Karolo ea ghrelin ka lijo moputso: phello ea ghrelin ka sucrose ho iketsetsa tsamaiso le mesolimbic dopamine le acetylcholine liphatsa tsa lefutso polelo (2012)

PMCID: PMC3298643

Sehlooho sena se bile teng e boletsoeng ke lihlooho tse ling ho PMC.

Eya ho:

inahaneloang

Qeto ea ho ja e susumetsoa haholo ke lintho tse seng malapeng tse kang ho latsoeha ha lijo. Ka 'nete, boleng bo khotsofatsang le bo susumetsang ba lijo bo ka feta lipontšo tsa homeostatic, tse lebisang ho ts'ebetsong e ntseng e eketseha mme ka hona, botenya. Ghrelin, hormone ea orexigenic e tsoang ka maleng, e na le karolo ea bohlokoa phepelong ea homeostatic. Haufinyane, leha ho le joalo, e hlahile e le modulator e matla ea tsela ea moputso oa mesolimbic dopaminergic, e fana ka maikutlo a karolo ea ghrelin moputsong oa lijo. Mona, re ile ra batla ho tseba hore na ghrelin le li-receptor tsa eona li bohlokoa bakeng sa ho matlafatsa tšusumetso bakeng sa moputso oa tsoekere ea tlhaho ka ho lekola karolo ea ts'isinyo ea ghrelin receptor (GHS-R1A) le blockade bakeng sa maemo a ts'ebetso ea ts'ebetso ea sucrose, ts'ebetso e sebelisetsoang ho lekanya drive e susumetsang ho fumana moputso. Ghrelin e sebetsanang le moeli le bohareng, e eketsehile haholo ha ba sebetsang ba ntse ba arabela, ka hona, ts'usumetso ea ho susumetsa sucrose. Re sebelisa mohanyetsi oa GHS-R1A JMV2959, re bonts'itse hore thibelo ea GHS-R1A e bonts'ang e fokotsehile haholo mohoebi ea arabelang sucrose. Re ile ra tsoela pele ho batlisisa litlamorao tsa ghrelin ho li-node tsa mesolimbic tsa moputso, sebaka sa ventral tegmental (VTA) le nucleus accumbens (NAcc), ka ho lekola litlamorao tsa kalafo e sa foleng ea ghrelin ponts'ong ea liphatsa tsa lefutso tse kenyelletsang moputso o moholo oa li-receptor tsa neurotransmitter, e leng dopamine le acetylcholine. Kalafo ea Ghrelin e ne e amahanngoa le keketseho ea dopamine receptor D5 le acetylcholine receptor nAChRβ2 polelo ea liphatsa tsa lefutso ho VTA le polelo e fokotsehileng ea D1, D3, D5 le nAChRcy3 ho NAcc. Lintlha tsa rona li bonts'a hore ghrelin e bapala karolo ea bohlokoa ho susumelletsang le ho matlafatseng sucrose le litlamorao ho polelo ea dopamine le liphatsa tsa lefutso tsa acetylcholine lipotolohong tsa mesolimbic. Liphuputso tsena li fana ka maikutlo a hore bahanyetsi ba ghrelin ba na le monyetla oa ho phekola botenya le ho thibela tšebeliso e fetelletseng ea lijo tse monate.

Keywords: Acetylcholine, dopamine, tšusumetso ea lijo, ghrelin, GHS-R1A, e sebetsang maemong

SELELEKELA

Ho thehiloe hantle hore "ghrelin" ea "potoloho e potoloha" e bapala karolo ea bohlokoa ho taolo ea matla (Kojima et al a. 1999; Nogueiras, Tschöp le Zigman 2008). E hlahisitsoe haholo ke mpa (Dornonville de la Cour et al a. 2001), ghrelin e phahamisa phello e matla ea orexigenic ka litoeba le ho monna (Wren et al a. 2000, 2001) ka ho tsosa mohopolo oa eona oa mantlha tsamaiso ea methapo (CNS) receptor (Salomeet al a. 2009a), kholo ea sekhukhu ea li-siriagogue receptor (GHS-R1A) (Howard et al a. 1996). Ho joalo, ghrelin e lebisa lipotolohong tsa "hypothalamic" le "brain" tse amanang le phepelo le matla homeostasis (Dickson, Leng & Robinson 1993; Bailey et al a. 2000; Hewson & Dickson 2000; Faulconbridge et al a. 2003, 2008). Boitšoaro ba ho fepa, leha ho le joalo, ha bo susumetsoe feela ke tlhoko ea phepelo ea limatlafatsi (ho bolela tlhoko ea ho khutlisetsa homeostasis); Lijo tse matlafatsang tse nang le mafura a mangata le / kapa tsoekere li ka u khothaletsa ho ja haholo leha o le boemong ba ho hlonama.Zheng et al a. 2009). Ho fetoloa hoa matla a matlafatsang a tlhaho a kang tsoekere ke sesosa se ka sehloohong se bakang seoa sa ho nona hona joale. E tlameha ho tsejoa hore na sistimi e tšoaeang ghrelin e bohlokoa bakeng sa tšebeliso ea tsoekere e seng lapeng, ka hona e fana ka sepheo sa bohlokoa sa pheko sa ho thibela ts'ebeliso ea lijo tse matlafatsang, tse monate le tse monate.

E susumetsoa ke liphumano tsa morao-rao hore ghrelin e sebelisana le libaka tsa mesolimbic tse kenyelletsang ho fepa ka lintlafatso tse seng lapeng / tsa moputso (Jerlhag et al a. 2007), re batlile ho lekola karolo ea ghrelin le receptor ea eona ho tšusumetso ea lijo le boits'oaro bo lebisitsoeng ho sepheo bakeng sa moputso o motle. Libaka tsena tsa mesolimbic haesale e le mohopolo oa lipatlisiso tsa bokhoba ba lithethefatsi kaha e le tsona sepheo se seholo ho lithethefatsi tse ngata tsa tlhekefetso (Engel 1977; Koob 1992). Tsela e lebisitsoeng ea mesolimbic bakeng sa ghrelin e kenyelletsa projeke ea dopamine ho tloha sebakeng sa ventral tegmental (VTA) ho ea ho li-nucleus accumbens (NAcc) (Jerlhag et al a. 2006, 2007), tsela e tsamaisang moputso ho tsoa litlamong ka bobeli tsa lithethefatsi tsa khemikhale le meputso ea tlhaho, ho kenyeletsoa le lijo (Koob 1992). Ho khahlisang, GHS-R1A e hlahisoa ho dopaminergic neurons (Abizaid et al a. 2006), e tšoaeang litlamorao tse ka bang teng tsa ghrelin tsamaisong ea VTA dopamine. Lintlha tsena tsa immunohistochemical li tlatsetsoa ke bopaki bo bokellanang ba boits'oaro le motlakase oa phello ea ghrelin ho VTA. Mohlala, tsamaiso ea intra-VTA ea ghrelin e eketsa ts'ebetso ea VTA dopamine neurons (Abizaid et al a. 2006) hape e eketsa tokollo ea dopamine ho NAcc (Jerlhag et al a. 2007). Ghrelin e boetse e eketsa ts'ebetso ea sehokela sa cholinergic-dopaminergic, tsela ea bohlokoa ea moputso. Ho joalo, bonyane karolo ea litlamorao tsa ghrelin ho dopamine e bonahala e kenella hare ke sistimi ea cholinergic (Jerlhag et al a. 2007).

Leha ho thehiloe hore ghrelin e na le tšusumetso e matla ea orexigenic ha lijo li fumaneha habonolo, ha ho tsejoe hore na litlamorao tsa matla tsa moea tsa moea li ka eketsoa ho kenyelletsa lintlha tse matlafatsang le tse matlafatsang tsa matlafatso a tlholeho joalo ka lijo tse monate tse fumanehang. the juhudi / Mosebetsi oo motho a ikemiselitseng ho o etsa ka har'a ona. Ho susumetsa le ho putsa katleho ea lithethefatsi tsa bokhoba ba litekanyetso ho ka lekanngoa mohlaleng oa ho itaola, oa maemo a sebetsang. Boemo ba ts'ebetso ke mokhoa o ka sehloohong oa ho sekaseka boitšoaro bo susumetsang bo lekolang boits'oaro bo ikemiselitseng ho fumana moputso. Ka ho lekanya palo ea mosebetsi oo thuto e ikemiselitseng ho e sebelisa ho fumana moputso, e fana ka tekanyetso ea boleng ba moputso (Hodos 1961). Libaka tsa Mesolimbic li bohlokoa bakeng sa likarolo tse susumetsang tsa boitšoaro ho kenyelletsa ho fepa 'me ho hlakile hore ghrelin e ama ts'ebetso ea neuronal libakeng tse loketseng tsa mesolimbic. Se e-so ka se bontšoa ke phello e tobileng ea ghrelin ho khothalletso ea lijo tse tsoekere tse phahameng. Morero oa mantlha oa thuto ea rona ke ho etsa lipatlisiso hore na mokhoa o bohareng oa ghrelin signaling o bapala karolo ea bohlokoa meputsong ea lijo tse nang le tsoekere e ngata kapa hore na khatello ea sistimi ena e sebelisa GHS-R1A antagonist antagonist JMV2959 (Salomeet al a. 2009a), e ka hatella tšusumetso ea ho fumana lipompong. GHS-R1A antagonists hajoale e ntse e hlahlojoa ka mokhoa oa kalafo bakuli ba lefu la tsoekere la 2 e le khatello ea ho bua ka ghrelin e na le litlamorao ho glucose homeostasis (Sun et al a. 2006), litlamorao tse ka u tsoelang molemo hape ka lebaka la ho fokotseha hoa lijo tse monate. Ho na le lintlha tse 'maloa tse fanang ka bopaki ba hore dopaminergic le cholinergic neurotransmission li bapala karolo ea bohlokoa boits'ebetsong ba moputso bo khothalletsoang. Ka hona, ho hlakisa litlamorao tsa ghrelin ho potolohong e kholo ea moputso, re ile ra lekola phello ea kalafo ea ghrelin ho dopamine le acetylcholine receptor gene expression expression in key nodes node, VTA and NAcc, after kalafo ea ghrelin.

METHODA

Animals

Likhoto tsa banna ba baholo ba Sprague-Dawley (200-250 g, Charles River, Jeremane) li ne li kentsoe mokelikeli oa nako ea hora oa 12 / lefifi le nang le chow le metsi a kamehla. ad libitum, ntle le ha ho bontšitsoe ho fapaneng. Tsamaiso eohle ea liphoofolo e entsoe ka tumello ea boitšoaro le ho latela tataiso ea Komiti ea Tlhokomelo ea Liphoofolo le Tlhahlobo ea Univesithi ea Gothenburg.

Phekolo

Bakeng sa liteko tsa boits'oaro tse lebisang CNS, cannula ea boraro ea li-ventricular (26 gauge; Plastics One, Roanoke, VA, USA; e hokahanya: bohareng ba mohala, 2 mm kamorao ho bregma, le 5.5 mm ventral to dura mater, e nang le injector e ikemiselitseng 7.5 mm ventral to the dura) e kentsoe tlasa anofhesia ea isoflurane. Cannulae li ne li hokelletsoe lehateng ka li-screws tsa meno le li-jeweler ebe li koaloa ka obturator, joalo ka ha ho hlalositsoe pejana (Skibicka, Alhadeff & Grill 2009). Ho beoa ha cannula ka har'a ventricle ea boraro ho netefalitsoe beke e le 'ngoe ka mor'a ho etsoa opereishene ka tekanyo ea karabelo ea glycemic e utloisang bohloko ea kenngoe bohareng ba 5-thio-D-glucose [210 µg ho 2 µl ea koloi (saline)]Ritter, Slusser le Lejoe 1981). Ho protocol ena ea netefatso ea sebaka, ho phahamisoa ka posine ea bonyane 100% ea boemo ba tsoekere ea plasma e hlokahalang bakeng sa ho kenyeletsoa ka taba. Bakeng sa teko ea polelo ea gene, likhoto li ne li sa anngoe (60-75 mg / kg Ketalar le 0.5 mg / kg Domitor ip; Pfizer, Sweden; Orion Co, Finland) le intracerebroventricular (ICV) cannula (ICV) e sa foleng. DURECT Corp, Cupertino, CA, USA) e kentsoe ka har'a ventricle ea morao e sebelisang lihokela tse latelang: 0.6 mm posterior from bregma, 1.4 mm lateral from midline, 2.3 ventral from sgeb. Cannula e ne e hokahane ka polathethylene catheter ho osmotic minipump (Alzet Mini-Osmotic Pump Model 2002, Durect, Cupertino, phallo ea metsi, 0.5 µl / hora bakeng sa matsatsi a 14) e kenelletse ka mokhoa o sa ts'oaneng ka morao ho liphoofolo.

Moetso oa maemo a sebetsang

didirisiwa

Liteko tsa maemo a sebetsang li etsahetse ka likamoreng tse robeli tsa maemo a sebetsang tse etselitsoeng likhoto (30.5 × 24.1 × 21.0 cm; Medical-Associates, Georgia, VT, USA), tse neng li behiloe ka har'a khabinete e nang le molumo o hlakileng. Kamore e 'ngoe le e' ngoe e ne e e-na le mokato oa gridi ea tšepe, likharetene tse peli tse ka bululeloang tse nang le mabone a masoeu a masoeu ka holim'a tsona le sehokelo sa lijo tse ka tsamaisang li-pellets tsa 45 mg sucrose (GlaxoSmithKline, Teko ea Lijo, Richmond, IN, USA) ho terei ea lijo. Ho bokella le ho sebetsa ho ne ho laoloa ke software ea MED-PC (Medical-Associates, Georgia, VT, USA).

koetliso ea

Ts'ebetso e sebelisitsoeng bakeng sa maemo a sebetsang e fetotsoe ho tsoa ho (la Fleur et al a. 2007) le (Tracy et al a. 2008). Liroto kaofela li ile tsa kenngoa paradigm e bonolo ea lithibelo tsa lijo nakong eo boima ba tsona ba 'mele bo ileng ba fokotsoa butle butle ho 90% nako e fetang beke. Bakeng sa likhoto tse khanneloang ICV, koetliso e qalile beke pele ho ts'ebetso ea bongaka. Pele a kenngoa ka har'a mabokose a sebetsang, likhoto li ile tsa pepesetsoa mabokose a pompong ea lehae ka makhetlo a mabeli. Ka mor'a moo, likhoto li ile tsa ithuta ho kenya mochini o hatellang bakeng sa li-pellets tsa sucrose tlasa kemiso e tsitsitseng ea FR1 e nang le likarolo tse peli ka letsatsi. Ho FR1, mochine o le mong ho lever e sebetsang o ile oa fella ka ho tsamaisoa ha pellet e le 'ngoe ea sucrose. Linako tsohle tsa FR li nkile metsotso ea 30 kapa ho fihlela litoeba li fumana li-pellets tsa 100, ke efe e etsahetseng pele. Boholo ba likhoto li fihletse li-pellets tsa 100 ka sekhetho se seng le se seng ka mor'a 10 ho li-15. Mechine ea khatiso ea lever e sa sebetseng e tlalehiloe empa ha ea ba le litholoana tse hlahisitsoeng. Mekhahlelo ea kemiso ea FR1 e ile ea lateloa ke FR3 le FR5 (ke hore, likhatiso tse tharo le tse hlano ka pellet, ka tatellano). Hape, ho ne ho hlokahala likarabo tse fokolang tsa 100 ka nako e ngoe ho lever e sebetsang bakeng sa nts'etsopele ho kemiso e latelang; boholo ba likhoto li hloka nako e le 'ngoe ho tse peli feela tsa li-FR3 le li-schedule tsa FR5 ho fihlella boemo bona. Lenaneo la FR5 le ile la lateloa ke kemiso e tsoelang pele (PR) nakong eo litšenyehelo tsa moputso li ntseng li eketseha ka mokhoa o tsoelang pele bakeng sa moputso o mong le o mong o latelang bakeng sa ho tseba hore na palo ea mosebetsi oo Rate o ikemiselitseng ho o kenya ho fumana moputso ke efe. Tlhokahalo ea karabelo e ile ea eketseha ho latela equation e latelang: karolelano ea karabelo = [5e (palo ea tlhahiso ea 0.2 ×)] - 5 ka letoto lena le latelang: 1, 2, 4, 9, 12, 15, 20, 25, 32, 40, 50 , 62, 77, 95, 118, 145, 178, 219, 268, 328. Seboka sa PR se felile ha rat e ne e sitiloe ho fumana moputso nakong ea metsotso ea 60. Sebaka sa khefu se ne se hlalosoa e le karolelano ea ho qetela e phethetsoeng pele karolo e fela. Ho arabela ho ne ho nkoa e le ho tsitsitseng ha palo ea li-pellets tsa lijo tse fumanoeng ka karolo e le ngoe e sa fapana ho feta 15% bakeng sa likarolo tse tharo tse latellanang. Maemong a mangata, ho araba ho tsitsitse nakong ea linako tse hlano ho isa ho tse supileng. Teko ea PR e ile ea etsoa ka nako e le 'ngoe / letsatsi. Linako li ile tsa nka, ka karolelano, metsotso ea 75, leha likhoto kaofela li lutse mabokoseng a sebetsang ho fihlela metsotso ea 120 ho lumella linako tsohle hore li fele. Likhoto li ile tsa fetisetsoa malapeng bakeng la tekanyo ea hora ea ho fepa mahala. Qetellong ea thupelo le pele ho liteko, likhoto li ile tsa khutlisetsoa ho ad libitum kemiso ea ho fepa.

Moralo oa liteko

Liroto kaofela li amohetse litheko tse kenelletseng (IP) kapa sehlopheng se arohaneng sa likokoana-hloko, li-ente tsa boraro tsa ICV) pele ho potoloho ea leseli (bakeng sa liteko tsa ghrelin) le morao ho potoloho ea leseli bakeng sa liteko tsa ghastin tsa antagonist pele ho ho qala. ea liteko tse sebetsang. Maemo ohle a arotsoe ke bonyane lihora tsa 20 mme a tsamaisoa ka mokhoa o hanyetsanang (rat e ngoe le e ngoe e ne e fumana maemo ohle ka matsatsi a fapaneng a tlhahlobo).

Teko ea 1: tšusumetso ea tsamaiso e potolohang kapa e bohareng ea ghrelin ho ts'ebetso ea PR e arabelang bakeng sa sucrose ho likhoto

Bakeng sa likhoto tsohle, likarabo tse hatisang tsa lever li ile tsa hlahlojoa kamora maemo a mabeli: kalafo ea IP ka saline kapa ligylated rat ghrelin (Tocris, Bristol, UK; 0.33 mg / kg boima ba 'mele ho 1 ml / kg). Motsoako o khethiloeng oa IP ghrelin o kile oa bontšoa pejana ho khothaletsa karabelo ea ho fepa ka likhoto (Wren et al a. 2000) le ho kenya ts'ebetsong ho tsoa ha dopamine le ts'ebetso ea litla-morao ho litoeba (Jerlhag 2008). Kamora liteko tsa ts'ebetso, likhoto li ile tsa lumelloa ho fihlella mahala, 'me ho ja ho ile ha lekanngoa kamora nako ea hora e le' ngoe. E latelang, sehlopheng se ikemetseng sa likhoto, re ile ra hlahloba likarabo kamora ho tsamaisoa ha lithethefatsi tsa CNS kamora maemo a mararo ka tsela e latelang: maemo a taolo ka saline ea boraro ea methapo, 0.5 µg kapa 1.0 µg ea li-ligrelin tsa ligylin (Tocris) ka molumo oa 1 µl. Mokhoa o khethiloeng oa ghrelin o kile oa bontšoa ho fana ka likarabo tsa ho fepa (Nakazato et al a. 2001). Bakeng sa lithuto tsa ICV le IP ghrelin ka bobeli, liteko tse hatellang li ile tsa etsoa maemong a sata (ke hore, ha lijo li tla tsamaisoa ka thepa e putsa ea lijo ho fapana le ho tsamaisa homeostatic). Hape, lithutong tsena ka bobeli, kamora tlhahlobo ea ts'ebetso, likhoto li ile tsa lumelloa ho fihlella mahala, 'me ho ja ho ile ha lekanngoa kamora nako ea hora e le' ngoe.

Teko ea 2: tšusumetso ea kalafo ea pheriterale kapa e bohareng e nang le mohanyetsi oa moea oa ghrelin (GHS-R1A) mothating oa ho khothaletsa moputso oa sucrose ka likhoto

Likarabo tsa ts'ebetso ea PR li ile tsa hlahlojoa kamora maemo a mararo ka tsela e latelang: maemo a taolo ka letsoai la IP, 1 mg / kg kapa 3 mg / kg ea JMV2959 (AEZS-123, AeternaZentaris GmBH, Frankfurt, Jeremane). Litekanyetso tsa JMV2959 li ile tsa khethoa ho latela Jerlhag et al a. (2009) le Egecioglu et al a. (2010) le tlhaiso-leseling ea pele, e bonts'itsoeng pele e fokotsa boitšoaro ba boikhethelo ba sebaka empa e se na phello e ikemetseng mesebetsing ea locomotor. Kamora liteko tsa ts'ebetso, likhoto li ile tsa lumelloa ho fumana mahala. Ho lekola litlamorao tsa ketso ea antagonist ea mantlha e sebetsang ka kotloloho, sehlopheng se arohaneng sa litoeba, ho ile ha hlahlojoa boits'oaro ka mor'a maemo a mararo a latelang: boemo ba taolo ka ente ea boraro ea saline, 5 µg kapa 10 µg ea JMV2959 ka bongata ba 1 µl. Motsoako o khethiloeng oa ICV oa JMV2959 lethal dose o ne o thehiloe ho Salomeet al a. (2009a) moo ts'ebetso ea orexigenic ea 1 µg ghrelin-e tsamaisitsoeng ea ICV e koetsoe. Kamora liteko tsa ts'ebetso, litoeba li ile tsa lumelloa ho fihlella mahala mahala ho ts'ebeliso ea 'mala le chow ho lekantsoe kamora nako ea hora e le' ngoe hape le ka lihora tsa 24 kamora ho ente ea pele. Lithuto tse mabapi le mohanyetsi oa GHS-R1A, ho fapana le tse entsoeng ka ghrelin (bona pejana), li ile tsa etsoa lipapaling kamora thibelo ea lijo ea hora ea 16 pele ho liente bakeng sa ho netefatsa maemo a phahameng a potoloho ea 'mele ea potoloho ea morao-rao (Cummings et al a. 2001).

Teko 3: liphetoho tse bakiloeng ke ghrelin tse hlahisang mofuta oa dopamine- le acetylcholine tse amanang le VTA le NAcc

Mona, re lahlile litlamorao tsa ho kenella ho sa foleng ha ICV ghrelin ka libeke tse peli ka polelo ea liphatsa tsa lefutso tse khethiloeng tse amehang phetisong ea dopaminergic le cholinergic litsing tse peli tsa bohlokoa tsa mesolimbic tsa tsela, VTA le NAcc. Liphatsa tsa lefutso tse khethiloeng tse amanang le dopamine e ne e le liphatsa tsa lefutso tse kenyelletsang li-dopamine receptors (D1A, D2, D3, D5), catechol-O-methyltransferase, tyrosine hydroxylase (ho VTA feela) le monoamine oxidase A. Liphatsa tsa lefutso tse amanang le acetylcholine e ne e le: li-receptor tsa nicotinic (α3 α6, β2, -3). Liphatsa tsa lefutso tseo re khethileng ho li hlahloba li kile tsa ameha liphellong tsa ghrelin le / kapa ho putsa / boits'oaro (Kelley et al a. 2002; Figlewicz et al a. 2006; Jerlhag et al a. 2006, 2007; Sibilia et al a. 2006; Dalley et al a. 2007; Kuzmin et al a. 2009; lee et al a. 2009; Nimitvilai & Brodie 2010; Perello et al a. 2010). Protocol e sa foleng ea ghrelin / saline e sebelisitsoe ho rata ente e mpe ho eketsa menyetla ea ho bona phello ea polelo ea gene; Ho feta moo, haeba ghrelin e le molaoli oa bohlokoa oa sistimi ea moputso ka nako e telele, e khothaletsa ho nona haholo le botenya, litlamorao tsa eona tse sa fetoheng ho fetola mekhoa ea meputso ea bohlokoa e kanna ea ba ea bohlokoa haholo.

Tsamaiso ea lithethefatsi le ho senyeha ha lisele

Pompo ea catheter le osmotic li ne li tlatsitsoe ke ghrelin ea motho ea acetylated (mpho e tsoang ho Rose Pharma, Copenhagen, Denmark) tharollo (8.3 µg / rat / day) kapa tharollo ea koloi ea saline (0.9% NaCl); lethal dose le bolelele ba kalafo esale li bontšoa ho ama polelo ea liphatsa tsa lefutso ho hypothalamus (Salomeet al a. 2009b). Matsatsi a leshome le metso e mene ka mor'a ho kenngoa ha liphoofotsoana tsena, likhoto li ile tsa bolaoa ke ho bola. Mehopolo e ile ea tlosoa kapele 'me VTA le NAcc tsa qhaloa ka ts'ebeliso ea ts'ebetso ea boko (meeli ea libaka ka seng e behiloe ho latela Paxinos le Watson 1986), e koahetsoe ke naetrojene e nang le metsi 'me e bolokiloe ho -80 ° C bakeng sa boikemisetso ba morao ba polelo ea mRNA.

Ho khetholloa ha RNA le polelo ea mRNA

Mehlala ea motho ka mong e ile ea homogenized Qiazol (Qiagen, Hilden, Jeremane) ho sebelisoa TissueLyzer (Qiagen). Kakaretso ea RNA e ntšitsoe ho sebelisoa RNeasy Lipid Tissue Mini Kit (Qiagen) kapa RNeasy Micro Kit (Qiagen), ka bobeli ba nang le kalafo ea tlatsetso ea DNAse (Qiagen). Boleng ba RNA le bongata li ile tsa hlahlojoa ke litekanyo tsa spectrophotometric (Nanodrop 1000, NanoDrop Technologies, Wilmington, DE, USA). Bakeng sa synthesis ea cDNA, RNA e felletseng e ile ea fetoloa e ngotsoe ka li-hexamers tse sa sebetseng (Applied Biosystems, Sundbyberg, Sweden) le Superscript III reverse transcriptase (Invitrogen Life Technologies, Paisley, UK) ho latela tlhaloso ea moetsi. Recombinant RNaseout Ribonuclease Inhibitor (Invitrogen) e ile ea eketsoa ho thibela tšenyo e bakiloeng ke RNase. Likarabo tsohle tsa cDNA li ne li tsamaisoa ka makhetlo a mararo. PCR ea phetisetso ea nako ea 'nete e sebelisitsoe ho sebelisoa liteko tsa TaqMan Custom Array. Li ne li entsoe ka probe ea TaqMan le li-primer sets tsa liphatsa tsa lefutso tse khethiloeng lenaneng la li-inthanete (Applied Biosystems). Boema-kepe bo bong le bo bong lipulong tsa TaqMan Array bo ne bo laetsoe ka cDNA e tsamaellanang le 100 R kakaretso RNA e kopantsoeng le metsi a se nang nuclease le 50 Tal TaqMan Gene Expression Master Mix (Applied Biosystems) ho ea ho 100 µl ea ho qetela. TaqMan Arrays e ile ea hlahlojoa ho sebelisoa sistimi ea 7900HT ka TaqMan Array Upgrade (Applied Biosystems). Maemo a libaesekele tse futhumetseng e ne e le: 50 ° C metsotso e 'meli, 94.5 ° C metsotso e 10, e lateloa ke lipotoloho tse 40 tsa 97 ° C metsotsoana e 30 le 59.7 ° C motsotso o le mong.

Likeletso tsa polelo ea geni li ile tsa baloa ho latela ΔΔCt mokhoa (Livak & Schmittgen 2001), moo sehlopha se phekotsoeng ka letsoai se neng se khethiloe e le calibrator. Ka bokhutšoanyane, ΔCt e emela potoloho (Ct) ea mofuta oa mofuta oa sepheo seo mofuta oa mofuta oa phepelo le "Ct e emetse ΔCt ba ghrelin ba ile ba phekola sehlopha sa batho ba fuoang moqapi oa marang-rang. Bongata bo amanang bo ile ba khethoa ho sebelisoa boholo ba equation = 2−ΔΔCt. Bakeng sa sampole ea calibrator, equation ke palo e lekanang = 2-0, e leng 1; ka hona, mohlala o mong le o mong o hlahisoa o amana le sena. Glyceraldehyde-3-phosphate dehydrogenase e sebelisitsoe e le mofuta oa index.

Lipalo-palo li

Litekanyetso tsohle tsa boits'oaro li ile tsa hlahlojoa ka tlhahlobo ea phapang e lateloang ke post hoc Tukey teko kapa t-Le liteko ha li loketse. Litlhahlobo tsa lipalopalo li ile tsa etsoa ho sebelisoa software ea Statistica (Tulsa, OK, USA). Bakeng sa ho sekaseka phello ea kalafo e matla ea "ghrelin" e sa feleng liphatlalatsong tsa lefutso, t-Test e sebelisitsoe, ka P- Litaelo tse baloang ho sebelisoa ΔCt-melo. Phapang e ne e nkuoa e le ea bohlokoa ho P <0.05. Lintlha li hlahisoa e le tse mpe ± SEM.

LIPOTSO

Teko ea 1: tšusumetso ea tsamaiso e potolohang kapa e bohareng ea ghrelin ho ts'ebetso ea PR e arabelang bakeng sa sucrose ho likhoto

Mona, re sebelisa paradigm e sebelisitsoeng ho etsa lipatlisiso tsa bokhoba ba litekanyetso ho lekola karolo ea ghrelin ho khothaletso ea lijo tse tsoekere le ho matlafatsa thepa ea tsoekere. Haholo-holo, ho fumana karolo ea tsamaiso ea phello ea ghrelin ho katleho ea moputso oa sucrose, re ile ra lekola boits'oaro ka tatellano ea karabelo e tsoelang pele ho likhoto tsa 20 metsotso ka mora ho entetsoa IP ea koloi kapa ghrelin. Mehato eohle ea boits'ebetso ea ts'ebetso e ile ea eketsoa haholo ho litoeba ka mor'a ho kenngoa ka har'a pherekano e matla ea pherese ea moea: ho tobetsa ka matla (P <0.05 bakeng sa lintlha tsa nako eohle), palo ea li-pellets tsa tsoekere tse fumanoeng (P <0.005 bakeng sa lintlha tsohle tsa nako) le ntlha ea khefu ea metsotso e 120 (P <0.005, 32.53 ± 3.4 le 41 ± 4.3 bakeng sa koloi le ghrelin, ka ho latellana; Feiga. 1a, b). Lingoliloeng li tšehetsa sebaka sa tšebetso se bohareng bakeng sa phello ea orexigenic ea ghrelin. Leha ho le joalo, GHS-R1A e boetse e hlahisoa kantle ho CNS libakeng tse loketseng taolo ea phepelo ea lijo, mohlala, methapong ea botona; ka hona, ho ke ke ha qheleloa ka thoko hore karolo ea litlamorao tse bonoang tsa IP ghrelin li buelloa ke li-receptor tsa pheriferale. Ente e bohareng ea molumo o tlase le lethal dose ea ghrelin, leha ho le joalo, e tsosa feela CNS GHS-R1A. Ka hona, molemong oa ho tseba phello e tobileng ea CNS ea ghrelin ho katleho ea moputso oa sucrose, re ile ra etsa thuto e tšoanang moo koloi kapa ghrelin li neng li tsamaisoa ka ente ea boraro ea ventricle, hape le metsotso e 20 pele ho paradigm e sebetsang. E tsamaellana le sebaka sa mantlha sa tšebetso, khopolo e matla ea ICV ghrelin ho likhoto (bobeli ba 0.5 µg le 1.0 µg tekanyetso) e ekelitse haholo mehato eohle e boletsoeng kaholimo ea boits'oaro bo sebetsang (Feiga. 2a, b). Nako ea likarabo tsa lever tse sebetsang lipatlisisong tsa ICV ghrelin e senotse hore le ha phello e hlahile butle nakong ea nako ea metsotso ea 10- le 30, e fihletse bohlokoa ho metsotso ea 60 [lever e sebetsang: Metsotso ea 10 F(2, 24) = 0.94, P = 0.41, metsotso ea 30 F(2, 24) = 3.13, P = 0.06, metsotso ea 60 F(2, 24) = 5.86, P <0.01, metsotso e 90 F(2, 24) = 6.42, P <0.01, metsotso e 120 F(2, 24) = 6.03, P <0.01; meputso e fumanoeng: metsotso e 10 F(2, 24) = 0.26, P = 0.78, metsotso ea 30 F(2, 24) = 2.76, P = 0.08, metsotso ea 60 F(2, 24) = 8.31, P <0.005, metsotso e 90 F(2, 24) = 10.16, P <0.001, metsotso e 120 F(2, 24) = 11.93, P <0.001; le ntlha ea khefu: F(2, 24) = 7.22, P <0.005 (17.31 ± 1.53, 33.15 ± 5.52, 36 ± 6.95 bakeng sa koloi, 0.5 µg le 1.0 µg ghrelin, ka ho latellana)], thupelo ea nako e lumellanang le litlaleho tse ling tsa latency e bakoang ke phepo ea ghrelin ha e fanoa ka tsela ena (Faulconbridge et al a. 2003). Litekong tsena ka bobeli, ts'ebetso ho lever e sa sebetseng e ne e le nyane ebile e sa fapana haholo pakeng tsa lihlopha tse fapaneng tsa kalafo (IP 4.1 ± 1.1, 4.1 ± 1.1 bakeng sa koloi le ghrelin, ka ho latellana; ICV 3.9 ± 1.1, 2.1 ± 0.7, 3.5 ± 1.6 for koloi, 0.5 µg le 1.0 µg ghrelin, ka ho latellana), e fana ka maikutlo a hore kalafo ha e hlahise liphetoho tse sa lebelloang tse senang sepheo mosebetsing. Hang-hang ka mor'a tlhahlobo e sebetsang, likhoto li ile tsa khutlisetsoa mekotleng ea tsona ea lapeng 'me tsa lumelloa ho fumana mahala; le likhoto tse kentsoeng ka ghrelin, ebang e fanoa kamehla.P <0.05) kapa boharengF(2, 24) = 12.64, P <0.001], ba batlile ba mena habeli lijo tsa bona tsa chow nakong ea hora ha ba bapisoa le lihlopha tse tšoaroang ke likoloi (Lifeiga 1c & 2c). Tumellanong le data e fetileng (Faulconbridge et al a. 2003) e bonts'a hore boholo ba phello ea hyperphagic ea pherekano e mpe ea bohareng ea ghrelin e etsahala nakong ea lihora tse tharo kamora ho ts'oaroa ente, ha ho na tšusumetso ea ho kenella ho hong ho boletsoeng thutong ea rona ka lihora tse tharo ho isa ho 24 kamora ho tsamaisoa ha ICV ka tekanyo e ngoe ea ghrelin [17.4 ± 1.12, 18.42 ± 1.34, 19.12 ± 1.43 koloi, 0.5 µg le 1.0 µg ghrelin, ka ho latellana, F(2, 24) = 2.27, P = 0.13].

Setšoantšo sa 1 

Ho kenella ka sekhahla sa mofuta oa ghrelin ho eketsa tšusumetso ea ho fumana lijo tse fumanehang habonolo ka har'a mofuta oa li-ratio tsa PR. Palo ea likarabo ho lever e sebetsang (a) le palo ea moputso oa 45 mg sucrose e fumanoeng (b) e eketseha haholo ka ...
Setšoantšo sa 2 

Ho tsamaisoa ha sepakapaka sa CNS (sa boraro ICV) ho eketsa boleng bo khotsofatsang ba sucrose ka har'a mofuta oa PR oa karolelano ea li-ratio. Palo ea likarabo ho lever e sebetsang (a) le palo ea moputso oa 45 mg sucrose e fumanoeng (b) e eketseha haholo ka boraro ...

Teko ea 2: tšusumetso ea kalafo ea pheriterale kapa e bohareng e nang le mohanyetsi oa moea oa ghrelin (GHS-R1A) mothating oa khothatso bakeng sa moputso oa sucrose ho likhoto

Ka mor'a moo, re ile ra hlahloba litlamorao tsa katleho ea lithethefatsi tsa GHS-R1A mabapi le katleho ea moputso oa sucrose. Ka hona, ho ikemela ka mokhoa o ikemetseng kemisong ea karabelo e tsoelang pele ho ile ha hlahlojoa lithupelong tse thibelitsoeng bosiu ke lijo ho netefatsa litekanyetso tse phahameng tsa metsotso e fetisisang ea semmuso ea 20 kamora ho ts'oaroa ka ente ea koloi kapa 1 mg / kg kapa 3 mg / kg ea JMV2959, GHS -R1A mohanyetsi. Mehato eohle ea boits'ebetso ea ts'ebetso e ne e fokotsehile haholo ho litoeba ka mor'a ho kenella ka hare ho junter ea JMV2959 [lever e sebetsang: metsotso e mehlano F(2, 24) = 11.53 P <0.0005, metsotso e 120 F(2, 24) = 11.27, P <0.001; meputso e fumanoeng: metsotso e mehlano F(2, 24) = 23.39 P <0.0005, metsotso e 120 F(2, 24) = 9.26, P <0.001 le ntlha ea khefu ho 120: F(2, 24) = 5.98, P <0.01 (45.31 ± 6.45, 42.08 ± 5.80, 30.0 ± 5.89 bakeng sa koloi, 1 mg / kg le 3 mg / kg JMV2959, ka ho latellana)]. Post hoc tlhahlobo e senotse hore phello e kholo e tsamaisoa ke lethalamo la 3 mg / kg (kgFeiga. 3a, b). Ho tseba karolo ea "ghrelin receptor" ea ts'ebetso e kholo ea moputso, ho ile ha etsoa phuputso e tšoanang eo ho eona koloi kapa JMV2959 (5 µg kapa 10 µg) e ileng ea fuoa metsotso e meraro ea 20 ea boraro pele ho mehato e sebetsang. Mehato eohle e boletsoeng esale pele ea boits'ebetso ea ts'ebetso e ile ea fokotseha haholo ho litoeba ka mor'a ho kenngoa ka matla ha karolo ea boraro ea methapo ea methapo ea JMV2959 (Feiga. 4a, b). Phello e bonoang e ne e le hanghang post hoc tlhahlobo e senole liphapang tse kholo hara lihlopha tsa kalafo ha feela kamora metsotso ea 10 ea tšebetso ka kamoreng ea ts'ebetso e neng e bolokiloe ho pholletsa le nako ea tlhahlobo [lever e sebetsang: Metsotso ea 10 F(2, 24) = 10.16, P <0.0005, metsotso e 30 F(2, 24) = 11.48, P <0.0005, metsotso e 60 F(2, 24) = 9.11, P <0.001, metsotso e 90 F(2, 24) = 8.30, P <0.001, metsotso e 120 F(2, 24) = 4.95, P <0.05; meputso e fumanoeng: metsotso e 10 F(2, 24) = 21.23, P <0.0001, metsotso e 30 F(2, 24) = 25.08, P <0.0001, metsotso e 60 F(2, 24) = 19.24, P <0.0001, metsotso e 90 F(2, 24) = 20.04, P <0.0001, metsotso e 120 F(2, 24) = 5.44, P <0.01; le ntlha ea khefu: F(2, 24) = 3.78, P <0.05 (51.4 ± 8.58, 38.13 ± 5.07, 33.67 ± 5.21 bakeng sa koloi, 5 µg le 10 µg JMV2959, ka ho latellana)].

Setšoantšo sa 3 

Ho tsamaisoa ka mokhoa o poteletseng oa mohanyetsi oa ghrelin receptor, JMV2959. e fokotseha tšusumetso ea ho fumana lijo tse fumanehang habonolo ka har'a mochini oa li-PR tsa maemo a sebetsang. Palo ea likarabo ho lever e sebetsang (a) le palo ea moputso oa 45 mg sucrose e fumanoeng ...
Setšoantšo sa 4 

Blockade e bohareng ea GHS-R1A e nang le JMV2959 e fokotsa tšusumetso ea ho fumana moputso oa lijo ka har'a mofuta oa li-PR tsa karolelano ea li-ratio tsa PR. Palo ea likarabo ho lever e sebetsang (a) le palo ea moputso oa 45 mg sucrose e fumanoeng (b) e fokotsehile haholo ...

Joalokaha ho lebelletsoe (Hodos 1961; Jewett et al a. 1995), lihlopha tsohle tsa kalafo, ho kenyelletsa le litsamaiso tsa tsamaiso tsa IP le ICV, phello ea khaello ea lijo karabong e sebetsang ea sucrose e ile ea bonahala (Lifeiga 3a & 4a) le phapanyetsano le se hlokometsoeng mmuso oa boemo bo phahameng.Lifeiga 1a & 2a). Ts'ebetso ho laver e sa sebetseng e ne e le nyane (IP 9.6 ± 3.0, 6.8 ± 2.2, 5.6 ± 1.9 bakeng sa koloi le 1 mg / kg kapa 3 mg / kg JMV2959; ICV 6.4 ± 1.3, 4.6 ± 1.3, 4.4 µg le 1.7 µg ea JMV5, ka tatellano) le hore na e tsamaisoa ho sa feleng kapa bohareng, JMV10 ha ea ka ea ba le phello e kholo mosebetsing oo (ketsahalo ena e ne e sa fapana haholo pakeng tsa lihlopha tse fapaneng tsa kalafo). Bakeng sa thuto ea ICV, hang kamora tlhahlobo ea opereishene, likhoto li ile tsa khutlisetsoa malapeng a tsona mme tsa lumelloa ho fumana mahala; Ka ho khahlisang, ha ho na tšusumetso ea ho ja lijo tsa chowon e boletsoeng ka hora e le 'ngoe (Feiga. 4c) kapa ntlha ea nako ea lihora tsa 24 (ya data ha e bontšoe). Sena se ka supa hore le ha ho saenaoa ghrelin ho hlokahala bakeng sa ts'usumetso ea lijo tse tlisoang ke ho fokotsoa, ​​ha ho bohlokoa bakeng sa phepelo ea mahala e hlahisoang ke ho futsaneha ha lihora tsa 16 mohlomong ka lebaka la mekhoa e meng e sa sebetseng e qalileng nakong ea ho hloka. Litekanyo tsohle tsa ho fepa mahala li etsahetse metsotso ea 140 ea postinjection ea moriana mme ka hona re ke ke ra khetholla hore ho haella ha phello ho bakoa ke ho hlatsoa lithethefatsi.

Teko 3: liphetoho tse bakiloeng ke ghrelin tse hlahisang mofuta oa dopamine- le acetylcholine tse amanang le VTA le NAcc

Thutong ea hona joale, re boetse re fumane hore na mefuta ea amanang le dopamine- le acetylcholine e fetotsoe ke ghrelin ho li-node tsa bohlokoa tsa mesolimbic, VTA le NAcc, ka ho hlahloba litlamorao tsa kalafo ea "ghrelin" e sa feleng mabapi le polelo ea li-receptor le dopamine tse khethiloeng tlhahiso ea dopamine le metabolism, paradigm e seng e thehiloe ho hlahisa liphetoho tse amanang le ghrelin ponts'ong ea gene ho hypothalamus (Salomeet al a. 2009b). Ho VTA dopamine receptor D5 le nicotinic acetylcholine receptor (nAChRβ2) e bile le polelo e eketsehang ea mRNA ka har'a likhoto tse phekotsoeng ke ghrelin ha li bapisoa le sehlopha se phekotsoeng ke saline (Setšoantšo sa 5a). Ho NAcc, ho ne ho na le polelo e fokotsehileng ea mRNA ea liphatsa tsa lefutso tse kopanyang li-dopamine receptors D1A, D3 le D5 hape le nicotinic acetylcholine receptor nAChRcy3 ho litoeba tse tšoaroang ke ghrel ha li bapisoa le sehlopha se phekotsoeng ka letsoai (Feiga. 5b).

Setšoantšo sa 5 

Dopamine le acetylcholine poleloana e amanang le gene ho VTA (a) le NAcc (b) kamora ho tsitsa ha ICV ghrelin kapa kalafo ea koloi. Ledata le emela moelelo oa phetoho ea foldara e amanang le kalafo ea saline. D1, dopamine D1 receptor; D2 dopamine D2 receptor; D3, dopamine ...

TŠOHLOA

Mona, re senola karolo bakeng sa sistimi e kholo ea li-ghrelin signature ho ts'usumetso ea ts'usumetso ea ts'usumetso le ho tiisa thepa ea moputso oa sucrose mme re bonts'a tšusumetso ea kalafo e tebileng ea "ghrelin" ea polelo ea genop ea dopaminergic le cholinergic receptors maemong a bohlokoa a mesolimbic node. Liphetho li bonts'a hore phallo ea moea o bohareng le o poteletseng e eketsa haholo mosebetsi oo phoofolo e ikemiselitseng ho o etsa ho fumana moputso o hlakileng. Ntle le moo, "systemic" kapa "blockade" ea "ghrelin" e amohelang tšebetso e ile ea qobella mosebeletsi ea arabelang molemong oa ho ipolaea. Kahoo, re ka tšoaetsoa hore ho supa matšoao a mofuta oa bophelo bo sa feleng ho bohlokoa bakeng sa tšusumetso ea moputso o motle. Seo re se fumaneng se lumellana le khopolo-taba ea hore karolo ea bohlokoa ea sistimi e kholo ea ho buella moea oa moea ke ho eketsa boleng ba meputso, ho kenyelletsa le lijo. Fuoa hore thibelo ea lijo e eketsa boleng bo khotsofatsang ba sucrose (Hodos 1961; Jewett et al a. 1995) le hore maemo a ghrelin a phahamisoa nakong ea lithibelo tsa lijo tsa nakoana (Gualillo et al a. 2002), ho ka etsahala hore nakong ea maemo a thibelo ea lijo / tlhokofatso, ghrelin ke e 'ngoe ea lintlha tse tlatsetsang tse eketsang boleng bo khotsofatsang ba khothatso ea lijo / lijo. Kannete, ho pepeseha ha moea oa ghrelin ho eketsa ts'ebetso ea ts'ebetso ho maemo a ts'oanang le a bonoang ke likhoto tse sa jelloang ke lijo, 'me ka lehlakoreng le leng, thibelo ea moea oa moea oa moea oa moea e fokotsang boits'oaro ba basebetsi ho fihla maemong a tsejoang ho likhoto tse sa hlokeng botsitso.

Joale ho bonahala ho hlakile hore keketseho ea lijo e eketsang mathata ka mokhoa o hlakileng e bonts'a ho fifala ha mekhoa ea mantlha ea moputso oa lijo, e kenyeletsang likarolo tse peli tsa hedonic le tse susumetsang. Joalo ka ha ho fepa mahala le ho fepisoa ka meputso ho bonahala e le liketsahalo tse peli tse arohaneng tse nang le dikarolo tse fapaneng tsa taolo ea neuroanatomical (Salamone et al a. 1991), ho bohlokoa ho li hlahloba ka bobeli ha ho hlahlojoa karolo ea baemeli ba amehang mokhoeng oa ho fepa. Liphello tse matla tsa orexigenic tsa Ghrelin li ithutiloe haholo mefuteng ea phepelo ea mahala ea ho fepa eo ho ka bang thata ho khetholla lipakeng tsa karolo ea eona ho tlatseng limatlafatsi le phepo e susumetsoang ke moputso. Thutong ea hajoale, re fumane hore li-ligands tsa GHS-R1A li kena-kenana le tšusumetso ea moputso oa sucrose, li sebelisa mohlala oa liteko o sebelisitsoeng maemong a mang ho bonts'a takatso le tšusumetso ea lithethefatsi tse tlatsetsang tsa tlhekefetso. Keketseho ea boits'oaro bo susumetsang e tloaelehile litlamong tsa lik'hemik'hale tse peli le thibelo ea kalori mme mohlomong ho kenyelletsa mekhoa e fetang ea methapo ea methapo. Thutong ea hajoale, re boetse re fumane keketseho e susumetsoang ke ghrelin ea ho fepa mahala lijo tse tloaelehileng tsa liphoofolo tse tšoanang liphoofolong tse sebelisitseng mosebetsi o mongata bakeng sa lijo ka phapusing e sebetsang. Ka hona, lintlha tsa rona, tse nkiloeng hammoho le litlaleho tsa pejana tsa litlamorao tsa ghrelin mefuteng ea phepo ea mahala (Wren et al a. 2000), li bontša hore ghrelin e na le bokhoni ba ho fepa ka ho fepa ka bolokolohi hammoho le tšusumetso ea ho fepa.

Kaha ho latela hore ghrelin receptor GHS-R1A e teng libakeng tsa bohlokoa tsa hypothalamic, hindbrain le mesolimbic tse kenyellelitsoeng molemong oa matla le moputso (Zigman et al a. 2006) le hore ente e bohareng ea methapo ea methapo ea methapo ea mmele ea GHS-R1A e ka fumana phihlello e pharalletseng libakeng tsena tsa CNS, ho ka ba le likarolo tse 'maloa tsa neuroanatomical tse loketseng sephetho sa sephetho sa moputso oa sucrose se bontšitsoeng mona. Ho bonahala eka ghrelin e sebetsa ka kotloloho libakeng tsa bohlokoa tsa mesolimbic ha ghrelin e buella VTA dopamine neurons (Abizaid et al a. 2006) le taolo e tobileng ea ghrelin ho VTA e eketsa ho lokolloa ha dopamine e tlisoang (Jerlhag et al a. 2007). Tumellanong le sena, re kile ra tlaleha litlamorao tsa intra-VTA ghrelin ho eketsa ts'ebeliso ea lijo tse nang le moputso / tse monate ka ho fepa paradigms tsa mahala le hore litla-morao tsa VTA e nyarosang ea moea e hlahisang lijo tse fumanehang habonolo (Egecioglu et al a. 2010). NAcc e kanna ea ba sepheo se tobileng bakeng sa ghrelin ho fetoheng likarolo tse susumetsang tsa takatso ea lijo; ha e kenngoa ka ho toba sebakeng sena, ghrelin e etsa karabelo ea ho fepa (Naleid et al a. 2005), leha ho ba teng ha GHS-R1A sebakeng sena ka litoeba ha hoa ka ha hlalosoa ke bafuputsi ba bang (Zigman et al a. 2006) ka hona, e hloka ho hlakisoa haholoanyane.

Kamehla, le karolo ea eona ea bohlokoa boits'oarong bo susumetsang, liphatsa tse 'maloa tsa lefu la dopamine li fetotsoe ke kalafo ea ghrelin e bohareng. Lintlha tsena li phahamisa monyetla oa hore taolo ea polelo ea dopamine receptor ke mochini oa nako e telele ka oona moea o amang ts'ebetso e amanang le moputso le ho supa. Teko ea li-receptor tsa dopamine ha e bohlokoa feela sebakeng sa ho lokolloa joalo ka NAcc empa hape le VTA joalo ka lebaka la tokollo ea dendritic dopamine (Cragg le Greenfield 1997), ho ka etsahala hore e sebetse sebakeng sa heno ho susumetsa boits'oaro bo susumetsang ba moputso. Mona, re fumane polelo e eketsehileng ea D5 ho VTA kamora kalafo ea ghrelin. Li-receptor tsa Dopamine D5 li teng mefuteng ea lisele ea dopaminergic VTA neurons (Ciliax et al a. 2000) mme ts'ebetso ea bona e hlokoa ho khutlisetsa ts'ebetso ea neuron ea VTA dopamine kamora nako ea boitlamo (Nimitvilai & Brodie 2010). Ho NAcc, re hlokometse polelo e fokotsehileng ea D1. Ebile, polelo e fokotsehileng ea receptor ena e bontšitsoe haufinyane ho NAcc ea lefu la ho ba le botenya empa eseng litheko tse thibelang botenya ho ja lijo tse nang le mafura a mangata e bonts'a karolo ea eona e ka bang NAcc ho batena le botenya bo feteletseng (Alsio et al a. 2010). Hape, polelo ea mefuta ea ho kenyelletsa D3 e fokotsoe ke ghrelin, ho fumana phaello e itseng ho fumaneng ho fokotseha ho fumaneha ha li-receptor tsa D2 / D3 ho rat ka bobeli le basebelisi ba lithethefatsi ba motho ba ikamahanya le tšusumetso e eketsehileng (Dalley et al a. 2007; lee et al a. 2009). Ho khahlisang, ha rea ​​bona liphetoho leha e le life tsa bohlokoa ho li-enzyme tse amehang ho dopamine synthesis kapa tlhahiso.

Karolo ea bohlokoa ea sistimi ea acetylcholine bakeng sa meputso ea lithethefatsi le lijo e ngotsoe hantle; mona, re bonts'a kalafo ea hore ghrelin e ne e amana le liphetoho tse hlahisoang ke liphatsa tsa lefutso tse amohelang likokoana-hloko tse ngata tsa acetylcholine nicotinic, e fana ka tsela e 'ngoe eo ka eona ghrelin e ka fetolang mosebetsi oa moputso. Ghrelin e ka laola li-neurons tsa VTA dopaminergic ka tsela e sa tobang ka ho nka bohato ba eona ho li-neuron tsa cholinergic sebakeng se latelang sa methapo ea methapo (LDTg), sebaka se ruileng ho GHS-R1A, e leng bohlokoa bakeng sa moputso oa joala o kenyang projeke ea cholinergic ho Sisteme ea VTA ea dopamine. Ebile, pejana, re bonts'itse hore ente ea bilrelin ea moea e kenang kahare ho LDTg ka litoeba e matlafatsa tlhahiso ea dopamine ka mokhoa o itšetlehileng ka cholinergic (Jerlhag et al a. 2007, 2008) hape e eketsa tšebeliso ea joala ka khetho e sa lefelloeng (joala / metsi) ea ho noa paradigm (Jerlhag et al a. 2009). Ho joalo, lithuto tsa morao-rao li hlahisitse khokahano ea moputso oa cholinergic-dopamineric moputsong oa lijo (Dickson et al a. 2010). Monyetla o mong o khahlisang ke hore ghrelin e ka ntlafatsa ho tšoaea ha cholinergic ho VTA ka ho eketseha ha li-receptor tsa cholinergic. Ehlile, data ea rona ea hona joale ea liphatsa tsa lefutso e bonahala e ts'ehetsa mochine oo ha maemo a VRNACVRβ2 mRNA a neng a eketsehile litlamong tse sebelisoang ke ghrelin.

Ts'ebetso ea NAcc cholinergic neurons le acetylcholine ho NAcc, ka lehlakoreng le leng, e bile tsekisano le litlaleho tse ling tse bonts'a karolo ea acetylcholine ho eketsa boitšoaro bo lebisitsoeng ho moputso (Pratt & Kelley 2005; Pratt & Blackstone 2009) empa tse ling tse bonts'a hore Ach ho NAcc a ka nka bohato ba ho thibela ho fepa le ho bapala karolo ea satiety mochine (helmete et al a. 2003; Hoebel et al a. 2007). Ho joalo, liphetho tsa rona li bonahala li lumellana le tsa morao-rao joalo ka ha kalafo ea ghrelin e ne e amahanngoa le polelo e fokotsehileng ea e 'ngoe ea li-subunits tsa nicotinic receptor, nAChRcy3. Ho bohlokoa ho hlokomela hore lithuto tsa liphatsa tsa lefutso, leha li le bohlokoa haholo ho bonts'a liphofu tse ka bang tlase tsa ghrelin, li fana ka maikutlo a mofuta oa kamano (upregulation kapa downregulation) e hlokahalang bakeng sa polelo ea karabo ea orexigenic- / moputso empa e sa e hlalose kaha ho ka ba thata ho ikarola ka kotloloho liphetohong tsa matšeliso. Ka hona, lithuto tsa rona tsa polelo ea liphatsa tsa lefutso li bonts'a khokahano mme li fana ka sethala sa lithuto tsa ka moso tsa lefutso le tsa bongaka tse khethollang karolo ea liphatsa tsa lefutso liphellong tsa ghrelin phepong ea mahala le e susumetsoang ke moputso.

Leha libaka tsa hypothalamic le brainstem li ka tlatsetsa haholo ho fepeng malapeng, re ke ke ra khetholla karolo e sa tobang bakeng sa lits'ebetso tsa hypothalamic le / kapa tsamaiso ea methapo ea ts'usumetso ho litheko tsa meputso ea lijo tsa ghrelin. Ho joalo, projeke ea "orexinergic neurons" e tsoang ho "hypothalamus" ea morao-rao ho isa mesolimbic ea ho kotula melemo ho kenyeletsa VTA le NAcc (Toshinai et al a. 2003; Harris et al a. 2005; Perello et al a. 2010). Neuropeptide Y (NPY) / AgRP methapo ea kutlo ea arcuate, sepheo se seng bakeng sa li-ligands tsa GHS-R1A (Dickson le Luckman 1997; Keen-Rhinehart le Bartness 2007a,b), e kanna ea bapala karolo ea bohlokoa. NPY e bontšitsoe ho eketsa katleho ea moputso oa chow hammoho le sucrose (Brown, Fletcher le Coscina 1998), athe AgRP e bonahala e eketsa katleho ea moputso oa lijo tse nang le mafura a mangata feela (Tracy et al a. 2008). Ghrelin o bonahala a e-na le seabo ho moputso o mong le o mong oa thuto ea morao-rao (thuto e teng hona joale) le moputsong o mafura a mangata (Perello et al a. 2010); leha ho le joalo, bohlokoa ba boleng ba li-neuron tsa NPY / AgRP bakeng sa litlamorao tsena tsa ghrelin li ntse li hlakisoa. Ka bokhutšoanyane, ghrelin e na le thepa ea ho tšireletsa lijo e nkang likarolo tsohle tsa phepo mme e ka ama likarolo tse ngata tsa boko ho hokahanya karabelo e kopanetsoeng ea boitšoaro ho khothaletsa ho fepa.

Le ha ho le joalo, ho tsamaisoa ka sepakapaka ho isa bokongBanks et al a. 2002), ghipin ea pherekano e bonahala e fihlella le ho tšoaea libaka tse kang hippocampus (Diano et al a. 2006) le VTA (Jerlhag 2008). Le ha ho ntse ho e-na le ngangisano mabapi le bohlokoa ba methapo ea vagus e le tsela e sa tobang ea litlamorao tsa ghrelin (Dornonville de la Cour et al a. 2005; letsatsi et al a. 2002; Arnold et al a. 2006), ketso e tobileng kahare ho CNS e bonahala e kanna ea ba le litlamorao tsa phepelo ea lijo tse fumanehang kahare ho lijo li ka khothalletsoang ke tsamaiso ea intra-VTA ea lira tsa ghrelin (Abizaid et al a. 2006). Ghrelin e hlahisoa kahare ho bokong (Cowley et al a. 2003), leha e ntse e tlameha ho tsejoa hore na sena se laoloa joang le hore na moea o tsoang ka bokong o fana ka letšoao la bohlokoa le hlahisoang ke lipakeng tsa takatso ea lijo le tšusumetso ea ho ja. Ho kopantsoe le taba ea hore ghrelin receptor GHS-R1A e sebetsa ka mokhoa o hlophisitsoeng (ke hore, e na le ts'ebetso ha ho sa na ghrelin ligand) (Holst et al a. 2003), ho hlaha potso ea hore na ghrelin e potolohang e fana ka lets'oao la 'mele la gut-health le lokelang ho khothatsa moputso oa lijo. Liphetho tsa boithuto ba hona joale, tse bonts'ang litlamorao tse tšoanang mosebetsing oa moputso oa sucrose li ka fumaneha ka tsamaiso e bohareng le e poteletseng ea li-ligands tsa GHS-R1A, li ka supa hore ho buuoa ka bohareng hammoho le ghrelin e tsoang ka kotloloho e ka ama tšusumetso ea lijo.

Qetellong, tlhaiso-leseling ea rona e ncha e fana ka bopaki bo bocha ba hore ho saena ghrelin ho bohlokoa molemong oa ho fumana moputso oa sucrose le phello ho polelo ea lefutso ea dopaminergic le cholinergic tseleng ea moputso oa mesolimbic. Liphuputso tsa rona li khothatsa lipotso tsa bohlokoa mabapi le karolo ea "ghrelin" e sa feleng ho tseba boleng ba khothatso bakeng sa meputso ea tlholeho joalo ka tsoekere, ka boits'oaro bo tloaelehileng le ho pathophysiology ea mathata a ho ja le botenya. Le ha mosebetsi oa bohlokoa o ntse o le teng ho pheta ka mokhoa o hlakileng liphetoho tsa limolek'hule ho dopamine le acetylcholine system ho ama ghrelin moputsong, tlhaiso-leseling ea rona e kanna ea supa mochini o mocha oo ghrelin e amang boitšoaro ba moputso. Ho utloisisa karolo ea ghrelin lits'ebetsong tsa meputso ho bohlokoa molemong oa kutloisiso ea mafu a amanang le methapo ea mafu a amanang le ho ja le ho lemalla lithethefatsi 'me e fana ka monyetla oa ho utloisisa etiology ea maloetse ana le nts'etsopele ea liphekolo tse ncha. Kamora nako, monyetla oa ho hatella ho ja ho fetelletseng ha lijo tse tsoekere tse nang le tatso o sebelisa bahanyetsi ba GHS-R1A e kanna ea ba le bohlokoa ba bongaka le kalafo bakeng sa litlamorao tse hlahang tsa metsoako e joalo bakeng sa taolo ea tsoekere ea mali (Sun et al a. 2006) ka mofuta oa bakuli ba lefu la tsoekere ba 2 (Esler et al a. 2007).

lumela hore baa fokola

Patlisiso e ts'ehetsoeng ke Lekhotla la Lipatlisiso la Sweden bakeng sa Bongaka (VR 2006-5663; 2009-S266), European Union 7th Framework (FP7-HEALTH-2009-241592; FP7-KBBE-2009-3-245009), ALF GteUM the Sweden Institute le Sweden Foundation for Strategic Research to Sahlgrenska Center for Cardiovascular and Metabolic Research (A7601-305). Hape re ka rata ho leboha Dr. Daniel Perrissoud (AeternaZentaris, GmBH, Jeremane) ka ho fana ka GHS-R188A antagonist JMV1 le Anders Friberg bakeng sa thuso ka tlhahiso.

Tlatsetso ea Bangoli

KPS e qalile, e qapile, ea etsa le ho sekaseka lithuto tsohle tsa boits'oaro. CH e entse le ho hlahlobisisa lithuto tsohle tsa mofuta oa gene. EE e kentse letsoho ho qaliseng thuto. SLD e ne e le sengoli se phahameng, mme e fana ka ts'ehetso le tšehetso ea lichelete bakeng sa lithuto tsohle. Buka e ngotsoeng ka letsoho e entsoe ke KPS le SLD, bangoli bohle ba kentse letsoho ho mongolo oa ho qetela.

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