Liphetoho tsa DeltaFosB-lipakeng tsa dopamine tse fetisisang li tloaelehile ke lijo tse nang le mafura a phahameng (2008)

THUTO E TLAHANG

Psychology ea Biol. 2008 Dec 1; 64 (11): 941-50. Epub 2008 Jul 26.

Teegarden SL, Nestler EJ, Bale TL.

mohloli o moholo

Lefapha la Biology ea liphoofolo, Univesithi ea Pennsylvania, Philadelphia, PA 19104-6046, USA.

inahaneloang

LITLHAHISO:

Kutloelo-bohloko ea ho fumana moputso e hlahisitsoe e le sesosa se rerang boitšoaro bo amanang le ts'ebeliso e mpe ea lithethefatsi hammoho le ho nona. Leha ho le joalo, mekhoa e sekametseng e kenyang menyetla ea meputso ha e tsejoe. Re khothalelitse hore ts'ebeliso ea dysamine ho saena dopamine e ka ba sesosa sa tebello e phahameng ea moputso eo ka eona mehopolo e nang le moputso e ka sebetsang ho etsa hore tsamaiso e lekane.

LITLHAHISO:

Re sebelisitse mofuta oa panya ea liphatsa tsa lefutso e eketsehang, phoofolo ea Delta FosB-everexpressing mouse, ho hlahloba liphetoho tsa tsela ea moputso ho latela lijo tse matlafatsang tse nang le mafura a mangata. Matšoao a tšoaeang moputso litoeba tsena a ile a hlahlojoa ka bobeli le ho latela libeke tsa 6 tsa ho pepesehela lijo tse fumanehang habonolo. Litsuonyana li ile tsa hlahlojoa tlhahlobong ea boits'oaro ka mor'a ho tlosa lijo tse nang le mafura a mangata ho lekola boteng ba mofuta ona oa ho tlosa tšusumetso e ntle.

LIKOTSO:

Liphetho tsa rona li bonts'a ts'ebetso e fetotsoeng ea moputso tseleng e tsamaeang le "nucleus accumbens-hypothalamic-ventral" e potolohileng ka lebaka la ho potoloha ha Delta FosB libakeng tse bokellanang ka bongata.. Maemo a phosphorylated cyclic adenosine monophosphate (cAMP) Karolo ea karabo e tlamang (pCREB), boko-derived neurotrophic factor (BDNF), le dopamine le cyclic adenosine monophosphate e laoloang phosphoprotein e nang le boima ba limolek'hule tsa 32 kDa (DARPP-32) ka har'a li-nucleus tsa li-nucleus li ile tsa fokotsoa ho litoeba tsa Delta FosB, tse fanang ka maikutlo a fokotsitsoeng a ho saena hoa dopamine. Libeke tse tšeletseng tsa ho pepesetsoa lijo tse nang le mafura a mangata li ntlafalitse liphapang tsena, 'me li senola bokhoni bo matla ba ho ja. Litoeba tsa Delta FosB hape li bonts'itse keketseho e kholo ea ts'ebetso ea locomotor le likarabo tse amanang le matšoenyeho lihora tsa 24 ka mor'a ho tlosoa ho mafura a mangata.

CONCLUSIONS:

Liphetho tsena li fana ka maikutlo a tebileng a liphetoho lipapatsong tse amanang le ho bala ha Delta FosB le dopamine signaling e ka fetoloang ka lijo tse bobebe mme e ka ba mokhoa o rerang esale pele ka mefuta e meng ea botena..

Selelekela

Leha ho na le tsebo e ntseng e eketseha ea lits'ebetso tsa neural tse laolang takatso ea lijo le ho ts'oenyeha, litekanyetso tsa botenya li ntse li eketseha United States. Phekolo ea hona joale ea lithethefatsi e na le katleho e lekanyelitsoeng, 'me phetoho ea boits'oaro e utloa bohloko ka lebaka la ts'ebetso e telele ea nako e telele (1). Ts'ebeliso ea lijo tse matlafatsang tse nang le letsoai le khokahano e hokahantsoe le liphetoho mokhoeng oa khatello ea kelello le moputso bokong, ho fana ka maikutlo a hore thepa ea moputso ea lijo tse joalo e ka fetisa matšoao a ho leka-lekanya matla (2-4). Lijo tse nang le mafura a mangata li fana ka meputso ea tlhaho, ho etsa hore litebele tsa moputso oa boko li sebetse ka tsela e ts'oanang le lithethefatsi tsa tlhekefetso, 'me ka lebaka leo li sebelisitsoe ho li-paradigms tsa boithati (5-8). Kahoo, ho ka etsahala hore boitšoaro le tšusumetso ea ho ja ho feta tekano le tšebeliso e mpe ea lithethefatsi li arolelane mekhoa e tloaelehileng, ka ho hlahisa menyetla e mecha ea kalafo bakeng sa maemo ana ka bobeli.

Ha re ithuta ka kamano lipakeng tsa lijo tse fumanehang habonolo le litsela tse laolang moputso le khatello kelellong, pejana re supile matšoao a limolek'hule le a biochemical a moputso o fokotsehileng le khatello e eketsehileng ea maikutlo kamora ho khaotsa ho ja lijo tse matlafatsang tse nang le mafura a mangata (HF). Hoa tšoana le lithethefatsi tsa tlhekefetso, ho pepesetsoa lijo tse matlafatsang lithutong tsa rona ho felletse ka litekanyetso tse eketsehang tsa ntlha ea phetisetso ΔFosB ho nucleus accumbens (NAc), sebopeho sa moputso oa boko bo bohareng (9, 10). Lits'oants'o tse nang le phepo e ntle haholo ea ΔFosB li bonts'a karabelo e matla bakeng sa moputso oa lijo (11), li ba etsa sesebelisoa sa bohlokoa sa ho lekola karolo ea tefo ea meputso le ho qeta nako e telele tsamaisong ea moputso molemong oa likarabo tsa limolek'hule le tsa biochemical ho lijo tse fumanehang habonolo.

Thutong ea hona joale, re sebelisitse litoeba tsa ΔFosB-overexpressing ho lekola liphetoho tsa nako e telele matšoao a moputso sebakeng sa li-neurocircuitry tsa NAc-hypothalamus-ventral tegmental sebakeng sa karabelo ea lijo tse matlafatsang tsa HF. Re ipapisitse le boithuto bo fetileng liphoofolong tsena tse hlokometseng moputso, re khothaletsa hore liphetoho tse hlahisitsoeng ke ΔFosB mabapi le meputso li kenyelletsa ho senyeha ha dopamine ho supa ho tsoa tlalehong ea NAc ho VTA. Ntle le moo, re ile ra nahana hore ho pepesetsoa moputso oa tlhaho oa lijo tse matla tse nang le mafura a HF ho tla etsa hore tsamaiso ea dopaminergic e litheko tsena li fetoloe, mme ho felle ka karabelo e fetelletseng ea khatello ea ho tlosoa ke lijo tsena tsa HF. Karolo e ikhethileng ea ho sebelisa lijo tse nang le phepo e ntle joalo ka ntho e nang le moputso e re lumella ho kenyelletsa litlatsetso tsa hypothalamic ho putsa li -rycytype ka mofuta oa phenotype o kanna oa ba oa ponelopele ea palo ea batho ba rerileng ho ba botenya bo thibang kalafo. Ho hlahloba tlhahiso-leseling ena, re ithutile matšoao a dopamine neurotransication, ho kenyelletsa pCREB, BDNF, le DARPP-32 ho NAc le tyrosine hydroxylase le transporter ea dopamine ho VTA, kamora ho hlahella ha HF. Re boetse re ile ra hlahloba matšoao a ikhethang a matla a tsejoang ho susumetsa tlhahiso ea dopamine, ho kenyelletsa leptin le li-orexin receptors ho polelo ea VTA le polelo ea orexin kahare ho hypothalamus ea morao.

Lisebelisoa le mekhoa

Animals

Litoeba tsa banna bitransgenic tse sa sebetseng hantle haholo ΔFosB ka li-neuron tsa li-dynorphin-positive ho NAc le dorsal striatum (Kelz et al., 1999) li entsoe ka semelo se kopaneng (ICR: C57Bl6 / SJL) Univesithing ea Texas Southwestern Medical Center mme e hlokometsoe ebile e hlokometsoe. tlhatlhobo Univesithing ea Pennsylvania. Litoeba tsohle li ile tsa bolokoa ho doxycycline (100 μg / ml metsing a nooang) ho fihlela li fihla Univesithing ea Pennsylvania. Ho kenya ts'ebetsong ea overexpression, Doxycycline e tlositsoe (n = 23) (12). Litoeba tsa taolo (n = 26) li ile tsa tsoela pele ho amohela lithethefatsi. Lice ba ile ba abeloa ho lihlopha tsa ja ka mor'a libeke tse robeli ka mor'a ho tlosoa ha dooxcyline ka nako eo polelo e bontšitsoeng ho fihlela maemo a phahameng (13). Lice li ne li bolokoa ka 12: potoloho e lefifi ea 12 (mabone ho 0700) e nang le lijo le metsi tse fumanehang lipapong. Lithuto tsohle li entsoe ho latela lipatlisiso tsa liteko tsa tlhahlobo tse amohetsoeng ke Komiti ea Tlhokomelo ea Liphoofolo le Tikoloho ea Univesithi ea Pennsylvania, mme lits'ebetso tsohle li ile tsa etsoa ho latela tataiso ea setheo.

Phatlalatso ea lijo

Lice li ne li bolokoa holima ntlo (n = 16) kapa li behiloe HF (n = 16-17) bakeng sa libeke tse tšeletseng. House chow (Purina Lab Diet, St. Louis, MO) e ne e na le 4.00 kcal / g, e na le protheine ea 28%, mafura a 12%, le 60% carbohydrate. Lijo tsa HF (Lipatlisiso tsa Lijo, New Brunswick, NJ) li ne li na le 4.73 kcal / g, e nang le protheine ea 20%, mafura a 45%, le 35% carbohydrate.

Biochemistry le polelo ea tlhaho

Ho ile ha hlahlojoa litoeba kamora libeke tse ts'eletseng tsa tlhaiso ea lijo. Mabili a ne a tlositsoe lehata ebile e ka ba leqhoa hohle leqhoeng le omileng kapa NAc e arotsoe (hoo e ka bang 0.5 - 1.75 mm ho tsoa bregma, ka botebo ba 3.5 - 5.5 mm) mme e hoamme ka nitrogen e nang le metsi. Lithane li ne li bolokiloe ka -80 ° C ho fihlela o ts'oaroa.

Tlhahlobo ea biochemical

Mekhoa ea li-blots tsa Bophirimela e hlalosoa ka lisebelisoa tsa tlatsetso. Li-antibodies tse sebelisitsoeng e ne e le: Cdk5, CREB, le BDNF (1: 500, Santa Cruz Biotechnology, Santa Cruz, CA) le phospho-CREB (pCREB) (Ser 133) (1: 500, Cell Signaling Technology, Danvers, MA).

Receptor autoradiography

Mekhoa e qaqileng ea autoradiography e hlalosoa ka lisebelisoa tsa tlatsetso. Li-ligands tse sebelisitsoeng e ne e le 2 nM H3 - SCH 23390 le 5 nM H3 - spiperone (PerkinElmer, Boston, MA).

Ho hybridization

Ts'ebetso ea lithane le ho nyalisoa ha li entsoe joalo ka ha ho hlalositsoe pele (14). Probe ea DARPP-32 e fanoe ka mosa ke P. Greengard (Univesithi ea Rockefeller), le tlhahlobo ea orexin ea J. Elmquist (Univesithi ea Texas Southwestern Medical Center). Li-Slide tse kenyellelitsoeng DARPP-32 li ile tsa kenngoa filimi bakeng sa matsatsi a 3, 'me li-slide tse natefeloang bakeng sa orexin li ile tsa etsoa filimi bakeng sa matsatsi a 4. Kananelo ea litšoantšo tsa lifilimi e entsoe joalo ka ha ho hlalositsoe pele (10).

QRT-PCR

RNA e ne e qheletsoe ka thoko ho VTA le polelo ea mofuta ka mong e hlahlobiloeng ho sebelisa mofuta oa polelo ea taqMan (Applied Biosystems, Foster City, CA). Mekhoa e qaqileng le tlhahlobo ea lipalo li ka fumanoa linthong tse tlatselletsang.

Litlhahlobo tsa boitšoaro

E le ho lekola litlamorao tsa ho ba le maikutlo a meputso mabapi le liphetoho tse bakoang ke ho ja, phepelo ea litoeba e ile ea tlosoa ho HF kamora libeke tse 'ne tsa ho pepesetsoa' me ea khutlela ntlong chow (n = taolo ea 9, n = 8 ΔFosB). Lihora tse mashome a mabeli a metso e mene ka mor'a ho tlosoa, litoeba li ile tsa pepesetsoa tlhahlobo e bulehileng ea tšimo ho ea ka paradigm (10) ea phepo ea rona ea phepo. Ka bokhutšoanyane, panya e ile ea beoa setsing sa lisebelisoa tse bulehileng tsa lebala 'me ea beoa leihlo metsotso e mehlano. Ho ne ho lekantsoe lifapano tsa mela, fecal boli, nako bohareng, le lifapano bohareng.

Lipalo-palo li

Lintlha tsohle ntle le li-blots tsa Bophirimela li ile tsa hlahlojoa ho sebelisoa ANOVA ea litsela tse peli e lateloang ke tlhahlobo ea Fisher's PLSD ka kalafo ea doxycycline (polelo ea ΔFosB) le boemo ba phepo e le mefuta e ikemetseng. Bakeng sa litlhahlobo tsa RT-PCR, boleng bo fokotsehileng ba P bo sebelisitsoe ho lokisa lipapiso tse ngata kahare ho lihlopha tsa liphatsa tsa lefutso tse amanang (bona lisebelisoa tsa tlatsetso). Li-blots tsa Bophirimela li ile tsa hlahlojoa ho sebelisoa t-teko ea moithuti ka kalafo ea doxycycline joalo ka phapano e ikemetseng, ho bapisoa le matšoenyeho a Optical ka har'a blot e tšoanang. Lintlha tsohle li hlahisoa e le tse mpe ± SEM.

Results

Phapang e fapaneng ea biochemical

Ho hlakisa litsela tsa limolek'hule tse matlafatsang kutlo ea moputso ho litoeba tsa osBFosB-overexpressing, litekanyetso tsa limolek'hule tse 'maloa tsa ho saena li ile tsa hlahlojoa ho NAc. Ho ne ho e-na le tloaelo ea ho eketseha ha maemo a Cdk5 ho NAc ea litoeba tsa ΔFosB ha li bapisoa le liphoofolo tse laolang litšila tse bolokiloeng ho doxycycline (F = 5.1, P = 0.08; Setšoantšo sa 1A). Litoeba tsa osBFosB li bontšitse maemo a fokotsehileng haholo a pCREB (F = 7.4, P <0.05; Setšoantšo sa 1B) hammoho le maemo ohle a CREB (F = 5.4, P = 0.05; Setšoantšo sa 1C). Phokotso e kholo ea BDNF e boetse e bonoe ho NAc ea litoeba tsa ΔFosB (F = 10.6, P <0.05; Fig. 1D).

Setšoantšo sa 1

ΔFosB e bonts'a matšoao a biochemical a leseli a fokotsehileng a dopamine ho NAc

Ho ja lijo le boima ba 'mele lijong tse phahameng tsa mafura

Ka mor'a moo re ile ra hlahloba litlamorao tsa phepo ea tlhaho ea HF ea tlhaho ka liphetoho tse bontšang limolek'hule ho litoeba tsa osBFosB-overexpressing. Ho ne ho se na phapang lipakeng tsa litoeba tsa ΔFosB le taolo ea lijo tse kenang ka tlung kapa HF. Leha ho le joalo, ho bile le phokotso e akaretsang ea khalori e tloahelehileng boima ba 'mele ha e pepesetsoa HF e neng e totobetse litoeba tsa ΔFosB (F = 11.2, P <0.01; Setšoantšo sa 2A). Qetellong ea libeke tse tšeletseng tsa phepelo ea lijo, litoeba tse amohelang HF li ne li le boima haholo ho feta tse fumanehang lijong tsa chow (F = 17.2, P <0.001), le litoeba tsa osBFosB li lekantsoe ka tlase ho taolo (F = 5.6, P <0.05; Fig. 2B). Phello ena e ne e totobetse liphapang lipakeng tsa lihlopha lijong tsa chow (P <0.05).

Setšoantšo sa 2

Limpho tsa ΔFosB tse fetang tekano li bontšitse ho se tšoane ha lijo tse jang kapa lijong tsa mafura a mangata (HF)

Phapang ea biochemical lijong tse phahameng tsa mafura

Ho fumana hore na phapang ea motheo ea NAc ho saena e ka fetoloa joang ke phepo ea HF, liprotheine tse tšoanang tse hlalositsoeng motheong oa motheo li ile tsa hlahlojoa liphoofolong tse neng li fumane libeke tse tšeletseng tsa HF. Ha ho na phapang e kholo maemong a Cdk5 (Fig. 3A). Maemo a pCREB le CREB ka kakaretso e ne e se e sa fapana kamora libeke tse tšeletseng tsa HF (Fig. 3B, C). Maemo a BDNF a ile a phahamisoa haholo ho litoeba tsa ΔFosB kamora libeke tse tšeletseng tsa ho pepesoa ha HF (F = 6.5, P = 0.05; Fig. 3D).

Setšoantšo sa 3

Lijo tse phahameng tsa mafura a mangata li bonts'a phapang e bonts'itsoeng ho NAc ea ΔFosB ovexpressing litoeba

Dopamine receptor autoradiography

Re sebelisitse receptor autoradiography ho lekola hore na liphetoho tse bakiloeng ke ΔFosB ho ho saeneleng dopamine ho NAc li amana le liphetoho ho polelo ea dopamine receptor (Setšoantšo sa 4A). Ho ja lijo tse nang le mafura a mangata ho bonahala ho eketsa letsoalo hanyane la D1 dopamine receptor binding (P = 0.14), mme phapang ena e ne e le kholo ho litoeba tsa osBFosB (Fig. 4B). Ho ne ho boetse ho na le tloaelo ea ho eketseha ha sebaka se tlamang sa D1 kamora HF (P = 0.06), mme tlhahlobo ea poso hoc e bonts'a sena e le sa bohlokoa ho litoeba tsa ΔFosB (P <0.05; Fig. 4C). Ho fapana le li-receptor tsa D1, ha ho na liphetoho ho bongata bo amohelang li-receptor tsa D2 (control chow = 97.6 ± 6.9, control HF = 101.1 ± 8.2, osBFosB chow = 91.6 ± 1.0, ΔFosB HF = 94.8 ± 9.5) kapa sebaka se tlamang (control chow = 47.3 ± 3.4, taolo HF = 53.8 ± 6.0, osBFosB chow = 51.9 ± 3.7, osBFosB HF = 49.0 ± 3.3) ho NAc e ile ea bonoa.

Setšoantšo sa 4

Lijo tse phahameng tsa mafura a mangata (HF) li lebisitse ho liphetoho ho D1 dopamine receptor e tlamang le polelo ea DARPP-32 ho li-nucleus accumbens (NAc) tsa iceFosB overexpressing litoeba

Polelo ea DARPP-32 ho NAc

In hybridization e ne e sebelisetsoa ho supa maemo a polelo ea DARPP-32 ho NAc (Setšoantšo sa 4D). Lijo tse nang le mafura a mangata li eketsehile haholo polelo ea DARPP-32 sebakeng sena sa boko (F = 5.1, P <0.05), mme ho bile le tšebelisano e kholo lipakeng tsa lijo le polelo ea osBFosB (F = 8.9, P <0.05), le litoeba tsa ΔFosB li bonts'a kholo phetoho e bakoang ke lijo (feiga 4E). Phapang ea mantlha ea polelo ea DARPP-32 lipakeng tsa taolo le litoeba tsa osBFosB e senotsoe ka tlhahlobo ea post hoc (P <0.01), hammoho le keketseho e kholo ea polelo ea DARPP-32 ho litoeba tsa ΔFosB ho HF (P <0.01).

Polelo ea Gene ho VTA

QRT-PCR e sebelisitsoe ho lekola liphetoho liphatseng tsa lefutso ho VTA, e shebile liphatsa tsa lefutso tse 'maloa tsa mantlha tse neng li ameha pejana taolong ea moputso. Mehlala eohle e ne e tloaetsoe ho ba act-actin. Ho etsa bonnete ba hore polelo ea β-actin ha e fetoloe ke kalafo, tlhahlobo e arohaneng e ile ea tsamaisoa ho bapisa β-actin le taolo ea bobeli ea ka hare, GAPDH. Ho ne ho se na phapang e kholo ponong ea β-actin (litekanyetso tsa ΔCT, β-actin - GAPDH: control chow = 2.29 ± 0.21, control HF = 2.01 ± 0.04, osBFosB chow = 2.32 ± 0.49, ΔFosB HF = 2.37 ± 0.10).

Tloaelo ea tšebelisano lipakeng tsa polelo ea ΔFosB le kalafo ea phepo e ile ea bonoa bakeng sa polelo ea tyrosine hydroxylase (F = 3.6, P <0.06; Setšoantšo sa 5A). Libeke tse tšeletseng tsa ho pepesehela HF ho bonahala ho fokotsa polelo ea tyrosine hydroxylase ho taolo ea litoeba le ho eketsa polelo ho litoeba tsa ΔFosB. Tšebelisano e bohlokoa lipakeng tsa polelo ea ΔFosB le ponahalo ea lijo e bonoe bakeng sa polelo ea mopalami oa dopamine (F = 6.7, P <0.03; Setšoantšo sa 5B). Joalo ka tyrosine hydroxylase, ho pepesehela HF ho fokolitse polelo ea Transporter ea dopamine ho litoeba tsa taolo le ho eketsa polelo haholo ho litoeba tsa ΔFosB (P <0.05). Phapang ea mantlha ea polelo ea mopalami oa dopamine lipakeng tsa taolo le litoeba tsa osBFosB ha ea ka ea fihlela bohlokoa (P = 0.16), empa kamora li-wks tsa 6 tsa HF, litoeba tsa osBFosB li hlahisitse maemo a phahameng haholo a mopalami oa dopamine ha a bapisoa le litsamaiso (P <0.05).

Setšoantšo sa 5

Phatlalatso e phahameng ea phepo e matla (HF) le polelo ea ΔFosB li lebisitse ho liphetoho ho polelo ea palo ea limolek'hule tse kholo ho VTA

Ho ne ho na le moetlo o bonts'ang phello ea polelo e ekelitsoeng ea osBFosB ho fokotsa maemo a TrkB ho VTA (F = 5.7, P <0.04; Fig. 5C). Le ha ho ne ho se na litlamorao ho polelo ea κ-opioid receptor, ho ne ho na le tloaelo ea ho fokotsa polelo ho litoeba tsa osBFosB (P = 0.08; Setšoantšo sa 5D). Pontšo ea receptor ea leptin le eona e ile ea khethoa ho VTA. Phello ea bohlokoa ea phepelo ea lijo e fumanoe (F = 6.1, P <0.03), ka HF e fokotsa haholo maemo a leptin receptor ho VTA ka bobeli ΔFosB le litoeba tsa taolo (Setšoantšo sa 5E). Pontšo ea orexin receptor 1 ho VTA le eona e ile ea hlahlojoa. Ho bile le phello e kholo ea lijo ha ho hlahisoa orexin receptor (F = 9.0, P <0.02), ka litoeba tse pepeselitsoeng HF e bonts'a maemo a holimo ho VTA (Setšoantšo sa 5F). Ho ne ho boetse ho na le tloaelo ea litoeba tsa ΔFosB ho hlahisa maemo a phahameng ka ho fetisisa a orexin receptor 1 sebakeng sena sa boko (P <0.05).

Polelo ea Orexin ho hypothalamus ea morao

Re lekantse maemo a orexin ho lateral hypothalamus, tšimoloho ea orexinergic innervation ea VTA, ka in situ hybridization (Setšoantšo sa 6A). Ho bile le tšebelisano e kholo lipakeng tsa polelo ea ΔFosB le ponahalo ea lijo ho orexin expression (F = 9.1, P <0.01), ka HF e eketsang haholo maemo a orexin ho litoeba tsa taolo (P <0.05) le polelo e fokotsehang ho litoeba tsa ΔFosB (Fig. 6B). Le ha ho ne ho se na phapang e kholo ho polelo ea orexin seterekeng sa basal, kamora li-wks tsa 6 tsa HF, litoeba tsa ΔFosB li bontšitse maemo a fokotsehileng haholo a orexin ha a bapisoa le litsamaiso (P <0.05).

Setšoantšo sa 6

Lijo tse nang le mafura a mangata li bile le litlamorao tse sa bonahaleng mabapi le polelo ea orexin taolong (Ctrl) le litoeba tsa ΔFosB tse tebileng haholo

Beboikoetliso

Ho lekola liphetoho tsa ho tsoha le maikutlo ka lebaka la phetoho ea phepo, litoeba li ile tsa pepesetsoa liteko tse bulehileng 24 hrs kamora ho tlohela phepo ea HF (10). Kakaretso ea lifapano tsa mohala, tse fumanoeng e le mokhoa oa ho tsosa takatso, li ile tsa angoa haholo ke polelo ea ΔFosB (F = 6.6, P <0.05) le lijo (F = 4.6, P <0.05; Setšoantšo sa 7A). Litoeba tsa osBFosB li ne li sebetsa haholo tikolohong ea lipale ho feta li-contril, mme tlhahlobo ea post hoc e bonts'a hore litoeba tse tlositsoeng ho HF li ne li le mafolofolo haholo ho feta tse pepesitsoeng ke chow (P <0.05). Fecal boli e ne e nkuoa e le mokhoa oa boitšoaro bo ts'oanang le matšoenyeho (10). Ho bile le phello e kholo ea polelo ea ΔFosB (F = 10.2, P <0.01), e nang le litoeba tsa osBFosB-overexpressing tse hlahisang li-boli tse ngata tikolohong ea lipale, haholo-holo lihlopheng tsa ntlo le tsa HF (Fig. 7B). Litoeba tsa osBFosB tse bolokiloeng lijong tsa HF li hlahisitse li-foli tse fokolang ho feta tse bolokiloeng ho chow le tse huliloeng lihora tse 24 pele ho tlhahlobo. Litoeba tsa taolo ha lia ka tsa bonahala li angoa ke lijo. Ho ne ho se na litlamorao tsa polelo ea ΔFosB kapa lijo ka nako e sebelisitsoeng bohareng ba tšimo (control chow = 14.5 ± 3.1 sec, control HF = 18.0 ± 3.2 sec, control W / D = 15.4 ± 1.9 sec, osBFosB chow = 16.9 ± 2.4 sec, ΔFosB HF = 13.1 ± 3.9 sec, osBFosB W / D = 19.8 ± 2.6 sec).

Setšoantšo sa 7

ΔFosB e buoang ka mokhoa o feteletseng e ne e ameha haholo ka litlamorao tsa ho khaola mafura a mangata (HF)

Puisano

Ka kalafo ea botena, ho na le tlhoko e hlokoang ea ho khetholla lintlha tse susumetsang ts'ebetso ea ho nona le ho nona haholo. Litsela tsa meputso ea bongo li phetha karolo ea bohlokoa ho susumetseng le ho arabela lijong tse bonolo le phetoho ea lijo (6, 10, 15, 16). Joalokaha li-orexigenic le li-anorexigenic signals li ka susumetsa ka kotloloho ho supa moputso ka ho potoloha ha hypothalamus-VTA-NAc, ho hlakisoa ha liphatsa tsa lefutso tse arabelang lijong tse matlafatsang tse fumanehang kahare ho litsi tsa meputso ho ka fana ka lipheo tsa nalane tsa kalafo ho kalafo ea botena (17, 18). Ka hona, re ile ra hlahloba matšoao a biochemical le limolek'hule le sepheo sa matla le ho supa molemong oa potoloho ea hypothalamus-VTA-NAc ha re arabela lijong tsa HF ho litoeba tsa ΔFosB-overexpressing e le mohlala oa kutloelo-pele e ntlafalitsoeng ea liphetoho meputsong (13, 19, 20) , le maikutlo a boits'oaro bo latelang ho tlosoa hoa lijo. Re ts'elisitse hore basal dysregulation ea dopamine signing ho ΔFosB e ka fetoloa ka litlamorao tse matlafatsang tsa lijo tsa HF, ho kenyelletsa ho kenella ha matšoao a tekanyetso ea matla le sistimi ea dopamine.

Ho hlahloba mats'oao a bonts'ang tšoaetso ea dysamine ho dopamine ho supa ho NAc, re ile ra hlahloba maemo a li-receptor tsa D1 le li-activator tse tlase. Le ha ho ne ho se na phapang ea bohlokoa ho li-receptor tsa D1, ho ne ho na le mokhoa oa ho pepesehela HF ho eketsa sebaka se tlamang ho litoeba tsa ΔFosB. Sena se a khahlisa e le ho kenyelletsoa ha ΔFosB ka meputso ea lithethefatsi le ea tlhaho ho bonahala e le eona ntho e ka sehloohong ho dynorphin-subtype e ntle ea li-spiny neurons tse hlahisang haholo li-receptors tsa D1 (9, 21). Mehato ea pCREB e theohelang tlaase ea dopamine e ile ea fokotsoa haholo ho litoeba tsa ΔFosB, tšehetso ea ts'ebetso ea li-receptor e fokotsitsoeng ea D1 sebakeng sena sa boko (22, 23). Ho khahlisang, re boetse re hlokometse ho fokotseha ho hoholo ha maemo a CREB ho litoeba tsa ΔFosB, ho fana ka tlhahiso ea bokhoni bo eketsehileng ba phokotso ea phetisetso ea matšoao a dopamine e ka bang morao ho karabelo e bakoang ke ho fokotseha ha nako e telele hoa pCREB (24). Polelo ea BDNF e laoloa ke pCREB, e phahamisitsoe ka ts'ebetso ea D1, mme ke mokena-lipakeng oa bohlokoa oa neuroplasticity e amanang le moputso ho NAc (25, 26). Ka lebaka leo, re bone ho fokotseha ho hoholo ha protheine ea BDNF ho litoeba tsa NAc tsa ΔFosB.

Li-neurons tsohle tse mahareng tse pakeng tsa NAc li bontša DARPP-32 (27). Liphetoho tsa eona tse ngata tse tlase li e etsa sebapali sa bohlokoa tseleng ea moputso (28), mme e bile le tšusumetso litabeng tsa lithethefatsi le lits'ebetsong tse ling tse amanang le sisteme ea dopamine ho kenyelletsa mathata a amanang le mathata le lefu la kelello. (27, 29). Re lemohile phokotso ea bohlokoa ea basal ho polelo ea DARPP-32 ho NAc ea osFosB litoeba. Polelo ea DARPP-32 e laoloa ke BDNF, ka hona polelo e fokotsehileng e ka amana ka kotlolloho le phokotso maemong a BDNF e fumanoeng litoeba tsa ΔFosB (27, 29, 30). Le liphetoho tse itekanetseng mmuso oa phosphorylation ea DARPP-32 li ka lebisa ho liphetoho tse kholo ho saenaeng hoa bohlokoa kahare ho NAc (27). Liphuputso tse fetileng ha li tlalehe hore ha ho na phetoho liprotheine tsa DARPP-32 ho litoeba tsa ΔFosB kamora ho tlosoa ha 12-wk ho doxycycline ha ho ne ho etsoa tlhahlobo e batsi ea striatal (31), fana ka maikutlo a hore litlamorao tsa ΔFosB ho DARPP-32 e kanna ea ba nako le sebaka ka ho khetheha.

Re ile ra kholoa hore phokotso e makatsang ho li-indices tsa dopamine ho supa ka NAc ea ΔFosB litoeba li ka kenyelletsa liphetoho lits'ebetsong tsa neurot ea VTA dopamine, leha e le hore ΔFosB ha e sa qaqisoa haholo ka har'a li-neuron tsena. Ka hona, re ile ra hlahloba polelo ea liphatsa tsa lefutso tse amanang le dopamine ho VTA, ho kenyelletsa tyrosine hydroxylase le transporter ea dopamine. Maemo a tyrosine hydroxylase le dopamine transporter a tsamaellana hantle le tlhahiso ea dopamine. Ho ne ho na le tloaelo ea hore litoeba tsa ΔFosB li bonts'e tyrosine hydroxylase le phokotseho e kholo ea transporter ea dopamine, tumellanong le dysregulation ea dopamine signature ho NAc. Ha liphetoho tsena tsa mantlha mehloling e amanang le dopamine ho VTA ea ΔFosB litoeba li bonts'a maikutlo a fetotsoeng a NAc nakong ea nako e telele ea ΔFosB, re hlahlobe polelo ea receptor ea BDNF, TrkB, e le mochini o ka khonehang oa karabo ea NAc ho VTA (32). Hoa tšoana le tyrosine hydroxylase le transporter ea dopamine, polelo ea TrkB le eona e bonts'itse mokhoa oa ho fokotseha haholo ho litoeba tsa ΔFosB tse sa fihletseng bohlokoa ha li lokisoa bakeng sa papiso e ngata. Mochine oa BDNF-TrkB o ka tsamaisoa ka mokhoa o sa khaotseng le ho nka khato ka har'a VTA ho ama polelo ea lehae le ho khothaletsa kholo ea lisele le tlhokomelo (33). Ho feta moo, ts'ebetso ea BDNF ea presynaptic TrkB ka hara NAc e ka susumetsa ka kotloloho dopamine neurotransication (32), e ts'ehetsa ho fokotsoa ha sesupo sa dopamine ho litoeba tsena.

Ts'ebetso ea Dynorphin ea li-receptor tsa κ-opioid e laola ho supa dopamine mme ke mokhoa o mong oo NAc e fanang ka karabo ho VTA (34). Re fumane hore polelo ea li-ept-opioid receptor ho VTA e bonts'itse mokhoa oa ho fokotseha ho litoeba tsa ΔFosB. Joalokaha ΔFosB overexpression e bontšitsoe hore e fokotse polelo ea dynorphin ho NAc (20), mohlomong litoeba tsa ΔFosB li na le phokotso e kholo ho net VTA κ-ts'ebetso ea opioid. Leha dynorphin signaling hangata e na le phello e thibelang li-dopamine neurons (35), likhoto tse bonts'ang taolo e ikemetseng ea lithethefatsi tsa tlhekefetso li bonts'a maemo a fokotsehileng a dynorphin ho NAc, e supang karolo ea ho theola lets'oao la dynorphin ho matlafatseng kutloisiso ea moputso (36 (37), XNUMX). Ts'oaetso ea sistimi ea dynorphin - κ-opioid e hokahantsoe le ho fumana le ho phehella ha ts'ebeliso e mpe ea lithethefatsi, ho ts'ehetsa tekano e kholo ea lets'oao la opioid ka ho tloaela litsela tsa dopamine (38).

Re ipapisitse le bokhoni bo khotsofatsang ba lijo tse matlafatsang tsa HF, re fane ka maikutlo a hore litheko tse tsoang ho dopamine le moputso oa opioid tse saenneng ho litoeba tsa wouldFosB li tla rera esale pele litoeba tsena ho ntlafatsa likarabo tsa moputso lijong tse joalo, ka ho etsa joalo ka ho fetolela mokhoa oa moputso ka ts'ebetso ea hypothalamus Potoloho ea -VTA-NAc. Nakong ea phutuho ea libeke tse ts'eletseng, ha ho phapano ea ho ja lijo lipakeng tsa ΔFosB le litoeba tsa taolo li hlokometsoe, ho fana ka maikutlo a hore liphetoho tse fumanoeng ho li-biochemical le limolek'hule tsa lipontšo tsa meputso ho notFosB lithebe li ne li se ka lebaka la liphapang tsa khalori e jeoang. Joalokaha ho lebelletsoe, liphapang tsa basal tse fumanoeng pCREB, CREB, BDNF, DARPP-32, le maemo a receptor receptor lipakeng tsa ΔFosB le litoeba tsa taolo li ile tsa fihleloa, mohlomong ka lebaka la tlhahiso e eketsehileng ea dopamine ho litoeba tsa ΔFosB ho HF (29, 39-41) .

Ho hlahlojoa ha tyrosine hydroxylase le transporter ea dopamine ho VTA ho senotse likarabo tse makatsang tsa ΔFosB le litoeba tsa taolo kamora HF. Litoeba tsa taolo li bontšitse ho fokotseha ha mofuta oa tyrosine hydroxylase le polelo ea transporter, ha litoeba tsa ΔFosB li bonts'itse polelo ea mefuta ena ka bobeli ea dopamine. Ho khahlisang, polelo ea tyrosine hydroxylase e fetoloa ho VTA ke tsamaiso ea cocaine e sa foleng kapa tsamaiso ea methamphetamine (42-44), e fana ka maikutlo a hore litoeba tsa BFosB li ka fumana moputso oa tlhaho oa HF haholo ho feta litoeba tsa taolo.

Bakeng sa ho lekola hore na menyetla e ka bang teng ea "hypothalamic" joang ho VTA e kanna ea khutlisa matšoao a bonts'ang tekanyo ea matla, polelo ea leptin receptor le orexin receptor-1 le tsona li ile tsa hlahlojoa. Maqhubu a potolohileng a leptin a eketsoa ke HF, 'me leptin e ka fetolela VTA ho fetola dopamine signaling (18, 45). VTA leptin receptor expression e ne e fokotsehile ka mokhoa o ts'oanang ke HF ka bobeli ba bothFosB le litoeba tsa taolo, ka ho boloka melemo e ts'oanang le boima ba ho ja ha o le HF. Mafura a phahameng a boetse a eketsehile polelo ea orexin receptor-1 ho VTA ea bobeli ba ΔFosB le litoeba tsa taolo. Orexin e kenya tšebetsong dopamine neurons ho VTA, e phahamisa polasetiki ea VTA, mme e eketsa maemo a dopamine ho NAc (46-48). Lijo tse nang le mafura a mangata li bontšitsoe ho eketsa polelo ea orexin ho litoeba, ho latela lipono tsa rona (49, 50). Kahoo, polelo e eketsehang ea li-receptor tsa orexin hammoho le liphetoho tse tsoang ho leptin ho VTA li ka phahamisa moputso oa lijo ho li-ΔFosB le litoeba tsa taolo, ho ts'ehetsa pherekano lipakeng tsa tsela tse tsamaisang matšoao a matla a matla le tse amanang ka kotloloho.

Ho hlahloba litlamorao tse bakang khatello ea maikutlo mabapi le ho tlosoa ha moputso, litoeba li ile tsa hlahlojoa tlhahlobo e bulehileng ea li-24 hrs kamora ho tlosoa ha HF. Litoeba tsa osFosB li ne li amehile haholo ka litlamorao tse bohloko tsa ho khaotsa ho ja lijo, li bonts'a tšebetso e tsoileng matsoho le tlhahiso ea boli ka har'a pale e bulehileng ha e bapisoa le lihlopha tsohle tse ling tsa taolo le lijo. IceFosB litoeba li boetse li bonts'a mokhoa o khahlisang oa boitšoaro litekong tsena tse lekang moputso le maikutlo a khatello ea maikutlo, ka lijo tsa HF qalong li fokotsa tlhahiso ea fecal boli e amanang le chow, le ho tlosa hape ho eketsa karabelo ena e amanang le ho tšoenyeha. Keketseho ena e hlokometsoeng ea ts'ebetso ea ts'imo e bulehileng ha e kopane le phetoho ea polelo ea orexin, ho fana ka maikutlo a kamano le maikutlo a tlisoang ke khatello ea maikutlo ao eseng feela ts'usumetso ea liphetoho liponong tsa orexin. Ka kakaretso, datha tsena li ts'ehetsa maikutlo a rona a hore litoeba tsa ΔFosB li ka ameha haholo ho litlamorao tse matla tsa ho khaotsa ho ja ka lebaka la tlhoko ea bona ea moputso e phahamisitsoeng.

Ho ba le nako e telele ea ΔFosB ka nako e telele ho NAc ho lebisa joang phetohong e joalo ea boits'oaro le moputso oa ho supa? Re hlahisitse mofuta oa tlhahlobo ea tšohanyetso ea VTA moo e fetotseng maikutlo ho tsoa ho NAc le hypothalamus e fetisang matšoao mabapi le boemo ba moputso ho khetholla molao oa tsamaiso ea dopamine e ka tšehetsang khokahano pakeng tsa moputso oa tsela ea ho tsitsa le tebello ea ho ba botenya (fig. 8). Nakong ea ponaletso ea HF, liphutheloana tse ngata tse bonts'ang matla a morolo le boemo ba meputso bo fihlella VTA. Keketseho ea letšoao la leptin le orexin hammoho le karabelo e fetotsoeng ho tsoa ho NAc ho ea ho hypothalamus ea morao e ka ama tsela eo matšoao ana a orexigenic a arabang HF ka litoeba tsa ΔFosB (17, 18, 45, 47, 51-53). Litlhoko tse phahameng tsa mafura tse tlisoang ke BDNF li kanna tsa fana ka maikutlo a moputso ho VTA, tsa nts'etsapele le phetoho holima polelo ea gene e amanang le dopamine.

Setšoantšo sa 8

Lijo tse phahameng tsa mafura a mangata li etsa hore moputso oa letlalo o se ke oa buoa ka litoeba tsa mFosB

Liphetho tsena li hlakisa matšoao a limolek'hule tsa kutloisiso ea moputso mme li bonts'a hore taolo ea nako e telele ea sisteme ea dopamine e ka etsa hore motho a lemale le ho ba botenya. Ntle le moo, datha tsena li fana ka mohato oa bohlokoa o supang lipheo tse ncha tsa kalafo ho kalafo le thibelo ea botena le mafu a mang a ka bang tsamaisong ea moputso. Nakong e tlang, ho tla ba bohlokoa ho etsa lipatlisiso hore na sistimi ena e arabela joang ho tlosetsoa lijo tsa HF, hammoho le ho etsa lipatlisiso ka phapang efe kapa efe ea thobalano e mabapi le maikutlo a ho putsa le ho pepesehela mafura a mangata.

Boitsebiso bo Eketsehileng

Pheha Mekhoa

Tlanya mona ho bona. (61K, doc)

lumela hore baa fokola

Bangoli ba lakatsa ho leboha Cathy Steffen ka thuso bakeng sa ho tsoala liphoofolo le ho li fetisetsa. Mosebetsi ona o tšehelitsoe ke chelete ea lithuso e tsoang Univesithing ea lefu la tsoekere la Pennsylvania (DK019525) le lithuso tse tsoang ho National Institute of Mental Health (R01 MH51399 le P50 MH66172) le National Institute on Drug Abuse (R01 DA07359).

Mongolo o botlaaseng ba leqephe

Liphatlalatso tsa Lichelete: Bangoli bohle ba phatlalatsa hore ha ba na lithahasello tsa lichelete kapa likhohlano tse ka ba teng.

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