DeltaFosB Ho fokotsa Matšoao a Mahlahahlaha a Mahlahahlaha a Mabeli a Ntseng a Hlaseloa ke Karolo ea Meriana ea Boipheliso, ea Maikutlo, le ea Optogenetic Stimuli (2013)

J Neurosci. 2013 Nov 20; 33 (47):18381-95. doi: 10.1523/JNEUROSCI.1875-13.2013.

Lobo MK, Sane S, Damez-Werno DM, Koo JW, Bagot RC, Dinieri JA, Nugent A, Finkel E, Chaudhury D, Chandra R, Riberio E, Rabkin J, Mouzon E, Cachope R, Cheer JF, Han MH, Dietz DM, Boitšoaro ba DW, Hlahisa YL, Vialou V, Nestler EJ.

mohloli o moholo

Lefapha la Anatomy le Neurobiology, Univesithing ea Maryland School of Medicine, Baltimore, Maryland 21201, Lefapha la Fishberg la Neuroscience le Friedman Brain Institute, Ikahn Sekolo sa Bongaka Thabeng ea Sinai, New York, New York 10029, Mekhatlo ea Psychiatry le ea Pharmacology le Systems Therapeutics, Icahn Sekolo sa Bongaka Thabeng ea Sinai, New York, New York 10029, Ofisi ea Psychiatry, Univesithing ea Texas Southwestern Medical Center, Dallas, Texas 75390, Lefapha la Pharmacology le Toxicology le Setsi sa Lipatlisiso ka Lithethefatsi, Univesithing ea Naha ea New York 14214, New York, New York, New York, le Institut National de la Santé et de la Recherche Médicale, U952, Scientific Research National Center, 7224 Research Mixte, UPMC, Paris, 75005, France.

inahaneloang

Bothata ba phetolelo, ΔFosB, bo susumelletseha ka matla le bo phehellang ka mokhoa o tsoileng matsoho ka litlhaselo tse sa foleng, tse kang lithethefatsi tsa tlhekefetso, lithethefatsi tsa antipsychotic, meputso ea tlhaho le khatello ea kelello. Leha ho le joalo, liphuputso tse fokolang haholo li 'nile tsa hlahloba tekanyo ea ΔFosB ho kenngoa ha likhahla tse peli tse nyenyane tse hlaselang tse nyenyane. Re sebelisa litoeba tsa transporter BAC tsa transporter fluorescent ho hlahloba ho kenngoa ha ΔFosB ka dopamine receptor 1 (D1) e ntlafalitsoeng le dopamine receptor 2 (D2) e ntlafalitseng metsoako ea MSN ka lehare la striatum, nucleus accumbens (NAc) shell le core, le dorsal striatum (dStr ) kamora ho pepesehela lithethefatsi tse 'maloa tsa tlhekefetso ho akarelletsa cocaine, ethanol, Δ (9) -tetrahydrocannabinol, le opiates; meriana e thibelang lefuba, haloperidol; ntlafatso ea bana; sucrose ho noa; khaello ea khalori; serotonin e khethollang reuptake inhibitor ho imeloa kelellong, fluoxetine; le ho hlōla khatello ea sechaba sechabeng. Liphuputso tsa rona li bonts'a hore ho pepeseha ho sa feleng ho susumelletseha ho hongata ho etsa hore DFF e sebetsane le MSN-subtype libakeng tsohle tse tharo tse hlaselang. E le ho hlahloba ho kenoa ha DFFB ho potoloha ho potoloha, re sebelisa optogenetics ho ntlafatsa mosebetsi oa libaka tsa boko ba maoto tse romelletsang li-synaptic ho kena ho NAc; libaka tsena li kenyelletsa sebaka sa ventral le libaka tse 'maloa tse nang le phapang: li-prefrontal cortex, amygdala, le hippocampus ea li-ventral. Lintho tsena tsa optogenetic li lebisa mekhoeng e fapaneng haholo ea ΔFosB ho kenngoa ha metsoako ea MSN ho NAC ea motheo le shell. Ka kakaretso, liphuputso tsena li theha mekhoa ea khethollo ea ΔFosB ka li-MSN tse hlaselang ka mokhoa o hlaselang ka lebaka la tšusumetso e sa foleng le ho fana ka temohisiso ea morao-rao mekhoeng ea potoloho ea DFF ho ​​kenya li-striatum.

Selelekela

Mathata a sa feleng, ho kopanyelletsa le lithethefatsi tsa tlhekefetso, lithethefatsi tsa antipsychotic, khatello ea kelello, le meputso ea tlhaho, etsa hore ho bokelleha ho tsitsitseng ha ΔFosB, sehlahisoa sa truncated sa FosB liphatsa tsa lefutso, li-striatum (mohlala, Hope et al., 1994; Hiroi le Graybiel, 1996; Hiroi et al., 1997; Moratalla et al., 1996; Perrotti et al., 2004, 2008; Muller le Unterwald, 2005; McDaid et al., 2006; Teegarden le Bale, 2007; Wallace et al., 2008; Solinas et al., 2009; Vialou et al., 2010, 2011; Kaplan et al., 2011). Ho bokella hona ho lebisa melao ea liphatsa tsa lefutso tse ngata ka DFFB sebakeng sena sa boko (McClung le Nestler, 2003; Renthal et al., 2008, 2009; Vialou et al., 2010; Robison le Nestler, 2011). The striatum e entsoe ka ho khetheha (~95%) ea GABAergic e bapalang spiny neurons (MSNs), e arotsoeng likaroloana tse peli tse thehiloeng ho ntlafatso ea liphatsa tsa lefutso tse ngata, ho akarelletsa le dopamine receptor 1 (D1) kapa dopamine receptor 2 (D2) (Gerfen, 1992; Graybiel, 2000; Lobo et al., 2006; Heiman et al., 2008) le ka liketso tsa bona tse sa tšoaneng ho mehaho e fapaneng ea litsela tse fapaneng (Albin le al., 1989; Gerfen, 1992; Kalivas le al., 1993; Graybiel, 2000; Nicola, 2007; Smith le al., 2013). Morao tjena, ho bile le litlaleho tse ngata tse bontšang khethollo ea li-molecule le tse sebetsang tsa li-subtypes tsena tsa MSN ho ventral striatum (nucleus accumbens [NAc]) le dorsal striatum (dStr) bakeng sa ho buisana le ho susumetsa maikutlo le boitšoaro bo bobe (Lobo le Nestler, 2011; Gittis le Kreitzer, 2012).

Liphuputso tse fetileng li bontšitse hore ΔFosB e kenyelletsoa haholo-holo ho D1-MSNs ka phekolo e sa foleng le cocaine kapa boloetse bo sa foleng, e leng moputso oa tlhaho (Moratalla et al., 1996; Werme et al., 2002; Lee le al., 2006), empa khatello ea kelello e sa foleng e etsa hore ΔFosB e be maemong a mabeli a MSN (Perrotti et al., 2004). Ho feta moo, bopaki bo qobellang ba mefuta-futa ea mefuta e mengata ea liphatsa tsa lefutso kapa ea liphatsa tsa kokoana-hloko ea kokoana-hloko e bontša hore ΔFosB ho kenngoa ha D1-MSNs ho eketsa polasetiki ea boitšoaro le ea moralo ho cocaine, likarabo tsa boitšoaro ho morphine, ho tsamaea ka likoloi, moputso oa lijo, le ho tiisetsa ho hlōloa ha sechaba ka nako e sa lekanyetsoang khatello ea kelello, athe DFFBB ho kenya li-D2-MSN e laola boitšoaro bo bobe ka liketso tsa boitšoaro (Kelz et al., 1999; Werme et al., 2002; Colby et al., 2003; Olausson et al., 2006; Zachariou et al., 2006; Vialou et al., 2010; Grueter et al., 2013; Robison et al., 2013).

Ka lebaka la karolo e bohlokoa ea DFFB ho laola mekhoa ena e sa foleng, e nang le liphello tse fapaneng ho D1-MSNs le D2-MSNs, re etsa mona thuto e pharaletseng ka mekhoa ea ΔFosB ho kenngoa ha MSN subtypes ka litlhahiso tse sa foleng tse sa foleng, tse akarelletsang ho pepeseha lithethefatsi tse sa feleng ho hlekefetsoa, ​​ho phekoloa ka nako e telele le lithethefatsi tsa antipsychotic, ho hlahella ka nako e sa lekanyetsoang ho ts'ebetsong ea tšusumetso le tšitiso, khatello ea maikutlo e sa foleng ea sechaba, le ho phekoloa ka nako e telele le motho ea imetsoeng kelellong. E le ho utloisisa mekhoa ea potoloho e laolang ΔFosB ho kenngoa ha li-striatum ka libaka tse 'maloa tsa bokooa ba likopi, re sebelisa theknoloji ea optogenetic ho etsa hore lihlopha tsa dibinergic kapa tsa glutamatergic li sebetsane le boko ba tsona khafetsa' me li hlahlobe ho hlahisoa ha ΔFosB ho MSN subtypes. Liphello tsa rona li fana ka temohisiso e ncha ea ho kenngoa ha DFBB ho D1-MSNs le D2-MSN ka mokhoa o sa foleng, 'me ka lekhetlo la pele, ho bontšoa ho kenyelletsoa ha DFBB ho statum le ka har'a metsoako ea MSN e khethollang.

Lisebelisoa le mekhoa

Liphoofolo.

D1-GFP or D2-GFP hemizygote litoeba (Gong et al., 2003) ka mokokotlo oa C57BL / 6 o ne o bolokiloe ka 12 h ho potoloha leseli le lefifi le ad libitum lijo le metsi. Liphuputso tsohle li ne li khannoa ho latela melao-motheo e behiloeng ke Likomiti tsa Litlhokomelo tsa liphoofolo le Likomiti tsa Ts'ebeliso Univesithi ea Maryland School of Medicine le Ikahn School of Medicine Thabeng ea Sinai. Litoeba tsa banna (libeke tsa 8) li ile tsa sebelisoa bakeng sa liteko tsohle. Litoeba tsohle li ne li sebelisoa hampe, 'me boko ba bokelloa nakong ea thapama ea potoloho ea leseli. Hemizygote D1-GFP 'me D2-GFP litoeba tsa C57BL / 6 kapa FVB / N limelo li bontšitsoe hore li lekana le litoeba tsa mofuta o mofuthu mabapi le boitšoaro, litsebi tsa mafu a D1-MSN le D2-MSN, le nts'etsopele ea MSNs (Lobo et al., 2006; Chan le al., 2012; Nelson et al., 2012). Ho feta moo, mekhoa eohle ea ΔFosB e hlalositsoeng thutong ena e tšoana le e bonoang liphoofolong tse hlaha tse nang le lisebelisoa tse sa khethollang lisele (mohlala, Perrotti et al., 2004, 2008).

Phekolo ea Cocaine.

D1-GFP (n = 4 kalafo kalafo) le D2-GFP (n = 4 ka phekolo) litoeba li fumane li-7 letsatsi le leng le le leng li-cocaine (20 mg / kg) kapa 0.9% saline lehaheng la lehae. Bakeng sa li-injection tsa 1 kapa 3 d cocaine (20 mg / kg), litoeba li amohetse 6 kapa 4 d tsa li-injection tsa saline tsa 0.9 tse lateloang ke 1 kapa 3 d ea liente tsa cocaine. Litoeba tsohle li ile tsa sebelisoa hampe 24 h ka mor'a hore e entsoe ka ho qetela. Mokhoa ona oa cocaine o khethiloe ho latela lithuto tsa pele (mohlala, Maze et al., 2010).

Kalafo ea Haloperidol.

D1-GFP (n = 3 kapa 4 kalafo kalafo) le D2-GFP (n = 4 ka phekolo) litoeba li fumane haloperidol (2 mg / kg) metsing a nooang, pH 6.0 (Narayan et al., 2007), kapa metsi a kamehla a nooang, pH 6.0, bakeng sa libeke tsa 3 (21 d). Litoeba li ne li sebelisoa hampe letsatsing la 22.

Phekolo ea Morphine.

D2-GFP litoeba (n = 4 kapa 5 bakeng sa kalafo) ba ne ba sa khotsofatsoa ke isoflurane 'me ba fuoa li-implants tse nyenyane tsa morphine (25 mg) kapa li-pellets tsa sham ka letsatsi la 1 le 3 ea letsatsi joalokaha ho hlalositsoe pele (Mazei-Robison et al., 2011). Litoeba li ne li sebelisoa hampe letsatsing la 5.

Kalafo ea Ethanol.

D2-GFP litoeba (n = 4 kapa 5 bakeng sa phekolo) li pepesehetse 10% ethanol (EtOH), tekanyo eo C57BL / 6 e bontšitsoeng ho e noa (Yoneyama et al., 2008). Litoeba li ile tsa fuoa tlhahlobo ea libaka tse peli bakeng sa 10% EtOH (botlolo A) le metsi (bottle B), athe D2-GFP lithibelo li fumane metsi ka libotlolo tse peli (botlolo A le B) bakeng sa 10 d. Litho tsohle tse fumanoang libotlolo tsa EtOH li bontšitse khetho ea EtOH e lekanngoa ka (100 × bottle A volume / [lebokose A molumo + botlolo B boleng]]. Litoeba tse ileng tsa fumana botlolo ea 10% EtOH li ne li ja EtOH haholoanyane ha li bapisoa le metsi, athe litoeba tse fumanang metsi ka libotlolong tseo ka bobeli li ne li sa bontše phapang pakeng tsa metsi a sebelisoang. Mantsiboeeng a letsatsi la 10, litoeba tsohle li ne li fuoa metsi a tloaelehileng a nooang 'me li ne li sebelisoa hampe letsatsing la 11.

D (9) -tetrahydrocannabinol (Δ (9) -THC kalafo.

D2-GFP (n = 3 ka phekolo) litoeba li fumane liente tsa intraperitoneal tsa Δ (9) -THC (10 mg / kg) kapa koloi (0.9% saline le 0.3% Tween) habeli ka letsatsi bakeng sa 7 d (Perrotti et al., 2008). Litoeba li ile tsa sebelisoa hampe 24 h ka mor'a hore e entsoe ka ho qetela.

Khokaine ea boipheliso.

D2-GFP litoeba (n = 4 kapa 5 bakeng sa kalafo) qalong ba ne ba koetliselitsoe ho e-na le lever bakeng sa 20 mg sucrose pellets ka karolelano e tsitsitseng ea 1 (FR1) ho matlafatsa ho fihlela mochine o fumanoang oa 30 sucrose pellets bakeng sa matsatsi a tlhahlobo a 3 a latellanang o fihletsoe ho latela mekhoa e tloaelehileng (Larson et al., 2010). Litoeba tse ithutileng li-press lever li ne li kenngoa ka mokokotlo e nang le catheter e nang le majoe a mangata e le hore li lumelloe ke tsamaiso ea lik'hok'heine. Beke e 'ngoe ka mor'a hore ba buuoe, litoeba li ile tsa tsejoa ka puso ea boipheliso nakong ea 2 letsatsi le leng le le leng ka lenane la FR1 la ho matlafatsa. Thepa ea boipheliso (Med Associates) e ne e hlophisitsoe e le hore karabo ea lever e sebetsang e hlahisitse li-cocaine (2.5 mg / kg / infusion ka mochine o nepahetseng oa sefofane) ka nako ea ho pepa (ha ho feta 0.5 s). e ne e se na liphello tse reriloeng. Kokaine e ikarabellang ka litoeba lenaneong la FR1 matsatsing a letsatsi le letsatsi la 2, 5 d ka beke, bakeng sa libeke tsa 3. D2-GFP litoeba tse fumanoang ka 0.9% liente tsa saline ka nako e lekanang li ne li sebelisoa e le taolo. Litoeba li ile tsa sebelisoa hampe 24 h ka mor'a ho qetella ho e-na le cocaine kapa tsamaiso ea saline.

Heroin boithati.

Pele ho bo-heroin bo ikemetseng, D2-GFP litoeba (n = 4 bakeng sa kalafo) ba koetliselitsoe mochine oa lever bakeng sa lipelisi tsa chokolete (BioServ, Dustless Precision Pellets) ka mananeo a supileng a 1 letsatsi ka leng. Litoeba tse ithutileng li-press lever li ne li kenngoa ka mokokotlo e nang le catheter e nang le majoe a mangata e le hore li lumelloe ke tsamaiso ea heroine e latelang. Beke e 'ngoe ka mor'a ho buuoa, litoeba li ile tsa tsejoa ka puso ea boipheliso nakong ea 3 h mananeo a letsatsi le letsatsi ka lenane la FR1 la ho matlafatsoa ho ea ka mekhoa e tloaelehileng (Navarro et al., 2001). Thepa ea boipheliso (Med Associates) e ne e hlophisitsoe e le hore karabo ea sehlahisoa se sebetsang se hlahisitsoe ho hlahisa (ka ho fetisisa 5) ea heroin (30 μg / kg / injection Lenaneo la Phepelo ea Lithethefatsi), athe karabo e sa sebetse lever e ne e se na liphello tse reriloeng. Liphoofolo li ile tsa fuoa monyetla oa ho sebelisa mokhoa oa heroin oa ho itlhokomela oa 14 d. D2-GFP litoeba tse fumanoang ka 0.9% liente tsa saline ka nako e lekanang li ne li sebelisoa e le taolo. Litoeba li ile tsa sebelisoa hampe 24 h ka mor'a heroine ea ho qetela kapa tsamaiso ea saline.

Ho rua mekhoa e metle bakeng sa tikoloho.

D2-GFP (n = 4 ka sehlopha) litoeba li ile tsa roloa ka tikolohong e ntlafalitsoeng kapa maemo a tloaelehileng a bolulo letsatsing la pelehi la lesea 21 (P21) a sebelisa paradigm e nkiloeng ho likhoto (Green le al., 2010). Sebaka se ntlafalitsoeng se ne se e-na le ntloana e kholoanyane ea hamster e nang le liphahlo tse entsoeng ka maruo (Andersons Laboratory bedding) tse tletseng lisebelisoa tse entsoeng ka maruo, tse kenyeletsang li-mouse, marulelo le mabili, ho khaba libolo, li-huo (Bio Serv) le lipapali tse ling. Litoeba li ne li lula liemong tsa bolulo bakeng sa libeke tsa 4 ho fihlela P50 ebe li ntšetsoa hampe.

Phekolo ea katleho.

D2-GFP litoeba (n = 4 kapa 5 bakeng sa kalafo) ba ile ba fuoa teko ea bobeli ba khetho ea botlolo bakeng sa 10% e tsoelang pele e tšoanang le thuto e fetileng (Wallace et al., 2008). Litoeba li ile tsa fuoa 10% sucrose (bottle A) le metsi (bottle B), athe D2-GFP lithibelo li fumane metsi ka libotlolong tse peli tsa 10 d. Mesepe eohle e fumanang libotlolo tsa sucrose e bontšitse khetho ea sucrose e balang ka (100 × bottle A volume / bottle A volume + bottle bottle B). Litoeba tse ileng tsa fumana botlolo ea 10% ea sucrose li ne li ja li-sucrose haholo ha li bapisoa le metsi, athe litoeba tse fumanang metsi ka libotlolong tseo ka bobeli li ne li sa bontše phapang pakeng tsa metsi a sebelisoang. Mantsiboeeng a letsatsi la 10, litoeba tsohle li ne li fuoa metsi a tloaelehileng a nooang 'me li ne li sebelisoa hampe letsatsing la 11.

Khaello ea khalori.

D2-GFP litoeba (n = 4 ka genotype) ba ile ba feta ka khalori restriction protocol, eo ka eona ba amohetseng 60% ea ad libitum lik'hilojule letsatsi le letsatsi (Vialou et al., 2011) bakeng sa 10 d. D2-GFP litoeba tsa ts'ebetso li fumane ho fihlella ka botlalo ho chow. Mantsiboeeng a letsatsi la 10, litoeba tsohle li fihletsoe ka ho feletseng ho chow 'me li sebelisoa hampe ka letsatsi la 11.

Ho imeloa kelellong.

D2-GFP litoeba (n = 4 kapa 5 ka sehlopha) o ile a fumana 10 d ea khatello ea kelello ea sechaba joalokaha e hlalositsoe pele (Berton et al., 2006; Krishnan et al., 2007). Litoeba li ne li pepesoa ho ba-breeders ba sehlōhō ba CD1 ba 5 motseng o moholo oa hamster. Joale litoeba li ne li kenngoa bakeng sa 24 h ka lekholong le le leng ka lehlakoreng le leng la mohlahloli oa perforated ho boloka puisano ea maikutlo. Letsatsing le hlahlamang litoeba li ne li pepesela mouse e ncha ea CD1 tlas'a maemo a tšoanang le matlo. Sena se ile sa phetoa bakeng sa 10 d ka CD1 e ncha letsatsi ka leng. Litoeba tsa taolo li ne li lula tlas'a maemo a tšoanang ntle le khatello ea maikutlo. Litoeba li ile tsa lekoa bakeng sa ho buisana le batho ka letsatsi 11. Li-mouse li ile tsa qala ho lekoa bakeng sa nako e sebelisitsoeng ho sebelisana le kamore ea libuka ka lebokoseng le sabaletseng ha ho na le mouse e hlahang (ho se na sepheo) ebe e hlahlojoa nako e sebelisitsoeng ho sebelisana le mouse ea CD1 (sepheo) se neng se le ka mor'a kamoreng (Berton et al., 2006; Krishnan et al., 2007). Litoeba li ne li arotsoe lihlopha tse nang le tšoaetso kapa tse tsitsitseng ho latela mekhahlelo e hlalositsoeng pele (Krishnan et al., 2007). Sena se kenyelitse nako e akaretsang ea nako e sebelisitsoeng le mouse ea romane le karolelano ea ho sebelisana: (nako e sebelisitsoeng ka sepheo / nako e se nang sepheo) × 100. Mokhoa ona o bontšitsoe ho netefatsa lihlopha tse tsitsitseng le tse tsitsitseng 'me li amana haholo le liphapang tse ling tsa boitšoaro (Krishnan et al., 2007). Litoeba tsohle li ile tsa sebelisoa hampe 24 h ka mor'a teko ea ho sebelisana le sechaba (48 h ka mor'a sekhetho sa ho qetela se hlōlang sechabeng).

Phekolo ea Fluoxetine.

D2-GFP litoeba (n = 3 kapa 4 ka sehlopha) o fumane li-14 letsatsi le leng le le leng liente tsa intraperitoneal tsa fluoxetine (20 mg / kg) kapa koloi (0.9% saline le 10% cyclodextrin) (Berton et al., 2006). Litoeba li ile tsa sebelisoa hampe 24 h ka mor'a hore e entsoe ka ho qetela.

Opereishene ea stereotaxic.

D2-GFP litoeba li ne li haelloa ke ketamine (100 mg / kg) / xylazine (10 mg / kg), li behoa sejaneng sa stereotaxic e nyenyane, 'me sebaka sa bona sa lehata se senoloa. Ho sebelisoa lisebelisoa tsa seringe tse mashome a mararo a metso e meraro e le hore ho sebelisoe li-0.5-1 μl ka tekanyo ea 0.1 μl ka motsotsoana, ea kokoana-hloko ea bobeli ka har'a sebaka sa ventral tekete (VTA), se-mediate prefrontal cortex (mPFC), amygdala kapa hippocampus ( vHippo). AAV [adeno-associated virus] -hSyn-ChR2 [channelrhodopsin 2] -EYFP kapa AAV-hSyn-EYFP e kenngoa VTA ea D2-GFP litoeba (n = 5 ka sehlopha) ho tsamaisanang le stereotaxic (anterior-posterior, -3.3 mm; kamora-moeli, 0.5 mm; mokokotlo, -4.4 mm, angle 0). Sena se ile sa lateloa ke cannula e kopanetsoeng (26-gauge), e nang le bolelele ba 3.9 mm, ho kenngoa hoa VTA (pele-ka morao-, -3.3 mm; kamora nako e khutšoanyane, 0.5 mm; mokokotlo, -3.7 mm) (Koo et al., 2012; Chaudhury et al., 2013). AAV-CaMKII-ChR2-mCherry kapa AAV-CaMKII-mCherry e ne e kenngoa ka mPFC (n = 4 kapa 5 ka sehlopha), amygdala (n = 3 kapa 4 ka sehlopha), kapa vHippo (n = 3 kapa 4 ka sehlopha) sa D2-GFP litoeba tse lateloang ke ho kenngoa ha 105 μm tse sa foleng tsa optic fibers (Sparta et al., 2011). Likopano li ne li le ka tsela e latelang: mPFC (infralimbic e ne e laoloa, empa re bone likokoana-hloko tse hlaselang libakeng tse ka pele ho moo: li-anterior-posterior, 1.7 mm; kamora-lehare, 0.75 mm; lehlakoreng le leng, -2.5 mm, angle ea 15) le optic fiber (dorsal-ventral, -2.1 mm); Amygdala (basolateral amygdala e ne e laoloa, empa re hlokometse hore kokoana-hloko ea kokoana-hloko e bohareng ba katiba ea amygdala; anterior-posterior, -1.6 mm; lateral-medial, 3.1 mm; angle-polar, -4.9 mm, angle 0 °) le optic fiber (dorsal-ventral, -4.9 mm); VHippo (ventral subiculum e ne e reretsoe, empa re hlokometse hore kokoana-hloko ea kokoana-hloko e ea libakeng tse ling tsa hippocampus ea ho hlasela; anterior-posterior, -3.9 mm; lateral-medial, 3.0 mm; angle-length, -5.0 mm, angle 0) le optic fiber (dorsal-ventral, -4.6 mm).

Maemo a Optogenetic.

etsoe Ka vivo taolo ea optical ea VTA neuronal ho chesa, le 200 μm core optic fiber patch cord e fetotsoe bakeng sa sekontiri sechabeng. Ha fiber e ne e sirelelitsoe mokokotlong, ntlha ea fere e fetisitsoe ~0.5 mm ka nģ'ane ho cannula (Lobo et al., 2010; Chaudhury et al., 2013). Bakeng sa Ka vivo ho laola optical mPFC, amygdala, le vHippo neuronal ho thunya, 62.5 μm e arohanngoa mohala oa fiber e ne e khomaretsoe lihlahisoa tse hlophisitsoeng tsa hlooho (Sparta et al., 2011). Lisebelisoa tsa optic li ne li khomaretsoe ka lisebelisoa tsa FC / PC ho ea di-laser 473 nm blue laser (Crystal Lasers, BCL-473-050-M), 'me likhahla tse khanyang li ne li entsoe ka stimulator (Agilent, 33220A). Bakeng sa VTA, leseli la buluse (473 nm) phasic pulses, 20 Hz bakeng sa 40 ms (Chaudhury et al., 2013), li ile tsa fanoa bakeng sa 10 min ka letsatsi ho feta 5 d. Bakeng sa mPFC, amygdala, le vHippo, leseli la buluse (473 nm), li-20 Hz tsa 30, li ne li fanoa bakeng sa 10 min ka letsatsi bakeng sa 5 d. Tlhaloso e khantšang e etsahetse mokoting oa matlo, 'me litoeba tsohle li ile tsa sebelisoa hampe 24 h ka mor'a ho ts'oara khanya ea ho qetela.

In vitro patch-clamp electrophysiology.

Litlaleho tsohle tsa lisele li fumanoe ho VTA dopamine neurons kapa mPFC glutamatergic neurons ka likarolo tse bobebe tsa boko ho tswa ho litoeba tse nang le likokoana-hloko tse boletsoeng ka holimo. Litlhaloso tsa likotoana li ne li etsoa ka litoeba tse se nang Ka vivo ho tsosolosa, empa ka 1 d ea sekhahla se ts'oantsang (1 d) kapa 4 d Ka vivo ts'usumetso le 1 d ea sehlahisoa sa slice (5 d). E le ho fokotsa khatello ea kelello le ho fumana likarolo tse phetseng hantle, litoeba li ne li ts'oaetsoe hang ka mor'a hore li tlisoe sebakeng sa electrophysiology ebe li sebelisoa hampe bakeng sa 40-60 s le aCSF e batang leqhoa, e nang le 128 mm NaCl, 3 mm KCl, 1.25 mm NaH2PO4, 10 mm d-glucose, 24 mm NaHCO3, 2 mm CaCl2, le 2 mm MgCl2 (oksijene le 95% O2 le 5% CO2, pH 7.4, 295-305 mOsm). Lihlahisoa tse bobebe tsa boko bo nang le mPFC kapa VTA li ne li khaola ka ho sebelisoa microslicer (Ted Pella) serame-sucrose-aCSF, e neng e nkiloe ke NaCl e ncha ka ho feletseng le 254 mm sucrose le e tletseng 95% O2 le 5% CO2. Lisebelisoa li ne li lula ka kamoreng e nang le aCSF bakeng sa 1 h ka 37 ° C. Li-pipettes tsa patch (3-5 MΩ), bakeng sa sele-kakaretso ea metsi, li ne li tletse tharollo ea ka hare e nang le tse latelang: gluconate ea potassium ea 115 mm, 20 mm KCl, 1.5 mm MgCl2, 10 mm phosphocreatine, 10 mm HEPES, 2 mm magnesium ATP, le 0.5 mm GTP (pH 7.2, 285 mOsm). Litlaleho tsohle tsa lisele li ne li etsoa ka ho sebelisa aCSF ka 34 ° C (palo ea phallo = 2.5 ml / min). Literene tse khanyang tse khanyang (20 Hz bakeng sa mPFC kapa phasic 20 Hz, 40 ms bakeng sa VTA) li entsoe ka stimulator e kopantsoeng ka adapter ea FC / PC ho XMUMX nm blue laser diode (OEM) mme e fetiselitsoe ka liphahla tsa mPFC le VTA ka 473 μm optical fiber. Liteko tsa hona joale tsa clamp li ne li etsoa ka amplifier ea Multiclamp 200B, mme ho fumanoa ha data ho ne ho etsoa ka pClamp 700 (Li-Molecular Devices). Sehlopha se hanyetsanoang se ile sa hlahlojoa nakong ea liteko, 'me maqhubu a mokokotlo le mekhahlelo e ne e tlhotliloeng ka 10 kHz (setšoantšo sa Bessel).

Immunohistochemistry.

Litoeba li ne li haelloa ke li-chloral hydrate li bile li sebelisoa hampe le 0.1 m PBS e lateloa ke 4% paraformaldehyde PBS. Bokooa bo ile ba postfixed ka 4% paraformaldehyde bosiung bo bong 'me ba cheropreserved ka 30% sucrose. Likopi li ne li arotsoe ka cryostat (Leica) ho 35 μm ho PBS le 0.1% sodium azide. Bakeng sa immunohistochemistry, likarolo li ne li koetsoe ka 3% tloaelehileng donkey serum le 0.01% Triton-X ho PBS bakeng sa 1 h ho shaker mocheso oa mohatsela. Likarolo li ne li kenngoa ka har'a li-antibodies tse ka sehloohong ka thibelo ka bosiu bo le bong mohahong o mocheso. Li-antibodies tse sebelisitsoeng ke tse latelang: mmutla o khahlanong le FosB (1: 2000, khamera # sc-48, Santa Cruz Biotechnology), mouse e khahlanong le NeuN (1: 1000, khamera #MAB377, Millipore), e khahlanong le GFP (1: 5000 , lethathamo # 10-20, Aves), le mmutla o khahlanong le CREB (karolo ea likarabo tsa cAMP e tlama protheine; 1: 1000, khamera # 06-863, Millipore). Letsatsing le hlahlamang, likarolo li ne li hlatsoa ka PBS li lateloa ke ho kenya li-antibodies tsa 1 ho li-antibodies tse ka sehloohong: CyxNUMX, anti-mouse ea anti-mouse Cy3, le Dy -ight 5 kapa Alexa-488 (Jackson ImmunoResearch Laboratories). Bakeng sa mCherry le tyrosine hydroxylase immunohistochemistry, liteko li ile tsa etsoa joalokaha ho hlalositsoe pele (Lobo et al., 2010; Mazei-Robison et al., 2011). Likarolo li ile tsa hlatsoa PBS, tse kenngoa li-slide, 'me tsa koaheloa.

Ho nahana le ho bala lisele.

Li-immunofluorescence li ne li etsoa litšoantšong tsa Zeiss Axioscope kapa microscope ea confusal ea Olympus Bx61. Ho bala lisele ho ne ho etsoa ka software ea ImageJ. Litšoantšo tsa sampling bregma 1.42-1.1 ea NAc (mantlha le shell) le dorsal striatum li nkiloe likarolong tsa 2 kapa 3 tsa bokooa / phoofolo (bona Feie. 1A). Kakaretso ea lisele tsa 400-500 li ne li baloa sebakeng se seng sa boko ka mouse ka ho sebelisa 250 μm × 250 μm litšoantšo. Lisele li ne li baloa li sebelisa mananeo a ImageJ a tšoanang le thuto e fetileng (Lobo et al., 2010). Hoo e ka bang metsoako ea NeNN ea 400-500 e ne e baloa sebakeng se seng sa boko ka mouse, ebe joale palo ea GFP+, GFP+: DFFB+, GFP-, le GFP-: DFFB+ lisele li ne li baloa sebakeng se seng le se seng. Lintlha li ne li hlahlojoa ka tsela e latelang: (GFP+: DFFB+ li-neurons × 100%) / (kakaretso ea GFP+ neurons) le (GFP-: DFFB+ li-neurons × 100%) / (kakaretso ea GFP- neurons). Lipatlisiso tsa statistical li ne li etsoa ka software ea GraphPad Prism. Litsela tse peli tsa ANOVA tse lateloang ke liteko tsa poso tsa Bonferroni li ne li sebelisoa bakeng sa litekanyetso tsohle tsa ho bala lisele.

Setšoantšo sa 1.  

Cocaine e sa feleng e kenyelletsa DFFB ho D1-MSNs libakeng tse hlaselang. A, Likarolo tsa Striatal ho tloha bregma + 1.42 ho ea ho 1.10 li ne li sebelisetsoa ho bala lisele. Setšoantšo sa D2-GFP karolo e hlaselang e bontša hore libaka tse tharo tse hlaselang li ithutile: NAC ea motheo, ...

Results

DFBB e kenyelletsoa ka tsela e fapaneng ho D1-MSNs le D2-MSNs ka mor'a hore li hlahelle hangata ho cocaine le haloperidol

Re ile ra qala ho hlahloba tlhahiso ea DFFB ho MSN subtypes ho D1-GFP 'me D2-GFP litoeba tse sebelisang li-cocaine tse sa tloaelehang tse neng li bontšitsoe pele li kenyelletsa ΔFosB protheine ho D1-MSNs (Moratalla et al., 1996). D1-GFP 'me D2-GFP BAC litoeba tsa transgenic, tse hlalosang liprotheine tse tala tse ntseng li eketseha ka tlase ho liphatsa tsa lefutso tsa D1 kapa D2 (Feie. 1A), o ile a fumana liente tsa intraperitoneal tsa cocaine (20 mg / kg) kapa saline bakeng sa 7 d, 'me boko ba bokelloa 24 h ka mor'a hore e entsoe ka ho qetela (Feie. 1B). Ka mor'a moo re ile ra etsa likarolo tsa bokooa tsa immunohistochemistry ho sebelisa NeuN, GFP, kapa FosB 'me ra ba le litšoantšo' me ra bala lisele ho NAC, NAC shell le dStr (Feie. 1A,C). Le hoja anti-fosB ea anti-FosB e nka FosB e feletseng le DFFBB, lipatlisiso tse ngata tse sebelisang Bophirimela kapa li-immunohistochemistry li tiisitse hore ΔFosB ke tsona feela mefuta e fumanehang habonolo ea nako ea ho tloha ha 24 (mohlala, Perrotti et al., 2008). Ka hona re sebelisitse 24 h kapa nako e telele ea nako ho bokella bokhoni ka mor'a hore maemo ohle a be teng thutong ena ho tiisa hore re fumana feela DFBB. Hobane MSN e hlaselang e kenyelletsa ~95% ea neurons eohle ho striatum, re sebelisitse NeuN immunolabeling ho khetholla GFP- li-neurons, tse ntlafalitsoeng ho fapaneng le subtype ea MSN (ke hore, D2-MSNs D1-GFP litoeba le D1-MSN ho eona D2-GFP litoeba). Re fumane seo D1-GFP litoeba tse tšoaroang ka k'hok'heine li bonts'itse karolo e kholo ea DFFB ho GFP+/ NeuN+ neurons (D1-MSNs) ho NAC core, NAc shell, le dStr, athe GFP-/ NeuN+ lisele (D2-MSNs) ha lia ka tsa bontša hore ho na le karolo e kholo ea DFFB libakeng tsohle tse hlaselang (Feie. 1D): tse peli tsa ANOVA, NAC e ka sehloohong: mofuta oa lithethefatsi le sele F(1,12) = 16.41, p <0.05, tlhahlobo ea poso ea Bonferroni: p <0.01; Khetla ea NAc: mofuta oa sele ea lithethefatsi F(1,12) = 12.41, p <0.05, tlhahlobo ea poso ea Bonferroni: p <0.001; dStr: lithethefatsi × mofuta oa sele F(1,12) = 12.07, p <0.05, tlhahlobo ea poso ea Bonferroni: p <0.01. Tumellanong le liphuputso tsena, re hlokometse ho D2-GFP litoeba ha li na tlhahiso e kholo ea ΔFosB ka GFP+/ NeuN+ li-neurone (D2-MSNs) empa ho kenyelletsoa ho matla ho DFBB ho GFP-/ NeuN+ (D1-MSNs) libakeng tsohle tse senyehang ka mor'a phekolo ea cocaine (Feie. 1D): tse peli tsa ANOVA, NAC e ka sehloohong: mofuta oa lithethefatsi le sele F(1,12) = 15.76, p <0.01, tlhahlobo ea poso ea Bonferroni: p <0.0001; NAc shell: mofuta oa sele ea lithethefatsi: F(1,12) = 20.33, p <0.05, tlhahlobo ea poso ea Bonferroni: p <0.01; dStr: mofuta oa sele ea lithethefatsi: F(1,12) = 35.96, p <0.01, tlhahlobo ea poso ea Bonferroni: p <0.001. Re hlahlobile kinetics ea ΔFosB induction ho li-MSN kamora liente tsa 1, 3, kapa 7 d tsa cocaine (20 mg / kg, ip). Re bone ho kenyelletsoa ha ΔFosB ho li-D1-MSNs ka 3 kapa 7 d ea kalafo ea cocaine ha e bapisoa le kalafo ea letsoai libakeng tsohle tsa striatal (Feie. 1F): setšoantšo sa graph ho tloha dStr; tsela e peli ea ANOVA, mofuta oa sele le letsatsi F(2,13) = 17.87, p <0.01, tlhahlobo ea poso ea Bonferroni: p <0.01, p <0.001. Sena se tsamaellana le thupelo ea nako ea ho bokella striFosB ho striatum e bonoeng pejana ke blotting ea Bophirimela (Hope et al., 1994) 'me e tiisa hore DFFB e khetholloa feela ka D1-MSNs ho pholletsa le ketsahalo ea k'hok'heine.

Ka mor'a moo re ile ra hlahloba tlhahiso ea ΔFosB ka immunohistochemistry ho MSN subtypes ka mor'a ho pepeseha ho sa feleng haloperidol (Feie. 2). Mosebetsi o pele o fana ka tlhahiso e sa tobang hore haloperidol e sa foleng e ka 'na ea etsa hore DFB e khetholle ka ho khetheha D2-MSNs (Hiroi le Graybiel, 1996; Atkins et al., 1999), le hoja sena se sa ntse se sa hlahlojoa ka ho toba. D1-GFP 'me D2-GFP litoeba li fumane haloperidol (2 mg / kg) metsing a nooang, pH 6.0, athe D1-GFP 'me D2-GFP li-mouse li ne li fumana metsi a nooang a kamehla, pH 6.0, bakeng sa 21 d (libeke tse 3) le boko ba bokelloa letsatsing la 22 (Feie. 2A). Joaloka ka cocaine, rea tseba hore tsohle tse ling tsa FosB tse kang immunoreactivity ho striatum ka nako ena e hlalosang ΔFosB, eseng bolelele bo bolelele ba FosB (Atkins et al., 1999). Re fumane seo D1-GFP litoeba tse amohelang haloperidol li sa bontšoe ka ho hlaka ho hlakileng ha DFBB ho GFP+/ NeuN+ li-neurone (D1-MSNs) ka NA core, NAc shell, kapa dStr; leha ho le joalo, keketseho e kholo ea DFFB e ile ea hlokomeloa ho GFP-/ NeuN+ neurons (D2-MSNs) libakeng tsohle tse hlaselang (Feie. 2B,C): litsela tse peli tsa ANOVA, NAC e ka sehloohong: mofuta oa lithethefatsi le sele: F(1,10) = 23.29, p <0.05, tlhahlobo ea poso ea Bonferroni: p <0.01; Khetla ea NAc: sethethefatsi: mofuta oa sele: F(1,10) = 30.14, p <0.05, tlhahlobo ea poso ea Bonferroni: p <0.01; dStr: mofuta oa sele ea lithethefatsi: F(1,10) = 37.63, p <0.001, tlhahlobo ea poso ea Bonferroni: p <0.0001. Sena se netefalitsoe ke tlhahlobo ea D2-GFP litoeba: re bone tlhokomelo e kholo ea ΔFosB ka GFP+/ NeuN+ li-neurone (D2-MSNs) libakeng tsohle tse tharo tse hlaseloang, empa ha ho phetoho e kholo ho ΔFosB ka GFP-/ NeuN+ (D1-MSNs) ka mor'a lefu la haloperidol (Feie. 2B,C): litsela tse peli tsa ANOVA, NAC e ka sehloohong: mofuta oa lithethefatsi le sele: F(1,12) = 24.30, p <0.05, tlhahlobo ea poso ea Bonferroni: p <0.05; NAc shell: mofuta oa sele ea lithethefatsi: F(1,12) = 26.07, p <0.01, tlhahlobo ea poso ea Bonferroni: p <0.001; dStr: mofuta oa sele ea lithethefatsi: F(1,12) = 21.36, p <0.01, tlhahlobo ea poso ea Bonferroni: p <0.01. Kaha re bone mokhoa o ts'oanang oa indFosB ho kenyelletsoa ho li-D1-MSN ka ho pepeseha khafetsa ea cocaine ka bobeli D1-GFP (GFP+/ NeuN+) le D2-GFP (GFP-/ NeuN+) litoeba, le ka ho pheta haloperidol ho D2-MSNs ho D1-GFP (GFP-/ NeuN+) le D2-GFP (GFP+/ NeuN+) litoeba, tse setseng tsa liteko tsa rona tse sebelisitsoeng D2-GFP litoeba tsa ho hlahloba hore DFBB e kenyelletsoa ho D1-MSNs (GFP-/ NeuN+) le D2-MSNs (GFP+/ NeuN+) ka mor'a hore ho be le lintho tse ling tse sa foleng tse sa foleng.

Setšoantšo sa 2.  

Haloperidol e sa feleng e kenyelletsa DFFB ho D2-MSNs libakeng tse hlaselang. A, Nako ea nako ea phekolo ea 21 d ea haloperidol (2 mg / kg, metsing a nooang) kapa metsi. B, Immunohistochemistry ea NAc shell ea D1-GFP 'me D2-GFP litoeba ka mor'a haloperidol ...

E le taolo, re ile ra hlahloba litekanyetso tsa pōpo ea CREB ka maemo a cocaine le haloperidol ho fumana hore na liphihlelo tsa rona li ka etsoa ka mabaka a mang a ngotsoeng (Feie. 3). Ha rea ​​ka ra bona phapang e khōlō ho polelo ea CREB pakeng tsa litoeba tsa taolo le lithethefatsi. Ho feta moo, ha rea ​​ka ra bona phapang pakeng tsa li-CREB pakeng tsa D2-MSNs le D1-MSNs (Feie. 3B,C).

Setšoantšo sa 3.  

Cocaine e sa foleng kapa haloperidol ha e susumetse CREB ho MSN subtypes. A, Immunostaining bakeng sa CREB le GFP ka striatum ea D2-GFP litoeba ka mor'a cocaine e sa foleng kapa haloperidol e sa foleng (Feie. 1 'me Le22 litlaleho tsa phekolo ea lithethefatsi). Sebaka sa sekala, 50 μm. ...

Mekhoa e fapaneng ea DFFB ho kenngoa ha li-MSN ka litlhare tsa tlhekefetso

Hobane liphuputso tsa pele li bontšitse hore lithethefatsi tse ling tsa tlhekefetso li ka kenyelletsa DFFB libakeng tse hlaselang (Perrotti et al., 2008), re ile ra hlahloba DFFB ka li-subtypes tsa MSN ka mor'a ho pepeseha li-opiates, EtOH, kapa Δ (9) -THC e sa feleng. Re ile ra qala ho hlahloba hore na ho itšireletsa ho sa foleng ha morphine ho fokotsa ΔFosB monoaneng o itseng oa MSN libakeng tse hlaselang. D2-GFP litoeba li ile tsa fumana li-implants tse peli tsa subcutaneous tsa a sham kapa morphine (25 mg) pellet ka matsatsi a 1 le 3, 'me boko ba bokelloa letsatsing la 5 (Feie. 4A) ha ΔFosB, empa e seng FosB, e susumetsoa (Zachariou et al., 2006). Ka phapang e fapaneng le k'hok'heine, bobeli ba MSN bo bontšitse keketseho e khōlō (le e batlang e ka bapisoa) le ΔFosB ho NAC, NAc shell le dStr sehlopheng sa morphine ha se bapisoa le taolo ea sham, e se nang phapang ea cell subtype induction ea ΔFosB e bonang bohle ba hlasela libaka (Feie. 4A): tsela e peli ea ANOVA; NAC core: lithethefatsi F(1,14) = 75.01, p <0.0001, tlhahlobo ea poso ea Bonferroni: p <0.01 (D2-MSN), p <0.001 (D1-MSN); Khetla ea NAc: sethethefatsi F(1,14) = 62.87, p <0.0001, tlhahlobo ea poso ea Bonferroni: p <0.01 (D2-MSN), p <0.05 (D1-MSN); dStr: lithethefatsi F(1,14) = 60.11, p <0.001, tlhahlobo ea poso ea Bonferroni: p <0.01 (D2-MSN), p <0.05 (D1-MSN).

Setšoantšo sa 4.  

Lithethefatsi tsa tlhekefetso li kenyelletsa ΔFosB maqheku a MSN libakeng tse hlaselang. A, Chronicle phephine kalafo (25 mg pellets ka matsatsi a 1 le 3) ho D2-GFP litoeba li fella ka ho kenngoa ha DFFB ka tsela e kholo maemong a mabeli a MSN a NAc core, NAc shell le dStr ...

Ka mor'a moo re ile ra etsa lipatlisiso mabapi le mokhoa oa ho qaptjoa ha DFBB maemong a mangata a MSN ka mor'a ho pepesehela EtOH nako e telele. D2-GFP litoeba li ile tsa fuoa tlhahlobo ea libaka tse peli bakeng sa 10% EtOH (botlolo A) le metsi (bottle B), athe D2-GFP lithibelo li ile tsa fuoa metsi ka libotlolong tse peli (libotlolo tsa A le B), bakeng sa 10 d le boko ba bokelloa letsatsing la 11 (Feie. 4B). Litoeba tse ileng tsa fumana botlolo ea 10% EtOH li ne li ja EtOH haholoanyane ha li bapisoa le metsi, athe litoeba tse fumanang metsi ka libotlolong tseo ka bobeli li ile tsa bontša phapang pakeng tsa metsi a sebelisoang (Feie. 4B): khetho bakeng sa botlolo Sehlopha sa metsi: 50.00 ± 4.551%, sehlopha sa EtOH: 84.44 ± 8.511%; Seithuti t teko, p <0.05. Tsamaiso e sa foleng ea EtOH e felletse ka ho kenyelletsoa ho hoholo ha ΔFosB ka boikhethelo ho D1-MSNs ho mantlha a NAc, NAc shell le dStr, ho se phetoho ho D2-MSNs (Feie. 4B): litsela tse peli tsa ANOVA, NAC e ka sehloohong: mofuta oa lithethefatsi le sele: F(1,14) = 24.58, p <0.05, tlhahlobo ea poso ea Bonferroni: p <0.05; NAc shell: mofuta oa sele ea lithethefatsi: F(1,14) = 36.51, p <0.01, tlhahlobo ea poso ea Bonferroni: p <0.01; dStr: mofuta oa sele ea lithethefatsi: F(1,14) = 29.03, p <0.01, tlhahlobo ea poso ea Bonferroni: p <0.01.

D2-GFP litoeba li ne li boetse li tšoaroa ka Δ (9) -THC (10 mg / kg, ip) habeli ka letsatsi bakeng sa 7 d, 'me boko ba bokelloa 24 h ka mor'a hore e entsoe ka lekhetlo la ho qetela. Joaloka k'hok'heine le maemo a EtOH, re bone ho eketseha ho hoholo ha DFBB e khethollang D1-MSNs libakeng tsohle tse hlaselang ka har'a litoeba tse fumanoang li le teng (9) -THC (Feie. 3E): tse peli tsa ANOVA, NAC e ka sehloohong: mofuta oa lithethefatsi le sele F(1,8) = 26.37, p <0.01, tlhahlobo ea poso ea Bonferroni: p <0.01; NAc shell: mofuta oa sele ea lithethefatsi: F(1,8) = 44.49, p <0.05, tlhahlobo ea poso ea Bonferroni: p <0.001; dStr: lithethefatsi × mofuta oa sele F(1,8) = 29.30, p <0.05, tlhahlobo ea poso ea Bonferroni: p <0.01.

Ka mor'a moo re ile ra hlahloba hore na mokhoa o bontšitsoeng oa ΔFosB ho kenngoa ha MSN subtypes ke mofuputsi oa tsamaiso ea cocaine kapa opiates e hlaha lipapaling tse nang le litsela tseo ho tsona litoeba li iketselitseng ho sebelisa moriana ona. Ntlha ea pele, D2-GFP litoeba li koetliselitsoe ho itlhokomela ka cocaine (0.5 mg / kg / infusion) lenaneong la FR1 bakeng sa letsatsi la 2 bakeng sa libeke tsa 3 le boko ba bokelloa 24 h ka mor'a ho phalla ha ho qetela (Feie. 4D), ha ΔFosB, empa e se FosB, e tsejoa hore e susumelitsoe (Larson et al., 2010). Litoeba li sebelisitse nako e ngata haholo ho hatella lebelo le sebetsang le le sa sebetse (Feie. 4D; Seithuti t teko, p <0.01). Tekanyo e tloaelehileng ea k'hok'heine ea letsatsi le letsatsi e ne e le 19.1 mg / kg ka methapo (Feie. 4D), e tšoanang le leihlo la 20 mg / kg e ka sebelisoang ka holimo (Feie. 1). Joalo ka ho pepesa k'hok'heine e sa phekoleheng (Feie. 1), re fumane hore k'hok'heine ea boipheliso e bakiloe ke DFNUMX-MSNs libakeng tsohle tse senyehang ha li bapisoa le ho pepeseha ha saline (Feie. 4D): tse peli tsa ANOVA, NAC e ka sehloohong: mofuta oa lithethefatsi le sele F(1,14) = 21.75, p <0.05, tlhahlobo ea poso ea Bonferroni: p <0.01; NAc shell: mofuta oa sele ea lithethefatsi: F(1,14) = 26.52, p <0.01, tlhahlobo ea poso ea Bonferroni: p <0.01; dStr: lithethefatsi × mofuta oa sele F(1,14) = 33.68, p <0.001, tlhahlobo ea poso ea Bonferroni: p <0.001. Ka mokhoa o ts'oanang, ka mokhoa o ts'oanang le ho pepeseha ha opiate (morphine) e sa amaneng le letho (Feie. 4A), re fumane seo D2-GFP litoeba tse nang le heroine tse nang le boithati (30 μg / kg ka ho phalla), ka lenane la FR1 le 3 ha letsatsi la libeke tsa 2 tse hlahlobang 24 h ka mor'a ho qetela ho sebelisoa lithethefatsi, li bontšitse bohlokoa ba DFNB ho kenya li-D2-MSN le D1-MSNs kaofela libaka (Feie. 4E): tsela e 'meli ea ANOVA, NAC ea mantlha: lithethefatsi F(1,12) = 68.88, p <0.001, tlhahlobo ea poso ea Bonferroni: p <0.01 (D2-MSN), p <0.05 (D1-MSN); Khetla ea NAc: sethethefatsi F(1,12) = 80.08, p <0.0001, tlhahlobo ea poso ea Bonferroni: p <0.01 (D2-MSN), p <0.001 (D1-MSN); dStr: lithethefatsi F(1,12) = 63.36, p <0.001, tlhahlobo ea poso ea Bonferroni: p < 0.05 (D2-MSN), p <0.05 (D1-MSN). Tekanyo ea letsatsi le letsatsi ea heroine e ne e le 0.459 mg / kg, 'me litoeba li qeta nako e ngata li hatella lever e sa sebetseng (Student's t teko, p <0.05) (Feie. 4E).

Tlhokomelo ea tikoloho le tšusumetso e susumetsang DFNB ho D1-MSN le D2-MSNs

Hobane liphuputso tsa pele li bontšitse hore meputso ea tlhaho e kenyelletsa ΔFosB libakeng tse hlaselang (Werme et al., 2002; Teegarden le Bale, 2007; Wallace et al., 2008; Solinas et al., 2009; Vialou et al., 2011), ka ho kenngoa ha likoloi ka likoloi tse khethiloeng bakeng sa D1-MSNs (Werme et al., 2002), re ile ra hlahloba hore na ho kenyelloa ha litlhahiso ke meputso e meng ea tlhaho ho bonts'itse hore na mocheso oa sele ke ofe. Re ile ra qala ka ho sebelisa li-paradigm tsa boithuto ba bana D2-GFP litoeba li ne li kenngoa tikolohong e ntlafalitsoeng ho tloha ho lla (Libeke tse 3) bakeng sa beke ea 4 (Feie. 5A). Mokhoa ona o ne o bontšoa pele ho etsa hore DFF e sebetse ka mouse NAC le dStr (Solinas et al., 2009; Lehmann le Herkenham, 2011). Ha ho bapisoa le maemo a tloaelehileng a bolulo, tikoloho e ntlafalitsoeng e eketsehile haholo DFBB libakeng tsohle tse senyehang empa ha ea ka ea etsa joalo ka mokhoa o khethehileng oa sele, e nang le likarolo tse ling tse bontšitsoeng ho D1-MSNs le D2-MSNs (Feie. 5A): tse peli tsa ANOVA, NAC ea motheo: tikoloho F(1,12) = 89.13, p <0.0001, tlhahlobo ea poso ea Bonferroni: p <0.0001 (D2-MSN), p <0.0001 (D1-MSN); Khetla ea NAc: tikoloho F(1,12) = 80.50, p <0.0001, tlhahlobo ea poso ea Bonferroni: p <0.001 (D2-MSN), p <0.001 (D1-MSN); dStr: tikoloho F(1,12) = 56.42, p <0.01, tlhahlobo ea poso ea Bonferroni: p <0.05 (D2-MSN), p <0.05 (D1-MSN).

Setšoantšo sa 5.  

Tlhahiso ea tikoloho le tšusumetso e susumetsang DFFB maemong a mabeli a MSN. A, D2-GFP litoeba tse neng li lula sebakeng se ntlafalitsoeng ho qala ho P21 bakeng sa libeke tsa 4 ho hlahisoa ha ΔFosB maemong a mabeli a MSN ho bohle ba hlaselang ...

Ka mor'a moo re ile ra hlahloba polelo ea DFFB ho li-subtypes tsa MSN ka mor'a hore ho be le tšusumetso e sa tloaelehang ea tšitiso. Re ile ra qala ho leka liphello tsa ts'oaetso e sa foleng ea sucrose, e neng e bontšitsoe nakong e fetileng hore e kenyelle fatše DFBB ho rat ea NAc (Wallace et al., 2008). D2-GFP litoeba li ile tsa fuoa tlhahlobo ea libaka tse peli bakeng sa 10% sucrose (bottle A) le metsi (bottle B), athe D2-GFP lithibelo li ile tsa fumana metsi ka libotlolong tse peli (botlolo A le B) bakeng sa 10 d le boko ba bokelloa letsatsing la 11 (Feie. 5B). Litoeba tse fumaneng 10% li-sucrose li ja lijo tse ngata haholo, athe litoeba tse fumanang metsi ka libotlolong tseo ka bobeli li ne li sa bontše phapang pakeng tsa metsi a sebelisoang (Feie. 5B): khetho ea botlolo A, metsi: 50.00 ± 4.749%, sucrose: 89.66 ± 4.473%; Seithuti t teko, p <0.001. Re fumane hore ts'ebeliso e sa foleng ea sucrose e hlohlellelitse ΔFosB mokokotlong oa NAc, khetla ea NAc, le dStr le hore sena se etsahetse ho li-subtypes tsa MSN ka bobeli (Feie. 5B): litsela tse peli tsa ANOVA, NAC ea motheo: phekolo F(1,12) = 76.15 p <0.0001, tlhahlobo ea poso ea Bonferroni: p <0.01 (D2-MSN), p <0.01 (D1-MSN); Khetla ea NAc: kalafo F(1,12) = 63.35, p <0.001, tlhahlobo ea poso ea Bonferroni: p <0.05 (D2-MSN), p <0.01 (D1-MSN); dStr: kalafo F(1,12) = 63.36, p <0.001, tlhahlobo ea poso ea Bonferroni: p <0.01 (D2-MSN), p <0.05 (D1-MSN).

Qetellong, re ile ra hlahloba polelo ea ΔFosB ka li-subtypes tsa MSN ka mor'a hore thibelo ea khalori e be teng hobane boemo bona, bo eketsang ts'ebetso ea moetsi le boemo bo susumetsang, bo ne bo bontšitsoe ho ntlafatsa litekanyetso tsa ΔFosB ka mouse NAc (Vialou et al., 2011). D2-GFP litoeba li pholletsa le protocol e thibelitsoeng ke khalori, eo ba ileng ba e fumana 60% ea ad libitum khalori letsatsi le leng le le leng bakeng sa 10 d le boko ba bokelloa letsatsing la 11 (Feie. 5C). Khaello ea khalori e eketsehile ΔFosB maemong a NAC ea core le NAc shell joalokaha ho bontšitsoe pejana (Vialou et al., 2011) le ho eketsa litekanyetso tsa ΔFosB ka dStr. Leha ho le joalo, re hlokometse hore ha ho na phapang e hlahang ho D1-MSNs ho ea ka D2-MSNs (Feie. 5C): litsela tse peli tsa ANOVA, NAC ea motheo: phekolo F(1,12) = 67.94 p <0.0001, tlhahlobo ea poso ea Bonferroni: p <0.01 (D2-MSN), p <0.01 (D1-MSN); Khetla ea NAc: kalafo F(1,12) = 67.84, p <0.0001, tlhahlobo ea poso ea Bonferroni: p <0.001 (D2-MSN), p <0.01 (D1-MSN); dStr: kalafo F(1,12) = 82.70, p <0.0001, tlhahlobo ea poso ea Bonferroni: p <0.001 (D2-MSN), p <0.001 (D1-MSN).

Ho hlōloa ha sechaba ka nako e telele khatello ea kelello le phekolo ea ho imeloa kelellong ho baka phapang e fapaneng ea ΔFosB ho MSN subtypes

Re kile ra bontša hore ΔFosB e eketsehile ho NAc ea litoeba ka mor'a khatello ea kelello ea sechaba e sa feleng.Vialou et al., 2010). Le hoja tlhahiso ena e ne e bonoa ka litoeba tse peli tse hlaselang (tse bontšang deleterious sequelae ea khatello ea kelello) hammoho le litoeba tse tsitsitseng (tse qobang boholo ba liphello tsena tse kotsi), ΔFosB e ne e le khōlō ho sehlopha se tsitsitseng 'me e bontšitsoe ka ho toba ho phelisetsa maemo a ho mamella. Phuputsong ea hona joale, re fumane ho tsebahala ha selefouno bakeng sa DFFB ho kenya lihlopha tsena tse peli tsa phenotypic. D2-GFP litoeba li ne li laoloa ke 10 ea ts'ebetsong ea khatello ea sechaba le ho arohanngoa ho batho ba nang le ts'oaetso le ba tsitsitseng ba itšetlehile ka mokhoa oa ho sebelisana le sechaba (Feie. 6A), e lumellanang haholo le matšoao a mang a boitšoaro (Krishnan et al., 2007). Litoeba tse ileng tsa hlahisa mekhoa ea ho itšoara ka mor'a ho hlōloa ha sechaba khatellong ea maikutlo li ile tsa bontša hore ho na le palo e kholo ea DFBB ho D2-MSNs ho NAc core, NAc shell le dStr ha li bapisoa le litoeba tse laolang le tse tsitsitseng, tse se nang tlhaho tse hlahang ho D1-MSNs. Ka phapang e tsotehang, litoeba tse tsitsitseng li bonts'a bohlokoa bo hlakileng ba DFNB ho D1-MSN ho pholletsa le libaka tsohle tse senyehang ha li bapisoa le ho hlasela le ho laola litoeba, ho se na tlhahiso e hlahang ho D2-MSNs (Feie. 6A;; Tsela e 'meli ea ANOVA, NAC ea motheo: sehlopha × cell type F(1,20) = 20.11, p <0.05, tlhahlobo ea poso ea Bonferroni: D2-MSN / susceptible p <0.05, D1-MSN / e tsitsitseng p <0.05; Khetla ea NAc: sehlopha sa mofuta oa sele F(1,20) = 27.79, p <0.01, tlhahlobo ea poso ea Bonferroni: D2-MSN / susceptible p <0.001, D1-MSN / e tsitsitseng p <0.01; dStr: sehlopha sa mofuta oa sele F(1,20) = 19.76, p <0.01, tlhahlobo ea poso ea Bonferroni: D2-MSN / susceptible p <0.05, D1-MSN / e tsitsitseng p <0.01).

Setšoantšo sa 6.  

Ho hlōloa ha sechaba ka nako e telele khatello ea kelello le fluoxetine e sa foleng ho etsa hore DFF e kenyelletsoe ka mokhoa o fapaneng oa li-MSN tse ling tsa statum. A, D2-GFP tse ka 'nang tsa hlaseloa ke ts'oaetso ea 10 ea ho hlōloa ha sechaba sechabeng se bontšitse DFFB ho kenya li-D2-MSNs hohle ho hlasela ...

Phekolo ea nako e telele le SSRI e sithabetsang, fluoxetine, e fetola mekhoa ea ho tepella maikutlong e bontšoang ke litoeba tse hlaselang ka mor'a khatello ea kelello e sa feleng ea sechaba (Berton et al., 2006). Ho feta moo, kalafo e joalo e baka ΔFosB ho NAc ea litoeba tse bonolo le tse laoloang, 'me re bontšitse hore ho kenella joalo ho hlokahala bakeng sa litlamorao tse ntle tsa boitšoaro ba fluoxetine (Vialou et al., 2010). Ka tsela eo, re ile ra hlahloba sebopeho sa selefouno sa DFFB ka mor'a hore ho se ke ha e-ba le tsamaiso e sa foleng ea fluoxetine. D2-GFP litoeba li fumane fluoxetine (20 mg / kg, ip) bakeng sa 14 d, 'me boko ba bokelloa letsatsing la 15 (Feie. 6B). Re bone palo e kholo ea DFBB ho D1-MSNs, empa eseng ka D2-MSNs, litoeba tse tšoaroang ke fluoxetine ha li bapisoa le ho laola likoloi (Feie. 6B;; Tsela e 'meli ea ANOVA, NAC ea mantlha: mofuta oa lithethefatsi le sele F(1,10) = 14.59, p <0.05, tlhahlobo ea poso ea Bonferroni: p <0.01; NAc shell: mofuta oa sele ea lithethefatsi: F(1,10) = 26.14, p <0.05, tlhahlobo ea poso ea Bonferroni: p <0.01; dStr: lithethefatsi × mofuta oa sele F(1,10) = 8.19, p <0.05, tlhahlobo ea poso ea Bonferroni: p <0.001).

Ka tsela e sebetsang ea optogenetic ea NAc e nang le boko ba libaka e baka mekhoa e khethollang ea ΔFosB ho kenngoa libakeng tse hlaselang le libaka tsa MSN.

Ho fanoe ka hore dopaminergic le glutamatergic liphapang tse entsoeng ho NAc li ka thusa ho batla moputso le ho fetola boitšoaro bo kang ba ho tepella maikutlo (Tsai et al., 2009; Covington et al., 2010; Adamantidis et al., 2011; Witten et al., 2011; Britt et al., 2012; Lammel et al., 2012; Stuber et al., 2012; Chaudhury et al., 2013; Kumar et al., 2013; Tye et al., 2013), re ile ra hlahloba tlhahiso ea DFFB ka li-MSN tse hlaselang ka mor'a hore li sebelise likarolo tse 'maloa tsa bokooa tse amanang le boko. Re ne re bonts'a ChR2 ho e nngwe le e 'ngoe ea libaka tse' maloa 'me re li tsositse ka leseli la buluse (473 nm) joalokaha ho hlalositsoe pele (Gradinaru et al., 2010; Yizhar et al., 2011). Hobane phuputso e entsoeng morao tjena e bontšitse hore phasic e hlasimollang ka leseli le putsoa, ​​ka mor'a polelo e sa khethollang sele ea ChR2 e VTA, e entse hore mokhoa o tšoanang oa phenotype e be o khethollang ChR2 phasic phaello ea VTA dopamine neurons (Chaudhury et al., 2013), re ile ra hlalosa ChR2 ho sebelisa AAV-hsyn-ChR2-EYFP ho VTA ea D2-GFP litoeba; Lintja li ne li kenngoa ka AAV-hsyn-EYFP. Lihlopha tsa VTA li ne li le coimmunostained le tyrosine hydroxylase le GFP ho bona eka chR2-EYFP e hlahisa maikutlo (Feie. 7C). D2-GFP litoeba tse hlalosang ChR2-EFYP kapa EYFP feela ka VTA e fumanoe 5 ea 10 ea metsotsoana ea leseli le leputsoa la boleng bo botala ba VTA joalokaha ho hlalositsoe pele (Koo et al., 2012; Chaudhury et al., 2013) (Feie. 7A), 'me boko ba bokelloa 24 h ka mor'a ho tsosoa ha ho qetela. Ho ne ho se na ts'oaetso ea bokhoni ba ChR2 ho etsa VTA dopamine neurons ka mor'a 5 d ea ts'usumetso (Feie. 7B). Re fumane hore ts'ebeliso ea phasic e mengata ea VTA neurons e buang ka ChR2-EYFP e eketsa ΔFosB maemong a mabeli a MSN a NAC, empa feela ka D1-MSNs ho NAc shell (Feie. 7C;; Tsela e 'meli ea ANOVA, NAC ea motheo: tšusumetso ea optogenetic F(1,16) = 51.97, p <0.0001, tlhahlobo ea poso ea Bonferroni: p <0.001; (ka bobeli li-subtypes tsa MSN) NAc shell: li-optogenetic stimuli × mofuta oa sele: F(1,16) = 13.82, p <0.05, tlhahlobo ea poso ea Bonferroni: p <0.01). Ha rea ​​ka ra bona ho kenyelletsoa ha ΔFosB ho dStr kamora ho hlasimoloha ha leseli le leputsoa ho VTA-e hlalosang ChR2-EYFP ha e bapisoa le taolo ea EYFP. Liphetho tsena li lokela ho tolokoa ka hloko, kaha ha rea ​​khetha liphofu tsa VTA dopamine neurons bakeng sa tšusumetso ea mahlo, mme lithuto tsa morao-rao li bonts'itse nondopaminergic projeke ea li-neuron ho VTA hammoho le ho se ts'oanehe ho hoholo ha VTA, e ka lebisang likarabong tse fapaneng tsa boits'oaro ho latela ho thunya Meeli le likaroloana tsa methapo ea kutlo tse amehilengTsai et al., 2009; Lammel et al., 2011, 2012; Witten et al., 2011; Kim et al., 2012, 2013; Tan et al., 2012; van Zessen et al., 2012; Stamatakis le Stuber, 2012; Chaudhury et al., 2013; Tye et al., 2013).

Setšoantšo sa 7.  

Ts'ebetso ea optogenetic ea libaka tsa boko tse hlokang tlhokomelo ea NAc li baka mekhoa e fapaneng ea ΔFosB ho kenngoa ha meralo ea MSN le libaka tse hlaselang. A, Optogenetic stimulation paradigm bakeng sa maemo ohle. Bokooa bo ne bo kotuloa 24 h ka mor'a 5 d ea optogenetic ...

Re latelang re sebelisa li-AAV-CaMKII-ChR2-mCherry le AAV-CaMKII-mCherry vectors ho hlalosa ChR2-mCherry, kapa mCherry feela e le taolo, mPFC, amygdala, kapa vHippo ea D2-GFP litoeba (Feie. 7D-F). ChR2 le polelo ea mCherry e tšehetsoeng ke kokoana-hloko ea CaMKII-ChR2 e kile ea bontšoa hore e tla khetholla ka polelo ea CaMKII, e nang le matšoao a mangata a glutamatergic neurons (Gradinaru et al., 2009; Warden et al., 2012). Re ile ra lumella lisele tse hlalosang ChR2 libakeng tsena ka 20 Hz leseli la buluse bakeng sa 10 min ka letsatsi bakeng sa 5 d, 'me boko ba bokelloa 24 h ka mor'a ho tsosoa ha ho qetela (Feie. 7A). Mokhoa ona oa ho susumetsa o ile oa etsa hore ~27-33 Hz e thuse, haholo-holo ka lebaka la ho hlokomoloha spiting doublet. Ha ho ts'oaetso e hlakileng ea ChR2 e etsahetseng ka 5 d ea ts'usumetso; Leha ho le joalo, re bone ho eketseha ho fokolang ha ho thunngoa ho tloha 1 ho ea ho 5 d (32-33 Hz) ea ts'usumetso. Re fumane hore ts'ebetso ea optogenetic ea mPFC neurons e hlahisitse hore DFNUMX-MSN e kenyelletsoe ka har'a core ea NAC, athe phosphoso ea DFBB e hlahile ka bobeli ba MSN ho NAc shell (Feie. 7D;; Tsela e 'meli ea ANOVA, NAC e ka sehloohong: li-optogenetic le li-cell type F(1,14) = 10.31, p <0.05, tlhahlobo ea poso ea Bonferroni: p <0.01; Khetla ea NAc: tšusumetso ea optogenetic F(1,14) = 57.17, p <0.001, tlhahlobo ea poso ea Bonferroni: p <0.05 (D2-MSN), p <0.01 (D1-MSN)). Ha ho phetoho maemong a ΔFosB e bonoeng ho dStr kamora ts'ebetso ea mPFC. Ka lehlakoreng le leng, ts'ebetso ea optogenetic ea li-amygdala neurons e bakileng ΔFosB ho li-subtypes ka bobeli tsa MSN mokokotlong oa NAc, le ho khetha li-D1-MSNs ho NAc shell, ho se phetoho e etsahalang ho dStr (Feie. 7E;; Tsela e 'meli ea ANOVA, NAC ea motheo: tšusumetso ea optogenetic F(1,10) = 78.92, p <0.0001, tlhahlobo ea poso ea Bonferroni: p <0.001 (D2-MSN), p <0.0001 (D1-MSN); Khetla ea NAc: mofuta oa sele oa optogenetic F(1,10) = 30.31, p <0.0001, tlhahlobo ea poso ea Bonferroni: p <0.0001). Kamora nako, ts'ebetso ea optogenetic ea vHippo neurons e bakile bohlokoa ba significantFosB ho kenella feela ho D1-MSNs kahare ea NAc le khetla ea NAc, hape ho se phetoho e bonoang ho dStr (Feie. 7F;; Tsela e 'meli ea ANOVA, NAC e ka sehloohong: li-optogenetic le li-cell type F(1,10) = 18.30, p <0.05, tlhahlobo ea poso ea Bonferroni: p <0.01; Khetla ea NAc: mofuta oa sele oa optogenetic F(1,10) = 22.69, p <0.05, tlhahlobo ea poso ea Bonferroni: p <0.01).

Puisano

Phuputso ea hona joale e hlahloba ho kenyelletsoa ha DFNUMX-MSN le D1-MSNs libakeng tse hlaselang ka mor'a hore ho be le mekhoa e mengata e sa foleng (Lethathamo 1). Re qala ho theha bokhoni ba ho sebelisa D1-GFP 'me D2-GFP melaetsa ea litaba tsa litaba ho bontša hore DFNUMX-MSNs e khetholloa ka khethollo ka mor'a k'hok'heine e sa foleng le ho D1-MSNs ka morao ho haloperidol e sa foleng. Li-cocaine li fumanoeng li lumellana le lithuto tsa pele (Moratalla et al., 1996; Lee le al., 2006) le karolo e thehiloeng bakeng sa DFFB ho D1-MSNs ho ntšetsa pele moputso oa cocaine (Kelz et al., 1999; Colby et al., 2003; Grueter et al., 2013). Re kile ra bontša hore mofuputsi- le k'hok'heine e fuoang boipheliso e kenyelletsa ΔFosB ho isa tekanyo e lekanang le NAc (Winstanley et al., 2007; Perrotti et al., 2008), mme ka ho bohlokoa re bonts'a mona hore mefuta e mabeli ea cocaine e kenya letsoho ho etsa hore DFB e khetholle ho D1-MSNs libakeng tsohle tse tharo tse hlaselang. Liphuputso tsa rona li lumellana le lithuto tsa khale tse bontšang hore k'hok'heine e matla e etsa hore liphatsa tsa lefutso tse ling tse potlakileng tsa pele le phosphorylation ea liprotheine tse ngata tse sebelisoang ke intracellular feela li fumanehe ho D1-MSNs (Bateup et al., 2008; Bertran-Gonzalez et al., 2008). Ka mokhoa o ts'oanang, mokhoa o fapaneng oa ΔFosB ho qaptjoa ka morao ho haloperidol e sa foleng o lumellana le ho thibeloa ha khopolo ena ea li-agonists tsa D2-like receptor (Atkins et al., 1999), mme ka khethollo e matla ea haloperidol ea liphatsa tsa lefutso tsa kapele le phosphorylation ea liprotheine tse 'maloa tse bontšang li-D2-MSNs (Bateup et al., 2008; Bertran-Gonzalez et al., 2008).

Tafole 1.  

ΔFosB e kenngoa ka mokhoa o hlaselang oa MSN ka mor'a lefuba le sa foleng la meriana, maikutlo le optogenetica

Joaloka ka cocaine, re fumane hore ho pepeseha ha lithethefatsi tse ling tse peli tsa tlhekefetso, EtOH le Δ (9) -THC, ho etsa hore ΔFosB e khetholle ho D1-MSNs libakeng tsohle tse hlaselang. Re kile ra bontša hore EtOH e susumetsa ΔFosB ho NAC core, NAc shell, le dStr, empa hore Δ (9) -THC e phahamisa haholo DFBB ho NAC, e nang le mokhoa o bonahalang libakeng tse ling (Perrotti et al., 2008). Ka ho tšoanang re ile ra hlokomela mona e kholo ea Δ (9) -THC e kenyelletsoang DFBB ho NAC e kholo ho D1-MSNs; bokhoni ba rona ba ho bonts'a ho hlahisa libaka tse ling tse hlaselang ke mohlomong ka lebaka la tlhahlobo e khethehileng ea sele. Hoa thahasellisa hore morphine ea sa foleng le heroine ea botho, ho fapana le lithethefatsi tse ling tsa ho hlekefetsoa, ​​e kentse ΔFosB maemong a mabeli a MSN ka mokhoa o ts'oanang le libakeng tsohle tse hlaselang. Phuputso ea morao tjena e bontšitse hore morphine e matla e etsa hore c-Fos e fumanehe ho D1-MSN, athe ho tlosoa ke lexone-morao ka mor'a lefu le sa foleng ho hlahisa c-Fos ho D2-MSNs (Enoksson et al., 2012). Le hoja re sa ka ra bona matšoao a ho tlosoa ha opiate ha re ntse re ithuta, ho na le maikutlo a hore ho khaotsa ho itšehla thajana ho tlisoang ke morphine kapa tsamaiso ea heroin nakong eo ho ithutoang ho eona ke boikarabello ba ΔFosB ho kenngoa ha D2-MSNs ho bona mona. Re bontšitse pejana hore ΔFosB ho D1-MSNs, empa eseng D2-MSNs, e eketsa likarabo tse khotsofatsang ho morphine (Zachariou et al., 2006). Hona joale e tla ba ho thahasellisang ho leka hore monyetla oa hore DFNB e kenyelletsoe ho D2-MSN e tlatsetsa liphellong tse senyang tsa ho tlosoa ha opiate. Ka mokhoa o ts'oanang, monehelo oa monyetla oa ho tlohela lithethefatsi le ho lakatsa ho bona DFFB ho fumanoa ka lithethefatsi tsohle ho lokela ho phenyekolloa.

Liphuputso tse fetileng li bontša hore ho ntlafatsa tikoloho nakong ea ntshetsopele ho hlahisa DFFB ho NAc le dStr (Solinas et al., 2009; Lehmann le Herkenham, 2011). Dintlha tsa rona li bonts'a hore ho bokella hona ho hlaha ka ho lekanang le D1-MSN le D2-MSNs libakeng tsohle tse hlaselang. Paradigm e ntlafalitsoeng e ne e bontšitsoe pele ho likarabo tse khotsofatsang le tse hohelang li-cocaine (Solinas et al., 2009); leha ho le joalo, mokhoa ona oa phenotype ha o hlahe ka lebaka la ΔFosB ho bokella hobane ΔFosB ho kenngoa ha D1-MSNs feela ho eketsa likarabo tsa boitšoaro ho cocaine, athe ho kenyelletsa joalo ho D2-MSNs ha ho na phello e hlakileng (Kelz et al., 1999; Colby et al., 2003; Grueter et al., 2013). Ho sebelisoa li-sucrose ka nako e telele ho ile ha bontšoa hore ho eketsa DFFB ho NAc, le ho feta ka ho feteletseng ha ΔFosB, ebang ke D1-MSNs feela kapa ka mahlakoreng a mabeli, Nac e ntlafatsa ho sebelisoa ha lijo (Olausson et al., 2006; Wallace et al., 2008). Ha re le moo, re ile ra bona DFFB e tšoantšetso ea li-MSN tse nyenyane ka NAc le dStr ka mor'a hore sucrose e noe. Qetellong, re bonts'itse pejana hore DFFB e ho NAC e fana ka likarabo tse ling tsa lik'halori tse thibelang lijo ka matla a mafura le ho fokotsa litšenyehelo tsa metsi (Vialou et al., 2011). Ka kakaretso, liphetho tsena li bontša hore ΔFosB e bokella ka NAc le dStr e hlaha ka bobeli D1-MSN le D2-MSNs ka lebaka la meputso e mengata ea tlhaho. Ho fumanoa sena ke ntho e tsotehang ka lebaka la maikutlo a hore ΔFosB e bokella ka D1-MSNs feela ka mor'a moputso o mong oa tlhaho, lebelo le sa foleng, le hore ho tlōla ho hoholo ha ΔFosB ka maqhubu a ntlafetseng a D1-MSNs athe DFNB-MSNs e fokotseha ka likoloi (Werme et al., 2002). Leha ho le joalo, ho khanna ho ka 'na ha etsa hore ho be le litsela tse fapaneng tsa likoloi, tse ikarabellang bakeng sa mokhoa oa eona o fapaneng oa tlhahiso ea ΔFosB. Leha ho le joalo, liphello le meputso e meng ea tlhaho li bontša hore ba laola DFFB ka tsela e fapaneng ha e bapisoa le melemo e mengata ea lithethefatsi, e kang cocaine, EtOH, le Δ (9) -THC. ΔFosB ho qaptjoa ka bobeli boemong ba MSN tlas'a maemo ana a khotsofatsang a tlhaho ho lumellana le phuputso ea morao tjena e bontšang hore ho qalisoa ha khato bakeng sa moputso oa lijo ho etsa hore bobeli ba MSN (Cui et al., 2013).

Ho hlōloa ha sechaba ka nako e telele ho imeloa kelellong ho fokotsa ΔFosB ho NAc shell ea litoeba tse tsitsitseng le tse tsitsitseng empa e le mokokotlo oa NAc feela litlamong tse tsitsitseng (Vialou et al., 2010). Ho feta moo, ΔFosB ho feta maikutlo ho D1-MSNs ho khothalletsa ho ba le botsitso ka mor'a khatello ea kelello e sa feleng ea sechaba. Phekolo e sa foleng e nang le fluoxetine e boetse e etsa hore DFB e bokelloe ho NAc ea litoeba tse nang le khatello ea kelello le litoeba tse hlasetsoeng ka mor'a khatello ea kelello ea sechaba e sa tsitsang, 'me ΔFosB e feteletse maikutlo e ile ea bontšoa ho rarolla bothata ba ho itšoara ka tsela e tšoanang le ea boitšoaro tlas'a maemo a ho qetela (Vialou et al., 2010). Qetellong, phuputso e fetileng e bontšitse hore FFBB e kenyelletsoa ka mahlakore a mabeli a MSN ka mor'a khatello ea maikutlo e sa foleng (Perrotti et al., 2004). Liphello tsa thuto ea hona joale, moo re bonts'ang hore DFNUMX-MSN e khetholloa ka mokhoa o khethollang li-mouse tsa D1-MSNs, empa ho khetholla ho D2-MSN ka litoeba tse senyehang, ho fana ka temohisiso ea bohlokoa liphuputsong tsena tsa pejana le ho tšehetsa khopolo ea hore DFBB e D1- Li-MSN li tšehetsa boits'oaro le boikemisetso ba ho imeloa kelellong, athe DFBB ho D2-MSNs e ka buisana le tšusumetso. Mosebetsi o eketsehileng o hlokeha hona joale ho hlahloba khopolo ena.

Mosebetsi oa morao-rao o sebelisang optogenetics o bonts'a karolo e matla ea li-dopaminergic le glutamatergic afferents ho NAc ho tsamaisa moputso le likarabo tsa khatello ea kelello (bona Liphetho). Re sebelisa lisebelisoa tsena tsa optogenetic ho hlahloba tlhahiso ea ΔFosB ho D1-MSNs le D2-MSNs ka mor'a ho ts'oaroa ha libaka tsa NAc ka makhetlo-khetlo. Re fumane hore phasic ea stimulating VTA neurons, kapa ts'ebetsong ea li-neurone tsa glutamatergic ka amygdala, e kenyelletsa DFFB ho D1-MSNs ho shell ea NAc le maemong a mabeli a MSN ho NAC. Ka lehlakoreng le leng, ts'ebetsong ea mPFC neurons e fella ka mokhoa o fapaneng oa ΔFosB, ho nang le litekanyetso tse eketsehileng ho D1-MSNs ho NAc core empa ho kenngoa ka bobeli ho MSN subtypes ho NAc shell. Qetellong, ts'ebetso ea optogenetic ea vHippo neurons e etsa hore DFBB e bokellane feela ka D1-MSNs ho NAC le shell. Liphuputso tsa VHippo li lumellana le lipatlisiso tsa morao tjena tse bontšang hore lits'ebeletso tsa hippocampal li fokotseha haholo ho D2-MSNs ha li bapisoa le D1-MSNs (MacAskill et al., 2012) le hore lisebelisoa tsena li laola ho lahleha ha mokokotlo oa cocaine (Britt et al., 2012). Ho feta moo, pontšo ea rona ea DFNB e kenngoa haholo ho D1-MSNs ka mekhoa eohle e lumellanang le lipatlisiso tsa pele tse bontšang hore DFBB ho D1-MSNs e eketsa likarabo tse khotsofatsang ho lithethefatsi tsa tlhekefetso hammoho le lithuto tse bontšang hore tlhahiso ea optogenetic ea VTA dopamine neurons kapa ea mPFC, amygdala, kapa li-terminal tsa Hippo ho NAc li fana ka moputso (Kelz et al., 1999; Zachariou et al., 2006; Tsai et al., 2009; Witten et al., 2011; Britt et al., 2012; Grueter et al., 2013).

Qetellong, ho ka etsahala hore ho na le li-ensembles tse khethollang li-neuronal tse ka hare ho tsena tse peli tse nyenyane tsa MSN tse khetholloang ka mokhoa o fapaneng ka li-stimuli tse ntle kapa tse fosahetseng. Sena se ka etsa hore re bone kamoo DFNUMX-MSN e kenyelletsoeng kateng ka D2-MSNs maemong a itseng a thabisang (li-opiates le meputso ea tlhaho) hammoho le maemo a hlaselang (social defeat). Striatum e fapane haholo ho feta menyetla e mengata ea MSN, ho kenyeletsa likarolo tsa patch le matrix ka bobeli le bo-ventral striatum (Gerfen, 1992; Watabe-Uchida et al., 2012). Ho feta moo, lipatlisiso tsa pele li bontša ho sebelisoa ha karolo e fokolang haholo ea lihlahisoa tse hlaselang tsa psycho-stimulants, le ho thehoa ha FosB liphatsa tsa lefutso li-neurons tse sebelisitsoeng (Guez-Barber et al., 2011; Liu et al., 2013), le hoja ho sa tsejoe hore na li-neurons tse sebelisitsoeng ke D1-MSN kapa D2-MSNs. Mosebetsi oa DFBB ka ho lekaneng le ho khetholla sekhahla ha ho sebelisoa mekhoa e khotsofatsang le e tsitsitseng e sa tsejoe. ΔFosB ho tlhalosa habonolo ho D1-MSNs ho ile ha eketseha li-synapses tse khutsitseng ka bobeli le lihlopha, empa polelo ho D2-MSNs e fokolitse li-synapses tse khutsitseng ka shell feela (Grueter et al., 2013). Ho feta moo, ΔFosB ho kenngoa ha motsoako o moholo ho feta shell ho ka etsahala hore e sebelisane ka mekhoa e sa tšoaneng, kaha re fumane CaMKIIa e khamisitsoeng ka cocaine e tsitsitseng ea ΔFosB ka khetla empa e se e ka sehloohong e lebisang ho ho feta ΔFosB ho bokella ka shell (Robison et al., 2013). Liphuputso tsa nakong e tlang tse hlalosang lihlopha tsa MSN tse ka sehloohong le likhetla, tse sebelisitsoeng ka neuronal ensembles, kapa tse ling tse nang le likarolo tsa matrix li tla thusa ho hlalosa karolo ea boitšoaro ea DFBB ka har'a libaka tsena tse sa tšoaneng.

Ka kakaretso, lisele tsena tse khethiloeng ka potoloho ea sele-ea-FosB ka NAc li bontša hore ho ba le mekhoa e metle le e bakang khatello e ikarabellang ho kenyelletsa ho khetholla Nac afferents ho kenyelletsa likarolo tse itseng tsa mekhoa ena. Liphello tsa rona ha li fane feela ka kutloisiso e felletseng mabapi le ho kenngoa ha ΔFosB ka mahlaseli a MSN a hlaselang ka ho ba le tšusumetso e sa foleng empa e boetse e bontša kamoo ho sebelisang ΔFosB e le letšoao la limolek'hule ho utloisisa liphello tsa nako e telele tsa lipotoloho tse nang le melapo ho susumetsa mosebetsi oa NAc.

Mongolo o botlaaseng ba leqephe

Bangoli ha ba phatlalatse lithahasello tsa lichelete.

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