I-CRF System Recruitment ixubene noMoya oMnyama weCompulsive Eating (2009)

IINKCUKACHA: I-CRF yi-neurotransmitter / ihormoni enxulunyaniswe ngokwasemoyeni nokuphendula koxinzelelo kunye nokwenza ukuba i-adrenal cortex isebenze. Uphando lweziyobisi luchonge njengomdlali ophambili ekufumaneni iziyobisi, ukubuyela umva kweziyobisi, kunye neempawu zokurhoxa. Olu phononongo luphonononge indima yeCRF kwikhoboka lokutya kunye nokutya okunyanzelekileyo. Guss yintoni? Inendima efanayo ngokutya okunyanzelekileyo njengoko kusenza kunye neziyobisi. Qaphela ukuba izilwanyana zazingatyebanga, ngenxa yoko ukutyeba kwakungekho ndima. Ubungqina obuninzi bokuba likhoboka lokuziphatha-kubandakanya iphonografi- baneendlela ezifanayo neziyobisi.

ISIFUNDO ESIPheleleyo: Ukuqeshwa kwenkqubo yeCRF kuPhakathi icala elimnyama lokutya okunyanzeliswayo

I-Proc Natl Acad Sci US A. 2009 Nov 24; I-106 (47): 20016-20020.

Ipapashwe kwi-intanethi ye-2009 u-Novemba 9. doi:  10.1073 / pnas.0908789106

Eli nqaku liye khankanywe ngu amanye amanqaku kwi-PMC.

Yiya e:

Abstract

Ukuhambisa umzimba ngokulawula ubunzima bomzimba kubandakanya imijikelezo yokuthintela ukutya okufumanekayo okunokukhuthaza ukutya okunyanzelekileyo. Uphononongo lwangoku lubonisa ukuba iigundane ezikhutshiweyo ekungeneni kokungeneka kukutya okufumanekayo kunokuboniswa kokuvuselelwa kokutya okunokufikeleleka okuhlaziyekileyo kunye nemeko-yokuchaphazela njengombuso oboniswe yi-corticotropin-ukukhulula factor-1 (CRF1) I-receptor antagonist-reversible behaviour, kubandakanya i-hypophagia, intsilelo ekhuthazayo yokufumana ukutya okungathatheka lula, kunye nokuziphatha okufana nexhala. Ukurhoxa bekuhamba kunye nokunyusa intetho yeCRF kunye neCRF1 Ukuphendula kwe-elektroniki kwi-nucleus esembindini ye-amygdala. Sicebisa ukuba kugaywe abantu abangaphezulu komvuzo kwi-extFypypalamalam CRF-CRF1 Iinkqubo ngexesha lokurhoxa kokutya okufumanekayo, ukubonwa kukungazisebenzisi iziyobisi gwenxa, kungakhuthaza ukunyanzelwa kokutya okuthandekayo, ukuzikhupha kwezinye iindlela ezisempilweni, kunye nemeko engathandekiyo yeemvakalelo xa kuthathwa ukutya okuthandekayo.

Internet: iingxaki zokutya, ukutyeba kakhulu, ukuxhomekeka kokutya, ukuxhomekeka ekutyeni, ukurhoxa

Iindlela zokutyeba kakhulu kunye neengxaki zokutya, ezifanayo neziyobisi, zinokuchazwa njengeemeko ezingapheliyo zokubuyela kwimeko kwakhona (okt, ukutya ngenjongo yokuphepha ukutya okungavumelekanga) nokubuyela umva (okt, kunyanzelekile, kuhlala kungalawuleki, ukutya ukutya okuphezulu ukutya okutyayo) okuqhubekayo ngaphandle kweziphumo ezibi (1). Nangona amandla aqinisayo okutya athathekayo ayaziwa ngoku (2, 3), kuthathelwe ingqalelo encinci kwizakhiwo zabo zokuqinisa (4-6), oko kukuthi, ukunyuka kokuphendula kokuziphatha ngendlela evelisiweyo ngokususwa kwenkuthazo (umz., ukutya okuthandekayo ukubuyisela imeko yeemvakalelo ezimbi). Imijikelezo engaphakathi yokusetyenziswa gwenxa kweziyobisi zokusetyenziswa gwenxa kunokukhokelela ku “kuxhomekeka ngokuzinzileyo,” okubonwa njengesidingo sokonyuka kunye / okanye izixa ezininzi zamachiza ukuze kugcinwe indawo ebekiweyo yeemvakalelo kunye nemeko yokungahambi kakuhle ngokweemvakalelo xa ushiyekile ukuthatha iziyobisi (7, 8). Ukurhoxa okunokubangela ukuba kugcinwe ukusetyenziswa kwaye kukhuthaze ukuphinda kubuyiswe kwakhona ngokusebenzisa iiprophathi zokuxhasa ezingezizo zokuqhubeka nokuqalisa ukusetyenziswa kweziyobisi, ngokulandelelana (7, 8).

Iinkqubo zoxinzelelo lwe-extrahypothalamic corticotropin-releasing factor (CRF) zibeka engxakini yokuguquka kokusetyenziswa kweziyobisi ukuxhomekeka, ngelixa lokusetyenziswa kweziyobisi gwenxa kuya kuba kukhuthazeka kwezi ndlela zikhohlisayo, endaweni yendlela elungileyo yokuqinisa. I-CRF idlala indima ebaluleke kakhulu ekurhoxisweni kwees syndromes zalo lonke ichiza lokuxhatshazwa, kubandakanya notywala, i-nicotine, icocaine, i-opiates, amphetamines, kunye ne-tetrahydrocannabinol (7, 8). Ngomlinganiso, imijikelezo ephindaphindiweyo yokudlula, ukufikelela okwandisiweyo kokutya okunencasa kakhulu kuye kwaqulunqwa ukuba kufundise inkqubo yeCRF neuroadaptations efanayo naleyo ibonwa kwiimodeli zokuxhomekeka kweziyobisi (4, 5, 9).

iziphumo

Ukungena ngaphakathi, ukufikelela okwandayo kokutya okunencasa ngokuthe ngcembe kukhokelela ekususeni ukutya ukutya okuthandwayo xa kungafumaneki ukutya kuthandekayo kunye nokutya kakhulu ukutya okuthandekayo xa ufikeleleko oluhlaziyiweyo (10-12). Ukuvavanya i-hypothesis eyiCRF1 Iinkqubo zivumela oku kulungelelwaniso lokondlayo, iigundane leWistar yamadoda (n = 20) babonelelwa ngesixhobo se-op sokutya (Chow / Chow) yonke imihla veki nganye okanye babonelelwa nge-ads aditumitum yeentsuku ze-5 (isigaba se-C) esilandelwa kukutya okunesondlo, ukutya okuneswekile kwiintsuku ze-2 (isigaba se-P) (Chow / Palatable ) (Jonga Umzobo weS1 yeshedyuli yokutya kunye Umzobo weS2 ngeziphumo zeshedyuli yokutya kukutya kunye nobunzima bomzimba). Emva kweeveki ze-7 zokuhamba ngebhayisikile yokutya, iigundane zifumene i-non-peptide CRF1 I-receptor antagonist R121919 (0, 5, 10, and 20 mg / kg, sc) kuyilo lweLatin-square (13). Unyango lwalunikwa i-1 h ngaphambi kokutshintsha kokutya okunencasa ukuya kwi-op okanye ukusuka kwelebhu ukuya kwisidlo esidala. Idosi ye-R121919-ixhomekeke ekunciphiseni ukutya okufumanekayo kunye nokunyuka kokutya okutyayo kwiChow / iigundane ezinokutya (Isigaba sokutya × Ishedyuli yokutya × iDose Dose: F3,54 = 7.25, P <0.001), ngaphandle kokutshintsha ukutya kwe-chow. I-R121919 iye yanciphisa ukutyiwa kokutya okumnandi kakhulu ekuhlaziyweni kokufikelela kokutya okumnandi (isigaba se-P) (Ikhiwane. 1A). Kwimvavanyo ezizimeleyo, iCRF1 Umamkeli we-receptor antagonist unyuse umthamo wokutya ongathandekiyo kwiChow / iirati ezinokuhanjiswa kwisidlo esinokutya (C isigaba) (Ikhiwane. 1B). Ke ngoko, ngokuqhawula zombini i-chow hypophagia kunye nokutya okugqithisileyo kokutya, i-R121919 ifumene ubungakanani bokuhamba ngebhayisikile (umahluko phakathi kokutya ngexesha lesigaba sokuqala seP kunye nokurhoxa okokuqala kwisigaba se-C C: Ukutya iShedyuli yeDosi yeDosi: F3,54 = 7.25, P <0.001) (Ikhiwane. 1C). Ukuxhasa ukufunwa okuqhubela phambili kweCRF-CRF1 Iinkqubo ezenzeka ngembali yokutya, endaweni yokuthathwa kukutya okubangelwa kukutya, i-R121919 ayikhange inciphise ukungena kokutya emva kokuvezwa kukutya okukodwa okanye yonyuse umthamo ngexesha lokurhoxa kokuqala ukutyaUmzobo weS3).

Umzobo 1. 

Iziphumo zeCRF1 I-receptor antagonist R121919 (−1 h i-pretreatment, i-0, i-5, i-10, kunye ne-20 mg / kg, i-sc) kwi-cumulative 3-h yokutya ngaphakathi (A) Isigaba se-P (ekuvuseleleni ukufikelela kokutya okufumanekayo), (B) C Isigaba C (xa iirati bezirhoxisiwe zisemagqabini ...

Ukurhoxa ekuhambeni kwexesha, ukufikelela okongeziweyo kokutya okunencasa nako kungonyusa indlela yokuziphatha enje ngexhala (11). Ukuvavanya i-hypothesis eyiCRF1 Ii-receptors ziyabandakanyeka kwiimpawu ezigwenxa zokuziphatha okungalunganga ezilandela ukurhoxa ekutyeni okufumanekayo, iigundane zazilawulwa i-R121919 (0, 20 mg / kg, sc, 1-h exreatment) kwaye kuvavanywa kuyilo oluphakathi kwezihloko kuluhlu oluphakanyisiweyo lwe-maze (14), I-5-9 h emva kokutshintshwa kwisidlo esidlamkileyo saya kwi-chow. Ukuchaphazeleka kweenqwelo-mafutha Ukuphathwa kweenqwelo-mafutha / iigundane ezinokuhonjiswa kuboniswe ixesha elincinci elivulekileyo kunolawulo lwe-chow-fed, kubonisa isiphumo esifana ne-anxiogenic, ngexesha lokurhoxiswa kweeveki ze7 zokuhamba ngebhayisikile (Ikhiwane. 2A), isiphumo esingekabonakali ngoku emva kwemijikelezo emibini yokukhupha (Umzobo weS4). Ukuqunjelwa nge-R121919 (20 mg / kg, idosi emodareyithisile ukugqithisa ukutya okunokufumaneka kwaye ukungafakwanga kwe-chow) kuthintele ukwehla kokuhlolwa okuvulekileyo kwengalo nguChow / iigundane ezithandekayo kwithamo elingakhange litshintshe isimangalo se-mer-maze kulawulo lwe-chow ( Ishedyuli yokutya × Idosi: F1,43 = 7.25, P <0.02; Ikhiwane. 2Ekhohlo). Ulawulo lwe-R121919 alukhange lutshintshe imisebenzi jikelele ebalwe njengamangeniso ezivaliweyo. Ke ngoko, i-R121919 ivimbe indlela yokuziphatha enxungupheleyo enxulunyaniswa nokushenxiswa, ukuya kufikelela kokutya okunokuthenjwa, ngaphandle kokutshintsha indlela yolawulo, iphakamisa ukuqeshwa kweCRF1 Iinkqubo.

Umzobo 2. 

Iziphumo zeCRF1 I-receptor antagonist i-R121919 (−1 h i-pretreatment, i-0, i-20 mg / kg, i-sc) kwindlela yokuziphatha ephakanyisiweyo kunye ne-maze (n = 47) kunye nenkqubela phambili yomndilili wokuphendula kukutya okungathandekiyo (n = 17) kwiigundane ezingamadoda ezi-Wistar ezikhutshwa kukutya okuthandekayo ...

Ukurhoxa ekuhambeni kwexesha, ukufikelela okongeziweyo kokutya okunokutya nako kungakhokelela ekuswelekeni kokunyanzeliswa kokufumana ukutya okuthandwayo okuncinci, isalathiso sendlela yokuziphatha ye-hypohedonic10). I-Analog, ukuphendula kubaxhasi abancinci be-gustatory phantsi kweeshedyuli zomgaqo wokuqiniswa kwangaphambili bezisetyenzisiwe ukukhombisa ukusilela kwentshukumo ebonwe ngexesha lokurhoxiswa kwamachiza (15). Ukufumanisa ukubandakanyeka kweCRF1 ii-receptors, sivavanye iziphumo ze-R121919 kwintsebenzo yeegundlo zokutya ezihamba ngebhayisikile ukufumana ii-chow zazo ezikhethiweyo phantsi kweshedyuli yomlinganiso oqhubekayo. Ukuqinisekisa iziphumo zangaphambili (10), i-Chow / iirati ezinokuthathwa zizithuthi zibonakaliswe zincitshisiwe inkuthazo yokusebenza ukuze ifumane i-chow emnandi engabonakaliyo, ebonakaliswe yindawo yokuphumla enciphisiweyo kwaye inciphisile iimpendulo ezikhutshiweyo xa kuthelekiswa neRow / Chow rats (10) (Umzobo weS5). Uxinzelelo lwe-R121919 (i-20 mg / kg, idosi esebenzayo yokwandisa i-chow hypophagia, ukunciphisa isidlo esimnandi sokutya kunye nokunciphisa indlela yokuziphatha efana nekaxinzelelo) bakhetha ukusilela kwintsebenzo eqhubekayo yokulinganisela kwindlela yokutya ejikeleze iidosi kwithamo elalingasebenzi kulawulo lwe-chow (indawo yokuqhawula: Ishedyuli yokutya × Isiyobisi: F1,15 = 8.17, P <0.02; Iimpendulo zizonke: Ishedyuli yokutya × iziyobisi: F1,15 = 9.14, P <0.01; Ikhiwane. 2B, khohlo). Ngokuchasene nolunye utoliko olwenziweyo lokuba i-R121919 iququzelele ukusebenza kwiChow / Ratableable rats ngokunciphisa isatiationtive satiation, R121919 block the deficits in ukuphendula kwangoko nge-5 min kwiseshoni (Ukutya iShedyuli × Drug: F1,15 = 2.55, P <0.05) (Ikhiwane. 2B Ekunene). Ke ngoko, iCRF1 Umchasi-receptor uchasene nokusilela okushukumisayo kwinqubo yokuphendula ngokomgangatho wokuqina ongafunekiyo obonwa kwizilwanyana eziyekisiweyo ukusuka kwixesha elizayo, ukufikelela okwandisiweyo kokutya okungathandekiyo.

Ukuvavanya i-hypothesis ethi ukurhoxa ekutyeni okunokutya kunokwenza inkqubo ye-CRF enxulumene noxinzelelo, amanqanaba e-CRF mRNA kunye ne-peptide kwi-nucleus ephakathi ye-amygdala ilinganiswe ngobuninzi bexesha le-PCR kunye ne-RIA, ngokulandelanayo. Iigundane zazikudla ngokujikeleza iiveki ze-7 okanye zondliwa ngokuqhubekayo. Emva kokwenza i-anesthesia kunye nokuhanjiswa kwemisipha, ukuqengqeleka kobuchopho obuvela kwi-nucleus esembindini ye-amygdala kwaqokelelwa ngexesha lokurhoxisa emva nasemva kokuvuselela ukufikelela kukutya okuthandekayo. Ukurhoxisa ukutya okuthandekayo kwiChow / iigundane ezinokutsalwa kubangele ukunyuka okuphindwe kabini kwinkcazo yeCRR mRNA kwikona engaphakathi yeamygdala kuthelekiswa neRow / Chow row (Ikhiwane. 3A). Kwelinye icala, i-CRF mRNA ibuyele kumanqanaba olawulo afana nokuhlaziywa kokutya okufumanekayo (F2,19 = 6.97, P <0.01). I-CRF mRNA expression in the central nucleus ye-amygdala ayitshintshanga xa iChow / iigundane ezinokuthandeka zibhayisekile kanye kuphela (iChow / Chow vs.Chow / Palatable: 5.5 ± 2.2 vs. 6.3 ± 1.7 ns), ixhasa ukugaywa okuqhubekayo kweCRF- I-CRF1 Iinkqubo ezenzeka ngembali yokutya, kunokuba zenzeke ngokutya. Ukongeza, i-CRF mRNA expression ayitshintshanga kwi-nucleus accumbens, i-cortex yangaphambili okanye i-cortex ye-insular, exhasa ubunyani bengingqi yokufumana (Umzobo weS6). Into enomdla kukuba akukho lutshintsho lubalulekileyo kwi-CRF mRNA expression eyaye yaqwalaselwa kwi-nucleventricular nucleus ye-hypothalamus okanye kwi-corticosterone ejikelezayo ngexesha elifanayo lokurhoxa kwiChow / iigundane ezithandekayo (Amantshontsho. I-S6 kunye ne-S7), ndicetyisa i-hypothesis etshintsha kwi-amygdalar, endaweni ye-hypothalamic, iinkqubo zoxinzelelo zeCRF zithumele uzinzo kwindlela yokuziphatha. Ngaphaya koko, ukugonyelwa kwe-peptide yeCRF kwiyunithi esembindini ye-amygdala yezilwanyana ezikhutshiweyo ekutyeni okunobungozi yayiyi-70% ingaphezulu kunezilwanyana ezondlekileyo, kodwa ibuyele kumanqanaba olawulo adityanisiweyo ngokufumana ukutya okutyayoF2,24 = 4.01, P <0.01) (Ikhiwane. 3B). Ke ngoko, ukurhoxisa ukutya okunencasa kusebenze inkqubo ye-peptide enxulumene noxinzelelo kwi-nucleus ye-amygdala, i-analogous kwiziphumo zodidi lweziyobisi kunye nokurhoxiswa kwe-ethanol (7, 8). Kungenxa yokuba ukufikelela okuvuselelekileyo kokutya okunesondlo kunciphise inkqubo ye-CRF ye-extrahypothalamic activation kwiyunithi esembindini ye-amygdala, apho kusebenze i-CRF inxulunyaniswa nexhala (16), iziphumo ezikhoyo zikwacebisa ukuba ukutya okufumaneka lula kunokufumana iipropathi zokuqiniswa ezingezizo ngokuphelisa iziphumo ezibi ezichasayo zokungakhathali (17).

Umzobo 3. 

Iziphumo zotshintshiselwano olunokutya okuthandekayo kwi (A) CRF mRNA kunye (B) Inkcazo ye-peptide yeCRF kwi-nucleus esembindini ye-amygdala. Iigundane (n = I-45) zazidityaniswa ngebhayisekile iiveki ze-7, kwaye iingqokelela yentloko ye-amygdala punches yaqokelelwa. Zombini CRF mRNA kunye peptide ...

Ukuvavanya i-hypothesis yokuba iirati kurhoxisiwe kukutya okunokutya kunokubonisa ukwanda kokuva kweCRF1 i-antagonist modulection ye-γ-aminobutyric acid (GABA) isibonakaliso kwi-nucleus ese-amygdala, eyenzeka ngexesha lokurhoxiswa kwe-ethanol (18), sivavanye umphumo we-R121919 ekuhanjisweni kwe-GABAergic ye-niphu ephakathi yee-neuron ze-amygdala kulungiselelo lwesilayi. Iigundane leWistar yamadoda (n = 14) zazityelwe ngebhayisekile iiveki ze-7 kwaye zenziwa amadini emva kokuba ziye zatshintshelwa kweleyokungathandeki kancinane. Ukuhanjiswa kwe-basal GABAergic kwi-nucleus esembindini ye-amygdala synapses ayifani ngokubhekisele kwimbali yokutya (n = Iiseli ze-23) kuzo zonke izinto ezishukumisayo ezisetyenziselwa ukukhupha i-GABA-inhibitory postsynaptic potentials (IPSP). Nangona kunjalo, i-20 min superfusion ene-R121919 (1 μM) yabangela ukunciphisa kakhulu kwi-GABA ekhutshiwe.A-I -PsPs kwi-nucleus esembindini ye-amygdala neurons yeChow / iigundane ezinokutsalwa (M ± SEM: 30 ± 6%, n = Iiseli ze-9) kunezo kulawulo lwe-chow-fed (M ± SEM: 12 ± 6%, P <0.05, n = Iiseli ze-11) (Ikhiwane. 4). Ukulandela ixesha lokuhlamba i-30 imizuzu, ii-IPSP zala maqela mabini abuyela kumanqanaba afanayo, asisiseko-ofanayo. Ke ngoko, ukuhambelana ngokuthe gabalala kwe-amygdala CRF-CRF1 Inkqubo kunye neziphumo ezibonwe ngexesha lokurhoxiswa kwe-ethanol (18), iigundane ezijikelezwe kukutya zibonisa imbonakalo eyonyukayo kwiziphumo zothintelo lweCRF1 I-receptor antagonist kwi-nucleus esembindini yokuhanjiswa kwe-amygdala GABAergic.

Umzobo 4. 

Iziphumo zeCRF1 I-receptor antagonist R121919 kwi-GABAA-I -PsPs kwi-nucleus esembindini ye-amygdala emva kwembali yokutshintsha ukutya okunokufikeleleka kumadlala eWistar yamadoda (n = 14) irhoxisiwe kukufikelela ekufumaneni ukutya. (A) I-R121919 yehle kakhulu ...

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Iziphumo ezidibeneyo zinika ubungqina obusebenzayo bokuba imbali yexesha elininzi, ukufikelela okwandisiweyo kokutya okungathandekiyo kukhokelela kwinkqubela phambili, ekukhuthazeni i-neuroadaptations efanelekileyo kwi-extrahypothalamic CRF-CRF1 iinkqubo. Ngokukodwa, CRF ekhethiweyo1 I-receptor antagonist R121919 ngokwahlukileyo kwaye ikukhethe ngokuchaphazeleka kokondla kwiigundane ezijikelezwe kukutya, ukwandisa ukutya rhoqo kunye nokunciphisa ukubakho kokutya okunokwamkelwa kakhulu ekufikeleleni nasekuvuseleleni ukufikelela. ICRF1 I-receptor antagonist ikwathintele ngokukhethekileyo ukunganyanzelwa kokuziphatha okufana nokuziphatha okushukumisayo ekuphenduleni i-chow ethandwayo engabonakaliyo ebonwa ngexesha lokurhoxa kukutya okuthandekayo. Ukurhola ukufikelela ekutyeni okunokuthenjwa kunyuke i-CRF gene kunye nenkcazo ye-peptide kwi-nucleus ephakathi ye-amygdala, iziphumo ezisuswe ngokufikelela okuvuselelweyo. Ukongeza, iigundane ezijikelezwe kukutya zibonisa imvakalelo ekonyukayo kwiziphumo zothintelo lweCRF1 I-receptor antagonist ekuhanjisweni kwe-GABAergic kwi-nucleus esembindini ye-amygdala, iphakamisa ngakumbi ukuthengiswa kwe-amygdala CRF-CRF1 inkqubo. Ukutya kakhulu ukutya okufumanekayo xa ufikeleleko oluhlaziyiweyo kunokubangelwa kukunyanzeliswa kwenkqubo yeCRF yexesha elisandula ukurhoxiswa, kubonwa njengokuthetha okwenyukayo kweCRF kunye nemvakalelo yokuzibona ngombane kwiCRF1 i-receptor blockade kwi-nucleus esembindini ye-amygdala. I-CRF1 Isimo sengqondo sokuchasa ngaphambi nje kokuba kufumaneke ukutya kutolikwa ukuze kuchaswe ubukho beCRF-CRF1 inkqubo egqithisileyo yokurhoxiswa Ikhosi emfutshane yokutya ukutya okufumaneka lula kubonwa ngenye indlela kwizilwanyana ezingafundanga (10) inokubonakalisa ikhosi yexesha apho intetho, ukukhutshwa, kunye neziphumo zeCRF peptide ziyenza kube lula ukufikelela kukutya okufumanekayo, njengoko kubonwe kwisifundo esikhoyo. Ke ngoko, ukutya ukutya okunesondlo rhoqo kunokukuguqula utshintsho kwiinkqubo zembuyekezo yobuchopho ngokugaya i-CRF-CRF engalunganga1 Iinkqubo kwindawo ephakathi ye-amygdala.

Ezi ziphumo zinefuthe kungekuphela kokutya okunyanzelekileyo, kodwa kunye nokukhuthaza ngokubanzi. Ukusebenza okuphindaphindiweyo kweenkqubo ze-hedonic zicebise iinkqubo ezichasayo-ezichasene nengqondo (okt, ukugaywa kwakhona kweCRF1 ukujikeleza) okwahlukileyo ekulahlekelweni lula komsebenzi kwiinkqubo zothumelo lomvuzo. Eziphakathi kweenkqubo neuroadaptations (19) kukwenzeka ngexesha lenguqu ukuxhomekeka kuzo zonke iziyobisi ezikhulu zokuxhatshazwa (7, 8). Ukudityaniswa ngokubanzi kukhuthazo olungelulo lweziyobisi kolu phando lukhoyo lubonisa ukuba iinkqubo ezikhuthazayo zinokuphazanyiswa kubantu abanamava okuphindaphindiweyo kubuninzi bexesha lokuqhubela phambili kwehedonic (20). Ngokuchaneka, ezi nkqubo zinokutshintsha ukufuna ukutya kunye nokuziphatha okuqinisekileyo kumandla oxineneyo, ukutya okunomvuzo ophezulu, ngelixa kulungiswa imizamo yokufumana ukutya okutyebileyo kwamandla, ukutya okunomvuzo ophantsi (okanye okungekuko ukutya), ukuziqhelanisa nokulunga xa kukho iindleko zokuzingela ukutya (umzekelo, ukubonakaliswa kweentshaba, ixesha elincinci kunye nezixhobo zamandla). Kwimeko-bume yanamhlanje, nangona kunjalo, iinkqubo ezifanayo zinokuqhuba ukutya okukhuthaza ukukhuluphala ngokwexabiso elinencasa encinci, kodwa mhlawumbi ezinye iindlela ezinesondlo.

Ke ngoko, utshintsho olunje ngeziyobisi kwiCRF1 iinkqubo zinganceda ukuqhuba (i) Ukutya ukutya okunencasa ye-eneji, (ii) Ukuqonda ngokungaphaya ezinye iindlela ezisempilweni, kunye (iii) imeko ehambelana nemvakalelo engahambelaniyo eyenzekayo xa kuthintelwa ukutya okuthandekayo4, 5, 10-12, 17). Iguqulelwe kwimeko yomntu, inkqubo yeCRF yokuvuselela inokukhuthaza ukuphinda utye ukutya ngokutyeba kakhulu kunye neengxaki zokutya ezinxulumene nayo kunye nokunye ukungqinelana okungafanelekanga kokungavunyelwa kokutya okujikelezayo kokutya okuthandekayo.

Impahla nenkqubo

I zifundo.

Iigundane leWistar yamadoda (n = 155, 180-230 g, 45 day ubudala) zaye zafunyanwa kuCharles River zaza zafakwa kwindlu enye zakuba zafakwa kwi-wire-topped, cage zeplastiki (19 × 10.5 × 8 intshi) kumatshini we-12 h: 12 h umjikelo wokukhanya komjikelo (10 h : Izibane ze-00 h zicinyiwe), umswakama- (60%) kunye nolawulo lobushushu (22 ° C) vivarium. Iigundane zazinokufikelela kwi-rodent-based rodent chow [Harlan Teklad LM-485 Diet 7012: 65% (kcal) carbohydrate, 13% fat, 21% protein, energy metabolizable 341 cal / 100 g] kunye ne-ads libitum yeveki ye-1 ngaphambi ukuqala kwezilingo. Inkqubo yokuvavanywa elandelwa kwiZiko leSizwe leSikhokelo sezeMpilo kuKhathalelo kunye nokuSetyenziswa kweeLebhu zeLebhu (i-NIH Inombolo yokupapasha i85-23, i1996 ehlaziyiweyo) kunye "neZiseko zokhathalelo lwelabhoratri" (http://www.nap.edu/readingroom / Iincwadana ezinemifanekiso) kwaye zamkelwa liQela loKhathalelo lweZilwanyana kunye neKomiti yokuSebenzisa yeZiko loPhando lweScript.

Iziyobisi.

I-R121919 yenziwa njengoko ichaziwe kwi-Chen et al. (21). I-R121919 ngumanyano oluphezulu (Ki = 3.5 nM) CRF ekhethiweyo1 I-antagonist ineempawu zomzimba ezibalaseleyo kunezinye i-CRF ezininzi1 abachasi (umzekelo, i-logP enciphile kunye ne-logD, ukunyuka kwamanzi okunyibilika) (13). Ukuvavanywa, i-R121919 yaqala ukunyibilikiswa kwi-1 M HCl (i-10% yevolumu yokugqibela), yaze yafakwa kwisithuthi sokugqibela se-20% (wt / vol) 2-hydroxypropyl-β-cyclodextrin (Sigma-Aldrich), ebuyiselwe umva ngomva I-NaOH kwi-pH 4.5. Isisombululo se-R121919 salawulwa nge-sc (sc) kumthamo we-2 mL / kg.

I-Ad Libitum Diet Alternation.

Emva kokunkcenkceshela, iigundane zahlulwa zangamaqela amabini afanelana nokutya, ubunzima bomzimba, kunye nokondla okufanelekileyo ukusuka kwiintsuku ze-3-4 zangaphambili. Iqela elinye lanikwa ukutya okutyayo ("Chow") iintsuku ze-7 ngeveki (Chow / Chow), kwaye iqela lesibini labonelelwa nge-chow ad libitum yeentsuku ze-5 veki nganye lilandelwa ziintsuku ze-2 zokungena kwe-ad libitum , itshokholethi enencasa, ukutya okune-sucrose enkulu (“Iyathandeka”; Chow / Palatable). Ukutya okumnandi kukutya okugqibeleleyo okunesondlo, i-chocolate-flavour, i-sucrose (i-50% kcal), ukutya okusekwe kwi-AIN-76A okuthelekiswa ngokulinganayo kwe-macronutrient kunye nobunzima bamandla ekutyeni kwe-chow [TestDiet; itshokholethi enencasa ye-chocolate 5TUL: I-66.8% (kcal) i-carbohydrate, i-12.7% inqatha, iprotein ye-20.5%, amandla e-3.48 kcal / g; yenziwe njenge-pNelleX yokutya ngokuchanekileyo ye-45-mg ukwandisa ukuthanda kwayo (22, 23)]. Ukulungiselela ukophula umthetho, Iintsuku zokuqala ze-5 (chow kuphela) kunye neentsuku zokugqibela ze-2 (chow okanye zibambekayo ngokweqela lokulinga) zeveki nganye kubhekiswa kuzo kuzo zonke iimvavanyo njengezigaba ze-C kunye no-P. Ukutya akuzange kufumaneke kwangaxeshanye. Ukutya kweChow nokuba nguHarlan Teklad LM-485 Diet 7012 [65% (kcal) carbohydrate, i-13% inqatha, i-21% iprotein, amandla e-metabolicable 341 cal / 100 g] okanye i-5TUM yokutya yenziwa njenge-4- ukuya kwi-5-g eyandisiweyo ye-65.5-g I-% (kcal) i-carbohydrate, i-10.4% inqatha, iprotein ye-24.1%, amandla e-metabolic 330 cal / 100 g; TestDiet]. Kuyafana nakwizifundo zangaphambili, iHarlan Teklad LM-485 chow isetyenziswe ekutyiseni nasekuphakamiseni uvavanyo lwe-macho-maze (11), ngelixa iTestDiet 5TUM chow (10) yasetyenziswa kwisilinganiselo sokuqhubela phambili, umlinganiso weCRF mRNA, umxholo weCRF peptide, corticosterone RIA kunye novavanyo lwe-electrophysiological.

Njengoko yayishicilelwe ngaphambili (10), ukuthanda ukutya okuhambelana nokutya, kubalwe njengepesenti yokutya kwemihla ngemihla (kcal) kokutya kokunxulumene nokutya kwesibini, kwaba oku kulandelayo: 5TUL Chocolate Diet (ukutya okuneswekile) ngokuhamba noHarlan LM-485 chow (M ± SEM ukuthanda i-90.7 ± 3.6%) kunye ne-5TUL Chokoleti yokutya (iswekile yokutya okuneswekile) kunye ne-5TUM chow Diet (M ± ukuthanda kwe-SEM 91.2 ± 3.7%).

Unyusiwe-Maze.

Uvavanyo oluphakanyisiweyo lwe-plus-maze lwenziwa njengoko kuchaziwe kwiCottone et al. (24). Iirow / Chtatable rats zazityi-cycled ubuncinci iiveki ze-7 emva koko ziye zenziwa isithuthi okanye i-20 mg / kg i-R121919 (−1 h, sc) kwaye yavavanywa i-5-9 h emva kokutshintshwa kukutya okuthandekayo ukuya kwi-chow (P → C isigaba). Iintambo zokulawula iChow / Chow ziye zavavanywa ngaxeshanye kuyilo oluphakathi lwezifundo (n = 47). Ukutya kweChow kwakufumaneka kwi-ad libitum kude kufike ixesha lovavanyo. Ngolwazi oluthe kratya, bona Isicatshulwa se-SI.

Ukuqhubela phambili-ukuHlela ishedyuli yokuqiniswa kokutya.

Ishedyuli eqhubekayo yokulinganisa yokuqinisa ukutya yenziwa njengoko kuchaziwe kwiCottone et al. (10). Izilwanyana zifumane i-ad libitum ye-A / I chow (i-5 g iiperits ezikhutshelweyo) kwizindlu zabo zasekhaya kulo lonke uvavanyo ngaphandle kokuba kuchazwe ngolunye uhlobo. Ukuqiniswa kokutya kwakuyi-pellets echanekileyo ye-45-mg chow-echanekileyo, ehambelana nokubumba kwendawo yokutya esekhayeni eyandisiweyo. Iiseshini ziphele xa izifundo zingakhange zigqibe umyinge we-14 min, kunye nomyinge wokugqibela ogqityiweyo ochazwa njengophule indawo. Iirow / Chrats ezinokutya zazenziwe ukuba zijikeleze iveki kangangesithuba seeveki ze-7 emva koko ziye zenziwa umlinganiso we-R121919 (−1 h, sc) ngelo xesha lokutshintshwa kwindlela yokutya yokutya kuyekeka kwi-chow (P isigaba se-C). Iintambo zokulawula iChow / Chow ziye zavavanywa ngaxeshanye kuyilo oluphakathi lwezifundo (n = 17). Iidosi ze-R121919 (0, 20 mg / kg ubunzima bomzimba, i-sc) zinikezwe ngaphakathi-kwezifundo, uyilo oluchasene nomjikelo wokutya omabini. Ngolwazi oluthe kratya, bona Isicatshulwa se-SI.

Ubungakanani bexesha lePCR.

Iigundane (n = 20) zazityhutyhwa zii-7 iiveki, zine-anesthetised, kwaye zanqunyulwa intloko ngexesha lokutya (iintsuku 5 kunye ne-7 kumjikelo weveki nganye). Iibongo zisuswe ngokukhawuleza zaza zacolwa zaza zalulayishwa ngokukhawuleza kwimithambo yengqondo, kunye ne-nucleus esembindini ye-amygdala, i-nucleus accumbens, i-insular cortex, kunye ne-preortal cortex punches zaqokelelwa kwinqanaba elibandayo lomkhenkce. Iyonke i-RNA yayilungiselelwe ukusuka kwingqindi nganye yobuchopho kusetyenziswa umthetho olandelwayo wokukhutshwa kwe-RNA kwizicubu zezilwanyana. Iyonke i-RNA (1 μg) yaphinda yatshintshwa yabhalwa phambi kwe-Oligo (dT) 20 ngokwemiyalelo yomenzi. Ubungakanani beempendulo ze-RT-PCR zenziwa ngevolumu ye-20-μL kusetyenziswa i-0.5 μM primers kunye ne-4 mM MgCl2. Iziphumo zahlalutywa ngeendlela ezisusela kwisibini kwaye zavakaliswa kwiiyunithi ezilandelanayo, efanekiselwa kumanqanaba enkcazo kuhlobo lwereferensi, iCypA. Zonke i-RT-PCR zeziphumo zokulandelelana okunikiweyo zenziwa ngaphakathi kwento enye. Ngolwazi oluthe kratya, bona Isicatshulwa se-SI.

I-Peptide Acid Extraction kunye neCRF RIA.

Iigundane (n = I-25) yayityelwe ukutya ngebhayisikile ubuncinci iiveki ze-7, ingafakwa i-anesthetised, kwaye yagqitywa ngexesha leemeko ezimbini zokutya (imihla ye-5 kunye ne-7 yomjikelo weveki nganye). Iingqondo zisuswe ngokukhawuleza kwaye zanyibilika kwi-coronally kwi-matrix yengqondo, kwaye i-nucleus ephakathi ye-amygdala punches yaqokelelwa kwinqanaba lokubandayo lomkhenkce. Ukukhutshwa kwe-peptide acid kulandela inkqubo esele isungulwe (25). I-CRF-efana nokugonywa njenge-immunoreactivity kwagqitywa nge-RIA enobuthathaka kunye nethe ngqo yesigaba sokuqina se-RIA esuswa kuZorrilla et al. (26). Ngolwazi oluthe kratya, bona Isicatshulwa se-SI.

ICorticosterone RIA.

Iigundane (n = 12) zazineebhayisekile zokutya ubuncinci iiveki ezisixhenxe, kunye nomsila wegazi isampulu ngexesha lokutya ezimbini (iintsuku 7 kunye ne5 kumjikelo weveki nganye). Amanqanaba e-Plasma ye-corticosterone-efana nokugonyelwa komzimba yagqitywa ngekhithi ye-RIA ekhoyo ngokorhwebo, ngokwemiyalelo yomenzi wayo (MP Biomedicals, Inc.) (26). Ngolwazi oluthe kratya, bona Isicatshulwa se-SI.

Izifundo ze-Electrophysiological

Ukulungiselela isilayida.

I-nucleus esembindini yeentambo ze-amygdala zalungiswa njengoko kuchaziwe ngaphambili (27, 28) kwiigundane (n = I-7 / iqela) ebikade itya ukutya ngebhayisikile ubuncinci iiveki ze-7, ingafakwa i-anesthetised, yaza yabekelwa ecaleni i-2-3 h emva kokurhoxiswa kukutya okuthandekayo. Iingqondo zisuswe ngokukhawuleza kwaye zabekwa kwi-ice-ebandayo ye-cerebrospinal fluid (aCSF) gassed nge-95% O2 kunye ne5% CO2. Izilayi zisikiwe, zafakwa kwisimo esibonakalayo esimalunga ne-30 min, kwaye yafakwa ngokupheleleyo emgangathweni kwaye ngokuqhubekayo igalelwe i-aCSF efudumeleyo. Iziyobisi zongezwa kwi-aCSF kwizisombululo zesitokhwe ukufumana ukugxila okwaziwayo kwi-superfusate. Kwixabiso le-2-4 mL / i-min ephezulu yexabiso elisetyenzisiweyo, ukugxila kweziyobisi kufikelela kwi-90% ye-reservoir concentration ngaphakathi kwe-2 min.

I-Electrophysiology.

Sirekhode i-nucleus esembindini ye-amygdala neurons enemikroskopu ezibukhali zisebenzisa i-discontinuous voltage- okanye imo yangoku ye-clamp. Sasibambe uninzi lwee-neurons kufutshane namandla abo okuphumla. Idatha yafunyanwa nge-preamplifier kwaye igcinwe kuhlalutyo kamva kusetyenziswa isoftware ye-PClamp. Amayeza eGABA awodwa kwezonyangoA i-receptor-Mediated inhibitory postynaptic potentials (GABAA-I -PsPs) zavuselelwa ngokuvuselela ngaphakathi kwindawo engaphakathi kumbindi we-amygdala ngokusebenzisa i-electrode eneempawu eziphefumulayo ngelixa igubungela i-glutamate receptor blockers CNQX kunye ne-APV ne-GABAB i-receptor blocker CGP 55845A. Ukuchonga iiparameter zempendulo kwiseli nganye, senze iprotocol yokukhupha iziphumo. Uluhlu lwee-currents zaye zasetyenziswa, ukuqala kumda wamanje ofunekayo ukuphakamisa i-IPSP ukuya kumthamo wombane ofunekayo ukuphakamisa indawo ephezulu. Silungelelanise ubungakanani bokuqinisela obuthathu bamanyathelo alinganayo (umbundu, umda wobukhulu, kunye nobukhulu) njenge-1-3 ×. Hyperpolarizing kwaye depolarizing amanyathelo akhoyo ngoku (kunyuka kwe-200-pA, ubude be750-ms) nako kwasetyenziswa ukwenza i-voltage-current (VI) curves. Sazicacisa iindawo eziphakanyisiweyo ze-IPSP kunye neempendulo zeVI ngokusebenzisa isoftware yaseClampfit. Onke amanyathelo athatyathwa ngaphambi kokunyanzelwa kwiCRF ekhethiweyo1 I-receptor antagonist R121919 (1 μM), ngexesha layo le-superfusion (i-20 min), kunye nokulandela ukuhlamba (i-30 min). Ngolwazi oluthe kratya, bona Isicatshulwa se-SI.

Izibalo.

Uthelekiso lweqela lusetyenzisiwe t-Imvavanyo (ukuthelekiswa kwamaqela amabini) okanye uhlalutyo lokwahluka (i-ANOVA) (ubuncinci bokuthelekisa amaqela amathathu), eli kamva litolikwa ngohlalutyo oluphambili lwesiphumo okanye iNewman-Keuls ngokuthelekisa emva kweziphumo ezibalaseleyo ze-omnibus (P <0.05). Idatha evela kuvavanyo lokondla yahlalutywa zii-ANOVA ezixubileyo ezintathu kunye neShedyuli yokutya njengezinto eziphakathi kwezifundo kunye neDose kunye neSigaba sokutya njengezinto ezingaphakathi kwezifundo. Idatha evela kuvavanyo oluphakamileyo lwe-plus-maze yahlaziywa ngeendlela ezimbini ze-ANOVA kunye neShedyuli yokutya kunye neDose njengezinto eziphakathi kwezifundo. Ishedyuli yenkqubela phambili yomlinganiso wovavanyo lokuqinisa, indawo yokuphuka kunye neempendulo zizonke zahlaziywa ngeendlela ezimbini ezixubeneyo ze-ANOVA kunye neShedyuli yokutya njengezinto eziphakathi kwezifundo kunye neDose njengezinto ezingaphakathi kwezifundo. Ikhosi yexesha lokuphendula ngexesha lemizuzu emi-5 yokuqala yahlalutywa ziindlela ezintathu ezixubeneyo ze-ANOVA kunye neShedyuli yokutya njengezinto eziphakathi kwezifundo kunye neDosi kunye nexesha njengezinto ezingaphakathi kwesihloko. Idatha evela kwizifundo ze-electrophysiological zahlalutywa phakathi kwe-ANOVA okanye ngaphakathi kwezifundo ze-ANOVA ngamanyathelo aphindaphindiweyo, ngokufanelekileyo. Idatha evela kwi-corticosterone RIA apho yahlalutywa khona ngeendlela ezimbini ezixubeneyo ze-ANOVA kunye neShedyuli yokutya njengesihloko esiphakathi kwesihloko kunye neSigaba seDiet njengeyona nto iphakathi kwesihloko. Iiphakheji zamanani ezazisetyenziswa yayizi-Instat 3.0, Prism 4.0 (GraphPad), Systat 11.0, kunye ne-SPSS 11.5 (SPSS).

Izinto ezongezelelweyo

Ukuxhasa ulwazi: 

Imibulelo.

Sibulela uMike Arends ngoncedo lomhleli, uMary Gichuhi ngoncedo lolawulo, kunye noBob Lintz, uJeanette Helfers, uStephanie Dela Cruz, kunye noMolly Brennan ngoncedo lobuchwephesha. Lo msebenzi uxhaswe liZiko leSizwe leSifo seSwekile kunye nokuSweleka kunye neZibonelelo zeZifo zeNtso kwi-DK70118, DK26741, kunye ne-P30DK56336; Iziko leLizwe leSibonelelo seSibonelelo seZiyobisi kwiPhondo Iziko leSizwe lokuSetyenziswa gwenxa kotywala kunye neziBonelelo zeAutywala I-AA023680 kunye ne-AA016731; IZiko leSizwe leNeurological Disfall kunye neSibonelelo seStroke IT015566NS32-061847A01; IZiko leSizwe kwiNkxaso-mali yokuGuga i-AG2; Intliziyo yeSizwe, iLung kunye neZiko leSibonelelo seGazi HL028040; Isiseko sezeMpilo sika-Ellison; kunye neZiko lePearson loTywala kunye noPhando ngeziyobisi. Inxalenye yalo msebenzi ixhaswe ziinkqubo zophando lweIntramural zeZiko leSizwe ngokuSetyenziswa gwenxa kweziyobisi kunye neZiko leSizwe ngokuSetyenziswa gwenxa kotywala kunye notywala. Le yinombolo ebhalwe ngesandla i-088083 evela kwiZiko loPhando lweScript.

Imihlathi

 

Ababhali bavakalisa ukuba akukho mpikiswano.

Eli nqaku lingeniso ngqo lwe-PNAS.

Eli nqaku liqulethe iinkcukacha ezixhasayo kwi-intanethi www.pnas.org/cgi/content/full/0908789106/DCSupplemental.

Ucaphulo

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