Ha ho Batla Tsokolate Ho Qobelloa: Gene-Environment Interplay (2015)

  • Enrico Patrono,
  • Matteo Di Segni,
  • Loris Patella,
  • Diego Andolina,
  • Alessandro Valzania,
  • Emanuele Claudio Latagliata,
  • Armando Felsani,
  • Assunta Pompili,
  • Antonella Gasbarri,
  • Stefano Puglisi-Allegra,
  • Rossella Ventur

E phatlalalitsoe: March 17, 2015

http://dx.doi.org/10.1371/journal.pone.0120191

inahaneloang

Background

Mathata a ho ja a bonahala a bakoa ke tšebelisano e rarahaneng lipakeng tsa tikoloho le liphatsa tsa lefutso, mme ho ja ka mokhoa o phehellang ho arabela maemong a mabe ho tšoaea mathata a mangata a ho ja.

Lisebelisoa le mekhoa

Re bapisitse ho ja joalo ka ho qobelloa ka mokhoa oa phepelo ea boemo bo fumanehang ba ho batla lijo tse fumanehang maemong a mabe maemong a sithabetsang a C57BL / 6J le litoeba tsa DBA / 2J, likharetene tse peli tse nang le tšobotsi e ntle, ho tseba tšusumetso ea ho ikopanya hoa liphatsa tsa gene tikolohong ena. phenotype. Ntle le moo, re lekile hypothesis ea hore ho fumaneha ha ntho e tlase ea D2 (R) ke kotsi ea liphatsa tsa lefutso le maemo a tikoloho a khothalletsang ho ja ka mokhoa o phehellang oa polelo ea D2R ho striatum. Ho fihlela sena, re lekantsoe polelo ea D1R le D2R mohatong oa striatum le D1R, D2R le cy1R ho medial prefrontal cortex, ka ho latellana, ka blot bophirima.

Results

Ho pepesehela maemo a tikoloho ho etsa hore motho a qobelloe ho ja joaloka mokhoa oa ho ja, ho latela semelo sa hae. Mokhoa ona oa boits'oaro o hokahane le phokotso ea phumaneho ea accumbal D2R. Ho feta moo, ho pepeseha maemo a itseng a tikoloho ho hlahisa D2R le ho fokotsa α1R ho "striatum" le "" "liphoofolo" tse qobelloang ". Liphumano tsena li tiisa ts'ebetso ea lipapatso tsa tikoloho ho hlahisa lijo tse qobelloang le ho ts'ehetsa maikutlo a hore ho fumaneha ha D2R ka tlase ke "kotsi" ea tlhaho ea lefutso bakeng sa boitšoaro bo qobelloang. Kamora nako, D2R upregulation le α1R ho eketseha ha "striatum" le "methapo ea methapo" pele ho nako, ke likarabo tse ka bang teng tse ka tsamaeang le phetoho e tlohang ho ts'usumetso e matla ea ho ja.

Tlhaloso: Patrono E, Di Segni M, Patella L, Andolina D, Valzania A, Latagliata EC, et al. (2015) Ha Batho ba Batlang Chocolate ba Qobelloa: Gene-Tikoloho ea Tikoloho. PloS ONE 10 (3): e0120191. Doi: 10.1371 / journal.pone.0120191

Mohlophisi oa thuto: Henrik Oster, Univesithi ea Lübeck, JEREMANE

Re amohetse: August 7, 2014; E amohetse: February 4, 2015; E phatlalalitsoe: March 17, 2015

Copyright: © 2015 Patrono et al. Ena ke sengolo se bulehileng sa phihlello se tsamaisitsoeng tlasa maemo a License ea Boikarabelo ba Creative Commons, e lumellang tšebeliso e sa thibeloang, phetiso, le phetiso ea mofuta o fe kapa o fe, ha fela ho ngolisitsoe mongoli oa mantlha le mohloli

Ho fumaneha ha Data: Lintlha tsohle tse nepahetseng li ka hare ho pampiri le lifaele tsa eona tsa Tšehetso.

Lithuso: Mosebetsi o ne o tšehelitsoe ke Ministero dell'Istruzione dell'Università e della Ricerca: Ateneo 2013 (C26A13L3PZ); FIRB 2010 (RBFR10RZ0N_001), Italy.

Lithahasello tse tsitsitseng: Bangoli ba boletse hore ho na le lithahasello tsa tlhōlisano tse teng.

Selelekela

Mathata a ho ja a bakoa ke maemo a tikoloho le liphatsa tsa lefutso le tšebelisano ea tsona e rarahaneng [1, 2]. Leha ho le joalo, ho na le lithuto tse fokolang tsa tikoloho mabapi le mathata a ho ja tsa batho [2] le lithuto tsa liphoofolo tse ileng tsa hlahloba lintlha tsa tikoloho le liphatsa tsa lefutso ho qobelletseng ho batla lijo le ho ja [3-6].

Liphihlelo tse sithabetsang li sebelisana le liphatsa tsa lefutso le ho eketsa kotsi ea boits'oaro bo tlatsetsang phetohong ea corticostriatal dopamine (DA) le lipontšo tsa norepinephrine (NE) tse fanang ka maikutlo a boits'oaro bo matla ba ho susumetsa batho [7-9]. Bopaki bo ntseng bo eketseha bo kentse li-receptor tsa dopamine ka boitšoaro bo susumetsang [10-14] le D2Rs phatlalatsong e lebisang boits'oarong bo khannoang, joalo ka ho lemalla [15-17].

Likokoana-hloko tsa litoeba tse ka hare li fana ka mehlala ea bohlokoa ea ho ithuta tšebelisano lipakeng tsa liphatsa tsa lefutso le tikoloho [18]. C57Bl6 ⁄ J (C57) le DBA2⁄ J (DBA) litoeba ke tse ling tsa li-inbred tse atisang ho ithutoa khafetsa mabapi le psychobiology hobane li supiloe ke ho se tšoane ho hlakileng lipotsong tse ngata tsa boitšoaro. Sebopeho se sebetsang le se boiqapelo ba lits'ebetso tsa bona tsa methapo ea kutlo, hammoho le litekanyetso tsa boits'oaro ba ho matlafatsa le ho tsilatsila, li hlahlobiloe haholo lits'ebetsong tsena, ka hona li fana ka leseli la bohlokoa la hore na karabelo ea litsamaiso tse fapaneng tsa neural ho susumetso e tšoanang ea tikoloho e amana joang. semelo sa liphatsa tsa lefutso, se lebisang ho liphetho tse fapaneng (kapa hape tse fapaneng) tsa boitšoaro [19-23]. Ka ho khetheha, litoeba tsa C57 le DBA li sebelisoa hangata lipatlisisong tsa tlhekefetso ea lithethefatsi ka lebaka la kutloisiso ea tsona e fapaneng le thepa ea tšusumetso ea, le karabelo tse fapaneng ho, lithethefatsi tse lemalloang, joalo ka joala, li-psychomotor activives, le opiates [7, 20, 21, 24-31]. Ho feta moo, mabapi le psychopathological endophenotypes [32-34], ho se utloane pakeng tsa C57 le litoeba tsa DBA ho li-phenotypes tse amanang le D2R li bonahala li itšetleha ka tšebelisano ea tikoloho ea gene [35-37].

Litoeba tsa DBA ha li arabele hantle ha ho hlohlelletsoa moputso ha o bapisoa le litoeba tsa C57, e leng boemo bo totobatsoang ke boiphihlelo bo sa foleng ba khatello ea maikutlo, bo eketsang karabelo ea lithethefatsi ho litoeba tsa DBA / 2 [24]. Kahoo, re nahana hore ho pepesetsoa khatello ea maikutlo ho sa feleng (tlhoko ea caloric) ho etsa hore ho be le lijo tse matlafatsang ka har'a khatello ea DBA. Re ile ra hlahloba lijo tse qobelloang mabapi le mokhoa o khothalletsoang oa ho batla lijo tse fumanehang tlasa maemo a mabe [38], ho C57 le litoeba tsa DBA. Thibelo ea lijo ka litoeba hangata e nkuoa e le maemo a sithabetsang a lebisang ho, har'a litlamorao tse ling, maikutlo a fetotsoeng a lits'ebetso tsa moputso oa boko le ho ama lits'ebetso tsa ts'usumetso ea sesapo8, 24, 39-42]. Ho feta moo, ho tlalehiloe hore maikutlo a eketsehileng a mokhoa oa moputso a ka lebisa ho jang lijo tse matlafatsoang haholo [38, 43, 44], le ho tsosa khafetsa litseleng tsa meputso ka lijo tse matlafatsoang haholo ho ka lebisa ho tloaelo ea methapo ea kutlo e etsang hore boits'oaro ba tahi bo phehelle ho ho feta [45]. Har'a mabaka a tikoloho a susumetsang mathata a ho ja, ho fumaneha ha lijo tse hohelang ke hona ho hlakileng haholo [45] mme ho bontšitsoe hore lijo tse fapaneng li theha maemo a fapaneng a boits'oaro bo khothalletsang [45, 46]. Ho lijo tsohle tse fumanehang habonolo, chokolete e bontšitsoe hore e na le thepa e khotsofatsang liphoofolong [9, 47-49], hape ke lijo tse atisang ho amahanngoa le litlaleho tsa takatso ea lijo ho batho. Kahoo, ho lakatsoe takatso ea lithethefatsi le bokhoba ba tahi e ho batho [50].

Hobane thibelo ea caloric ke boiphihlelo bo sithabetsang [24], liphoofolo li ne li beoa lenaneong la thibelo ea lijo tse itekanetseng [38], hape hobane ho pepesetsoa lijo tse fumanehang habonolo ke ntlha ea bohlokoa mathateng a ho ja [51], ba ne ba boetse ba pepesetsoa chokolete. Ho hlahloba ho arolelana likarolo tse 'maloa tsa neural ka mokhoa o qobelloang oa ho batla lithethefatsi [52, 53]. E ipapisitse le tšebetso ea li-receptors tsa DA litloaelong tse amanang le lithethefatsi le lijo [17, 51, 54, 55], re lekantsitse litekanyetso tsa D1R le D2R subtype ho caudate putamen (CP), li-nucleus accumbens (NAc), le medial prefrontal cortex (mpFC) le alpha-1 adrenergic receptors (α1Rs) ho mpFC hobane lijo tsa pele tsa NE li hlokahala bakeng sa lijo tsa pele. -seeking [38] le α1Rs li-mediate susumetso le litlamorao tsa ho matlafatsa lithethefatsi [56-58].

Re fumane hore ho pepesehela maemo a tikoloho ho etsa hore motho a qobelloe ho ja, ho latela semelo sa hae. Mokhoa ona oa boits'oaro o ne o hokahane le ho fokotseha ho fumaneha ha li-D2Rs tse fumanehang. Ho feta moo, tlhahiso e joalo e ile ea hlakola li-D2R le li-α1R tse theohileng ka har'a striatum le medial prefrontal cortex, ka ho fapana, ea liphoofolo tse qobelloang.

Liphumano tsena li tiisa ts'ebetso ea lipapatso tsa tikoloho ho hlahisa lijo tse qobelloang le ho ts'ehetsa maikutlo a hore ho fumaneha ha D2R ka tlase ke ntho e "kotsi" ea tlhaho ea tlhaho ea ts'ebetso e joalo. Ka hona re fana ka maikutlo a hore ho eketseha ha D2R le ho qaptjoa ha X1R ho striatum le medial prefrontal cortex, ka ho tšoanang, ke likarabo tse ka bang tsa neuroadaptive tse tsamaellanang le phetoho ho tloha ho khothalletsoang ho ja ho tlamang.

Lisebelisoa le mekhoa

Animals

Male C57BL / 6JIco le litoeba tsa DBA / 2J (Charles River, Como, Italy), 8-9 libeke tsa khale ka nako ea liteko, li ne li bolokiloe ka sehlopha 'me li bolokiloe mochineng oa leseli oa12-h / 12-h / leseli le lefifi (leseli pakeng tsa 7 AM le 7 PM, joalo ka ha ho hlalositsoe [9, 38]. Liteko tsohle li entsoe ka Molao oa Setaliana (Decreto Legislativo no. 116, 1992) le European Communities Council Directive ea November 24, 1986 (86 / 609 / EEC) e laolang tšebeliso ea liphoofolo bakeng sa lipatlisiso. Liteko tsohle tsa phuputso ena li amohetsoe ke komiti ea melao ea boitšoaro ea Lekala la Bophelo la Italy mme ka hona e ts'oaroe ka tlasa lengolo la tumello / tumello #: 10 / 2011-B, ho latela melaoana ea Italy mabapi le ts'ebeliso ea liphoofolo bakeng sa lipatlisiso (molao DL 116 / 92 ) le tataiso ea NIH mabapi le tlhokomelo ea liphoofolo. Ho ile ha nkuoa mehato e lekaneng ho kokobetsa bohloko le ho se khotsofale ha liphoofolo. Lihlopheng tsa taolo li ne li fuoa "chokolete e khutshwane feela ea chokolete" (matsatsi a 2); Lihlopheng tse sithabetseng li ile tsa fuoa "chokolete ea pele ho chokolete", "caloric thibelo" le "pepesetso e khutšoane" ea chokolete pele ts'ebetso ea khatello ea tumello e qala (bona ka holimo bakeng sa lintlha tsa mokhoa).

Liteko tsohle li entsoe nakong ea lebone.

Ts'ebetso ea Khatello ea Boemo

Lisebelisoa tsa tlhahlobo ea khatello ea boemo bo boletsoeng esale pele li hlalositsoe pele [38]. Sekhooa sa Plexiglas (bophara ba 3.8 cm) se ne se beoa ka phapusing e 'ngoe le e' ngoe 'me se beiloe ho thibela motsamao: Senoelo sa 1 se ne se na le 1 g ea chisi ea lebese (Kraft) (Chocolate-Chamber, CC),' me senoelo se seng se ne se sena letho (Empty Safe-Chamber , ESC).

Ka bokhutšoanyane, ts'ebetso e ne e le ka tsela e latelang: ho tloha ka Letsatsi la 1 ho ea ho Letsatsi la 4 (karolo ea boikoetliso), litoeba (Taolo, lihlopha tse hatelletsoeng bakeng sa khatello e ngoe le e ngoe) li behiloe ka bonngoe ka har'a alley, 'me mamati a thellang a ile a buloa ho ba lumella ho kena likamoreng ka bobeli ka bolokolohi le ho hlahloba lisebelisoa tsohle tsa metsotso ea 30. Ka Letsatsi la 5, liphoofolo li ile tsa pepesetsoa liaparo tse tšosang tsa maoto. Ho fumaneha ha motsoako o nang le maemo (CS) (leseli) -shock ho thehiloe sesebelisoa se fapaneng, se nang le phaposi ea 15 × 15 × 20 cm Plexiglas e nang le paterone e ntšo le e metala-e metala marakong a 2 (ho e khetholla ho fapana le lisebelisoa tse nang le maemo a ho hatella) le folete ea tšepe e se nang tšepe eo litšitiso li neng li tsamaisoa ka eona. Leseli le hlahisitsoe ke lebone la halogen (10W, Lexman) tlasa mokato oa gridi o neng o buloa bakeng sa 5, 20-sec linako tsohle tsa 100 sec .; ka nako e 'ngoe le e' ngoe, ka mor'a hore leseli le khanye bakeng sa 19 sec, 1-sec 0.15-mA makala a nyaroang a maoto a ile a tlisoa. Seboka sena sa mokhatlo se thothomelang se ile sa nka metsotso e 10 mme sa lateloa ke nako ea phomolo ea 10-min, kamora moo ho ile ha tsamaisoa seboka se seng se tšoanang sa 10-min light network ka kakaretso, litoeba li amohetse li-pair tsa 10 tsa maoto a khanyang ka sebopeho sa 30-min. Ka matsatsi a 6-8, litoeba li ne li siuoe li sa khathatsoe mokhoabong oa bona. Ka Letsatsi la 9, boemo bo hatelletsoeng ba ho batla chokolete bo ile ba lekanngoa lenaneong la liteko (le leng le le leng la khatello ea maikutlo), moo litoeba li ileng tsa fumana chokolete ho 1 ea likamore tsa 2 moo chokolete e neng e kentsoe nakong ea thupelo. Ka kamoreng e nang le chokolete (CC), CS (leseli) e ile ea hlahisoa ho latela paradigm bakeng sa mokhatlo oa mahlaseli a maoto a bobebe (ntle le nako ea phomolo ea 10-min, e ileng ea felisoa). Leseli le hlahisitsoe ke lebone la halogen tlasa grid ea lefatše e neng e buloe bakeng sa linako tsa 20-sec sec 100 sec ka ngoe. Seboka sena se nkile metsotso ea 20; ka kakaretso, litoeba li fumane linako tsa 10 20-sec ka nako ea 20-min.

Seboka sa liteko se qalile ka ho phatloha ha khanya ea 20-sec pele. Nako e sebelisitsoeng kamoreng e 'ngoe le e' ngoe ea 2 e tlalehiloe nakong eohle ea thuto. Liteko tsohle li entsoe ka likamoreng tsa liteko tse nang le molumo tse neng li bonesitsoe ka mokhoa o sa tobang ke lebone le tloaelehileng (60 W). Bakeng sa liteko tsohle tsa boits'oaro, tlhaiso-leseling e ile ea bokelloa 'me ea hlahlobisoa ho sebelisoa “EthoVision” (Noldus, The Netherlands), sistimi ea ho ikatela ea video e ikemetseng. Letshwao le fumanehang la dijithale le ile la sebetsoa ke software ho hlahisa “nako e sebelisitsoeng” (ka motsotsoana) ka likamoreng, e neng e sebelisoa e le data e tala bakeng sa likhetho tsa ho khetha / ho hloea karolong e 'ngoe le e' ngoe ea lisebelisoa bakeng sa thuto ka 'ngoe.

Lihlopha tse peli tsa litoeba bakeng sa khatello e 'ngoe le e' ngoe li sebelisitsoe tlhahlobo e lekantsoeng ea taolo: taolo (Control n = 6) mme ea hatelloa (E hatelletsoe n = 8).

Ts'ebetso ea Teko

Ts'ebetso ea liteko e bontšoa ho Feie. 1.

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Mofuta oa 1. Lenane la tatellano ea liteko. (Bona mekhoa bakeng sa lintlha.)

http://dx.doi.org/10.1371/journal.pone.0120191.g001

Ho pepesetsoa chokolete pele

Liphoofolo tse lihlopheng tse hatisitsoeng (tse hatisitsoeng C57 le StBA DBA) li ile tsa pepesetsoa chokolete ka matsatsi a 7 ho fihlela 18 (ho tloha ka letsatsi -24 ho fihlela ka letsatsi -18, Feie. 1) matsatsi pele tsamaiso ea maemo a khatello e qalile. Litsuolo li ne li “khetheloa ka thoko” letsatsi le letsatsi ka lihora tsa 4; chokolete ea lebese le lijo tse tloaelehileng li ile tsa tlisoa ad libitum. Matsatsi a mabeli kamora ho fela ha kemiso ena (letsatsi -15, Feie. 1), litoeba sehlopheng se hatisitsoeng li ne li behiloe ka thibelo ea caloric (thibelo ea lijo, FR).

Thibelo ea Caloric

Liea li ne li fuoa mofuta oa phepo: ka bobeli ba ne ba fuoa lijo ad libitum (Lihlopheng tsa taolo) kapa li ne li fuoe regimen e thibeloang lijo (FR, lihlopha tse sithabetseng). Boemong ba thibelo ea caloric, lijo li ne li fanoa hang ka letsatsi (07.00 pm) ka tekanyo e fetotsoeng ho baka tahlehelo ea 15% ea boima ba 'mele ba mantlha. Ka har'a ad libitum boemo, lijo li ne li fanoa hang ka letsatsi (07.00 pm) ka bongata bo fetotsoeng ho feta ts'ebeliso ea letsatsi le letsatsi [38].

Liphoofolo li ile tsa beoa lenaneong le leka-lekaneng la FR [29] bakeng sa matsatsi a 10 (ho tloha ka letsatsi -15 ho isa letsatsing -6, Feie. 1), ho fihlela matsatsi a 6 pele ts'ebetso ea khatello ea maemo e qalile (letsatsi la 1, Feie. 1). Matsatsi a tšeletseng pele karolo ea thupelo e qala, liphoofolo li ile tsa khutlisetsoa ho ad libitum fepa ka mokhoa oa ho thibela litlamorao tsa ho haelloa ke lijo ka letsatsi le hlahlobang la khatello.

Ho pepesetsoa chokolete ka bokhutšoanyane

Ho thibela likarabo leha e le life tse sa tsejoeng tsa chokolete lihlopheng tse sa kenngoeng ke maemo a "ho pepesetsoa" a hlalositsoeng ka holimo (Lihlopheng tsa taolo), lihlopha tsa khatello le khatello, li ile tsa pepesetsoa chokolete e tšoanang kemisong ea matsatsi a 2, matsatsi a 2 pele ts'ebetso ea ho hatella e nang le maemo e qalile ("ho pepesoa ha nakoana").

Ho ja chokolete le boima ba phoofolo

Ho ja chokolete nakong ea mekhahlelo e fapaneng ea mokhoa oa ho hatella (pele ho pepesoa, koetliso, tlhahlobo) ho ile ha lekanngoa boima ba liphoofolo. Litsuonyana li ile tsa beoa: letsatsi la pele la tlhahlobo (pele ts'ebetso ea liteko e qala), matsatsi a karolo ea koetliso, le letsatsi la tlhahlobo ea khatello.

Polelo ea Dopaminergic le noradrenergic receptors ka taolo le khatello ea litoeba tsa DBA

α1R, D1R le polelo ea li-receptors tsa D2R libakeng tsa boko ba 3 [mpFC (α1R, D1R, D2R); NAc (D1R, D2R); le CP (D1R, D2R)] e lekantsoe ke blot in control (Control DBA n = 6) le liphoofolo tse hatelitsoeng (E hatelitsoeng DBA n = 8), lihlopha tse tšoanang tse sebelisitsoeng molemong oa tlhahlobo ea khatello.

Dopaminergic le noradrenergic receptor expression in naïve C57 le litoeba tsa DBA

Baseline D1R, le D2R receptors expression ho mpFC, NAc, and CP hammoho le basement α1R ho mpFC e lekantsoe liphoofolong tsa na ofve tsa mefuta ena ka bobeli [naïve C57 (n = 6) le naïve DBA (n = 6) ka bophirima blot. Teko ena e entsoe liphoofolong tse sa fuoeng maemo a tikoloho (ho pepesetsoa chokolete, FR) kapa mokhoa oa ho hatella (lihlopha tsa Naïve) e le hore a leke maikutlo a hore ho fumaneha ha li-striatal D2 tse fumanehang ke karolo ea kotsi ea tlholeho ea lijo. -e joalo ka boits'oaro.

Bophahamo ba Bophirimela

Litoeba li ne li etsoa sehlabelo ka mokokotlo, 'me masapo a tlosoa 1 h kamora tlhahlobo ea khatello ea maemo, ntle le bakeng sa lihlopha tsa naïve. Lithane tse tlang pele, tse senyehang le tse amanang le boea li ile tsa qhaloa 'me tsa bolokoa ka nitrogen e nang le metsi. Li-punches tsa mpFC, NAc, le CP li fumanoe ho tsoa ho linama tse tsoang ho boea ba serame joalo ka ha ho tlalehiloe [59] (S1 Fig.) 'me e bolokiloe ka naetrojene e mokeli ho fihlela ka letsatsi la thobalano. Mohlala o mong le o mong oa tishu o ne o homogenized ho 4 ° C ho lysis buffer (20 mM Tris (pH 7.4), 1 mM EDTA, 1 mM EGTA, 1% Triton X-100) na proteinase inhibitor cocktail (Sigma-Aldrich, St. Louis, MO , USA).

Khaba ea lithane e ne e le centrifuged ho 12,000 g ho 4 ° C bakeng sa 30 min. The supernatant e ile ea tšoaroa ka tsela e ts'oanang le lithapo tse tsoang. Qetellong, The supernatant e tlositsoe 'me ea bolokoa ho 80 ° C.

Litaba tsa protheine li lekantsoe ke Bradford assay (BioRad Laboratories, Hercules, CA, USA).

MpFC, NAc, le CP li ile tsa hlahlojoa li sebelisoa, 60 ug, 30 ug, le 30 ug, ka ho latellana, ea sampole e ngoe le e ngoe ka mor'a ho kenyelletsa sampole (0.5 M Tris, 30% glycerol, 10% SDS, 0.6 M dithiothreitol, 0.012 % bromophenol putsoa) le pheha bakeng sa 5 min ho 95 ° C. Liprotheine li ile tsa aroloa ke li-electrophoresis ho li-gels tsa 10% acrylamide / bisacrylamide mme li fetisetsoa ho electrophoretically ho li-membrane tsa nitrocellulose, tse neng li koetsoe 1 h ho 22 ° C-25 ° C ho Tris-buffered saline (ka mM: 137 NaCl le HNUMX , pH 20), e nang le 7.5% Pakeng tsa 0.1 (TBS-T) le 20% lebese le mafura a tlase.

Li-membrane li ne li entsoe ka li-antibodies tsa mantlha [li-anti-dopamine D1 (Saense ea Mahlale) le rab-anti-dopamine D2 receptor (Sciunological Science), 1 e senotsoeng: 800 ho TBS-T e nang le mafura a 5% a tlase, kapa rabi anti-alpha1- adrenergic receptor (Abcam), e kentsoeng 1: 400 e nang le lebese le mafura a tlase la 1% ka bosiu bo le bong ho 4 ° C. Kamora ho hlatsuoa haholo ho TBS-T, litho li ile tsa fufuleloa 1 h ka mocheso oa kamore (22 ° C-25 ° C) ka li-antibodies tsa anti-le-IgG tse amanang le HRP tse kenyellelitsoeng 1: 8000 (mahlale a immunological) ho TBS- T le 5% lebese le mafura a tlase] mme e thehiloe le ECL-R (Amersham). Matšoao ana a ne a hlahlojoa le ho hlakoloa a sebelisa sisteme ea setšoantšo sa densitometric (setšoantšoj 64), sa tloaelehang hore e be tubulin.

Lipalo-palo li

Teko ea Tlhatlhobo e Behiloeng.

Bakeng sa tlhahlobo ea khatello ea boemo bo phahameng, ho ile ha etsoa tlhahlobo ea lipalo bakeng sa nako (sec) e sebelisitsoeng setsing (sec) se neng se sebelisitsoe setsing sa (CH) le phapusing e se nang letho (ES-C) nakong ea thupelo (ka kakaretso) moelelo oa matsatsi a koetliso ea 4) le ka letsatsi la tlhahlobo ea khatello ea boemo bo tlase. Lintlha li ile tsa hlahlojoa ho sebelisoa mehato ea khafetsa ea ANOVA, e nang le 2 lipakeng tsa sehlopha-mathata (khatello, maemo a 2: C57, DBA; kalafo, maemo a 2: Taolo, khatello) le 1 kahare ho sehlopha (phaposi, maemo a 3: CT, CC , ESC). Nako e boleloang ke nako e sebelisitsoeng ka phapusing ea CC le ES-C e ne e bapisoa le ho sebelisoa ka makhetlo-khetlo ANOVA ka har'a sehlopha ka seng. Lipapiso lipakeng tsa sehlopha li ile tsa hlahlojoa ha ho loketse ke ANOVA e le 'ngoe.

Ho ja chokolete le boima ba 'mele.

Ho ja chokolete nakong ea thupelo (bokahohle ba matsatsi a 4) le ka nako ea tlhahlobo ea khatello ea maemo e ile ea hlahlojoa ke mekhoa e 'meli ea ANOVA (khatello, maemo a 2: C57, DBA; kalafo, maemo a 2: Taolo, E sithabetse). Ts'ebetso ea chokolete nakong ea karolo ea pele ho pepesoa e hlahlobiloe ke ANOVA e le 'ngoe (khatello: E sithabetse C57, E sithabetse DBA). Boima ba liphoofolo bo ne bo boetse bo tlalehiloe ka letsatsi la pele la liteko (pele ho ts'ebetso ea liteko), nakong ea thupelo, le ka letsatsi la tlhahlobo ea khatello. Lintlha li ile tsa hlahlojoa ke mekhoa e 'meli ea ANOVA (khatello, maemo a 2: C57, DBA; kalafo, maemo a 2: Taolo, E sithabetse).

Polelo ea Dopaminergic le noradrenergic receptors ka taolo le khatello ea litoeba tsa DBA.

Polelo ea D1R le D2R ho mpFC, NAc, le CP le D1R, D2R, le litekanyetso tsa α1R maemong a hatisitsoeng a DBA dhidi ea DBA li ile tsa hlahlojoa ke tsela e le 'ngoe ea ANOVA (kalafo, maemo a 2: kudhibiti DBA).

Dopaminergic le noradrenergic receptors expression in naïve C57 le litoeba tsa DBA.

Polelo ea D1R le D2R ho mpFC, NAc, le CP le D1R, D2R, le α1R maemong a naïve C57 le DBA liphoofolo (naïve C57, naïve DBA) li ile tsa hlahlojoa ke tsela e le 'ngoe ea ANOVA (strain, 2) .

Results

Teko ea khatello ea maikutlo: Boiteko ba ho batla lijo ho litoeba tsa DBA tse hatisitsoeng

Bakeng sa ho lekola tšebelisano lipakeng tsa semelo sa liphatsa tsa lefutso le maemo a tikoloho ponahalong ea tšebeliso ea boitšoaro bo qobelloang, nako e sebelisitsoeng ho CC le ES-C maemong a fapaneng (thupelo le teko) ea ts'ebetso ea maemo a khatello e bonts'itsoeng ke lihlopha tsa khatello le taolo tsa liteko tseo ka bobeli li ile tsa hlahlojoa (Control C57, Control DBA, Stress C57, Stended DBA).

Ha re sekaseka mohato oa thupelo, re bone khatello e kholo ea kalafo x kalafo ea likamore (F (1,72) = 6.52; p <0.001). Papiso ea nako e sebelisitsoeng ho CC le ES-C sehlopheng ka seng e bontšitse hore ke feela lihlopha tsa Control C57 le Stress DBA tse ratang CC khahlanong le ES-C nakong ea thupelo (Control C57: F (1,10) = 6.32; p <0.05; DBA e hatelletsoeng: F (1,14) = 15.60; p <0.05) (Feie. 2), ho qeta nako e ngata ho CC ho feta ES-C.

Mofuta oa 2. Thupelo e Felletseng ea Thupelo ho litoeba tsa C57 le DBA.

Nako e sebelisitsoeng (sec ± SE) ka phapusing e nang le chokolete (CC) le ka kamoreng e se nang letho e sireletsehileng (ES-C) nakong ea thupelo ke lihlopha tsa Control C57 / DBA (n = 6 bakeng sa sehlopha ka seng) (A) le khatello ea maikutlo C57 / Litoeba tsa DBA (n = 8 bakeng sa sehlopha ka seng) (B). * p <0.05 ha e bapisoa le ES-C.

http://dx.doi.org/10.1371/journal.pone.0120191.g002

Mabapi le liphetho tsa liteko, re bone tšebelisano e kholo lipakeng tsa khatello, kalafo le kamore (F (1,72) = 6.0; p <0.001). Mefuta e 'meli e bonts'itse mekhoa e fapaneng ea nako e sebelisitsoeng ho CC le ES-C. Lihlopha ka bobeli tsa taolo (C57, DBA) li qetile nako e ngata ho ES-C ha li bapisoa le phapusi e nang le chokolete (CC), moo ho neng ho le teng (CS) stimulus (CS) (C57: F (1,10) = 6.04; p <0.05; DBA: F (1,10) = 12.32; p <0.01), e bonts'a khatello ea maemo a ho batla chokolete nakong ea tlhahiso ea CS. Ka lehlakoreng le leng, athe litoeba tse hatelletsoeng tsa C57 li ne li sa bontše tšekamelo kapa tšabo bakeng sa phaposi e ngoe (F (1,14) = .381; ns), liphoofolo tse hatelletsoeng tsa DBA li qetile nako e ngata ho CC ha li bapisoa le ES-C, (F ( 1,14) = 7.38; le <0.05) (Feie. 3), ka tsela eo e bonts'a mokhoa oa ho batla lijo leha o ka ba le litlamorao tse mpe.

 

Mofuta oa 3. Teko e Ngotsoeng ea Khatello ho C57 le litoeba tsa DBA.

Nako e sebelisitsoeng (sec ± SE) ka phapusing e nang le chokolete (CC) le ka kamoreng e se nang letho e bolokehileng (ES-C) nakong ea tlhahlobo ea khatello ea maemo ke lihlopha tsa Control C57 / DBA (n = 6 bakeng sa sehlopha ka seng) (A) le khatello ea maikutlo C57 Litoeba tsa DBA (n = 8 bakeng sa sehlopha ka seng) (B). * p <0.05; ** p <0.01 ha e bapisoa le CC.

http://dx.doi.org/10.1371/journal.pone.0120191.g003

Liphetho tsena li bonts'a hore ho pepesehela maemo a tikoloho ea rona ho ne ho etsa hore batho ba batlang kotlo ea chokolete ba se ke ba amoheloa ke matšoao a kotlo, ba fetole mokhoa o phehellang oa ho batla lijo hore o batle ka litheko tsa DBA feela (Feie. 3).

Ho ja chokolete le boima ba 'mele

Ho lekola tšebeliso ea chokolete e bonts'itsoeng ke lihlopha tsa taolo le khatello ea methapo ka bobeli (Control C57, Control DBA, Stress C57, Stended DBA), ts'ebeliso ea chokolete e ile ea hlahlojoa nakong ea mekhahlelo e fapaneng (ho pepesoa, koetliso, tlhahlobo) ea maemo ts'ebetso ea khatello.

Mabapi le tšebeliso ea chokolete molemong oa ho pepeseha, ho ne ho se na phapang e kholo lipakeng tsa khatello ea C57 le litoeba tse hatisitsoeng tsa DBA (F (1,14) = 0.83; ns) (Feie. 4).

 

Mofuta oa 4. Ts'ebetso ea chokolete ho C57 / DBA Control le lihlopha tse hatellehileng.

Ho ja chokolete ho C57 / DBA Control (n = 6 bakeng sa sehlopha ka seng) le khatello ea maikutlo (n = 8 bakeng sa sehlopha ka seng) liphoofolo tse tlalehiloeng nakong ea pele ho pepeseha (A), koetliso (B) le teko (C). Lintlha li hlahisoa joalo ka ligrama tse bolelang (kakaretso ea matsatsi a ± SE bakeng sa A le B) * p <0.05; *** p <0.001 ha e bapisoa le sehlopha sa taolo ea mofuta o tšoanang. ### p <0.001 ha e bapisoa le sehlopha se le seng sa mofuta o mong.

http://dx.doi.org/10.1371/journal.pone.0120191.g004

Mabapi le ts'ebeliso ea chokolete nakong ea thupelo, ho bile le tšebelisano e kholo lipakeng tsa khatello le kalafo F (1,24) = 20.10; P <0.001). Ha re bapisa sehlopha ka seng, re hlokometse phapang e kholo lipakeng tsa Control DBA le Stress DBA ((F (1,12) = 46.17; p <0.001), Control C57 khahlanong le Stress C57 ((F (1,12) = 24.25 ; p <0.001), le khatello ea maikutlo C57 khahlanong le khatello ea litoeba tsa DBA ((F (1,14) = 27.52; p <0.001) (Feie. 4). Liphoofolo tse tepelletseng tsa DBA li bontšitse tšebeliso e phahameng haholo ea chokolete ha e bapisoa le lihlopha tse ling kaofela.

Tlhahlobo ea phepelo ea chokolete ka letsatsi la liteko e senotse tšebelisano e kholo ea kalafo x (F (1,24) = 21.48; p <0.005). Papiso ea motho ka mong pakeng tsa sehlopha e bontšitse phapang e kholo lipakeng tsa taolo le khatello ea maikutlo DBA ((F (1,12) = 38.49; p <0.001), Control and Stress C57 ((F (1,12) = 7.90; p <0.05) and Ho hatelloa C57 le litoeba tsa khatello ea DBA ((F (1,14) = 33.32; p <0.001) (Feie. 4). Liphoofolo tse nang le khatello ea kelello tsa DBA li ile tsa fumana tšebeliso ea chokolete e kholo haholo ha e bapisoa le lihlopha tse ling, ho fana ka tlhahiso ea tšebeliso e khothalletsoang ea chokolete, tumellanong le boitšoaro bo batlang tekong ea khatello ea maemo.

Kamora nako, mabapi le sephetho sa boima ba 'mele, tlhahlobo ea lipalo-palo e bontšitse hore boima ba liphoofolo bo ne bo sa fapana haholo pakeng tsa lihlopha ka letsatsi la pele la teko (pele ts'ebetso ea liteko e qala (F (1,24) = 2.22; ns), mothating oa koetliso (F ( 1,24) = 2.97; ns) le ka letsatsi la tlhahlobo ea boemo bo hatelletseng (F (1,24) = 0.58; ns) (Feie. 5).

Mofuta oa 5. Boima ba liphoofolo.

Weight in Control (n = 6 bakeng sa sehlopha se seng le se seng) mme e hatelletsoe (n = 8 bakeng sa sehlopha ka seng) Lihlopheng tsa C57 / DBA tse lekantsoeng pele ho thetso ho qala (A), ka letsatsi la pele la koetliso (B) le ka letsatsi la Teko (C). Lintlha li hlahisitsoe e le gram ± SE.

http://dx.doi.org/10.1371/journal.pone.0120191.g005

Ka kakaretso, datha ea rona e bonts'a tšebelisano e matla lipakeng tsa liphatsa tsa lefutso le maemo a tikoloho polelong ea ho ja ka mokhoa o qobelloang, e lumellanang le lithuto tse fetileng tse tlalehileng ts'ebetso e matla ea lintlha tsena likhatellong tse ling tsa ho ja [3-5, 38].

Polelo ea Dopaminergic le noradrenergic receptor ho mpFC, NAc, le CP ea khatello ea khatello ea DBA vs Control DBA

Ho lekola polelo ea li-receptor tsa dopaminergic le noradrenergic ho phoofolo e bonts'ang mokhoa o qobelloang oa ho ja (Stended DBA), polelo ea α1R, D1R le D2R ho mpFC le D1R le D2R ho NAc le CP li ile tsa hlahlojoa ho Stended vs. Laola litoeba tsa DBA (Feie. 6).

 

Mofuta oa 6. Pontšo ea DA le NE Receptors maemong a DBA.

Tlhaloso ea D1R le D2R ho CP le NAc (A) le D1R, D2R le α1 ho mpFC (B) ea khatello ea maikutlo DBA (n = 8) le sehlopha sa taolo (n = 6). * p <0.05; ** p <0.01 ha e bapisoa le sehlopha sa taolo. Lintlha li bonts'oa e le karolelano e lekanyelitsoeng ± SE.

http://dx.doi.org/10.1371/journal.pone.0120191.g006

Li-D2R li ile tsa phahamisoa ho NAc (F (1,12) = 5.58; p <0.05) le ho CP (F (1,12) = 10.74; p <0.01) ea khatello ea maikutlo DBA ha e bapisoa le litoeba tsa Control DBA (Feie. 6), e bonts'ang phello e khethollang li-receptors tsa striatal D2 liphoofolong tse bonts'ang boitšoaro bo qobelloang joaloka ho ja. Ha ho na phello ea bohlokoa e neng e bonahala ho li-receptor tsa D1. Polelo ea α1R e ne e le tlase ho mpFC ea khatello ea sehlopha sa DBA ha e bapisoa le litoeba tsa Control DBA (F (1,12) = 7.27; p <0.05) (Feie. 6). Ha ho na phello e bohlokoa e hlokometsoeng bakeng sa polelo ea pele ea D1R kapa D2R receptors.

Dopaminergic le noradrenergic receptor expression ho mpFC, NAc, le CP ea naveve DBA bapisoa le naveve C57 litoeba

Bakeng sa ho lekola ho fumaneha ha li-receptor tsa motheo tsa α1R, D1R le D2R, polelo ea α1R, D1R le D2R ho mpFC le D1R le D2R ho NAc le CP li hlahliloe ka lihlopha tse peli tsa li-naï. naïve C57 le naïve DBA) (Feie. 7).

 

Mofuta oa 7. Pontšo ea DA le NE Receptors ho naïve C57 le liphoofolo tsa DBA.

Tlhaloso ea D1R le D2R ho CP le NAc (A) le D1R, D2R, le α1 ho mpFC (B) ea naïve C57 / DBA lihlopha (n = 6 bakeng sa sehlopha ka seng). ** p <0.01 ha e bapisoa le sehlopha sa naïve sa mofuta o mong. Lintlha li bonts'oa e le karolelano e lekanyelitsoeng ± SE.

http://dx.doi.org/10.1371/journal.pone.0120191.g007

Re hlokometse ho fumaneha ha D2R ka tlase ho NAc ea naïve DBA khahlanong le litoeba tsa C57 (F (1,10) = 11.80; p <0.01). Ha ho phapang e ngoe ea bohlokoa e bonoeng ho D1R, D2R, kapa α1R libakeng tse ling tsa boko (Feie. 7). Liphetho tsena, li lumellana le data e fetileng [4, 54, 60, 61], ts'ehetsa maikutlo a hore ho fumaneha ha "D2R" ke "kotsi" ea tlhaho. e bakang tlokotsi ea ho ja hampe.

Puisano

Re ile ra lekola lijo tse qobelloang ho latela lijo tse fanang ka maikutlo a hore ho ka ba le lijo tse ka jang lijo tse matlafatsang / ho ja ka tlasa maemo a mabe [38] ho C57 le litoeba tsa DBA. Ho pepesehela maemo a tikoloho ho kenyellelitse mokhoa o joalo oa ho qobella ho ja, ho latela semelo sa mofuta. Ntle le moo, mokhoa ona oa boits'oaro o ne o bonahala o hokahane le phumaneho e tlase ea li-receptor tsa D2 tse fumanehang. Re boetse re hlokometse ho eketseha ha D2R le ho hloleha ho qoela ha X1R ka har'a striatum le mpFC, ka tsela e tšoanang - karabelo e ka 'nang ea e-ba teng ea phetoho e tšoanang le phetoho e tlohang ho ts'usumetso e joalo ea boits'oaro ba ho ja.

Liteko tsa rona li fana ka maikutlo a hore tšebelisano lipakeng tsa phihlello ea chokolete e tlisoang ke chokolete le phetoho ea khalori e fana ka mokhoa oa ho batla chokolete o sa keneleng matšoao a kotlo, o fetola boitšoaro bo ts'oanang ba ho ja lijo hore o be mokhoa o qobelloang oa ho ja. Haholo-holo, boitšoaro bona bo latela ka matla ho genotype. Liphetho tsa tlhahlobo ea khatello ea boemo bo bontša hore ke liphoofolo tse hatisitsoeng feela tsa DBA tse bonts'itseng mokhoa oa ho batla lijo, leha o ka ba le litlamorao tse mpe.

Phello ena e ka se fuoe phapang ea kutloelo-bohloko ea ho tsitsipanya pakeng tsa C57 le litoeba tsa DBA, joalo ka ha ho bontšitsoe ke teko e tšehetsang (bona Mekhoa ea S1 'me S2 Fig.) le joalo ka ha ho tlalehiloe ke lihlopha tse ling [62]. Ntle le moo, boitšoaro bo batlang lijo bo ile ba ntlafala, ho liphoofolo tse hatisitsoeng tsa DBA, ka mokhoa o ts'oanang le litloaelo tsa ho ja joalo ka ha li bonts'itsoe ke tšebeliso e phahameng ea chokolete e bontšitsoeng ke sehlopha sena. Leha ho ja lijo tse ngata tse matlafatsoang ho ka supa takatso e matla ea lijo, ho etsa joalo leha ho na le litlamorao tse mpe, joalo ka ho mamella kotlo ho e fumana, ho bonts'a tšusumetso ea lijo (ho qobelloa) [5].

Kahoo, athe litoeba tsa DBA ke "mohlala o motle" oa ho hanela lithethefatsi tsa tlhekefetso [24] le mathata a amanang le lijo tlasa maemo a tloaelehileng (liphetho tsa hona joale), a ba le bothata ba lithethefatsi haholo [24] le litlamorao tse amanang le lijo ha li le tlas'a khatello e ikhethang ea tikoloho. Ho feta moo, liteko tsa pele li bonts'a hore ho pepesehela e le 'ngoe feela ea lintho tsena tse fapaneng (ho pepesetsoa chokolete kapa thibelo ea caloric, ka thoko) ho hloleha ho susumetsa phenotype ena (Mekhoa ea S1 'me S3 Fig.). Kahoo, ke feela tšusumetso e matla ea maemo a tikoloho (ho pepesetsoa chokolete le thibelo ea "caloric") e etsang hore boitsoaro ba ho ja bo hanane le matšoao a kotlo (boitšoaro bo qobelloang joalo ka ho ja). Sephetho sena se lumellana le bopaki bo bonts'ang hore ho fumaneha hoa monate [46, 51], khatello ea maikutlo [1, 63-65], le kamano pakeng tsa khatello le thibelo ea khalori ke lintho tsa bohlokoahali tse khothalletsang mathata a ho ja ho batho le mehlala ea liphoofolo [65-67].

Phetoho e tlohang ho tšusumetso e tsoang ho qobello e kang ea ho ja e bonts'itsoeng ke litoeba tse hatisitsoeng tsa DBA ho bonahala e amana le polelo e fetotsoeng ea dopaminergic le noradrenergic receptors potoloho ea PFC-NAc-CP. Ebile, litene tsa StBA tsa DBA, tse bonts'itseng mokhoa o qobelloang oa ho ja (joalo ka ha ho bontšitsoe ke ho se be teng ha khatello ea maemo), e bonts'itse ho eketseha ha D2R ho NAc le CP le ho theoha ha α-1AR ho mpFC, ha ho bapisoa le taolo ea DBA. Ho etsa qeto ea hore litlamorao tse bonojoang li ka susumetsoa ke tšebeliso ea chokolete e fapaneng lenaneong la liteko le bonts'itsoeng ke Taolo le Stended DBA, ho ile ha etsoa tlhahlobo e 'ngoe. Maemo a liteko le ts'ebetso li bile joalo ka ha li hlalositsoe bakeng sa taolo le khatello ea maikutlo DBA, empa polelo ea li-receptors e ile ea etsoa kelellong e tlositsoeng ho litoeba ntle le ts'ebeliso ea chokolete (ka letsatsi la liteko). Liphetho tsa tlhahlobo ena (Mekhoa ea S1 'me S4 Fig.), ntle le ho qaqisa taba ea hore ntlafatso ea D2R ho NAc le CP le ho theoha ha α-1AR ho mpFC e bonts'itsoeng ke Stended DBA ho ka hohela tšebeliso ea chokolete.

Liphetho tse bonoeng ho NAc le CP ea litoeba tsa DBA tse hatisitsoeng ha li re lumelle ho fumana litlamorao ho phetisetso ea DA - ke hore, haeba liphetoho li eketsa molumo oa dopaminergic, li hloka leseli le felletseng ka foromo ea li-receptor tsa D2 - mohlala, karolo ea 2 mefuta e meng ea mRNA splice, D2R-long (D2L) le D2R-khutšoanyane (D2S) - libakeng tsa 2, hobane karolo e lekanyelitsoeng ea isoforms lithutong tsa striatum e ama leural le boits'oaro ba D1R le D2 / XNUMR68-70]. Re kholoa hore keketseho ea li-receptor tsa postynaptic le ho phahama hoa phetisetso ea phetisetso ea dopamine ho matlafatsa le ho matlafatsa boitšoaro bo batlang lijo [11]. Leha ho le joalo, ho na le lipatlisiso tse ling tsa lintlha tse hlokahalang ho etsa lipatlisiso hore na ke li-D2R tse amehang ts'ebetsong ea rona ea liteko.

Ho eketseha ha polelo ea D2R e ntseng e eketseha ho litoeba tsa DBA tse hatisitsoeng ho bonahala ho fapane le khopolo-taba e reng ho nyarosoa ha D2R ke karabelo e natefisang mabapi le ho fetoloa hoa lijo tse monate. Le ha ho le joalo, ho nyatsuoa ho tlase ha D2R e tlalehiloe e le karabelo e khahlisang ho feteng lijo tse matlafatsang le ho ja lithethefatsi ho batho le liphoofolo [4, 44, 60, 71-75] empa hape le sesosa sa kotsi ea liphatsa tsa lefutso tse tlokotsing ea ho ja hampe "4, 54, 60, 61, 75]. Polelo e kholo ea "striatal D2R" eo re e boneng thutong ena e kanna ea hlahisoa ke karabelo e khahlisang maemong a tikoloho ea rona (ho pepeseha, thibelo ea khalori) tlasa letšoao le itseng (ho ja ka mokhoa o qobelloang) le arolelanoang ke mathata a mang a thata, a ho ja. Phehisano ka taba ena hangata e hlokometse botenya le mathata a ho ja, moo mekhoa e rarahaneng ea boits'oaro (joalo ka boima ba 'mele, linako tsa ho iphepa tse fumanehang nako e telele, phihlello ea ho ja lijo tse nang le mafura a mangata) nts'etsopele-e seng mokhoa o tlamang oa ho ja ka bobeli, joalo ka ha ho lekotsoe thutong ena.

Bopaki bo ntseng bo eketseha bo beha DriNALXR le D1R moqoqong oa melemo ea theko o khethang boikemisetso ba ho sebelisa matla ho fumana moputso o ratoang, ka hona o ama boits'oaro bo susumetsang [10-14]. Ho feta moo, boits'oaro bo nepahetseng bo lebisitsoeng ho sepheo le sepheo li bonahala li lumellana le maemo a phahameng a D2R ho striatum [12, 76-79]. Boithuto ba rona bo bonts'a hore polelo e fetelletseng ea D2R e boetse e hokahanngoa le ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea methapo, e hlahisang khopolo ea hore polelo e nepahetseng ea D2R ke seterata sa neural sa boitšoaro bo nepahetseng bo lebisitsoeng ho sepheo.

Sephetho se seng sa bohlokoa e bile ho fumaneha ka tlase ho D2R ho NAc ea naïve DBA bapisoa le naveve C57 litoeba. Joalokaha ho se ho tšohliloe, polelo ea D2R e fokotsehileng e khothalelitsoe e le sesosa sa kotsi ea tlokotsi ea ho ja habonolo "4, 54, 60, 61, 75]. Ho feta moo, ho fokotseha ho fumaneha ha D2 / D3 dopaminergic receptor ka har'a ventral striatum ho reriloe ho fana ka tekanyo e eketsehileng ea ho nyopisa ho ja lithethefatsi le ho li lokisa ka tšusumetso e phahameng [16, 79, 80]. Ho feta moo, litoeba tsa DBA / 2 ho tlalehiloe hore li na le maemo a phahameng a ho tsitsipanya [81, 82]. Kahoo, re hakanya hore ho fumaneha ha theko e tlase ea D2R ho hlokometsoe litlalehong tsa litoeba tsa DBA bakeng sa karohano ea ho ja lijo tse qobelloang tlas'a maemo a ikhethang a tikoloho, thibelo e joalo ea caloric le ho fumaneha ha lijo tse fumanehang habonolo - lintlha tse amang nts'etsopele le polelo ea mathata a ho ja [4, 46, 64, 83, 84].

Re bone re fokotsehile polelo ea pele ea α1R ho Stase bapisoa le litoeba tsa DBA. Leha phetisetso ea pele ea NE e khothalelitsoe ho hlokahala bakeng sa boitšoaro bo susumetsoang bo amanang le lijo [9] mme le ha li-neuron (haholo-holo ka α1Rs) li loants'ela litlamorao tse matlafatsang tsa lithethefatsi tsa tlhekefetso [57, 58, 85], ha ho na lipatlisiso tse hlokometseng ho kenella ha li-receptor tsa pele ho nako tsa Noradrenergic maemong a qobelloang joaloka ho ja. Liphetho tsa rona li holisa liphumano tse fetileng mabapi le ts'ebetso ea phetiso ea pele ea NE maemong a susumetsang a amanang le lijo, e fana ka maikutlo a hore li-receptors tse ikhethang li laola tšusumetso e fetelletseng e amanang le ho ja ka matla. Downregulation ea α1R ho mpFC e ka ba sesupo sa ts'ebetso e lumellanang e tlatselletsang phetoho ho tloha boits'ebetsong bo qobelloang, bo tsamaisoa ke karolo e felileng ea cortex le ts'ebetso e kholo ea striatum. Leha ho le joalo, ho hlokahala liphuputso tse ling ho fuputsa khopolo ena.

Hypothalamus ke e 'ngoe ea likarolo tsa bohlokoahali tsa boko tse laolang ho ja lijo [86-88]. Leha ho le joalo, li-circuits tse fapaneng tsa boko, ntle le tse laolang tlala le ho hlonama, ho khothalelitsoe ho nka karolo ts'ebelisong ea lijo [60, 89]. Ho feta moo, li-neurotransmitters le lihormone tse ngata, ho kenyeletsoa DA, NE, acetylcholine, glutamate, cannabinoids, opiods le serotonine, hammoho le li-neuroptides tse kenyelletsoeng taolong ea homeostatic ea takatso ea lijo, joalo ka orexin, leptin le ghrelin, li na le tšusumetso litlamorao tsa lijo. [60, 90-92]. Kahoo, taolo ea tšebeliso ea lijo ke hypothalamus e bonahala e amana le mekotla e fapaneng ea neural e sebetsanang le likarolo tse khotsofatsang le tse khothatsang tsa ho ja lijo [60], joalo ka sisteme ea prefrontal-accumbal. Ke ho hlokomela hore litoeba tsa C57 le DBA li bonts'a phapang e fapaneng ea boits'oaro le litšobotsi tse sebetsang le tsa anatomical tsa methapo ea boko ea methapo ea kutlo li se li hlahlobiloe haholo mefuteng ena ea tlhaho [19, 23], ka hona ho fana ka maikutlo a fapaneng, a ts'epahalo ea khatello ea maikutlo, taolo ea tšusumetso, moputso, ho ithuta, le li-circuits tsa taolo.

Mokhoa o thehiloeng hamolemo o kenyelletsoeng ho sebetsanang le likarolo tse khotsofatsang le tse khothatsang tsa lijo (le lithethefatsi) ke mokokotlo oa moputso oa dopaminergic [45, 51, 60]. Ho hlohlelletsa khafetsa litseleng tsa moputso tsa DA ho lumeloa hore ho baka liphetoho tsa methapo ea methapo makaleng a fapaneng a neural, ka hona ho etsa hore ho batla "ho be thata" mme ho lebise ho tahlehelo ea taolo ea tahlehelo ea lijo (kapa lithethefatsi) [51, 60].

Ho fanoe ka maikutlo a hore maemong a fapaneng a phihlello, matla a hohelang a lijo tse fumanehang habonolo a ka tsamaisa phetoho ea boits'oaro ka liphetoho tse amanang le methapo likarolong tsa kelello tse amanang le tšusumetso, ho ithuta, ho lemoha le ho etsa liqeto tse bontshang liphetoho tse tlisoang ke tlhekefetso ea lithethefatsi [83, 93-99]. Haholo-holo, liphetoho moputsong, khothatsong, mohopolong le lipoteng tse latelang ho pepesetsoa lijo tse monate li tšoana le liphetoho tse bonoang kamora ho pepesetsoa hoa lithethefatsi khafetsa [60, 95]. Bathong ba hlaselehang habonolo ke liphetoho tsena, ho ja lijo tse matlafatsang (kapa lithethefatsi) ho ka senya tsitsipano lipakeng tsa khothatso, moputso, ho ithuta, le taolo, ka hona ho eketsa boleng bo matlafatsang ba lijo (kapa lithethefatsi) le ho fokolisa li-circuits tse laolang [51, 60].

Motheong oa tlhokomeliso ena le litlamorao ho tsoa thutong ea hona joale, ho ka sisinya hore phetoho ea ho tloha boits'oarong bo susumetsang ho ea ho boits'oaro bo matla ba ho ja bo shebiloeng ho litoeba tsa DBA e ka amana le khokahano lipakeng tsa kotsi ea liphatsa tsa lefutso (tlhaiso e tlase ea D2 receptors e bonoang thutong ena hammoho le phapang lipakeng tsa li-neurotransmitters le lihormone tse amehang liseketeng tse amanang le lijo) le ho pepesehela maemo a tikoloho ao, ho kenyelletsa ho eketseha ha D2R le α1R ho ts'oarana ka striatum le mpFC, ka ho latellana, ho ka lebisang ho sebelisaneng “ho sa lekanang” lipakeng tsa liserekisi tse susumetsang boitšoaro le li-circuits tse laolang le tse sitisang likarabo tse ka bang teng pele [60, 95].

Nahanisisa

Ho na le lithuto tse fokolang mabapi le tšebelisano-tikoloho ea liphatsa tsa lefutso mathateng a ho ja hoa batho [2]. Moetso oa phoofolo oo re o khothalletsang mona o ka sebelisoa ho utloisisa hore na maemo a tikoloho a ikamahanya le mathata a liphatsa tsa lefutso le mabaka a amanang le kutlo ea moea joang ho khothaletsa tšebeliso ea mokhoa o joalo oa ho qobella ho ja, le ho fana ka leseli le lecha tlatsong ea lithethefatsi.

Ho tšehetsa Boitsebiso

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Boemo ba moemeli oa ho penya ho medial preF Pambal Cortex (mpFC) (A), Nucleus Acumbens (NAc) le Caudate-Putamen (CP) (B).

S1 Fig. Boemo ba ho pepa.

Boemo ba moemeli oa ho penya ho medial preF Pambal Cortex (mpFC) (A), Nucleus Acumbens (NAc) le Caudate-Putamen (CP) (B).

doi: 10.1371 / journal.pone.0120191.s001

(TIFF)

S2 Fig. Tšitiso ea kutloelo-bohloko e tšosang ho C57 le litoeba tsa DBA.

Ho utloahala ho tšosang ho liphoofolo tsa C57 le DBA (Mekhoa ea S1). Metsi a ho sisinya (μA ± SE) a lemohileng a C57 le liphoofolo tsa DBA.

doi: 10.1371 / journal.pone.0120191.s002

(TIFF)

S3 Fig. Teko e Ngotsoeng ea Khatello ho litoeba tsa DBA.

Nako e sebelisitsoeng (sec ± SE) ka phapusing e nang le chokolete (CC) kamore e se nang tšireletso (ES-C) nakong ea Teko ea Khatello e Ngotsoeng ke Lihlopheng tse thibelitsoeng ke DBA le DBA.

doi: 10.1371 / journal.pone.0120191.s003

(TIFF)

S4 Fig. Pontšo ea DA le NE Receptors litoeba tsa DBA.

Tlhaloso ea li-receptor tsa D2 ho CP le NAc hammoho le ea α1 ho mpFC ea litoeba tse hatelletsoeng le taolo ea DBA (n = 6 bakeng sa sehlopha ka seng). * p <0.05 ha e bapisoa le sehlopha sa Taolo. Lintlha li bonts'oa e le karolelano e lekanyelitsoeng ± SE.

doi: 10.1371 / journal.pone.0120191.s004

(TIFF)

Mekhoa ea S1. Lisebelisoa tse Tšehetsang le Mekhoa.

doi: 10.1371 / journal.pone.0120191.s005

(DOC)

lumela hore baa fokola

Re leboha Dr. Sergio Papalia ka thuso ea hae e bohlale.

Menehelo ea Mongoli

O ile a amohela le ho hlophisa liteko: RV EP MDS. O entse liteko: EP MDS DA ECL AF LP AV. Ho hlahlobisisa data: RV AP AG SPA. Li-reagents tse kentsoeng / lisebelisoa / lisebelisoa tsa tlhahlobo: AF EP MDS. Ngola pampiri: RV SPA EP MDS.

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