Sucrose Ingestion e Etsa Hore Haufinyane ho rekisoe thekiso ea Receptor (2013) ka potlako

J Neurosci. Mongolo o ngotsoeng ka letsoho; e fumanehang ho PMC Oct 3, 2013.
E hatisitsoe ka mokhoa o qetelle o hlophisitsoeng e le:
Phetolelo ea ho qetela ea sengoliloeng sa sengoliloeng sena e fumaneha mahala ho J Neurosci
Sheba lihlooho tse ling ho PMC hore Qotsa sehlooho se hatisitsoeng.

inahaneloang

Mokhoa oo litlhahiso tsa tlhaho tse kang tsoekere e amanang le phetoho ea synaptic le boitšoaro ba oona li sa sebelisoe haholo. Mona, re batlisisa molao oa tsamaiso ea nucleus accumbens synapses ka sucrose lijo. Liphuputso tse fetileng li bontšitse hore ho rekisa thepa ea AMPA ke mokhoa o ka sehloohong oa ho laola matla a synaptic, le seo a vitro, ho rekisa li-receptor tsa AMPA tse nang le lihlopha tsa GluA1 li etsahala ka mehato e 'meli e tsamaisang le ho tsamaisa lijo tsa extrasynaptic le synaptic receptor. Re tlaleha hore ka rat, ho kenngoa letsatsi le leng le le leng ea 25% solution ea sucrose ka nako e telele ho phahamisitse khohlano e itekanetseng mme e ka 'na ea bokella li-synapses tsa mantlha ka ho kenngoa ha Ca2+li-receptors tsa AMPA tse sa sebetseng (CPARs), tse nang le GluA1, tse nang le li-receptor tsa GluA2 Electrophysiological, biochemical le quantitative elektrone ea microscopy e senotse hore koetliso ea sucrose (matsatsi a 7) e entse hore ho be le botsitso (> 24 hr) e kenelletseng ea GluA1, le hore likhotleng tsena sekhahla se le seng sa sucrose se potlakile (5 min) empa nakoana (<24 hr) se phahame GluA1 libakeng tsa extrasynaptic. Ho ne ho hlokahala li-CPAR le dopamine D1 receptors in vivo bakeng sa locomotion e phahameng ka mor'a ho tšela ho kenella. Habohlokoa, letsatsi le leng le le leng la 7 letsatsi le leng le le leng la ho kenngoa ha 3% tharollo ea saccharin, e seng monate oa caloric, e entsoeng ka synaptic GluA1 ka tsela e tšoanang le 25% ea sucrose ingestion. TLiphuputso tsa maqheku li bontša phapanyetsano ea mekhoa e mengata ea GluA1, e hlalositsoeng pele a vitro, e le mokhoa oa ho laola phetoho e matla ea synaptic Ka vivo ka moputso oa tlhaho ea orosensory. Ho rekisoa ho susumetsoa ke tsela ea chemosensory e sa itšetleheng ka bohlokoa ba caloric ea sucrose.

Selelekela

Ho tsuba haholo-holo ke bothata bo boholo ba bophelo bo botle ba sechaba (Hu le Malik, 2010), empa mekhoa eo mehloli ea tlhaho ea orosensory e nang le eona e kang sucrose e tsamaisoang ho fetisa boitšoaro ha e tsejoe. Synaptic plasticity e nucleus accumbens, karolo ea bohlokoa ea boko ba moputso circuitry (Sesack le Grace, 2010), e tlatsetsa mefuteng e mengata ea boitšoaro bo susumelletsang, ho akarelletsa le thuto ea moputso (Letsatsi le Carelli, 2007), likarabo ho khatello ea kelello ea sechaba (LaPlant et al., 2010), le lithethefatsi pathologies (Luscher le Malenka, 2011). Ho hlahisa k'hok'heine e pheta-phetoang ho etsa hore polasetiki ea synaptic e be le methapo ea accumbens le sebaka sa ventral tegmental (VTA) (Brebner et al., 2005; Grueter et al., 2010; Mameli et al., 2009; Pascoli et al., 2012; Thomas et al., 2001; Ungless et al., 2001). Ha ho e-na le phihlelo e eketsehileng ea k'hok'heine ea botho e lateloang ke ho tlohela nako e telele, synapses e ka ba teng ka ho kenngoa ha Ca2+-a utloahalang, GluA2-e haelloa ke mofuta oa AMPA-mofuta oa glutamate receptors (CPARs), eo pontšo ea eona e amanang le ho lakatsa ha cocaine (Conrad et al., 2008; McCutcheon et al., 2011a). Ho tšoana le cocaine, orosensory moputso o kang sucrose ka matla ho phahamisa accumbens dopamine (Smith, 2004), empa ho kenngoa ha moputso oa orosensory oa accumbens polasetiki ha hoa phenyekolloa.

Li-receptors tsa AMPA (AMPARs) ke babuelli ba mantlha ba tsamaiso ea methapo ea methapo ea phekolo, 'me khoebo ea bona e tlatsetsa mekhoeng e sa tšoaneng ea neural, ho akarelletsa ho ithuta le ho hopola (Nedelescu et al., 2010; Rumpel et al., 2005; Whitlock et al., 2006). Li-AMAR li na le lihlopha tse 'nè tse fapaneng, GluA1-4. GluA2-e nang le AMPARs ke Ca2+-a senyehe le sephethephethe se na le li-synapses, athe GluA2-ha e na li-receptors (CPARs), tse ka sehloohong li-hommers tsa GluA1, boitšoaro Ca2+ le ho bonts'oa ka hare. GluA1 e tsamaisana le khoebo ea synaptic e itšetlehileng ka mosebetsi ka tsela e 'meli eo Ser 845 e fokolang ka eona ka protein kinase (PKA) le ea itšetlehileng ka CAMP-le protheine kinase II (cGKII) e khothalletsa batho hore ba fumane li-site tse ling tse ling tse ka hare ho pampiri ea plasma (Esteban et al., 2003; Serulle et al., 2007; Letsatsi le al., 2008; Letsatsi le al., 2005). Ka mor'a hore li-synapse li fapane ka nako e telele, phosphorylation ea Ser 818 ke PKC e tsitsisa AMPAR ka hare ho synapse (Boehm et al., 2006), e tšehetsoeng ho sebete sa postsynaptic (Ehlers et al., 2007; Oh le al., 2006; Serulle et al., 2007). Ca2+/ calododulin-e itšetlehileng ka protheine kinase II (CaMKII) phosphorylation ea Ser 567 le Ser 831 e boetse e tlatsetsa ho kenyelletsano ea synaptic le ho hohella ho eketsehileng (Lu et al., 2010; Roche et al., 1996), ka ho latellana. Leha ho le joalo, ha ho tsejoe hore na Ka vivo ho kenngoa ha CPARs ho sebelisa mehato ena e potlakileng, e mengata e hlalositsoeng a vitro.

Ho etsa lipatlisiso mabapi le mekhoa eo orosensory e putsang ka eona joaloka sucrose e tsamaisana le synapses e tsitsitseng, re sebelisitse paradigm ea khutšoanyane ea sucrose ho kenngoa le liphetoho tse lekaneng tsa phetisetso ea synaptic ho bokelleng neurons. Re hlokomela hore ho pheta-pheta ho tsuba ho ka etsa hore ho be le li-synapses ka ho kenngoa ha li-CPARs, le hore phoofolo e koetlisitsoeng ka sucrose, motsoako o le mong oa sucrose o lekane ho etsa khoebo ea GluA1 ka potlako libakeng tse ling tse ngata. Hobane ha li-saccharin, tse sa hlahisoang ke li-caloric, li bakoa ke khoebo ea synaptic e tšoanang le ea sucrose, ho rekisoa ke karabo ho orosensory ho e-na le litsela tsa caloric. Ho feta moo, thibelo ea CPAR e thibelitse ho phahamisoa ha li-sucrose tse entsoeng ka mokhoa o itekanetseng Ka vivo, ho khetholla ka ho eketsehileng ho bokella li-CPAR e le tsa bohlokoa tsa tsamaiso ea likarabo ho meputso ea tlhaho.

Lisebelisoa le mekhoa

Lihlooho le mekhoa ea ho buoa

Lihlooho tsena e ne e le litoeba tsa banna tsa Sprague-Dawley (Taconic; liteko tsa boitšoaro) tse boima ba ligrama tsa 150-300 ha li fihla le basali ba E18 ba nang le likokoana-hloko tsa marang-Dawley (liteko tsa Taconic; Lipotlolo li ne li hahoa 2 ka cage bakeng sa liteko tsa boitšoaro thuputsong ea 12h / 12h e khanyang (e khantšang ka 18: 00) mme e na le phihlelo ea lijo le metsi ad libitum ka linako tsohle. Mekhoa eohle ea liteko e ile ea amoheloa ke Komiti ea New York University ea Meriana ea Mekhatlo ea Meriana ea Litlhare le Komiti ea Ts'ebeliso 'me ea etsoa tumellanong le "Melao-motheo ea Bohlokomeli ba Liphoofolo" (NIH khatiso ea 85-23).

Koetliso ea li-sucrose le litekanyetso tsa mahahlauli

Li-rats li ile tsa isoa kamoreng ea tlhahlobo ea 3 matsatsi a latellanang bakeng sa 2 h / day matlong a bona a koaletsoeng malapeng. Letsatsing la bone libotlolo tse nang le metsi kapa 25% sucrose li ile tsa hlahisoa ka sekoahelo sa cage bakeng sa 5 min. Joale lihlopha li ne li lekanngoa. Bakeng sa liteko tsohle, likhofu li ne li hlokoa ho noa bonyane 1 g ea sucrose nakong ea ho fumana 5 min metsing matsatsing a 3 a ho qala ho koetlisoa ho kenngoa thutong; Ha e le hantle, litoe tsohle li na le moelelo ona. Ka mor'a hore ho tlosoe botlolo, likhooe li ile tsa lula ka kamoreng ea tlhahlobo ea 30 pele e khutlela setsing sa liphoofolo. Letsatsing la sehlabelo, likhoto li ile tsa e-ba le tsebo ea letho ka CO2, ho fokotsoa ke guillotine, le lisele tsa mahlaseli li ile tsa bokelloa holim'a leqhoa. Bakeng sa liteko tsa lisebelisoa, likhoto li ne li kenngoa likamoreng tsa litekanyetso tsa motlakase (Accuscan, Columbus, OH) bakeng sa kakaretso ea metsotsoana ea 35. Kamora 'mino oa 15 ka kamoreng eo, botlolo e nang le khama ea likhahla e ile ea hlahisoa ka holimo ho kamoreng eo' me ea tsitsisoa. Botlolo e ile ea tlosoa holimo ho kamoreng ka morao ea 5, 'me likhoele li ne li lutse ka kamoreng bakeng sa makhetlo a eketsehileng a 15 ka mor'a hore ho tlosoe botlolo. Tsamaiso ena e phetiloe ka mokhoa o tšoanang bakeng sa matsatsi a 7 a latellanang. Leeto le selelele le ne le lekanyelitsoe ho sebelisa VersaMax System (Accuscan, Columbus, OH), e neng e shebelletse mesebetsi ea liphoofolo ka marang-rang a lisele tse khanyang tsa 16 × 16 tse tsamaeang le cage ea liphoofolo (42 × 42 × 30 cm) ho ea ka morao ho ea ka ho le letšehali . Tlhahisoleseding mabapi le boemo ba sefate, e hlahlojoang ka tekanyo ea linako tse ling tsa 100 ka motsotsoana, e bolokiloe ho disk. Ketsahalo e ne e hlahisoa e le sebaka se lekanang le ho feta se lekaneng ka cm nakong ea li-12 tse nyenyane tsa 3 tse fapaneng nakong ea thupelo ea 35 (bina ea ho qetela e ne e le metsotsoana ea 2).

Koetliso ea Saccharin

Ho bapisa khoebo e entsoeng ka sucrose ea GluA1 le liphello tsa ho bolaoa ha saccharin, li-rats tse khōlō tsa banna ba 12 (250 g) li ne li lutse setsing sa liphoofolo ka lihora tsa 12 leseli le lefifi. Ka nako eo likokoanyana kaofela li ne li tloaetse ho ea kamoreng ea tlhahlobo ka ho isoa kamoreng ea teko, li setseng lihora tsa 2, ebe li khutlisetsoa setsing sa liphoofolo. E 'ngoe ea letsatsi la 4th (kamora matsatsi a 3 a tloaelehileng), linoko li ile tsa fuoa libotlolo tsa ho fumana tse nang le metsi, sucrose, kapa saccharin. Lipotlolo tsa 4 li ile tsa fanoa ka botlolo ea metsi a nang le metsi a lutseng ka holim'a cage ka spout e kenang kahare ka sekoahelong. Nako ea ho fihla e ne e le metsotso ea 5, joale botlolo e tlosoa, 'me ka mor'a metsotsoana e meng ea 15 metsotso e khutlisetsoa setsing sa liphoofolo. Lipotlolo tsa 4 li ile tsa fuoa monyetla oa ho fumana tharollo ea 25% sucrose le likhopo tsa 4 li ile tsa fuoa monyetla oa ho fumana 3% saccharin solution (Sweet'n Low). Boima ba metsi a neng a jeoa bo ne bo lekantsoe. Tsamaiso ena e phetiloe bakeng sa matsatsi a 7. Letsatsing la 7th la ho noa, hang-hang ka mor'a ho tlosoa ha li-bottle, likhofu li ne li hlajoa 'me li bokelloa mantlha li ne li kotuloa' me litekanyetso tsa GluA1 li ne li ts'oaroa ke thibelo ea Bophirimela.

Electrophysiology

Li-rats li ne li koetlisoa ka tsela e hlalositsoeng ka holimo likhethong tse hlakileng tsa polasetiki, 'me, ka mor'a ho tlosoa ka botlolo letsatsing la 7, li ne li sa sebelisetsoe ketamine (100 mg / kg ip) le xylazine (10 mg / kg ip) le ho sebelisoa ha transcardially ka saline e batang (liteko tsa mEPSC) kapa ho fokotseha ka potlako (liteko tsa ho lokisoa). Bokooa bo ile ba tlosoa ka potlako ho e-na le mokelikeli oa maiketsetso (ACSF) o entsoeng ka tse latelang (mM): bakeng sa liteko tsa mEPSC: NaCl (118), KCl (2.5), CaCl2 (3), MgCl2 (1), NaHCO3 (26), NaH2PO4 (1), D-glucose (10), osmolarity e fetiselitsoeng ho 325 mOsm mme e hlahisoa ke 95% O2/ 5% CO2 (pH 7.4); bakeng sa liteko tsa ho lokisoa: 75 sucrose, 87 NaCl, 2.5 KCl, 1.25 NaH2PO4, 0.5 CaCl2, 7 MgCl2 6 H2O, Nahco 253, 10 dextrose, e phunyeletsoang ka 95% O2 / 5% CO2 (pH 7.4). Lihlahisoa tsa Coronal (300μm thick) tse nang le nucleus accumbens li ne li khaola ka ACSF e batang leqhoa li sebelisa vibrotome (Leica, VT1200S) 'me li lula li kenngoa ka ACSF (ACSF, mM: 124 NaCl, 2.5 KCl, 1.25 NaH2PO4, 2.5 CaCl2, 1.5 MgSO4 7H2O, Najco 263, le 10 dextrose) bakeng sa <30 min; e ntan'o bolokoa ka selae sa pele ho mochine ka mocheso oa kamore bonyane hora e le 'ngoe ho lumella ho hlaphoheloa. Bakeng sa liteko tsa mEPSC: selae se le seng se ile sa fetisetsoa phapusing ea ho rekota moo se neng se ts'oeroe se koaetsoe ke letlooa la nylon ho 1 ° C ka TC32B in-line solution hitara le molaoli (Warner Instruments, CT). Kamore e ne e ts'ebetsoa khafetsa ke ACSF ka sekhahla se sa fetoheng sa 324 ml / min. Li-neurone tse mahareng tsa spiny tse tsoang sebakeng sa mantlha sa bokellane li fumanoe tlasa tataiso ea pono ho sebelisa tšoaetso ea infrared-phapano e fapaneng le microscopy ea video (Hamamatsu C2) e nang le microscope e emeng ea Olympus BX5405WI e nang le sepheo sa ho qoelisoa ka metsi sa 50x. Patch li-electrode (40-4 MΩ) tse nang le tharollo ea "intracellular pipette" e nang le (mM): CsCl (6), HEPES (145), EGTA (10), le MgATP (0.5). Osmolarity e ile ea fetoloa ho 5 mOsm le sucrose, 'me pH ea fetoloa ho 290 le CsOH. Metsotso e nyane ea thabo ea kamora 'synaptic (mEPSCs) e tlalehiloe boteng ba bicuculline (7.4μM) le tetrodotoxin (10μM) e sebelisa seholisa sa Axopatch 1B (Molecular Devices, CA) mme e fetotsoe ka Digidata 200A (Molecular Devices, CA). Bakeng sa liteko tsa tokiso: lilae li ile tsa fetisetsoa phapusing ea ho rekota 'me tsa sebelisoa (1322-2.0 ml min-1) ka ACSF ea oksijene ho 33-35 ° C e nang le 50 μm picrotoxin ho arola EPSCs. Lisebelisoa tse nang le li-sesebelisoa tsa Somatic li ne li entsoe ka li-neurons tse nang le li-spin neurons tse ka hare-hare ho motlakase-li koahela le Multiclamp 700B amplifier (Li-Molecular Devices) li sebelisa micro-microscopy ea IR-DIC. Li-pipettes tsa patch (4-6 MΩ) li ne li tletse tharollo ea intracellular (mM: 125 Cs-gluconate, 2 CsCl, 5 TEA-Cl, 4 Mg-ATP, 0.3 GTP, 10 phosphocreatine, 10 HEPES, 0.5 EGTA, le 3.5 QX -314). Lintlha li ne li tlhotliloeng ka 2 kHz, tse nkiloeng ka 10 kHz, le ho hlahlojoa ka Clampfit 10 (Li-Molecular Devices). Khatiso ea extracellular (0.01-1 ms, 5-150 μA, 0.2 Hz) e ne e sebelisoa ka khalase e nyenyane ea bipolar 0.05-0.5 mm ho tloha ho electrode ea ho rekota. Ka mor'a hore ~ ​​~ 10 min e rekotole ho rekota, tharollo e nang le Naspm (200 μM) e ile ea kenngoa mofuteng ka ho sesa bakeng sa 10 min. Liphetoho tsa litekanyetso tsa EPSC li ne li lekantsoe pele le ka mor'a kopo ea lithethefatsi ha li e-na le menyetla ea -70, -50, -30, 0, + 20, + 40 le + 60 mV. Lenane la ho lokisoa (ir) e ne e baloa ka ho lokisoa leha e le efe liphetoho tse ka khonang ho fetola 'me li lekanngoa ho tsoa ho tse latelang: ir = (I-70 / 70) / (I+ 40 / 40), moo I-70 'me I+ 40 ke EPSC amplitudes e tlalehiloeng -70 mV le + 40 mV, ka ho latellana.

Karolo ea li-subcellular le Western blotting

Ho bokella ho ne ho bokelloa holim'a leqhoa joalokaha ho hlalositsoe ka holimo. Ha motsoako le khetla li arohanngoa ka ho arohana, karohano e ile ea tiisoa ka ho hlahloba likaroloana tsa synaptosoma bakeng sa dopamine β-hydroxylase, enzyme e fumanoang li-terminals tsa axons ho shell empa e se motheo (Sesack le Grace, 2010). Likaroloana tsohle tsa cell, synaptosome, le PSD li ile tsa lokisetsoa joalokaha ho hlalositsoe pele (Jordan le al., 2004). Li-pellets tsa synaptosomal li ile tsa tsosolosoa ka 200 μl 25 mM Tris le 1% Triton X-100, e phunyelelitsoeng 4 ° C bakeng sa 30, mme e centrifuged ho 13,800 × g bakeng sa 15 metsotsoana ho microcentrifuge pellet pelt. Pelo e nang le PSD e se nang thuso e ile ea tsosolosoa ka 25 mM Tris ka 2% SDS. Likaroloana li ne li hlahlojoa ke thibelo ea Bophirimela ho li-gels tsa SDS-PAGE joalokaha ho hlalositsoe pele (Jordan le al., 2004). Li-antibodies tse latelang li ne li sebelisoa: dopamine β-hydroxylase (1: 1,000, Abcam), GluA1 (1: 1,000, Millipore), phosphor-Ser 845 GluA1 (1: 1,000, Millipore), GluA2 (1: 1,000, Millipore) le tubulin (1: 10,000, Sigma).

Electron microscopy

Ka letsatsi la kotulo ea mahlaseli (letsatsi la 7 la koetliso ea sucrose), likhofu tse tsoang lihlopha tsa tlhahlobo tsa 3 (Metsi, Sucrose / Metsi, Sucrose; likhohlo tsa 3 / sehlopha sa teko) li behiloe likamoreng tsa tekanyo ea likhoeli tsa 15; ho 15-metsotso ea botlolo e ile ea hlahisoa ka holimo ka kamoreng. Lihlopha tse sehlopheng sa Metsi li ile tsa amohela metsi, likhofu tsa sehlopha sa acrose se fumanoa 25% sucrose, likhoto ka sehlopha sa Sucrose / Metsi, se neng se fetile 25% sucrose matsatsi a 6, se fumane metsi. Li-rats li ne li sa rutehe haholo ka Nembutal (50 mg / kg ip) le transcardially e sebelisoa hampe le 0.1 M phosphate buffer (pH 7.4) e nang le 4% paraformaldehyde le 0.1% glutaraldehyde ka tekanyo ea 50 ml / min nakong ea pele ea 3, tekanyo ea 20 ml / min bakeng sa metsotsoana ea 7 e atlehileng. Li-tissu li ne li lokiselitsoe ho ngolisa litšoantšo le litšoantšo ka morao (PEG) le litšoantšo li ile tsa haptjoa joalokaha li hlalositsoe pele (Nedelescu et al., 2010). Li-immunolabels li ile tsa aroloa ho ea ka boemo ba tsona bo amanang le PSD ka lihlopha tsa synaptic tse sa tloaelehang joaloka "cleft," "haufi le PSD" (ka hare ho 1 bophara ba PSD ho tloha PSD), "PSD," "e tsitsitseng," kapa "extrasynaptic membrane." phoofolo e 'ngoe le e' ngoe, li-synapses tsa 93 e ne e le lisebelisoa tse tsoang mokokotlong oa accumbens. Mehlala e sa lebelloang e ile ea tiisoa ka ho hlahloba li-synapses tsohle tsa 93 tseo re ileng ra kopana le tsona hangata ha re ntse re tsamaea ka tsela e hlophisitsoeng ka tsela e hlophisitsoeng, ebe re kenya palo e lekanang ea li-synapses ho e mong le e mong oa liphoofolo tse tharo tse ileng tsa fumana phekolo e tšoanang le ea lefu. Mefuta e 'meli ea quantification e ne e etsoa. E 'ngoe e ne e le ho hlahloba boemo ba GluR1-immunoreactivity level, ka ho fetisa palo ea likaroloana tsa PEG tse ileng tsa etsahala libakeng tse sa tšoaneng tsa mokokotlo. E 'ngoe e ne e le ho hlahloba palo ea synapses e ngotsoeng PSD ka palo efe kapa efe ea PEG. Esita le li-synapse tse ngotsoeng ka karolo ea 1 PEG feela li ne li nkoa li ngotsoe, li thehiloe mosebetsing oa pejana li bonts'a mokhoa o hlakileng oa mokhoa oa GluR1-PEG (Nedelescu et al., 2010). Litla-morao tsa phekolo ka tekano le tekanyo ea GluR1-immunolabeling li ile tsa hlahlojoa ka tsela e le 'ngoe ANOVA le litšoantšiso tse fanoeng ka morao-rao (Fisher's LSD). E le hore ho felisoe mekhoa ea boipheliso, lintlha li ne li foufalitsoe ka makhetlo a mararo: e mong oa liteko o ile a etsa koetliso ea sucrose 'me a boloka litlaleho tsa liphoofolo lihlopha tse tharo tsa tlhahlobo, e' ngoe ea liteko e ile ea theha li-electron micrographs mme ea abeloa code e ncha ea alphanumeric ho micrograph e 'ngoe' me e boloka tiiso e tiisitsoe , le liteko tse ling tse tharo tsa liteko li ile tsa hlahloba micrographs le likaroloana tse nyenyane tsa PEG. Ka mor'a hore quantification ea PEG e phethe, bafuputsi ba ile ba bokana ho senola boitsebiso ba micrograph ka 'ngoe.

Ho kenya li-cannula le li-injection tse sa sebetsaneng

Sejo se entsoeng ka ho hlahisa li-intracranial se ne se sebelisetsoa ho fana ka Naspm le APV ho accumcums core. Bakeng sa ho kenngoa ha khauta, joalokaha ho hlalositsoe pele (Carr et al., 2010), likhoto li ne li sa ts'oaroe ke ketamine (100 mg / kg ip) le xylazine (10 mg / kg ip) ebe e kenngoa hamorao ka benamine ea analgesic (1 mg / kg subcutaneous). Li-rats li ne li e-na le stereotaxically e nang le li-26-gauge guide cannulae tse peli (PlasticsOne, Roanoke, VA) li kopane ka makhetlo a mabeli motseng oa accumbens le li-coordinate: 1.6 mm pele ho moo ho bregma; Karolo ea 2.9 mm ho suture ea sagittal, litlhahiso tse ling tsa 8 ° ho ea bohareng ba bohareng, 5.6 mm ventral ho ea lehata. Cannulae e ne e tšoareloa sebakeng sa 'mino oa acrylic le patency e ile ea lula e e-na le setaele sa maemo. Bakeng sa li-injection tse sa sebetsaneng, metsoako ea Naspm le APV e ne e kenngoa ka bolelele ba cm cm ea 30 ea PE-50 tubing e kopantsoeng ka lehlakoreng le leng ho ea ho metsoako ea 25-μl ea Hamilton e tletseng metsi a nang le distilled 'me ka lehlakoreng le leng ho 31-gauge injector cannulae, e neng e eketsa 2.0 mm ka nģ'ane ho tataiso e behiloeng. Li-sering li ne li kenngoa mafahla a pompe ea Harvard 2272 microliter sering e neng e fana ka likheo tsa injection ea 0.5 μl ka nako ea khekhe ea 100. Metsotso e seng mekae ka mor'a hore liente li phethoe, injector cannulae e ile ea tlosoa libukeng, mechine ea li-style e ile ea nkeloa sebaka, 'me liphoofolo tsa kenngoa likamoreng tsa ho hlahloba li-sucrose. Ka mor'a ho etsa sehlabelo sa liphoofolo, likarolo tsa boko ba cryogenic li ile tsa hlahlojoa bakeng sa libaka tsa mahae; 2 ho tsoa liphoofolong tsa 15 ha ea ka ea kenngoa thutong ka lebaka la ho behoa ha mokhoa o sa lokelang.

Tlhahlobo ea statistical

Tsela e 'ngoe ANOVA e lateloang ke liteko tsa poso ea ho thibela litlhapi e ne e sebelisoa bakeng sa elektronike ea microscopy, immunocytochemistry le liteko tsa biotinylation. Litlhahlobo tse peli tsa Tlhōlisano ea Seithuti li ile tsa sebelisoa bakeng sa electrophysiology. Bakeng sa li-sucrose li-experiments tse fokolang maikutlo, tsela e 'meli ea ANOVA e ne e sebelisoa, e lateloa ke liteko tsa poso tsa ho thibela Fisher.

LIPOTSO

Tšobotsi ea sucrose ingestion paradigm

Re ile ra sebelisa paradigm e entrose ho senya liphello tsa moputso oa tlhaho, orosensory ho tsamaiso ea synaptic (Setšoantšo sa 1A). Likokoanyana tse kholo li ile tsa isoa kamoreng ea tlhahlobo ka matsatsi a mararo a latellanang. Letsatsing la bone (letsatsi la pele la koetliso), likhofu li ne li behoa kamoreng ea litekanyetso. Kamora 'metsotso ea 15 ea ho etsa lintho tse ling ka kamoreng, likopa tse nang le metsi (bakeng sa liphoofolo tsa Metsi) kapa 25% sucrose tharollo (bakeng sa liphoofolo tsa Sucrose) li ile tsa kenngoa likamoreng tsa tekanyo ka likoting tse sepakapakeng sa kamore. Likopi tsena li ile tsa tlosoa ka mor'a metsotso ea 5 mme mosebetsi oa ho lokisa o ne o lekantsoe ka metsotso e eketsehileng ea 15 pele liphoofolo li khutlisetsoa matlong a koaletsoeng malapeng. Re pheta mokhoa ona bakeng sa matsatsi a 7 a latellanang. Litsing tse ling, koetliso ea sucrose e fetiselitsoe ho 8th letsatsi. Tlhaloso ena e khutšoanyane, e sa phekoleheng ea tharollo e khonehang haholo e ile ea re lumella hore re batlisise liphello tse peli tse matla le tse amanang le ts'ebetso ea sucrose, kaha liphoofolo li tsitsitsoe ka matla ka katleho nakong ea fensetere ea ho kena ka hare ho matsatsi a mararo a koetliso (Setšoantšo sa 1B). Maemo ana a liteko a ile a nolofalletsa ho bapisoa ha lihlopha tsa tlhahlobo hang ka mor'a ho khaotsa ho kenngoa. Tsela ea rona ea ho kenngoa thutong e ne e le hore likhofu li qala ho ja bonyane gram e le 'ngoe ea sucrose ka nako ea ho fihlella pele matsatsi a mararo a qala ho koetlisoa; ha ho liphoofolo tse neng li sa kenyelletsoa thutong ho latela moelelo ona.

Setšoantšo sa 1  

Ho pheta-pheta lijo tse nang le li-sucrose li etsa hore ho be le mekhoa ea nakoana ea ho tsuba.

Re hlokometse hore pele matsatsi a mararo a koetlisoa, liphoofolo tsa Sucrose li ne li ja mocheso oa sucrose haholo ho feta liphoofolo tsa metsi tse jang metsi (Setšoantšo sa 1B). Ho phaella moo, le hoja ho se na phapang e khōlō ea ho itokolla ho sa tloaelehang ho ile ha etsoa matsatsing a koetliso 1-6 (data e sa bontšoang), re bone boholo ba sebaka se selelele se tsamaeang le liphoofolo tsa Sucrose ha li bapisoa le liphoofolo tsa metsi ka metsotso e meraro ka mor'a hore ho tlosoe botlolo letsatsing la 7 (Setšoantšo sa 1D), 'me phapang ena e ne e boetse e teng letsatsing la 8 (Setšoantšo sa 1E). Ha ho na phapang pakeng tsa maeto a fapaneng a tsamaisoang lipakeng tsa metsi le liphoofolo tsa sucrose metsotso e meraro pele ho kenyelletso ea botlolo ho matsatsi leha e le afe a tlhahlobo (Setšoantšo sa 1C), ho fana ka maikutlo a hore ho hoholo ho hoholo ho ne ho e-na le karabelo e matla ho sucrose ho kenella ka ho khethehileng ho rat e entsoeng ka sucrose, ho e-na le ho arabela ka mofuthu ho kamoreng ea mohaho. Tumellanong le monyetla ona, ho ne ho e-na le kopano e ntle pakeng tsa palo ea sucrose e jang le kakaretso ea sebaka se tsamaeang (Setšoantšo sa 1F). Ho ne ho se na phapang pakeng tsa mefuta ea liphoofolo pakeng tsa Sucrose le Lihlopha tsa Metsi pele kapa kamora matsatsi a 7 a koetliso (data e sa bontšoa).

Ho kenngoa ha li-sucrose ho kenyelletsa kenyelletso ea CPAR

Koetliso ea katleho e lebisitse ho phahama ha nako e telele ea ho tsuba ha letsatsi le ho qetela. Ho fumana hore na sephetho sena sa ho tsuba sejo se ne se tsamaisana le liphetoho tsa electrophysiological nucleus accumbens, sebaka se laolang boitšoaro, re lokisitse lilae tsa nucleus accumbens kapele ka mor'a ho tlosoa ha botlolo letsatsing la 7 le ho tlalehoa ho tloha neurons ea accumbens core (Setšoantšo sa 2A). Ts'ebetso ea mantlha e 'nile ea kenngoa likarabong tsa batho ba nang le mekhoa e metle bakeng sa mekhoa e metle (Sesack le Grace, 2010). Re fumane hore bobeli le makhetlo a mabeli a mongobo a mongobo oa postsynaptic (mEPSCs) a ne a le kholo haholo ha a bokella moloko oa liphoofolo tsa Sucrose ho bapisoa le liphoofolo tsa metsi (Setšoantšo sa 2B). Sena se ile sa bontša hore ho pheta-pheta mocheso ka makhetlo a mangata ho ka etsa hore ho be le phetoho ea synaptic mokokotlong oa nucleus accumbens. Ho fumana hore na ho kenyeletsoa ha CPAR ho ne ho phetha karolo efe ka bokhoni ka mor'a sucrose, re ile ra etsa li-indices tsa ho lokisoa bakeng sa ho bokella li-neurons tsa mantlha ka ho lekanya li-EPSC ka mekhoa e sa tšoaneng ea membrane (Litšoantšo tsa 2C, 2D le 2E). Ma-CPAR a ntse a tsosolosa ka hare ho menyetla e senyehileng ka lebaka la ho thibeloa ha polyamine e sa feleng. Re bone phetoho e kholo ho litlaleho tsa li-neurons tsa liphoofolo tsa Sucrose, joalokaha ho bontšoa ka ho se na kamano le kamano ea I / V, ho bapisoa le liphoofolo tsa metsi (Setšoantšo sa 2E), ho phaella hoketseho e kholo ea index ea ho lokisoa (Setšoantšo sa 2F).

Setšoantšo sa 2  

Ho bokella li-synapses tsa mantlha li ka 'na tsa e-ba teng ka mor'a hore li phekole hangata.

Ho tiisa ho phahama ha litekanyetso tsa CPAR ka mokhoa o mong, re tlalehile ho tloha accumbens core neurons ka mor'a hore ho kenyeletsoe blocker e itseng ea CPAR, 1-Naphthylacetyl spermine (Naspm) bathing. Re fumane hore Naspm e theohile haholo ho EPSC bophahamo ba litlaleho tse tsoang li-neurons tse tsoang Sucrose empa eseng liphoofolo tsa metsi (Litšoantšo 3A-C). Ho phaella moo, ka mor'a phekolo ea Naspm, likamano tsa I / V li-neurons tsa liphoofolo tsa Sucrose li ile tsa fetoha tse nyenyane, tse bontšang ho thibela li-CPARs li-synapses tsa liphoofolo tsa Sucrose, ha ho se na likamano tse kholo kamanong ea I / V e ileng ea hlokomeloa ka morao ho phekolo ea Naspm li-neurons ho liphoofolo tsa metsi (Litšoantšo tsa 3D). Liphetho tsena li bonts'a hore ho pheta-pheta ho ts'ula ho hlahisa ho kenngoa ha CPARs ka synapses ea accumbens mantlha.

Setšoantšo sa 3  

Ho kenngoa ha li-sucrose ho baka ho kenyelletsoa ha Ca2 + -e nang le maemo a amohelehang a AMPA.

Ho kenngoa ha sucrose ho etsa hore ho be le khoebo ea GluA1

Li-CPAR ke li-receptor tsa AMPA tse se nang karolo ea sehlopha sa mokhatlo oa GluA2 AMPA. Ka hona, kenyelletso ea synaptic ea CPARs hangata e kenyelletsa khoebo ea synaptic e itšetlehileng ka mesebetsi ea GluA1 subunit (He et al., 2009; Isaac et al., 2007; Liu le Zukin, 2007; Plant et al., 2006). E le hore re netefatse CPAR synaptic incorporation ho latela koetliso ea sucrose, re ile ra batlisisa hore na tsoekere ea sucrose e eketseha polelo ea synoptic ea GluA1. Li-rats li ile tsa fuoa monyetla oa ho fumana sucrose joalokaha ho hlalositsoe ka holimo bakeng sa matsatsi a 7 a latellanang. Ka matsatsi a 1, 3, 5, le 7, re arolelitse likaroloana tsa cell, synaptosome le postsynaptic (PSD) tse tsoang libakeng tse tharo tsa boko: accumbens core (core), accumbens shell (shell) le cortex (cortex) e mengata. Re ile ra hlahloba likaroloana tsohle tsa sele le tsa PSD ka thibelo ea Bophirimela bakeng sa polelo ea GluA1 le GluA2.

Ha rea ​​ka ra fumana liphetoho ho GluA1 kapa GluA2 ka likaroloana tsohle tsa sele tsa li-lysate tse bokellang matsatsing a tlhahlobo a hlahlojoang, ho fana ka maikutlo a ho pheta-pheta sesebelisoa ha ho laole karolo e akaretsang ea liprotheine tsena (Litšoantšo 4A-C). Li-fractions tsa PSD tsa accumbens, leha ho le joalo, GluA1 e eketsehile ka ho fetisisa ka letsatsi 7 mokokotlong empa e se ka khetla ha GluA2 e sa fetohe haholo ka karoloana (Litšoantšo tsa 4D-4F le data e sa bontšoang). Ha rea ​​ka ra bona keketseho e kholo ea GluA1 meleng ea metsoako ea PSD ea metsoako matsatsing a pele a tlhahlobo (Litšoantšo 4D-F) le GluA1 kapa GluA2 ha ea ka ea fetoha likaroloaneng tsa PSD matsatsing ohle a tlhahlobo (data e sa bontšoang). Ho eketseha ha GluA1, haholo-holo ho latela GluA2, ho bokellana meholo ea PSDs ka mor'a hore ho phethoe ho kenngoa ha lijo ho lumellana le ho eketseha ha phetoho e fumanoeng ho accumbens core neurons, joalokaha ho hlalositsoe ka holimo.

Setšoantšo sa 4  

Botsoako ba Postsynaptic GluA1, empa e se GluA2, e eketseha ka nucleus accumbens core ka mor'a hore sucrose e kenelle.

Khoebo ea GluA1 e itšetlehileng ka mosebetsi-ts'ebetso e bontšitsoe ho tlatsetsa polasetiki ea synaptic a vitro le hape Ka vivo (Lu le Roche, 2011). Mokhoa o potlakileng oa mehato ea ho rekisoa ha GluA1 o bontšitsoe a vitro (Serulle et al., 2007; Letsatsi le al., 2008; Letsatsi le al., 2005). Ho fihlela joale, leha ho le joalo, monehelo oa mekhoa ena e mengata ho GluA1 synaptic accumulation Ka vivo ha e e-s'o hlahlojoe. Ho fumana hore na tlhahiso ea sucrose e etsa hore ho be le khoebo ea GluA1 hantle ka mekhoa e mengata, re GluA1 e sebakeng sa heno sekheo sa li-synapses tsa liphoofolo tsa sucrose le tse koetlisitsoeng ka metsi ka li-microscopy tse ngata. Ho bokella lisele tsa mantlha li ne li kotuloa ka letsatsi la bosupa la sucrose koetliso ea lihlopha tsa lipompong tsa 3. Tsena e ne e le likhoto tse latelang: 1) li noa metsi bakeng sa matsatsi a 7 (Metsi), 2) li ne li ja sucrose matsatsi a 7 (Sucrose), le 3) li ja sucrose matsatsi a 6 le metsi letsatsing 7 (Sucrose / Water). Li-rats li ne li nyeheloa ka 7th letsatsi, metsotso ea 5 ka mor'a ho sebelisoa ha sucrose kapa metsi. Ka hona, ho bapisa lihlopha tse peli tsa tlhahlobo, liphoofolo tsa Sucrose / Metsi le li-Sucrose, ho tse ling le ho liphoofolo tsa Metsi li senola linako tse ling tsa liphetoho tsa morao-rao tse bakoang ke ts'ebetso ea sucrose lireng tse koetlisitsoeng ka sucrose. Re ile ra lekanya GluA1 e nang le li-immunogold (PEG) tse nang le likarolo tse fapaneng tsa postsynaptic: dendritic spine cytosol (intraspinous), membrane ea plasma e feteletseng (psbr), PSD, haufi le PSD le synaptic cleft, 'me likarolo tse tharo tsa ho qetela li kopane hammoho' PSD ' '(Setšoantšo sa 5A). Ho felisa mekhoa ea boipheliso, tlhahlobo ea electron micrograph sehlopha sa boitsebiso ba batho ba ne ba foufalitsoe ka makhetlo a mararo.

Setšoantšo sa 5  

Electros microscopy e senola ho kenngoa ha mekhoa e mengata ea ho rekisoa ha GluA1 ka ho tšela ho kenngoa ha lijo.

Lihlahisoa tse peli tsa Sucrose le Sucrose / Metsi li bontšitse GluA1 e sa sebetsaneng haholo le liphoofolo tsa metsi (Setšoantšo sa 5B le 5C). Sena se fana ka maikutlo a hore ts'ebetso ea sucrose e sa foleng e eketsa letamo la li-intraellular la GluA1 tse nang le li-receptor AMPA tse haufi le li-synaptic, li-receptors tse ka fumanoang habonolo bakeng sa ho rekisoa ka synaptic, 'me, ho bohlokoa, hore letamo lena la masapole le se ke la tsoela pele lihora tsa 24 ka mor'a ho sebelisoa ha sucrose . Re ntan'o hlahloba potso ea bohlokoa ea hore na ho na le tšusumetso e matla ea sucrose e ka kenyang khoebo ea GluA1 ka potlako. Re hlokometse hore lesapo le nang le lero la plasma la gluA1 le ne le eketseha haholo liphoofolong tsa Sucrose ha li bapisoa le liphoofolo tse peli tsa Sucrose / Metsi le Metsi (Litšoantšo tsa 5B le 5D). Maikutlo ana a bontša hore moputso oa tlhaho, kapa oa tlhaho o fanoang ke ntho e le 'ngoe ea sucrose e ka potlakang (<5 min) empa nakoana (nako ea ho bola <24 h) e phahamisa palo ea batho ba extrasynaptic ba li-receptor tsa GluA1 tse nang le AMPA, e thehang letamo la labile leo li-receptor li tsoang ho lona e ka sephethephethe ho synapse.

Habohlokoa, a vitro Liphuputso li bontšitse hore motsoako oa synaptic oa receptors ea AMPA o etsahala litsing tsa 2. Ka lekhetlo la pele, ser X -UMX phosphorylation e itšetlehileng ka glutamate kapa ea dopamine e phahamisa maemong a mangata ho libaka tse ling tse eketsehileng tse ka lekaneng la plasma (Esteban et al., 2003; Serulle et al., 2007; Letsatsi le al., 2008; Letsatsi le al., 2005), ha e ntse e le ea bobeli, ser 818 phosphorylation e khothalletsa synaptic incorporation (Boehm et al., 2006). Papiso ea rona ea microscopy ea li-microscopy ea liphoofolo tsa Sucrose tse nang le liphoofolo tsa Sucrose / Metsi le Metsi li bontša hore mohato oa pele oa khoebo ea GluA1 e hlokometse a vitro (Makino le Malinow, 2009), ho rekisa ka potlako ho lesela la extrasynaptic, ho boetse ho etsahala Ka vivo ho latela tokisetso ea moputso oa orosensory.

Tumellanong le electrophysiology le liphello tsa lik'hemik'hale tsa tlhaho tse hlalositsoeng ka holimo, PEG EM e bontšitse hore sucrose e kenelle e boetse e entse mohato oa bobeli mofuteng oa ho rekisa GluA1 ho amohela molaetsa ho synapse ho tloha ha tekanyo ea GluA1-immunoreactivity PSD e ne e le khōlō haholo bakeng sa Sucrose ha e bapisoa le likhoho tsa metsi, 'me ho ne ho e-na le mokhoa oa ho eketsa GluA1 ho Sucrose / Metsi ho bapisoa le likhoto tsa metsi (Lipalo 5B le 5E). Ho eketseha ha liphoofolo tsa Sucrose / Metsi ho lumellana le ho kenngoa ka potlako ha GluA1 e bolaeang ka nako ea halofo ea bophelo ea ~ 24 hr ,, kapa ho kenngoa ka potlako ha GluA1 le ho nkeloa sebaka ke synaptic GluA1 / 2 ka nako e tšoanang. Palo ea li-synapse tse hlalosang GluA1 ho PSD e ne e boetse e le khōlō haholo linthong tsa Sucrose ho bapisoa le likhoto tsa metsi (Setšoantšo sa 5F), Ho fana ka maikutlo a hore GluA1 e rekisitsoe ka li-synapses tse neng li se na GluA1 pele. Sena se boetse se fana ka maikutlo a hore keketseho ea bophahamo ba mEPSC e bonoang likhotleng tsa Sucrose e bakoa ke keketseho ea synaptic GluA1, le hore keketseho ea maqhubu a mEPSC e ka hlaha ka lebaka la ho hiroa ha GluA1 ho isa ho li-synapses tse neng li khutsitse pele, leha matla a ho lokolloa ha glutamate a ke ke a lahloa. Re boetse ra lekanya palo ea li-synapses sehlopheng ka seng sa lihlopha tse tharo tsa liteko ho bona hore na sucrose e kenella ka lebaka la synaptogenesis; ho ne ho se na liphapang lipakeng tsa lihlopha tse tharo tsa liteko (data e sa bontšitsoeng). Re fihlela qeto ea hore ho kenella khafetsa ha sucrose ho phahamisa letamo le tsitsitseng la> GluA24, 'me leqhubu le le leng la sucrose ho rat e koetlisitsoeng (matsatsi a 1) e lekane ho phahamisa GluA6 ka potlako lera la extrasynaptic plasma, mohlomong ho hula li-receptor ho tsoa letamong la tlhaho. Re fana ka maikutlo a hore karolo e 'ngoe ea li-receptor tsena tsa extrasynaptic e kentsoe ka mokhoa o ts'oarehang ho PSD, e lebisang ho index ea tokiso e hlokometsoeng le liphetoho tsa PSD GluA5, pele letangoana la extrasynaptic le khutlela mohatong oa pele ho 1 h kamora ho hlasimolla. Liphetho tsena li senola hore moputso oa tlhaho o ka baka khoebisano e potlakileng ea GluA1 ho phoofolo e koetlisitsoeng.

Mosebetsi oa CPAR o hlokeha bakeng sa ho khaola ho hoholo ka mor'a hore o tšollele ho kenngoa

Li-neurons tse nyenyane tse nyenyane li amohela bobeli ba li-dopaminergic le glutamatergic (Calabresi, et al., 1992). E le hore re hlahlobe ho kenya letsoho ha pontšo ea glutamate ka mokhoa o phahameng oa ho lokoloha ka nako e telele oo re o boneng ka mor'a hore re tsoele pele ho kenella ka sucrose likhoto tse koetlisitsoeng, re kenyelitse li-cannula ho e-na le metsoako ea likhoto, le liphoofolo tse koetlisitsoeng likamoreng tsa litekanyetso tse hlalositsoeng ka holimo. Letsatsing la 8 la koetliso ea sucrose, re kenya microplase Naspm kahare ho pele ho kenngoa kamoreng ea tlhahlobo ea lisebelisoa. Lejoe le ile la fokotsa kakaretso ea maeto a liphoofolo tsa Sucrose 'me la felisa phapang pakeng tsa liphoofolo tsa Sucrose le Metsi tse bonngoeng kapele ka mor'a ho tlosoa ha libate (Setšoantšo sa 6A). E le ho netefatsa hore khatello ea kelello e bakiloeng ke ho sebetsana le liphoofolo e ne e sa ama tšusumetso ea sucrose, re ne re kenya letsoai mokokotlong letsatsing le hlahlamang (letsatsi la 9 la koetliso ea sucrose); hape ho ne ho e-na le ts'ebetso e kholo ea ho ts'oaea ha liphoofolo liphoofolo tsa Sucrose hang ka mor'a hore ho tlosoe botlolo (Setšoantšo sa 6B). Sena se bontša hore Naspm e ne e thibela ka ho khetheha ho nyoloha ha mokokotlo oa ho tsuba. Ho hanyetsoa ke mohanyetsi oa NMDAR, APV, kahare ho matsatsi a latelang le hona ho felisitse phapang lipakeng tsa liphoofolo tsa sucrose le tsa metsi (Setšoantšo sa 6C), ho bontša hore li-NMDAR li boetse li hlokoa bakeng sa ho phahama ha mokokotlo oa nakoana ka mor'a hore o tsoe ka mali. E le ho fumana hore na karabo ea boemo bo botle ho kamore ea tlhahlobo e bile le karolo efe ho kenyellets'oa ha liphoofolo, liphoofolo li behiloe ka kamoreng ea 35 min ntle ho kenyelletso ea botlolo; ho se lumellane ha sebaka se tsamaeang le maoto ho ne ho bonoa pakeng tsa Surose le liphoofolo tsa metsi (Setšoantšo sa 6D). Naspm le APV ha lia ka tsa ama sucrose (Setšoantšo sa 6E), ho bonts'a hore maqheku a CPAR le a NMDAR ha a hlokehe bakeng sa ho ja ka matla ho sucrose. Liphoofolo tseo li-cannula li sa kang tsa kenngoa ka tsona mobbensong oa core (2 ho tsoa liphoofolong tsa 15), ha li hlahlojoa ka mor'a sehlabelo (Setšoantšo sa 6F), ha baa ka ba kenngoa thutong. Qetellong, litlhaloso tsena hammoho li bonts'a hore tšebeliso ea sucrose ke rat e koetlisitsoeng ka sucrose e etsa hore ho be le khoebo ea synoptic ea GluA1 ka metsotso ea 5, mme ho thibeloa ha mekhoa ea matsoho e laolang khoebo ena ho thibela ho phahama ha mosebetsi oa boipheliso ka mor'a nakoana.

Setšoantšo sa 6  

Ho khaola ho hoholo ha nako e telele ka mor'a ho kenella ho kenella ho hloka CPARs le NMDARs.

Ho ka nahanoa hore litsela tse peli tsa sucrose ho etsoa. E 'ngoe, e leng tsela e tiileng ea lik'hemik'hale kapa ea li-orosensory, e qalisoa ke sucrose e tlama ho monate o monate oa lijo, o lumellanang le protheine ea methapo ea liphatsa tsa lefutso e bitsoang G-protein, receptor complex, T1R2 / T2R3 (Kitagawa le al., 2001; Max et al., 2001; Nelson et al., 2001; Sainz et al., 2001). Limatlafatsi tse nang le lik'halori li ka boela tsa laola boko bo sebetsang ka litsela tse ts'oanang le mefuta e sa itšetleheng ka tatso, le hoja mekhoa e sa utloisisoe hantle (de Araujo et al., 2008). Ho khetholla pakeng tsa mekhoa ena e 'meli bakeng sa tsela ea khoebo ea GluA1 e bakoang ke sucrose, re pheta lenaneo la koetliso ka lihlopha tse tharo tsa likhoto (rats / sehlopha sa 4) tse filoeng monyetla oa metsotso ea 5 ho libotlolo tse nang le metsi, 25% sucrose , kapa 3% saccharin (e ntle le e tlaase). Likopa tsena li ile tsa tlosoa 'me litoebe tsa sala metsotsoana ea 15 nako e teletsana nakong ea koetliso ea koetliso. Koetliso e ne e pheta matsatsi a 7. Mefuta e mengata ea metsi e neng e sebelisoa ke lihlopha tsa testro ea sucrose le li-saccharin li ne li sa fapane ka ho fapaneng, 'me tse peli li ne li le khōlō ho feta tse sebelisoang ke sehlopha sa metsi, se lumellanang le moputso oa lintho tse peli tse monate (Setšoantšo sa 7A). Letsatsing la 7th la ho noa, hang-hang ka mor'a ho tlosoa likokoana-hloko, likhofu li ne li etsoa sehlabelo, ho bokelloa mahlaseli a mantlha ho kotuloa le ho kopanngoa bakeng sa sehlopha se seng le se seng sa tlhahlobo, karoloana ea PSD e arohaneng le mekhahlelo ea GluA1 e sebelisoang ke Bophirimela Bophirimela (Setšoantšo sa 7B). Joalokaha pele ho moo, liphoofolo tse neng li ja sucrose li ne li bontša GluA1 e phahameng karolong ea PSD e amanang le sehlopha sa metsi (Setšoantšo sa 7C). Habohlokoa, GluA1 e ne e boetse e phahamisitsoe ho karoloana ea liphoofolo tsa PSD tse neng li ja saccharin. Ho ne ho se na phapang e khōlō maemong a GluA1 ka likaroloana tsohle tsa seleng ho tloha accumbens ea motheo oa metsi, li-sucrose le liphoofolo tsa saccharin, ho fana ka maikutlo a hore keketseho ea GluA1 e ne e totobetse karoloana ea synaptic (Setšoantšo sa 7D). Hobane li-saccharin li susumetsa mokhoa o tšoanang oa liprotheine tsa G-heteromeric tse kopantsoeng ka mokhoa o ratoang oa receptor e le sucrose (Masuda le al., 2012; Nelson et al., 2001), empa ha e na bohlokoa ba lik'halori, re etsa qeto ea hore ho tsosoa ha monate oa lijo tse monate ho lekane ho qala ho saena ho phahamisa likhahla tsa GluA1 nucleus accumbens core synapses.

Setšoantšo sa 7  

Koetliso ea Saccharin e Susumetsa ho Eketseha ha Synaptic GluA1 Ho Tšoana le Koetliso ea Sucrose.

Puisano

Re bontsitse hore moputso oa orosensory, o tsitsitsoeng ka makhetlo a mangata, o ka etsa hore ho be le motsoako oa GluA1 synaptic ka mekhoa e mengata ea ho rekisa mekhoa e fetileng e hlalositsoeng a vitro. Ho pheta li-sucrose matsatsi a fetang 6-7 matsatsi a khonang ho bokella synapses ea motheo electrophysiologically ka ho kenngoa ha CPARs. Phello ena e ne e tsamaea le ho bokella GluA1 empa e se GluA2 ho PSD ea mantlha, 'me e ne e le sebakeng se itseng le ka nakoana, kaha ha ho liphetoho tse ileng tsa etsoa pele ho letsatsi la koetliso 7,' me ha ho phetoho e ileng ea bonoa sekhethong sa accumbens kapa kortex e kaalo. Tlhahlobo e nyenyane ea elektronike e bontšitse hore ho pheta-pheta ho kenella ka mongobo ho ne ho phahame haholo (t1/2 > Lihora tse 24) palo ea li-receptors tse kenang kahare tsa GluA1. Sucrose le eona ka potlako (5 min) le nakoana (t1/2 <24 hrs) maemo a phahameng a li-receptors tse nang le GluA1 libakeng tsa extrasynaptic liphoofolong tse koetlisitsoeng ka sucrose, ho eketsa palo ea batho ba li-AMPAR ba khonang ho hasana hamorao ho synapse. Synaptic GluA1, ka bobeli e emeloang ke karoloana ea PSD ebile e fumanoe ke PEG-EM, e ile ea eketsoa haholo Sucrose ha e bapisoa le liphoofolo tsa Metsi. Ho tsoa liphethong tsena re etsa tlhahiso ea hore mehato e 'meli ea extrasytaptic exocytosis e lateloang ke thekiso ea synaptic bakeng sa kenyelletso ea AMPAR synaptic e hlalositsoeng pejana a vitro (Boehm et al., 2006; Makino le Malinow, 2009; Oh le al., 2006; Serulle et al., 2007; Letsatsi le al., 2005) e ka qalisoa ka potlako Ka vivo ka moputso oa tlhaho, orosensory.

Liphetoho tsa synaptic GluA1 maemong a ne a hlokomeloa feela ka mor'a lithupelo tsa 7, ho fana ka maikutlo a hore mokhoa o mongata oa letsatsilong o hlokahalang bakeng sa bokhoni. Liteko tsa likokoana-hloko Ka vivo, ha rea ​​ka ra bona keketseho e kholo ea accumbens ea mantlha ea PSD GluA1 matsatsing a 1, 3, le 5 ea koetliso ea sucrose; hang ka mor'a matsatsi a 7 a sucrose koetliso e ne e le GluA1 ho PSD e phahameng haholo. Ka lisebelisoa tsa microscopy ea elektronike, re hlokometse hore liphoofolo tsa Sucrose / Water, tse neng li sebelisitsoe sucrose tse koetliselitsoeng matsatsi a 6 empa li sa fuoa li-sucrose lihora tsa 24, li bontšitse mokhoa oa ho eketsa PSD GluA1. Liphoofolo tsena li ne li boetse li bonts'a GluA1 e phahameng haholo e bapisoang le liphoofolo tsa metsi, empa ha ho phetoho ea membrane ea extrasynaptic GluA1 e ileng ea boleloa. Ho tsoa liphethong tsena re fumana liqeto tse tharo. Pele, GluA1-e nang le AMPA receptors e bokella ka ho toba ka metsoako e latellanang ea sucrose. Ho filoe hore lithuto tsa pele li bontšitse hore sucrose ho kenella ho etsa hore ho be le tokoloho ea dopamine ho accumbens (Cacciapaglia et al., 2012; McCutcheon et al., 2012; Rada et al., 2005), le hore D1Rs e ka khanna phetolelo ea GluA1 ea sebakeng sa dendrites (Smith le al., 2005), dopamine e lokolloa ka mor'a hore sucrose e kenelle e ka etsa hore GluA1 ea sebaka sa heno e lebise ho bokelleng ha GluA1 e sa tloaelehang. Ntle le moo keketseho e ke keng ea lekanngoa e ka 'na ea bontša ho rekisoa ha GluA1 ho tloha libakeng tse sabaletseng. Ho ka etsahala hore ho rekisoa ha exocytotic ho tloha letamong lena le phahameng haholo ho tlatsetsa letamong le nang le letlalo la polasetiki. Ntlha ea bobeli, ho hlokomoloha ho eketseha ha membrane ea extrasynaptic membrane GluA1 e Sucrose, empa e seng ka liphoofolo tsa Sucrose / Metsi kapa tsa Metsi ho fana ka maikutlo a hore li-receptor tse eketsehileng li ka fetela mohato oa bobeli ho ea synapse kapa li fihletsoe ka hare ho 24 hr ka mor'a ts'ebeliso ea li-sucrose, letamo le leng le le leng la ho feta. Ntlha ea boraro, ho phahama ha phoofolo ea Sucrose PSD GluA1 e bapisoa le liphoofolo tsa metsi, empa ha ho liphoofolo tsa Sucrose / Metsi hape li fana ka tlhahiso ea hore ka mor'a hore ts'ebetso e 'ngoe le e' ngoe ea sucrose, li-receptors li tsamaee ka morao ho tloha ka letamo la li-receptor tse tsamaisoang ka potlako ho ea litebelong tse ling tsa plasma. Re ke ke ra hlokomoloha hore barekisi ba GluA1 ka kotloloho ho tloha letamong le sa tloaelehang ho ea synapse. Leha ho le joalo, ho bonahala eka ha ho bonolo hore liphuputso tse bonts'a GluA1 li kenngoe extrasynaptically (Boehm et al., 2006; Makino le Malinow, 2009; Oh le al., 2006; Serulle et al., 2007; Letsatsi le al., 2005). Liphuputso tsena li emela pontšo ea pele ea hore nako ea khoebo ea GluA1 (<5 min) le tsela e hlokometsoeng a vitro li boetse li hlokomeloa Ka vivo. Ho phaella moo, liphello tsa rona li bontša hore litlhahiso tse tsoelang pele tse khotsofatsang li fetola bokhoni ba monyetla oa ho lumellana ka ho phahamisa letamo la li-receptor tse sa khonehang ho tšoaroa.

Hobane saccharin e kentse khoebo ea GluA1 ka tsela e tšoanang le sucrose, lijo tsa caloric tsa sucrose ha lia hlokeha. Saccharin e susumetsa mofuta o tšoanang oa monate oa lijo, T1R2 / T2R3, e le sucrose (Masuda le al., 2012; Nelson et al., 2001), sKopo e sebetsang ka ho feteletseng ea mokelikeli ona ho ka etsahala hore e qale ho kenngoa ha GluA1 ho li-synapses tsa MSN. Sucrose e phahamisa dopamine ho lokolloa ha accumbens ho tloha ho VTA neurons (Cacciapaglia et al., 2012; McCutcheon et al., 2012; Rada et al., 2005) lho isa khoebong ea GluA1 holim'a metsi. Ka hona tsela e kopanyang monate oa lijo tse monate ho VTA e ka 'na ea e-ba bohareng ba polasetiki e ithutoang mona.

Ho ka 'na ha e-ba le hore khoebo ea GluA1 e potlakileng ka mor'a hore sucrose e kenngoe e phethe karolo ea ho laola mokhoa oa ho tsuba. Ha e le hantle, liphoofolong tse entsoeng ka sucrose, ho thibela li-CPAR ho thibela ho phahama ha mosebetsi oa ho lokisa lintho hang-hang hang ka mor'a ho ts'ula. Kakaretso ea lik'hamphani ka mor'a ts'ebeliso ea lijo e lekantsoeng ka matsatsi a latellanang e ne e phahame haholo ka nako ea 3 min hang ka mor'a hore ts'oaetso e sebelisoe letsatsing la bosupa la koetliso. Mosebetsi o eketsehileng kapele ka mor'a hore sucrose e hlokomeloe ho qala ka letsatsi la 3 la koetliso, empa ha ea ka ea fapana haholo ho fihlela letsatsing la 7. Ketsahalo ena ea nako ena e tsamaisana le nako ea ho bokella GluA1 ho accumbens core dendrites. Ho tsuba ha lits'ebeletso ho ile ha e-ba le phello e sebetsang ea khoebo ea CPAR ho li-synapses tsa MSN mokokotlong oa accumbens ho tloha ha ente ea Naspm e le mokokotlo o thibelitseng ho eketseha ha mosebetsi. Ho thibela ho ts'oloha ha metsi ho phahameng ho e-na le mokelikeli oa NMDA ho inhibitor ho ile ha bontša hore ho hlahisa glutamate ka li-receptors tsa NMDA hammoho le CPAR ho ne ho hlokahala hore ho phahamisa mosebetsi oa likoloi. Leha ho le joalo, ho ja lijo tse ling ha hoa ka ha ameha ka ho thibela letšoao la glutamate, ho latela liphuputso tsa khale tse bontšang hore motsoako oa accumbens o ameha ho etsoa lipapali tsa likoloi tse amanang le moputso oa orosensory empa ha o sebelisoe ka boeona (Smith, 2004). Nako e tšoanang ea nako bakeng sa nts'etso-pele ea phekolo ea mali e tlalehiloe bakeng sa nts'etsopele ea phekolo e tsitsitseng ea liphoofolo liphoofolong tse fepang lijo tsa bona tsa letsatsi le letsatsi sebakeng se ikhethang (Matthews le al., 1996). Haeba karabelo ea hona joale e ne e le boikutlo ba ho se ts'oanelehe bo hlahang ho tloha pakeng tsa moelelo le sucrose, leha ho le joalo, ho ka be ho bile teng pele ho tsamaiso ea sucrose, e neng e sa elelloe. Ho ka etsahala hore lihlooho li bontša tsoho ea ho hlahloba. Ho ne ho tla hlokahala liteko tse ling ho khetholla hore na ho phahama ho hoholo ha metsi a ts'ila pele ho kenngoa ha metsi ho tsosoa ha tlhahlobo ho fapana le mofuta oa motlakase oa motlakase kapa boitšoaro bo bong. Ho sa tsotellehe boemo leha e le bofe, ho phahama ha ho itlosa bolutu ho sa hlokahaleng ho ne ho hlokahala hore ho bontšoe glutamate, 'me ho bile le phello, bonyane ka karolo e itseng, ho kenngoa ha CPARs mokokotlong oa accumbens.

Mosebetsi o eketsehileng oa ho lokisa ka mor'a ho kenella ho kenngoa ha metsi o ka hlahisa ka kotloloho bokhoni ba ho bokella li-syntapses tsa mantlha, kaha ho eketsoa ho tsoa tseleng e tobileng ea basalli ho khothalletsa ho tlosoa ha metsi ka ho thibela motlakase oa thalamus (Sesack le Grace, 2010). Teo a ka khonang ho etsa hore synapses e lule e le tseleng e tobileng e bokella li-neurons tsa mantlha, tse hlalosang D1Rs. Mokhoa o tobileng oa litsela tse ts'oanang le oa synopses o tla fella haeba mosebetsi oa D1R o kenyelletsa khoebo ea GluA1 e nang le AMPAR ho li-synapses li-neurons tsena ka mor'a ho lokolloa ha dopamine e matla. Monyetla o ka bakoang ke o tla eketsa ts'ebetso ea ho thibela mekhoa ea ho itšireletsa ka tsela e tobileng ea basal ganglia output nuclei, kahoo ho thibela thalamus ea motlakase le ho ntšetsa pele motlakase oa motlakase (Gerfen le Surmeier, 2011; Kravitz et al., 2010; Sesack le Grace, 2010). Tsela eo synaptic e nang le eona e bonngoeng ka mor'a hore e tsoele pele e kenella ka mongobo, e ka etsahala ka ho khetheha ka li-neurons tse ka ho toba hobane dopamine e sebetsang ka mokelikeli oa D1 e ka kenyelletsa phosphorylation ea GluA1 S845, e lebisang khoebong ea holimo.

Liphuputso tse 'maloa li hlahlobile liphello tsa ho tsosolosa khafetsa le k'hok'heine e lateloa ke ho tlosoa, phekolo e nang le liphello tse tebileng mosebetsing oa tsamaiso ea moputso mme qetellong e lebisa tlhokomelong ea k'hok'heine, e tsejoang ka ho phahamisa k'hok'heine ea motlakase, ho lakatsa lithethefatsi le ho khutlela morao hape (Kalivas le al., 1998). Ho kenngoa hoa IP le cocaine bakeng sa matsatsi a 5-10 a latetsoeng ke ho tlosoa ho entse hore ho eketsehe butle ho feta matsatsi a 14 ka holim'a GluA2 e nang le li-receptors tsa AMPA (Boudreau et al., 2007; Kourrich et al., 2007). Leha ho le joalo, matsatsing a 45 a ho tlohela ka morao ho 10 d ea boipheliso ba botho, keketseho e kholo ea tlhahiso ea ho lokisoa e ile ea hlokomeloa ho Rat MSNs (McCutcheon et al., 2011b) e bontšang keketseho ea CPARs. Ka hona, khoebo ea CPAR e 'nile ea hlokomeloa ka mor'a hore bobeli bo kopane, hajoale mosebetsing oa hona joale, le k'hok'heine ea botho, ho sa tsotellehe maemo a fapaneng haholo a kalafo. Hobane liphello tsa hang-hang tsa k'hok'heine ea boipheliso kapa lisebelisoa (mohlala, ka 5 metsotso e poso) ha li tsejoe, liketso tsa cocaine li ke ke tsa bapisoa ka ho toba le mosebetsi oa hona joale oa sucrose. Ka mokhoa o ts'oanang, ha ho tsejoe hore na ma-CPAR a ntse a tsoela pele ka li-synapses tsa MSN tsa liphoofolo tse koetlisitsoeng ka sucrose ka mor'a ho khaotsa koetliso ea sucrose kapa haeba liphoofolo tse joalo li bontša tsoelo-pele ea sucrose ka mor'a ho tlohela nako e telele.

Ho utloisisa kamoo ho hlophisoang ha mokhoa o hlophisitsoeng ho bokellang polasetiki le boitšoaro ho bohlokoa kateng ho sebetsana le ho lemalla, ho ba le papali ea chelete, ho bapala papali ea chelete, le mathata a mang a boitšoaro (Basar et al., 2010; Berridge, 2009; Luscher le Malenka, 2011). Tsoekere e feteletseng e tlisa bothata ba ho ba botenya haholo (Hu le Malik, 2010), le hoja e ka 'na eaba e tšoana le tšebeliso e mpe ea lithethefatsi (Avena et al., 2008), mokhoa oa eona ha o e-s'o hlahlojoe haholo. Liphuputso tsa morao-rao li theha likarolo tsa motheo tsa polasetiki e bakoang ke moputso oo lithuto tsa nakong e tlang li ka sebetsanang le taolo ea boitšoaro bo rarahaneng, ho ka 'na ha fana ka mekhoa e mecha ea ho loantša mafu a amanang le moputso.

lumela hore baa fokola

Re leboha litho tsa Laboraro la Ziff, tsa nakong e fetileng le tsa hona joale, ka thuso ea mahlale le lipuisano tse thusang, ho kenyeletsoa H. Girma, L. Lee le Dr. B. Fernholz, B. Jordan, W. Lu, G. Rameau, S. Restituito le Y. Serulle. Mosebetsi ona o ne o tšehelitsoe ke Setsi sa Naha sa Mental Health Predoctoral Fellowship F31MH76617-01 le NIH Training Grant 5T32DC000063 ho Lenaneo la Koetliso ea Univesithi ea New York ho Neurosciences (DST), R01NS061920 ho tsoa National Institute of Neurological Disorders and Stroke (EBZ), 1R21MH091445- 01 ho tsoa Setsing sa Naha sa Bophelo ba Kelello le Ofisi ea Patlisiso mabapi le Bophelo ba Basali, Klarman Family Foundation Grants Programme ho Lipatlisiso tsa Mathata a ho ja, Letlole la Phephetso la NYU la Phuputso le P30EY13079 (CA), Setsi sa Naha sa Tlhekefetso ea Lithethefatsi DA003956 le Moputso o Ikemetseng oa Mofuputsi ho tsoa NARSAD (KDC), Setsi sa Naha sa Bokooa le Mathata a mang a Khokahano se fana ka DC009635 ho RCF, le ka thuso ea peo Setsing sa Bokhabane ba Tlhekefetso ho tsoa Setsing sa Bongaka sa Langone sa New York.

Mongolo o botlaaseng ba leqephe

Khohlano ea thahasello: Bangoli ha ba phatlalatse lithahasello tsa lichelete.

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