Koetliso e entsoeng ka cocaine e entsoeng ka mokokotlo ea li-dendritic ho D1 le D2 dopamine e nang le li-spin neurons tse nang le mefuta e meholo e nucleus accumbens (2006)

Proc Natl Acad Sci US A. Feb 28, 2006; 103 (9): 3399-3404.
E phatlalalitsoe marang-rang Feb 21, 2006. Doi:  10.1073 / pnas.0511244103
PMCID: PMC1413917
Khopolo-taba
Sehlooho sena se bile teng e boletsoeng ke lihlooho tse ling ho PMC.

inahaneloang

Phetoho ea ts'ebetso ea Psychostimulant e susumetsang ea li-dendritic spines ho dopaminocepts neurons ho li-nucleus accumbens (NAcc) e kentsoe ts'ebetso e le karabelo e feto-fetohang ea neuronal e amanang le boits'oaro ba nako e telele ba ho lemalla. NAcc e kopantsoe haholo le likarolo tse peli tse ikhethileng tsa li-neuron tsa spiny tse mahareng tse hlahisang maemo a phahameng a dopamine D1 kapa D2 receptors. Thutong ea hona joale, re ile ra sekaseka dendritic spine density kamora kalafo e sa foleng ea koae ka D1 kapa D2 receptor e nang le li-spiny neurons tse bohareng bo boholo ho NAcc. Lithuto tsena li sebelisitse litoeba tsa transgenic tse neng li supa EGFP tlasa taolo ea D1 kapa D2 receptor promoter (Drd1-EGFP kapa Drd2-EGFP). Kamora matsatsi a 28 a kalafo ea koae le matsatsi a 2 a ho tlohela, khatello ea lesapo la mokokotlo e ile ea eketseha ka har'a li-neuron tsa Drd1-EGFP- le Drd2-EGFP. Leha ho le joalo, keketseho ea letsoalo la lesapo la mokokotlo e ile ea bolokoa feela matsatsing a XdUMN-EGFP-e ntle ea 1 ka mor'a ho khaotsa lithethefatsi. Haholo-holo, polelo ea "ΔFosB" e ntseng e eketseha e boetse e bonoe ho li-neuron tsa Drd30-EGFP- le tse ntle tsa Drd1-EGFP kamora matsatsi a 2 a ho khaotsa lithethefatsi empa e le matsatsing a XdNNXX-EGFP a nang le tšoaetso ka mor'a matsatsi a 2 a ho tlohela lithethefatsi. Liphetho tsena li bontša hore letsoalo le matla la lesapo la mokokotlo le hlokometsoeng kamora kalafo ea cocaine e sa tsitsang le tsitsitseng feela ho li-neuron tse nang le D1 le hore polelo ea ΔFosB e amana le ho etsoa le / kapa tlhokomelo ea methapo ea methapo ho D30 hammoho le li-neurons tsa D1. ho NAcc.

Tsela ea mesolimbic dopaminergic tsela e entsoe ka li-neurons tse sebakeng sa "ventral tegmental" tse ka hare tsa methapo ea methapo ea methapo ea methapo (NAcc), tubercle ea olgicory, preortalal cortex le amygdala (1), athe nigrostriatal dopaminergic neurons ka har'a substantia nigra (pars compacta) e fana ka khakanyo e nyolohang ho dorsal striatum (2). Psychostimulants e phahamisa mohopolo oa dopamine ho NAcc: cocaine, ka ho thibela ho ts'oaroa ha dopamine ho tloha synaptic cleft, le amphetamine, ka ho khothaletsa ho lokolloa ha dopamine litsing tsa methapo ea kutlo (3-5). Tsamaiso e phetoa-phetoang, ea nakoana ea li-psychostimulants e baka karabelo ea boitšoaro bo makatsang (maikutlo a ho ama) litlamorao tse matla tsa litlhare tsena (6-8). Bongata ba bopaki bo fana ka maikutlo a hore liphetoho tse feto-fetohang tikolohong ea "ventral tegmental area" NAcc dopaminergic system li bohlokoa bakeng sa liphetoho lipolotiking tse itšetlehileng ka boiphihlelo tse susumetsang boitšoaro bo susumetsoang ke lithethefatsi.

Ntle le dopamine, glutamate e hlokahala bakeng sa nts'etsopele ea boits'oaro ba boits'oaro ho arabela ho li-psychostimulants (9, 10). Li-spiny neuron tse boholo bo bohareng (MSNs) ka har'a li-ventri striatum li fumana lipono tse nyakallisang tsa glutamatergic tse tsoang pele cortex e ka pele e kenella lihloohong tsa methapo ea methapo ea methapo. Li -MSN le tsona ke sepheo se seholo bakeng sa li-axon tsa dopaminergic tse kenellang molaleng oa lesapo la mokokotlo (1, 11, 12). Ka hona, li-spendritic spines ho li-MSN li emela komporo ea maqhubu moo phetisetso ea dopaminergic le glutamatergic li kopaneng pele.

Dopamine e sebetsa liketsahalong tse peli tse kholo tsa li-receptor subfamily, D1 subfamily (D1 le D5 subtypes) le D2 subfamily (D2, D3, le D4 subtypes) (13). Ka dorsal striatum, lithuto tsa anatomical li bonts'itse hore li-stNatonigral MSN li na le li-receptor tsa D1 (hammoho le P le dynorphin), athe li-stNatopallidal MSNs li bua haholo ka li-receptor tsa D2 (hammoho le enkephalin) (14-17). Morero o tsoang ho NAcc o rarahane ho feta ho dorsal striatum, moo likhetla le likarolo tsa mantlha tsa NAcc li rerileng ho hlahisa likarolo tse fapaneng tsa "ventral pallidum" le sebakeng sa sepheo sa "ventral tegmental" le "substantia nigra"18). Le ha li-receptor tsa D2 le enkephalin li hlahisoa haholo lipakaneng tsa li-ventral pallidum, li-receptor tsa D1 le ntho P li fumanoa li arolelitsoe ka mokhoa o tšoanang ka projeke ea sebaka sa ventral pallidum le ventral tegmental (19). Boithuto ba li-agonists le bahanyetsi ba khethang li-receptors tsa D1 kapa D2 li bontšitse hore li-receptor tsa D1 le D2 li hlokahala bakeng sa liphetoho tsa boitšoaro tse itšetlehileng ka psychostimulant -20-25). Leha ho le joalo, likarolo tsa li-receptor tsena li bonahala li fapane. Mohlala, ts'usumetso ea li-receptors tsa D1 e bonts'a koae e batlang e ts'oaroang ke liente tsa priming cocaine le likhokahano tsa tikoloho tse amanang le koae, athe ts'usumetso ea li-receptors tsa D2 e thusa ho khutlisetsoa hoa koae (ke koae).26-28).

Boitšoaro bo bobe ba boitšoaro bo amanang le ts'ebeliso ea lithethefatsi tsa psychostimulant bo telele haholo. Ka hona, ho bile le thahasello e kholo ea ho khetholla liphetoho tsa nako e telele tse hlahisitsoeng ke lithethefatsi maemong a limolek'hule le a sebopeho makaleng a neuronal a laoloang ke dopamine le glutamate (29-32). Haholo, ho pepesetsoa nako e telele ea cocaine kapa amphetamine ho fumanoe ho eketsa palo ea lintlha tsa lekala la dendritic le li-spine tsa li-MSN ho NAcc (33-35). Liphetoho tsena tsa sebopeho li bonts'itsoe ho phehella ho fihlela months1-3.5 likhoeli kamora ho pepeseha ha lithethefatsi tsa ho qetela (30, 35) 'me ho fanoe ka tlhahiso ea hore e fetole liphetoho tse telele tsa nako e telele ho polasetiki ea synaptic e amanang le ho pepesetsoa hoa psychostimulant.

Morero oa thuto e teng hona joale e ne e le ho hlahloba liphetoho tse entsoeng ka koae ka likarolo tse ling tsa li-MSN tse hlahisang D1 kapa D2 receptors. Lithutong tsena, re sebelisitse litoeba tsa bacterial chromosome (BAC) tse hlahisang EGFP tlasa taolo ea D1 (Drd1-EGFP) kapa D2 (Drd2-EGFP) dopamine receptor promoter (36). Liphetho li bonts'a hore, le ha letsoalo le matla la mokokotlo le eketsehile qalong le ba le li-MSNs tse amohelang li-DNNUMX le li-receptor tse nang le D1, letsoalo le fetotsoeng la lesapo la mokokotlo le tsitsitse feela ho li-neuron tsa D2. Ntle le moo, re fumana liphetoho tse tšoanang polelong ea transcript factor ΔFosB, e fanang ka maikutlo a hore ΔFosB e ka ameha ho etsoang le / kapa ho lokiseng methapo ea methapo ho D1 hammoho le li-neurons tse nang le li-receptor tsa D1 ho NAcc.

Results

Tlhahlobo ea li-MSN ho Drd1-EGFP le Drd2-EGFP BAC Transgenic Mice.

Tsela ea projeke ea li-MSNs tse tsoang dorsal le ventral striatum ho Drd1-EGFP kapa Drd2-EGFP BAC transgenic litha e bontšitsoe ka tlhahlobo ea polelo ea GFP (36). Polelo e khethollang ea GFP ho li-MSN tsa dorsal striatum e lumellana hantle le ea li-receptor tsa D1 kapa D2, ka ho latellana (36). Re boetse re hlahlobisitse polelo e khethollang ea GFP ho NAcc ho Drd1-EGFP kapa litoeba tsa Drd2-EGFP (Feie. 1a 'me b). Le ha ≈58% ea li-neuron ho NAcc e bontšitse GFP ho litoeba tsa Drd1-EGFP (Feie. 1a), ≈48% ea li-neuron ho NAcc e bontšitse GFP ho litoeba tsa Drd-2-EGFP (Feie. 1b). Li-MSN li emela 90-95% ea li-neuron tsohle ho NAcc (12, 37). Li-receptor tsa D1 li hlahisoa feela ho li-MSN, mme li-receptor tsa D2 li hlahisoa ho li-MSN le li-interneurons tsa cholinergic, tse emelang 1-3% ea li-neuron tsa striatal (37). Ho nka lintlha tsena, liphetho li fana ka maikutlo a hore, bonyane, ≈10-15% ea li-MSN ho NAcc li khona ho hlahisa li-receptor tsa D1 le D2 ka bobeli.

Setšoantšo sa 1. 

Tlhahlobo ea li-MSNs ho Drd1-EGFP le litoeba tsa Drd2-EGFP. (a 'me b) Likhechana tsa kelello tse tsitsitseng tsa NAcc tsa Drd1-EGFP (a) kapa Drd2-EGFP (b) Litoeba tsa transgenic tsa BAC li ne li kentsoe GFP le NeuN (joalo ka lesupa le akaretsang la neuronal). Litšoantšo tse kopaneng li bonts'a, ka 'mala o mosehla, colocalization ...

Ts'ebetso ea Li-Spendritic Spines ho Drd1-EGFP le Drd2-EGFP lithunya.

Polelo ea GFP ho Drd1-EGFP le litoeba tsa Drd2-EGFP e ne e thusa ho qopitsa 'mele ea methapo ea sele. Leha ho le joalo, lets'oao la GFP ho dendrites le dendritic spine le ne le fokola haholo ho lumella tlhahlobo ea bona kamora ho itšireletsa ka li-antibodies tsa anti-GFP. Ho fana ka dae ea fluorescent e kopaneng le karolo e bohareng ho sa tsoa sebelisoa ho bitsa palo ea batho ka methapo e potlakileng le e sebetsang (38). Li-neuron tsohle li ka ngolloa ho sebelisoa mokhoa ona, 'me mokhoa o bonahala o bapisoa le lits'oants'o tsa Golgi-Cox. Ho sekaseka morendology ea dendritic ea li-neuron ho NAcc, ho ne ho ngotsoe mantsoe a seng makae a kopaneng le lipophilic fluorescence dae 1,1'-diotadecyl-3,3,3 ′, 3'-tetramethylindocarbocyanine perchlorate (DiI) ka ho sebelisa sethunya sa mofuta oa gene. Mohlala oa MSN e nang le lits'oants'o tsa marang-rang o bontšitsoe ho Feie. 1c. Tlas'a maemo a sebelisitsoeng, ka tloaelo re ne re bona li-neurons ntle le ho fetisa li-dendrites tse tsoang ho li-neuron tse ling tse ngotsoeng. Ha a phahamisa boleng bo phahameng, ho ka bonoa lintlha tse hlakileng tsa "dendritic morphology" ho kenyeletsa le methapo ea dendritic (Feie. 1d).

Ka mor'a moo re ile ra sebelisa motsoako oa DiI labeling le immunohistochemistry bakeng sa GFP ebang ke Drd1-EGFP kapa Drd2-EGFP lithaelese tsa transgenic, tse ileng tsa etsoa ka ts'ebeliso e tlase ea sesepa sa thibelo bakeng sa tumello ea lithane (bona mekhoa). Ka papiso e hlokolosi ea letheba la DiI le polelo ea GFP ka har'a 'mele ea lisele tsa li-MSN, re ka khona ho supa li-DiI- le GFP-positive kapa diI-positive le GFP-negative neurons ho Drd1-EGFP (Feie. 2a) kapa Drd2-EGFP (Feie. 2b) litoeba. Bakeng sa lithuto tse latelang, re ile ra sekaseka dendritic morphology ho li-neuron tse nepahetseng tsa DiI- le GFP feela tse tsoang ho litoeba tsa Drd1-EGFP kapa Drd2-EGFP.

Setšoantšo sa 2. 

Ho hlahlojoa ha methapo ea dendritic ho litoeba tsa Drd1-EGFP le Drd2-EGFP. Neurons ka NAcc ea litoeba tsa Drd1-EGFP (a) kapa litoeba tsa Drd2-EGFP (b) tsa pele li ile tsa ngoloa ka DiI (khubelu) ebe li kenngoa immunohistochemistry li sebelisa anti-GFP antibody (EGFP, botala). Feela ...

Phekolo e sa foleng ea Cocaine e hlahisa ho eketseha ha letsoalo la Spine ho li-MSNs tse hlalosang kapa Drd1-EGFP kapa Drd2-EGFP.

Drd1-EGFP kapa litoeba tsa Drd2-EGFP li ile tsa kenngoa khafetsa le cocaine (30 mg / kg) kapa saline bakeng sa libeke tse nne tse latellanang (bona mekhoa). Matsatsi a mabeli (2WD) kapa matsatsi a 30 (30WD) kamora kalafo ea ho qetela ea lithethefatsi, likelello li ile tsa sebetsoa bakeng sa ho ngolisoa ha DiI le immunohistochemistry joalokaha ho hlalositsoe ka holimo. Phuputso e fetileng e boletse hore kalafo e sa foleng e nang le amphetamine e ile ea eketsa letsoalo la lesapo la mokokotlo empa eseng dendrites tsa proNimal tsa li-MSN ho NAcc (35). Ka hona, re fokotsa tlhatlhobo ea rona ho li-dendrites tsa distal (ke hore, tse nang le makala a bobeli kapa a boraro), ho kenyeletsoa libaka tsa terminal. Ha ho hlahlojoa ho 2WD, letsoalo la lesapo la mokokotlo le ile la fumanoa le eketseha ho Drd1-EGFP-positive MSNs (128% ea sehlopha sa saline) (Feie. 3a 'me c) le ho isa tekanyong e nyane ho li-neuron tse ntle tsa Drd2-EGFP (115% ea sehlopha sa letsoai) (Feie. 3 b 'me d). Kamora 30WD, letsoalo le matla la lesapo la mokokotlo le ile la bolokoa ho Drd1-EGFP-positive neurons (118% ea taolo ea letsoai) (Feie. 3 a 'me c) empa eseng ho li-neuron tse ntle tsa Drd2-EGFP (Feie. 3 b 'me d).

Setšoantšo sa 3. 

Keketseho e sa feleng ea kokeine e bakoang ke lesapo la mokokotlo ho Drd1-EGFP- kapa Drd2-EGFP-positive MSNs in NAcc. (a 'me b) Drd1-EGFP (a) kapa Drd2-EGFP (b) litoeba li ne li tšoaroa ka saline (Sal) kapa cocaine (Coc, 30 mg / kg) bakeng sa libeke tsa 4. Mouse brains 2WD kapa 30WD e ile ea sebetsoa ...

Morphology ea dendritic spines e fapana ho ea ka bolelele ba tsona le bophara ba hlooho ea lesapo. Ka hona re arotse li-protocol tsa dendritic ka lihlopha tse 'ne tsa lesapo la mokokotlo (leqhubu, li-mushroom, tšesaane le filopodia) ho 2WD ho tsoa cocaine (data e sa bonts'itsoeng). Sekhahla sa mofuta oa li-mushroom (119.7 ± 4.0%, P <0.01) le likhahla tse tšesaane (120.0 ± 3.4%, P <0.01) e ile ea eketsoa ka kalafo ea k'hok'heine ho li-MSN tsa Drd1-EGFP, athe botenya ba stubby (182.4 ± 21.6%, P <0.05) le mokokotlo oa li-mushroom (122.5 ± 5.0%, P <0.01) e eketsehile ho li-MSN tsa Drd2-EGFP. Ho ne ho se na keketseho e kholo ea methapo e makatsang ho li-neurons tsa Drd1-EGFP kapa li-spines tse tšesaane ho li-neuron tse ntle tsa Drd2-EGFP.

Chronic Cocaine Induces ΔFosB Phatlalatso ho Drd1-EGFP- kapa Drd2-EGFP-Positive MSNs ho NAcc.

ΔFosB ke setho sa lelapa la Fos la lintlha tse tsoang. Le ha tsamaiso ea cocaine e matla e etsa hore ho be le li-fofs tse seng kae tsa nakoana tsa li-Fos ho NAcc, ho iponahatsa khafetsa ka koae ho eketsa boemo ba ΔFosB. Ntle le moo, keketseho ea polelo ea ΔFosB e phehella ho NAcc libeke tse ngata ho isa likhoeli kamora ho khaotsa ho pepesetsoa lithethefatsi mme ho fanoe ka maikutlo a ho nka karolo taolong ea nako e telele ea polelo ea gene, esita le ka mor'a ho khaotsa ho sebelisa lithethefatsi (29, 39, 40).

Ho hlahloba tlhahiso ea ΔFosB ho NAcc ho tsoa ho Drd1-EGFP kapa litoeba tsa Drd2-EGFP kamora kalafo ea koae, re ile ra sekaseka polelo ea FosB le GFP ka ho ngola habeli (Feie. 4 'me Lethathamo 1) Anti anti-FosB e amohela mefuta eohle ea FosB, empa re nahana hore immunostain e eketsehang e emela representsFosB (bona mekhoa bakeng sa lipuisano tse ling). Mahloaneng a phekoloang a letsoai, 16% ea li-neurons tse ntle tsa Drd1-EGFP le 15% ea li-neuron tse ntle tsa Drd2-EGFP e bontšitse ho se sebetse ha FosB ka matla a fokolang a fokolang (Feie. 4 a 'me b 'me Lethathamo 1). Phekolo e pheta-phetoang ea koae e lateloang ke 2WD e hlahisitse keketseho e kholo ea palo ea li-neurons tse ntle tsa Drd1-EGFP tse kopantseng ΔFosB (55% ea li-neurons tse ntle tsa GFP) (Feie. 4c 'me Lethathamo 1). Keketseho e nyane, empa e ntse e le ea bohlokoa ea polelo ea ΔFosB e fumanoe ho li-neurons tsa Drd2-EGFP-positive neurons (25% ea li-neurons tse ntle tsa GFP) (Feie. 4d 'me Lethathamo 1). Joalo ka liphetoho tsa letsoalo la lesapo la mokokotlo, polelo e ntseng e eketseha ea wasFosB e ile ea bolokoa ho li-neurons tsa Drd1-EGFP-positive neurons (46% ea li-neurons tse ntle tsa GFP) empa eseng ho li-neurons tsa Drd2-EGFP-tse ntle (15% ea li-neurons tse ntle tsa GFP) kamora 30WD (Feie. 4 e 'me f 'me Lethathamo 1). Hlokomela hore polelo ea "ΔFosB" e bonts'itsoeng e bonts'itsoe ho Feie. 4f e teng ka li-neuron tsa Drd2-EGFP-negative.

Setšoantšo sa 4. 

Kankere e sa foleng e qobella polelo ea ΔFosB ho Drd1-EGFP- kapa Drd2-EGFP-positive MSNs in NAcc. Drd1-EGFP (a, c, 'me e) kapa Drd2-EGFP (b, d, 'me f) litoeba li ne li tšoaroa ka saline kapa cocaine e sa foleng joalo ka ha ho hlalositsoe ho Feie. 3. 2WD (c 'me d) kapa 30WD (e 'me ...
Tafole 1. 

Quanifying of NELFP Khong Khong expressing expressing expressingFosB

Puisano

Liphetoho tse tšoarellang halelele ho dopaminergic neurotransication ho lumeloa hore li ka ba le boitšoaro bo tlatselletsang bo amanang le lithethefatsi tsa psychostimulant. Haholo-holo, keketseho ea kelello ea psychostimulant e bakelitsoeng ho dendritic spine density ea li-MSN ho NAcc e kentsoe hypothesed hore e hokahane le ho hlophisoa bocha ha khokahano ea synaptic (30). NAcc e kopantsoe haholo le litlatsetso tse peli tse ikhethileng tsa li-MSN tse hlalosang maemo a phahameng a li-D1 kapa D2 dopamine receptors. Thutong ea hona joale, re hlahlobile letsoalo la mokokotlo ho D1 kapa D2 receptor-e nang le li-MSNs ho NAcc kamora kalafo ea koae e sa foleng. Liphetho tse fumanoeng li bonts'a hore, le ha letsoalo le matla la mokokotlo le eketsehile qalong le ba le li-MSNs tse amohelang li-DNNUMX le li-receptor tse nang le D1, "spine density" e fetotsoeng lesapo la mokokotlo e tsitsitse feela ho li-neuron tsa D2-receptor. Ntle le moo, re fumana mohlala o tšoanang oa liphetoho phetohong ea criptionFosB ea transcript factor ho D1 le D1 receptor-e nang le li-MSN.

Lithuto tsena li sebelisitse litoeba tsa BAC transgenic tse hlalosang GFP maemong a ikhethileng a li-MSN tlasa taolo ea morekisi oa D1 kapa D2. Ntle le moo, re qapile mokhoa oa ho ngola mabitso habeli o kopanyang immunohistochemistry bakeng sa GFP le ho ngola ka bongaka ba methapo ea kutlo bo sebelisang DiI. Lithuto tse fetileng li sebelisitse mokhoa oa Golgi-Cox ho sekaseka phello ea li-psychostimulants ho letsoalo la lesapo la mokokotlo (34), le mokhoa oa DiI o sebelisitsoeng mona o fane ka liphetho tse neng li bapisoa ka bongata. Re thehile mokhoa oa ho ngola mabitso a mabeli hobane Golgi stain ha e lumellane le immunohistochemistry. Ho se ente hangata ho hloka hore ho sebetsanoe le lithane tsa sesepa, ntho eo hangata e lebisang ho moriana oa dae ea lipophilic ho tsoa membrane (38). Leha ho le joalo, lithutong tsa rona tsa hona joale, ho koaloa ha GFP ho ne ho sa hloke khatello e matla ea sesepa bakeng sa khaello ea lisele mme ka hona e ka sebelisoa ka kopanelo le dae ea lipophilic. Mokhoa oa rona oa ho ngola mabitso habeli o lokela ho ba o sebetsang bakeng sa lithuto tsa liphetoho tsa sebopeho lipakeng tsa dendritic, mohlala ha o sebelisoa bakeng sa tlhahlobo ea mela ea litoeba tsa BAC moo GFP e hlahisoang ka bongata ba li-neurons ho cortex (36).

Le ha e ntse e le likhang ka mokhoa o itseng, ho lumeloa hore li-receptors tsa D1 le D2 li arotsoe haholo ka tsela e tobileng ho "striatonigral" le "irriatopallidal" striatal projektion neurion, ka ho latellana (17, 41). Tšobotsi ea mantlha ea bosholu ba GFP ho litoeba tsa Drd1-EGFP le Drd2-EGFP e ne e lumellana le sephetho sena (36). Ho feta moo, tlhahlobo ea rona ea palo ea li-neurons tse nang le GFP tse ntle ho NAcc tse tsoang ho Drd1-EGFP le litoeba tsa Drd2-EGFP li lumellana le sephetho sa hore ≈50% ea li-MSN e bua feela li-receptors tsa D1, hore ≈35-40% e bua feela li-receptors tsa D2, le hore ≈10-15% coexpress ka bobeli D1 le D2 receptors. Boleng bona ba coexpression bo tšoana le bo hlahisoang ke lithuto tsa dorsal striatum tse kopantseng tlhahlobo ea methapo ea methapo ea methapo e le 'ngoe ea methapo le mekhoa ea RT-PCR ea ho qolla le ho holisa li-mRNA (≈17% coexpression ea enkephalin le ntho P) (42). Re lokela ho tseba hore lithuto tsa rona tsa hajoale ha li arabe potso ea polelo ea D3, D4, le D5 receptors, ebile ha li bue ka bothata ba polelo e tlase ea li-receptors tsa D1 ho li-MSN tse hlalosang maemo a phahameng a li-receptor tsa D2 kapa tse fapaneng.

Boithuto bo 'maloa ba pejana bo hlahlobe ho hlaka ha neuronal ha polelo ea Fost psychantimulant-ikiwa kapa karolo ea D1 le D2 receptors (43-45). Lithuto tseo li ile tsa tšehetsa sephetho sa hore Fos le ΔFosB induction e kenelletsoa ke ts'ebetso ea li-receptors tsa D1. Leha ho le joalo, tikoloho ea selefounu ea polelo ea Fos e susumetsoa ke tikoloho eo ho eona ho sebelisoang lithethefatsi tsa psychostimulant (46, 47). Mohlala, amphetamine kapa cocaine e fanoeng ka tlung ea lapeng e kenya liphatsa tsa lefutso tsa pele (ho kenyeletsa Fos) ka ho khetheha liseleng tsa P-positive tse tsamaisang li-receptor tsa D1. Ka lehlakoreng le leng, lithethefatsi tsena li ka susumetsa polelo ea Fos ho li-D1 le D2 receptor e nang le li-MSN ha li fanoa tikolohong ea lipale. Protocol e sebelisitsoeng lithutong tsa rona tsa hajoale ha e kenyeletse ho kenya ente ea lithethefatsi ka ho pepesehela tikoloho e ncha. Leha ho le joalo, re ke ke ra fana ka khetho ea mofuta o mong oa khatello ea maikutlo e ikarabellang bakeng sa polelo ea ΔFosB ho D2 e nang le li-receptor tse nang le li-MSN.

Karolo e hlokomelehang ea sephetho sa hona joale e ne e le mokhoa o ts'oanang oa letsoalo le matla la lesapo la mokokotlo le ntseng le eketseha. Ho eketsa letsoalo la lesapo la mokokotlo le polelo ea ΔFosB qalong ho etsahetse ho li-MSN tse hlalosang Drd1-EGFP le Drd2-EGFP. Leha ho le joalo, liphetoho tsena li ne li tsitsitse feela ho li-neurons tsa D1 tse nang le li-receptor. Tlhaloso e le 'ngoe e ka fumanoang bakeng sa tlhokomeliso e eketsang letsoalo la lesapo la mokokotlo le polelo ea ΔFosB e fumanoe butle-butle ho li-neurons tse nang le D2 ke hore sena se etsahetse karolong e nyane ea li-MSN tse kopanyang D1 le D2 dopamine receptors. Kahoo, mofuta oa nakoana oa keketseho ena o kanna oa amahanngoa le litlamorao tsa ts'ebetso ea li-receptor tsa D2 lits'ebetsong tse tšoaeang tsa D148). Hoa thahasellisa hore liphetoho tse mabapi le lesapo la mokokotlo le polelo ea ΔFosB li ile tsa khutlisetsoa morao, tse ka bontšang bokhoni ba lits'oaetso tse tsamaeang le methati ea D2 tse tsamaeang le ho amohela ho tsitsisa ha ΔFosB.

Tlhokomeliso ea hore ho na le liphetoho tse ts'oanang polelong ea osFosB le letsoalo la lesapo la mokokotlo e lumellana le mohopolo oa hore ΔFosB e kentse letsoho pōpong ea mantlha le polokeho ea morao-rao ea methapo ea methapo ho D1 li-receptor tse nang le li-neurons ho NAcc. Pontšo ea ΔFosB e laoloa ke tsela ea ho ts'oaea li-D1 / DARPP-32 / PP1.49). Boithuto bo 'maloa bo bontšitse hore ΔFosB e bapala karolo ea bohlokoa liketsong tse thabisang le tse matlafatsang tsa li-psychostimulants (39), mohlomong ka ho susumetsa polelo ea liphatsa tsa lefutso tse ngata tse kenyelletsang li-neurotransmitter receptors, liprotheine tse tšoaeang, le liprotheine tse kenyang taolo ea morphology ea neuronal (50). Leha ho le joalo, mekhoa e ikhethileng ea limolek'hule tse amehang ho etsoang ka lesapo la mokokotlo le sa tsoakoang ke koae ha e tsejoe hona joale. Lithuto tsa rona tse fetileng li bonts'itse hore infraaccumbal infusion ea Cdk5 inhibitor roscovitine attenuated eketseha ea koae e hlahisang cocaine -51). Ntle le moo, Cdk5 ke mofuta oa sepheo se tlase sa ΔFosB mme e bile le tlatsetso ho liphetoho tse lumellanang tse amanang le kalafo ea koae e sa foleng (52). Ka hona, phetoho ho phosphorylation e itšetlehileng ka Cdk5 ke moelelo o sebetsang o ka tlas'a mokokotlo oa mokokotlo oa cocaine-ikiwa le / kapa botsitso ba lesapo la mokokotlo. PAK (53), β-catenin (54), PSD-95 (55), le spinophilin (56) ke likarolo tse ka tlase tsa Cdk5 'me kaofela li amehile ka taolo ea mokokotlo oa mokokotlo (57-60). Tšebeliso e eketsehileng ea likarolo tsena tse ling tsa Cdk5 le masapo a mokokotlo e tla fana ka leseli mabapi le mekhoa e amehang taolong ea sebopeho sa lesapo la mokokotlo ke li-psychostimulants.

mekhoa

Liphoofolo.

Lice tse tsamaisang transgene ea EGFP tlasa taolo ea D1 kapa D2 dopamine receptors li hlahisitsoe ke projeke ea Gensat BAC transgenic (36). Litoeba tsa transgenic tse sebelisitsoeng thutong ena li ne li le libeke tsa 4-5 li bile li le mothating oa Swiss-Webster. Lice li ne li bolokoa ka har'a 12: 12-h light / potoloho e lefifi 'me e lula ka lihlopha tsa 2-5 ka lijo le metsi a fumanehang a libitum. Liprotheine tsohle tsa liphoofolo li ne li ipapisitse le Setsi sa Naha sa Tataiso ea Bophelo bakeng sa Tlhokomelo le Ts'ebeliso ea Liphoofolo tsa Laboraro 'me se amohetsoe ke Komiti ea Tlhokomelo ea Liphoofolo le Tikoloho ea Rockefeller University.

Phekolo ea Lithethefatsi.

Phekolo ea kalafo ea koae e sa foleng (30 mg / kg, letsatsi le letsatsi) ho tlalehiloe hore e hlahisa keketseho e matla masapo a mokokotlo oa li-MSN ka bobeli le khetla ea NAcc ho tsoa ho rat, empa lethalinyana le tlase (15 mg / kg) le eketsehile letsoalo la mokokotlo ho khetla (61). Ka hona re sebelisitse tekanyo e phahameng ea koae ho kenyelletsa phetoho ea likarolo likarolong ka bobeli tsa NAcc. Mice o ile a fumana ente e le 'ngoe (ip) ea 30 mg / kg cocaine-HCl (kapa saline) letsatsi le leng le le leng bakeng sa matsatsi a 5 a latellanang, a lateloa ke matsatsi a se nang ente ea 2, mme ts'ebetso ena e ile ea phetoa libeke tse latellanang tsa 4. Metsoako e ne e etsoa ka holong ea lapeng. 2WD kapa 30WD, masapo a panya a ne a sebetsoa bakeng sa ho ngolisoa ha DiI le / kapa immunohistochemistry.

Ballistic Labeling le Fluorescent Dye DiI.

Lintsu li ne li sa anngoe ka 80 mg / kg sodium pentobarbital 'me li tšeloe li-transcancer ka 5 ml ea PBS, tsa lateloa ke ho tlotsoa ka potlako ka 40 ml ea 4% paraformaldehyde ho PBS (20 ml / min). Li-brains li ile tsa tlosoa ka potlako ho lehata 'me tsa ngolisoa ka 4% paraformaldehyde bakeng sa 10 min. Lingoloa tsa Brain (100 μm) li ne li ngotsoe ke ho tlisoa ha dae ea fluorescent DiI (Molecular Probes) joalo ka ha ho hlalositsoe ho Ref. 38. Mokhoa o kopaneng oa DiI labeling-immunohistochemistry o ile oa qaptjoa ka mofuta o fokolang oa sesepa. Likarolo tse ngolisitsoeng ka DiI li ne li ngolisitsoe ka 0.01% Triton X-100 ho PBS bakeng sa 15 min ebe li kenngoa ka 0.01% Triton X-100 le 10% serum ea poli e tloaelehileng ho PBS bakeng sa 1 h ho fokotsa ho ngoloa ha nonspecific. Likarolo tsa mesifa li ne li kengoe ka 1% tloaelehileng serum / 0.01% Triton X-100 le anti-GFP antibody (Abcam, Cambridge, MA) bakeng sa 2 h ka mocheso oa kamore, o hlatsoitsoe, 'me o kentsoe 1: 1,000 dilution ea FITC- antijeketsara ea bobeli e kopantsoeng (Li-cell Molest). Likarolo li ne li behiloe ka li-slide tsa microscope mme li koaheloa ka sekoaelo se phahameng. Mokhoa oa ho ngola ka mokhoa oa "ballistic" o ile oa lumella tlhahlobo e qaqileng ea sebopeho sa lesapo la mokokotlo, mme liphetho tse fumanoeng li lekantsoe hantle le ka tekanyo e kholo ha li bapisoa le lithuto tse fetileng tse sebelisang mokhoa oa ho ngola oa Golgi-Cox maemong a bori a rat (34). Leha ho le joalo, ho fapana le lithuto tsa pejana, re ne re sa bone lihlooho tse peli li-neuron tse nang le methapo ea methapo. Phapano ena e kanna ea bakoa ke ho ts'oaroa ha mekhoa ea lits'oants'o kapa ho feto-fetoha ha litoeba (boithuto bona) Khahlano le lisele tsa rat (34).

Immunohistochemistry.

Liphoofolo li ne li sa tšoaroe li bile li entsoe ka mokhoa o hlalositsoeng ka holimo. Li-brains li tlositsoe mme li bolokiloe bosiu ho 4% paraformaldehyde ho 4 ° C. Li-brains li fetiselitsoe ho 30% sucrose ka tharollo ea PBS ea cryoprotection. Likarolo tsa Coronal (12 μm) li ne li khaoloa ka microtome ea leqhoa (Leica) ebe li kenngoa tšebetsong ea immunohistochemistry. Likarolo tsa methapo li ile tsa boela tsa ngolisoa ka bongata ho 0.3% Triton X-100 ho PBS bakeng sa 15 min le ho ts'oaroa habeli ho PBS. Likarolo li ne li entsoe pele ho 10% serum ea poli e tloaelehileng ho PNS ea 1 h ho 37 ° C, e hlahisitsoe ke li-antibodies tsa mantlha (tse kenngoeng ka 1% serum ea poli e tloaelehileng ho PBS) bosiu ho 4 ° C, ebe e ts'oaroa ka PBS 'me e kenelletse ka sekepeng. li-antibodies tsa 1 h ho 37 ° C. Li-antibodies tse latelang li sebelisitsoe: rabi anti-pan-FosB (SC-48, 1: 500; Santa Cruz Biotechnology), anti-NeuN (Chemicon), anti-GFP ea rabi, FITC-conjugated anti-rabi IgG, le rhodamine- anti-mouse IgG (Likhatiso tsa Limolek'hule). Bakeng sa ho ngolla ka makhetlo a mararo (ΔFosB, NeuN, le GFP), likarolo tsa boko li ile tsa kenngoa pele ka anti-pan FosB antibody le anti-NeuN antibodies tsa morao-rao ka antibodies tsa bongaka tsa (Igodamine-conjugated anti-rabi IgG le cyan-conjugated anti-mouse IgG ). Likarolo tse nang le likarolo tse peli tsa boko li ile tsa sebetsoa hape bakeng sa ho itšireletsa ha GFP ka ho sebelisa theknoloji ea ho ngolla ea Zenon (Zenon Alexa Fluor 488, Likhetho tsa Molelek'hule). Anti-pan-FosB antibody e phahamiselitsoe ho terminus ea N ea FosB mme e amohela ΔFosB le FosB ea bolelele bo felletseng (62). Ho latela liphuputso tse fetileng tse bonts'itseng hore ΔFosB empa eseng FosB kapa li-antigen tse ling tse amanang le Fos li hlalosoa hantle kamora kalafo e sa foleng ea koae, re nahana hore keketseho ea nako e telele ea ts'ireletso e emela polelo e tsitsitseng ea ΔFosB. Leha ho le joalo, ha ho tsejoe hore na lets'oao la immosoreactive FosB le fumanehang ho litoeba tse tšoeroeng ke letsoai. Tlhahlobo ea lipalo ho Lethathamo 1 o sebelisitse tsa Baithuti t teko.

Tlhatlhobo ea Spine ea Dendritic.

Li-MSN ka seqo ho NAcc li ile tsa khethoa bakeng sa tlhahlobo ea lesapo ho latela mekhoa e mengata. (i) Ho ne ho e-na le sebaka se fokolang kapa se sa kopaneng le lisele tse ling tse ngotsoeng ho netefatsa hore lits'ebetso tse tsoang liseleng tse fapaneng li ke ke tsa ferekana. (ii) Bonyane li-dendrites tse tharo tsa mantlha tse hlokahalang hore li bonahale bakeng sa lisele tse tla sebelisoa ho hlahlojoa. (iii) Li-dendrites tse hole (li-dendrites tsa terminal kapa haufi le terminal dendrite) li ile tsa hlahlojoa. Bahlahisi ba tsoang li-MSN ka bobeli khubung le khetla ea NAcc ba ile ba hlahlojoa. Le ha re ile ra bona li-MSN tse qalikaneng (spiny mofuta oa II), re ile ra sekaseka li-MSN tse hlabang haholo (mofuta oa spiny I). Ho bala boleng ba mokokotlo, bolelele ba dendrite (> 20 μm bolelele) bo ile ba latelloa ka ho sebelisa microscope e patiloeng (Zeiss LSM 510) e nang le lense ea qoeliso ea oli (× 40). Litšoantšo tsohle tsa li-dendrites li nkuoe ka ho fapana z maemo (0.5-1 μm botebo ba linako) ho hlahloba morphology ea dendritic spines. Litekanyo tsohle li entsoe ka software ea tlhahlobo ea litšoantšo ea metamorph (Universal Imaging, Downingtown, PA). Tlhahlobo ea lipalo-palo e sebelisitse tlhahlobo ea Kolmogorov-Smirnov.

Li-protrusions tse tsoang ho dendrites li ne li arotsoe ka mefuta e mene ho latela bolelele ba bona joalo ka ha ho hlalositsoe ho li-refs. 63 'me 64. Li-protrusions tsa sehlopha sa 1, tse bitsoang li-stubby protuberances, li ne li le <0.5 μm ka bolelele, li haelloa ke hlooho e kholo ea mokokotlo, 'me li sa bonahale li na le molala; sehlopha sa 2, kapa mokokotlo o bopehileng joaloka li-mushroom, li ne li le pakeng tsa 0.5 le 1.25 μm bolelele mme li ne li khetholloa ka molala o mokhutšoane le hlooho e kholo ea mokokotlo; sehlopha sa 3, kapa methapo e mesesaane, e pakeng tsa 1.25 le 3.0 μm mme e ne e lelefalitse melala ea mokokotlo ka lihlooho tse nyane; sehlopha sa 4, kapa litlatsetso tsa filopodial, e ne e le maqhubu a malelele a se nang hlooho ea mokokotlo.

lumela hore baa fokola

Mosebetsi ona o ne o tšehelitsoe ke Grant Public Service Service Grant DA10044 (ho PG le ACN) le The Simons Foundation, Peter J. Sharp Foundation, Picower Foundation, le FM Kirby Foundation.

khutsufalitsoeng

  • NAcc
  • nucleus accumbens
  • MSN
  • boholo bo boholo bo bohareng ba "mele" oa spiny
  • BAC
  • bacterial chromosome
  • Drd1
  • dopamine receptor D1 e hlohlelletsoa haholo
  • Drd2
  • dopamine receptor D2 e hlohlelletsoa haholo
  • Dil
  • 1,1'-diotadecyl-3,3,3 ′, 3'-tetramethylindocarbocyanine perchlorate
  • 2WD
  • Matsatsi a 2 kamora kalafo ea lithethefatsi tsa ho qetela
  • 30WD
  • Matsatsi a 30 kamora kalafo ea lithethefatsi tsa ho qetela.

Mongolo o botlaaseng ba leqephe

 

Khohlano ea polelo ea thahasello: Ha ho likhohlano tse boletsoeng.

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