Biol Psychiatry. 2008 Dec 1; 64 (11): 941-50. Epub 2008 Jul 26.
Teegarden SL, Nestler EJ, Bale TL.
gwero
Dipatimenti ya Zamoyo Zanyama, University of Pennsylvania, Philadelphia, PA 19104-6046, USA.
Kudalirika
MALANGIZO:
Kukhudzidwa kuti munthu apereke mphotho kumaphatikizapo chifukwa chokhala ndi makhalidwe okhudzana ndi kugwiritsa ntchito mankhwala osokoneza bongo komanso kudya mopitirira muyeso. Komabe, njira zowonjezera zomwe zimapereka mphotho yachisomo sizidziwika. Tinaganiza kuti kugwidwa kwa dopamine kuwonetsetsa kungakhale chifukwa chachikulu cha mphotho yowonjezereka yowonjezera mphamvu zomwe zimapindulitsa zowonongeka zomwe zingachititse kuti chizoloŵezi chikhale chokhazikika.
ZITSANZO:
Tinagwiritsira ntchito ma genetic chitsanzo cha kuwonjezeka kwa mphoto, mphamvu ya Delta FosB-overexpressing mouse, kuyesa mphoto njira kusintha posankha chakudya chokoma kwambiri mafuta. Zisonyezero za malipiro owonetsera m'maguluwa adayang'anitsitsa zonse pamodzi ndikutsatira masabata a 6 a zakudya zovuta. Mphungu zinayesedwa pamayesero a khalidwe pambuyo pa kudya zakudya zamtengo wapatali zowonongeka kuti aone kuopsa kwa chitsanzo ichi kuchotseratu zokopa zopindulitsa.
ZOKHUDZA:
Zotsatira zathu zikuwonetseratu mphotho yopititsa patsogolo njira yowonjezera njira yomwe ili pamtunda wa nucleus accumbens-hypothalamic-ventral zone circuitry chifukwa cha kudandaula kwakukulu kwa Delta FosB mu nucleus accumbens ndi zigawo zosautsa. Maseŵera a phosphorylated cyclic adenosine monophosphate (cAMP) chipangizo chopangira mapuloteni (pCREB), vuto la ubongo lochokera ku ubongo (BDNF), ndi dopamine ndi cyclic adenosine monophosphate yomwe inkalamulidwa ndi phosphoprotein ndi maselo a 32 kDa (DARPP-32) mu nucleus accumbens inachepetsedwa mu nthata za Delta FosB, zomwe zimasonyeza kuchepa kwa dopamine. Masabata asanu ndi limodzi a zakudya zam'mafuta aatali kwambiri amathandiza kwambiri kusiyana kumeneku, akuwululira mphamvu yowonjezera yokwanira ya zakudya zabwino. Mafinya a Delta FosB anasonyezanso kuwonjezeka kwakukulu kwa ntchito zomwe zimagwira ntchito komanso machitidwe okhudzana ndi nkhaŵa Maola a 24 akutsatira kuchotsa mafuta.
MAFUNSO:
Zotsatira izi zimakhazikitsa mphamvu zowonjezera kusintha kwa mphotho yokhudzana ndi kusokonezeka kwa Delta FosB ndi chizindikiro cha dopamine chomwe chingakhale chodziwika ndi zakudya zokoma ndipo zingakhale zowonongeka kwambiri mu mitundu ina ya kunenepa kwambiri.
Introduction
Ngakhale kuti tikudziwa zambiri zokhudza machitidwe a neural omwe amachititsa kuti chilakolako chofuna kudya chikhale chokwanira, chiwerengero cha kunenepa kwambiri chikupitirira kuwonjezeka ku United States. Masiku ano mankhwala osokoneza bongo alibe mphamvu, ndipo kusinthika kwa makhalidwe kumakhala kochepa kwambiri (1). Kugwiritsa ntchito zakudya zowonongeka, zowonongeka zakhala zikugwirizana ndi kusintha kwa maganizo ndi mphotho mu ubongo, kutanthauza kuti chakudya chokoma cha zakudya zoterechi chikhoza kupitirira mphamvu zowononga mphamvu (2-4). Zakudya zokhudzana ndi mafuta zimapindulitsa monga chilengedwe, kuyambitsa mphotho za ubongo m'njira yofanana ndi mankhwala osokoneza bongo, ndipo zakhala zikugwiritsidwa ntchito pazinthu zowonongeka (5-8). Choncho, zikutheka kuti khalidwe ndi cholinga chodyera ndi kugwiritsira ntchito mankhwala osokoneza bongo zimagwirizana ndi njira zowonongeka, zomwe zingatsegule njira zatsopano zothandizira zikhalidwe zonsezo.
Powerenga mgwirizano pakati pa zakudya zokoma ndi njira zoyang'anira mphotho ndi nkhawa mu ubongo, Takhala tikudziŵa kale kuti maselo ndi zamoyo zam'thupi zimachepetsa mphotho ndi kupsinjika kwambiri chifukwa chosiya kudya zakudya zolimbitsa thupi (HF). Mofanana ndi mankhwala osokoneza bongo, kuwonetsa zakudya zopatsa chidwi m'maphunziro athu kunachititsa kuwonjezeka kwa chiwerengero cha ΔFosB mu nucleus accumbens (NAc), kapangidwe ka mpangidwe ka ubongo (9, 10). Nthanga zomwe inducibly overexpress ΔFosB zikuwonetsa kuwonjezeka kuthandizira kupempha chakudya (11), kuzipanga kukhala chida chamtengo wapatali pofufuza udindo wa mphotho kukhudzidwa ndi kuwonongeka kwa nthawi yaitali kwa mphotho mu ma maselo ndi zamoyo zomwe zimayankha chakudya chokoma.
Mu phunziro lino, tagwiritsa ntchito mbewa za ΔFosB-overexpressing kuti tiwone kusintha kwa nthawi yaitali mu zizindikiro za mphotho ku NAC-hypothalamus-ventral tegmental area (VTA) neurocircuitry potengera chakudya chokometsa cha HF. Malingana ndi kafukufuku wakale mu makoswe ogwiritsira ntchito mphotho, tinaganiza kuti kusintha kwa DFF-kusintha kwa mphotho yokhudzana ndi mphotho kumaphatikizapo kuwonongedwa kwa dopamine kufotokoza chifukwa cha NAc ndemanga kwa VTA. Kuwonjezera apo, tinaganiza kuti kuwonetsera kwa mphotho ya chilengedwe cha chakudya chamtundu wambiri wa HF chikhoza kuonetsetsa kuti dopaminergic imayendetsedwa bwino m'maguluwa, zomwe zimapangitsa kuti asamangokhalira kupanikizika ndi matendawa.. Mbali yapadera yogwiritsira ntchito zakudya zopatsa thanzi monga mankhwala opindulitsa imatithandiza kuti tiziphatikizapo zofuna zapadera kuti tipereke mpata woyendayenda mu phenotype yomwe ingakhale yowonongeka ya chiwerengero cha anthu omwe sanagwiritsidwe ntchito kwambiri chifukwa cha kunenepa kwambiri. Pofufuza izi, tinaphunzira zizindikiro za dopamine neurotransmission, kuphatikizapo pCREB, BDNF, ndi DARPP-32 mu NAc ndi tyrosine hydroxylase ndi dopamine transporter mu VTA, kutengera HF. Tinaonanso mndandanda wa mphamvu zamagetsi zomwe zimadziwika kuti zimakhudza dopamine, kuphatikizapo leptin ndi orexin receptors mu VTA ndi orexin mawu mkati of lateral hypothalamus.
Zida ndi njira
nyama
Nkhono zazing'ono zamwamuna zomwe zimapangitsa kuti inducibly overexpress ΔFosB mu dynorphin-positive neurons mu NAc ndi dorsal striatum (Kelz et al., 1999) zinayambika pamtundu wosiyanasiyana (ICR: C57Bl6 / SJL) ku University of Texas Southwestern Medical Center ndipo anayesedwa ku yunivesite ya Pennsylvania. Mphungu zonse zinasungidwa pa doxycycline (100 μg / ml m'madzi akumwa) mpaka kufika ku yunivesite ya Pennsylvania. Pofuna kupambanitsa, doxycycline inachotsedwa (n = 23) (12). Mankhwala oletsa (n = 26) anapitiriza kulandira mankhwala. Nkhumba zinapatsidwa kwa magulu odyera masabata asanu ndi atatu atachotsa doxycyline nthawi yomwe mawu amasonyezedwa kuti afike maulendo apamwamba (13). Nkhumba zinasungidwa pa 12: 12 kuwala-mdima (kuwala kwa 0700) ndi chakudya ndi madzi zilipo ad libitum. Maphunziro onse anachitidwa molingana ndi mapulogalamu ovomerezeka ovomerezedwa ndi University of Pennsylvania Institutional Animal Care ndi Komiti Yogwiritsira ntchito, ndipo njira zonse zinkachitidwa molingana ndi malangizo othandizira.
Kudya zakudya
Nkhumba zinasungidwa pa chow ya nyumba (n = 16) kapena kuikidwa pa HF (n = 16-17) kwa milungu isanu ndi umodzi. Nyumba chow (Purina Lab Diet, St. Louis, MO) ili ndi 4.00 kcal / g, yopangidwa ndi 28% mapuloteni, 12% mafuta, ndi 60% mafuta. Zakudya za HF (Zofufuzira Zofufuza, New Brunswick, NJ) zili ndi 4.73 kcal / g, zopangidwa ndi 20% mapuloteni, 45% mafuta, ndi 35% mafuta.
Katswiri wa zamoyo ndi majini
Nkhumba zinasanthuledwa patapita masabata asanu ndi limodzi ndikudya. Ubongo unachotsedwa ku gazi ndipo zonsezi zimakhala zowonongeka ndi madzi oundana kapena NAC inafalikira (pafupifupi 0.5 - 1.75 mm kuchokera ku bregma, pamtunda wa 3.5 - 5.5 mm) ndi mazira ozizira mu nayitrogeni. Zosungunuka zinasungidwa pa -80 ° C mpaka kuyesedwa.
Katswiri wa zamoyo amafufuza
Njira za kumadzulo za kumadzulo zimatchulidwa muzipangizo zina. Mankhwala omwe amagwiritsidwa ntchito anali: Cdk5, CREB, ndi BDNF (1: 500, Santa Cruz Biotechnology, Santa Cruz, CA) ndi phospho-CREB (pCREB) (Ser 133) (1: 500, Cell Signaling Technology, Danvers, MA).
Zojambula zojambula
Njira zowonetsera zojambula zithunzi zikufotokozedwa muzinthu zina zowonjezereka. Mankhwala ogwiritsidwa ntchito anali 2 nM H3 - SCH 23390 ndi 5 nM H3 - spiperone (PerkinElmer, Boston, MA).
Inchi hybridation
Kugwiritsa ntchito minofu ndi kusakanizidwa kunkachitika monga momwe tafotokozera kale (14). Pulogalamu ya DARPP-32 inaperekedwa mokoma mtima ndi P. Greengard (Yunivesite ya Rockefeller), ndi kafukufuku wa orexin ndi J. Elmquist (University of Texas Southwestern Medical Center). Zojambula zamayendedwe a DARPP-32 zinatchulidwa ku filimu masiku a 3, ndipo zithunzi zoyesedwa za orexin zinatchulidwa ku filimu masiku a 4. Kuyimitsa zithunzi za mafilimu kunkachitika monga momwe tafotokozera kale (10).
QRT-PCR
RNA inalekanitsidwa ndi VTA ndi maonekedwe a majini omwe amayesedwa pogwiritsa ntchito njira za TaqMan gene (Applied Biosystems, Foster City, CA). Njira zowonjezereka ndi kufufuza kwa chiŵerengero zingapezekedwe m'zinthu zina zowonjezereka.
Kusanthula khalidwe
Pofuna kufufuza zotsatira za mphotho yokhudzana ndi zakudya zomwe zimayambitsa kusintha kwa thupi, katsamba kameneka kanachotsedwa ku HF patatha masabata anayi akuwonekera ndikubwerera kunyumba chow (n = 9 control, n = 8 ΔFosB). Maola makumi awiri mphambu anayi atatha kutaya, mbewa zinayesedwa pamayesero otseguka mogwirizana ndi chakudya chomwe chatsopano chinatulutsidwa paradigm (10). Mwachidule, mbewayi inayikidwa pakati pa zipangizo zotseguka ndikuyang'aniridwa kwa mphindi zisanu. Mizere yonse ya mzere, fecal boli, nthawi pakati, ndi mitanda mkatikati adayesedwa.
Statistics
Deta yonse kupatula mabala akumadzulo anafufuzidwa pogwiritsa ntchito njira ziwiri za ANOVA zotsatiridwa ndi mayeso a Fisher a PLSD ndi mankhwala a doxycycline (ΔFosB expression) ndi chikhalidwe cha zakudya monga zosiyana zodziimira. Pofufuza za RT-PCR, kutsika kwa P kunagwiritsidwa ntchito kukonza kuyerekezera kambiri m'magulu amitundu yofanana (onani zowonjezera zowonjezera). Mabala akumadzulo adasanthulidwa pogwiritsa ntchito mayeso a wophunzira ndi mankhwala a doxycycline ngati chosinthika chodziyimira pawokha, poyerekeza kuchuluka kwa kuwala komweko. Zambiri zimafotokozedwa ngati zopanda tanthauzo ± SEM.
Results
Kusiyanasiyana kwa zinthu zachilengedwe
Kufotokozera njira zamagulu zomwe zimapangitsa kuti phindu likhale lopindulitsa mu mbewa za osBFosB-overexpressing, magulu a mamolekyu angapo ofunikira anafufuzidwa mu NAc. Panali njira yowonjezera ya Cdk5 mu NAC ya ΔFosB mbewa poyerekeza ndi zinyama zowononga zinyalala zomwe zimasungidwa pa doxycycline (F = 5.1, P = 0.08; mkuyu 1A). ΔFosB mbewa zimawonetsa kuchepa kwambiri kwa pCREB (F = 7.4, P <0.05; mkuyu. 1B) komanso magulu onse a CREB (F = 5.4, P = 0.05; mkuyu 1C). Kuchepetsa kwakukulu kwa BDNF kunawonekeranso mu NAc ya mbewa za ΔFosB (F = 10.6, P <0.05; mkuyu 1D).
Chithunzi 1
Mankhwala osokoneza bongo ΔFosB anawonetsa zizindikiro za tizilombo ta kuchepa kwa dopamine mu NAC
Kudya zakudya ndi kulemera kwa thupi pa zakudya za mafuta
Kenako tinayang'ana zotsatira za chakudya chopatsa thanzi cha HF posintha ma molekyulu mu mbewa za osBFosB-overexpressing. Panalibe kusiyana pakati pa mbewa za ΔFosB ndikuwongolera pazakudya m'nyumba iliyonse kapena HF. Komabe, panali kuchepa kwathunthu kwa caloric kudya kozolowereka kulemera kwa thupi atadziwitsidwa kwa HF komwe kunali kofanana ndi mbewa za ΔFosB (F = 11.2, P <0.01; mkuyu. 2A). Kumapeto kwa milungu isanu ndi umodzi yakudya, mbewa zomwe zimalandira HF zimalemera kwambiri kuposa zomwe zimadya chow (F = 17.2, P <0.001), ndi mbewa za FFB zolemera zochepa kuposa zowongolera (F = 5.6, P <0.05; Chith. 2B). Izi zidali zachindunji pakusiyana pakati pamagulu pa chow zakudya (P <0.05).
Chithunzi 2
ΔFosB overexpressing mbewa sankasonyeza kusiyana kwa kudya kudya chow kapena mafuta (HF) zakudya
Kusiyanasiyana kwa zinthu zakuthupi pa zakudya zapamwamba za mafuta
Kuti mudziwe momwe kusiyana pakati pa NAC kungasinthidwe ndi zakudya za HF, mapuloteni omwe amawerengedwa pazowonjezera anawunika nyama zomwe zinalandira masabata asanu ndi limodzi a HF. Panalibe kusiyana kwakukulu m'magulu a Cdk5 (Mkuyu. 3A). Mipata ya pCREB ndi CREB zonse sizinali zosiyana pambuyo masabata asanu ndi limodzi a HF (mkuyu 3B, C). Maseŵera a BDNF anali okwezeka kwambiri mu makoswe ΔFosB pakapita masabata asanu ndi limodzi a kutuluka kwa HF (F = 6.5, P = 0.05; Fig. 3D).
Chithunzi 3
Mafuta aatali (HF) zakudya amavomereza kusonyeza kusiyana komwe kunachitika mu NAc ya ΔFosB overexpressing mbewa
Dopamine receptor kujambula zithunzi
Tidagwiritsa ntchito receptor autoradiography kuti tiwone ngati kusintha kwa ΔFosB komwe kumapangitsa kuti dopamine isayine mu NAc ndikogwirizana ndi kusintha kwa mawu a dopamine receptor (mkuyu 4A). Zakudya zamafuta ambiri zimawoneka kuti zikuwonjezera pang'ono kuchuluka kwa D1 dopamine receptor binding (P = 0.14), ndipo kusiyana kumeneku kunali kwakukulu mu mbewa za osBFosB (mkuyu 4B). Panalinso chizolowezi chakuwonjezeka kwa malo omangiriza a D1 kutsatira HF (P = 0.06), ndipo kuyesa kwa post hoc kukuwonetsa izi kukhala zofunikira mu mbewa za osBFosB (P <0.05; mkuyu. 4C). Mosiyana ndi ma D1 receptors, palibe kusintha kwa D2 receptor binding density (control chow = 97.6 ± 6.9, control HF = 101.1 ± 8.2, osBFosB chow = 91.6 ± 1.0, ΔFosB HF = 94.8 ± 9.5) kapena malo omangirira (control chow = 47.3 ± 3.4, control HF = 53.8 ± 6.0, osBFosB chow = 51.9 ± 3.7, osBFosB HF = 49.0 ± 3.3) mu NAc adawonedwa.
Chithunzi 4
Zakudya zapamwamba kwambiri (HF) zinapangitsa kusintha kwa D1 dopamine receptor kumangirira ndi DARPP-32 mawu mu nucleus accumbens (NAc) ya ΔFosB overexpressing mbewa
Mawu a DARPP-32 mu NAC
Kusakanikirana kwa situ kunkagwiritsidwa ntchito kudziwa kuchuluka kwa DARPP-32 mu NAc (mkuyu. 4D). Zakudya zamafuta kwambiri zidakulitsa kufotokozera kwa DARPP-32 m'dera lino laubongo (F = 5.1, P <0.05), ndipo panali kulumikizana kwakukulu pakati pa zakudya ndi kufotokozera kwa osBFosB (F = 8.9, P <0.05), pomwe mbewa za ΔFosB zikuwonetsa zazikulu kusintha komwe kumadza chifukwa cha zakudya (mkuyu 4E). Kusiyana kwakukulu pamalingaliro a DARPP-32 pakati pa kuwongolera ndi mbewa za osBFosB zidawululidwa poyesa posachedwa (P <0.01), komanso kuwonjezeka kwakukulu kwa kufotokozera kwa DARPP-32 mu mbewa za ΔFosB pa HF (P <0.01).
Gene mawu mu VTA
QRT-PCR idagwiritsidwa ntchito poyesa kusintha kwa momwe majini amathandizira mu VTA, ikuloza majini angapo ofunikira omwe adakhudzidwa kale pakukhazikitsa mphotho. Zitsanzo zonse zidasinthidwa kukhala β-actin. Kuonetsetsa kuti β-actin sanasinthidwe ndi chithandizo chamankhwala, kuyesa kwina kunayendetsedwa kuti kuyerekezera β-actin kuwongolera kwachiwiri, GAPDH. Panalibe kusiyana kwakukulu pamawu a β-actin (ΔCT values, β-actin - GAPDH: control chow = 2.29 ± 0.21, control HF = 2.01 ± 0.04, osBFosB chow = 2.32 ± 0.49, ΔFosB HF = 2.37 ± 0.10).
Njira yolumikizirana pakati pa kufotokozera kwa DFBB ndi chithandizo chazakudya zidawonetsedwa posonyeza tyrosine hydroxylase (F = 3.6, P <0.06; mkuyu. 5A). Masabata asanu ndi limodzi owonekera ku HF adawoneka kuti achepetsa tyrosine hydroxylase expression mu mbewa zowongolera ndikuwonjezera kufotokozera kwa mbewa za ΔFosB. Kuyanjana kwakukulu pakati pa kufotokozera kwa osBFosB ndi kuwonetsa zakudya kunawonetsedwa pofotokozera dopamine transporter (F = 6.7, P <0.03; mkuyu. 5B). Mofananamo ndi tyrosine hydroxylase, kufalikira kwa HF kunachepetsa kufotokozera kwa dopamine poyendetsa mbewa ndikuwonjezera kufotokozera kwa mbewa za ΔFosB (P <0.05). Kusiyanitsa koyambira pakufotokozera kwa dopamine Transporter pakati pa mbewa ndi ΔFosB mbewa sizinafikire tanthauzo (P = 0.16), koma pambuyo pa ma 6 wks a HF, ΔFosB mbewa zidawonetsa kuchuluka kwakunyamula kwa dopamine poyerekeza ndi zowongolera (P <0.05).
Chithunzi 5
Zakudya zapamwamba za mafuta (HF) ndipo kufotokoza kwaFFB kunachititsa kusintha kusintha kwa maulendo angapo a VTA mu VTA
Panali zochitika zomwe zikuwonetsa kuwonjezeka kwa kufotokozera kwa ΔFosB kuti muchepetse kuchuluka kwa TrkB mu VTA (F = 5.7, P <0.04; mkuyu. 5C). Ngakhale panalibe zovuta zazikulu pamawu a κ-opioid receptor, panali njira yochepetsera kufotokozera mu mbewa za osBFosB (P = 0.08; mkuyu 5D). Kufotokozera kwa leptin receptor kunatsimikiziranso mu VTA. Zomwe zimachitika pakupezeka kwa zakudya zimapezeka (F = 6.1, P <0.03), pomwe HF imachepetsa kwambiri milingo ya leptin receptor mu VTA mu ΔFosB ndi mbewa zowongolera (mkuyu 5E). Kufotokozera kwa orexin receptor 1 mu VTA kunayesedwanso. Panali zotsatira zabwino zakadyedwe posonyeza orexin receptor (F = 9.0, P <0.02), mbewa zowonekera kwa HF zikufotokoza milingo yayikulu mu VTA (Mkuyu 5F). Panalinso chizolowezi cha mbewa za ΔFosB kuti ziwonetse kuchuluka kwa orexin receptor 1 mdera lino laubongo (P <0.05).
Mawu a Orexin mu lateral hypothalamus
Tidayesa kuchuluka kwa orexin mu lateral hypothalamus, komwe kunachokera orexinergic kusungidwa kwa VTA, mwa situ hybridization (mkuyu. 6A). Panali kulumikizana kwakukulu pakati pa kufotokozera kwa DFBB komanso kuwonetsa zakudya pa orexin expression (F = 9.1, P <0.01), pomwe HF ikukulitsa kuchuluka kwa orexin mu mbewa zowongolera (P <0.05) ndikuchepa kwamawu mu ΔFosB mbewa (mkuyu. 6B). Ngakhale panalibe kusiyana kwakukulu pamawu a orexin m'boma loyambira, kutsatira ma 6 wks a HF, ΔFosB mbewa zimawonetsa kuchepa kwa orexin poyerekeza ndi zowongolera (P <0.05).
Chithunzi 6
Mafuta aatali (HF) zakudya anali osiyana kwambiri ndi orexin kufotokoza (Control) (Ctrl) ndi ΔFosB overexpressing mbewa
BeKusanthula Zosintha
Kuti muwone kusintha kwakudzuka ndi kutengeka chifukwa cha kusintha kwa zakudya, mbewa zinawonekera pamayeso otseguka 24 hrs atachotsa chakudya cha HF (10). Mitanda yonse, yomwe idatengedwa ngati njira yodzutsira, idakhudzidwa kwambiri ndi kufotokozera kwa ΔFosB (F = 6.6, P <0.05) ndi zakudya (F = 4.6, P <0.05; Chith. 7A). ΔFosB mbewa zinali zotsogola kwambiri kuposa ma contrils, ndipo kuyesa kwa hoc kunawonetsa kuti mbewa zomwe zidachotsedwa ku HF zinali zotsogola kwambiri kuposa zomwe zimadziwika ndi chow (P <0.05). Fecal boli amawerengedwa ngati mkhalidwe wamavuto (10). Panali zotsatira zazikulu za kufotokozera kwa ΔFosB (F = 10.2, P <0.01), yokhala ndi mbewa za osBFosB-overexpressing zomwe zimapanga boli wambiri m'malo amtunduwu, makamaka munyumba zow chow ndi HF zochotsa magulu (mkuyu. 7B). ΔFosB mbewa zomwe zimasungidwa pa chakudya cha HF zimatulutsa mafuta ochepa kuposa omwe amasungidwa pa chow ndi omwe adachotsedwa maola 24 asanakwane mayeso. Kuwongolera mbewa sikuwoneka kuti kwakhudzidwa ndi zakudya. Panalibe zovuta zakutulutsa kwa ΔFosB kapena zakudya zomwe zidagwiritsidwa ntchito nthawi yakutchire (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 mphindikati, ΔFosB HF = 13.1 ± 3.9 mphindikati, osBFosB W / D = 19.8 ± 2.6 mphindikati).
Chithunzi 7
Mankhwala opitirira-kufotokozera ΔFosB anali omvera kwambiri zotsatira za kuchotsa mafuta aatali (HF) kuchotsa
Kukambirana
Mukamadwala kwambiri, pali chofunikira chodziwitsa zinthu zomwe zimakhudza kukhudzidwa ndi kudya kwambiri ndi kulemera. Kupeza mphotho za ubongo kumathandiza kwambiri pakukhudzidwa ndi zakudya zowonjezera komanso kusintha kwa zakudya (6, 10, 15, 16). Monga orexigenic ndi anorexigic zizindikiro zingakhudze mwachindunji mphoto kudzera mu hypothalamus-VTA-NAc woyang'anira, kufotokoza kwa majeremusi okhudzana ndi zakudya zowonjezera mphamvu zopatsa mphamvu mkati mwa malo opatsa mphotho zingapereke zowonjezera zovuta zothandizira pakamwa kwambiri (17, 18). Choncho, tinayang'ana zizindikiro za biochemical ndi maselo a mphotho ndi mphamvu zomwe zimagwiritsidwa ntchito pa hypothalamus-VTA-NAc woyang'anira dera chifukwa cha chakudya cha HF mu ΔFosB-overexpressing mbewa ngati chitsanzo cha mphamvu yowonjezera kusintha kwa mphotho (13, 19, 20) , ndi khalidwe lokhazika mtima pansi pakudya chakudya chotsatira. Tinaganiza kuti kusokonezeka kwa dopamine kumalonda a ΔFosB kungakhale kovomerezeka ndi zotsatira zopindulitsa za zakudya za HF, zomwe zimaphatikizapo kayendetsedwe ka mphamvu zamagetsi ndi dopamine system.
Pofufuza zizindikiro zomwe zimasonyeza kuti vutoli likuwoneka mu dothi la NAC, tinayang'ana maulendo a D1 ndi otsika pansi. Ngakhale kuti panalibe kusiyana kwakukulu kwa D1 receptor kumanga, panali njira yowonjezera HF kuonjezera dera lokhazikika pamagulu a ΔFosB. Izi zimakhala zosangalatsa monga kudulidwa kwa ΔFosB ndi madalitso ndi masoka achilengedwe akuwonekera makamaka mu dynorphin-positive subtype ya spin neurons yeniyeni yomwe imayankhula kwambiri D1 receptors (9, 21). Maseŵera a dopamine omwe amatsikira kumtunda pCREB adachepetsedwa kwambiri mu makoswe ΔFosB, othandizira kuchepetsedwa kwa D1 kulandirira m'dera lino la ubongo (22, 23). Chochititsa chidwi, tinapezanso kuchepa kwakukulu kwa chiwerengero cha CREB mu mbewa za ΔFosB, zomwe zikusonyeza kuperewera kwina kwa mphamvu ya kusintha kwa chizindikiro cha dopamine chomwe chingakhale chachiwiri ku mayankho chifukwa cha kuchepa kwa nthawi yaitali pCREB (24). Kufotokozera BDNF kumayendetsedwa ndi pCREB, kukwezedwa ndi D1 activation, ndipo ndi mkhalapakati wothandizira okhudzana ndi mpweya mu NAC (25, 26). Choncho, tinazindikira kuchepa kwakukulu kwa mapuloteni a BDNF mu NAC ya ΔFosB mbewa.
Mitundu yonse yowonjezera yotchedwa neurons mu NAC ikufotokoza DARPP-32 (27). Zowonjezera zowonjezera zomwe zimapangitsa kuti zikhale zofunikira kwambiri pamsewu wopatsa malipiro (28), ndipo zakhala zikukhudzidwa ndi mankhwala osokoneza bongo komanso mavuto ena okhudza dopamine dongosolo kuphatikizapo matenda opatsirana ndi schizophrenia (27, 29). Tinawona kuchepetsa kwakukulu kwa mawu a DARPP-32 mu NAC ya mbewa za ΔFosB. Mawu a DARPP-32 amalembedwa ndi BDNF, choncho malingaliro ochepa angagwirizane kwambiri ndi kuchepetsa ma level BDNF amadziwika mu ΔFosB mbewa (27, 29, 30). Ngakhale kusintha kwakukulu mu dera la phosphorylation la DARPP-32 kungayambitse kusintha kwakukulu mu chizindikiro cha intracellular mkati mwa NAc (27). Kafukufuku wam'mbuyo asananene kuti palibe kusintha kwa mapuloteni a DARPP-32 mu ΔFosB mbewa pambuyo pa kuchotsedwa kwa 12-wk kuchoka ku doxycycline pamene kufufuza kwakukulu kwambiri kunayambitsidwa (31), kutanthauza kuti zotsatira za ΔFosB pa DARPP-32 zingakhale nthawi ndi dera.
Tinaganiza kuti kuperewera kwakukulu kwa zizindikiro za dopamine ku chizindikiro cha NAC cha ΔFosB mbewa mwina zimakhudza kusintha kwa VTA dopamine kulingalira neurons, ngakhale kuti ΔFosB sichidziwitsidwa kwambiri m'matendawa. Choncho, tinayang'ana za majeremusi okhudzana ndi dopamine mu VTA, kuphatikizapo tyrosine hydroxylase ndi dopamine transporter. Miyeso ya tyrosine hydroxylase ndi dopamine transporter imagwirizanitsidwa bwino ndi dopamine zotuluka. Panali chizoloŵezi cha ntchentche za FFB kuti ziwonetsedwe kuchepetsa tyrosine hydroxylase ndi kuchepetsa kwakukulu mu dopamine transporter, malingana ndi kuchepetsa kwa chizindikiro cha dopamine ku NAc. Pamene kuchepetsa kwapadera kwa majeremusi okhudzana ndi dopamine mu VTA a ΔFosB mbewa mwachionekere akuwonetsa ndemanga yosinthidwa kuchokera ku NAc pa nthawi yaitali ΔFosB yowonongeka, tinayang'ana ndemanga ya BDNF receptor, TrkB, ngati njira yothetsera NAC yankho kwa VTA (32). Mofananamo ndi tyrosine hydroxylase ndi dopamine transporter, kutanthauzira kwa TrkB kunasonyezanso kuti chizoloŵezi chocheperachepera mu mbewa za ΔFosB zomwe sizinafike pofunika pamene zikonzedwera kwa kufanizirana kochuluka. BDNF-TrkB yovuta ikhoza kutengedwera mobwerezabwereza ndikugwira ntchito mkati mwa VTA kuti iwononge mauthenga am'deralo ndikulimbikitsa kulimbitsa maselo ndi kukonza (33). Kuwonjezera apo, BDNF kuyambitsa mphamvu ya TrkB mkati mwa NAC ikhoza kutulutsa dopamine neurotransmission (32), kumathandizira kuchepa kwa dopamine kufotokoza mu mbewa izi.
Dynorphin activation of κ-opioid receptors imayambitsa dopamine chizindikiro ndipo ndi njira ina yomwe NAC ikupereka ndemanga kwa VTA (34). Tapeza kuti κ-opioid receptor expression mu VTA yawonetsa kuti chizoloŵezi chichepetsere pa ΔFosB mbewa. Monga momwe kufotokoza kwa DFFB kunasonyezedwa kuti kuchepetsa dynorphin mawu mu NAc (20), mbewa za ΔFosB zikhoza kukhala zocheperachepera kwambiri mu net VTA κ-kuyambitsa opioid. Ngakhale kuwonetsa kwa dynorphin nthawi zambiri kumalepheretsa ma dopamine neurons (35), makoswe omwe amawonetsa kudziyendetsa pawokha kwa mankhwala osokoneza bongo amawonetsa kuchepa kwa dynorphin mu NAc, kuloza gawo loti lachepetse kuwonetsedwa kwa dynorphin kukulitsa chidwi cha mphotho (36) , 37). Kuwonongeka kwa dynorphin-κ-opioid system kulumikizidwa ndikupeza ndikupitilizabe kugwiritsa ntchito mankhwala osokoneza bongo, kuthandizira kuwonetsa kwakukulu kwa ma opioid pakukhazikitsa njira za dopamine (38).
Malingana ndi mphamvu yowonjezera ya chakudya chamadzimadzi cha HF, tinaganiza kuti kupweteka kwa dopamine ndi opioid mphotho kuzindikiritsa kuti ΔFosB mbewa zimayambitsa makoswewa kuti apindulitse mphotho zowonjezereka pa zakudya zotere, motero kuonetsetsa kuti mphothoyi ikuyendetsedwa ndi hypothalamus -VTA-NAc woyang'anira. Pa sabata zisanu ndi chimodzi sabata, palibe kusiyana pakati pa chakudya cha FFB ndi makoswe, kutanthawuza kuti kusintha komwe kumapezeka m'magulu a zachilengedwe ndi maselo a mphotho kuwonetsera mu ΔFosB mbewa sizinali chifukwa cha kusiyana kwa ma calories omwe amadya. Monga momwe zinalili, kusiyana kwapadera kunkapezeka pCREB, chiwerengero chonse cha CREB, BDNF, DARPP-32, ndi maselo a recepor κ-opioid pakati pa ΔFosB ndi makoswe amatha kuchepetsedwa, mwinamwake chifukwa cha kuchulukitsidwa kwa dopamine mu ΔFosB mbewa pa HF (29, 39-41) .
Kupenda kwa tyrosine hydroxylase ndi dopamine wonyamulira mu VTA kunawonekera zodabwitsa zotsutsana ndi ΔFosB ndi makoswe omwe akutsatira HF. Manyowa amasonyeza kuchepa kwa tyrosine hydroxylase ndi dopamine transporter kufotokoza, pamene ΔFosB mbewa zinasonyeza kuchuluka kwa kufotokoza kwa mitundu yonseyi ya jini zokhudzana ndi dopamine. Chochititsa chidwi ndi chakuti tyrosine hydroxylase mawu amasinthidwa mu VTA ndi matenda a cocaine kapena methamphetamine (42-44), kutanthauza kuti ΔFosB mbewa zingapeze mphotho yachilengedwe ya HF yochuluka kusiyana ndi makoswe olamulira.
Pofuna kufufuza momwe zizindikiro zogwirira ntchito za VTA zikhoza kukhalira zikhoza kutumiza zizindikiro zomwe zimasonyeza mphamvu zowonongeka, kufotokoza kwa leptin receptor ndi orexin receptor-1 nawonso anayesedwa. Kuthamanga maulendo a leptin akuwonjezeka ndi HF, ndipo leptin ikhoza kuchitapo kanthu pa VTA kuti isinthe chizindikiro cha dopamine (18, 45). VTA leptin receptor expression inanso inachepetsedwa ndi HF onse ΔFosB ndi makoswe olamulira, mofanana ndi phindu lofanana ndi zakudya zomwe zimadya pa HF. Mafuta akuluakulu amathandizanso kufotokozera orexin receptor-1 mu VTA ya bothFosB ndi makoswe. Orexin imayambitsa dopamine neurons mu VTA, imalimbikitsa VTA pulasitiki, ndipo imapanga ma dopamine mu NAC (46-48). Zakudya zamtengo wapatali zasonyezedwa kuti zowonjezera orexin kufotokoza mu mbewa, mogwirizana ndi zomwe tawona (49, 50). Motero, kuwonjezeka kwa kufotokoza kwa orexin receptor komanso kusintha kwa leptin kuzindikiritsa mu VTA kungalimbikitse zakudya m'zipatso zonse ΔFosB ndi kulamulira makoswe, zomwe zimathandiza kupatukana pakati pa njira zowonetsera mphamvu zowonjezera mphamvu ndi omwe amangiriridwa mwachindunji kuti apereke mphotho.
Pofufuza zotsatira zopweteka za mphotho yopereka mphoto, mbewa zinayesedwa pamayeso oyambirira a 24 atatha kuchotsedwa kwa HF. Nkhono zaFosB zinali zoganizira kwambiri za zotsatira zovuta za kusuta zakudya, kusonyeza ntchito yowonongeka kwambiri komanso kupanga ma boli m'mabuku oonekera poyerekeza ndi magulu ena olamulira ndi zakudya. Maseŵera a FosB anasonyezanso njira yosangalatsa ya khalidwe mchiyeso ichi chowonetsa mphotho ndi kupsinjika maganizo, ndi chakudya cha HF poyamba kuchepetsa kutentha kwa boli ndi chow, ndipo kuchotsedwa kachiwiri kukuwonjezeranso yankho lokhudza nkhawa. Izi zimawonetsa kuti kuwonjezeka kwa ntchito yopita kumalo osatseguka sikugwirizana ndi kusintha kwa mawu orexin, kutanthauza kuti kugwirizana ndi kukakamizidwa kochititsa chidwi komwe sikungokhala chabe kusintha kwa chizindikiro cha orexin-mediated. Zonsezi, detayi imachirikiza lingaliro lathu lakuti mbewa zaFFB zikhoza kukhala zovuta kwambiri ku zotsatira zovuta za kuwonongeka kwa zakudya chifukwa cha mphotho yawo yowonjezera mphamvu.
Kodi kuwonjezereka kwa nthawi yaitali kwa ΔFosB mu NAC kumayambitsa kusintha kotani mu khalidwe ndi mphotho? Tinapanga chitsanzo cha VTA coincident detection momwe kusintha kwa NAc ndi hypothalamus kukuthandizira zizindikiro zokhudzana ndi mphotho kuti zidziwitse dongosolo la dopamine lomwe lingathandize mgwirizano pakati pa mphotho ya njira yochepetseratu ndi kuikapo kunenepa kwambiri (mkuyu 8). Panthawi ya HF, zinthu zambiri zomwe zikuwonetsa mphamvu zowonjezera mphamvu komanso mphoto zimasintha pa VTA. Kuwonjezeka kwa leptin ndi orexin kusonyeza komanso kusintha maganizo kuchokera kwa NAc mpaka lateral hypothalamus kungakhudze momwe izi orexigenic zizindikiro ku HF mu mbewa ΔFosB (17, 18, 45, 47, 51-53). Zakudya zamakono zowonjezera zakudya zamtundu wa BDNF zingapereke mphotho kwa VTA, kupititsa patsogolo kusintha kwa ma genetic gene.
Chithunzi 8
Mafuta aatali (HF) zakudya amaonetsetsa kuti mphotho yowonongeka mu ΔFosB mbewa
Zotsatira izi zimapangitsa kuti zizindikiro zapadera zokhudzana ndi mphotho ziwonongeke komanso zimasonyeza kuti kuwonongeka kwa nthawi yaitali kwa dopamine kungapangitse munthu kukhala woledzera ndi kunenepa kwambiri. Komanso, detayi imapanga sitepe yofunikira poyang'ana zowonjezera zatsopano zothandizira pa chithandizo ndi kupewa kutaya kunenepa ndi mavuto ena omwe angapangidwe pa mphoto. M'tsogolo, zidzakhala zofunikira kufufulira momwe dongosolo lino likuyankhira pa kuchotsedwa kwa chakudya cha HF, komanso kufufuza kusiyana kwa kugonana kulimbikitsanso kupereka mphotho komanso zakudya zamakono.
Zowonjezera Zowonjezera
Thirani. Njira
Dinani apa kuti muwone (61K, doc)
Kuvomereza
Olembawo akufuna kuthokoza Cathy Steffen kuti athandizidwe ndi kuswana ndi kusamutsa nyama. Ntchitoyi inathandizidwa ndi ndalama kuchokera ku University of Pennsylvania ya Diabetes Center (DK019525) ndi ndalama kuchokera ku National Institute of Mental Health (R01 MH51399 ndi P50 MH66172) ndi National Institute on Drug Abuse (R01 DA07359).
Mawu a M'munsi
Zolinga zachuma: Olemba onse amalengeza kuti alibe zofuna zachuma kapena zovuta zotsutsana.
Zothandizira
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