisuoa tsa 'mele tsa litoeba tse mafura

• Ho se sebetse ka matla meleng ho ba le liphello tse ngata ho feta sesosa sa boima ba 'mele

Summary

Botenya bo amahanngoa le ho se sebetse, ho eketsa liphello tsa bophelo bo botle ba boima ba 'mele. Leha ho le joalo, mekhoa e sebelisang mokhatlo ona ha e tsejoe. Re ne re nahana hore litšenyehelo tse teng ka pontšo ea dopamine li tlatsetsa ho se sebetseng ho matlafala ha botenya. E le ho batlisisa sena, re ile ra qotsa likarolo tse ngata tsa dopamine tse bontšang liphio tse omeletseng le tse phatsima. Re fumane hore tiiso ea D2-type receptor (D2R) e tlama tumelong ea striatum, empa e seng mefuta ea D1 ea tumello ea ho amohela kapa ea dopamine, e fokotsoe ka litoeba tse ngata haholo. Ho tlosa li-D2R ka mokhoa o fokolang ho li-neuron tse nang le mefuta-futa e fokolang ho ne ho lekaneng ho fokotsa liketso tsa motlakase ho litoeba tse mahlahahlaha, empa ho tsosolosa G_i ho bonts'a li-neurons tsena ho eketsehile ts'ebetsong ka litoeba tse ngata. Ho tsotehang, le hoja litoeba tse nang le D2Rs tse fokolang li sa sebetse, li ne li se li sa khoneha ho ba le boima ba ho feta ho laola litoeba. Re etsa qeto ea hore litšenyehelo tsa D2R tse hlaselang li kenya letsoho ho sitoang ho sebetsa ka matla ho feta botenya, empa ho se sebetse ho ba le liphello tse ngata ho feta sesosa sa botenya.

Graphical Abstract

Mokhoa oa ho khetha

Keywords

• botenya;
• dopamine;
• ho ikoetlisa;
• boikoetliso;
• D2;
• striatum;
• e feta;
• boima ba 'mele

Selelekela

Botenya bo amana le ho se sebetse hantle (Brownson et al., 2005 'me Ekkekakis et al., 2016), e nang le liphello tse mpe tsa bophelo bo botle ba lefu la tsoekere la mofuta oa II le lefu la pelo (de Rezende et al., 2014 'me Sharma et al., 2015). Mekhoa e tsamaisang mokhatlo ona ha e tsejoe, 'nete e bontšoa ka ho hloka mehato e atlehileng ea ho fetola maemo a ho ikoetlisa a batho ba nang le botenya haholo (Ekkekakis et al., 2016). Ho thahasellisang ke hore botenya bo 'nile ba amahanngoa le liphetoho ho bontša letšoao le hlabang la dopamine (DA), e leng se lebisitseng mehopolong ea ho se sebetse ho se nang matla (Blum et al., 2011, Kenny, 2011 'me Volkow le Bohlale, 2005). Le hoja DA e hlaselang e hokahane haholo le motlakase, liphuputso tse fokolang li 'nile tsa batlisisa hore liphetoho tse bakoang ke lijo tse bakoang ke dopaminergic li ka etsa hore motho a se ke a khona ho sebetsa. Re etsa qeto ea hore pontšo ea DA e hlaselang e senyehile ka botenya le hore sena se tlatsetsa ho sa sebetse. Ho utloisisa lisosa tsa tlhaho tsa ho se sebetse ho ka etsa hore ho be le mehato e atlehang bakeng sa ho eketsa mosebetsi, 'me kahoo ntlafatsa bophelo bo botle, ho batho ba nang le botenya haholo.

DNA ea AIDS e ameha haholo ka ho laola likoloi. Sena se bonahala ka mathata a motlakase a kang lefu la Parkinson, le tsejoang ke lefu la dopaminergic neurons lilemong tsa bobeli le ho felloa ke taolo ea DA (Hornykiewicz, 2010). Batho ba babeli ba methapo ea neurons e hlaselang ka mokhoa o hlalositsoeng ke DA ba tsejoa e le tsela e tobileng le e sa tobang ea li-spiny neurons (dMSNs le iMSNs) (Alexander le Crutcher, 1990, DeLong, 1990 'me Gerfen et al., 1990). dMSNs e hlalosa G_se amohelang D1 receptor (D1R) le morero ho ea ho substantia nigra le karolong e ka hare ea globus pallidus, athe iMSN e hlalosa G_iD2R e kopantsoeng le morero ho karolo e ka ntle ea globus pallidus (GPe) (Gerfen et al., 1990, Le Moine le Bloch, 1995 'me Levey et al., 1993). Ho felisoa ha liphatsa tsa lefutso tsa D2R ho tloha ho iMSNs, kapa ho susumetsa optogenetic ea iMSNs, ho lekane ho fokotsa tsamaiso (Kravitz et al., 2010 'me Lemos et al., 2016). E itšetlehile ka likhokahanyo pakeng tsa ho se sebetse ha D2R le botenya, re ne re nahana hore liphoofolo tse ngata li fetotse phetoho ea iMSN, e leng se etsang hore motho a se ke a sebetsa.

Mona, re hlahlobile likarolo tse ngata tsa ts'oaetso ea DA ho litoeba tse mahlahahlaha le tse fokotsang lijo. Tšebeletso ea D2R e fokotsehile ka litoeba tse ngata, athe li-D1R li tlama le litekanyetso tsa DA tsa extracellular li ntse li sa fetohe. Mantsoe a mangata a ile a boela a bonahatsa ho ferekana ha ho thunngoa le ho fokotsa leeto. Ho felisa li-D2R ho tloha ho iMSNs ho fokotseha ts'ebetso ho litoeba tse bobebe, empa ho tsosolosa G_i ho bonts'a li-iMSN ho eketsehile mosebetsi ho litoeba tse ngata. Liphetho tsena li theha hore pontšo ea D2R li-iMSN e ka tsamaisa boikoetliso ba 'mele. Re ile ra botsa hore na litoeba tse nang le letšoao le tlase la D2R li ne li le tlokotsing ea ho fumana boima ba 'mele ka ho ja lijo tse ngata, ka lebaka la mesebetsi ea bona e tlaase. Ho etsa sena, re ile ra hlahloba phaello ea boima mabapi le phapang ea tlhaho ea D2R e tlamang har'a litoeba, hammoho le litoeba tse nang le liphatsa tsa lefutso tsa D2R tse hlaselang. Le hoja litoeba tse nang le maemo a tlase a D2R li ne li e-na le maemo a tlase a ho ikoetlisa, li ile tsa e-ba boima ka tekanyo e tšoanang le litoeba tse nang le li-D2R tse tiileng. Sena se hanyetsa kamano e matla ea likarolo pakeng tsa liketso tsa 'mele le phaello ea boima. Re etsa qeto ea hore ho senyeha ha D2R ho kenya letsoho ho etsa hore motho a se ke a khona ho etsa boima bo botle empa hore ho se sebetse ha ho bolele ho fumana boima ba 'mele.

Results

Lijo Tse Ntle-Tse Neng li Ntle li ne li Amana le ho se Ts'oanehe ha 'mele

C57BL6 / J litoeba tse tona (likhoeli tse 3-4) li fepiloe ka li-chow (standard, n = 8) kapa lijo tse nang le mafura a mangata (botenya, n = 8) bakeng sa libeke tse 18 (Setšoantšo sa S1A). Ho qala bekeng ea 2 le ho phehella bekeng ea 18, litoeba tse nonneng li ne li na le boima ba 'mele le mafura a mangata haholo ho feta litoeba tse otileng (p <0.0001; Litšoantšo 1A le S1B). Boima bo boima ha boa fetoha haholo (Setšoantšo sa S1C). Re lekantse maemo a tšebetso tšimong e bulehileng libeke tse ling le tse ling tse 2 bakeng sa libeke tse 18 (Ethovision; Noldus Information Technologies). Litoeba tse nonneng li ne li e-na le tšebetso e tlase ho feta litoeba tse otileng tse qalang bekeng ea 4 le ho phehella bekeng ea 18 (p <0.0001; Litšoantšo 1B le 1C). Ka beke ea 18, litoeba tse nonneng li qetile nako e nyane li tsamaea (p = 0.005), li na le metsamao e fokolang (p = 0.0003), hape e ne e tsamaea butle butle ha e tsamaea (p = 0.0002; Setšoantšo sa 1D) mabapi le litoeba tse omeletseng. Ho hōlisa le boitlhopho ha hoa fetoha haholo (Setšoantšo sa 1D). Litoeba tse nonneng le tsona li ne li matha ka tlase ho litoeba tse otileng ha li fuoa phihlello ea mabili a ntlo (p = 0.0005; Setšoantšo sa 1E). Re ile ra hlahloba hore na phaello ea mokhatlo e amana le boima ba 'mele sehlopheng se bolileng. Le hoja phaello ea boima e ne e amana le ho ja lijo tse nang le mafura a mangata (Setšoantšo sa 1F), e ne e sa tsamaisane le litekanyetso tsa ts'ebetso tšimong e sa bulehileng kapa ka matla a sebelisoang nakong ea lijo tsa mafura a mafura (Litšoantšo 1G le 1H). Ho thahasellisang ke hore litšebelisano tsena tse tšoanang li ile tsa tšoaroa ha re hlahloba lijo tsa ho ja lijo bekeng ea pele ea teko (Litšoantšo 1I-1K), e leng se bontšang hore mefuta ea pele ea ho ja lihlahisoa tse mafura (empa ha e tsamaee kapa e sebelisoang ke matla) e ne e le esale pele ea ho fumana boima ba morao.

Setšoantšo sa 1. 

Ho ja lijo tse sa foleng tse sa feleng ho lebiselitsoe ho se sebetse

(A) Litoeba li fepa lijo tse mafura haholo li lekanngoa ho feta litoeba tse feptjoang tse qalang bekeng 2 le ho tsoela pele beke 18 (F_(18,252) = 62.43, p <0.0001).

(B) Mohlala oa lipalangoang tsa tšebetso ea tšimo e bontšang hore (C) litoeba tse fokolang li fokolitse tšebetso ea 'mele ha li bapisoa le litoeba tse otlolohileng ho tloha bekeng ea 4 le ho tsoela pele ho fihlela beke 18 (F_(10,140) = 4.83, p <0.0001).

(D) Kamora libeke tse 18 lijong tse nang le mafura a mangata, litoeba tse nonneng li fokotse nako eo li e qetileng li tsamaea (t₍₁₄₎ = 3.32, p = 0.005), ho fokotsa makhetlo a motsamao (t₍₁₄₎ = 4.74, p = 0.0003), le ho fokotsa lebelo ha o ntse o tsamaea (t₍₁₄₎ = 4.69, p = 0.0002) e amanang le lits'oants'o tse bobebe. Litoeba tse nang le botenya li bonts'itse mokhoa oa ho holisa hanyane (p = 0.07).

(E) Ha ho fanoa ka tumello ea ho khanna ka lehae la malapa, litoeba tse ngata li ne li e-na le mabili a seng makae a fapaneng ho latela litoeba tse omeletseng (t₍₁₄₎ = 4.55, p = 0.0005).

(F-H) Kakaretso ea boima ba 'mele e thehile khokahano ea bohlokoa le (F) matla a kenang nakong ea teko (r = 0.74, p = 0.04), empa eseng (G) tšebeliso ea matla (r = 0.52, p = 0.19) kapa (H) lebelo la masimo a bulehileng (r = 0.19, p = 0.65).

(IK-K) Kakaretso ea boima ba 'mele e thehile khokahano ea bohlokoa le (I) karolelano ea matla a kenang bekeng ea pele (r = 0.88, p = 0.004), empa eseng (J) tšebeliso ea matla (r = -0.19, p = 0.66) , kapa (K) lebelo la masimo a bulehileng (r = 0.36, p = 0.38).

Tlhahlobo ea statistical. (A le C) Tsela e 'meli-khafetsa-mehato ea ANOVA e lateloa ke teko ea poso le palo ea boitsebiso ba bohata ba Benjamin-Hochberg; (D le E) tlhahlobo ea Seithuti e sa sebetseng; (F-H) ts'ebetso e nepahetseng; ^*p <0.05, ^**p <0.01, ^***p <0.0001 ha e bapisoa le ho sekama. (I-K) khatello e lekanang; ^***p <0.001 khahlanong le litoeba tse otileng.

Mokhoa oa ho khetha

Botenya bo ne bo amahanngoa le ho fokotseha ha Dopamine D2R ho koala

Ho khetholla mekhoa ea ho se sebetse, re ile ra qotsa likarolo tse ngata tsa DA ho bontša litoeba tse omeletseng le tse batle. Tumellanong le litlaleho tsa pele ho litoeba, D2R-joaloka receptor e tlamisa ³H-spiperone, ho tloha hajoale e bitsoang tlamo ea D2R) e ne e le tlase ho litoeba tse nonneng tse amanang le litoeba tse otileng (p <0.0001; Litšoantšo 2A le 2B), sephetho se neng se le bohlokoa likarolong tsohle tse tharo tsa striatal (dorsomedial: p = 0.004; dorsolateral: p <0.0001; ventral: p <0.001; Litšoantšo S2A le S2B). Leha ho le joalo, tlamo ea D2R e ne e sa tsamaellane le mafura a 'mele sehlopheng se omeletseng kapa se nonneng (p> 0.55 ka bobeli; Setšoantšo sa 2C), ho fana ka maikutlo a hore, le hoja D2R e tlama le ho boloka mafura ka bobeli e fetotsoe ke lijo tse sa foleng tse mafura, mefuta ena e ka 'na ea se ke ea amahanngoa.

Setšoantšo sa 2. 

Lijo tse phahameng tsa lijo tse nang le bokooa Dopamine ea mafu a se nang matla D2R

(A) Litšoantšo tsa ho bolaea D2R li tlama ka mokhoa o lekanyelitsoeng ³H-spiperone.

(B) Thibelo ea Striatal D2R e ne e fokotsehile ka bo-mpole ho latela litoeba (t₍₂₅₎ = 5.02, p <0.0001).

(C) Ho tlama ha St2atal D0.95R ho ne ho sa amane le liperesente tsa mafura a 'mele ho itsetlehileng (p = 0.56) kapa litoeba tse nonneng (p = XNUMX).

(D-F) (D) Tlhōlisano ea DNA-D1R e tlama (t₍₂₄₎ = 1.31, p = 0.20), (E) kakaretso ea litaba tsa dopamine (DA; t₍₁₃₎ = 0.85, p = 0.41), le (F) tyrosine hydroxylase (TH) segokanyipalo (t₍₁₄₎ = 0.48, p = 0.64) li ne li sa fapane lipakeng tsa lihlopha tsa lijo.

Tlhahlobo ea lipalo-palo. Bolela ka litoeba ka bomong; n = 8-19 litoeba / sehlopha; Teko ea moithuti (B le D-F) kapa regression e nyane (C); ^*p <0.01.

Mokhoa oa ho khetha

Re ile ra leka ho khetholla mochine o thibelang ho ba motenya haholo-o fokolisitsoeng molemong oa ho tlama D2R. Ho etsa sena, re ne re batla ho se tšoane Drd2 mRNA (ka in in hybridization) mme ea e fumana e sa fetohe likhethong tsohle tse tharo tsa striatal (dorsomedial: p = 0.92; dorsolateral: p = 0.90; ventral: p = 0.34; Setšoantšo sa S2C). Re sebelisitse libaka tse ka bophirima ho lekanya lipalo tsa protheine ea D2R mme ha re bone phetoho lipakeng tsa 50- kapa 70-kDa, tseo ho nahanoang hore li emela linaha tse fapaneng tsa glycosylation tsa D2R (bobeli ba p> 0.95 Litšoantšo S2D le S2E) (Johnson le Kenny, 2010). Qetellong, re ile ra hlahloba likarolo tsa ho se sebetse ha metsoallo ka litoeba tse mahlahahlaha le tse ngata ho bona hore na li ka 'na tsa amana le ho fokotseha ha D2R joalokaha ho tlalehiloe pele (Dunn et al., 2012). Litoeba tse nang le botenya li ne li e-na le k'holeseterole e potlakileng haholo ea ho itima lijo (p <0.0001), leptin (p <0.0001), glucose (p = 0.0002), insulin (p = 0.001), le tlhahlobo ea mofuta oa homeostatic ea mofuta oa khanyetso (HOMA-IR) (p <0.001) , empa eseng triglycerides kapa mahala fatty acid (Litšoantšo S1D-S1J). Leha ho le joalo, ha ho le e 'ngoe ea lintho tsena tse amanang le D2R tse tlamang litoeba tse ngata (data e sa bontšoang).

D1R-e tšoana le e tlamang (ka mokhoa oa ho iketsetsa setšoantšo ka ³H-SCH23390, ho tloha joale e bitsoang tlamo ea D1R) e ne e sa fapane lipakeng tsa litoeba tse nonneng le tse otileng (p = 0.20; Setšoantšo sa 2D). Ho ne ho boetse ho se na phapang lipakeng tsa litaba tsa DA tsa pelehi, tse lekantsoeng ka ts'ebetso e phahameng ea mokelikeli oa mokelikeli (HPLC) oa litebele tse otlang pelo (p = 0.41; Setšoantšo sa 2E), kapa tyrosine hydroxylase immuno-labeling (p = 0.64; Setšoantšo sa 2F). Ka lebaka la litlaleho tse ngata tsa phapang pakeng tsa DA ea basal ka litoeba tse ngata haholo (Carlin et al., 2013, Davis et al., 2008, Vucetic et al., 2012 'me Wang et al., 2014), re ile ra boela ra hlahloba ntlha ena re sebelisa no-net flux microdialysis (litoeba tse ncha, n = 6 ka sehlopha). Ha rea ​​ka ra bona liphapang tsa DA ea kantle ho lisele (p = 0.99) kapa e 'ngoe ea li-metabolite tsa eona tse peli, 3,4-dihydroxyphenylacetic acid (DOPAC) (p = 0.85) le homovanillic acid (HVA) (p = 0.68, Setšoantšo sa S3), ka mokhoa ona, o bontšang hore botenya ha bo amane le ho fokotseha ha molumo oa DA oa extracellular ho liteko tsena.

Tlhōlisano ea Striatal e amanang le Molala e ile ea ferekanngoa ke Mantsoe a Mabeli

Re sebelitse ka vivo electrophysiology ho hlahloba hore na ho thelloa ha D2R ho tlamang ho ka fokotsa liphetoho tsa methapo ea methapo joang, ka tsela eo ho kenya letsoho phokotsong ea motsamao. Re ngotse ho tsoa ho dorsomedial striatum ea litoeba tse otileng le tse nonneng (n = litoeba tse 3 ka sehlopha, histology ho Setšoantšo sa 3F). Le ha litoeba tse nonneng li ne li sa tsamaee ka kakaretso, lebelo la mekhatlo e bolailoeng le ne le sa fapane lipakeng tsa lihlopha tsena (p = 0.55; Setšoantšo sa 3A), e re lumellang ho bapisa ho thunya ho amanang le motsamao lipakeng tsa litoeba tse otileng le tse nonneng. Litekanyetso tsa basal multi-unit spiking li ne li sa fapane lipakeng tsa litoeba tse otileng le tse nonneng (itsetlehe, 2.1 ± 0.4 Hz; botenya, 2.0 ± 0.7 Hz; p = 0.93). Leha ho le joalo, ho ata ha li-unit tse sebelisoang ke motsamao (Setšoantšo sa 3B) e ne e le tlase haholo litoeba tse nonneng (p <0.0001; Setšoantšo sa 3C). Sena ha sea itšetleha ka litlhaloso tsa lipalo-palo tsa li-unit tsa "activ-activated", joalo ka ha re boetse re bone ho fokotseha ha li-spiking ho potoloha metsamao karabong e karolelano ea li-unit tsohle tse tlalehiloeng ho litoeba tse nonneng haholo ho fapana le tse otileng (tšebelisano ke ANOVA, p <0.0002; Litšoantšo 3D le 3E). Re etsa qeto ea hore tekanyo ea litekanyetso e fokolang ea statum e ne e sa tšoane, empa mokhatlo oa li-spikes ho potoloha mokhatlo o ne o ferekanngoa ke litoeba tse ngata.

Setšoantšo sa 3. 

Litlhapi Tse Amanang le Moifo Tlas'a Striatum li ne li ferekanngoa ke Mantsoe a Bobebe

(A) Liketsahalo tsa mokoloko li ne li e-na le lebelo le tšoanang ho litoeba tse omeletseng le tse phetseng hantle.

(B) Mehlala ea phetoho e sebetsang le e sa amoheleng ka li-neurons tse hlaselang.

(C) Ho ata ha methapo e tsamaisang matla e ne e le tlase ho litoeba tse nonneng (p = 0.002).

(D) Kakaretso ea lifofane tse amanang le tsamaiso ea li-neurone tsohle tse tlalehiloeng.

(E) Chefo e amanang le mokoloto e ne e le tlase haholo ka mor'a ho ja lijo tse fapaneng (lijo le ho tsamaisana ha tsamaiso, F_(1,171) = 14.77, p <0.0002).

(F) Ts'ebetso (e fetotsoe ho tloha Franklin le Paxinos, 1997Ho bonts'a ho beoa ka bongata ka litoeba tse rekotang tse nonneng le tse nonneng (n = 3 ka 'ngoe).

Tlhahlobo ea statistical. (C) teko e nepahetseng ea Fisher. (D le E) Tsela e 'meli ea ho pheta-mehato ea ANOVA.

Mokhoa oa ho khetha

Ho thibela Likarolo tsa Mosebetsi tsa IMSN tsa Tsoelo-Qhooa Metsing e Bohlokoa

E le ho hlahloba hore na ho fokotsa palo ea li-iMSN e ka eketsa ho tsamaea ka litoeba tse ngata, re sebelisitse leano la ho itšetlehile ka Cre-recombinase (Cre) ho hlalosa ho thibela G_ie kopantsoeng ka mofuthu oa kappa opioid receptor designer e sebelisitsoeng feela ke lithethefatsi tse entsoeng ka moqapi (KOR-DREADD) ho iMSNs ea litoeba tse batenya haholo (Setšoantšo sa 4A). Le hoja mouse ea adenosine 2A-receptor Cre (A2A-Cre) e 'nile ea tiisoa ka nako e le' ngoe ka ho itšireletsa mafung ho bontša hore polelo ea Crete e totobetse ho iMSNs e hlaselang (Cui et al., 2013 'me Lemos et al., 2016), Re sebelisitse netefatso e 'ngoe ea mohala ona ka fluorescent e habeli in hybridization. Hoo e ka bang li-neuron tsohle (98.7% ± 0.6% ea 1,301 e baloang li-neuron) li hlahisitse ka bobeli Cre 'me Drd2 mRNA, athe ke ba fokolang haholo (1.3% ± 0.6%) ba hlalositseng Cre or Drd2 mRNA, empa eseng ka bobeli, ho netefatsa hore molaetsa oa A2A-Cre o finyella ka botšepehi iMSNs ( Setšoantšo sa S4).

Setšoantšo sa 4. 

Tšoaetso e kenyelelitsoeng ea DREADD ea iMSNs Ho tsosolosoa Ketsahalo ea Kelello ho Mantsoe a Bobebe

(A) Setšoantšo sa polelo ea KOR-DREADD, le merero (e fetotsoe ho tloha Franklin le Paxinos, 1997) ho bonts'a libaka tsa likokoana-hloko tsa lik'hemik'hale tsa KOR-DREADD tsohle maqebeng a A2A-Cre; opacity e bontša palo ea litoeba tse tšoaetsang kokoana-hloko sebakeng se fanoeng.

(B) Litoeba tse ngata li ile tsa tsamaea haholo ha li entsoe ka SalB ha li bapisoa le DMSO (t₍₇₎ = 3.056, p = 0.02).

(C-G) Ka mor'a ho tsamaisoa ha SalB, litoeba tse ngata li ne li bontša liphetoho tse seng tsa bohlokoa ho (C) mokoloko oa mehato, (D) nako e tloaelehileng ea ho tsamaea, le (E) lebelo la ho tsamaea, ho ea ka ha ho tsamaisoa DMSO. (F) Puso ea Sal-B e ekelitse ho ba le nako ea ho hōlisa (t₍₇₎ = 3.116, p = 0.02), empa (G) ha ea ka ea fetola haholo makhetlo a boitlhopho.

(H) Litoeba tse omeletseng li ile tsa tsamaea haholo ha li entsoe ka SalB ha li bapisoa le DMSO (t₍₉₎ = 3.3, p = 0.01).

(I) SalB ha ea ka ea ama ho sisinyeha ha litoeba tsa mofuta o hlaha tse sa hlahiseng KOR-DREADD (p = 0.77).

Tlhahlobo ea lipalo-palo. (B – I) T ea Seithuti sa Paired t liteko; bolela le litoeba ka bomong; n = 6-10 litoeba / sehlopha.

Mokhoa oa ho khetha

Liente tsa KOR-DREADD agonist salvinorin-B (SalB) li ekelitse sebaka se tsamailoeng ke litoeba tse nonneng tse hlalosang KOR-DREADD (p = 0.02; Setšoantšo sa 4B). SalB e boetse e ekelitse makhetlo a ho holisa (p = 0.02; Setšoantšo sa 4F) le ho etsa hore ho be le mekhoa ea ho eketseha ha makhetlo (t₍₇₎ = 1.64, p = 0.12), empa eseng bolelele kapa lebelo, la motsamao (Litšoantšo 4C-4E). Liente tsa SalB le tsona li eketsehile ho tsamaea ka litoeba tse omeletseng (p = 0.01; Setšoantšo sa 4H), empa eseng litoeba tsa mofuta o hlaha tse sa hlahiseng KOR-DREADD (p = 0.73; Setšoantšo sa 4I). Re etsa qeto ea hore ho fokotsa sehlahisoa sa li-iMSN ho lekane ho eketsa lebelo la liphatsa tsa liphoofolo tse peli tse omeletseng le tse phetseng hantle.

Litekanyo tse fokolang tsa D2R U se ke Ua Etsa Liphoofolo Hore li Fumane Boima ba 'Mele

Qetellong, re ile ra hlahloba hore na ho na le phapang e neng e le teng pele ho pontšo ea D2R e ka 'nang ea etsa hore litoeba tse ling li be le botenya ba ho ja haholo. Ho rarolla potso ena, re ile ra etsa micro-positron emission tomography (micro-PET) le ¹⁸F-fallypride ho fumana boleng ba basebetsi ba D2R pele ho lihlahisoa tsa mafura a mafura a phahameng (Setšoantšo sa 5A). Re hlokometse phapang e phahameng ea ts'ebetsong ea D2R har'a litoeba, joalo ka ba bang ba bontšitse (Constantinescu et al., 2011). Phapang ea batho ka bomong ho fumaneha ha D2R e ne e tsamaellana hantle le motsamao lebaleng le bulehileng (p = 0.045; Setšoantšo sa 5B), e tsamaellanang le karolo ea li-D2R ha li tsamaea. Kamora ho hlahlojoa ha micro-PET, liphoofolo li ile tsa bolokoa lijong tse nang le mafura a mangata bakeng sa libeke tse 18, ho leka hore na litoeba tse nang le li-D2R tse tlase li ka ba tlokotsing ea boima ba 'mele bo bakoang ke lijo. Ho makatsang ke hore re fumane mokhoa o lebisang ho litholoana tse ntle tse kamano lipakeng tsa phumaneho ea pele ea D2R le ho fumana boima ba 'mele tekong ena (p = 0.10; Setšoantšo sa 5C). Le hoja ts'ebetsano ena e se ea bohlokoa, e hanyetsa khopolo ea hore bongata bo fokolang ba D2R kapa ho se sebetse ka tlaase ho 'mele ho etsa hore liphoofolo li kotsing ea ho fumana boima ba' mele. Hona ho ne ho boetse ho lumellana le liphuputso tsa rona tseo e seng karolo ea tšimo e sa bulehileng, kapa mosebetsi oa tšimo o bulehileng hohle tekong eohle, e amanang le boima ba 'mele (Litšoantšo 1F-1K).

Setšoantšo sa 5. 

Basal D2R Binding ha ea ka ea bolela esale pele Bokamoso bo fumanoang

(A) Mohlala o fumanehang D2R micro-PET o fumaneha ka striatum le cerebellum e sebelisoang ¹⁸F-fallypride.

(B le C) (B) Matla a tlamang a amanang le motsamao oa basal open field movement (r = 0.56, p = 0.045), le (C) ba tloaetseng ho ba le kamano e ntle le mafura a bakoang ke ho ja lijo tse nang le mafura a mangata (r = 0.50, p = 0.10, n = litoeba tse 12-14).

(D) Boemeli ba D2R bo ikemetseng ka litoeba tse nang le li-D2R tse sa tšoaneng (ka holimo) le iMSN-Drd2-KO litoeba (ka tlase).

(E le F) (E) iMSN-Drd2-KO litoeba li fokolitse mosebetsi oa boipheliso tšimong e bulehileng (t₍₈₎ = 2.99, p = 0.02) le (F) ka mabili a marang-rang a matha (p = 0.01, n = 5-19 litoeba / sehlopha).

(G) iMSN-Drd2-KO litoeba le Drd2lisebelisoa tsa littermate tse nang le lisebelisoa li fumane boima bo lekanang le ho ja lijo tse ngata (F_(5,70) = 1.417, p = 0.23; n = 6-10 litoeba / sehlopha).

(H – J) (H) Ho ne ho se na phapang e kholo ts'ebeliso ea matla a tloaelehileng (p = 0.60), (I) tšebeliso ea matla (p = 0.47), kapa (J) RER (p = 0.17) lipakeng tsa iMSN-D2R-KO litoeba le lits'oants'o tsa litšila.

Tlhahlobo ea statistical. (B le C) Ts'ebetso e tloaelehileng; (E, F, le H-J) tlhahlobo ea Seithuti e sa sebetseng; (G) ka makhetlo a mabeli-makhetlo a mabeli ANOVA, ^*p <0.05.

Mokhoa oa ho khetha

Ho tsoela pele ho hlahloba kamano pakeng tsa liphapang tsa pele ho teng le likarolong tsa mosebetsi le ho fumana boima ba 'mele, re sebelisitse mokhoa oa ho etsa liphatsa tsa lefutso ka mokhoa oa ho tlosoa Drd2 liphatsa tsa lefutso ho tloha ho iMSNs (iMSN-Drd2-KO) empa e boloketsoe polelo ka mefuta e meng ea sele ( Dobbs et al., 2016 'me Lemos et al., 2016). Joalokaha ho boletsoe pejana, iMSN-Drd2Litoeba tsa -KO li tsamaile ka tlase ho taolo ea litsila sebakeng se bulehileng (p = 0.02; Setšoantšo sa 5E) le mabiling a ntlo ea ntlo (p = 0.01; Setšoantšo sa 5F). Tumellanong le liteko tse ka holimo, iMSN-Drd2Litoeba -KO ha lia ka tsa nona boima ho feta taolo ea tsona ha li beoa lijong tse nang le mafura a mangata (p = 0.23; Setšoantšo sa 5G). E le hore re hlahlobe matla a bona a ho sebelisa matla, re ile ra etsa liteko tse sa tobang tsa lik'hamera ho bapisa iMSN-Drd2-KO litoeba ho laola litsila tse lahliloeng. Ha rea ​​hlokomela phapang e kholo ea tšebeliso ea matla (p = 0.60), tšebeliso ea matla (p = 0.47), kapa karolelano ea phapanyetsano ea phefumoloho (RER) (karolelano ea CO₂ tlhahiso ho O₂ ho sebelisoa [VCO₂/ VO₂], p = 0.17) lipakeng tsa litoeba tsa iMSN-Drd2-KO le lits'oants'o tsa tsona tsa litšila, ho bonts'a hore phokotso ea motsamao oa litoeba tsa IMSN-Drd2-KO ha ea ka ea fetolela liphetoho ts'ebelisong ea matla (Litšoantšo 5H-5J). Qetellong, re ile ra hlahloba hore na ho fokotsoa ho fokolang ha D2R (e kang e fumanoang litoebeng tsa rona tse feteletseng) ho ka fokotsa ho tsamaea le boima ba 'mele. Ho etsa sena, re sebelisitse mola oa mouse o fellang ho 30% -40% ea ho fokotseha ha o hlasela Drd2 mRNA (iMSN-Drd2-Het) ( Lemos et al., 2016). Litoeba tsena li boetse li bonts'a motsamao o fokotsehileng, ho bonts'a hore ho kokota ha karoloana ea D2R ho lekane ho hlahisa likhaello tsa makoloi (p = 0.04; Setšoantšo sa S5A). Ho tšoana le litoeba tsa iMSN-Drd2-KO, litoeba tsa iMSN-Drd2-het li ne li sa hlaseloe habonolo ke mafura a mangata a bakoang ke ho ja lijo tse matlafatsang (p = 0.89; Setšoantšo sa S5B). Re etsa qeto ea hore liphetoho li-D2R tse hlaselang li lekane ho fetola mokhoa oa ho tsamaea, empa ha li lekane le caloric kapa boima ba 'mele ho litoeba.

Puisano

Botenya bo amahanngoa le ho se sebetse, ha hangata ho lumeloa hore ho tlatsetsa boima ba 'mele. Ho phaella moo, ho eketseha hoa matla ho fetisetsoa ho kenya letsoho maemong a tlaase a mesebetsi ho batho ba nang le botenya haholo (Ekkekakis le Lind, 2006 'me Westerterp, 1999), le hoja khopolo ena e le thata ho leka ka ho toba. Ho thahasellisang ke hore batho ba fokolang boima ba 'mele ba sebelisa lijo (de Boer et al., 1986, de Groot et al., 1989, Martin et al., 2007 'me Redman et al., 2009) kapa opereishene ea bariatric (Berglind et al., 2015, Berglind et al., 2016, Bond et al., 2010 'me Ramirez-Marrero et al., 2014) u se ke ua eketsa lits'ebeletso tsa bona, ho ngangisana le boima ba boemo bo bakang ho se sebetse. Ha re le mona, re ile ra batlisisa khopolo ea hore botenya bo bakoang ke ho ja bo bakoang ke ho ja bo bongata bo baka ho se sebetse ka tsela e fokolang ka phetisetso ea AIDS e hlaselang. Tumellanong le mosebetsi o fetileng, re fumane hore lijo tse sa foleng tse ngata tse fokolang li fokotsehile ho thibela ho hlasela D2R (Hajnal et al., 2008, Huang et al., 2006, Narayanaswami et al., 2013, van de Giessen et al., 2012 'me van de Giessen et al., 2013). Hape re bone phaello ea ho thunngoa ha likoloi tsa li-neurons tse hlaselang liphiring tse ngata haholo. Ho thibela iMSN ka G_iDREADD e kopantsoeng e pholositsoe ts'ebetsong ka litoeba tse ngata, ho bontša hore litoeba tse nang le matla a mangata li ka tsamaea ka mokhoa o tloaelehileng ha tlhahiso ea basal gangne ​​e tsosolosoa. Leha ho le joalo, ho tsotehang, leha ho le joalo, litekanyo tsa basebetsi tsa D2R kapa lisebelisoa tsa 'mele li amana le boima ba' mele, ntlha eo re e boneng litekong tse ngata. Sena se fapana le thuto ho likhoto, tse ka 'nang tsa bontša mefuta e fapaneng kapa liteko tsa teko (Michaelides et al., 2012). Re etsa qeto ea hore ho fokotseha ha D2R le ho se sebetse ka tsela e itseng ea 'mele ke liphello tsa botenya, empa ha ho joalo hore li kopantsoe ho ntlafatsa boima ba litoeba.

Tšebelisano pakeng tsa pontšo ea D2R e fetotsoeng le botenya e ile ea fumanoa pele ho batho 'me qalong e ile ea qaptjoa ke ba bang (de Weijer et al., 2011, Kessler et al., 2014, Volkow et al., 2008 'me Wang et al., 2001). Leha ho le joalo, mosebetsi oa morao-rao o 'nile oa re potso ena ke potso (Caravaggio et al., 2015, Cosgrove et al., 2015, Dunn et al., 2012, Guo et al., 2014, Karlsson et al., 2015, Karlsson et al., 2016, Steele et al., 2010 'me Tuominen et al., 2015). Le hoja ho etsoa lipatlisiso tse eketsehileng ho utloisisa ho se lumellane ho etsoang lipakeng tsa lithuto tsa litsebi, li ka 'na tsa bonahatsa lintho tse rarahaneng tse amanang le lithuto tsa bongaka le litšoantšo tsa PET. Ka mohlala, raclopride, radio-ligand e sebelisoang lithutong tse ngata, e ka lelekoa ke DA e sa mameleng, kahoo ho tlamisoa ho ka susumetsoa ke ho se tšoane ha molumo oa DA oa basal (Horstmann et al., 2015). Ho phaella moo, kamano pakeng tsa litekanyetso tsa D2R le botenya bo ka 'na ba e-ba bo sa tloaelehang, joalo ka hore liphetoho li-D2R li ka etsahala ka tsela e fapaneng ho bakuli ba nang le botenya bo fapaneng ba botenya (Horstmann et al., 2015). Qetellong, lintlha tse kang nako ea boroko (Wiers et al., 2016) le ho noa ka caffeine (Volkow et al., 2015) e ka boela ea ama D2R, 'me ha e tlalehe kapa e laoloa lithutong tse ngata tsa kliniki. Mehloli ena ea phapang e ka fokotsoa lithutong tsa liphoofolo, e leng setšoantšo se ts'oanang sa ho fokotseha ha meriana ea D2R (Mathes et al., 2010 'me Zhang et al., 2015), protheine (Adams et al., 2015 'me Johnson le Kenny, 2010), le receptor ho tlama (Hajnal et al., 2008, Huang et al., 2006, Narayanaswami et al., 2013, van de Giessen et al., 2012 'me van de Giessen et al., 2013) ka feta li-rite. Mosebetsi oa rona o fetisetsa sehlopha sena sa lingoliloeng ka ho tlaleha hore likarolo tse ling tsa ts'ebetso ea DA li lula li sa fetohe litoeba tse ngata, esita le tse fokotsang li-D2R. Ho phaella moo, re fane ka ho fokotseha ha rona ho boloka D2R ³H-spiperone, empa ha ho phetoho pholong e feletseng ea D2R kapa Drd2 MRNA, re lumela hore liphetoho ho D2R li ka 'na tsa akarelletsa liphetoho tsa morao-phetolelo tse kang receptor internalization. Le hoja dintlha tsa rona di bontša hore ho fokotsa d2R ho lekanyetsa ho fokotsa ts'ebetso ea 'mele ka botenya, ho ikoetlisa ho susumetsoa ke maemo a mangata ho akarelletsa le liphatsa tsa lefutso le tikoloho ( Bauman et al., 2012). Re lumela hore ha ho bonahale hore D2R ke eona feela phetoho ea meriana e amanang le ho se sebetse ho hoholo ho feta tekano. Ka mohlala, liphetoho tse tsamaisang li-hormone tse kang ghrelin, leptin le insulin li etsa li-neuron tsa dopaminergic 'me li ka susumetsa mosebetsi (Murray et al., 2014). Qetellong, le hoja re sa ka ra bona liphetoho ho D1Rs, re ke ke ra khona ho etsa liphetoho ka ho thunngoa ha neuronal ea litsela tse tobileng tse ka boela tsa ama tšebetso ea 'mele.

Ha ho hlaka hore na phapang ea ho fumaneha ha D2R e etsa hore batho ba be le boima ba 'mele. Batho ba nang le Drd2 Taq1A e feletse e fokotsitse ho fumaneha ha D2R le kotsi e eketsehileng ea ho nona haholo ( Blum et al., 1996, Mmetli le al., 2013, Noble et al., 1991, Stice et al., 2008 'me Thompson et al., 1997). Ho phaella moo, litoeba tse nang le ho tlosoa ha D2R ka ho fetisisa lefatšeng li ile tsa fumana boima bo phahameng ka ho ja lijo tse ngata, tse neng li bitsoa ho se sebetse hantle (Beeler et al., 2015). Ka lehlakoreng le leng, ho fapana ha tlhaho (tlhaho kapa tlhahiso ea liphatsa tsa lefutso) ka D2R e hlaselang e amana le litekanyetso tsa liketsahalo thutong ea rona, empa ha ho na letho le amanang le boima ba 'mele. Phapang ea bohlokoa thutong ea rona e ne e le hore mokhoa oa rona oa liphatsa tsa lefutso o tlosa D2Rs feela ho tloha ho iMSNs. Ho phaella moo, litekanyo tse hlokolosi tsa tšebeliso ea lijo le matla a matla a lijo li senoletse hore ho hlophisa D2s ho li-neurone tsena ha hoa fetola matla a tekanyo ea matla. Ka hona, liphuputso tse bontšang likopano pakeng tsa mosebetsi oa lefats'e la D2R le matla a tekanyo ea matla a ka 'na a shebella liphello tsa D2R ka mefuta e meng ea sele. Liteko tsa rona li tšehetsa qeto ea hore ho se sebetse ke phello ea botenya empa ka boeona ha hoa lekana ho etsa liphetoho boima ba 'mele.

Ho sa tsotellehe bopaki bo ntseng bo eketseha ba hore ho ikoetlisa ho amana le ntlafatso ea bophelo bo botle ba pelo le ho fokotsa kotsi bakeng sa mafu a mang a mangata a sa foleng, ho ikoetlisa ho lula ho le tlaase ho batho ba nang le botenya haholo (Ekkekakis et al., 2016). Ho haelloa ke mehato e atlehileng ea ho eketsa litebelisuoa tsa 'mele ho bontšoa ka ho hloka kutloisiso ea mekhoa ea lisele le ea limolek'hule tse etsang hore batho ba nang le botenya ba se ke ba khona ho sebetsa. Ha re le moo, re kopanya ho se sebetse ha 'mele ho fetola liphetoho tsa basal ganglia, ho fana ka tlhaloso ea likokoana-hloko ka lebaka la ho haelloa ke ho ikoetlisa ho batho ba nang le botenya.

Mekhoa ea Boiteko

Lihlooho le Lijo

Lithutong tsohle, litoeba li ne li lula ka bonngoe tlasa maemo a tloaelehileng (leseli la 12-hr / potoloho e lefifi, 21-22 ° C), ka phihlello ea libitum ea lijo le metsi. Litoeba li fuoe lijo tse tloaelehileng tsa chow (5001 Rodent Diet; 3.00 kcal / g le 29% eneji e tsoang liprotheine, 13% mafura, le 56% ho tsoa khabohaedreite; LabDiet) kapa phepo e mafura a mangata (D12492; 5.24 kcal / g le Matla a 20% a tsoang liprotheine, 60% ho tsoa mafura, le 20% ho tsoa k'habohaedreite; Lipatlisiso tsa Lijo). Mekhoa eohle e ile ea etsoa ho latela tataiso ho tsoa ho Komiti ea Tlhokomelo ea liphoofolo le Ts'ebeliso ea Setsi sa Naha sa Lefu la Ts'oaetso le Ts'oaetso le Mafu a liphio.

Ho kokota ka tsela e feteletseng ea i-NMSN-Drd2-Li-mouse tsa KO li ne li hlahisoa ke ho tšela litoeba tse hlalosang Cre tse khannoang ke likarolo tse laoloang tsa liphatsa tsa lefutso tsa adenosine 2A (Adora2a) (B6.FVB (Cg) -Tg (Adora2a-Cre) KG139Gsat / Mmucd; GENSAT; 036158-UCD) e nang le litoeba tse nang le maemo Drd2 Li-alle alleles B6.129S4 (FVB) -Drd2^{tm1.1Mrub / J}, JAX020631 (Bello et al., 2011).

Ho ikamahanya ha 'mele le Matšeliso a Matla a Matla

Sebopeho sa 'mele se ne se lekanngoa libeke tse ling kaofela ¹H-NMR spectroscopy (EchoMRI-100H; Echo Medical Systems). Matšeliso a matla a matla a ne a ikemiselitse ho sebelisa tekanyo ea ho lekanya matlaGuo et al., 2009 'me Ravussin et al., 2013):

Energyexpenditure = Metabolizableenergyintake- (Δfatmass + Δfat-freemass).

Bulela MathJax

Mosebetsi o sa bulehileng

Liteko tsa masimo a bulehileng li ne li khannoa litsing tsa PhenoTyper (30 × 30 cm; Noldus IT), le software ea EthoVision ea tlhahlobo ea video (Version 11; Noldus IT) e ne e sebelisetsoa ho latela litoeba nakong eohle ea liteko.

Home Cage Wheel Running

Ho matha mabili ho ne ho lekanngoa ka ho beha mabili a boemo bo tlase a sa sebetseng mohala (Med Associates) ka matlong a litoeba malapeng a 72 hr libeke tse ling le tse ling tse 3 (liteko tse bakoang ke ho nona) kapa ka ho tsoelang pele (iMSN-Drd2-KO liteko).

Mehato ea Mali

Mali a li-ocular veine ho tloha liphoofolong tse entsoeng ka mahlabelo a ne a sebelisetsoa ho hlahlojoa metabolites le lihomone tsa serum ka mor'a 4-hr ka potlako.

Dopamine Receptor Autoradiography

Li-hemisection tsa ka ho le letona li ile tsa khetholloa boemong ba striata (-0.22, 0.14, 0.62, le 1.18 mm ho tloha bregma, e koahelang boholo ba striatum) likarolong tsa 12-mm. Li-slide li ile tsa qhibilihisoa 'me tsa tlatsetsoa ka har'a buffer ea liteko (20 mM HEPES, 154 mM NaCl, le 0.1% bovine serum albumin [BSA]; pH 7.4) bakeng sa 20 min ho 37 ° C. Ho tlama D1R ho ile ha hlahlojoa ka ho kenya li-slide mochini oa liteko o nang le 1.5 nM tritium e ngotsoeng SCH-23390 (Perkin-Elmer) le 100 nM ketanserin bakeng sa 60 min ho 37 ° C. Ho tlama D2R ho ile ha hlahlojoa ka ho kenya li-slide ka 600 pM tritium-labeled spiperone (Perkin-Elmer) le 100 nM ketanserin bakeng sa 100 min ho 37 ° C. Kamora ho kenella ka radioligand e loketseng, li-slide li ile tsa hlatsuoa habeli bakeng sa 10 min ho 4 ° C mochini oa ho hlatsoa (10 mM Tris-HCl, 154 mM NaCl), ebe e kenella ka metsing (0 ° C) ebe e lumelloa ho omella bosiu bo le bong. Li-slide li ile tsa pepesetsoa lipoleiti tsa phosphor-imaging bakeng sa 7 (D1R e tlamang) kapa matsatsi a 11 (D2R e tlamang) mme ea ntlafatsoa ho sebelisoa phosphoimager (Leholiotsoana; Perkin-Elmer). Bakeng sa tlhahlobo, libaka tse khahlisang li hlalositsoe le ho hlahlojoa ho sebelisoa software ea Optiquant ea tlhahlobo ea litšoantšo (Perkin-Elmer).

Bophirimela ba Blotting

Li-blots tsa Bophirimela li ne li kenngoa ka mouse ea anti-D2DR antibody (1: 500; Santa Cruz; sc-5303) kapa mouse anti-GAPDH antibody (1: 1,000; Santa Cruz; sc-32233) 'me ka mor'a moo ka poli-anti-mouse IgG- HRP (1: 1,000; Santa Cruz; sc-2005). Pontšo ea chemiluminescence e ne e entsoe ka ho sebelisa li-chemiluminescence tse ka bophirimela tse thibelang li-reagents (Bio-Rad) le visualized ka Chemidoc Imaging System (Bio-Rad).

In Hybridization In Situation

Sesebelisoa sa RNAscope multiplex fluorescent assay kit se sebeliselitsoe in situ hybridization (Advanced Cell Diagnostics). Ka bokhutšoanyane, likarolo tse sa fetoheng tsa formalin li ne li felloa ke metsi ka har'a ethanol e ileng ea lateloa ke ho pepeseha ha protease. Likarolo li ile tsa ntlafatsoa ka li-probes tsa RNAscope oligonucleotide khahlanong le tsona Drd2. Ka mor'a ho ts'oaea ha lisebelisoa, li-slide li ne li kenngoa ka pontšo ea amplifier ho latela li-protocol tsa RNAscope. Ka mor'a moo lilabola li hlatsuoa ka mochine o hlatsoang oa RNAscope. Qetellong, li-slide li ne li kentsoe ka DAPI counterstain.

Chromatography e Phahameng ea Ts'ebetso e Nang le Likokoana-hloko tsa Electrochemical

Ho fokotsa ho hlasela ho ile ha sebelisoa bakeng sa ho lemoha ha DA e sebelisang chromatography e phahameng ea likarolo tse phahameng tse sebetsang ka matla le ho hlahloba electrochemical (HPLC-EC), joalokaha ho hlalositsoe pele (Kilpatrick et al., 1986).

Tyrosine Hydroxylase Immunohistochemistry

Likarolo tse kentsoeng ka li-slide li ile tsa hlophisoa ka 10% e sa jeleng paate, e hlatsoitsoeng ka 0.1 M TBS (pH 7.5) mme e kenngoe ka tharollo ea mantlha ea antibody e nang le 3% serum e tloaelehileng ea esele, 0.3% Triton X-100, le anti-tyrosine hydroxylase antibody (1: 1,000; Millipore; MAB152) bosiu bo le bong ho 23 ° C. Letsatsing le hlahlamang, likarolo tsa lisele li ile tsa hlatsuoa ho TBS mme tsa kenella ka tharollo ea bobeli ea li-antibody e nang le 3% serum e tloaelehileng ea esele, 0.3% Triton X-100, le anti-mmutla ea poli e kopantsoeng le Alexa Fluor 555 (Millipore; AQ132F). Bakeng sa toeba e 'ngoe le e' ngoe, ho ile ha hlahlojoa likarolo tse peli tsa striatal, ntle le litoeba tse 'ne (tse peli tsa HFD, tse peli tsa Chow) moo karolo e le' ngoe feela e ileng ea hlahlojoa ka lebaka la lisele tse mpe kapa boleng ba setšoantšo.

Micro-PET

Litoeba li ne li kenngoa ka tsona ¹⁸F-fallypride e nang le ts'ebetso e ikhethileng ea 2.5 ± 0.34 mCi / nmol ka bophahamo ba 130 μL ka methapo ea mohatla ha e le tlasa anofhesia ea isoflurane. Sesepa sa micro-PET se entsoe ka hr ea 2, nakong eo liforeimi tse 25 li fumanoeng bakeng sa tlhahlobo. Nako ea ketsahalo ea nako ea ¹⁸F-e hlaselang libakeng tse thahasellisang (ROIs) e ne e ntšitsoe ka ho sebelisa software ea AFNI (https://afni.nimh.nih.gov/afni) le likarolo tsa kinetic li ne li lekana le mekhoa e mene ea lik'haravene e sebelisang MATLAB script (e nang le cerebellum e sebelisoang e le lisebelisoa tsa litokomane) ho fumana hore na D2R e ka tlama eng (Lammertsma le Hume, 1996).

Ho Vivo Electrophysiology

Lirekoto li entsoe ka mofuta oa eleketrode o nang le li-microwires tse 32 tsa Teflon-coated tungsten (35-mm bophara) e kentsoeng unilaterally ho dorsomedial striatum (anterior / posterior [A / P]: +0.8; medial / lateral [M / L]: +1.5 ; mokokotlo / moea [D / V]: −2.6 mm ka bregma), 'me e sebetsoa ka software ea khoebo (Offline Sorter le Neuroexplorer; Plexon).

Stereotaxic Injecting ea Vector ea Viral

Litoeba li ile tsa koaloa hanyane ka ponaletso ea isoflurane. Hang ha e thethefalitsoe ka botebo, ho ile ha etsoa lehare le le leng haufi le midline, lehata la pepesoa, mme craniotomy ea linaha tse peli ea etsoa (A / P: +0.5; M / L: ± 1.5 mm ka bregma). Vector vector e nang le thibelo ea KOR-DREADD (Syn-DIO-hKORD-IRES-mCit-WPRE; 0.5 μL) e ile ea kenoa kahare ho dorsomedial striatum (D / V, -2.8 mm ho tloha kaholimo ho lehata) mme ea lumelloa ho hlahisa bakeng sa Libeke tse 9 pele ho liteko.

No-Net Flux Microdialysis le Dopamine Analysis

Litekanyo tsa basal extracellular DA, DOPAC, le HVA ho dorsal striatum ea litoeba li entsoe ka mokhoa oa no-net flux microdialysis. Unilateral 2-mm probes (18-kDa membrane cutoff) li ile tsa kenngwa stereotaxically beke ea 1 kamora ho kenngwa ha cannula ka pompo e tsoelang pele ea mokelikeli oa maiketsetso oa cerebrospinal fluid (aCSF) ho 1 μL / min bakeng sa 4 hr pele ho pokello ea sampole (bona Mekhoa ea Tlhahlobo ea Litlhahiso). Ha ho na teko ea phallo ea marang-rang ea ho lekanya maemo a DA a kantle ho lisele a ileng a etsoa ka ho qhekella maemo a tšeletseng a fapaneng a DA (0, 2.5, 5, 10, 20, le 40 nM) ho aCSF ka lipatlisiso tsa dialysis. Khokahano e ngoe le e ngoe ea DA e sentsoe ka metsotso e 30, ebe sampole ea 2 × 10-min e bokelletsoeng ho 2.5 μL ea 100 mM HCl le 1 mM EDTA ho thibela ho senyeha ha catecholamine le ho hatsela ho -80 ° C. Bakeng sa litlhahlobo tsa methapo ea methapo, tsamaiso ea semolao ea HPLC e kopaneng le tlhahlobo ea amperometric e sebelisitsoe (HPLC-EC; BASi LC-4C). Ke litoeba feela tse nang le ts'ebetso e nepahetseng ea lipatlisiso tse kenyellelitsoeng tlhahlobisong (Setšoantšo sa S3E).

Lipalo-palo li

Tlhahlobo ea lipalo-palo e entsoe ho sebelisoa GraphPad Prism (Version 6.07; Software ea GraphPad). Ntle le ha ho boletsoe, Seithuti sa mehatla e 'meli se ile sa sebelisoa. Ho seng joalo, li-tail tse peli tse nang le mehatla e 'meli, mehato e pheta-phetoang ea li-ANOVA kapa mehato e pheta-phetoang ea li-ANOVA e sebelisitsoe ha ho loketse joalo ka ha ho boletsoe. Li-ANOVA li ile tsa lateloa ke t liteko tsa papiso ea poso. Liphetho li ne li nkuoa li le bohlokoa ho alpha ea p <0.05, kapa ka alpha e khethiloeng ke Bejamini-Hochberg sekhahla sa ho sibolla leshano (FDR), moo ho loketseng.

Menehelo ea Mongoli

DMF, KD, TJO, MS, AK, IPSGRVAA, MR, KDH le AVK, ba thehile liteko. DMF, KD, TJO, MS, le AVK, ba ile ba etsa le ho sekaseka liteko tsa boits'oaro. IP e entse liteko tsa ho hlakola bophirima. DMF, le AVK li sebelitse le ho hlahlojoa ka vivo data ea electrophysiological. DMF, J.-SL, JG, le AVK li entse le ho lekola liteko tsa micro-PET. DMF, KD, TJO, le AVK ba ngotse buka eo e ngotsoeng ka letsoho. Bangoli bohle ba buile ka liphetho mme ba fana ka maikutlo ka sengoloa se ngotsoeng ka letsoho.

lumela hore baa fokola

Mosebetsi ona o ne o tšehetsoa ke Lenaneo la Lipatlisiso la Ntaramane ea NIH, Setsi sa Sechaba sa lefu la tsoekere le mafu a likobo le a liphio (NIDDK). Re rata ho leboha Metabolism Core ho NIDDK bakeng sa ho hlahloba metabolites le lihomone tsa serum, Andres Buonanno ka thuso ea hae ho theha dopamine microdialysis liteko, le Dr. Judith Walters, Dr. Kristin Dupre le Dr. Claire Delaville ho thusoa le HPLC tlhahlobo ea lisele tsa dopamine. Hape re rata ho leboha Dr. Scott Young bakeng sa tšebeliso ea lisebelisoa tsa hae tsa laboratori le thuso ka lithuto tse tlamang. Ke leboha le litho tsa laboratori ea AVK, Marc Reitman, le Nick Ryba bakeng sa ho kenya letsoho moqapi oa liteko le ho bala ka hloko se ngotsoeng ka letsoho.

Boitsebiso bo tlatsetso

Tokomane S1. Litsela le litekanyetso tsa liteko tsa S1-S5.

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Tokomane S2. Article hammoho le Supplemental Information.

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Ho qotsa lihlooho (220)

20.   

• Kessler et al., 2014
• RM Kessler, DH Zald, MS Ansari, R. Li, RL Cowan
• Liphetoho tsa dopamine ho lokolloa le dopamine D2 / 3 sekhahla sa mokuli le tsoelo-pele ea boima bo bobe
• Synapse, 68 (2014), maq. 317-320
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Ho qotsa lihlooho (18)

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• Kilpatrick et al., 1986
• IC Kilpatrick, MW Jones, OT Phillipson
• Tsela ea ho hlahloba litapole tsa catecholamine, li-indoleamines le metabolite e meng e tummeng libakeng tse nyenyane tsa tsamaiso ea methapo: mokhoa oa HPLC oa puso ea Molimo o sebelisang tlhahlobo ea li-coulometric le tlhahiso e nyane ea sesebelisoa
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Ho qotsa lihlooho (167)

2.      

• Kravitz et al., 2010
• AV Kravitz, BS Freeze, PR Parker, K. Kay, MT Thwin, K. Deisseroth, AC Kreitzer
• Tlhophiso ea mekhoa ea likoloi tsa li-parkinsonia ka ho laola optogenetic ea potoloho ea basal ganglia
• Tlhaho, 466 (2010), maq. 622-626
• CrossRef

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Ho qotsa lihlooho (591)

3.      

• Lammertsma le Hume, 1996
• AA Lammertsma, SP Hume
• Tlhahlobo e bonolo ea litlhaku tsa lipatlisiso tsa PET
• Nako ea mokokotlo, 4 (1996), maq. 153-158
• Sehlooho se

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Ho qotsa lihlooho (1170)

4.      

• Le Moine le Bloch, 1995
• C. Le Moine, B. Bloch
• D1 le D2 dopamine receptor liphatsa tsa lefutso ho ratatum ea rat: manonyeletso a cRNA a bontšang khethollo e hlaheletseng ea meriana ea D1 le D2 ho batho ba ikhethileng ba neuronal ba sekhahla le li-ventral striatum
• J. Comp. Neurol., 355 (1995), maq. 418-426
• CrossRef

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Ho qotsa lihlooho (382)

5.      

• Lemos et al., 2016
• JC Lemos, DM Friend, AR Kaplan, JH Shin, M. Rubinstein, AV Kravitz, VA Alvarez
• Ho fetisoa ha GABA ho khanna bradykinesia ka mor'a ho lahleheloa ke dopamine D2 ho amohela pontšo
• Neuron, 90 (2016), maq. 824-838
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6.      

• Levey et al., 1993
• AI Levey, SM Hersch, DB Rye, RK Sunahara, HB Niznik, CA Kitt, DL Price, R. Maggio, MR Brann, BJ Ciliax
• Sebaka sa sebaka sa D1 le D2 dopamine receptors bokong le li-antibodies tse itseng
• Proc. Natl. Acad. Sci. USA, 90 (1993), maq. 8861-8865
• CrossRef

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Ho qotsa lihlooho (410)

7.      

• Martin et al., 2007
• CK Martin, LK Heilbronn, L. de Jonge, JP DeLany, J. Volaufova, SD Anton, LM Redman, SR Smith, E. Ravussin
• Phello ea thibelo ea lik'halori bakeng sa ho phomola tekanyo ea lik'hemik'hale le ho ikoetlisa
• Botenya (Silver Spring), 15 (2007), maq. 2964-2973
• CrossRef

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Ho qotsa lihlooho (99)

8.      

• Mathes et al., 2010
• WF Mathes, DL Nehrenberg, R. Gordon, K. Hua, T. Garland Jr., D. Pomp
• Dopaminergic dysregulation ho litoeba tse iketselitseng ho ikoetlisa ka tsela e feteletseng kapa botenya haholo
• Behav. Boemo Res, 210 (2010), maq. 155-163
• Sehlooho se

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Ho qotsa lihlooho (48)

9.      

• Michaelides et al., 2012
• M. Michaelides, PK Thanos, R. Kim, J. Cho, M. Ananth, GJ Wang, ND Volkow
• Papiso ea PET e bolela esale pele hore na boima ba 'mele le bokhoni ba cocaine bo tla ba joang nakong e tlang
• Nako ea mokokotlo, 59 (2012), maq. 1508-1513
• Sehlooho se

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Ho qotsa lihlooho (24)

10.   

• Murray et al., 2014
• S. Murray, A. Tulloch, MS Gold, NM Avena
• Mekhoa ea Hormonal le ea neural ea lijo, moputso le boitšoaro bo botenya
• Nat. Rev. Endocrinol., 10 (2014), maq. 540-552
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Ho qotsa lihlooho (36)

11.   

• Narayanaswami et al., 2013
• V. Narayanaswami, AC Thompson, LA Cassis, MT Bardo, LP Dwoskin
• Botenya bo bakoang ke ho ja lijo: ts'ebetso ea dopamine ea ho tsamaisa, ho se ts'oane le ho susumetsa
• Int. J. Obes., 37 (2013), maq. 1095-1103
• CrossRef

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Ho qotsa lihlooho (26)

12.   

• Noble et al., 1991
• EP Noble, K. Blum, T. Ritchie, A. Montgomery, PJ Sheridan
• Mokhatlo o hlophisitsoeng oa liphatsa tsa lefutso tsa D2 dopamine receptor tse nang le litšobotsi tsa ho amohela joala
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• CrossRef

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Ho qotsa lihlooho (470)

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• Ramirez-Marrero et al., 2014
• FA Ramirez-Marrero, J. Miles, MJ Joyner, lefu la TB
• Boikoetliso bo ikhethang le bo ikemetseng bo etsoang ka morao ka mor'a ho buuoa, batho ba baholo ba nang le bokooa bo feteletseng le ba nang le boits'oaro: ho kopana le ho hlophisa 'mele le ho fokotsa pelo
• J. Mmele. Nka khato. Bophelo, 11 (2014), maq. 145-151
• CrossRef

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Ho qotsa lihlooho (3)

14.   

• Ravussin et al., 2013
• Y. Ravussin, R. Gutman, CA LeDuc, RL Leibel
• Ho lekanyetsa litšenyehelo tsa matla ho litoeba ho sebelisa mokhoa oa ho leka-lekanya matla
• Int. J. Obes., 37 (2013), maq. 399-403
• CrossRef

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Ho qotsa lihlooho (15)

15.   

• Redman et al., 2009
• LM Redman, LK Heilbronn, CK Martin, L. de Jonge, DA Williamson, JP Delany, E. Ravussin, Sehlopha sa Pennington CALERIE
• Litšenyehelo tsa metabole le tsa boitšoaro ho arabela thibelo ea lik'halori: sepheo sa ho boloka boima ba 'mele
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• Sharma et al., 2015
• S. Sharma, A. Merghani, L. Mont
• Ho ikoetlisa le pelo: botle, bobe le bobe
• EUR. Heart J., 36 (2015), maq. 1445-1453
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17.   

• Steele et al., 2010
• Ke Steele, GP Prokopowicz, MA Schweitzer, TH Magunsuon, AO Lidor, H. Kuwabawa, A. Kumar, J. Brasic, DF Wong
• Liphetoho tsa li-receptor tse ka sehloohong pele le ka morao li hlahisa opereishene
• Lihlahisoa. Surg., 20 (2010), maq. 369-374
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Ho qotsa lihlooho (85)

18.   

• Stice et al., 2008
• E. Stice, S. Spoor, C. Bohon, DM Nyenyane
• Likamano pakeng tsa botenya le ho arabela ka mokhoa o fokolang oa lijo li nkiloe ke TaqIA A1 allele
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• Thompson et al., 1997
• J. Thompson, N. Thomas, A. Singleton, M. Piggott, S. Lloyd, EK Perry, CM Morris, RH Perry, IN Ferrier, JA Lekhotla
• D2 dopamine receptor liphatsa tsa lefutso (DRD2) Taq1 A polymorphism: fokotsoe dopamine D2 receptor e tlamang karolong ea motho e amanang le mohopolo oa A1
• Pharmacogenetics, 7 (1997), maq. 479-484
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• Tuominen et al., 2015
• L. Tuominen, J. Tuulari, H. Karlsson, J. Hirvonen, S. Helin, P. Salminen, R. Parkkola, J. Hietala, P. Nuutila, L. Nummenmaa
• Aberrant mesolimbic dopamine-opiate ho buisana ka botenya
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• van de Giessen et al., 2012
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• Mefuta e phahameng ea mafura a khetholloang le e se nang khethollo e ama tsoalo ea datalin dopamine D2 / 3 receptor, lijo tsa caloric, le adiposity
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2.      

• van de Giessen et al., 2013
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• Boikarabello bo phahameng ba mafura / lik'habohaedreite empa ha e sebelise matla a mangata ho etsa hore ho be le bothata bo fokolang ba D2 / 3 ho fumanoa ke botenya bo bakoang ke ho ja haholo
• Int. J. Obes., 37 (2013), maq. 754-757
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3.      

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• Sehlooho se

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