Mmetụta dị iche iche nke protein FosB na Pụrụ Iche Ebumnobi na Họrọ Họrọ Nchịkọta Ọgwụ Egwu na Mmetụta Ahụhụ (2016)

  • Paula A. Gajewski,
  • Gustavo Turecki,
  • Alfred J. Robison

Bipụtara: August 5, 2016

http://dx.doi.org/10.1371/journal.pone.0160355

nkịtị

Ejikọtala nhụsianya na-adịte aka na nrụgide ma ọ bụ ọgwụ eji eme ihe n'ụzọ na-agbanwe agbanwe na mkpụrụ ndụ ihe nketa na-agbanwe n'ime ahụ dum, na mgbanwe nke mkpụrụ ndụ ihe nketa na mpaghara ụbụrụ nwere uche na-ebute ọtụtụ ọrịa mgbaka, gụnyere nnukwu nsogbu ịda mbà n'obi na ịṅụ ọgwụ ọjọọ. Ụdị nke mbụ nke nsogbu ndị a enyela ihe akaebe maka usoro nke okwu mkpụrụ ndụ ihe nketa a gbanwere, gụnyere ihe odide ederede, mana ihe akaebe na-akwado ọrụ maka ihe ndị a na ndị ọrịa mmadụ adịla ngwa ngwa pụta. A na-ebute ihe odide ΔFosB na prefrontal cortex (PFC) na hippocampus (HPC) nke òké na nzaghachi maka nrụgide ma ọ bụ cocaine, na okwu ya na mpaghara ndị a na-eche na ọ ga-ahazi njikwa "elu ala" ha nke ụgwọ ọrụ ụgwọ ọrụ, gụnyere nucleus. accumbens (NAc). N'ebe a, anyị na-eji biochemistry nyochaa okwu nke FosB Ezinụlọ nke ihe odide ederede na ebumnuche mkpụrụ ndụ ha nwere ike ịdị na PFC na HPC nlele postmortem sitere na ndị ọrịa dara mbà n'obi na ndị riri cocaine. Anyị na-egosi na ΔFosB na ndị ọzọ FosB isoforms na-agbadata na HPC ma ọ bụghị PFC na ụbụrụ nke ma ndị dara mbà n'obi na ndị riri ahụ. Ọzọkwa, anyị na-egosi na ebumnuche ederede ΔFosB, gụnyere GluA2, na-agbadakwa na HPC mana ọ bụghị PFC nke ndị na-eri cocaine. Ya mere, anyị na-enye ihe àmà mbụ nke FosB mkpụrụ ndụ ihe nketa na HPC mmadụ na PFC na ọrịa psychiatric ndị a, na n'ihi nchọpụta ndị na-adịbeghị anya na-egosi ọrụ dị oke mkpa nke HPC ΔFosB na ụdị mmụta na ebe nchekwa, data ndị a na-atụ aro na ibelata ΔFosB na HPC nwere ike ịkpata mmebi nke uche na-esonyere mmetọ cocaine na-adịghị ala ala. ma ọ bụ ịda mbà n'obi.  

Ntughari: Gajewski PA, Turecki G, Robison AJ (2016) Ngosipụta dị iche iche nke protein FosB na mkpụrụ ndụ ihe nwere ike ime na Họrọ mpaghara ụbụrụ nke riri ahụ na ndị ọrịa ịda mbà n'obi. PLoS ONE 11 (8): e0160355. doi:10.1371/journal.pone.0160355

Editor: Ryan K. Bachtell, Mahadum Colorado Boulder, United States

Natara: February 29, 2016; Anakwere: July 18, 2016; E bipụtara: August 5, 2016

Copyright: © 2016 Gajewski et al. Nke a bụ akụkọ ohere mepere emepe ekesara n'okpuru usoro nke License Akara Creative Commons, nke na-enye ikikere iji ojiji, nkesa, na mmepụta n'ime usoro ọ bụla, ọ bụrụ na a na-akwụnye edemede na isi edemede mbụ.

Nweta data: All data dị mkpa dị n'ime akwụkwọ.

Ego: Onye ode akwụkwọ PAG nwetara nkwado ụgwọ ọnwa site na onyinye enyere onye edemede AJR sitere na Whitehall Foundation. Ndị na-enye ego enweghị ọrụ na nhazi ọmụmụ, nchịkọta data na nyocha, mkpebi ibipụta, ma ọ bụ nkwadebe nke ihe odide ahụ.

Ihe na-emetụ aka: Ndị dere ekwupụta na ọ dịghị asọmpi asọmpi.

Okwu Mmalite

Usoro molekụla na ọkwa sekit nke ọrịa mgbaka dị ka ịda mbà n'obi na iri ahụ aghọtachaghị nke ọma, na ihe ọmụma a dị oke mkpa maka mmepe ezi uche nke ọgwụgwọ ọhụrụ na nke ka mma. Mgbanwe na okwu mkpụrụ ndụ ihe nketa na nucleus accumbens (NAc) na mpaghara ụbụrụ nke na-achịkwa ọrụ NAc, dị ka prefrontal cortex (PFC) na hippocampus (HPC), abanyela na pathogenesis nke riri ahụ na ịda mbà n'obi site n'ọtụtụ ọmụmụ. na ma ụdị ntule na n'ime ụbụrụ mmadụ nwụrụ anwụ [1-5]. Ọtụtụ ọgwụgwọ ugbu a maka ịda mbà n'obi na-arụ ọrụ site na nkwalite na-adịghị ala ala nke serotonergic na / ma ọ bụ dopaminergic, yana ihe fọrọ nke nta ka ọ bụrụ ọgwụ ọjọọ niile na-emetụta akara ngosi dopamine na NAc. Ọzọkwa, ahụ riri ahụ na ịda mbà n'obi na-enwekarị mgbagwoju anya, ebe ihe fọrọ nke nta ka ọ bụrụ otu ụzọ n'ụzọ atọ nke ndị ọrịa nwere nnukwu nsogbu ịda mbà n'obi na-enwekwa nsogbu iji ọgwụ eme ihe na nsogbu na-enye ohere dị elu nke igbu onwe ya na nnukwu nsogbu mmekọrịta mmadụ na ibe ya.6, 7]. N'ịchịkọta ọnụ, data ndị a na-atụ aro na mmebi ahụ na-adịghị ala ala na sekit mesolimbic dopamine na ihe ejikọrọ nwere ike ịkpata ma riri ahụ na ịda mbà n'obi, na mgbanwe nke mkpụrụ ndụ ihe nketa nwere ike ịrụ ọrụ dị mkpa na mmebi ndị a.

Ka ịda mbà n'obi na ịṅụ ọgwụ ọjọọ na-etolite ka oge na-aga ma nwee ike jikọta ya na ikpughe na-adịghị ala ala na nchekasị na / ma ọ bụ ọgwụ ọjọọ [8, 9], na n'ihi na-ahụkarị antidepressants nke na-elekwasị anya serotonergic na dopaminergic mgbaàmà chọrọ izu nke ọgwụgwọ ka ọ dị irè [10], o yiri ka a ga-ejikọta pathogenesis nke ọrịa ndị a na usoro ọgwụgwọ ha ogologo oge mgbanwe na mkpụrụ ndụ ihe nketa. Mgbanwe ndị dị otú ahụ nwere ike ịmalite site na mgbanwe epigenetic nke usoro mkpụrụ ndụ ihe nketa, na n'ezie ihe akaebe na-arị elu maka ọrụ dị mkpa maka DNA methylation na mgbanwe histone na ma riri ahụ na ịda mbà n'obi.11-14]. Agbanyeghị, nke a anaghị ewepụ ọrụ nwere ike ị nweta ihe ndenye n'ime usoro ndị a, ọkachasị ihe ederede kwụsiri ike na-ebute site na ịgbalite neuronal na-adịghị ala ala. Otu ihe odide ederede bụ ΔFosB [1, 15, 16], a splice iche iche emepụtara na FosB mkpụrụ ndụ ihe nketa. N'adịghị ka protein FosB zuru oke, ΔFosB kwụsiri ike ma e jiri ya tụnyere ngwaahịa mkpụrụ ndụ ndị ọzọ ozugbo (ọkara ndụ ruo ụbọchị 8 na ụbụrụ [XNUMX]17]), n'ụzọ bụ isi n'ihi nkwụsị nke ngalaba degron abụọ na c-terminus [18], yana phosphorylation na-eme ka ọ kwụsie ike na Ser27.19, 20]. A na-ebute ΔFosB n'ime ụbụrụ ụbụrụ, gụnyere NAc na ihe ndị metụtara ya, site na nrụgide [21-23, antidepressants [22] na ọgwụ ọjọọ [24]. Ọzọkwa, ụdị òké na-emetụta okwu ΔFosB na NAc na iri ahụ abụọ [20, 25] na nkụda mmụọ [26, 27], na nnyocha ndị na-adịbeghị anya na-atụ aro ọrụ maka ΔFosB na ọrịa ndị a na PFC [21na HPC [28]. Na NAc, okwu ΔFosB na-akwalite mmụba nke psychomotor na ụgwọ ọrụ sitere na psychostimulants na òké [20, 25]. NAc ΔFosB na-arụkwa ọrụ dị ka ihe na-agbanwe agbanwe na ụdị ịda mbà n'obi nke ịda mbà n'obi na-adịghị ala ala, na okwu ya dị mkpa maka ọrụ antidepressant.26]. N'ụzọ dị iche, nkwupụta nke ΔFosB na PFC na-akwalite ike imeri nchekasị ọha na eze na ụmụ oke [21], na-atụ aro na ΔFosB na-arụ ọrụ dị iche iche na sekit ụgwọ ọrụ na mpaghara ụbụrụ na-etinye ya n'ime ya. N'ikpeazụ, ΔFosB na-akpalite na HPC dorsal òké site n'ịmụta na ọrụ ya a chọrọ maka nhazi ebe nchekwa ohere.28], na-enye usoro ga-ekwe omume maka ụkọ ọgụgụ isi na-esokarị mkpughe ọgwụ na-adịghị ala ala na / ma ọ bụ ịda mbà n'obi [29-31].

Dị ka ΔFosB bụ ihe ntụgharị ederede, a na-echekarị na ọ na-arụ ọrụ ndụ ya site na mgbanwe nke okwu nke mkpụrụ ndụ ihe nketa ahọrọ, na ọtụtụ n'ime mkpụrụ ndụ ihe nketa ndị ahụ etinyewo aka na ịda mbà n'obi na riri ahụ. ΔFosB na-achịkwa okwu nke ọtụtụ subunits nke α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) - na N-methyl-D-aspartate (NMDA) -ụdị ndị na-anabata glutamate.25, 26, 32], na ndị a na-anabata ya etinyewo aka na ọgwụ ahụ.33, 34], nkụda mmụọ [35, 36na-arụ ọrụ antidepressant.36, 37]. ΔFosB na-achịkwa okwu nke ụmụ irighiri ihe na-egosi, dị ka calcium / calmodulin-based protein kinase II α (CaMKIIα), nke ejikọtara na ọtụtụ ọrịa psychiatric [38], na anyị egosila na iwu a nke okwu CaMKII n'ime ụmụ oke na-eme ka mmetụta uche nke psychomotor na cocaine.20na ọrụ antidepressant [27]. Na mgbakwunye, ΔFosB na-achịkwa okwu nke kinase 5 (cdk5) dabere na cyclin.39], nke a na-ebute na striatum site na ikpughe uche na nrụgide psychostimulant [40-42] ma na-achịkwa psychomotor na nzaghachi mkpali na cocaine.43]. Ya mere, enwere ihe akaebe siri ike na ụdị òké na ntinye nke ΔFosB n'ọtụtụ mpaghara ụbụrụ site na nrụgide, antidepressants, na ọgwụ ọjọọ nwere ike ịhazi àgwà ndị metụtara ịda mbà n'obi na ịṅụ ọgwụ ọjọọ site n'ịgbanwe okwu nke mkpụrụ ndụ ihe nketa ahọrọ na mpaghara ụbụrụ nwere uche.

Ọ bụ ezie na ụdị ọgwụgwọ riri ahụ na ịda mbà n'obi amụbawo nke ọma, ọ dị mkpa ịkwado nchoputa sitere na ụdị anụmanụ nwere ihe akaebe sitere na ọmụmụ mmadụ ma ọ bụrụ na anyị na-atụ anya ịsụgharị usoro mkpụrụ ndụ nwere ike ịbụ nhọrọ ọgwụgwọ ọhụrụ. Anyị egosila na mbụ na ΔFosB na-edozi na NAc nke ndị na-eri cocaine.20] ma belata na NAc nke ndị mmadụ dara mbà n'obi [26]. Otú ọ dị, ụkpụrụ nke FosB mkpụrụ okwu mkpụrụ ndụ ihe nketa na HPC na PFC, ndị na-ahụ maka nchịkwa dị egwu nke NAc neuronal activation, amụbeghị ya na ụbụrụ mmadụ, ma ọ bụ nwee iwu nke okwu mkpụrụ ndụ ebumnuche ΔFosB nwere ike. Ya mere, anyị na-enyocha okwu nke FosB ngwaahịa mkpụrụ ndụ ihe nketa, yana nkwupụta nke mkpụrụ ndụ ihe nketa ΔFosB nwere ike, na PFC na HPC nke ndị ọrịa na-arịa nnukwu nsogbu ịda mba ma ọ bụ ọgwụ cocaine.

Akụrụngwa na ụzọ

Nlereanya mmadụ

E nwetara anụ ahụ ụbụrụ mmadụ nwụrụ anwụ site na Douglas Bell-Canada Brain Bank (Douglas Mental Health University Institute, Montreal, Quebec, Canada). Enwere ike ịhụ ozi eji eme ihe gbasara ndị riri cocaine mmadụ, ndị ọrịa ịda mbà n'obi, na njikwa dakọtara na Isiokwu 1. Nchekwa anụ ahụ gara n'ihu dịka akọwara [44]. Na nkenke, ozugbo ewepụtara ya, a na-etinye ụbụrụ na ice mmiri n'ime igbe Styrofoam wee gbaga n'ụlọ akụ Brain Bank Douglas Bell-Canada. A na-ekewa Hemispheres ozugbo site na ịkpụ sagittal n'etiti ụbụrụ, ụbụrụ ụbụrụ, na cerebellum. A na-ekewakarị arịa ọbara, pineal gland, choroid plexus, ọkara cerebellum, na ọkara ụbụrụ ụbụrụ site na akụkụ aka ekpe nke a na-egbutu ya n'ụzọ nkịtị n'ime mpekere 1 cm buru ibu tupu oyi. A na-ebipụ ọkara cerebellum nke ikpeazụ na sagitally n'ime mpekere 1cm nke nwere oke tupu oyi. A na-ekpochapụ anụ ahụ ọkụ na 2-methylbutane na -40°C maka ~60 sec. A na-edobe anụ ahụ niile jụrụ oyi n'ime akpa rọba na -80 Celsius maka nchekwa ogologo oge. A na-ekesa mpaghara ụbụrụ kpụ ọkụ n'ọnụ site na mpekere coronal oyi kpọnwụrụ n'elu efere igwe anaghị agba nchara nwere ice kpọrọ nkụ gburugburu iji chịkwaa ọnọdụ okpomọkụ nke gburugburu ebe obibi. Ihe nlele PFC sitere na mpaghara Brodmann 8/9, a na-ewerekwa nlele HPC site na oke etiti nke nhazi hippocampal (Fig 1).

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Fig 1. Eserese nke mpaghara dissection maka nlele ụbụrụ mmadụ.

Eserese na-anọchite anya akụkụ azụ (A) na azụ (B) nke ụbụrụ mmadụ ejiri mee nkesa nke ihe nlele PFC, yana (C) nlele HPC. Igbe na-acha uhie uhie na-egosipụta mpaghara nkesa. SFG: gyrus ihu dị elu; MFG: gyrus ihu etiti; IG: gyrus insular; FuG: fusiform gyrus.

http://dx.doi.org/10.1371/journal.pone.0160355.g001

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Tebụl 1. Ndabere nke ihe, toxicology, na iji ọgwụ antidepressant na ndị na-eri ọgwụ cocaine, ndị ọrịa ịda mbà n'obi, na ndị na-achịkwa ndị kwekọrọ.

http://dx.doi.org/10.1371/journal.pone.0160355.t001

Ihe nlele òké

Ọmụmụ ihe ahụ gbasoro ntuziaka akọwapụtara na Nduzi maka nlekọta na ojiji nke umu anu ohia, mbipụta nke asatọ (Institute of Laboratory Animal Resources, 2011). Tupu ule ọ bụla, kọmitii nlekọta na ojiji nke Institutional Animal Care na Mahadum Michigan State kwadoro usoro nnwale niile. Ọ bụrụ na anụmanụ ọ bụla na-egosipụta enweghị ejiji, ọrịa, oke ibu dị arọ, ma ọ bụ enweghị ike imegharị ahụ, anụ ahụ ga-emechu ya. Ọ dịghị anụmanụ chọrọ ụdị euthanization dị otú ahụ tupu njedebe nnwale na ọmụmụ ihe ugbu a. Mgbe ọ bịarutere n'ụlọ ọrụ ahụ, ụmụ oke nwoke C7BL / 57 dị izu 6 (The Jackson Laboratory, Bar Harbor, ME, USA) nọ n'otu ụlọ 4 n'otu ọnụ ụlọ nke edobere na okpomọkụ mgbe niile (23 Celsius C) ma ọ dịkarịa ala. 3 ụbọchị tupu nnwale na a 12 h ìhè / ọchịchịrị okirikiri na ad libidum nri na mmiri. E nyere ụmụ oke na-adịghị ala ala (ụbọchị 7) ma ọ bụ nnukwu (otu injection) cocaine (15 mg / kg) ma ọ bụ saline na-adịghị mma (0.9% saline) site na intraperitoneal (ip) injection, ma chụọ àjà site na nkwụsị cervical otu awa mgbe nkwụsị ikpeazụ gasịrị. A na-egbute anụ ahụ ozugbo (Fig 2) ma ọ bụ n'oge dị iche iche mgbe a chụrụ àjà (Fig 3).

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Fig 2. Ntụle nke mmadụ na òké FosB protein.

(A) Western blot nke protein hippocampal nwere ọgwụ mgbochi FosB na-ekpughe ọtụtụ ụdọ ndị ọzọ n'ụdị HPC riri ahụ mmadụ cocaine ma e jiri ya tụnyere cocaine na-adịghị ala ala (15 mg / kg maka ụbọchị 7) òké HPC. Otu egwu ọhụụ pụtara na 20 kDa, 23 kDa (akụ ọcha), na 30 kDa (akụ ojii). (B) Mmekọrịta na ahịrị nkwụghachi azụ nke nkwupụta protein maka ìgwè ọ bụla n'ime ihe nlele mmadụ na etiti oge ọnwụ (oge n'etiti ọnwụ na ụbụrụ na-ekpo ọkụ) maka nlele mmadụ ọ bụla. Ahịrị nwere ntụpọ na-anọchite anya oge ntụkwasị obi 95%; Enweghị mkpọda nkwụghachi azụ ahịrị dị iche na 0.

http://dx.doi.org/10.1371/journal.pone.0160355.g002

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Fig 3. Ngosipụta nke protein FosB na òké HPC mgbe ogologo oge gafere.

A hapụrụ ụbụrụ ụmụ oke nyere nnukwu ịgba ọgwụ cocaine (15 mg / kg ip). na ọnọdụ maka 0, 1, ma ọ bụ 8 awa mgbe a chụrụ àjà tupu owuwe ihe ubi HPC. Western blot na-ekpughe mwube nke 23 kDa n'ime anụmanụ awa asatọ, mana egosighi ụgbụ ndị ọzọ achọtara na nlele HPC mmadụ.

http://dx.doi.org/10.1371/journal.pone.0160355.g003

Western Blotting

A na-ewepụta ụbụrụ òké ngwa ngwa na ice wee kewaa ya n'ime akụkụ 1 mm, wee wepụ hippocampus dorsal site na ntụ ntụ nlele iri na abụọ wee kpochaa ozugbo na ice kpọrọ nkụ. Ma mmadụ na òké samples e homogenized site ìhè sonication na gbanwetụrụ RIPA nchekwa (12 mM Tris base, 10 mM sodium chloride, 150 mM EDTA, 1% sodium dodecyl sulfate, 0.1% Triton X-1, 100% sodium deoxycholate, pH 1, ndị na-egbochi protease na phosphatase [Sigma Aldrich]). A tụrụ nlebara anya site na iji DC Protein Assay (BioRad) wee hazie nlele gel maka protein zuru oke. Ekewapụrụ protein na 7.4-4% polyacrylamaide gradient gels (Criterion System, BioRad), na Western blotting mere site na iji chemiluminescence (SuperSignal West Dura, Thermo Scientific). A na-enyocha mkpokọta protein site na iji Swift Membrane Stain (G Biosciences) yana agbakọ protein site na iji ngwanrọ ImageJ (NIH). A na-eji ọgwụ mgbochi nke mbụ chọpụta FosB isoforms (15G5; 4: 1; Cell signaling, 500), GluA2251/2 (3: 1; Millipore, 1,000-07), CaMKIIα (598: 1; Milipore, 1,000-05), cdk532 (5:1; Santa cruz, sc-1,000), GAPDH (173:1; Ịrịbama mkpụrụ ndụ, 20,000).

Statistics

Ejiri ngwungwu sọftụwia Prism 6 (GraphPad) mee nyocha ndekọ ọnụ ọgụgụ niile. A na-eji nyocha regression linear iji chọpụta ma okwu nke FosB Ejikọtara ngwaahịa mkpụrụ ndụ ihe nketa na etiti oge ọnwụ nwụrụ. A nwalere mkpọda nke ahịrị nlọghachị ahịrị ọ bụla maka nnukwu ọdịiche na efu. A na-eji t-ule nwata akwụkwọ maka ntụnyere amamihe dị n'etiti njikwa na ndị riri ahụ cocaine (gosiri na nsonaazụ ebe enyere t uru). A na-eji ANOVA otu ụzọ mee ihe maka ọtụtụ ntụnyere n'etiti njikwa, ndị dara mbà n'obi nwere antidepressants n'ime ụgbọ, ma ọ bụ ndị dara mbà n'obi na-enweghị antidepressants (gosiri na Nsonaazụ ebe F uru nyere). Tukey sochiri ANOVA otu ụzọ post hoc ule. P E weere 0.05 dị mkpa.

Results

Ọmụmụ ihe anyị na-adịbeghị anya na-egosi na ngwaahịa atọ bụ isi nke FosB gene na ụbụrụ, FosB zuru oke (~ 50 kDa), ΔFosB (~ 35-37 kDa), na Δ2ΔFosB (~ 25 kDa), na-ebute ụzọ dị iche iche na mpaghara ụgwọ ọrụ ụbụrụ ụbụrụ na nzaghachi na nrụgide na ọgwụgwọ antidepressant.22], na antigens ndị ọzọ metụtara Fos nwere ike imepụta ya FosB A hụkwara mkpụrụ ndụ ihe nketa na ụbụrụ òké [45-47]. Ya mere, anyị buru ụzọ chọọ ịchọpụta ma ụbụrụ mmadụ ọ na-egosipụta ụkpụrụ nke FosB ngwaahịa mkpụrụ ndụ ihe nketa yiri nke a na-ahụ na ụbụrụ òké. Anyị tụlere ihe nlele HPC na-ahụkarị site na onye riri cocaine mmadụ (Isiokwu 2) na HPC site na òké nyere cocaine na-adịghị ala ala (15 mg / kg, ip maka ụbọchị 7). Isi atọ niile FosB Achọtara ngwaahịa mkpụrụ ndụ ihe nketa na mause na anụ ahụ ụbụrụ mmadụ, mana ahụrụ eriri ndị ọzọ na nlele mmadụ ma e jiri ya tụnyere òké (Fig 2A). Nke kacha pụta ìhè, ụgbụ dị na ~ 30 kDa, ~ 23 kDa, na ~ 20 kDa pụtara na nlele mmadụ mana ahụghị ya na nlele òké. Anyị kwuputara na ndị agha ndị a nwere ike ịnọchite anya ngwaahịa proteolytic sitere na nbibi nke FosB ma ọ bụ ΔFosB n'ihi ogologo oge postmortem (PMI) na nlele mmadụ anyị.Isiokwu 2). Agbanyeghị, enweghị njikọ dị n'etiti ike nke egwu akwụkwọ akụkọ ndị a na PMI (Fig 2B), ma ọ bụ n'etiti PMI na ngwaahịa mkpụrụ ndụ ihe nketa, FosB, ΔFosB, na Δ2ΔFosB (Fig 2Bya bụ, ọ dịghị nke ọ bụla n'ime ahịrị ndọghachi azụ nwere mkpọda dị nnọọ iche na efu. Ya mere, ụgbụ akwụkwọ akụkọ ndị a nwere ike ọ gaghị abụ ngwaahịa mmebi proteolytic nke sitere na ogologo oge n'etiti ọnwụ na nsị anụ ahụ.

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Tebụl 2. Demographics nke ndị na-eri ọgwụ cocaine, ndị ọrịa ịda mbà n'obi, na ndị otu njikwa dakọtara.

http://dx.doi.org/10.1371/journal.pone.0160355.t002

Iji nwetakwuo nyocha nke a, anyị nyere ụmụ oke otu ntụtụ nke cocaine (15 mg / kg, ip) ma ọ bụ saline ma chụọ ha àjà site na nkwụsị cervical otu awa ka e mesịrị. A hapụrụ ụbụrụ ụbụrụ na ọnọdụ maka efu, otu ma ọ bụ awa asatọ tupu ewee ihe nlele. Anyị hụrụ ụfọdụ ngwaahịa mmebi iwu (Fig 3), nke kacha pụta ìhè bụ ~ 23 kDa, mana usoro nke si na ya pụta emeghị ka nke a hụrụ na nlele HPC mmadụ. Ejikọtara ọnụ, data ndị a na-egosi na enwere antigens metụtara Fos na ụbụrụ mmadụ nke nwere ike ịnọchite anya akwụkwọ akụkọ FosB ngwaahịa mkpụrụ ndụ ihe nketa na o yighị ka ọ ga-abụ nsonaazụ proteolysis nke FosB ma ọ bụ ΔFosB.

Anyị mechara chọpụta ma ịdabere na cocaine, ịda mbà n'obi a na-agwọghị, ma ọ bụ ịda mbà n'obi yana ikpughe na ọgwụ antidepressant na-ejikọta ya na mgbanwe ndị dị na ya. FosB ngwaahịa mkpụrụ ndụ ihe nketa na HPC ma ọ bụ PFC mmadụ. A họọrọ ndị ọrịa na ndị na-achịkwa ihe ndị dị otú ahụ na enweghị nnukwu ọdịiche dị na nkezi afọ, okike, ụbụrụ pH, ma ọ bụ PMI (Isiokwu 1). N'ihe atụ sitere na ndị ọrịa na-adabere na cocaine, Western blot kpughere enweghị ọdịiche dị na nkwupụta nke FosB isoform ọ bụla na PFC ma e jiri ya tụnyere njikwa (Fig 4A na 4B). Agbanyeghị, anyị hụrụ mbelata nke ọma na HPC nke ndị dabere na cocaine na FosB zuru oke (t(35) = 2.67, p = 0.012), ΔFosB (t(31) = 2.81, p = 0.009), yana n'òtù akwụkwọ akụkọ atọ niile, 30 kDa (t(34) = 2.71, p = 0.011), 23 kDa (t(15) = 2.7, p = 0.016), na 20 kDa (t(13) = 2.43, p = 0.031), na omume maka mbelata na Δ2ΔFosB (t(29) = 2.03, p = 0.052). N'otu aka ahụ, na ihe nlele sitere na ndị ọrịa na-enwe ịda mbà n'obi, enweghị ọdịiche dị na nkwupụta nke FosB isoform ọ bụla na PFC, ebe HPC gosipụtara mbelata na FosB zuru oke (F(2,35) = 1.98, p = 0.048) na ΔFosB (F (2,30) = 1.38, p = 0.027), yana na 23 kDa band (F (2,21) = 2.05, p = 0.022) na 20 kDa band (F (2,18) = 0.97, p = 0.028) (Mkpụrụ fig 4C na 4D). Data ndị a na-egosi na FosB A na-ebelata okwu mkpụrụ ndụ ihe nketa na HPC n'ọtụtụ ọnọdụ uche ebe okwu PFC enweghị mmetụta.

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Fig 4. Ngosipụta nke protein FosB na HPC na PFC nke ịṅụ ọgwụ ọjọọ cocaine na ndị ọrịa ịda mbà n'obi.

(A) Ebe ọdịda anyanwụ nke protein FosB sitere na HPC na PFC nke ndị na-eri cocaine mmadụ (Coc) na njikwa (Con). (B) Ọnụ ọgụgụ na-ekpughe mbelata dabere na cocaine na ọtụtụ protein FosB na HPC mana ọ bụghị PFC (*: p <0.05, #: p = 0.05). (C) Western blot nke protein FosB sitere na HPC na PFC nke ndị ọrịa ịda mbà n'obi mmadụ kwụsịrị (Dep) ma ọ bụ na antidepressants (Dep + AD) na njikwa (Con). (D) Ọnụ ọgụgụ na-ekpughe mbelata nke ịda mbà n'obi na-adabere na ụfọdụ protein FosB na HPC ma ọ bụghị PFC (*: p <0.05). Ogwe mperi na-egosi pụtara +/- SEM.

http://dx.doi.org/10.1371/journal.pone.0160355.g004

Ihe akaebe ziri ezi maka ebumnuche mkpụrụ ndụ ihe nke ΔFosB na HPC dị obere, yana naanị protein kinase 5 (cdk5) dabere na cyclin bụ ebumnuche enwetara mgbe mkpali electroconvulsive na ụmụ oke.39]. Agbanyeghị, ọtụtụ mkpụrụ ndụ ihe nketa ndị ọzọ amaara ebumnuche maka iwu ederede ΔFosB na mpaghara ụbụrụ ndị ọzọ, ọkachasị na NAc. Ndị a gụnyere ọtụtụ mkpụrụ ndụ ihe nketa dị mkpa maka ọrụ cell hippocampal na plastik synapti, dị ka GluA2 [48] na CaMKII [20]. Ya mere, anyị na-eji Western blot iji nyochaa ọkwa nke mkpụrụ ndụ ihe nketa nke ΔFosB na HPC na PFC nke ndị ọrịa cocaine dabere na ndị dara mbà n'obi. Anyị ahụghị ọdịiche dị ịrịba ama na ọkwa protein nke mkpụrụ ndụ ihe nketa nwa akwụkwọ na PFC nke ndị na-adabere na cocaine, ebe HPC gosipụtara mbelata dị ukwuu na GluA2 (t (34) = 2.31, p = 0.027) na usoro siri ike na-ebelata na mbelata. Ọkwa CaMKII (t (35) = 1.99, p = 0.053) okwu, ebe cdk5 agbanwebeghị (Fig 5A na 5B). Na PFC na HPC nke ndị ọrịa dara mbà n'obi ọ dịghị mgbanwe na nkwupụta nke mkpụrụ ndụ ihe nketa ΔFosB (Mkpụrụ fig 5C na 5D). Ihe omuma a na-egosi na ΔFosB nwere ike na-achịkwa okwu nke mkpụrụ ndụ ihe nketa nwere ike ime na HPC mmadụ, na ụkpụrụ a nwere ike ịbụ mpaghara ụbụrụ na ọrịa kpọmkwem.

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Fig 5. Ngosipụta nke nwere ike ime ΔFosB gene lekwasịrị anya protein na HPC na PFC nke cocaine riri mmadụ na ndị ọrịa ịda mbà n'obi.

(A) Ebe ọdịda anyanwụ nke nwere ike ΔFosB gene lekwasịrị anya protein sitere na HPC na PFC nke ndị na-eme cocaine mmadụ (Coc) na njikwa (Con). (B) Ọnụ ọgụgụ na-ekpughe mbelata dabere na cocaine na GluA2 na CaMKII niile na HPC mana ọ bụghị PFC (*: p <0.05, #: p = 0.05). (C) Western mgbochi nke nwere ike ΔFosB gene lekwasịrị anya protein sitere na HPC na PFC nke ndị ọrịa ịda mbà n'obi mmadụ kwụsịrị (Dep) ma ọ bụ na antidepressants (Dep + AD) na njikwa (Con). (D) Ọnụ ọgụgụ na-egosi enweghị mgbanwe dabere na ịda mbà n'obi. Ogwe mperi na-egosi pụtara +/- SEM.

http://dx.doi.org/10.1371/journal.pone.0160355.g005

Nkwurịta

Ebe a, anyị na-ewetara ndị mbụ chịkọtara FosB ngwaahịa mkpụrụ ndụ ihe nketa na nyocha protein nke ΔFosB na hippocampus na cortex prefrontal nke ndị na-eri cocaine na ndị ọrịa dara mbà n'obi. A maara mpaghara ụbụrụ ndị a ka ha na-arụ ọrụ dị mkpa na pathophysiology nke ọrịa ndị a, na iji ihe nlele nke mmadụ na-eme ka ọ bụrụ mmadụ na-enye anyị ohere: 1) chọpụta ma mgbanwe mkpụrụ ndụ nke a na-ahụ n'ụdị òké nke ọrịa ndị a na-emegharị nke ọma na ụmụ mmadụ. ; 2) chọpụta ụzọ ọhụrụ maka ọmụmụ ihe n'ụdị òké maka enyemaka ọgwụgwọ nwere ike. Nyocha anyị lekwasịrị anya na okwu nke FosB ngwaahịa mkpụrụ ndụ ihe nketa, dịka a tụrụ aro ka okwu ha na mpaghara ndị a ka ha na-ekere òkè na ịda mbà n'obi ma na-akpalite site na ikpughe cocaine na ụdị òké.21, 22, 24]. Mgbe ị na-enyocha ọkwa protein FosB na nlele mmadụ, o doro anya na mgbochi FosB achọpụtala ọtụtụ eriri karịa ka ndị otu anyị na ọtụtụ ndị ọzọ kọwapụtara na mbụ na ụbụrụ ụbụrụ.1, 22]. N'ihi na ụbụrụ mmadụ na-ajụ oyi awa mgbe ọ nwụsịrị ebe a na-ewepụ ihe nlele òké wee kpochie ya n'ime nkeji abụọ nke àjà, anyị hapụrụ ụbụrụ òké. na ọnọdụ mgbe a chụrụ n'àjà ruo awa asatọ iji chọpụta ma ụdị egwu a ga-apụta. Otú ọ dị, n'ihi na anyị edebeghị otu ụkpụrụ nke protein FosB dị na ihe atụ nke mmadụ, na n'ihi na anyị ahụghịkwa njikọ dị n'etiti ogologo PMI na ọkwa dị iche iche dị n'ụdị mmadụ, anyị kwubiri na ọtụtụ n'ime ìgwè ndị ahụ. Nlere anya ụbụrụ mmadụ enweghị ike ịbụ n'ihi mmebi proteolytic nke isoforms FosB buru ibu. Ọ bụ ezie na anyị enweghị ike iwepụ ọdịiche dị na igwe proteolytic dị n'etiti ụdị, anyị ga-atụ aro na ụfọdụ n'ime ìgwè mmadụ nwere ike ịpụta na ọdịiche dị iche iche nke FosB mRNA, ọmụmụ ihe n'ọdịnihu ga-aza ajụjụ a.

Nsonaazụ gara aga sitere na ọmụmụ òké achọpụtala mmụba na FosB isoforms na HPC na PFC mgbe cocaine na-adịghị ala ala.24]. Agbanyeghị, site na otu anyị nke ndị dabere na cocaine anyị hụrụ mbelata na isoforms FosB niile na HPC, na-enweghị mgbanwe na PFC ma e jiri ya tụnyere ndị mmadụ na-achịkwa. Anyị kwenyere na nke a nwere ike ịbụ n'ihi ọdịiche dị n'etiti ọmụmụ òké na ihe gbasara ahụ mmadụ riri ahụ. Ọmụmụ ihe iri ahụ cocaine na-adịru maka ntakịrị akụkụ nke ndụ anụ ahụ, ọ nweghịkwa ọmụmụ ihe ntinye ΔFosB gafere ụbọchị 14 nke ikpughe cocaine na-aga n'ihu.1, 20]. Ndị ọrụ cocaine nwere ike bụrụ ndị na-eri ahụ ruo ogologo oge, nke nwere ike ịkpata mmetụta homeostatic na-akpata FosB A ga-ebelata mkpụrụ ndụ ihe nketa na HPC. Ọzọkwa, ọtụtụ ọmụmụ egosila na ịṅụ ọgwụ ike na-adịte aka na psychostimulants na-esonyere mbelata ọrụ ọgụgụ isi [9, 49]. Ọrụ anyị na-adịbeghị anya na-egosi na HPC ΔFosB na-arụ ọrụ dị oke mkpa na mmụta [28], ya mere mbelata nke HPC FosB Okwu mkpụrụ ndụ ihe nketa na ndị na-eri cocaine nke egosiri ebe a nwere ike ịnọchite anya usoro maka mbelata ọgụgụ isi na riri ahụ psychostimulant. Na mbelata okwu nke FosB gene na HPC, anyị hụkwara mbelata na ọkwa protein nke nwa akwukwo ΔFosB lekwasịrị anya mkpụrụ ndụ ihe nketa GluA2 na CaMKII, na mkpụrụ ndụ abụọ a dịkwa oke egwu maka ọrụ HPC na mmụta [50] na e jikọtara ya na mbụ na iri ahụ [38, 51].

Na HPC nke ndị ọrịa dara mbà n'obi, anyị hụrụ mbelata nke ọtụtụ protein FosB, dabere ma ndị ọrịa na-ewere antidepressants. Nke a nwere ike igosi na antidepressants nwere mmetụta dị iche iche na splicing ma ọ bụ nkwụsi ike nke FosB ngwaahịa mkpụrụ ndụ ihe nketa, ọ bụ ezie na ọmụmụ ihe gara aga na rodents ekpughere ọdịiche dị otú ahụ [22]. Agbanyeghị, enweghị ọdịiche dị na nkwupụta mkpụrụ ndụ ihe nketa nwere ike ịdị na HPC ma ọ bụ PFC nke ndị ọrịa a. Ọ bụ ezie na nnukwu ịda mbà n'obi na-esokarị nsogbu ọgụgụ isi [52], o yikarịrị ka HPC ΔFosB abụghị naanị ihe gbanwere na nzaghachi na ịda mbà n'obi. Ọ bụ ezie na ndị na-eri ahụ cocaine gosipụtara mgbanwe na HPC ΔFosB na n'echiche mkpụrụ ndụ ihe mgbaru ọsọ, ịda mbà n'obi nwere ike na-eduga na usoro nkwụghachi ụgwọ dị iche iche na-egbochi mbelata na GluA2 ma ọ bụ CaMKII okwu. Ya mere, ọmụmụ ihe n'ọdịnihu ga-akọwapụta ma mgbanwe na nkwupụta mkpụrụ ndụ HPC na ịda mbà n'obi na ịṅụ ọgwụ ọjọọ sitere na usoro ndị yiri ya.

Ọ dị mkpa iburu n'obi na ọnụ ọgụgụ mmadụ ejiri mee ihe ọmụmụ a enweghị nkwekọ nke rodent preclinical ma ọ bụ ụdị primate. Dị ka ihe atụ, mmadụ ise n'ime ndị ahụ dara mbà n'obi nwere mmanya na-aba n'anya, abụọ nwekwara opiate n'ụgbọ ahụ mgbe ha nwụrụ. N'otu aka ahụ, mmadụ isii n'ime ndị na-adabere na cocaine ejirila ọgwụ antidepressants mee ihe n'ime ọnwa atọ tupu ọnwụ. Ọ bụ ezie na nke a abụghị ihe ijuanya, ebe ọ bụ na ịda mbà n'obi na ịṅụ ọgwụ ọjọọ na-enwe ọganihu dị elu.6, 7], ọ na-akpaghasị nkọwa nke nsonaazụ. Anyị anaghị achọpụta ọdịiche dị ịrịba ama na usoro ọ bụla nke biochemical anyị n'etiti ndị na-adabere na cocaine bụ ndị nwere antidepressants na ụgbọ mmiri na ndị na-enweghị, ma ọ bụ na anyị anaghị ahụ ọdịiche dị n'etiti ndị ọrịa dara mbà n'obi bụ ndị nwere ihe ndabere na ndị na-emeghị (data egosighi). ). Otú ọ dị, nke a na-ewepụ mmetụta nke ịda mbà n'obi na ịṅụ ọgwụ ọjọọ na usoro anyị. N'ụzọ megidere nke ahụ, ka anyị na-ahụ mbelata yiri nke ahụ na HPC FosB isoform nkwupụta na ịda mbà n'obi na ahụ riri ahụ, ọ ga-ekwe omume na mbelata HPC. FosB Okwu mkpụrụ ndụ ihe nketa bụ usoro a na-ahụkarị n'etiti ọnọdụ abụọ a ma nwee ike itinye aka n'ọrịa. Nnyocha nke echiche a ga-achọ ka ndị otu n'ime ihe ndị mmadụ na-eme ihe na ọmụmụ ihe ndị ọzọ.

N'ikpeazụ, anyị na-ahụ nke ahụ ọtụtụ FosB A na-agbadata ngwaahịa mkpụrụ ndụ ihe nketa na HPC, mana ọ bụghị PFC, nke ụmụ mmadụ na-ata ahụhụ site na ahụ riri ahụ na ịda mbà n'obi. Ọ bụ ezie na anyị enweghị ike ịme njikọ etiological n'etiti ihe a na ọrịa na-ekwu, ọ ga-ekwe omume na mbelata na HPC ΔFosB na / ma ọ bụ ndị ọzọ FosB isoforms nwere ike n'akụkụ ụfọdụ na-akpata mgbaghara nke metụtara ịda mbà n'obi na ahụ riri ahụ, ma ọ bụ na-enye aka na comorbidity nke psychiatric ndị a. nsogbu.

Nkweta

Ndị ode akwụkwọ ga-amasị ikele Kenneth Moon maka enyemaka aka ọrụ dị mma.

Onye nyere onyinye

  1. Chepụtara ma chepụta nnwale ndị a: AJR PAG.
  2. Emere nnwale ndị a: AJR GT PAG.
  3. Nyochaa data: PAG AJR.
  4. Ngwa reagents/ihe akụrụngwa/nyocha enyere aka: GT.
  5. Dee akwụkwọ a: PAG AJR.

References

  1. 1. Robison AJ, Nestler EJ. Usoro ntụgharị na epigenetic nke riri ahụ. Nat Rev Neurosci. 2011;12 (11):623–37 . Epub 2011/10/13. doi: 10.1038/nrn3111 nrn3111 [pii]. pmid:21989194; PubMed Central PMCID: PMC3272277.
  2. 2. Fass DM, Schroeder FA, Perlis RH, Haggarty SJ. Usoro epigenetic na nsogbu ọnọdụ uche: na-ezubere neuroplasticity. Sayensị sayensị. 2014;264:112–30 . doi: 10.1016/j.neuroscience.2013.01.041 pmid:23376737; PubMed Central PMCID: PMC3830721.
  3. View edemede
  4. PubMed / NCBI
  5. Google Ọkà mmụta
  6. View edemede
  7. PubMed / NCBI
  8. Google Ọkà mmụta
  9. View edemede
  10. PubMed / NCBI
  11. Google Ọkà mmụta
  12. View edemede
  13. PubMed / NCBI
  14. Google Ọkà mmụta
  15. View edemede
  16. PubMed / NCBI
  17. Google Ọkà mmụta
  18. 3. Menard C, Hodes GE, Russo SJ. Pathogenesis nke ịda mbà n'obi: nghọta sitere na ọmụmụ mmadụ na òké. Sayensị sayensị. 2015. doi: 10.1016/j.neuroscience.2015.05.053 pmid:26037806.
  19. View edemede
  20. PubMed / NCBI
  21. Google Ọkà mmụta
  22. View edemede
  23. PubMed / NCBI
  24. Google Ọkà mmụta
  25. View edemede
  26. PubMed / NCBI
  27. Google Ọkà mmụta
  28. View edemede
  29. PubMed / NCBI
  30. Google Ọkà mmụta
  31. View edemede
  32. PubMed / NCBI
  33. Google Ọkà mmụta
  34. View edemede
  35. PubMed / NCBI
  36. Google Ọkà mmụta
  37. View edemede
  38. PubMed / NCBI
  39. Google Ọkà mmụta
  40. View edemede
  41. PubMed / NCBI
  42. Google Ọkà mmụta
  43. View edemede
  44. PubMed / NCBI
  45. Google Ọkà mmụta
  46. View edemede
  47. PubMed / NCBI
  48. Google Ọkà mmụta
  49. View edemede
  50. PubMed / NCBI
  51. Google Ọkà mmụta
  52. View edemede
  53. PubMed / NCBI
  54. Google Ọkà mmụta
  55. View edemede
  56. PubMed / NCBI
  57. Google Ọkà mmụta
  58. View edemede
  59. PubMed / NCBI
  60. Google Ọkà mmụta
  61. View edemede
  62. PubMed / NCBI
  63. Google Ọkà mmụta
  64. View edemede
  65. PubMed / NCBI
  66. Google Ọkà mmụta
  67. View edemede
  68. PubMed / NCBI
  69. Google Ọkà mmụta
  70. View edemede
  71. PubMed / NCBI
  72. Google Ọkà mmụta
  73. View edemede
  74. PubMed / NCBI
  75. Google Ọkà mmụta
  76. View edemede
  77. PubMed / NCBI
  78. Google Ọkà mmụta
  79. View edemede
  80. PubMed / NCBI
  81. Google Ọkà mmụta
  82. View edemede
  83. PubMed / NCBI
  84. Google Ọkà mmụta
  85. View edemede
  86. PubMed / NCBI
  87. Google Ọkà mmụta
  88. View edemede
  89. PubMed / NCBI
  90. Google Ọkà mmụta
  91. View edemede
  92. PubMed / NCBI
  93. Google Ọkà mmụta
  94. View edemede
  95. PubMed / NCBI
  96. Google Ọkà mmụta
  97. View edemede
  98. PubMed / NCBI
  99. Google Ọkà mmụta
  100. View edemede
  101. PubMed / NCBI
  102. Google Ọkà mmụta
  103. View edemede
  104. PubMed / NCBI
  105. Google Ọkà mmụta
  106. View edemede
  107. PubMed / NCBI
  108. Google Ọkà mmụta
  109. View edemede
  110. PubMed / NCBI
  111. Google Ọkà mmụta
  112. View edemede
  113. PubMed / NCBI
  114. Google Ọkà mmụta
  115. View edemede
  116. PubMed / NCBI
  117. Google Ọkà mmụta
  118. View edemede
  119. PubMed / NCBI
  120. Google Ọkà mmụta
  121. View edemede
  122. PubMed / NCBI
  123. Google Ọkà mmụta
  124. View edemede
  125. PubMed / NCBI
  126. Google Ọkà mmụta
  127. View edemede
  128. PubMed / NCBI
  129. Google Ọkà mmụta
  130. View edemede
  131. PubMed / NCBI
  132. Google Ọkà mmụta
  133. View edemede
  134. PubMed / NCBI
  135. Google Ọkà mmụta
  136. View edemede
  137. PubMed / NCBI
  138. Google Ọkà mmụta
  139. View edemede
  140. PubMed / NCBI
  141. Google Ọkà mmụta
  142. View edemede
  143. PubMed / NCBI
  144. Google Ọkà mmụta
  145. View edemede
  146. PubMed / NCBI
  147. Google Ọkà mmụta
  148. View edemede
  149. PubMed / NCBI
  150. Google Ọkà mmụta
  151. View edemede
  152. PubMed / NCBI
  153. Google Ọkà mmụta
  154. 4. Keralapurat MM, Briggs SB, Wagner JJ. Nlekọta onwe nke Cocaine na-ebute mgbanwe na nnyefe synapti na plasticity na ventral hippocampus. bayoloji iri ahụ. 2015. doi: 10.1111/adb.12345 pmid:26692207.
  155. 5. Loureiro M, Kramar C, Renard J, Rosen LG, Laviolette SR. Mbufe Cannabinoid na Hippocampus na-eme ka Nucleus Accumbens Neurons rụọ ọrụ ma na-agbanwe ụgwọ ọrụ yana nhụsianya mmetụta mmetụta nke metụtara ịkpọasị. Nkà mmụta uche nke ndu. 2015. doi: 10.1016/j.biopsych.2015.10.016 pmid:26681496.
  156. 6. Davis L, Uezato A, Newell JM, Frazier E. Nnukwu ịda mbà n'obi na nsogbu iji ihe eji eme ihe. Echiche dị ugbu a na psychiatry. 2008;21 (1):14–8 . doi: 10.1097/YCO.0b013e3282f32408 pmid: 18281835.
  157. 7. Mmekọahụ: Ihe riri ahụ na ọrịa uche ndị ọzọ. Na: Ọrụ USDoHaH, nchịkọta akụkọ.: National Institute on Drug Abuse; 2010.
  158. 8. Tafet GE, Nemeroff CB. Njikọ dị n'etiti nrụgide na ịda mbà n'obi: Psychoneuroendocrinological, Genetic, and Environmental mmekọrịta. Akwụkwọ akụkọ Neuropsychiatry na Clinical neurosciences. 2015:appineuropsych15030053. doi: 10.1176/appi.neuropsych.15030053 pmid:26548654.
  159. 9. Cadet JL, Bisagno V. Nsonaazụ Neuropsychological nke Ọgwụ Ọgwụ Na-adịghị Ala: Mkpa maka Ọgwụgwọ Ọgwụgwọ. Frontiers na psychiatry. 2015;6:189 . doi: 10.3389/fpsyt.2015.00189 pmid:26834649; PubMed Central PMCID: PMC4713863.
  160. 10. Blier P. Pharmacology nke putative mmalite mmalite antidepressant atụmatụ. Neuropsychopharmacol. 2003;13 (2):57–66 . nkeji: 12650947. doi: 10.1016/s0924-977x(02)00173-6
  161. 11. Januar V, Ancelin ML, Ritchie K, Saffery R, ​​Ryan J. BDNF onye na-akwalite methylation na mgbanwe mkpụrụ ndụ ihe nketa na ịda mbà n'obi n'oge ndụ. Ntụgharị uche gbasara mmụọ. 2015;5:e619 . doi: 10.1038/tp.2015.114 pmid:26285129; PubMed Central PMCID: PMCPMC4564567.
  162. 12. Covington HE 3rd, Maze I, LaPlant QC, Vialou VF, Ohnishi YN, Berton O, et al. Omume antidepressant nke histone deacetylase inhibitors. J Neurosci. 2009;29 (37):11451–60 . Epub 2009/09/18. 29/37/11451 [pii] doi: 10.1523/JNEUROSCI.1758-09.2009 pmid:19759294; PubMed Central PMCID: PMC2775805.
  163. 13. Maze I, Covington HE 3rd, Dietz DM, LaPlant Q, Renthal W, Russo SJ, et al. Ọrụ dị mkpa nke histone methyltransferase G9a na plasticity nke cocaine kpatara. Sayensị. 2010;327 (5962):213–6 . Epub 2010/01/09. 327/5962/213 [pii] doi: 10.1126/sayensị.1179438 pmid:20056891; PubMed Central PMCID: PMC2820240.
  164. 14. Massart R, Barnea R, Dikshtein Y, Suderman M, Meir O, Hallett M, et al. Ọrụ nke DNA methylation na nucleus na-agbakọta na ntinye nke agụụ cocaine. Akwụkwọ akụkọ nke neuroscience: akwụkwọ akụkọ gọọmentị nke Society for Neuroscience. 2015;35 (21):8042–58 . doi: 10.1523/JNEUROSCI.3053-14.2015 pmid:26019323.
  165. 15. Ruffle JK. Neurobiology nke anụ ahụ riri ahụ: kedu ihe niile (Delta)FosB gbasara? Akwụkwọ akụkọ America nke ịṅụ ọgwụ ọjọọ na ịṅụbiga mmanya ókè. 2014;40 (6):428–37 . doi: 10.3109/00952990.2014.933840 pmid:25083822.
  166. 16. Nestler EJ. FosB: Onye na-ahụ maka ntụgharị uche na nzaghachi antidepressant. Ọnụ ego J Pharmacol. 2014. doi: 10.1016/j.ejphar.2014.10.034 pmid:25446562.
  167. 17. Ulery-Reynolds PG, Castillo MA, Vialou V, Russo SJ, Nestler EJ. Phosphorylation nke DeltaFosB na-edozi nkwụsi ike ya na vivo. Sayensị sayensị. 2009;158 (2):369–72 . Epub 2008/12/02. S0306-4522 (08)01596-0 [pii] doi: 10.1016/j.neuroscience.2008.10.059 pmid:19041372; PubMed Central PMCID: PMC2734485.
  168. 18. Carle TL, Ohnishi YN, Ohnishi YH, Alibhai IN, Wilkinson MB, Kumar A, et al. Usoro nke dabere na Proteasome na -onwe maka nbibi FosB: njirimara nke ngalaba FosB degron na ihe ọ pụtara maka nkwụsi ike DeltaFosB. Ọnụ ego J Neurosci. 2007;25 (10): 3009–19 . Epub 2007/06/15. EJN5575 [pii] doi: 10.1111/j.1460-9568.2007.05575.x pmid:17561814.
  169. 19. Ulery PG, Rudenko G, Nestler EJ. Iwu nke DeltaFosB kwụsie ike site na phosphorylation. J Neurosci. 2006;26 (19): 5131–42 . Epub 2006/05/12. 26/19/5131 [pii] doi: 10.1523/JNEUROSCI.4970-05.2006 pmid:16687504.
  170. 20. Robison AJ, Vialou V, Mazei-Robison M, Feng J, Kourrich S, Collins M, et al. Azịza omume na nhazi nke Cocaine na-adịghị ala ala chọrọ loop ntinye aka na-emetụta DeltaFosB na Calcium/Calmodulin-Dependent Protein Kinase II na Nucleus Accumbens Shell. J Neurosci. 2013;33 (10):4295–307 . doi: 10.1523/JNEUROSCI.5192-12.2013 pmid:23467346.
  171. 21. Vialou V, Bagot RC, Cahill ME, Ferguson D, Robison AJ, Dietz DM, et al. Prefrontal cortical sekit maka ịda mbà n'obi- na omume metụtara nchegbu nke cholecystokinin na-elekọta: ọrụ nke DeltaFosB. J Neurosci. 2014;34 (11):3878–87 . doi: 10.1523/JNEUROSCI.1787-13.2014 pmid:24623766; PubMed Central PMCID: PMC3951691.
  172. 22. Vialou V, Thibault M, Kaska S, Cooper S, Gajewski P, Ugo A, et al. Mwepụta dị iche iche nke FosB isoforms na ụbụrụ niile site na fluoxetine na nrụgide na-adịghị ala ala. Neuropharmacology. 2015;99:28–37 . doi: 10.1016/j.neuropharm.2015.07.005 pmid:26164345.
  173. 23. Perrotti LI, Hadeishi Y, Ulery PG, Barrot M, Monteggia L, Duman RS, et al. Ntinye nke deltaFosB na arụ ọrụ ụbụrụ metụtara ụgwọ ọrụ mgbe nrụgide na-adịghị ala ala. J Neurosci. 2004;24 (47):10594–602 . Epub 2004/11/27. 24/47/10594 [pii] doi: 10.1523/JNEUROSCI.2542-04.2004 pmid:15564575.
  174. 24. Perrotti LI, Weaver RR, Robison B, Renthal W, Maze I, Yazdani S, et al. Ụdị dị iche iche nke DeltaFosB ntinye n'ụbụrụ site na ọgwụ ọjọọ. Synapse. 2008;62 (5):358–69 . Epub 2008/02/23. doi: 10.1002/syn.20500 pmid:18293355; PubMed Central PMCID: PMC2667282.
  175. 25. Kelz MB, Chen J, Carlezon WA Jr., Whisler K, Gilden L, Beckmann AM, et al. Ngosipụta nke ihe odide ederede deltaFosB na ụbụrụ na-achịkwa mmetụta nke cocaine. Ọdịdị. 1999;401 (6750):272–6 . Epub 1999/09/28. doi: 10.1038/45790 pmid:10499584.
  176. 26. Vialou V, Robison AJ, Laplant QC, Covington HE 3rd, Dietz DM, Ohnishi YN, et al. DeltaFosB na sekit ụgwọ ọrụ ụbụrụ na-eme ka nkwụsi ike na nrụgide na nzaghachi antidepressant. Nne Neurosci. 2010;13 (6):745–52 . Epub 2010/05/18. nn.2551 [pii] doi: 10.1038/nn.2551 pmid:20473292; PubMed Central PMCID: PMC2895556.
  177. 27. Robison AJ, Vialou V, Sun HS, Labonte B, S AG, Dias C, et al. Fluoxetine Epigenetically na-agbanwe CaMKIIalpha Promoter na Nucleus Accumbens iji hazie DeltaFosB Binding and Antidepressant mmetụta. Neuropsychopharmacology. 2013. doi: 10.1038/npp.2013.319 pmid:24240473.
  178. 28. Ugo AL, Gajewski PA, Yang M, Kechner ME, Al Masraf BS, Kennedy PJ, et al. Ahụmịhe-dabere na ntinye nke mmụta nchịkwa Hippocampal DeltaFosB. J Neurosci. 2015;35 (40):13773–83 . doi: 10.1523/JNEUROSCI.2083-15.2015 pmid:26446228.
  179. 29. Papakostas GI, Culpepper L. Nghọta na ijikwa cognition na onye ọrịa dara mbà n'obi. J Clin psychiatry. 2015;76 (4):418–25 . doi: 10.4088/JCP.13086ah1c pmid:25919832.
  180. 30. Evans VC, Iverson GL, Yatham LN, Lam RW. Mmekọrịta dị n'etiti neurocognitive na psychosocial na-arụ ọrụ na nnukwu nsogbu ịda mbà n'obi: nyochaa nhazi. J Clin psychiatry. 2014;75 (12):1359–70 . doi: 10.4088/JCP.13r08939 pmid:25551235.
  181. 31. Osisi S, Sage JR, Shuman T, Anagnostaras SG. Psychostimulants na cognition: ihe na-aga n'ihu nke omume na mgbake uche. Pharmacol Mkpu. 2014;66(1):193–221. doi: 10.1124/pr.112.007054 pmid:24344115; PubMed Central PMCID: PMC3880463.
  182. 32. Hiroi N, Marek GJ, Brown JR, Ye H, Saudou F, Vaidya VA, et al. Ọrụ dị mkpa nke mkpụrụ ndụ fosB na molikula, cellular, na omume omume nke ọdịdọ electroconvulsive na-adịghị ala ala. J Neurosci. 1998;18 (17):6952–62 . Epub 1998/08/26. nkeji: 9712664.
  183. 33. Pierce RC, Wolf ME. Neuroadaptations na-akpata Psychostimulant na nucleus na-ebute nnyefe nnabata AMPA. Echiche Cold Spring Harbor na ọgwụ. 2013; 3 (2): a012021. doi: 10.1101/cshperspect.a012021 pmid:23232118; PubMed Central PMCID: PMC3552338.
  184. 34. Luscher C. Cocaine-evoked synaptik plasticity nke excitatory nnyefe na ventral tegmental mpaghara. Echiche Cold Spring Harbor na ọgwụ. 2013;3 (5): a012013. doi: 10.1101/cshperspect.a012013 pmid:23637310; PubMed Central PMCID: PMC3633178.
  185. 35. Greybeal C, Kiselycznyk C, Holmes A. Nsogbu na-akpata nrụgide na cognition na mmetụta mmetụta uche: ọrụ nke glutamate. Curr Top Behav Neurosci. 2012;12:189–207 . doi: 10.1007/7854_2011_193 pmid:22261703; PubMed Central PMCID: PMC3877736.
  186. 36. Duman RS. Pathophysiology nke ịda mbà n'obi na ọgwụgwọ ọhụrụ: imezi njikọ synapti glutamatergic. Mkparịta ụka Clin Neurosci. 2014;16 (1):11–27 . pmid:24733968; PubMed Central PMCID: PMC3984887.
  187. 37. Zarate C, Duman RS, Liu G, Sartori S, Quiroz J, Murck H. Paradigms ọhụrụ maka ịda mbà n'obi na-eguzogide ọgwụgwọ. Ann NY Acad Sci. 2013; 1292:21–31 . doi: 10.1111/nyas.12223 pmid:23876043; PubMed Central PMCID: PMC3936783.
  188. 38. Robison AJ. Ọrụ CaMKII na-apụta na ọrịa neuropsychiatric. Trends Neurosci. 2014;37 (11):653–62 . doi: 10.1016/j.tins.2014.07.001 pmid:25087161.
  189. 39. Chen J, Zhang Y, Kelz MB, Steffen C, Ang ES, Zeng L, et al. Ntinye nke kinase 5 na-adabere na cyclin na hippocampus site na njide electroconvulsive na-adịghị ala ala: ọrụ nke [Delta] FosB. J Neurosci. 2000;20 (24):8965–71 . Epub 2000/01/11. 20/24/8965 [pii]. nkeji: 11124971.
  190. 40. Mlewski EC, Krapacher FA, Ferreras S, Paglini G. Transient kwalite okwu nke Cdk5 activator p25 mgbe nnukwu na-adịghị ala ala d-amphetamine nchịkwa. Ann NY Acad Sci. 2008; 1139:89–102 . doi: 10.1196/annals.1432.039 pmid:18991853.
  191. 41. Bignante EA, Rodriguez Manzanares PA, Mlewski EC, Bertotto ME, Bussolino DF, Paglini G, et al. Ntinye aka nke septal Cdk5 na mpụta oke nchegbu nke nrụgide kpatara. European neuropsychopharmacology: akwụkwọ akụkọ nke European College of Neuropsychopharmacology. 2008;18 (8):578–88 . doi: 10.1016/j.euroneuro.2008.02.007 pmid:18406108.
  192. 42. Seiwell AP, Reveron ME, Duvauchelle CL. Mmụba okwu Cdk5 na-abawanye na oke ka ọ nwesịrị obere oge na cocaine na-elekọta onwe ya, mana ọ bụghị mgbe nnọkọ ogologo oge gasịrị. Neurosci Lett. 2007; 417 (1): 100–5 . doi: 10.1016/j.neulet.2007.02.043 pmid:17339080; PubMed Central PMCID: PMC1876973.
  193. 43. Taylor JR, Lynch WJ, Sanchez H, Olausson P, Nestler EJ, Bibb JA. Mgbochi nke Cdk5 na nucleus accumbens na-eme ka locomotor-na-arụ ọrụ na mkpali-akpali mmetụta nke cocaine. Proc Natl Acad Sci US A. 2007;104(10):4147–52. Epub 2007/03/16. 0610288104 [pii] doi: 10.1073/pnas.0610288104 pmid:17360491; PubMed Central PMCID: PMC1820723.
  194. 44. Quirion R, Robitaille Y, Martial J, Chabot JG, Lemoine P, Pilapil C, et al. Ụbụrụ mmadụ na-anabata autoradiography na-eji akụkụ akụkụ akụkụ nke akụkụ ahụ dum: usoro izugbe nke na-ebelata artefacts anụ ahụ. Synapse. 1987;1 (5):446–54 . Epub 1987/01/01. doi: 10.1002/syn.890010508 pmid:2850625.
  195. 45. Olileanya BT, Nye HE, Kelz MB, Self DW, Iadarola MJ, Nakabeppu Y, et al. Ntinye nke mgbagwoju AP-1 na-adịte aka nke nwere protein ndị dị ka Fos gbanwere na ụbụrụ site na cocaine na-adịghị ala ala na ọgwụgwọ ndị ọzọ na-adịghị ala ala. Neuron. 1994;13 (5): 1235–44 . Epub 1994/11/01. 0896-6273(94)90061-2 [pii]. nkeji: 7946359. doi: 10.1016/0896-6273(94)90061-2
  196. 46. ​​Nye HE, Hope BT, Kelz MB, Iadarola M, Nestler EJ. Ọmụmụ ọgwụ na-ahụ maka iwu nke induction antigen metụtara FOS na-adịghị ala ala site na cocaine na striatum na nucleus accumbens. J Pharmacol Exp Ther. 1995;275(3):1671–80 . Epub 1995/12/01. nkeji: 8531143.
  197. 47. Chen J, Kelz MB, Hope BT, Nakabeppu Y, Nestler EJ. Antigens metụtara Fos na-adịghị ala ala: ụdị kwụsiri ike nke deltaFosB na-ebute ụbụrụ site na ọgwụgwọ adịghị ala ala. J Neurosci. 1997;17 (13):4933–41 . Epub 1997/07/01. nkeji: 9185531.
  198. 48. Kelz MB, Chen J, Carlezon WA, Whisler K, Gilden L, Beckmann AM, et al. Ngosipụta ihe odide ederede [Delta] FosB na ụbụrụ na-achịkwa mmetụta nke cocaine. Ọdịdị. 1999;401 (6750):272–6 . http://www.nature.com/nature/journal/v401/n6750/suppinfo/401272a0_S1.html. nkeji: 10499584
  199. 49. Buchta WC, Riegel AC. Cocaine na-adịghị ala ala na-akpaghasị usoro mmụta mesocortical. Brain Res. 2015; 1628 (Pt A): 88–103 . doi: 10.1016/j.brainres.2015.02.003 pmid:25704202; PubMed Central PMCID: PMC4739740.
  200. 50. Shonesy BC, Jalan-Sakrikar N, Cavener VS, Colbran RJ. CaMKII: mkpụrụ mkpụrụ ndụ maka plastik synapti na ebe nchekwa. Ọganihu na bayoloji molecular na sayensị ntụgharị asụsụ. 2014; 122:61–87 . doi: 10.1016/B978-0-12-420170-5.00003–9 pm:24484698.
  201. 51. Loweth JA, Tseng KY, Wolf ME. Mgbanwe na nnyefe AMPA nnabata na nucleus na-enye aka na ntinye nke agụụ cocaine. Neuropharmacology. 2014;76 Pt B:287–300 . doi: 10.1016/j.neuropharm.2013.04.061 pmid:23727437; PubMed Central PMCID: PMC3836860.
  202. 52. Culpepper L. Mmetụta nke nnukwu nsogbu ịda mbà n'obi a na-agwọghị na cognition na ọrụ kwa ụbọchị. J Clin psychiatry. 2015;76 (7): e901. doi: 10.4088/JCP.13086tx4c pmid:26231021.