CRF system recruitment e kopanya lehlakore le lefifi la ho qobella ho ja (2009)

. 2009 Nov 24; 106 (47): 20016-20020.

E hatisitsoe Inthaneteng 2009 Nov 9. doi:  10.1073 / pnas.0908789106

PMCID: PMC2785284

inahaneloang

Ho ts'oara ho laola boima ba 'mele ho kenyelletsa mekhahlelo ea ho haelloa ke lijo tse fumanehang habonolo tse ka khothalletsang ho ja ka matla. Boithuto bo teng hona joale bo bonts'a hore likhoto li tlohelitsoe ho fihlella lijo tse fumanehang habonolo li bontša ho natefeloa ha lijo tse matlafatsoang phihlelong e nchafalitsoeng le boemo bo ts'oanang le ba ho ikarola bo tšoanang le bo khetholloang ke corticotropin-releading factor-1 (CRF)1) boits'oaro bo botle ba receptor antagonist-reversible, bo kenyeletsang hypophagia, bofokoli bo susumetsang ba ho fumana lijo tse bobebe haholo, le boits'oaro bo ts'oenyang. Ho tlohela ho ne ho tsamaisana le polelo e eketsehileng ea CRF le CRF1 karabelo ea electrophysiological karolong e bohareng ea khubu ea amygdala. Re fana ka tlhahiso ea hore ho hira motho ea hanang moputso extrahypothalamic CRF-CRF1 Lits'ebeletso nakong ea ho khaotsa lijo tse matlafatsang, mokhoa o makatsang oa ho tlohela lithethefatsi tse sebelisoang hampe, li ka khothaletsa khetho ea lijo tse matlafatsang, ho li senya mefuta e meng e phetseng hantle, le boemo bo bobe ba maikutlo ha ho ja lijo tse monate.

Keywords: mathata a ho ja, botenya, ho buoa ka linako tse ling, ho tsepamisa maikutlo ka lijo, ho itokolla

Mefuta ea botenya le mathata a ho ja, a ts'oanang le ts'ebeliso ea lithethefatsi, e ka hlalosoa e le maemo a sa foleng a ho khutla (ho re, ho ja ho qoba lijo tse “sa lumelloang”) le ho khutlela morao (ke ho re, ho qobella, hangata ho se laolehe, ho ja haholo. Lijo tse matlafatsang) tse tsoelang pele ho sa na le litlamorao tse mpe (). Leha boleng bo matlafatsang ba lijo tse matlafatsoang bo tsejoa hantle (, ), tlhokomelo e nyane e fuoe thepa ea bona e matlafatsang (-), e leng kholo ea monyetla oa karabelo ea boits'oaro e hlahisoang ke ho tlosoa ha maikutlo a susumetsang (mohlala, ho ja lijo tse matlafatsang ho imolla maemo a mabe a maikutlo). Mehato e sa khaotseng ea tšebeliso e feteletseng ea lithethefatsi tsa tlhekefetso e ka lebisa hanyane ka hanyane "ho itšetleheng ka tsona," e le tlhoko ea lithethefatsi tse phahameng le / kapa khafetsa ho boloka boemo bo behiloeng molemong oa maikutlo le boemo bo bobe ba maikutlo ha a tlohela tšebeliso ea lithethefatsi (, ). Ho khaotsa ho joalo ho ka boloka ts'ebeliso le ho khothaletsa ho oela hape ka thepa e matlafatsang ea ho tsoela pele le ho qala ts'ebeliso ea lithethefatsi, ka ho fapana (, ).

Ts'ebetso ea khatello ea kelello ea extrahypothalamic corticotropin-releasing factor (CRF) e kenella haholo phetohong ea ts'ebeliso ea lithethefatsi ho ea ho ts'epahalo, nakong eo ts'ebeliso ea lithethefatsi tse hlekefelitsoeng e bang le ts'usumetso ea mekhoa ena e mebe, ho fapana le e matla, e matlafatsang. CRF e bapala karolo ea bohlokoa e susumetsang litokelong tsa tlhekefetso bakeng sa lithethefatsi tsohle tse kholo tsa tlhekefetso, ho kenyelletsa joala, nicotine, cocaine, opiates, amphetamines le tetrahydrocannabinol (, ). Ka ho tšoana, nako le nako ea ho ja lijo tse fumanehang habonolo, ho ile ha theoloa maikutlo ho khothaletsa mokhoa oa CRF neuroadaptations tse ts'oanang le tse bonoang mehlaleng ea ts'ebeliso ea lithethefatsi (, , ).

Results

Ho kenella kahare, ho fihlella lijo tse matlafatsoang butle-butle ho lebisa khaellong ea lijo tse sa rateheng ha lijo tse fumanehang habonolo li sa fumanehe le ho natefeloa ke lijo tse matlafatsoang phihlelong e nchafalitsoeng (-). Ho leka hypothesis eo CRF1 Sistimi e kenella litekong tsena tsa phepelo, likhoto tsa banna tsa Wistar (n = 20) ba fuoe kopi ea lipapatso tsa Chok (Chow / Chow) letsatsi le leng le le leng ka beke kapa ba fuoe kop ad libitum bakeng sa matsatsi a 5 (C phase) e lateloang ke lijo tse matlafatsoang, tse tsoekere bakeng sa matsatsi a 2 (P phase) (Chow / Palatable ) (Bona Setšoantšo sa S1 bakeng sa kemiso ea ho ja le Setšoantšo sa S2 bakeng sa litlamorao tsa kemiso ea ho ja lijong le boima ba 'mele). Kamora libeke tsa 7 tsa libaesekele tsa lijo, likhoto li amohetse CRF e seng peptide1 receptor antagonist R121919 (0, 5, 10, le 20 mg / kg, sc) ka moralo oa Latin-mraba (). Kalafo e ile ea fuoa 1 h pele e fetoloa ho tloha lijo tse matlafatsang ho ea chow kapa ho tloha chow ho ea lijong tse monate. Tekanyetso ea R121919-e theotsoe ka kotloloho ho ja lijo tse matlafatsang le keketseho ea lijo tse matlafatsang ho Likhomo tsa Likhomo tsa Lijo (Lijo Lenaneo la Tekanyetso la lijo tsa 'Mele. F3,54 = 7.25, P <0.001), ntle le ho fetola tšebeliso ea taolo ea chow. R121919 e fokotsehile ho ja lijo tse hlabosehang ha phihlello e nchafalitsoeng ea lijo tse latsoehang (P phase) (Feie. 1A). Litekong tse ikemetseng, CRF1 morekisi oa "receptor antagonist" o eketsa ho ja ho seng bonolo ha a fumaneha ho Chow / likhoto tse monate tse tlosoa lijong tse matlafatsoang (C phase) (Feie. 1B). Kahoo, ka ho kopanya bobeli hypopgia le ho nona lijo tse matlafatsoang, R121919 e bontsitse bophahamo ba ho ja baesekele (phapang lipakeng tsa ho ja nakong ea karolo ea pele e monate ea P le ho khaotsa ho ea pele C mophatong: Dijo Lenaneo la Tsamaiso ea Lijo: F3,54 = 7.25, P <0.001) (Feie. 1C). Ho ts'ehetsa ho hira motho ea tsoelang pele oa CRF-CRF1 Lits'oaetso nalane ea nalane ea lijo, ho e-na le ho ba le phello e matla ea lijo, R121919 ha ea ka ea fokotsa takatso ea lijo ka mor'a ho pepesehela lijo kapa ea eketsa ho ja nakong ea ho khaotsa lijo tse matlafatsang.Setšoantšo sa S3).

Setšoantšo sa 1. 

Litlamorao tsa CRF1 receptor antagonist R121919 (−1 h pretreatment, 0, 5, 10, and 20 mg / kg, sc) on a compumorative 3-h supplementsA) Karolo ea maqhubu a (ka mokhoa o mocha oa ho fumana lijo tse fumanehang habonolo), (BKarolo ea C (ha likhoto li ne li tlositsoe ho monate ...

Ho tloheloa nako le nako, ho fihlella lijo tse fumanehang habonolo le hona ho ka eketsa boitšoaro bo kang ba ho tšoenyeha.). Ho leka hypothesis eo CRF1 li-receptors li kenella liponong tse mpe tsa boits'oaro bo bobe bo latelang ho tlosa lijo tse matlafatsoang, likhoto li ile tsa tsamaisoa R121919 (0, 20 mg / kg, sc, 1-h pretreatment) 'me tsa lekoa ka moralo o lipakeng tsa li-design tse holimo-le-maze (), 5-9 h ka mor'a hore e fetoloe ho tsoa ho lijo tse matlafatsoang ho li-chow. Likhoto tse tšoeroeng ke koloi Chow / Latsatsia tse bonts'itsoeng li bonts'itse nako e bulehileng ea letsoho ho feta taolo e fepeloang, e bonts'a phello e kang ea ho tšoenyeha, nakong ea ho tlohela libeke tsa 7 tsa ho ja libaesekele (Feie. 2A), phello e e-so bonoe kamora metsotso e 'meli feela ea ho ntša (Setšoantšo sa S4). Ho hlohlona ka R121919 (20 mg / kg, lethal e lekantsoeng ho tlatsa lijo tse matlafatsoang le ho se ts'oaroe ke chow) ho thibetse ho fokotseha ha ho batloa ha letsoho le bulehileng ke likhoto tsa Chow / Palatable ka tekanyetso e sa kang ea fetola boitšoaro ba bo-maze ho laolang chow ( Lenaneo la Lijo: F1,43 = 7.25, P <0.02; Feie. 2Leqheka). Tsamaiso ea R121919 ha ea ka ea fetola tšebetso e akaretsang e lekantsoeng joaloka liphihlelo tse koetsoeng tsa letsoho. Ka hona, R121919 e thibetse boitšoaro bo kang ba ho tšoenyeha bo amanang le ho khaotsa nako le nako, ho fihlella lijo tse fumanehang habonolo, ntle le ho fetola mekhoa ea taolo, ho fana ka maikutlo a ho hira CRF1 Litsamaiso.

Setšoantšo sa 2. 

Litlamorao tsa CRF1 receptor antagonist R121919 (−1 h pretreatment, 0, 20 mg / kg, sc) ho boitsoaro bo phahameng ba mofuta-oa-maze (n = 47) le karabelo e tsoelang pele ea lijo tse fumanehang habonolo (n = 17) ho likhoto tsa Wistar tse tona li tlositsoeng lijong tse fumanehang habonolo ...

Ho tlosoa khafetsa, ho fihlella lijo tse fumanehang habonolo ho ka lebisa ho phokotsong e khothalletsang ho fumana lijo tse ratoang haholo, index ea boitšoaro bo kang hypohedonic (). Ka mokhoa o makatsang, ho arabela bakeng sa litlatsetso tse nyane tse sa rateheng tlas'a litekanyetso tsa tsoelo-pele tsa ts'ebetso ea matlafatso li kile tsa sebelisoa ho supa bofokoli bo susumetsang bo bonoang nakong ea ho tlohela lithethefatsi (). Ho fumana ho nka karolo ha CRF1 li-receptors, re lekile litlamorao tsa R121919 mabapi le ts'ebetso ea likhoto tse tsamaeang le li-cycled ho fumana chow ea bona e sa rateheng tlasa kemiso e tsoelang pele ea karolelano. Ho netefatsa liphumano tse fetileng (), likhoto tse phekotsoeng ke likoloi tse tsamaeang le likoloi tsa likoloi tse bonts'itsoeng ke koloi li fokotse tšusumetso ea ho sebetsa ho fumana chow e sa fumaneheng habonolo, e bonts'itsoeng ke sepheo se theohileng mme e fokotse likarabo tsohle tse hlahisoang ha li bapisoa le likhoto tsa Chow / Chow () (Setšoantšo sa S5). R121919 pretreatment (20 mg / kg, tekanyetso e sebetsang ho eketsa hypophagia, e fokotsa lijo tse matlafatsang le ho fokotsa boitšoaro bo tšoanang le ausi) ka mokhoa o ikhethileng o hahelle liphoso ts'ebetsong e tsoelang pele ea karolelano ea litekanyetso tsa lijo tse potiloeng ka tekanyo e neng e sa sebetse hantle ho taolo ea chowon (karohano: Lenaneo la Lijo: Lithethefatsi: F1,15 = 8.17, P <0.02; likarabo kaofela: Lenaneo la Lijo × Lithethefatsi: F1,15 = 9.14, P <0.01; Feie. 2B, letšehali). Khahlano le tlhaloso e 'ngoe eo R121919 e thusitseng ts'ebetso ho litheko tsa Chow / Palatable ka ho fokotsa ho satiation ea postingestive, R121919 e koaletse bofokoli ha a araba joalo ka ha 5 min e kena sethaleng (Dijo Lenaneo la Lijo: F1,15 = 2.55, P <0.05) (Feie. 2B Ka nepo). Ka hona, CRF1 receptor antagonist blunits the deficits activistic in butle-butle ratiing ea ho arabela li-gforatory tse matlafatsang tse bonoang liphoofolong li tloheletsoe nako e telele, phihlello ea ho fumana lijo tse fumanehang habonolo.

Ho leka hypothesis ea hore ho tlohela lijo tse fumanehang habonolo ho ka kenya ts'ebetsong tsamaiso ea CRF e amanang le khatello ea maikutlo, maemo a CRF mRNA le peptide karolong e bohareng ea amygdala e ne e lekantsoe ka bongata ba nako ea nnete ea PCR le RIA. Likhoto li ne li fuoa lijo tsa li-cycled bakeng sa libeke tsa 7 kapa li feptjoa nako le nako. Kamora ho hlohlona le ho hlohlona, ​​ho otloa hoa boko bokong bo bohareng ba amygdala ho ile ha bokelloa nakong ea ho tlohela le ka mor'a ho nchafatsa phihlello ea lijo tse matlafatsang. Ho tlohela lijo tse fumanehang habonolo ho likhoto tsa Chow / tse tummeng ho bakile keketseho ea makhetlo a mahlano a polelo ea CRF mRNA karolong e bohareng ea amygdala ha e bapisoa le likhoto tsa Chow / Chow (Feie. 3A). Ka lehlakoreng le leng, CRF mRNA e khutletse mehatong e laoloang ka mokhoa o mocha oa ho fumana lijo tse fumanehang habonolo (F2,19 = 6.97, P <0.01). Polelo ea CRF mRNA bohareng ba amygdala ha ea ka ea fetoha ha likhoto tsa Chow / Palatable li ne li palame libaesekele hanngoe feela (Chow / Chow vs. Chow / Palatable: 5.5 ± 2.2 vs. 6.3 ± 1.7 ns), ho ts'ehetsa ho hiroa hoa CRF- CRF1 lits'ebetso tse nalane ea nalane ea lijo, ho fapana le ho bakoa ke phepo e matla ea lijo. Ntle le moo, polelo ea CRF mRNA ha e fetohe ho bokong ba li-nucleus, "preortalal cortex" kapa "cortex" e tšehetsang boemo bo fumanehang ba tikoloho (Setšoantšo sa S6). Ho khahlisang, ha ho liphetoho tse kholo mabapi le polelo ea CRF mRNA tse ileng tsa bonoa mokokotlong oa "patothricular" oa hypothalamus kapa ho potoloha corticosterone ka nako e ts'oanang ea ho tlosa ho likhoto tsa Chow / Palatable (Likokonyana. S6 le S7), ho fana ka tlhahiso ea maikutlo e fetohang ho amygdalar, ho fapana le hypothalamic, lits'ebetso tsa khatello ea maikutlo tsa CRF hoo e ka bang li bolokile liphetoho tsa boitšoaro. Ntle le moo, ts'oaetso ea peptide ea CRF phuleng e kahare ea amygdala ea liphoofolo tse tlositsoeng lijong tse matlafatsoang e ne e le 70% e phahame ho feta liphoofolong tse fepeloang, empa e khutletse mehatong e laoloang e nang le phepo e fihlellehang.F2,24 = 4.01, P <0.01) (Feie. 3B). Kahoo, ho tlosa lijo tse fumanehang hantle ho ile ha etsa hore tsamaiso ea peptide e amanang le khatello ea kelello e be teng mokokotlong o bohareng ba amygdala, maikutlo a fumanoeng mehlaleng ea ho tlosoa hoa lithethefatsi le ethanol (, ). Hobane ts'ebetso e nchafalitsoeng ea lijo tse fumanehang habonolo e fokotse ts'ebetso ea sistimi ea extrahypothalamic CRF karolong e bohareng ea amygdala, moo ts'ebetso ea CRF e hokahaneng le matšoenyeho (), liphetho tsa hona joale li boetse li fana ka maikutlo a hore lijo tse fumanehang habonolo li ka fumana thepa e matlafatsang ka ho imolla litlamorao tse mpe tse tlisoang ke ho ila ().

Setšoantšo sa 3. 

Liphello tsa phetoho e ntle ea lijo ka (A) CRF mRNA le (B) Polelo ea peptide ea CRF mokokotlong o bohareng ba amygdala. Likhoto (n = 45) li ne li tsamaisoa ka li-cycled bakeng sa libeke tsa 7, 'me liteishene tse bohareng tsa punche ea amygdala li ile tsa bokelloa. Ka bobeli CRF mRNA le peptide ...

Ho leka tšebeliso ea maikutlo ea hore likhoto li tlohelloa lijo tse fumanehang habonolo li ka bonts'a kutloisiso e kholo ea CRF1 antagonist modulation of γ-aminobutyric acid (GABA) signature bokong bohareng ba amygdala, bo etsahalang nakong ea ho tlosoa hoa ethanol (), re ile ra hlahloba phello ea R121919 ho phetiso ea GABAergic ea li-nucleus tsa methapo ea methapo ea kutlo ea amygdala ha re ntse re itokisa. Maleke a Wistar (n = 14) li ne li tsamaisoa ka li-cycled bakeng sa libeke tsa 7 'me li entsoe sehlabelo ka mor'a hore li fetoheloe ho chowatable. Phetisetso ea Basal GABAergic karolong e bohareng ea li-synapses tsa amygdala ha ea fapana mabapi le nalane ea lijo (n = Lisele tsa 23) ho matla ohle a ho hlohlelletsa a sebelisitsoeng ho etsa hore GABA-inhibitory postsynaptic potentials (IPSP). Leha ho le joalo, 20 min superfusion e nang le R121919 (1 μM) e kentse phokotso e kholo ho GABA e ts'oeroengA-SIPPs tse ka har'a khubu ea methapo ea kutlo ea li-amygdala neurons tsa Chow / Latsatsine (M ± SEM: 30 ± 6%, n = Lisele tsa 9) ho feta lits'ebetsong tsa lits'oants'o tsa chow-fed (M ± SEM: 12 ± 6%, P <0.05, n = Lisele tsa 11) (Feie. 4). Kamora nako ea ho hlatsoa li-30 min, IPSP ea lihlopha tsena ka bobeli e khutletse maemong a tšoanang, a motheo. Ka hona, e lumellana le ho fetelletse hoa amygdala CRF-CRF1 sistimi le litlamorao tse bonoang nakong ea ho tlosoa hoa ethanol (), likhoto tse potiloeng ke lijo li bontšitse kutloisiso e eketsehileng ea litlamorao tsa CRF1 receptor antagonist holima bokahare bo bohareng ba phetisetso ea amygdala GABAergic.

Setšoantšo sa 4. 

Litlamorao tsa CRF1 receptor antagonist R121919 ho GABAA-SUPPs mo khubung e bohareng ea amygdala kamora pale ea ho feto-ja lijo tse fumanehang habonolo ho likhoto tsa banna tsa Wistar (n = 14) e hulletsoe phihlelong ea lijo tse fumanehang habonolo. (A) R121919 e fokotsehile haholo ...

Puisano

Liphetho tse kopaneng li fana ka bopaki bo sebetsang ba hore nalane ea nako le nako, phihlello ea ho fumana lijo tse matlafatsoang e tlisa tsoelo-pele, li-neuroadaptations tse tsoelang pele maemong a amanang le khatello ea maikutlo e amanang le khatello ea maikutlo e tlisoang ke khatello ea kelello ea nako e telele.1 litsamaiso. Ka ho khetheha, CRF e khethang1 R121919 e khahlanong le "receptor antagonist" RXNUMX ka mokhoa o fapaneng le ka mokhoa o amehileng oa ho fepa litepising tse tsamaeang le li-cycled, ho eketsa ho ja kamehla le ho fokotsa ts'ebeliso ea lijo tse fumanehang habonolo molemong oa ho fihlella bocha. CRF1 morekisi oa receptor o boetse o thibetse ka mokhoa o ikhethileng boits'oaro bo ts'oanang le ho ts'oenyeha ha a arabela karabelo e sa rateheng e ileng ea bonoa nakong ea ho tlohela lijo tse monate. Ho tlohela ho fihlella lijo tse matlafatsoang ho matlafalitse mofuta oa CRF le polelo ea peptide karolong e bohareng ea amygdala, litlamorao tse felisitsoeng ka phihlello e nchafalitsoeng. Ntle le moo, likhoto tse tsamaeang le lijo tse tsamaeang le potoloho e bontšitse kutloelo-bohloko e eketsehileng mabapi le litlamorao tsa CRF1 receptor antagonist mabapi le phetisetso ea GABAergic karolong e bohareng ea amygdala, e fana ka tlhahiso e eketsehileng ea ho eketseha ha amygdala CRF-CRF1 sistimi. Ho eketseha ha lijo tse matlafatsoang phihlelong e nchafalitsoeng ho ka bakoa ke ts'ebetso e eketsehang ea CRF ea nako e sa tsoa felisoa ea ho tlohela mosebetsi, e bonoang e le polelo e eketsehang ea CRF le kutlo ea motlakase ho CRF1 li-receptor blockade karolong e bohareng ea amygdala. CRF1 Qeto ea ho hanyetsa pele feela e ka fumaneha habonolo ka lijo, ka hona e hlalosoa e le ho hanyetsa qalo ea CRF-CRF1 tsamaiso e feteletseng ea ho tlohela. Nako e khuts'oanyane ea lijo tse matlafatsang tse nang le phepo e ngata e bonoang ho liphoofolo tse sa phekoloang () e ka bonts'a nako ea nako eo polelo, ho lokolloa le litlamorao tsa CRF peptide e fetolelang hang ha monyetla oa ho fumana lijo tse fumanehang habonolo o fumaneha hape, joalo ka ha ho bonoa thutong ea morao tjena. Kahoo, ho ja lijo tse matlafatsoang nako le nako ho ka baka phetoho e kholo mefuteng ea meputso ea boko ka ho hira CRF-CRF e sa khahliseng1 lits'ebetso tse ka sehlohlolong se bohareng ba amygdala.

Liphetho tsena ha li na moelelo ho ja ka qobello feela, empa hape le khothaletso ka kakaretso. Ts'ebetso e pheta-phetoang ea li-system tsa hedonic e ile ea tsosa mekhahlelo e kang ea mohanyetsi (ke hore, ho haptjoa ha CRF1 circry) tse neng li fapane le tahlehelo e bonolo ea ts'ebetso lits'ebetsong tsa phetisetso ea moputso. Li-neuroadaptations tse lipakeng tsa) hape etsahala nakong ea phetoho ho itšetleha ka lithethefatsi tsohle tse kholo tsa tlhekefetso (, ). Kakaretso ea ts'usumetso e seng ea lithethefatsi thutong ea hona joale e bonts'a hore lits'ebetso tse susumetsang li ka ts'oaroa ke batho ba nang le lipapatso tse fapaneng le ho ba matla ha nako le nako (). Ka mokhoa o ikamahanyang, lits'ebetso tse joalo li ka fetisetsa boits'oaro ba ho batla lijo le boits'oaro ho lijong tse nang le matla a mangata, tse nang le moputso o phahameng, ha li ntse li lekola boiteko ba ho fumana lijo tse nang le matla a fokolang, tse nang le moputso o tlase (kapa tseo eseng tsa lijo), phetoho e ka bang le thuso ha ho na le litšenyehelo tsa ho iphelisa (mohlala, ho pepeseha liphoofolo tse jang liphoofolo, nako e fokolang le lisebelisoa tsa matla). Tikolohong ea sejoale-joale, lits'ebetso tse ts'oanang li ka khanna ho ja lijo tse khothalletsang botenya ka litšenyehelo tsa litlolo tse seng monate, empa mohlomong tse ling tse nang le phepo e ntle.

Ka hona, liphetoho tse kang bokhoba ba lithethefatsi ho CRF1 mekhoa e ka thusa ho khanna (i) ja lijo tse matlafatsang tse matlafatsang, (ii) ts'ebeliso e mpe ea mekhoa e phelisang hantle, hape (iii) boemo bo amanang le maikutlo a sithabetsang bo etsahalang ha ho thibeloa lijo tse fumanehang habonolo (, , -, ). E fetoleloa ho latela boemo ba motho, ts'ebetso ea ts'ebetso ea CRF e ka khothaletsa ho ja hape bothateng le mathata a amanang le ho ja hammoho le tšusumetso e mpe ea cyclic ea ho ila lijo tse fumanehang habonolo.

Lisebelisoa le mekhoa

Lintho.

Lipoe tsa banna ba Wistar (n = 155, 180-230 g, matsatsi a 45 g) e fumanoe ho Charles River le ntlo e le 'ngoe ha e fihla ka lisenthara tse kentsoeng ka enjene, mekotla ea polasetiki (19 x 10.5 x 8 inches) ka 12 h: 12 h reverse rearching light : Mabone a 10 h a tima), mongobo- (00%) le vivarium e laoloang ke mocheso (60 ° C). Likhoto li ne li na le phihlello ea li-rodent chow tse hahelletsoeng ka poone [Harlan Teklad LM-22 Lijo 485: 7012% (kcal) carbohydrate, 65% mafura, 13% protheine, matla a metaboliki 21 cal / 341 g] le libanete tsa metsi bakeng sa 100 beke pele ho qalo ea liteko. Ts'ebetso ea liteko e lateloa ho Tataiso ea Sechaba ea Tlhahiso ea Bophelo bakeng sa Tlhokomelo le Ts'ebeliso ea Liphoofolo tsa laboratori (Nomoro ea phatlalatso ea XH 1-85, 23 e ntlafalitsoeng) le "Molao-motheo oa tlhokomelo ea liphoofolo ka laboratoring" (http://www.nap.edu/readingroom / libuka tsa libuka) 'me tsa amoheloa ke Setsi sa Tlhokomelo ea Liphoofolo le Ts'ebeliso ea Setsi sa Lipatlisiso tsa Thepsps.

Lithethefatsi.

R121919 e ne e entsoe ka mokhoa o hlalositsoeng ho Chen et al. (). R121919 ke kamano e phahameng (Ki = 3.5 nM) CRF e khethang1 antagonist e nang le thepa ea 'mele e phahametseng tse ling tse ngata tsa CRF1 antagonists (mohlala, ho fokotseha ha logP le logD, ho eketsa solubility ea metsi) (). Bakeng sa liteko, R121919 e qhibilisitsoe pele ho 1 M HCl (10% ea molumo oa ho qetela), ebe e kenngoa koloing ea ho qetela ea 20% (wt / vol) 2-hydroxypropyl-β-cyclodextrin (Sigma-Aldrich), e khutliselitsoeng morao-rao ka NaOH ho pH 4.5. Tharollo ea R121919 e fanoe ka sc (sc) ka bophahamo ba 2 mL / kg.

Ad Libitum Lijo Alternation.

Kamora ho hlonama, likhoto li ile tsa aroloa ka lihlopha tse peli tse lekanang le lijo, boima ba 'mele, le ts'ebeliso ea phepo e nepahetseng ho tloha matsatsing a 3-4 a fetileng. Sehlopha se seng se ile sa fuoa phepelo ea "chow" ea Chow / ChowX ka beke (Chow / Chow), 'me sehlopha sa bobeli sa fuoa kop ad libitum bakeng sa matsatsi a 7 beke e' ngoe le e ngoe se lateloa ke matsatsi a 5 a phihlelletso ea lipapatso ho batho ba fumanehang habonolo , chokolete e nang le phepo e ntle, e nang le phepo e phahameng (“e nkoang”; Chow / e Natefisoa). Lijo tse natefisang lijo tse nang le phepo e ntle li na le phepo e nepahetseng, e nang le chokolete e nang le phepo e ntle, e nang le 'mala o mongata (2% kcal), lijo tse thehiloeng ho AIN-50A tse bapisoang le boholo ba sejo sa macronutrient le matla a methari ea lijo tsa chow. [TestDiet; K'habeche e nang le chokolete e nang le chokolete: 76% (kcal) carbohydrate, 5% mafura, 66.8% protheine, matla a metabolism 12.7 kcal / g; e hlophisitsoe e le li-pellet tsa lijo tse nepahetseng tsa 20.5-mg ho eketsa ho rata ha eona (, )]. Bakeng sa bosholu, matsatsi a 5 a pele (chow feela) le matsatsi a ho qetela a 2 (chow kapa a fumanehang ho latela sehlopha sa liteko) bekeng e ngoe le e ngoe ho buuoa ka liteko tsohle joalo ka mekhahlelo ea C le P. Lijo li ne li sa fumanehe ka nako e le ngoe. Lijo tsa Chow e ne e ka ba Harlan Teklad LM-485 Diet 7012 [65% (kcal) lik'habohaedreite, 13% mafura, 21% protheine, matla a metabolizing 341 cal / 100 g] kapa 5TUM lijo tse entsoe ka 4- ho 5-g extruded pellets [ % (kcal) lik'habohaedreite, mafura a 65.5%, protheine ea 10.4%, matla a metabolism 24.1 cal / 330 g; TestDiet]. Hoa tšoana le lithuto tse fetileng, Harlan Teklad LM-100 chow e sebelisitsoe litekong tsa ho fepa le ho phahamisa litlatsetso (), ha u ntse u le TestDiet 5TUM chow () e sebelisitsoe ka tekanyo e tsoetseng pele, CRF mRNA, CRF peptide, corticosterone RIA le liteko tsa electrophysiological.

Joalokaha ho phatlalalitsoe pele (), likhetho tsa motho ea amanang le ho ja, tse baloang e le liperesente tsa ho ja lijo tsa letsatsi le letsatsi (kcal) tsa lijo tsa pele mabapi le lijo tsa bobeli, e ne e le tse latelang: 5TUL Chocolate Diet (Lijo tse nang le phepo e ntle) vs. Harlan LM-485 chow (M ± SEM ratang 90.7 ± 3.6%) le 5TUL Chocolate Diet (Lijo tse nang le tsoekere) le 5TUM chow Diet (M ± SEM pre XXUMX ± 91.2%).

Elevated Plus-Maze.

Teko e phahameng le e kopantsoeng ea maze e entsoe joalo ka ha ho hlalositsoe ho Cottone et al. (). Likhoto tsa Chow / tse lutlehang li ne li fuoa lijo tsa li-cycled bakeng sa bonyane libeke tsa 7 ebe li etsoa ka koloi kapa 20 mg / kg R121919 (−1 h, sc) 'me tsa lekoa 5-9 h kamora ho hlatsoa lijo tse matlafatsoang ho ea chow (P → Mohato oa C). Likhoto tsa taolo ea Chow / Chow li ile tsa lekoa ka nako e le ngoe le moralo oa li-process tse mahareng (n = 47). Lijo tsa Chow li ne li fumaneha ka lipapatso ho fihlela nakong ea tlhahlobo. Bakeng sa lintlha tse ling, bona Sengoloa sa SI.

Kemiso ea Ts'ebetso ea Tsoelo-pele ea Matlafatso ea Lijo.

Lenane la tsoelo-pele la ntlafatso ea lijo le entsoe joalo ka ha ho hlalositsoe ho Cottone et al. (). Liphoofolo li fumane lipapatso tsa A / I chow (li-pellets tsa 5 g tse kentsoeng) malapeng a tsona ho pholletsa le liteko ntle le ha ho boletsoe ka tsela e ngoe. Matlafatso ea lijo e ne e le li-pellets tsa 'nete tsa 45-mg chow-usahihi, tse ts'oanang ka sebopeho sa sejo sa kantle ho lijo tsa lehae. Nako e fela ha lithuto li sa phethe karo ea 14 min, le karolelano ea ho qetela e hlalositsoeng e le karohano. Likhoto tsa Chow / tse lutlang li ne li fuoa lijo tsa li-cycled bonyane libeke tsa 7 ebe li qhekelloa ka R121919 (−1 h, sc) ka nako ea ha e ne e fetoloa ho tloha lijong tse matlafatsoang ho ea kop (P → C phase). Likhoto tsa taolo ea Chow / Chow li ile tsa lekoa ka nako e le ngoe le moralo oa li-process tse mahareng (n = 17). Litekanyetso tsa R121919 (0, 20 mg / kg boima ba 'mele, sc) li fanoe ka moralo o kahare, sebopeho se hanyetsanang le mekhahlelo e' meli ea lijo. Bakeng sa lintlha tse ling, bona Sengoloa sa SI.

Kakaretso ea Nako ea 'Nete ea PCR.

Likhoto (n = 20) li ne li tsamaisoa ka libaesekele bakeng sa libeke tse 7, li thethefatsoa, ​​'me li theoloa hlooho nakong ea maemo a mabeli a ho ja (matsatsi a 5 le 7 a potoloho e ngoe le e ngoe ea beke le beke). Boko bo ile ba tlosoa kapele 'me ba tšeloa likotoana ka har'a mokokotlo oa boko,' me khubung ea bohareng ea amygdala, nucleus accumbens, insular cortex le prefrontal cortex punches li ile tsa bokelloa sethaleng se batang sa leqhoa. Kakaretso ea RNA e ne e lokiselitsoe ho tsoa kotong e 'ngoe le e' ngoe ea boko ho sebelisa protocol e tloaelehileng bakeng sa ho ntšoa ha RNA ho lisele tsa liphoofolo. Kakaretso ea RNA (1 μg) e ile ea fetoloa e ngotsoe ka pel'a Oligo (dT) 20 ka litaelo tsa moetsi. Likarabo tse ngata tsa RT-PCR li entsoe ka molumo oa 20-μL ho sebelisoa li-primers tsa 0.5 μM le 4 mM MgCl2. Liphetho li ile tsa hlahlojoa ka mekhoa ea boipheliso ea bobeli 'me ea hlahisoa ka likarolo tse hanyetsanang, tloaelo ho ea maemong a tšibollo ea mofuta oa mofuta oa patlisiso, CypA. Liphetoho tsohle tsa RT-PCR bakeng sa tatellano e fanoeng li entsoe ka nako e tšoanang. Bakeng sa lintlha tse ling, bona Sengoloa sa SI.

Peptide Acid Extraction le CRF RIA.

Likhoto (n = 25) li ne li tsamaisoa ka li-cycled bonyane libeke tsa 7, li ne li sa phekoloe, li bile li hlakoloa nakong ea maemo a mabeli a ho ja (matsatsi a 5 le 7 ea potoloho ea beke le beke). Masapo a kelello a ile a tlosoa kapele le ho nyekeloa ka sekhoneng ka mokokotlong oa bokong, 'me a bokelloa ka methapo e bohareng ea li-punch tsa amygdala sethaleng sa serame. Ho ntšoa ha peptide acid ho latela mokhoa o seng o ntse o thehiloe (). Tissue CRF-like immunoreacuction e ile ea hlakoloa ka RIA e sa tsotelleng le e ikhethang e hlophisitsoeng ho tloha Zorrilla et al. (). Bakeng sa lintlha tse ling, bona Sengoloa sa SI.

Corticosterone RIA.

Likhoto (n = 12) li ne li tsamaisoa ka libaesekele bonyane libeke tse 7, 'me mali a mohatla a ile a sampuoa nakong ea maemo a mabeli a ho ja (matsatsi a 5 le 7 a potoloho e' ngoe le e 'ngoe ea beke le beke). Maemo a Plasma a kang ho itšireletsa mafung a corticosterone a ile a khethoa ka sesebelisoa sa RIA se fumanehang khoebong, ho latela litaelo tsa moetsi (MP Biomedicals, Inc.) (). Bakeng sa lintlha tse ling, bona Sengoloa sa SI.

Lithuto tsa Electrophysiological

Litokisetso tsa Slice.

Li-nucleus tse bohareng tsa liseke tsa amygdala li ne li hlophisitsoe joalokaha ho hlalositsoe pele (, ) ho tsoa ho likhoto (n = 7 / group) e neng e ntse e ja li-cycled ka bonyane libeke tsa 7, e sa sebetse, 'me ea tsebisoa 2-3 h ka mor'a ho tlosoa lijong tse monate. Borena bo ile ba tlosoa ka potlako 'me ba kenngoa ka har'a sefuba se sa sebetseng se tsoang ka leqhoa (aCSF) se tsamaeang le 95% O2 le 5% CO2. Slices e ne e khaotsoe, e kenelletse sebopeho sa sebopeho sa bonyane li-30 min, mme e kentsoe ka botlalo 'me e tsoelapele ka mokhoa o ts'oanelang le li-aCSF tse futhumetseng. Lithethefatsi li ile tsa eketsoa ho aCSF ho tsoa ho tharollo ea setoko ho fumana tsepamiso e tsebahalang. Ho litekanyetso tsa 2-4 mL / min superfusion tse sebelisitsoeng, litebello tsa lithethefatsi li fihla 90% ea mahloriso a polokelo kahare ho 2 min.

Elektroniki.

Re hatisitse li-pakati tsa li-neuron tsa amygdala tse nang le li-micropipette tse bohale tse sebelisang mokhoa o fokotsang motlakase- kapa mokhoa oa hona joale oa clamp. Re ne re tšoere li-neuron tse ngata haufi le bokhoni ba tsona ba ho phomola ba lera. Lintlha li fumanoe ka preamplifier 'me li bolokiloe tlhahlobisong ea morao-rao e sebelisang software ea pClamp. Ratsana le Gaba ea limelaA receptor-mediated inhibitory postynaptic potentials (GABAA-IPSPs) li ile tsa tsosoa ka ho hlohlelletsa kahare ho khubung e bohareng ea amygdala ka "electrode" e phefumolohang e phefumolohang ha e ntse e ts'oenya glutamate receptor blockers CNQX le APV le GABAB receptor blocker CGP 55845A. Ho tseba likarolo tsa karabo bakeng sa sele ka 'ngoe, re entse protocol ea tlhahiso ea eona. Ho ile ha sebelisoa mefuta e mengata ea marang-rang, ho qala ka mokhoa oo hona joale o hlokahalang ho phahamisa IPSP ho fihlela motlakase o hlokahalang ho phahamisa bophahamo bo phahameng. Re fetoletse maemo a mararo a ntlafatsang a mehato e lekanang (monyako, halofo-boholo, le boholo) re le 1-3 ×. Mehato ea hajoale ea Hyperpolarizing le depolarizing hona joale (200-pA extension, 750-ms duration) le tsona li ile tsa sebelisoa ho hlahisa li-curve tsa voltage-current (VI). Re hlalositse lipalo tse sa tsitsang tsa IPSP le likarabo tsa VI ka ho sebelisa software ea Clampfit. Mehato eohle e nkuoe pele ho superfusion le CRF e khethiloeng1 receptor antagonist R121919 (1 μM), nakong ea superfusion ea eona (20 min), le ho latela washout (30 min). Bakeng sa lintlha tse ling, bona Sengoloa sa SI.

Lipalopalo.

Papiso ea sehlopha e sebelisitsoe ea Student tLitekanyetso (lipapiso tse peli (lihlopha tse peli) kapa tlhaiso ea phapang (ANOVA) (bonyane lipapiso tsa lihlopha tse tharo), e hlalositsoeng ke tlhaiso-leseling e bonolo ea sephetho kapa papiso ea Newman-Keuls kamora litlamorao tse kholo tsa omnibus (P <0.05). Lintlha tse tsoang tekong ea ho fepa li ile tsa hlahlojoa ke li-ANOVA tse tsoakiloeng ka mekhoa e meraro le Setsi sa Lijo e le sesosa se pakeng tsa lithuto le Phase ea Lijo le Lijo e le lintho tse kahare ho lithuto. Lintlha tse tsoang tekong e phahameng ea `` maze '' li ile tsa hlahlojoa ke li-ANOVA tse peli tse nang le Lijo schedule le Dose e le lintlha tse lipakeng. Bakeng sa kemiso e tsoelang pele ea karolelano ea liteko tse matlafatsang, li-breakpoint le likarabo tse felletseng li ile tsa hlahlojoa ke li-ANOVA tse tsoakiloeng ka litsela tse peli le Setsi sa Lijo e le sona se pakeng tsa lithuto le Dose e le sesosa sa kahare ho lithuto. Nako ea ho arabela nakong ea metsotso e 5 ea pele e ile ea hlahlojoa ke li-ANOVA tse tsoakiloeng ka makhetlo a mararo le Setsi sa Lijo e le sona se pakeng tsa lithuto le Dose le Nako joalo ka lintlha tsa sehlooho. Lintlha tse tsoang lithutong tsa electrophysiological li ile tsa hlahlojoa ka ANOVA kapa lipakeng tsa ANOVA ka mehato e phetoang, ka moo ho loketseng. Lintlha tse tsoang ho corticosterone RIA moo e ileng ea hlahlojoa ke ANOVA e tsoakiloeng ka mahlakore a mabeli le Setsi sa Lijo e le sona se pakeng tsa sehlooho le Phase ea Lijo e le sona se kahare ho sehlooho. Lipapaka tsa lipalo-palo tse sebelisitsoeng e ne e le Instat 3.0, Prism 4.0 (GraphPad), Systat 11.0, le SPSS 11.5 (SPSS).

 

Boitsebiso bo Eketsehileng

Tlhahisoleseling e Tšehetsang: 

Liteboho.

Re leboha Mike Arends ka thuso ea bongoli, Mary Gichuhi ka thuso ea tsamaiso, le Bob Lintz, Jeanette Helfers, Stephanie Dela Cruz, le Molly Brennan bakeng sa thuso ea tekheniki. Mosebetsi ona o ne o tšehelitsoe ke National Institute of Diabetes and Digestive and Kidney Diseants Grants DK70118, DK26741, le P30DK56336; Setsi sa Naha sa Tjello ea Tlhekefetso ea lithethefatsi DA023680; Setsi sa Naha sa Tjello ea Ts'ebeliso e Mpe ea Joala le Tahi ea Tai Joala AA016731 le AA015566; Setsi sa Naha sa Mathata a Neurological le Grant Grant IT32NS061847-01A2; Setsi sa Naha sa Grant ea Agging AG028040; Pelo ea Sechaba, Lung le Setsi sa Mali sa Grant HL088083; the Ellison Medical Foundation; le Setsi sa Pearson sa Alcoholism le Tlhatlhobo ea Bokhoba. Karolo e 'ngoe ea mosebetsi ona e tšehelitsoe ke Intramural Research Programs ea National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism. Ena ke nomoro e ngotsoeng ea 19807 e tsoang ho The DRMps Research Institute.

Mongolo o botlaaseng ba leqephe

 

Bangoli ba phatlalatsa hore ha ho na likhohlano tsa thahasello.

 

 

Sengoliloeng sena ke Tlhahiso ea Direct ea PNAS.

 

 

Sengoliloeng sena se na le tlhahisoleseling e tšehetsang marang-rang ho www.pnas.org/cgi/content/full/0908789106/DCSupplemental.

 

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