Ụzọ Mgbochi Mgbochi nke Mbụ maka Mmetụta Mmetụta - na Ụdị Ejiri Nchegbu Ndị Na-eme Ka Cholecystokinin Kwadoro: Ọrụ nke ΔFosB (2014)

J Neurosci. 2014 Mar 12; 34 (11): 3878-3887.
doi: 10.1523 / JNEUROSCI.1787-13.2014

PMCID: PMC3951691

Vincent Vialou,^1,^6,^7,⁸ Rosemary C. Bagot,¹ Michael E. Cahill,¹ Deveroux Ferguson,¹ Alfred J. Robison,² David M. Dietz,³ Barbara Fallon,² Michelle Mazei-Robison,² Stacy M. Ku,¹ Eileen Harrigan,¹ Catherine A. Winstanley,⁴ Tej Joshi,¹ Jian Feng,¹ Olivier Berton,⁵ na Eric J. Nestler¹

Onye na-ede ihe ọmụma ► Ihe ederede ► Ozi Ikike na ikikere ►

Nke a bu zoro aka na ya ndị ọzọ na PMC.

nkịtị

Ejikọtara ọnụ ọgụgụ ndị na-emepụta ihe na-eme n'ọdịnihu nke na-eme ka ndị mmadụ na-eme ihe na-adịghị mma. Otú ọ dị, usoro ihe omimi nke na-akpata ọrụ mPFC na-ebelata na ọrụ prodepressant ọ na-amaghị. Anyị na-egosi ebe a na ịmepụta ihe odide transcript ΔFosB na mPFC, kpọmkwem na mpaghara prelimbic (PrL), mgbasa ozi nwere ike ime ka nrụgide. ΔFosB induction na PrL mere nhọrọ na ụmụ anụ nwere ike imeri nrụgide, na ikwu okwu nke ΔFosB na mpaghara a, ma ọ bụghị na mpaghara infralimbic (IL) dị nso, na-eme ka nchekasị dịkwuo njọ. ΔFosB mepụtara mmetụta ndị a site na ntinye nke cholecystokinin (CCK) -B: CCKB na-egbochi na mPFC na-adọta phenotype resilient, ebe CCK na-achịkwa na mPFC na-emetụta nchegbu nchegbu nke ndị mmadụ na nchegbu. Anyị achọpụtalarị na mkpali optogenetic nke mpo na mPFC n'ime ụmụ nnụnụ nwere ike ịghaghachị ọtụtụ ihe ọjọọ ndị a hụrụ mgbe nrụgide na-adịghị ala ala na-emeri nrụgide. Ya mere, anyi chere na optogenetic mkpali nke uzo ozo ga-anaputa ihe omuma nke CCK na mPFC. Mgbe CCK infusion na mPFC, anyị na-akpali optogenetically mpFC projections ka amygdala akwa ma ọ bụ nucleus accumbens, abụọ akụkụ subcortical abuana ke ụkpụrụ ọnọdụ. Mgbalị nke projections corticoamygdala egbochi mmetụta nchegbu nke CCK, ọ bụ ezie na enweghi mmetụta ọ bụla na ihe mgbaàmà ndị ọzọ nke mmeri ndị mmadụ. N'aka nke ozo, mkpali nke uzo corticoaccumbens mere ka CCK megharia ihe ndi mmadu na-acho na ndi mmadu choro ka ha choro ya, ma obughi nchegbu. Otu ihe a na-egosi na nrụgide mmekọrịta mmadụ na ibe ya na-emetụta akụkụ ụfọdụ nke mpempe akwụkwọ na-emetụta ΔFosB na CCK site na ntụgharị ihu ala nke dị iche iche.s.

Keywords: ezumike, amygdala, nchegbu, CCK, ịda mbà n'obi, mPFC

Okwu Mmalite

A na - ejikọta ọtụtụ mpaghara na ụbụrụ ụbụrụ na - arụ ọrụ na - arụ ọrụ na - arụ ọrụ, gụnyere ọnụọgụ mbụ nke mgbochi (mPFC), hippocampus, amygdala, na nucleus accumbens (NAc), na - echekwa isi ihe mgbaàmà nke ịda mbà n'obi na nchekasị (Bremner, 1999; Drevets, 2001; Keedwell et al., 2005; Mayberg et al., 2005; Bremner, 2006, 2007; Krishnan na Nestler, 2008; Feder et al., 2009). Dịka ọmụmaatụ, enweghi nzaghaghachi cortical na amygdala na-ejikọta mmetụta uche dysphoric ma laghachi na ọkwa nkịtị n'ogoro nke ọma. Mmetụta ndị na-emetụta antidepressant nke ụbụrụ miri emi na-akpali mkpụmkpụ nke na-emepụta ihe dị iche iche, akụkụ nke mPFC, jikọtara ya na mweghachi nke nkwonkwo ụbụrụ na nkwonkwo ụbụrụ na ọkwa nkịtị (Mayberg et al., 2005; Nahas et al., 2010). N'otu aka ahụ, mmetụ ụbụrụ nke NAC bụ ihe nkwụsị na nchekasị ma na-adaba na metabolism gbanwere na NAc, amygdala, na mPFC (Schlaepfer et al., 2008; Bewernick et al., 2010; Grubert et al., 2011). Data ndị a na-akwado nkwupụta ụbụrụ netwọk nke nsogbu ọnọdụ uche nke ọgwụgwọ antidepressant, n'agbanyeghị usoro, na-emezi ihe omume na ihe ndị na-adịghị mma na ndị na -Kennedy et al., 2001; Mayberg et al., 2005; Kennedy na Giacobbe, 2007; Fales et al., 2008; Fales et al., 2009; Leistedt na Linkowski, 2013).

Ụdị anụmanụ nke na-ekpugheghị na nchekasị anụ ahụ ma ọ bụ nke uche na-emebi usoro na ọrụ nke neurons na mPFC (Radley et al., 2006), amygdala (Akirav na Maroun, 2007), hippocampus (Surget et al., 2011), NAc (Vialou et al., 2010; Christoffel et al., 2011). Ogologo oge a na-emeri nrụgide, ụdị ezigbo mbà n'obi nke ịda mbà n'obi (Berton et al., 2006), belata mPFC neuronal ọrụ dị ka inferred si belata okwu nke Zif268 na c-Fos (Covington et al., 2005; Covington et al., 2010). Ọzọkwa, optogenetic mkpali nke mPFC reverses ndị a deficits na-eme antidepressant-dị ka mmetụta (Covington et al., 2010), na-ekwenye na mkpa mPFC na-emetụta ọnọdụ uche. Tya na mPFC, dịka na primates, na-achịkwa omume mmetụta uche site na ntinye anya na amygdala (BLA) na NAc (Vogt et al., 1992; Barbas na Blatt, 1995; Heidbreder na Groenewegen, 2003). Ka o sina dị, usoro ihe omimi nke na-akwado ọrụ a nke mPFC nọgidere na-amaghị.

Ihe ọmụmụ a na-amụ ugbu a na-amalite na ΔFosB, ihe na-eme ka a na-edegharị akwụkwọ na NAC site na imerụ nrụgide ebe ọ na-emegide nrụgide nchekasị (Vialou et al., 2010). Anyị na-eji ndepụta ụbụrụ nke ΔFosB eme ihe n'ụbụrụ mgbe anyị merisịrị nchegbu ma chọpụta ya, dị ka ọmụmụ mbụ (Perrotti et al., 2004; Nikulina et al., 2008; Lehmann na Herkenham, 2011), siri ike ntinye na mPFC. N'ụzọ dị ịtụnanya, anyị chọpụtara na mmịnye ΔFosB dị na mPFC na-akwalite nchekasị. Anyị kwuru na onye na-anabata cholecystokinin (CCK) -B dị ka ihe a na-ahụ anya nke ΔFosB na mPFC, ebe CCKergic neurotransmission abanyela na nsogbu nchekasị na nchekasị nke nrụgide mmekọrịta (Becker et al., 2001, 2008). Anyị chọpụtara na ọrụ CCK na mPFC dị mkpa ma zuo oke maka nchekasị - na mmetụta ịda mbà n'obi-dịka mmetụta nke nrụgide mmekọrịta. Ọzọkwa, site na iji optogenetic abịaru nso, anyị na-egosipụta omume CCK ụfọdụ na mPFC subcircuits: CCK na profaịlụ mPFC-BLA na-ebute mgbaàmà nchegbu, ebe CCK na profaịlụ mPFC-NAc kwadoro mgbaàmà ịda mbà n'obi.

Akụrụngwa na ụzọ

Nleta 1: nhazi dum nke ụbụrụ nke ΔFosB site na mmerụ mmadụ na-emeri nrụgide.

Ụmụaka ụmụ nwanyị C57BL / 6J dị izu asatọ ka edoro nsogbu nke ụbọchị 10 dị ka akọwapụtara na mbụ (Berton et al., 2006; Krishnan et al., 2007; Vialou et al., 2010) (lee Isiokwu 1; Fig. 1A). N'okpuru nkenke, a na-ekpughere onye ọ bụla na-amaghị ihe na CD1 na-eme ihe ike maka 5 min kwa ụbọchị. Mgbe ya na onye omekorita CD1 (5 min) na-emekọrịta ihe, a na-etinye ụmụ anụmanụ na mpaghara dị nso nke otu ụlọ ahụ maka 24 h na-esote na sensory, ma ọ bụghị nke anụ ahụ, kọntaktị. Ejiri ụmụ anụmanụ na-achịkwa na-ejikọta ha n'otu ọnụ ụlọ kama ha na ndị òtù otu nsogbu ahụ. A na-enyocha ule mmekọrịta mmekọrịta 24 h mgbe ụbọchị ikpeazụ nke mmeri. A tụlere nsogbu mmekọrịta ọha na eze na CD1 na-amaghị nwoke dịka agbanyere ederede. A tụrụ oge eji "mpaghara mmekọrịta" (eriri 8-cm gburugburu gburugburu). Ekeware oke oke ndi mmadu aka n'ime ndi mmadu ndi mmadu nwere ike ime ya dika akowara na mbu (Krishnan et al., 2007; Vialou et al., 2010). Ebe ọ bụ na ọtụtụ ụmụ oke na-achịkwa na-etinyekwu oge na-akpakọrịta na mmekọrịta mmadụ na ibe ha karịa ka ha na-etinye ihe mgbaru ọsọ efu, enwere mmekọrịta mmekọrịta nke 100 (oge hà nhata na mpaghara mmekọrịta na ọnụnọ na enweghị mmekọrịta mmadụ na ibe ya) ejiri mee ihe dị ka ihe nkwụsị: ụmụ oke nwere akara <100 ka akpọrọ "ngwangwa," ndị nwere ọtụtụ ≥100 ka "ndị nwere ume." Omume, biochemical, na nyocha nke electrophysiological sara mbara na-akwado nkwado nke ndị a dị iche iche na-agbanwe agbanwe ma na-agbanwe agbanwe (Krishnan et al., 2007; Wilkinson et al., 2009; Vialou et al., 2010).

Nọmba pụtara (± SEM) nke FosB-nuclei immunoreactive kwa mm² na ụbụrụ ụbụrụ nke na-achịkwa, enwere ike, ma na-amụba ụmụ oke 24 h mgbe ndị na-adịghị ala ala (10 d)

Nyocha 1.

Ntinye nke ΔFosB na mPFC na-akwalite inwe nsogbu na nrụgide. A, Mpempe akwụkwọ ndị nnọchiteanya nke ΔFosB immunohistochemistry na mPFC 24 h mgbe ikpeazụ nke 10 mmeri mmeri. B, Ntinye nke ΔFosB anaghị eme na GABAergic ...

Ozugbo a nwalere mmekọrịta mmadụ na ibe ya, a na-eme ka ụmụ irighiri ihe dị na ya ma jiri ya na 4% paraformaldehyde / PBS gụnye ya. Ọnụ ọgụgụ Cell dị maka ΔFosB⁺ enwere neurons na NAc dị ka akọwapụtara na mbụ (Vialou et al., 2010). A na-eji ụbụrụ 30% sucrose na ngalaba coronal (30 μm) kpoo ahụ ụkwụ na-egbuke egbuke ma na-edozi maka immunohistochemistry. Mpaghara ndị na-ese n'elu mmiri na-egbuke egbuke na-echekwa na nchekwa na-egbochi na-enwe 0.3% Triton na 3% nkịtị akpụkpọ ewu. Achọpụtara ΔFosB site na iji ọgwụ mgbochi polyclonal nke rabbit zụlitere megide akụkụ N-terminal nke protein (1 / 1000 Santa Cruz Biotechnology, catalog # sc-48) na otu ihe ahụ, wee dezie ya na biovidylated goat anti-rabbit Igbodies na avidin-biotin usoro siri ike peroxidase na DAB dị ka mkpụrụ (Vector Laboratories). A na-anọgide na-enwe mgbe ọ bụla a na-emepụta ihe na-eme ka ọ bụrụ na ọ na-eme ka ọ bụrụ mgbe ọ bụla ọnọdụ (100 s). A na-etinye mkpụrụ osisi, na-akpọ nkụ, ma na-ekpuchi. ΔFosB-cell immunopositive gosiri otu akpụkpọ anụ na-acha uhie uhie na ngwongwo ya ma bụrụ onye onye na-ahụ ihe na-ahụ anya na-akọwa ya na ọnọdụ ọgwụgwọ na-eji microscope (20 × magnification). A họọrọ ụbụrụ ụbụrụ atọ a na-ahọpụta akụkụ nke ọ bụla n'ụbụrụ maka òké maka nhazi. A na-emepụta akụkụ nke ụbụrụ nke ọ bụla site na atụnyere ngalaba ahụ na mkpịsị ụbụrụ ụbụrụ Paxinos. A na-ahazi usoro maka immunohistochemistry iji belata nzụlite dị elu na opekempe nke na-ekwe ka njirimara ziri ezi nke mkpụrụ ndụ ΔFosB-positive. A na-agbakọ ọnụ ọgụgụ dị mkpa maka anụmanụ ọ bụla ma weere ya dịka nchọpụta nke mmadụ maka nyochapụta ọnụ ọgụgụ. Ọ bụ ezie na mgbochi a na - eji amata ma ΔFosB na FosB zuru oke, anyị maara site na nkwụsị nke Ebe Ọdịda Anyanwụ na naanị ΔFosB nwere ike ịchọpụta n'okpuru ọnọdụ amụrụ (Perrotti et al., 2004; Vialou et al., 2010).

Nleta 2: njirimara nke nrụgide na-elekọta mmadụ ΔFosB neuronal phenotype na mPFC.

Iji nyochaa okwu nke ΔFosB na mkpanaka GABAergic cortical, anyị na-eji anụ ndị sitere na ụmụ GAD2-tdTomato gosipụtara mmerụ na-adịghị ala ala na-emeri nrụgide na ntụpọ maka ΔFosB dị ka a kọwara n'elu (lee Fig. 1B). Eke site na ozuzu kụrụ aka GAD2-Cre ụmụ oke (Gad2tm2 (cre) Zjh / J; JAX nọmba ahịa 010802) (Taniguchi et al., 2011) na (B6.Cg-Gt (ROSA) 26Sortm9 (CAG-tdTomato) Hze / J; JAX nọmba nsonye 007908) nke na-ebu ngwụsị-akwụsị ịchịkwa tdTomato (RFP variant).

Nleta 3: mmetụta omume ΔFosB overexpression na prelimbic (PrL) na infralimbic (IL) cortex.

Ejiri ịwa ahụ mgbochi na ụmụ oke okenye (8 izu) iji gbanye HSV-ΔFosB-GFP ma ọ bụ HSV-GFP n'ime mpaghara PrL ma ọ bụ mpaghara MPFC. Na nkenke, a na-eme ka ụmụ irighiri ihe na-eji ngwakọta nke ketamine (10 mg / kg) na xylazine (1 mg / kg), na nchịkọta stereotaxic ndị a na-esote maka nnyefe viral maka PrL: 1.8 mm (n'ihu / posterior), 0.65 mm (mpụta ), -2.2 mm (dorsal / ventral); na maka IL: 1.9 mm (ihu / azụ), 0.75 mm (mpụta), -2.8 mm (dorsal / ventral) n'otu akụkụ nke 10 ° site na midline (gbasara bregma). Ọnụ ọgụgụ nke 0.5 μl nke nje ọcha bụ nke a napụtara bilaterally karịa oge oge 5 (0.1 μl / min) na 5 min nke ezumike. E gosipụtara saịtị ndị na-agba ọgwụ mgbochi site na iji usoro akụkọ ihe mere eme (lee Fig. 1C). Ọ bụ ezie na ọ gaghị ekwe omume iji nlezianya dozie PrL versus IL na ụmụ oke na oke zuru oke, data na Nyocha 1C gosiputa na o nwere ike imebi otu mpaghara ma obu nke ozo. N'ezie, mmetụta omume dị iche iche e nwetara site na icheta mpaghara abụọ ahụ (lee Nsonaazụ) na-egosi nke a. A na-eji nchịkọta mbụ nke ụmụ oke na-eme ihe n'ụzọ zuru ezu na-emeri nnwale (lee Fig. 1D). Ụbọchị atọ mgbe a wachara ya ahụ, e tinyere ụmụ nnụnụ abụọ na nhụjuanya abụọ n'otu ụbọchị ahụ ma nwalee maka mmekọrịta 24 mgbe ọ bụla. A kwadoro usoro mmeri a dị oke mma n'oge gara aga iji kpughee phenotypes na-aga nke ọma na-esochi aka mkpụrụ ndụ (Krishnan et al., 2007; Vialou et al., 2010).

A na-eji nchịkọta nke ugbo abụọ anwale maka nchekasị na-ada mbà- na omume ịda mbà n'obi (lee Fig. 1E-J). Otu ụbọchị mgbe a wachara ha ahụ, ụmụ anụ ahụ nọ na-enweta ihe ngwọta 1% (w / v) sucrose. N'echi ya, ụmụ oke nwere ike ịhọrọ n'etiti otu mmiri mmiri na igbe 1% sucrose, gbanwere kwa ụbọchị. Aghapụtara ngwọta ngwọta nke 24 h n'oge nke anọ na nke ise mgbe a gwọchara ya ma kọwaa dịka pasent nke ngụkọta mmiri mmiri. A nwalere ụmụ oke n'ọhịa (ụbọchị 3), elu elekere (4 XNUM), mmekọrịta mmekọrịta (ụbọchị 5), na mmiri a na-agba mmiri (nke 5 n'ehihie) na-adabere na usoro ederede (Vialou et al., 2010). Anyị achọpụtala na, na usoro nyocha nke a, ọ na - apụta na nyocha ndị ọzọ agaghị emetụta ndị gara aga (Krishnan et al., 2007). A na-edekọ ọrụ nke ụmụ oke n'èzí maka 5 min site na iji usoro videotracking (Ethovision) n'okpuru ọnọdụ ọkụ uhie. Uzo elu a di elu nwere uzo ozo di n'etiti 60 cm n'elu ala ma kewaa n'ime oghere abuo na abuo. A na-etinye ụmụ nnụnụ n'otu n'otu n'etiti etiti ahụ ma kwe ka iji nyochaa ogwe aka ọ bụla maka oge 5 min. N'ọhịa oghe na elu elu, a na-eji oge etinye aka na etiti na ogwe aka, dịka ntụzigharị ntụgharị nke mmeghachi omume metụtara nchegbu. Otu ụbọchị a na-anwale ule mmiri mmiri maka oge 5 min. Ogologo oge nke omume na-eme mgbe a na-anwale ule mmiri a na-agba mmiri ka a sụgharịrị dịka àgwà omume mmechi. A na-eji otutu ule 1 eme ihe ugbu a n'ime ụmụ oke ma mee ka ọ bụrụ ihe dị irè, dịka ọgwụ ọgwụ ndị na-egbochi ọgwụ ọjọọ na-ebelata oge na-enweghị ego.

N'ikpeazụ, otu ìgwè dị iche iche nke ụmụ oke anwụrụ intra-mOFC na HSV-ΔFosB ma nwaa maka mmekọrịta mmadụ na ibe ya mgbe e merisịrị mmeri (lee Fig. 1K).

Enwetara HSV vectors sitere na Rachael Neve (Massachusetts Institute of Technology). Mkpụrụ ndụ nke mmasị (ΔFosB na GFP) dị n'okpuru onye nkwalite CMV. A nabatara ngwa ngwa ndị a na akwụkwọ ndị bu ụzọ (dịka, Maze et al., 2010).

Nlekọta 4: mmetụta nke nrụgide mmekọrịta na-adịghị ala ala na ọkwa CCKB na mPFC.

Na 24 h mgbe a chọpụsịrị mmekọrịta mmadụ na ibe ya, a napụrụ ngwa ngwa ngwa ngwa na sliced, na mPFC na-agbasasị ngwa ngwa ma na-ekpo ọkụ n'elu akọrọ akpọrọ (lee Fig. 2A,B). RNA nkewa, qPCR, na nyocha data mere dika edewara na mbu (Maze et al., 2010; Vialou et al., 2010). Ejiri trigon TriZol (Invitrogen) wepụ RNA ma jiri ya mejupụta kpochapụm RNAeasy na QIAGEN. Ihe nyocha RNA nile kpebisiri ike inwe 260 / 280 na 260 / 230 maka ≥1.8. A na-eji nsụgharị ntụgharị mee ihe site n'iji iScript (Bio-Rad). Ejiri SYBR Green (Quanta) mee ihe na usoro 7900HT RT PCR na-eme ihe na-esonụ: 2 min na 95 ° C; 40 cycles nke 95 Celsius C maka 15 s, 59 Celsius C maka 30 s, na 72 Celsius C maka 33 s; na kpochapu ọkụ na 95 Celsius C iji mee ka ihe nkwụsịtụ maka nkwenye nke otu PCR ngwaahịa. A na-enyocha data site na iji C atụnyere ya_t Ụkpụrụ nke ọnọdụ ọgwụgwọ (nwere ike ịnagide ma ọ bụ na-achịkwa ụmụ anyị, ma ọ bụ HSV-ΔFosB vs HSV-GFP) na ΔΔC_t usoro (Tsankova et al., 2006). qPCR primers bụ ndị a: ΔFosB, n'ihu, AGGCAGAGCTGGAGTCGGAGAT na azu, GCCGAGGACTTGAACTTCACTCG; CCKB, gaa n'ihu, ACCCTTATATGCGGTGATCTTTC ma gbanwee, ATGAGCACGTTTCCGCCAA; CCK, gaa n'ihu, AGCGCGATACATCCAGCAG na azu, ACGATGGGTATTCGTAGTCCTC; GAPDH, gaa n'ihu, AGGTCGGTGTGAACGGATTTG ma gbanwee, TGTAGACCATGTAGTTGAGGTCA.

Nyocha 2.

Blockade nke CCKB na-enweta ihe nkwado, mmetụta antidepressant-dịka. A, Mmetụta ndị mmadụ na-eme ka ọkwa CCKB dị na mPFC naanị na ụmụ oke mgbochi (n = 8-10). *p <0.05, jiri ya tụnyere njikwa (otu ụzọ ANOVA). **p <0.05 ...

Nleta 5: mmetụta nke ΔFosB na nnabata CCKB na ọkwa CFos.

Ejiri ụmụ irighiri intra-PrL na HSV-ΔFosB. Na 72 h mgbe ịwachara ahụ, na ọnụ ọgụgụ kasị elu nke overexpression, a na-ekesa ebe ndị ogbugba n'okpuru microscope fluorescent (lee Fig. 2C). RNA nkewa, qPCR, na nyocha data mere dika akọwara n'elu. qPCR primers bụ ndị a: c-fos, gaa n'ihu, AATCCGAAGGGAACGGAATAAGA ma gbanwee, TGCAACGCAGACTTCTCATCT.

Nleta 6: mmetụta nke ΔFosB na-egbochi nrụgide CCKB na nsogbu na resilience.

A na-agbara ụmụ oke ụmụ ahụhụ bilada na HSV-GFP ma ọ bụ HSV-ΔJunD n'ime PrL (lee Fig. 2N 'F). ΔJunD bụ onye na-ejikọta ọnụ na N-terminal nke JunD nke na-eme dị ka onye na-emegide onye na-adịghị mma nke ΔFosB. A na-emeri ụmụ nwanyị ugboro abụọ kwa ụbọchị maka 5 d. Nke a na-eme ka usoro mgbasa ozi ndị mmadụ na-emewanye ngwa ngwa, dị mkpirikpi ka o kwekọọ na oge kachasị okwu HSV transgene, e jiriwo mee ihe n'oge gara aga ma gosiputa ime ka ndị mmadụ ghara ịba uru (Covington et al., 2011). Na 24 h mgbe nsogbu nrụgide ikpeazụ gasịrị, e bepụrụ oke oke na-enweghị ọgwụ iji zere mmetụta nke ọgwụ na-akụnwụ ahụ na protein protein. E wepụrụ anụ ahụ nje ahụ na PBS nwere protease (Roche) na phosphatase (Sigma-Aldrich) ndị na-eme ihe iji akara ntanye 15 wee mee ka mmiri kpọnwụrụ ngwa ngwa. Ihe nlere site na sonication nke dị na nchekwa RIPA gbanwere ihe atụ: 10 mm Tris base, 150 mm sodium chloride, 1 mm EDTA, 0.1% SDS, 1% Triton X-100, 1% sodium deoxycholate, pH 7.4, na protease na phosphatase inhibitors dị ka n'elu. Mgbe mgbakwunye nke nchekwa Laemmli, e kewara ndị na-edozi na 4-15% polyacrylamaide gradient gels (Criterion System; Bio-Rad), na Western blotting rụrụ site na iji usoro Odyssey (Li-Cor) dị ka usoro nke onye nrụpụta. Ehichapụrụ Membranes na CCKB onye na-anabata ihe (1/1000, Acris, katalọgụ # AP01421PU-N). A gbanyekwara ìgwè ọzọ nke ụmụ oke na AAV-ΔJunD ma ọ bụ AAV-GFP na PrL na mgbe ahụ, izu 5 mgbe a wachara ya ahụ iji kwe ka okwu transgene kachasị elu, e nyefere ụmụ oke ahụ na usoro mmeri nke submaximal. A nwalere ha maka mmekọrịta mmadụ na ibe ya 24 h mgbe mmeri ikpeazụ gasịrị.

Nlekọta 7: mmetụta nke intra-mPFC CI-988, onye na-emegide CCKB, na nrụgide mmekọrịta-nke mere ka a zere ihe na-eme ka ọha na eze ghara ime ihe.

Osisi nwere ike ịbanye (1.0 mm cannula na anya cannula, oghere 1.8 mm, injector -2.2 mm dorsal / ventral) na-echebe mPFC ka a na-etinye n'ime ụmụ oke nwere ike ịhụ (lee Fig. 2G,H). Otu izu mgbe a gwọchara gị, 10 ng nke CI-988 tinyere mPFC, nke bụ isi PrL. A na-anwale ụmụ nwanyị maka àgwà mmekọrịta ha na ibe ha. A na-atụle mmasị na-atụ aro maka nke fọdụrụ na 24 h. CI-988 (Tocris Bioscience) gbazere na saline, edozi ya, na oyi. A kwadebere mgbatị ikpeazụ n'ụbọchị nnwale ahụ. E mere nnwale ọzọ na ụmụ anụ ndị nwere ike ịbanye na CI-988 bụ 2 mg / kg) nke na-elekọta 30 min n'ihu nyocha mmekọrịta mmekọrịta.

Nleta 8: mmetụta nke CCKB agonist na-enwe mmetụta nke nrụgide mmekọrịta na mgbanwe site na nkwalite optogenetic nke mPFC projections ka BLA ma ọ bụ NAc.

AAV-CaMKII-ChR2-EYFP ma ọ bụ AAV-CaMKII-EYFP abanye n'ime mPFC ziri ezi, ọzọ na-elekwasị anya bụ PrL (lee Fig. 3A-G). Izu ise mgbe e mesịrị, a na-etinye eriri ntinye na NAc ziri ezi (1.4 ihu / azụ, 2.6 mpụta, -4.7 dorsal / ventral na n'akuku 25 Celsius site na midline) ma ọ bụ BLA (-1.6 ihu / azụ, 3.1 mpụta, -4.7 dorsal / ventral na-enweghị akụkụ site midline). N'oge a na-arụ ọrụ ahụ, a na-esite na mPFC banye na mpFC (lee n'elu). A na-enye Cannulae na eriri aka na okpokoro isi na ciment. A na-ahapụzi ụmụ ndị mmadụ ka izu 1 gbakee tupu mmalite nke mmezi omume. A na-emeri ụmụ oke ahụ, mgbe ahụ nwalere 24 h mgbe e mesịrị maka mmekọrịta mmekọrịta, nke a na-esote ya na ndị ọzọ maka ọchịchọ nke sucrose maka 24 h. Na 30 min tupu enwere mmekọrịta mmekọrịta, ọkara nke ụmụ oke e nyere CCK-8 (10 ng) n'ime mPFC ka ọkara nke ọzọ natara ụgbọala (saline). A na-anwale ụmụ oke abụọ (ụgbọ-na akara CCK-8, tinyere AAV-GFP ma ọ bụ AAV-ChR2). CCK-8 (Sigma) gbazere na saline, edozi ya, na oyi kpọnwụrụ. A kwadoro nbibi ikpeazụ nke ụbọchị nnwale ahụ.

Nyocha 3.

CCK-8-na-ebute nrụgide nchekasị dabere na ntụgharị ihu ndị dị mkpa. A, Na 24 h mgbe mmeri nke obere na 30 min mgbe CCK-8 jikọtara, mpaghara mPFC na-atụgharị na-laser-kpaliri n'oge ule maka mmekọrịta mmekọrịta. CCK-8 infusion ...

A na-eme mkpali na-arụ ọrụ dịka usoro iwu si edepụta (Covington et al., 2010). A na-ejikọta eriri ngwa ngwa (Thor Laboratories) na njikọta PC / PC na dioner dio laser 473 (Crystal Lasers, BCL-473-050-M). A na-eji stimulator (Agilent, #33220A) mee ihe maka ịmepụta ọkụ ọkụ. N'oge mkpali niile, 40 ms bursts nke 100 Hz (9.9 ms spike width) a na-enye ihe ọkụ ọkụ na-acha anụnụ anụnụ ọ bụla 3 s ruo mpaghara mpaghara na BLA ma ọ bụ NAc karịa ogologo oge nyocha nke mmekọrịta mmadụ na ibe ya, iji mee ka ihe dị ka nke dị na cortical ọrụ. E gosipụtara ike nke ìhè nyocha opi tupu ojiji nke ọ bụla, na-eji ụda ọkụ (Thor Laboratories, S130A), ọkụ ọkụ bụ ~15 mW. Nke a na-akpali akpali protocol, nke e validated electrophysiologically na mbụ (Covington et al., 2010), emeghị ka ọkpụkpụ na-adabere na omume omume na enweghi okwu c-Fos na-abụghị nke optogenetically kpaliri n'ógbè (Covington et al., 2010).

Nleta 9: mmetụta nke agonist CCKB na arụ ọrụ mPFC na-emeghị ka ọ bụrụ na a tụrụ ya site na ọkwa cRoos C-Fos.

Enwere ike ịbanye na ụmụ anụ ndị toro eto na mPFC (lee Fig. 3H). Mgbe izu izu zuru ezu, e meriri ụmụ oke na-emetụta CCK-8 24 mgbe e mesịrị. A na-ewere mpe ntụpọ mPFC 30 min mgbe ọgwụ ọgwụ na-aṅụ ọgwụ, na ihe atụ ndị akwadoro maka mRNA analysis dị ka akọwapụtara n'elu.

Ụlọ anụmanụ.

Eji C57BL / 6J ụmụ oke anụ asatọ (The Jackson Laboratory) mee ihe. Azụ anụ niile nọ na-elekọta anụ ụlọ anụ ọhịa ma ọ dịkarịa ala izu 1 tupu ha emee nchọpụta ma nọgidere na-enwe na 23 Celsius C-25 ° C na nsonye 12 h / ọchịchịrị (ọkụ na 7: 00 AM) na ad libitum nweta nri na mmiri. E mere nlere anya dịka ntụziaka nke Society maka Neuroscience na Ụlọ Ọrụ Nlekọta Ụmụ anụmanụ na Nlekọta anụmanụ na Icahn School of Medicine na Ugwu Saịnaị.

Nnyocha nchịkọta akụkọ.

E gosipụtara ngosipụta data dị ka pụtara ± SEM (nọchiri anya ya dị ka ogwe ntụhie). Ejiri otu ANOVA mee ihe iji tụnyere ihe nchịkwa, nke nwere ike isi na ya, ma na-eme ka ụmụ ya nwee ike ịmịnye ume na ọgwụ ndị na-emepụta ọgwụ, usoro ọgwụ, na nyocha nke omume. Eji ANOVA na-eme ihe iji tụnyere ụzọ n'etiti njikwa GFP na ΔFosB overexpression na PrL ma ọ bụ IL na ogige, ogige dị elu, mmiri mmiri a na-agba mmiri, na nyocha nke sucrose. E jiri ụzọ ANOVA mee ihe abụọ iji tụnyere ihe jikọrọ GFP, njikwa, ΔFosB-PrL, na ΔFosB-IL na ule mmekọrịta mmekọrịta. Eji ANOVA ụzọ abụọ jiri akara CCK-8 tụnyere ma ọ bụ na-enweghị optogenetic mkpali na nyocha niile omume, yana mmetụta nke ΔFosB overexpression ma ọ bụ CI-988 infusion na izere mmekọrịta. Mgbe o kwesiri, post hoc nyochaa e mere site na iji Bonferroni post hoc nwalee. Mmụta t a na-eji nyocha iji nyochaa isi ihe maka mmetụta nke CI-988 infusion na nhọrọ sucrose na ule a na-egwu mmiri egwu, na nke CCK-8 na c-Fos eto mRNA. A na-ewere esemokwu dị n'etiti ọnọdụ nchọpụta dịka ihe dị ịrịba ama mgbe p ≤ 0.05.

Results

Mbipụta nke ọnụọgụ azụ nke ΔFosB site na mmerụ mmadụ na-emeri nrụgide

Anyị buru ụzọ nyochaa ΔFosB ntinye nke immunohistochemistry na nchịkwa, enweghi ike, ma na-eme ka ụmụ irighiri ihe na-aga n'ihu, mgbe usoro ihe na-adịghị ala ala (10 d) na-emetụta nrụgide, na-elekwasị anya n'ememe ụbụrụ na mpaghara midbrain bụ ndị nwere nsogbu n'oge gara aga. A na-enyocha ụmụ anụmanụ na 24 h mgbe mmeri ikpeazụ meriri. Ahụhụ na-adịghị mma na-emetụta ΔFosB n'ọtụtụ ebe ụbụrụ na-enwe ihe dị iche iche dị iche iche na-ahụ n'etiti ụmụ nnụnụ na ndị nwere ike ịda mbà. Dị ka egosiri na Isiokwu 1 na Nyocha 1A, IL, BLA, denty gyrus of hippocampus, dorsal striatum, na NAc gosipụtara nkwado dị mma na ụmụ oke resịient; ihe ndị dị na NAc kwekọrọ na nchọpụta a bipụtara (Vialou et al., 2010). N'iche dị iche, ụmụ oke nwere ike ịmalite ịmalite na PrL, septum larịị, na ụra nke stria terminalis. Ọtụtụ mpaghara ụbụrụ gosipụtara ntinye nke ΔFosB na ụmụ oke nwere ike ime ka ha sie ike; ndị a gụnyere orbitofrontal cortex (OFC, mpaghara ọzọ nke PFC), Nac shell, dorsal raphé, na periaqueducal agba ntụ (PAG).

Iji chọpụta ntinye ntanetụ nke na-egosipụta duction nke ΔFosB na mpaghara ndị dị na cortical, GAD2-tdTomato ụmụ na-edozi nrụgide na-adịghị ala ala. Achọpụtaghị ΔFosB na ụmụ anụ ndị nwere ike ịbụ ndị na-adịghị ahụkebe na GABAergic neurons (Fig. 1B), nke na-akwado nchoputa nke mbụ nke ntinye nke ΔFosB na uzo pyramidal cortical mgbe e mechara ihe ndi ọzọ na -Perrotti et al., 2004). Na ụmụ oke na-achịkwa ụmụ oke, isi nchịkọta ΔFosB n'ofe ụbụrụ ụbụrụ yiri nke ndị ahụ kọrọ na ọmụmụ ihe gara aga (Perrotti et al., 2004, 2008) na ọkwa dị elu nke dị elu na NAc na dorsal striatum ma e jiri ya tụnyere mpaghara ọ bụla ọzọ, na otu nkwụsị nke denty gyrus, nke gosipụtara ogoogo ndị dị na mpaghara ndị dị na mpaghara (Isiokwu 1).

ΔFosB na mPFC na-akwalite ihe nrụgide na nrụgide

Iji nyochaa nchọpụta ndị a, anyị lekwasịrị anya na PrL n'ihi na anyị gosipụtara na mmalite nke optogenetic nke mpaghara a gosipụtara mmetụta ndị na-emetụta antidepressant na mmeri nke mmadụ (Covington et al., 2010). Iji nyochaa arụ ọrụ sitere na ntinye nke ΔFosB na ụbụrụ ụbụrụ a, anyị kwupụtara ΔFosB na PrL nke akara ụmụ oke (Fig. 1C) ma mee ha ka ha bụrụ ihe ga-eme ka a ghara imeri nrụgide, nke na-adịghị eme ka mmadụ zere anụmanụ na anụmanụ. Mice overexpressing ΔFosB na PrL bụ ndị ọzọ susceptible ka mmadụ mmeri karịa GFP-injected akara ụmụ oke na na ha gosiri izere omume omume mgbe submaximal mmadụ mmeri (mmekọrịta, F_(2,38) = 2.847, p > 0.05, isi mmetụta nke nje, F_(2,38) = 6.013, p <0.05; Bonferroni nyocha t = 2.447, p <0.05) (Fig. 1D). Ụmụ oke ndị a egosikwara ụbawanye ego na nsonye 1 nke a na-agba mmiri egwu (F_(2,31) = 6.448, p <0.05; Bonferroni nyocha t = 3.518, p <0.05) (Fig. 1E), mmetụta dị iche na nke ahụ na-eji ọgwụ ọjọọ emepụta. N'adịghị iche, ΔFosB overexpression na PrL agbanweghị ọtụtụ usoro nhazi nke omume nchegbu, nhọrọ sucrose, mmekọrịta mmekọrịta mmadụ na ibe ya, ma ọ bụ ọrụ ntinye ala (Fig. 1F-J). Otu a, nchọpụta ndị a na-akwado nkwenye ahụ na ntinye aka nke ΔFosB na PrL nke ụmụ nnụnụ nwere ike itinye aka na nrụgide na nsogbu ya. N'ụzọ dị iche, ΔFosB overexpression na mpaghara ọzọ nke mPFC, IL, enweghị mmetụta na àgwà mmetụta uche ma ọ bụ nzaghachi maka nsogbu nrụrụ aka mmadụ. (Fig. 1D-J), ma ΔFosB overexpression na medial OFC na-eche ihu n'ịkwalite mgbanwe iji merie mmeri ndị na-adịghị ala ala, ọ bụ ezie na mmetụta a eruteghị ihe ndekọ statistical (mmekọrịta, F_(1,31) = 1.741, p > 0.05, isi mmetụta nke oge mmekọrịta, F_(1,31) = 14.170, p <0.05; Bonferroni nyocha t = 3.860, p <0.05 n'ime otu GFP; t = 1.960, p <0.05 n'ime ΔFosB otu; mmetụta nke nje, t = 2.447, p <0.05) (Fig. 1K).

ΔFosB na-akwado nkwalite CCKB na mPFC

Nnukwu ihe àmà na-akwado echiche ahụ bụ na CCK, bụ ụbụrụ neuropeptide dị ukwuu, na-arụ ọrụ dị mkpa na usoro ihe ndị na-adịghị na-akpata nsogbu na nchekasị (Rotzinger na Vaccarino, 2003). Karịsịa, ntọhapụ nke CCK na MPFC n'oge nrụgide mmekọrịta na oke nwere njikọ metụtara àgwà nchegbu (Becker et al., 2001). Ọ bụ ezie na itinye aka nke CCK na ịda mbà n'obi mmadụ ka nọgidere na-edoghị anya, ihe àmà ndị na-adịbeghị anya na-egosi ọrụ ya na mmeri ndị mmadụ-eme ka omume ụmụ ịda mbà n'obi na -Becker et al., 2008). Anyị si otú ahụ chee na mgbanwe na ọkwa nke CCK ma ọ bụ CCKB (nke a makwaara dị ka CCK2) na-enweta na mPFC nwere ike itinye aka na ọdịiche dị n'etiti ụmụ oke nwere ike ịkụzi. Na 48 h mgbe mmeri ikpeazụ meriri, ọkwa CCKB mRNA na-ebelata na mPFC nke ụmụ irighiri ihe na -F_(2,18) = 8.084, p <0.01; Bonferroni post ule, t = 3.104, p <0.05 vs njikwa; t = 5.113, p <0.01 na-adighi ike) (Fig. 2A). Enweghị ọdịiche dị na ọkwa CCR mRNA dị na ụmụ oke ma ọ bụ na-edozi (data egosighi). Anyị hụrụ mmụba na ΔFosB MRNA na-eto eto nanị na anụ ndị nwere ike ime ihe kwekọrọ na protein data kọrọ n'elu (F_(2,18) = 5.246, p <0.01; Bonferroni nyocha t = 3.336, p <0.05 na-adighi ike; t ule t₍₁₂₎ = 2.138, p <0.05 vs njikwa) (Fig. 2B). N'ihi na ΔFosB na-achịkwa nsụgharị nke ọtụtụ mkpụrụ ndụ ihe nketa (McClung na Nestler, 2003; Winstanley et al., 2007), anyi lere anya na o nwere ike idozi okwu CCRB mRNA. Iji zaa ajụjụ a, anyị kwupụtara ΔFosB na PrL mbụ ma chọpụta na nhazi a na-eme ka CCKB mRNA nọ n'ọnọdụ a (t₍₁₂₎ = 2.012, p <0.05 na GFP) (Fig. 2C). N'ụzọ na-akpali mmasị, anyị na-ahụkwa ọnụ ọgụgụ c-Fos MRNA ọkwa mgbe ΔFosB overexpression (t₍₁₁₎ = 3.382, p <0.01) (Fig. 2C). Tihe nchoputa nke ozo na-egosi na mmuta ΔFosB na PrL nke oke ohia nwere ike ime ihe site na igbochi mkpochapu nke CCKB a na-ahuta n'ime oke umuaka.

Iji mee ka nkwenye ndị a dịkwuo ike, anyị kwusiri ike na ΔJunD, onye mmekọ ΔFosB nke na-enweghị ọrụ transactivation na-eme ka ọ bụrụ onye na-eme ihe na-adịghị mma, ma kpebie mmetụta ya na okwu CCKB kpatara nrụgide. Anyị kwadoro na mmerụ ahụ na-adịghị ala ala na-eme ka nrụrụ CCKB mụbaa na PrL nke ụmụ irighiri anụ ahụ (t ule t₍₁₂₎ = 2.289, p <0.05 vs njikwa) (Fig. 2D,E). Ozokwa, ụdị mmeghe a kpam kpam site na ΔJunD overexpression na mpaghara a (F_(2,20) = 6.306, p <0.01, Bonferroni post nyocha t = 3.615_, p <0.01) (Fig. 2D,E), na-akwado nkwenye ahụ na ΔFosB na-akwado nrụgide - mejupụtara okwu CCKB. Ọzọkwa, igbochi ọrụ ΔFosB na PrL, site na okwu mpaghara ΔJunD, na-akwalite resilience iji merie nrụgide (t ule t₍₁₆₎ = 2.114, p = 0.05 na njikwa) (Fig. 2F). Usoro nke na-adabere na ukpuru CCKB na ụmụ ya na-ebugharị na-anọgide na-ebuli elu.

Ọrụ nke CCKB na nkwụsi ike na nrụpụta nke nrụgide

Iji nyochaa kpọmkwem ọrụ nke CCKB iwu na PrL na ịkọwa ihe na-adabere na resilience, anyị tinyere CK-988 (10 ng) onye na-anabata ihe CCKB ozugbo na ụbụrụ nke ụbụrụ nke nwere ike ịbanye. CI-988 na-akwado ndị nabatara CCKB n'ụzọ dị irè na vivo n'ihi na ọ na-egosipụta njikọta nanomolar na nnukwu selectivity maka CCKB receptor subtype (Noble et al., 1999). Ịgbachibido ọrụ CCKB siri ike mụbaa mmekọrịta mmekọrịta mmadụ na ibe ya (Fig. 2G) (mmekọrịta, F_(1,20) = 7.795, p <0.05; ogwu F_(1,20) = 5.38, p <0.05, Bonferroni post nyocha t = 3.615_, p <0.01). Mkpụrụ-CI-988 na-atụgharịkwa ụkọ na mmasị sucrose a hụrụ na ụmụ oke nwere ike ịmalite (t₍₈₎ = 2.681, p <0.05) (Fig. 2H). Ihe abụọ omume gosipụtara na nchichi nke CCK edinam na PrL na-egosipụta mmetụta dị ike nke antidepressant-dị ka mmetụta. N'ụzọ na-adọrọ mmasị, mgbe a na-eme ya na intraperitoneally, CI-988 adịghị arụ ọrụ n'ịghagharịa nzere ọha na eze (data egosighi).

Iji nyochaa mkparịta ụka ahụ, mmalite nke CCKB na PrL nwere ike ime ka ihe ize ndụ nke ọha na eze kwụsị ma mee ka ndị mmadụ nwee mmerụ sucrose site na imeri nrụgide, anyị nyochachara mmetụta nke mmikpu nke CCK-8 (10 ng), ụdị CCK kachasị na ụbụrụ , na ịda mbà n'obi- na omume ndị nchegbu. A họọrọ ọgwụ nke ọgwụ ahụ dabere na nsonaazụ gara aga na akwụkwọ (De Witte et al., 1987; Rotzinger na Vaccarino, 2003; Zanoveli et al., 2004). Ụmụ nwanyị na-egosiputa na ha ga-emeri nrụgide 24 h tupu enwele akpa àgwà (Fig. 3A). CCK-8, nyere 30 min n'ihu ule, zuru ezu iji mee ka a zere ọha na eze na nlekọta mmekọrịta mmekọrịta yana mgbatị na oge a na-emeghe na ogwe aka dị elu (SI: BLA, mmekọrịta, F_(1,22) = 0.79, p > 0.05; isi mmetụta nke ọgwụ, F_(1,22) = 11.75, p <0.05; Bonferroni nyocha t = 2.957_, p <0.05; NAc: mmekọrịta, F_(1,26) = 6.688, p <0.05, Bonferroni post nyocha t = 2.816_, p <0.05; EPM: BLA, mmekọrịta, F_(1,22) = 8.0, p <0.01; Bonferroni nyocha t = 2.509_, p <0.05 ọgwụ mmetụta; t = 2.528, p <Nsogbu 0.05; NA, t ule t₍₁₇₎ = 1.961; p <0.05 ọgwụ na-emetụta n'ime ìgwè eYFP) (Fig. 3B-E, n'aka ekpe). Enweghi esemokwu di na chorose (Fig. 3F,G, n'aka ekpe). N'ikpeazụ, CCK-8 infusion enweghị mmetụta n'àgwà (mmekọrịta mmadụ na ibe ya ma ọ bụ ndị ọzọ dị elu) nke ụmụ irighiri ihe ndị a na-enweghị atụ na nyocha ndị a (data egosighi). Tihe ndị a na-egosi na mmụba ΔFosB na-arịwanye elu na ọrụ CCKB na PrL nke ụmụ irighiri ihe ndị dị na ya, ma e jiri ya tụnyere ụmụ oke, na-enye aka na ụfọdụ mmejọ omume na-akpata nrụgide nke ụmụ anụmanụ ndị a na-egosipụta.

Blockade nke CCK-emetụta ihe omume na nrụgide site na mbido nke cortical projections ka BLA versus NAc

Mmebe nke mPFC na-adakpọ na ịda mbà n'obi-dị ka omume ụmụ oke, na-akpali akpali nke optogenetic nke mPFC nke mkpụrụ ndụ nke nwere ike na-emepụta antidepressant-dị ka mmetụta (Covington et al., 2010). Anyị si otú ahụ kwenye na CCK nwere ike ime ihe na PrL site n'ịgbachi ọrụ mmechi ahụ ma si otú ahụ na-akpata omume ịda mbà n'obi. N'ikwekọ na nkwupụta a, anyị hụrụ ọnụ na c-Fos mita mRNA na PrL nzaghachi na CCK infusion n'ime mpaghara ụbụrụ a (t₍₁₃₎ = 2.235, p <0.05) (Fig. 3H).

Anyi kwuputara na optogenetic stimulation of mPFC na-eme ya antidepressant omume site na-eguzogide mmetụta nke CCK na ọrụ neuronal. N'ule ule a, anyị nyochachara akụkụ ndị na-edozi nsogbu nchegbu nke CCK. Ngwurugwu pyramidal nke oru ngo mPFC na-arụ ọrụ na NAc na BLA, ogwe aka abụọ dị iche iche nke na-etinye aka na omume na nrụgide. A gosipụtara ọrụ gbanwere nke ma ụbụrụ ụbụrụ ka ọ rụọ ọrụ dị mkpa na okwu nke nchekasị- na ụdị ịda mbà n'obi (dịka omume)Vialou et al., 2010; Tye et al., 2011). Ya mere, anyi nyochaa ma mmetuta nke uzo ogugu site na PrL rue NAc ma obu BLA ga-emegide mmechi nke CCK microinfusion n'ime PrL (Fig. 3A). Anyị tinyere AAV-CaMKII-ChR2-EYFP, ma ọ bụ AAV-CaMKII-EYFP dị ka njikwa, n'ime PrL. A maara onye nkwado nke CaMKII iji lelee okwu ịrịa ahụ na glutamatergic neurons na mpaghara obodo. Anyị na-ahapụ oge zuru ezu (6 izu) maka transgenes ka a na-ebute na nkwụsị akwara ndị a pyramidal neurons na NAc na BLA (Fig. 3I). Umu ndi mmadu natara mmeri ndi ozo; 24 mgbe e mesịrị, anyị nyere CCK-8 n'ime PrL na, 30 min mgbe nke ahụ gasịrị, a na-enwe mmekọrịta mmekọrịta n'etiti optogenetic mkpali nke njedebe glutamatergic na NAc ma ọ bụ BLA. Ozugbo a nwalere mmekọrịta mmadụ na ibe ya, a na-enyocha ụmụ oke na elu iji chọpụta àgwà metụtara nchekasị na mgbe ahụ maka maka sucrose ịchọrọ ịchọta ozizi.

Ọganihu optogenetic nke PrL glutamatergic projections na NAc kpụgharịrị ihe omume ọha na eze site na intra-PrL CCK-8 (mmekọrịta, F_(1,26) = 6.688, p <0.05, enweghị mmetụta ọgwụ na otu ChR2) (Fig. 3C). N'ụzọ dị iche, ụdị PrL a na-akpali NNA enweghị mmetụta na omume nchekasị dị ka a tụrụ ya n'ọtụtụ dị elu (Fig. 3E); Otú ọ dị, mmetụ dị otú ahụ na-eme ka mmasị sucrose dabaa na oke ụmụ anụ (mmekọrịta, F_(1,20) = 5.77, p <0.05; Bonferroni nyocha t = 2.998_, p <0.05 na-akpali akpali n'ime CCK-8 ọgwụgwọ anụmanụ) (Fig. 3G).

A hụrụ ụkpụrụ omume dịgasị iche iche na mkpali optogenetic nke PrL glutamatergic projections na BLA. Mmetụta dị otú ahụ egbochighị ịbịara ọha na eze site na intr-PrL CCK-8 infusion (mmekọrịta, F_(1,22) = 0.79, p > 0.05; isi mmetụta nke ọgwụ, F_(1,22) = 11.75, p <0.05; enweghị mmetụta na otu kpaliri, t ule t₍₁₂₎ = 2.054, p <0.05) (Fig. 3B). Otú ọ dị, mmelite nke ndị na-ebupụta na BLA nwere mmetụta yiri nchekasị dị ka egosipụtara site na oge dị ukwuu na ogwe aka nke elu na mbido (mmekọrịta, F_(1,22) = 8.0, p <0.01; Bonferroni nyocha t = 2.528, p <0.05 nje virus n'ime CCK-8 ndị otu a gwọrọ) (Fig. 3D). Mgbugbu nke ịmịnye glutamatergic na BLA enweghị mmetụta dị ịrịba ama na mmasị sucrose (mmekọrịta, F_(1,22) = 2.08, p > 0.05) (Fig. 3F).

Nkwurịta

Nsonaazụ nke ọmụmụ ihe ugbu a na-enye ihe akaebe nke mgbanwe mmebi ahịrị na-eme na PrL nke na-eme ka nrụgide ndị mmadụ nwee nsogbu. Anyị na-egosi ntinye nke ΔFosB na mpaghara subregion mPFC mgbe enweghi nsogbu na-emeri nrụgide, ebe ΔFosB overexpression na-akwalite nchekasị. Anyị mara na onye na-anabata CCKB dị ka ọnụọgụ nke mkpụrụedemede nke ΔFosB nyere na PrL, o yiri ka ọ na-akpali protein CCKB n'ime anụ ndị nwere ike ịnwụ na igbochi nchịkwa nke okwu CCKB nke na-eme nhọrọ n'ime ụmụ oke. Anyị gosikwara n'ihu na nsị nke agonist CCK n'ime PrL na-akwalite ịda mbà n'obi- na nchekasị-dị ka mmebi omume na-eme ka a ghara inwe nrụgide mmekọrịta, ebe nchikota nke ọrụ nlekota CCKB na mpaghara a nke ụmụ oke nwere ike imebi mmetụta ndị a. Anyị na-eji usoro optogenetic eme ihe iji chọpụta na microcircuitry na-etinye aka na arụmụka na-arụ ọrụ na CCL na PrL. Ọ bụ ezie na cortico-NAc glutamatergic projections na-akwado ụgwọ ọrụ deficits egosipụtara site izere ọha na eze ma belata sucrose mmasị, nke a microcircuit adịghị emetụta mmetụta anxiogenic nke CCK tinye n'ime PrL. N'aka nke ozo, ihe omuma nke di na BLA bu ihe ngosi nke omume ndi nwere nchegbu ma enweghi mmetuta na nchegbu ndi mmadu - eme ka ndi mmadu ghara ime ka ndi mmadu ghara ime ihe. Otu n'ime ihe ndị a na-egosi na ngbanwe na ọrụ PrL mgbe nrụrụ aka na-adịghị ala ala na-emetụta ọtụtụ nsogbu nke omume site na njedebe ndị doro anya.

ΔFosB: ịmepụta nrụpụta nsogbu nke nsogbu limbic na ọrụ na mPFC

ΔFosB immunohistochemistry na-emepụta ọkpụkpụ na-emetụta nrụgide na-adịghị ala ala na mkpebi nke otu-cell ma jiri ya mee ihe maka ịkepụta nrụpụta nhụjuanya na-edozi ahụ (na-Perrotti et al., 2004; Nikulina et al., 2008; Lehmann na Herkenham, 2011). Anyị jiri usoro a gosipụta na nrụgide na-adịghị ala ala na-emetụta nrụgide na-ebute ΔFosB n'ọtụtụ ebe ụbụrụ nwere ọdịiche dị iche n'etiti ndị na-arụ ọrụ na ndị nwere ike ịmalite, na mpaghara ụfọdụ na-egosi ntinye n'ime ụmụ oke, na ndị ọzọ na -Isiokwu 1). Ọrụ ndị gara aga gosipụtara na ntinye nke ΔFosB na NAc ma ọ bụ ventral PAG na-akwalite resilience na nrụgide na-adịghị ala ala ma na-enye aka na nzaghachi antidepressant (Berton et al., 2007; Vialou et al., 2010).

Mmetụta nke ΔFosB na PrL nke ụmụ irighiri ihe ndị dị na ya, yana nchọpụta gara aga na optogenetic mkpali nke mpaghara a na-eme mmetụta na-akpata antidepressant (Covington et al., 2010), kpaliri anyị ka anyị mụọ mmetụta nke ΔFosB na mpaghara ebe a. N'ihe dị iche iche na nchoputa na NAc na ventral PAG, anyị chọpụtara na ΔFosB na PrL na-akwalite inwe ike ime ka nrụgide na-adịghị ala ala na-emeri nrụgide ma na-emepụta mmetụta nchịkwa-dị ka nyocha nke mmiri na-agba mmiri, n'ebughị ụzọ metụta ụdị nchekasị ma ọ bụ mmasị sucrose. N'adịghị ka PrL, anyị enweghị mmetụta nke ΔFosB overexpression na nso nso IL. Nnyocha e mere n'oge na-adịbeghị anya chọpụtara ọkwa elu dị elu nke ΔFosB na IL na ụmụ nnụnụ na-arụ ọrụ ma tinye aka na mpaghara mpaghara a ka ha wee nwee ike ịda mbà n'obi (Lehmann na Herkenham, 2011). Ọ dị mkpa iji nlezianya nyochaa ọrụ ndị dị iche iche maka mpaghara abụọ mPFC ndị a, bụ nke egosiri na ha ga-emepụta mmetụta ndị ọzọ na mpaghara ndị ọzọ na-akpa àgwà (Sierra-Mercado et al., 2011; Burgos-Robles et al., 2013; Richard na Berridge, 2013). Anyị kwuru na mbụ na ndị dara mbà n'obi na-egosipụta ọkwa dị ala nke ΔFosB na NAc nyochaa akwụkwọ akụkọ (Vialou et al., 2010), wenwere ọkwa dị elu karị nke ΔFosB egosipụtawo na PFC (Brodmann ebe 46) nke ụmụ mmadụ dara mbà n'obi (Teyssier et al., 2011). A dịghị atụle mpaghara ndị ọzọ na-egbuke egbuke n'ọmụmụ ihe ikpeazụ. Ka o sina dị, nchọpụta ndị a na-akwado nkwado na-adabaghị na mpaghara ΔFosB na ịda mbà n'obi mmadụ, ebe ihe odide ahụ na-arụ ọrụ dịgasị iche iche na nrụgide nsogbu. Ọ ga-adọrọ mmasị n'ọmụmụ ihe n'ọdịnihu iji nyochaa mmetụta nke ΔFosB n'ọtụtụ ụbụrụ ụbụrụ ndị ọzọ ebe a na-ebute ya (Isiokwu 1) na nzaghachi nsogbu.

Otu usoro nke ΔFosB induction na PrL nwere ike inye aka na-akpa àgwà dị ka mmegbu bụ site na iwepụ nke PrL ọrụ. A gosipụtara ΔFosB iji gbochie azịza AMPA glutamate, na c-Fos okwu, na NAc spiny neurons (Renthal et al., 2008; Vialou et al., 2010; Grueter et al., 2013). N'otu aka ahụ, anyị hụrụ ọnụ ala c-Fos okwu mgbe ΔFosB overexpression na PrL. Ya mere, ntinye nke ΔFosB na PrL nwere ike ibu ọrụ maka imepụta ọrụ nụ na mpaghara mpaghara a mgbe nrụgide na-adịghị mma na-emeri nrụgide. Ụdị ụda olu dị otú ahụ nke PrL n'elu ihe mgbakwasị ụkwụ ya, dịka BLA na NAc, ga-atụ anya ịkwalite nkwupụta egwu na enweghị ike ịkwụsị mmetụta uche na nrụgide (Fales et al., 2008, 2009). Ọzọkwa, ọnya MPFC na-eme ka azịza na nchekasị na-eme ka nchebe ghara ịdị egwu (Holson, 1986; Silva et al., 1986; Diorio et al., 1993; Milad na Quirk, 2002), na-atụ aro na mmerụ ahụ nke nrụgide nke mPFC, nke a na-emegharị site na ΔFosB induction, nwere ike inye aka na ịda mbà n'obi na nsogbu ndị ọzọ metụtara nrụgide (Choi et al., 2012).

Ọrụ nke CCK na nrụgide nsogbu

Anyị na-enye ihe akaebe na onye na-anabata CCKB bụ ΔFosB, nke mere na ntinye ΔFosB na PrL nke ụmụ anụ nwere ike ịbụ otu usoro nke ΔFosB na-eme mmetụta dị iche iche na-emetụ n'ahụ na mpaghara a. Ọ bụ ezie na arụmọrụ CCK dị iche iche na circuit circuit mPFC anọgideghị na-edoghị anya, na mkpanaka CCK ka a na-emepụta n'ime GABAergic internalurons (Somogyi et al., 1984). A na-eche na ọ ga-ebelata ọrụ nke pyramidal pyramidal site na ịmepụta ntọala GABA na-eme na ndị na-anabata CCKB nke pyramidal neurons (Yaksh et al., 1987; Benoliel et al., 1992; Pérez de la Mora et al., 1993; Gallopin et al., 2006). N'ihi ya, CCKergic neurotransmission nwere ike inye aka na ọrụ PrL dị ala ahụ e kwuru n'elu.

CCK bụ onye na - ahụ maka nsogbu nchegbu, na nchịkwa usoro nke CCKB agonists na - ebute mwakpo egwu na ndị ọrụ afọ ofufo siri ike. Ndị ọrịa na-achọ ịmalite ịlụ ọgụ na-aghọ nke a na-akpọ hypersensitized mgbe ikuku CCK (de Montigny, 1989; Bradwejn et al., 1991). Ọtụtụ nnyocha akwadoro mmetụta CCK na-akpata na-akpata nsogbu na òké (Rotzinger na Vaccarino, 2003). A na-ahapụ CCK na mPFC n'oge a na-emeri nrụgide na oke dị na àgwà nchegbu (Becker et al., 2001); Ekebeghi usoro ndi isi na Prl na IL na ihe omumu a. N'oge na-adịbeghị anya, usoro nhazi, CCKB na CI-988 na-adịghị egbochi mmetụta na-emetụta ya na oke (Becker et al., 2008). CI-988 na-eme ka oge na-adịghị mma na oge nyocha a na-egwu mmiri. O gbochikwara hypothalamic-pituitary-adrenal axis hyperactivity, belata hippocampal olu na ntinye ụlọnga, na ịbelata sucrose mmasị na-ebutekarị site na mmeri mmeri. N'ebe a, anyị na-akwado nsonaazụ ndị a site n'igosi mmetụta nke antiopressant nke CI-988 tinye n'ime PrL nke ụmụ nnụnụ nwere ike ịgbanye ya, ọ bụ ezie na otu ịgbanye usoro ihe ọ bụla adịghị emetụta mmetụta a.

Na mgbakwunye na nnukwu omume nke CCK na PrL, anyị chọpụtara ọkwa nke CCKB mRNA na ụmụ oke, nke nwere ike ịbụ ngbanwe ihu ala na-adabere na resilience. N'ezie, ngbanwe nke ụda CCKergic, nke bụ ọkwa CCKB, bụ usoro dị mkpa maka okwu nchegbu. Mice ndị na-emegharị anya na CCKB na-egosi na enwekwu nchegbu na egwu egwu (Chen et al., 2006). Nchọpụta anyị gbanwere ọkwa CCKB gbanwere n'etiti ụmụ oke nwere ike ịnagide ma na-esiri ike nwere ike itinye aka na esemokwu phenotypic na nchekasị na mmụọ ịda mba. N'ebe a, anyị na-egosipụta PrL dị ka mkpụrụedemede anatomical dị egwu maka mmetụta nchegbu na prodepressant nke CCK n'ihe metụtara nrụgide mmekọrịta mmadụ na ibe ya. Ka o sina dị, ọtụtụ mpaghara ụbụrụ ndị ọzọ na-etinye aka na omume omume CCK, gụnyere BLA, hippocampus, NAc, na PAG (De Witte et al., 1987; Belcheva et al., 1994; Noble na Roques, 1999; Zanoveli et al., 2004; Rezayat et al., 2005). Nakwa, anyị hụrụ mmụba na ogo CCKB, ma ọ bụghị mRNA, na mPFC nke anụ nwere ike ịdaba. Nchọpụta ndị a na-emesi ike na, ọ bụ ezie na ọkwa mRNA na - ejikọta ya na protein, nke a abụghị ihe ahụ (Gygi et al., 1999).

Nnyocha nke optogenetic anyị na-egosi na ịbawanye ụba nke mmepụta glutamatergic site na PrL na NAc ma ọ bụ na BLA na-eme ka mmetụta nke CCK na PrL na-apụta. A choputara ihe omumu di iche iche iji gosiputa na enwere ike imuta ihe omuma nke optogenetic site na otu uzo PrL nke CCK na-acho. N'ụzọ na-akpali mmasị, data anyị na-egosi ọrụ dị iche iche nke microcircuits abụọ a n'ịgbazi akụkụ dị iche iche nke abnormalities omume. Ntughari nke cortico-NAc na-achịkwa ozizi na ụgwọ ọrụ; eziokwu ahụ bụ na ọ na-achịkwa nnwere onwe ọha na eze na-akwado na mgbaàmà a bụ ihe ngosipụta nke mkpali na mbelata maka mmekọrịta mmadụ na ibe ya ma ọ bụghị ịba ụba nchegbu ọha na eze. Nkwubi okwu a kwekọrọ na enweghị ike nke benzodiazepines iji dozie nsogbu a (Berton et al., 2006), na ihe ngosi na-adịbeghị anya na mPFC mmalite nke NA na-eweta ụgwọ ọrụ na mkpali maka ọgwụ ọjọọ eme ihe (Britt et al., 2012). N'ụzọ dị iche, nkedo cortico-BLA na-achịkwa mgbaàmà ndị metụtara nchegbu, na-akwado nnukwu akwụkwọ dị na nchara na ụmụ mmadụ (lee n'elu).

Na ngwụcha, ihe nchoputa nke ugbua na - achoputa atumatu akwara ogwu na - emetuta n'ime umu anumanu, na - egosiputa mgbanwe na PrL nke na - akwalite onodu. Mgbanwe ndị a gụnyere itinye ntinye nke ΔFosB na ntinye nke nnabata CCKB. N'ụzọ dị iche, igbochi ihe CCK na PrL na-akwalite antidepressant- na mmetụta yiri nchekasị. Anyị na-egosipụtakwa ihe mgbakwasị ụkwụ ndị a nke pyramidal cortical ndị a na-emepụta ihe ndị a, na-enwe mkpapụta cortico-NAc dị mkpa maka àgwà metụtara ịda mbà n'obi, na nlekọta cortico-BLA dị mkpa maka àgwà ndị nchegbu. Ọ bụ ezie na ọmụmụ gbasara ọmụmụ nke CCKB na-emegide ndị ọrịa dara mbà n'obi na 1990s ekwughị mmepụta nkwa, nchọpụta ndị dị ugbu a na-egosi uru ịchọtaghachi ikike nke ọgwụgwọ ndị dị otú ahụ na ndị na-arịa ọrịa nwere nnukwu nsogbu nke nrụgide.

Ihe odide ala

Ọrụ a kwadoro site n'aka National Institute of Mental Health (EJN) na Brain & Behavior Research Foundation National Alliance for Research on Schizophrenia na Depression Award Investigator Award to VV

Ndị na-ede akwụkwọ ekwupụtaghị ihe gbasara ego.

References

Akirav I, Maroun M. Ọrụ nke ndị na-ahụ maka ọdịmma nke mbụ nke amygdala dị na nchegbu na-emetụta mbibi nke egwu. Ngwurugwu Neural. 2007; 2007: 30873. dị: 10.1155 / 2007 / 30873. [PMC free article] [PubMed] [Cross Ref]
Barbas H, Blatt GJ. Ihe omuma nke hippocampal nke a na-ele anya na-eleba anya nke oma di iche iche n'olu rhesus. Hippocampus. 1995; 5: 511-533. ma ọ bụ: 10.1002 / hipo.450050604. [PubMed] [Cross Ref]
Becker C, Thièbot MH, Touitou Y, Hamon M, Cesselin F, Benoliel JJ. Mkpụrụ ndụ cholecystokinin dị ka ihe atụ na-eme ka ọ bụrụ ihe atụ nke atụmanya nke oke nkịta. J Neurosci. 2001; 21: 262-269. [PubMed]
Becker C, Zeau B, Rivat C, Blugeot A, Hamon M, Benoliel JJ. Mmetụta ịda mbà n'obi na-emetụta ndị mmadụ ugboro ugboro-dị ka mmụgharị àgwà na nke ndụ na oke: itinye aka na cholecystokinin. Ọrịa ụbụrụ. 2008; 13: 1079-1092. ma ọ bụ: 10.1038 / sj.mp.4002097. [PubMed] [Cross Ref]
Belcheva I, Belcheva S, Petkov VV, Petkov VD. Mmetụta dị na omume na cholecystokinin microinjected n'ime rat nucleus accumbens na amygdala. Neuropharmacology. 1994; 33: 995-1002. nke a: 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, ndị na-eme ma ndị GABAA na ndị GABAB, na-egbochi ịhapụ cholecystokinin-like material from the rat ratal in vitro. Nkwụsị Brain. 1992; 590: 255-262. nke a: 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, Onwe DW, Nestler EJ. Ọrụ BDNF dị mkpa na ụzọ mesolimbic dopamine na-emeri nrụgide. Sayensị. 2006; 311: 864-868. ma ọ bụ: 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. Mmetụta nke δFosB na ntụpọ periaqueductal site na nrụgide na-akwalite mmeghachi omume na-arụ ọrụ. Neuron. 2007; 55: 289-300. ma ọ bụ: 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. Oju mmiri na-eme ka ụbụrụ miri emi na-eme ka ọnụ ọgụgụ nke ịda mbà n'obi na nchekasị ghara ịda mbà n'obi. Ọrịa Ọrịa. 2010; 67: 110-116. ma ọ bụ: 10.1016 / j.biopsych.2009.09.013. [PubMed] [Cross Ref]
Bradwejn J, Koszycki D, Shriqui C. Na-enwe mmetụta dị ukwuu na cholecystokinin tetrapeptide na nsogbu ụbụrụ: nchọpụta ahụike na akparamàgwà. Arch Gen Ọrịa. 1991; 48: 603-610. ma ọ bụ: 10.1001 / archpsyc.1991.01810310021005. [PubMed] [Cross Ref]
Bremner JD. Nrụgide ọ na-emebi ụbụrụ? Ọrịa Ọrịa. 1999; 45: 797-805. nke a: 10.1016 / S0006-3223 (99) 00009-8. [PubMed] [Cross Ref]
Bremner JD. Nchegbu egwu: mmetụta dị na ụbụrụ. Dialogues Clin Neurosci. 2006; 8: 445-461. [PMC free article] [PubMed]
Bremner JD. Neuroimaging na nsogbu nrụgide posttraumatic na nsogbu ndị ọzọ metụtara nchekasị. Neuroimaging Clin North Am. 2007; 17: 523-538. a: 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 na profaịlụ profaịlụ nke ọtụtụ glutamatergic ntinye na nucleus accumbens. Neuron. 2012; 76: 790-803. ma ọ bụ: 10.1016 / j.neuron.2012.09.040. [PMC free article] [PubMed] [Cross Ref]
Burgos-Robles A, Bravo-Rivera H, Quirk GJ. Nkọwapụta nke prelimbic na infralimbic dị iche iche dị iche iche nke mmegharị ngwa ngwa. Ejiri otu. 2013; 8: e57575. a: 10.1371 / journal.pone.0057575. [PMC free article] [PubMed] [Cross Ref]
Chen Q, Nakajima A, Meacham C, Tang YP. Igwe cholecystokininergic dị elu bụ usoro ihe dị mkpa nke na-echekwa nchekasị na ntanetị. Proc Natl Acad Sci US A. 2006; 103: 3881-3886. dị: 10.1073 / pnas.0505407103. [PMC free article] [PubMed] [Cross Ref]
Choi DC, Gourley SL, Ressler KJ. Nkọwapụta BDNF na TrkB prelimbic na-achịkwa nkwakọba nke mmụta ma ọ bụ nke mgbagwoju anya. Transl Psychiatry. 2012; 2: e205. dị: 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. ICHB kinase na-achịkwa mmeri na-emeri nrụgide - nke synaptic na akpa plasticity. J Neurosci. 2011; 31: 314-321. dị: 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. Mkparịta ụka dị mkpirikpi na-emeri nrụgide: mmetụta dị ogologo na-adịgide adịgide na cocaine na-ewere n'oge ụyọkọ na okwu zif268 mRNA na amygdala na cortex mbụ. Neuropsychopharmacology. 2005; 30: 310-321. dị: 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. Mmetụta na-emetụta ọgwụ optogenetic nke medial prefrontal cortex. J Neurosci. 2010; 30: 16082-16090. dị: 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. Ọrụ maka methylation histone repressive na cocaine-emetụta vulnerability ka nrụgide. Neuron. 2011; 71: 656-670. ma ọ bụ: 10.1016 / j.neuron.2011.06.007. [PMC free article] [PubMed] [Cross Ref]
de Montigny C. Cholecystokinin tetrapeptide na-ebute egwu-dị ka mwakpo ndị ọrụ afọ ofufo ahụike: nchoputa mbụ. Arch Gen Ọrịa. 1989; 46: 511-517. ma ọ bụ: 10.1001 / archpsyc.1989.01810060031006. [PubMed] [Cross Ref]
De Witte P, Heidbreder C, Roques B, Vanderhaeghen JJ. Mmetụta ndị na-akpata cholecystokinin octapeptide (CCK-8) na tetrapeptide (CCK-4) mgbe ọ gbanyechara n'ime okwute nke oghere ahụ ma ọ bụ n'ime akụkụ akụkụ ya na ventricles ụbụrụ. Neurochem Int. 1987; 10: 473-479. nke a: 10.1016 / 0197-0186 (87) 90074-X. [PubMed] [Cross Ref]
Diorio D, Viau V, Meaney MJ. Ọrụ nke cortex na-ahụ maka ọdịmma (cingulate gyrus) n'ime usoro nke hypothalamic-pituitary-adrenal responses to stress. J Neurosci. 1993; 13: 3839-3847. [PubMed]
Drevets WC. Neuroimaging na neuropathological ọmụmụ nke ịda mbà n'obi: ihe na-apụta maka àgwà-mmetụta mmetụta nke nsogbu uche. Curr Opin Neurobiol. 2001; 11: 240-249. nke a: 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. Nwee nkwụsịtụ mmetụta uche nke na-emetụta mmetụta na nchekasị nke ụbụrụ na-enwe mmetụta nke ịda mbà n'obi. Ọrịa Ọrịa. 2008; 63: 377-384. ma ọ bụ: 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. Usoro ọgwụgwọ na-eme ka a na-edozi hypoactivity na cortex mbụ na-eche ihu n'oge nrụrụ nkwụnye mmetụta uche na ịda mbà n'obi. Nsogbu Na - emetụta. 2009; 112: 206-211. ma ọ bụ: 10.1016 / j.jad.2008.04.027. [PMC free article] [PubMed] [Cross Ref]
Feder A, Nestler EJ, Charney DS. Psychobiology na mkpụrụ ndụ ihe nketa nke nnwere onwe. Nat Rev Neurosci. 2009; 10: 446-457. ma ọ bụ: 10.1038 / nrn2649. [PMC free article] [PubMed] [Cross Ref]
Gallopin T, Geoffroy H, Rossier J, Lambolez B. Cortical sources CRF, NKB, na CCK na mmetụta ha na sel pyramidal na neocortex. Cereb Cortex. 2006; 16: 1440-1452. doi: 10.1093 / cercor / bhj081. [PubMed] [Cross Ref]
Chuburu C, Hurlemann R, Bewernick BH, Kayser S, Hadrysiewicz B, Axmacher N, Sturm V, Schlaepfer TE. Nchekwa nke Neuropsychological nke ogidi na-eme ka ụbụrụ miri emi nwee mmetuta nke ịda mbà n'obi: mmetụta nke mmelite 12 ọnwa. World J Biol Ọrịa. 2011; 12: 516-527. dị: 10.3109 / 15622975.2011.583940. [PubMed] [Cross Ref]
Grueter BA, Robison AJ, Neve RL, Nestler EJ, Malenka RC. ΔFosB dị iche iche na-eme ka ihe dị mgbagwoju anya na-arụ ọrụ na-enweghị isi. Proc Natl Acad Sci US A. 2013; 110: 1923-1928. dị: 10.1073 / pnas.1221742110. [PMC free article] [PubMed] [Cross Ref]
Gygi SP, Rochon Y, Franza BR, Aebersold R. Nkọwa n'etiti protein na mRNA n'ụba na yist. Mol Cell Cell. 1999; 19: 1720-1730. [PMC free article] [PubMed]
Heidbreder CA, Groenewegen HJ. Ọkpụkpụ na-ahụ maka ụbụrụ a na-ahụ anya na rat: ihe akaebe maka ọdịiche dorso-ventral nke dabeere na njirimara na ọdịdị anatomical. Neurosci Biobehav Mkpuchi 2003; 27: 555-579. ma ọ bụ: 10.1016 / j.neubiorev.2003.09.003. [PubMed] [Cross Ref]
Holson RR. Ọrịa na-egbuke egbuke na mberede na ụbụrụ: M. Nkịtị anụ ahụ. 1986; 37: 221-230. nke a: 10.1016 / 0031-9384 (86) 90224-6. [PubMed] [Cross Ref]
Keedwell PA, Andrew C, Williams SC, Brammer MJ, Phillips ML. Ihe anhedonia na-eme ka ọ bụrụ nsogbu na-ada mbà n'obi. Ọrịa Ọrịa. 2005; 58: 843-853. ma ọ bụ: 10.1016 / j.biopsych.2005.05.019. [PubMed] [Cross Ref]
Kennedy SH, Giacobbe P. Nsogbu nke ọgwụgwọ na-eguzogide ọgwụ: ọganihu na usoro ọgwụgwọ. Ann Clin Psychiatry. 2007; 19: 279-287. dị: 10.1080 / 10401230701675222. [PubMed] [Cross Ref]
Kennedy SH, Evans KR, Krüger S, Mayberg HS, Meyer JH, McCann S, Arifuzzman AI, Houle S, Vaccarino FJ. Mgbanwe dị na ụbụrụ glucose metabolism bụ nke a na-atụle na ihe nkiri na-emetụta ihe ọkụkụ na-ekpo ọkụ mgbe a gbasasịrị ọgwụ na-akpata nke ịda mbà n'obi. Am J Ọchịachukwu. 2001; 158: 899-905. dị: 10.1176 / appi.ajp.158.6.899. [PubMed] [Cross Ref]
Krishnan V, Han MH, Graham DL, Berton O, Carhal 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, Onwe DW, Lee FS, et al. Mgbanwe ndị na-emeghị ka ọkpụkpụ mee ihe na-adabere na nkwụsị nke mmeri na ụbụrụ ụbụrụ. Cell. 2007; 131: 391-404. ma ọ bụ: 10.1016 / j.cell.2007.09.018. [PubMed] [Cross Ref]
Krishnan V, Nestler EJ. Mkpụrụ ndụ ihe omimi nke ịda mbà n'obi. Nature. 2008; 455: 894-902. ma ọ bụ: 10.1038 / nature07455. [PMC free article] [PubMed] [Cross Ref]
Lehmann ML, Herkenham M. Mmepụta ihe dị n'ime gburugburu ebe obibi na-eme ka nchekasị nwee ike imeri site na ụzọ ụzọ ntananatomical na-adabere na cortex. J Neurosci. 2011; 31: 6159-6173. dị: 10.1523 / JNEUROSCI.0577-11.2011. [PMC free article] [PubMed] [Cross Ref]
Leistedt SJ, Linkowski P. Brain, netwọk, ịda mbà n'obi, na ihe ndị ọzọ. Eur Neuropsychopharmacol. 2013; 23: 55-62. ma ọ bụ: 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. Mmetụta ụbụrụ miri emi maka ịda mbà n'obi na-eguzogide ọgwụgwọ. Neuron. 2005; 45: 651-660. ma ọ bụ: 10.1016 / j.neuron.2005.02.014. [PubMed] [Cross Ref]
Maze I, Covington HE, 3rd, Dietz DM, LaPlant Q, Sweefer A, Nestler EJ. Ọrụ dị mkpa nke histone methyltransferase G9a na cocaine-emetụta plasticity. Sayensị. 2010; 327: 213-216. ma ọ bụ: 10.1126 / science.1179438. [PMC free article] [PubMed] [Cross Ref]
McClung ca, Nestler EJ. Iwu nke okwu ihu igwe na cocaine ụgwọ site CREB na DeltaFosB. Nat Neurosci. 2003; 6: 1208-1215. dị: 10.1038 / nn1143. [PubMed] [Cross Ref]
Milad MR, Quirk GJ. Neurons na medial prefrontal cortex signal signal maka egwu mkpochapụ. Nature. 2002; 420: 70-74. ma ọ bụ: 10.1038 / nature01138. [PubMed] [Cross Ref]
Nahas Z, Anderson BS, Borckardt J, Arana AB, George MS, Reeves ST, Takacs I. Nsogbu ọkpụkpụ nke mbụ na-akpata ọgwụgwọ na-eguzogide ọgwụ. Ọrịa Ọrịa. 2010; 67: 101-109. ma ọ bụ: 10.1016 / j.biopsych.2009.08.021. [PMC free article] [PubMed] [Cross Ref]
Nikulina EM, Arrillaga-Romany I, Miczek KA, Hammer RP., Jr Ngbanwe dị ogologo n'oge mesocorticolimbic mgbe emesịrị imeri nrụgide na oke: oge nke mRNA na FosB / DeltaFosB immunoreactivity. Eur J Neurosci. 2008; 27: 2272-2284. dị: 10.1111 / j.1460-9568.2008.06176.x. [PMC free article] [PubMed] [Cross Ref]
Nkwa F, Roques BP. Onye nkata CCK-B: onwu, onodi ihe omumu, biochemistry na onu ogwu. Prog Neurobiol. 1999; 58: 349-379. nke a: 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. Nhazi, nkesa, na ọrụ nke cholecystokinin receptors. Ihe nyocha Pharmacol Rev. 1999; 51: 745-781. [PubMed]
Pérez de la Mora M, Hernandez-Gómez AM, Méndez-Franco J, Fuxe K. Cholecystokinin-8 abawanye K (+) - evoked [³H] gamma-aminobutyric acid na-ahapụ ya site na akụkụ ụbụrụ dị iche iche. Eur J Pharmacol. 1993; 250: 423-430. nke a: 10.1016 / 0014-2999 (93) 90029-H. [PubMed] [Cross Ref]
Perrotti LI, Hadeishi Y, Ulery PG, Barrot M, Monteggia L, Duman RS, Nestler EJ. Mmetụta nke δFosB na ụbụrụ ụbụrụ na-akwụ ụgwọ mgbe nrụgide na-adịghị ala ala. J Neurosci. 2004; 24: 10594-10602. dị: 10.1523 / JNEUROSCI.2542-04.2004. [PubMed] [Cross Ref]
Perrotti LI, Weaver RR, Robison B, Ogbugbu W, Maze I, Yazdani S, Elmore RG, Knapp DJ, Selley DE, Martin BR, Sim-Selley L, Bachtell RK, Self DW, Nestler EJ. Ụdị dị iche iche nke ụbụrụ DeltaFosB na-eji ụbụrụ eme ihe n'ụzọ ụbụrụ. Synapse. 2008; 62: 358-369. dị: 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. Nchegbu ugboro ugboro na-ebute ọnwụ nrịba dendritic na oke ntu na pregateal cortex. Cereb Cortex. 2006; 16: 313-320. a: 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. FBB Delta na-ebute mpempe akwụkwọ epigenetic nke c-fos gene mgbe emphetamine na-adịghị ala ala. J Neurosci. 2008; 28: 7344-7349. dị: 10.1523 / JNEUROSCI.1043-08.2008. [PMC free article] [PubMed] [Cross Ref]
Rezayat M, Roohbakhsh A, Zarrindast MR, Massoudi R, Djahanguiri B. Cholecystokinin na GABA mmekọrịta na hippocampus dorsal nke ụmụ oke na nnukwu elu-ule ule nke nchegbu. Nkịtị anụ ahụ. 2005; 84: 775-782. ma ọ bụ: 10.1016 / j.physbeh.2005.03.002. [PubMed] [Cross Ref]
Richard JM, Berridge KC. Ọhụụ na-ebute ihu na mbido na-emepụta ihe na-eme ka ọ ghara ịmalite ịṅụbiga mmanya ókè. Ọrịa Ọrịa. 2013; 73: 360-370. ma ọ bụ: 10.1016 / j.biopsych.2012.08.009. [PMC free article] [PubMed] [Cross Ref]
Rotzinger S, Vaccarino FJ. Subtypes nke cholecystokinin: na-ekere òkè n'usoro nke ụdị àgwà nchegbu na ụgwọ ọrụ na ụdị anụmanụ. J 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, Mbụ V. Mkpụrụ obi dị nro na-eme ka mgbakọ ụgwọ kwadoro anhedonia na oké ịda mbà n'obi. Neuropsychopharmacology. 2008; 33: 368-377. dị: 10.1038 / sj.npp.1301408. [PubMed] [Cross Ref]
Sierra-Mercado D, Padilla-Coreano N, Quirk GJ. Ọrụ ndị a na-adịghị ahụkebe nke prelimbic na infralimbic cortices, ventral hippocampus, na amygdala zuru oke na okwu na mbibi nke egwu egwu. Neuropsychopharmacology. 2011; 36: 529-538. dị: 10.1038 / npp.2010.184. [PMC free article] [PubMed] [Cross Ref]
Silva MG, Boyle MA, Mkpịsị aka S, Numan B, Bouzrara AA, Almli CR. Mmetụta dị iche iche nke ọnya buru ibu na obere ọnya nke rat medial frontal cortex. Ntughari nke Brain. 1986; 65: 176-181. [PubMed]
Somogyi P, Hodgson AJ, Smith AD, Nunzi MG, Gorio A, Wu JY. Ọnụ ọgụgụ dịgasị iche nke eriri GABAergic na cortex anụ ahụ na hippocampus nke pusi nwere ihe somatostatin- ma ọ bụ cholecystokinin-immunoreactive. J Neurosci. 1984; 4: 2590-2603. [PubMed]
Akwa A, Tanti A, Leonardo ED, Laugeray A, Rainer Q, Touma C, Palme R, Griebel G, Ibarguen-Vargas Y, Hen R, Belzung C. Antidepressants nabatara ọhụrụ ọgbara ọhụrụ iji melite usoro nzaghachi nrụgide. Ọrịa ụbụrụ. 2011; 16: 1177-1188. dị: 10.1038 / mp.2011.48. [PMC free article] [PubMed] [Cross Ref]
Taniguchi H, Ọ 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. A na-emepụta ihe ndị e ji emepụta usoro ịkwọ ụgbọala maka mkpụrụ ndụ ihe atụ nke GABAergic neurons na cortex cerebral. Neuron. 2011; 71: 995-1013. ma ọ bụ: 10.1016 / j.neuron.2011.07.026. [PMC free article] [PubMed] [Cross Ref]
Teyssier JR, Ragot S, Chauvet-Gélinier JC, Trojak B, Bonin B. Ịrụ ọrụ nke mkpụrụedemede DeltaFOSB na-emepụta ihe dị na cortex mbụ nke ndị ọrịa nwere nsogbu ịda mbà n'obi. Nsogbu Na - emetụta. 2011; 133: 174-178. ma ọ bụ: 10.1016 / j.jad.2011.04.021. [PubMed] [Cross Ref]
Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ. Ụkpụrụ chromatin n'usoro hippocampal kwadoro na ngosipụta nke ịda mbà n'obi na nrụrụ antidepressant. Nat Neurosci. 2006; 9: 519-525. dị: 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 na-ekwusara ike na ịchịkwa ịchịkwa nchegbu. Nature. 2011; 471: 358-362. ma ọ bụ: 10.1038 / nature09820. [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 na ụbụrụ ụgwọ ọrụ ụbụrụ na-adabere na nrụgide na ngwọta antidepressant. Nat Neurosci. 2010; 13: 745-752. dị: 10.1038 / nn.2551. [PMC free article] [PubMed] [Cross Ref]
Vogt BA, Finch DM, Olson CR. Okerogeneity na-arụ ọrụ na cingulate cortex: ndị isi na ngalaba na-atụle. Cereb Cortex. 1992; 2: 435-443. nke a: 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. Usoro ọgwụgwọ na ịmalite ịmalite na-egosi ụdị chromatin n'usoro dị na ngwongwo òké na-adakwasị n'ụdị ịda mbà n'obi. J Neurosci. 2009; 29: 7820-7832. dị: 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, Onwe DW, Nestler EJ. Ntinye nke DeltaFosB na orbitofrontal cortex na-egbochi imegide cocaine na-eme ka a ghara inwe mmerụ. J Neurosci. 2007; 27: 10497-10507. dị: 10.1523 / JNEUROSCI.2566-07.2007. [PubMed] [Cross Ref]
Yaksh TL, Furui T, Kanawati IS, Gaa VL. Ntọhapụ cholecystokinin si rat cerebral cortex na vivo: ọrụ nke usoro GABA na glutamate. Nkwụsị Brain. 1987; 406: 207â € "214. nke a: 10.1016 / 0006-8993 (87) 90784-0. [PubMed] [Cross Ref]
Zanoveli JM, Netto CF, GuimarÃ £ es FS, Zangrossi H., Jr Systemic na intra-dorsal periaqueductal isi awọ nke cholecystokinin sulfated octapeptide (CCK-8s) na-eme ka a na-atụ egwu na oke e nyefere na T-maze. Peptides. 2004; 25: 1935â € "1941. ma ọ bụ: 10.1016 / j.peptides.2004.06.016. [PubMed] [Cross Ref]