DeltaFosB ho The Nucleus Accumbens ke ea bohlokoa bakeng sa ho ntlafatsa liphello tsa monehelo oa thobalano. (2010)

LITLHAHISO: Delta FosB ke letšoao la lithethefatsi tsohle, tsa boitšoaro le tsa lik'hemik'hale. Ha molek'hule ena e ntse e eketseha potolohong ea moputso le boits'oaro bo lemalloang. Ke e 'ngoe ea limolek'hule tse amehang liphetohong tsa methapo ea pelo. Teko ena e bonts'a hore e ea eketseha ka boiphihlelo ba thobalano, ka mokhoa o ts'oanang le ka moo e etsang ka lithethefatsi tsa lithethefatsi. Tekong ba sebelisitse boenjineri ba liphatsa tsa lefutso ho eketsa maemo a eona ho feta "tloaelehileng". Sena se felletse ka nts'etsopele e ntlafalitsoeng ea thobalano. Re nahana hore sena se etsahala ka ho lemalla lit soant so tsa bootsoa.

THUTO E TLAHANG

Pitchers KK, Frohmader KS, Vialou V, Mouzon E, Nestler EJ, Lehman MN, Coolen LM.

Brain Behav. 2010 Oct; 9 (7): 831-40 doi: 10.1111 / j.1601-183X.2010.00621.x. Epub 2010 Aug 16.

Lefapha la Anatomy le Cell Biology, Sekolo sa Bongaka sa Schulich le Phekolo ea meno, Univesithi ea Western Ontario, London, Ontario, Canada.

HO HLOKA

Boitšoaro ba thobalano ho likhoto tsa banna boa putsa ebile boa tiisa. Leha ho le joalo, ha ho tsejoehale ka mekhoa e ikhethileng ea lisele le limolek'hule tse amanang le moputso oa thobalano kapa litholoana tse matlafatsang tsa moputso ponahalong e latelang ea boitšoaro ba thobalano. Boithuto bona bo leka boikaketsi ba hore ΔFosB, sebopeho sa FosB se hlalositsoeng hantle, e bapala karolo ea bohlokoa ho matlafatsong ea boitšoaro ba thobalano le boithuto bo susumetsang ba thobalano le ts'ebetso.

Boiphihlelo ba thobalano bo bonts'itsoe ho baka ho bokellana ha ΔFosB libakeng tse 'maloa tsa bokong ba mmele ho kenyelletsa le nucleus accumbens (NAc), medial prefrontal cortex, sebaka sa patralal seterata le caudate putamen empa eseng medial preoptic nucleus.

Kamora moo, ho kenngoa ha c-Fos, sepheo se tlase sa (qoelisoa) sa ΔFosB, ho ile ha lekanngoa liphoofolong tse nang le tsebo le thobalano. Palo ea lisele tse sa sebetseng tsa c-Fos-immunoreactive e ile ea fokotseha haholo liphoofolong tse nang le thobalano ha e bapisoa le taolo ea naïve ea thobalano.

Kamora nako, maemo a ΔFosB le tšebetso ea eona ho NAc li ile tsa qhekelloa ho sebelisa phetiso ea botona e tsamaeang le vaerase ho ithuta karolo ea eona ea ho hanana le boiphihlelo ba thobalano le boiphihlelo bo susumetsang ts'ebetso ea thobalano. Liphoofolo tse nang le ΔFosB overexpression li bonts'itse ts'ebetso e ntlafalitsoeng ea ts'ebetso ea thobalano le boiphihlelo ba thobalano e amanang le taolo. Ho fapana le hoo, polelo ea ΔJunD, molekane ea tummeng hampe oa ΔFosB, ea nang le boiphihlelo bo matla ba thobalano le tlhotlheletso ea ts'ebetso ea thobalano le tlhoko e telele ea nako e telele ea papiso ha e bapisoa le protheine e tala ea fluorescence le lihlopha tsa osFosB tse tebileng.

Ka kopanelo, liphumano tsena li ts'ehetsa karolo ea bohlokoa bakeng sa polelo ea ΔFosB ho NAc bakeng sa litlamorao tse matlafatsang tsa boitšoaro ba thobalano le boiphihlelo bo susumetsang ba thobalano.

SELELEKELA

Boitšoaro ba thobalano bo na le moputso o matla ebile bo matlafatsa ho litoeba tsa banna (Coolen et al. 2004; Pfaus et al a. 2001). Ho feta moo, boiphihlelo ba botona le botšehali bo fetola boitšoaro bo latelang ba thobalano le moputso (Tenk et al a. 2009). Ka boiphihlelo bo khahlisang ba bocha, boitšoaro ba thobalano bo a nolofalletsoa kapa "bo matlafatsoa", bo bonahatsoa ke ho fokotseha hoa lits'ebetso ho qala ho kena lenyalong le ho tsamaisa ts'ebetso ea thobalano (Balfour et al a. 2004; Pfaus et al a. 2001). Leha ho le joalo, mekhoa e ka tlas'a sekhele ea cellular le molek'hule ea moputso oa thobalano le matlafatso ha e utloisisoe hantle. Boitšoaro ba thobalano le mekhoa e tloahelehileng ea ho nyalana e bonts'oa butle-butle ho ts'oara sebopeho sa c-fos sa pele ho ts'ebetso ea mesolimbic ea likhoto tsa banna (Balfour et al a. 2004; Pfaus et al a. 2001). Ho feta moo, haufinyane ho bontšitsoe hore boiphihlelo ba thobalano bo etsa hore motho a phele nako e telele tsamaisong ea semorimbic ea banna.Frohmader et al a. 2009; Pitchers et al a. 2010). Ntle le moo, ho litoeu tsa banna, boiphihlelo ba thobalano bo bontšitsoe ho susumetsa ΔFosB, a Setho sa lelapa sa Fos, ka har'a li-nucleus accumbens (NAc) (Wallace et al a. 2008). ΔFosB, mofuta o ferekaneng oa khaba ea FosB, ke setho se ikhethileng sa lelapa la Fos ka lebaka la botsitso ba lona bo boholo (Carle et al a. 2007; Ulery-Reynolds et al a. 2008; Leihlo et al a. 2006) hape e bapala karolo ea matlafatso e ntlafalitsoeng le moputso bakeng sa lithethefatsi tsa tlhekefetso le ts'ebetso ea nako e telele ea neural plasticity mediationNestler et al a. 2001). ΔFosB e theha heteromeric transcript factor factor (activator protein-1 (AP-1) le liprotheine tsa Jun, ka ho khetheha JunD (Chen et al a. 1995; Hiroi et al a. 1998). Ka tšebeliso e sa sebetseng ea ΔFosB, e ts'ehetsoeng feela ho striatum e sebelisang litoeba tsa bi-transgenic, mokhoa oa ts'ebetso o ts'oanang le lithethefatsi o hlahisoa le ha o sa hlahisoe ke lithethefatsi tse fetileng (McClung et al a. 2004). Mofuta ona oa boits'oaro o kenyelletsa karabelo e ntlafalitsoeng ea locomotor ho koae (cocaine)Kelz et al a. 1999), keketso e ratoang ea koae (Kelz et al a. 1999) le morphineZachariou et al a. 2006), le keketseho ea boikoetliso ba koae (Colby et al a. 2003).

Hoa tšoana le moputso oa lithethefatsi, ΔFosB e ts'oaroa ka boits'oaro bo botle ba moputso le ho kenyelletsa polelo ea boits'oaro bona. Tlhahiso e fetang ea ΔFosB ho NAc e sebelisa mehlala ea methapo e eketsa lebili la boithaopo (Werme et al a. 2002), mochini o arabelang lijo (Olausson et al a. 2006), tloaelo ea ho ja (Wallace et al a. 2008), 'me e thusa e tona (Wallace et al a. 2008) le mosali (Bradley et al a. 2005) boits'oaro. Kahoo, ΔFosB e ka ameha ho arolelana litlamorao tsa liphihlelo tsa mahlohonolo a tlhaho. Tthuto ea hajoale e atoloha lithutong tse fetileng ka ho batlisisa karolo ea ΔFosB ho NAc liphellong tsa nako e telele tsa boiphihlelo ba thobalano ka boits'oaro bo latelang ba ho hola le neural activation tsamaisong ea mesolimbic.

  • Pele, ho ile ha thehoa libaka tsa boko tse kenyelletsang moputsong oa moputso le boitšoaro ba thobalano bo hlalosang experienceFosB ea thobalano.
  • Kamora moo, phello ea boiphihlelo ba thobalano e ileng ea susumetsa ΔFosB puong e susumetsang ea c-Fos, sepheo se tlase se theotsoeng ke ΔFosB (Renthal et al a. 2008), ho ile ha etsoa lipatlisiso.
  • Kamora nako, phello ea ho laola mesebetsi ea ΔFosB ho NAc (mofuta o fetisang polelo le polelo ea molekane ea matla ea tlamang) ka boitšoaro ba thobalano le boithuto bo susumetsang ba takatso ea thobalano le ts'ebetso bo anngoe ka ho sebelisa theknoloji ea ho tsamaisa vetera ea vaerase.
Eya ho:

METHODA

Animals

Likhoto tsa banna ba baholo ba Sprague Dawley (ligrama tsa 200-225) li fumanoe ho Charles River Laboratories (Senneville, QC, Canada). Liphoofolo li ne li kenngoa ka har'a mekotla ea Plexiglas e nang le thapo ea kotopo likotong tse ts'oanang tsa thobalano nakong ea liteko. Kamore ea kolone e ne e laoloa ke mocheso ebile e lula le leqhubu le lefifi la 12 / 12 hr ka lijo le metsi tse fumanehang ad libitum ntle le nakong ea tlhahlobo ea boitšoaro. Li-femme tsa Stimulus (210-220 ligrama) bakeng sa mananeo a ho emisa li amohetse semmuso se kenang se nang le 5% estradiol benzoate le 95% cholesterol e latelang bilatal ovariectomy tlasa anesthesia e tebileng (0.35g ketamine / 0.052g Xylazine). Boitšoaro ba thobalano bo ile ba susumetsoa ke tsamaiso ea 500µg progesterone ho 0.1 mL sesame oli hoo e ka bang lihora tsa 4 pele ho liteko. Ts'ebetso tsohle li ananetsoe ke Likomiti tsa Tlhokomelo ea Liphoofolo le Ts'ebeliso ea Univesithi ea Western Ontario mme li lumellana le litataiso tsa CCAC tse kenyeletsang liphoofolo tse amanang le liphoofolo tse amanang le lefu la matsoho.

Boitšoaro ba Thobalano

Linako tsa ho ruruha li etsahetse nakong ea mohato oa pele o lefifi (pakeng tsa lihora tsa 2-6 kamora ho fifala ha nako e lefifi) tlasa khanya e khubelu e lefifi. Pele ho liteko, liphoofolo li ne li arotsoe ka lihlopha ka lihlopha. Ka nako ea kemiso ea ho lisa likhoto tsa banna li ne li lumelloa ho kopanya ho ejaculation kapa hora ea 1, mme litekanyetso tsa boitšoaro ba thobalano li tlalehiloe ho kenyeletsoa: Mount latency (ML; nako ho tloha ho hlahisoeng ha mosali ho fihlela thabeng ea pele), intromission latency (IL; nako ho tloha kenyelletsong ea e tšehali ho fihlela ea pele e kenang kahare ea botšehali), ejaculation latency (EL; nako ho tloha kemisong ea pele ho isa ho emong), nako ea kemiso ea kemiso (PEI; nako ho tloha kemisong ea pele ho ea pele ho kenella ka hare), palo ea limmete (M; pelvic thrigue ntle le vaginal ho kenella ka hare), palo ea ho kenella (IM; ho kenyelletsa ho kenella kahare ho setho sa botšehali) le katleho ea ho sebetsa (CE = IM / (M + IM)) (Agmo 1997). Lipalo le lipalo tse sa kenngoeng ha lia ka tsa kenyelletsoa tlhahlobisong ea liphoofolo tse sa kang tsa bonala. Litaba tse phahameng tsa ho hloa le ho kenella ka hare ke likarolo tse bonts'ang maikutlo a susumetsang ka thobalano, athe ejaculation latency, palo ea litheko le ho sebetsa hantle ha ts'ebetso ho bontša ts'ebetso ea thobalano (Hull 2002).

Teko 1: Khatiso ea ofFosB

Ka thobalano likhoto tsa banna ba nayes ba ne ba lumelloa ho nyalana mesebetsing e hloekileng ea liteko (60 × 45 × 50 cm) bakeng sa 5 ka ho latellana, linako tsa ho kopanya tsa letsatsi le letsatsi kapa ho lula le naveve ea thobalano. Letlapa le tlatsetsang 1 e fana ka lintlha tse amanang le boitšoaro bo sebelisoang bakeng sa lihlopha tsa liteko: naïve no sex (NNS; n = 5), sex sex (NS; n = 5), ba ne ba sa kopanele thobalano (ENS; n = 5) le bootsoa ba nang le boiphihlelo (ES; n = 4). Liphoofolo tsa NS le ES li ile tsa etsoa sehlabelo ka hora ea 1 kamora ho ts'oaroa ka letsatsi la hoqetela ho etsa lipatlisiso mabapi le polelo ea c-Fos ea ho kopanya batho ba bang. Liphoofolo tsa NNS li ne li etsoa sehlabelo ka nako e tšoanang le liphoofolo tsa ENS 24 lihora tse ngata kamora seboka sa hoqetela sa ho emisa ho hlahloba boiphihlelo ba botona le botšehali ba indFosB. Lihlopha tse nang le tsebo ea thobalano li ne li bapisoa le boitšoaro ba thobalano pele ho tlhahlobo e latelang. Ha ho liphapang tse kholo tse fumanoeng lipakeng tsa lihlopha bakeng sa mekhoa efe kapa efe ea boits'oaro kahare ho seboka se loketseng sa tlhakiso ea botona le ts'usumetso ea takatso ea thobalano e bontšitsoeng ke lihlopha ka bobeli tse nang le boiphihlelo (Letlapa le tlatsetsang 2). Litaolo li ne li kenyelletsa banna ba na sexuallyve ba ho kopanela liphate ba tšoaroang ka nako e le 'ngoe le liphoofolo tse holisang tse etsang bonnete ba hore ba pepesehela monko oa basali le mantsoe ntle le ho tobana le basali ka kotloloho.

Bakeng sa sehlabelo, liphoofolo li ne li anesthetised haholo li sebelisa sodium pentobarbital (270mg / kg; ip) mme li entsoe ka mokhoa o ikhethileng ka 50 mL ea 0.9% saline, e lateloa ke 500 mL ea 4% paraformaldehyde ho 0.1 M phosphate buffer (PB). Li-brains li ile tsa tlosoa tsa ba tsa romelloa bakeng sa 1 h ka mocheso oa kamore ka mokhoa o tšoanang oa phepelo, joale tsa qoelisoa ka 20% sucrose le 0.01% sodium azide ho 0.1 M PB 'me ea bolokoa ho 4 ° C. Likarolo tsa Coronal (35 µm) li ne li khaotsoe ka microtome ea leqhoa (H400R, Micron, Jeremane), e bokelletsoeng ka tatellano tse 'ne tsa tharollo ea "cryoprotectant" (30% sucrose le 30% ethylene glycol ho 0.1 M CB)' me e bolokiloe ho −20 ° C. Likarolo tse phaphametseng tsa metsi a phallang a ile a hlatsuoa haholo ka letsoai la 0.1 M phosphate-buffered (PBS; pH 7.3-7.4) lipakeng tsa poloko. Likarolo li ile tsa pepesoa 1% H2O2 bakeng sa 10 min ka mocheso oa kamoreng ho senya endo native peroxidases, ebe e koetsoe tharollo ea ho incubation ea PBS, e leng PBS e nang le 0.1% bovine serum albin (buka ea likhatiso 005-000-121; Jackson ImmunoResearch Laboratories, West Grove, PA) le 0.4% Triton X -100 (lethathamo la tse thathamisitsoeng BP151-500; Sigma-Aldrich) ea 1 h. Likarolo li ile tsa kenngoa bosiu ka bongata bosiu ho 4 ° C ka mokhoa oa anti-polyclonal antibody (1: 5K; sc-48 Santa Cruz Biotechnology, Santa Cruz, CA, USA). Anti-panos FosB e phahamisitsoe khahlanong le sebaka se kahare se arolelanoang ke FosB le ΔFosB. Lisele tsa ΔFosB-IR li ne li hlile li na le ΔFosB hobane ka nako ea kamorao ho boitšisinyo (lihora tsa 24) tsohle FosB tse susumetsang tse susumetsang li theotsoe (Perrotti et al a. 2004; Perrotti et al a. 2008). Ntle le moo, boitekong bona, liphoofolo tse lumellanang ka letsatsi la ho qetela (NS, ES) li ile tsa etsoa sehlabelo ka 1 h kamora ho nyaloa, ka hona pele ho polelo ea FosB. Tlhahlobo ea blot Bophirimela e netefalitse ho fumanoa ha ΔFosB hoo e batlang e le 37 kD. Kamora ho kenella ka bongata anti-antibody, likarolo li ile tsa kenyetsoa 1 h ho biotin-conjugated poli anti-rabi IgG (1: 500 in PBS +; Vector Laboratories, Burlingame, CA, USA) le 1 h ho avidin-biotin-hoseradish peroxidase (ABC elite ; 1: 1K ho PBS; Vector Laboratories, Burlingame, CA, USA). Kamora likarolo tsena tsa ho incubation ho ile ha sebetsoa ka tsela e 'ngoe e latelang:

1. Single peroxidase labeling

Likarolo tsa liphoofolo tsa NNS le ENS li ile tsa sebelisoa bakeng sa tlhahlobo ea boko ea ho bokella boiphihlelo ba sexualFosB. Kamora ho kenella ka har'a ABC, mochine oa peroxidase o ile oa bonoa ka mor'a kalafo bakeng sa metsotso ea 10 ho fihlela karabo ea chromogen e nang le 0.02% 3,3'-diaminobenzidine tetrahydrochloride (DAB; Sigma-Aldrich, St. Louis, MO) e ntlafalitsoeng ka 0.02% nickel sulfate ho 0.1 M PB e nang le 0.015 M nPB hydrogen peroxide (0.1%). Likarolo li ile tsa hlatsuoa hantle ka 0.3 M PB ho felisa karabelo 'me tsa kenngoa ka har'a li-slide tsa khalase tsa Superfrost le khalase (Fisher, Pittsburgh, PA, USA) ka XNUMX% gelatin ho ddH20. Kamora ho felloa ke metsi 'meleng, li-slide tsohle li ile tsa koaheloa ke DPX (dibutyl phthalate xylene).

2. Dun immunofluorescence

Likarolo tsa lihlopha tsohle tse 'ne tsa liteko tsa NAc le mPFC li sebelisitsoe bakeng sa tlhahlobo ea ΔFosB le c-Fos. Ka mor'a ho kenella ka kotloloho ea ABC, likarolo li ile tsa kenyetsoa metsotsoana ea 10 ka biopinylated tyramide (BT; 1: 250 ho PBS + 0.003% H2O2 Kitramid Signal Amplification Kit, Saense ea Bophelo ba NEN, Boston, MA) le bakeng sa 30 min le Alexa 488-conjugated strepavidin (1: 100; Jackson Immunoresearch Laboratories, West Grove, PA). Likarolo li ile tsa ts'oaroa bosiu le mothapo oa polyclonal oa mmutla ka ho khetheha a hlokomela c-Fos (1: 150; sc-52; Santa Cruz Biotechnology, Santa Cruz, CA), ea lateloa ke 30 min incubation le poli ea anti-sung ea cy3 (1: 200; Jackson Immunoresearch Laboratories, West Grove, PA, USA). Kamora lits'oants'o, likarolo li ile tsa hlatsuoa hantle ka 0.1 M PB, tsa beoa ka har'a li-slide tsa khalase tse nang le 0.3% gelatin ho ddH20 le sekoaelo se thellelitsoeng se nang le metsi a kenang a akaretsang (Gelvatol) a nang le moemeli ea hanyetsang ho felloa ke matla 1,4-diazabicyclo (2,2) octane (DABCO; 50 mg / ml, Sigma-Aldrich, St. Louis, MO). Litaolo tsa immunohistochemical li kenyelletsa ho siea ha li-antibodies tsa mantlha kapa tse peli tse ka pele, ho felletseng ka hore ho se ke ha ngolloa lenaneong le loketseng.

Boitsebiso ba Lintlha

Tlhahlobo ea Brain ea ΔFosB

Liteko tse peli tse sa boneng kalafo li ile tsa etsa tlhahlobo ea boko ho li-slide tse ngotsoeng. Lisele tsa ΔFosB-immunoreactive (-IR) ho pholletsa le boko li ile tsa hlahlojoa ka bongata li sebelisa sekala ho emela palo ea lisele tse ntle tsa ΔFosB joalo ka ha li hlalositsoe ho Lethathamo 1. Ntle le moo, ho ipapisitsoe le lipatlisiso tse entsoeng ka bongata, lipalo tsa lisele tsa ΔFosB-IR li baliloe li sebelisa libaka tse tloaelehileng tsa tlhahlobo libakeng tsa boko tse kenyellelitsoeng moputsong le boits'oaro ba thobalano ba sebelisa kh'amera ea khamera ea lucida e hokeletsoeng microscope ea Leica DMRD (Leica Microsystems GmbH, Wetzlar , Jeremane): NAc (konokono (C) le khetla (S); 400 × 600µm) e hlahlobiloe maemong a mararo a rostral-caudal (Balfour et al a. 2004); sebaka sa tefo ea likarolo tsa moea (VTA; 1000 × 800µm) e hlahlobiloe maemong a mararo a rostral-caudal (Balfour et al a. 2004) le mohatla oa VTA (Perrotti et al a. 2005); prefrontal cortex (anterior cinglulate area (ACA); prelimbic cortex (PL); infralimbic cortex (IL); 600 × 800µm e le 'ngoe); caudate putamen (CP; 800 × 800µm); le medial preoptic nucleus (MPN; 400 × 600 µm) (Litlhaku tse tlatsetsang 1-3). Likarolo tse peli li ile tsa baloa ka ho latellana, 'me karolelano ea liphoofolo ka' ngoe e balloa sehlopha. Ka thobalano le naveve ea sehlopha sa batho ba nang le boiphihlelo ba sehlopha sa ΔFosB-IR ba ile ba bapisoa bakeng sa subregion ka 'ngoe ba sebelisa liteko tsa t-tepa tse sa lefelloeng.

Lethathamo 1    

Kakaretso ea polelo ea ΔFosB ka liphoofolo tsa bootsoa le naveve le liphoofolo tse nang le boiphihlelo
Tlhahlobo ea ΔFosB le c-Fos

Litšoantšo li ile tsa nkuoa ho sebelisoa k'hamera e koahetsoeng ea CCD (Microfire, Optronics) e hokahantsoeng le microscope ea Leica (DM5000B, Leica Microsystems; Wetzlar, Jeremane) le software ea Neurolucida (MicroBrightfield Inc) e nang le likhakanyo tse tsitsitseng tsa khamera bakeng sa lithuto tsohle (li sebelisa sepheo sa 10x). Palo ea lisele tse hlalosang c-Fos-IR kapa ΔFosB-IR libakeng tse tloaelehileng tsa tlhahlobo ho NAc konokono le khetla (400 × 600µm ka ngoe; Setšoantšo sa tlatsetso 1) le ACA ea mPFC (600 × 800µm; Setšoantšo sa tlatsetso 3) li ile tsa baloa ka letsoho ke motho ea neng a foufalitse lihlopha tsa liteko, ka likarolo tsa 2 ka phoofolo e 'ngoe le e' ngoe e sebelisang software ea Neurolucida (MBF Bioscience, Williston, VT) le karolelano ea liphoofolo ka bomong. Karolelano ea lihlopha ea lisele tsa c-Fos kapa ΔFosB li ne li bapisoa li sebelisa mekhoa e 'meli ea ANOVA (Lintlha: boiphihlelo ba thobalano le ketso ea thobalano) le Fisher LSD bakeng sa papiso ea hoc hoc ka boleng ba 0.05.

Teko 2: ΔFosB polelo e qhekella

Transfer ea Gene ea Viral e se nang likokoana-hloko

Malepo a sa rarahanang a liroboto Sprague Dawley a ile a aroloa ka boomo ka lihlopha pele ho ts'ebetso ea bongaka e sa sebetseng. Liphoofolo tsohle li ile tsa amohela li-virinalions tse amanang le mefuta ea li-viroptisi tse amanang le adeno tse amanang le ramatiki (RAAV) tse kenyeletsang GFP (taolo; n = 12), mofuta oa hlaha oa ΔFosB (n = 11) kapa molekane ea tlamang oa ΔFosB ea bitsoang ΔJunD (n = 9) ho NAc. ΔJunD e fokotsa ho hatisoa ha osFosB ka tlholisano ea heterodimerizing le withFosB pele ho tlama sebaka sa AP-1 ka har'a baphatlalatsi ba gene (Winstanley et al a. 2007). Virer titer e ile ea khethoa ke qPCR mme ea hlahlojoa Ka vivo pele thuto e qala. Titer e ne e le 1-2 × 1011 likokoana-hloko tse tšoaetsanoang ka ml. Lirosa tsa RAAV li ile tsa kenngoa ka bongata bophahamong ba 1.5 µL / lehlakoreng la metsotso ea 7 (lihokela: AP + 1.5, ML +/− 1.2 e tsoang Bregma; DV −7.6 ho tloha ka lehata ho latela Paxinos le Watson, 1998) e sebelisa seletsa sa Hamilton (5µ ; Harvard Apparatus, Holliston, MA, USA). Lierekisi ha li hlahise chefo e kholo ho feta infusions ea taolo feela.Winstanley et al, 2007; bakeng sa lintlha tsa tokisetso ea AAV, bona Hommel et al., 2003). Liteko tsa boits'oaro li qalile libeke tsa 3 kamora liente tsa vector tse lumellang ts'oaetso e nepahetseng le e tsitsitseng ea vaerase (Wallace et al a. 2008). Polelo ea Transgene mefuteng ea murine e phahameng ka matsatsi a 10 mme e lula e phahame bonyane likhoeli tsa 6 (Winstanley et al a. 2007). Qetellong ea tlhahlobo, liphoofolo li ile tsa etsoa ka mokhoa o fetisisang mme likarolo tsa NAc li ile tsa sebetsoa bakeng sa GFP (1: 20K; rabi anti-GFP antibody; Molecular Probes) e sebelisang mokhoa oa ABC-peroxidase-DAB (joalo ka ha ho hlalositsoe kaholimo) ho latela nalane. netefatsa libaka tsa ente e sebelisang GFP e le lesupa (Setšoantšo sa tlatsetso 4). Lirosa tsa ΔFosB le ΔJunD le tsona li na le karolo e bonts'ang GFP e arotsoe ke sebaka sa kantle sa ribosomal, e lumellang netefatso ea sebaka sa ente ke pono ea GFP ho liphoofolo tsohle. Ke liphoofolo feela tse nang le libaka tsa ente le ho ata ha vaerase tse thibelitsoeng ho NAc feela tse kenyellelitsoeng tlhaisong ea lipalo. Ho hasana ka vaerase ka kakaretso ho ne ho lekanyelitsoe ho karolo ea NAc mme ha e a ka ea jala rostral-caudally ho pholletsa le konopo. Ho feta moo, ho ata ha vaerase ho ile ha bonahala e le feela likhetla kapa bohareng. Leha ho le joalo, phapang ea libaka tsa ente le ho hasana kahare ho NAc ha e ea ka ea ama litlamorao ho boits'oaro. Kamora nako, liente tsa GFP ha li a ka tsa ama boits'oaro ba thobalano kapa boiphihlelo bo khothalletsang boits'oaro ba thobalano ha bo bapisoa le liphoofolo tse sa sebetseng opereishene tse tsoang lithutong tse fetileng (Balfour et al a. 2004).

Boitšoaro ba Thobalano

Libeke tse tharo kamora ho tsamaisoa ha vaerase ea vaerase, liphoofolo li emisoa ka kemiso e le 'ngoe (kapa bakeng sa hora ea 1) bakeng sa 4 ka ho latellana, nako le nako tsa ho arolelana maikutlo ho fumana boiphihlelo ba botona le botšehali (liteko tsa boiphihlelo) mme kamora moo li ile tsa lekoa bakeng sa polelo ea nako e telele ea boiphihlelo e khothalletsoang ho tsamaisa boitšoaro ba thobalano 1 le libeke tsa 2 (likarolo tsa liteko 1 le 2) kamora seboka sa boiphihlelo ba ho qetela. Litekanyetso tsa boitšoaro ba thobalano li ne li tlalehiloe nakong ea mananeo ohle a ho hanana joalokaha ho hlalositsoe ka holimo. Phapang ea lipalo bakeng sa liparamente tsohle nakong ea thupelo e 'ngoe le e' ngoe ea ho ikatisa e ne e bapisoa kahare le pakeng tsa lihlopha tse sebelisang mehato e 'meli e pheta-phetoang ANOVA (Lintlha: kalafo le seboka sa ho arola) kapa li-ANOVA tse le' ngoe (ejaculation latency, palo ea litheko le ho kenella; ntlha thuto) e lateloang ke liteko tsa Fisher LSD kapa Newman-Keuls bakeng sa papiso ea hoc ea hoc maemong a bohlokoa a 0.05. Haholo-holo, litlamorao tsa boiphihlelo ba boiphihlelo ba botona le botšehali ho matšoao a ho hola li ne li bapisoa pakeng tsa seboka sa boiphihlelo 1 (naïve) le likarolo tsa boiphihlelo 2, 3, kapa 4 ka 'ngoe, le lipakeng tsa lihlopha tsa liteko nakong ea karolo e ngoe le e ngoe ea boiphihlelo. Ntle le moo, ho sekaseka litlamorao tsa kalafo (vector) mabapi le ho thusa ka nako e telele molemong oa boitšoaro ba thobalano, matšoao a mating a ne a bapisoa pakeng tsa seboka sa boiphihlelo 4 le seboka sa liteko 1 le 2 ka har'a sehlopha ka seng sa kalafo, le ho bapisoa lipakeng tsa lihlopha tsa liteko nakong ea thuto ka 'ngoe.

Eya ho:

LIPOTSO

Boiphihlelo ba thobalano bo baka ho bokella ΔFosB

Pele ho ne ho etsoa liphuputso tse senang palo tsa ho bokellana ha ΔFos ho ea bokong bohle ho banna ba nang le bohlola ho bapisoa le taolo ea na comparedve. Kakaretso ea liphetho ka kakaretso e fanoa ka Lethathamo 1. Tlhahlobo ea ΔFosB-IR e matlafalitsoe ka ho fumana palo ea lisele tsa ΔFosB-IR libakeng tse 'maloa tse amanang le boko tse sebelisang libaka tse tloaelehileng tsa tlhahlobo. Setšoantšo sa 1 e bonts'a litšoantšo tsa baemeli ba DAB-Ni ho boloka NAc ea liphoofolo tsa thobalano le liphoofolo tse nang le boiphihlelo. Molaoana oa bohlokoa oa ΔFosB o fumanoe meahong e mPFC (Setšoantšo sa 2A), NAc ea mantlha le khetla (2B), caudate putamen (2B) le VTA (2C). Ho NAc, phapang e kholo e bile teng maemong ohle a mantlha a mantlha a mantlha a NAc le khetla, le datha e bonts'itsoeng ho Setšoantšo sa 2 ke karolelano ea maemo ohle a rostro-caudal. Ka lehlakoreng le leng, ha ho na keketseho e kholo ea ΔFosB-IR ho "hypothalamic medial preoptic nucleus" (NNS: Avg 1.8 +/− 0.26; ENS: Avg 6.0 +/− 1.86).

Setšoantšo sa 1    

 

Litšoantšo tsa baemeli tse bonts'a lisele tsa ΔFosB-IR (tse ntsho) ho NAc ea naïve ha ho na thobalano (A) mme ha ba na lihlopha tsa thobalano (B). aco: bareng ea Scale ea Scale e bonts'a 100 µm.
Setšoantšo sa 2     

Palo ea lisele tsa ΔFosB-IR ho: A. infralimbic (IL), prelimbic (PL) le subterions cterex cortex (ACA) ea anterior cortex; B. Nucleus e bokella mantlha le khetla, le caudate putamen (CP); C. Rostral, bohareng, caudal le mohatla ...

Boiphihlelo ba botona le botšehali bo bonts'a tlhalo-tlhoko ea c-Fos

Kameho ea boiphihlelo ba botona le botšehali maemong a ΔFosB ho NAc e netefalitsoe ho sebelisa mekhoa ea ho senya ea fluorescence. Ntle le moo, litlhahlobo tsa boiphihlelo ba thobalano mabapi le polelo ea c-Fos li ile tsa hlahlojoa. Setšoantšo sa 3 e bonts'a litšoantšo tsa baemeli ba ΔFosB- (botala) le c-Fos (khubelu) -IR lisele ka lihlopha tsohle tsa liteko (A, NNS; B, NS; C, ENS; D, ES). Boiphihlelo ba thobalano bo eketsehile haholo polelo ea ΔFosB ho mantlha ea NAc (Setšoantšo sa 4A: F1,15 = 12.0; p = 0.003) le khetla (Setšoantšo sa 4C: F1,15 = 9.3; p = 0.008). Ka lehlakoreng le leng, ho tsamaisana le 1 hora pele ho mafura, ho ne ho sena tšusumetso ho polelo ea ΔFosB (Setšoantšo sa 4A, C) mme ha ho na ho sebelisana pakeng tsa boiphihlelo ba thobalano le ho nyaloa kapele pele ho tlotsoa ho fumanoe. Ho bile le phello e akaretsang ea ho tlolelana le tlholeho pele ho litlatsetso mabapi le polelo ea c-Fos maemong a mabeli a NAc (Setšoantšo sa 4B: F1,15 = 27.4; p <0.001) le khetla (Setšoantšo sa 4D: F1,15 = 39.4; P <0.001). Ho feta moo, phello e akaretsang ea boiphihlelo ba thobalano e fumanoe mokokotlong oa NAc (Setšoantšo sa 4B: F1,15 = 6.1; p = 0.026) le khetla (Setšoantšo sa 4D: F1,15 = 1.7; p = 0.211) le tšebelisano lipakeng tsa boiphihlelo ba thobalano le ho nyaloa pele ho tlholeho ho fumanoe mookotong oa NAc (F1,15 = 6.5; p = 0.022), e nang le mokhoa o etselitsoeng ho khetla (F1,15 = 1.7; p = 0.211; F1,15 = 3.4; p = 0.084). Tlhahlobo ea hoc ea morao-rao e bonts'itse polelo ea c-Fos ea ho hlekefetsa bohareng le khetla ea banna ba thobalano (naïve)Setšoantšo sa 4B, D). Leha ho le joalo, ho banna ba nang le thobalano, c-Fos ha ea ka ea eketseha haholo molemong oa NAc (Setšoantšo sa 4B) 'Me e kenelletse haholo likhetleng (Setšoantšo sa 4D). Kahoo, boiphihlelo ba thobalano bo bakile phokotso ea polelo ea c-Fos e hohelang batho ba bang. P-boleng bakeng sa papiso e ikhethang ea bohlale-bo-bobeli e litlalehong tsa lipalo.

Setšoantšo sa 3     

Litšoantšo tsa moemeli tse bonts'ang ΔFosB (botala) le c-Fos (bofubelu) ho NAc bakeng sa sehlopha ka seng sa liteko. Scale bar e bonts'a 100 µm.
Setšoantšo sa 4     

Tlhahlobo ea thobalano e hlohlellelitsoeng ΔFosB le tlhalo-tlhoko ea c-Fos. Lipalo tsa ΔFosB (Core, A; Shell, C; ACA, E) kapa c-Fos (Core, B; Shell, D; ACA, F) lisele tse kenang bakeng sa sehlopha ka seng: NNS (n = 5), NS (n = 5), ENS (n = 5) kapa ES (n = 4). Lintlha li hlahisitsoe ...

Litlamorao tsa boiphihlelo ba botona le botšehali ho maemo a c-Fos a amanang le ho nyaloa ha lia ka tsa fella feela ho NAc. Kamohelo e ts'oanang ea polelo ea c-Fos e ile ea bonoa ho ACA liphoofolong tse nang le thobalano e bapisoa le taolo ea naïve ea thobalano. Phihlelo ea thobalano e bile le phello e kholo puong ea ΔFosB ho ACA (Setšoantšo sa 4E: F1,15 = 154.2; P <0.001). Ho nyalana pele ho pherekano ho ne ho se na tšusumetso ho polelo ea osBFosB (Setšoantšo sa 4C) empa e eketsehile haholo c-Fos (Setšoantšo sa 4F: F1,15 = 203.4; p <0.001) ho ACA. Ho feta moo, polelo ea c-Fos e bakoang ke ho nyalana ka ACA e fokotsehile haholo ka boiphihlelo ba thobalano (Setšoantšo sa 4F: F1,15 = 15.8; p = 0.001). Kamano e habeli pakeng tsa boiphihlelo ba thobalano le ho nyaloa pele ho tlholeho e fumanoe bakeng sa polelo ea c-Fos (Setšoantšo sa 4F: F1,15 = 15.1; P <0.001). Litekanyetso tsa P bakeng sa papiso e khethehileng ea bohlale ba bobeli li lipapaling tsa batho. Kamora nako, ho ne ho se na phokotso e kholo ho polelo ea c-Fos e bakiloeng ke ho nyalanya mokokotlong oa preoptic (NS: Avg 63.5 +/− 4.0; ES: Avg 41.4 +/- 10.09), sebaka seo boiphihlelo ba ho nyalanya bo sa bakang bohlokoa keketseho ea polelo ea ΔFosB, e bontšang hore polelo ea c-Fos e hlohlellelitsoeng ke ho nyalanya ha e amehe libakeng tsohle tsa boko.

ΔFosB ea NAc e thusa ho matlafatsa boitšoaro ba thobalano

Ho hlahloba mokhoa o ka 'nang oa hlaha oa molek'hule oa ho matlafatsa boitšoaro ba thobalano joalo ka ha o bonts'itsoe ke ts'usumetso e susumetsang ea boitšoaro ba thobalano, litlamorao tsa ho qhekelloa ha maemo a ΔFosB le ts'ebetso ea hae ea ho ngola e ikemiselitse. Boiphihlelo ba botona le botšehali nakong ea lithuto tse 'ne tse latellanang bo bile le phello e matla ho ho latellana (Setšoantšo sa 5A: F1,23 = 13.8; p = 0.001), latency ea ho kenellaSetšoantšo sa 5B: F1,23 = 18.1; p <0.001), le ejaculation latency (Setšoantšo sa 5C: GFP, F11,45 = 3.8; p = 0.006). Liphoofolo tse laoloang ke GFP li bonts'itse ts'ebetso e lebelletsoeng ea ts'usumetso ea ts'ebetso ea thobalano mme e bonts'a lits'oants'o tse tlase haholo ho tsa pele, ho kenella pele le ho nyonya nakong ea boiphihlelo ba 4 ha ho bapisoa le karolo ea boiphihlelo 1 (Setšoantšo sa 5A-C; bona leano la lipalo bakeng sa boleng ba p. Ts'usumetso ena e susumetsang ea boitšoaro ba thobalano e boetse e bonoe sehlopheng sa ΔFosB bakeng sa ho nyoloha le ho kenella, empa ho ne ho se na phapang e kholo e fumanoeng ho ejaculation latency (Setšoantšo sa 5A-C). Ka lehlakoreng le leng, liphoofolo tsa ΔJunD li bonts'itse mokhoa o makatsang; leha maqhubu a litefiso, ho kenella ka hare ho 'mele, le ejukoation li ile tsa fokotseha ka linako tse ngata tsa ho tlolelana ha liphoofolo, ha ho le e' ngoe ea likhakanyo tsena tse fihletseng bohlokoa ba lipalo ha e bapisoa pakeng tsa lithuto tsa 1 le 4 (Setšoantšo sa 5A-C). Lipakeng tsa papiso ea sehlopha bakeng sa karolo ka 'ngoe ea boiphihlelo e bonts'a hore ΔJunD e ne e na le maeto a malelele a ho hloa, ho hlohlona le ho hlaba ka linako tsa boiphihlelo ha ho bapisoa le ΔFosB le GFP (Setšoantšo sa 5A-C). Ntle le moo, boiphihlelo ba bong ka bobeli ba thobalano le kalafo li bile le litlamorao tse kholo mosebetsing oa ho qopitsa (Setšoantšo sa 5F: boiphihlelo ba thobalano, F1,12 = 22.5; p <0.001; kalafo, F1,12 = 3.3; p = 0.049). Banna ba ΔFosB ba ne ba bile le bokhoni bo eketsehileng ba ho qopitsa nakong ea thuto ea 4 ha ba bapisoa le seboka sa boiphihlelo 1 (Setšoantšo sa 5F). Ntle le moo, liphoofolo tsa ΔFosB li ne li le tlase haholo hanyane ka hanyane nakong ea thuto ea 4 ea boiphihlelo, ha li bapisoa le thuto 1 (Setšoantšo sa 5D: F10,43 = 4.1; p = 0.004), le hore banna ba ΔJunD ba bile le litheko tse phahameng haholo ho feta kemiso ea peleho, ka hona ba fokotsehile haholo ts'ebetso ea ho qopitsa, ho feta a mang a lihlopha tse ling tse peli (Setšoantšo sa 5D le F). Kahoo, liphoofolo tsa GFP le ΔFosB li bonts'itse ts'ebetso ea ts'ebetso ea thobalano le ts'ebetso ea thobalano, athe liphoofolo tsa ΔJunD ha li joalo.

Setšoantšo sa 5     

Boitšoaro ba thobalano ba GFP (n = 12), ΔFosB (n = 11) le liphoofolo tsa ΔJunD (n = 9): Mount latency (A), intromission latency (B), ejaculation latency (C), palo ea litheko (D), palo ea maqhubu a ho kenella (E) le katleho ea ho sebetsa (F). Lintlha li hlahisitsoe ...

Ho leka tšibollo ea maikutlo ea hore polelo ea ΔFosB e bohlokoa bakeng sa polelo ea nako e telele ea ts'usumetso e nang le boits'oaro ea thobalano, liphoofolo li ile tsa lekoa beke ea 1 (beke ea liteko 1) le libeke tsa 2 (seboka sa liteko tsa 2) kamora seboka sa boiphihlelo sa ho qetela. Ehlile, ts'ebetso ea ts'ebetso ea thobalano e ne e bolokiloe ka bobeli ho lihlopha tsa GFP le osFosB kaha ha ho le e 'ngoe ea litekanyetso tsa boitšoaro tse fapaneng pakeng tsa lithuto tsa 1 kapa 2 le karolo ea ho qetela ea boiphihlelo 4, ka har'a lihlopha tsa GFP le ΔFosB (Setšoantšo sa 5A-C; kantle ho ejaculation latency le katleho ea ho ikopanya lenaneong la liteko la 1 bakeng sa liphoofolo tsa ΔFosB). Ho ile ha fumanoa liphapang tse ngata lipakeng tsa liphoofolo tsa ΔJunD le GFP kapa lihlopha tsa ΔFosB litekong tse peli tsa liteko bakeng sa liparamente tsohle tsa boitšoaro ba thobalano (Setšoantšo sa 5A-F). Ha ho na liphapang tse fumanoeng lipakeng tsa kapa pakeng tsa lihlopha ha ho bapisoa lipalo tsa lipalo, PeI, kapa liperesente tsa liphoofolo tse emisitsoeng (100% ea ba batona lihlopheng tsohle tse ntšitsoeng nakong ea mananeo a mane a ho emisa).

Eya ho:

TŠOHLOA

Phuputso ea morao-rao e bontšitse hore boiphihlelo ba thobalano bo baka ho bokellana ha ΔFosB libakeng tse 'maloa tse amanang le bokong, ho kenyeletsa mantlha ea NAc le khetla, mPFC, VTA le putuden ea caudate. Ntle le moo, boiphihlelo ba thobalano bo bonts'a polelo e susumetsang ea c-Fos ea NAc le ACA. Kamora nako, ΔFosB ho NAc e bonts'itsoe e le ea bohlokoa ho tsamaisanang le ts'ebetso ea ho nyaloa nakong ea ho fumana boiphihlelo ba thobalano le polelo ea nako e telele ea tlholiseho e susumetsang ea boitšoaro ba thobalano.. Haholo-holo, ho fokotsa mongolo oa ΔFosB-mediated o fumaneng boiphihlelo ba ts'usumetso ea ts'usumetso ea thobalano le ts'ebetso, ha polelo ea ΔFosB e feta NAc e bakile ts'ebetso e ntlafalitsoeng ea boitšoaro ba thobalano, mabapi le ts'ebetso e eketsehileng ea thobalano e nang le boiphihlelo bo fokolang. Hammoho, liphetho tsa hona joale li tšehetsa khopolo ea hore hypFosB ke mosireletsi ea bohlokoa oa molek'hule bakeng sa polasetiki ea nako e telele ea neural le ea boits'oaro e susumetsoang ke boiphihlelo ba thobalano.

Liphumano tsa morao-rao li eketsa lithuto tsa pejana tse bonts'ang boiphihlelo ba sexFosB ka hara NAc ka likhoto tsa banna (Wallace et al a. 2008) le likhahla tse tšehali (Li-Hedges et al a. 2009). Wallace et al. (2008) e bonts'a rAAV-ExpressionFosB ea polelo e fetang ea NAc e ntlafalitse boitšoaro ba thobalano le liphoofolo tsa thobalano nakong ea kemiso ea pele ea mating, jwaloka ha ho bonahala ka ho kenella hanyane ka hanyane ho emong le ponts'ong e khuts'oane ka mor'a ho hlaseloa, empa ha ho na phello ho banna ba nang le thobalano (Wallace et al a. 2008).

Ha ho bapisoa, thuto ea hajoale e bontšitse ho se be le litlamorao tsa ho bua ka ΔFosB ka botona ho botona ba botona le botšehali nakong ea teko ea pele, empa haholoholo nakong ea ho latela ho fumana boiphihlelo ba thobalano. Lits'oants'o tse fetang 4 tsa FosB li bonts'itse ts'ebetso e eketsehileng ea thobalano (ts'ebetso e kholo ea ts'ebetso) ha e bapisoa le liphoofolo tsa GFP

Ntle le moo, thuto ea morao-rao e ile ea leka karolo ea ΔFosB ka ho thibela sengoloa sa ΔFosB se mameloang se sebelisa veΔ ea vaerase ea ΔJunD. Thibelo ea keketseho e bakoang ke boiphihlelo ea ΔFosB expression e sitisang ts'usumetso ea takatso ea thobalano.

Kahoo, datha tsena ke tsa pele ho bonts'a karolo e tlamang bakeng sa ΔFosB phihlelong ea ts'usumetso ea ts'usumetso ea boitšoaro ba thobalano. Ntle le moo, datha tsena li bonts'a hore ΔFosB e kenella ka mokhoa o hlakileng puong ea nako e telele ea boits'oaro bo khothalletsoang bo nang le boiphihlelo. Re khothaletsa hore polelo ena ea nako e telele ea boits'oaro e tataisitsoeng e emetse mofuta oa mohopolo bakeng sa moputso oa tlhaho, ka hona ΔFosB ho NAc ke mokena-lipakeng oa mohopolo oa moputso. Boiphihlelo ba thobalano le bona bo ile ba eketsa maemo a ΔFosB ho VTA le mPFC, libaka tse kentsoeng moputsong le mohopolong (Balfour et al a. 2004; Phillips et al a. 2008). Ho hlokahala lithuto tsa nako e tlang ho hlakisa bohlokoa ba -FosB-regulation libakeng tsena bakeng sa mohopolo oa moputso.

Polelo ea ΔFosB e tsitsitse haholo, ka hona e na le monyetla o moholo oa ho ba 'muelli oa limolek'hule tsa liphetoho tse tsoelang pele tsa boko kamora ho lits'isinyeho tse sa foleng (Nestler et al a. 2001). ΔFosB e bontšitsoe hore e eketseha butle butle ho NAc holim'a liente tse ngata tsa koae 'me e phehella ho fihlela libeke tse' maloa (tšepo et al a. 1992; tšepo et al a. 1994). Liphetoho tsena puong ea NAc ΔFosB li amahanngoa le maikutlo le bokhoba ba taolo ea lithethefatsi (Chao le Nestler 2004; McClung le Nestler 2003; McClung et al a. 2004; Nestler 2004, 2005, 2008; Nestler et al a. 2001; Zachariou et al a. 2006). Ha ho bapisoa, karolo ea ΔFosB ho arolelanang moputso oa tlhaho ha e ea pepesoa. Bopaki ba morao-rao bo bontšitse hore ΔFosB induction ea NAc e kenya letsoho moputsong oa tlhaho. Maemo a ΔFosB le 'ona a eketsehile ka tsela e tšoanang ho NAc e latelang ho kenella le ho tsamaisoa ke mabili. Polelo e fetelletseng ea overFosB mokhoeng ona o sebelisang litoeba tsa bitransgenic kapa livaer tsa vaerase likhosong li etsa hore ho be le keketseho ea batho ba jang, tšusumetso e ntlafalitsoeng ea lijo le lebelo la mokokotlo le ntseng le eketseha (Olausson et al a. 2006; Wallace et al a. 2008; Werme et al a. 2002). Lintlha tse teng hona joale li eketsa litlaleho tsena hape li tšehetsa maikutlo a hore ΔFosB ke mokena-lipakeng oa bohlokoa oa ho matlafatsa meputso le memori ea moputso oa tlhaho.

ΔFosB e kanna ea thusa ho matlafatsa boiphihlelo ba boits'oaro ba thobalano ka ho kenyelletsa tšebetso ea polasetiki tsamaisong ea mesolimbic. Ka sebele, boiphihlelo ba thobalano bo baka liphetoho tse ngata tsa nako e telele tsamaisong ea mesolimbic (Bradley & Meisel 2001; Frohmader et al a. 2009; Pitchers et al a. 2010). Amaemong a boits'oaro, karabelo ea locomotor e lemohuoang ho amphetamine le moputso o ntlafalitsoeng oa amphetamine li bonts'itsoe ho likhoto tsa banna ba nang le thobalano (Pitchers et al a. 2010); Karabelo e fetotsoeng ea locomotor ho amphetamine e boetse e bonoe le li-hamsters tsa basali (Bradley & Meisel 2001). Ntle le moo, keketseho ea palo ea methapo ea dendritic le ho rarahana ha marako a dendritic li fumanoe kamora nako ea thobalano le boiphihlelo ba thobalano ho litoeba tsa banna (Pitchers et al a. 2010). Boithuto ba hona joale bo fana ka maikutlo a ΔFosB e ka ba 'muelli oa molek'hule ea liphetho tsa nako e telele tsa boiphihlelo ba thobalano. Ka tumellano, ΔFosB e sa tsoa bontšoa e le ea bohlokoa bakeng sa ho susumetsa liphetoho tsa lesapo la mokokotlo bakeng sa taolo ea ts'ebetso ea cocaine e sa foleng (Dietz et al a. 2009; kolonnenweg et al a. 2010).

Ha ho hlake hore na ke li-neurotransmitter tse hlahelletseng tse ikarabellang ho susumetsa ΔFosB ho NAc, empa DA e reriloe e le mokhethoa (Nye et al a. 1995). Hoo e batlang e le lithethefatsi tsohle tsa tlhekefetso, ho kenyelletsa cocaine, amphetamine, opiate, cannabinoids le ethanol, hammoho le meputso ea tlhaho, e eketsa ΔFosB ho NAc (Perrotti et al a. 2005; Wallace et al a. 2008; Werme et al a. 2002). Ka bobeli lithethefatsi tsa tlhekefetso le meputso ea tlhaho li eketsa khatello ea maikutlo ea DA ho NAc (Damsma et al a. 1992; Hernandez le Hoebel 1988a, b; Jenkins le Becker 2003). UctionFosB e kenyellelitsoeng ke lithethefatsi tsa tlhekefetso e bonts'itsoe ho receptor ea DA e nang le lisele le "cocaine-ikiwa" e koetsoe ke D1 DA receptor antagonist (Nye et al a. 1995). Ka hona, tokollo ea DA e tšerehantsoe ho khothaletsa polelo ea ΔFosB mme ka hona, medioplasticity e amanang le moputso. Ho ts'ehetsa hape mohopolo oa hore maemo a "osFosB a ts'epahalitsoe ke DA ke ho fumana hore libaka tsa boko moo maiphihlelo a thobalano a fetotsoeng ΔFosB a fumanang phetoho e matla ho tsoa ho VTA, ho kenyeletsa medort preortal cortex le amygdala ea basolateral..

Leha ho le joalo, ka lehlakoreng le leng, "osFosB ha e eketsehe sebakeng sa moropele oa maikutlo le hoja sebaka sena se fumana dopaminergic, leha e le ho tsoa mehloling ea hypothalamic (Miller & Lonstein 2009). Lithuto tsa nako e tlang lia hlokahala ho hlahloba hore na polelo ea matFosB e susumetsang motho hore a kopanele liphate le litlamorao tsa ts'ebetso ea thobalano ka tšusumetso ea thobalano le ts'ebetso li its'etleha ketsong ea DA. Karolo eo DA e e etsang moputsong oa thobalano ho likhoto tsa banna hajoale ha e hlakile hantle (Agmo le Berenfeld 1990; Pfaus 2009). Ho na le bopaki bo bongata ba hore DA e lokolloa ho NAc nakong ea ho pepesehela mosali kapa ho nyaloa (Damsma et al a. 1992) le li-neuron tsa DA li butsoe nakong ea boitšoaro ba thobalano (Balfour et al a. 2004). Leha ho le joalo, li-ente tsa systemic tsa DA receptor antagonist ha li thibele ho rata ha moputso oa thobalano.Agmo le Berenfeld 1990) le khopolo-taba ea hore DA e bohlokoa bakeng sa ts'usumetso ea bohlola e sa netefatsoe.

Ha ho hlake hape hore na balateli ba tlase ba litlamorao tsa ΔFosB litabeng tsa boitšoaro ba thobalano. ΔFosB e bontšitsoe hore e sebetsa joaloka mohatisi ea hatisang le ho hatella ka mochine o itšetlehileng oa AP-1 (McClung le Nestler 2003; Peakman et al a. 2003). Ho fumanoe mefuta e mengata ea sepheo ea morero, ho kenyeletsoa mofuta oa c-fos oa pele (tšepo et al a. 1992; tšepo et al a. 1994; Morgan le Curran ka 1989; Renthal et al a. 2008; Zhang et al a. 2006), cdk5 (Bibb et al a. 2001), dynorphin (Zachariou et al a. 2006), sirtuin-1 (Renthal et al a. 2009), NFN ea Subunits (Ang et al a. 2001), And AMPA glutamate receptor GluR2 subunit (Kelz et al a. 1999). Liphetho tsa hona joale li bonts'a hore maemo a c-Fos a neng a hlohlelletsa batho ba bang ka thobalano a fokotsoe ke boiphihlelo ba thobalano libakeng tsa boko ka ΔFosB (NAc le ACA). Ho hatelloa ha c-Fos ho bonahala ho ipapisitse le nako ho tloha nakong ea ho omella le ho pheta-pheta ha nako, joalo ka lithutong tse fetileng, ho fokotseha ho joalo ha c-Fos ha hoa ka ha bonoa ho likhoto tsa banna tse ileng tsa lekoa 1 bekeng kamora seboka sa ho qetela sa ho emola (Balfour et al a. 2004) kapa kamora boiphihlelo ba thobalano e nang le karolo e le 'ngoe feela ea ho ikatisa (Lopez & Ettenberg 2002). Ho feta moo, seo ba se fumanang hona joale se lumellana le bopaki ba hore ΔFosB e hatella mofuta oa c-fos kamora ho pepeseha ho matla hoa amphetamine (Renthal et al a. 2008). Tumellanong le liphumano tsena, ts'ebetso ea li-mRNA tsa pele tsa gene (c-fos, fosB, c-jun, junB, le zif268) e ile ea fokotseha ka mor'a ho entoa ka makhetlo a seng makae ka koae ea lithethefatsi (tšepo et al a. 1992; tšepo et al a. 1994), mme cphe famine ea amphetamine e ile ea hatelloa kamora ho khaotsa ho tsoa ts'ebetsong ea amphetamine (Jaber et al a. 1995; Renthal et al a. 2008). Kameho e sebetsang ea taolo e tlase ea polelo ea c-Fos kamora kalafo e sa foleng ea lithethefatsi kapa boiphihlelo ba thobalano e lula e sa hlaka, mme ho fanoe ka tlhahiso ea hore ke mokhoa oa bohlokoa oa homeostatic oa ho laola maikutlo a phoofolo ho pepesehela moputso khafetsa (Renthal et al a. 2008).

Qetellong, thuto ea morao-rao e bonts'a hore ΔFosB ea NAc e bapala karolo ea bohlokoa mohopolong oa moputso oa thobalano, e ts'ehetsang monyetla oa hore osFosB e bohlokoa bakeng sa ts'ebetso ea moputso o akaretsang. Liphumano tse tsoang liphuputsong tsa morao-rao li totobatsa kutloisiso ea rona ea mekhoa ea lisele le ea limolek'hule tse arabelang moputso oa thobalano le tlhotlheletso, mme li eketsa ho sengolo sa lingoliloeng tse bonts'ang hore ΔFosB ke sebapali sa bohlokoa ntlafatsong ea bokhoba ba tahi, ka ho bonts'a karolo ea ΔFosB moputsong oa tlhaho Matlafatso.

Eya ho:

Boitsebiso bo Eketsehileng

Fana ka feiga S1-S4 & Tafole S1-S2

Eya ho:

Liteboho

Patlisiso ena e ne e tšehelitsoe ke lithuso ho tsoa ho Canadian Institutes of Health Research to LMC, National Institute of Mental Health ho EJN, le Litsebi tsa Saense tsa Tlhaho le Boenjiniere ba Canada ho ea KKP le LMC.

Eya ho:

LITLHAHISO

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