Mefuta e tloaelehileng ea lisele le mekhoa ea limolek'hule ka botenya le ho lemalla lithethefatsi (2011)

Tlhaho ea tlhaho Neuroscience 12, 638-651 (November 2011) | tse pedi: 10.1038 / nrn3105

Paul J. Kenny1  Mabapi le mongoli

Melemo ea lijo ea hedonic e ka khothaletsa mokhoa oa ho iphepa le ha litlhoko tsa matla li fihletsoe, li tlatsetsa ho matlafeng le botenya. Ka mokhoa o ts'oanang, litlamorao tse matla tsa lithethefatsi tsa tlhekefetso li ka susumetsa takatso ea bona ea ho fetella, ea fella ka ho lemalla. Bokoali bo tloaelehileng bo laola likarolo tse matla tsa lijo tse matlafatsang le lithethefatsi tse lemalloang, 'me litlaleho tsa morao-rao li bontša hore tšebeliso e feteletseng ea lijo kapa lithethefatsi tsa tlhekefetso e etsa hore likarabelo tse tšoanang tsaurouro ho potoloha ka likopi tsa boko li sebetse hantle. Mona, re lekola bopaki bo fanang ka maikutlo a hore botenya le ts'ebeliso ea lithethefatsi li ka arolelana mekhoa e tloaelehileng ea limolek'hule, lisele le tsamaiso.

O mong oa mesebetsi ea mantlha ea boko nakong ea matla a seng makae ke ho khutlisetsa litšebeletso molemong oa ho fumana le ho ja lijo, ka ho etsa joalo, ho nchafatsa mabenkele a matla a felisitsoeng ke tšebeliso ea caloric. Ho tsejoa ho hongata ka li-circuits tsa hypothalamic le hindbrain tse laolang matla homeostasis le lihormone tse laolang tlala le ho tsitsa, joalo ka leptin, ghrelin (hape e tsejoang ka hore ke takatso ea taolo ea li-hormone) le insulin, makaleng ana (Feie. 1). Ntle le lits'ebeletso tsena tsa matla a homeostatic, lits'ebetso tsa moputso li na le likarolo tsa bohlokoa ho tataiseng boits'oaro ba phepo. Haholo-holo, lits'ebetso tsa moputso oa boko li laola ho ithuta ka thepa ea lijo ea hedon, ho phahamisa tlhokomelo le boiteko ho fumana meputso ea lijo le ho laola boleng ba lijo kapa tse susumetsang tikoloho tse bolelang esale pele ka meputso ea lijo. Li-regormine tsa matla a homeostasis li ka sebetsa hape ho lisekhete tsa moputso oa boko, haholo ts'ebetsong ea dopamine ea mesoaccumbens1, ho eketsa kapa ho fokotsa boleng ba tšusumetso ea lijo ho latela litlhoko tsa matla. Leha ho le joalo, ho ts'oaroa hoa motlakase kapa lik'hemik'hale libakeng tsa bokong tse fanang ka moputso oa lijo ho ka baka ho nona joaloka ho ja lijo tse ngata esita le ho liphoofolo tse sa tsoa feptjoa tseo ho tsona ho neng ho entsoe lipontšo tsa ho satiety tsa lapeng.2, 3. Sena se fana ka maikutlo a hore ho fumana litholoana tse khahlisang tsa lijo ke tšusumetso e matla e ka fetisang matšoao a satiety a homeostatic, mme ka tumellano le sena, lijo tse nang le lijo tse fumanehang habonolo ka tloaelo li jeoa khafetsa le ka boholo bo boholo ho feta tse nang le mefuta e sa foleng ea monate. lijo4. Joalo ka lijo tse le 'ngoe tsa boholo bo lekaneng bo ka baka tšebeliso ea lijo ka matsatsi a mangata5, ho nona ho feta tekano ho ka ba karolo ea bohlokoa molemong oa ho nona le ho holisa botona.

Setšoantšo sa 1 | Kakaretso ea li-circuits tsa phepo ea lapeng.

Setšoantšo sa 1: Kakaretso ea li-circuits tsa phepo ea lapeng. Ka bomalimabe ha re khone ho fana ka lingoloa tse ling tse fumanehang bakeng sa sena. Haeba o hloka thuso ho fihlella setšoantšo sena, kapa ho fumana litlhaloso tsa mongolo, ka kopo ikopanye le nppn@nature.coma | Hormonal balaoli ba tlala, satiety le adiplings ba lokolloa ho tsoa periphery. Tsena li kenyelletsa leptin le li-adipokine tse ling, hammoho le li-cytokin tse haellang, tse tsoang lithong tsa adipose. Insulin le pancreatic polypeptide (PP) li bolokiloe pancreas. Ho feta moo, ghrelin (e tsejoang hape ka hore ke takatso e laolang takatso ea lijo), pancreatic peptide YY3-36 (PYY3-36), glucagon-like peptide 1 (GLP1, sehlahisoa se hlakileng sa glucagon) le cholecystokinin (CCK) li lokollotsoe ho tsoa mpeng ea gastrointestinal. Tsamaiso ena ea li-hormonal ea matla a lekantsoeng la matla e sebetsa libakeng tsa boko le tsa hypothalamic ho susumetsa tlala le ho seta. b | Matšoao a Hormonal a tsoang ho viscera e laolang tekanyo ea matla, le karolo ea methapo ea methapo ea setho sa botšehali e amanang le ho ts'oaroa ke mala ka mor'a ho ja lijo, ts'ebetso ea ho feto-fetoha ha methapo ea methapo ho "nucleus tre" solusus (NTS). NTS e fetisetsa tlhahisoleseling e amanang le tekanyo ea matla ho li-circuits tsa phepo ea homeostatic ho hypothalamus. c| Ho "arcuate nucleus" ea "mediobasal hypothalamus", "li-neurons" tse amanang le agouti tse amanang le agouti tse amanang le agouti (agRP) le neuropeptide Y (NPY) li hlahisoa ke matšoao a orexigenic le ho thibela li-neuron tse bitsoang li-odara tsa bobeli tse hlalosang melanocortin 4 receptor (MC4R), 'me sena ka tekanyetso e thibela boitšoaro ba ho fepa. Ka lehlakoreng le leng, lipontšo tsa anorexigenic li kenya li-neuron tsa pele-pele tse nang le cocaine- le amphetamine-regulated transcript (CART) le proopiomelanocortin (POMC), e khothalletsang tokollo ea α-melanocyte-e susumetsang ea hormone (αMSH), sehlahisoa sa cleavage sa POMC. Sena se fella ka ts'ebetso ea li-neuron tsa MC4R le thibelo ea boitšoaro bo fepa.


Ha liserekisi tse tloaelehileng tsa boko li laola thepa ea ho ja lijo tse matlafatsang le lithethefatsi tsa tlhekefetso, mme joalo ka ha ho na le ho ts'oana ho makatsang pakeng tsa ho nona ho feta tekong le ts'ebeliso e mpe ea lithethefatsi ho lemeng, ho ka se makatse hore ebe mafu ana a reriloe ho arolelana mabaka a tloaelehileng methapo ea methapo ea kutlo1. Leha ho le joalo, ho bohlokoa ho supa hore ho na le ngangisano e ngata e tsoelang pele ka mohopolo oa hore lijo li ka 'lemalla' ka tsela e ts'oanang le lithethefatsi tsa tlhekefetso.6, 7. Mona, re fana ka kakaretso ea sistimi ea boko e sebetsanang le tlhaiso-leseling e amanang le thepa ea hedonic le boleng ba khothatso ea lijo tse monate, hape re buisana ka hore na lithethefatsi tse lemalloang li ka 'utsoetsa' lits'ebetso tsena joang. Ntle le moo, re totobatsa lisebelisoa tse tloaelehileng tsa lisele le limolek'hule ho li-circuits tsena tse ka tlatsetsang botenya le ho lemalla lithethefatsi.

Sistimi ea boko e kenyeletsa lijo tse fumanehang habonolo

Mabaka a liphatsa tsa lefutso a bapala karolo e kholo ho laoleng tšoaetso ea botenya, mme maemo a ho amohela a bontšoa e le tšobotsi e khahlisang haholo (lebokose 1). Maemong a mangata, liphatsa tsa tlhaho tse amanang le boima ba 'mele bo tlatsetsa bothateng ka ho eketsa ho rata lijo tse monate. Ho thehiloe hantle hore lijo tse fumanehang habonolo tse nang le tsoekere e ngata le tse tsoekere li ka baka hyperphagia. Lijo tse matlafatsang tse nang le mafura a mangata li khothaletsa lijo tse kholo ka ho fetesisa tsa lijo tse nang le mafura a mangata ho feta lijo tse nang le lik'habohaedreite tse tlase tse mafura.8. Kahoo, ho tsebahala hore lijo li ka fumaneha hantle ho etsa hore ho be bohlokoa ho feta tekong le ho nona. Litšobotsi tsa maikutlo tsa lijo, haholo tatso ea eona, monko, ho shebahala le ho shebahala, li na le likarolo tsa bohlokoa ho khetholleng ho nepahala ha tsona. Tlhahisoleseling ea kutlo e nkiloeng ke ho kenella ha lijo tse matlafatsoang e kenyelelitsoe karolong e ka sehlohlolong le e bohareng ea mokokotlo (Feie. 2). Li-neuros tsa Chemosensory tse kahara molomo tse kenelletseng morerong oa ho lemoha ho latsoa ho "nucleus" tropus solitarius (NTS) bokong ba kelello9. Li-NTS le tsona li etsa projeke ho gumorum thalamus (VPM) thalamic nucleus10, e kahare ea "gustatory cortex" e ka sehloohong ka har'a insula le operculum10. Joalokaha lebitso le bolela, PGC e kenella ka matla ho ts'ebetsong tlhahisoleseling e amanang le tatso ea lijo le boleng ba eona ba hedonic11. Barekisi ba porojeke ea PGC ho ea sebakeng sa "caudolateral orbitofrontal cortex" (OFC) ba ile ba reha mokokotlo oa bobeli oa gustatory cortex (SGC). Ntle le tatso, mefuta e meng ea kutlo ea kutlo e amanang le ho tsebahala ka lijo (mohlala, monko, pono le sebopeho) le tsona li hlaha ho PGC le SGC10. Morero oa PGC le SGC ho striatum, haholo-holo li-nucleus accumbens (NAc), ka ho etsa joalo ho fetola tšebetso ea methapo ea methapo molemong oa phepelo e amanang le striatohypothalamic le striatopallidal.1. Li-circuits tsena tsa phepelo ea striatal le tsona li susumetsoa ke ho kenella ha mesolimbic le nigrostriatal dopaminergic.1. Ho thehiloe hantle hore striatum e laola ts'ebeliso ea lijo tse fumanehang habonolo le lithethefatsi tsa tlhekefetso1, 12. Joalokaha ho hlalositsoe ka botlalo ka tlase, bopaki ba morao-rao bo bonts'a hore likarolo tse ling tsa ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea lijo - haholo NTS, insula le OFC - le taolo ea ts'ebeliso ea lithethefatsi tse lemalloang.

Setšoantšo sa 2 | Mesebetsi ea methapo e laolang lijo le tšebeliso e mpe ea lithethefatsi.

Setšoantšo sa 2: Neurocircuitry e laolang lijo tse matlafatsang le tšebeliso ea lithethefatsi. Ka bomalimabe ha re khone ho fana ka lingoloa tse ling tse fumanehang bakeng sa sena. Haeba o hloka thuso ho fihlella setšoantšo sena, kapa ho fumana litlhaloso tsa mongolo, ka kopo ikopanye le nppn@nature.comHo tsebahala ha lijo ho amana le ho ama le mocheso oa eona, mme e sebetsoa haholo ke mechanoreceptors molomong oa molomo o ka reng ho ea gustatory thalamus. Ho kopanya ho boetse ho etsa hore ho be bonolo, 'me ho ka bapala karolo ea bohlokoa ho fumaneng mafura a fumanehang lijong. Latsoalo e bapala karolo ea bohlokoa ho bonoeng ba lijo, ka li-chemoreceptor tse khethollang tatso e lelemeng le kenang lenaneong la methapo ea methapo. Monko oa lijo o sebetsoa ka bulb ea olgicory (OB) le pyriform cortex. Ponahalo ea lijo tse fumanehang habonolo e sebetsoa ka li-cortices tse bonoang (V1, V2 le V4) ebe o fetisa ka hare ho "temport visual cortex" (ITVc) e kahare. Tlhahisoleseling e amanang le ho fumaneha ha lijo ho tsoa mefuteng ena e fapaneng ea methapo ea kutlo e kenang ho amygdala, insort cortex le orbitof Pambal cortex (OFC), le ho tloha moo ho ea ho lipotoloho tsa phepelo ka striatum le lateral hypothalamus (LH). Melemo ea maikutlo ea lithethefatsi tsa tlhekefetso e ka kenya tšebetsong ts'ebetso e tšoanang le ea lijo tse fumanehang habonolo. Ho feta moo, lithethefatsi tsa tlhekefetso li kenella ho CNS ebe li sebetsa ka kotloloho litsamaisong tsena tsa boko. Lisaete tsa tšebetso tsa lihlopha tse kholo tsa lithethefatsi tse tlatsetsang ho ts'ebetso ea methapo ea kutlo tse laoloang ke lijo (li bonts'itsoe ke metsu e hlasetsoeng). Ntle le moo, NTS e na le karolo e hlahelletseng ea ho laola moputso oa opiate le nts'etsopele ea boits'epo.


Nuklea ea "trusususitarius" moputsong oa lijo le lithethefatsi

Li-Neurons tse hlahisang li-neurotransmitters tsa catecholamine ke sehlopha se ka sehloohong kahare ho NTS e kenyelletsang ho laola boitšoaro ba fepa (Feie. 3). NTS e fumana tlhahisoleseling ho tsoa ho li-chemosensory neurons ka har'a molomo o sebelisang tatso ea lijo, 'me merero e nyolohang e fetisetsa tlhahisoleseling ena libakeng tsa boko ba thalamic. Ntle le moo, li-neurons tsa NTS catecholamine li hlahisoa ke liphatlalatso tse tsoang pampiring ea gastrointestinal tse fanang ka phallo ea lijo kapa phallo ea mpeng, le ka ho potoloha matšoao a satiety joalo ka cholecystokinin (CCK)13. NTS e fetisetsa tlhahisoleseling ena ea visceral libakeng tsa phepo ea homeostatic ho hypothalamus. Ka mokhoa o tsotehang, likhoto kapa litoeba tse bolokiloeng lijong tse matla kapa litoeba tse tloaeloang ho ba le botenya li fokotsehile ka ho arabela ha li-neuron tsa NTS catecholamine ho kenella ka lipid14, 15. Sena se fana ka maikutlo a hore hyperphagia e amanang le ts'ebeliso ea lijo tse matlafatsang tse nang le mafura a mangata e kanna ea tsamaellana le karabelo tse feto-fetohang ho NTS, ea baka ho fokotseha ha kutloelo-bohloko ea lihormone tsa marenene tse bonts'ang ho nyehlisa.

Setšoantšo sa 3 | Nucleus trus solitarius lijong le tšebeliso ea lithethefatsi.

Setšoantšo sa 3: Naus e bitsoang "nucleus trus solitarius" ea lijo le ts'ebeliso ea lithethefatsi. Ka bomalimabe ha re khone ho fana ka lingoloa tse ling tse fumanehang bakeng sa sena. Haeba o hloka thuso ho fihlella setšoantšo sena, kapa ho fumana litlhaloso tsa mongolo, ka kopo ikopanye le nppn@nature.comNusus trusususitarius (NTS) e fumana phepelo ho tsoa mpeng ea mpa, 'me e fetohela mererong ea bongoana, thalamic, hypothalamic, limbic le cortical brain tse amehang ho sebetsanang le phepo ea lijo, likarolo tsa lijo le lithethefatsi tsa tlhekefetso. , le litlamorao tsa khatello ea maikutlo mabapi le lijo le tšebeliso ea lithethefatsi. NTS e bonts'a bongata bo fapaneng ba li-neuron tse kenyelletsang ho laola lijo le lithethefatsi, ho kenyelletsa le catecholaminergic neurons tse hlahisang enzyme tyrosine hydroxylase (TH+), tse hlalosang proopiomelanocortin (POMC) le tse hlahisang "glucagon" tse kang peptide 1 (GLP1, sehlahisoa se hlakileng sa glucagon). BNST, mokokotlo oa bethe ea stria terminalis.


Ntle le libaka tsa phepo ea thalamic le hypothalamic, NTS catecholaminergic neurons - haholo-holo e sebakeng sa A2 sa NTS e hlahisang Noradrenaline - hape e sebetsa ka matla ho likarolo tsa bokong ba litho tsa karolo tsa khatello ea maikutlo le ho lokisa moputso, ho kenyelletsa le sebaka sa khetla la NAc, bohareng. nucleus ea amygdala (CeA) le khubu ea mohala oa stria terminalis (BNST)16 (Feie. 3). Libaka tsena tsa boko, e le karolo ea kholo ea kholo e sebetsang, sebopeho se amanang le ts'ebeliso ea lik'hemik'hale tse bitsoang amygdala, li na le likarolo tsa bohlokoa ho laoleng thepa e matlafatsang ea lithethefatsi tsa tlhekefetso le nts'etsopele ea ts'ebeliso ea lithethefatsi nakong ea ts'ebeliso e mpe ea lithethefatsi17 (bona lebokose 2 bakeng sa puisano ea karolo ea khatello ea boteng le boteneng. Ka mokhoa o tsotehang, nikotine e sebelisoang lelemeng la likhoto e natefisetsa methapo ea kutlo ho NTS mme ka nako e tšoanang e fokotsa ho arabela ha eona ho mefuta e fapaneng ea tastants18. Sena se fana ka maikutlo a hore liketso tsa nicotine le lithethefatsi tse ling tsa tlhekefetso ho lits'ebetso tsa kutlo tsa phello li kopana ho li-neurons tsa NTS19, 20, kapa liketso tse tobileng tsa lithethefatsi tsena ka har'a NTS, li ka kenya letsoho bokhoni ba tsona ba tlhekefetso. Tumellanong le monyetla ona, thepa ea moputso ea morphine e tlatsitsoe ka botlalo ho litoeba tsa dopamine β-hydroxylase (DBH), tse ke keng tsa kopanya noradrenaline21. Leha ho le joalo, ts'oaetso e khutliselitsoeng ka har'a vaerase ea DBH ho li-NTS tsa litoeba tsa "knockout" li thehile kutlo ea bona ea moputso oa morphine21. Ntle le moputso oa lithethefatsi, NTS e boetse e bapala karolo ea bohlokoa ntlafatsong ea ts'ebeliso ea lithethefatsi le litlamorao tse tlisoang ke ho khaotsa lithethefatsi. Ts'ebetso ea NTS e eketseha ho likhoto tse tlisoang ke ho tlosoa ha opiate, e lebisang maemong a holimo a phetiso ea noradrenaline ho amygdala e atolositsoeng.22, e tlatsetsang ho hlahiseng likarolo tse nyarosang tsa ho tlohela22. Ts'ebetso e tsoelang pele ea NTS nakong ea ts'ebeliso e mpe ea lithethefatsi likotong tse itšetlehileng ka tsona ho boetse ho ntlafatsa kutloelo-bohloko ea matla a susumetsang a lithethefatsi tse lemalloang le ho eketsa tlokotsi ea ho khutlisetsoa ho matla kelellong ea boits'oaro ba lithethefatsi (ke hore, ho khutlela morao)16. Boikutlo bo eketsehang ba moputso oa lithethefatsi ho litheko tse ntseng li le teng nako le nako ha bootsoa bo kopantsoe le maikutlo a fokotsehileng a moputso oa lijo23. Kahoo, liphetoho tsa nako e telele tšebetsong ea NTS li ka kenya letsoho molemong oa litheko tsa lithethefatsi tse tlatsetsang le boleng bo fokotsehileng ba lijo le tse ling tsa tlholeho Matlafatsang tse hlahang ho batho ba lemaletseng lithethefatsi23.

Litlhaloso li se li qala ho hlaha liketsahalong tsa ho bua ka limolek'hule ho NTS tse tlatsetsang boteng le bothateng ba lithethefatsi. Mohlala, mothapo oa "vagus" o fetisetsa tlhahisoleseling e amanang le karohano ea ka mpeng ho NTS24, 'me ts'ebetso ea methapo ea setho sa botšehali e hatella ho ja lijo ho likhoto25 le batho26. Boithuto ba mehopolo ea kelello ea motho bo bonts'itse hore sesebelisoa se kenyelletsang ho eketsoa hoa ts'ebetso ea mpa ho arabela ts'usumetsong ea methapo ea setho sa botšehali se eketsa metabolism libakeng tsa kelello tse kenyellelitsoeng moputsong oa lijo le palatability, ho kenyeletsoa OFC, striatum le hippocampus27. Ka ho makatsang, ho buuoa ka bariatric ho batho ba fetang boima ba 'mele ho ka eketsa tšebeliso ea joala28. Liphumano tsena li ts'ehetsa mohopolo oa hore li-NTS li susumetsa ts'ebetso ho li-circuits tsa moputso oa boko mme ka hona li laola ho ja le ho ja lithethefatsi. Litšebelisong, tšusumetso ea methapo ea botšehali e pheta-phetoang e eketsa polelo ea phetisetso ea ΔFOSB ho NTS29. Ka mokhoa o ts'oanang, nts'etsopele ea ts'ebetso ea ho ts'epa opiate ho likhoto e boetse e amahanngoa le polelo e eketsehang ea NTS ea ΔFOSB30. ΔFOSB ke phapang e fapaneng ea sehlahisoa sa mofuta oa FOSB se bolelele bo felletseng31 'me e tsejoa ka hore e bokellana maemong a kelello le a mang a amanang le moputso ka har'a litoeba le litoeba nakong ea ho pepesehela lithethefatsi tse fapaneng,' me e tsoela pele nako e telele kamora hore tlhahiso ea lithethefatsi e khaotse. Ntle le moo, ΔFOSB e eketsa menyetla ea lithethefatsi tse lemalloang, mohlomong ka ho etsa hore ho be le liphetoho lipakeng le likarolong tse eketsang karabelo ea tsona lithethefatsing le litlamong tse amanang le lithethefatsi.32. Kahoo, ho ka etsahala hore ho supa ha ΔFOSB ho NTS ho ka kenya letsoho kholisong ea botena. Ntle le moo, ho bokellana ha ΔFOSB ho NTS ho ka baka keketseho e ts'oanang ea kutloisiso ea litheko tsa lithethefatsi le ho fokotseha hoa kutloisiso ea moputso oa lijo, o hlalositsoeng kaholimo, liphoofolong tse ntseng li tsoela pele ho se fumane lithethefatsi.

Li-neuropeptide tsa nyutlelie e bitsoang "trusususitarius" ka moputso oa lithethefatsi. Ntle le catecholaminergic neurons ho NTS, palo e arohaneng ea li-neuronal e hlahisa li-neuropeptides tse kang proopiomelanocortin (POMC) kapa glucagon-like peptide 1 (GLP1, sehlahisoa se hlakileng sa glucagon). Ka mokhoa o ts'oanang le li-neuron tse nang le li-neurons, li-neurons tsa NTS POMC li kenngoa ts'ebelisong ke balekane ba vagal ho tsoa mokokotlong oa mpa le liphatlalatso tse potolohang satiety, mme ba kenya letsoho ho fokotsa ts'ebeliso ea lijo.33. Ho ntlafatsa phetiso ea POMC ho NTS ho ka baka boima ba 'mele le ho itšireletsa khahlanong le botenya bo khothalletsoang ke ho ja34. Ka ho tsotehang, ts'oaetso ea NTS ea opiates, e tsebahalang ho eketsa takatso ea lijo, e thibela li-neurons tsa POMC33, e fana ka maikutlo a hore lisele tsena li ka bapala karolo ea moputso le opeite ea opiate. GLP1 e hlophisitsoe haholo-holo ke lisele tsa L ea mala, 'me e sebeletsa ho fokotsa litekanyetso tsa tsoekere ea mali le ho tsosa secretion35. GLP1 e boetse e hlahisoa ke palo e nyane ea li-neuron ho NTS e thibelang ho ja lijo36, haholo-holo ha a araba karabelo ea hae ea ka mpeng37, khatello ea maikutlo le bokuli38. Ho sitisoa ha tlhahiso ea GLP1 ho NTS kapa GLP1 receptor ho supa bokong ho fella ka hyperphagia ho likhoto38, ho fana ka tlhahiso ea hore ho nona ho feta tekano ho ka baka bofokoli bohareng ba GLP1 receptor e kenyang letsoho la ho ba le botenya. Ho kenngwa tshebetsong ha li-receptor tsa GLP1 ho NTS mohlomong ho fokotsa tšebeliso ea lijo ka mochine o kenyang protheine kinase C (PKC) -mediated concversal inhibition of AMP-activated protein kinase (AMPK) le li-activation tsa mitogen-activated protein kinase (MAPK)39. Ho fihla joale, likarolo tsa li-receptor tsa GLP1 bokong, mme AMPK le MAPK ho NTS, ho laola moputso oa lithethefatsi le ho its'etleha ha li e-so fumanoe lipatlisiso.

Cortex e kahare ho botenya le bokhoba ba lithethefatsi

Insula le operculum li kenyelletsa le ho boloka tlhaiso-leseling e amanang le valence (ho rata lijo kapa ho se natse) le boholo ba thepa ea hedonic ea lijo tse fumanehang habonolo.1, 10 (Feie. 2). Ntle le karolo ea eona mohopolong oa tatso, semolao se ka boela sa laola boiphihlelo ba litakatso le litakatso tse hlakileng40. Batho kapa litoeba tse nang le phihlello ea lijo tse fumanehang habonolo li bontša ho fokotseha hoa ts'ebeliso ha lijo tse fumanehang habonolo ho feta tse neng li lebelletsoe li fumaneha, ketsahalo e bitsoang phapang e mpe41, 42. Phetoho ena molemong oa lijo tse matlafatsang tse fumanehang, le ho hana lintho tse sa fumaneheng habonolo, li ka bapala karolo ea bohlokoa ho ntlafatseng botena ka ho kenya letsoho ho matlafatseng ts'ebeliso ea lijo tse matlafatsang tse matlafatsang.41, 42. Haholo-holo, marang-rang a tsoang molemong oa ho felisa litlatsetso tse amanang le phepo e mpe43. Ka mokhoa o ts'oanang, lesapo ho "gustatory thalamus" e fumanoang kahare ho NTS, mme merero ea phetoho ho ea lits'oants'o, le eona e felisa phapang e amanang le phepo e amanang le phepo.44. Lithuto tsa batho ba batenya li bonts'a matla a ho hokahanya a sebetsang ho cortex e ka tlasa maemo a phomolo45, mohlomong e bonts'a taolo e fokotsehileng holim'a ts'ebetso ea bohlasoa. Tumellanong le tlhaloso ena, batho ba batenya haholo ba bonts'a ts'ebetso e matlafatsang ea ho amohela lijo tse fumanehang habonolo46. Ho feta moo, batho ba baholo ba kotsing ea ho ba le botenya (batsoali ka bobeli ba ne ba e-na le palo ea 'mele ea boima ba' mele (BMI) ea -27) ba bonts'a ts'ehetso e ntlafalitsoeng ea ts'ebetso le ts'ebetso ea operculum ho arabela meputso ea chelete kapa ea lijo ha e bapisoa le bacha ba kotsing e tlase ea ho holofala. botenya (bobeli ba batsoali ba nang le lintlha tsa boima ba 'mele ba <25)47. Sena se fana ka maikutlo a hore karabelo e ntlafalitsoeng ea boroko, e ka bakang kutloisiso e eketsehileng ea tatso ea lijo tse matlafatsang le phetoho ea takatso ea lijo mabapi le lijo tse joalo, e eketsa tlokotsi ea botenya1.

Ntle le karolo ea eona mohopolong oa tatso le khetho ea lijo, insula e boetse e phetha karolo ea bohlokoa tšebelisong ea lithethefatsi. Ho tsuba ho tsubang ho tsubang ho tsubang ho tsubella ho tsubang ho kopantsoe le ts'ebetso ea mokokotlo oa mokokotlo48. Haholo-holo, tšenyo e amanang le seteraeke e tsubang ea batho ba tsubang e ka baka tšitiso ea ho lemalla koae, e tsejoang ke ho khaotsa ho tsubang ha tloaelo ea ho tsuba le takatso e tlase ea ho tsuba kamora moo49. Ho litoeba, ho kenella ka har'a lik'hemik'hale tsa insula, kapa ho senyeha ha mofuta oa hypocretin receptor 1 (eo hape e tsejoang e le mofuta oa mofuta oa XeUMX orexin receptor mohahong ona, ho fokotseha boits'oaro bo ikemetseng ba nicotine self-management50 le boitšoaro bo batlang amphetamine51. Ka har'a li-neurons tse kenang, kalafo ea koae52 kapa ho pepesehela litloaelo tsa tikoloho tse bolelang hore ho na le lijo tse fumanehang habonolo53 keketseho ea mofuta oa pele oa gene ea pele le phetisetso ea karapo ea karabelo ea peleho ea kholo ea phetoho ea 1 (e tsejoang hape ka hore ke transcript factor ZIF268), e phethang karolo ea bohlokoa ho li-neuronal polasetiki le sebopeho sa memori sa nako e telele. Sena se fana ka maikutlo a hore lijo tse fumanehang habonolo le lithethefatsi tsa tlhekefetso li ka baka likarabo tse ts'oanang ho cortex e kenang. Limpho tse lumelletsoeng ho ja lijo tse fumanehang habonolo li bonts'a ho eketseha ha letšoao la 'mele la MAPK ka kotlaneng e sa keneng.54. Ho feta moo, keketseho ena ea ho saena hoa liphatsa tsa 'mele ea MAPK, mohlomong ka lebaka la NMDA le ts'ebetso ea metabotropic glutamate 5 receptor activation55, e laola ho kenngoa ha memori ea tatso ea nako e telele56. Hanyane hanyane ho tsejoa ka litlamorao tsa lithethefatsi tsa tlhekefetso ho ho saena hoa MAPK ho bohlasoa le ho nka karolo ha hae litloaelong tse batlang lithethefatsi.

Orbitofrontal cortex ka botena le bokhoba

Ho fapana le mohala, o kenyelletsang tlhahisoleseling e amanang le bophahamo le boholo ba thepa ea hedonic ea lijo, OFC e shebahala e tsoela pele ho ntlafatsa leseli le amanang le boleng bo khothalletsoang ba lijo tse fumanehang habonolo, tse ipapisitseng le tlhaiso-leseling e tsoang methating ea metabolic kapa hedonic bokong.57. Kahoo, mohlomong OFC e bapala karolo ea bohlokoa ntlafatsong ea satiety e tobileng maikutlo nakong ea lijo ka lebaka la boleng bo fokotsehileng ba ts'usumetso ea lijo tse filoeng, ntle le liphetoho molemong oa matla a eona a ho phethahala57. Phuputsong e sa tsoa etsoa, ​​baithaopi ba ileng ba botsoa ho nahana ho ja lijo tse lakatsehang (chokolete kapa chisi) ka makhetlo-khetlo ba ile ba ja lijo tse fokolang haholo ha li hlile li le teng ha li bapisoa le palo e jeoang ke batho ba neng ba nahana ho ja lijo tse fokolang. , ba neng ba nahana ho ja mofuta o mong oa lijo tse monate kapa ba sa kang ba nka lijo ho hang58. Ts'ebeliso ea lijo e fokotsehileng e ne e sa amane le phetoho ea boleng bo phahameng ba hedonic, barupeluoa ba ne ba e lakatsa hanyane (ke hore, ba ne ba e-na le satiety e ikhethileng e latelang tšebeliso ea monahano58. Liphumano tsena li bonts'a ka mokhoa o bonolo hore boleng ba tšusumetso ea lijo bo ka arohanngoa le thepa ea eona ea hedon58, 'me li bonts'a bohlokoa ba litsi tsa kholo ea cortical ea tatellano e phahameng e amehang lipapatsong tsa kelello ho hlahisa boleng bo khothalletsoang ba ntho efe kapa efe e fuoeng lijo. Ho shebisisa karolo ea bohlokoa ea OFC mabapi le boleng ba lijo59, liphumano tsena le tse ling tse amanang li fana ka maikutlo a hore ho sitisoa ha ts'ebetso ea OFC ho ka baka tšenyo e sa nepahalang ea boleng bo khothalletsang lijo, ho hlahisang phaello ea boima ba 'mele60. Tumellanong le monyetla ona, botenya ho batho bo amahanngoa le bofokoli bo tšoaeang metabolism ea OFC60. Ntle le moo, 'dementia ea pele ho nako e bakang atrophy ea OFC le insula e baka ho hlaha ha lijo tse ngata tse monate bathong.61. Haufinyane, ho bonahetse hore ts'ebetso ea li-receptor tsa mu opioid ho OFC e kenya hyperphagia ka likhoto62. Sena se fana ka maikutlo a hore phetisetso ea opioid receptor ea lehae ho OFC62, e ka susumetsang ts'ebetso ea lipotoloho tse thellelisang ka tlase ho striatum (bona ka tlase), e laola boitšoaro ba ho fepa.

OFC e kanna ea bapala karolo ea bohlokoa ho hlahiseng boleng ba tšusumetso ho koae le lithethefatsi tse ling tsa tlhekefetso. Inactivation ea lik'hemik'hale ea OFC e entse likhoto li sa ananele liphetoho lipakeng tsa boleng bo matlafatsang ba litekanyetso tse fapaneng tsa cocaine tse neng li fumaneha bakeng sa ho itaola ka matla63. Metsoako ea OFC e boetse e thibela bokhoni ba likoluoa ​​tsa tikoloho tse kengoang ke lithethefatsi tse bolelang esale pele hore lijo tse fumanehang habonolo kapa ho fumaneha ha lithethefatsi ho khanna boits'oaro bo batlang64, 65, mohlomong ka ho senya ts'oaetso ea ho se tsotelle lintho tse sebelisoang ke lijo kapa tse tlisoang ke lithethefatsi66. Nalane ea ts'ebetso ea ts'ebetso ea ts'ebetso ea koae ka har'a litoeba, kapa ho pepesetsoa khafetsa ho amphetamine, e baka liphetoho lipakeng tsa OFC ea likhoto tse amanang le bofokoli mosebetsing oa ts'ebeliso ea kelello ea koae ea koae.67, 68. Ho latela liphumano tsena le tse ling tse tšoanang, ho hlahisitsoe tlhahiso ea hore tšebeliso ea lithethefatsi ea OFC e ka kenya letsoho phetohong ea ho tloha ts'ebetsong e laoloang ho ts'ebeliso e sa laoloang ea lithethefatsi ho lemeng.67, 69. Mehato ea motheo ea limolek'hule tse kenyang ts'ebetsong ea ho sebetsoa ke OFC e se e qala ho hlaha. Litšebelisong, tšebeliso ea nakoana ea koae kapa joala bo bongata bo eketsa tlhahiso ea increasesFOSB ea sengoloa ho OFC70. Keketseho ena ea polelo ea ΔFOSB ho OFC e mpefatsa keketseho ea boits'oaro bo sa ts'oaneng le bo bonoang nakong ea ho khaotsa ho itaola ka nako e telele ea koae.71. Ha keketseho ea khetho e sa qobelloang e nahanoa hore e eketsa tlokotsi ea ho lemalla, ho eketsoa ke lithethefatsi ho ΔFOSB ho OFC ho ka tsamaisa nts'etsopele ea bokhoba ba tahi. Ka hona ho tla ba bohlokoa ho tseba hore na tšebeliso e matla ea lijo tse matlafatsoang ka mokhoa o ts'oanang e eketsa polelo ea ΔFOSB ho OFC, le hore na sena se na le ts'oaetso ea ho ba motenya.

Sisteme ea Mesostriatal ea botena le bokhoba ba tahi

Tlhahisoleseling e amanang le matla a kutlo a lijo tse monate, tse sebetsoang ho OFC le mehahong e meng ea cortical, e fetisetsoa ho lipotoloho tse amanang le ho fepa ka striatum, haholoholo ho tse bitsoang 'libaka tse chesang tsa hedonic' sebakeng sa khetla sa NAc. Libaka tse chesang tsa Hedonic ho bokelletseng morero le ho laola tšebetso ea libaka tsa bokong tsa 'mele tsa hypothalamic le pallidal. Ts'ebetso ena ea striatohypothalamic le striatopallidal, e laoloang sebakeng sa heno ke lets'oao la opioid le endocannabinoid hape le phetiso ea dopamine e hlahang ho mesoaccumbens le nigrostriatal input, taolo ea karabelo ho tšusumetso ea tikoloho e bolelang esale pele ho fumaneha ha lijo le ho ba bonolo, mokhoa oa boitšoaro le boits'oaro ba boleng ba tšusumetso lijong tse hlabosehang.1.

Ntle le matla a ho hlahisa lijo tse matlafatsoang, striatum e boetse e bapala karolo ea bohlokoa ho arabeleng litlamorao tsa ho kenella kahare tsa metabolism ea lijo72. Haholo-holo, ho lokolloa ha li-macronutrients tse tsoang lijong tse matla-ngata ho ka matlafatsa lits'ebetso tse tšoaeang metabolic ho viscera mme ka tsela eo tsa tsosa mats'eliso a dopamine ho li-circuits tsa phepelo ka striatum, ka boikemelo ba thepa ea maikutlo73, 74. Sesebelisoa se sebetsang sa nakoana se fumanehang se ka sebelisang mocha oa 5 (TRPM5) se hlokahala bakeng sa ho fumana tastants e monate, e bohloko le amino acid (umami).75. E hlatsoehileng mahlo Trpm5 litoeba tse tsoang mona ha li bonts'e khetho ea ho ikapesa metsi ha e hlahisoa hakhutšoanyane ka khetho pakeng tsa tharollo ka bobeli73, 74, ho netefatsa ho hloleha ha bona ho fumana tharollo e monate. Leha ho le joalo, ha Trpm5 litoeba tse tsoang mona li ne li lumelloa khafetsa ho fihlela metsi kapa li-sucrose dilores libakeng tse haelloang ke liteko, ka hona li khona ho hokahanya litlamorao tsa metsi kapa tsa boits'oaro ka boitšoaro ba tsona ba ho phethela, li bonts'a khetho e hlakileng bakeng sa tharollo ea sucrose. Habohlokoa, the Trpm5 litoeba tse tsoang mona ha lia ka tsa khetha ho khetholla scralose e seng caloric tlasa maemo a teko e le 'ngoe, ho bonts'a hore litlamorao tsa ho chesoa ke moea ka mor'a sucrose li ikarabella bakeng sa ho eketseha ha khetho ea sucrose ho litoeba tsa ho kokota73, 74. Sucrose e ile ea eketsa maemo a dopamine ho NAc le dorsal striatum ea Trpm5 Litoeba73, 74, e fana ka maikutlo a hore matšoao a senang metabolism a sa hlokofatsoang ka har'a litoeba tsa Knoutout a ne a lekane ho tsosa li-neurb tsa dopamine neurons tse tsamaisang khetho ea litharollo tse matla tsa khalori. Ka ho makatsang, Trpm5 liteishene tse lelemeng le tsona li laola likarabelo tsa tatso ho nicotine le joala, hape li kenya letsoho ho ts'ebeliso ea bona e fokolang76, 77. Sena se fana ka maikutlo a hore, ntle le liketso tsa bona tse tobileng bokong, leseli la maikutlo le amanang le lithethefatsi tse sebelisitsoeng khafetsa kapa tse tahiloeng ka molomo li tlatsetsa ho bona.

Ho bontša liketsahalo tse theohelang nokeng ea dopamine receptors. Lijo tse bobebe kapa lithethefatsi tsa tlhekefetso, le litloaelo tsa tikoloho tse boletseng peleho ea tsona, li eketsa phetisetso ea dopamine ka striatum, ka hona li susumetsa li-circriatohypothalamic le li-striatopallidal potoloho tse laolang thepa ea hedonic le e khothalletsang lithethefatsi le lithethefatsi tse hlekefelitsoeng.1. Karolo ea phetisetso ea dopamine ho fetofetoha hoa botenya, ho kenyelletsa le menehelo ea liphetoho tse amanang le phepo le lijo tse ntlafalitsoeng mosebetsing oa dopamine receptor e hlahlobiloe ka botlalo libakeng tse ling.1, 12, 78. Mona, ho tla shebanoa bopaki bo hlahang bo fanang ka maikutlo a hore lithethefatsi tsa tlhekefetso le lijo tse fumanehang habonolo li kopana lits'oants'o tse tloaelehileng tsa "cretas" le "li-" "midprain dopamine neurons" tse ts'ebetsong ea striatum, tse tlatsetsang tlatsong ea lithethefatsi le boteng (Feie. 4). Cocaine le lithethefatsi tse ling tsa tlhekefetso li eketsa polelo ea ΔFOSB hohle striatum, haholo-holo ka D1 dopamine receptor le dynorphin e bontšang lipakeng tsa "spiny neurons" tse bohareng. tsela e otlolohileng79. Ntle le moo, ho bokelloa ha ΔFOSB butle-butle ka ts'ebeliso ea ts'ebeliso ea lithethefatsi ho eketsa thepa ea bona e khothalletsoang, eo ho nahanoang hore e kenya letsoho kholisong ea bokhoba ba lithethefatsi80. Ho khahlisang, litoeba tse ileng tsa pepesetsoa lijo tse nang le mafura a mangata nakong ea pelehi kamora ho peleho (matsatsi a morao-rao a 21-28) bakeng sa beke ea 1 li ile tsa rateha haholo bakeng sa ho ja mafura a mafura tsebong81, 'me sena se eketsehile se ratoang ke lijo tse letsoalo tse matla li kopantsoe le liphetoho lipakeng tsa phetoho ea limolek'hule tsa dopamine receptor signaling81. Ka ho khetheha, maemo a ΔFOSB a ile a eketseha ho NAc ea litoeba tsena81. Ka mokhoa o ts'oanang, polelo ea "ΔFOSB" e ntseng e eketseha setulong e fumanoe litoeba tsa batho ba baholo tse neng li lumelloa ho ja lijo tse matla tse phahameng kapa tse matla.82, 83, 84, mme phello ena e ne e amahanngoa le tšusumetso e ntlafalitsoeng ea ho ja lijo tse matlafatsang. Ntle le moo, litoeba tse nang le phihlello ea lijo, ka hona li ne li lapile ebile li susumetsoa haholo ho ja lijo, le tsona li bonts'itse polelo ea riFOSB e eketsehang85.

Setšoantšo sa 4 | Intracellular signature cascades in the striatum and mesoaccumbens dopamine tsela e laolang ho ja lijo le tšebeliso ea lithethefatsi.

Setšoantšo sa 4: li-cascade tse bonts'ang linthla tse tsamaeang tseleng ea striatum le mesoaccumbens dopamine tseleng e laolang ho ja lijo le tšebeliso ea lithethefatsi. Ka bomalimabe ha re khone ho fana ka lingoloa tse ling tse fumanehang bakeng sa sena. Haeba o hloka thuso ho fihlella setšoantšo sena, kapa ho fumana litlhaloso tsa mongolo, ka kopo ikopanye le nppn@nature.comLi-receptors tsa leptin, insulin le neurotrophic factor (TRKB) li hlahisoa sebakeng se bitsoang ventral tegmental area (VTA) dopamine neurons, moo li laolang phosphinositide 3-kinase (PI3K )ssine / threonine kinase AKT-mammali sepheo sa rapamycin ( mTOR) sesupo sa bohlasoa. Leptin e ka laola le JAK-STAT (Janus kinase-sign transducer le activator of transcript) tsela e bonts'a tsela. Leptin, insulin le BDNF ho saena hoa hlokahala ho boloka dopamine homeostasis, mohlomong ka liketso tse kenyelletsang papali ea PI3K ea sesupo. Lithethefatsi tsa tlhekefetso joalo ka koae li ka baka PI3K-AKT-mTOR ho tšoaea li-neuron tsa midbrain dopamine. Li-receptor tsa insulin le tsona li ka hlalosoa ka mokhoa o hlakileng maemong a dopamine a bokong ba li-nucleus, le li-postynaptically tse methapong ea methapo e bohareng, tse hlahisang dopamine D1 kapa D2 receptors, seo ho thoeng ke li-neurons tsa tsela tse tobileng le tse sa tobang. Li-insulin receptor ka har'a li -benbens li khothalletsa ho lokolloa ha dopamine le ho ntlafatsa tšebetso ea phepelo ea dopamine (DAT), 'me ka tsela eo e bapala karolo ea bohlokoa ho accopal dopamine homeostasis. Mohlomong ketso ena e kenya letsoho liketsong tse amanang le insulin tsa insulin le bokhoni ba eona ba ho fokotsa lijo tse fumanehang habonolo. Ka lehlakoreng le leng, lithethefatsi tsohle tse kholo tsa tlhekefetso li hlohlelletsa ho lokolloa hoa dopamine ka hara li-bokells, ketso e nkuoang e le bohlokoa ho thepa ea bona e susumetsang. Dopamine signature ka har'a li-accumbens e hlophisa tšebetso ea ΔFOSB, cyclic AMP-e arabelang e tlamang protheine (CREB), protheine phosphatase 1 subunit 1B (DARPP32) le li-cyclin-based kinase 5 (CDK5) tse tsamaisang methapo ea methapo le methapo ea methapo ea methapo le methapo ea methapo ea methapo Melemo ea lijo le lithethefatsi tse lemalloang. Li-Neuropeptides tse hlahisoang hamorao ho hypothalamus (LH) le tsona li ka fetola tšebetso ea VTA dopamine le li-neuron tsa striatal. Li-neuron tsa LH tse hlahisang hypocretin (eo hape e tsejoang e le orexin), li qala ho VTA le ho laola li-neuropel tsa VTA le ho arabela ha tsona lijong tse fumanehang habonolo le lithethefatsi tse lemaletseng. Li-neurons tsa LH tse hlahisang morero oa li-hormone tsa melanin-tsepisang kelello (MCH) ho li-accumbens le ho laola thepa e susumetsang ea lijo le lithethefatsi tse tlatsetsang, hape le karabelo ea li-neuron tsa spiny tse bohareng, ka li-receptors tsa MCH tse boletsoeng sebakeng sena. Litsi tsa mantlha tsa ketso tsa lihlopha tse kholo tsa lithethefatsi tse lemallo li bontšitsoe (li bonts'itsoe ka mabokose a bofubelu). IRS, insulin receptor substrate; HCRTR1, mofuta oa hypocretin receptor 1; S6K, protheine ea ribosomal S6 kinase β1.


Transgenic overexpression ea ΔFOSB ka har'a striatum, haholo-holo ka li-neurons tsa tsela e tobileng, e hlahisitse likarabo tse kholo bakeng sa meputso ea lijo tlasa lenane la kemiso e tsitsitseng le e tsoelang pele ea matlafatso, a fana ka maikutlo a hore ΔFOSB e eketsa thepa e matlafatsang ea lijo86. Liphumano tsena li ts'oana hantle le karabelo tse ntlafalitsoeng tsa koae ka tlasa kemiso e tsitsitseng le e tsoelang pele ea kemiso e khothalletsoang ke ts'ebetso ea indFOSB87. Tšebeliso ea lijo tse matlafatsang tse nang le mafura a mangata li ka fetisa liphokotso tse ngata tse amanang le dopamine receptor-signaling cascades seterekeng sa litoeba tsa ΔFOSB-overexpressing88. Lits'oaetso tsena li kenyelletsa ho fokotseha ha protocol factor cyclic AMP-reactionful element binding protein (CREB), protein phosphatase 1 subunit regunit 1B (DARPP32) le neurotrophic factor (BDNF)88. Ntle le moo, matšoao a tlhahiso ea dopamine le tokollo, haholo-holo tyrosine hydroxylase, tekanyo e fokotsang sekhahla sa tlhahiso ea dopamine, le protheine ea dopamine transporter (DAT) e ile ea fokotseha sebakeng sa "ventral tegmental" (VTA) -striatum axis ea ΔFOSB- litoeba tse ngata tse nyenyefatsang88, e fana ka tlhahiso ea hore litoeba tsa ΔFOSB-overexpressing li fokotse tlhahiso ea dopamine lits'ebetsong tsa midbrain le ho fokotsa tlhahiso ea dopamine ho striatum. Bopaki ba pherekano ea dopamine e fetisitsoeng ho litoeba tsa ΔFOSB-overexpressing bo ile ba ntlafatsoa ke phihlello ea lijo tse nang le mafura a mangata bakeng sa libeke tsa 688. Sena se fana ka maikutlo a hore lijo tse fumanehang hantle li kanna tsa eketsa boleng ba susumetso ho litoeba hobane li ka hlakola bofokoli ba dopamine signaling. Ha e kopantsoe hammoho, lintlha tsena li khothaletsa matla a hore matšoao a senang maikutlo a riFOSB a laola likarolo tse susumetsang tsa lijo le lithethefatsi tsa tlhekefetso. Ho bohlokoa ho hlokomela, leha ho le joalo, hore phaello ea boima ba 'mele e ts'oana le mofuta oa litoeba tse hlaha le tsa ΔFOSB-oxpxpinging ka fihlella ho tloaelehileng chow kapa lijo tse nang le mafura a mangata.88. Ka hona ke monyetla o makatsang oa hore ts'ebeliso ea caloric kapa likarolo tse ling tsa metabolism li ka eketsoa ho litoeba tsa ΔFOSB-overexpressing ho lefella khothatso ea bona e eketsehileng ea ho batla lijo, monyetla o sa kang oa lekoa.

Likarolo tse ling tsa dopamine receptor signing ka striatum e boetse e laola thepa ea ts'usumetso ea lithethefatsi ka bobeli tsa tlhekefetso le lijo. Mohlala, polelo ea cyclin-based kinase 5 (CDK5) ho striatum e laoloa ke ΔFOSB le cocaine89, 90. Ts'oarelo ea pharmacological kapa genetic ea CDK5 signaling in striatum e eketsa moputso oa koae ka litoeba91, 92. Sena se fana ka maikutlo a hore keketseho e bakoang ke lithethefatsi ho polelo ea CDK5 ka striatum e kanna ea ba karabelo e lumellanang liseketeng tsa meputso ea kelello ho loants'ana le litlamorao tsa koae 'me ka hona e sirelle khahlano le ts'ebeliso ea lithethefatsi.93. Ho sitisoa ha matšoao a CDK5 ho bokong ho boetse ho eketsa litšusumetso tsa lijo tse susumetsang92, e fana ka maikutlo a hore mekhoa e tloaelehileng ea biochemical ho striatum e laola thepa e khothalletsoang ea lithethefatsi tse lemalloang le lijo. Qetellong, ts'ebetso ea D1 dopamine receptor signature striatum e tsejoa ho baka dephosphorylation ea DARPP32 libakeng tse setseng tsa serine 97. Ho khutlisoa ha serine 97 le sebaka sa bolulo sa alanine, ka tsela eo ho thibela molao oa phosphorylation-mediated oa DARPP32 ka sebaka sena sa marang-rang, ho fella ka ho fokotseha ho hoholo ha maikutlo a thepa ea khothalletso ea koae le meputso ea lijo.94. Ha ho etsoa liphuputso tsena, re fana ka bopaki bo matla ba hore li-cascade tse tšoanang tse entsoeng ka dopamine seterekeng li laola lintho tse khothatsang tsa lithethefatsi tsa tlhekefetso le lijo, le hore tšitiso ea likhase tsena li ka kenya letsoho kholisong ea botena kapa bokhoba.

Neuropeptide le ho ts'oaroa hoa li-hormone

Ntle le liketsahalo tse theohelang tse tlase tse amanang le ts'ebetso ea dopamine receptor, lijo tse fumanehang habonolo le lithethefatsi tsa tlhekefetso li ka baka li-neuroplasticity literekeng tsa phepelo ea striatal ka li-regonal tsa li-hormone le li-neuropeptide tsa botsitso. Li-neuropeptide tse peli tse kholo tse hlahisoang ho hypothalamus ea morao le tse tsejoang ka ho fetola mekotla ea phepelo ea striatal le tlhahiso ea dopamine litseleng tsena, ke li-hormone tsa "melanin" (MCH) le hypocretin (eo hape e tsejoang e le orexin). MCH le hypocretin li hlahisoa ho hypothalamus ea morao95 - tikoloho ea boko e kenyelletsang ho laola boits'oaro ba ho fepa le ho lokisa moputso - le keketseho ea MCH kapa hypocretin signaling e hlohlelletsang boitšoaro ba ho fepa96, 97. Ho khahlisang ke hore, liphatsa tsa lefutso tse tsoang ho hypocretin neurons ho hypothalamus ea morao-rao li lebisa ho nona ho feta tekano, ho nona le ho nona haholo ho litoeba.98, ho fana ka maikutlo a hore phetisetso ea hypocretin e bapala karolo e thata ho laoleng ho ja lijo le ho nona ka boima ba 'mele. Li-receptors tsa MCH li hlahisoa ho NAc, ka ts'ebetso ea li-receptors tsena tse susumetsang boitšoaro ba phepo99 le ho thibela ho thunya ha neuron ea neuron100. Litlamorao tsena li ka kenyelletsa ho fokotseha hoa ts'ebetso ea cymbase ea adenylyl, le phokotso e latelang ea ts'ebetso ea CREB, le ho fokotsoa ha polelo ea AMPA glutamate receptor subunit 1 (GluR1)100. Tšitiso ea ho saena hoa li-MCH receptor ho NAc e thibela litlamorao tse thabisang le tse fumanehang tsa moputso oa koae ho litoeba101. Ntle le moo, ho fokotseha hoa ho sa sebetseng hoa MCH receptor ho NAc ho boetse ho fokotsa ho itaola kahare ho koae le ho thibela boits'oaro bo tšoanang.101. Morero oa li-neurons o nang le "Hypocretin" o tsoang ho "lateral hypothalamus" ho ea ho VTA, moo mofuta oa hypocretin receptor 1 (HCRTR1; hape o tsejoang e le mofuta oa mofuta oa li-orexin receptor 1) o bapala karolo ea bohlokoa ho tsamaiseng phetiso ea mesolimbic dopamine le thepa e tlisang melemo ea lithethefatsi tse fapaneng tsa tlhekefetso le lijo. mohlomong ka taolo ea li-cascade tse tsamaeang le PKC tse ts'ehetsang102, 103, 104. Ka kakaretso, li-neuropeptide tse amanang le phepo, joalo ka MCH le hypocretin, li na le likarolo tsa bohlokoa ho laola tšebeliso ea lijo le lithethefatsi ka ho fetoloa hoa ts'ebetso ea meputso, mme mohlomong li kenya letsoho kholisong ea botena le bokhoba.

Leptin o supa sebakeng se sarolohang sa ventral. Ntle le li-neuropeptide tsa hypothalamic, li-hormone tse laolang takatso ea lijo tse hlahisoang ka viscera li ka etsa mosebetsi oa moputso oa boko. Mohlala, ghrelin, e hlahisoang ka mpeng le manyeme, e ka eketsa takatso ea lijo le takatso ea lijo. Karrelin e sebetsa ka tsela e 'ngoe ka ho susumetsa phetiso ea thobalano ea dbamine mme ka tsela eo e eketsa sepheo sa lijo kapa lithethefatsi tsa tlhekefetso105. Taolo e 'ngoe e kholo ea li-hormone ea matla a lekanyetsang tšebetso ea moputso oa boko ke leptin. Khaello ea Congenital leptin e baka ts'ebetso e matla ea ts'ebetso ea striatal ho arabela litšoantšo tsa lijo106, le phekolo e nkang leptin e fana ka ts'ebetso e matla ea ho rata lijo ho batho bao106. Leptin e ka fetolela likarabo tsa striatal lijong ka ho laola mesolimbic dopamine pathways. Li-receptor tsa Leptin li hlahisoa ka li-neuron tsa midbrain dopamine107, 108, 109, le ho kenngoa ha leptin ho VTA ho thibela tšebetso ea li-dopamine neurons109, e fokotsa takatso ea lijo109, 110, 111 le induces ka kakaretso e fokotseha ha kutloisiso ea maikutlo ho fumana moputso ka likotlo111. Ka lehlakoreng le leng, ho kokota ha li-leptin receptors ho VTA ka likhoto ho eketsa ho rata lijo tse fumanehang habonolo109 'me e ntlafatsa likarolo tsa khothalletso tsa lijo112. Literekeng tsa hypothalamic, jak-STAT (Janus kinase-sign transducer le activator of transcript) ke tsela e kholo eo ka eona leptin e tšoaeang molaetsa oa eona anorexigenic liphello113. Ts'oaetso ea leptin ho VTA, litekanyetso tse fokotsang boits'oaro ba phepo, li kenya ts'ebetsong papali ea JAK-STAT109, 110, le inhibition ea JAK-STAT signaling ho VTA e bonts'a litlamorao tsa leorein110. Phekolo e sa foleng ea koae e bontšitsoe ho tšoaetsoa hoa JAK-STAT ho VTA114. Ka hona ho reriloe hore ho eketsoa hoa koae ka lebaka la cocaine e hlahisitsoeng ke JAK-STAT ho saena le VTA ho ka kenya letsoho litokisetsong tsa nako e telele li-circuits tsa meputso ea boko tse tlatsetsang ho lemalleng koae ea koae. Ntle le moo, ka ho sebetsa ka mokhoa o ts'oanang leptin, ho ka etsahala hore keketseho e hlahisoang ke koae ho JAK-STAT ho saena ho VTA ho ka kenya letsoho mefuteng ea anorexigenic ea lithethefatsi.

Insulin e tšoaea sebaka sa "ventral tegmental" sebakeng. Insulin ke molao o mong o laolang li-hormone ea matla o ka susumetsang tšebeliso ea lijo ka ho fetola li-circuits tsa phepelo ea striatal le lipilisi tsa "midbrain dopamine" ho li-circuits tsena. Insulin e kenya tšebetsong insulin receptor le cascade e tšoaeang e kenyeletsang insulin receptor substrate (IRS) -mediated activation of phosphoinositide 3-kinase (PI3K). PI3K hamorao e kenya tšebetsong tyrosine-protein kinase BTK (e tsejoang hape e le ATK), e ntan'o qobella sepheo sa phoofolo ea matsoalloa a rapamycin (mTOR) le phello ea eona e theohelang ea protos ribosomal S6 kinase β1 (S6K1). Li-receptor tsa insulin li hlahisoa ho striatum115 le li-neuron tsa midbrain dopamine neurons107. Ho kenngoa ha insulin ho VTA ho fokotsa ho kenella ha lijo ho likhoto111, 116, ka lehlakoreng le leng, ho tlosoa ha li-insulin receptor ka har'a li-neuron tsa dbamine ka har'a litlamorao ho hlahisa hyperphagia le ho eketsa boima ba 'mele ha ho bapisoa le litoeba tse laolang.117. Litlamorao tsena li amana le tahlehelo ea lipontšo tsa insulin tse susumetsoang ke insulin117. Likhoto tsa lefu la tsoekere li fokotsehile haholo litekanyetso tsa dopamine libakeng tsa boko le maqhubu a kelello 'me ha li amehe haholo ka mehloli e metle ea methamphetamine ho feta likhoto tse laolang insulin.118, 119, ho bonts'a hore ho tšoaea insulin hoa hlokahala ho boloka phetisetso ea dopamine. Lintlha tsena li fana ka maikutlo a hore ts'ebetso e matla ea li-insulin receptor ho VTA e ka fokotsa ts'ebetso ea li-neuron tse nang le dopamine sebakeng sena sa boko. Leha ho le joalo, insulin e shebahala e sebetsa ka tsela ea neurotrophic ho VTA joalo ka tšitiso ea insulin signaling e baka bofokoli phetisong ea dopamine.

Tšitiso ea polelo ea BDNF ho pholletsa le 'mele o kenelletseng, kapa ka ho khetheha ho VTA, e baka hyperphagia le phaello ea boima ba litoeba, haholoholo ha ho lumelloa ho fihlella lijo tse matlafatsang tse nang le mafura a mangata.120, e ts'oanang le litlamorao tsa ho koala li-insulin receptor ho VTA. Ho feta moo, depletion e bohareng ea BDNF e amahanngoa le khaello e kholo ho lets'oao la dopamine ho NAc, e fana ka maikutlo a hore, joalo ka insulin, BDNF e bohlokoa ho boloka maemo a nepahetseng a mesolimbic dopamine a saena120. Ka ho tsotehang, ntle le litlamorao tse matla tsa leptin ho li-neurons tse nang le VTA dopamine le boits'oaro bo hlalositsoeng ka holimo109, 121, hyperphagic ob / ob litoeba, tseo ho tsona lets'oao la leptin le sitisoang, li na le litheko tse tlase tsa tyrosine hydroxylase ho li-midbrain dopamine neurons, senotlolo sa bohlokoa ka har'a biosynthesis ea dopamine108. ob / ob litoeba le tsona li fokolitse tlhahiso ea dopamine ho NAc108 mme e fokotse mabenkele a somatodendritic vesicular a dopamine ho VTA122. Mefokolo ena ho ho saena ha dopamine e thatafatsoa ka kalafo e nang le leptin ea kantle108. Hammoho, liphuputso tsena li fana ka maikutlo a hore insulin, BDNF le leptin, tseo kaofela li ka tšoaeang ka phallo ea PI3K-serine / threonine kinase AKT-mTOR, lia hlokahala bakeng sa tlhahiso e nepahetseng ea dopamine le phetiso ea matšoao. Khaello liketsong tsa bona e sitisa mesoaccumbens dopamine system le ho eketsa boits'oaro ba phoofolo ho ja lijo tse nang le mafura a mangata haholo le ho holisa botenya. Ho fapana le matla a susumetsang a lijo tse hlabosehang le boima ba 'mele ho litoeba tse nang le insulin e senyehileng, BDNF kapa leptin e tšoaeang ho VTA, litoeba tsena li bonts'a ho fokotsa kutloisiso ho litlamorao tsa ts'usumetso ea kelello le amphetamine.108, 117. Ntle le moo, tšitiso ea papali ea PI3K-AKT-mTOR e bonts'a VTA, e fumanoang ka polelo e tšoaelitsoeng ke vaerase ea proteni e ngata e mpe ea insulin receptor substrate 2 (IRS2), e fumana thepa ea moputso ea koae le morphine ho litoeba.123, 124. Kahoo, ho ka etsahala hore tšitiso ea insulin, BDNF le leinin signing ho VTA ha e eketse feela tekanyo ea ho ba motenya, e leng ho ka bonts'ang ho tsitsipana ha hedonic ho hlola mmuso o mobe o amanang le ts'ebetso e sa sebetseng ea midbrain dopamine1, empa hape e fokotsa kutloisiso ho thepa e ruisang ea lithethefatsi tse lemalloang joalo ka koae kapa morphine.

Insulin e tšoaea striatum. Insulin e eketsa polelo ea DAT le ho sebetsa ho striatum ka tsela e hlophisitsoeng ea IRS-PI3K125. Ho feta moo, insulin e hlahisa litlamorao tsa cocaine e lokollotsoeng ho dopamine litheong tsa dopamine, phello e thibetsoeng ke thibelo ea PI3K125. Ka mokhoa o tsotehang, ho kenella ka mokhoa o tobileng oa insulin ho NAc ho mpefatsa ho hlaha ha boits'oaro bo sa ts'oaneng le litheko tse tšoaroang ka koae.125, joalo ka ha ho lekantsoe molemong oa khetho ea metsotso e mehlano ea ho khetha. Maemo a phahameng a ho ba le ts'usumetso mosebetsing ona o tsejoa ho bolela tlokotsi ho nts'etsapele boits'oaro bo ts'oanang le "cocaine" bo litloaelong126, 'me batho ba nang le maemo a phahameng a phello e phahameng ea tlhaselo ba kotsing e kholo ea ho lemalla lithethefatsi kapa botenya127. Ka hona, insulin e bolelang sebakeng sa heno striatum e ka ba le ts'oaetso ea ho lemalla ho lemalla ka hara Cascade ea IRS-PI3K-AKT-mTOR. Mohopolo oa hore sekhukhu sa PI3K-AKT-mTOR se na le karolo ea ho lemalla se boetse se ts'ehetsoa ke ho fumana hore pharmacological inhibition ea mTOR signaling sebelisa rapamycin, haholo-holo ho NAc, e fokotsa thepa e khothalletsoang ea koae ka litoeba le litoeba128. Qetellong, tsela ea PI3K-AKT-mTOR e tsejoa e bapala karolo ea bohlokoa ho tepelletseng ha nako e telele (LTD)129, ts'ebetso eo matla a eona a synaptic pakeng tsa li-neuron a fokotsehang ka nako e telele. Striatal LTD hape e its'etleha holima endocannabinoid le metabotropic glutamate receptor signature le sethala sa nakoana se fumanehang sa "cation" sethaleng sa V setho 1 (TRPV1), tseo kaofela li tsebahalang ho laola thepa ea moputso ea lithethefatsi tse lemalloang le tšusumetso ea ho sebelisa lijo tse fumanehang habonolo. Ka mokhoa o tsotehang, ho tlohela khoebo ea koae ho ka baka liphoso tsa ho kenya ts'ebetsong ea striatum130 hape ho lumellana hoa fokotseha ha e bua ka mokhoa o hlakileng oa likarolo tsa mantlha tsa PI3K-AKT-mTOR signaling Cascade131. Khaello ena ho LTD butle-butle ea hlaphoheloa nakong ea nako e telele ea ho ithibela ho sethethefatsi sa "cocaine" ka litoeba130. Leha ho le joalo, ho se atlehe ho hlaphoheloa ha striatal LTD kamora nako ea ho fihlella koae ka nako e telele ho amana le ho hlaha ha boits'oaro bo joalo ba bokhoba.130. Kamora nako, lijo tse bitsoang lijo tsa bophirimela, tse nang le tsoekere e ngata le mafura, li na le mafura a mangata a mafura a omega 3, 'me ka lebaka leo, batho ba batenya ha ba na khaello ea phepo ena ea bohlokoa.132. Khaello ea Omega 3 ho litoeba e etsa hore ho be le khaello e makatsang naheng ea LTD132, e fana ka tlhahiso ea hore bofokoli ba "striatal LTD" bo bakoang ke bofokoli ba lijo bo ka kenya letsoho kholisong ea bokhoba ba lithethefatsi le botenya.

Ho ruruha bothateng le bokhobeng ba lithethefatsi

Bopaki bo hlahang bo fana ka maikutlo a hore induction ea PI3K-AKT-mTOR-e itšetlehileng ka USB bokong e itšetlehile haholo ka "caspase 3", molek'hule e bonts'a ho ruruha le apoptosis. Ka ho khetheha, ts'ebetso ea li-receptor tsa NMDA ho arabela ts'ebetsong ea synaptic e eketsa litekanyo tsa calcium tsa intracellular, e sebetsang ka calcium e itšetlehileng ka calcium phosphatase calcineurin133. Sena le sona se eketsa tokollo ea cytochrome c ho tloha mitochondria ka mochine o itšetlehileng ka lintlha tsa pro-apoptotic BCL-XL (BCL2 antagonist ea lefu la sele), XIAP (baculoviral IAP e pheta-phetang e nang le protheine ea 4) le theopoposis registara BAX133, 134. Cytochrome c le eona e kenya ts'ebetsong caspase 3, eo ka nako eo e laolang sebopeho sa AMPA receptor subunits le induces LTD ka tsela ea AKT133, 134. Habohlokoa le ho feta, Caspase 3 e bapala karolo ea bohlokoa ho tšoaetsong ha lets'ollo bokong, ho kenyeletsoa libaka tsa dopamine tsa striatal le midbrain135, 136, e fana ka maikutlo a hore tsela ea ho ruruha bokong e ka thusa ho lemalla lithethefatsi le boteng.

Nuclear factor-κB e supang botenya le bokhoba ba tahi. Ho qala ts'ebetso ea li-cascade tse tšoaetsanoang ho baka ts'ebetso ea nyutlelie-κB (NF-κB), ntho e hatisang e eketsang phetisetso ea li-cytokines tsa proinfigueatory le mefuta e meng e amehang karabong ea cellular ho senya, ts'oaetso le khatello ea maikutlo (Feie. 5). Adipocytes e hlahisa li-cytokine tse ngata tse fokotsang, 'me botenya bo amahanngoa le boemo bo sa foleng ba ho ruruha liseleng tse poteletseng.137. Ho ruruha libakeng tsa boko tse nkang karolo ho laoleng lijo tse ka jang karolo ea bohlokoa ho holiseng botona. Ho litoeba tse lumelletsoeng ho ja lijo tse nang le mafura a mangata le boima bo feteletseng ob / ob litoeba, inhibitor ea NF-κB kinase subunit-β (IKKB) -NF-κB signaling e phahamisitsoe ka mokhoa o sa tloaelehang ho li-neurons tsa mediobasal hypothalamus (MBH)138. Ho feta moo, pherekano ea liphatsa tsa lefutso ea IKKB-NF-κB e tšoaeang MBH, haholo-holo ka li-neurons tse amanang le peptide (AgRP) tse amanang le agouti setsing sena (Feie. 1), e sireletsa litoeba boteng ha li lumelloa ho ja lijo tse nang le mafura a mangata138, ha ts'ebetso ea ectopic ea ts'ebetso ea IKKB-NF-κB e tšoaea MBH e baka insulin e bohareng le ho hanyetsoa hoa leptin (likarolo tsa bohlokoa tsa 'mele tsa botena)138. Ho tlosoa hoa ka ho khetheha ha bosholu ba MyD88, protheine ea bohlokoa ea adaptara eo ka eona li-receptor tse tsoang ho eona (likarolo tsa mantlha tsa sesole sa kahare sa motlakase) li hlahisang ho saena NF-κB, hape e sirelletsang litoeba ho ho nona boima le ho nts'etsapele leptin lijo tse nang le mafura a mangata139, e ts'ehetsang karolo ea ho pepeseha hoa lets'ollo bokong bo bateng. Ntle le ho nona ho feta, ho saena hoa NF-κB e matlafalitsoeng ho hypothalamus, haholo-holo ka har'a li-neurons tsa POMC ho MBH, ho ka baka mathata a mang a amanang le botenya bo kang khatello ea mali.140. Ho nona ho ne ho boetse ho amahanngoa le ho ruruha libakeng tsa boko tsa extrahypothalamic tse kenyelletsang likarolo tsa hedonic tsa boitšoaro bo fepa. Sebelisa MRI, lithuto tsa batho ba batenya haholo li ile tsa bontšoa li na le ts'oaetso e sa feleng ea OFC, sebaka sa bohlokoa sa boko se kenyelletsoeng molemong oa boleng ba tšusumetso ho lijo tse fumanehang habonolo (bona kaholimo)141. Motheong oa ho fumana hona, ho ile ha etsoa tlhahiso ea hore ts'oaetso libakeng tsa bokong ba cortical, mme mohlomong le libakeng tsa maoto le matsoai tse amehang ho laoleng tšebeliso ea lijo tse matlafatsang, li ka kenya letsoho kholong ea botena.

Setšoantšo sa 5 | Nuclear factor-κB signing le tsamaiso ea eona ke SIRT1.

Setšoantšo sa 5: Nuclear factor-κB signature le tsamaiso ea eona ke SIRT1. Ka bomalimabe ha re khone ho fana ka lingoloa tse ling tse fumanehang bakeng sa sena. Haeba o hloka thuso ho fihlella setšoantšo sena, kapa ho fumana litlhaloso tsa mongolo, ka kopo ikopanye le nppn@nature.comMatšoao a sa tsitsang a mmele, a ho fokola le a khatello ea maikutlo ho striatum converge ho inhibitor ea Nuclear factor-κB (NF-κB) kinase subunit-β (IKKB). Ts'ebetso ea Neuronal e qalang ka lebaka la koae, li-neurotrophin kapa phetisetso ea glutamate le eona e kenya tšebetsong IKKB. IKKB ebe phosphorylates I VerB. IvanoB ke eona ntho e ka sehloohong e thibelang NF-κB (hangata e le sebopeho se tebileng se kenyelletsang p65 le p50 subunits) ho cytoplasm mme e thibela ts'ebetso ea eona le ho fetisetsoa ho konopo. Phosphorylation ea IcacB ea IKKB e lebisa ho IcyB ubiquitylation le protheine, e fanang ka NF-κB e lokolohileng ho fetela ho nucleus. I VerB e ka boela ea etsoa ka phosphorylated ke li-kinases tse ling tse kentsoeng polasetiki ea synaptic, tšebeliso ea lithethefatsi le boits'oaro ba ho fepa, ho kenyelletsa RAF proto-oncogene serine / threonine protein kinase (RAF1), protein kinase A (PKA), proteinin kinase 2 (CK2), proteinin kinase C (PKC) le mofuta oa mofuta oa II oa protein ea calcium ("CMC"). Ka har'a khubu, NF-κB e sebetsang e tlama likarolo tsa karabelo ho bahlahisi ba liphatsa tsa lefutso tsa NF-κB tse kang histone deacetylases (HDACs), proteni e tlamang CREB (CBP) le p300. Peroxisome proliferator-activated receptor-γ (PPARγ) e na le litlamorao tse fokotsang ts'oaetso ka ts'ebetso ea inhibitory ts'ebetsong ea NF-κB, mohlomong ka ho khetha li-activ activist tse sebetsang tsa ts'ebetso joaloka p300 le CBP. Ka mokhoa o ts'oanang, deodetylase sirtuin 1 (SIRT1) e nang le ts'oaetso e na le liketso tse khahlanong le ho ruruha ka bokhoni ba eona ba ho qaqisa p65 subunit ea NF-κB le ho thibela ts'ebetso ea eona. Ac, acetyl; NEMO, NF-κB module ea bohlokoa; Ub, ubiquitin.


Cocaine le lithethefatsi tse ling tsa tlhekefetso le tsona li ka baka likarabo tsa khatello ea kelello bokong. Ho litoeba, koae e etsa tlhahiso ea NF-κB ho NAc142, 143, e lebisang keketseho ea maemo a BDNF le kutloisiso e ntlafalitsoeng ea moputso oa koae142. Cocaine e kenyellelitsoeng ke cocoaine e hlahisang NF-κB e boetse e bakile ntlafatso ea sebopeho ho NAc, ea baka palo e eketsehang ea methapo ea methapo ho li-neuron tsa NAc142, eo e ka bang karabelo e tsitsitseng e eketsang tlokotsi ea ho lemalla142. Ntle le cocaine, tšebeliso ea lino tse tahang e boetse e etsa hore ho be le sesupo sa NF-κB bokong, mme ho fanoe ka tlhahiso ea hore sena se kenya letsoho kholisong ea botaoa ba joala.144.

SIRT1 boteng le boteneng. Ka lebaka la bohlokoa ba ho supa ha NF-κB ho phahamisa boima ba 'mele le moputso oa lithethefatsi, mohlomong ha ho makatse hore liprotheine tse laolang ho saena hoa NF-κB - joalo ka NAD-deacetylase sirtuin 1 (SIRT1) le tsona li na le tšusumetso ho boteng le bokhoba ba lithethefatsi. . SIRT1 e na le liketso tse khahlanong le ho ruruha, haholo-holo ka ho etsa deacetylating le ho thibela subunit ea P65 NF-κB145. Phapang liphatseng tsa lefutso ho SIRT1 gene e amahanngoa le lintlha tse tlase tsa BMI bathong145, le tlatsetso ea liphatsa tsa lefutso ea SIRT1 ho li-neuroth ea POMC neurons e eketsa tlokotsi ea litoeba ho botenya bo tlisoang ke ho ja ka ho fokotsa ts'ebeliso ea matla146. Cocaine e eketsa polelo ea SIRT1 ho striatum147 le ts'ebetso e ntlafalitsoeng ea ts'ebetso ea SIRT1 e ntlafatsa thepa ea khothalletso ea koae147. Liphumano tsena li fana ka maikutlo a hore SIRT1 ho hypothalamus le striatum e laola lijo le lithethefatsi ka ho latellana. E tla ba ho khahlisang ho tseba hore na liketso tsena li amana le NF-κB signaling, le hore na ts'ebetso ea SIRT1 ho striatum e boetse e laola thepa ea hedonic ea lijo tse monate.

Li-vistas tse ncha ho botenya le lipatlisiso tsa bokhoba ba tahi

Ho nyakallela ho bona lintho tse ncha ho senola boemo ba litsamaiso tse ncha le mekhoa ea likokoana-hloko eo le eona e ka amehang bothateng le bokhobeng. Mohlala, morethetho oa li-circadian o ka susumetsa maikutlo a li-circuits tsa moputso oa boko mme ka hona o laole boitšoaro ba ho fepa le tšebeliso ea lithethefatsi. Lintho tse hatisitsoeng CLOCK le BMAL1 ke likarolo tsa mantlha tsa potoloho ea li-circadian master, e fumanehang ho suprachiasmatic nucleus (SCN) ea hypothalamus. LITLHAKU TSE KHOLO tse holofetseng li batenya148, e tsotella haholo moputso oa koae ho feta litoeba tsa mofuta o hlaha mme e bonts'a thabo e ntlafalitsoeng ea li-neuron tsa dbamine tsa "149. Ka hona e tla ba ho khahlisang ho tseba hore na liphatsa tsa lefutso tsa CLOCK-BMAL li susumetsa tšebeliso ea lijo le lithethefatsi joang.

RNA editing ke ts'ebetso ea post-transcriptal eo masala a adenosine a hlophiselitsoeng ho inosine ka tatellano ea lingoliloeng tsa mRNA tse holileng, tse ka lebisang ho diphetoho khoutu ea Amino-acid ea protheine e fetoletsoeng.150. RNA e hlophisitsoeng e thathamisitsoe ke li-adenosine deaminases tse habeli tsa RNA tse ikhethang, 'me mohlomong sengoloa se tsebahalang haholo sa mRNA se kentsoeng phetong ea RNA bokong ke serotonin 2C (5-HT2C) receptor151. Ho fokotseha ha ts'ebetso ea ADAR2 ho litoeba (ADAR2 e tsejoa ho hlophisa AMPA mme kainate glutamate receptor subunits) e baka hyperphagia le botenya ho litoeba. Ntle le moo, nalane e nyane ea RNA HBII 52 e laola ho hlophisoa ha 5HT2C Li-receptors152, le li-microdeletions tsa chromosomal tsa HBII 85 li kenya letsoho likarolong tsa lefu la neurodevelopmental disorder Prader-Willi153, e leng letšoao le ka sehloohong la lona la botena. Li-MicroRNA li boetse li kenya letsoho taolong ea liphatsa tsa lefutso le karolo ea bohlokoa bakeng sa li-microRNA ho laola thepa ea khothalletso ea koae ho likhoto le litoeba ho hlaha154. Li boetse li kenelletse haholo ho adipogeneis, tsoekere ea glucose le tlhahiso ea insulin. Le ha ho le joalo, ha ho tsejoe letho ka karolo ea boitšoaro ba ho fepa.

Li-agonists tsa peroxisome proliferator-activated receptor-γ (PPARγ), joalo ka rosiglitazone (Avandia; GlaxoSmithKline plc), li sebelisoa e le baemeli ba susumetsang insulin ho phekola lefu la tsoekere la 2. PPARγ e boetse e laola adipogenesis mme e 'ngoe ea litlamorao tse kholo tsa li-agonists tsa PPARγ ke boima ba' mele, haholoholo ka ho shebisa PPARγ e hlahisoang bokong155, 156. PPARγ e buisana le balaoli ba tsebahalang ba tšebeliso ea lithethefatsi, ho kenyelletsa NF-κB (Feie. 5), SIRT1 le CDK5, le li-agonists tsa PPARγ li fokotsa tšebeliso ea lino tse tahang le boits'oaro bo tšoanang ba ho khutlela morao157. Kahoo, ho tla ba bohlokoa ho utloisisa mekhoa e nepahetseng eo PPARγ le li-receptor tse ling tsa nyutlelie li tsamaisang tšebeliso ea lijo le lithethefatsi, le ho tseba hore na li sebetsa ka mekhoa e ts'oanang ea lets'oao.

Qetellong, lithethefatsi tsa tlhekefetso li fokotseha neurogeneis, e leng ts'ebetso eo li-neuron tse ncha li tsoaloang le ho holisoa tsebong ea methapo ea batho ba baholo158. Ka mokhoa o ts'oanang, apoptosis ea li-neuron tse sa tsoa tsoaloa ho bulb ea olodo, e leng mokhoa o ka laolang memori e amanang le monko, o eketseha ka litoeba nakong ea nakoana ka mor'a prandial159. Sena se fana ka maikutlo a hore neurogenesis e leng bulb ea olodo mme mohlomong libaka tse ling tsa boko li ka kenya letsoho likarolong tsa ho fepa le ho sebelisa lithethefatsi. Kahoo, ho tla ba bohlokoa ho etsa lipatlisiso tsa liphallelo tsa mekhoa e hlahang ea methapo ea methapo le liphatsa tsa lefutso bokong ho isa lintlheng tsa hedonic tsa boitšoaro bo fepang le litheko tse ntle tsa lithethefatsi tse lematsang.

Summary

Joalokaha ho hlalositsoe ho Tlhahlobo ena, lits'ebetso tse ngata tsa boko tse tšoanang li laola ts'ebeliso ea lijo le lithethefatsi, 'me likarabo tse tšoanang li ka qholotsoa lits'ebetsong tsa moputso oa boko ka lithethefatsi tsa tlhekefetso le lijo tse monate. Ka lebaka leo, botenya bo hangata bo hlalosoa e le mofuta oa boitšoaro bo khothalletsang bo kopanang le bokhoba ba lithethefatsi. Kahoo, kutlwisiso ea rona ea methapo ea kutlo ea lithethefatsi e ka fana ka sebopeho se kopanyang ho otlolla bakhanni ba motenya. Qetellong, ho hatelloa haholo ke ho hlalosa litla-morao tsa lijo tse fumanehang habonolo liphatlalatsong tsa moputso oa boko tse amehang tlatsong ea lithethefatsi. Leha ho le joalo, ho boetse ho bohlokoa hore u nahane ka kamano e fapaneng e pakeng tsa methapo ea phepo ea lapeng ho hypothalamus le ts'ebetso ea kelello ho laola tšebeliso ea lithethefatsi tse lemalloang. Nikotine le lithethefatsi tse ling tsa tlhekefetso li ka tsosa mekotla ea phepelo ea hypothalamic 'me ka hona tsa ba le tsusumetso ea ho nona160. Ke monyetla o makatsang oa hore li-circuits tsena tsa phepo e matla li ka boela tsa laola moputso oa lithethefatsi le ho kenya letsoho tahlehelong ea taolo ea ts'ebeliso ea lithethefatsi e khethang ho lemalla.

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Liteboho

Sengoli se tšehetsoa ke lithuso tse tsoang ho US National Institute on Drug Abuse (NIDA). Ena ke nomoro e ngotsoeng ea 21309 e tsoang ho The DRMps Research Institute.

Phatlalatso ea lithahasello

Sengoli ha se phatlalatse lithahasello tsa tlholisano ea lichelete.

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References

  1. Kenny, PJ Mokhoa oa ho putsa botenya: lintlha tse ncha le litaelo tsa nakong e tlang. Neuron 69, 664-679 (2011).

  2. Wyrwicka, W., Dobrzecka, C. & Tarnecki, R. Seboka Ts'ebelisong ea mochine o hlophisitsoeng o hlahisitsoeng ke ts'usumetso ea motlakase oa hypothalamus. Science 130, 336-337 (1959).

  3. E tla, MJ, Pratt, WE & Kelley, AE Ts'oaetso ea pharmacological ea ho fepa mafura a mangata ho susumetsoa ke ts'usumetso ea opioid ea ventral striatum. Physiol. Behav. 89, 226-234 (2006).

  4. McCrory, MA, Suen, VM le Roberts, SB Litšusumetso tsa boikoetliso mabapi le tšebeliso ea matla le boima ba batho ba baholo. J. Nutriti. 132, 3830S-3834S (2002).

  5. Kelly, MT et al a. Ho eketseha ha karolo ho lebisa keketseho e tsitsitseng ea ho ja matla ho feta 4 d maemong a tloaelehileng le a boima ba banna le basali ba fetang boima. Br. J. Nutr. 102, 470-477 (2009).

  6. Benton, D. Ho utloahala ha bokhoba ba tsoekere le karolo ea bona ho botenya le mathata a ho ja. Clin. Lijo. 29, 288-303 (2010).

  7. Corsica, JA le Pelchat, ML Tlatsetso ea lijo: 'nete kapa bohata? Borr. Opin. Gastroenterol. 26, 165-169 (2010).

  8. Warwick, ZS Ho batla lisosa tsa hyperphagia ea lijo tse nang le mafura a mangata: mokhoa o qholotsang. Neurosci. Biobehav. Tšen. 20, 155-161 (1996).

  9. Schwartz, GJ Karolo ea litho tsa botona le botšehali taolong ea taolo ea lijo: litebello tsa hona joale. Nutrition 16, 866-873 (2000).

  10. Rolls, ET Mechine e sebelisang matla a tlhaho e khathollang tatso le takatso ea lijo. Bafil. Trans. R Soc. Monyaluoa. Letoto la B 361, 1123-1136 (2006).
    Kakaretso e ntle ea li-neurocircuitries tse laolang pono ea ho tsebahala ha lijo.

  11. Nyane, DM, Zatorre, RJ, Dagher, A., Evans, AC le Jones-Gotman, M. Liphetoho tšebetsong ea bokong tse amanang le ho ja chokolete: ho tloha ho thabo ho ea ho boithati. boko 124, 1720-1733 (2001).
    Pampiri ea bohlokoa e bonts'ang lits'ebetso tsa ts'ebetso ea ts'ebetso ea ts'ebetso ea satiety le libaka tse hloahloa ho fokotsa ts'ebeliso e eketsehileng.

  12. Volkow, ND, Wang, GJ le Baler, RD Moputso, dopamine le taolo ea takatso ea lijo: se boleloang ke botenya. Litsela tsa Tsela. Sci. 15, 37-46 (2011).

  13. Appleyard, SM et al a. Barekisi ba li-Visceral ba kenya ka ho toba li-neurone tsa catecholamine kahare ho "solite" ea methapo ea methapo. J. Neurosci. 27, 13292-13302 (2007).

  14. Covasa, M. & Ritter, RC Fokotsa kutloisiso ea phello ea satiation ea intestine oleate ho likhoto tse ikhethileng ho ja lijo tse nang le mafura a mangata. Am. J. Physiol. 277, R279-R285 (1999).

  15. Donovan, MJ, Paulino, G. & Raybould, HE Ho kenya tšebetsong li-neuron tsa hindbrain ha ho arabela ka mpeng ea mpa ho fumanoa ka mafura a mangata, lijo tse nang le phepo e matla litleneng tse atisang ho natefeloa ke lijo.. Resin ea Boko. 1248, 136-140 (2009).

  16. Smith, RJ le Aston-Jones, G. Phetisetso ea Noradrenergic ho amygdala e atolositsoeng: karolo ea ho batla lithethefatsi le ho khutla hape nakong ea ho khaotsa ho sebelisa lithethefatsi. Sebopeho sa Brain. Funct. 213, 43-61 (2008).

  17. Koob, G. & Kreek, MJ Khatello ea maikutlo, ho putlama ha litsela tsa moputso oa lithethefatsi, le phetoho ho ts'ebeliso ea lithethefatsi. Am. J. Psychiatry 164, 1149-1159 (2007).

  18. Simons, CT, Boucher, Y., Carstens, MI le Carstens, E. Tlhatlhobo ea Nikotine ea likarabo tsa gustatory tsa li-neuron bokong ba seterata se le seng. J. Neurophysiol. 96, 1877-1886 (2006).

  19. Bohlale, RA & Kiyatkin, EA Ho khetholla liketso tse potlakileng tsa koae. Tlhaho Moruti Neurosci. 12, 479-484 (2011).

  20. Lenoir, M. & Kiyatkin, EA Karolo e mahlonoko ea liketso tsa ho senya tsa nicotine e kenang hare ho tsona lipakeng tsa litlamorao tsa eona. Neuropsychopharmacology 36, 2125-2138 (2011).
    Pampiri ea bohlokoa e bonts'ang hore liketso tsa nicotine tseo e seng tsa boko li ka kenya letsoho ho matlafatsa thepa ea eona. E fana ka maikutlo a hore lithethefatsi tse lemalloang li ka sebetsa ka mekhoa e ka qholotsoang ho etsa hore motho a lemalle joala.

  21. Olson, VG et al a. Karolo ea ho saena ea Noradrenergic ke "nucleus treus solitarius" ea ho kenella moputsong oa opiate. Science 311, 1017-1020 (2006).

  22. Delfs, JM, Zhu, Y., Druhan, JP le Aston-Jones, G. Litlhahiso. Noradrenaline e ka hare ea sefahleho sa bohlasoa e bohlokoa bakeng sa bokhopo bo etsang hore motho a se ke a tlohela letho. Nature 403, 430-434 (2000).

  23. Harris, GC le Aston-Jones, G. Ts'ebetso ho amygdala e atamelaneng e ts'oana le phetoho e fetotsoeng ea hedonic nakong ea ho iketla ha morphine. Behav. Resin ea Boko. 176, 251-258 (2007).

  24. Garcia-Diaz, DE, Jimenez-Montufar, LL, Guevara-Aguilar, R., Wayner, MJ le Armstrong, DL Merero ea Olodo le ea visceral ho isa bokong ba seterata se le seng. Physiol. Behav. 44, 619-624 (1988).

  25. Ziomber, A. et al a. Matla a tšusumetso ea matla a tlhaho a ts'oaetso ea vagus le boits'oaro ba ho fepa ka likhoto. J. Physiol. Pharmacol. 60, 71-77 (2009).

  26. Burneo, JG, Ho rutoa, E., Knowlton, R., Morawetz, R. & Kuzniecky, R. Ho fokotsa boima ba 'mele bo amanang le ho hlohlelletsa nko ea vagus. Neurology 59, 463-464 (2002).

  27. Wang, GJ et al a. Ho hlohlelletsa ka mpeng lithutong tse batenya ho etsa hore hippocampus le libaka tse ling tse amehang ho tsamaiseng moputso bokong. Proc. Natl Acad. Saense USA 103, 15641-15645 (2006).

  28. Ertelt, TW et al a. Tšebeliso e mpe ea tahi le ho itšepa pele le ka mor'a ho buuoa ka bariatric: tlhahlobo ea lingoliloeng le tlaleho ea sete e ncha ea data. Surg. Lintho. Pheta. Dis. 4, 647-650 (2008).

  29. Cunningham, JT, Mifflin, SW, Gould, GG le Frazer, A. Seboka Ho kenyelletsa ts'oaetso ea cFos le ΔFosB bokong ba rat ka ho hlohlelletsoa ke Vagal nerve. Neuropsychopharmacology 33, 1884-1895 (2008).

  30. Nunez, C. et al a. Ho hlahisoa ha FosB / ΔFosB lits'ebetsong tse amanang le khatello ea kelello nakong ea ts'oaetso ea morphine le ho ikhula. J. Neurochem. 114, 475-487 (2010).

  31. Mumberg D., Lucibello FC, Schuermann M., Muller R. Ho petsoha ho seng kae ha mengolo ea fosB ho etsa hore li-mRNA tse hlahisitsoeng ka mokhoa o fapaneng li hlahise liprotheine tse hanyetsang. Genese Dev. 5, 1212-1223 (1991).

  32. McClung, CA le Nestler, EJ Taolo ea polelo ea gene le moputso oa koae ka CREB le ΔFosB. Neurosci ea tlhaho. 6, 1208-1215 (2003).

  33. Appleyard, SM et al a. Li-neurons tsa Proopiomelanocortin ho "nucleus treus solitarius" li hlahisoa ke liphatlalatso tsa visceral: melaoana ke cholecystokinin le opioids. J. Neurosci. 25, 3578-3585 (2005).

  34. Zhang, Y. et al a. Ho fetisoa hoa mofuta oa pro-opiomelanocortin ho isa bokong ba pina e le 'ngoe empa ha ho tsose li-nucleus ameliorates ho kula ho tlisoang ke botenya. Khopolo-taba 169, 1662-1671 (2010).

  35. Holst, JJ Physiology ea glucagon-e tšoanang le peptide 1. Physiol. Tšen. 87, 1409-1439 (2007).

  36. Turton, MD et al a. Karolo ea glucagon-kama peptide1 moemong o bohareng oa phepelo. Nature 379, 69-72 (1996).
    Pampiri ea bohlokoa e bonts'ang hore GLP1 e hlahisoang NTS e ka laola tšebeliso ea lijo. Lithuto tse ling li tla hlokahala ho tseba hore na GLP1 e boetse e laola tšebeliso ea lithethefatsi.

  37. Hayes, MR, Bradley, L. & Grill, HJ Ts'ebetso ea "receptor" ea phepelo ea tlhaho ea hindbrain endoolo e kenya letsoho taolong ea takatso ea lijo ka ho tsamaisana le ho emella ka mpeng. Endocrinology 150, 2654-2659 (2009).

  38. Barrera, JG et al a. Hyperphagia le keketseho e ngata ea mafura mefuteng e 'meli ea ho se sebetse hantle ha "glucagon" e kang peptide1. J. Neurosci. 31, 3904-3913 (2011).

  39. Hayes, MR et al a. Matšoao a Intracellular a pakeng a amanang le litabatabelo tsa lijo tse matlafatsang tsa glucagon tse kang peptide1 activation activation. Setsi sa Metab. 13, 320-330 (2011).

  40. Paulus, MP Motheo oa Neural oa moputso le ho lakatsa-pono ea homeostatic. Clin ea Dialogues. Neurosci. 9, 379-387 (2007).

  41. Johnson, PM le Kenny, PJ Dopamine D2 receptors ka ho lemalla ho lemalla ho lemala le ho qobella ho ja likokoanyana tse ngata. Neurosci ea tlhaho. 13, 635-641 (2010).
    Pampiri ena e bonts'a hore tšebeliso ea lijo tse matlafatsoang e ka ba ntho e qobelloang ka mokhoa o tšoanang le oo tšebeliso ea lithethefatsi tse lemalloang e ka ba tlamang. E ts'ehetsa monahano oa hore botenya le bokhoba ba tsona li arolelana metheo e tloaelehileng.

  42. Cottone, P., Sabino, V., Steardo, L. & Zorrilla, EP Phapang e sa lebelloang e amanang le opioid le phallo e kang ea ho itlopa lijo literekeng tse nang le phihlello ea lijo tse ratoang haholo. Neuropsychopharmacology 33, 524-535 (2008).
    Pampiri ena e bonts'a hore likhoto li tla fetisetsa thatohatsi ea tsona nthong e fumanehang habonolo 'me li tla hana mokhoa o mong o bonolo, esita le oo li neng li o sebelisa habonolo, kamora nako ea ho pepesehela ntho e fumanehang habonolo. Bangoli ba bontša hore sena se bitsoang phapang e mpe e laoloa ke li-receptors tsa opioid.

  43. Lin, JY, Moroma, C. & Reilly, S. Cortex e kahare le phapang e lumellanang e sa nepahalang moreneng. Behav. Neurosci. 123, 810-814 (2009).

  44. Reilly S., Bornovalova M. le Trifunovic, R. Liso tse ntle tsa "talam" tse ntle tsa "gustatory thalamus" li hlahisa maemo a fapaneng ka nako e le 'ngoe empa li tlosa phapang e sa lebelloang: bopaki bo khahlano le ho haelloa ke mohopolo. Behav. Neurosci. 118, 365-376 (2004).

  45. Kullmann, S. et al a. Boko ba ho nona haholo: ho kopana ha index ea boima ba 'mele le kutloisiso ea insulin le khokahano ea ts'ebetso ea marang-rang. Hum. Brain Mapp. 21 Apr 2011 (Doi: 10.1002 / hbm.21268).

  46. Stice, E., Spoor, S., Bohon, C., Veldhuizen, MG & Nyane, DM Kameho ea moputso o tsoang lijong tsa lijo le litabatabelo tsa lijo tse lebelletsoeng ho botenya: thuto e nahanang ea matla a matla a makatsang. J. Abnorm. Psychol. 117, 924-935 (2008).

  47. Stice, E., Yokum, S., Burger, KS, Epstein, LH & Nyane, DM Bacha ba kotsing ea ho ba le botenya ba ts'ebetso e kholo ea libaka tse haufi le tse ling tsa lijo. J. Neurosci. 31, 4360-4366 (2011).
    Pampiri ea bohlokoa e bonts'ang phapang e tebileng ea ho supa ha boko e ka etsa hore batho ba be le botenya.

  48. Wang, Z. et al a. Litekanyetso tse ka tlase tsa moea tsa ho tsuba tse tsubang tse hohelang ba tsubang ba sa ts'oanehe. J. Neurosci. 27, 14035-14040 (2007).

  49. Naqvi, NH, Rudrauf, D., Damasio, H. le Bechara, A. Tšenyo ea hau ea kelello e kenella ho ho lemalla ho tsuba koae. Science 315, 531-534 (2007).
    Pampiri ea bohlokoa e fanang ka maikutlo a hore batho ba kenang botlamuoeng ba ka ameha tšebelisong ea lithethefatsi.

  50. Hollander, JA, Lu, Q., Cameron, MD, Kamenecka, TM le Kenny, PJ. Ho fetisoa ha hypocretin ho laola moputso oa nicotine. Proc. Natl Acad. Saense USA 105, 19480-19485 (2008).

  51. Contreras, M., Ceric, F. le Torrealba, F. Ho kenella ha mohopolo o kopanetsano ho sitisa takatso ea lithethefatsi le malaise e hlahisoang ke lithium. Science 318, 655-658 (2007).

  52. Unal, CT, Beverley, JA, Willuhn, I., le Steiner, H. Tekanyetso ea nako e telele ea polelo ea gene ho li-circuits tsa corticostriatal ka mor'a kalafo e pheta-phetoang ea koae ho litoeba tsa batho ba baholo: litlamorao ho zif 268 le Homer 1a. EUR. J. Neurosci. 29, 1615-1626 (2009).

  53. Schiltz, CA, Bremer, QZ, Landry, CF & Kelley, AE Litloaelo tse amanang le lijo li fetola tšebeliso ea tšebetso ea 'mele ha li lekantsoe ka mofuta oa pele oa mofuta le polelo ea proenkephalin. BMC Biol. 5, 16 (2007).

  54. Metsoako Swank, MW & Sweatt, JD Keketseho ea histone acetyltransferase le ts'ebetso ea lysine acetyltransferase le ts'ebetso ea biphasic ea CasK ea ERK / RSK ka har'a cortex ea insular nakong ea ho ithuta tatso ea lipale.. J. Neurosci. 21, 3383-3391 (2001).

  55. Simonyi, A., Serfozo, P., Parker, KE, Ramsey, AK & Schachtman, TR Metabotropic glutamate receptor 5 e boemong ba ho ithuta tatso ea ho rata tatso. Neurobiol. Ithute. Mem. 92, 460-463 (2009).

  56. Berman, DE, Hazvi, S., Rosenblum, K., Seger, R. & Dudai, Y. Ho hlakile Ts'ebetso e ikhethang le e fapaneng ea ts'ebetso ea li-protein tsaasease tsa mitogen tse hlahisoang ke tatso e sa tloaelehang mokokotlong oa "infort" oa "rat". J. Neurosci. 18, 10037-10044 (1998).

  57. Rolls, ET Ketso e monate ea tatso ea mumami: ke eng se etsang hore umami e be monate? Na. J. Clin. Lijo. 90, 804S-813S (2009).

  58. Morewedge, CK, Huh, YE le Vosgerau, J. Ho nahanoa ka lijo: ts'ebeliso e nahanoang e fokotsa tšebeliso ea nnete. Science 330, 1530-1533 (2010).
    Sephetho se khahlisang se bonts'ang hore lipontšo tsa kelello tsa ho ja lijo tse itseng li ka lekana ho baka tsitsipano ha ho hlile ho se na lijo. Pampiri e totobatsa bohlokoa ba libaka tse phahameng ka ho fetisisa tsa boko ba cortical ho laoleng boleng ba tšusumetso ea thepa e itseng ea lijo.

  59. Salzman, CD & Fusi, S. Khatello, maikutlo le boemo ba kelello boemong ba amygdala le prefrontal cortex. Annu. Moruti Neurosci. 33, 173-202 (2010).

  60. Volkow, ND et al a. Li-receptor tse fokolang haholo tsa dopamine tse nang le dopamine li amahanngoa le metabolism ea prefrontal lihloohong tse ngata: ho ka khoneha ho thusa. Nako ea mokokotlo 42, 1537-1543 (2008).
    Pampiri ea bohlokoa e bonts'ang boemo bo fetohileng ba D2 receptor density e amana le ts'ebetso e fetotsoeng ea cortical ho batho ba batenya, e ka bang le tšusumetso ho bokhoni ba bona ba taolo ea lijo.

  61. Woolley, JD et al a. Ho itlopa lijo ho tsamaisana le "orbitofrontalinsularstriatal atrophy" ea "demotrate" ea methapo pele ho nako. Neurology 69, 1424-1433 (2007).

  62. Mena, JD, Sadeghian, K. & Baldo, BA Ho hlahisoa ha hyperphagia le tšebeliso ea lik'habohaedreite ke li-mu-opioid receptor tse susumetsang libakeng tse potileng tsa cortex ea pele.. J. Neurosci. 31, 3249-3260 (2011).

  63. Kantak, KM, Mashhoon, Y., Silverman, DN, Janes, AC & Goodrich, CM Karolo ea cortex ea orbitofrontal le dorsal striatum ho laola litlamorao tse amanang le lethal dose tsa koae e ipehelang. Behav. Resin ea Boko. 201, 128-136 (2009).

  64. Burke, KA, Franz, TM, Miller, DN le Schoenbaum, G. Karolo ea cortex ea orbitofrontal ho phehelleng thabo le meputso e tobileng haholoanyane. Nature 454, 340-344 (2008).

  65. Lipere, A., Parkinson, JA, Hopewell, L., Everitt, BJ & Roberts, AC Methapo ea orbitof Pambal empa e seng ea setlhare ea cortex e senyehileng e senola boemo bo matlafatsang maemong a khale.. J. Neurosci. 23, 11189-11201 (2003).

  66. Hutcheson, DM le Everitt, BJ Litlamorao tsa ho khetha li-cortine tse khethiloeng ke orbitof Pambal ho fumana le ho sebetsa ha koae e laoloang ke cueine e laoloang ke likhoto. Ann. NY Acad. Saense 1003, 410-411 (2003).

  67. George, O., Mandyam, CD, Wee, S. & Koob, GF Keketso e pharalletseng ea ho itlhokomela ka koae e hlahisa ho senyeha ha nako e telele pele ho nako. Neuropsychopharmacology 33, 2474-2482 (2008).

  68. Homayoun, H. & Moghaddam, B. Tsoelo-pele ea liphetoho tsa methapo ea methapo ea methapo ea methapo ea pele le e ka lehlakoreng la mokokotlo oa mokokotlo ho arabela khafetsa amphetamine. J. Neurosci. 26, 8025-8039 (2006).

  69. > Schoenbaum, G. & Shaham, Y.> Karolo ea cortex ea orbitofrontal litabeng tsa bokhoba ba lithethefatsi: tlhahlobo ea lithuto tsa preclinical. Biol. Psychiatry 63, 256-262 (2008).

  70. Winstanley, CA et al a. ΔFosB induction ea orbitofrontal cortex e mamellana mamellong ea ho se sebetse hantle ha koae. J. Neurosci. 27, 10497-10507 (2007).

  71. Winstanley, CA et al a. Ho eketsa khatello ea maikutlo nakong ea ho khaotsa ho itaola: ho nka karolo ea ΔFosB ho cortex ea orbitofrontal. Cereb. Cortex 19, 435-444 (2009).
    Pontšo e ntle e arabelang likarabo tsa OFC mabapi le lithethefatsi tse sebelisang tlhekefetso e ka ba le mekhoa e rarahaneng ea boits'oaro, e ka bang le tšusumetso ea ho ba kotsing ea ho theha boits'oaro bo matla ba ho batla lithethefatsi.

  72. Sclafani, A. Litla-morao tse ntle tsa taolo ea boits'oaro bo bobe ba ho ingestive. Takatso ea lijo 36, 79-83 (2001).

  73. Ren, X. et al a. Khetho ea nama ha ho se na li-receptor tse latsoang tatso. J. Neurosci. 30, 8012-8023 (2010).

  74. de Araujo, IE et al a. Moputso oa lijo ha o sa latsoe tatso ea li-receptor. Neuron 57, 930-941 (2008).
    Pampiri ea seminal e bonts'ang litlamorao tsa lijo tse fumanehang habonolo, tse ikemetseng tatso ea bona, e ka ts'ehetsa moputso oa lijo le ho tsamaisa khetho ea lijo tse phahameng haholo linthong tse ngata tse kang mafura le tsoekere.

  75. Perez, CA et al a. Sesebelisoa se ka amohelang monko oa nakoana se hlahisoang liseleng tse amohelang tatso. Neurosci ea tlhaho. 5, 1169-1176 (2002).

  76. Oliveira-Maia, AJ et al a. Nikotine e etsa hore ho be le litsela tse ts'oanang le tse ikemetseng tsa TRPM5. Proc. Natl Acad. Saense USA 106, 1596-1601 (2009).

  77. Blednov, YA et al a. Pono ea tatso e monate e bohlokoa bakeng sa tšebeliso ea lino tse tahang ka litoeba. Genese Brain Behav. 7, 1-13 (2008).

  78. Vucetic, Z. & Reyes, TM Central dopaminergic circry e laolang takatso ea lijo le moputso: litlamorao bakeng sa taolo ea botenya. Wiley Khokhon. Moruti Syst. Biol. Moedi 2, 577-593 (2010).

  79. Muller, DL le Unterwald, EM D1 dopamine receptors moduction ΔFosB in rat striatum kamora tsamaiso ea nakoana ea morphine. J. Pharmacol. Exp. Ther. 314, 148-154 (2005).

  80. Nestler, EJ Tlhahlobo. Mekhoa e meng ea ho lemalla: karolo ea ΔFosB. Bafil. Trans. R Soc. Monyaluoa. B 363, 3245-3255 (2008).

  81. Teegarden, SL, Scott, AN & Bale, TL Ho pepesetsoa bophelo ba pele ho lijo tse phahameng tsa mafura ho etsa hore ho be le liphetoho tsa nako e telele lithahasellong tsa lijo le ho saena moputso bohareng. Khopolo-taba 162, 924-932 (2009).

  82. Christiansen, AM, Dekloet, AD, Ulrich-Lai, YM le Herman, JP "Ho fokotseha" ho baka karabelo ea nako e telele ea likarabo tsa khatello ea kelello ea HPA le ntlafatso ea polelo ea bokhabane ea FosB / ΔFosB likotong. Physiol. Behav. 103, 111-116 (2011).

  83. Wallace, DL et al a. Tšusumetso ea ΔFosB bokong e bokellana holim'a boitšoaro bo amanang le moputso oa tlhaho. J. Neurosci. 28, 10272-10277 (2008).
    Pampiri ena e bonts'a hore ntho e ngotsoeng e bohlokoa ho lemeneng le eona e ka ama tšebeliso ea meputso ea tlhaho joalo ka lijo.

  84. Teegarden, SL le Bale, TL Ho fokotseha ha lijo tse hlahisang lijo li eketseha maikutlong le kotsing ea ho khutla ha lijo. Biol. Psychiatry 61, 1021-1029 (2007).

  85. Setempe, JA, Mashoodh, R., van Kampen, JM & Robertson, HA Thibelo ea lijo e ntlafatsa maemo a phahameng a corticosterone, ts'ebetso ea tšebeliso ea koae, le polelo ea ΔFosB ka har'a boksi. Resin ea Boko. 1204, 94-101 (2008).

  86. Olausson, P. et al a. ΔFosB bokong ba methapo e laola boitšoaro bo matlafatsang ba sesebelisoa le ts'usumetso. J. Neurosci. 26, 9196-9204 (2006).

  87. Colby, CR, Whisler, K., Steffen, C., Nestler, EJ & Boithati, DW Striatal cell Type overexpression e khethehileng ea ΔFosB e ntlafatsa ts'usumetso ea koae. J. Neurosci. 23, 2488-2493 (2003).

  88. Teegarden, SL, Nestler, EJ le Bale, TL Liphetoho tse tlisoang ke Delta FosB tse amanang le dopamine li etsoa ka tloaelo ke lijo tse matlafatsang tse nang le mafura a mangata.. Biol. Psychiatry 64, 941-950 (2008).

  89. Bibb, JA et al a. Litlamorao tsa ho pepesehela cocaine e sa feleng li laoloa ke protheine ea neuronal Cdk5. Nature 410, 376-380 (2001).

  90. Kumar, A. et al a. Chodatin remodeling ke mochine oa bohlokoa o hlahisang polasetiki e entsoeng ka koae ho striatum. Neuron 48, 303-314 (2005).

  91. Taylor, JR et al a. Thibelo ea Cdk5 bokong ba nyutlelie e ntlafatsa sephetho sa cocaine. Proc. Natl Acad. Saense USA 104, 4147-4152 (2007).

  92. Benavides, DR et al a. Cdk5 modulates moputso oa koae, tlhotlheletso, le striatal neuron thabo. J. Neurosci. 27, 12967-12976 (2007).

  93. Gupta, A. & Tsai, LH Neuroscience. A kinase ho fokotsa litlamorao tsa cocaine? Science 292, 236-237 (2001).

  94. Stipanovich, A. et al a. Phoso ea phosphatase eo ka eona e fanang ka karabelo e khothatsang ea ho laola li-nucleosomal. Nature 453, 879-884 (2008).

  95. Skofitsch, G., Jacobowitz, DM le Zamir, N. Homuninistochemical lehae ea "melonin" e kenang ka hare ho "peptide" ea "hormone" ea "rat". Resin ea Boko. Bull. 15, 635-649 (1985).

  96. de Lecea, L. et al a. Li-hypocretins: li-peptide tse khethehileng tsa hypothalamus tse nang le ts'ebetso ea neuroexcitatory. Proc. Natl Acad. Saense USA 95, 322-327 (1998).

  97. Qu, D. et al a. Karolo ea li-hormone tse amanang le melanin ho taolo e bohareng ea boits'oaro. Nature 380, 243-247 (1996).

  98. Hara, J. et al a. Ho koala liphatsa tsa lefutso ka li-neuron tsa orexin ho litoeba ho baka narcolepsy, hypophagia, le botena. Neuron 30, 345-354 (2001).
    Pampiri ea bohlokoa e bonts'ang hore phetisetso ea hypocretin e laola tšebeliso ea lijo.

  99. Georgescu, D. et al a. Li-hormone tsa hypothalamic neuropeptide melanin tse kenang ka bongata molek'huleng ea methapo ea kelello ho fetolela mokhoa oa ho iphepa le ts'ebetso e qobelloang.. J. Neurosci. 25, 2933-2940 (2005).

  100. Sears, RM et al a. Taolo ea tšebetso ea li-nucleus e bokellanang ke lihormone tse tsepamisang maikutlo tsa hypothalamic melopinide. J. Neurosci. 30, 8263-8273 (2010).

  101. Chung, S. et al a. Sisteme ea hormone ea "melanin" e fetohang modulates moputso oa koae. Proc. Natl Acad. Saense USA 106, 6772-6777 (2009).

  102. Zheng, H., Patterson, LM le Berthoud, HR Ho supa ha Orexin sebakeng sa ho saroloha ha moea ho hlokahala bakeng sa takatso ea mafura a mangata e hlahisoang ke ts'usumetso ea opioid ea li-nucleus accumbens. J. Neurosci. 27, 11075-11082 (2007).

  103. Uramura, K. et al a. Orexina e kenya tšebetsong phospholipase C le protheine kinase Cmediated Ca2+ ho supa li-neurop tsa dopamine tsa sebaka se khubung ea ventral. Neuroreport 12, 1885-1889 (2001).

  104. Cason, AM et al a. Karolo ea orexin / hypocretin ha ho batloa moputso le ho lemalla: litlamorao tsa ho nona. Physiol. Behav. 100, 419-428 (2010).

  105. Skibicka, KP, Hansson, C., Alvarez-Crespo, M., Friberg, PA le Dickson, SL Ghrelin e shebile ka kotloloho sebaka se sengoathoana sa moea hore a eketse tšusumetso ea lijo. Khopolo-taba 180, 129-137 (2011).

  106. Farooqi, IS et al a. Leptin e laola libaka tsa litoro le boitšoaro ba motho ba ho ja. Science 317, 1355 (2007).
    Pontsho e ntle eo leptin e ka susumetsang ts'ebetso ts'ebetsong ea meputso ea boko mme ka hona e laole ho ja lijo.

  107. Figlewicz, DP, Evans, SB, Murphy, J., Hoen, M. & Baskin, DG. Khopolo ea li-receptor bakeng sa insulin le leptin sebakeng sa ventral tegmental / substantia nigra (VTA / SN) ea rat. Resin ea Boko. 964, 107-115 (2003).

  108. Fulton, S. et al a. Leptin regulation ea tselengaccumbens dopamine tsela. Neuron 51, 811-822 (2006).

  109. Hommel, JD et al a. Leptin receptor e tšoaetsang li-midbrain dopamine neurons e laola ho fepa. Neuron 51, 801-810 (2006).

  110. Morton, GJ, Blevins, JE, Kim, F., Matsen, M. & Figlewicz, DP Ketso ea leptin sebakeng sa ho putlama ha methapo ea methapo ho fokotsa ho ja lijo e itšetlehile ka ho supa ha Jak2. Am. J. Physiol. Endocrinol. Metab. 297, E202-e210 (2009).

  111. Bruijnzeel, AW, Corrie, LW, Rogers, JA le Yamada, H. Litlamorao tsa insulin le leptin sebakeng sa ho kenella ka mokokotlong le ho ts'oaroa ke "hypothalamic" ka nko ea lijo le ho etsa mosebetsi oa moputso oa boko litekong tsa basali. Behav. Resin ea Boko. 219, 254-264 (2011).

  112. Davis, JF et al a. Leptin e laola tekano ea matla le tšusumetso ka liketso liketsahalong tse fapaneng tsa neural. Biol. Psychiatry 69, 668-674 (2011).

  113. Vaisse, C. et al a. Leptin activation ea Stat3 ho hypothalamus ea mofuta oa hlaha le litoeba tsa obb empa eseng db / db. Sebaka sa tlhaho. 14, 95-97 (1996).

  114. Berhow, MT, Hiroi, N., Kobierski, LA, Hyman, SE le Nestler, EJ Tšusumetso ea koae tseleng ea JAK-STAT tseleng ea mesolimbic dopamine. J. Neurosci. 16, 8019-8026 (1996).

  115. Zahniser, NR, Goens, MB, Hanaway, PJ & Vinych, JV Sebopeho le taolo ea li-insulin receptors bokong ba rat. J. Neurochem. 42, 1354-1362 (1984).

  116. Figlewicz, DP, Bennett, JL, Aliakbari, S., Zavosh, A. & Sipols, AJ Insulin e sebetsa libakeng tsa CNS tse fapaneng ho fokotsa ho ja ka matla le ho itlhomme hantle litulong tsa litoeba. Am. J. Physiol. Regul. Kopanya. Comp. Physiol. 295, R388-R394 (2008).

  117. Konner, AC et al a. Karolo ea ho tšoaea insulin ho catecholaminergic neurons taolong ea matla homeostasis. Setsi sa Metab. 13, 720-728 (2011).

  118. Kamei, J. & Ohsawa, M. Litlamorao tsa lefu la tsoekere ho methamphetamine e hlahisang khetho ea litoeba. EUR. J. Pharmacol. 318, 251-256 (1996).

  119. Murzi, E. et al a. Lefu la tsoekere le fokotsa dopamine ea limbic extracellular ho likhoto. Neurosci. Lett. 202, 141-144 (1996).

  120. Cordeira, JW, Frank, L., Sena-Esteves, M., Pothos, EN & Rios, M. Borat-based neurotrophic factor e laola phepo ea hedonic ka ho sebetsa tsamaisong ea mesolimbic dopamine. J. Neurosci. 30, 2533-2541 (2010).

  121. Krugel, U., Schraft, T., Kittner, H., Kiess, W. & Illes, P. Ho lokolloa ha dopamine ea basal le ho fepa-evokile ka har'a li-nucleus tsa rubus ho sithabetsoa ke leptin. EUR. J. Pharmacol. 482, 185-187 (2003).

  122. Roseberry, AG, Setaki, T., Mareka, GP & Williams, JT Li-dopamine tsa "dopamine" tse fokotsehileng li fokotsoe ka lebenkeleng le litekong tse haellang. J. Neurosci. 27, 7021-7027 (2007).

  123. Iniguez, SD et al a. Insulin receptor substrate2 sebakeng se potoloho ea ventral e laola likarabo tsa boitšoaro ho koae. Behav. Neurosci. 122, 1172-1177 (2008).

  124. Russo, SJ et al a. Tsela ea IRS2-Akt ho midbrain dopamine neurons e laola likarabo tsa boitšoaro le tsa mahlale ho li-opiates. Neurosci ea tlhaho. 10, 93-99 (2007).

  125. Schoffelmeer, AN et al a. Insulin modulates ts'ebetso ea transporter ea cocaine e hlokoang ke kankere le boits'oaro bo sa tsotelleng. J. Neurosci. 31, 1284-1291 (2011).

  126. Belin, D., Mar., AC, Dalley, JW, Robbins, TW le Everitt, BJ Ho ts'oaroa ho hoholo ho bolela esale pele phetoho ea ho tsuba koae. Science 320, 1352-1355 (2008).

  127. Brewer, JA le Potenza, MN Neurobiology le genetics ea mathata a laoloang ke tšusumetso: likamano le bokhoba ba lithethefatsi. Likokoana-hloko. Pharmacol. 75, 63-75 (2008).

  128. Wang, X. et al a. Nucleus e bokella sepheo sa mantlha sa phoofolo ea matsoalloa a lehae ea rapamycin e tseleng e bohlokoa bakeng sa ho khutlisetsa moea o matlafatsang oa cocaine ho litheko. J. Neurosci. 30, 12632-12641 (2010).

  129. Hou, L. & Klann, E. Ho kenya ts'ebetsong sepheo sa phosphoinositide 3kinaseAkt-mammalian ea rapamycin signalingway ho hlokahala bakeng sa khatello ea methapo ea methapo ea methapo ea methapo ea methapo ea methapo.. J. Neurosci. 24, 6352-6361 (2004).

  130. Kasanetz, F. et al a. Phetoho ea ho lemalla e amahanngoa le ho senyeha ho sa khaotseng ho polasetiki ea synaptic. Science 328, 1709-1712 (2010).

  131. Brown, AL, Flynn, JR, Smith, DW le Dayas, CV Polelo ea "gene" e laoloang ka tlase bakeng sa liprotheine tse amanang le "protaptic" tse amanang le polokeho ea methapo le ho khutlisetsa liphoofolo tse tlokotsing. Int. J. Neuropsychopharmacol. 14, 1099-1110 (2010).

  132. Lafourcade, M. et al a. Khaello ea omega3 ea phepo e nepahetseng e felisa mesebetsi ea methapo ea endocannabinoid-Mediated. Neurosci ea tlhaho. 14, 345-350 (2011).
    Pampiri ena e bonts'a hore acid e nang le mafura hangata e fumanoang litlhaping tse nang le mafura e ka susumetsa ho tšoaea hoa endocannabinoid - karolo ea bohlokoa ea lits'ebetso tsa moputso oa boko.

  133. Jiao, S. & Li, Z. Ts'ebetso ea nonapoptotic ea BAD le BAX maemong a sithabetsang a nako e telele a phetisetso ea synaptic. Neuron 70, 758-772 (2011).

  134. Li, Z. et al a. Caspase3 activation ka mitochondria e hlokahala bakeng sa khatello ea maikutlo ea nako e telele le AMPA receptor Internation. Cell 141, 859-871 (2010).

  135. Burguillos, MA et al a. Caspase sesupo se laolang ts'ebetso ea Microglia le neurotoxicity. Nature 472, 319-324 (2011).

  136. Bishnoi, M., Chopra, K. & Kulkarni, SK Ho kenya ts'ebetsong ha babuelli ba tšoaetso ea striatal le Caspase3 ke karolo ea bohlokoa ea haloperidol-indoses orofacial dyskinesia. EUR. J. Pharmacol. 590, 241-245 (2008).

  137. Hotamisligil, GS Ho ruruha le mathata a metabolic. Nature 444, 860-867 (2006).

  138. Zhang, X. et al a. Hypothalamic IKKβ / NF-κB le khatello ea maikutlo tsa ER li hokahanya ho nona ho feta tekano le ho se leka-lekane ha matla le botenya. Cell 135, 61-73 (2008).
    Pampiri ea seminal e bonts'ang hore li-cytokine tse potileng li ka ama ts'ebetso ea hypothalamic mme ka hona li susumetsa takatso ea lijo.

  139. Kleinridders, A. et al a. Ho supa ha MyD88 ho CNS hoa hlokahala bakeng sa nts'etsopele ea ho loants'oa ha leptin le mafura. Setsi sa Metab. 10, 249-259 (2009).

  140. Purkayastha, S., Zhang, G. & Cai, D. Ho otlolla mekhoa ea botena le khatello ea mali ka ho tšoaea hypothalamic IKK-β le NF VerB. Meriana ea tlhaho 17, 883-887 (2011).

  141. Lik'hasete, F., Cohen, JI, Yau, PL, Talbot, H. & Convit, A. Ho ruruha ho kopaneng le botenya ho ka senya potoloho ea boko e laolang ho ja lijo. Resin ea Boko. 1373, 101-109 (2011).

  142. Russo, SJ et al a. Nuclear factor κ B ho saena ho laola neuronal morphology le moputso oa koae. J. Neurosci. 29, 3529-3537 (2009).
    Pampiri ea bohlokoa e bonts'ang hore ho ruruha lits'ebetsong tsa moputso oa boko ho ka kenya letsoho ho lemeng ha lithethefatsi.

  143. Ang, E. et al a. Ho hlahisoa ha nyutlelie ea bohlokoa ba 'mele ea nyutlelie ka taolo ea cocaine e sa foleng. J. Neurochem. 79, 221-224 (2001).

  144. Basebetsi, FT, Zou, J. & Qin, L. Ho kenella liphatseng tsa lefutso tse ka hare tsa tlhaho bokong ho bopa neurobiology ea ho lemalla. Brain Behav. Immun. 25, S4-S12 (2011).

  145. Yeung, F. et al a. Modulation ea NF VerBdependent transcript le pholoho ea lisele ke SIRT1 deacetylase. EMBO J. 23, 2369-2380 (2004).

  146. Ramadori, G. et al a. SIRT1 deacetylase ho li-neurons tsa POMC e hlokahala bakeng sa ts'ireletso ea homeostatic khahlanong le botenya bo khothalletsoang ke ho ja. Setsi sa Metab. 12, 78-87 (2010).

  147. Renthal, W. et al a. Tlhahlobo e pharalletseng ea molao oa chromatin ka cocaine e senola karolo ea Sirtuins. Neuron 62, 335-348 (2009).

  148. Turek, FW et al a. Ho nona haholo le lefu la metabolic ho litoeba tsa circaan Clock mutant. Science 308, 1043-1045 (2005).

  149. McClung, CA et al a. Taolo ea phetiso ea dopaminergic le moputso oa koae ke mofuta oa Clock. Proc. Natl Acad. Saense USA 102, 9377-9381 (2005).

  150. Maas, S. Melao ea lihlahisoa tsa lihlahisoa tsa lihlahisoa tsa Gene. Discov. Moedi 10, 379-386 (2010).

  151. Burns, CM et al a. Taolo ea coupling ea serotonin-2C Gprotein ka tokiso ea RNA. Nature 387, 303-308 (1997).

  152. Kishore, S. & Stamm, S. SnoRNA HBII52 e laola mefuta e meng ea mela ea serotonin receptor 2C. Science 311, 230-232 (2006).

  153. Sahoo, T. et al a. Prader-Willi phenotype e bakoang ke bofokoli ba bo-ntate bakeng sa sehlopha sa HBII85 C / D lebokose le lenyane la nucleolar RNA. Sebaka sa tlhaho. 40, 719-721 (2008).

  154. Hollander, JA et al a. Striatal MicroRNA e laola tšebeliso ea koae ka ho ho saena hoa CREB. Nature 466, 197-202 (2010).

  155. Ryan, KK et al a. Karolo ea tsamaiso ea methapo ea methapo ea mantlha PPAR-γ taolong ea matla a lekantsoeng. Tlhaho Med. 17, 623-626 (2011).

  156. Lu, M. et al a. Brain PPAR-γ e khothalletsa botenya mme e hlokahala bakeng sa phello ea maikutlo a insulin ea thiazolidinediones. Tlhaho Med. 17, 618-622 (2011).
    Letlapa lena hape le 156 e buang hape e bonts'a hore PPARγ bokong e kanna ea laola tšebeliso ea lijo.

  157. Stopponi, S. et al a. Ts'ebetso ea li-receptor tsa nyutlelie tsa PPARγ ke moemeli oa "antidiabetes" pioglitazone o hatella joala mme o khutlela ho ts'ebeliso ea joala.. Biol. Psychiatry 69, 642-649 (2011).

  158. Noonan, MA, Bulin, SE, Fuller, DC & Eisch, AJ Phokotso ea batho ba baholo ba hippocampal neurogeneis e fana ka ts'ireletso ea mofuta oa phoofolo ea ho lemalla koae. J. Neurosci. 30, 304-315 (2010).

  159. Yokoyama, TK, Mochimaru, D., Murata, K., Manabe, H., Kobayakawa, K., Kobayakawa, R., Sakano, H., Mori, K., Yamaguchi, M. Ho felisoa ha li-neurons tse tsoetsoeng e le batho ba baholo ka bongata bulb ea olenzi ho khothalletsoa nakong ea kemiso. Neuron 71, 883-897 (2011).

  160. Kahara, YS et al a. Nikotine e fokotsa ho kenella ha lijo ka ts'ebetsong ea li-neuron tsa POMC. Science 332, 1330-1332 (2011).

  161. Kereke, C. et al a. Ho tšetšethoa ho matla ha Fto ho lebisa ho eketseheng ha lijo mme ho fella ka botenya. Sebaka sa tlhaho. 42, 1086-1092 (2010).

  162. Vucetic, Z., Kimmel, J., Totoki, K., Hollenbeck, E. & Reyes, TM Matšoao a amanang le phepo e phahameng ea bo-'mè a fetolang lijo tse nang le phepo e phahameng ea 'mele le polelo ea mofuta oa genopamine le liphatsa tsa lefutso tse amanang le opioid. Endocrinology 151, 4756-4764 (2010).

  163. Vucetic, Z., Kimmel, J. & Reyes, TM Lijo tse nang le mafura a mangata tse matlafatsang li-registe tsa postpiatal epigenetic ea receptor ea mu-opioid bokong. Neuropsychopharmacology 36, 1199-1206 (2011).
    Phumano ea bohlokoa e fanang ka maikutlo a hore liphetoho tse teng ho methapo ea methapo ea methapo ea methapo ea methapo ea kutlo li ka baka tlokotsing ea ho lemalla.

  164. Dunn, GA & Bale, TL Litholoana tsa lijo tse matlafatsang tse nang le phepelo e phahameng ea 'mele molatong oa motho oa boraro oa mosali ka leloko la ntate. Endocrinology 152, 2228-2236 (2011).
    Pampiri ena ea bohlokoa e fana ka maikutlo a hore lijo li ka baka liphetoho tse amanang le epigenetic tse ka susumetsang khetho ea lijo mme tsa fetisoa ka meloko.

  165. Dallman, MF et al a. Ho imeloa kelellong le botenya haholo: pono e ncha ea "lijo tsa matšeliso". Proc. Natl Acad. Saense USA 100, 11696-11701 (2003).

  166. Cottone, P. et al a. Mokhatlo oa CRF oa ho hira o kopanya lehlakore le lefifi la ho qobella ho ja. Proc. Natl Acad. Saense USA 106, 20016-20020 (2009).

  167. Koob, GF Karolo ea li-peptide tse amanang le CRF le CRF lehlakoreng le lefifi la ho lemalla. Resin ea Boko. 1314, 3-14 (2010).

  168. Macht, M. Liphello tsa lijo tse matlafatsang le tse se nang matla ka tlala, ts'ebetso ea 'mele le maikutlo a pherekano ea maikutlo. Takatso ea lijo 26, 71-88 (1996).

  169. Oswald, KD, Murdaugh, DL, King, VL le Boggiano, MM Ho susumetsa lijo tse matlafatsoang leha ho na le litlamorao molemong oa phoofolo ea ho itlopa lijo. Int. J. Ela Disord. 44, 203-211 (2010).

  170. Hagan, MM et al a. Moetso o mocha oa phoofolo ea ho itlopa joala: karolo ea bohlokoa ea ho lumellana ha khatello ea khatello ea kelello le khatello ea maikutlo. Physiol. Behav. 77, 45-54 (2002).

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Litlamo tse amanang le lingoli

  1. Laboraro la Boitšoaro ba Boitšoaro ba Maqhubu le Molek'hule, Lefapha la Phekolo ea Limolek'hule, le Lefapha la Neuroscience, The Studiops Research Institute Florida, 130 Scripps Way, Jupiter, Florida 33458, USA.
    Email: [imeile e sirelelitsoe]

E phatlalalitsoe marang-rang 20 Mphalane 2011