Njira zamagulu ndi ma maselo okhuta kwambiri ndi kuledzera (2011)

Kudalirika

Chakudya cha hedonic chingayambitse khalidwe lodyetsa ngakhale pamene zowonjezera zowonjezera zowonjezera mphamvu zimagwira ntchito, zomwe zimapangitsa kuti pakhale kulemera komanso kunenepa kwambiri. Mofananamo, zotsatira za hedonic za mankhwala osokoneza bongo zingachititse kuti azidya mowa mwauchidakwa, zomwe zimachititsa kuti azisokonezeka. Malo omwe amagwiritsa ntchito ubongo amachititsa kuti zakudya zamakono komanso mankhwala osokoneza bongo azisokoneza, ndipo mauthenga am'mbuyo amasonyeza kuti kumwa mowa mopitirira muyeso kapena mankhwala osokoneza bongo kumayambitsa mayankho omwe amachititsa kuti azitha kulandira mphoto. Pano, timakumbukira umboni womwe umasonyeza kuti kunenepa kwambiri ndi mankhwala osokoneza bongo kungagwirizane ndi njira zamagulu, maselo ndi njira zowonongeka.

Chimodzi mwazinthu zofunikira kwambiri za ubongo munthawi yamagetsi yopanda mphamvu ndi kubwezeretsanso zinthu kuti mugule ndi kuwononga chakudya, potero kubwezeretsanso m'masitolo amagetsi omwe athera mphamvu ndi kuwononga ndalama. Zambiri zimadziwika za ma hypothalamic ndi hindbrain circuits omwe amawongolera mphamvu homeostasis ndi mahomoni owongolera a njala ndi kukomoka, monga leptin, ghrelin (yemwe amadziwikanso ngati chilangizo-cholamula mahomoni) ndi insulin, pamagawo amenewa (Chith. 1). Kuphatikiza pa makina amomwe timagwiritsa ntchito mphamvu, makina opindulira amakhalanso ndi udindo waukulu pakukhazikitsa njira zodyetsera. Makamaka, machitidwe aubwino muubongo amalamulira kuphunzira za kuchuluka kwa chakudya, kusintha chidwi ndi kuyesetsa kupeza chakudya komanso kuwongolera phindu la chakudya kapena zolimbikitsa zachilengedwe zomwe zimaneneratu kupezeka kwa mphotho ya chakudya. Ma Hormonal owongolera mphamvu homeostasis amathanso kuchitapo kanthu poyang'anira masupulo aubongo, makamaka pa dongosoloaccumbens dopamine¹, kuchulukitsa kapena kuchepetsa kufunikira kwa chakudya malinga ndi mphamvu zamagetsi. Komabe, kusunthidwa kwamagetsi kapena mankhwala aubongo komwe kumayendetsa mphotho ya chakudya kumatha kubweretsa chakudya chochuluka kwambiri ngakhale mu nyama zomwe zangodyetsedwa kumene kumene zizindikiritso zapakhomo zakhala zikupangika.^{2, 3}. Izi zikusonyeza kuti kupeza chakudya chosangalatsa ndichinthu champhamvu chomwe chitha kupitiliza zizindikiritso zakunyumba, ndipo mogwirizana ndi izi, chakudya chomwe chimakhala ndi chakudya chokoma nthawi zambiri chimadyedwa pafupipafupi komanso kukula kwake kokwanira kusiyana ndi zomwe zimakhala zosakhazikika bwino chakudya⁴. Monga chakudya chimodzi chokha chomwe chikukulitsidwa kungayambitse kuchuluka kwa chakudya masiku angapo⁵, kudya kwambiri kwa hedonic kungakhale kothandiza kwambiri pakukula kwa thupi komanso kukulitsa kunenepa.

Monga momwe magawo a ubongo amagwirira ntchito amawongolera zakudya zopatsa mphamvu komanso mankhwala osokoneza bongo, komanso popeza pali zozizwitsa zofanana pakati pa kudya kwambiri kunenepa kwambiri komanso kugwiritsa ntchito mankhwala osokoneza bongo mopitirira muyeso, mwina sizodabwitsa kuti zovuta izi zafotokozedwa kuti zigawane zomwe zimafala masiku ano mitsempha ya neurobiological¹. Komabe, ndikofunikira kunena kuti pali kutsutsana kwakukulu pamalingaliro akuti chakudya chitha kukhala "choledzeretsa" chimodzimodzi ndi mankhwala osokoneza bongo^{6, 7}. Apa, timapereka chithunzithunzi cha maubongo omwe amasintha zomwe zimagwirizana ndi ma hedonic komanso phindu la chakudya chokoma, ndikukambirana momwe mankhwala osokoneza bongo 'angabera' machitidwewa. Kuphatikiza apo, tikunena za njira zamagulu ndi ma cell m'mayendedwe awa omwe angapangitse kunenepa kwambiri komanso kugwiritsa ntchito mankhwala osokoneza bongo.

Bongo machitidwe encoding chakudya chakudya

Zotsatira zamtundu zimagwira gawo lalikulu pakuwongolera chiopsezo cha kunenepa kwambiri, ndipo milingo yodziyimira yasonyezedwa kuti ndi mkhalidwe wofalikira kwambiri (Bokosi 1). Nthawi zambiri, majini omwe amalumikizidwa ndi kunenepa kwambiri kwa thupi amathandizira kunenepa kwambiri pakuwonjezera kukondweretsa kwa chakudya chosavuta. Ndikukhazikika kuti chakudya chamafuta chomwe chimakhala ndi mafuta komanso shuga wokwanira chimayambitsa hyperphagia. Chakudya chamafuta ambiri chopatsa thanzi chimakulitsa kukula kwake kwakukulu, kusakhazikika kwa chakudya chambiri komanso kudya kwambiri zopatsa mphamvu kuposa zakudya zomwe zimakhala ndi chakudya chamafuta kwambiri koma zamafuta ochepa⁸. Chifukwa chake, kuchuluka kwa chakudya komwe kumadziwika kumathandizira kuti azikhala ndi chidwi kwambiri ndikukula thupi. Makhalidwe azakudya, makamaka kakomedwe kake, kununkhira kwake, kapangidwe kake ndi mawonekedwe ake, ndizofunikira kwambiri pofufuza momwe zimakhalira. Zambiri zamalingaliro zomwe zimatengedwa chifukwa cha kumeza kwa chakudya chopatsa mphamvu zimaphatikizidwa mu malo oyambira komanso apamwambaChith. 2). Chemosensory neurons pamlomo wamkati yomwe imakhudzidwa ndikuwonongeka kwakumapeto kwa nyukiliya ya trusus solitarius (NTS) mu ubongo⁹. NTS inanso imathandizira ku gustatory thalamus (ventroposteromedial (VPM) thalamic nucleus)¹⁰, yomwe imalowa mkati mwa gustatory cortex (PGC) mu insula ndi operculum¹⁰. Monga momwe dzinalo likunenera, PGC imatanganidwa kwambiri pakukonza zokhudzana ndi kukoma kwa chakudya komanso kuchuluka kwake¹¹. Omwe amathandizira kuchokera ku PGC polojekiti yomwe imayang'anira dera la caudolateral orbitofrontal cortex (OFC) amatchedwa yachiwiri gustatory cortex (SGC). Kuphatikiza pa kulawa, mitundu inanso yamalingaliro am'malingaliro okhudzana ndi kuthekera kwa chakudya (mwachitsanzo, kununkhira, kupenya ndi mawonekedwe) zimasinthananso pa PGC ndi SGC¹⁰. Ntchito ya PGC ndi SGC ku striatum, makamaka ma nucleus accumbens (NAc), potero kusinthira zochitika za mitsempha muzakudya zokhudzana ndi striatohypothalamic ndi striatopallidal district¹. Mabwalo amadyetsedwe abwinowa nawonso amatengeka ndi zolowetsa ma mesolimbic ndi nigrostriatal dopaminergic¹. Ndikokhazikika kuti striatum amawongolera kudya zakudya zabwino komanso kugwiritsa ntchito mankhwala osokoneza bongo^{1, 12}. Monga tafotokozera mwatsatanetsatane pansipa, umboni waposachedwa ukusonyeza kuti mbali zina za ubongo zomwe zimayendetsedwa pakukonza chakudya - makamaka NTS, insula ndi OFC - zimathandizanso pakumwa mankhwala osokoneza bongo.

Nucleus treus solitarius mu chakudya ndi mphotho ya mankhwala

Neurons zomwe zimapanga catecholamine neurotransmitters ndi gulu lalikulu mkati mwa NTS yomwe imakhudzidwa ndikukhazikitsa njira zodyetsera (Chith. 3). NTS imalandira chidziwitso kuchokera ku chemosensory neurons mumkamwa wamkamwa womwe umakonza kukoma kwa chakudya, ndikukwera kolosera zomwe zimafalitsa izi ku malo aubongo a thalamic. Kuphatikiza apo, NTS catecholamine neurons imayendetsedwa ndi othandizira am'mimba kuti amalembetse kudya kapena kulowetsa m'mimba, komanso pozungulira zizindikiritso za satiety monga cholecystokinin (CCK)¹³. NTS imapereka chidziwitso chowonekera ichi ku malo operekera homeostatic mu hypothalamus. Chochititsa chidwi, makoswe kapena mbewa zomwe zimasungidwa pakudya chamafuta kwambiri kapena mbewa zomwe zimakonda kukhala ndi kunenepa kwambiri zimawonetsa kuchepa kwa ma NTS catecholamine neurons kutsira kwa lipid^{14, 15}. Izi zikusonyeza kuti hyperphagia yomwe imakhudzana ndi kumwa kwamafuta ambiri okhathamira imatha kukhala yokhudzana ndi mayankho osinthika mu NTS, zomwe zimapangitsa kutsika kwa chidwi cha ma mahomoni am'matumbo omwe amawonetsa kukwiya.

Kuphatikiza pa malo operekera zakudya za thalamic ndi hypothalamic, NTS catecholaminergic neurons - makamaka iwo a mdera la A2 la NTS omwe amapanga noradrenaline - amathandizanso kwambiri kumadera aubongo omwe ali ndi vuto la kukonzekera ndi kulandira mphotho, kuphatikiza chigawo cha chipolopolo cha NAc, chapakati nyukiliya ya amygdala (CeA) ndi bedi pakati pa stria terminalis (BNST)¹⁶ (Chith. 3). Magawo omwewa a ubongo, palimodzi mu gawo limodzi lalikulu la magwiridwe antchito, mwapangidwe ndi makina okhudzana ndi ubongo amatchedwa amygdala, ali ndi gawo lalikulu pakukhazikitsa mphamvu yolimbikitsira mphamvu ya mankhwala osokoneza bongo komanso kukulitsa kudalira kwa mankhwala pakukhudzana ndi mankhwala¹⁷ (onani Bokosi 2 pakukambirana za gawo la kupsinjika mu kunenepa kwambiri komanso kuzolowera. Chodabwitsa, chikonga chomwe chimagwiritsidwa ntchito polankhula ndi makoswe chimayambitsa ma neuroni a gustatory mu NTS ndipo munthawi yomweyo amachepetsa kuyankha kwawo pamankhwala osiyanasiyana¹⁸. Izi zikusonyeza kuti zochita za chikonga komanso mankhwala ena ogwirira ntchito zamagetsi zamagetsi zimakumana ndi ma neurons a NTS^{19, 20}, kapena machitidwe achindunji a mankhwalawa omwe ali mu NTS, atha kuyambitsa mwayi pazakuchitidwa nkhanza. Malinga ndi kuthekera uku, zopindulitsa za morphine zimadzaza kwathunthu mu mbewa za dopamine β-hydroxylase (DBH), zomwe sizingapangike noradrenaline²¹. Komabe, kuyambiranso kwa kachilombo ka DBH mu NTS ya mbewa zogogoda kunakhazikitsanso chidwi chawo chotsatira mphotho ya morphine²¹. Kuphatikiza pa mphotho ya mankhwala, NTS imathandizanso pakukula kwa kudalira mankhwala osokoneza bongo komanso zotsatira zoyipa zobwera chifukwa chosiya mankhwala. Ntchito za NTS zimachulukitsidwa m'makola omwe amachokera ku opiate kuchoka, zomwe zimapangitsa kuchuluka kwambiri kwa kufalikira kwa noradrenaline mu amygdala²², zomwe zimapangitsa kuti anthu asamakhulupirire kusiya²². Kulimbikira kugwira ntchito kwa NTS munthawi ya kudziletsa kwa mankhwala osokoneza bongo makoswe wodalirika amathandizanso chidwi cha mphamvu ya mankhwala osokoneza bongo ndikuwonjezera chiopsezo chobwezeretsanso nkhawa zomwe zimayambitsa kubwezeretsa mikhalidwe yofunafuna mankhwala (ndiko kuti, kubwereranso)¹⁶. Kuchuluka kwamphamvu kwa mphotho ya mankhwala osokoneza bongo mu makoswe omwe akudutsa kwakanthawi kokhazikika kumayenderana ndi kuchepa kwa chidwi ndi mphotho ya chakudya²³. Mwakutero, kusintha kwa nthawi yayitali mu ntchito ya NTS kumatha kupangitsa kuti mankhwala osokoneza bongo azithandizira komanso kuchepa kwa chakudya ndi zinthu zina zachilengedwe othandizira zomwe zimawonekera mwa anthu omwe amwa mankhwala osokoneza bongo²³.

Maseru akuyamba kutuluka mu zochitika zosonyeza ma cell mu NTS zomwe zimapangitsa kunenepa kwambiri komanso kudalira mankhwala. Mwachitsanzo, mitsempha ya vagus imapereka chidziwitso chomwe chimakhudzana ndi kufalikira kwa chapamimba ku NTS²⁴, ndipo mitsempha ya ukazi imachepetsa kudya mu makoswe²⁵ ndi anthu²⁶. Kafukufuku wamaganizidwe aubongo wamunthu wawonetsa kuti chida chobisika chomwe chimayambitsa kukula kwa m'mimba poyankha kukondoweza kwamitsekedwe ya nyini chimakulitsa kagayidwe kazinthu mu gawo laubongo lomwe limakhudzidwa ndi mphotho ya chakudya ndi palatability, kuphatikizapo OFC, striatum ndi hippocampus²⁷. Chodabwitsa, opaleshoni ya bariatric mwa anthu onenepa kwambiri imatha kuwonjezera kumwa²⁸. Zotsatira izi zikugwirizana ndi lingaliro loti ma NTS amathandizira kuchita mu magawo a mphotho zamaubongo ndipo potero amawongolera kudya ndi kugwiritsa ntchito mankhwala osokoneza bongo. Mu makoswe, kubwereza kwa mitsempha ya ukazi kumawonjezera mawu a criptionFOSB mu NTS²⁹. Mofananamo, kukulitsa kudalira kwa opiate mu makoswe kumayanjananso ndi kuwonjezeka kwa mawonekedwe a NTS a ΔFOSB³⁰. ΔFOSB ndi mitundu yazipatso za mtundu wanthawi zonse wa FOSB³¹ ndipo amadziwika kudziunjikira mu striatum ndi malo ena okhudzana ndiubongo mu mbewa ndi mbewa panthawi yodziwika bwino ndi magulu osiyanasiyana a mankhwala osokoneza bongo, ndipo amapitilira nthawi yayitali atasiya kugwiritsa ntchito mankhwala. Kuphatikiza apo, ΔFOSB imakulitsa mphamvu yogwiritsa ntchito mankhwala osokoneza bongo, mwina poyambitsa kusintha kwa magwiridwe antchito omwe amapangitsa kuti iwonso azikhudzana ndi mankhwala osokoneza bongo komanso chidwi chokhudzana ndi mankhwala³². Chifukwa chake, ndizotheka kuti ΔFOSB kuwonetsa mu NTS kungathandizire kukulitsa kunenepa kwambiri. Kuphatikiza apo, kuchulukana kwa ΔFOSB mu NTS kungayambitse kuchuluka kwa nthawi yomweyo kwamphamvu pamankhwala osokoneza bongo komanso kuchepa kwa chidwi cha mphotho ya chakudya, yomwe tafotokozeredwa pamwambapa, mu nyama zomwe zikupezeka kuti zimadziwikanso pakukhudzana ndi mankhwala.

Nucleus traus solitarius neuropeptides mu mphotho ya mankhwala. Kuphatikiza pa catecholaminergic neurons mu NTS, kuchuluka kwa ma neuronal komwe kumatulutsa ma neuropeptides monga proopiomelanocortin (POMC) kapena glucagon-ngati peptide 1 (GLP1, chogulitsa cha cleavage cha glucagon). Mofananamo ndi ma neurons okhala ndi mitsempha ya neuradrenaline, ma NTS POMC neurons amathandizidwa ndi othandizira kumidzi kuchokera pamatumbo am'mimba komanso kuzungulira kwa satiety, ndipo amathandizira kuchepetsa kuchepa kwa chakudya³³. Kupititsa patsogolo kufala kwa POMC mu NTS kumathandizira kuchepetsa thupi komanso kuteteza ku kunenepa kwambiri kochokera kunenepa³⁴. Chodabwitsa, kulowetsedwa kwa NTS ya opiates, yomwe imadziwika kuti imawonjezera kudya, imalepheretsa ma neuroni a POMC³³, kutanthauza kuti maselowa atha kutenga nawo gawo mu mphotho ya opiate ndi kudalira. GLP1 imapangidwa makamaka ndimatumbo a L, ndipo imathandizira kutsitsa shuga m'magazi ndikulimbikitsa kutulutsa kwa insulin³⁵. GLP1 imapangidwanso ndi ma neurons ochepa mu NTS omwe amalepheretsa kudya³⁶, makamaka poyankha kutsekeka kwa m'mimba³⁷, kupsinjika ndi kudwala³⁸. Kusokonekera kwa kupanga kwa GLP1 mu NTS kapena GLP1 receptor kuwonetsa muubongo kumapangitsa hyperphagia mu makoswe³⁸, ndikuwonetsa kuti kudya kwambiri kumatha kubweretsa zovuta mu chapakati cha GLP1 cholandirira cholandirira chomwe chimapangitsa kunenepa kwambiri. Kutsegula kwa zolandila za GLP1 mu NTS mwina kumachepetsa kudya kudzera mwa makina omwe amaphatikiza mapuloteni kinase C (PKC) -kuwonetsedwa kwapakati pakokha kwa AMP-activated protein kinase (AMPK) ndi kukondoweza kwa mitogen-activated protein kinase (MAPK)³⁹. Pakadali pano, maudindo a GLP1 receptors muubongo, ndipo AMPK ndi MAPK mu NTS, pakuwongolera mphotho ya mankhwala ndi kudalira sizinafufuzidwe.

Insort cortex mu kunenepa kwambiri komanso kugwiritsa ntchito mankhwala osokoneza bongo

Insula ndi operculum imakhala yokhazikika ndikusunga zidziwitso zokhudzana ndi valence (makonda kapena opanda nkhawa) ndi kukula kwa mphamvu ya chakudya chopatsa mphamvu^{1, 10} (Chith. 2). Kuphatikiza pa ntchito yake pakukumbukira kukoma, okonzekerawo amathanso kuwongolera zochitika ndi zikhumbo zachidziwitso⁴⁰. Anthu kapena makoswe okhala ndi chakudya cham'mawonekedwe amawonetsa kuchepa kwa chakudya akamagula chakudya chochepa kwambiri kuposa momwe amayembekera kupezeka, chochitika chimatchulidwa kuti chosiyana ndi izi^{41, 42}. Kusintha kumeneku mwa kukonda chakudya chotetemera chomwe chilipo, komanso kukana zakudya zosavutikira, zitha kutenga gawo lalikulu pakukula kwa kunenepa kwambiri mwakupangitsa kuti chakudya chokwanira kwambiri chikhale chopatsa mphamvu.^{41, 42}. Makamaka, zotupa pa insula zimathetsa mavuto omwe amabwera chifukwa chakudya⁴³. Mofananamo, chotupa cha galamala thalamus, yomwe imagwiritsidwa ntchito ndi NTS ndikuwongolera polojekiti, imathetsanso kusiyana komwe kumayenderana ndi zakudya⁴⁴. Zolemba za anthu zomwe zimawoneka zachepa mphamvu yolumikizira inalimba mu insorte yolimba mkati mwa kupumula⁴⁵, mwina kuwonetsa kuchepetsedwa kuwongolera pakuyambitsa kutulutsa. Mogwirizana ndi matanthauzidwe amenewa, anthu onenepa amawonetsa kukhudzika kwamphamvu chifukwa cha chakudya chabwino⁴⁶. Kuphatikiza apo, achinyamata omwe ali pachiwopsezo chokunenepa kwambiri (makolo onsewa anali ndi kuchuluka kwa thupi (BMI) kwa ≥27) adawonetsa kulowetsedwa kwa insula ndi operculum kuyambitsa poyankha mphotho zandalama kapena chakudya poyerekeza ndi achinyamata omwe ali pachiwopsezo chochepa chotukuka kunenepa kwambiri (makolo onse awiri okhala ndi kuchuluka kwa thupi kwa <25)⁴⁷. Izi zikusonyeza kuti kusinthasintha kwa chakudya komwe kumapangitsa chidwi cha chakudya champhamvu, zomwe zimapangitsa chidwi cha chakudya champhamvu komanso kusintha kwa zakudya zomwe zimakonda chakudya chotere, kumawonjezera chiopsezo cha kunenepa kwambiri.¹.

Kuphatikiza pa udindo wake pakukonzekera kukumbukira komanso kukonda zakudya, insulayi imathandizanso kwambiri pakukonda mankhwala osokoneza bongo. Kusuta komwe kumayambitsa kusuta komwe kumasuta osuta kumakhudzana kwambiri ndi kagwiritsidwe ntchito kotengera kolimba⁴⁸. Makamaka, kuwonongeka chifukwa chakuthwa kwa anthu omwe amasuta fodya kumatha kubweretsa kusokonezeka kwa chizolowezi cha kusuta fodya, komwe kumadziwika ndi kusiya chizolowezi chosuta fodya komanso kusuta fodya pambuyo pake.⁴⁹. Mu makoswe, kupangika kwa mankhwala a insula, kapena kusokoneza kwa hypocretin receptor mtundu 1 (wotchedwanso orexin receptor mtundu 1) kusainira mu mawonekedwe awa, kumachepetsa kukhudzika kwa chikonga chazisankho⁵⁰ komanso kufunafuna amphetamine⁵¹. Mothandizidwa ndi minyewa yotupa, mankhwala a cocaine⁵² kapena kuwonetsedwa kwa zinthu zachilengedwe zomwe zimaneneratu zakupezeka kwa chakudya chamafuta⁵³ kuwonjezeka kwa jini yoyambirira komanso zolembera zoyambirira poyambira kukula kwa puloteni 1 (yomwe imadziwikanso kuti transcript factor ZIF268), yomwe imagwira gawo lalikulu mu kupindika kwa neuronal ndi mapangidwe a kukumbukira kwa nthawi yayitali. Izi zikusonyeza kuti chakudya chabwino komanso kugwiritsa ntchito mankhwala osokoneza bongo zimatha kuyambitsa zomwe zimachitika mu insortort. Makoswe omwe amaloledwa kudya zakudya zabwino kwambiri akuwonetsa akuwoneka akuwoneka aku MAPK posonyeza kakhola⁵⁴. Kuphatikiza apo, kuwonjezeka kwa ma signature a MAPK, mwina chifukwa cha NMDA komanso metabotropic glutamate 5 receptor activation⁵⁵, imayendetsa kuphatikizidwa kwa kukumbukira kwanthawi yayitali⁵⁶. Zochepa zomwe zimadziwika pazochitika za kugwiritsa ntchito mankhwala osokoneza bongo pa MAPK siginecha mu insula ndi kutengapo gawo kwake pakuchita zinthu zosokoneza bongo.

Orbitofrontal cortex mu kunenepa kwambiri komanso kuzolowera

Mosiyana ndi insula, yomwe imalowetsa chidziwitso chazakudya komanso kukula kwa chakudya cha hedonic, OFC imawoneka ngati ikusintha zambiri zokhudzana ndi kuchuluka kwa chakudya champhamvu, potengera zambiri za kagayidwe kakang'ono ka metabolic kapena hedonic mu ubongo.⁵⁷. Mwakutero, OFC mwina ili ndi gawo lofunikira pakukonza zokhuza kukhudzika kwachakudya pakudya chifukwa chakuchepa kwa phindu lazinthu zilizonse zopatsidwa, popanda kusintha kwamalingaliro ake osakhazikika⁵⁷. Pakafukufuku waposachedwa, odzipereka omwe anafunsidwa kuti ayerekeze kudya zakudya zofunikira (chokoleti kapena tchizi) pomaliza pake ankadya zochepa kwambiri pomwe chakudya chinapezeka kupezeka poyerekeza ndi kuchuluka kwa anthu omwe amaganiza kuti amadya zochepa , omwe amaganiza kuti amadya zakudya zamtundu wina kapena omwe sanadye chakudya⁵⁸. Zakudya zochepetsedwa sizinali zokhudzana ndi kusintha kwa kusintha kwa mphamvu ya hedonic, otenga nawo mbali adangokhumba zochepa (ndiye kuti, adakumana ndi zovuta zokhudzana ndi satiety potsatira momwe amaganizira)⁵⁸. Zotsatira izi zikuwonetsa momwe phindu la chakudya lingasiyanitsidwe ndi zinthu zake zonse⁵⁸, ndipo akuwonetsa kufunikira kwa malo apamwamba kwambiri amtundu wa ubongo omwe amaphatikizidwa ndikuyimira malingaliro popereka mtengo wa chakudya womwe wapatsidwa. Poganizira gawo lofunikira la OFC pakupereka phindu la chakudya⁵⁹, izi ndi zina zofananira ndikuwonetsa kuti kusokonezeka kwa ntchito ya OFC kumatha kubweretsa vuto losayenera la phindu la chakudya, zomwe zingayambitse kulemera⁶⁰. Pakugwirizana ndi kuthekera uku, kunenepa kwambiri mwa anthu kumalumikizidwa ndi kuperewera kwakukulu mu OFC metabolism⁶⁰. Kuphatikiza apo, kusokonezeka kwa chidwi cham'maso komwe kumayambitsa chidwi cha OFC ndi insula kumapangitsa kuti pakhale kudya kwakudya kwambiri kwa anthu⁶¹. Posachedwa, zidawonetsedwa kuti activation ya mu opioid receptors mu OFC imapangitsa hyperphagia mu makoswe⁶². Izi zikusonyeza kuti kufalikira kwa opioid receptor mu OFC⁶², yomwe imatha kukopa zochitika zamagulu akudya pansi mu striatum (onani pansipa), amawongolera machitidwe odyetsa.

The OFC itha kuchita mbali yayikulu pakupereka phindu la cocaine ndi mankhwala ena ozunza. Kuchulukana kwamankhwala kwa OFC kunapangitsa makoswe kukhala osaganizira kusintha kwina kogwirizira phindu la mankhwala osiyanasiyana a cocaine omwe amapezeka kuti azitha kudzilamulira okha⁶³. Zilonda za OFC zimalepheretsanso kuthekera kwa njira zachilengedwe zopangira mankhwala zomwe zimaneneratu chakudya chosavuta kapena kupezeka kwa mankhwala oyendetsa omwe akufuna^{64, 65}, mwina mwa kusokoneza mayendedwe amisala chifukwa cha zakudya- kapena zovala zophatikizika ndi mankhwala⁶⁶. Mbiri yakale ya intravenous cocaine wodziyendetsa payekha m'makola, kapena kuwonetsedwa mobwerezabwereza ku amphetamine, kumapangitsa kusintha kwa magwiridwe antchito komanso ntchito mu OFC yama makoswe omwe amafanana ndi zoperewera pakuchita kwamtundu wa OFC wodalira^{67, 68}. Kutengera zomwe zapezedwa ndi izi, akuti anthu omwe akukonzanso mankhwala a OFC angathandizire kusintha kuchokera pa kugwiritsa ntchito mankhwala osokoneza bongo posokoneza bongo^{67, 69}. Ma molekyulu oyamba amomwe amathandizira ku kuvuta kwa OFC ayamba kutuluka. Mu makoswe, kumwa pang'ono mankhwala a cocaine kapena mowa kumawonjezera mawu a ΔFOSB pa cholembera⁷⁰. Kuchulukitsidwa kwa mawu a ΔFOSB ku OFC kumachulukitsa kuchuluka kwamakhalidwe osayenera omwe amawonedwa pakudziyendetsa pawokha kwa cocaine⁷¹. Momwe kuchuluka kwa zosankha zomwe zikuwoneka kuti kukukulira chiwopsezo cha kuledzera, kuchuluka kwa mankhwala ΔFOSB mu OFC kungachititse kuti munthu ayambe kusuta. Chifukwa chake ndikofunikira kudziwa ngati kuchuluka kwa chakudya cham'mimba kwambiri kumawonjezera kuchuluka kwa ΔFOSB mu OFC, komanso ngati izi zimapangitsa kuti kunenepa kwambiri.

Dongosolo la Mesostriatal mu kunenepa kwambiri komanso kuzolowera

Zambiri zokhudzana ndi chidwi cha chakudya chotsekemera, chomwe chimakonzedwa mu OFC ndi zida zina zamtunduwu, zimatumizidwa kuma circuits okhudzana ndi kudyetsa mu striatum, makamaka kwa omwe amatchedwa 'hedonic hot spots' mdera la NAc. Mawanga otentha a Hedonic mu accumbens projekiti, ndikuwongolera zochitika za, ofananira ndi hypothalamic and pallidal brain. Ma striatohypothalamic and striatopallidal system, omwe amayendetsedwa kwanuko ndi ma opioid ndi endocannabinoid signaling komanso kufalitsa kwa dopamine kochokera ku mesoaccumbens ndi nigrostriatal input, kuwongolera kuyankha kuzinthu zachilengedwe zomwe zimaneneratu za kupezeka kwa chakudya ndi kusasinthasintha, mayendedwe amakono ndi kupatsa mphamvu yolimbikitsira chakudya chokoma¹.

Kuphatikiza pamalingaliro azakudya zabwino, striatum imathandizanso pakuyankha zotsatira zoyipa zomwe zimachitika chifukwa cha chakudya⁷². Makamaka, kumasulidwa kwa ma macronutrients ku chakudya chopatsa mphamvu kumatha kuyambitsa ma metabolic akuwonetsa njira mu viscera ndipo potero amalimbikitsanso zolowetsa dopamine kupita kuzakudya zamagawo mu striatum, modziyimira pawokha pazakudya^{73, 74}. Ntchito yogwira ntchito mosakhalitsa ya receptor canfrily sub subtamily M membala 5 (TRPM5) ndiyofunikira kuti tipeze owawa, okoma ndi amino acid (umami)⁷⁵. Lawani khungu Trpm5 Ziphuphu zogogoda sizikuwonetsa kukondera kwamadzi ndikamaperekedwa mwachidule ndikusankha pakati pazothetsera zonsezi^{73, 74}, kutsimikizira kulephera kwawo kuti athe kupeza mayankho okoma. Komabe, pamene Trpm5 mbewa zogogoda zinali zololedwa kupitilira madzi kapena kusungunulira madzi m'malo opimikirako poyeserera, ndipo chifukwa chake amatha kuyanjana ndi vuto lakumadzi kapena kogwiritsa ntchito njira yawo yodzikakamiza, adawonetsa kukonda njira zachinsinsi. Makamaka, a Trpm5 mbewa zogwedeza sizinapangitse zokonda za sucralose ya caloric pansi pamayeso omwewo, kuwonetsa kuti zotsatira zoyipa pambuyo pake za sucrose ndizo zimayambitsa kukondera kwakukulu chifukwa cha mbewa zogontha^{73, 74}. Sucrose kuchuluka kuchuluka kwa dopamine mu NAc ndi dorsal striatum ya Trpm5 mbewa^{73, 74}, kutanthauza kuti kusayendetsedwa bwino kwa mbewa mu mbewa zogontha kunali kokwanira kulimbikitsa ma midbrain dopamine neurons omwe amayendetsa chidwi cha mayankho owopsa. Chodabwitsa, Trpm5 Mayendedwe pa lilime amathandizanso kuyankha kwa chikonga ndi mowa, ndikuthandizira pakumwa kwawo kwakanthawi^{76, 77}. Izi zikusonyeza kuti, kuwonjezera pa machitidwe awo achindunji muubongo, zidziwitso zokhudzana ndi zovuta zomwe zimagwiritsidwa ntchito pakamwa kapena kumwa mankhwala osokoneza bongo zimawonjezera kudya kwawo.

Kuwonetsa zochitika kumunsi kwa dopamine receptors. Zakudya zabwino kapena kugwiritsa ntchito mankhwala ozunza¹. Maudindo a kufalikira kwa driatal dopamine mu kunenepa kwambiri, kuphatikiza zopereka zofunikira komanso zosinthidwa mu chakudya mu dopamine receptor, awunikanso mwatsatanetsatane kwina^{1, 12, 78}. Apa, chidwi chikhala pa umboni womwe ukutanthauza kuti mankhwala osokoneza bongo komanso zakudya zabwino zosakanikirana zimasanjika pamakalata am'mimba komanso mu midbrain dopamine neurons zomwe zimayambitsa striatum, zomwe zimapangitsa kuti azikhala osokoneza bongo komanso kunenepa kwambiri (Chith. 4). Cocaine ndi mankhwala ena ozunza amathandizira kufotokoza kwa ΔFOSB mu striatum yonse, makamaka mu D1 dopamine receptor ndi dynorphin-akuwonetsa ma spiny neurons apakati pa njira yolunjika⁷⁹. Kuphatikiza apo, kudziunjikira pang'onopang'ono kwa ΔFOSB poyang'anira kugwiritsa ntchito mankhwala kumawonjezera mphamvu zawo, zomwe zimaganiziridwa kuti zimathandizira kukulitsa mankhwala osokoneza bongo⁸⁰. Chosangalatsa ndichakuti, mbewa zomwe zimapezeka pakudya chamafuta kwambiri m'masiku oyambilira pambuyo pa kubereka (masiku a 21-28) ya sabata la 1 idakulitsa kuchuluka kwa mafuta akudya akakula⁸¹, ndipo kuwonjezereka kwa chakudya chophatika chamakola kumalumikizidwa ndi kusintha kwa maselo osakanikirana am'mimba a dopamine receptor signature⁸¹. Makamaka, milingo ya ΔFOSB idakulitsidwa mu NAc ya mbewa izi⁸¹. Mofananamo, kuchuluka kwa ΔFOSB mu striatum kunapezeka mu mbewa zachikulire zomwe zimaloledwa kudya zakudya zamafuta kwambiri kapena zosafunikira^{82, 83, 84}, ndipo izi zimagwirizanitsidwa ndi zolimbikitsidwa zofunikira kudya zakudya zabwino. Kuphatikiza apo, mbewa zomwe zinali zoletsedwa kupeza chakudya, zomwe zinali zanjala komanso zolimbikitsa kudya, zimawonetsanso kulankhulika kwa riFOSB⁸⁵.

Transgenic overexpression ya ΔFOSB mu striatum, makamaka mu neurons yanjira yolunjika, idabweretsa mayankho ochulukirapo pa mphotho ya chakudya pansi makonzedwe okhazikika ndi opita patsogolo zolimbitsa, kunena kuti ΔFOSB imachulukitsa mphamvu ya chakudya⁸⁶. Zotsatira izi zikufanana kwambiri ndi mayankho olimbikitsidwa a cocaine omwe ali mokhazikika komanso pang'onopang'ono pazowonjezera zolimbitsa zomwe zimayambitsidwa ndi striatal overexpression ya ΔFOSB⁸⁷. Kudya kwamafuta ambiri okhathamira kungakonzetse zolakwika zambiri zokhudzana ndi dopamine receptor-signature cascades mu striatum ya ΔFOSB-overexpressing mbewa⁸⁸. Zofooka izi zimaphatikizapo kuchepa kwa cholembera factor cyclic AMP-reaction factor bind bind protein (CREB), protein phosphatase 1 regunit 1B (DARPP32) ndi neurotrophic factor (BDNF)⁸⁸. Kuphatikiza apo, zodziwika za kupanga dopamine ndikumasulidwa, makamaka tyrosine hydroxylase, kuchuluka kwa ma enzymme pakupanga dopamine, komanso mapuloteni othandizira a dopamine (DAT) adachepetsedwa mu dera la ventral tegmental (VTA) -striatum axis ya ΔFOSB- mbewa zopitilira muyeso⁸⁸, ndikuwonetsa kuti mbewa za ΔFOSB-overexpressing zachepetsa kupanga dopamine m'matimu a midbrain ndikuchepetsa kutulutsidwa kwa dopamine mu striatum. Umboni wa kusokonezeka kwa striatal dopamine kudzera mu mbewa za ΔFOSB-overexpressing unakopeka ndikupeza zakudya zamafuta kwambiri a masabata a 6⁸⁸. Izi zikusonyeza kuti zakudya zabwino zitha kukhala zowonjezereka chifukwa cha mbewa chifukwa zimatha kusintha zovuta zomwe zikuwoneka ngati dopamine. Kutengedwa palimodzi, izi zimatsimikizira mwamphamvu kuti striatal ΔFOSB chizindikiro chimalimbikitsa mphamvu ya chakudya ndi mankhwala ozunza. Ndikofunikira kudziwa kuti kuchuluka kwa kulemera ndizofanana mumtundu wakuthengo komanso ΔFOSB-oxpxpinginginging mwayi wofikira wow wamba kapena zakudya zamafuta kwambiri⁸⁸. Chifukwa chake ndizotheka kudziwa kuti kugwiritsidwa ntchito kwa caloric kapena zina mwazinthu zokhudzana ndi metabolism zitha kuwonjezeka mu mbewa za ΔFOSB-overexpressing kuti zitheke kulimbikitsa chidwi chawo chowonjezereka chofunafuna chakudya, mwayi womwe sunayesedwebe.

Zida zina za dopamine receptor siginecha mu striatum imayang'ananso mphamvu za zonse zogwiritsidwa ntchito ndi mankhwala ozunza ndi chakudya. Mwachitsanzo, kufotokozera kwa cyclin-based kinase 5 (CDK5) mu striatum kumayendetsedwa ndi ΔFOSB ndi cocaine^{89, 90}. Kusokonekera kwa pharmacological kapena ma genetic a CDK5 chizindikiro mu striatum kumawonjezera mphotho ya cocaine mu mbewa^{91, 92}. Izi zikuwonetsa kuti kuwonjezeka kwa mankhwala mu CDK5 mu striatum kungakhale kuyankha kogwirizana ndi magawo a mphotho zamaubongo kuthana ndi zotsatira za mankhwala a cocaine ndipo potero atetezere kuti asatengeke⁹³. Kusokonezeka kwa ma CDK5 kutsegula mu ubongo kumathandizanso kulimbikitsa chidwi cha chakudya⁹², ndikuwonetsa kuti njira zingapo zamankhwala amtunduwu zomwe zimapangidwa mu striatum zimayang'anira zothandizira zamankhwala osokoneza bongo komanso chakudya. Pomaliza, kuyambitsa kwa D1 dopamine receptor signature mu striatum kumadziwika kuti kumayambitsa dephosphorylation ya DARPP32 ku serine residue 97. Kubwezeretsanso kwa serine 97 ndi okhala ndi alanine, potero kuletsa kuyendera kwa phosphorylation-mediated ya DARPP32 kudzera patsamba lino, kumapangitsa kutsika kwakukulu pakumvetsetsa komwe kumapangitsa mphamvu ya cocaine komanso mphotho ya chakudya⁹⁴. Kutengedwa palimodzi, izi zikuwunikira umboni wokwanira kuti ma dopamine-ochita kutumiza akuwonetsa makanema omwe ali mu striatum amawongolera mphamvu zolimbikitsira zamankhwala osokoneza bongo komanso chakudya, ndikuti kusokonekera kwa makhwawa awa kumathandizira kukulitsa kunenepa kapena uchidakwa.

Neuropeptide ndi kuwonetsera kwa mahomoni

Kuphatikiza pa zochitika zotsika zomwe zikukhudzana ndi dopamine receptor activation, chakudya cham'mimba komanso mankhwala osokoneza bongo zimatha kuyambitsa matenda a neuroplasticity m'magawo odyetsa odwala kudzera mu mahomoni ndi ma neuropeptide oyang'anira mphamvu zamagetsi. Ma neuropeptides awiri akuluakulu omwe amapangidwa mu lateral hypothalamus komanso omwe amadziwika kuti amasintha ma striatal feed circuits ndi dopamine kulowetsera njirazi, ndi melanin-imaging hormone (MCH) ndi hypocretin (yomwe imadziwikanso kuti orexin). MCH ndi hypocretin amapangidwa mu lateral hypothalamus⁹⁵ - gawo laubongo lomwe limakhudzidwa pakukhazikitsa njira zonse zodyetsera komanso kukonza mphoto - ndikuwonjezeka kwa MCH kapena hypocretin signing^{96, 97}. Chosangalatsa ndichakuti, kubadwa kwa ma genocretin neurons mu hypotalamus yapamtima kumayambitsa kudya kwambiri, kunenepa kwambiri komanso kunenepa kwambiri pa mbewa.⁹⁸, kutanthauza kuti kufalitsa kwa Hypocretin kumathandizira kuti pakhale chakudya chamagulu komanso kunenepa kwambiri. Ma receptor a MCH akuwonetsedwa mu NAc, ndikuwonetsa kwa ma receptor awa olimbikitsa kudya machitidwe⁹⁹ ndi kulepheretsa kuwombera kwa NAc kwamitsempha¹⁰⁰. Zotsatirazi zikuyenera kuphatikizira kuchepa kwa ntchito ya adenylyl cyclase, komanso kutsata kwotsatira m'ntchito ya CREB, ndikuchepetsa mawonekedwe a AMPA glutamate receptor subunit 1 (GluR1)¹⁰⁰. Kusokonezeka kwa MCH receptor signature mu NAc kumalepheretsa zotsatira zabwino za mphotho ya cococaine mu mbewa¹⁰¹. Kuphatikiza apo, kugwiriridwa kwa MCH receptor signature mu NAc kumachepetsa kulowetsedwa kwa cocaine wodziletsa komanso kumalepheretsa kuyambiranso kuchita zinthu.¹⁰¹. Hypocretin-munali ma neurons pulojekiti kuchokera ku lateral hypothalamus kupita ku VTA, komwe hypocretin receptor mtundu 1 (HCRTR1; wotchedwanso orexin receptor mtundu 1) imathandizira pakuyendetsa matenda a mesolimbic dopamine komanso zopindulitsa zomwe zimagwiritsa ntchito mankhwala osiyanasiyana ogwirira ndi chakudya, mwina kudzera pakulamula makaseti odalira a PKC^{102, 103, 104}. Mwachidule, ma neuropeptides okhudzana ndi kudyetsa, ngati MCH ndi hypocretin, ali ndi maudindo ofunika kwambiri pakuwongolera kudya ndi kugwiritsa ntchito mankhwala osokoneza bongo mwa kusintha dongosolo la mphotho, ndipo mwina amathandizira kukulitsa kunenepa kwambiri komanso kuzolowera.

Leptin akuwonetsa mu dera lachiberekero chamkati. Kuphatikiza pa hypothalamic neuropeptides, mahomoni owongolera chilimbikitso omwe amapangidwa mu viscera amatha kusintha ntchito yaubwino muubongo. Mwachitsanzo, ghrelin, yomwe imapangidwa m'mimba ndi kapamba, imatha kuwonjezera chilimbikitso ndi kudya kwambiri. Ghrelin amatenga gawo limodzi polimbikitsa kufalitsa kwa midbrain dopamine ndipo potero amalimbikitsa chilimbikitso cha chakudya kapena mankhwala osokoneza bongo¹⁰⁵. Chowongolera china chachikulu cha mphamvu zamagetsi chomwe chimasintha ntchito yamalipiro muubongo ndi leptin. Kuchepa kwa Congenital leptin kumapangitsa kuti chiwonetsero chambiri chikhale cholimba poyankha zithunzi za chakudya¹⁰⁶, ndi leptin m'malo mwake amathandizira kukhazikika kwa chakudya chomwe anthuwa amakonda¹⁰⁶. Leptin amatha kusintha mayankho a chakudya pakawongolera mesolimbic dopamine njira. Leptin receptors amawonetsedwa pa midbrain dopamine neurons^{107, 108, 109}, ndi kulowetsedwa kwa leptin mu VTA kumalepheretsa ntchito ya dopamine neurons¹⁰⁹, amachepetsa kudya^{109, 110, 111} ndipo zimapangitsa kuti zikhale zambiri zimachepetsa kuzindikira¹¹¹. Komanso, kugogoda kwa ma leptin receptors mu VTA mu makoswe kumawonjezera kukondera kwa chakudya chamkati¹⁰⁹ ndipo imathandizira mphamvu chakudya¹¹². M'mabwalo a hypothalamic, JAK-STAT (Janus kinase-sign transducer and activator of transcript) ndi njira yayikulu yomwe leptin imasainira anorexigenic zotsatira¹¹³. Kulowetsedwa kwa leptin mu VTA, Mlingo womwe umachepetsa kudya, umayambitsa masewera a JAK-STAT^{109, 110}, ndikulepheretsa kwa JAK-STAT chizindikiro mu VTA kumatsimikizira zotsatira za leptin¹¹⁰. Matenda a cocaine osachiritsika awonetsedwa signature a JAK-STAT mu VTA¹¹⁴. Chifukwa chake akuti ati kukwezedwa kwa cocaine kochokera ku JAK-STAT kusainira mu VTA kungathandizire kuti mapangidwe azomwe akhala akuchita pakubwera kwa ubongo. Kuphatikiza apo, pochita zinthu ngati leptin, ndizotheka kuti kuchuluka kwa cococaine komwe kumapangitsa kuti JAK-STAT asaine mu VTA atha kupereka gawo la mankhwala a anorexigenic.

Insulin akuwonetsa m'dera la ventral tegmental. Insulin ndi gawo lina lolimbitsa thupi la mphamvu zamagetsi lomwe limatha kusintha chakudya momwe mungagwiritsire ntchito masheya odyetserako zakudya ndi ma midbrain dopamine pamagetsi amenewa. Insulin imayendetsa insulin receptor ndi ma cascade osonyeza omwe amaphatikizapo insulin receptor substrate (IRS) -mediated activation ya phosphoinositide 3-kinase (PI3K). PI3K pambuyo pake imayambitsa tyrosine-protein kinase BTK (yomwe imadziwikanso kuti ATK), yomwe imayendetsa cholinga chazinyama cha rapamycin (mTOR) ndi proteinor yayo yotsikira ya proteinos S6 kinase β1 (S6K1). Maselo a insulin amafotokozedwa mu striatum¹¹⁵ ndi ma midbrain dopamine neurons¹⁰⁷. Kulowetsedwa kwa insulin mu VTA kumachepetsa kudya kwa makoswe^{111, 116}, komanso, kusankha kufufutira kwa insulin zolandilira mu midbrain dopamine neurons mu mbewa kumayambitsa Hyperphagia ndi kuchuluka kwa kulemera poyerekeza ndi mbewa zowongolera¹¹⁷. Zotsatira izi zimakhudzana ndi kuchepa kwa insulin-yolimbikitsidwa ya PI3K kuwonetsa mu dopamine neurons¹¹⁷. Makoswe a matenda ashuga achepetsa kwambiri ma dopamine m'malo amkati komanso ubongo wama striatal ndipo samvera kwenikweni zabwino za methamphetamine kuposa makoswe owongolera a insulin^{118, 119}, kuwonetsa kuti chizindikiro cha insulin ndikofunikira kuti chisungidwe cha dopamine chikhale. Izi zikuwonetsa kuti kuthandizira kwambiri kwa insulin receptors mu VTA kumatha kuchepetsa ntchito ya ma dopamine okhala ndi ma neurons mu tsamba lino la ubongo. Komabe, insulin imawoneka kuti ikuchita mwanjira ya neurotrophic mu VTA monga kusokonekera kwa ma insulin chizindikiro kumabweretsa kuchepera pakufalitsa kwa dopamine.

Kusokonezeka kwa mawu a BDNF kudutsa msana, kapena makamaka mu VTA, kumapangitsa Hyperphagia ndi kuwonda kwambiri makoswe, makamaka akaloledwa kupeza chakudya chamafuta kwambiri¹²⁰, zofananira ndi zotsatira za kugogoda ma insulin receptors mu VTA. Kuphatikiza apo, kuchepa kwapakati pa BDNF kumalumikizidwa ndi kuchepa kwakukulu kwa chizindikiro cha dopamine mu NAc, ndikuwonetsa kuti, monga insulini, BDNF ndiyofunikira kuti isungidwe koyenera kwa mesolimbic dopamine kusaina¹²⁰. Chodabwitsa, kuphatikiza pazovuta zazovuta za leptin pa VTA dopamine yomwe ili ndi ma neurons komanso machitidwe odyetsa omwe afotokozedwa pamwambapa^{109, 121}, hyperphagic ob / ob mbewa, momwe leptin chizindikiro chimasokonekera, ali ndi kuchepa kwa tyrosine hydroxylase mu midbrain dopamine neurons, kiyi yofunika kwambiri mu biosynthesis ya dopamine¹⁰⁸. ob / ob mbewa zachepetsa kutulutsa dopamine mu NAc¹⁰⁸ ndikuchepetsa mashopu a somatodendritic vesicular a dopamine mu VTA¹²². Zofooka izi posonyeza dopamine zimasinthidwa ndi chithandizo ndi exptic leptin¹⁰⁸. Pamodzi, zomwe apezazi zikuwonetsa kuti insulin, BDNF ndi leptin, zomwe zimatha kuwonetsa kudzera pa PI3K-serine / threonine kinase AKT-mTOR Cascade, ndizofunikira pakupanga dopamine koyenera komanso kufalitsa ma siginolo. Zolephera zomwe amachita zimasokoneza mawonekedwe a mesoaccumbens dopamine ndikuwonjezera kuchuluka kwa nyama kuti idye chakudya chamafuta ambiri komanso chokhalitsa kunenepa kwambiri. Mosiyana ndi zomwe zimapangitsa chidwi cha chakudya chokoma ndi kulemera kwa mbewa zomwe zasokoneza insulin, BDNF kapena leptin signature mu VTA, mbewa izi zikuwonetsa kuchepa kwachisangalalo pazomwe zimakhudzanso chidwi cha cocaine ndi amphetamine^{108, 117}. Kuphatikiza apo, kusokonezeka kwa PI3K-AKT-mTOR siginecha mu VTA, komwe kumatheka chifukwa cha mapuloteni oyambitsa matenda a insulin receptor gawo lapansi la 2 (IRS2), kumapatsa mphamvu ya cocaine ndi morphine mu mbewa^{123, 124}. Chifukwa chake, ndizotheka kuti kusokonezeka kwa insulin, BDNF ndi leptin akuwonetsa mu VTA sikuti kumangokulitsa kuchuluka kwa kukhala wonenepa, zomwe zingawonetse kudya kwambiri kwa hedonic kuti muthane ndi boma loipa lomwe limagwirizanitsidwa ndi kusokoneza midbrain dopamine kusayina¹, komanso amachepetsa chidwi cha mankhwala osokoneza bongo monga mankhwala a cocaine kapena morphine.

Insulin akuwonetsa mu striatum. Insulin imakulitsa kufotokoza kwa DAT ndikugwira ntchito mu striatum kudzera mu ovomerezeka a IRS-PI3K njira¹²⁵. Kuphatikiza apo, insulini imapangitsa kuti zotsatira za cocaine zizipezeka pazochotsa dopamine, zomwe zimatsekedwa ndi zoletsa za PI3K¹²⁵. Chodabwitsa, kulowetsedwa mwachindunji kwa insulin mu NAc kumapangitsa kuti pakhale machitidwe omwe amakhala osafunikira mu makoswe omwe amathandizidwa ndi cocaine¹²⁵, monga akuyerekezera ndi nthawi isanu yoyeserera yochitira ntchito. Mitundu yayikulu yakukakamizidwa pantchitoyi amadziwika kuti anganene zachitetezo chamtundu wa cocaine wokhazikika¹²⁶, ndipo anthu omwe ali ndi vuto lalikulu kwambiri wokhala pachiwopsezo chambiri amakhala pachiwopsezo chotenga mankhwala osokoneza bongo kapena kunenepa kwambiri¹²⁷. Chifukwa chake, insulin yotanthauza kwanuko munthawi ya striatum ikhoza kuyambitsa chiopsezo chokhala pachiwopsezo cha mankhwala osokoneza bongo a IRS-PI3K-AKT-mTOR. Lingaliro loti PI3K-AKT-mTOR cascade ili ndi gawo lowonjezera pamathandizo limathandizidwanso ndikuwona kuti pharmacological zoletsa za mTOR zikusonyeza kugwiritsa ntchito rapamycin, makamaka ku NAc, amachepetsa mphamvu ya cocaine m'makola ndi mbewa¹²⁸. Pomaliza, njira ya PI3K-AKT-mTOR imadziwika kuti imagwira gawo lofunikira pakukhumudwa kwazitali (LTD)¹²⁹, njira yomwe mphamvu yolumikizira pakati pa ma neuroni imacheperachepera. Striatal LTD imadaliranso endocannabinoid ndi metabotropic glutamate receptor signature ndi kanthawi kochepa receptor angathe cation chiteshi subfamily V membala 1 (TRPV1) njira, zonsezi zomwe zimadziwika kuti zimayang'anira zabwino zomwe zimapatsa mankhwala osokoneza bongo komanso chidwi chofuna kudya zakudya zabwino. Chodabwitsa ndichakuti kudzipatula pa utsogoleri wokha wa cocaine kungayambitse kuperewera kwa LTD mu striatum¹³⁰ ndipo kufanana kwachepa posonyeza kukhudzika kwa zigawo zikuluzikulu za PI3K-AKT-mTOR ma siginecha¹³¹. Zoperewera ku LTD pang'onopang'ono zimachokeranso nthawi yayitali yodziletsa pakakhalidwe ka cocaine wokhazikika m makoswe¹³⁰. Komabe, kulephera kubwezeretsa striatal LTD patapita nthawi yochulukirapo yopezeka ndi cocaine kumayenderana ndi zomwe zimapangitsa kuti azichita zikhalidwe zosokoneza bongo¹³⁰. Pomaliza, zakudya zotchedwa zakumadzulo, zomwe zili ndi shuga ndi mafuta ambiri, ndizosakwanira mu mafuta a omega 3 acids, ndipo chifukwa chake anthu onenepa nthawi zambiri amakhala osowa mu michere yofunika iyi.¹³². Kuperewera kwa Omega 3 mu mbewa kumapangitsa kusowa kochititsa chidwi ku LTD mu striatum¹³², zikusonyeza kuti kuchepekedwa kwa striatal LTD komwe kumadza chifukwa cha kusowa kwa zakudya kungapangitse kuti pakhale vuto la kuchuluka kwa mankhwala osokoneza bongo komanso kunenepa kwambiri.

Kutupa mu kunenepa kwambiri komanso kugwiritsa ntchito mankhwala osokoneza bongo

Umboni womwe ukubwera ukuonetsa kuti kukhazikitsidwa kwa PI3K-AKT-mTOR-amadalira LTD mu ubongo kumadalira kwambiri XPUMX, molekyula yosindikiza yomwe imakhudzana ndi kutupa ndi apoptosis. Makamaka, kuyambitsa kwa NMDA receptors poyankha ntchito ya synaptic kumawonjezera kuchuluka kwa calcium, komwe kumayambitsa calcium calcium yodalira phosphatase calcineurin¹³³. Izi zimawonjezera kutulutsidwa kwa cytochrome c kuchokera ku mitochondria kudzera mumakina omwe amadalira pro-apoptotic zinthu BCL-XL (BCL2 antagonist of cell shoa), XIAP (baculoviral IAP mobwerezabwereza yomwe ili ndi protein 4) ndi apoptosis Administrator BAX^{133, 134}. Cytochrome c nayenso imayendetsa caspase 3, yomwe imayang'anira mawonekedwe a AMPA receptor amagonjera ndikuwongoletsa LTD kudzera pamsewu wa AKT^{133, 134}. Moyenera, caspase 3 imagwira gawo lofunikira pakuwonetsa mauthenga muubongo, kuphatikiza mawebusayiti a striatal ndi midbrain dopamine^{135, 136}, kutanthauza kuti njira zotupa muubongo zitha kuthandizanso kuti munthu azingomwa mankhwala osokoneza bongo komanso kunenepa kwambiri.

Nuclear factor-κB ikuwonetsa ku kunenepa kwambiri komanso kusuta. Kuyambitsidwa kwa ma signcase a signature a kutupa kumayambitsa activation ya nyukiliya-κB (NF-κB), chinthu cholemba chomwe chimakulitsa kusintha kwa proinfigueatory cytokines ndi majini ena omwe amakhudzidwa ndi mayankho a ma cell kuwonongeka, matenda ndi kupsinjika (Chith. 5). Ma Adipocytes amatulutsa ma cytokines ochulukitsa kwambiri, ndipo kunenepa kwambiri kumalumikizidwa ndi nyengo yayitali ya kutupa mu ziwopsezo za zotumphukira.¹³⁷. Kutupa m'magawo aubongo omwe akukhudzidwa pakukhazikitsa chakudya kungakhale ndi gawo lofunikira kwambiri pakukula kwa kunenepa kwambiri. Makoswe omwe amaloledwa kudya zakudya zamafuta kwambiri komanso kunenepa kwambiri ob / ob mbewa, zoletsa wa NF-κB kinase subunit-β (IKKB) -NF-κB siginecha imakwezedwa modabwitsa mu neurons ya mediobasal hypothalamus (MBH)¹³⁸. Komanso, kusokonezeka kwa majini a IKKB-NF-κB chizindikiro mu MBH, makamaka mu agouti okhudzana ndi peptide (AgRP) neurons mu tsamba lino (Chith. 1), amateteza mbewa ku kunenepa kwambiri zikavomerezedwa kudya zakudya zamafuta kwambiri¹³⁸, pomwe ectopic activation ya IKKB-NF-κB chizindikiro mu MBH imayambitsa insulini yapakati komanso kukana kwa leptin (mbali zazikulu za thupi za kunenepa kwambiri)¹³⁸. Kuchotsa kwina kwa ubongo¹³⁹, kumathandizanso gawo lothandizira kutulutsa mu ubongo mu kunenepa kwambiri. Kuphatikiza pa kudya mopitirira muyeso, kutsegulira ma NF-κB ku hypothalamus, makamaka mkati mwa ma POMC neurons ku MBH, kumatha kuyambitsa zovuta zina zomwe zimakhudzana ndi kunenepa kwambiri monga matenda oopsa.¹⁴⁰. Kunenepa kwambiri kunaphatikizidwanso ndi kutukusira kwa malo amtundu wa bongo wa extrahypothalamic omwe amakhudzidwa ndi gawo la hedonic la kudya. Kugwiritsa ntchito MRI, anthu onenepa kwambiri adawonetsedwa kuti ali ndi kutupa kwakuthupi kwa OFC, tsamba lofunikira laubongo lomwe limakhudzidwa ndikuwonetsa phindu la chakudya chopatsa thanzi (onani pamwambapa)¹⁴¹. Kutengera ndi zomwe apeza, akuti kuti kutupa m'magazi a ubongo wama cortical, komanso m'malo a limbic, striatal ndi midbrain omwe akukhudzidwa ndikukhazikitsa zakudya zabwino, zitha kuthandiza kukulitsa kunenepa kwambiri.

Cocaine ndi mankhwala ena ozunza amathanso kubweretsa mayankho mu ubongo. Mu mbewa, cocaine imayambitsa siginecha ya NF-κB mu NAc^{142, 143}, zomwe zikuwonjezera kuwonjezeka kwa misinkhu ya BDNF ndikuwonjezera chidwi cha mphotho ya cocaine¹⁴². Cocaine-inachititsa NF-κB kutsegulanso idapangitsanso kukonzanso mu NAc, zomwe zimapangitsa kuchuluka kwa ma dendritic pa NAc neurons¹⁴², komwe kungakhale kuyankha kosinthasintha komwe kumawonjezera chiopsezo cha kusuta¹⁴². Kuphatikiza pa cocaine, kumwa mowa kumathandizanso kuti NF-κB iwonetse bongo, ndipo akuti izi zikuthandizira kukulitsa uchidakwa¹⁴⁴.

SIRT1 mu kunenepa kwambiri komanso kusuta. Popeza kufunikira kwa NF-κB kusainira pakukula kwa thupi ndi mphotho ya mankhwala, mwina sizosadabwitsa kuti mapuloteni omwe amawongolera ma NF-κB siginecha - monga NAD-deacetylase sirtuin 1 (SIRT1) amathandizanso kunenepa kwambiri komanso kugwiritsa ntchito mankhwala osokoneza bongo . SIRT1 ili ndi machitidwe othana ndi zotupa, makamaka kudzera mu deacetylating ndikuletsa p65 NF-κB¹⁴⁵. Kusintha kwamtundu mu SIRT1 jini imalumikizidwa ndi ma ScI otsika a BMI mwa anthu¹⁴⁵, komanso kubadwa kwa ma genetic a SIRT1 mu hypothalamic POMC neurons kumawonjezera chiopsezo cha mbewa kutha kunenepa kwambiri chifukwa chochepetsa mphamvu zake¹⁴⁶. Cocaine imawonjezera kufotokoza kwa SIRT1 mu striatum¹⁴⁷ komanso kuyambiranso kwa ntchito ya SIRT1 kumakulitsa mphamvu ya cocaine¹⁴⁷. Zotsatira izi zikuwonetsa kuti SIRT1 mu hypothalamus ndi striatum amawongolera kudya komanso kugwiritsa ntchito mankhwala osokoneza bongo, motsatana. Zidzakhala zosangalatsa kudziwa ngati izi zikugwirizana ndi NF-κB signing, komanso ngati ntchito ya SIRT1 mu striatum imayang'ananso magawo a hedonic pazakudya zabwino.

Vistas zatsopano mu kunenepa kwambiri ndi kafukufuku wazowonjezera

Kukhumudwitsa zomwe zatsopano zikuwonetsa pang'ono za njira zatsopano ndi njira zachilengedwe zomwe zingathenso kuthandizira kunenepa kwambiri komanso kusuta. Mwachitsanzo, mizere ya circadian imatha kukopa chidwi cha maubwino aubongo mu ubongo wake ndipo potero amalamula machitidwe odyetsa ndi kugwiritsa ntchito mankhwala osokoneza bongo. Zolemba CLOCK ndi BMAL1 ndi zigawo zikuluzikulu za wotchi ya circadian, yomwe ili mu suprachiasmatic nucleus (SCN) ya hypothalamus. Mbewa zosinthika bwino ndi zonenepa¹⁴⁸, amakhala ndi chidwi kwambiri ndi mphotho ya cocaine kuposa mbewa zamtchire ndipo amawonetsa kukhathamira kwa midbrain dopamine neurons¹⁴⁹. Chifukwa chake zidzakhala zosangalatsa kudziwa momwe majini amtundu wa CLOCK-BMAL amathandizira kudya komanso kugwiritsa ntchito mankhwala osokoneza bongo.

Kusintha kwa RNA ndi njira yolemba pambuyo pomwe zotsalira za adenosine zimasinthidwa kukhala inosine motsatizana ndi zolembedwa zokhwima za mRNA, zomwe zingayambitse kusintha kwa mapangidwe a amino-acid a mapuloteni osinthidwa¹⁵⁰. Kusintha kwa RNA kumapangidwa ndi ma RNA-adenosine deaminases wapadera wokhala ndi mitundu iwiri ya ADNA, ndipo mwina cholembedwa cha mRNA chodziwika bwino chomwe chimayikidwa mu RNA mu ubongo ndicho serotonin 2C (5-HT_2C) cholandirira¹⁵¹. Kusokonezeka kwa ntchito ya ADAR2 mu mbewa (ADAR2 amadziwika kuti amasintha AMPA ndi kainate glutamate receptor subunits) kumapangitsa hyperphagia ndi kunenepa kwambiri mu mbewa. Kuphatikiza apo, nucleolar RNA HBII 52 yaying'ono imawongolera kusintha kwa 5HT_2C Zovomerezeka¹⁵², ndi ma microdeletions a chromosomal a HBII 85 amathandizira pa vuto la neurodevelopmental matenda a Prader-Willi¹⁵³, chizindikiro chachikulu chomwe ndi kunenepa kwambiri. Ma MicroRNA amakhudzidwanso pakuwongolera mtundu wama gene ndi gawo lofunikira la ma microRNA pakukhazikitsa mphamvu ya cocaine m'makola ndi mbewa zikutuluka¹⁵⁴. Athandizidwanso kwambiri mu adipogeneis, kagayidwe kazakudya kagayidwe kazakudya ndi ma insulin chizindikiro. Komabe, zochepa kwambiri zimadziwika ndi udindo wodyetsa khalidweli.

Agonists a peroxisome proliferator-activated receptor-γ (PPARγ), monga rosiglitazone (Avandia; GlaxoSmithKline plc), amagwiritsidwa ntchito ngati othandizira othandizira insulin kuchitira mtundu wa matenda a shuga a 2. PPARγ imayang'aniranso adipogenesis ndipo imodzi mwazotsatira zoyipa za PPARγ agonists ndiko kulemera kwakukulu, makamaka poyang'ana PPARγ yomwe ikuwonetsedwa mu ubongo^{155, 156}. PPARγ imalumikizana ndi owongolera omwe amamwa mankhwalawa, kuphatikizapo NF-κB (Chith. 5), SIRT1 ndi CDK5, ndi agonists a PPARγ amachepetsa kumwa komanso kusinthanso ngati¹⁵⁷. Chifukwa chake, ndikofunikira kumvetsetsa njira zomwe PPARγ ndi ma hormone ena a nyukiliya amalowerera pakudya ndi kugwiritsa ntchito mankhwala osokoneza bongo, komanso kuti adziwe ngati akuchita munjira zofananira.

Pomaliza, mankhwala ozunza amachepetsa neurogeneis, njira yomwe minyewa yatsopano imabadwira ndikukhwima, mu ubongo wamakutu akuluakulu¹⁵⁸. Momwemonso, apoptosis ya ma neuron omwe abadwa kumene mu bulimia ya ophodo, njira yomwe imatha kuwongolera zochitika zokhudzana ndi fungo, imakulitsidwa mu mbewa nthawi yayitali¹⁵⁹. Izi zikusonyeza kuti neurogeneis mu bulb yolonic komanso mwina madera ena aubongo angapangitse gawo la machitidwe odyetsa ndi kugwiritsa ntchito mankhwala osokoneza bongo. Chifukwa chake, ndikofunikira kufufuza zopereka za njira zomwe zikubwera za neuroplasticity ndi gene regolo mu ubongo kupita ku hedonic zokhudzana ndi kudyetsa Khalidwe ndi zabwino zopindulitsa za mankhwala osokoneza bongo.

Chidule

Monga tafotokozera mu Ndemanga iyi, maubongo ambiri omwewo amawongolera kudya ndi kugwiritsa ntchito mankhwala osokoneza bongo, ndipo mayankho ofananawo amatha kuyambitsa machitidwe aubwino muubongo ndi mankhwala osokoneza bongo komanso zakudya zabwino. Zotsatira zake, kunenepa kwambiri nthawi zambiri kumatsimikizika ngati njira yolimbikitsira kuchita zinthu monga kugulitsa mankhwala osokoneza bongo. Chifukwa chake, kumvetsetsa kwathu njira zamankhwala osokoneza bongo zomwe zingayambitse vuto la kugwiritsa ntchito mankhwala osokoneza bongo kungatipatse njira yolimbikitsira oyendetsa omwe ali ndi kunenepa kwambiri. Pomaliza, kutsimikizika kwakukulu kukufotokozeredwa zakuperewera kwa chakudya cham'magawo a mphoto zamaubongo zomwe zikuphatikizidwa mu mankhwala osokoneza bongo. Komabe, ndikofunikanso kuganizira za kubwezeretsanso ubale womwe ulipo pakati pa magulu azakudya a homeostatic mu hypothalamus ndi brainstem pakuwongolera kumwa kwa mankhwala osokoneza bongo. Nikotini ndi mankhwala ena ozunza amatha kulimbikitsa mabwalo azakudya za hypothalamic ndipo potero zimapangitsa kulemera¹⁶⁰. Ndizotheka chidwi kuti mabwalo azodyetsa a hypothalamic awa amathanso kuwongolera mphotho ya mankhwala ndikuthandizira kutha kwa ulamuliro pa kugwiritsa ntchito mankhwala osokoneza bongo omwe amadziwika kuti ali osokoneza bongo.

Links

ZINTHU ZINA

• Tsamba lofikira la Paul J. Kenny

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Zothokoza

Wolemba amathandizidwa ndi zopereka kuchokera ku US National Institute on Drug Abuse (NIDA). Nambala ya manambala a 21309 yochokera ku The DRMps Research Institute.

Nkhani zofuna chidwi

Wolemba walengeza kuti palibe akupikisana naye pazachuma.

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Zothandizira

1. Kenny, PJ Zopereka mphotho za kunenepa kwambiri: zidziwitso zatsopano ndi kutsogolo kwa mtsogolo. Neuron 69, 664-679 (2011).

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   • ChemPort

2. Wyrwicka, W., Dobrzecka, C. & Tarnecki, R. Wyrwicka, W. Pazida zofunikira zomwe zimayambitsidwa ndi kukondoweza kwa magetsi a hypothalamus. Science 130, 336-337 (1959).

3. Kodi, MJ, Pratt, WE & Kelley, AE Pharmacological mawonekedwe a mafuta ambiri kudyetsa yoyambitsidwa ndi opioid kukondoweza kwa ventral striatum. Physiol. Behav. 89, 226-234 (2006).

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4. McCrory, MA, Suen, VM & Roberts, SB (Adasankhidwa) Zomwe zimathandizira pakupanga mphamvu zamagetsi ndikuwonjezera kulemera kwa akulu. J. Nutriti. 132, 3830S-3834S (2002).

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Ogwirizana nawo

1. Laborator of Behavioral and Molecular Neuroscience, department of Molecular Therapeutics, and department of Neuroscience, The Scripps Research Institute Florida, 130 Scripps Way, Jupiter, Florida 33458, USA.
   Email: [imelo ndiotetezedwa]

Wolemba pa intaneti 20 October 2011