O le Faʻasologa o le Cortical Circuit mo le Faʻavaivai- ma Faʻafitauli Faʻapitoa E faʻasalalau e le Cholecystokinin: Matafaioi a le ΔFosB (2014)

lē faʻatino

O le faʻaitiitia o le medial frontfront cortex (neuronal activity) e fesoʻotaʻi ma le faʻalavelave faʻaleagafesoʻotaʻi le faʻavaivai-ma le popole-pei o amioga i le maunu. Ae ui i lea, o le mole mole masini e faavae ai le faʻaitiitiga o le mPFC ma lona taʻutaʻua o le tiute e le o iloa. Matou te faʻaali atu iinei o le faʻaliliuina o le numera o le transaction ΔFosB i le mPFC, aemaise lava i le vaega muamua (PrL), o le aufaasālalau e mafai ona faʻalavelaveina. O le atinaʻe o le ΔFosB i le PrL na faia ma le filifilia i ni mice matagofie pe a maeʻa ona faʻavaivaia le faʻaleagaina o le agavaʻa, ma le faʻailoaina o le ΔFosB i lenei eria, ae le o totonu o le infralimbic (IL) lata ane, faʻateleina le faʻalavelave mamafa. O le ΔFosB na faʻapenaina nei aʻafiaga e ala i le faʻaaogaina o le cholecystokinin (CCK) -B le faʻataʻitaʻiga: CCKB poloka i le mPFC e faʻaosofia ai se faʻapitoa faʻapitoa, ae o le pulega a le CCK i le mPFC e aʻafia ai popolega popolega-pei o faʻalavelave faʻalavelave faʻafitauli. Na matou maua i le taimi muamua o le faaosofia o le optogenetic o neo mPFC i mice matagofie e fesuiai ai le tele o mea e le masani ai na vaaia ina ua mavae le faʻalavelave faʻaletonu masani. O le mea lea, matou te manatu o le faaosofia o le optogenetic o faʻataʻitaʻiga faʻapitoa o le a laveaʻi ai aʻafiaga o le CCK i le mPFC. A maeʻa le CCK i le mPFC, matou te osofaʻia ma le faʻamalosia i le mPFC projections i le amygdala mataʻutia poʻo le nucleus accumbens, e lua ni faʻavae faʻavae e aofia i tulafono faatonutonu. O le faʻamalosia o faʻataʻitaʻiga corticoamygdala na taofia ai le popolega o le CCK, e ui lava e leai se aafiaga na matauina i isi faailoga o le faʻatoʻilaloina o tagata. I le isi itu, o le faʻaosofia o faʻataʻitaʻiga corticoaccumbens na faʻafitia ai le CCK-faʻaaogaina le aloese mai le vafealoaloai ma le faʻasolosolo o mea e le fiafia i ai ae leai ni faʻalavelave popole. Faʻatasi, o nei faʻaiʻuga o loʻo faʻaalia ai o faʻafitauli faʻaletonu o amioga faʻaagafesootai o loʻo faʻatalanoaina i se vaega e ala i fetuunaiga mole mole i le mPFC e aofia ai le ΔFosB ma le CCK e ala i faʻataʻitaʻiga faʻasolosolo e vaʻaia ai le pito i lalo.s.

uputatala: faʻanoanoa, amygdala, popolega, CCK, atuatuvale, mPFC

faʻatomuaga

O le tele o vaega o le faiʻai limbic e fesoʻotaʻi ma fesoʻotaʻi, e aofia ai le medial prefrontal cortex (mPFC), hippocampus, amygdala, ma le nucleus accumbens (NAc), o loʻo aʻafia i le faʻatalanoaina o faʻamaoniga autu o le atuatuvale ma le popole.; ; ; ; , ; ; ). Mo se faʻataʻitaʻiga, o le leai o ni faʻamatalaga faʻapitoa i le amygdala e fesoʻotaʻi ma lagona dysphoric ma toe foʻi i tulaga masani pe a manuia togafitiga. O aʻafiaga faʻamaʻi o le faʻaosofia o le faiʻai loloto o le cingulate cortex subgenual, o se vaega o le mPFC, e fesoʻotaʻi ma le toe faʻaleleia o gaioiga uma o le faiʻai ma le faʻasolosolo i tulaga masani (; ). E faʻapea foʻi, o le loloto o le faiʻai faʻaosofia o le NAc o le antidepressant ma le popole ma fesoʻotaʻi ma le suia o le metabolism i le NAc, amygdala, ma le mPFC (; ; ). O nei faʻamatalaga e lagolagoina ai le manatu o fesoʻotaʻiga neural o faʻafitauli o le mafaufau lea e togafitia ai togafitiga faʻamaʻi, e tusa lava po o le a le masini, faʻapenaina le gaioiga i le le atoatoa o le cortical ma le overactive subcortical circuits (; ; ; ; ; ).

O faʻataʻitaʻiga manu e aofia ai le faʻaalia faifaipea i faʻalavelave faʻaletino poʻo le mafaufau e faʻaleagaina ai le fausaga ma le gaioiga o neu i le mPFC (), amygdala (), hippocampus (), ma le NAc (; ). Fa'atiga fa'aletonu fa'aagafesootai, o se fa'ata'ita'iga fa'ale-aganu'u o le atuatuvale (), faʻaitiitia le gaioiga o le neuronal mPFC e pei ona faʻaalia mai le faʻaitiitia o faʻamatalaga o Zif268 ma c-Fos (; ). E le gata i lea, o le optogenetic stimulation o le mPFC e suia ai nei faaletonu ma faʻaalia ai aʻafiaga e pei o le antidepressant (), faʻamaonia le taua o le mPFC i faʻalavelave faʻapitoa. To ia rodent mPFC, e pei o primates, pulea amioga faʻalagona i se vaega e ala i faʻataʻitaʻiga i le amygdala basolateral (BLA) ma le NAc (; ; ). Ae ui i lea, o masini molioo e faʻatalanoaina lenei matafaioi a le mPFC e le o iloa.

O le suʻesuʻega o loʻo i ai nei na taulaʻi muamua ile ΔFosB, o se faʻamaumauga mautu o loʻo faʻaosoina ile NAc e ala ile faʻalavelave faʻalavelave faʻaagafesootai masani pe a faʻafeagai ma faʻafitauli faʻafitauli. (). Na matou faia le faʻafanua lautele o le faiʻai o le ΔFosB induction ina ua maeʻa le faʻavaivai ma maua, tutusa ma suʻesuʻega muamua (; ; ), fa'aoso malosi i le mPFC. O le mea e ofo ai, na matou iloa ai o le ΔFosB induction i le mPFC e faʻateleina ai le faʻafitauli. Na matou faʻaalia le cholecystokinin (CCK) -B o se faʻamoemoega mole mole o le ΔFosB i le mPFC, lea na aʻafia ai le neurotransmission CCKergic i aʻafiaga uma e lua o le atuatuvale ma le faʻalavelave o faʻalavelave lautele (, ). Na matou iloa o le CCK galuega i le mPFC e talafeagai uma ma talafeagai mo popolega-ma le faʻavaivai-pei o aʻafiaga o popolega lautele. E le gata i lea, e ala i le faʻaaogaina o optogenetic approaches, matou te faʻaalia ai faʻataʻitaʻiga patino a le CCK i subcircuits mPFC: CCK i faʻataʻitaʻiga mPFC-BLA e faʻafetaui faʻamaoniga popolega, ao CCK i mPFC-NAc faʻatalanoaina faʻamaoniga o le atuatuvale.

Mea ma Metotia

Faʻataʻitaʻiga 1: faʻafanua-lautele ole faiʻai ole ΔFosB induction e ala ile faʻalavelave faʻalavelave faʻaagafesootai masani.

E valu vaiaso le matua C57BL/6J tama'i isumu na feagai ma fa'alavelave fa'aletonu fa'aagafesootai mo 10 aso soso'o e pei ona fa'amatalaina muamua (; ; ) (tagai Laulau 1; Mati. 1A). I le faapuupuuga, o faʻaoga taitasi na faʻaalia i se tamaititi e le masani ai, o le CD1 male faifaatoaga faʻatoʻaga mo le 5 min i le aso. Ina ua maeʻa le fegalegaleaiga ma le CD1 aggressor (5 min), sa tuu manu i se vaega lata ane o le fale e tasi mo le 24 i le isi X ma le lagona, ae le o le tino, faafesootai. O manu faʻataʻitaʻi na tuʻuina i totonu o vaʻa tutusa ae o loʻo i ai sui o le faafitauli e tasi. Sa faia faʻataʻitaʻiga fegalegaleaiga faʻasalalau 24 h i le maeʻa ai o le aso mulimuli o le faatoilaloina. O le aloese mai le vafealoaloai i se CD1 e le masani ai male kiore sa iloiloina e tusa ai ma faʻasalalauga lolomiina. O le taimi na faʻaalu i le "fefaʻasoaʻiga" (o le 8-cm-lautele le taʻamilosaga o loʻo siomia ai le fale) na fuaina. O le vavaeina o mailei ua paʻu i totonu o le faʻaaogaina o le pitonuʻu ma le faʻamalosia o le tino na faia e pei ona faʻamatalaina muamua (; ). Talu ai o le tele o isumu faʻataʻitaʻiga faʻaaluina tele taimi fegalegaleai ma le agafesootai sini nai lo le gaogao tapulaʻa faʻatulagaina, o le fesuiaʻiga o fua faʻatusatusa o le 100 (tutusa taimi faʻaalu i totonu o le sone faʻafesoʻotaʻiga i le i ai vs leai o se agafesootaʻi sini) o loʻo avea o se cutoff: isumu ma togi <100 ua faʻaigoaina o le "susceptible," ma i latou ma togi ≥100 o "resilient." O le lautele o amioga, biochemical, ma le electrophysiological auiliiliga lagolagoina le aoga o nei eseʻese susceptible ma resilient subpopulation (; ; ).

Laulau 1.  

Fuainumera numera (± SEM) o le FosB-nuclei faʻamalosi mo le m2 i vaega ole fai'ai e pulea, ma'ale'ale, ma maunu 24 itula pe a mae'a fa'ama'i (10 d) fa'alavelave fa'aagafesootai.
Ata 1.  

O le amatalia o le ΔFosB i le mPFC e faʻalauiloaina ai le gasegase i le atuatuvale. A, Photomicrographs sui o le ΔFosB immunohistochemistry i le mPFC 24 h ina ua maeʻa le 10 faʻalavelave faʻale-agafesootai. B, E le tupu i le GABAergic le faʻaogaina o le ΔFosB ...

I le mae'a ai o le su'ega o fegalegaleaiga fa'aagafesootai, na fa'amama le isumu ma fa'ainu i totonu ole fatu ile 4% paraformaldehyde/PBS. Tau sela mo le ΔFosB+ neurons i le NAc na faia e pei ona faʻamatalaina muamua (). O Brains na tagi i le 30% sucrose ma vaega o le coronal (30 μm) na tipiina i luga o se masini vailaau malulu ma gaosia mo le immunohistochemistry. O vaega faʻavalea-fuʻa na faʻapipiʻi i totonu o se pusa pa puipui o loʻo aofia ai le 0.3% Triton ma le 3% faʻamaʻo masani. Na maua le ΔFosB i le faʻaaogaina o anticorps rabbit polyclonal e faasaga i le vaega N-muta o le polotini (1 / 1000 Santa Cruz Biotechnology, catalogue # sc-48) i le lava malutaga, ona togafitia lea i le biotinylated goat anti-rabbit IgG antibodies and avidin-biotin faʻalavelave faʻapitoa peroxidase ma le DAB e fai ma sui (Vector Laboratories). O taimi faʻasili o le Diaminobenzidine sa faʻaauau ona tumau mo tulaga uma (100 s). O fasi fasi laau sa faapipiiina, faamalolo, ma ufiufi. O vailaʻau ΔFosB-immunopositive na faʻaalia ai se mea lanu enaena mafiafia i totonu o le maota ma sa faʻatusatusaina e se tagata tauaso tauaso i tulaga togafitiga e faʻaaoga ai se microscope (20 × magnification). O vaega filifilia o le faiʻai na filifilia i vaega taitasi o le faiʻai na filifilia i le mouse mo le faʻatusatusaga. O le vavaega faʻaanatura o vaega o faiʻai taitasi na faia e ala i le faʻatusatusaina o le vaega faʻatasi ma paʻu o le faiʻai o le pause Paxinos. O tuutuuga mo le immunohistochemistry na faʻamoemoeina e faʻaitiitia ai tulaga lautele i le pito i lalo e mafai ai ona saʻo le faʻamaonia o sene ΔFosB-positive. O fuainumera taua na fuafuaina mo manu taʻitasi ma ua faʻamauina o se tagata suʻesuʻe tasi mo suʻesuʻega fuainumera. E ui o le antibody faaaoga e amanaʻia uma le ΔFosB ma le FosB atoa, ae matou te iloa i le Western Western blotting e naʻo le ΔFosB e mafai ona iloa i lalo ole tulaga suʻesuʻeina (; ).

Faʻataʻitaʻiga 2: faʻamaoniga o faʻalavelave faʻaagafesootai-faʻaosoina ΔFosB neuronal phenotype i le mPFC.

Ina ia suʻesuʻeina le faʻaaliga o le ΔFosB i cortical GABAergic neurons, matou te faʻaogaina masini mai GAD2-tdTomato mice faʻaalia i le faʻalavelave faʻaleagaina lautele ma pisia mo le ΔFosB e pei ona faamatalaina i luga (vaai Mati. 1B). Na fa'atupuina isumu e ala i le fa'atupuina o isumu tu'itu'i GAD2-Cre (Gad2tm2(cre)Zjh/J; numera fa'atau JAX 010802) () fa'atasi ai ma le (B6.Cg-Gt(ROSA)26Sortm9(CAG-tdTomato)Hze/J; numera fa'asoa JAX 007908) o lo'o tauaveina le tdTomato pulea fa'afefete-stop (RFP variant).

Faʻataʻitaʻiga 3: aʻafiaga o amioga a le ΔFosB overexpression i le prelimbic (PrL) ma le infralimbic (IL) cortex.

Sa faia le taotoga i luga o tamaʻitaʻi matutua (8 vaiaso) e aʻafia ai le HSV-ΔFosB-GFP poʻo le HSV-GFP i le vaega PrL poʻo IL o le mPFC. I le faapuupuuga, o mice na faʻaaogaina e faʻaaoga ai le paluga o le ketamine (10 mg / kg) ma le xylazine (1 mg / kg), ma le faʻamaopoopoina o mea nei mo le faʻataʻitaʻiga voli mo le PrL: 1.8 mm (pito / tua), 0.65 mm (taala ), -2.2 mm (faʻasalaga / vaʻaia); ma mo le IL: 1.9 mm (pito / tua), 0.75 mm (lautele), -2.8 mm (pito i tua / alamaʻe) i le tulimanu o le 10 ° mai le midline (e faatatau i le bregma). O le 0.5 μl o le siama faʻamamaina sa faʻapitoaina i luga o se vaitaimi 5 min (0.1 μl / min) sosoo ai ma 5 min o malologa. Ua faʻamautuina nofoaga o inisiua faʻamaonia e faʻaaogaina ai metotia faʻasolopito (standard) Mati. 1C). E ui lava e le mafai ona filifili filifilia le PrL versus IL i isumu ma le saʻo atoatoa, o faʻamaumauga i totonu. Ata 1C fa'ailoa mai e matua'i mafai lava ona fa'ato'a fa'atatau i le tasi itulagi po'o le isi. O le mea moni, o a'afiaga uiga ese'ese na maua mai le fa'atatauina o itulagi e lua (silasila I'uga) e fa'amaonia ai lenei faiga. O le vaega muamua o isumu na faʻaaogaina faʻapitoa i se faʻataʻitaʻiga faʻaleagaina lautele (vaai Mati. 1D). E tolu aso talu ona uma le taotoga, na faʻaleagaina ai isumu i le aso e tasi ona faʻataʻitaʻiina lea mo fegalegaleaiga lautele 24 h mulimuli ane. O lenei faiga fa'ato'ilaloina fa'ato'ilalo na fa'amaonia muamua e fa'aalia ai fa'afitauli fa'apitoa e fa'atatau i le fa'ata'ita'iina o kenera (; ).

O le vaega lona lua o isumu na faʻaaogaina e suʻe ai le popole-ma le faʻanoanoa-pei o amioga (vaai Mati. 1E-I). I se aso talu ona uma le taotoga, sa masani ona faʻaaogaina fuamoa i le 1% (w / v) le fofose solution. O le aso e sosoo ai, e mafai ai e filifili ona filifili i le va o se fagu vai ma se 1% sucrose solution fagu, e faʻaaogaina i aso uma. Suʻesuʻega fofo mo le 24 h sa fuaina i le aso lona fa ma le lima talu le taotoga ma faʻamatalaina o se pasene o le aofaiga atoa o le faʻamalosia o le suavai. O masini na tofotofoina i le malae vaalele (aso 3), faʻalauteleina ma pasese (aso 4), fegalegaleaiga faʻaagafesoʻotaʻi (aso 5 taeao), ma faʻamalosia le taʻele (aso 5 aoauli) faʻataʻitaʻiga e faavae i luga o faʻasalalauga faʻasalalau (). Ua matou iloa, faatasi ai ma lenei faasologa o suʻega, o faʻaiʻuga i suʻega mulimuli ane e le afaina i suʻega muamua (). O le gaioiga a mio i luga o le avanoa na tusia mo le 5 min e faʻaaogaina ai se masini vitiō (Ethovision) i lalo o le lanu lanumumu. O le maualuga o le paso e aofia ai laina tuusao saʻo e lua e faʻatutu ai le 60 cm i luga ae o le fola ma vaevaeina i ni lua tatala ma lua lima o loʻo fusia. O tamaʻi taʻitasi na tuʻuina i le ogatotonu o le paso ma mafai ai ona suʻesuʻe saoloto i lima taʻitasi mo se vaitaimi o 5 min. I totonu o le malae vaʻavaʻai ma faʻateleina faʻasolosolo faʻataʻitaʻiga, taimi na faʻaaluina i le ogatotonu ma faʻalautele lima, taʻitasi, na faʻaaogaina e avea o se faasologa o le faʻaogaina o tali tali atu. O se tasi aso na faʻamalosia ai le suʻega aau i le vaitau o 5 min. Faʻateleina le taimi o le le faʻamaoni i le taimi o le suʻeina o le aau e faʻamatalaina o se amio faʻapope-pei o amio. O lenei suega o le 1 i le tele o taimi na faʻaaogaina i mumini ma faʻamaonia e avea ma fuataga o le faʻataʻitaʻiga, i le faʻaaogaina o fualaau faʻasaina e faʻaitiitia ai taimi le tumau.

Mulimuli ane, o se isi vaega o isumu na tui i totonu-mOFC ma le HSV-ΔFosB ma faʻataʻitaʻiina mo fegalegaleaiga faʻaagafesootai ina ua maeʻa le toilalo (vaai Mati. 1K).

HSV vectors na maua mai ia Rachael Neve (Massachusetts Institute of Technology). O kenera o tului (ΔFosB ma le GFP) o loʻo i lalo o le CMV faʻalauiloa. O nei vectors ua matua fa'amaonia i lomiga muamua (fa'ata'ita'iga, ).

Faʻataʻitaʻiina le 4: aʻafiaga o faʻasalaga faʻasalalau masani ile CCKB laʻasaga i le mPFC.

I le 24 itula talu ona maeʻa le suʻega fegalegaleaiga faʻaagafesootai, na vave ona aveese le faiʻai ma tipi faʻasolosolo, ma faʻavave le mPFC ma faʻamaʻaisa i luga o le aisa matutu (vaai Mati. 2A,B). RNA iso, qPCR, ma suʻesuʻega faʻamaumauga na faia e pei ona faʻamatalaina muamua (; ). Na vavae ese le RNA i le Trizol reagent (Invitrogen) ma sa faʻamamaina atili i kuki RNAeasy mai QIAGEN. O faʻataʻitaʻiga RNA uma sa faʻamoemoe e maua le 260 / 280 ma le 260 / 230 i le ≥1.8. Faʻaaogaina faʻamatalaga e faʻaaoga ai le iScript (Bio-Rad). qPCR e faʻaaoga ai le SYBR Green (Quanta) na faʻatinoina i le faʻaaogaina o le 7900HT RT PCR system Applied Biosystems 2HT ma le faasologa o taamilosaga nei: 95 min i 40 ° C; 95 tau o 15 ° C mo 59 s, 30 ° C mo 72 s, ma le 33 ° C mo 95 s; ma faʻamafanafanaina le afi i le XNUMX ° C e faʻavaeina ai pupuni mo le faʻamaoniga o mea PCR e tasi. Na suʻesuʻeina faʻamatalaga i le faʻatusatusaina o le Ct tulaga taua o le togafitiga (mafatia pe maufetu vs pulea isumu, poʻo HSV-ΔFosB vs HSV-GFP) ma le ΔΔCt auala (). qPCR primers e fa'apea: ΔFosB, luma, AGGCAGAGCTGGAGTCGGAGAT ma tua, GCCGAGGACTTGAACTTCACTCG; CCKB, i luma, ACCCTTTATGCGGTGATCTTTC ma tua, ATGACACGTTTCCGCCAA; CCK, i luma, AGCGCGATACATCCAGCAG ma tua, ACGATGGGTATTCGTAGTCCTC; GAPDH, i luma, AGGTCGGTGAACGGATTTG ma tua, TGTAGACCATGTAGTTGAGGTCA.

Ata 2.  

Pupuni o le CCKB receptor ua i ai se tulaga agavaʻa, aʻafiaga o aʻafiaga. A, Fa'aletonu fa'aagafesootai e fa'aitiitia ai le maualuga o le taliaina o le CCKB i le mPFC na'o isumu maufetu'i (n = 8-10). *p <0.05, faʻatusatusa i le faʻatonutonu (one-way ANOVA). **p <0.05 ...
Faʻamatalaga 5: aʻafiaga o le ΔFosB i le CCKB receptor ma le maualuga o le CFos.

O isumu na tui i totonu-PrL ma le HSV-ΔFosB. I le 72 itula i le maeʻa ai o le taotoga, i le pito i luga o le viral overexpression, o nofoaga o tui na vaevaeina i lalo o le microscope fluorescent (silasila i Mati. 2C). RNA vavaeeseina, qPCR, ma faʻamaumauga faʻamaumauga na faia e pei ona faʻamatalaina i luga. qPCR primers e fa'apea: c-fos, luma, AATCCGAAGGAACGGAATAAGA ma tua, TGCAACGCAGACTTCTCATCT.

Faʻataʻitaʻiga 6: aʻafiaga o le poloka ΔFosB i luga ole faʻalavelave faʻafefe CCKB maualuga maualuga ma le maufetuunaʻi.

Iʻamea matutua matutua na faʻasolosolo faʻatasi ma le HSV-GFP poʻo le HSV-ΔJunD i le PrL (vaai Mati. 2D-F). ΔJunD o se tasi o le sui ole N-termina o le JunD o loʻo galue e avea o se taʻaloga malosi-le faʻaleagaina o le ΔFosB. Na faalua faalua ona fausiaina tamaʻitaʻi i le faaluaina i le aso mo 5 d. O lenei faʻagasologa faʻavavega o agavaʻa faʻale-agafesootai, faʻapuupuu e fetaui ma le vaitaimi o le maualuga o le HSV transgene expression, sa faʻaaogaina muamua ma faʻaalia ai le faʻaaogaina o tulaga maualuga o le aloese mai le vafealoaloai (). I le 24 itula i le maeʻa ai o le faʻamamafaina o le tino, na tipiina ai isumu e aunoa ma se vai faagase e aloese ai mai aafiaga o vailaʻau i luga o le neuronal protein. Na aveʻesea mea na pisia i le PBS-o loʻo iai protease (Roche) ma le phosphatase (Sigma-Aldrich) faʻapipiʻi le faʻaaogaina o le 15 fua o le tui ma faʻavaʻa loa ile aisa mago. Faʻataʻitaʻiga na homogenized e le malamalama sonication i fesuiaʻiga RIPA buffer: 10 mm Tris faʻavae, 150 mm sodium chloride, 1 mm EDTA, 0.1% SDS, 1% Triton X-100, 1% sodium deoxycholate, pH 7.4, ma protease ma phosphatase inhibitors pei i luga Ina ua maeʻa ona faʻaopopoina le buffer a Laemmli, o proteins na tuʻu eseʻese i le 4-15% polyacrylamaide gradient gels (Criterion System; Bio-Rad), ma Western blotting na faʻatinoina le faʻaaogaina o le Odyssey system (Li-Cor) e tusa ai ma tulafono faʻavae a le kamupani gaosi oloa. Na faʻamaʻaina le Membranes ile CCKB receptor antibody (1/1000, Acris, lisi # AP01421PU-N). O leisi vaega o isumu na tuiina i le AAV-ΔJunD poʻo le AAV-GFP i le PrL ma, 5 vaiaso talu ona maeʻa le taotoga e faʻataga ai le faʻateleina o transgene expression, na tuʻuina atu ia isumu i le submaximal toilalo maliega. Na tofotofoina i latou mo fegalegaleaiga lautele 24 itula ina ua maeʻa le faiaina mulimuli.

Faʻataʻitaʻiga 7: aʻafiaga o le intra-mPFC CI-988, o se CCKB faʻafeagai, i luga o faʻalavelave faʻaagafesootai-faʻaoso faʻaagafesootai aloese ma anhedonia.

Bilateral cannula (1.0 mm cannula i cannula mamao, 1.8 mm i luma, injector -2.2 mm dorsal / ventral) faʻatatau i le mPFC na totoina i isumu maʻaleʻale (vaai Mati. 2G,H). I le vaiaso talu ona faia le taotoga, na faʻaoga saʻo ai le 10 ng o CI-988 i le mPFC, faʻamuamua le PrL. Ona tofotofoina lea o masini mo a latou amioga fegalegaleaiga lautele. O le mea e sili ona fiafia i ai na fuaina mo le 24 o loʻo totoe. CI-988 (Tocris Bioscience) na faʻamaʻapeina i le saline, faʻaaogaina, ma tio. O le faʻasalaga mulimuli na saunia i le aso o le suʻega. O se isi suesuega na faia i ni mice mamaʻi ma le CI-988 o loʻo faʻatonuina i le initaneti (2 mg / kg) 30 min ao leʻi faia le suʻega faʻasalalauga lautele.

Faʻataʻitaʻiga 8: aʻafiaga o le CCKB agonist i luga o le faʻafefe i le faʻalavelave faʻaagafesootai ma le fesuiaʻiina e ala i le faʻaosofia o le optogenetic o faʻataʻitaʻiga mPFC i le BLA poʻo le NAc.

AAV-CaMKII-ChR2-EYFP poʻo AAV-CaMKII-EYFP na tui i totonu o le mPFC saʻo, toe faʻatatau i le PrL (vaai Mati. 3A-G). I le lima vaiaso mulimuli ane, na totoina ai filo filo i le taumatau NAc (1.4 tua / pito i tua, 2.6 pito i tua, -4.7 i tua o le 25 ° mai le laina ogatotonu) poʻo BLA (-1.6 tua / tua, 3.1 laupepa, -4.7 tua / faʻasalalauga e aunoa ma se laina mai le ogatotonu). I le taotoga lava lea e tasi, na totoina ai le cannula lua i le mPFC (silasila i luga). Sa faʻamautuina Cannulae ma fipa i le ulupoʻo ma le sima. Ona faatagaina ai lea o masini i le 1 vaiaso e toe faʻaleleia ao leʻi amataina le suʻesuʻeina o amioga. Na toesea le maso i lalo, ona tofotofoina lea o le 24 mulimuli ane mo fegalegaleaiga faaagafesootai, na sosoo ai ma le maualuga ma le masini ma mo le sologa manuia o le 24 h. I le 30 min ao le i faia le suʻega faʻafefegaleaiga faʻafeusuaiga, o le afa o muse sa faʻaogaina i le CCK-8 (10 ng) i le mPFC ae o le isi afa na maua le taavale (saline). O suʻe na tofotofoina i paiga (o se taavale-ma se kosi CCK-8, ma AAV-GFP poʻo AAV-ChR2). CCK-8 (Sigma) na faʻamaʻapeina i le saline, faʻaaogaina, ma le malulu. O le faʻasalaga mulimuli na saunia le aso o le suʻega.

Ata 3.  

E mafai e le CCK-8 ona faʻamalosia le faʻaogaina o aʻafiaga i luga o faʻalavelave faʻapitoa. A, I le 24 h i le maeʻa ai o le toilalo faʻaagafesootai ma le 30 min ina ua maeʻa le CCK-8 infusion, o le mPFC projection regions na faʻamalosia le laser i le taimi o se suʻega mo fegalegaleaiga faʻaagafesootai. CCK-8 tui ...

O faʻataʻitaʻiga faʻapitoa sa faia e tusa ai ma faʻamaumauga tusitusia (). O le tele o laupepa (Thor Laboratories) na faʻapipiʻi ma faʻafesoʻotaʻi e ala i le FC / PC i le 473 nm laser diode (Crystal Lasers, BCL-473-050-M). O se stimulator (Agilent, #33220A) na faʻaaogaina e gaosia ai pulupulu lanumoana. I taimi uma na osofaia ai, 40 ms burst of 100 Hz (9.9 ms sosolo lautele) o pulupulu lanumoana lanumoana na tuʻuina atu i 3 s i vaega taʻutaʻu i BLA poʻo le NAc le umi o le suʻesuʻega fegalegaleaiga faʻaagafesootai, na o le faʻaaogaina o se mamanu faʻapitoa o le faʻaoga gaoioiga. Na faʻamaonia le malosi o le malamalama filo i luma o le faʻaaogaina, faʻaaogaina o se malamalama malamalama (Thor Laboratories, S130A), ma o le malosi o le eletise o le --15 mW. O lenei faiga faʻaosofia, lea na aloaia ai le electrophysiologically previously (), e leʻi faʻaosoina le faoa faamalosi e faʻavae i luga o faʻataʻitaʻiga o amioga ma le leai o se faʻamatalaga c-Fos i fafo atu o itulagi faʻaosofia optogenetically ().

Fa'ata'ita'iga 9: a'afiaga ole CCKB agonist ile mPFC neuronal gaioiga e pei ona fua ile c-Fos mRNA maualuga.

O le cannulae faʻapitoa na totoina i luga o tamaʻi matutua e faʻatatau i le mPFC (silasila Mati. 3H). Ina ua maeʻa le vaiaso malolo, o isumu na paʻu i lalo o le toilalo ma faʻapipiʻi i le CCK-8 24 itula mulimuli ane. mPFC punches na ave i le 30 min ina ua maeʻa le vailaʻau faʻasaina, ma faʻataʻitaʻiga saunia mo suʻesuʻega mRNA e pei ona faʻamatalaina i luga.

Fale o manu.

E valu vaiaso le matua C57BL/6J male isumu (The Jackson Laboratory) sa fa'aaogaina. O isumu uma na masani i le fale manu mo le itiiti ifo i le 1 vaiaso aʻo leʻi faia faʻataʻitaʻiga faʻataʻitaʻiga ma tausia i le 23 ° C-25 ° C i luga o le 12 h malamalama / pogisa (moila i le 7:00 AM) ma ad libitum avanoa i meaai ma vai. O faʻataʻitaʻiga na faia e tusa ai ma taʻiala a le Sosaiete mo Neuroscience ma le Komiti Faʻatonu Faʻatonu ma Faʻaaogaina Manu i le Icahn School of Medicine i le Mauga o Sinai.

Suʻesuʻega faʻamaumauga.

O faʻamaumauga o loʻo faʻaalia e pei o le ± SEM (o loʻo faʻatusalia o faʻamaumau sese). O se tasi o auala ANOVA na faʻaaogaina e faʻatusatusa ai le uiga o le puleaina, faʻafeiloaʻi, ma le faʻamalosia o niusi i totonu o le toto o meaola, mea oona, ma iloiloga o amioga. E tasi le auala ANOVA na faʻaaogaina e faʻatusatusa ai auala i le va o GFP-control ma le ΔFosB faʻamatalaga manino i le PrL poʻo le IL i totonu o le avanoa, faʻalautele ma le pasene, faʻamalosia o le aau, ma suʻega sili ona fiafia. O auala e lua auala o le ANOVA na faʻaaogaina e faʻatusatusa ai auala i le va o GFP-control, ΔFosB-PrL, ma le ΔFosB-IL i le suʻega faʻasalalauga lautele. O auala e lua ala o le ANOVA na faʻaaogaina e faʻatusatusaina ai le CCK-8 i le i ai poʻo le leai foi o le faʻamalosia o le optogenetic i faʻataʻitaʻiga uma o amio, faʻapea foʻi le aʻafiaga o le ΔFosB overexpression poʻo le CI-988 infusion i le aloese o tagata. A talafeagai, faʻailoga iloiloga sa faia e faʻaaoga ai le Bonferroni faʻailoga tofotofoga Tamaiti aʻoga t suʻega na faʻaaogaina e faʻatusatusa ai auala mo le aʻafiaga o le CI-988 infusion i luga o le sucrose ma suʻega faʻamalosi aau, ma le CCK-8 i luga c-Fos MRNA laʻasaga. O eseesega i le va o faʻataʻitaʻiga na faʻamoemoeina e faʻapitoa i fuainumera p ≤ 0.05.

i'uga

Fa'afanua-lautele fa'afanua o le ΔFosB induction e ala i fa'alavelave fa'ale-agafesootai masani

Na matou suʻesuʻeina muamua le ΔFosB induction e le immunohistochemistry i le pulea, faʻafeiloaʻi, ma le toe faʻaaogaina o musele, pe a maeʻa le agavaʻa (10 d) agavaʻa faʻaleagaina, faʻatasi ai ma le taulai atu i le forebrain ma le ogatotonu o le ogatotonu o loʻo aʻafia muamua i tali faʻafitauli. Na suʻesuʻeina e manuʻa 24 h i le maeʻa ai o le mea na tupu. Faʻalavelave faʻalavelave faʻalavelave e aʻafia ai le ΔFosB i le tele o vaega o faiʻai ma mamanu mamanu e vaʻaia i le va o mūmalie ma faʻafeiloaʻi. E pei ona faʻaalia i Laulau 1 ma Ata 1A, IL, BLA, gyrus dentate o le hippocampus, dorsal striatum, ma le NAc autu na faʻaalia ai le faʻaosoina faʻapitoa i isumu faʻamalosi; o ia taunuuga i le NAc e ogatasi ma suʻesuʻega faʻasalalau (). I le tulaga ese, o isumu maaleale na faʻaalia le tele o le faʻaogaina i le PrL, septum lateral, ma le moega o le stria terminalis. E tele vaega o faiʻai na faʻaalia ai le faʻatusatusaina o le ΔFosB induction i isumu maʻaleʻale ma faʻamalosi; o nei mea e aofia ai orbitofrontal cortex (OFC, isi vaega o le PFC), NAc shell, dorsal raphé, ma periaqueducal gray (PAG).

Ina ia iloa le subtype neuronal o loʻo faʻaalia ai le ΔFosB induction i totonu o le cortical regions, GAD2-tdTomato mice na aʻafia i faʻalavelave faʻalavelave faʻaagafesootai. ΔFosB immunoreactivity i isumu faigofie e le mafai ona iloa i GABAergic neurons (Mati. 1B), lea e faʻamaonia ai suʻesuʻega muamua o le faʻaogaina patino o le ΔFosB i cortical pyramidal neurons pe a maeʻa isi ituaiga o faʻamaʻi masani (). I nai mailei e le faʻaaogaina, laina faavae ΔFosB maualuga i vaega o faiʻai e tutusa ma na lipotia i suʻesuʻega muamua (, ) faʻatasi ai ma maualuga maualuga maualuga i le NAc ma le dorsal striatum pe a faʻatusatusa i soʻo se isi itulagi, seʻi vagana ai le dentate gyrus, lea e faʻaalia tulaga faʻatusatusa ma i latou o loʻo i totonu o itulagi. (Laulau 1).

ΔFosB i le mPFC e faʻamalosia le faʻaleagaina i le atuatuvale

Ina ia tulitatao nei suʻesuʻega, matou te taulaʻi atu i le PrL aua na matou faʻaalia muamua o le faʻaogaina o le optogenetic o lenei itulagi na faʻaalia ai aʻafiaga e pei o le antidepressant i le faʻataʻitaʻiga faʻaleagaina lautele (). Ina ia faʻataʻitaʻiina taunuuga aoga o le ΔFosB induction i totonu o lenei faiʻai eria, matou te faʻaalia le tele o le ΔFosB i le PrL o isumu pulea. (Mati. 1C) ma tuʻuina atu i latou i se ala maualalo o faʻalavelave faʻalavelave faʻaagafesootai, lea e le faʻaosoina ai le aloese mai tagata masani i manu masani. O isumu o loʻo faʻaalia le ΔFosB i le PrL na sili atu ona aʻafia i le toilalo faʻaagafesootai nai lo le GFP-injected control mice i latou na latou faʻaalia amioga aloese mai agafesootai pe a maeʻa le toilalo lautele. (fegalegaleaiga, F(2,38) = 2.847, p > 0.05, mafuaʻaga autu o siama, F(2,38) = 6.013, p <0.05; Bonferroni post suʻega t = 2.447, p <0.05) (Mati. 1D). O nei kusi na faʻaalia foi le faateleina o le le lelei i se aso 1 faʻamalosia ai le aau (F(2,31) = 6.448, p <0.05; Bonferroni post suʻega t = 3.518, p <0.05) (Mati. 1E), o se a'afiaga e fa'afeagai ma le mea na gaosia e vaila'au fa'ama'i. I se faʻatusatusaga, ΔFosB overexpression i le PrL e leʻi suia ai le tele o fua faʻatatau o le popole-pei o amioga, sucrose manaʻoga, fegalegaleaiga faʻaagafesootai, poʻo le gaioiga o locomotor (Mati. 1F-J). Faʻatasi, o nei suʻesuʻega e lagolagoina ai le manatu e faʻapea o le filifilia o le ΔFosB i le PrL o isumu faigofie e fesoasoani i le faʻafitauli i le atuatuvale ma ona aʻafiaga leaga. I se faʻatusatusaga, ΔFosB overexpression i se isi itulagi o le mPFC, IL, e leai se aʻafiaga i uiga faʻalagona faʻavae poʻo luga o tali i faʻalavelave faʻalavelave faʻaagafesootai. (Mati. 1D-J), ae o le ΔFosB overexpression i medial OFC agaʻi atu i le faʻalauiloaina o le maufetuunaʻi i le faʻaleagaina faʻaagafesootai masani, e ui lava o lenei aafiaga e leʻi oʻo i le taua o fuainumera. (fegalegaleaiga, F(1,31) = 1.741, p > 0.05, mafuaʻaga autu o fegalegaleaiga taimi, F(1,31) = 14.170, p <0.05; Bonferroni post suʻega t = 3.860, p <0.05 i totonu o le GFP kulupu; t = 1.960, p <0.05 i totonu o le vaega osFosB; aafiaga o siama, t = 2.447, p <0.05) (Mati. 1K).

ΔFosB faʻateleina le CCKB i totonu o le mPFC

O se vaega tele o faʻamaoniga e lagolagoina le manatu e faapea o le CCK, o se neuropeptide tele i le faiʻai, e iai sona sao taua i faiga neurobiological o le atuatuvale ma le popole. (). Aemaise lava, o le tuʻuina atu o le CCK i le mPFC i le taimi o faʻalavelave faʻaagafesootai i isumu e fesoʻotaʻi ma amioga e fesoʻotaʻi ma popolega (). E ui o le aʻafia o le CCK i le atuatuvale o tagata e tumau pea le le manino, o faʻamaoniga lata mai o loʻo faʻaalia ai lona sao i amioga faʻaleagaina faʻaagafesootai-e pei o le atuatuvale-pei o amioga i isumu (). O lea na matou manatu ai o suiga i le maualuga o le CCK poʻo lona CCKB (faʻapitoa foi o le CCK2) talitali i le mPFC e mafai ona saofagā i le eseesega i le va o isumu maʻaleʻale. I le 48 itula talu ona maeʻa le mea na tupu mulimuli ane, na faʻaititia le maualuga o le CCKB mRNA i le mPFC o naʻo isumu faʻamalosi (F(2,18) = 8.084, p <0.01; Bonferroni post test, t = 3.104, p <0.05 vs faʻatonutonu; t = 5.113, p <0.01 vs faigofie) (Mati. 2A). E leai se eseesega na maitauina i le CCK mRNA maualuga i isumu faʻaletonu pe faʻamalosi (faʻamatalaga e le o faʻaalia). Na matou matauina le faateleina o le ΔFosB tulaga mRNA na'o i isumu faigofie e ogatasi ma fa'amaumauga o porotini na lipotia i luga (F(2,18) = 5.246, p <0.01; Bonferroni post suʻega t = 3.336, p <0.05 vs faigofie tele; t suʻega t(12) = 2.138, p <0.05 vs control) (Mati. 2B). Talu ai ona o le ΔFOSB e faatonutonu le faʻaliliuga o le tele o kene (; ), matou mafaufau i le avanoa e mafai ai ona faʻatonutonu CCKB mRNA faʻamatalaga. Ina ia taliina lenei fesili, na matou faʻaalia muamua le ΔFosB i le PrL ma iloa ai o lenei togafiti e faʻaleleia ai le CCKB mRNA maualuga i lenei itulagi (t(12) = 2.012, p <0.05 vs GFP) (Mati. 2C). O le mea e malie ai, matou te maua foi se faaitiitia o c-Fos MRNA laʻasaga mulimuli ane ΔFosB overexpression (t(11) = 3.382, p <0.01) (Mati. 2C). TO nei suʻesuʻega o loʻo faʻaalia atili ai o le ΔFosB induction i le PrL o isumu maʻaleʻale o se faiga malosi o le faʻaogaina e ala i le puipuia o le taofiofia o le CCKB o loʻo vaʻaia i isumu.

Ina ia faʻamalosia atili nei faʻamatalaga, matou te faʻaalia le ΔJunD, o se paaga faʻapipiʻi ΔFosB e leai sona vaega faʻasalalauga ma faʻapea ona avea o se faʻalavelave le lelei, ma fuafua lona aʻafiaga i faʻamatalaga CCKB faʻaosoina. Na matou faʻamaonia o le faʻalavelave faʻaleagaina faʻaagafesootai masani na faʻateleina le maualuga o le protein CCKB i le PrL o isumu faʻafefe (t suʻega t(12) = 2.289, p <0.05 vs control) (Mati. 2D,E). E le gata i lea, o sea induction na poloka atoa e le ΔJunD overexpression i lenei itulagi (F(2,20) = 6.306, p <0.01, Bonferroni post test t = 3.615, p <0.01) (Mati. 2D,E), lagolagoina le manatu o le ΔFosB e faʻasalalau le faʻaaliga CCKB faʻaosoina. E le gata i lea, o le poloka o le ΔFosB gaoioiga i le PrL, e ala i le faʻaaliga ΔJunD i le lotoifale, na faʻamalosia ai foi le maufetuunaʻi e faʻatoʻilaloina le atuatuvale (t suʻega t(16) = 2.114, p = 0.05 ma le pule) (Mati. 2F). O le faiga o loʻo faʻavaeina ai le faʻaititia o le CCKB i isumu faʻamalosi e tumau pea ona faʻamalamalamaina.

Matafaioi a le CCKB i le maufetuunaʻi ma le gasegase i le atuatuvale

Ina ia faʻataʻitaʻi saʻo le matafaioi a le CCKB tulafono faatonutonu i le PrL i le faʻatalanoaina o faʻafitauli ma le maufetuunaʻi, matou te tuʻuina saʻo le CCKB receptor antagonist CI-988 (10 ng) i totonu o le faiʻai eria o isumu. O le CI-988 e fa'afefeteina lelei CCKB talitali i vivo aua e faʻaalia ai le vavalalata ma le filifilia maualuga mo le subtet receptor CCKB (). O le puipuiina o le CCKB galuega na faʻatupulaia malosi ai fegalegaleaiga faʻaagafesootai (Mati. 2G) (fegalegaleaiga, F(1,20) = 7.795, p <0.05; fualaʻau F(1,20) = 5.38, p <0.05, Bonferroni post test t = 3.615, p <0.01). CI-988 infusion na toe suia ai foi le faaletonu o le suka o le suka na matauina i isumu maaleale (t(8) = 2.681, p <0.05) (Mati. 2H). O fa'ai'uga uma e lua e fa'ailoa mai ai o le polokaina o le gaioioiga o le CCK i le PrL o lo'o fa'atupuina ai a'afiaga e pei o le antidepressant. O le mea e malie ai, pe a faʻatonuina i totonu, CI-988 e le aoga i le fesuiaʻiina o le aloese mai tagata (faʻamatalaga e le o faʻaalia).

Ina ia tofotofoina le felafolafoaiga, o le amataina o le CCKB i le PrL e mafai ona faatalatalanoa ai le aloese ma le faaitiitia o le faasosia o le gasegase e mafua mai i le faasolosolo masani o le atuatuvale, matou te suesueina le aafiaga o le fusi o le CCK-8 (10 ng), o le ituaiga CCK i le mafaufau , i luga o le atuatuvale- ma amioga e popole ai. O le fualaau o le fualaau faasaina na filifilia e faavae i luga o iuga na i ai i tusitusiga (; ; ). O isumu na faʻaalia i le faʻalavelave faʻaleagaina lautele i le 24 itula aʻo leʻi faia suʻega amio (Mati. 3A). CCK-8, faʻapipiʻi 30 min aʻo leʻi suʻeina, na lava e faʻaosofia ai le aloese mai agafesootai i le suʻega fegalegaleaiga faʻaagafesootai faʻapea foʻi ma le faʻaitiitia o le taimi faʻaalu i lima matala i le maualuga ma le paso (SI: BLA, fegalegaleaiga, F(1,22) = 0.79, p > 0.05; aafiaga autu o vailaʻau, F(1,22) = 11.75, p <0.05; Bonferroni post suʻega t = 2.957, p <0.05; NAc: fegalegaleaiga, F(1,26) = 6.688, p <0.05, Bonferroni post test t = 2.816, p <0.05; EPM: BLA, fesoʻotaʻiga, F(1,22) = 8.0, p <0.01; Bonferroni post suʻega t = 2.509, p <0.05 vailaʻau aoga; t = 2.528, p <0.05 aafiaga o siama; NAc, t suʻega t(17) = 1.961; p <0.05 vailaʻau aafiaga i totonu o le kulupu eYFP) (Mati. 3B-E, taumatau). Leai se eseesega na matauina i le fiafia (Mati. 3F,G, taumatau). Mulimuli ane, o le CCK-8 infusion e leai se aafiaga i le amio (fegalegaleaiga faʻaagafesootai ma le maualuga faʻatasi ma le paso) o isumu e le faʻaleagaina i nei suʻega (faʻamatalaga e le o faʻaalia). TO nei faʻaiʻuga ua faʻaalia ai o le ΔFosB-mediated siʻitia i le CCKB gaoioiga i le PrL o isumu faigofie, faʻatusatusa i isumu faʻamalosi, e saofagā i nisi o faʻalavelave faʻaleagaina o amioga faʻaalia e nei manu.

O le poloka o le CCK-faʻaosoina le faʻalavelave i le faʻalavelave e ala i le faʻagaoioia o faʻasologa o le cortical i le BLA versus NAc

O le faʻaitiitia o le gaioiga o le mPFC e fesoʻotaʻi ma amioga e pei o le atuatuvale i isumu, faʻatasi ai ma le faʻaosofia o le mPFC neurons o isumu faigofie e maua ai aʻafiaga e pei o le antidepressant (). O lea na matou manatu ai e mafai e le CCK ona galue i le PrL e ala i le taofiofia o le gaioiga o le neuronal ma mafua ai le faʻaleagaina o amioga. E tusa ai ma lenei manatu, na matou matauina le faʻaitiitia o le c-Fos mRNA i le PrL i le tali atu i le CCK infusion i totonu o lenei vaʻa faiʻai (t(13) = 2.235, p <0.05) (Mati. 3H).

Na matou taʻua mulimuli ane o le faaosofia o le optogenetic o le mPFC o loʻo faʻaaogaina ana faatinoga o le antidepressant e ala i le tetee atu i aafiaga o le CCK i luga ole gaioiga. I le suʻeina o lenei faʻaoga, matou te suʻesuʻeina le faʻaogaina o fausaga faʻapitoa e faʻatautaia ai popolega popolega-ma le faʻaleagaina o le CCK. O le tele o laina o le mPFC i le NAc ma le BLA, e lua fausaga o le tino na aafia i tali o amioga i le atuatuvale. Gaoioiga fesuisuiai o itu uma o le faiʻai ua faaalia e faia se vaega taua i le faaalia o popolega-ma le atuatuvale-e pei o amio (; ). O lea na matou faʻataʻitaʻia ai pe o le faʻaosofiaina o faʻataʻitaʻiga o le glutamatergic mai le PrL i le NAc poʻo le BLA o le a tetee i aʻafiaga leaga o le CCK microinfusion i le PrL (Mati. 3A). Na matou tui AAV-CaMKII-ChR2-EYFP, poʻo AAV-CaMKII-EYFP e fai ma pule, i totonu o le PrL. O le faʻalauiloaina o le CaMKII ua lauiloa e faʻatatau i faʻamatalaga viral i glutamatergic pyramidal neurons i totonu o le cortical regions. Ona matou faʻatagaina lea o se taimi talafeagai (6 vaiaso) mo le transgenes e feaveaʻi i le nerve terminals o nei pyramidal neurons i NAc ma BLA (Mati. 3I). Mice na maua le faʻaititia o le vaeluaga o le va o tagata; 24 i se taimi mulimuli ane, na matou faʻaaogaina CCK-8 i PrL ma, 30 min ina ua mavae lena, na fefaasoaaʻi fegalegaleaiga faʻaagafesoʻotaʻi i le faaosofia o le optogenetic o faʻamaʻi pipisi i le NAc poʻo le BLA. I le taimi lava na uma ai le suʻega o fegalegaleaiga faʻaagafesoʻotaʻi, sa iloiloina ai masini i le maualuga ma le paso e iloilo ai amioga e faʻatonu i le atuatuvale ona sosoo ai lea ma le sili atu le fiafia i le suʻesuʻeina o le anedonia.

Optogenetic stimulation o le PrL glutamatergic projections i le NAc na suia atoa ai le aloese mai agafesootai na mafua mai i le intra-PrL CCK-8 (fegalegaleaiga, F(1,26) = 6.688, p <0.05, leai ni vailaʻau aoga i le ChR2 kulupu) (Mati. 3C). I se faʻatusatusaga, o ia PrL i le NAc faʻaosofia e leai se aʻafiaga i amioga e pei o le popole e pei ona fuaina i le maualuga ma le paso (Mati. 3E); peita'i, o ia fa'aosofiaga na fa'atuputeleina ai le fiafiaga o le sucrose pe a fa'atusatusa i isumu e le'i fa'aosoina (feso'ota'iga, F(1,20) = 5.77, p <0.05; Bonferroni post suʻega t = 2.998, p <0.05 aafiaga faʻaosofia i totonu o manu togafitia CCK-8) (Mati. 3G).

O se faʻataʻitaʻiga uiga eseʻese na vaʻaia i le optogenetic stimulation o le PrL glutamatergic projections i le BLA. O ia faʻaosofia e leʻi taofia ai le aloese mai agafesootai na mafua mai i le intra-PrL CCK-8 infusion (fegalegaleaiga, F(1,22) = 0.79, p > 0.05; aafiaga autu o vailaʻau, F(1,22) = 11.75, p <0.05; leai se aoga i le faʻaosofia vaega, t suʻega t(12) = 2.054, p <0.05) (Mati. 3B). Ae ui i lea, o le faʻaosofiaina o le BLA afferents na faʻaalia ai se aʻafiaga e pei o le popole e pei ona faʻaalia i le faʻateleina o le taimi faʻaalu i lima matala o le maualuga ma le paso (fegalegaleaiga, F(1,22) = 8.0, p <0.01; Bonferroni post suʻega t = 2.528, p <0.05 aafiaga o siama i totonu o vaega ua togafitia CCK-8) (Mati. 3D). O le faʻamalosia o faʻataʻitaʻiga o le glutamatergic i le BLA e leai se aʻafiaga taua i le fiafia o le sucrose (fegalegaleaiga, F(1,22) = 2.08, p > 0.05) (Mati. 3F).

Talanoaga

O fa'ai'uga o su'esu'ega o lo'o iai nei e maua ai fa'amaoniga o suiga mole mole o lo'o tutupu i le PrL lea e fa'avae ai le fa'alavelave i fa'alavelave fa'aagafesootai. Matou te faʻaalia le faʻauluina o le ΔFosB i lenei mPFC subregion pe a maeʻa le faʻalavelave faʻalavelave faʻaagafesootai, lea e faʻaalia ai e le ΔFosB overexpression le faʻalavelave faʻalavelave. Na matou faʻailoaina le CCKB receptor o se tasi faʻasologa o kenera faʻatulafonoina e le ΔFosB i le PrL, e foliga mai o loʻo faʻaosoina le porotini CCKB i isumu faigofie ma puipuia le faʻaitiitia o le faʻaaliga CCKB e tupu faʻapitoa i isumu maufe. Na matou faʻaalia atili o le faʻapipiʻiina o le CCK agonist i totonu o le PrL e faʻateleina ai le atuatuvale-ma le popole-pei o amioga faʻaletonu i le tali atu i faʻalavelave faʻaagafesootai, ae o le poloka o le CCKB gaioiga faʻafeiloaʻi i lenei itulagi o isumu maaleale poloka poloka nei aʻafiaga. Na matou toe faʻaaogaina mea faigaluega o le optogenetic e faʻamaonia ai le microcircuitry o aʻafia i le faʻasolosolo- vs faʻataʻitaʻiga tutusa pei o CCK i le PrL. E ui lava o le cortico-NAc glutamatergic projections e faʻatalanoa ai le le lava o le tau e molimauina e ala i le aloese mai le vafealoaloai ma faʻaitiitia le filifilia o le sucrose, o lenei microcircuit e le aʻafia ai aafiaga popolega o le CCK ua tuʻuina i le PrL. I se isi itu, o faʻasalaga faʻaogaina i le BLA e faʻatalatalanoa ai le faʻaalia o uiga popolega e aʻafia ai ae leai sona aafiaga i le faʻalavelave faʻalapotopotoga-faʻalavelaveina le aloese mai le vafealoaloai poʻo le faʻasolosolo mea e le fiafia i ai. Faʻatasi, o nei faʻamatalaga o loʻo faʻaalia ai o suiga i le PrL galuega pe a maeʻa faʻalavelave faʻalavelave faʻaagafesootai faʻalavelave faʻalavelave faʻaletonu le tele o amioga e ala i faʻataʻitaʻiga faʻapitoa faʻapitoa.

ΔFosB: faʻasologaina o se fesoʻotaʻiga i le mPFC

O le ΔFosB immunohistochemistry e iloa ai neu e aʻafia i le faʻamaʻi faʻamaʻi faʻatasi ma le tasi-cell iugafono ma sa faʻaaogaina mo le faʻafanua o le faʻatonuina o le neuronal circuitry (; ; ). Na matou faʻaogaina lenei metotia e faʻaalia ai o le faʻalavelave faʻaleagaina faʻaagafesootai masani e faʻaosoina ai le ΔFosB i le tele o vaega o faiʻai ma ni faʻataʻitaʻiga manino i le va o vaega faʻamalosi ma faʻafitauli, faʻatasi ai ma nisi o itulagi o loʻo faʻaalia le faʻaogaina i na o isumu, o isi i na o isumu, ae o isi i lalo o tulaga uma e lua (Laulau 1). O galuega talu ai na faʻaalia ai o le ΔFosB induction i le NAc poʻo le ventral PAG e faʻamalosia ai le maufetuunaʻi i le faʻalavelave masani ma fesoasoani i tali faʻamaʻi. (; ).

Induction o le ΔFosB i le PrL o isumu faʻafefe, faʻatasi ai ma suʻesuʻega muamua o le faʻaosofia o le optogenetic o lenei itulagi e faʻaalia ai aʻafiaga faʻamaʻi. (), uunaia i matou e suesue le aafiaga o le ΔFosB i lenei itulagi cortical. Faʻafeagai ma suʻesuʻega i le NAc ma le ventral PAG, na matou iloa ai o le ΔFosB i le PrL e faʻamalosia ai le faʻalavelave i le faʻalavelave faʻalavelave faʻaagafesootai ma maua ai se faʻalavelave faʻapitoa i le suʻega aau faʻamalosi, e aunoa ma le afaina ai o le popole-pei o amioga poʻo le sucrose fiafia. I le faʻatusatusa i le PrL, matou te leʻi mauaina se aʻafiaga o le faʻaalia o le ΔFosB i le IL lata ane. O se suʻesuʻega talu ai nei na maua ai le maualuga o le ΔFosB i le IL i isumu faʻamalosi ma faʻaalia ai lenei vaega i le faʻamalosia i popolega lautele (). O isi suʻesuʻega e manaʻomia e faʻatalanoa ai tulaga eseese mo nei vaega e lua o le mPFC, lea na faʻaalia e maua ai aʻafiaga faʻafeagai i isi vaega o amioga (; ; ). Na matou lipotia muamua o tagata mafatia e faʻaalia le maualalo o le ΔFosB i le NAc suʻesuʻeina postmortem (), wo nei tulaga maualuga o le ΔFosB ua faaalia i le PFC lautele (Brodmann area 46) o tagata mafatia (). O isi eria e le i suesueina i suesuega mulimuli. I soʻo se mea e tupu, o nei suʻesuʻega e lagolagoina ai faʻafitauli faʻapitoa i le itulagi i le ΔFosB expression i le lotovaivai o le tagata, lea o loʻo i ai le tele o aʻafiaga o faʻamatalaga i luga o le faʻafitauli faigata. O le a manaia i suʻesuʻega i le lumanaʻi le suʻesuʻeina o le aafiaga o le ΔFosB i le tele o isi faiʻai i le mea e osofaia ai (Laulau 1) i luga o tali faʻafitauli.

O se tasi o masini e mafai ai e le ΔFosB induction i le PrL ona saofagā i le faʻalavelave-pei o amioga e ala i le taofiofia o le gaioiga PrL. ΔFosB ua faʻaalia e taofiofia tali AMPA glutamate, ma c-Fos faʻamatalaga, i le NAc e faʻaogaina ai le neurons (; ; ). E faapena foi, na matou maua se faaitiitia o c-Fos faʻamatalaga ina ua maeʻa le ΔFosB faʻamalosi i le PrL. O le mea lea, o le ΔFosB induction i le PrL e mafai ona nafa ma le faʻaitiitia o le gaioiga o gaioiga o loʻo vaaia i lenei itulagi pe a maeʻa ona faʻavaivaia le faʻaleagaina o tagata. O le faʻaitiitia o le leo o le PrL i luga o ona sini autu, e pei o BLA ma le NAc, o le a faʻamoemoeina e faʻaleleia ai le fefe ma le le mafai ona faʻaumatia tali faʻalagona i le atuatuvale (, ). E le gata i lea, o faʻamaʻi o le mPFC e faʻaosofia ai le faʻalavelave faʻalavelave ma le le atoatoa i le fefe e faʻaumatia (; ; ; ), fautua mai o le faʻalavelave faʻaleagaina o le mPFC, faʻatalanoaina i se vaega e ala i le ΔFosB induction, e mafai ona saofagā i le atuatuvale ma isi faʻalavelave faʻalavelave faʻalavelave ().

Matafaioi a le CCK i le faʻafitauli faigata

Matou te tuʻuina atu faʻamaoniga o le CCKB receptor o se faʻamoemoega o le ΔFosB, e pei o le ΔFosB induction i le PrL o isumu faʻamaʻi naʻo le tasi le masini e faʻaogaina ai e le ΔFosB ona aʻafiaga e pei o le faʻaleagaina i lenei itulagi. E ui lava o gaioiga patino a le CCK i le mPFC e tumau pea le le manino, i rodents CCK o loʻo faʻaogaina i totonu ole GABAergic interneurons (). E manatu e taofiofia le gaioiga a cortical pyramidal neurons e ala i le faʻaleleia o le GABA i le lotoifale ma galue saʻo i luga o CCKB faʻafeiloaʻi faʻaalia e pyramidal neurons (; ; ; ). O le mea lea, e mafai e le CCKergic neurotransmission ona saofagā i le faʻaitiitia o le gaioiga PrL o loʻo taʻua i luga.

O le CCK ose so'o fa'alavelave, fa'atasi ai ma le fa'atonuina o le CCKB agonists e fa'aoso osofa'iga fa'apopoleina i volenitia soifua maloloina. O tagata ma'i e fa'amata'u i osofa'iga fa'amata'u e o'o ina fa'ama'i pe a uma ona fa'aalia le CCK (; ). E tele suʻesuʻega ua faʻamaonia ai le CCK ile faʻapopolevalega o iʻuga (). O le faʻamalolo o le CCK i le mPFC i le taimi o le faʻalavelave faʻalavelave i isumu e fesoʻotaʻi ma amioga e fesoʻotaʻi ma popolega (); E le'i 'ese'ese 'ese'ese vaega o le PrL ma le IL i lenei su'esu'ega. Talu ai nei lava, o le fa'alavelave fa'afuase'i o le CCKB fa'atasi ma le CI-988 na fa'aolaina ai a'afiaga e pei o le antidepressant i isumu (). CI-988 faʻamaonia le le tumau le taimi i le faʻataʻitaʻiga o le aau. Na taofia ai foi le hypothalamic-pituitary-eletise o le eletise, faaitiitiga o le hippocampal ma le faateleina o le cell, ma le faaitiitia o le fiafia i le suauu e masani lava ona faasalalauina e ala i le faatoilaloina o aganuu. O lenei, matou te faʻamaonia nei taunuʻuga e ala i le faʻaalia o le aʻafiaga e pei o le CI-988 i le PrL o mice e ono mafai ona gafatia, e ui lava e tasi le tui na le mafai ona faʻamaonia ai lenei aafiaga.

I le faaopoopo atu i gaioiga a CCK i le PrL, ua matou iloa ai le laʻititi o le maualuga o le mRNA CCKB i mumumu e mafai ona toe faʻaaogaina, lea e ono mafai ona avea ma suiga mole mole mautu. O le mea moni, o suiga i le CCKergic tone, aemaise lava CCKB, o se mea taua mo le faʻaalia o le popole. O fualaau feʻaveaʻi o le CCKB i luma o le faʻaaliga ua faʻaalia ai le faateleina o popolega ma tali fefe (). O la matou sailiga o fesuiaʻiga tulaga CCKB i le va o isumu mafai gafatia ma faigofie gafatia ono saofaga i le phenotypic eseesega i le popole ma amioga faʻapopole. Lenei, matou te faʻaalia le PrL o se faitioga faʻatosina loloto mo le popolevale ma le faʻatupuina o aafiaga o le CCK i le tulaga o mafatiaga lautele. E ui i lea, e tele isi vaega o faiʻai o loʻo aafia i amioga a CCK, e aofia ai le BLA, hippocampus, NAc, ma le PAG (; ; ; ; ). E le gata i lea, na matou maua se faʻaopoopoga i le CCKB protein maualuga, ae le o le mRNA, i le mPFC o manu faʻafefe. O nei suʻesuʻega o loʻo faʻamamafa ai, e ui lava o le mRNA e masani ona fesoʻotaʻi ma le maualuga o le porotini, e le o le tulaga lea ().

O a matou suʻesuʻega o le opotogenetic o loʻo faʻaalia ai o le faateleina o le gaioiga o faʻataʻitaʻiga faʻamalosi mai le PrL i le NAc poʻo le BLA e faʻataʻitaʻia ai aafiaga o CCK i le PrL. O isi suʻesuʻega e manaʻomia e faʻamautu ai o lenei aafiaga o le faʻamalosia o le optogenetic e faʻatalanoaina e le lava PrL neurons o loʻo pulea e CCK. O le mea e maofa ai, oa tatou faʻamatalaga e faʻaalia ai tulaga eseese o nei microcircuits e lua i le faʻatalanoaina o vaega eseese o mea le talafeagai. O le suʻesuʻega cortico-NAc e pulea ai le faʻasetonia ma le taui; o le mea moni e faʻasaʻo ai le aloese mai le va fealoai e faʻamaonia ai o lenei uiga e sili atu ona atagia ai le faʻaitiitia o le faʻamalosia ma le taui mo amio faʻapisinisi ae le o le faateleina o popolega lautele. O lenei faaiuga e o gatasi ma le le mafai ona maua o benzodiazepines e faasaʻo ai lenei faaletonu (), ma faʻatasi ai ma le faʻataʻitaʻiga talu ai nei o le faʻamalosia o le mPFC o le NAc e faʻapupulaina ai le taui ma le faʻaosofia mo fualaau o le faʻaleagaina (). I se faʻatusatusaga, o le cortico-BLA projection e pulea faʻamaoniga e fesoʻotaʻi ma popolega, e ogatasi ma le tele o tusitusiga i rodents ma tagata (silasila i luga).

I le faaiuga, fa'ai'uga o su'esu'ega o lo'o iai nei e fa'ailoa mai ai se fa'ata'ita'iga o vaega o fai'ai limbic e a'afia i manu fa'aa'e ma fa'aolaola, ma fa'aalia suiga i le PrL e fa'atupu ai le fa'aletonu. O nei suiga e aofia ai le faʻaogaina o le ΔFosB ma lona faʻaogaina o le CCKB receptor. I le eseesega, o le poloka poloka o CCK i le PrL e faʻaalia ai le antidepressant- ma aʻafiaga faʻapitoa. Matou te faʻatuina foi le faʻamoemoega o nei laʻau faʻamalosi o loʻo faʻatalanoa nei gaioiga, ma se kesi cortico-NAc e manaʻomia mo amioga e aʻafia ai le atuatuvale, ma o se taʻavale cortico-BLA e manaʻomia mo amioga faʻafefefe. E ui lava o suʻesuʻega a le CCKB i tagata mamaʻi i le 1990s e leʻi tuʻuina atu i ai ni folafolaga folafolaina, o loʻo maua mai i le taimi nei le taua o le toe faʻafouina o le gasegase o gasegase o ia sooupu i vaega o tagata mamaʻi e faʻaalia i tulaga maualuga o le atuatuvale.

Faamatalaga Faʻamatalaga

 

O lenei galuega sa lagolagoina e le National Institute of Mental Health (EJN) ma le Brain & Behavior Research Foundation National Alliance for Research on Schizophrenia and Depression Young Investigator Award i le VV.

 

 

O tusitala e leai se tauvaga tautupe tauva.

 

mau faasino

  • Akirav I, Maroun M. O le matafaioi a le medial prefrontal cortex-amygdala circuit i faʻalavelave faʻalavelave i le faʻaumatiaina o le fefe. Neural Plast. 2007;2007:30873. doi: 10.1155/2007/30873. [PMC free article] [PubMed] [Cross Ref]
  • Barbas H, Blatt GJ. O fa'ata'ita'iga fa'apitoa o le hippocampal e fa'atatau i vaega pito i luma o le manuki rhesus. Hippocampus. 1995;5:511–533. doi: 10.1002/hipo.450050604. [PubMed] [Cross Ref]
  • Becker C, Thièbot MH, Touitou Y, Hamon M, Cesselin F, Benoliel JJ. Faʻaleleia le maualuga o le cortical extracellular maualuga o mea e pei o le cholecystokinin i se faʻataʻitaʻiga o le faʻamoemoeina o le toilalo faʻaagafesootai i le iole. J Neurosci. 2001;21:262–269. [PubMed]
  • Becker C, Zeau B, Rivat C, Blugeot A, Hamon M, Benoliel JJ. Fa'asolo fa'aagafesootai fa'ato'ilalo-fa'aoso fa'anoanoa-pei o amio ma suiga fa'aletino i isumu: a'afiaga o le cholecystokinin. Mol Psychiatry. 2008;13:1079–1092. doi: 10.1038/sj.mp.4002097. [PubMed] [Cross Ref]
  • Belcheva I, Belcheva S, Petkov VV, Petkov VD. Asymmetry i tali amio i le cholecystokinin microinjected i rat nucleus accumbens ma amygdala. Neuropharmacology. 1994;33:995–1002. doi: 10.1016/0028-3908(94)90158-9. [PubMed] [Cross Ref]
  • Benoliel JJ, Bourgoin S, Mauborgne A, Pohl M, Legrand JC, Hamon M, Cesselin F. GABA, o loʻo galue i le GABAA ma le GABAB receptors, faʻalavelaveina le tuʻuina atu o mea e pei o le cholecystokinin mai le rat spinal cord in vitro. Fai'ai Re. 1992;590:255–262. doi: 10.1016/0006-8993(92)91103-L. [PubMed] [Cross Ref]
  • Berton O, McClung CA, Dileone RJ, Krishnan V, Renthal W, Russo SJ, Graham D, Tsankova NM, Bolanos CA, Rios M, Monteggia LM, Self DW, Nestler EJ. Matafaioi taua o le BDNF i le mesolimbic dopamine auala i le faʻaleagaina faʻaleagaga faʻaleagaina. Saienisi. 2006; 311: 864-868. doi: 10.1126 / science.1120972. [PubMed] [Cross Ref]
  • Berton O, Covington HE, 3rd, Ebner K, Tsankova NM, Carle TL, Ulery P, Bhonsle A, Barrot M, Krishnan V, Singewald GM, Singewald N, Birnbaum S, Neve RL, Nestler EJ. Induction o le δFosB i le periaqueductal grey e ala i le atuatuvale e faʻamalosia ai le faʻaogaina o tali. Neuron. 2007;55:289–300. doi: 10.1016/j.neuron.2007.06.033. [PubMed] [Cross Ref]
  • Bewernick BH, Hurlemann R, Matusch A, Kayser S, Grubert C, Hadrysiewicz B, Axmacher N, Lemke M, Cooper-Mahkorn D, Cohen MX, Brockmann H, Lenartz D, Sturm V, Schlaepfer TE. Nucleus accumbens loloto faaosofia le faiʻai e faʻaitiitia ai faʻataʻitaʻiga o le atuatuvale ma le popole i le faʻafitauli e tetee atu i togafitiga. Biol Psychiatry. 2010;67:110–116. doi: 10.1016/j.biopsych.2009.09.013. [PubMed] [Cross Ref]
  • Bradwejn J, Koszycki D, Shriqui C. Faʻaleleia le lagona i le cholecystokinin tetrapeptide i le faʻalavelave faʻalavelave: suʻesuʻega faʻapitoa ma amioga. Arch Gen Psychiatry. 1991;48:603–610. doi: 10.1001/archpsyc.1991.01810310021005. [PubMed] [Cross Ref]
  • Bremner JD. Pe fa'aleagaina ea le fai'ai o le fa'apopoleina? Biol Psychiatry. 1999;45:797–805. doi: 10.1016/S0006-3223(99)00009-8. [PubMed] [Cross Ref]
  • Bremner JD. Fa'alavelave fa'alavelave: a'afiaga i le fai'ai. Fa'atalanoaga Clin Neurosci. 2006;8:445–461. [PMC free article] [PubMed]
  • Bremner JD. Neuroimaging i le posttraumatic stress disorder ma isi faʻalavelave faʻalavelave faʻalavelave. Neuroimaging Clin North Am. 2007;17:523–538. doi: 10.1016/j.nic.2007.07.003. [PMC free article] [PubMed] [Cross Ref]
  • Britt JP, Benaliouad F, McDevitt RA, Stuber GD, Wise RA, Bonci A. Synaptic ma le faʻatautaia o amioga faʻapitoa o le tele o mea faʻaaogaina i le nucleus accumbens. Neuron. 2012; 76: 790-803. Pule: 10.1016 / j.neuron.2012.09.040. [PMC free article] [PubMed] [Cross Ref]
  • Burgos-Robles A, Bravo-Rivera H, Quirk GJ. Prelimbic ma infralimbic neu fa'ailoga vaega tu'ufa'atasi o le fa'aogaina o mea faigaluega. PLoS Tasi. 2013;8:e57575. doi: 10.1371/journal.pone.0057575. [PMC free article] [PubMed] [Cross Ref]
  • Chen Q, Nakajima A, Meacham C, Tang YP. O le maualuga o le cholecystokininergic leo e aofia ai se masini mole / neuronal taua mo le faʻaalia o le popole i le isumu. Proc Natl Acad Sci US A. 2006;103:3881–3886. doi: 10.1073/pnas.0505407103. [PMC free article] [PubMed] [Cross Ref]
  • Choi DC, Gourley SL, Ressler KJ. Prelimbic BDNF ma TrkB fa'ailoga e fa'atulafonoina ai le tu'ufa'atasiga o a'oa'oga fa'alagona ma le fa'anoanoa. Transl Psychiatry. 2012;2:e205. doi: 10.1038/tp.2012.128. [PMC free article] [PubMed] [Cross Ref]
  • Christoffel DJ, Golden SA, Dumitriu D, Robison AJ, Janssen WG, Ahn HF, Krishnan V, Reyes CM, Han MH, Ables JL, Eisch AJ, Dietz DM, Ferguson D, Neve RL, Greengard P, Kim Y, Morrison JH , Russo SJ. IκB kinase fa'atulafonoina fa'aagafesootai fa'ato'ilalo fa'apopoleina fa'aoso fa'amamafa ma fa'ama'i palasitika. J Neurosci. 2011;31:314–321. doi: 10.1523/JNEUROSCI.4763-10.2011. [PMC free article] [PubMed] [Cross Ref]
  • Covington HE, 3rd, Kikusui T, Goodhue J, Nikulina EM, Hammer RP, Jr, Miczek KA. Pu'upu'u fa'ato'ilalo fa'aagafesoota'i fa'alavelave: umi umi a'afiaga i luga o le cocaine i le taimi o se fa'aaliga ma le zif268 mRNA i le amygdala ma le pito i luma. Neuropsychopharmacology. 2005;30:310–321. doi: 10.1038/sj.npp.1300587. [PubMed] [Cross Ref]
  • Covington HE, 3rd, Lobo MK, Maze I, Vialou V, Hyman JM, Zaman S, LaPlant Q, Mouzon E, Ghose S, Tamminga CA, Neve RL, Deisseroth K, Nestler EJ. Faʻafitauli aʻafiaga o le faʻamalosia o le optogenetic o le vailaʻau o le pito i luma. J Neurosci. 2010; 30: 16082-16090. Nu: 10.1523 / JNEUROSCI.1731-10.2010. [PMC free article] [PubMed] [Cross Ref]
  • Covington HE, 3rd, Maze I, Sun H, Bomze HM, DeMaio KD, Wu EY, Dietz DM, Lobo MK, Ghose S, Mouzon E, Neve RL, Tamminga CA, Nestler EJ. O se matafaioi mo le faʻaleagaina o le histone methylation i le faʻalavelave faʻaosoina o cocaine i le atuatuvale. Neuron. 2011;71:656–670. doi: 10.1016/j.neuron.2011.06.007. [PMC free article] [PubMed] [Cross Ref]
  • de Montigny C. Cholecystokinin tetrapeptide faʻaosofia osofaʻiga faʻafefe i tagata volenitia soifua maloloina: suʻesuʻega muamua. Arch Gen Psychiatry. 1989;46:511–517. doi: 10.1001/archpsyc.1989.01810060031006. [PubMed] [Cross Ref]
  • De Witte P, Heidbreder C, Roques B, Vanderhaeghen JJ. O aʻafiaga faʻafeagai o le cholecystokinin octapeptide (CCK-8) ma le tetrapeptide (CCK-4) pe a uma ona tuʻiina i totonu o le caudal vaega o le nucleus accumbens poʻo totonu o lona vaega rostral ma le cerebral ventricles. Neurochem Int. 1987;10:473–479. doi: 10.1016/0197-0186(87)90074-X. [PubMed] [Cross Ref]
  • Diorio D, Viau V, Meaney MJ. Le matafaioi a le medial prefrontal cortex (cingulate gyrus) i le faatonutonuina o tali o le hypothalamic-pituitary-adrenal i le atuatuvale. J Neurosci. 1993;13:3839–3847. [PubMed]
  • Drevets WC. Neuroimaging ma suʻesuʻega neuropathological o le atuatuvale: aʻafiaga mo uiga faʻalagona-lagona o faʻafitauli o le mafaufau. Curr Opin Neurobiol. 2001;11:240–249. doi: 10.1016/S0959-4388(00)00203-8. [PubMed] [Cross Ref]
  • Fales CL, Barch DM, Rundle MM, Mintun MA, Snyder AZ, Cohen JD, Mathews J, Sheline YI. Suia fa'alavelave fa'alagona fa'agaioiga i le fa'aosoina ma le mafaufau-pulea fai'ai i le tele o le atuatuvale. Biol Psychiatry. 2008;63:377–384. doi: 10.1016/j.biopsych.2007.06.012. [PMC free article] [PubMed] [Cross Ref]
  • Fales CL, Barch DM, Rundle MM, Mintun MA, Mathews J, Snyder AZ, Sheline YI. Togafitiga faʻamaʻi faʻamaʻi faʻaleaganuʻu le hypoactivity i le dorsolateral prefrontal cortex aʻo faʻalavelave faʻalagona gaioiga i le tele o le atuatuvale. J Aafiaga Faalavelave. 2009;112:206–211. doi: 10.1016/j.jad.2008.04.027. [PMC free article] [PubMed] [Cross Ref]
  • Feder A, Nestler EJ, Charney DS. Psychobiology ma genetics mole o le maufetuuna'i. Nat Rev Neurosci. 2009;10:446–457. doi: 10.1038/nrn2649. [PMC free article] [PubMed] [Cross Ref]
  • Gallopin T, Geoffroy H, Rossier J, Lambolez B. Cortical puna o CRF, NKB, ma CCK ma o latou aafiaga i sela pyramidal i le neocortex. Cereb Cortex. 2006;16:1440–1452. doi: 10.1093/cercor/bhj081. [PubMed] [Cross Ref]
  • Grubert C, Hurlemann R, Bewernick BH, Kayser S, Hadrysiewicz B, Axmacher N, Sturm V, Schlaepfer TE. Neuropsychological saogalemu o le nucleus accumbens loloto le faiʻai faaosofia mo le atuatuvale tele: aafiaga o le 12-masina faaosofia. Lalolagi J Biol Psychiatry. 2011;12:516–527. doi: 10.3109/15622975.2011.583940. [PubMed] [Cross Ref]
  • Grueter BA, Robison AJ, Neve RL, Nestler EJ, Malenka RC. ΔFosB faʻapitoa e faʻapipiʻi ai nucleus accumbens faʻasologa saʻo ma le faʻaalatua. Faʻaalia Natl Acad Sci US A. 2013; 110: 1923-1928. doi: 10.1073 / pnas.1221742110. [PMC free article] [PubMed] [Cross Ref]
  • Gygi SP, Rochon Y, Franza BR, Aebersold R. Fa'atasiga i le va o le porotini ma le mRNA tele i le fefete. Mol Cell Biol. 1999;19:1720–1730. [PMC free article] [PubMed]
  • Heidbreder CA, Groenewegen HJ. Le medial prefrontal cortex i le isumu: faʻamaoniga mo se faʻailoga-ventral faʻavae e faʻavae i luga o uiga faʻaoga ma faʻataʻitaʻiga. Neurosci Biobehav Rev. 2003;27:555–579. doi: 10.1016/j.neubiorev.2003.09.003. [PubMed] [Cross Ref]
  • Holson RR. Meal mua'i fa'ama'i fa'ama'i ma matamuli i isumu: I. Fa'agaoioiga i fa'aoso fa'aleaga. Amioga Faaletino. 1986;37:221–230. doi: 10.1016/0031-9384(86)90224-6. [PubMed] [Cross Ref]
  • Keedwell PA, Andrew C, Williams SC, Brammer MJ, Phillips ML. O fesoʻotaʻiga neura o le anhedonia i le faʻafitauli tele o le atuatuvale. Biol Psychiatry. 2005;58:843–853. doi: 10.1016/j.biopsych.2005.05.019. [PubMed] [Cross Ref]
  • Kennedy SH, Giacobbe P. Togafitiga faʻafitauli faʻafitauli: faʻalauteleina i togafitiga somatic. Ann Clin Psychiatry. 2007;19:279–287. doi: 10.1080/10401230701675222. [PubMed] [Cross Ref]
  • Kennedy SH, Evans KR, Krüger S, Mayberg HS, Meyer JH, McCann S, Arifuzzman AI, Houle S, Vaccarino FJ. Suiga i le fai'ai fa'aitulagi kulukose metabolism fua i positron emission tomography ina ua uma le paroxetine togafitiga o le atuatuvale tele. Am J Psychiatry. 2001;158:899–905. doi: 10.1176/appi.ajp.158.6.899. [PubMed] [Cross Ref]
  • Krishnan V, Han MH, Graham DL, Berton O, Renthal W, Russo SJ, Laplant Q, Graham A, Lutter M, Lagace DC, Ghose S, Reister R, Tannous P, Green TA, Neve RL, Chakravarty S, Kumar A , Eisch AJ, le tagata lava ia o le DW, Lee FS, et al. Faʻafeiloaʻi i luga o mea faʻapitoa e mafai ai ona faʻamalosia ma teteʻe atu i faʻafitauli faʻale-agafesootai i itu o faiʻai taui. Cell. 2007; 131: 391-404. Pule: 10.1016 / j.cell.2007.09.018. [PubMed] [Cross Ref]
  • Krishnan V, Nestler EJ. O le neurobiology mole o le atuatuvale. natura. 2008;455:894–902. doi: 10.1038/natura07455. [PMC free article] [PubMed] [Cross Ref]
  • Lehmann ML, Herkenham M. O le faʻaleleia o le siosiomaga e faʻamalosia ai le faʻamalosia o le faʻalavelave i le faʻatoʻilaloina faʻale-aganuʻu e ala i se ala o le neuroanatomical-cortex-cortex. J Neurosci. 2011; 31: 6159-6173. Nu: 10.1523 / JNEUROSCI.0577-11.2011. [PMC free article] [PubMed] [Cross Ref]
  • Leistedt SJ, Linkowski P. Brain, fesoʻotaʻiga, atuatuvalega, ma isi. Eur Neuropsychopharmacol. 2013;23:55–62. doi: 10.1016/j.euroneuro.2012.10.011. [PubMed] [Cross Ref]
  • Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM, Kennedy SH. Fa'aosofia le fai'ai loloto mo le fa'afitauli e tete'e togafitiga. Neuron. 2005;45:651–660. doi: 10.1016/j.neuron.2005.02.014. [PubMed] [Cross Ref]
  • Maze I, Covington HE, 3rd, Dietz DM, LaPlant Q, Renthal W, Russo SJ, Mechanic M, Moulon E, Neve RL, Haggarty SJ, Ren Y, Sampath SC, Hurd YL, Greengard P, Tarakhovsky A, Schaefer A, Nestler EJ. Matafaioi taua o le histone methyltransferase G9a i le siakiina o siama. Saienisi. 2010; 327: 213-216. doi: 10.1126 / science.1179438. [PMC free article] [PubMed] [Cross Ref]
  • McClung CA, Nestler EJ. Faʻatonutonuina o faʻamatalaga o kenera ma taui cocaine e CREB ma DeltaFosB. Nat Neurosci. 2003;6:1208–1215. doi: 10.1038/nn1143. [PubMed] [Cross Ref]
  • Milad MR, Quirk GJ. Neurons i le medial prefrontal cortex faʻailoga manatua mo le fefe faʻaumatia. natura. 2002;420:70–74. doi: 10.1038/natura01138. [PubMed] [Cross Ref]
  • Nahas Z, Anderson BS, Borckardt J, Arana AB, George MS, Reeves ST, Takacs I. Bilateral epidural prefrontal cortical stimulation mo le faʻalavelave faʻalavelave togafitiga. Biol Psychiatry. 2010;67:101–109. doi: 10.1016/j.biopsych.2009.08.021. [PMC free article] [PubMed] [Cross Ref]
  • Nikulina EM, Arrillaga-Romany I, Miczek KA, Hammer RP., Jr Suiga umi i fausaga mesocorticolimbic pe a uma le faʻalavelave faʻaleagaina faʻaagafesootai i isumu: taimi ole mu-opioid receptor mRNA ma FosB / DeltaFosB immunoreactivity. Eur J Neurosci. 2008;27:2272–2284. doi: 10.1111/j.1460-9568.2008.06176.x. [PMC free article] [PubMed] [Cross Ref]
  • Noble F, Roques BP. CCK-B talitali: kemisi, biology mole, biochemistry ma vailaau mo togafitiga. Prog Neurobiol. 1999;58:349–379. doi: 10.1016/S0301-0082(98)00090-2. [PubMed] [Cross Ref]
  • Noble F, Wank SA, Crawley JN, Bradwejn J, Seroogy KB, Hamon M, Roques BP. International Union of Pharmacology: XXI. Fausia, tufatufaina, ma galuega a le cholecystokinin receptors. Pharmacol Rev. 1999;51:745–781. [PubMed]
  • Pérez de la Mora M, Hernandez-Gómez AM, Méndez-Franco J, Fuxe K. Cholecystokinin-8 faateleina K(+)-evoked [3H] gamma-aminobutyric acid fa'asa'olotoina i fasi vaega mai vaega eseese o fai'ai. Eur J Pharmacol. 1993;250:423–430. doi: 10.1016/0014-2999(93)90029-H. [PubMed] [Cross Ref]
  • Perrotti LI, Hadeishi Y, Ulery PG, Barrot M, Monteggia L, Duman RS, Nestler EJ. Faʻaaogaina o le δFosB i faʻaleleia o faiʻai i le taui pe a mavae le faʻalavelave masani. J Neurosci. 2004; 24: 10594-10602. Nu: 10.1523 / JNEUROSCI.2542-04.2004. [PubMed] [Cross Ref]
  • Perrotti LI, Weaver RR, Robison B, Renthal W, Maze I, Yazdani S, Elmore RG, Knapp DJ, Selley DE, Martin BR, Sim-Selley L, Bachtell RK, Self DW, Nestler EJ. O mamanu maʻoti o le DeltaFosB induction i le faiʻai e ala i fualaau faasaunoa. Synapse. 2008; 62: 358-369. doi: 10.1002 / syn.20500. [PMC free article] [PubMed] [Cross Ref]
  • Radley JJ, Rocher AB, Miller M, Janssen WG, Liston C, Hof PR, McEwen BS, Morrison JH. O le fa'alavelave fa'afuase'i e fa'aosoina ai le gau o le tuasivi dendritic i le iole medial prefrontal cortex. Cereb Cortex. 2006;16:313–320. doi: 10.1093/cercor/bhi104. [PubMed] [Cross Ref]
  • Renthal W, Carle TL, Maze I, Covington HE, 3rd, Truong HT, Alibhai I, Kumar A, Montgomery RL, Olson EN, Nestler EJ. O le Delta FosB e fa'atalanoaina le epigenetic desensitization o le c-fos gene pe a uma ona fa'aalia le amphetamine masani. J Neurosci. 2008;28:7344–7349. doi: 10.1523/JNEUROSCI.1043-08.2008. [PMC free article] [PubMed] [Cross Ref]
  • Rezayat M, Roohbakhsh A, Zarrindast MR, Massoudi R, Djahanguiri B. Cholecystokinin ma GABA fegalegaleaiga i le dorsal hippocampus o isumu i le suʻega faʻaopoopo-maze maualuga o le popole. Amioga Faaletino. 2005;84:775–782. doi: 10.1016/j.physbeh.2005.03.002. [PubMed] [Cross Ref]
  • Richard JM, Berridge KC. Prefrontal cortex fa'afetaui le mana'o ma le fefe fa'atupuina e nucleus accumbens glutamate fa'alavelave. Biol Psychiatry. 2013;73:360–370. doi: 10.1016/j.biopsych.2012.08.009. [PMC free article] [PubMed] [Cross Ref]
  • Rotzinger S, Vaccarino FJ. Cholecystokinin receptor subtypes: matafaioi i le faʻaogaina o amioga popole ma faʻatatau i taui i faʻataʻitaʻiga manu. J Psychiatry Neurosci. 2003;28:171–181. [PMC free article] [PubMed]
  • Schlaepfer TE, Cohen MX, Frick C, Kosel M, Brodesser D, Axmacher N, Joe AY, Kreft M, Lenartz D, Sturm V. O le faaosofia o le faiʻai loloto e taui ai le circuitry e faʻaitiitia ai le anhedonia i le atuatuvale tele. Neuropsychopharmacology. 2008;33:368–377. doi: 10.1038/sj.npp.1301408. [PubMed] [Cross Ref]
  • Sierra-Mercado D, Padilla-Coreano N, Quirk GJ. O matafaioi faʻapitoa o faʻamaʻi ma infralimbic cortices, ventral hippocampus, ma basolateral amygdala i le faʻaaliga ma le faʻaumatia o le fefe faʻafefe. Neuropsychopharmacology. 2011;36:529–538. doi: 10.1038/npp.2010.184. [PMC free article] [PubMed] [Cross Ref]
  • Silva MG, Boyle MA, tamatamailima S, Numan B, Bouzrara AA, Almli CR. O a'afiaga o a'afiaga o manu'a tetele ma laiti o le iole medial frontal cortex. Exp Brain Res. 1986;65:176–181. [PubMed]
  • Somogyi P, Hodgson AJ, Smith AD, Nunzi MG, Gorio A, Wu JY. Eseese faitau aofa'i o GABAergic neurons i le va'aiga va'aia ma le hippocampus o pusi o lo'o i ai somatostatin- po'o cholecystokinin-immunoreactive mea. J Neurosci. 1984;4:2590–2603. [PubMed]
  • Surget A, Tanti A, Leonardo ED, Laugeray A, Rainer Q, Touma C, Palme R, Griebel G, Ibarguen-Vargas Y, Hen R, Belzung C. Antidepressants e faʻaaogaina neu fou e faʻaleleia ai le faʻatonutonuina o le faʻalavelave. Mol Psychiatry. 2011;16:1177–1188. doi: 10.1038/mp.2011.48. [PMC free article] [PubMed] [Cross Ref]
  • Taniguchi H, He M, Wu P, Kim S, Paik R, Sugino K, Kvitsiani D, Fu Y, Lu J, Lin Y, Miyoshi G, Shima Y, Fishell G, Nelson SB, Huang ZJ. O se puna'oa o laina aveta'avale Cre mo le fa'atulagaina o kenera GABAergic neurons i le cerebral cortex. Neuron. 2011;71:995–1013. doi: 10.1016/j.neuron.2011.07.026. [PMC free article] [PubMed] [Cross Ref]
  • Teyssier JR, Ragot S, Chauvet-Gélinier JC, Trojak B, Bonin B. Faʻagaoioia o se faʻataʻitaʻiga faʻataʻitaʻiga faʻalagolago i le DeltaFOSB i le pito i luma o le pito i luma o tagata mamaʻi o loʻo maua i le maʻi faʻafitauli tele. J Aafiaga Faalavelave. 2011;133:174–178. doi: 10.1016/j.jad.2011.04.021. [PubMed] [Cross Ref]
  • Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ. Fa'atulafonoina o le hippocampal chromatin i se faʻataʻitaʻiga o le isumu o le atuatuvale ma le faʻamaʻi. Nat Neurosci. 2006;9:519–525. doi: 10.1038/nn1659. [PubMed] [Cross Ref]
  • Tye KM, Prakash R, Kim SY, Fenno LE, Grosenick L, Zarabi H, Thompson KR, Gradinaru V, Ramakrishnan C, Deisseroth K. Amygdala circuitry mediating reversible ma bidirectional pulea popolega. natura. 2011;471:358–362. doi: 10.1038/natura09820. [PMC free article] [PubMed] [Cross Ref]
  • Vialou V, Robison AJ, Laplant QC, Covington HE, 3rd, Dietz DM, Ohnishi YN, Mouzon E, Rush AJ, 3rd, Watts EL, Wallace DL, Iñiguez SD, Ohnishi YH, Steiner MA, Warren BL, Krishnan V, Bolaños CA, Neve RL, Ghose S, Berton O, Tamminga CA, et al. DeltaFosB i le vaʻaia o taui i le faiʻai e faʻatautaia ai le tali atu i faʻafitauli ma le tali atu. Nat Neurosci. 2010; 13: 745-752. doi: 10.1038 / nn.2551. [PMC free article] [PubMed] [Cross Ref]
  • Vogt BA, Finch DM, Olson CR. Tulaga fa'apitoa i le cingulate cortex: o le pito i luma o le pulega ma le pito i tua o le iloiloga. Cereb Cortex. 1992;2:435–443. doi: 10.1093/cercor/2.6.435-a. [PubMed] [Cross Ref]
  • Wilkinson MB, Xiao G, Kumar A, LaPlant Q, Renthal W, Sikder D, Kodadek TJ, Nestler EJ. Imipramine togafitiga ma le maufetuuna'i fa'aalia tulafono tutusa chromatin i le nucleus o le isumu fa'aputu i fa'ata'ita'iga fa'anoanoa. J Neurosci. 2009;29:7820–7832. doi: 10.1523/JNEUROSCI.0932-09.2009. [PMC free article] [PubMed] [Cross Ref]
  • Winstanley CA, LaPlant Q, Theobald DE, Green TA, Bachtell RK, Perrotti LI, DiLeone RJ, Russo SJ, Garth WJ, Self DW, Nestler EJ. DeltaFosB induction i le orbitofrontal cortex e faʻasalalau le faapalepale i le cocaine-induced cognitive dysfunction. J Neurosci. 2007;27:10497–10507. doi: 10.1523/JNEUROSCI.2566-07.2007. [PubMed] [Cross Ref]
  • Yaksh TL, Furui T, Kanawati IS, Alu VL. Faʻasaʻolotoina o le cholecystokinin mai le rat cerebral cortex in vivo: matafaioi a le GABA ma le glutamate receptor system. Fai'ai Re. 1987;406:207–214. doi: 10.1016/0006-8993(87)90784-0. [PubMed] [Cross Ref]
  • Zanoveli JM, Netto CF, Guimarães FS, Zangrossi H., Jr Systemic ma intra-dorsal periaqueductal tui efuefu o le cholecystokinin sulfated octapeptide (CCK-8s) faʻaosofia se tali faʻafefe-pei o isumu tuʻuina atu i le T-paso maualuga. Peptides. 2004;25:1935–1941. doi: 10.1016/j.peptides.2004.06.016. [PubMed] [Cross Ref]