I-Dopamine eyahlukileyo Ukukhululwa kweMandla kwiNucleus Accumbens Core kunye neShell eveza izalathisi ezongezelelweyo zeNkohlakalo Ukubikezela kunye nokukhuthaza i-Incentive Motivation (2015)

  1. URegina M. Carelli 2

+Bonisa ukusebenzisana

Igalelo lababhali: I-MPS kunye ne-FC yenzelwe uphando; I-MPS kunye ne-FC zenze uphando; Idatha ye-MPS kunye ne-FC yahlalutya idatha; I-MPS, i-RMW, kunye ne-RMC babhale iphepha.

Abstract

I-Mesolimbic dopamine (DA) ikhutshwa ngokubonakalayo ngexesha lokuziphatha, nangona kukho ukungavisisani okukhulu malunga nenjongo ethile yezi zimpawu ze-DA. Umzekelo, impazamo yokuxela kwangaphambili (i-PE) imodeli iphakamisa indima yokufunda, ngelixa iimodeli zokuzikhuthaza (IS) zibonisa ukuba umqondiso we-DA uphembelela ixabiso kwaye ngokwenza njalo uvuselela inkuthazo yokuziphatha. Nangona kunjalo, ngaphakathi kweepateni ze-nucleus accumbens (NAc) zokukhutshwa kwe-DA zinokwahluka ngokulingeneyo phakathi kwemimmiselo, kwaye ngenxa yoko, kunokwenzeka ukuba ezi patheni zinegalelo ngokwahlukeneyo kumanqaku e-PE kunye ne-IS. Ukuvavanya oku, silinganise ukukhutshwa kwe-DA ngokwamacandelo e-NAc ngexesha lokuziphatha okwahlulahlulwa ngokwasempilweni ngokungathandabuzekiyo. Iindlela ze-Electrochemical zazisetyenziselwa ukulinganisa ukukhutshwa kwe-subcond NAc dopamine embindini kunye neqokobhe ngexesha leshedyuli yezixhobo ezifundiswe kakuhle apho iigundane zaqeqeshelwa ukushicilela i-lever (ifuna; i-SL) ukufumana ukufikelela kwi-lever yesibini (ukuthatha; i-TL) edibene ne ukuhanjiswa kokutya, kwaye kwakhona ngexesha lokuphela. Embindini, ukukhutshwa kwe-phasic ye-DA yayinkulu ngokulandela inkcazo yokuqala ye-SL, kodwa incinci kwi-TL elandelayo kunye neminyhadala yomvuzo. Ngokwahlukileyo, i-phasic shell DA ibonise ukukhutshwa okuqinileyo kuyo yonke imicimbi. Ukutywina kunciphile phakathi kwesiqalo kunye nesiphelo seeseshoni kwigobolondo, kodwa hayi engundoqo. Ngexesha lokuphela, ukukhutshwa kwe-DA eqongeni kubonise ukwehla komgangatho kwi-SL kwaye ikhefu ekukhupheleni ngexesha elilindelweyo lemivuzo, ngelixa ikhephu lokukhululwa kwe-DA lehlile ikakhulu ngexesha le-TL. Ezi ntshukumo zokukhutshwa zibonisa ukuba imiqondiso ye-DA ehambelana nayo inokuxhasa iiyantlukwano zekhowudi yokuziphatha.

INKCAZO YOKUFUNDA Ukubonisa uphawu lwe-Dopamine ebuchosheni kubalulekile kwimisebenzi eyahlukeneyo yokuqonda, njengokufunda kunye nenkuthazo. Ngokwesiqhelo, kucingelwa ukuba uphawu olunye lwe-dopamine lwanele ukuxhasa le misebenzi yokuqonda, nangona ithiyori ezikhuphisanayo zingavumelani ngendlela i-dopamine enegalelo ngayo kwindlela yokuziphatha esekwe kumvuzo. Apha, sifumene ukuba ukukhutshwa kwe-dopamine yexesha lokwenyani ngaphakathi kwe-nucleus accumbens (ekujoliswe kuyo ephambili ye-midbrain dopamine neurons) ngendlela eyahlukileyo phakathi kokungaphantsi kunye neqokobhe lokuhanjiswa. Embindini, amandla edopamine ahambelana nethiyori -kufunda (ezinje ngephutha lokuxela umvuzo) ngelixa kwigobolondo, dopamine iyahambelana nethiyori ezisekelezisayo (umzekelo, ukunyusa isikhukula). Ezi zinto zifunyanisiweyo zibonisa ukuba i-dopamine idlala iindima ezininzi kunye ezihambelanayo ngokusekwe kwizangqa zedesika ezinceda izilwanyana zikhulise isimilo esihle.

intshayelelo

Ukuqonda kakuhle indima yokubonakaliswa kwe-dopamine (DA) ngokunxulumene nokufunda, indlela yokuziphatha kunye nokulutha ngumcimbi ophambili ekuziphatheni kwe-neuroscience. Iithiyori zexesha elizayo ziyahambelana nombutho otomical wenkqubo ye-mesolimbic ye-DA, apho inani elincinci labemi be-DAergic neurons kwindawo ye-ventral tegmental tegmental (VTA) ithumela i-collarals kuyo yonke ingqondo ukuze ijikeleze ngokubanzi imijikelezo yokufunda kunye nokwenza. Nangona kunjalo, ubungqina bamva nje buchaza ukuba ukusayina kwe-DA kunokuba yinto enkulu kunakuqwalaselwa ngaphambili. Umzekelo, i-phasic DA ikhupha ulwazelelo olulandelayo lomvuzo oqikelelwayo ngenani lomvuzo olindelekileyo wenowuthi yenowuthi (NAc), kodwa hayi iqokobhe (Imini et al., 2010; I-Sugam et al., 2012). Ngokwahlukileyo, utshintsho olwenziwayo ekusebenzeni kwe-hedonic ye-tastants ehambelana neziyobisi yenzelwe ukuba utshintsho kwi-phasic ukukhutshwa kwe-DA kwibhola ye-NAc, kodwa hayi engundoqo (I-Wheeler et al., 2011). Ukongeza, thina nabanye babonisa ukuba ukukhutshwa kwe-DA ngexesha lemisebenzi efundwe kukufaka isikhumbuzo ngokwahlukileyo phakathi komongo kunye neqokobhe (I-Aragona et al., 2009; I-Owesson-White et al., 2009; I-Badrinarayan et al., 2012; Cacciapaglia et al., 2012). Endaweni yomqondiso we-DA wehlabathi, ke ezi zinto zifunyanisiweyo zicebisa ukuba i-DA inokubekwa ngokukuko kwaye ilungelelaniswe kakuhle kwimimandla ekujoliswe kuyo ukuxhasa iplasitiki ngaphakathi kwezijikelezo ezichaziweyo ezinxulumene nokufunda, ukukhuthaza kunye nentshukumo.

Nangona kunjalo, imisebenzi echanekileyo yale miqondiso ye-heterogenible ye-DA ayiqondwa kakuhle. Imodeli enye eneempembelelo iceliwe ukuba i-DA ibonelela ngomqondiso wokufundisa ukuvelisa okulindelekileyo kwiziphumo ezizayo nokuba ezo ziqikelelwe zichanekile [impazamo yokuqikelela (i-PE)]. I-neurons ye-DA ibonakalisa oluhlobo lokufaka ikhowudi (Schultz et al., 1997; I-Schultz kunye ne-Dickinson, 2000; I-Waelti et al., 2001; UTobler et al., 2003), nangona iziphumo zamva nje ziqinisekisa ukuba ngokuyintloko zonke ii-neuron ze-DA ezichazwe kwi-optogenetically kwiVTA zibonisa uphawu lwePearl (UCohen et al., 2012). Ngokwahlukileyo, iimodeli zokunyusa amandla (IS) zemodeli zibonisa ukuba i-DA yenza isenzo sokuphembelela ngokuqiniswa okuqinisiweyo, idala ukuqhubela phambili kwezi ziphumo (EBerridge noRobinson, i-1998; URobinson noBerridge, i-2008; Zhang et al., 2009; EBerridge, 2012). Nangona ezifanayo, iimodeli ze-PE kunye ne-IS zenza uqikelelo olwahlukileyo lomsebenzi we-DA ngokubhekisele kwimfuno yokufunda, ukukhuthaza, kunye nokusetyenziswa kweziyobisi (Phinda ubomvu, 2004; I-Tindell et al., 2009; Bromberg-Martin et al., 2010; EBerridge, 2012).

Kwimisebenzi elula yokulungisa imeko, kunzima ukwazi ukuba kukhutshwa yintoni i-phasic ye-DA (okt, ngaba uqikelelo lomvuzo, okanye ukubekwa kwesisa?). Nangona kunjalo, ngokukhetha umhlaba ngokungathandabuzekiyo kunye nokuvuselela amandla ngaphakathi kwinto efanayo, kunokwenzeka ukubonakalisa amanqaku athile okufunda kunye nokuthatha amanyathelo okuzahlula izinto, njengokuxela kwangaphambili, isimilo sokuziphatha, intshukumisa kunye nokuphelisa. Ukuphelisa lento, sisebenzise umsebenzi weshedyuli yezixhobo apho oomatshini bokushicilela basebenzela i-lever [abafuna i-lever (SL)] banika ukufikelela koomatshini bokushicilela kumnini wesibini (i-TL), kunye noxinzelelo kwi-TL kukhokelela ekuhanjisweni kokutya. Ngaphaya koko, sisebenzisa ngokukhawuleza iskena se-cyclic voltammetry (FSCV) ukulinganisa iipateni ze-DA zexesha lokwenyani okanye isiseko se-NAc okanye iqokobhe kumagundane aqeqeshiwe kakuhle, sahlula-hlula indlela imisebenzi ekhethiweyo yokufaka ikhowudi ye-DA ukwahlulwa kumda we-NAc. Okokugqibela, siqwalasele indlela eziguqulwe ngayo ezi mqondiso xa iinkalo zentshukumisa (inqanaba lendlala) kunye noqikelelo (ukutshabalala) zatshintshwa. Sajonga iipatheni ezahlukileyo zokukhutshwa kwe-DA kumbindi kunye neqokobhe elihambelana kakhulu neemodeli ze-PE kunye ne-IS, ngokulandelanayo, kwaye ngokubanzi siyayixhasa ingcinga yemiqondiso emininzi ye-mesolimbic ye-DA enokuxhasa umbandela ohlukileyo kodwa ohlukileyo wokuziphatha ojolise kwinjongo.

Impahla nenkqubo

Izilwanyana.

Iigundane ezilishumi elinambini zamadoda iSprague-Dawley enobunzima be-280-330 g zisetyenziswe njengezifundo. Iigundane zazigcinwe ngokukodwa kunye nomjikelo we-12 h wokukhanya / umnyama kwaye ukutya okukhawulelwe kungabikho ngaphantsi kwe-90% isisindo sokutya esimahla (i-10-15 g ye-Purina elebhu mihla le, ukongeza kwi-∼2.7 g ye-sucrose etyiwayo ngexesha leseshoni yemihla ngemihla. ). Ukuthintelwa kokutya bekuyindawo yexesha lokuvavanywa kokuziphatha ngaphandle kwexesha lokubuyisa ixesha lokufumana, xa ukutya kunikwe i-ad libitum. Zonke iinkqubo zenziwa ngokungqinelana neDyunivesithi yaseNyakatho yeCarolina kwiKholeji yeChapel Hill yoKhathalelo lweZilwanyana kunye neKomiti yokuSetyenziswa.

Uqeqesho lokuziphatha kakuhle: Ishedyuli yokuhamba.

Amagumbi okuvavanya aqulathe ii-levers ezimbini ezinokuhanjwa ezinokukhanya kwe-cue ngaphezulu kompheki ngamnye kunye nesixhobo sokutya esimiswe kakuhle ngokulinganayo phakathi kweziqa njengoko kuchaziwe ngaphambili (Cacciapaglia et al., 2012). Kwisifundo ngasinye, kwaqeshwa i-lever enye (umzekelo, ngasekhohlo) kwi-TL kunye nomnye u-lever (umzekelo, ngasekunene) njenge-SL ngalo lonke ixesha lokuqhutywa kweseshoni zovavanyo. Icala le-TL kunye ne-SL lalichasene nezifundo zonke.

Iigundane zaqeqeshwa kuqala ukufumana i-sucrose pellets (45 mg, Purina) kwindawo yokufumana indebe yokutya. Ngexesha leseshoni yokumitha eyodwa, i-pellets ye-50 yathunyelwa ngokungacwangciswanga phantse kube kanye kwi-30 s. Iigundane ke ziye zaqeqeshwa ukuzilungiselela iipellets ze-sucrose ngexesha leseshoni enye yemihla ngemihla. Ukuyila amandla okuphendula, izilwanyana ziqale zaqeqeshwa ukucinezela i-TL. Ityala ngalinye ngexesha lokuqulunqa laqala ngokukhanyiswa kwe-cue ukukhanya ngokuthe ngqo kwi-TL kudityaniswa kunye nokwandiswa kwe-TL kwigumbi lovavanyo [ukuthatha i-lever ngaphandle (TLO)]. Umatshini ngamnye othatha i-lever [TLP; umda osisigxina 1 (FR1) ngaphakathi kwe-15 s yolwandiso luphumele ekuhanjisweni kwe-pellet ye-sucrose eyodwa (45 mg) kwisithintelo, ukukhutshwa kweTL, kunye nokupheliswa kokukhanya kwe-cue. Ukuba izilwanyana ziye zasilela ukucinezela i-TL ngaphakathi kwe-15 s, i-lever yacinywayo, ukukhanya kwe-cue kucinyiwe, kunye nokulingwa kwabalwa njengokushiywa. Izilingo zahlulwe ngenxa yokuphakathi kwexesha lokuguquguquka okuphakathi kunye nomndilili we-15 s (uluhlu: 5-25 s; imihla yokuqulunqa i-1 kunye ne-2), emva koko yonyuswa yaya kwi-avareji ye-45 s ngeentsuku zokuyilwa kwe-3-4 (Uluhlu: 30-60 s).

Emva kokusekwa kokuphendula ngokuzinzileyo kwi-TL (okt, akukho ngaphezulu kweempazamo zokushiya kwi-2 kwiseshoni) kwaziswa ishedyuli (Ikhiwane. 1 A), eguqulwe ukusuka I-Olmstead et al. (2000). Uvavanyo ngexesha leshedyuli yeshedyuli yaqala ngokwandiswa kwe-SL kunye nokukhanya kwangaxeshanye kokukhanya kwe-cue ngqo ngaphezulu kwayo (SLO). I-SL nganyeP (FR1) kukhokelele ekurhoxisweni kwe-SL kunye nokucima i-cue, kulandelwa kukubonakaliswa kwe-TLO (ulwandiso lwe-lever, ukukhanya kwe-cue). Njengoku ngasentla, i-TL cinezela ukuba i-TL icinywe, icinywe ukukhanya kwekhandlela kunye nokuhanjiswa kwepellet yokutya kwikomityi yokutya. Izilingo zahlulwe ngenxa yexesha eliguquguqukayo le45 s (uluhlu: 30-60 s), kwaye iseshoni nganye yayiquka izilingo ze30. Ngomhla I-1 yeshedyuli ekhonkxiweyo, kwakungekho kulibaziseka phakathi kokurhoxiswa kwe-SL nokwandiswa kwe-TL. Ngeentsuku ezilandelayo, isithuba sokuphumla (VI) se3-5 s saziswa phakathi kokukhutshwa komatshini opapashiweyo we-SL kunye nokwandiswa kwe-TL. Ukongeza, i-VI 1-3 s yaziswa phakathi komshicileli we-TL kunye nokuhanjiswa kokuqiniswa kwe-sucrose. Ukulibaziseka okunokubakho kwasetyenziswa ngexesha loqeqesho (okt, zonke iiseshini ngaphambi kokurekhodwa kwe-FSCV) ukususa amandla egazi ukuya kwixesha lokuhanjiswa kwangaphambili kweziganeko. Iigundane zaqeqeshelwa i-5 d kolu luhlu lwenkqubo yemixokelelwano okanye de zabonisa ukusebenza okuzinzileyo kweeseshini ezimbini ezilandelelanayo ngaphandle kokushiywa nokuba kukwi-SL okanye kwi-TL, emva kokuba zilungiselelwe ngogonyo ukurekhodwa.

Uqeqesho lokuziphatha kakuhle: Ukupheliswa.

Emva kweseshoni yokugqibela yokurekhoda, izilwanyana ezisezantsi zatshabalala (urekhodo oluphambili: n = 3; urekhodo lweqokobhe: n = 7). Ngexesha lokuphela, i-SLO Iinkcazo-ntetho zibonise ukuqala kwetyala elitsha. Izilingo zazilingana nezo zazikwiseshoni yovavanyo, apho imithombo yeendaba ye-SL yakhokelela ekunikezelweni kwe-TLO I-4 s emva kwexesha, kodwa iingcinezelo kwi-TL azizange ziqiniswe. Iiseshoni zokuphelisa ziyaqhubeka kude kube iigundane ziyekile ukuphendula kwi-SL ye-10 izilingo ezilandelelanayo (Ikhiwane. 1 B).

Izifundo zangaphambili (Schoenbaum et al., 2003; Saddoris et al., 2005) bonise ukuba ulungelelwaniso lwe-neural yomsebenzi we-limbic lujongile kakhulu kutshintsho ekufundeni kunye nakwimeko ekhuthazayo, kwaye ke apha sisebenzise izikhombisi ze-latency ezichazayo iibhloko zesifundo ngasinye (Ikhiwane. 1 B). Ibloko lokuqala yayikukutshatyalaliswa kwangoko, ekuphenduleni kwe-SLP Impendulo ibifana kwiseshoni evuziweyo. Emva koko, i-SL yokuqalaP impendulo latency ebibuncinci be-2 SD ixesha elide kunelixesha leseshini ehlawulwa umvuzo ngaphambili ibonakalisa ukuqala kokupheliswa. Okokugqibela, zonke iimvavanyo ezilandele impendulo yokuqala eshiyekileyo yayikwibhlokhi yokuphela kokuphela, kwaye zahlelwa ngokuthi i-rat ishiye i-SLP Impendulo (phezolo akukho cinezelo) okanye iphinde yaphendulwa kwakhona (kumaphepha-ndaba emva kwexesha). Yonke indlela yokuzibhubhisa yathelekiswa neshedyuli eyandisiweyo eyandisiweyo.

Iinkqubo zokuphanda.

Emva koqeqesho lokuziphatha, izilwanyana bezilungiselelwe ngokurekhodwa urekhodo lwe voltammetric njengoko kuchaziwe ngaphambili (Cacciapaglia et al., 2012). Ngokufutshane, iigundane zazingafakwanga ngenaliti ye-ketamine hydrochloride (100 mg / kg, im) kunye ne-xylazine hydrochloride (20 mg / kg). Isikhokelo se-cannula (ii-Bioanalytical Systems) safakelwa ngaphezulu kwe-NAc igobolondo (+ 1.7 mm AP, + 0.8 mm ML) okanye isiseko (+ 1.3 mm AP, + 1.3 mm ML) kunye ne-bipolar evuselelayo ye-electrode (Plastics One). i-VTA (−5.2 mm AP, + 1.0 mm ML kunye −7.8 DV). Olunye isikhokelo se-cannula yesalathiso se-Ag / AgCl electrode yabekwa kwindawo yendawo yokuhlala. Izinto ezihlanganisiweyo zazikhuselwe kwisithsaba ngezikhonkwane kunye nesamente ye-cranioplastic.

Ukurekhodwa kweVoltammetric.

Iindlela zokurekhoda ze-FSCV ezisetyenziswe apha bezichaziwe ngokweenkcukacha ngaphambili (Cacciapaglia et al., 2012; I-Sugam et al., 2012). Ngokufutshane, emva koqhaqho, iigundane zazivunyelwe ukuba ziphinde ziphinde zikhululeke emzimbeni (ubuncinci be-5 d yokubuyisela kwimeko yesiqhelo). Ngomhla wokuvavanywa, i-microelectrode ye-carbon-fiber yahliselwa kwiqokobhe le-NAc okanye kwisiseko esine-microdrive (iSebe le-Chemistry iSebe le-elektroniki, iYunivesithi yase North Carolina, Chapel Hill, NC), emva kokubeka i-Ag / AgCl i-electrode kwi kwi-contralateral hemisphere. I-microelectrode ye-carbon-fiber yabanjwa kwi-−0.4 V ngokuchasene ne-Ag / AgCl i-electrode. Ngamaxesha athile yafunyanwa i-cyclic voltammogram (100 ms intervals) ngokusebenzisa isikali esingunxantathu esiqhuba amandla kwi-1.3 V kwaye sibuyele kwi-−0.4 V. Ngaphambi kokuqala kweseshoni nganye yokurekhoda, safumana ukhuphelo lwe-DA olwakhuphela ngaphandle kombane kwimicimbi yokuqhuba i-bipolar evuselelayo i-electrode kwi-VTA kwaye irekhoda iziphumo ze-DA ezikhutshwayo kwi-NAc. Ukuba ukuvuseleleka akuphumelelanga ekukhuliseni i-DA, i-electrode yehliselwa kwindawo entsha kwaye inkqubo iphindaphindwe. Nje ukuba amandla ombane akhuphe ngempumelelo ukuphuma kwe-DA kwi-NAc, iseti yoqeqesho yokukhutshwa kwe-DA yenziwa kusetyenziswa indibaniselwano yokuvuselela (phakathi kwe-10 kunye ne-60 Hz) kunye nenombolo ye-biphasic pulses (ukusuka kwi-4 ukuya kwi-25) kwi-bipolar VTA electrode. Kwiseti erekhodishiweyo, iseti yoqeqesho eyongezelelweyo yenziwa emva kokuphela kweseshoni yokuziphatha ukuqinisekisa uzinzo lwe-electrode ngaphezulu kweseshoni. Kwiseti yangaphantsi yeempuku (n = 9), emva kokurekhoda iseshoni epheleleyo yezilingo ezingama-30, i-electrode yathotywa enye ∼300 μm de kwafunyanwa enye indawo ekhutshiweyo, ngelo xesha enye irekhodi yathathwa yesinye iseshoni yezilingo ezingama-30. Uhlalutyo lwedatha ye-FSCV (Uhlalutyo lwe-HDCV) kusetyenziswa uhlalutyo lwecandelo le-chemometric ukwenza utshintsho okwangoku ngenxa ye-DA isebenzisa uqeqesho ngalunye lombane oluvuselelwe ngombane olusekwe kwiseshoni yokurekhoda enxulumene nayo ngaphambi kovavanyo, njengoko bekuchaziwe ngaphambili (Heien et al., 2005; Keithley et al., 2010). Kwingingqi nganye (engingqini kunye neqokobhe), umndilili we-DA wokuxinanisa ulungelelwaniso kwisigameko ngasinye sokuziphatha kwaye uthelekiso noxinaniso lwe-DA ngaphezulu kwesiseko se-5 s ngaphambi nje kwe-SLO ukuqala usebenzisa imodeli emibini exubeneyo ye-ANOVA (imiba: isiganeko, umda) kwiziphindaphindo zezihloko.

Kwiiseshoni zokutshabalalisa, ukulandelwa kwe-DA kwakulungelelaniswa ngokufanayo nemicimbi yokuziphatha. Nangona kunjalo, ngenxa yokuba uninzi lwe-SLO Iingcaciso-ntetho azange zilandelwe nakuphi na ukushicilelwa, isetyenziso sohlalutyo ezimbini ezahlukeneyo. Okokuqala, ukulandelwa kwe-DA kwahambelana ne-SLO kwaye zihlelwe ngokwenqanaba lokuphela (bona Ikhiwane. 6), kwaye kuhlalutywe kusetyenziswa iindlela eziphindiweyo eziphindiweyo kusetyenziswa isigaba sokuphela kunye nomnyhadala wokunyusa njengezinto. Uhlalutyo lwesibini, zizilingo kuphela apho ireyini yacinezela i-TLP zisetyenzisiwe kwaye kugxilwe kakhulu kwi-DA (okt, ubuninzi be-DA ukukhutshwa ngaphakathi kwe-300 ms emva komsitho) zifunyenwe zombini i-TLP kunye nomvuzo, kwaye ngokufanayo zahlalutywa ngeendlela-ezimbini eziphindaphindiweyo-amanyathelo i-ANOVA isebenzisa isigaba sokuphelisa kunye nokunyusa umsebenzi njengezinto. Zonke iposi uthelekiso olwenziwe ngababini kwenziwa kusetyenziswa i-HSD yeTukey, yalungiswa ngokungalingani N xa kufanelekile. Lonke uhlalutyo lweenkcukacha-manani lwenziwa kusetyenziswa i-Prism 4.0 yeWindows (isoftware yeGrafPad) okanye iStatistica yeWindows (StatSoft).

Histology.

Emva kovavanyo ngalunye, iigundane zazingafakwanga ntetho ngeketamine (100 mg / kg) / xylazine (20 mg / kg) (im). I-tungsten electrode egcinwe kwimacrosanipulator efanayo esetyenzisiweyo ngexesha lovavanyo yathathelwa indawo yovavanyo lokurekhoda kwaye kwenziwa isilonda esincinci se-electrolytic (50-500 μA, 5 s) ukumakisha isikhundla senqaku le-electrode. Izilonda ezininzi apho kwenziwa khona ukurekhodwa okuninzi kwenziwe. Ingqondo nganye isusiwe, yaqiniswa kwi-4% i-formaldehyde, emva koko yaqanduselwa kwi-−80C ngaphambi kokuba ibethwe kumacandelo e-coron ye-40 μm nge-cryostat. Amacandelo abekwe kwizilayidi, abonwe ngemicroscopy ekhanyayo kunye nomfanekiso okwiDijithali (Ikhiwane. 1 C).

Thelekisa ukukhuthaza kunye nomcimbi okhutshiwe ukukhutshwa kwe-DA kumbindi kunye neqokobhe.

Kungenzeka ukuba umahluko obonwe phakathi kwesiseko kunye nokukhutshwa kwe-DA ukukhululwa kwimicimbi yokuziphatha ngenxa yokungafani komehluko wokukhulula, kodwa kunoko kungafani kwi-kinetics yokucaca kwe-DA phakathi kwemimandla. Umzekelo, ukukhutshwa kwe-striatal ye-DA kunye nokuthatha amandla okucothayo kuhamba kancinci kwigobolondo kunesiseko ngenxa yokuxinana okuncinci kwendawo yokuhambisa dopamine kwigobolondo (UJones et al., 1996; UBudygin et al., 2002). Kananjalo, umahluko phakathi kwesiseko kunye neqokobhe kwimicimbi yamva (umzekelo, TLO, umvuzo) unokuchazwa ngokuqhubeka kwe-DA yentsalela kwingingqi ye-synaptic kwibhombu.

Ukujongana nale nkxalabo, siye safanisa ukukhutshwa kwe-DA kunye neepateni ezithathekisayo neziganeko zokuziphatha (okt SLO) Ngexesha leshedyuli yomsebenzi kwi-DA ephakanyiswe kukugqabhuka okufutshane kombane okhuthaza umbane weVTA. Ekuqaleni, ukukhuthazwa kombane (i-2 ms biphasic pulses) ye-VTA fibers yayiqhutywa kuluhlu olubanzi lokuhamba (10-60 Hz) kunye neenombolo zokubetha (4-25 pulses) ukufumana ukubonwa okupheleleyo kwamandla okuhambisa ngenjongo yokwakha iseti yoqeqesho lwechemometric. Kananjalo, inani elikhulu lezinto ezikhuthazayo zombane zazinkulu kakhulu (umzekelo, i-2000 nm) kunokuba ibonwe ngokwenzeka ngokwendalo okwenzeka ngokwendalo (ngesiqhelo i-40-150 nm). Kwindawo enkulu kakhulu yokukhutshwa kwe-DA, kunokwenzeka ukuba umthuthi we-DA abe nokugcwala, okukhokelela ekucothweni kwekinetics kancinci kunokuba bekuya kubonakala kuluhlu oluqhelekileyo. Ukujongana ngqo nale nto, sikhethe kuphela "izilingo" zokukhuthaza umbane apho ukukhutshwa kwe-DA kwakuyi- <200 nm. Ngokunjalo, sikhethe kuphela izilingo zokuziphatha apho ukukhutshwa kwe-DA kukwahambelana ne-SLO ubuncinci i-100 nm. Kwisifundo ngasinye, zonke izilingo ezifanelekileyo ziye zahlaziywa ukuze zihlalutywe. Sisebenzisa le metric, safumana ii-23 zokunyusa umbane kunye neeseshoni ze-15 cue-ekhutshwe embindini, kunye nokunyusa kwamandla ombane kwe-14 kunye neeseshoni ze11 zekratshi ezakhutshwa kwiqokobhe.

Ukuthelekiswa kwe-cue- ngokuchasene nokukhutshwa kwe-DA okwasuswa ngombane kwenziwa kwenziwa kusetyenziswa iimetrikhi ezininzi. Okokuqala, i-peak ye-DA yayithatyathwe kwimicimbi yokuziphatha e-SLO (okt, eyona nto inkulu ye-DA ngaphakathi kwe1.5 s SLO ukuqala), TLO (Olona hlaselo lukhulu lwe-DA phakathi kwe4 kunye ne-5.5 s ilandelayo nge-SLO isiphelo) kunye nomvuzo (eyona inkulu ye-DA phakathi kwe-6.5-8 s kulandela i-SLO ukuqalisa) kwiminyhadala yecue, kunye namaxesha ahambelana nawo kweziganeko ezikhuthazwe ngombane (okt, amanqaku afanayo, kodwa emva kolwazelelo kuqala kune-SLO ukuqala). Okulandelayo, imizila yokucacisa yaphononongwa kusetyenziswa iimitha zangaphambili ezipapashiweyo (Yorgason et al., 2011). Ngokukodwa, sajonga ixesha lokuphila kobomi (isiqingatha sexesha lokuxineka) emva kwencopho, T 20 (ixesha le-20% ukubola kwincopho) kunye T 80 (ixesha le-80% ukubola kwincopho). La maxabiso athelekiswa kusetyenziswa umfuziselo ongumxube we-ANOVA usebenzisa ummandla (umda, iqokobhe), uhlobo lokukhuthaza (SLO zihambelana, zikhuthazwe ngombane) njengezinto eziphakathi kwezihloko kunye nokuxinzezeleka kwi-DA kuhlobo ngalunye lomsitho (okwandlalela, SLO, TLO, kunye nomvuzo) okanye umlinganiso obonakalayo (umda wokuphakama, T 20, isiqingatha sobomi, kwaye T 80, ngokulandelanayo) njengenyathelo eliphindaphindiweyo. Post post uthelekiso lwenziwe kusetyenziswa ukungalingani kwe-HSD yeTukey N.

iziphumo

Ukuziphatha okunyanzelisiweyo kweshedyuli yokuziphatha

Amagundane afunde ngokukhawuleza umsebenzi weshedyuli. Kwiseshoni yokugqibela yokukhuseleka, iigundane ngokomyinge ogqityiweyo we-99.8% yezilingo ngokuchanekileyo. Ngeli thuba leseshini, iigundane zithathe i-avareji ye-783 ms 253 ms yokucinezela ukulandela i-SLO, kunye ne-588 ± 298 ms yokucinezela emva kwe-TLOUmahluko ophantse wabaluleka, t (17) = 1.77, p = 0.085 Nangona kunjalo, kwiintsuku zokurekhodwa kweposti, iigundane kwakhona zenze phantse akukho zikhutshiweyo (99.5%), kodwa zabonisa ngokukhawuleza iimpendulo ze-TL ezikhawulezayoP (I-999 ± 64 ms) kune-SLP (444 ± 39 ms), t (29) = 7.48, p <0.0001. Ngokubalulekileyo, kwiintsuku zokurekhoda, kwakungekho mahluko ekuphenduleni kokugqibela kwezilwanyana ezirekhodwe kwigobolondo xa kuthelekiswa nomxholo, t (29) = 0.78, p = 0.48. Ke, iigundane kuwo omabini amaqela (isentloko kunye neqokobhe) zazinokwazi ngokulinganayo ukugqiba ishedyuli xa umsebenzi uqinisiwe.

Ukukhutshwa okwahlukileyo kwe-DA kwisiseko se-NAc kunye neqokobhe ngexesha lokuqiniswa kwekhonkco

Okulandelayo, sisebenzise i-FSCV ukufumana iirekhodi ze-DA zexesha langempela nokuba sisiseko se-NAc (n = 13) okanye iqokobhe (n = 12) ngexesha lokusebenza kwishedyuli efundwe kakuhle (Ikhiwane. 1 C). Kwiigundane apho kwathatyathwa khona urekhodo oluninzi, inqaku le-electrode lancitshiswa ubuncinci i-300 μm phakathi kweeseshoni zokuqinisekisa ukuba inqaku le-100 μm ye-carbon-fiber electrode yayisisiporo esitsha kwitrekhodo ngalinye. Iyahambelana zombini PE kwaye IS iimodeli, sifumene ukomelela okumandla kwe-phasic DA eqale ngokuqala kwe-SL kunye nokukhanya kwe-cue (SLO) kuzo zombini ezingundoqo kunye neqokobhe. Imizekelo yoku kungqinwa ukusuka kwiiseshoni zokurekhodwa ezimele (eziphakathi kwiilingo ze-30) zibonisiwe kwisiseko (Ikhiwane. 2 A) kunye negobolondo (Ikhiwane. 2 B), kunye nemibala yemibala kwisilwanyana ngasinye. I-DA e-signaling yahlukile ngokubonakalayo phakathi kwemimmiselo. Kuzo zonke iigundane, kumbindi (Ikhiwane. 2 C-E, ukulandelela abamnyama), i-DA yanda ngokukhawuleza kakhulu ekuqaleni kwembonakalo enkulu (SLO isiqalo) kwaye ke sinqabile ngokukhawuleza ukwesekwa ngexesha le-TLP. Ngokwahlukileyo, kwiqokobhe (Ikhiwane. 2 C-E, ukulandelwa kweengwevu), ukunyuka okukhawulezileyo kuxinzelelo lwe-DA kwenzeka kunye ne-SLO Inkcazo-ntetho kwaye ihlale iphakanyisiwe ngenxa yezinye izizathu ezisisisongelo sentsingiselo ezincinci kwi-TLO kunye nokuhanjiswa kwembuyekezo ngaphambi kokuba kubuyiselwe kwisiseko sokuphela kwetyala.

Umzobo 1. 

A , Inkqubo yokuyilwa kwemisebenzi. Ngexesha leshedyuli, enye i-lever (SL) yandiswa kwigumbi lovavanyo ngaxeshanye njengoko ukukhanya kwekhandlela kwakukhanyisiwe ngaphezulu kwe-lever (SL)O). I-SLP ucime isibane kwaye ucime i-lever. Emva kokulibaziseka, omnye umkhwetha kwigumbi (TL) wandisiwe kwaye ukukhanya okunxulumene nokukhanya kwakukhanyisiwe (TLO). Ukulandela umatshini wokushicilela kwi-TL (TLP) iigundane zifumene ukuqiniswa kokutya emva kokulibaziseka (R). B , Ukuphela kokuziphatha kwizilwanyana ezinerekhodi ye-FSCV kumbindi okanye kwigobolondo. Ukuziphatha kunye nohlalutyo ekuphelisweni kwahlelwa ibhloko ngokubhekisele kwindlela yokuziphatha komlinganiso. Izilingo kwimisebenzi eyandulelayo yetyathanga zazisetyenziselwa ukuthelekisa iminyhadala yokuphela. Ukupheliswa kwangoko zonke zaziluvavanyo de impendulo yokuqala yokulibaziseka kwi-SL, ngelixa ukuphela kokulibaziseka yayililingo phakathi kokulibaziseka kokuqala kwe-SLP Umshicileli wokuqala oshiyekileyo ulandela iSLO intetho Ngaphakathi kwibhlokhi yokuphela kwayo, umahluko wawenziwe phakathi kokuba isifundo sishicilele okanye sashiya impendulo. C , Imbali yokufakwa kwe-electrode ngaphakathi kumbindi (imijikelezo emnyama) kunye neqokobhe loku medial (isangqa esimpunga).

Umzobo 2. 

Ukusebenza kweshedyuli ebanjiweyo kuvelise iindlela ezahlukeneyo zokukhululwa kwe-DA kwi-NAc. Dopamine ukukhutshwa kwamandla kwi-basic ( A ) kunye negobolondo ( B ) ye-NAc ehambelana nexesha lolwandiso lwe-SL kwigumbi (SLO). Faka imibala kwindawo nganye ebonisa umxholo ophuma kummeli oyintloko kumbindi kunye neqokobhe ngokulandelelana. Ixesha eliphakathi (time) loncedo lwe-TL (TLO) kunye nomvuzo (R) kunye nohlu (± 2 SD) isihlobo se-SLO ziboniswe ngezantsi. C - E , Isiseko se-Across sithetha ukukhutshwa kwe-DA kuzo zonke izinto ezirekhodiweyo kumbindi (omnyama) kunye neqokobhe (ngwevu) elinxulumene ( C ) I-SLO, ( D ) I-SLP, kunye nolwandiso lwe-TLO I-4 s emva kwexesha, kunye ( E ) TLP, kunye nomvuzo (R) wokutya kuhanjiswa nge-2.5 s emva komatshini wokushicilela. Umgca owonakalisiweyo ubonakalisa i-SEM ye-avareji yommandla ngamnye. Umqolo ongezantsi ( F - H ) bonisa umndilili wokukhululwa kwe-DA kwisigulo ngasinye sokuziphatha. *p <0.05 xa kuthelekiswa nesiseko; †p <0.05 isiseko kuthelekiswa negobolondo.

Sikucacisile oku kuqatshelweyo ngokujikeleza konke ukurekhodwa kuthathwe kumphambili okanye iqokobhe, elilungelelaniswe kwisiganeko ngasinye sokuziphatha kwishedyuli yomtya (Ikhiwane. 2 C-H). Kwiiseshoni zokurekhoda ze-FSCV, ixesha phakathi kwe-SLP kunye ne-TLO yayilungisiwe (i-4 s) njengoko yayilixesha phakathi kwe-TLP kunye nonikezo lomvuzo (i-2.5 s) ukuvumela ulungelelwaniso olungcono lwesikhuthazo somsebenzi sohlalutyo lwe-DA. Ke ngoko, ulungelelwaniso kwi-SLO, SLP/ TLO, kunye ne-TLP/ Umvuzo uvumele ulungelelwaniso lwazo zonke iimpawu zokuziphatha kunye nohlalutyo oluvumelekileyo lwenqaku lokukhutshwa kwe-DA malunga nezi ziganeko.

Indlela-mbini ye-ANOVA ngokuthelekisa incopho (ubuninzi be-DA bokuxinana ngaphakathi kwe-300 ms elandelayo isehlo) Ugxininiso lwe-DA kuwo wonke ummandla (isiseko, iqokobhe) nomsitho (ukusisiseko, i-SLO, SLP, TLO, TLP, umvuzo) ubonise ukuba iqokobhe likhuphe uninzi lwe-DA ngokubanzi kunesiseko, F (1,24) = 13.63, p <0.002. Ngokubalulekileyo, unxibelelwano olubonakalayo lwengingqi x umsitho, F (5,120) = 9.88, p <0.0001, ityhile ukuba i-DA isayina kwisiseko kunye neqokobhe liphendule ngokwahlukileyo kwimicimbi yokuziphathaIkhiwane. 2 F-H). Ngokukhethekileyo, isiseko se-DA sokukhula sanda kakhulu kwi-SLO, isihlobo esisiseko (p <0.0001), kwaye yahlala ngaphezulu kwesiseko ngexesha le-SLP (p <0.0001), nangona iphantsi kakhulu kune-SLO (p <0.05). Nangona kunjalo, kwakungekho mahluko kwincopho ye-DA kumbindi kuthelekiswa nesiseko sayo nayiphi na umsitho we-TL (TLO Isiseko, p = 0.59; TLP Isiseko, p = 1.0), kwaye akukho mehluko ukusuka kwisiseko ngexesha lokufumana umvuzo (p = 1.0).

Ngokwahlukileyo, ukugxininiswa kwe-DA ekwigobolondo kubonise ukukhutshwa okubalulekileyo kwe-DA kuyo yonke imicimbi. Yonke imicimbi yayanyaniswa nokukhululwa okukhulu kune-DA kunasiseko (yonke uthelekiso vs BL, p <0.0002), ngelixa kungekho namnye umsitho ohluke kakhulu komnye nomnye (zonke ii-SL ezilandelelanaO, SLP, TLO, TLP, kunye nomvuzo othelekiso, p > 0.96).

Ukuthelekisa ngokuthe ngqo isiseko kunye neqokobhe, safumana umohluko obalulekileyo wokutyikitya kwe-DA phakathi kwemimandla. Nangona kungekho mahluko ekukhulisweni kwe-DA ngexesha nokuba kusekwe (p = 1.0) okanye imicimbi ye-SL (SLO, p = 1.0; I-SLP, p = 0.22), igobolondo kwi-DA yaphakanyiswa kakhulu xa kuthelekiswa nesiseko sayo yonke imicimbi ye-TL (TLO, p <0.01; TLP, p <0.001) kunye nomvuzo (p <0.0005; Ikhiwane. 3 D-F).

Umzobo 3. 

Utshintsho kwi-DA etywina phakathi kokuqala kweseshoni (kwangoko; iimvavanyo zokuqala ze-5 zeshedyuli yecandelo) ngokuchaseneyo nokuphela kweseshoni (emva kwexesha; ulingo lwe-5 yokugqibela). A , Umndilili woxinzelelo lwe-DA kumbindi we-NAc ukusuka kumndilili wesifundo ngasinye kwizilingo ezintlanu zokuqala (ukukhanya okuluhlaza okwesibhakabhaka) kunye nezilingo ezintlanu zokugqibela (ezimfusa). B Embindini, ngaphakathi-kwezifundo zincinci ukutyikitya kwe-DA kwakungaguqukanga phakathi kokuqala kweseshoni kunye nokuphela. C , Umndilili wokugxila kwe-DA kwiqokobhe le-NAc ukusuka kumndilili wesifundo ngasinye kwizilingo ezintlanu zokuqala (ezibomvu) kunye nezilingo ezintlanu zokugqibela (iorenji). D , I-Shell DA ibonise ukwehla okukhulu ngaphakathi kwezifundo kwi-SLP kunye ne-TLP Iimpawu kunye nomvuzo (**p <0.01), ngelixa ukwehla kwe-SLO Icue ibiphantse yabaluleka (#p = 0.073). Imivalo yeempazamo ibonisa SE umahluko (kwangethuba ngaphambi kwexesha).

Iinguqu ezikhethekileyo zommandla ekukhululweni kwe-DA phakathi kokuqala nokuphela kweseshoni

Okulandelayo, sithelekise ukukhutshwa kwe-DA kumbindi kunye neqokobhe ngexesha lomsebenzi oqinisiweyo weshedyuli ekuqaleni kweseshoni (izilingo zokuqala ze-5) ngokuthelekiswa nesiphelo seseshoni (izilingo zokugqibela ze-5; Ikhiwane. 3). Oku kwakubalulekile kuvavanyo ukuze kuqinisekiswe ukuba i-electrode izinzile kwiseshoni yonke (okt, ukuba umbane awuphulukanga nobunkunkqele ekuhambeni kwexesha), kunye nokuvavanya ukuba ingaba i-DA ilandelela naluphi na utshintsho olucashileyo kwimeko yentshukumo (umzekelo, ngenxa yazo naziphi na iziphumo yokuncipha kwendlala emva kokutya ukutya) ulwaziso olulandelayo lwesikhuthazo esahlukileyo.

Embindini (Ikhiwane. 3 A), i-ANOVA yendlela-mbini ibonise umphumo ophambili wesiganeko (BL, SLO, SLP, TLO, TLP, Rew; F (5,65) = 35.03, p <0.0001), kodwa akukho siphumo sesigaba seseshoni (kwangoko emva kwexesha; F (1,13) = 3.55, p = 0.08), okanye unxibelelwano phakathi kwesigqeba seseshiniF (5,65) = 0.82, p = 0.54). Post post uthelekiso phakathi kweebhloko zokuqala kunye nezasemva kwexesha zibonakalise ukuba ikhefu le-DA lokukhululwa lihambelana neziganeko zokuziphatha kumbindi kuhlala kunjalo phakathi kwesiqalo nesiphelo seseshoni (iTukey: yonke kwasekuqaleni ngokuthelekisa ixesha lesibini ngokuthelekisa kwe-BL, SLO, SLP, TLO, TLP, kunye nomvuzo, p > 0.50; Ikhiwane. 3 B).

Nangona kunjalo, ukukhutshwa kwe-phasic ye-DA ukuya kwimisebenzi eyandayo iyancipha ngokugqibeleleyo kwiseshoni eseqokobheni (Ikhiwane. 3 C,D), kunye neziphumo eziphambili zesehlo (F (5,55) = 13.52, p <0.0001), isigaba seseshoni (F (1,11) = 6.95, p = 0.02), kunye nonxibelelwano phakathi kwesiganeko kunye nesigaba seseshini (F (5,55) = 3.74, p = 0.006). Njengasembindini, iposi Uvavanyo alubonisanga mahluko kwi-BL, kodwa kuncipha okukhulu kukakhululwa kwe-DA kwi-SLP, TLP, kunye nomvuzo (Tukey: zonke p <0.0005), imeko eya kubaluleka kwi-SLO cue (p = 0.060), kodwa akukho mehluko kwi-TLO cue (p = 0.36). Ke ngoko, utshintsho kugobolondo (kodwa ayilulo oluphambili) lwalunqunyelwe ikakhulu kwizenzo ezikhuthazayo kunye nokusetyenziswa komvuzo ngokwahluka (nangona kuthobekile) kwiziphumo zokuhlaselwa. Olu tshintsho kwiseshoni yokukhutshwa kwe-DA belungekho ngenxa yotshintsho ngokubanzi kubuntununtunu be-electrode kodwa endaweni yoko bacebisa ukuba iinguqu ezikhuthazayo- kunye notshintsho kwiipateni zokukhutshwa kwe-DA zibonisa ulwazi malunga nokutshintsha kokubaluleka kwesistim somsebenzi kwizilingo eziphindaphindiweyo. Ngenxa yokuba izilwanyana zitye ubuncinci iipellethi ezingama-25 ngokomndilili ukuphela kweseshoni nganye yokurekhoda (okt, i-1144 mg, okanye i-7.6% yesisindo sobunzima beerim yimihla yokutya), ezi ziphumo zibonisa ukonyuka kokutya iyinciphise ngempumelelo imeko yendlala ekhuthazayo kwisilwanyana, ebibonakala kutshintsho kwigobolondo kodwa hayi eyona nto iphambili kwiseshoni.

I-Cue-evuswe ngokuchasene nombane ivuselele amandla e-DA asembindini kunye neqokobhe

I-bakoat enye kwezi zinto zifunyanisiweyo inokuba isiseko kunye neqokobhe zineendlela ezahlukeneyo zokucaciswa kwe-DA ngenxa yoxinzelelo olusezantsi lokuhanjiswa kwe-DA kwibhola xa kuthelekiswa nesiseko.UJones et al., 1996; UBudygin et al., 2002). Ke, kunokwenzeka ukuba iqokobhe le-DA elibonwe kwi-TL kunye nemisitho yomvuzo kungenxa yokukhutshelwa kwentsalela ye-DA ngexesha le-SLO, kodwa ayikwazi kucocwa ukusuka kwi-synaptic yokugqagqana okucocekileyo kakuhle njengakumbindi. Ukujongana noku, sithelekise ukukhutshwa kwe-DA okwasuswa ngombane kwindawo enye yombane ngexesha lorekhodo lwerekhodi ukubona ukuba ingaba amandla ombane avuselelwa ngombane ahambelana nomxholo we-cue-wakhuphela kumbindi kunye neqokobhe (Ikhiwane. 4 A). Saxela kwangaphambili ukuba ukubangacothisi kwemeko esecaleni kweqokobhe yayinoxanduva lokwahluka kotyhilo olulandelayo (umzekelo, TLO) phakathi kwentloko kunye neqokobhe, emva koko ukukhutshwa kombane kunye nokukhululwa kwe-cue-ekhutshwayo kumacandelwana abo afanele ukulandela phantse iipateni ezifanayo zokukhutshwa kunye nokucaciswa. Ngokwahlukileyo, ukuphambuka okubalulekileyo kukhuthazo lombane kungacebisa ukuba ukukhutshwa kwe-DA kuloo ndawo kulandelela imisitho enxulumene nomsebenzi ngendlela engenakuchazwa yi-synaptic clearance kwamandla.

Umzobo 4. 

Thelekisa ukuthengiswa kombane ngokuchaseneyo nokutshixeka kwe-DA yokutsala uphawu kwi-NAc engumbono kunye neqokobhe. A I-avareji uxinzelelo lwe-DA oluhambelana ne-SLO ukukhuselwa okanye ukukhutshwa kombane kokuqalisa kobushushu beVTA. Ixesha lokuqalisa kwe-TLO Ixabiso kunye nomvuzo kuqikelelwa kuluhlu lwamaxesha empendulo kwezi ziphumo zilandelayo kwi-SLO (lithetha ixesha lokuphendula eliboniswe ngunxantathu; ububanzi bubonisa ± 95% isithuba sokuzithemba). B , Thelekisa ukuthengiswa okuphakathi kwesiseko (i-BL) ye-DA yokufikelela kuxinzelelo lwe-DA ngaphakathi kwe1 s ye-SLO okanye ukukhuthaza kombane (Istrim / SLO), kwaye ngaphakathi kwe-95% yokuphumla uluhlu lwamaxesha ahambelana ne-TLO okanye umvuzo umvuzo. C Ubungakanani bethambeka lokulandelwa kwe-SLO okanye ukuvuselelwa kombane (i-Peak Lat) kunye nokubola okulandelayo (ukucaciswa) okulandelayo ukukhutshwa kumbindi kunye neqokobhe. T20 kunye T80 ngamaxesha apho umqondiso uye wehla i-20% kunye ne-80% kude kwincopho, ngokulandelelana, ngelixa isiqingatha sobomi sisiqalo esilandela ukufikelela kwincam yehafu ephezulu. *p <0.0001, ukuvuselela umbane / SLO ngokuchaseneyo nokusisiseko; †p <0.0001, uShell: Cue mkhulu [DA] kunazo zonke ezinye iintlobo zokukhuthaza; ‡ p <0.0001, uShell: Cue ukubambezeleka okukhulu ukubola ukusuka kwincopho yazo zonke ezinye iintlobo zokukhuthaza. Iimpazamo zemivalo zibonisa i-SE yomahluko (cue vs electric).

Lilonke, safumanisa ukuba isiseko kunye neqokobhe zahluke ngokupheleleyo kubudlelwane babo phakathi kwe-cue-ekhutshwe kunye nokukhutshwa kwe-DA ngombane.Ikhiwane. 4 B). Ujonge ukugxila kwencopho yeminyhadala yemisebenzi, kwabakho umahluko obonakalayo kuxinzelelo lwe-DA njengothethathethwano lwengingqi (isiseko / igobolondo) uhlobo lwenkuthazo (umbane ngokuchasene necala) × umsitho (BL, SLO, TLO, Rew; F (3,174) = 12.31, p <0.0001). Eyona nto iphambili kuyo, ukugxila kwe-DA kwinto ekhutshiweyo kunye nokuvuselelwa kombane bekuphantse kwafana; kwakungekho mahluko weenkcukacha manani phakathi kwezi ntlobo zokukhuthaza kwisiseko, SLO, TLO, okanye umvuzo we-epochs (Tukey: zonke p > 0.80). Ngokwahlukileyo, iqokobhe labonisa ipatheni eyahlukileyo ye-dynamics phakathi kombane- kunye ne-cue-evuse iipateni zokukhutshwa kwe-DA. Nangona kwakungekho mahluko koxinaniso kwisiseko okanye kwi-SLO (Tukey: bobabini p > 0.98), i-DA yayinkulu kakhulu kwi-TLO kunye nokuvuza ii-epochs kwizilingo ezi-cared xa kuthelekiswa nokunyusa umbane (zombini p <0.0001).

Ngokunjalo, ireyithi yokukhutshwa kunye nokucaciswa okulandelayo ukusuka kwisoftware kubonise ipatheni efanayo (Ikhiwane. 4 C). Ukujonga amaxabiso okucoca njengomsebenzi wokubola ukusuka kwincopho, bekukho unxibelelwano olubalulekileyo phakathi kwengingqi20, isiqingatha sobomi, T80; F (3,174) = 80.23, p <0.00001). Njengasentla, ukucoca okungundoqo kunye nokubola okuguqukayo kwakungahlukanga phakathi kweendlela zokukhutshwa kunye nokukhutshwa kombane. Ukubambezeleka ukuya phezulu, T 20, isiqingatha sobomi, kwaye T 80 Zonke zazifana ngokwezibalo ngaphandle kohlobo lokukhuthaza (zombane ngokuhambelana; p > 0.95). Ngokwahlukileyo, amanqanaba e-DA kwigobolondo abonisa ukulibaziseka okubolileyo kwisiseko esilandelayo se-SLO imiboniso-nkqubo enxulumene novavanyo olunokukhuthaza ngombane. Ngelixa ukunyuka kwethanga kwaye T 20 Ziyafana phakathi kokukhutshwa kwetyala kunye nokuchukunyiswa ngombane (p > 0.98), latency ukuya kwisiqingatha sobomi (p <0.0001), kunye T 80 (p <0.0001) zilibazisekile kakhulu kwizilingo ezinamakhonkco ezinxulumene nokukhuthaza kombane. Ngokudibeneyo, ezi zinto zifunyanisiweyo zibonisa ukuba umahluko ongaphakathi ekucaciseni i-kinetics kwigobolondo kunye nomxholo awonelanga ukuchaza umahluko ekubonakalisweni kwe-DA ngexesha lokuziphatha.

Ukuziphatha okungapheliyo

Iigundane zibonise isimilo sokucima ngexesha leseshoni xa umvuzo wokutya wawushiyiwe ngokwandisa ngokuthe ngcembe ukucofa iindlela ezahlukeneyo ngexesha leseshoni yokuphela. Sivelise izigaba ezichaziweyo zokuziphatha ngokusekwe kwezi nguqulelo ze-latency ezinxulumene nokucofa kwi-SL nakwi-TL ngexesha leseshoni yangaphambi kokuqiniswa. Isigaba sokuqala sachazwa njengezilingo apho latency zazifana ngexesha leseshoni eqinisiweyo. Xa iigundane zacinezela i-lever ngokucotha kakhulu (okt,> 2 SD) kunesiqhelo, oku kwabizwa ngokuba sisigaba sokulibaziseka esivela kwimpendulo yokuqala yokulibaziseka de umxholo washiya impendulo. Zonke izilingo emva kolu shiyeko lokuqala zibizwa ngokuba zisesigaba emva kwexesha ngokusekwe ekubeni i-rat icinezelwe (emva kwexesha ucinezelwe) okanye ushiye impendulo (emva kwexesha akukho cinezela).

Kuqala, sivavanye inani leemvavanyo ezenziweyo ngaphambi kokuba iigundane zibonise utshintsho olususela kwangoko ukuya kwisigaba sokulibazisa, kunye nenani lezilingo kuvavanyo lokuqala olushiyelelweyo (okt, utshintsho kwinqanaba lokugqibela) lwe-SL kunye ne-TL, ngokulandelelana (Ikhiwane. 5 A). Iigundana zicothisile ukuphendula kwi-TL ngokubalulekileyo ngaphambi kokuba benze njalo kwi-SL, paired t uvavanyo: t (7) = 2.49, p = I-0.04, iphakamisa ukuba i-TL (mhlawumbi ngenxa yobudlelwane bayo obusondeleyo kunye nomvuzo) yayinovelwano ngakumbi lokushiyeka kune-SL. Ngokwahlukileyo, inani lezilingo ngaphambi kokwenza ukushiywa kokuqala laliphantse labafana kwi-SL nakwi-TL levers (p > 0.9), mhlawumbi ibonisa ukuba iimpendulo ezishiyiweyo zazikhutshelwa kuphela xa ukuxelwa kwangaphambili komvuzo kuhlaziywe ngokuchanekileyo ukuya ku-zero ekuqaleni kwetyala. Iyahambelana noku, kunqabile ukuba sifumane izilingo apho izilwanyana zenze i-SLP kodwa ishiye i-TL elandelayoP Impendulo (kuphela i-4 / 140 izilingo ezifike kade zesigaba; i-2.9%), iphakamisa ukuba iigundane ziphantse zenziwa ngokukodwa ngokulandelelana kwemixokelelwane okanye hayi kwaphela. Ngenxa yoko, kushiyeka kusenokwenzeka ukuba kuqhagamshelwe ngakumbi kulwazi olukhoyo kwi-SL kune-TL.

Umzobo 5. 

Ukuziphatha okuphelileyo kwizilwanyana ezirekhodiweyo ze-FSCV embindini okanye kwigobolondo. A , Inani lezilingo ngaphambi kokuba iigundane zibonise kuqala ukunyuka okubonakalayo kokuhamba ukusuka ekuqaleni ukuya kwisigaba sokulibaziseka sokupheliswa (ngasekhohlo) kunye nokushiya impendulo (ekunene) kwi-SL (ngwevu yokukhanya) kunye ne-TL (ngwevu emnyama). Iigundane zibonise ukutshintsha kwe-TL kwi-TL kwizilingo ezimbalwa kakhulu kune-SL, nangona inani lezilingo ngaphambi kokuba ityala lishiywe lalifana phakathi kokufuna kunye nokuphendula. *p <0.05 SL xa ithelekiswa neTL. B , Impendulo latency yokuphendula kwi-SL (ekhohlo) nakwi-TL (ngasekunene) kwizigaba zokupheliswa. Ukuphendula kumva kwenyuka kwiibhloko zonke, kwaye bekukude kakhulu kulibaziseko kunye nokupheliswa kade kwee-block ngenxa yokushicilela kwe-SL. Oomatshini bokushicilela kwi-TL babekhawuleza ngokuthembekileyo kunabo bakwi-SL ngaphakathi kwibhloko nganye. *p <0.05, **p <0.01 vs I-Ext kwangoko.

Emva koko, sahlola umndilili ophakathi kwi-SLP kunye ne-TLP kwisigaba ngasinye esisekwe kwezi ndlela zibekiweyo. Iindlela ezimbini eziphindaphindiweyo eziphindaphindiweyo ze-ANOVA ngokuthelekisa iimpendulo zokugqibela kumanqwanqwa ahlukeneyo (i-SL, TL) ngexesha lezigaba ezahlukeneyo zomsebenzi (umxokelelwano, ukupheliswa kwangoko, ukupheliswa kokulibaziseka, umatshini wokushicilela emva kwexesha) ubonise umphumo ophambili we-lever (F (1,4) = 45.7, p = 0.003), ebibangelwa ziimpendulo ezikhawulezayo kwi-TL kune-SL (Ikhiwane. 5 B), ehambelana nokusebenza ngexesha leeseshini eziqhelekileyo zokuqinisa, kunye nesiphumo esiphambili sesigaba sokupheliswa (F (3,12) = 14.5, p <0.001). Kwi-SL, SLP Iimpendulo ngexesha lokutshabalala kwangoko zazifana nezo ngexesha lokuqiniswa kwetyathanga (Tukey: p = 1.0), kodwa kuncitshiswe kakhulu ngokulibaziseka (p = 0.02 vs kwangoko) kunye nomatshini wokushicilela emva kwexesha (p = I-0.003 vs zakuqala) izigaba. Nangona kunjalo, ucinezelo lwe-latency kwi-SL luyafana phakathi kokulibaziseka kunye nokufika kade (p = 0.89). Kumatshini wokushicilela we-TL, iinguqu zokuhamba kwexesha lokugqibela zazicekeceke, inqanaba lokuLibaziseka kancinci kancinci kunokuba kwinqanaba lesigaba sokuqala (p = 0.04). Nangona kunjalo, ulungelelwaniso olulinganayo lubalwa njengowona mda mkhulu womehluko kwiTL latency shift (F (1,4) = 11.08, p = 0.03; I-86% yomahluko osisiseko), ngelixa i-SL, ngokuthelekisa ityathanga kunye nokuhamba kwangoko kunye nokulibaziseka kunye nezigaba zokufika kade zibalwa ngokobukhulu bokwahluka kwesiphumo (F (1,4) = 15.42, p = 0.02; I-97% yokwahluka kwesiphumo).

Ukupheliswa: Isiphumo esishiyiweyo sokuqaqamba ngokongezwa kwe-augments kunye nophawu lwe-DA

Umqondiso onxulumene nomcimbi we-DA kwi-NAc utshintshiwe njengoko ireyithi iqhubela phambili ngokwamanqanaba achaziweyo okuziphatha. Indlela yokufakwa kwe khowudi kwi-DA kuchatshazelwe ngokuphelileyo okwahluke ngokupheleleyo phakathi komphambili kunye neqokobhe (Ikhiwane. 6).

Umzobo 6. 

Ukukhutshwa kweDA kumbindi ( A - C ) kunye negobolondo ( D - F ) ngexesha lokuphela. A Ulungelelwaniso kwi-SLO embindini kutyhila ukwehla okungapheliyo kokukhutshwa kwe-DA engqingqwa malunga nokulingwa kokutshabalala (imigca eluhlaza okwesibhakabhaka) ngokuhambelana neeseshini zamatsheyini avuzayo (umgca omnyama). Ukukhutshwa kwe-BvCore ye-DA kwiimpendulo zomsebenzi kunye nomvuzo ngexesha leshedyuli eqinisiweyo (emnyama) kunye nokupheliswa kwangoko (okwesibhakabhaka) kuhambelana ne-TLP umcimbi. Ibreyidi yeGrey ibonisa uluhlu oluphezulu kunye nobuncinci bokugxila kwi-DA ngexesha lokwandlalela. C , I-Peak ye-DA ehambelana neSLP, TLP, kwaye uvuze ngeshedyuli eqinisiweyo kunye nokupheliswa kwangoko. D Ulungelelwaniso kwi-SLO Kwigobolondo (imigca ebomvu) kutyhila ukuncipha okungakumbi kokwehliswa kwe-phasic ye-DA ukuya kwi-cue ngaphezulu kwezilingo zokupheliswa kokulinganiswa okuhambelana neseshoni ze-chain ezivuyiweyo (umgca omnyama). E I-DA ityikitya i-TLP Kwigobolondo ekutshatyalalisweni kwangoko (okubomvu) kunye neshedyuli yomxokelelwano eqinisiweyo (mnyama). F , I-Peak DA kwibhombu yayingatshintshiwe kwi-SLP, kodwa yabonisa ukwehla okukhulu kwi-TLP kunye nomvuzo. *p <0.05, **p <0.01, ikhonkco ngokuchasene nokuphela kwangoko; †p <0.05, ukushiyeka ngaphantsi kwesiseko.

Siqale sahlola uphawu lwe-DA embindini ngexesha lokuphela. Inxulumene neSLOI-DA yancipha kakhulu kwaye ngokulandelelana kwehla kuzo zonke izigaba ezahlukeneyo zokupheliswa kwendibano kwiseshoni ye-chain evuyiweyo, (ukusebenzisana: isigaba se-x cue; i-SLO Isiseko; F (4,157) = 33.19, p <0.0001; Ikhiwane. 6 A. Thumela hoc Ukuthelekisa ngababini kubonise ukuba loo ntlawulo ye-DA kwi-SLO Ukuhla ngokukhawuleza phakathi konxinzelelo kunye nezigaba zokupheliswa kwangoko (iTukey: p <0.0001), kwaye kwakhona phakathi kokuphela kwangoko kunye nokuphela kade (p <0.0001). Nangona kunjalo, i-DA ngexesha lokupheliswa kokulibaziseka ibingahlukanga kwi-block block emva kwexesha (p = 0.64) kunye ne-Peak DA ayikhange ihlukane kwisigaba sokugqibela ngokusekwe nokuba umlinganiso uphendule okanye hayi (mzuzu cofa emva kwexesha p = 0.99). Ukongeza, ukukhutshwa kwe-DA ngexesha le-SLO yayinkulu kakhulu kunokwesiseko kwikhonkco (p <0.0001), ukuphela kwangoko (p <0.0001), kunye nokulibaziseka kokuphela (p <0.001), kodwa hayi kumaphephandaba okanye emva kwexesha akukho zigaba zokushicilela (zombini p > 0.5). Ezi ziphumo zibini zixhase imeko engalunganga yomgama (F (1,157) = 94.77, p <0.0001), enika ingxelo yesininzi (71%) yomahluko wesiphumo.

Okulandelayo, uphawu olunye lweempawu ze-PE kwingqondo bubukho beemposiso ezimbi ngexesha lokufumana umvuzo olindelweyoSchultz et al., 1997). Sasilindele ukuba le miqondiso iya kuba yomelele ngakumbi ekutshatyalalisweni xa isifundo sinethemba elipheleleyo lokuba umvuzo uya kusiwa. Embindini (Ikhiwane. 6 B), i-ANOVA yendlela-mbini ibonise ukusebenzisana okukhulu kwesigaba F (3,57) = 3.24, p = 0.029). Ngokukodwa, nangona iphezulu i-DA ikhupha isalamane kwi-SL yangaphambiliP sancitshiswa kakhulu ekuphelisweni kwangaphambi kokuba kugqitywe kwiseshoni eqinisiweyo, (Tukey: p = 0.019), ukukhutshwa kwe-DA kwi-TLP ayikhathalelwanga (p = 0.41). Ngokucacileyo, i-DA esisiseko ibonise ubungqina besiphosiso esingesosenzi ngexesha lokutshatisa (Ikhiwane. 6 B) okokuthi ukukhutshwa kwe-DA ngexesha lokulindela kodwa umvuzo oshiyelelweyo ube usezantsi kakhulu kunakwiseshoni yokuqinisa (p = 0.003). Ewe ngenene, ukonyuka kwe-DA ukuya kumvuzo kwakwahlukile kwisiseko ngexesha leseshoni yomculo eyomeleleyo (p = 0.99), itshintshele kwinto engaphantsi kwesiseko ngexesha lokufika komvuzo (p = 0.03). Ke, imiqondiso ye-DA embindini ngexesha lokutsala kwangoko yabonisa zombini iinguqu ezikhululekileyo ekukhuliseni inyanzeliso lwe-SL kunye nezenzo, akukho lutshintsho luyelelwano kwi-TL cue, kunye nesiphosiso esibi sokuxela umvuzo.

Igobolondo ibonise iphethini eyahlukileyo yokukhutshwa kwe-DA kwisalamaneO cue (Ikhiwane. 6 D). Apha, umxholo we-cue-evuswe ngu-DA kwi-SLO Uguquko olunamandla ngokutshintsha kuzo zonke izigaba, (unxibelelwano: isigaba x cue; F (2,24) = 7.95, p <0.0005), kodwa ngokungafaniyo nomxholo, iqokobhe le-DA alitshintshanga phakathi kwesigaba setyathanga kunye nokuphela kwangoko, (p = 0.74), kodwa i-DA isayina kwi-SLO sehliswe kakhulu ngexesha lokulibaziseka kokupheliswa kwesigaba sokudibanisap = 0.041) kunye nenqanaba lokuqala lokuphelap = 0.02), ehambelana nokutshintsha kweempuku kwindlela yokuziphatha (Ikhiwane. 5). Ukubonisa i-DA kunciphise kakhulu phakathi kwesigaba sokulibaziseka kunye nezigaba ezifike mva (kushicilelo lwasemva kwexesha, p = 0.03; mva nje akukho kushicilelwa, p = 0.004), kodwa kwakungekho mahluko kumanqanaba e-DA phakathi kwezigaba ezigqityiweyo (cinezela ngokuchasene ne-Press, p = 0.43). Njengasembindini, ukukhutshwa kwe-DA ngexesha le-SLO ibingaphezulu kwesisiseko ngexesha lokuxinana, ukupheliswa kwangoko kunye nezigaba zokupheliswa kokulibaziseka (Tukey: konke p <0.001), kodwa akukho zigaba zasemva kwexesha ezahluke kakhulu kwisiseko. Yiyo ke loo nto, ukukhutshwa okungundoqo kwe-DA kukhutshwa ngokukhawuleza nangokuqhubekekayo kulandelelwa utshintsho kuqikelelo lwesona siqikelelo, ngelixa iipateni zokukhutshwa kwe-DA kwindawo efanayo kwigobolondo endaweni yoko zilandelela utshintsho kwimeko yenkuthazo phakathi kwezigaba zokuphela.

Ukujonga ukucinezela kunye nokubonelela ukutyikitya, ukukhutshwa kweqokobhe kwi-DA kwahlukile kwipateni kwisiseko (Ikhiwane. 6 E,F). Indlela ezimbini ze-ANOVA ezivavanya i-DA kwizilingo ezizodwa ngohlobo lokukhuthaza (i-BL, SLP, TLP, umvuzo) kunye nesigaba sokutshabalala (isixokelelwano, ukutshabalala kwangoko) kufumene intsebenzo ebalulekileyo phakathi kovuselelo × ukutshabalala (F (3,108) = 11.5, p <0.0001; Ikhiwane. 6 D). Ngokungafaniyo nesiseko, kwakungekho mahluko kukhuphiswano lwe-DA ekhutshwe kwi-SLP kwangoko ngaphambi kokuphelap = 0.44). Endaweni yoko, ukupheliswa kubangele ukwehla okukhulu kokukhutshwa kwe-DA kuzo zombini i-TLP (p = 0.01) nangexesha lokuyeka komvuzo ukufunyanwa komvuzo (p <0.0001) ngokunxulumene nexesha elingqinelanayo ngexesha leshedyuli eqinisiweyo. Ngexesha leseshoni yomvuzo we-Chain, i-DA yaphakanyiswa kakhulu ngaphezulu kwesiseko (p <0.0001), kodwa ngexesha lokushiywa komvuzo, iDA yayinkulu ngokwamanani, kodwa yayingahlukanga ngokwezibalop = 0.07). Ke ngoko, ngokungafaniyo nesiseko, safumana ubungqina obunqamlekileyo kwiimpazamo zokuxelwa kwangaphambili kwangaphambili, kwaye endaweni yoko ukuncipha kokukhutshwa kwe-DA xa kuthelekiswa ne-TL (kodwa ingeyiyo i-SL) kunye nokupheliswa kokukhutshwa kwe-DA kumvuzo obonwe ngexesha leshedyuli eqinisiweyo.

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Iipasic zenkqubo yokukhutshwa kweDVD ilandelwe isikhumbuzo esahlukileyo phakathi kokubhaliswa kwe-NAc ngendlela ehambelana nethiyori yomsebenzi we-DA. Kumsebenzi weshedyuli efundwe kakuhle, iDA kwi-NAc ngokuyintloko ikhe yafumana eyona ntelekelelo, kwaye ilandelela ngokuthe ngqo umlinganiso kwixabiso lokuxela kunye neempazamo ngexesha lokutshatyalaliswa. Ngokwahlukileyo, ukukhutshwa kwe-phasic DA kwibhola ye-NAc kulandelwe konke okuvuselelayo xa umsebenzi uvuyiswayo, kwaye zombini ngaphakathi kweseshini nangexesha lokutshabalala kwabonisa utshintsho ekuboniseni ukungqinelana notshintsho kwisizathu. Kananjalo, sicebisa ukuba le miqondiso ye-DA ifumaneke ngaxeshanye kwisilwanyana ngexesha lokuziphatha, ivumela ulwazi oluqikelelayo nolushukumisayo ukukhokela ukufunda kunye nentshukumo.

Ukukhutshwa kwe-DA kwezitshixo zokulandela ngengozi

Embindini, i-DA inyuke okwethutyana ngexesha lokuboniswa kwe-SL kwaye yanqaba kwisiseko sokuxelwa kwangaphambili kweziganeko ezizayo (umzekelo, TL, umvuzo), ngokufana noko kufunyanwe ngaphambili (Roitman et al., 2004; Cacciapaglia et al., 2012). Le pateni yomsebenzi ihambelana neemodeli zokuxela kwempazamo, ezichaza ukuba ubukhulu bezinto ezixeliweyo kufuneka zenze ukuba kukhululwe i-DA ephezulu (okt, ukuxela), ngelixa iziganeko ezichaziweyo kufanelekile zikhuphe ukukhutshwa okuncinci kwe-DA (okt, impazamo yokuxela kwangaphambili). Ke, njengoko i-TL nomvuzo waxelwa kwangaphambili ngokuchanekileyo yi-SL, bavelisa impazamo encinci ekunikezelweni kwabo, kwaye bakhupha ukukhutshwa okuncinci okunxulumene ne-DA (Schultz et al., 1997; I-Schultz kunye ne-Dickinson, 2000).

Elebhu yethu kunye nabanye babonakalisile ukuba imiqondiso ye-DA esisiseko ijonge umahluko kwixabiso eliqikelelweyo, kwaye iguqulwa ngezinto ezinjengokhetho lomngcipheko kunye nokulibaziseka kokuqiniswa (Imini et al., 2010; Gan et al., 2010; I-Sugam et al., 2012; Saddoris et al., 2013, 2015). Umzekelo, kwiigundane ezenza umsebenzi onobungozi wokuthatha izigqibo, i-DA engundoqo yanyuka ngeendlela ezixela kwangaphambili ukhetho lwerati, kwaye yehla ngokukhawuleza ngaphantsi kwesiseko xa kulindelwe imbuyekezo, impazamo yokuxela kwangaphambili (I-Sugam et al., 2012). Ngokunjalo apha, eyona nto iphambili kwi-DA ilandelele zombini ixabiso leziphumo ebeziqikelelwe, kwaye iguqulwe ngokukuko ngokusekelwe kuqikelelo lwexabiso le-cue ngexesha lokuphela. Ewe, ukukhutshwa kwe-DA kwi-SLO Bekungafani nokwahlulwa sisiseko xa irali yaqala ukushiya iimpendulo ngexesha lokuphela, nokuba impendulo yenziwa okanye hayi, ukucebisa iDA ibonise ixabiso elindelweyo lokuphendula, endaweni yokunyanzelwa ukuba lipapashe. Ngaphaya koko, ukubuyiswa kwembuyekezo kwangaphambi kokuphela kokumiswa kwengqondo kuphuculwe ukukhutshwa kwe-DA, ngokuhambelana nesigama esibi sokuxela.

I-Shell DA ilandelwa ngokushukumisayo

Ukukhutshwa kwe-DA kwibhombu kwakulandelwa ukulandela umkhondo wazo zonke izinto ezixhasayo (SLO, TLO, R). Ezi mapateni azikwazanga ukucaciswa ngokucothisa kwakhona i-kinetics, kwaye endaweni yoko zibonakalise ukubonisa i-encoding yexesha lokwenyani yeziganeko eziphikisanayo (I-Pan et al., 2005) kwaye wafumana ukunyusa isikhukula (EBerridge noRobinson, i-1998; EBerridge, 2012; Wassum et al., 2012). Yiyo loo nto, imicimbi ye-DA ikhuphe imicimbi ebinombhalo ocacileyo kunye nemivuzo kwimbumba, kodwa kuphela iingqondo eziqikelelayo ezingumbongo (Cacciapaglia et al., 2012).

Sibufumene ubungqina beli candelo lenkuthazo yokutyhilwa kweqokobhe le-DA. Kuqala, ukumakishwa kwe-DA kwigobolondo ukuya kwisikhuthazo kuncitshisiwe phakathi kokuqala kunye nokuphela kweeseshoni, ezingabonwanga emanqindini. Enye inkcazo yeyokuba amagundane esiphelweni sesifundo ayedla ngokwenziwa (ngokwenkcazo, babedle ukutya okuninzi kunasekuqaleni kweseshini), kwaye ngenxa yoko, iinkozo zokucamngca ngokutya zibonakalisa imeko yokwehla kwesilwanyana . Ngokuchasene noko, ii-cues zisabikezela ngokuchanekileyo ukuhanjiswa kwe-pellet ye-sucrose, ke ngoko uhlobo lwe-encoding encinci ye-PE yayingaphantsi ichaphazeleka kolu tshintsho lwenyusa.

Okwesibini, ngexesha lokutshatyalaliswa, ukukhutshwa kwe-DA kwibhombu kwi-SLO yahlala izinzile ngelixa i-rat yayisenza umsebenzi kwinqanaba elifanayo lokukhuthaza (njengoko kubonisiwe yimpendulo yokuphendula kunye nokuchaneka), kodwa yehle kakhulu emva kokuba inkuthazo yeempuku yenqabile (okt, impendulo yokubambezeleka) ngaphezulu kokuphela. Ngokwahlukileyo, sabona ukwehla okukhawulezileyo kukukhutshwa kwe-phasic DA ngexesha le-TL. Ngaba iimodeli ziqikelela ukuba iindlela ezinciphisa ukungaqiniseki kufuneka zidale inkuthazo enkulu kunye nenkuthazo yokuqina (Zhang et al., 2009; Smith et al., 2011), ethethwe apha ngokungafaniyo ne-TL, njengoko ichaza kwangaphambili ukusiwa komvuzo. Ewe, i-infra-NAc ye-infusions yeqokobhe ye-amphetamine ngokukhetha amandla okufaka ikhowudi yeekhonkrithi ezibaluleke kakhulu ekuzisweni komvuzo kwi-pavlovian yomsebenzi oboshwe, kodwa ube nefuthe elincinci kulayini wokuqala ngokulandelelana (Smith et al., 2011). Yiyo loo nto, ukufaka iikhowudi kwi-TL ye-TL kwakunovelwano ikakhulu ekulahlekelweni kwangaphambili kokuhanjiswa kwembuyekezo ekuphelisweni. Okothusayo, ukubuyiswa komvuzo akuzange kube nesiphumo sokukhutshwa kwe-DA ngezantsi kwesiseko, kucebisa ukuba iqokobhe i-DA yayingaphantsi kokufaka imposiso yesiphosiso esibi kunesiseko. Ngokudibeneyo, le patheni yokubonakalisa ngaphakathi kweqokobhe le-NAc yahluke ngokucacileyo kwisiseko, kwaye iphakamisa ukucaciswa kwe-IS-hlobo encoding.

Kwinkxaso, iqokobhe le-NAc liye labethelelwa kwiindlela ezahlukeneyo zokuqhutywa kwesishukumiso. Umzekelo, ukutya ngetyuwa, apho isisombululo setyuwa sihlala siphambuka, kunokuba nomvuzo ukuba isilwanyana sitsaliwe. Kuzo zombini iimeko, isiphumo esichaziweyo (ityuwa) siyafana, kodwa intshukumisa yokufumana eso siphumo yahlukile phakathi kwezilwanyana eziqhelekileyo nezaswele ityiwa (I-Tindell et al., 2009). Ukufakwa kwe-nec neural encoding yesisombululo setyuwa kuyalungiswa kwigobolondo kusekwe kwinqanaba lokunyusa ityuwa, ngelixa ii-neurons eziphambili zisilele ukubonisa ukungqinelana okusekwe kurhulumente.U-Loriaux et al., 2011). Ngokufanayo, i-intra-NAc iqokobhe le-microinfusions ye-amphetamine inika amandla amandla okhuthazo kwi-lever cinezela ebusweni be-cue ngexesha lokudluliselwa kwe-pavlovian-to-instrumental (PIT), njengoko namava e-pretransfer engapheliyo kunye necocaine (Wyvell noBerridge, i2000; Saddoris et al., 2011; I-LeBlanc et al., 2013). Ewe, amava kunye necocaine efumaneka ngokwakho elawula indlela yokuziphatha ye-PIT ikwenyusa ngokukhethekileyo i-NAc shell neural encoding isihlobo.Saddoris et al., 2011).

Le patheni ye-IS kunye ne-PE kwigobolondo kunye nomphambili ubonakala ulandelela zombini iindlela zokunqwenela ukutya kunye nokuphikisa. Kwimeko yokwesaba i-pavlovian, i-phasic DA inyuka kwiqokobhe le-NAc kwi-cultal eveververs cices, ngelixa ukhuphelo oluphambili lwe-DA lubona ukunciphisa kunye nokuma kokukhupha ukubonakaliswa kohlobo lwePP yesiphumo esibi.I-Badrinarayan et al., 2012). Ke ngoko, kwanezinto ezimbi (kodwa ezizezona zibalulekileyo) zinokuchazwa ngemodeli yohlobo lwe-IS ngaphakathi kweqokobhe, ngelixa ukhuphelo olusisiseko lwe-DA luhlala luhlanganisene ngokuqikelela malunga nexabiso lesiphumo.

Ukudideka kwe-PE kunye ne-IS kubonakalisa kwimeko yokuma

Enye ye-caatat kukuba kwimeko ye-pavlovia, izilwanyana ezisebenzisana ngokukhethekileyo nezinto ezixelwa kwangaphambili ("ii-trackers trackers)) zibonisa ukukhutshwa kwe-DA kumgangatho we-NAc xa kuthelekiswa naleyo isiya kwikomityi yokutya (" abo balandeli beenjongo '; I-Flagel et al., 2011). Olu longezo lomkhondo oluchaziweyo luchazwa njengesekela i-IS, njengoko indawo iye yaba sisixhasi esisinyanzelo esikwaziyo ukusebenza njengamandla osixokelelwano kwaye ihambelana neziphumo ezifanayo kumbindi (I-Aragona et al., 2009; Peciña kunye neBergridge, i-2013; Wassum et al., 2013; Ostlund et al., 2014). Oku kubonakala kukungahambelani kakuhle nesabelo sethu se-PE ucalucalulo kumbindi kunye ne-IS kwigobolondo.

Kubalulekile ukuba uqaphele ukuba iindima ezichaphazelekayo zophawu lwe-DA kumbindi kunye neqokobhe zinokuba nzima. Umzekelo, bambalwa kwezi zifundo zingasentla abaye baphanda ngokuzimeleyo ngendima yeqokobhe kunye nengumqobo kule misebenzi, ke ukunyuka kwe-DA embindini kwizilwanyana zokulandela ngomkhondo kunokubonakalisa ukwanda ngokubanzi kwemiqondiso ye-DA yenkuthazo kwindlela ye-mesolimbic. Ngapha koko, asikhuthazi ukwahlula ngokupheleleyo; Sifumene ukhutshelo lwe-DA kwi-TLO embindini, nangona iDA ukuya kwi-SLO kwibhola eqengqelekayo ngaphandle kweenguqu zentshukumisa ngexesha lokuphela, ephakamisa ukuba amanqaku e-IS anokubakho embindini kunye ne-PE kwiqokobhe (nangona kumanqanaba asezantsi kwaye / okanye engaphenduli kangako kumandla omsebenzi). Endaweni yoko, sicebisa ukuba eyona nto iphambili kunye neqokobhe libonisa ukukhetha okunobungqangi kwi-Pe- kunye neendlela ze-IS zokukhowelisa, ezihambelana nokwenziwa komgangatho ngokwenyani kwe-striatal anatomy (Haber, 2014).

Iziphumo zokulutha

Umahluko osekwe kwimodeli kwi-core kunye ne-shell ye-signaling ye-DA ineempembelelo ezibalulekileyo ngaphaya kokufunda komvuzo wemvelo. Umzekelo, nangona iziyobisi zokuphathwa gadalala zinomvuzo kwasekuqaleni, ixesha elingaphezulu, inkuthazo enxulumene neziyobisi inokubangela imvakalelo yokunqwenela okungagungqisi, ibeke imeko engalunganga eqhuba ukufuna iziyobisi (UKoob noLe Moal, i-1997). Ukuyekiswa ixesha elide kweziyobisi kunyusa ifuthe lokuvuselela okunxulumene neziyobisi nangona inkqubo eyaziwa ngokuba kukuzibandakanya kwenkanuko (I-Grimm et al., 2001; I-Hollander kunye neCarelli, 2005; Ukukhetha i-et al., 2011). Iziphumo ezixelwe kwangaphambili (iziyobisi) azitshintshi kwimeko yangoku kunye nokungabikho, kodwa kukho ukwanda okukhulu kwisizathu sokuqhubeka nokuthatha iziyobisi kwizifundo ezingafakwanga. Oku kuphakamisa utshintsho olubalulekileyo kwezo zinto zikhuthazayo kwaye kunokuxela kwangaphambili ukuba utshintsho olunxulumene nokuyeka kufuneka lubonwe ngokukhethekileyo kwigobolondo. Ngokunxulumene noko, xa iigundane ezizilawula ngokwamachiza ziveliswa ngemikhombandlela yecocaine ebangela imeko yenkuthazo, utshintsho kumkhondo wokubonisa we-DA imeko yokuphindana kwesilwanyana kwigobolondo kodwa hayi eyona nto iphambili kuyo (I-Wheeler et al., 2011). Ngokudibeneyo, ezi zinto zifunyanisiweyo ziyaxhasa ukuba igalelo elingaphakathi kunye neqokobhe leDA ekufundeni nakwinkuthazo ziyafana kuzo zombini izibonelelo zendalo kunye neziyobisi.

Imihlathi

  • Ifunyenwe ngoJuni 18, 2015.
  • Uhlaziyo lufunyenwe ngoJulayi 8, 2015.
  • Yamkelwe ngoJulayi 15, 2015.

  • Lo msebenzi uxhaswe ngamaZiko eSizwe kwiZibonelelo zokuSetyenziswa gwenxa kweziyobisi i-DA028156 kunye ne-DA035322 ukuya kwi-MPS kunye ne-DA017318 kunye ne-DA034021 ukuya kwi-RMC, kunye ne-DA010900 ukuya kwi-RMW Simbulela uGqr. West West ngezimvo zawo kwangoko.

  • Ababhali bavakalisa ukuba akukho mfuno yemali ekhuphisanayo.

  • Imbalelwano mayibhekiswe kuGqr Michael Saddoris, iSebe lezeMpilo yeengqondo kunye ne-Neuroscience, iYunivesithi yaseColorado Boulder, Muenzinger, UCB 345, Boulder, CO 80309-0345. [imeyile ikhuselwe]

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