I-Biol Psychiatry. 2008 Dec 1;64(11):941-50. Epub 2008 Jul 26.
Teegarden SL, Nestler EJ, Bale TL.
imvelaphi
ISebe le-Biology yeZilwanyana, iYunivesithi yasePennsylvania, ePhiladelphia, PA 19104-6046, eU.SA.
Abstract
UMGQUBO:
Ukuqonda ukufumana umvuzo kuye kwabandakanywa njengento ebangela ukuba iziphathamandla ezinxulumene nokusetyenziswa kakubi kweziyobisi kunye nokutya ngokutya. Nangona kunjalo, iindlela ezisisiseko ezifaka isandla ekuvuzeni ubukhulu bentliziyo aziwazanga. Sifumanisa ukuba ukutshatyalaliswa kwe-dopamine ukusayinzeka kungabangela imbangela yokwenza umvuzo wokuphakamisa umvuzo apho ukuhlaziywa kwemivuzo kunokusebenza ngokumisela inkqubo.
IINDLELA:
Sisebenzise imodeli yemouse yemfuza yokwandisa ubuntununtunu bomvuzo, i-Delta FosB-overexpressing mouse, ukujonga utshintsho lwendlela yomvuzo ekuphenduleni ukutya okunamafutha aphezulu. Iimpawu zokubonisa umvuzo kwezimpuku zavavanywa ngokusisiseko kwaye zilandela iiveki ezi-6 zokuvezwa kokutya okunencasa. Iimpuku zavavanywa kuvavanyo lokuziphatha emva kokurhoxiswa kokutya okunamafutha aphezulu ukuvavanya ukuba sesichengeni kwale modeli ekususeni isivuseleli esivuzayo.
IINKCUKACHA:
Iziphumo zethu zibonisa uguqulo lwendlela yomvuzo eguquliweyo ecaleni kwe-nucleus accumbens-hypothalamic-ventral tegmental area circuitry ngenxa yokuxinana kwe-Delta FosB kwi-nucleus accumbens kunye nemimandla yokufa.. Amanqanaba e-phosphorylated cyclic adenosine monophosphate (cAMP) impendulo yesiqalelo sokubopha iprotheni (pCREB), Ingqondo ephuma kwi-neurotrophic factor (BDNF), kunye ne-dopamine kunye ne-cyclic adenosine monophosphate elawulwa yi-phosphoprotein ene-molecular mass ye-32 kDa (i-DARPP-32) kwi-nucleus accumbens yancitshiswa kwiigundane ze-Delta FosB, ebonisa ukunciphisa ukubonakaliswa kwe-dopamine. Iiveki ezintandathu zokuvezwa kokutya okunamafutha aphezulu ziwuphucule ngokupheleleyo lo mahluko, zityhila amandla anomvuzo wokutya okunencasa. Iigundane ze-Delta FosB nazo zibonise ukwanda okukhulu komsebenzi we-locomotor kunye neempendulo ezinxulumene nexhala kwiiyure ze-24 emva kokurhoxiswa kwamafutha amaninzi.
IMISEBENZI:
Ezi ziphumo ziseka ubuntununtunu obusisiseko kutshintsho kumvuzo onxulumene nedysregulation ye-Delta FosB kunye nokubonakaliswa kwe-dopamine enokuthi iqheleke ngokutya okunencasa kwaye inokuba yi-phenotype ebeka phambili kwezinye iindlela zokutyeba..
intshayelelo
Ngaphandle kolwazi lwethu olwandayo lweenkqubo ze-neural ezilawula ukutya kunye nokuhlutha, amazinga okutyeba ayaqhubeka nokunyuka e-United States. Unyango lwangoku lwamachiza lunokusebenza okulinganiselweyo, kwaye uhlengahlengiso lokuziphatha lunengxaki yokuthotyelwa kwexesha elide (1). Ukusetyenziswa kokutya okunekhalori-ezixineneyo, okunencasa kunxulunyaniswe notshintsho kuxinzelelo kunye neendlela zomvuzo engqondweni, ecebisa ukuba iipropathi ezinomvuzo zoko kutya zinokugqitha imiqondiso yolungelelwaniso lwamandla (2-4). Ukutya okunamafutha amaninzi kusebenza njengembuyekezo yendalo, ukuvula amaziko okuvuza ingqondo ngendlela efana neziyobisi zokusetyenziswa kakubi, kwaye ngenxa yoko kusetyenzisiwe kwiiparadigms zokuzilawula (5-8). Ke, kusenokwenzeka ukuba izimilo kunye nenkuthazo yokutya kakhulu kunye nokusetyenziswa kakubi kweziyobisi zabelana ngeendlela eziqhelekileyo ezisisiseko, ezinokuvula iindlela ezintsha zonyango kuzo zombini iimeko.
Ekufundeni ubudlelwane phakathi kokutya okunencasa kunye neendlela ezilawula umvuzo kunye noxinzelelo engqondweni, Siye sachonga ngaphambili iimpawu zemolekyuli kunye ne-biochemical zomvuzo oncitshisiweyo kunye noxinzelelo olwandisiweyo emva kokurhoxa kwisidlo esinamafutha aphezulu (HF). Ngokufana neziyobisi zokusetyenziswa kakubi, ukuvezwa kokutya okunencasa kwizifundo zethu kukhokelele kumanqanaba okwanda kwento ekhutshelweyo ΔFosB kwi-nucleus accumbens (NAc), isiseko somvuzo wengqondo (9, 10). Iimpuku ezibonisa i-inducibly overexpress ΔFosB zibonisa ukunyuka kwesixhobo sokuphendula kumvuzo wokutya (11), zizenza isixhobo esixabisekileyo sokuvavanya indima yobuntununtunu bomvuzo kunye noxinzelelo lwexesha elide lwenkqubo yomvuzo kwiimpendulo zemolekyuli kunye ne-biochemical kukutya okunencasa.
Kuphononongo lwangoku, sisebenzise iimpuku ze-ΔFosB-overexpressing ukujonga utshintsho lwexesha elide kumanqaku omvuzo kwindawo ye-NAc-hypothalamus-ventral tegmental (VTA) neurocircuitry ekuphenduleni ukutya okunencasa kwe-HF. Ngokusekwe kwizifundo zangaphambili kwezi mpuku zisiva umvuzo, siye saqikelela ukuba i-ΔFosB-inguqu eyenziwe kumvuzo wobuntununtunu ibandakanya idysregulation kuphawu lwe-dopamine olubangelwa yingxelo ye-NAc kwi-VTA. Ngaphaya koko, sicinge ukuba ukuvezwa kumvuzo wendalo wokutya okuxineneyo kwamandla e-HF kuya kuthi ke kuqheleke inkqubo ye-dopaminergic kwezi mpuku, kubangele impendulo ebaxiweyo kuxinzelelo lokurhoxa koku kutya kwe-HF.. Umba okhethekileyo wokusebenzisa ukutya okunencasa njengento enomvuzo usivumela ukuba sibandakanye amagalelo e-hypothalamic ukuvuza ukujikeleza kwi-phenotype enokuthi ibe nokuqikelelwa kwangaphambili kwabantu abathambekele ekutyebeni okunganyangekiyo kunyango. Ukuphonononga le ngcamango, sifunde iimpawu ze-dopamine neurotransmission, kubandakanywa i-pCREB, i-BDNF, kunye ne-DARPP-32 kwi-NAc kunye ne-tyrosine hydroxylase kunye nomthuthi we-dopamine kwi-VTA, emva kokuvezwa kwe-HF. Sikwavavanye iimpawu ezithile zolungelelwaniso lwamandla olwaziwayo ukuphembelela ukuphuma kwe-dopamine, kubandakanya i-leptin kunye ne-orexin receptors kwi-VTA kunye ne-orexin expression ngaphakathi kwe-hypothalamus esecaleni.
Impahla nenkqubo
izilwanyana
Iimpuku zeBitransgenic eziyindoda ezityhalela phambili ngokugqithisileyo i-ΔFosB kwi-dynorphin-positive neurons kwi-NAc kunye ne-dorsal striatum (Kelz et al., 1999) zenziwe kwimvelaphi exubeneyo (ICR: C57Bl6 / SJL) kwiYunivesithi yaseTexas Southwestern Medical Centre kwaye igcinwe kwaye ihlolwe kwiYunivesithi yasePennsylvania. Zonke iigundane zagcinwa kwi-doxycycline (i-100 μg / ml emanzini okusela) de yafika kwiYunivesithi yasePennsylvania. Ukubangela ukugqithisa, i-doxycycline yasuswa (n = 23) (12). Iigundane zokulawula (n = 26) zaqhubeka zifumana iyeza. Iigundane zabelwa amaqela okutya kwiiveki ezisibhozo emva kokususwa kwe-doxycyline ngelo xesha ukubonakaliswa kubonakaliswe ukufikelela kumanqanaba aphezulu (13). Iigundane zigcinwe kumjikelezo we-12: 12 ukukhanya-mnyama (izibane kwi-0700) kunye nokutya kunye namanzi akhoyo ad libitum. Zonke izifundo zenziwa ngokweeprothokholi zokulinga ezivunywe yiYunivesithi yasePennsylvania Institutional Animal Care and Use Committee, kwaye zonke iinkqubo zenziwa ngokuhambelana nezikhokelo zeziko.
Ukuvezwa kokutya
Iigundane zagcinwa kwi-house chow (n = 16) okanye zibekwe kwi-HF (n = 16-17) kwiiveki ezintandathu. I-House chow (i-Purina Lab Diet, iSt. Louis, MO) iqulethe i-4.00 kcal / g, equkethe i-protein ye-28%, i-12% ye-fat, kunye ne-60% ye-carbohydrate. Ukutya kwe-HF (Ukutya koPhando, i-New Brunswick, i-NJ) iqulethe i-4.73 kcal / g, equkethe i-protein ye-20%, i-45% ye-fat, kunye ne-35% ye-carbohydrate.
I-biochemistry kunye ne-gene expression
Iigundane zahlalutywa emva kweeveki ezintandathu zokuvezwa kokutya. Ubuchopho basuswa kukhakhayi kwaye nokuba ngumkhenkce ngokupheleleyo kumkhenkce owomileyo okanye i-NAc yachithwa (malunga ne-0.5 - 1.75 mm ukusuka kwi-bregma, kubunzulu be-3.5 - 5.5 mm) kwaye ifakwe kwi-nitrogen engamanzi. I-tissue igcinwe kwi -80 ° C de ibe ihlolwe.
Uhlalutyo lwezinto eziphilayo
Iindlela zamablothi aseNtshona zichazwe kwizinto ezongezelelweyo. I-antibodies esetyenzisiweyo yayiyi: Cdk5, CREB, kunye neBDNF (1: 500, Santa Cruz Biotechnology, Santa Cruz, CA) kunye ne-phospho-CREB (pCREB) (Ser 133) (1: 500, Cell Signaling Technology, Danvers, MA).
I-autoradiography ye-receptor
Iindlela ezicacileyo ze-autoradiography zichazwe kwizinto ezongezelelweyo. I-Ligands esetyenzisiweyo yayiyi-2 nM H3 - SCH 23390 kunye ne-5 nM H3 - i-spiperone (PerkinElmer, Boston, MA).
In situ hybridization
Ukulungiswa kwezicubu kunye nokuxutywa kwe-hybridization kwenziwa njengoko kuchaziwe ngaphambili (14). I-DARPP-32 probe yanikezelwa ngobubele nguP. Greengard (iYunivesithi yaseRockefeller), kunye ne-orexin probe ngu-J. Elmquist (iYunivesithi yaseTexas Southwestern Medical Centre). Izilayidi ezivavanyelwe i-DARPP-32 zacetywa ukuba zenze ifilimu ngeentsuku ze-3, kwaye izilayidi ezivavanyelwe i-orexin zacetywa ukuba zenze ifilimu kwiintsuku ze-4. Ubungakanani bemifanekiso yefilimu yenziwe njengoko kuchaziwe ngaphambili (10).
QRT-PCR
I-RNA yabekwa yodwa kwi-VTA kunye nokubonakaliswa kofuzo lomntu ngamnye oluvavanyiweyo kusetyenziswa i-TaqMan gene assays (Applied Biosystems, Foster City, CA). Iindlela ezineenkcukacha kunye nohlalutyo lwamanani lunokufumaneka kwizinto ezongezelelweyo.
Uhlalutyo lokuziphatha
Ukuze uvavanye iziphumo zobuntununtunu bomvuzo kutshintsho lwendlela yokuziphatha, iseti yeempuku yarhoxiswa kwi-HF kulandela iiveki ezine zokuvezwa kwaye yabuyela kwi-chow yendlu (n = 9 control, n = 8 ΔFosB). Iiyure ezingamashumi amabini anesine emva kokurhoxiswa, iimpuku zavezwa kuvavanyo lwendawo evulekileyo ngokuhambelana ne-paradigm yethu yokurhoxisa yokutya epapashwe ngaphambili (10). Ngokufutshane, impuku yabekwa embindini wesixhobo esivulekileyo kwaye yajongwa imizuzu emihlanu. Iyonke iminqamlezo yomgca, i-boli ye-fecal, ixesha eliphakathi, kunye neminqamlezo embindini yayilinganiswa.
Statistics
Zonke iinkcukacha ngaphandle kwamablothi aseNtshona zahlalutywa kusetyenziswa indlela emibini ye-ANOVA elandelwa luvavanyo lwe-Fisher lwe-PLSD ngonyango lwe-doxycycline (i-ΔFosB expression) kunye nemeko yokutya njengeenguqu ezizimeleyo. Kuhlahlelo lwe-RT-PCR, ixabiso le-P elincitshisiweyo lisetyenziselwe ukulungisa uthelekiso oluninzi ngaphakathi kwamaqela eejeni ezinxulumeneyo (jonga izinto ezongezelelweyo). Iibhulothi zaseNtshona zahlalutywa kusetyenziswa uvavanyo lwe-t yomfundi kunye nonyango lwe-doxycycline njengenguqu ezimeleyo, ukuthelekisa ukuxinana kwe-optical ngaphakathi kwe-blot efanayo. Zonke iinkcukacha zinikezelwe njengentsingiselo ± SEM.
iziphumo
Umahluko weBasal biochemical
Ukucacisa iindlela zeemolekyuli eziphantsi kovakalelo oluphuculweyo lomvuzo kwi-ΔFosB-overexpressing mice, amanqanaba eemolekyuli ezininzi ezibonisa umqondiso wavavanywa kwi-NAc. Kwakukho umkhwa wokunyuka kwamanqanaba e-Cdk5 kwi-NAc ye-ΔFosB iimpuku xa kuthelekiswa nezilwanyana zokulawula i-littermate ezigcinwe kwi-doxycycline (F = 5.1, P = 0.08; Umzobo 1A). Iimpuku ze-ΔFosB zibonakalise amanqanaba ancitshisiweyo kakhulu e-pCREB (F = 7.4, P <0.05; Umzobo 1B) kunye namanqanaba ewonke e-CREB (F = 5.4, P = 0.05; Umzobo 1C). Ukunciphisa okuphawulekayo kwi-BDNF kwabonwa kwakhona kwi-NAc ye-ΔFosB iigundane (F = 10.6, P <0.05; Umzobo 1D).
Umzobo 1
I-Mice overexpressing overexpressing ΔFosB ibonise iziphawuli ze-biochemical zokubonisa okuncitshisiweyo kwe-dopamine kwi-NAc
Ukutya kunye nobunzima bomzimba kwi-fat fat diet
Ngokulandelayo sivavanye iziphumo zokutya okunemivuzo ngokwendalo kwe-HF kutshintsho ekuboniseni iimolekyuli kwiimpuku ze-ΔFosB-overexpressing. Kwakungekho mahluko phakathi kweempuku ze-ΔFosB kunye nolawulo ekutyeni kokutya nokuba yeyiphi na indlu okanye i-HF. Nangona kunjalo, kukho ukuhla ngokubanzi kwi-caloric intake eqhelekileyo kubunzima bomzimba xa kubonakaliswe kwi-HF eyayithe ngqo kwiigundane ze-ΔFosB (F = 11.2, P <0.01; Umzobo 2A). Ekupheleni kweeveki ezintandathu zokuvezwa kokutya, iimpuku ezifumana i-HF zinobunzima obukhulu kunezo zikwi-chow diet (F = 17.2, P <0.001), kunye ne-ΔFosB yeempuku ezinobunzima obungaphantsi kolawulo (F = 5.6, P <0.05; Umzobo. 2B). Esi siphumo sasithe ngqo kwiiyantlukwano phakathi kwamaqela kwi-chow diet (P <0.05).
Umzobo 2
Iimpuku ze-ΔFosB ezibonisa ngokugqithisileyo azibonakalisi mahluko ekutyeni kokutya nokuba kukutya okunamafutha aphezulu (HF)
Umahluko we-Biochemical ekudleni okunamafutha aphezulu
Ukufumanisa ukuba i-basal iyantlukwano ekubonakalisweni kwe-NAc ingatshintshwa njani ngokutya kwe-HF, iiprotheyini zokubonisa ezifanayo ezifundwe kwisiseko zihlolwe kwizilwanyana ezifumene iiveki ezintandathu ze-HF. Kwakungekho nantlukwano ebalulekileyo kumanqanaba eCdk5 (Umfanekiso 3A). Amanqanaba e-pCREB kunye ne-CREB epheleleyo ayengasahlukanga emva kweeveki ezintandathu ze-HF (Umfanekiso 3B, C). Amanqanaba e-BDNF anyuswe kakhulu kwiimpuku ze-ΔFosB kulandela iiveki ezintandathu zokuvezwa kwe-HF (F = 6.5, P = 0.05; Umzobo 3D).
Umzobo 3
Ukutya okunamafutha aphezulu (HF) kuphuculwe umahluko wesignali oqatshelwe kwi-NAc ye-ΔFosB overexpressing iimpuku
I-Dopamine receptor autoradiography
Sisebenzise i-autoradiography ye-receptor ukuvavanya ukuba ngaba i-ΔFosB-induced alterations kwi-dopamine signing kwi-NAc inxulumene notshintsho kwi-dopamine receptor expression (Fig. 4A). Ukutya okunamafutha aphezulu kubonakala kwandisa kancinane ubuninzi be-D1 dopamine receptor binding (P = 0.14), kwaye lo mahluko wawumkhulu kwiigundane ze-ΔFosB (Fig. 4B). Kwakhona kwakukho umkhwa wokunyuka kwendawo yokubopha i-D1 elandela i-HF (P = 0.06), kunye novavanyo lwe-post hoc lubonise oku kubaluleke kakhulu kwiigundane ze-ΔFosB (P <0.05; Umzobo 4C). Ngokwahlukileyo kwi-D1 receptors, akukho lutshintsho kwi-D2 receptor ebopha ukuxinana (control chow = 97.6 ± 6.9, lawula i-HF = 101.1 ± 8.2, ΔFosB chow = 91.6 ± 1.0, ΔFosB HF = 94.8 ± 9.5) okanye indawo yokubopha = 47.3. ± 3.4, ukulawula i-HF = 53.8 ± 6.0, ΔFosB chow = 51.9 ± 3.7, ΔFosB HF = 49.0 ± 3.3) kwi-NAc yabonwa.
Umzobo 4
Ukutya okunamafutha aphezulu (HF) kukhokelele kutshintsho kwi-D1 dopamine receptor dinding kunye ne-DARPP-32 expression kwinucleus accumbens (NAc) ye-ΔFosB overexpressing mice.
Inkcazo ye-DARPP-32 kwi-NAc
I-in situ hybridization yayisetyenziselwa ukumisela amanqanaba okubonakalisa i-DARPP-32 kwi-NAc (Umfanekiso we-4D). Ukutya okunamafutha aphezulu kunyuse kakhulu ukubonakaliswa kwe-DARPP-32 kulo mmandla wobuchopho (F = 5.1, P <0.05), kwaye bekukho intsebenziswano ebalulekileyo phakathi kokutya kunye nokubonakaliswa kwe-ΔFosB (F = 8.9, P <0.05), kunye neempuku ze-ΔFosB ezibonisa okukhulu utshintsho olubangelwa kukutya (Umfanekiso 4E). Umahluko osisiseko kwinkcazo ye-DARPP-32 phakathi kolawulo kunye neempuku ze-ΔFosB zatyhilwa ngovavanyo lwe-post hoc (P <0.01), kunye nokunyuka okubonakalayo kwe-DARPP-32 intetho kwi-ΔFosB yeempuku kwi-HF (P <0.01).
Ukubonakaliswa kweGene kwi-VTA
I-QRT-PCR isetyenziselwe ukuvavanya utshintsho kwimbonakalo yemfuza kwi-VTA, ijolise kuhlobo lwemfuza oluphambili olwalubandakanyekile kulawulo lomvuzo. Zonke iisampulu zenziwe ukuba zibe yi-β-actin. Ukuqinisekisa ukuba i-β-actin ibonakaliso ayizange iguqulwe ngonyango, i-assay eyahlukileyo yaqhutyelwa ukuthelekisa i-β-actin kulawulo lwesibini lwangaphakathi, i-GAPDH. Kwakungekho mahluko ubalulekileyo kwi-β-actin expression (amaxabiso e-ΔCT, β-actin - GAPDH: control chow = 2.29 ± 0.21, lawula i-HF = 2.01 ± 0.04, ΔFosB chow = 2.32 ± 0.49, ΔFosB HF = 2.37) ± 0.10).
Umkhwa wokunxibelelana phakathi kwenkcazo ye-ΔFosB kunye nonyango lokutya kwabonwa ukubonakaliswa kwe-tyrosine hydroxylase (F = 3.6, P <0.06; Umzobo 5A). Iiveki ezintandathu zokuvezwa kwe-HF zibonakale zinciphisa intetho ye-tyrosine hydroxylase kulawulo lweempuku kunye nokwandisa ukubonakaliswa kwiimpuku ze-ΔFosB. Ukusebenzisana okubalulekileyo phakathi kwenkcazo ye-ΔFosB kunye nokuvezwa kokutya kwajongwa ukubonakaliswa komthuthi we-dopamine (F = 6.7, P <0.03; Umzobo 5B). Ngokufana ne-tyrosine hydroxylase, ukuvezwa kwi-HF kuncitshiswe ukubonakaliswa kwesithuthi se-dopamine kwiimpuku zolawulo kunye nokwandisa kakhulu ukubonakaliswa kwi-ΔFosB iimpuku (P <0.05). Umahluko osisiseko kwinkcazo yesithuthi se-dopamine phakathi kolawulo kunye neempuku ze-ΔFosB azifikelelanga ukubaluleka (P = 0.16), kodwa emva kweeveki ezi-6 ze-HF, iimpuku ze-ΔFosB zibonakalise amanqanaba aphezulu kakhulu e-dopamine transporter xa kuthelekiswa nolawulo (P <0.05).
Umzobo 5
Ukutya okunamafutha aphezulu (HF) ukuvezwa kunye nokubonakaliswa kwe-ΔFosB kukhokelele kutshintsho ekubonakalisweni kwenani leemolekyuli eziphambili kwi-VTA.
Kwakukho umkhwa obonisa umphumo wokunyuswa kwe-ΔFosB yokubonisa ukunciphisa amanqanaba e-TrkB kwi-VTA (F = 5.7, P <0.04; Umzobo 5C). Nangona bekungekho ziphumo ziphambili kwi-κ-opioid receptor expression, bekukho umkhwa wokunciphisa intetho kwiimpuku ze-ΔFosB (P = 0.08; Umzobo 5D). Ukubonakaliswa kwe-leptin receptor kwagqitywa kwakhona kwi-VTA. Isiphumo esibalulekileyo sokuvezwa kokutya kwafunyanwa (F = 6.1, P <0.03), kunye ne-HF yokunciphisa kakhulu amanqanaba e-leptin receptor kwi-VTA kuzo zombini i-ΔFosB kunye neegundane zokulawula (umzobo 5E). Ukubonakaliswa kwe-orexin receptor 1 kwi-VTA nayo yavavanywa. Kwakukho umphumo obalulekileyo wokutya ekubonakalisweni kwe-orexin receptor (F = 9.0, P <0.02), kunye neegundane ezivezwe kwi-HF ezibonisa amanqanaba aphezulu kwi-VTA (Fig. 5F). Kwakukho nentsingiselo yeempuku ze-ΔFosB zokubonisa amanqanaba aphezulu aphezulu e-orexin receptor 1 kulo mmandla wobuchopho (P <0.05).
Ukubonakaliswa kwe-Orexin kwi-hypothalamus esecaleni
Silinganise amanqanaba e-orexin kwi-hypothalamus esecaleni, imvelaphi ye-orexinergic innervation ye-VTA, nge-situ hybridization (Umfanekiso 6A). Bekukho intsebenziswano ebalulekileyo phakathi kwenkcazo ye-ΔFosB kunye nokuvezwa kokutya kwintetho ye-orexin (F = 9.1, P <0.01), kunye ne-HF yokunyusa kakhulu amanqanaba e-orexin kulawulo lweempuku (P <0.05) kunye nokunciphisa ukubonakaliswa kwiimpuku ze-ΔFosB (Fig. 6B). Nangona bekungekho mahluko ubalulekileyo ekubonakalisweni kwe-orexin kwi-basal state, kulandela ii-6 wks ze-HF, iimpuku ze-ΔFosB zibonakalise amanqanaba ancitshisiweyo e-orexin xa kuthelekiswa nolawulo (P <0.05).
Umzobo 6
Ukutya okunamafutha aphezulu (HF) kube neziphumo ezahlukileyo kwintetho ye-orexin kulawulo (Ctrl) kunye ne-ΔFosB ebonisa ngokugqithisileyo iimpuku.
BeHavioral Uhlalutyo
Ukuvavanya ukuguqulwa kokuvuswa kunye neemvakalelo ngenxa yokutshintsha kokutya, iigundane zavezwa kuvavanyo oluvulekileyo lwe-24 hrs emva kokurhoxiswa kokutya kwe-HF (10). Iminqamlezo yomgca epheleleyo, efunyenwe njengomlinganiselo wokuvuswa, ichaphazeleke kakhulu ngokubonakaliswa kwe-ΔFosB (F = 6.6, P <0.05) kunye nokutya (F = 4.6, P <0.05; Umzobo 7A). Iimpuku ze-ΔFosB bezisebenza ngakumbi kwindawo yenoveli kune-contrils, kwaye uvavanyo lwasemva kwe-hoc lubonise ukuba iimpuku ezikhutshiweyo kwi-HF bezisebenza kakhulu kunezo zivezwe kwi-chow (P <0.05). I-fecal boli yayibalwe njengomlinganiselo wokuziphatha okuxhalabileyo (10). Bekukho isiphumo esiphambili sokuchazwa kwe-ΔFosB (F = 10.2, P <0.01), kunye neempuku ze-ΔFosB-overexpressing ezivelisa i-fecal boli ngakumbi kwindawo yenoveli, ngakumbi kwi-house chow kunye namaqela okurhoxiswa kwe-HF (Fig. 7B). Iimpuku ze-ΔFosB ezigcinwe kukutya kwe-HF zivelise i-fecal boli encinci kunezo zigcinwe kwi-chow kunye nezo zirhoxisiwe kwiiyure ezingama-24 ngaphambi kovavanyo. Iimpuku zokulawula azizange zibonakale zichatshazelwa kukutya. Kwakungekho ziphumo zibalulekileyo zenkcazo ye-ΔFosB okanye ukutya ngexesha elichithwe embindini webala elivulekileyo (control chow = 14.5 ± 3.1 sec, control HF = 18.0 ± 3.2 sec, control W/D = 15.4 ± 1.9 sec, ΔFosB chow = 16.9 ± 2.4 isekhondi, ΔFosB HF = 13.1 ± 3.9 isekhondi, ΔFosB W/D = 19.8 ± 2.6 imizuzwana).
Umzobo 7
Iimpuku ezibonisa ngaphezulu kwe-ΔFosB zazinobuntununtunu kwiziphumo zokutya okunamafutha aphezulu (HF) ukurhoxiswa
ingxoxo
Kunyango lokukhuluphala, kukho isidingo esibalulekileyo sokuchongwa kwezinto ezichaphazela ukuchaphazeleka kokutya kunye nokuzuza ubunzima. Iindlela zomvuzo wobuchopho zidlala indima ebalulekileyo ekukhuthazeni nasekuphenduleni ukutya okunencasa kunye notshintsho lokutya (6, 10, 15, 16). Njengoko imiqondiso ye-orexigenic kunye ne-anorexigenic inokuphembelela ngokuthe ngqo ukubonakaliswa komvuzo ngesekethe ye-hypothalamus-VTA-NAc, ukucaciswa kofuzo oluphendula kukutya okunencasa okutyebileyo kumaziko omvuzo kunokubonelela ngeenjongo zonyango ezinoveli kunyango lokutyeba (17, 18). Ke ngoko, siye savavanya amanqaku e-biochemical kunye neemolekyuli zomvuzo kunye ne-energy balance signing ecaleni kwesekethe ye-hypothalamus-VTA-NAc ekuphenduleni ukutya kwe-HF kwi-ΔFosB-overexpressing iimpuku njengemodeli yobuntununtunu obuphuculweyo bokutshintsha umvuzo (13, 19, 20) , kunye nobuntununtunu bokuziphatha emva kokuyeka ukutya. Siye saqikelela ukuba i-basal dysregulation yokubonisa i-dopamine kwi-ΔFosB iimpuku ziya kwenziwa ziqheleke ziziphumo ezinomvuzo wokutya kwe-HF, okubandakanya ukudityaniswa kweempawu zokulinganisa amandla kunye nenkqubo ye-dopamine.
Ukuphonononga iimpawu ezibonisa idysregulation kwi-dopamine signing kwi-NAc, sivavanye amanqanaba e-D1 receptor kunye neziphumo ezisezantsi. Nangona bekungekho mahluko ubalulekileyo kwi-D1 receptor ebophayo, bekukho umkhwa wokuvezwa kwe-HF yokunyusa indawo ebophelelayo kwiimpuku ze-ΔFosB. Oku kunomdla njengoko ukufakwa kwe-ΔFosB ngamachiza kunye nembuyekezo yendalo ibonakala iphambili kwi-dynorphin-positive subtype ye-medium spiny neurons ebonisa ikakhulu i-D1 receptors. (9, 21). Amanqanaba ethagethi esezantsi ye-dopamine yokubonisa i-pCREB ancitshiswe kakhulu kwiimpuku ze-ΔFosB, ezixhasa ukunciphisa ukusebenza kwe-D1 receptor kulo mmandla wobuchopho (22, 23). Okubangela umdla kukuba, siye safumanisa ukuhla okubalulekileyo kumanqanaba e-CREB ewonke kwiimpuku ze-ΔFosB, sicebisa ukuba kuncitshiswe ngakumbi umthamo wokuhanjiswa komqondiso we-dopamine onokuthi ube ngowesibini kwingxelo ebangelwa kukwehla kwexesha elide kwi-pCREB (24). Intetho ye-BDNF ilawulwa yi-pCREB, iphakanyisiwe ngokusebenza kwe-D1, kwaye ingumlamli obalulekileyo we-neuroplasticity enxulumene nomvuzo kwi-NAc (25, 26). Ngokufanelekileyo, sifumanise ukuhla okubalulekileyo kwiprotheyini ye-BDNF kwi-NAc yeempuku ze-ΔFosB.
Zonke ii-neurons ze-spiny eziphakathi kwi-NAc zibonisa i-DARPP-32 (27). Iimpembelelo zayo ezininzi ezisezantsi ziyenza ibe ngumdlali obalulekileyo kwiindlela zomvuzo (28), kwaye iye yabandakanyeka kumlutha weziyobisi nakwezinye iziphazamiso ezibandakanya inkqubo ye-dopamine kubandakanya ukuphazamiseka kwe-affective kunye ne-schizophrenia. (27, 29). Sibone ukuncitshiswa okunzulu kwe-basal kwi-DARPP-32 intetho kwi-NAc yeempuku ze-ΔFosB. Inkcazo ye-DARPP-32 ilawulwa yi-BDNF, kwaye ngoko ukuchazwa okuncitshisiweyo kunokunxulumana ngokuthe ngqo nokunciphisa amanqanaba e-BDNF afunyenwe kwiigundane ze-ΔFosB (27, 29, 30). Kwanotshintsho oluphakathi kwimeko ye-phosphorylation ye-DARPP-32 inokukhokelela kutshintsho olukhulu kwisignali ye-intracellular ngaphakathi kwe-NAc (27). Izifundo zangaphambili ziye zaxela ukuba akukho tshintsho kwiprotheni ye-DARPP-32 kwiimpuku ze-ΔFosB ezilandela ukususwa kwe-12-wk kwi-doxycycline xa uvavanyo olubanzi lwe-striatal lwenziwa (31), icebisa ukuba iziphumo ze-ΔFosB kwi-DARPP-32 inokuba lixesha kunye nendawo ethile.
Siye saqikelela ukuba ukucutha okumangalisayo kwezalathisi ze-dopamine signing kwi-NAc ye-ΔFosB iimpuku kunokwenzeka ukuba zibandakanye utshintsho kwi-VTA dopamine projection neurons, nangona i-ΔFosB ayichazwanga kakhulu ngaphakathi kwezi neurons.. Ke ngoko, siye savavanya ukubonakaliswa kofuzo olunxulumene ne-dopamine kwi-VTA, kubandakanya i-tyrosine hydroxylase kunye nesithuthi se-dopamine. Amanqanaba e-tyrosine hydroxylase kunye ne-dopamine transporter anxulunyaniswa ngokufanelekileyo nemveliso ye-dopamine. Kwakukho umkhwa weempuku ze-ΔFosB ukubonisa i-tyrosine hydroxylase encitshisiweyo kunye nokuncipha okubalulekileyo kwesithuthi se-dopamine, ngokuhambelana nokuphazamiseka kokubonakaliswa kwe-dopamine kwi-NAc.. Njengoko oku kuncitshiswa kwesiseko kuhlobo olunxulumene ne-dopamine kwi-VTA ye-ΔFosB iimpuku ngokuqinisekileyo kubonakalisa impendulo etshintshileyo evela kwi-NAc ngexesha elide le-ΔFosB yokuxinezeleka kakhulu., sihlolisise ukubonakaliswa kwe-BDNF receptor, TrkB, njengendlela enokwenzeka ye-NAc impendulo kwi-VTA (32). Ngokufana ne-tyrosine hydroxylase kunye nesithuthi se-dopamine, intetho ye-TrkB ikwabonise umkhwa wokuncitshiswa ngokusisiseko kwiimpuku ze-ΔFosB ezingafikelelanga ukubaluleka xa zilungiswa kuthelekiso oluninzi. I-complex ye-BDNF-TrkB inokuthuthwa ngokutsha kwaye isebenze ngaphakathi kwe-VTA ukuchaphazela ukubonakaliswa kofuzo lwendawo kunye nokukhuthaza ukukhula kweeseli kunye nokugcinwa (33). Ngaphaya koko, ukusebenza kwe-BDNF ye-presynaptic TrkB ngaphakathi kwe-NAc kunokuvuselela ngokuthe ngqo i-dopamine neurotransmission (32), ixhasa ukuncipha okuphantsi kokubonakaliswa kwe-dopamine kwezi mpuku.
Ukusebenza kweDynorphin ye-κ-opioid receptors ilawula ukubonakaliswa kwe-dopamine kwaye yenye indlela apho i-NAc ibonelela ngengxelo kwi-VTA. (34). Sifumene ukuba i-κ-opioid receptor expression kwi-VTA ibonise umkhwa wokuncitshiswa kwiimpuku ze-ΔFosB. Njengoko i-ΔFosB overexpression ibonakaliswe ukunciphisa intetho ye-dynorphin kwi-NAc (20), iimpuku ze-ΔFosB zinokuncitshiswa okunzulu kwi-VTA yomnathaukusebenza kwe-opioid. Nangona umqondiso we-dynorphin uqhele ukwenza i-inhibitory effect kwi-dopamine neurons (35), iigundane ezibonisa ukuzilawula okuphuculweyo kweziyobisi zokusetyenziswa kakubi zibonakalisa amanqanaba ancitshisiweyo e-dynorphin kwi-NAc, esalatha indima yokunciphisa umqondiso we-dynorphin ekwandiseni ubuntununtunu bomvuzo (36) , 37). I-Dysregulation ye-dynorphin - inkqubo ye-κ-opioid idibaniswe nokufumana kunye nokuzingisa kokusetyenziswa gwenxa kweziyobisi, ukuxhasa ibhalansi ebalulekileyo yokubonakaliswa kwe-opioid kwi-normalization ye-dopamine pathways. (38).
Ngokusekwe kumthamo ovuzayo wokutya okuxineneyo kwamandla e-HF, sicinge ukuba i-dysregulation kwi-dopamine kunye ne-opioid umvuzo wokusayinwa kwi-ΔFosB iimpuku zinokubeka phambili ezimpuku ekuphuculweni kweempendulo zomvuzo kukutya okunjalo, ngoko ke kuqheleke inkqubo yomvuzo ngokusebenza kwe-hypothalamus. -VTA-NAc isiphaluka. Ngexesha leeveki ezintandathu zokuvezwa kokutya, akukho mahluko ekutyeni phakathi kwe-ΔFosB kunye neempuku zokulawula, icebisa ukuba utshintsho olufunyenwe kwiimpawu zebhayoloji kunye neemolekyuli zokubonisa umvuzo kwiimpuku ze-ΔFosB azibanga ngenxa yomahluko kwiikhalori ezisetyenzisiweyo. Njengoko bekulindelwe, umahluko we-basal ofunyenwe kwi-pCREB, i-CREB iyonke, i-BDNF, i-DARPP-32, kunye ne-κ-opioid amanqanaba e-receptor phakathi kwe-ΔFosB kunye neempuku zolawulo ziye zathotywa, mhlawumbi ngenxa yokonyuka kwemveliso ye-dopamine kwi-ΔFosB yeempuku kwi-HF (29, 39-41) .
Uvavanyo lwazo zombini i-tyrosine hydroxylase kunye nesithuthi se-dopamine kwi-VTA sibonakalise iimpendulo ezimangalisayo ezichaseneyo ze-ΔFosB kunye neempuku zolawulo ezilandela i-HF.. Ulawulo lweempuku lubonise ukuhla kwe-tyrosine hydroxylase kunye ne-dopamine transporter expression, ngelixa iimpuku ze-ΔFosB zibonisa ukubonakaliswa okwandisiweyo kuzo zombini ezi ntlobo zofuzo ezinxulumene ne-dopamine. Okubangela umdla kukuba, intetho ye-tyrosine hydroxylase iguqulwa kwi-VTA yi-cocaine engapheliyo okanye ulawulo lwe-methamphetamine (42-44), icebisa ukuba iimpuku ze-ΔFosB zinokufumana umvuzo wendalo we-HF ubaluleke ngakumbi kunolawulo lweempuku.
Ukuze uhlolisise indlela igalelo le-hypothalamic elinokubakho kwi-VTA enokuthi idlulisele izibonakaliso ezibonisa ukulingana kwamandla, ukubonakaliswa kwe-leptin receptor kunye ne-orexin receptor-1 nayo yavavanywa. Amanqanaba e-leptin ajikelezayo anyuswa yi-HF, kwaye i-leptin inokujika isebenze kwi-VTA ukuguqula ukubonakaliswa kwe-dopamine (18, 45). Inkcazo ye-VTA leptin receptor iye yehliswa ngokufanayo yi-HF kuzo zombini i-ΔFosB kunye neempuku zolawulo, ngokugcina ubunzima obufanayo kunye nokutya kokutya ngelixa ukwi-HF. Amafutha aphezulu anyuse ukubonakaliswa kwe-orexin receptor-1 kwi-VTA yazo zombini i-ΔFosB kunye neempuku zolawulo. I-Orexin yenza i-dopamine neurons isebenze kwi-VTA, ikhuthaza iplastiki ye-VTA, kwaye yonyusa amanqanaba e-dopamine kwi-NAc (46-48). Ukutya okunamafutha aphezulu kuye kwaboniswa ukwandisa ukubonakaliswa kwe-orexin kwiigundane, ngokuhambelana nokuqwalaselwa kwethu (49, 50). Ke ngoko, ukubonakaliswa okwandisiweyo kwe-orexin receptor kunye notshintsho kwisignali ye-leptin kwi-VTA inokukhuthaza umvuzo wokutya kuzo zombini i-ΔFosB kunye neempuku zokulawula, ukuxhasa ukwahlukana phakathi kweendlela ezihambisa imiqondiso yebhalansi yamandla kunye nezo zibotshelelwe ngokuthe ngqo emvuzweni.
Ukuphonononga iziphumo ezixhokonxa uxinzelelo lokurhoxiswa komvuzo, iimpuku zavavanywa kuvavanyo oluvulekileyo lwe-24 hrs emva kokususwa kwe-HF. Iimpuku ze-ΔFosB bezinobuntununtunu ngakumbi kwiziphumo ezibukhali zokurhoxiswa kokutya okukhethiweyo, zibonisa umsebenzi owongezelelweyo wokuvusa kunye nemveliso ye-fecal boli kwindawo evulekileyo yenoveli xa kuthelekiswa nawo onke amanye amaqela olawulo kunye nokutya. Iimpuku ze-ΔFosB zikwabonise indlela yokuziphatha enomdla kolu vavanyo olucebisa umvuzo kunye novakalelo loxinzelelo, kunye nokutya kwe-HF ekuqaleni kunciphisa imveliso ye-boli enxulumene ne-chow, kunye nokurhoxa kwakhona konyusa le mpendulo inxulumene nokuxhalaba. Oku kubonwe ukwanda komsebenzi ovulekileyo akuzange kuhambelane notshintsho kwintetho ye-orexin, iphakamisa ubudlelwane bokuvuswa koxinzelelo olungeyiyo nje impembelelo yotshintsho kwi-orexin-mediated signing. Ngokubanzi, ezi datha zixhasa i-hypothesis yethu yokuba iimpuku ze-ΔFosB ziya kuba nobuntununtunu ngakumbi kwiziphumo ezibukhali zokurhoxiswa kokutya okukhethiweyo ngenxa yokunyuswa kwabo komvuzo..
Ingaba ukugqithiswa kwexesha elide kwe-ΔFosB kwi-NAc kukhokelela njani kutshintsho olunjalo kwindlela yokuziphatha kunye nokubonisa umvuzo? Sicebise imodeli yokubhaqwa kwe-VTA ngengozi apho kuguqulwe impendulo evela kwi-NAc kunye ne-hypothalamus ihambisa imiqondiso malunga nemeko yomvuzo ukumisela ukulawulwa kwenkqubo ye-dopamine enokuxhasa ikhonkco phakathi komvuzo we-dysregulation kunye ne-predisposition yokutyeba (Fig. 8). Ngexesha lokuvezwa kwe-HF, amagalelo amaninzi abonisa ibhalansi yamandla kunye nembuyekezo yemeko yokuguqula kwi-VTA. Ukonyuka kokubonisa i-leptin kunye ne-orexin kunye nengxelo etshintshileyo evela kwi-NAc ukuya kwi-hypothalamus esecaleni inokuchaphazela indlela ezi zibonakaliso ze-orexigenic eziphendula ngayo kwi-HF kwiimpuku ze-ΔFosB (17, 18, 45, 47, 51-53). Ukutya okuphezulu okubangelwa kukutya okutyebileyo kwi-BDNF kunokubonelela ngengxelo yomvuzo kwi-VTA, ikhuthaze ngakumbi utshintsho kwimbonakalo yemfuza enxulumene ne-dopamine.
Umzobo 8
Ukutya okunamafutha aphezulu (HF) kulungelelanisa ukubonakaliswa komvuzo ongalawulekiyo kwiimpuku ze-ΔFosB
Ezi ziphumo zichaza iimpawu zeemolekyuli zobuntununtunu bomvuzo kwaye zibonisa ukuba ixesha elide ukungasebenzi kakuhle kwenkqubo ye-dopamine kunokubangela ukuba umntu abe likhoboka kunye nokutyeba kakhulu. Ngaphaya koko, ezi datha zibonelela ngenyathelo elibalulekileyo ekuchongeni iithagethi ezintsha zonyango ezinokubakho kunyango kunye nothintelo lokutyeba kakhulu kunye nezinye iziphazamiso ezinokugxila kwinkqubo yomvuzo. Kwixesha elizayo, kuya kubaluleka ukuphanda ukuba le nkqubo iphendula njani ekususweni kokutya kwe-HF, kunye nokuphanda naluphi na umahluko ngokwesondo kubuntununtunu bokuvuza kunye nokuvezwa kokutya okunamafutha aphezulu.
Izinto ezongezelelweyo
Supp. Iindlela
Cofa apha ukujonga. (61K, doc)
Imibulelo
Ababhali banqwenela ukubulela uCathy Steffen ngoncedo lokufuya nokudluliselwa kwezilwanyana. Lo msebenzi wawuxhaswa yinkxaso-mali evela kwiYunivesithi yasePennsylvania Diabetes Centre (DK019525) kunye nezibonelelo ezivela kwiNational Institute of Mental Health (R01 MH51399 kunye ne-P50 MH66172) kunye neZiko leSizwe lokuSebenzisa iziyobisi (R01 DA07359).
Imihlathi
Ukuchazwa kwezeMali: Bonke ababhali babhengeza ukuba abanayo imidla yezemali ye-biomedical okanye iingxabano ezinokubakho zomdla.
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