Phetoho ea Phatlalatso ea Matšoao a Bobeli le a Ntle a Khothatsang ka VTA Dopamine Neuronal Populations (2011)

Tlhaloso: Wang DV, Tsien JZ (2011) Ts'ebetso ea Convergent ea Li-Signals tse ntle le tse mpe tsa Motheo ke VTA Dopamine Neuronal Populos. PLoS ONE 6 (2): e17047. doi: 10.1371 / journal.pone.0017047

mohlophisi: Hiromu Tanimoto, Max-Planck-Institut für Neurobiologie, Jeremane

Re amohetse: Novemba 9, 2010; E amohetse: Pherekhong 19, 2011; E phatlalalitsoe: February 15, 2011

Copyright: © 2011 Wang, Tsien. Ena ke sengolo se bulehileng se fihletsoeng tlasa tumellano ea Lichelete ea Tlhahiso ea Creative Commons Attribution, e lumellang tšebeliso e sa thibeloang, phetiso, le tlhahiso hape ka mofuta o mong le o mong, ha feela moqapi oa mantlha le mohloli ba ngoliloe.

Lithuso: Mosebetsi ona o ne o tšehelitsoe ke lichelete ho tsoa ho NIMH (MH060236), NIA (AG024022, AG034663 & AG025918), USAMRA00002, le Georgia Research Alliance (kaofela ho ea JZT). Bafani ba lichelete ba ne ba sena karolo ho moralo oa boithuto, pokello ea lintlha le tlhahlobo, qeto ea ho e phatlalatsa kapa ho hlophisa sengoloa.

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

Selelekela

Li-dopamine neurons tse sebakeng sa "ventral tegmental" (VTA) ka tloaelo li ithutetsoe bakeng sa karolo ea tsona khothatsong e amanang le moputso kapa bokhoba ba lithethefatsi. [1]-[3]. Leha ho le joalo, li-neuron tsa VTA dopamine li boetse li lumeloa hore li bohlokoa bakeng sa tšusumetso e mpe [1]-[4]. Ka lingoliloeng, karolo ea "dopamine neuron" e susumetsang e thehiloe hantle 'me e tšehelitsoe ke liphuputso tse ngata tse bonts'ang moputso (mohlala, lijo, lero) le meputso e fumanehang (e phehellang moko-taba) e tsosang mofuthu oa nakoana (50-110 ms) le nako e khuts'oane (~ 200 ms) ea ho phatloha hoa neuron ea dopamine [5]-[9]. Karabelo ea dopamine neurons ena e bonahala e kenyelletsa mefuta e mengata e fapaneng ea lipale tsa lipale le tse amanang le moputso ka molao oa phoso ea bolepi [5]-[9]. Ketsahalo ea dopamine ea VTA e boetse e bontšitsoe e bapala karolo ea bohlokoa ho tšebeliso ea lithethefatsi: hoo e batlang e le lithethefatsi tsohle tse tlatsetsang li eketsa tekanyo ea dopamine ea synaptic sebakeng sa nucleus e fumanang liphetho tse pharaletseng tsa dopaminergic ho tsoa sebakeng sa VTA. [10]-[12].

Karolo ea neuron ea VTA dopamine ho ts'usumetso e mpe e boetse e hlokometsoe. Lipatlisiso tse 'maloa li fumane hore liketsahalo tse khopisang (mohlala, ho kenella ka molomo ha quinine kapa LiCl) kapa lipalo tse mpe (mohlala, ho tlohela lithethefatsi) ho ka fetola ho tsepamisa mohopolo oa dopamine libakeng tsa boko tse saoloang ke li-neurons tsa VTA dopamine [13]-[15]. Ntle le moo, tšitiso ea phetisetso ea dopamine mehahong e tlase ea VTA e lebisa ho maemo a sa tsitsang ho liphihlelo tse khopisang kapa tse tšosang [16], [17]. Ho feta moo, litekanyetso tsa dopamine li ka bonts'a mesebetsi e fapaneng khahlanong le boitšoaro: boemo bo tlase ba dopamine ho li-nucleus accumbens ho lumeloa hore bo ntlafatsa kotlo- empa bo sitisa ho ithuta ho thehiloeng ho moputso, ha boemo bo phahameng ba dopamine bo ntlafatsa moputso- empa bo sitisa thuto e thehiloeng ho kotlo e thehiloeng ho kotlo [18]. Lithuto tsena tse kaholimo li khothaletsa ka matla hore VTA dopamine neurons le eona e bapala karolo ea bohlokoa ho ts'ebetsong matšoao a fosahetseng a susumetsang. Leha ho le joalo, karolo e tobileng ea VTA dopamine neuron ka tšusumetso e mpe ha e hlake hantle.

Ka lehlakoreng le leng, liphuputso tsa morao-rao li fumane hore dopamine neurons ka har'a substantia nigra pars compacta (SNc) e ka arabela moputsong ka bobeli (mohlala, lero la tholwana) le maikutlo a aversive (mohlala, moea puff) le lipalo tse peli tsa SNc dopamine neurons li ka fetisa ka mokhoa o hlakileng. le matšoao a fosahetseng a susumetsang [9], [19]. Leha ho le joalo, ho hlahisitsoe lipelaelo mabapi le hore na ho tšoloha moea matlalong, kapa seemahale sa boemo bo boletseng ho ba le ho phatloha hoa moea, ho hlile ho ferekanya litšoene hafeela mesebetsi e joalo e nkuoa e se kotsi. [9]. Ntle le moo, li-neuron tsa SNc dopamine li tsejoa ho sebetsa likarolo tse fapaneng tsa tlhaiso-leseling, 'me ka tlhahlobo-leseling e fapaneng ea tlhahiso ea methapo ea kutlo le VTA [5]. Ka hona, ho na le tjantjello e kholo ea ho etsa lipatlisiso hore na li-neurons tsa VTA dopamine li etsa liphihlelo tse mpe joang, le hore na ho na le li-dopamine neuron tse ikhethileng tse inehelang ho etsa tlhaiso-leseling e ntle le e fosahetseng.

Ho araba lipotso tsena tsa bohlokoa, re sebelisitse rekoto ea extracellular ea extracellular tse ngata ka bolokolohi 'me ra sebelisa mefuta e' meli ea liketsahalo tse tšabehang (ho oa le ho sisinyeha mahala) [20] e le mokhoa oa ho ithuta karolo ea li-neurons tsa VTA ha ho sebetsoa matšoao a fosahetseng a susumetsang. Re boetse re koetlisitse litoeba ho kopanya molumo oa ho se jele paate le lijo tse tlang ka morao ho moo, tse re lumelletseng ho etsa lipatlisiso tsa hore na tlhalo e tšoanang ea VTA dopamine neuron e ka etsa lipontšo tse ntle joang. Ho feta moo, hobane tlhahisoleseling e mabapi le tikoloho ke karolo ea bohlokoa ea boiphihlelo bo bongata ka kakaretso, re ile ra botsa hore na maemo a tikoloho a ka bapala karolo efe ho khetholla moputso kapa tlhaiso-leseling. Mabapi le sena, re ile ra boela ra etsa liteko tse ngata moo re koetlisitseng litoeba ho matahanya molumo o le mong ka moputso oa lijo le ketsahalo e tšosang empa maemong a fapaneng, a re lumelletseng ho tseba hore na likarabelo tsa VTA dopamine neural li ile tsa susumetsoa ka mokhoa o hlollang joang ke tikoloho ea tikoloho. Liphetho tsa rona li bontša hore li-neurons tsa VTA dopamine li ka sebelisa leano la ho kenyelletsa litaba bakeng sa ho sebetsana le liphihlelo tse ntle le tse mpe.

Results

Tlhophiso ea li-neurone tsa dopamine tse behang

Re kentse lits'oants'o tse tsamaeang tsa li-tetrode tse 8 (liteishene tse 32) ho VTA ea hemisphere e nepahetseng ea litoeba, mme maemo a li-electrode a ho rekota a netefalitsoe ke histology qetellong ea teko ea rona (Setšoantšo sa 1A). Tlhahisoleseling e tsoang ho litoeba tse 24 tseo re hatisitseng li-neuroption tsa dopamine li sebelisitsoeng tlhahlobisong ea hajoale. Kakaretso ea li-unit tse 210 tse nang le li-waveform tse hlakileng tse tlalehiloeng ho tsoa ho litoeba tsena tse 24 (ka mehlala ea likarolo tse ikhethileng hantle, bona Setšoantšo sa S1). Ho tsona, likolo tsa 96 li ne li thathamisitsoe e le li-neuron tsa dopamine tse tlatsitsoeng ho latela mohlala oa tsona oa ho thunya (bona Lisebelisoa le mekhoa), 'me likarolo tse ling tse 114 li ne li nkuoa e le li-neuron tse se nang dopamine. Li-neuroplopathy tse behiloeng ka mokokotlong tse khethiloeng ka mokhoa o hlakileng li bonts'a bokhoni bo pharaletseng, bo pharacas ba liketso (Setšoantšo sa 1B, bofubedu), leha e le ka phapang, ha li-neuron tse se nang dopamine li bonts'itse lintho tse fokolang tse ka fokotsang kapa tsa phasic.Setšoantšo sa 1B, e putsoa le e ntšo, ka ho latellana). Habohlokoa ke li-neuron tse nang le litekanyetso tse tlase tsa ho thunya tse tlase (0.5-10 Hz; Setšoantšo sa 1C), karolelano ea nako e telele ea li-inter-spike (> 4 ms) le paterone e tloaelehileng ea ho thunya e ile ea beoa e le putative dopamine neurons. Ka lehlakoreng le leng, li-neuron tse sa khethollang tsa dopamine hangata li bonts'a sekhahla se phahameng sa ho thunya (> 10 Hz; Setšoantšo sa 1C) le / kapa phetoho ea bohlokoa modulong oa ho thunya nakong ea motsamao, e tsamaeang le ho khutsa [21]-[23].

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Setšoantšo sa 1. Ho rekota ha Muti-tetrode le tatellano ea methapo ea VTA.

(A) Morero oa li-arrrode tse hlophisitsoeng o bonts'itsoeng ka karolo ea boko ba coronal (ka holimo-ka ho le letona) le libaka tsa malebela a tlhophiso ea elektrode (ho tloha litoeba tse 21) ho litšoantšo tsa karolo ea atlas [52]. Likwere tse putsoa li emela libaka tseo ho tsona ho tlalehiloeng mofuta oa 1/2 oa li-neurons tsa DA; likhetla tse khubelu li emela libaka tseo ho tsona ho tlalehiloeng li-neuron tsa mofuta oa 3; mabala a pherese a emela libaka tseo ho tsona ho tlalehiloeng mofuta oa 1/2 le mofuta oa mofuta oa 3 (bona Setšoantšo sa 2 bakeng sa karohano ea mefuta e meraro ea li-neuron tse mpe tsa DA). (B) Mehlala ea li-waveform tse hatisitsoeng ka tloaelo tsa li-neurons tsa DA tse khubelu (tse khubelu) le tse seng tsa DA (tse putsoa le tse ntšo). Bophara ba halofo ea AP e ne e lekantsoe ho tloha ka sekhorong ho ea fihla tlhōrōng e latelang ea matla a ketso. (C) Litefiso tsa ho thunya hoa motheo le bophara ba halofo ea AP ea li-neuron tse khethiloeng tsa (red) le li-neuron tse seng tsa DA (batsho). DA, dopamine; Batho bao e seng DA, bao e seng dopamine; AP, monyetla oa ts'ebetso.

doi: 10.1371 / journal.pone.0017047.g001

Mefuta e meraro ea li-neuron tse arabelang tsa VTA putative dopamine

Re sebelisitse mefuta e 'meli ea liketsahalo tse tšabehang (ho oa le ho sisinyeha mahala) ho hlahloba hore na li-neurons tsa VTA li ka arabela joang liphihlelong tse mpe [20]. Kamora hore litoeba li hlaphoheloe lingakeng tse buoang le ho rekota tse tsitsitseng li fihlelletsoe (hangata kamora libeke tse 1 ho tse peli tsa ho buuoa), re ile ra qala liteko. Mouse e 'ngoe le e' ngoe e ile ea kenngoa ka kamoreng ea ho oa ntle le ho oela, moo liteko tse ka bang 2 tsa ho oa kapa ho tsitsinyeha ha liketsahalo li neng li fanoa ka nako e ngoe le e ngoe ka nako ea metsotso e le 20-1 lipakeng tsa liteko (Setšoantšo sa 2A). Nako e pakeng tsa mananeo ke hangata ka lihora tse 1-2. Kamehla re ne re lekola botsitso ba likarolo tse rekotiloeng ka ho hlahloba sebopeho sa spike waveform, boemo ba ho thunya hoa basement, le karolelano ea lihlopha tsa lihlopha pele le ka mor'a liketsahalo le ka liteko tsohle. Re ile ra lekola hore ha ho na tahlehelo ea nakoana ea li-unit nakong ea liketsahalo tse peli tse tšosang ka ho hlahloba li-unit tse rekotiloeng ka nako e le 'ngoe (mohlala, likarolo tse peli tse tlalehiloeng ho tloha tetrode e le ngoe li bonts'a liphetoho tse fapaneng tsa ho thunya) (Setšoantšo sa S2). Re boetse re netefalitse hore ha ho na lithapo tsa motlakase tsa maiketsetso kapa tsa maiketsetso tse kentsoeng data e rekotiloeng ka ho lekola libonase pele, nakong le ka morao ho liketsahalo tse tšosang (Setšoantšo sa S3). Ka kakaretso, li-neuropathy tsena tsa dopamine (n = 96) li ne li arotsoe haholo ka mefuta e meraro e meholo ho latela likarolo tsa bona tsa karabo liketsahalong tse peli tse tšosang: mofuta-1 (59%, 57/96), mofuta-2 (13%, 12 / 96) le mofuta-3 (25%, 24/96).

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Setšoantšo sa 2. Mefuta e meraro ea li-neuron tsa VTA putative dopamine (DA).

(AC) Li-rasters tsa ketsahalo ea Peri (liteko tsa 1-20, ho tloha holimo ho ea tlase) le li-histogram tsa mehlala e meraro ea VTA putative dopamine neurons (A: mofuta-1, B: mofuta-2, le C: mofuta-3) ho arabela mahala. oa (li-panels tse ka letsohong le letšehali), sisinya (liphanele tse bohareng), le molumo o nang le boemo bo boletseng ka nepo ts'ebetso ea pellet ea tsoekere (liphanele tse nepahetseng) (D) Liperesente tsa mefuta e fapaneng ea li-neurons tsa DA tse behang. (E,F) Liperesente tsa khatello e hatelletsoeng (E: mofuta-1 le 2) le tšabo e nang le tšabo (F: mofuta-3) li-neurons tse behang DA tse neng li entsoe ka mokhoa o hlakileng ke molumo o nang le boemo o neng o bolela esale pele tsoalo ea tsoekere ka tsoekere. Ho oa mahala, 30 cm ka bolelele; Shake, 0.2 sec; Tone, 5 kHz, 1 sec.

doi: 10.1371 / journal.pone.0017047.g002

Type-1 VTA putative dopamine neurons ha ea ka ea bontša khatello ea bohlokoa feela ea ho thunya ha bona ka likarabo tsa ho oa le ho sisinyeha hoa mahala (Setšoantšo sa 2A, liphanele tse tlohelang le tse bohareng) ((P<0.05, teko ea boemo bo saennweng ea Wilcoxon), empa hape le nyakallo e matla e felisang bofokoli bofelong ba liketsahalo ka bobeli. Re hlalositse nyakallo e phetohileng joalo ka sekhahla sa ho thunya se phahameng sa offset (se khabisitsoeng ka sefahleho sa Gaussian) ho ba bonyane makhetlo a mabeli ho feta sekhahla sa ho thunya sa mantlha mme ka li-z-lintlha tse kholo ho feta 2. Nyakallo e joalo e boetseng e ka supa polokeho qetellong ea liketsahalo tse tšosang kapa tšusumetso ea liketsahalo tse joalo. Eaba re botsa hore na mofuta ona-1 dopamine neurons o ne o arabela ho putsa matšoao. Ha re pheta molumo o sa nke lehlakore khafetsa le ho tsamaisoa ha pellet ea tsoekere, re fumane hore li-neuron tsena le tsona li eketsehile haholo ho thunya ha tsona ho molumo o boletsoeng esale pele o tšepisang moputso (Setšoantšo sa 2A, sethala se nepahetseng). Ka hona, li-neurons tsena tsa mofuta oa 1 dopamine li ne li ikarabella ho moputso le lipontšo tse seng ntle.

Mofuta oa mofuta oa VTA oa "" "" "" "" "Dopamine" dopamine "e bonts'a khatello e kholo (P<0.05, teko ea boemo bo saennweng ba Wilcoxon) nakong ea ho oa kapa ho sisinyeha ha mahala, empa ha ba ka ba ba le ts'ebetso ea ts'ebetso kamora hore liketsahalo tsena li felisoe (z-scores <2) (Setšoantšo sa 2B, likharetene tse setseng le tse bohareng). Hoa tšoana le mofuta oa mofuta oa 1 oa li-dopamine neurons, li-neuron tsa mofuta ona li ile tsa eketsa ho thunya ha tsona ka mokhoa o hlakileng ho molumo o hlakileng o ileng oa bolela moputso ka mokhoa o tšepahalang (Setšoantšo sa 2B, sethala se nepahetseng). Kahoo, mefuta ea mofuta oa 1 le mofuta oa 2 dopamine neurons li bonts'a phetisetso ea liketsahalo tse sa hlakang le tse ntle, ke hore, ba fokotse ho thunya ha bona liketsahalong tse tšosang ha ba ntse ba eketsa ho thunya ha bona ho ea ho moputso.

Ka mokhoa o tsotehang, re boetse re tlaleha mofuta oa boraro oa li-neuron tse kang dopaminergic, tse arolelanang ho ts'oana le li-neurop tsa dopamine tsa mofuta-1/2 ho fapana le li-neuron tse sa kopaneng. Li-neurons tsena tsa mofuta-3 (hoo e ka bang 25% ea li-neuropathy tsohle tse rekotiloeng tse tlalehiloeng) li ile tsa eketsa ho thunya hoa tsona ka bobeli ho oa le ho sisinyeha hoa liketsahalo (Setšoantšo sa 2C, liphanele tse tlohelang le tse bohareng) ((P<0.05, teko ea boemo bo saennweng ba Wilcoxon). Ho thunya ha bona ho eketsehileng ho ne ho lateloa ke khatello ea offset. Ho feta moo, mofuta ona-3 dopamine neurons o ka eketsa ho thunya ha bona ho arabela molumo o boletsoeng esale pele oa moputso (Setšoantšo sa 2C, sebaka se nepahetseng). Li-neuron tsa mofuta ona, tse ileng tsa eketsa ho thunya ha tsona liketsahalong tse ntle le tse mpe, li fapane haholo le mofuta oa mofuta oa 3 le mofuta oa 1 dopamine neurons. Sena se bontša ka matla phapang ea palo ea baahi ba VTA dopamine neuron [24], [25].

Ka kakaretso, mofuta oa mofuta oa 1 le li-neurons tsa mofuta oa 2 li hlahisa bongata ba lipalo-palo ea batho ba bitsoang VTA setative dopamine neuronal, athe li-neurons tsa mofuta-72 li etsa karolo ea 3%, empa li-neuroproption tsa 25% tse setseng li sa arabele. liketsahalo tse tšosang (Setšoantšo sa 2D). Ho feta moo, litlhahlobo tsa rona li fana ka maikutlo a hore likarabo tsena tsohle tsa methapo ea kutlo liketsahalong tse mpe li tloaetse ho ts'oana ka tsela e tšoanang (li-neuron tse 45 tse lekiloeng bakeng sa ho oa ha mahala le ho sisinya liketsahalo), ke hore, li-neurone tse hatelletsoeng (kapa tse kentsoeng tšebetsong) ke ketsahalo ea mahala ea ho oa li ne li lula li le teng. hatelloa (kapa butswe) ke liketsahalo tse ling tse tšosang, joalo ka ketsahalo ea sisinya, le ka ho le leng. Ho tsoa ho li-dopamine neurons tse hatelloang ke tšabo (mofuta-1 le mofuta-2) tseo re li hlahlobileng ho arabela lipontšo tsa moputso, 96% ea tsona (44/46) e bonts'itse ts'ebetso e kholo ka molumo o putsang (Setšoantšo sa 2E) (P<0.05, teko ea boemo bo saennweng ba Wilcoxon). Sena se bonts'a ka ho hlaka hore bongata ba mofuta-1 le mofuta-2 VTA dopamine neurons ba khona ho arabela ka lehlakore liketsahalong tse ntle le tse mpe, ke hore, ba bonts'a nyakallo ka tlhaiso-leseling ea moputso ha ba hatelloa ke liphihlelo tse tšosang. Ka lehlakoreng le leng, hoo e ka bang 71% ea mofuta-3 putative dopamine neurons (12/17) e ileng ea ts'oaroa ke liketsahalo tse tšosang le eona e ka ts'oaroa ke matšoao a moputso (Setšoantšo sa 2F) (P<0.05, teko ea boemo bo saennweng ba Wilcoxon). Sena se fana ka maikutlo a hore liketsahalo tse tšosang, eseng feela moputso, li ka thabisa tse ling tsa VTA putative dopamine neurons.

Mekhoa ea ho thunya le sebopeho sa pharmacology

Leha a ts'oana le ho ts'oana ha bona mohaleng oa ho thunya le li-waveform tsa mefuta e meraro ea li-neuron tsa putop dopamine (mohlala ,. Setšoantšo sa 3A-C), re hlokometse liphapang tse ling hara bona. Taba ea pele, mofuta oa 3 oa "dopaminergic-like neurons" o bonts'a monyetla o tlase haholo (9 ± 2.3%, ho bolelang ± sem) oa ho phatloha ho hoholo ha ho bapisoa le mofuta-1 (55.2 ± 2.5%) kapa mofuta-2 (32.0 ± 3.8%) neurons (Setšoantšo sa 3D le E). Ntlha ea bobeli, li-neurons tsa mofuta-3 li bonts'itse sekheo se tlase sa ho thunya hoa basement (2.15 ± 0.33 Hz, se bolelang ± sem; n = 24) ha se bapisoa le mofuta-1 (5.66 ± 0.27 Hz; n = 57) kapa mofuta-2 (4.92 ± 0.49 Hz; n = 12) methapo ea kutlo (Setšoantšo sa 3F).

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Setšoantšo sa 3. Mekhoa ea ho thunya le sebopeho sa pharmacology.

(A-C) Mehlala e meraro ea li-neuropter neuropoto tse rekotiloeng tse rekisang li-topode (mofuta oa 1, mofuta-2, le mofuta-3) le li-waveforms tsa baemeli ba tsona ba baemeli. PC1 le PC2 li emela likarolo tsa mantlha tsa bobeli le tsa bobeli tlhahlobisong ea karolo e kholo, ka ho tšoanang. Matheba a maputsoa a emela li-spikes ka bomong bakeng sa li-neuron tse ikhethileng tsa dopamine; matheba a matšo a bontša li-spikes ka bomong tsa li-neuron tse ling tse sa sebetseng tsa VTA. (D) Nako le nako pakeng tsa mehlala e meraro ea li-neuron tsa putopu tsa mofuta oa mofuta oa 1 (mofuta oa 2, mofuta oa 3 le mofuta-XNUMX). (E) Peresente ea ho phatloha ho hoholo hoa lithunya tsa mefuta e meraro ea li-neuron tse mpe tsa "dopamine". Mekoallo ea liphoso, sem; ***P<0.001, ea Seithuti t-etona. (F) Motheo oa litheko tsa ho fofa tsa mefuta e meraro ea li-neuron tsa putopu tsa putop. Mekoallo ea liphoso, sem; ***P<0.001, ea Seithuti t-etona. (G) Cumulative spike shughuli ea hau ea mehlala ea li-neuropine tsa dopamine tse tlisoang (mofuta oa 1, mofuta oa 2, le mofuta-3) ha a araba dopamine receptor agonist apomorphine. Ho ile ha hlokomeloa hore mofuta-1 le mofuta-3 putative dopamine neurons li tlalehiloe ka nako e le ngoe ho tsoa ho tetrode e le 'ngoe. (H 'me I) Litekanyetso tsa mantlha le tsa ho thunya lithethefatsi ka mor'a lithethefatsi tsa "putrop dopamine" H) le "non" dopamine (I) neurons. Linta li ile tsa kenngoa ka dopamine receptor agonist apomorphine (1 mg / kg, ip) mme litekanyetso tsa ho thunya li ne li atisoa ka makhetlo a 30 min le 30 min kamora ho entoa ea apomorphine.

doi: 10.1371 / journal.pone.0017047.g003

Re boetse ra kenya litoeba le "dopamine receptor agonists apomorphine" (1 mg / kg, ip) le / kapa quinpirole (1 mg / kg, ip) e bonts'itsoeng haholo ho thibela ts'ebetso ea methapo ea methapo ea dopamine [6], [8], [24], [25]. Kakaretso ea li-neurons tsa VTA tse 77 (ho kenyelletsa le li-neurons tse 33 tse hlalositsoeng tsa "dopamine neurons" le 44 tse seng dopamine) li ile tsa lekoa le dopamine receptor agonists. Liphetho tsa rona tsa meriana li senotse hore bongata bo boholo (96%; 23/24) ea mofuta-1 le mofuta-2 putative dopamine neurons li ne li hatelletsoe haholo, athe ho makatsang ke hore mofuta oa 3 neurons (n ​​= 9) o bonts'itse boithabiso ke apomorphine (Setšoantšo sa 3H). Ntle le moo, li-neurons tse 4 tsa sehlopha sa "dopamine" tse khethiloeng li ile tsa lekoa ka bobeli ka apomorphine le quinpirole (ka matsatsi a fapaneng). Li-neurons tsena tsa 4 tsa "dopamine" tse hlahisoang li ile tsa hlahisa likarabo tse tšoanang ho apomorphine le quinpirole: li-neuron (n = 2) tse hatisitsoeng ke apomorphine le tsona li hatelitsoe ke quinpirole; methapo ea kutlo (n = 2) e hlahisitsoeng ke apomorphine le eona e ile ea qaptjoa ke quinpirole. Ka lehlakoreng le leng, li-neurons tsa VTA tse se nang dopamine (n = 44) li bontšitse liphetoho tse fokolang kapa tse se nang sekhahla sa ho thunya kamora ho kenngoa ka ente ea apomorphine kapa quinpirole (Setšoantšo sa 3I).

Likarabo tsa VTA putative dopamine neurons ho durations tse fapaneng le matla a liketsahalo tse tšosang

Ho utloisisa ho eketsehileng thepa ea ho kenyelletsa ea VTA dopamine neurons bakeng sa liketsahalo tse tšosang, re ile ra etsa lethathamo la liteko tsa parametric. Bophahamo bo fapaneng ba ho oa mahala (10 le 30 cm) le linako tse fapaneng tsa ho sisinyeha (0.2, 0.5 le 1 sec) li entsoe ka litaelo tse sa reroang nakong ea liteko tsa ho rekota. Re fumane hore VTA dopamine neurons e bonts'a liphetoho tse fetohileng tsa nakoana tsa ts'ebetso tse neng li lekana le linako tsa liketsahalo tse tšosang. Joalokaha ho bontšitsoe Setšoantšo sa 4A, mofuta-1 putative dopamine neurons e bonts'a khatello ea nako e itšetlehileng ka nako ea liketsahalo nakong ea liketsahalo tsa mahala tsa ho oa (10 cm vs 30 cm high). Tlhahlobo ea palo ea baahi e bontšitse hore, ho arabela liketsahalong tsa ho oa ntle ho 10 le 30 cm (Setšoantšo sa 4B), litheolelo tsa morao-rao tse tloheletsoeng tse felisitsoeng (latency ea theiple e felileng ea peterole) ea mofuta-1 putative dopamine neurons e ne e le 293 ± 38 ms (e bolelang ± sd, n = 15) le 398 ± 28 ms (n = 20), ka ho latellana (P<0.001, ea Seithuti t-etete). Liphetho tsena li fana ka maikutlo a hore likarabo tsa mofuta-1 putative dopamine neurons e lumellana le nako ea liketsahalo tse tšosang (Setšoantšo sa 4B, sethala se nepahetseng). Ho ile ha hlokomeloa hore sekhahla sa ho thunya tlhōrō ea offset se ne se phahame hanyane nakong ea ketsahalo ea ho oa ntle le 30 cm (30.9 ± 6.6 Hz; bolela ± sd) ha ho bapisoa le ketsahalo ea 10 cm (26.3 ± 5.9 Hz) (P = 0.04, Seithuti t-test), a fana ka maikutlo a hore likarabo tsa mofuta-1 VTA dopamine neurons ho tse mpe li ka bonts'a, ho isa tekanyong e tlase, botebo ba liketsahalo tsa ho oa ntle ho tefo.

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Setšoantšo sa 4. Likarabo tsa VTA mofuta-1 putative dopamine neurons ho ea ho linako tse fapaneng le matla a liketsahalo tse tšosang.

(A) Li-rasters tsa ketsahalo ea (Peri-liketsahalo) (liteko tsa 1 - 20) le li-histogram tsa mofuta o le mong oa mofuta-1 neuron ho arabela li-10 cm (ka letsohong le letšehali le liketsahalo tse 30 cm) tsa ho oa. (B) Kakaretso ea kakaretso ea li-peri-ketsahalo tsa sechaba tse qetehileng (ka letsohong le letšehali) le li-latency tsa offset (ka ho le letona) tsa mofuta oa mofuta oa 1 ho arabela ka 10 cm (mola o moputsoa; n = 15) le 30 cm (mola o khubelu; n = 20) Liketsahalo tsa ho oela mahala . (C) Li-rasters tsa ketsahalo le li-histogram tsa mofuta o mong-1 neuron ho arabela 0.5 sec (ka ho le letšehali) le 1 sec (ka ho le letona) liketsahalo tse sisinyehang. (D) Kakaretso ea kakaretso ea li-peri-ketsiso ea baahi ba qotsitsoeng (ka letsohong le letšehali) le li-latency tsa offset (ka ho le letona) tsa mofuta oa mofuta oa 1 neurons ha li arabela ka sec sec: (line line; n = 0.2), 13 sec (blue line; n = 0.5), le 20 sec (red line; n = 1) sisinya liketsahalo. (E) Li-rasters tsa ketsahalo le li-histogram tsa mofuta o mong-1 neuron ha li arabela maemong a tlase ((ka ho le letšehali) le liketsahalo tse phahameng (tse ka letsohong le phahameng) tse sisinyehang. (F) Pale ea liketsahalo tsa sehloho tsa batho ba qotsitsoeng ka bongata (ka ho le letšehali) le litheko tsa tlhaselo ea tlhonamo ea mabothobotho (ka ho le letona) ea li-neurons tsa mofuta oa 1 ho arabela ka tlase - (mola o khubelu; n = 9) le ho teba haholo (mohala o mofubelu; n = 9) sisinyeha liketsahalo. Mekoallo ea liphoso, sd; *P<0.05, ***P^-8, Seithuti t-etona.

doi: 10.1371 / journal.pone.0017047.g004

Ka mokhoa o ts'oanang, li-neuron tsa mofuta ona li bonts'itse karabelo e itšetlehileng ka karabelo ea nako ho liketsahalo tsa Shake (Setšoantšo sa 4C le D). Litekanyo tsa boholo ba tlatsetso ea offset e ne e le 374 ± 25 ms (bolela ± sd, n = 13), 672 ± 52 ms (n = 20) le 1169 ± 35 ms (n = 14) bakeng sa liketsahalo tse sisimosang tse ileng tsa nka 0.2, 0.5, le Sekethe sa 1, ka ho latellana (P<0.001, ANOVA ea tsela e le 'ngoe). Latela Seithuti sa tLiteko li bonts'itse phapang e kholo papisong ka 'ngoe (Setšoantšo sa 4D, phanele e nepahetseng). Leha ho le joalo, ho ne ho se na phapang e kholo litekanyetsong tsa tlhaselo ea litheko tsa offset nakong e fapaneng ea liketsahalo tsa Shake (P> 0.05; tsela e le 'ngoe ANOVA). Re boetse re fapane le matla a ketsahalo ea sisinyeho: li-neuron tsa mofuta oa 1 li bonts'itse tlhoro e nyane ea nyakallo ka likhahla tse matla tsa ho sisinya ha li bapisoa le tse matla haholo (Setšoantšo sa 4E le F; 29.1 ± 7.7 vs. 23.5 ± 9.5 Hz, bolela ± sd). Liphetho tsena tse kaholimo li fana ka maikutlo a hore likarabo tsa VTA mofuta-1 putative dopamine neurons lia lumellana le nako ea liketsahalo tse tšosang, le ho fihlela tekanyo e tlase, matla a liketsahalo tse tšosang.

Ntle le moo, nako e telele ea li-neurons tsa mofuta oa 3 le dopaminergic e tšoanang e ne e tsamaisana le nako ea liketsahalo tse tšosang. Ho arabela liketsahalong tsa ho oa ntle ho 10 le 30 cm (Setšoantšo sa 5A le B), linako tse qotsitsoeng e ne e le 251 ± 29 ms (bolela ± sd, n = 8), le 345 ± 33 ms (n = 10), ka ho latellana (P<0.001, ea Seithuti t-etete). Ho arabela liketsahalong tsa 0.2, 0.5 le 1 sec li sisinya (Setšoantšo sa 5C le D), linako tse hlahisitsoeng tsa mofuta oa li-neuron tsa mofuta oa 3 e ne e le 294 ± 53 ms (n = 10), 573 ± 80 ms (n = 9) le 1091 ± 23 ms (n = 7), ka ho latellana (P<0.001, ANOVA ea tsela e le 'ngoe). Latela Seithuti sa t-Tlhahlobo e bonts'itse phapang e kholo haholo papisong ka 'ngoe (Setšoantšo sa 5D, phanele e nepahetseng). Ha a arabela botebo bo fapaneng ba liketsahalo tsa ho sisinyeha, li-neurons tsa mofuta-3 li bonts'a tlhoro e phahameng ea ho makatsoa ke liketsahalo tse phahameng tsa ho sisinyeha ha li bapisoa le matla a tlase haholo (Setšoantšo sa 5E le F; 24.2 ± 4.6 vs. 15.5 ± 1.3 Hz, bolela ± sd).

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Setšoantšo sa 5. Karabelo ea li-neurons tsa VTA tsa mofuta oa 3 tsa dopaminegic ho ea ho linako tse fapaneng le matla a liketsahalo tse tšosang.

(A) Li-rasters tsa ketsahalo ea Peri-1 (liteko tsa 20-3) le li-histogram tsa mofuta o le mong-10 neuron ha li arabela ka 30 cm (ka letsohong le letšehali) le liketsahalo tsa mahala tsa XNUMX cm. (B) Kakaretso ea kakaretso ea li-peri-ketsahalo tsa sechaba tse qetehileng (ka letsohong le letšehali) le li-latency tsa offset (ka ho le letona) tsa mofuta oa mofuta oa 3 ho arabela ka 10 cm (mola o moputsoa; n = 8) le 30 cm (mola o khubelu; n = 10) Liketsahalo tsa ho oela mahala . (C) Li-rasters tsa ketsahalo le li-histogram tsa neuron e tšoanang (joalo ka ha li bonts'itsoe ho A) ha li araba 0.5 sec (ka ho le letšehali) le 1 sec (ka ho le letona) liketsahalo tse sisinyehang. (D) Kakaretso ea kakaretso ea li-peri-ketsiso ea baahi ba qotsitsoeng (ka letsohong le letšehali) le li-latency tsa offset (ka ho le letona) tsa mofuta oa mofuta oa 3 neurons ha li arabela ka sec sec: (line line; n = 0.2), 10 sec (blue line; n = 0.5), le 9 sec (red line; n = 1) sisinya liketsahalo. (E) Li-rasters tsa ketsahalo le li-histogram tsa mofuta o mong oa 3-neuron ha li arabela maemong a tlase (ka ho le letšehali) le liketsahalo tse phahameng (tse ka letsohong le phahameng) tse sisinyehang. (F) Pale ea liketsahalo tsa sehloho tsa batho ba qotsitsoeng ka bongata (ka ho le letšehali) le litheko tsa tlhaselo ea tlhonamo ea mabothobotho (ka ho le letona) ea li-neurons tsa mofuta oa 3 ho arabela ka tlase - (mola o khubelu; n = 5) le ho teba haholo (mohala o mofubelu; n = 5) sisinyeha liketsahalo. Mekoallo ea liphoso, sd; *P<0.05, ***P^-5, Seithuti t-etona.

doi: 10.1371 / journal.pone.0017047.g005

Ka bobeli, liphetho tsena li fana ka maikutlo a hore liphetoho tsa nakoana tsa ho thunya ha VTA putative dopamine neurons li tsamaellane hantle le linako tse khothatsang tsa liketsahalo tse tšosang, ka khatello e hatelletsoeng ea mofuta oa 1 le mofuta oa mofuta oa 2 le ho thunya ho hoholo ha mofuta oa 3 neurons. Liphetoho tsa bona tsa ho thunya li ka tsamaisana le botebo ba liketsahalo tse tšosang, empa ho isa tekanyong e fokolang.

Khokahano e kopantsoeng ea liketsahalo le maemo

Boko bo tloaetse ho etsa liphihlelo tsa bohlokoahali maemong a tikoloho, 'me sena ke' nete le bakeng sa boits'oaro bo bobebe. Tlhahisoleseling ea litaba e 'nile ea khothalletsoa hore e bohlokoa bakeng sa ho arabela ha li-dopamine neurons ho putsa likhau tse boletsoeng esale pele [26]. Re ile ra botsa hore na maemo a tikoloho a bile le seabo ho kenyeletsa liketsahalo tse mpe, 'me ka bohlokoa le ho feta, hore na li-neurons tsa VTA dopamine li ka arabela joang ho cue e tšoanang empa li hokahantsoe le maemo a ikhethileng a ka bolelang sephetho se fapaneng (mohlala, moputso khahlanong le sepheo se nyarosang) .

Kahoo, re ile ra etsa liteko tse ling moo litoeba li neng li le maemong a bosebeletsi (moputso ka bobeli le boemo bo khelohileng). Re sebelisitse molumo o le mong oa ho se nke lehlakore e le tšusumetso e hlophisitsoeng (CS) ea ho ikamahanya le maemo a ikhethileng (US, ebang ke pellet ea tsoekere kapa ho oa hoa mahala) libakeng tse fapaneng (Setšoantšo sa 6A). Re ile ra beha litoeba maemong a Pavlovian bakeng sa beke e le 'ngoe moo litoeba li ileng tsa amohela li-200 tsa XNUMX / li-US bakeng sa moputso le boemo bo fapaneng (bona Lisebelisoa le mekhoa). Kamora boikoetliso, litoeba li ile tsa ea sethaleng sa tsoekere ka potlako, hangata ka secha sa 3-10 (sec tse 4.3 ka karolelano) kamora ho qaleha ha molumo o boemo, empa ka ho hloka ts'ebetso ho sejana sa taolo se sa amohelang li-pellets tsa tsoekere. mofuta o ikhethang oa thuto ea moputso e amanang le ona (Setšoantšo sa 6B, sethala sa leqele). Ka lehlakoreng le leng, karabo ea molumo o neng o boletse esale pele ketsahalo ea ho oa mahala ka phapusing ea ho oela mahala, litoeba li bonts'itse kholo e matla ea morao ha e utloa molumo o theohileng (Setšoantšo sa 6B, sethala se nepahetseng), e ka bonts'ang ho qoba hoa phoofolo kapa boits'ireletso [27]. Likarabo tse phahameng tsa tšabo / ho tšoenyeha ho litoeba tsena li ile tsa bonahala hape ho tloha ho holofalitsoeng le ho choachoasela ka kamoreng ea ho oela mahala ho bapisoa le moputso kapa likamore tse sa nke lehlakore (Setšoantšo sa 6C).

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Setšoantšo sa 6. Ho sebelisa likhakanyo tsa tataiso ea Bi-bi-signals tse ntle le tse mpe ka molumo o tšoanang oa maemo maemong a fapaneng.

(A) Schematic ea paradigm ea liteko bakeng sa maemo a bitsang. Molumo o le mong (5 kHz, 1 sec) e sebelisitsoe hohle: e ne e bolela esale pele phepelo ea pellet ea tsoekere ka phapusing ea moputso (holimo); e boletse esale pele ketsahalo ea ho oela mahala ka phapusing ea ho oela mahala (bohareng); mme ha e a ka ea bolela letho ka phapusing ea ho se nke lehlakore (tlase). (B) Ka ho le letšehali, ho lieha ha mokhoa oa ho jella ka mor'a ho qalella ha molumo o theohileng o boletseng pelehi ea tsoekere. Ka ho le letona, litoeba li bontšitse ho phahama ho hoholo morao ka mora ho qala ha molumo o neng o boletse esale pele ketsahalo ea ho oela mahala. (C) Litloaelo tse joalo ka ho kheloha (khafetsa defecation le urination) tse phahamisitsoeng ka phapusing ea ho oela mahala ho bapisoa le moputso kapa kamore e sa nke lehlakore. Mekoallo ea liphoso, sem; n = 10; *P<0.05, **P<0.01, ***P<0.001, ea Seithuti t-etona. (D, E) Li-rasters tsa ketsahalo ea peri (liteko tsa 1 - 20) le li-histogram tsa mehlala e 'meli ea VTA putative dopamine neurons ha li araba molumo o tšoanang o neng o bolela esale pele ho tsamaisoa ha tsoekere (ka ho le letšehali), e ileng ea bolela esale pele ketsahalo ea ho oa mahala (bohareng), mme seo ha se a ka sa bolela esale pele eng kapa eng (ka ho le letona), ka karohano ea 1-2 h h pakeng tsa mananeo. (F) Kakaretso ea baahi ba theotsoeng maikutlo ba peri-ketsahalo ea mofuta oa 1 le ea 2 ea li-dopamine tsa karabelo ho arabela ka mokhoa o tšoanang oa boemo bo boletsoeng esale pele pellet ea tsoekere (phanele ea leqele; n = 16), e boletseng ketsahalo ea ho oa ntle ho tefo ; li-neuron tse 16 tse tšoanang le tse bonts'itsoeng papaling e ka letsohong le letšehali), mme seo ha se a ka sa bolela letho (phanele e nepahetseng; n = 10). Ho oa mahala, 30 cm e phahameng.

doi: 10.1371 / journal.pone.0017047.g006

Lirekoto tsa tšebetso ea Neuronal ka litoeba tsena tse maemong a tlase (kamora thupelo ea beke e le 'ngoe) li senoletse hore VTA putative dopamine neurons e ile ea arabela ka mokhoa o hlakileng ho boemo ba molumo bo boletseng esale pele pellet ea tsoekere ka phapusing ea moputso (Setšoantšo sa 6D, phanele e siiloeng). Ho khahlisang, li-neurons tsa VTA tse tšoanang le tsona li arabile ka mokhoa o tšepahalang ka molumo o tšoanang ha o ne o bolela esale pele ho oela mahala ka phapusing ea ho oela mahala (Setšoantšo sa 6D, phanele e bohareng). Ha molumo o tšoanang oa boemo bo ne o tlisoa ho litoeba ka kamoreng e sa nke lehlakore e neng e sa amane le ketsahalo efe kapa efe, ha e hlahise liphetoho tse kholo ho thunya (Setšoantšo sa 6D, phanele e nepahetseng).

Ka kakaretso, re tlaleha li-neurons tse 16 tsa tšabo (mofuta-1 le mofuta-2) tse tsoang ho litoeba tse neng li le tlas'a protocol ea maemo a ho batla. Li-neurons tsena kaofela li bontšitse keketseho e kholo ea litekanyetso tsa ho thunya kamora ho qaleha ha molumo o boemo bo neng bo boletse esale pele pellet ea tsoekere (Setšoantšo sa 6D-F, li-panels tse letšehali) (P<0.001, teko ea boemo bo saennweng ba Wilcoxon). Ho arabela molumo o ts'oanang o neng o boleletse ketsahalo ea ho oa ha mahala, halofo ea li-neurone (8/16) e bonts'itse phokotso e kholo ea sekhahla sa ho thunya (Setšoantšo sa 6D, sethala se bohareng) (P<0.05, teko ea boemo bo saennweng ba Wilcoxon), ha halofo e 'ngoe (8/16) e bonts'itse tlhoro e khuts'oane ea ts'ebetso (bonyane makhetlo a mabeli ho feta sekhahla sa ho thunya sa mantlha mme ka li-z-lintlha tse kholo ho feta 2) e lateloang ke khatello e kholo (Setšoantšo sa 6E, sethala se bohareng) (P<0.05, teko ea boemo bo saennweng ba Wilcoxon). Ho arabela molumo o ts'oanang o emeloang kamoreng e sa jeleng paate, ho bile le liphetoho tse fokolang kapa ha ho liphetoho lithunya (Setšoantšo sa 6D-F, liphanele tse nepahetseng). Liphetho tsena li fana ka maikutlo a hore mofuta oa 1 le mofuta-2 VTA putative dopamine neurons li ka kenya letsoho ka mokhoa o hlakileng matšoao a kopaneng le a seng matle (tlhahisoleseling e nang le boemo le tlhaiso-leseling e kopaneng) ka ho eketsa le ho fokotsa ho rata ha tsona, ka ho latellana.

Bohlokoa ba maemo ha a hlahisa likarabo tse fapaneng le tse ling ho ile ha bonahala hape ho li-neuron tsa mofuta oa 3 tsa dopaminergic-like. Mohlala, mofuta oa "neuron" o arabile haholo moelelong oa boemo bo neng bo amana le pellet ea tsoekere ka phapusing ea moputso (Setšoantšo sa 7A, sethala sa leqelekapa ho oela mahala ka phapusing ea ho oela mahala (Setšoantšo sa 7A, phanele e bohareng). Ka lehlakoreng le leng, e ne e sa bonts'e phetoho ea tekanyo ea ho thunya ha molumo o ne o bapaloa ka phapusing ea ho se nke lehlakore (Setšoantšo sa 7A, sethala se nepahetseng). Tlhahlobo ea palo ea baahi hape, e netefalitse hore li-neurons tsa mofuta ona 3 li eketsehile ho thunya ha tsona ka molumo o tšoanang meputsong le likamoreng tsa ho oela mahala (Setšoantšo sa 7B, likamore tse ka letsohong le letšehali le tse bohareng), empa eseng ka phapusing e sa nke lehlakore (Setšoantšo sa 7B, sethala se nepahetseng(P <0.05, Seithuti t-etete). Ka kopanelo, liteko tse kaholimo tsa tlhahlobo li bonts'a hore leseli le emeloang karolong ea VTA dopamine neuron le sebetsoa haholo mme le kopantsoe ka mokhoa o ts'oanelang ho hlophisa liketsahalo tse khothatsang kapa tse mpe tse khothatsang tse amanang le maemo a tikoloho.

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Setšoantšo sa 7. Likarabo tsa mofuta oa 3 oa dopaminergic-neurons ho li-signals tse ntle le tse mpe ka molumo o tšoanang oa maemo maemong a fapaneng.

(A) Li-rasters tsa ketsahalo (liteko tsa 1 - 20) le li-histogram tsa mofuta oa 3-neuron ha li araba molumo o tšoanang o boletseng tsoalo ea tsoekere ka letsohong le letšehali, tse boletseng esale pele ketsahalo ea ho oa mahala (bohareng), le tse sa kang tsa bolela esale pele eng kapa eng ka kamoreng e sa nke lehlakore (ka ho le letona). (B) Kakaretso ea kakaretso ea li-peri-3 tsa batho ba qotsitsoeng ba natefisoa ke mofuta oa 6 neurons (n ​​= 30) ha ba araba lentsoe le tšoanang le le boletseng tsoala ea tsoekere (ka ho le letšehali), e neng e profeta ketsahalo ea ho oa mahala (bohareng), mme e sa kang ea bolela letho ( le letona). Ho oa mahala, XNUMX cm e phahameng.

doi: 10.1371 / journal.pone.0017047.g007

Karabelo ea ho qala ho latency ea VTA dopamine neurons

Ka mor'a moo re ile ra itlhatlhoba hore na karabelo ea methapo ea methapo ea methapo e tla hlahisa moputso le liketsahalo tse tšosang hakae. Li-histogram tsa ketsahalo ea liketsahalo tsa 10 le 30 cm ea ho oa le liketsahalo tsa peri-ea liketsahalo tsa 0.2, 0.5, le 1 sec li ile tsa kopanngoa bakeng sa li-neurone tsa dopamine ka bomong bakeng sa lipalo tsa karabelo ea peleho ea karabelo. Karabelo ea ho qala karabelo e ile ea khethoa ka ho qala ho fumana sekhahla sa ho thunya ho bolelang (bolela) le ho kheloha ho tloaelehileng (sd) ho tsoa ho likheo tsa 1000 (bin = 10 ms) hang pele ho ho qala. Karabelo ea karabelo e ile ea nkuoa hore e be nako e tsamaellanang le moqomo oa pele oa bins tse tharo tse latellanang le Z-scores ≥2 kamora ho qala ts'ebetso. Ka lebaka la sekhahla se tlase sa ho thunya ha dopamine neuron, li-histogram tsa peri-tukio (bin = 10 ms) li ile tsa ntlafatsoa ka faele ea Gaussian (bophara ba filthara = 3 likotlo) bakeng sa lipalo tsa ts'ebetso ea ho qala ts'ebetso ea khatello nakong ea khatello. -1 le li-neurons tsa mofuta oa 2 ho oela ho oa, ho sisinyeha le CS e hlaselang.

Liphetho tsa rona li bonts'itse hore mofuta oa 1 le mofuta-2 putative dopamine neurons li bonts'itse karabelo e ts'oanang ea ho qala ho theoha ho oela le ho sisinya liketsahalo (90.6 ± 31.3 ms vs. 108.4 48.6 XNUMX ms; bolela mean sd) (Setšoantšo sa 8A le E). Mofuta oa mofuta oa 3 oa "dopaminergic-like" neurons le tsona li bonts'itse karabelo e ts'oanang ea ho qala liketsahalong tse peli tse tšosang (43.5 .20.6 46.8 ms vs. 24.2 ± 75.7 ms), hammoho le lisosa tse peli tse boemo bo tlase (19.0 ± 62.9 ms vs. 12.5 vs XNUMX ms ) ((Setšoantšo sa 8B, D le F). Ka lehlakoreng le leng, li-neurons tsa mofuta oa 1 le mofuta-2 li bonts'itse karabelo e telele ho feta (ea khatello) ho CS e phetoang ha e bapisoa le karabelo ea ho qala ts'ebetso (ea ts'ebetso) ho moputso CS (181.6 ± 51.9 ms vs. 67.1 ± 19.0 ms) (Setšoantšo sa 8C le E). Ka kakaretso, qaleho ea khatello ea khatello e ne e le telele ho feta tšitiso ea ho qala ts'ebetso ho papiso efe kapa efe (Setšoantšo sa 8E le F).

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Setšoantšo sa 8. Karabelo ea ho qala ho arabela ha li-neuron tsa VTA tse hlahisang dopamine.

(A) Likarabelo tsa ho qala karabelo tsa mofuta oa motho oa 1 le 2 dopamine neurons ho oela le ho sisinyeha ha liketsahalo. (B) Likarabelo tsa ho qala karabelo tsa mofuta oa 3-dopamine neurons ho lokoloha ho oa le ho sisinya liketsahalo. (C) Karabelo ea ho qala karabelo ea mofuta o le mong oa 1 le 2 dopamine neurons ho moputso oa CS o boletseng esale pele pellet ea tsoekere le CS ea boiphetetso e boletseng esale pele ho oa. (D) Karabelo ea ho qala karabelo ea mofuta o le mong oa 3-dopamine neurons ho moputso oa CS o boletseng esale pele pellet ea tsoekere le CS e phetetsang e boletseng esale pele ho oa. (E) Karolelano ea karabelo ea karo-karolelano ea palo ea batho ba qalang mofuta oa 1 le 2 dopamine neurons (ho tsoa ho data e ts'oanang le e bonts'itsoeng ho A le C) le (F) mofuta-3 li-neurons (ho tloha data e ts'oanang le e bonts'itsoeng ho B le D). Karabelo ea ho qala ho arabela ea li-neuron tsa mofuta oa 1/2 ho oa ho oa, ho sisinyeha le ho hloea CS ho tsamaisana le latency ea khatello; athe tse ling li tsamaellana le boits'oaro ba ts'ebetso. Mekoallo ea liphoso, sd

doi: 10.1371 / journal.pone.0017047.g008

Synchrony har'a sete e ikhethang ea VTA dopamine neurons

Kaha litekanyetso tsa dopamine libakeng tsa sepheo li 'nile tsa hokahanngoa le liphetho tse fapaneng tsa kelello, e bile ha nako e telele e nahana hore ho thunngoa ha li-neurop tsa dopamine ho ka emisa mochine oa neural bakeng sa ho sebelisa leano lena la lik'hemik'hale la neural [28], [29]. Khopolo ena e tšehetsoa ke lithuto tse bonts'ang hore li-subsets tsa dopamine neurons ka har'a substantia nigra pars compacta (SNc) li bonts'itse mosebetsi o kopantsoeng oa ho ikatisa [24], [30]. Ka ho sebelisa ho rekota li-tetrode tse ngata litekong tsa rona, re bile le monyetla oa ho lekola likamano tse matla lipakeng tsa li-putative dopamine neurons ka nako e le 'ngoe ho VTA (e nang le li-putative dopamine neurons tse ka bang hlano tse tlalehiloeng ka nako e le ngoe). Litlhahlobo tsa rona li senotse hore boholo ba li-putative dopamine neurons li bonts'a ho thunya ka nako e le 'ngoe, ho sa tsotelehe potoloho ea phoofolo ea ho robala (Setšoantšo sa 9). Mohlala, ho ikopanya ha likarolo tse peli tse tlalehiloeng tsa mofuta oa 1 tsa li-dopamine ho ne ho bohlokoa haholo (Setšoantšo sa 9A le B). Ho tloha tlhahlobisong ea li-database tse kopaneng, ka bongata, boholo (83%; liphahlo tse 48/58) tsa li-neuron tsa mofuta oa 1 tse tlalehiloeng ka nako e le ngoe li bontšitse khokahano ea bohlokoa (peak z-score> 11) ka fensetere ea nako e ka bang 100 ms ho sa tsotelehe hore na litoeba li itšoara ka bolokolohi kapa li robetse (Setšoantšo sa 9C). Ka mokhoa o ts'oanang, ho ne ho boetse ho na le khokahano ea bohlokoa lipakeng tsa nako e le 'ngoe tse rekotiloeng tsa mofuta oa 1 le mofuta oa 2 tse behelang dopamine neurons (Setšoantšo sa 9D-F). Ho tsoa ho mofuta o mong o tlalehiloeng oa mofuta oa 1 le mofuta-2 dopamine neuron, 75% (6/8) ea bona e bonts'itse khokahano ea bohlokoa ha litoeba li ne li phela ka bolokolohi kapa li robala (Setšoantšo sa 9F).

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Setšoantšo sa 9. Synchrony har'a sete e ikhethang ea li-neurons tsa VTA tse hlahisang dopamine.

(A) Li-rasters tsa ketsahalo ea Peri (liteko tsa 1-20) le li-histogram tsa li-neurons tse peli tse tlalehiloeng ka nako e le 'ngoe ka karabelo ea ketsahalo ea ho oa mahala, le (B) segokahano sa sefapano lipakeng tsa methapo ena e 'meli ea nama nakong eo panya e neng e phela ka bolokolohi. (C) Meetso e arolelanoang pakeng tsa li-neurons tse tlalehiloeng ka nako e le 'ngoe li-neurons tse 1 (lipara tse 48 nakong ea boitšoaro bo lokolohileng, le lipara tse 35 nakong ea boroko). (D) Li-rasters tsa ketsahalo le li-histogram tsa li-neurons tse peli tse rekotiloeng ka nako e le 'ngoe ka mofuta o le mong oa 1 ho arabela ketsahalo ea ho oa mahala, le (E) setšoantšo sa sefapano se pakeng tsa methapo ena e 'meli nakong ea boitšoaro bo lokolohileng. (F) Litšoantšo tse kopantsoeng pakeng tsa lifapano tse pakeng tsa 1 le li-neurons tsa mofuta oa 2 (lipara tse 6 nakong ea boitšoaro le boroko bo lokolohileng). (G) Li-rasters tsa ketsahalo le li-histogram tsa li-neurons tse peli tse tlalehiloeng ka nako e le 'ngoe ka karabelo ea ketsahalo ea ho oa mahala, le (H) setšoantšo sa sefapano se pakeng tsa methapo ena e 'meli nakong ea boitšoaro bo lokolohileng. (I) Meetso e arolelanoang pakeng tsa li-neurons tse tlalehiloeng ka nako e le 'ngoe li-neurons tse 3 (lipara tse 15 nakong ea boitšoaro bo lokolohileng, le lipara tse 12 nakong ea boroko). (J) Li-rasters tsa ketsahalo le li-histogram tsa mefuta e 'meli ea mofuta oa 1 le li-neurons tsa mofuta oa 3 (ka nako e le' ngoe li tlalehiloeng ho tsoa ho tetrode e le 'ngoe) ho arabela ketsahalo ea ho oela mahala, le (K) setšoantšo sa sefapano se pakeng tsa methapo ena e 'meli nakong ea boitšoaro bo lokolohileng. (L) Meetso e kopaneng ea sefapano pakeng tsa li-neurons tsa mofuta oa 1 le li-mofuta tsa 3 (lipara tse 12 nakong ea boitšoaro bo sa lefelloeng, le lipara tse 10 nakong ea boroko). Ho oa mahala, 30 cm e phahameng.

doi: 10.1371 / journal.pone.0017047.g009

Ntle le moo, khokahano ea bohlokoa e ile ea boela ea bonoa kahare ho palo ea 3-putative dopamine neuron ea sechaba (Setšoantšo sa 9G-I). Ho tsoa ho mofuta o mong le o mong oa mofuta oa 3 dopamine neuron e tlalehiloeng ka nako e le 'ngoe, karolo ea 79% (15/19) ea bona e bonts'itse khokahano ea bohlokoa (Setšoantšo sa 9I). Ka lehlakoreng le leng, ha li-neurons tsa mofuta oa 1 le li-neurone tsa mofuta oa 3, kapa mofuta-2 le mofuta oa 3 dopamine neurons (n ​​= lipara tse 12) li baliloe bakeng sa khokahano ea tsona ea sefapano, ha e hlahise tumellano efe kapa efe ea bohlokoa (Setšoantšo sa 9J-L). Hammoho, ts'ebetso e kopantsoeng har'a li-neuropine tsa "transopamine" tsa mofuta oa 1 le mofuta oa 2, hammoho le mofuta oa li-neurons tse tšabehang tse fanang ka maikutlo a hore li-transpoplication tse fapaneng tsa li-neuroprous dopamine li ka fumana litlatsetso tse fapaneng tse tsoang libakeng tse arohaneng tsa boko. hape e kopantsoe le likhokahano tse ikhethileng [25], [31], [32].

Puisano

Lirekoto le tlhahlobo ea rona tse kaholimo li fane ka bopaki ba karolo ea li-neurop tsa dopamine ho ts'ebetsong liphihlelo tse ntle le tse mpe. Re fumane hore VTA dopamine neurons e bonts'a thepa ea karabelo e fapaneng le boholo ba li-neuropine tsa "dopamine" tse fanang ka maikutlo li arabela moputsong oa bobeli oa moputso le tšabo. Leano lena la ho fetolela litaba le fetoletsoeng ke VTA dopamine neurons le khahla ha ho bapisoa le lipatlisiso tse bontšitsoeng ho litšoene tse tsohileng, tse bonts'ang hore li-dopamine neurons li ikhethile ka mokhoa o ikhethileng ka takatso ea lijo ho fapana le boleng bo susumetsang. [33]. Tsusumetso e matla e kang ho hula moea o sebelisitsoeng thutong ena ke tšusumetso e bonolo ha e bapisoa le liketsahalo tse peli tse tšosang tse sebelisitsoeng boitekong ba rona. Bafuputsi ba bang ba hlahisitse maikutlo a hore mokoallo o khathollang joaloka moea oa ho hula moea o ka 'na oa se ke oa bontša boleng bo bobe hobane litšoene li ka ithuta ho koenya kapa ho koala mahlo hore li se ke tsa susumetsa maikutlo. [9], [34]. Ka lehlakoreng le leng, lipatlisiso tsa morao-rao tsa litšoene tse falimehileng li bonts'a ho ba teng ha mefuta e fapaneng ea li-dopamine neurons ka har'a substantia nigra pars compacta (SNc) ea ho fetisa lipontšo tse ntle le tse mpe [5], [9], [19]. Ka hona, li-neuron tsa VTA le SNc dopamine li ka latela leano le kopaneng la ho fetolela phetisetso ea matšoao a khothatsang le a fosahetseng.

Ho VTA, phuputso e entsoeng pejana e bontšitse hore palo e fapaneng ea VTA putative dopamine neurons e ile ea kenngoa kapa ea hatelloa ke maemo a tšabo a fapaneng. [35]. Haufinyane tjena, ho tlalehiloe hore li-dopamine neurons tse karolong e kenellang ea VTA li ile tsa qaptjoa ke footshocks ho litoeba tse sa sebetseng [36]. Leha ho le joalo, lithuto tsena tse peli ha lia ka tsa hlahloba hore na li-neuropathy tse tšoanang tsa dopamine li tla etsa joang ho fumana moputso kapa liketsahalo tse ntle. Ka ho nka monyetla oa ho phela ka bolokolohi litoeba tsa rona tsa ho rekota, re ile ra hlahisa litoeba ka tse khothatsang le tse mpe mme ra fumana hore boholo ba li-neuron tsa VTA dopamine li amohela meputso le liphihlelo tse mpe.

Ho bohlokoa ho hlokomela hore mokhoa oa rona oa ho rekota oa extracellular oa hona joale ha o na bokhoni ba ho bona mefuta e fapaneng ea li-neuropel tsa "dopamine" tse teng tlhahlobong ea rona. Re hakanya hore mofuta oa 3 oa "dopaminergic-like neurons" tse tlalehiloeng tlhahlobong ea rona li bonahala li fumaneha ka kotloloho kapa ka ntle sebakeng sa VTA (Setšoantšo sa 1A, likhetla tse khubelu le tse pherese). Leha ho le joalo, ho ile ha hlokomeloa hore bonyane lipara tse 12 tsa mofuta oa mofuta oa 1/2 le li-neurons tsa mofuta-3 li tlalehiloe ka nako e le ngoe le maemong a 'maloa tse tlalehiloeng ho tsoa ho tetrode e le' ngoe (mohlala ,. Setšoantšo sa 3G; Setšoantšo sa 9J). Liteko tse ling tse hlokolosi tsa anatomic li kanna tsa hloka ho rarolla bothata bona. Leha ho le joalo, liphetho tsa rona tsa ho tsoha ka bolokolohi litoeba li ts'ehetsa mohopolo oa hore le ha boholo ba VTA putative dopamine neurons e bonts'a ts'ebetso e fokotsehileng, sehlopha se senyenyane sa li-neuron tse kang dopaminergic se ka kengoa ts'ebetsong ke liketsahalo tse mpe kapa tse khehlang. Mofuta oa 3-joaloka li-neuron tse kang dopaminergic tse tlalehiloeng tekong ea rona li arolelitse ho tšoana le mofuta-1/2 putative dopamine neurons ho fapana le li-non-dopamine neurons: mefuta eohle e meraro ea li-neuron e bonts'itse sekhahla se tlase sa ho thunya (0.5-10 Hz), e telele karohano ea li-inter-spike (> 4 ms) le paterone e tloaelehileng ea ho thunya. Ka lehlakoreng le leng, VTA non-dopamine neurons hangata e ne e bonts'a sekhahla se phahameng sa ho thunya (> 10 Hz) le molumo o matla oa motsamao [21]-[23]. Ho arabela liketsahalo tse tšosang tse peli, bongata ba li-neuron tsena tse seng tsa dopamine (> 70%) li bonts'itse ts'ebetso e kholo le ka mefuta e fapaneng ea mekhoa ea ho thunya ka nakoana. Mosebetsi o rarahaneng oa mantlha, hammoho le likarolo tsa karabelo ea li-neuron tsena tse seng tsa dopamine liketsahalong tse peli tse tšosang li kaholimo ho puisano mona.

Liphumano tsa rona tsa hajoale li boetse li fana ka leseli la lipale tse 'maloa mabapi le karolo ea VTA dopamine neurons ka bobeli ba sepheo se nepahetseng le se fosahetseng. Taba ea mantlha, li-neurons tsa VTA tse tlamang li-dopamine li arabela maemong a fapaneng a mabe ka mekhoa e tšoanang liphoofolong tse tsohileng. Ka mantsoe a mang, li-neurons tse arabileng ka ho oela mahala li ne li lula li arabela ka ho sisinyeha ka mokhoa o ts'oanang (khatello ea mofuta oa 1 le li-neurons tsa mofuta-2, ts'ebetso ea li-neurons tsa mofuta-3). Likarabo tse ikhethileng tsa liketsahalo tse mpe tse ka har'a mofuta o fanoeng oa li-neuron tsa VTA li tšoana le karabelo ea bona lipapatsong tse fapaneng tsa lipale le lipale tse amanang le moputso. [5], [37].

Karolo ea bobeli e hlokomelehang ke mofuta o matla oa phepelo e tlisoang ke "mofuta oa" dopamine neurons qetellong ea ho oela kapa ho sisinyeha ha liketsahalo. Tlatsetso ena e tlisoang ke liphoofolo tse nang le boits'oaro bo lokolohileng e ka kenyeletsa leseli le senang khutso nakong ea liketsahalo tse joalo tse tšosang. [38]-[40], empa mohlomong e fana ka mefuta e meng ea matšoao a susumetsang (mohlala, tšusumetso ea ho pholoha). Ho ka etsahala hape ka mokhoa o lekanang hore tšibollo ea offset-offound e ka bapala karolo ea bohlokoa ho kenyelletseng boits'oaro bo khahlisang (mohlala, lipapali tse feteletseng, ho palama ha Tower of Terror ho Disney World). Hoa hlokomeleha ho supa hore ts'ebetso ea "rebound activation" ea VTA dopamine e boetse e tlalehiloe ha ho felisoa ha sepheo sa "footshock" litotong tse sa sebetseng [36]. Leha ho le joalo, ho tla ba monate haholo ho tsoela pele ho hlahloba tšebetso ea ts'ebetso ea dopamine neuron mekhoeng e fapaneng ea boits'oaro.

Taba ea boraro, li-neurons tsa VTA tse hlahisang dopamine li bonts'a mesebetsi ea nakoana ea nakoana e lumellanang hantle le nako ea liketsahalo tse tšosang. Ts'ebeliso ea phetoho ea ts'ebetso ea nakoana bakeng sa ho kenyeletsa nako e ts'abehang ea ketsahalo e bonahala e utloahala hobane khatello e haella haholo ka lebaka la sekhahla se tlase sa ho thunya ha methapo e mengata ea dopamine. Sena sea khahlisa ha se bapisoa le seo ba se fumaneng hore dopamine neurons e bontša likarabo tse fapaneng tsa tlhoro ea boleng bo fapaneng ba meputso. [41]. Ha ho nahanoa mehloli e tsamaisang khatello ea methapo ea mofuta oa 1 le mofuta-2 dopamine neurons, liphuputso tsa morao tjena li fana ka maikutlo a hore methapo ea morao ea habenular nucleus (LHb) le GABAergic rostromedial tegmental nucleus (RMTg) li bapala likarolo tsa bohlokoa [42]-[45]. Taba ea mantlha, li-nuclei tsena li bonts'a likarabo tse hanyetsanang le tšusumetso e khahlisang kapa e faposang ha e bapisoa le likarabo tsa dopamine neuron ho tšusumetso e tšoanang. [42], [44]. Ntlha ea bobeli, li-neuron tsa dopamine li hatelloa ka matla ka mor'a ts'ebetso ea LHb kapa RMTg [43], [45].

La bone, re boetse re senola hore VTA dopamine neurons e ka bonts'a phetoho e fapaneng ka ho felletseng mesebetsing ea bona ke tšusumetso e tsebahalang ea ho supa moputso kapa liketsahalo tse tšosang tse etsahetseng tlasa maemo a ikhethileng (Setšoantšo sa 6). Sena se fana ka maikutlo a hore ts'ebetso ea neural e etsahalang maemong a VTA e kopantsoe haholo mme tlhaiso-leseling ke karolo ea bohlokoa ea ts'ebetso ea ho kenyeletsa bakeng sa liphihlelo tse ntle le tse mpe. Ho fumana hona ho lumellana le bopaki ba anatomical le li-hypotheses tse fetileng tsa hore li-neurons tsa VTA li fumana leseli le ntlafalitsoeng haholo ho tsoa ho likarolo tsa forebrain tse kang hippocampus le cortex ea pele. [37], [46]-[48]. Khokahano ena e phahameng ea boiphihlelo le liketsahalo liketsahalong tsa methapo ea methapo ea VTA e kanna ea hlalosa hore na ke hobaneng tikoloho e bapala karolo e kholo ho phahamiseng takatso kapa ho tiisa mekhoa.

Kamora nako, mekhoa ea rona ea ho rekota e ts'oanang e re lumelletse ho bonts'a khokahano ea bohlokoa pakeng tsa li-neurop tsa mofuta oa 1 le mofuta-2 putative dopamine, hammoho le har'a li-neurons tsa mofuta-3. Bohlokoa ba khokahano e joalo ea ho thunya e khahla haholo, ha ho nahanoa ka tlhophiso ea tlhophiso ea netweke ea VTA. Sena se fana ka maikutlo a hore VTA putative dopamine neurons e ka sebelisa merero e 'meli e lumellanang haholo ea ho ntlafatsa le ho tsamaisa phetisetso ea dopamine ebe ka tsela ena e fana ka phetoho e kopanetsoeng ea likarolo tse tlase joalo ka li-nucleus accumbens. Ho haelloa ke mosebetsi o kopantsoeng pakeng tsa mofuta oa 3 le li-neurons tsa mofuta oa 1/2 ho lumellana le liphapang tse ling tse ngata har'a tsona, ka bobeli li-electro-physiologically le pharmacologically (Setšoantšo sa 3). Haholo-holo, ho fapana le mofuta oa 1 le mofuta oa 2 oa li-dopamine neurons, hoo e ka bang kaofela (96%; 23/24) eo e bonts'a khatello e matla, li-neuron tsa mofuta oa 3 ho seng joalo li bonts'a boithabiso ke dopamine receptor agonists (Setšoantšo sa 3H). Hoa hlokomeleha hore li-neurons tsa "dopamine neurons" li tlalehiloe li sa ameha haholo kapa li sa angoe ke dopamine receptor agonist lithutong tse fetileng. Ke liphuputso tse fokolang feela tse tlalehileng hore li-neuron tse ling tsa dopamine li ka sebetsoa ke dopamine receptor agonists [24], [25], mohlomong hobane li-neuron tse butsoitseng li ne li mpa li nkuoa e le li-neuron tse se nang dopamine lithutong tse fetileng. Haholoholo, palo e nyane ea VTA dopamine neurons eo hape e leng TH-positive, ho tlalehiloe hore e qaliloe ke dopamine receptor agonist [25]. Liteko tsa nako e tlang, mohlomong li sebelisa optogenetics, li tla hlokoa ho netefatsa hore na li-neurons tsa mofuta oa 3 tse tšeretsoeng e ne e le dopamine neurons. 'Me ho amoheloa ha li-neurons tsa mofuta ona e le li-neuron tsa dopamine ho lokela ho ba hlokolosi ho fihlela joale.

Ka kakaretso, re bonts'a hore boholo ba VTA putative dopamine neurons bo khona ho arabela likarolong tsa moputso le tse tsamaeang le tšabo ka boikhohomoso. Li-neuron tsena tsa "dopamine neurative" li arabela liketsahalong tse fapaneng tse fapaneng ka mokhoa o ts'oanang 'me habohlokoa le ho feta, linako tsa tsona tsa nakoana tsa liphetoho tse tummeng tsa ho thunya li lekana le linako tsa liketsahalo tse tšosang. VTA putative dopamine neurons e boetse e kopanya lintlha le lintlha tse amanang le phapang pakeng tsa moputso le liketsahalo tse tšosang. Ha re kopantsoe hammoho, re fana ka maikutlo a hore VTA dopamine neurons e ka sebelisa leano la ho kenyelletsa barekisi maemong a marang-rang a batho bakeng sa ho sebetsana le liphihlelo tse ntle le tse mpe. Ho kenyelletsa maikutlo joalo ka boiphihlelo le hona ho kopantsoe haholo le lintlha le maemo a tikoloho ho matlafatsa boits'oaro bo itseng.

Lisebelisoa le mekhoa

Melao ea boits'oaro

Liphoofolo tsohle tse sebelisitsoeng thutong ena li ne li le ho latela lits'ebetso tse amohetsoeng ke Institutional Animal Care and Use Use Committee, Georgia Health Sciences University mme li ngotsoe tlasa protocol ea BR-07-11-001.

Lihlooho

Ho ne ho sebelisitsoe litoeba tse tona tse 71 tsa C57BL / 6J bakeng sa ho rekota 'me ka bonngoe li bolokiloe mochineng o lefifi oa 12-h / 12-h. Ke data feela e tsoang ho litoeba tse 24 eo re tlalehileng li-dopamine neuron tse sebelisang tlhahlobo ea hajoale.

Opereishene

Leqhubu la li-tetrode tse 32 (e leng sephutheloana sa li-tetrode tse 8), marang-rang (boima ba 'mele <1 g), mefuta e mengata ea eleketrode e tsamaeang e tsamaeang e hahiloe ka mokhoa o ts'oanang le o hlalositsoeng pejana [49]. Tetrode ka 'ngoe e ne e na le lithapo tse' ne tsa bophara ba 13-µm Fe-Ni-Cr (Stablohm 675, California Fine Wire; ka litšitiso tsa terata ea 2-4 MΩ bakeng sa terata e ngoe le e ngoe) kapa bophara ba 17- µm Platinamo (90% Platinum 10% Iridium, California Wine Fine; e na le litšitiso tse tšoanang le tse ling tsa 1-2 M3 bakeng sa terata e ngoe le e ngoe. Bekeng e le 'ngoe pele ho ts'ebetso ea ho buuoa, litoeba (li le likhoeli tse 6 ho isa ho tse 40) li ile tsa tlosoa mokotleng o tloaelehileng' me tsa bolokoa malapeng a etselitsoeng lapeng (20 × 25 × 80 cm). Ka letsatsi la ho buuoa, litoeba li ne li sa anngoe ka ketamine / Xylazine (12/3.4 mg / kg, ip); bokaholimo ba motlakase bo ile ba kenngoa ho VTA ka hemisphere e nepahetseng (0.5 limilimithara tse ka morao ho bregma, 3.8 mm lateral le 4.0 mm mm ho ea bokong bokong) mme e sirelelitsoe ka samente ea meno.

Tetrode Rekhoto le Li-Units Isatul

Matsatsi a mabeli kapa a mararo ka mor'a ho buuoa, li-elektrone li ne li hlahlojoa letsatsi le leng le le leng bakeng sa ts'ebetso ea neural. Haeba ho se na li-neuron tsa dopamine tse fumanoeng, lethathamo la li-electrode le ne le tsoetse pele ho 40 ~ 100 µm letsatsi le letsatsi, ho fihlela re ka rekota ho tsoa ho neuron ea putop dopamine. Ho rekota lirafshoa tse ngata li ne li tšoana le se hlalositsoeng pejana [49]. Ka bokhutšoanyane, li-spikes (tse tlhotliloeng ho 250-8000 Hz; li-digitized ho 40 kHz) li tlalehiloe nakong ea ts'ebetso eohle ea liteko ka ho sebelisa sistimi ea ts'ebetso ea Plexon multichannel processor processor (Plexon Inc.). Boitšoaro bo botle ba 'mele bo ile ba rekisoa ka nako e le' ngoe ba sebelisa sistimi ea ho ts'oara ea Plexon CinePlex. Li-spikes tse rekotiloeng li ile tsa qheleloa ka thoko ho sebelisa software ea Plexon OfflineSorter: Methati e mengata ea ho hlophisa li-spike (mohlala, tlhaiso ea likarolo, tlhahlobo ea matla) e ile ea sebelisoa bakeng sa karohano e ntle ka ho fetisisa ea li-waveform tse tlalehiloeng tsa tetrode. Ho kopanya botsitso ba mekhoa ea ho rekota ea li-tetrode tse ngata le mekhoa e mengata ea ho itšehla thajana e fumanehang ho OfflineSorter (mohlala, tlhaiso ea karolo ea motheo, tlhahlobo ea matla), li-neurons tsa VTA ka bomong li ka ithutoa ka lintlha tse ngata, maemong a mangata ka matsatsi (Setšoantšo sa S1).

Liketsahalo tse Tšosang

Liketsahalo tse peli tse tšosang, ho oela mahala (ho tloha ho 10 le 30 cm) le ho sisinyeha (bakeng sa 0.2, 0.5 le 1 sec), li entsoe ka mokhoa o sa reroang litekong tsa rona ka karohano ea lihora tse 1-2 pakeng tsa linako. Re ne re sebelisa sekwere (10 × 10 × 15 cm) kapa kamore e chitja (11 cm ka bophara, 15 cm ka bolelele) bakeng sa ketsahalo ea ho oa mahala. Re sebelisitse kamore e chitja (bophara ba 12.5 cm, bophara ba 15 cm) bakeng sa liketsahalo tsa ho sisinyeha. Sebokeng se seng le se seng sa ho oa kapa ho sisinyeha ha konopo, ho ne ho beoa panya ka setsing sa ho oela sa bolulo kapa ho sisinyeha (toeba e ka tsamaea ka bolokolohi kahare ho likamore). Kamora ho lula ka makhetlo a 3, liteko tse ka bang 20 tsa ho oa mahala (kapa ho sisinyeha) liketsahalo li ile tsa fanoa ka karohano ea metsotso e 1-2 pakeng tsa liteko. Kamore ea ho oela mahala e ile ea phahamisoa (e ka ba bolelele ba 10 cm kapa 30 cm) mme e hokelloa ho sistimi ea solenoid (Magnetic Sensor Systems, Series S-20-125) pele ho ketsahalo e 'ngoe le e' ngoe ea ho oa mahala. Ketsahalo ea ho oa mahala e ile ea fanoa ka ho fana ka taolo e nepahetseng ea mochine (WPI, PulseMaster A300) ea sisteme ea solenoid ho lokolla ropo e emisitsoeng. Kamore ea mahala e oeleng ka nako eo e ile ea fihla setulong se bobebe se ileng sa fokotsa likhahla haholo le ho thibela lits'enyehelo tse ka bang teng tsitsitseng ea ho rekota (Litšoantšo S2 'me S3). Nako ea ho oa ha mahala e baliloe ka equation: T = SQRT (2 × h / g), moo h e leng bolelele ba ho oa ha mahala, mme g ke ho potlakisa matla a khoheli a lefats'e. Ha ho nahanoa ka ho lieha ho lula ka nako e telele, likhakanyo tse hakantsoeng tsa ho oa ha 10 le 30 cm mahala e ne e le 230 le 340 ms, ka ho latellana. Ketsahalo ea ho sisinya e ile ea fanoa ka ho fana ka taolo e nepahetseng ea mochini oa vortex mochini (Thermolyne Maxi Mix II Type 37600 Mixer) ka lebelo le phahameng la 3000 rpm hohle ntle le haeba e le matla a tlase, a neng a ka ba 1500 rpm.

Kamehla re ne re lekola botsitso ba diyuniti tse rekotiloeng ka ho hlahloba likarolo tsa seiketsetso, boemo ba ho hlaseloa ka motheo, le kabo ea lihlopha tsa lihlopha pele le liketsahalong le kamora liteko. Re mpa re kenyelletsa lethathamo la lintlha tse tsoang liphoofolong tse fihletseng litekanyetso tsena tsa ho rekota bakeng sa tlhahlobo-leseling ea data. Joalokaha ho bontšitsoe Litšoantšo S1, S2, 'me S3, li-neuron tsa dopamine tse thathamisitsoeng thutong ea morao-rao li ne li tlalehiloe haholo 'me li arotsoe hantle nakong ea ho oa ka bolokolohi le ho sisinyeha ha liketsahalo, ntle le tahlehelo ea nakoana ea yuniti kapa lerata / tšilafalo ea maiketsetso.

Haholo-holo re nkile mehato e meraro ho netefatsa hore li-spikes ha li na tšilafalo ke lisebelisoa tsa maiketsetso: 1) Re fokotse ts'itiso ea ho rekota ka ho theola lisebelisoa tsohle tsa liteko. Re fumane hore lisebelisoa tsa motlakase tse hlahisitsoeng nakong ea ho oa le ho sisinyeha ha liketsahalo mahala li ne li le boemong bo ts'oanang le ba nakong ea phuputso ea locomotor. 2) Re boetse re hlakolotse lisebelisoa tsa khale tse entsoeng ke Moreki oa Plexon Referencing tse re lumelletseng ho khetha mocha o se nang likarolo tse shebahalang hantle joalo ka seterata sa boits'oaro. Sena se ile sa tlosa lerata le litumelo tsa khale haholo. 3) Haeba ho ne ho setse li-waveform tse ling tsa maiketsetso, re tla li tlosa nakong eo ho neng ho etsoa liphetoho tsa li-spike waveforms tse sebelisang Plexon Offline Sorter hobane li -formform tsa li-syntact wave li ne li fapane haholo le li-waveform tsa neuronal spike.

Boemo ba moputso le Bi-mwelekeo

Limpisi li ne li thibetsoe lijo pele ho koetliso ea mokhatlo oa moputso. Boemong ba moputso, litoeba li ne li beoa ka phapusing ea moputso (bophara ba 45 cm, bolelele ba 40 cm). Litsi li ne li koetliselitsoe ho kopanya molumo (5 kHz, 1 sec) le ho tsamaisoa ha pellet ea tsoekere bonyane matsatsi a mabeli (liteko tsa 40-60 ka letsatsi; nako ea metsotso e 1 pakeng tsa liteko). Molumo o hlahisitsoe ke moetsi oa letšoao la molumo oa A2-12 (33-ms e bopehileng le ho oa; hoo e ka bang 5 dB bohareng ba kamore) (Lisebelisoa tsa Coulborn). Pellet ea tsoekere (80 mg) e tsamaisoa ke setsi sa lijo (ENV-14-203P, Med. Associates Inc.) mme ea oela ho e 'ngoe ea likhakanyo tse peli (14 × 12 × 7 cm) ho felisoa ha molumo (e mong sesebelisoa se ne se sebelisoa e le taolo, moo pellet ea tsoekere e sa kang ea amoheloa).

Ka mokhoa o fapaneng oa liteko, litoeba li ile tsa koetlisetsoa maemo a mahlakore a mabeli (moputso ka bobeli le boemo bo ferekanyang). Molumo o nang le maemo (5 kHz, 1 sec) o sebelisitsoeng o ne o tšoana, empa maemong a fapaneng: nakong ea boemo ba moputso (kamoreng ea moputso; cm cm 45, bophara ba 40 cm), molumo o ne o tsamaisoa ka phutho ea tsoekere; nakong ea maemo a phallang (ka phapusing ea ho oela mahala), molumo o tšoanang o ne o pentiloe ka ketsahalo ea ho oa mahala (30 cm high). Limpisi li ile tsa koetlisoa beke e le 'ngoe kapa ho feta' me tsa hanyetsoa: halofo ea litoeba tsa fumana moputso ka matsatsi a 1 le a 2, tsa lateloa ke maemo a pherekano ka matsatsi a 3 le 4 (liteko tsa 40-60 ka letsatsi); halofo e 'ngoe ea litoeba e ile ea amohela maemo ka a 1 le a 2, ea lateloa ke maemo a moputso ka matsatsi a 3 le 4 (liteko tsa 40-60 ka letsatsi). Ka matsatsi a 5 le kamora moo, ho ile ha fanoa ka likarolo tse tharo ka nako e le ngoe ka tatellano, ho kenyelletsa moputso, boemo bo sa tsitsang, le kamore ea boraro e sa nke lehlakore (20 × 30 × 55 cm e neng e ruisitsoe ka lintho tsa ho bapala. ) moo modumo o sa kang oa bolela letho. Nako e pakeng tsa mananeo e ne e le lihora tse 30-30; karohano lipakeng tsa liteko e ne e le 1-2 metsotso. Tsela ea latency ea tsoekere / taolo ea ho amohela kamora ho qaleha boemo bo hlophisitsoeng e ile ea hlahlojoa ka letsatsi la 1. Litekanyetso tse telele ho feta 2 sec li ne li nkuoa e le sec sec; ntlheng ea hore panya e ne e le kahare ho kamohelo nakong ea molumo oa boemo, latency e ne e sa sebelisoe bakeng sa lipalo. Boitšoaro ba mokokotlo oa mokokotlo (hlooho le / kapa maoto kapa matsoho a sisinyehelang morao) kamora ho qala molumo o boemo bo ile ba boela ba hlahlojoa ka letsatsi la 7.

Netefatso ea Histori ea Sebaka sa Rekoto

Kamora liteko, boemo ba li-electrode ba ho qetela bo tšoailoe ka ho fetisa 10-sec, 20-µA ea hona joale (Stimulus Isolator A365, WPI) ka li-electrode tse peli. Lintsu li entsoe ka mokhoa o tebileng li bile li entsoe ka letsoai la 0.9% le lateloang ke 4% paraformaldehyde. Ka nako eo, li-brains li ile tsa tlosoa tsa ba tsa beoa kaholimo ho paraformaldehyde bonyane 24 h. Mabili a ile a hoamisoa ka potlako le ho khangoa ka sekontiri se bitsoang cryostat (likarolo tse 50-µm tsa coronal) mme a entsoe ka cresyl violet. Liteko tsa nalane li ile tsa etsoa ka litoeba tse 21 (ka litoeba tse ling tse 3 likarolo tsa boko li ne li sa lokisoe hantle). Liphetho tsa rona tsa histology li netefalitse hore li-dopamine neurons li tlalehiloe ho tsoa sebakeng sa VTA ka litoeba tse 17 le ho tsoa sebakeng sa moeli oa VTA-SNc ho litone tse 4 (Setšoantšo sa 1A).

Boitsebiso ba Lintlha

Li-spikes tsa neural tse hlophisitsoeng li ile tsa sebetsoa le ho hlahlojoa ho NeuroExplorer (Nex Technologies) le Matlab. Dopamine neurons li ile tsa aroloa ho latela lintlha tse tharo tse latelang: 1) sekhahla se tlase sa ho thunya (0.5-10 Hz); 2) karohano e telele ea li-inter-spike (li-classified putative dopamine neurons tsohle li na le li-ISI> 4 ms kahare ho boemo ba boits'epo ba -99.8%). ISI e khuts'oane haholo eo re e tlalehileng e ne e le 4.1 ms tlasa maemo afe kapa afe tekong ea rona (ho ne ho sebelisoa feela likarolo tse ikhethileng tse nang le bophahamo -0.4 mV bakeng sa ho bala ISI e khuts'oane). Li-ISIs tse khutšoane ka ho fetesisa e ne e le 6.8 ± 2.2 ms (Mean ± sd; n = 36). Ka lehlakoreng le leng, ISI ea li-neuron tse seng tsa dopamine e ka ba khuts'oane joalo ka 1.1 ms; 3) mokhoa oa ho thunya khafetsa ha litoeba li ne li itšoara ka bolokolohi (ho feto-fetoha ha maemo <3 Hz). Mona, ho feto-fetoha ha maemo ho emela ho kheloha ho tloaelehileng (sd) ea litekanyetso tsa ho thunya tsa histogram bar (bin = 1 sec; e tlalehiloeng bonyane metsotsoana e 600). Ntle le moo, ho ile ha hlokomeloa hore boholo (89%; 56/63) ba li-dopamine neurons tse hlophisitsoeng ba lekiloeng ba bonts'itse ts'ebetso e kholo ho arabela molumo oa moputso oa ho bolela esale pele (Setšoantšo sa 2E le F). Ho ile ha boela ha hlokomeloa hore boholo ba sehlopha sa "dopamine neurons" se khethollotsoeng (70%, 23/33; mofuta-1 le 2) se bontšitse khatello ea bohlokoa (≤30% basiling kiwango cha ho thunya) le tse ling tsa 27% mofuta-3 neurons (n = 9) e bonts'itse ts'ebetso (Setšoantšo sa 3H). Ka lehlakoreng le leng, li-neurons tsa VTA tse se nang dopamine li bontšitse phetoho e fokolang kapa e se nang palo ea ho thunya ke dopamine receptor agonists (Setšoantšo sa 3I). Linoko tse halofo tsa AP ea li-spike waveforms li ile tsa lekanngoa ho tloha meqobong ho isa litlhōrōng tse latelang tsa bokhoni ba ts'ebetso (Setšoantšo sa 1B). Halofo ea bophara ba AP e pharalletseng ho feta 0.8 ms e ne e nkuoa e le 0.8 ms. Bakeng sa palo ea monyetla oa ho thunya ha methapo ea dopamine neuron, ts'ebetso ea mantlha ha litoeba li ne li itšoara ka bolokolohi li ne li sebelisoa ho latela litekanyetso tse fetileng tse qalileng (qaleho e qalang, ISI ea -80 ms; offset e phatlohileng, ISI ea ~ 160 ms) [50].

Liphetoho tsa ts'ebetso ea Neuronal ho maemo a amohetsoeng le a se nang maemo a ne a bapisoa le nako ea taolo ea 10-sec pele ho qaleho ea ts'usumetso tekong e 'ngoe le e' ngoe ka fensetere ea nako e khethiloeng (ho ipapisitse le linako tsa ts'usumetso) o sebelisa tlhahlobo ea sebaka sa Wincoxon e saenneng. Bakeng sa liketsahalo tsa ho oa ntle ho 10 le 30 cm, lifensetere tsa nako e ne e le 100-230 le 100 ms kamora ho qala ketsahalo ea ho oa mahala, ka ho latellana; bakeng sa liketsahalo tsa 340, 0.2 le 0.5 sec tse sisinyehang, lifensetere tsa nako e ne e le 1-100, 200-100, le 500-100 ms kamora ho qala ketsahalo ea Shake, ka ho latellana (ho hlokometsoe hore mefuta e 'maloa-1000/1 putative dopamine neurons , ~ 2%, e boetse e bonts'itse ts'ebetso e nyane nakong ea 10 ms ea pele hang kamora ho oa ho oa le ho sisinyeha ha liketsahalo tsa mahala). Bakeng sa maemo a moputso, fensetere ea nako e ne e le 100-50 ms ka mor'a ho qaleha ha molumo oa boemo; bakeng sa maemo a feto-fetohang, fensetere ea nako e ne e le 600-200 ms ka mor'a ho qaleha ha molumo oa boemo.

Li-rasters tsa ketsahalo ea Peri (liteko tsa 1 - 20, ho tloha holimo ho ea tlase) le li-histogram li ile tsa etsoa ho NeuroExplorer (Nex Technologies). Litsela tsohle li ile tsa etsoa ka har'a NeuroExplorer li sebelisa sefahleho sa Gaussian (bophara ba li-= = bins). Litlhakiso tsa sefapano li ne li etsoa lipakeng tsa li-dopamine neuron ka nako e le 'ngoe ha litoeba li ne li phela ka bolokolohi (ntle le tšusumetso ea kantle) kapa ho robala lapeng. Bakeng sa lipalo tsa z-lintlha tsa boleng ba tlhapano ea sefapano, nalane ea sefapano sa khokahano e ntlafalitsoe ho fumana boleng bo phahameng; litlolo tse mpe le tse tloaelehileng li fumanoe ho li-spikes tsa shuffled (randomized) ho Matlab [51]. Hoa hlokomeleha hore likarolo tse kopaneng li emela li-neurone tsa dopamine tse fapaneng ho fapana le li-neuron tse tšoanang. Re laetse monyetla oa hore likarolo tse kopaneng li tlalehiloe ho tsoa kapa li silafalitsoe ke neuron e le 'ngoe (ha ho etsahala, ho tla ba le tlhoro e phahameng ka nako e le ngoe mohlolohali oa ~ 1 ms sebakeng sa ~ 100 ms joalo ka ha ho bonts'itsoe ho Setšoantšo sa 9).

Ho tšehetsa Boitsebiso

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feiekabelo ea

jarolla

Li-neuron tsa VTA dopamine li tlalehiloe ka mokhoa o tsitsitseng 'me li arotsoe hantle. (A) Mohlala oa mofuta o ikemetseng oa mofuta oa 1 dopamine neuron (matheba a maputsoa) ho Hlahloba ea Karolo ea Bohlokoa ea likarolo tse 2 le li-waveforms tsa eona tse emetseng (tse tlalehiloeng ke tetrode) ka letsatsi la 1 (konopo e kaholimo) le letsatsi la 2 (phanele e tlase) . Ho ikarola ka Spike ho ile ha etsoa ho sebelisoa Plexon OfflineSorter (Plexon Inc. Dallas, TX). PC1 le PC2 li emela likarolo tsa mantlha tsa bobeli le tsa bobeli, ka ho latellana. Matheba a maputsoa a emela spikes ka bomong bakeng sa neurop e ka thoko ea dopamine; matheba a matšo a bontša li-spikes ka bomong tsa li-neuron tse ling tsa VTA. (B) Mohlala oa mofuta o ikemetseng oa mofuta oa 2 dopamine neuron (matheba a maputsoa) le li-waveforms tsa moemeli ka letsatsi la 1 (konopo e kaholimo) le letsatsi la 2 (phanele e tlase). (C) Mohlala oa mofuta o ikhethileng oa 3-dopamine neuron (matheba a maputsoa) le li-waveforms tsa eona tse emelang ka letsatsi 1 (phanele e kaholimo) le letsatsi la 2 (phanele e tlase).

Setšoantšo S1.

Li-neuron tsa VTA dopamine li tlalehiloe ka mokhoa o tsitsitseng 'me li arotsoe hantle. (A) Mohlala oa mofuta o ikemetseng oa mofuta oa 1 dopamine neuron (matheba a maputsoa) ho Hlahloba ea Karolo ea Bohlokoa ea likarolo tse 2 le li-waveforms tsa eona tse emetseng (tse tlalehiloeng ke tetrode) ka letsatsi la 1 (konopo e kaholimo) le letsatsi la 2 (phanele e tlase) . Ho ikarola ka Spike ho ile ha etsoa ho sebelisoa Plexon OfflineSorter (Plexon Inc. Dallas, TX). PC1 le PC2 li emela likarolo tsa mantlha tsa bobeli le tsa bobeli, ka ho latellana. Matheba a maputsoa a emela spikes ka bomong bakeng sa neurop e ka thoko ea dopamine; matheba a matšo a bontša li-spikes ka bomong tsa li-neuron tse ling tsa VTA. (B) Mohlala oa mofuta o ikemetseng oa mofuta oa 2 dopamine neuron (matheba a maputsoa) le li-waveforms tsa moemeli ka letsatsi la 1 (konopo e kaholimo) le letsatsi la 2 (phanele e tlase). (C) Mohlala oa mofuta o ikhethileng oa 3-dopamine neuron (matheba a maputsoa) le li-waveforms tsa eona tse emelang ka letsatsi 1 (phanele e kaholimo) le letsatsi la 2 (phanele e tlase).

doi: 10.1371 / journal.pone.0017047.s001

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Setšoantšo S2.

Ha ho tahlehelo ea nakoana ea yuniti nakong ea ho oa ha mahala le ho sisinya liketsahalo. (A) Likarabo tsa tse 'ne tsa VTA dopamine le li-non-dopamine neurons ka nako e le ngoe nakong ea liketsahalo tsa mahala tsa ho oa. Hlokomela hore likarolo tse tlalehiloeng ho tetrode e le 'ngoe li ka hlahisa likarabo tse fapaneng (mohlala, tetrode # 5 unit 1 & 2; tetrode # 8 unit 1 & 2), ho fana ka maikutlo a hore ho rekota ho ne ho tsitsitse ntle le tahlehelo ea nakoana ea li-unit. (B) Likarabo tsa li-neurone tse 'ne tsa VTA nakong ea liketsahalo tsa ho sisinya. (C) Mefuta e emelang maqhubu a li-neurone tse tšoanang tsa VTA 1 h pele, nakong ea ho oa ka bolokolohi le ho sisinya ketsahalo ea ketsahalo, le hora e le 'ngoe kamora moo.

doi: 10.1371 / journal.pone.0017047.s002

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Setšoantšo S3.

Ha ho lerata / tšilafalo ea maiketsetso nakong ea ho oela mahala le ho sisinya liketsahalo. . Hlokomela hore li-waveform ha li a bonts'a phetoho ea bohlokoa kamora ho oa le ho oa ketsahalo ea mahala, ho fana ka maikutlo a hore ha ho na lerata / tšilafalo ea maiketsetso. .

doi: 10.1371 / journal.pone.0017047.s003

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lumela hore baa fokola

Re leboha Ngaka Rhea-Beth Markowitz ka ho hlophisa buka e ngotsoeng ka letsoho le Kun Xie ka ho fana ka tšehetso ea mahlale.

Menehelo ea Mongoli

Rea tseba le ho hlophisa liteko: DVW JZT. O entse liteko: DVW. Hlahloba data: DVW JZT. Ngola pampiri: DVW JZT.

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