Ukusabalalisa kwe-Optogenetic ye-prefrontal cortex circuitry ephakathi (2014)

Ulwazi lomlobi ► Isihloko se-Article ► Ulwazi lobunikazi nelayisense ►

Lesi sihloko siphelile okukhulunywe ngu ezinye izihloko ku-PMC.

I-medial prefrontal cortex (mPFC) ibandakanyeka ngokuningiliziwe emisebenzini eminingi yokuqonda, kufaka phakathi ukunakwa, ukulawulwa kokuvimbela, ukwakheka komkhuba, inkumbulo yokusebenza nememori yesikhathi eside. Ngaphezu kwalokho, ngokuxhumana kwayo okukuxubana nezifunda ezingaphansi (isib, i-thalamus, i-striatum, i-amygdala ne-hippocampus), i-mPFC kucatshangwa ukuthi inamandla okuphatha okuphezulu ngaphezulu kokulawula okwenzelwa ukuvusa inkanuko nokuthokozela. Ngoba i-mPFC ifakwe umfutho ekucutshungweni kwezinhlobonhlobo zezinto ezishukumisayo nezingokomzwelo, kucatshangwa ukuthi isebenza njengesixhumi esimaphakathi ekubonakaleni kwezimpawu zokuphazamiseka kwengqondo kwengqondo. Ubuchwepheshe obusha be-optogenetics buvumela i-anatomical and functional dissection yokujikeleza kwe-mPFC ngokulungiswa okungakaze kube khona kwendawo nokubamba okwesikhashana. Lokhu kuhlinzeka ngemininingwane ebalulekile yenoveli ekunikeleni kwe-neuronal subpopulations ethile kanye nokuxhumeka kwabo ekusebenzeni kwe-mPFC ezifundweni zezempilo nezifo. Kulesi sibuyekezo, sethula ulwazi lwamanje olutholwe ngezindlela ze-optogenetic eziphathelene nomsebenzi we-mPFC kanye nokusebenza kwengqondo bese sihlanganisa lokhu nokutholwa okuvela ezindleleni zokungenelela kwendabuko ezisetshenziselwa ukuphenya ukujikeleza kwe-mPFC ezimodeli zezilwane zokucubungula ingqondo nokuphazamiseka kwengqondo.

Ukuhlelwa kwe-cytoar ye-mPFC

Inethiwekhi ye-mPFC yendawo iqukethe amaseli e-pyramidal ejabulisayo (i-80-90% yenani eliphelele) kanye nama-inhibitory GABAergic interneurons (10-20% yesibalo sabantu), womabili lawo angahlukaniswa futhi ahlukaniswe izinhlobo ezahlukene zeseli ngokususelwa ku-morphological, izakhiwo zomzimba kanye nama-molecule (Ascoli et al., 2008; DeFelipe et al., 2013). Ama-subtypes afundwe kahle we-GABAergic interneuron afaka phakathi kwe-perisomatic kwelitshe okusheshayo kwe-spiking parvalbumin (PV), kanye ne-dendritic kwelitshe somatostatin (SOM) interneurons. Ama-interneurons we-PV anentshisekelo ethile yomtholampilo, njengoba amanani awo aziwayo ukuthi ancipha kwiziguli ze-schizophrenia (okuxoxwe ngazo ngezansi) (uBeasley noReynolds, 1997; Lewis et al., 2005). Lezi zinhlobo zombili ze-interneuron zinamandla okulawula ukujikeleza kwasendaweni, ngoba ziyakwazi ukuvumelanisa umsebenzi we-spiking wamaseli we-pyramidal akhiqiza ama-neuronal oscillations (Kvitsiani et al., 2013). Izithombe ezikhethiwe zokuxhumana kwe-ChR2-expression PV kanye ne-SOM ku-mPFC yegundane kuboniswe ukukhiqiza izimpendulo zesifunda ezihlukile (Kvitsiani et al., 2013). Ama-neurons eParvalbumin atholakale elawula ukuphuma kwe-neurons eyinhloko ye-pyramidal, njengoba bekhipha isivinini esikhulu, esinamandla futhi esivumelana ngokufanayo ekuqhumeni iseli eyinhloko (uKvitsiani et al., 2013; I-Sparta et al., 2014). I-Somatostatin neurons ngakolunye uhlangothi iguqule okokufaka okutholakele i-nepyramidal neurons kanye nomphumela we-inhibitory photos of synchronous photostimulation of these neurons were weak, more variable and kutambeka isikhathi eside (Kvitsiani et al., 2013). Izindlela ze-optogenetic ziqinisekisile ukuthi umnikelo obucayi wokudubula we-GABAergic interneuron ukudubula kwe-gamma nokuziphatha okungokomzwelo (ama-Vertes, 2006; Cruikshank et al., 2012; I-Yizhar, 2012; Omncane noCarter, 2013). Ama-neuron we-Pyramidal ku-ungqimba V (bheka ngezansi) we-mPFC angabonakala njengamasudi aminyene, amaseli wokuqasha ngokungenamkhawulo futhi njengamaseli amancane, ama-projektha akhiqiza amandla amakhulu (i-Dembrow noJohnston, 2014). Ukuguqulwa kwe-optogenetic kuveze ukuthi amangqamuzana afaka ngokungenamkhawulo ngendlela eyehlukile ahlukanisa ama-subtypes futhi akhombise ukuthi ama-PV interneurons prehibntially inhibit subcortically projimenti ye-pyramidal neurons (Lee et al. 2014a). I-Ptyramidal cell subtypes nayo ingahlukaniswa ngokususelwa ekuvezweni kwe-dopamine D1 noma i-dopamine D2 receptor (D1-R ne-D2-R), lapho ama-neurons we-D1-R efakwe kulawulo lokudla ngokusetshenziswa kwe-optogenetic ekhethiwe yalesi sigaba ( Umhlaba et al., 2014).

Izendlalelo nokuxhumeka kwe-mPFC

Inhlangano ye-laminar ye-rodent mPFC ihluke kancane kunakwezinye izifunda ze-cortical, ezinobubanzi obuhlukile bokufaka u-IV (Uylings et al., 2003). Ukuqagela okusebenzayo kwama-cortice agudwini ezindaweni ezingaphansi komhlaba avela ezingxenyeni ezijulile ze-V ne-VI, futhi ukuxhumana kwe-cortico-cortico kwe-granular kwenziwa ikakhulukazi ngama-neurons ezingxenyeni ezingaphezulu II kanye no-III (Douglas noMartin, 2004). I-rodent mPFC kodwa-ke ayinalo ungqimba lwe-IV yokufaka (i-Uylings et al., 2003). Ngaphezu kwalokho, zombili izingqimba ze-mPFC ezijulile nezingaphezulu zithola ukufakwa kobude obude kusuka ezifundeni ze-cortical and subcortical kanye nephrojekthi kuya kwezinye izakhiwo (ze-limbic) (Sesack et al., 1989; UGabgt et al., 2005; I-Hoover ne-Vertes, 2007).

Iphethini le-laminar linemiphumela ebalulekile ekucutshungweni kwesiginali ku-mPFC. Ukuqagela okungafani okuvela ezifundeni ezinamandla kanye ne-cortical ikakhulukazi kugxile ezingxenyeni ezingaphezulu kwe-I ne-II / III (i-Romanki et al., 1999). Okwesikhathi eside, izingqinamba zobuchwepheshe ziphazamise ukwakhiwa kwemephu kokuxhumeka okusebenzayo, njengoba ukunqwabelana komgogodla ne-axic nericonal akuvezi ukuxhumeka okusebenzayo futhi ukuqoshwa okubhangqiwe akulungile ekuhlolweni kokuxhunyaniswa kobubanzi obude (uPetreanu et al., 2007). Ngaphezu kwalokho, iningi okokufaka okudala uhla okujabulisayo kubekwa ezicucwini ezibucayi, kuthikameza ukukalwa ngogesi. Ukwenza kusebenze kwe-optogenetic ye-ChR2-echaza isiphetho se-presynaptic kubonise ukuthi ungqimba II PLC pyramidal neurons ithole okufakwayo okuvela ku-mPFC yesivumelwano, i-midline thalamic nucleus (MTN), basolateral amygdala (BLA), ne-ventral hippocampus (HPC; Little and Carter, 2012). Le micu yokufaka iguqulwe ezindaweni ezihlukile zokuhlobisa, ezivame ukubikezelwa kabi nge-anatomy kuphela, futhi ukuxhumeka kukhombisa ukwenzelela kokuphindaphindeka kwezinhlaka zomthamo ohlukile (Little noCarter, 2012). Njengoba ivolumu yomgogodla iphakanyisiwe ukuthi ihambisane namandla e-Posynaptic yamanje (EPSC; Humeau et al., 2005), lokhu kufakwa kahle kwe-anatomical nokwenziwe kahle kuxhumanisa indawo kahle i-mPFC ukuze ihlanganise futhi idlulise imininingwane evela emithonjeni ehambelana nayo ekhethekile. Zombili i-dmPFC ne-vmPFC zixhumene kakhulu ne-thalamus (Gabbott et al., 2005; Vertes, 2006). Ukuxhumana kwe-Thalamocortical kubalulekile kuzinqubo zokulamula zokuqonda, ukuqonda, nokwazi (John, 2002; U-Alitto no-Usrey, 2003). Ngaphezu kokufaka kwe-thalamic okutholwe nge-ungqimba II neurons (Encane neCarter, 2012), ama-neuron e-thalamic aguqukela ku-mPFC ungqimba lwama-neuron nawo akhonjwe ngama-optogenetics (Cruikshank et al., 2012). I-Photostimulation ye-thalamocortical projekthi eqhamuka ku-midline kanye ne-paralaminar thalamic nuclei iqhube izimpendulo ze-synaptic ezisheshayo nezingamasendlalelo engxenyeni ye-interneurons ye-late-spiking, eyayithokozela kakhulu kunamaseli we-pyramidal (Cruikshank et al., 2012). Lezi zinkampani zangaphakathi kwangaphakathi zakwazi ukuhambisa i-feed phambili ekuvinjelweni kwamaseli we-pyramidal ungqimba II / III (Cruikshank et al., 2012). Ngokuphambene, ukusebenza kwe-pharmacological ye-ungqimba I-interneurons ye-neocortical isebenzisa i-cholinergic agonists akuzange kunqande ukuphazamisa phambili kokudla (uChristophe et al., 2002). Ngaphezu kwalokho, izimpendulo ze-synaptic ze-mPFC interneurons zazisekelwa phezu kwe-photostimulation ephindaphindwayo yokuqagela kwe-thalamocortical (Cruikshank et al., 2012). Lokhu okutholwe yi-optogenetic kusikisela ukuthi ama-neuron we-thalamocortical projektha ayakwazi ukushayela ukudluliselwa esikhathini esilingana nesikhathi (imizuzu), esidingekayo ekusebenzeni inkumbulo yokusebenza (okuxoxwe ngayo ngezansi).

Izigatshana ze-mPFC nazo zixhunyaniswa ngokuxhunyaniswa (Heidbreder and Groenewegen, 2003). Ukuxhumana phakathi kwe-ILC ne-PLC kuhlolwe izindlela zokulandela umkhondo futhi muva nje futhi ngamathuluzi we-optogenetic (Vertes, 2004; UJi noNegebauer, 2012). UJi noNegebauer bakhombisile ukuthi ukwenziwa kwezithombe kwamangqamuzana e-pyCidal e-ILC kunciphise izinto ezizenzelayo nezishukumisayo kumaseli we-pyramidal e-PLC, okungenzeka ukuthi alawulwa yi-feed phambili inhibition (Ji and Neugebauer, 2012). Ngokuphambene nalokho, zombili izinto ezenziwa ngokuzikhulula nezishukumisayo ku-ChR2 eveza isendlalelo se-neuron se-pyramidal se-ILC sanda sanda lapho kusebenze ukusebenza kwalaba bantu be-neuronal, ngaphandle kokuthinta i-ILC inhibitory neuron spiking behaviour (Ji and Neugebauer, 2012). Njengoba iphrojekthi ye-ILC ne-PLC ihlukile kunobuchopho futhi inezindima ezihlukile ezinqubweni eziningi, kufaka phakathi ukuzijwayeza, ukuvezwa kwesimo sokuziphatha kanye nokuziphatha umlutha (Killcross noCoutureau, 2003; Vertes, 2004; UVan den Oever et al., 2010; I-Sierra-Mercado et al., 2011), le ndlela ingavumela i-ILC ukuthi ivimbele ukuphuma kwe-PLC, ngenkathi isebenze ngasikhathi sinye izifunda zayo eziqondisiwe.

I-mPFC iphrojekthi kakhulu kwezinye izifunda zobuchopho kanye ne-subcortical, eyenza ukuthi ikwazi ukulawula imisebenzi ye-visceral, automatic, limbic and cognitive (Miller and Cohen, 2001; I-Hoover ne-Vertes, 2007). Ukulandelela izifundo kukhombise ukuguquka kwe-dorsoventral eceleni kwe-mPFC kusuka ezifundeni ezigxile kakhulu kwe-sensorimotor ye-dmPFC kuya ezifundeni ze-limbic target ze-vmPFC (Sesack et al., 1989; I-Hoover ne-Vertes, 2007). Ukuqagelwa kwe-Glutamatergic kwe-mPFC kumgogodla we-nucleus accumbens (NAc) negobolondo kuchazwe kahle futhi kwaqinisekiswa izindlela zokusebenzisa i-optogenetic (Britt et al., 2012; USuska et al., 2013). Ngokuthabisisayo, nge-microinjection yesekeli elithembele ku-ChR2 AAV eDlxi12b :: Amagundane eCre, uLee et al. (I-2014c) unikeze ubufakazi bokuthi kukhona ama-mPFC GABAergic neurons anebanga elide le-NAc. Lokhu kukhombisa ukuthi akuwona wonke ama-Gabaergic neurons ahlala ku-mPFC angama-interneurons asendaweni. Ngaphezu kwalokho, ukuqagela kwe-glutamatergic PLC kwi-BLA kufundwe kusetshenziswa ubuchwepheshe be-optogenetics. Le ndlela kucatshangwa ukuthi ibalulekile ukuhlanganisa ukucubungula okuphezulu kwengqondo nezimpendulo zangaphakathi zemizwa (Yizhar, 2012), inqubo esetshenzisiwe ekuphazamisweni kwemizwa (embozwe imininingwane eminingi engezansi). Omncane noCarter (2013) i-optogenetically iqonde ku-PLC ungqimba II futhi ikhombe izigaba ezimbili ezihlukile zeseli zephiramidi ngaphakathi kwalolu ungqimba ezingaphrojusa ku-mPFC yesivumelwano noma kwi-BLA. Lama-neurons wokuqagela we-PLC ayefana ezintweni zomzimba nezomzimba, ukuhlolisisa ukuhlolwa komsebenzi wawo wesifunda. I-Photostimulation ye-mPFC yesivumelwano noma i-BLA ChR2-ekhipha iziteshi ezivezwa ngokunqotshwa okune cell-cell okuqoshwe i-mPFC noma i-BLA ephumeza ama-pyramidal neurons iveze ukuthi i-BLA to BLA-proing PLC neurons ikhombisa ukuxhumana okunamandla kwe-synaptic. Ukuhanjiswa kwe-synaptic okuthuthukisiwe kule ndlela kuhlanganiswe nokuqina kokuqina komgogodla, umthamo omkhulu womgogodla nokuqondiswa kwe-synaptic. Ngaphezu kwalokho, okokufaka kwe-BLA kuhloselwe umgogodla eduze kwe-soma ye-PLC-BLA neurons, ekwazile ukuhola ama-EPSC anamandla kunokuqagela okuqondiswe ku-dendrite (Little and Carter, 2013). Ukuqagelwa kwe-PLC-BLA futhi kubhekise ingcosana yama-interneuron we-GABAergic e-BLA, okuthi kwezinye izimo kudale ukuvimbela okuphambili kokudluliselwa kwe-GABAergic (Hübner et al., 2014). Lokhu kuhlangana okuyingqayizivele phakathi kwe-PLC ne-BLA kungavumela ukuxhumana okusebenzayo okuqondile okuphathelene nokuxhumana, okungabaluleka ngokulawula okuphezulu kokuphendula ukuphendulwa yimizwelo.

Lokhu kuphenywa kokuqala kukhombisa amathuba angafani we-optogenetics wokuhlola ukujikeleza kwe-mPFC ezingeni lamaseli ngamanye, ukuxhumeka kwe-intra-mPFC kanye nokuqagela okude nokuhambisana. I-Photostimulation kumalungiselelo wesikebhe oshisayo kuyindlela efaneleke kakhulu yokuxhuma ukuxhumana kokusebenza kokulinganisa nokukala izakhiwo ze-synaptic phakathi kwabantu abahlukahlukene be-neuronal. Kodwa-ke, ukuthola ukuthi ukuxhumana okuthile kubandakanyeka yini ngenqubo yokuqonda ecacisiwe, vivo modulection of umsebenzi we-neural uyadingeka. Ezigabeni ezilandelayo, sizodingida okutholakele kokungenelela kwe-optogenetic ekuhambeni kwezilwane ngokukhululeka.

Ukusebenza kokusebenza kwememori, ukuqwashisa nokulawula okwesikhashana

Ukusebenza kwememori kuyinqubo eyinkimbinkimbi yobuchopho ebhekisa kwisitoreji solwazi sesikhashana (isikali sesikhathi semizuzwana kuya kumizuzu) esidingekayo ekusebenzeni kwengqondo (Baddeley, 1992). I-mPFC ifakwe umfutho kule nqubo njengoba kutholakale ukuthi ukwenziwa kwe-pharmacological okuphinde kusebenze kwememori yokusebenza ye-PLC okhubazekile yokusebenza (Gilmartin and Helmstetter, 2010). Ukusebenza kwememori yokusebenza kungavivinywa kusetshenziswa umsetyenzana wokuhambisa isimo sokusaba, lapho isikhuthazo esinemibandela silandelwa yisikhuthazo esingaphenduki ngemuva kokulibaziseka kwemizuzwana eminingana. Ama-neuron angaphambili ayaziwa ukuthi akhombisa ukudubula okuphikelelayo ngesikhathi sokulibala (Gilmartin and McEchron, 2005), okuphakamisa indima ye-mPFC ekugcineni izethulo zesikhuthazo esinezimo ngenkathi kubambezeleka. Kodwa-ke, ubufakazi bokubangela kwesidingo somsebenzi we-mPFC we-neuronal obamba ukubambezeleka buvele buhlinzekwe nje ngokungenelela kwe-optogenetic. UGilmartin et al. (2013) iveze i-ArchT kuma-neurons e-PLC (isebenzisa umgqugquzeli we-CAG ongakhethi) ukuvumela ukungavinjelwa ikakhulukazi ngesikhathi sokulibala somsebenzi wokulandela umkhondo wokulandela umkhondo. Ngempela, i-photoinhibition ngesikhathi sokulibala kokufunda okungahambi kahle kwenhlangano phakathi kwesikhuthazo esinemibandela futhi esingenamibandela, okuqinisekisa ukuthi i-spC yama-neurons ye-PLC iyadingeka ekusebenzeni ukusebenza kwememori ngesikhathi sokulandela isimo sokwesaba. Umsebenzi ohlukile wokulinganisa ukusebenza kwememori yokusebenza kuwumsebenzi obambezelayo we-alternation, lapho izilwane zishintshana nabashintshi be-lever ngokubambezelela kusengaphambili ukuthola umvuzo (Dunnett et al., 1999). Izilonda ezi-Excitotoxic kanye nokuqanjwa kwemithi kwe-mPFC kutholakala ngqo ekutholakaleni kanye nesisho somsebenzi obambezelekile ngokubambezeleka ngokubambezeleka isikhathi eside, okubonisa ukuthi umsebenzi we-MPFC ubalulekile lapho izimfuno zememori yokusebenza ziphakeme (i-Rossi et al., 2012). Izilonda ze-ventral striatum noma i-dorsal hippocampus, izindawo ezixhunywe kakhulu ne-mPFC, aziholelanga ekunciphiseni ukusebenza kokubambezeleka okubambezelekile. Ngokubalulekile, ukusebenza kwe-ChR2-Mediated activation kwe-PV ku-PLC ngokukhetha phakathi kokubambezeleka nakho kusebenza kabi kakhulu kulo msebenzi (i-Rossi et al., 2012). Ngokubambisana, lezi zifundo zibonisa ukuthi umsebenzi we-PLC uyadingeka ekusebenzeni kwememori ukusebenza futhi akhombisa ukuthi ukuthwebula izithombe kwe-PV interneurons kungalingisa imiphumela ye-lesion engapheli kanye ne-pharmacological inactivation ngendlela yesikhathi nangendlela yesikhashana.

Ukusebenza kwememori yokusebenza kwe-mPFC kulungiswa amasistimu amaningana we-monoamine, kufaka phakathi uhlelo lwe-Noradrenaline ne-dopamine (DA) (Rossetti neCarboni, 2005; URobbins noRobert, 2007). Ngesikhathi sokukhumbula ukusebenza kwendawo, ama-extracellular noradrenaline akhuphuka kwi-mPFC kanye nokukhuthaza okwenziwe ngamakhemikhali kwe-adrenoreceptors ye-alpha-2A ku-PLC ithuthukise ukusebenza kwememori yokusebenza (i-Rossetti neCarboni, 2005; URamos et al., 2006). Isebenzisa i-optogenetics, kutholakale ukuthi ukufakwa kwesithombe kwe-ChR2-eveza ukuqagela kwe-noradrenergic kusuka ku-locus coeruleus kwavuselela ukudubula okuphikelelayo, isilungisi seselula sememori yokusebenza, ku-PLC kanye ne-ACC pyramidal neurons, ebilawulwa ngokusebenza kwe-presynaptic alpha1 ne-postsynaptic alpha2 adrenXeptum ZrenXeptor ZrenXeptors et al., 2013). I-cortical noradrenaline ayigcinanga ukusebenza kumemori yokusebenza kuphela, kepha kukholakala ukuthi ihambelana kakhulu nezindawo ezinakwa, ukuphaphama nokuvuselela (iBerridge, 2008). Carter et al. (2010) isebenzise ukungenelela kwe-optogenetic ukuvusa ngokunembile ukudluliswa kwe-noradrenaline nokutadisha ithonya layo ekuqapheleni kumagundane. Ukukhanya kwe-NpHR-expression locus coeruleus noradrenergic neurons kunciphise ukuphaphama ngesikhathi sokusebenza kwesilwane futhi kwabangela ukwehla kwamazinga we-extracellular noradrenaline ku-mPFC. Ngokuhambisana nalokhu, i-tonic ne-phasic photostimulation ye-ChR2-eveza i-locus coeruleus neurons ikhiqize izinguquko ngokushesha zokulala nokuvuka. Kuyathakazelisa ukuthi ukwenziwa kwe-tonic kukhuphule umsebenzi we-locomotor ojwayelekile, kanti ukwenziwa kwe-phasic kube nomphumela ohlukile. Ngaphezu kwalokho, ukwenziwa kwesithombe okuvama kakhulu (> 5 Hz) kwe-locus coeruleus neurons kuvuse isimo sokuboshwa kokuziphatha. UCarter et al. (2010) bonisa ukuthi lo mphumela wokugcina ungadonswa wukuncipha kwezitolo ze-mPFC noradrenaline, njengoba isikhathi eside ukuthathwa kwezithombe ze-noradrenaline ku-mPFC, futhi ukuboshwa kokuziphatha kutholwe yi-Noradrenaline reuptake inhibitors. Lolu cwaningo oluhle lukhombisa ukuthi ukukhishwa kwangaphambili kwe-noradrenaline kuklanywe kahle ukuze kuthonye ukuphaphama, noma umehluko ocashile ube nemiphumela ebalulekile ekuguqukeni kokuvuka komuntu nokuvuka.

Imemori yokusebenza isebenza kubhekwa njengemelela inkumbulo yezinzwa ezimbili zemizwa ezihlukaniswe ukulibaziseka. Ukulandelela isikhathi noma inkumbulo yesikhathi esichaziwe ngesikhathi sokukhishwa kwemizuzwana kucatshangwa ukuthi kubandakanya uhlelo lwewashi langaphakathi, lapho ukujikeleza kwe-mPFC nakho kuye kwaba nomthelela khona (uKim et al., 2013). Ikakhulu, ukuhanjiswa kwe-DA ku-mPFC kuye kwagcizelelwa esikhathini sokuphumula okuchaziwe kusetshenziswa umsebenzi wesikhathi sesikhathi esimisiwe (Drew et al., 2003). Ocwaningweni lwakamuva, ukudluliselwa kwe-D1-R ku-mPFC kuboniswe ukuthi kunendima ebucayi yokulawulwa kwesikhashana kokuqondisa kufinyelela kugoli (umvuzo) ngesikhathi sokuchazwa sesikhathi (Narayanan et al., 2012). I-Pharmacological blockade ye-D1-R, kepha hhayi i-D2-R e-ILC kanye ne-PLC eyonakalisiwe yesikhashana yokulawula ukuphendula emsebenzini wesikhathi sokunqunyelwe. Ukusekelwa kwendima ethile ye-D1-Rs, i-NpHR-Mediated inhibition optical ye-mPFC D1-R eveza ama-neurons okhubazekile wesikhathi sokusebenza sesikhathi esinqunyelwe (i-Narayanan et al., 2012). Ngokumangalisa, i-ChR2-Mediated stimulation of D1-R neurons ngesikhathi sokugcina se-10 s sokuphumula kwe-20-s kuthuthukisiwe ukuphendula kuphela ku-20 s. Ngokusekelwe kulobu bufakazi, ababhali baphikisana nokuthi uhlelo lwe-mPFC D1 lulawula ukulawulwa kwesikhashana kokuziphatha okuqondiswe kunhloso, kunokufaka ikhodi yokuhamba kwesikhathi.

Naphezu kwentuthuko enkulu eminyakeni yamuva, kuningi okusamele kufundwe mayelana nokufakwa kwengqondo kwe-neurobiological yememori yokusebenza nemisebenzi ehlobene ngokuqhathanisa ukungenelela kwe-optogenetic ye-mPFC emisebenzini ehlukene ngaphakathi kwesilwane esifanayo. Lokhu kufanelekile, ngokwesibonelo, ukuhlola okufana nokwehlukana kwezindlela zokujikeleza ze-mPFC ezilawula isikhathi sokuphumula nokusebenza kwememori yokusebenza. Ukudutshulwa kahle kwe-mPFC D1 ne-neurons kuqondise ngokulawulwa okuqondayo kwesikhashana kokuqondisa okuqondiswe ekuphenduleni, kepha noma ngabe (umsebenzi ogciniwe) walesi sakhi se-neuronal uyadingeka futhi ekusebenzeni kahle kwenkumbulo yokusebenza okusetshenziswayo (i-Narayanan et al., 2012; UGilmartin et al., 2013). Ngaphezu kwalokho, yize izindlela zokusebenzisa ngobuqili zibonisa ukuthi uhlelo lwe-mPFC cholinergic lubambe iqhaza elibalulekile kwimemori yokusebenza (Chudasama et al., 2004), ngaphakathi kwe-mPFC, lolu hlelo lwe-neurotransmitter aluzange luqondiswe ngqo kubuchwepheshe be-optogenetics.

Ukufunda, inkumbulo kanye nokuqothulwa

I-mPFC icatshangelwa ukuthi inamandla okusebenzisa ukuqonda okulawula ukuphendulwa okushukumisayo okungaphendukiyo nokunomvuzo ngokuhlanganisa imininingwane ephathelene nezimo kanye nemicimbi enokuhlangenwe nakho (u-Euston et al., 2012). Iparadigm yesimo sokwesaba iyimodeli yezilwane esetshenziswa kabanzi ukutadisha ukufunda nokusebenza kwememori, kanye nokuqothulwa kwezinkumbulo ezitholakele zokuthola ukwesaba (i-LeDoux, 2000; IMilad neQuirk, 2012; UMaren et al., 2013). Izindima ezithile ze-subareas ze-mPFC sezisunguliwe ekuvezweni kwememori yokwesaba enesimo, ngezindawo ezingena dorsal ezifaka phakathi ukufakwa phakathi kwezwi kanye nencazelo yememori yokwesaba nezindawo ezi-ventral ezineqhaza ekuhlanganiseni nasekuboniseni inkumbulo yokuqothula (Peters et al., 2009; UCortin et al., 2013). Lokhu okutholakele kusekelwa izilonda, ama-inactivations wemithi kanye vivo ukuqoshwa kwesikiki (uMorgan noLeDoux, 1995; IMilad neQuirk, 2002; UCortin et al., 2013). Kodwa-ke, ucwaningo ngegalelo lesikhashana lezinto ezithile zokujikeleza kwe-mPFC selisunguliwe muva nje. Isebenzisa optogenetics, uCortin et al. (2014) isungule ukuthi ukuvimbela kwe-phasic of dmPFC PV interneurons kugcizelela ukwesaba, njengoba kuhlolwa ngokuziphatha kweqhwa kupharadesi elisebenza ngokwesaba. Baqale bakhombisa ukuthi umsebenzi wokuqanjwa okuthile kwe-GABAergic interneurons uvinjiwe ngesikhathi kwethulwa khuthazo olunesimo oluhambisana nokuthuthumela konyawo. Okulandelayo, lokhu kususwa kukhonjwe njenge-interneurons ye-PV, ngoba i-ChR2- ne-ArchT-mediated modulection modical ye-PV neurons, ngokulandelana, ukuvezwa noma ukuhanjiswa kwesimo sokukhathazeka okunemibandela. Ngokumangazayo, ukuvimbela kokubona kwalezi zinzwa futhi kwavuselela indlela yokuziphatha kweqhwa ngaphambi kwesimo sesimo sokukhathazeka kanye nokubuyiselwa kwenkulumo yokwesaba ngemuva kokuqeqeshwa kokuqothula (uCortin et al., 2014). Bathole ukuthi impendulo yokuphendula ngokwesaba ye-PV neuron ilawulwa ngokusetha kabusha i-oscillations yesigaba se-mPFC kanye nokukhipha disinhibition kwamaseli we-pyramidal aqala ukusebenza kwi-BLA, ngokusekelwa kwendima yokuqagela kwe-mPFC-BLA ekuphatheni ngokomzwelo. Lolu cwaningo luphinde lwakhomba inani lesibili labantu abangena ngaphakathi kwe-inhibitory ekhombisa ukwanda komsebenzi ngesikhathi sesaba. Ababhali bacabanga ukuthi lokhu kusatshalaliswa kungavimba ama-PV interneurons futhi kuthola okokufaka okuvela ezifundeni zobuchopho (isib. I-hippocampus, BLA) eqhuba isisho sokusaba (uCortin et al., 2014), isithasiselo esithandekayo esisafanele sidingidwe ngocwaningo lwekusasa. Ukuqothulwa kokusatshiswa okunemibandela kuhambisana nokuncipha kokudluliselwa kwamandla kwe-mPFC kumaseli we-BLA pyramidal, kepha akuzange kuthinte ukuphuma kwe-GABAergic BLA interneurons kanye namaseli ahlanganyele, njengoba kuboniswa kusetshenziswa ama-optogenetics (Cho et al., 2013). Njengomphumela, ukulinganisela / kokuvinjwa (i-E / I) kule ndlela kungenzeka kuguqulwe, kuthanda ukunqandwa futhi kuholele ekucindezelweni kwempendulo yokwesaba isimo (Cho et al., 2013). Lezi zifundo ze-optogenetic ziqinisekisa iqhaza le-dmPFC ekushayeleni izimpendulo zokwesaba futhi zivuselele umnikelo wesikhashana wokuqanjwa kwe-GABAergic interneurons kulokhu kuziphatha. Ucwaningo oluthokozisayo nguLee et al. (I-2014c) kubonise ukuthi ukuthathwa kwezithombe kwamaphrojekthi we-GABAergic mPFC aqhamuke ku-NAc kuhoxile ekugwemeni indawo yangempela, okubonisa ukuthi le ndlela yenoveli ingalawula nokuphendula okushukumisayo.

Ukuziphatha komkhuba

Imisebenzi ichazwa njengamaphethini wokuziphatha angazwisi kuzinguquko zenani lomphumela. Ukuziphatha okujwayelekile kulawulwa ngokuhlukile yi-mPFC subareas; kanti i-PLC ikhuthaza ukuguquguquka, ukusebenza kwe-ILC kuvimbela ukuguquguquka futhi kuthuthukise ukuqina kokuziphatha (Killcross neCoutureau, 2003). Ucwaningo lwangaphambilini luveze ukuthi i-lesion kanye ne-cosacological inactivation ye-ILC yenza ushintsho kusuka ekuphenduleni kokuya kokuphendula okuguqukayo (Coutureau and Killcross, 2003). Ukulawulwa kwesikhashana kwama-neuron e-ILC ekuziphatheni okungumkhuba kuqinisekisiwe futhi kwahlaziywa ngokuguqulwa okuphindaphindekayo kwe-optogenetic modulation. Izithombe ezimfishane zamaseli we-pyramidal we-ILC avimbele ukwakheka nokuchazwa kokuziphatha okujwayelekile, kepha impendulo elandelayo yokuziphatha yayixhomeke esikhathini sokuvinjelwa (uSmith et al., 2012; USmith noGraybiel, 2013). Kulezi zifundo, indlela yokuziphatha ejwayelekile ihlolwe ngokuqeqesha amagundane ukuze ithole umvuzo ngomsebenzi we-T-maze obonakalayo. Ukulandela ukweqa ngokweqile, amagundane awazange azwakale ekubambeni phansi komvuzo. Izilwane ziyaqhubeka nokuziphatha okuqondiswe emgomweni lapho amaseli we-pyramidal e-ILC ethululwa ngokuphelele lapho kwenziwa umkhuba, kepha kwathi lapho umkhuba usuveziwe ngokuphelele, isithombe sanyusa indlela entsha. Ngaphezu kwalokho, lapho i-photoinhibition iphindwa ngenkathi kwenziwa lo mkhuba omusha, izilwane zaphinde zaveza umkhuba wokuqala (uSmith et al., 2012). Lokhu kushintshwa okusheshayo phakathi kokuziphatha okujwayelekile kukhombisa ukuthi ngisho nokuziphatha kwe-semiautomatic kulawulwa yi-cortical ngenkathi kwenziwa. Isifunda esiqondiswe ku-ILC esivumelana nokushintsha phakathi kwemikhuba asikakhonjwa kuze kube manje, kepha ukuqagela ku-dorsolateral striatum kuyisithakazelo esithile, njengoba iphethini efanayo yomsebenzi wespike yabonwa kuzo zombili lezi zifunda ngemuva kokuqalwa komkhuba (uSmith noGraybiel, 2013). Ngokusekelwe kulobu bufakazi, ababhali baphakamise ukuthi ukuthuthukiswa kokusebenza okujwayelekile kunqunywa ngokulingana komsebenzi we-sensorimotor striatal kanye nomsebenzi we-ILC obonisa ukubaluleka. Ngokuthabisisayo, izingqimba ze-ILC ezingaphezulu kuphela ezilingisa umsebenzi we-spiking ku-dorsolateral striatum (uSmith noGraybiel, 2013), sigcizelela isidingo sokusebenzisa i-ungqimba- nendlela yendlela ecacisiwe ye-optogenetic ukuze ufunde izigaba zomkhuba ngokuningiliziwe.

Ukucindezeleka

I-Major Depression Disorder (MDD) ingenye yokuphazamiseka kwengqondo okubhebhetheka kakhulu, okucatshangelwa ukuthi kuthinta cishe i-5% yabantu bomhlaba wonke futhi ngenxa yalokho kubhekwe njengembangela ehamba phambili yokukhubazeka emhlabeni jikelele (World Health Organisation, 2012). Izinqubo zokuxilongwa kwe-Major Depression Disorder diagnost zifaka isimo sokudangala kanye ne-anhedonia (ukuncipha kwekhono lokuthola injabulo) eqhubeka isikhathi eside futhi ethinta nakho kwempilo yansuku zonke (American Psychiatric Association, 2013). Ngaphezu kwalokho, ukuxilongwa kwe-MDD kufaka phakathi imiphumela ethile, njengokuphazamiseka ekudleni kokudla (ukunciphisa isisindo noma inzuzo), ekulaleni (ukuqwasha noma i-hypersomnia), kanye namazinga omsebenzi we-psychomotor (ukuyaluza noma ukubuyiselwa emuva). Ukwehla kwengqondo okubonakaliswa kukhubazeka kokusebenza kwememori nokwenza izinqumo, ukulahleka kokuxineka nokubhekisisa okubhekwe nakho kubhekwa njengento esemqoka ekuqhubekeleni phambili isimo sokudangala (Murrough et al., 2011). Amabinzana we-phenotypic we-multifaceted ahambisana nokudangala abangelwa izinqubo ezingasebenzi kahle ezindaweni eziningi zobuchopho kanye nokujikeleza, kufaka phakathi umklomelo wobuchopho, izikhungo zokubamba iqhaza nezokuphatha.

Njengoba i-mPFC ibhekwa njengehabhu yesekethe ekhuthaza ukusebenza kwengqondo okuhlelekile okuphezulu futhi inikeze ukulawulwa okuphansi kwezinqubo ezisebenzayo ezihlobene nezinhlelo ze-limbic (Clark et al., 2009; UMurrough et al., 2011; I-Treadway ne-Zald, 2011), kuphakanyiswa ukuthi kubambe iqhaza elibalulekile ekushiyekeni okuphathelene nokuqonda okuhambisana nokudangala. Ebantwini, izindawo ezicindezelayo zixhunyaniswa nokuphazamiseka okwenziwa ngaphambili (hyper- or hypo-activation) kanye ne-morphology, okucatshangelwa ukuthi kunomthelela ekusebenzeni kokukhubazeka kwememori, ukulawula okungalungile kwemizwelo (i-anhedonia, ukuthinta okungekuhle), ukukhetha okubonakalayo kanye nokwenza izinqumo okungahambi kahle ( I-Southwick et al., 2005; Fales et al., 2008; I-Beevers et al., 2010; I-Disner et al., 2011). Ukuvezwa kwengcindezi, okuhlangene kakhulu nokuqala kanye nokuthuthuka kwesimo sokucindezelwa, kuthathwa njengokulimaza ukusebenza kwe-mPFC. Ukusebenza okufanele kwe-mPFC kuyadingeka ukuze kulungiswe ukuzivumelanisa nokuziphatha okuthonywe kokucindezelwa kanye nokusebenzisa amandla wokulawula ezifundeni ezingaphansi kokucindezelwa (Amat et al., 2005; UCzéh et al., 2007; I-Arnsten, 2009; UDias-Ferreira et al., 2009; I-Treadway et al., 2013). Eminyakeni yamuva, ibhokisi lamathuluzi emitholampilo lokwelapha ukucindezelwa kwenwetshiwe ngokuvuselelwa kobuchopho obujulile (DBS) be-PFC. Lezi zifundo zakamuva zikhombisile ukuthi ukugqugquzelwa okungapheli kwe-cgenex cortex (Cg25), okulingana nomuntu ne-rodent vmPFC (Hamani et al., I-2010b; Chang et al., 2014), ibuyisa ukusilela kokusebenza kokucindezelwa okuphathelene nokucindezela futhi inciphise izimpawu ezigulini ezinengcindezi ezingalapheki (iMayberg et al., 2005). Izifundo ezalandela zokuhumusha ezingemuva zaqinisekisa ukubandakanyeka kwe-mPFC kuzimpendulo ezinjenge-antidepressant, njengoba ukuvuswa kukagesi okuvama kakhulu kwethonya le-PLC kuncishiswa ukuphelelwa yithemba kokulinganisa kuhlolo oluphoqelelwe lokubhukuda (FST; Hamani et al., 2010a), ehambelana nokuvumelanisa, ukuzivumelanisa nokusebenziseka kwezimo eziyinselele. Ngokufanayo, kulandela ukucindezelwa okungatheni okungalindeleki okungatheni, i-vmPFC DBS engapheli ihlehlise i-anhedonia ehlobene nokudangala, njengoba kuhlolwe isivivinyo sokuthandelwa kwe-sucrose kumagundane futhi yakhululeka ekugwemeni komphakathi ekuhlaselweni amagundane ekucindezelekeni kokwehluleka kokuhlulwa komphakathi (Hamani et al., 2012; I-Veerakumar et al., 2014). Kuhlanganiswe ndawonye, ​​ngokuhamba kweminyaka ucwaningo lwezokwelapha nolweqiniso luye lwathonya i-mPFC njengomlamuleli obalulekile we-discomaticology (Koenigs and Grafman, 2009), esidale ukufunwa kokudalulwa kanye nokucaciswa kwamagalelo ngqo wokuqokwa kwe-mPFC kanye nokuqagela kwabo okuhambisanayo futhi okusebenzayo ekuthuthukiseni ukuphazamiseka kanye nokuphendula okuphikisana nalokho.

Ukuhlolwa kokuqala kwe-optogenetic okuhlolwe ngokuqondile indima yomsebenzi we-mPFC ekuziphatheni okunjengengcindezelo kuqinisekisile ukuthi ukwenziwa kwe-neuron ye-vmPFC kubuyisela emuva isibonakaliso esinjengesimo sokuxineka kubantu ababuthakathaka bezimpisi (Covington et al., 2010; Umfanekiso I-Figure1) .1). Kulolu cwaningo, ababhali basebenzise i-paradigm engapheli yokuhlulwa komphakathi, imodeli yokudangala enobuso obuphakeme, ukuqagela nokwakha ubuqiniso (uNestler noHyman, 2010) ukwahlukanisa amagundane ekuqineni kwabo / nokuba sengozini kwengcindezi yomphakathi. I-Photostimulation ye-vmPFC itholwe kusetshenziswa i-virus ye-herpes simplex (HSV) ikhodi yokuhlola ye-ChR2 eqhutshwa yi-IE4 / 5 promoter, ebheke i-ChR2 kuma-neuron we-mPFC ngendlela engakhethi (i-Covington et al., 2010). Ngokukhethekile, i-ILC ne-PLC yemigundane ebangelwa ukucindezelwa yathuthukiswa ngephethini efana namapharamitha e-DBS ayekade edambisa izimpawu ezicindezelayo, alingisa ukudutshulwa kwe-cortical cortical (Hamani et al., 2010a). I-Photostimulation ibuyisele ngokuphelele izikolo zokuxhumana komphakathi futhi inciphise i-anhedonia, njengoba kuveziwe ekuthandeni ukuphuza isixazululo se-sucrose ngaphezulu kwamanzi, ngaphandle kokushintsha amazinga okukhathazeka noma ukusebenza kwememori yenhlalo (Covington et al., 2010). Ngokugqamile, ukusizakala kwe-mPFC kwendabuko kuholele ekubonweni okuphikisanayo. Isibonelo, izilonda ezijwayelekile ze-mPFC ziholele ekuvezweni kokuziphatha okucindezelayo, kufaka phakathi usizo lokufunda (Klein et al., 2010), kanti ukuthathwa kwemithi okwenziwe okwesikhashana kwe-ILC kuholele ekuphenduleni okuphikisayo, njengoba kuhlolwe yi-FST (Slattery et al., 2011). Lokhu okutholakele okuphikisanayo kungaqhamuka kusixazululo sesikhashana sezindlela kanye / noma ezifundeni ezihlukile (ezingezansi) ezihloliwe, isib, i-mPFC ephelele (Klein et al., 2010) vs. vmPFC (Covington et al., 2010) noma i-ILC (i-Slattery et al., 2011). Njengokuthi kusebenze optogenetic kwe-vmPFC nguCovington et al. (2010) belingacacisanga i-subtype ethile ye-neuronal, ukuqondiswa komphumela wenethonya wokukhuthaza ezingeni lesekethe kuhlala kungalungiswa. Le mininingwane ingahle iveze umehluko wokubandakanyeka kwe-mPFC ebonwe ezifundweni zabantu, esekela noma incishisiwe noma inyuswe imisebenzi yezindawo eziqonde phambili ekuvezweni kwesimo sokucindezela.

  

Umfanekiso we-1

Ubufakazi be-optogenetic bokuhileleka kwe-mPFC ekuziphatheni okunjengokudangala nokukhathazeka. I-Flash flash: isithombe; ukukhanya okuluhlaza okwesibhakabhaka: ukuthwebula izithombe ↑ = imiphumela yokudideka / yokuxineka; ↓ = imiphumela yokubulala izinhlungu / yokwelapha. ¹Covington ...

Esifundweni esilandelile, uKumar et al. (2013) isendlalelo esiqashiwe se-V se-pramidal cell ethize ye-PLC ukuhlola umnikelo walesi sigatshana se-mPFC ku-dalili ezifana nokudangala. Kuze kube manje, i-Thy1 :: amagundane e-Chr2 azwakalisa i-ChR2 kumaseli we-pyramidal aqhamuka kwizakhiwo ze-limbic, kufaka phakathi indawo ye-ventral tegmental (VTA), BLA ne-NAc. Ukugqugquzela okwenzeka ku-PLC ezilwaneni ze-naïve kubangele impendulo efana ne-antidepressant, njengoba kuvezwa ekunciphiseni ukungasebenzi kwe-FST. Ngokufanelekile, ezilwaneni ezifakwa ngaphansi kwemodeli yokunqotshwa komphakathi okungapheli, ukukhuthazeka okungapheli kwamaseli we-pyramidal we-PLC kwafaka umphumela wokukhathazeka okuhlala isikhathi eside kuhlolo oluphakanyisiwe lwe-maze (EPM), ukuhlolwa kwe-classical ukuhlola ukukhathazeka. Ngokungeziwe emiphumeleni yokuziphatha kokugqugquzelwa kwe-PLC, ababhali babike umsebenzi ovumelanisiwe we-oscillatory kuzo zonke izinhlaka ze-PLC ezihlosiwe ze-limbic (VTA, BLA ne-NAc), banikeza ubufakazi bemiphumela eyehlayo yokushintshwa kwamaseli e-PLC pyramidal kumasifunda angaphansi okubhekele ukucubungula okuhlobene nokuvuza. . Ngokubalulekile, ushintsho olufanayo emsebenzini we-neuronal kule sekethe lubonwe ezigulini ezicindezelekile (Sheline et al., 2010) futhi ingahle ibe nemiphumela efana ne-antidepressant-mPFC DBS kubantu (Mayberg et al., 2005). Kuyathakazelisa ukuthi, ngokungafani nokwenza kusebenze kwe-vmPFC, ukuvuselelwa kweseli kwe-pyramidal kwe-PLC akuzange kuguqule ukuguqulwa kokuthambekele kokugwema ukuzivikela komphakathi okwenziwe kahle (Kumar et al., 2013). Lokhu kungafani kungahle kubangelwe ngamapharamitha wokukhuthaza imvamisa ahlukahlukene asetshenzisiwe noma izinhlobo ezahlukahlukene zamaselula kanye nezendlalelo ze-MPFC eziqondisiwe. Ngokubalulekile, njengoba i-fiber ye-opic kulolu vivinyo ibhekiswe ku-ChR2 + somata ku-mPFC, ukuqagela okuqondile okuveze imiphumela efana ne-antidepressant kufana nokuthi kunqunywe ngokuqondisa okuqondile.

UWarden et al. ihlole indima yemisebenzi emihle ye-mPFC ekuziphatheni okucindezelayo, kugxilwe kokuqagelwa ku-dorsal raphe nucleus (DRN) kanye ne-lateren habenula (LHb; Warden et al., 2012), izifunda ezifakwe kakhulu kwi-MDD (Sartorius et al., 2010; UWillner et al., 2013; U-Albert et al., 2014; UMahar et al., 2014). Ukuqagela kwe-mPFC-DRN kuyathakazelisa ikakhulukazi, njengoba umphumela we-vmPFC DBS kumagundane uhambisana nezinguquko ezihlelekile nezisebenzayo ku-serotoninergic DRN neurons (Veerakumar et al., 2014) futhi ichithwe ngokuphelele ngemuva kokudangala kweserotoninergic e-DRN (Hamani et al., 2012). Ezilwaneni ze-naïve, ukusebenza kwe-optogenetic kwe-mPFC-DRN okuthokozisayo kukhanya ngokukhanyiselwa kwe-mPFC terminals e-DRN kuthuthukise ukusebenza kokuziphatha ku-FST (Warden et al., 2012). Ngokuphikisana nalokhu, ukwenziwa kwe-photoactivation kwamatheminali we-mPFC ku-LHb kubangele ukungasebenzi kahle ku-FST, kuyilapho ukukhanya kwe-vmPFC imizimba yeseli ye-pyramidal bekungasebenzi. Muva nje, umnikelo we-vmPFC-DRN ndlela eya esifundazweni esidabukisayo ihlolwe kusetshenziswa ubuhlakani bokwehluleka kwezenhlalo (Challis et al., 2014). Kwezilwane ze-naïve, ukusebenza okuphindaphindwayo kwe-ChR2-Mediated kwe-vmPFC-DRN kukhuphushe ukugxila kwonjiniyela, kukhomba ku-phenotype efana nokucindezela. Ngokuhambisana nalokhu, isithombe-mbumbulu se-Arch-mediated somzila ofanayo sivimbele ukuthuthukiswa kokuhoxa komphakathi ezilwaneni ezihlulwa ukuhlulwa komphakathi (Challis et al., 2014). Ababhali banikeza ubufakazi bokuthi ama-neurm we-vmPFC ikakhulukazi abhekelela ama-Gabaergic neurons e-DRN, okungenzeka ukuthi avimbela ama-neurot we-serotonergic, echaza imiphumela edabukisayo eye yabona. Kodwa-ke, imininingwane yabo ayihambelani nemiphumela yokulwa nokudangala, yokutholwa etholakale ku-FST elandelayo yokuvuselelwa kwendlela ye-vmPFC-DRN (Warden et al., 2012). Lokhu kuphakamisa ukuthi indlela ye-mPFC-DRN ingahle ibambe iqhaza ngokuhlukile kulawulo lokuxhumana komphakathi kanye nokuphelelwa yithemba kokuziphatha, lokhu kuziphatha okubili kwakha lezi zivivinyo zokuhlola. Ngenye indlela, ukubonwa okuhlukile kungahle kuchazwe ngumphumela ohlukile we-acute (Warden et al., 2012) vs. ukuphindaphindwa kwe-photoactivation okuphindwe kabili kwendlela ye-vmPFC-DRN (Challis et al., 2014) ekubonakaliseni kokuziphatha okucindezelayo. Noma kunjalo, lokhu kuhlolwa kukhombisa ukunikela kwe-mPFC kumthamo oguqukayo ngaphansi komzimba (proactive vs. passive reacaction) noma ngokomzwelo (izinqumo ezithathayo) ukwenza izinqumo, eziphazamiseka kakhulu ekucindezelekeni (Gotlib et al., 2008; UDerntl et al., 2011; Volman et al., 2011; Cruwys et al., 2014). Vialou et al. (2014) kubonise ukuthi ukuqagelwa kwe-PLC-NAc kanye ne-PLC-BLA kuhileleke ngendlela ehlukile ekucindezelekeni nasekuphatheni okuhlobene nokukhathazeka. Bathola ukuthi ukucindezelwa okungapheli kwezenhlalo kunciphisa i-ΔFosB e-PLC, eyayixhunyaniswe nokwandiswa kwe-cholecystokinin B (CCKB) receptor kanye nokungeniswa kwe-phenotype yokucindezelwa kwezilwane ezivezwe ukucindezelwa kokuncipha kokuncipha kwengqondo (Vialou et al. , 2014). Ukusekelwa kwalokhu, ukusetshenziswa kwendawo kwe-CCK agonist (CCK-8) ku-PLC kuthuthukise ukuvuselelwa okungenzeka kanye ne-ChR2-Mediated stimulation ye-PLC glutamatergic terminals in the NAc kuvimbele ukuphathwa okwenziwe yi-CCK-8 (i-Vialou et al. , 2014). Ukungeniswa kwe-CCK-8 ku-PLC nakho kuveze umphumela we-anxiogenic ku-EPM futhi lo mphumela waphindwaphindwa ukwenziwa kwezithombe kwe-PLC-BLA, kodwa hhayi i-PLC-NAc, indlela. Yenziwe kanyekanye, le mininingwane iqokomisa ukubaluleka kokusebenzisa ukuqagela okukhethekile kwe-mPFC ukunquma iqhaza labo kulokulawulwa okuphezulu kwezakhiwo ezingaphansi kokuziphatha okucindezelayo kanye (mal) nokuphendula okuguqukayo kwabaxinzayo (uLebo et al., 2012; I-Yizhar, 2012; UShenhav noBotvinick, 2013).

Ngaphezu kokuguqulwa kokuqagela okuhle, ama-optogenetics asetshenziselwe futhi ukungenelela ngezinhlelo ze-mPFC ezihambelana ne-DA (Chaudhury et al., 2013; UFriedman et al., 2014; UGunaydin et al., 2014). Ukukhohlisa ukukhetha kwe-VTA-mPFC DA, Chaudhury et al. (2013) i-Microinjected a retrograde travel pseudorabies virus coding for Cre ku-mPFC kanye ne-CreR-chR2 noma i-NPHR veector ethembele ku-VTA. I-Photoinhibition yendlela ye-VTA-mPFC yanciphisa ukuhlangana komphakathi kumagundane abesehlulwa ukunqotshwa okungaphansi komphakathi (Chaudhury et al., 2013). Ngokuthokozisayo, bathola nokuthi izinga lokudutshulwa kwama-neurons we-VTA DA lelo projekthi ku-mPFC lehlisiwe kakhulu kumagundane athambekele elathola ingcindezi yokuhlulwa komphakathi. Ngokubambisana, lokhu kukhombisa ukuthi ukukhishwa kwe-DA ku-mPFC kungavimbela ukwakhiwa komoya ocindezelekile ophazamisekile. Ukusebenza kwe-Channelrhodopsin-2-Mediated activation kwendlela ye-VTA-mPFC akuzange kuthinte ukuthuthukiswa kohlobo lwe-phenotype etholakalayo kulandela ukunqotshwa komkhawulo wokunqotshwa komphakathi (Chaudhury et al., 2013). Kodwa-ke, ukuvuselelwa okuphindaphindiwe kwe-ChR2-expression VTA-mPFC neurons kwabuyisela ukugwema umphakathi emphakathini onobunzima bokucindezeleka kulandela ukuhlulwa okungapheli kwezenhlalo (Friedman et al., 2014). Imiphumela ephikisanayo ibanjiwe ye-ChR2-Mediated stimulation of the VTA-mPFC DA indlela in naïve amagundane, okukhombisa ukuthi akukho zinguquko ekuxhumaneni nomphakathi, kodwa esikhundleni salokho kukhombise ukukhuphuka kokuziphatha okufana nokukhathazeka nendawo yokuphikiswa yendawo (Gunaydin et al., 2014). Ngokubambisana, lezi zifundo zikhombisa ukuthi ukuqondiswa kwemiphumela yokuziphatha kuxhomeke esimweni sokuziphatha kwesilwane. Ezilwaneni ezithambekele ekucindezelekeni, ushintsho ekusebenzeni kwe-mPFC ehambelana ne-DA kwanele ukuthuthukisa ubungozi bokukhulisa isimo sokudangala noma ukuguqula indlela yokuziphatha ecindezelayo.

Ukulawulwa kwe-optogenetic ye-mPFC kanye nezifunda zobuchopho ezixhunyiwe kuthuthukise kakhulu ukuqonda kwethu ukuqonda okungaphansi kwengcindezelo ye-neurobiological (Lammel et al., 2014). Ikakhulu, izinyathelo ezibalulekile zenziwe ekuhlukaniseni kokunikezwa kokuqagelwa kwe-mPFC okuqondile kwezici ezithile zokuziphatha zesimpawu esidabukisayo, njengezenhlalo, ukukhathazeka nokuziphatha okuhlobene nomvuzo. Kuyamangaza ukuthi lolu cwaningo seluveze izindlela zokuqina, kufaka phakathi i-anatomical (VTA-mPFC DA projection) kanye nemizila (CCK) yemigwaqo, engakhombisa ukusetshenziswa okukhulu empini yokulwa nalesi sifo esidabukisayo. Ngokuzayo, ukuphrofayili kwezinguquko zezakhi zofuzo kanye neproteyini ku-mPFC ekuvuseleleni kwe-optogenetic kunganikeza ukuqonda kuzindlela zamangqamuzana angaphansi kokucabanga nokuqina kokuziphatha okucindezelayo futhi kungavula izindlela ezintsha zokungenelela kwezokwelapha (uLebo et al., 2012).

Ngaphandle kwalokhu kuthuthuka okwenziwe ukuthi kwenzeke ngamathuluzi we-optogenetic, izingqinamba eziningana ezifanele zomtholampilo azikakhulunywa okwamanje. Njengoba ukudangala kubonakaliswa yizwi elisuselwa kumuntu ngamunye le-phenotypic, ne-Symbomatology esebenzayo, ukuhlolwa okwakheka okukodwa kokuziphatha okucindezelayo kanye nokukhathazeka kusetshenziswa indlela yokuziphatha elula (FST, EPM, ukukhetha kwe-sucrose) kungakhawulela inani lokuhumusha lalokhu okutholakele (i-Belzung et al., 2014), ukuphikisana ngentuthuko kanye nokusetshenziswa kwamamodeli ane-uhalti oluthuthukisiwe lokufunda isimo sokudangala. Ngokubalulekile, ukukhohlisa okuphathelene nokukhubazeka okuthinta ukusebenzisana kwezilwane ezilwaneni akubonisi uphawu oluthile lokudabukisa, kepha kungakhombisa izindlela ezisekela ukuziphatha komphakathi jikelele. Ngakho-ke, imijikelezo ye-mPFC ekhonjwayo ingahle ibambe iqhaza kwezinye izimo zengqondo ezivezwa ukugula komphakathi, isib, ukuphazamiseka kwe-autism-spectrum, ukuphazamiseka kokukhathazeka ne-schizophrenia (bona ngezansi; i-Yizhar, 2012; Allsop et al., 2014). Ngaphezu kwalokho, ngokuya ngokuziphatha kokufundwa (isib., Emphakathini noma i-anhedonia), ukungenelela kwe-optogenetic kungaba nomphumela wokuhlukanisa (i-Albert, 2014), ukuhumusha okuqhubekayo okunzima kwendima yezinto ezithile zomjikelezo esimweni sokuziphatha esiyinkimbinkimbi. Okokugcina, ukuqondiswa kokuwohloka kokujikeleza okunciphisa ukucindezelwa okubangelwa ukuqondiswa kwengqondo, okuyisici esibucayi sengozi yokubekezela kwale nkinga, kuhlale kuyindawo engathandeki maqondana nokukhohlisa kwe-optogenetic, kepha kunesithembiso esikhulu sokucacisa imigomo yenoveli engasetshenziselwa ukwelashwa yale nkinga yokugula kwengqondo.

schizophrenia

I-Schizophrenia ibonakala ngokuqamba okukhulu kakhulu (inkumbulo yokusebenza, ukunakwa), okuhle (ukuqagela, izinkomba) kanye nezimpawu ezingezinhle (ezithinta flat, i-anhedonia), kanye nenkulumo engahleliwe kanye nokuziphatha okungahambi kahle kwezimoto (American Psychiatric Association, 2013). I-pharmacotherapy yamanje ibhekela ingxenye encane yezimpawu, ngobuningi bezokwelapha bunqunyelwe ekulawuleni ukusilela okuhlobene nomqondo kanye nokungakwazi ukubhekela imbangela eyinhloko yokukhubazeka, ie, ukwehla kwengqondo (Ross et al., 2006; U-Cho no-Sohal, 2014). Njengoba i-pathogenesis ye-schizophrenia ihlala ingacaci futhi ingahle ibandakanye nokujikeleza okuyinkimbinkimbi kwe-neural, i-optogenetic disgment ye-neural substrates ne neuroadaptations izosiza ekuqondeni lokhu kuphazamiseka kwengqondo okunzima futhi okwenzeka manje (Peled, 2011; U-Cho no-Sohal, 2014).

Iningi lokushoda kokuqonda okuhambisana ne-schizophrenia, njengokukhubazeka kokusebenza kanye nenkumbulo ye-episodic nokulawulwa okungathintekiyo kokutholwa, kuthathelwe emuva emuva emsebenzini we-PFC, okuholele ekushintsheni kokuxhumana okushintshiwe nezindawo ezingaphansi, njenge-amygdala, striatum kanye ne-hippocampus ( URoss et al., 2006; I-Meyer-Lindenberg, 2010; U-Arnsten et al., 2012). Kunemibono eminingana ephathelene nokuguqulwa kwe-mPFC okubangela izimpawu ze-schizophrenia, kufaka phakathi ukushintshwa kokushintshwa kwe-dopaminergic, ushintsho ekulinganiseni kwe-E / I nomsebenzi oscillatory osezingeni lobubanzi be-gamma (Meyer-Lindenberg, 2010; I-Lisman, 2012). Izindlela ze-optogenetic seziqalile ukubhekela ukufanela kwalezi zinkolelo-mbono ngokunikeza ukuqonda kwezimbangela zezindlela ezisetshenziswayo zezimpawu ezivelele ze-schizophrenia, ikakhulukazi ukungasebenzi kwengqondo nokudluliswa kolwazi okuhlobene nalokhu kuphazamiseka (iWang noCarlén, 2012; ITraiño et al., 2013).

Iqhaza elimbili le-dopamine lifakwe uphawu lokufaka isandla ekuthuthukisweni kwe-schizophrenia. Ikakhulu, kucatshangelwa ukuthi ukwanda kokudluliselwa kwe-DA ohlelweni lwe-mesolimbic kanye nokufana kwe-DA ku-akhawunti ye-mPFC ukuvezwa kwezimpawu ze-schizophrenic (Brisch et al., 2014; U-Cho no-Sohal, 2014). Ngaphezu kwalokho, kusebenze ngokungalingani kwama-cortical D1-Rs ne-D2-Rs, anethonya eliphikisayo ku-neuronal excitability (Beaulieu naseGainetdinov, 2011), kubhekwa njengokubalulekile ekucutshungulweni kolwazi olungalungile kanye nokubonakaliswa kwezimpawu ezinhle nezingalungile ku-schizophrenia (Seamans and Yang, 2004; I-Durstewitz namaSeamans, 2008; UBrisch et al., 2014). Ukubandakanyeka kwe-D2-Rs kusekelwa iqiniso lokuthi wonke ama-antipsychotic asetshenziswa ukwelapha izimpawu ezinhle ze-schizophrenia, block D2-R function (Cho and Sohal, 2014). Ngaphezu kwalokho, ama-D2-Rs angaphambili aneqhaza elibalulekile ezinqubweni zokuqonda eziphazamisekile ku-schizophrenia, kufaka phakathi inkumbulo yokusebenza kanye nokuvalelisa kwe-sensorimotor, njengoba kunqunywa ngamagundane angenelele kanye nokungenelela kwemithi (Ralph et al., 1999; Ama-Seamans kanye neYang, 2004; I-Durstewitz namaSeamans, 2008). Ukuguqulwa kwe-optogenetic ye-D2-R ukuveza ama-neurons ku-mPFC kunikeze ukuqonda okusha ekusebenzeni kwama-D2-Rs kanye neqhaza lawo elingaba khona kwizimpawu ze-schizophrenia. Ukufakwa kwe-Intra-mPFC kwesekeli elithembele ku-ChR2 elizinze ku-D2-R :: Cre amagundane anike amandla ukuvezwa okuqinile kweChR2 ekubekeni kwamaseli angqimba we-V pyramidal aqhamuka ku-thalamus (Gee et al., 2012). Ukuqoshwa kwesilayidi esisebenzayo kubonise ukuthi, ngokwesisekelo, i-quinpirole ye-D2-R inethonya elincane kumijovo wamanje kuma-D2-R neurons, noma kunjalo, ukwehla okukhulu emva kokudiliza kwenzeka lapho isicelo se-quinpirole sandulelwe ukwenziwa kwe-optogenetic activation yesivumelwano se-D2-R- Ukuzwakalisa ama-neurons we-mPFC wokuqagela, odala ukushintshashintsha kwamandla kagesi kanye nokushayiza ngamakhulu ama-milliseconds (Gee et al., 2012). Njengoba kunikezwe ukucaciswa kwesisho se-D2-R ku-cortico-thalamic projecting ungqimba V we-Vorton, i-D2-R-Mediated after-depolarization ingahle ikhuphumele ukuphuma ezakhiweni ezingaphansi. Ngaphansi kwezimo ze-pathological, ezifana ne-D2-R overrepresentation ebonwe ku-schizophrenia (Seman and Kapur, 2000), lokhu kukhuliswa kwesiginali okuqhubekayo kungakhuphula izinga lomsindo ku-mPFC, ngaleyo ndlela kuhlanekezelwe ukudluliselwa kolwazi ezindaweni ezisezindaweni eziphakeme futhi kungathuthukisa ukwanda kwe-psychosis. Njengoba izinga lomsindo ngaphakathi kwe-mPFC licatshangwa ukuthi lenyuka ezigulini ze-schizophrenic (okuxoxwe ngalo ngezansi), ukwehlisa i-D2-R-Mediated after-depolarization kungaba yisisekelo se-neurophysiological somphumela onenzuzo wama-antipsychotic ezimpawu ze-schizophrenia. Ucwaningo olwengeziwe usebenzisa vivo amamodeli kuzodingeka aqinisekise ukuthi ngabe i-D2-R eyenziwe ngemuva kokudonswa komhlaba iyabandakanyeka ekungasebenzi kahle kwengqondo okubonwe ku-schizophrenia.

Umbono we-E / I ulinganisa ukuthi ukuphakama kwesilinganiso samaseli e-cortical E / I, okuvunyelwe nge-hyperexcitability yamaseli we-pyramidal noma i-hypoactivity ye-inhibitory interneurons, kugcizelela izimpawu zokuziphatha nezokuqonda ze-schizophrenia, kufaka phakathi ukungasebenzi kahle komphakathi (Lisman, 2012; UWang noCarllen, 2012). Imiphumela yenethiwekhi nokuziphatha kokulinganisa kwe-E / I okuguquliwe ku-mPFC kubhekenwe nakho kusetshenziswa isinyathelo esiteji sokusebenza kwe-opsin (SSFO), i-ChR2 mutant enesikhathi esinciphile sokukhipha amandla (~ 30 min) (Yizhar et al., I-2011b; I-Yizhar, 2012) ekubukeni ngokudonsa okukodwa kokukhanya okuluhlaza okwesibhakabhaka, ngaleyo ndlela kunciphise umkhawulo wokudubula okungenzeka kwesenzo ku-neuron eveza i-SSFO. Ukuthwebula isithombe okufushane kwe-SSFO eveza imisipha ye-pPidal ye-SSFO kukhuphule ibhalansi ye-E / I, ukucubungula ulwazi ngezinga lamaselula nokwandisa umsebenzi wejubane eliphezulu, kufana nezinkomba zokwelashwa ze-schizophrenia (Yizhar et al., I-2011b) (bheka isigaba esingezansi). Ezingeni lokuziphatha, lokhu kudalwa kwenkohliso kwakwanele ukuqeda ngokuphelele ukuxhumana komphakathi kanye nokubuyiselwa okubuthaka kwememori enesimo. Ukulinganisa kwe-E / I okuthuthukisiwe ku-cortex eyindilinga ebonakalayo akuzange kuguqule ukusebenza komphakathi, okubandakanya ukubaluleka kwe-mPFC ekulameni lokhu kusilela kokuziphatha. Kuyathakazelisa ukuthi ukudonswa kwenhliziyo kwe-SSFO-expression ye-mPFC GABAergic PV akuzange kuthinte ukusebenzisana komphakathi nokwesaba okuleso simo (uYizhar et al. I-2011b), ngaphandle kokuthi inciphise kakhulu ukusebenza kwe-spiking nomsebenzi we-synaptic. Kodwa-ke, ukushiyeka komphakathi okubonwe ngemuva kokuguqulwa kwesithombe kwamaseli we-piramidi e-SSFO ahlangulwe ngokwengxenye ngokusebenzisana kwe-ChR2-expression PV neurons (Yizhar et al., I-2011b). Njengoba sekuxoxwe ngaphambili, ukuvimbela ama-mPFC PV neurons kungahle kuholele ekusweleni inkumbulo yokusebenza kanzima (i-Rossi et al., 2012), kugcizelela futhi ukubaluleka kwephimbo lokujabulisa elilinganayo le-cortical. Ngokuphawulekile, ibhalansi ye-E / I ephakeme ngaphakathi kwe-mPFC nayo kucatshangelwa ukuthi inomthelela ekungasebenzi kahle komphakathi okuhambisana nokuphazamiseka kwe-autism spectrum (Yizhar et al., I-2011b), ngakho-ke, lokhu okutholakele kungakhomba enkambisweni ye-pathophysiological elamula ukulimala okuvamile ekuziphatheni komphakathi. Noma ukusetshenziswa kwezinsiza kusebenza ze-SSFOs ekuchazeni umphumela we-mPFC E / I elilinganiselwe ezingeni lamaselula nasekusebenzisaneni kwezenhlalo, ukushintshwa kwe-E / I ibhalansi ku-schizophrenia ne-autism kungenzeka kube ngumphumela we-arhente ye-neurodevelopmental mechanism. Ngakho-ke, ezigulini, ibhalansi ye-E / I iphakanyiselwe isikhathi sesikhathi esingaphezu kwesilinganiso sesikhathi sokusebenza sama-SSFO atholakalayo njengamanje. Imiphumela emibi “yokushisisa” yokushintshwa kwe-E / I yokulinganisa ezilwaneni ezijwayelekile zokuthuthuka kufanele ihunyushwe ngokuqapha. Lokho okushiwoyo, ukukhohlisa okwenziwa nge-optogenetic kusetshenziswa ama-SSFO okokuqala kukhombisile imiphumela eyingqayizivele yoshintsho ku-mPFC E / I ukulingana emsebenzini wenethiwekhi nokuziphatha. Ngaphezu kwalokho, ama-SSFO angasetshenziswa ukuhlola ukuthi ngabe i-E / I ibhalansi itholakala kwezinye izifo zezifo zengqondo, kufaka phakathi i-autism, ukudangala kanye nomlutha, okungenzeka kuhlanganisa i-etiology yalokhu kuphazamiseka (i-Tye ne-Deisseroth, 2012).

Indlela yesithathu ehlose ukuchaza ukusilela kokuqonda kweziguli ze-schizophrenia kubandakanya i-gamma isigqi, i-30-80 Hz neuronal oscillations edlala indima ebaluleke kakhulu ekuvumelaniseni umsebenzi we-neuronal ngaphakathi naphakathi kwezindawo, ezaziwa njengokufuneka kokusebenza kwememori, ukuqonda nokunaka (Lewis et al., 2005; UWang noCarllen, 2012), futhi kungenzeka ukuthi ibalulekile kweminye imisebenzi eminingi yobuchopho. Ezigulini ze-schizophrenia, kuye kwenzeka ukubonwa okungafani nokujwayelekile kwe-gamma, futhi kuhambelana nezinguquko kumemori yokulawula nokusebenza kwengqondo (Uhlhaas et al., 2008; I-Uhlhaas ne-Singer, 2010). Lapho ukusebenza kwe-PV neuron kukhubazekile, i-drive subhibtory inhibitory drive kuholela ekuthini kube yi-desynchronization, okunomthelela ekuguqukeni kwesigqi se-gamma futhi ngokunokwenzeka ekusebenzeni kokukhubazeka kwememori okuhlobene ne-schizophrenia (Lewis et al., 2005). Ngokuhambisana nalomqondo, ukuhlanganiswa kwe-GABA yendawo kanye nokuphinda kubuye kuncishiswe ku-PFC yeziguli ze-schizophrenia futhi lolu shintsho luqondiswe ngokuthe ngqo yi-PV neurons, okusho ukusebenza kokuhlukumezeka kwalaba bantu abathile be-interneuron (Lewis et al., 2005). Ngokunjalo, kuncishiswe ukugonywa kwe-PV ku-PFC yeziguli ezinesifo sokuqaqanjelwa (iBeasley noReynolds, 1997). Izifundo ze-optogenetic zikuqinisekisile ukubaluleka okubaluleke kakhulu kwe-cortical PV interneurons ekushayeleni ama-gamma oscillations (Cardin et al., 2009; USohal et al., 2009). USohal et al. (2009) kukhombise ukuthi ukwenziwa kwe-Photostimulation kwe-ChR2-eveza amaseli we-pyramidal e-PFC aphakamise ama-oscillations we-gamma vivo, noma kunjalo, i-NPHR-Mediated inhibition ye-PV + yama-interneurons ngesikhathi esisodwa icindezela amandla we-gamma, iphakamisa ukuthi ukuvuswa kwamaseli we-pyramidal kusebenze kwehle ama-PV neurons. Ngokubalulekile, lapho kufakwa i-pyramidal neurons ekufakweni kwe-gamma-frequency, ukuhanjiswa kwesiginali ye-microcircuit kwenziwa ngcono ngokunciphisa umsindo wesifunda nokwandisa amasiginali wesifunda, okufaka amasignali kuma-interneurons endawo (Sohal et al., 2009). I-Parvalbumin interneuron eqhutshwa yi-gamma-Mediated neurch synchrony incike ekusetshenzisweni kwe-NMDA receptor, njengoba kuhlosiwe ukususwa kwe-NMDA receptor ku-PV neurons impaired optogenetic induction of oscillations we-gamma futhi kwaholela ekwehleni kokukhetha okucishe kufane, okufana nokushoda kwe-schizophrenic (Carlén et al. 2012). Ngokubambisana, i-optogenetic modulection modulation ekhethiwe yomsebenzi we-PV iqinisekisile ukuthi le subtype ye-neuronal isebenzisa ama-oscillations e-gamma, akhuthaza ngokuqondile ukucubungula kolwazi okusheshayo nokuqondisiwe; "ukucijiswa" kwempendulo ye-cortical kokufakwa kokuzwa (uWang noCarllen, 2012). Izinguquko ekuvumelwaneni kwe-oscillation nazo kucatshangwa ukuthi zibhekana nezinye izimo zengqondo, kufaka phakathi ukuphazamiseka kwengqondo ngokuphefumula kanye ne-autism, kanye nesithuthwane (i-Uhlhaas neSinger, 2006; Sheline et al., 2010). Ngakho-ke, imizamo ehlose ukucacisa eminye imigwaqo yesifunda neyamaseli enomthelela ekuphethiseni isizukulwane se-neuronal oscillations ibaluleke kakhulu.

Njengoba yenziwe ndawonye, ​​okokuqanjwa kokuqala kwe-optogenetic yesifunda se-mPFC okungenani kuqinisekisiwe ingxenye ethile yemibono ekhona ehlose ukuchaza izindlela ze-neuropathological eziyisisekelo ze-schizophrenia. I-drive ejabulisayo yokuphefumula, ngokungenzeka njengomphumela we-D2-R overexpression, okuholele ekuhanjisweni kwe-neurynronite kanye ne-cortical yolwazi olungejwayelekile inikela kuzimpawu ezihambisana nale nkinga. Uma unikezwe isimo semvelo esiningi futhi esiyinkimbinkimbi se-schizophrenia, kungenzeka kube nzima ukulingisa isibuko esigcwele se-phenotypic kumodeli yezilwane. Yize ukukhohlakala kwe-optogenetic ebuchosheni be-rodent kubaluleke kakhulu ekunikezeni izinkomba ezintsha kulo mkhakha wokucwaninga, inani lokuhumusha lezinqubo elibonakalayo lihlala liyinselelo edinga ukubhekelelwa esikhathini esizayo.

Addiction

Abantu abayimilutha babonisa i-repertoire yokuziphatha evinjelwe imijikelezo ephindaphindwe yokufuna izidakamizwa, ukusetshenziswa kanye nokululama ekusebenziseni izidakamizwa naphezu kwemiphumela emibi kakhulu njalo (i-Hyman, 2005). Umlutha wezidakamizwa uwukuphela kochungechunge lwezinguquko kusuka kokuqala, ukusetshenziswa kwezidakamizwa kwe-hedonic kuya ekusetshenzisweni kwezidakamizwa okwenziwa futhi okuphoqelela, okuhambisana nokuvumelana okuhlala isikhathi eside kumasekethe e-neural (Robinson and Berridge, 1993; I-Kalivas neVolkow, 2005). Izinga eliphakeme lokubuyela emuva liyinkinga enkulu ekwelapheni umlutha, njengoba abantu abayimilutha behlala bethambekele kakhulu ekuphinde basebenzise ngisho nangemva kokuhlala isikhathi eside (izinyanga kuze kube yiminyaka) kokuyeka (i-Kalivas ne-O'Brien, 2008). Lokhu kuthikamezeka okuphikelelayo kucatshangelwa ukuthi kugcinwa ngezinkumbulo ezihlobene futhi eziphikelelayo zokuhlangana kwemiphumela yezidakamizwa kanye nezinto zokuzithokozisa zezendawo (iHyman et al., 2006). Ukujikeleza kobuchopho okusekela umlutha kuyinkimbinkimbi, kepha ubufakazi obuningi bukhombisa ukuthi i-mPFC ineqhaza elibalulekile ekuthuthukiseni nasekuqhubekeni kokuziphatha komlutha (Kalivas, 2009). Ngokucacile, i-mPFC ifakwe umfutho ophambili wokuthola amandla okuvuselela umvuzo, ukusebenzisa izidakamizwa okuphoqayo, izinkulumo zezinkumbulo ezihlobene nezidakamizwa nokubuyela emuva ekufuneni izidakamizwa (Van den Oever et al., 2010; UHogarth et al., 2013; UPeter et al., 2013). Izindlela ze-Optogenetic ziqinisekisile umsebenzi obalulekile we-mPFC ezilwaneni zezilwane zokuziphatha umlutha futhi yanikeza ukuthakazelelwa okusha ngomthelela wesikhashana wokuzithoba nokuqagela kwe-mPFC kwi-NAc ukuphoqelela ukuthatha izidakamizwa nokuziphatha okufuna izidakamizwa.

Ubufakazi obuvela ocwaningweni lwe-neuroimaging luveza ukuthi i-hypofunction ye-mPFC inomthelela ekulahlekelweni kokulawula kokunciphisa ukubamba imingcele kubantu abayimilutha yabantu (iGoldstein neVolkow, 2011). Le hypothesis isanda kubhekanwa nayo kusetshenziswa ama-optogenetics kumagundane aqhubeka nokuzilawula i-cocaine naphezu kokubhangiswa komvuzo we-cocaine ngokulethwa kwe-noxious stimulus (i-foot-shock). Chen et al. (2013) kubonise ukuthi ukuzilawula isikhathi eside kwe-cocaine kunciphise ukukhululeka kwe-neuron ye-PLC, kube nomphumela omelele kakhulu kumagundane alwa nokuphikiswa. Ukubuyisela umsebenzi we-piramidi we-PLC ngokuvuselelwa kwe-optogenetic kudambisa ukudonsa kwe-cocaine emagundweni alwa nokuthambekela (Umdwebo (Umdwebo2A) .2A). Ngokuphambene nalokho, lapho i-neuron ye-PLC ithuliswa umlomo ngokuthula, amagundane angavimbeli ukuzibandakanya nokuzilawula kwe-cocaine nge-shock shock. Lolu cwaningo lukhombisa ukuthi lapho ukusetshenziswa kwe-cocaine kubhangqwe ngomphumela omubi, ukuqina kwamaseli we-pyramidal we-PLC kunomthelela ekulahlekelweni kokulawulwa kokuvinjwa kokudla okwenziwa ngenkani kwe-cocaine.

  

Umfanekiso we-2

Ubufakazi be-optogenetic bokubandakanyeka kwe-mPFC ekuziphatheni okuluthayo. I-Flash eluhlaza: i-photoinhibition; ukukhanya okuluhlaza okwesibhakabhaka: ukuthwebula isithombe. ↑ = Ukuthathwa kwezidakamizwa / okuthuthukisiwe; ↓ = Ukunciphisa ukuthatha izidakamizwa / ukufuna. Ukukhwabanisa kwe-optogenetic kukhombisa ...

Ukungenelela kwamakhemikhali kumodeli yezilwane yokufuna izidakamizwa enesimo kukhombisa ukuthi i-dmPFC ne-vmPFC banegalelo ngokwehlukile ekubonakalisweni kwalokhu kuziphatha okuthize (UPil. Et al., 2009; UVan den Oever et al., 2010). Ngenkathi umsebenzi we-dmPFC kucatshangwa ukuthi ushayela izimpendulo ezifuna izidakamizwa, i-vmPFC ingaqhakambisa noma ivimbele izimpendulo ezifuna izidakamizwa ngokuya ngohlobo lomuthi owalawulwa ngaphambilini kanye nokuqaliswa kwezikhathi zokuqothulwa ngaphambi kobufakazi obufuna izidakamizwa.t (McLaughlin futhi Bona, 2003; UPeter et al., 2008; Roger et al., 2008; Koya et al., 2009; Muhlenkamp kanye neMcNally, 2013; Ama-Lubber et al., 2014). Eqinisweni, imigqa eminingana yobufakazi iphakamisa ukuthi i-ILC ixhumanise ukuhlanganiswa kanye nenkulumo yememori yokuqothula (uPeter et al., 2008; LaLumiere et al., 2010), futhi ngenxa yalokho, ukuvimbela lesi sifunda ngemuva kokuqothulwa kokufunda kukhipha ukuvela kwempendulo yokuqala yokufuna i-cocaine. Ukukhohlisa kwe-optogenetic ye-vmPFC kwandise lokhu okutholakele ngokukhombisa ukuthi amaseli we-vmPFC pyramidal empeleni anengxenye ekubonakaliseni nasekuqothulweni kokufuna i-cocaine enesimo, kepha ngendlela encike ngesikhathi (uVan den Oever et al., 2013; Umfanekiso Umfanekiso2B) .2B). Isiteshi se-Channelrhodopsin-2-Mediated activation of vmPFC seli pyramidal seli activated ukuqothulwa kwenkumbulo yendawo ye-cocaine enendawo ekhethekile (i-CPP) kuphela lapho ukufakwa kwe-photostimulation sekusetshenziswe emavikini e-3 ngemuva, kepha hhayi ngosuku lwe-1 ngemuva kokulungiswa. Ngokuhambisana nalokhu okubukwayo, i-NpHR-inediitionedied inhibition yalezi zi-neurons ivimbe ukuqothulwa kwememori ye-CPP ye-3 emavikini ngemuva kokulungiswa. Ngokumangazayo, isithombe se-photoinhibition sikhethe ngokungakhethi imemori ye-cocaine yosuku lwe-1. Ngokubambisana, ukukhohlisa kwe-optogenetic yamaseli we-pyramidal kwakhomba ekuhlelweni kabusha kwesikhashana komjikelezo olawula ukubonakaliswa kwezinkumbulo ezihlobene ne-cocaine kanye nendima ehlukile ye-vmPFC ekuphatheni kwe-cocaine enesimo esifuna isikhathi.

Ucwaningo lwe-optogenetic luqinisekisile ukuthi umsebenzi we-PLC uyadingeka ekubuyiselweni kokufuna kwe-cocaine ezilwaneni ezikhutshiwe. Ifana ne-cosacological inactivation, i-photoinhibition ye-PLC neurons (isebenzisa isengezi esingakhethi) sinciphise ukubuyiselwa okuyisisekelo kwe-cocaine (Stefanik et al., 2013). Ngaphezu kwalokho, iqembu elifanayo lakhombisa ukuthi indlela ye-BLA-PLC ibandakanyeke kakhulu ekubuyiselweni kwe-cocaine ekuvinjelweni kwama-terminals e-BLA e-PLC (UStefanik noKalivas, 2013). I-Optogenetic inhibition ye-dmPFC pyramidal neurons iphinde yathola ukubuyiselwa kwengcindezi okukhona kokudla okuthandekayo okufuna kumagundane (UCdu et al., 2013), kuphakamisa ukuthi izindlela ezahlukahlukene zenza ukujikeleza kwe-dmPFC kuvuse ukubuyiselwa kokufuna umvuzo. Ngaphezu kwalokho, lokhu kukhombisa ukuthi umsebenzi we-PLC ushayela ukubuyiselwa kwe-cocaine nokufuna umvuzo wemvelo, kanti umsebenzi owengeziwe wezinzwa ezifanayo ucindezela ukuthatha i-cocaine (i-Chen et al., 2013). Umsebenzi ophikisayo i-PLC ungahle uxhomeke ekubeni khona noma ukungabikho kwe-cocaine esivivinyweni esisebenzayo. Lokhu kusekelwa ukubonwa kokuthi isithombe esibonisa amaseli we-PLC pyramidal cell athuthukise ukuzilawula kwe-cocaine futhi athola ukubuyiselwa kokufuna kwe-cocaine kumagundane atholakala esimisweni sokudla kakhulu i-cocaine (Martín-García et al., 2014). Ama-interneurons we-GABAergic awenzelwanga amandla okwamanje kumamodeli wokulutha, kodwa iqhaza lokufundwa nokuqothulwa kwe-PV kusanda kuhlolisiswa muva nje. Ukusebenza kwe-Channelrhodopsin-2-Mediated activation kwe-PLC PV akuzange kuthinte ukutholwa kokuzibusa komvuzo we-sucrose, kepha kwasheshisa ukuqothulwa komvuzo ofuna ukuvimbela umsebenzi wenethiwekhi we-PL (Sparta et al., 2014). Ukuthi umsebenzi we-PLC PV futhi uthinta ukuqothulwa kokufuna izidakamizwa kuhlala kuyisihloko sokucwaninga esizayo.

Ngokuhlanganisa okokufaka okuvela emithonjeni efana ne-BLA, VTA kanye ne-HPC futhi kudlulisa umphumela ophumelelayo kwi-NAc, kucatshangelwa ukuthi i-mPFC ilawula ukujikeleza kwezimoto ukulawula ukuphendula izidakamizwa kanye nokugqugquzela okuhambisana nezidakamizwa. (Kalivas et al., 2005). Izifunda ze-Dorsal ze-mPFC ikakhulukazi zisebenza kumaphakathi we-dorsolateral striatum kanye ne-NAc, kanti izifunda zangaphakathi zivimbela kakhulu i-dorsomedial striatum kanye ne-NAc igobolondo (UVoorn et al., 2004). Pizivivinyo zokuvimbela ingozi ezinobungozi ziwuthinte kakhulu umgogodla we-dmPFC-NAc kanye ne-vmPFC-NAc igobolondo lendlela ye-cocaine yezidakamizwa kanye ne-cueine. (McFarland et al., 2003; I-LaLumiere neKalivas, 2008; UPeter et al., 2008; UBossert et al., 2012), kepha ngale ndlela imiphumela emigudwini engaqondile ayikwazi ukukhishwa. I-Photoinhibiton yezindawo zokugcina ze-PLC zasenxenyeni ye-NAc eyisisekelo se-cocaine-primed ekubuyiselweni kokufuna i-cocaine (uStefanik et al., 2013), eqinisekisa ukuthi ukuqagelwa kwe-monosynaptic glutamatergic kusuka ku-PLC kuye ku-NAc core kuneqhaza elikhulu kulokhu kusabela kokuziphatha. Ubufakazi be-optogenetic bokubandakanyeka kwendlela yamagobolondo ye-mPFC-NAc bunikezwe ngokuguqulwa kwe-optic ye-ILC ezikhungweni zobuchopho ze-NAc ezitholwe ezilwaneni ezivezwe i-cocaine (uSuska et al., 2013). Lokhu kuveze ukuthi okokufaka okufika phambili kwe-mPFC esikhungweni se-NAc kwaqiniswa ngemuva kokuqedwa (kwezinsuku ezingama-1) nokuchayeka isikhathi eside (izinsuku ze-45) ukungazibandakanyi ekuchayweni kwe-cocaine kodwa akunakuphikwa. ngokuhamba kwesikhathi. Ukuthuthuka kwe-presynaptic kwabangelwa ukwanda kwamathuba wokukhishwa kwe-glutamate, kunokuba kwandiswe usayizi omningi wokukhishwa kwe-glutamatergic noma inani lamasayithi wokukhishwa asebenzayo (uSuska et al., 2013). Kuyathakazelisa ukuthi ukudalulwa kwe-cocaine akuzange kuthinte ukudluliselwa kwe-presynaptic ekubonakalweni kwegobolondo ye-BLA-NAc (Suska et al., 2013), okuphakamisa ukuthi okokufaka kusuka ku-mPFC kuthakazelelwa ngokufaka kwe-BLA ngemuva kokuphathwa kwe-cocaine. Esifundweni esihle kakhulu sikaMa et al. (2014) kuboniswe ukuthi ukuzilawula kwe-cocaine kuholele ekuvumelaneni okuthe cwaka ku-mPFC-NAc indlela. Ngokuthabisako, ama-synapses athule endaweni yomugqa we-ILC-NAc avuthwa ngokuqasha i-GluA2-engekho ama-AMPA-Rs (abonwa ngosuku i-45 yokulahlwa), kanti kuthulekile okuthe cwaka emzileni onguthelawayeka we-PLC-NAc oqashe i-GluA2-equkethe i-AMPA-Rs. Ama-receptors we-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid entula isendlalelo se-GluA2 are calcium permeable, abe nokusebenza kwesiteshi okuthe xaxa, akhombisa ukushesha kokubonisa isiteshi, ngaleyo ndlela abe neqhaza ekusayinweni okusheshayo kwe-synaptic signaling, homeostatic synapticaling ukufiphala okufushane nokwesikhathi eside (ngokubuyekezwa okuhle bheka u-Isaac et al., 2007). I-Optogenetically ikhiphe ukudangala isikhathi eside (i-1 Hz ye-10 min) iphinde yaphinda yaveza ama-synapses athule kuzo zombili izindlela, kepha lokhu kungathuthukisa (igobolondo le-ILC-NAc) noma kuncishisiwe (i-PLC-NAc core) ngokulandela i-cocaine (Ma et al., 2014), futhi isekela izindima ezihlukile ze-dmPFC ne-vmPFC kulokhu kuziphatha.

Isibalo esikhulu samaseli e-NAc siqukethe ama-GABAergic medium spiny neurons (ama-MSNs) angahlukaniswa phakathi kwe-D1-R ne-D2-R eveza inani labantu, kuhlangene ne-90-95% yawo wonke ama-NAc neurons (uLebo et al., 2006). Inkulumo ekhethiwe ye-ChR2 kwisizwe ngasinye se-NAc MSN ikhombisile ukuthi kusebenze i-D1-R neurons kuthuthukise ukufunda ngomklomelo we-cocaine ku-CPP paradigm, kanti ukusebenza kwe-D2-R neurons kube nomphumela ophambene (uLebo et al., 2010). I-Photostimulation yamaphethelo we-mPFC enkambeni ye-NAc yenziwa ngokuqondile isisulu se-ΔFosB ku-D1-R neurons, kanti kugobolondo le-NAc, inkulumo ye-ΔFosB yafakwa kuzo zombili izingqikithi ze-D1-R ne-D2-R (Lobo et al., 2013). Lokhu kuphakamisa ukuthi ukusatshalaliswa kwama-terminal we-mPFC kuma-neuron e-NAc kuyahluka ngegobolondo kanye nomongo (Lobo et al., 2013). Noma kunjalo, lokhu kuzodinga ukuqinisekiswa ukuqoshwa kweselula yonke. Ukubaluleka kokusebenza kwe-mPFC ku-NAc D1-R MSNs ukuqagelwa kuboniswe nguPascoli et al. (2012) obekhombisile ukuthi i-frequency ephansi (i-1 Hz) ye-ILC-NAc indlela yokuhamba kwegobolondo ibuyisele emuva i-non-contingent cocaine-induced synaptic potentiation ku-D1-R neurons kanye nomuzwa we-locomotor. Muva nje, leli qembu elifanayo lisebenzise ama-optogenetics ukwambula ubukhona be-AMlu-Rs engekho e-GluA2 kuma-ILC-NAc D1-R MSN projection 1 ngenyanga ngemuva kokuzibusa kwe-cocaine (Pascoli et al., 2014). I-Photostimulation yale ndlela ku-13 Hz, kodwa hhayi i-1 Hz, iguqule ukuvumelanisa ngokwe-synaptic ngemuva kokuzibusa kwe-cocaine futhi yaqeda ukufuna kwe-cocaine okwenziwe. Ababhali bacabanga ukuthi ukukhuthaza i-13-Hz kwakudingeka ngalo mphumela ngoba lokhu kuvusa ukudana okuhlala isikhathi eside kwe-mGluR, inqubo ephumelelayo yokususa i-synaptic GluA2-ehlile ye-AMPA-Rs (Lüscher neHuber, 2010). Kodwa-ke, lokhu okutholayo kuyaphikisana nokuqashelwa nguMa et al. (2014); (kuxoxwe ngenhla). Umehluko ekucacisweni kwesekethe (ukushintshwa kwama-optogenetic kokuqagela kuma-neuron we-D1-R vs. ukuqagela kubo bonke ama-NAc shell MSN neurons) nakuhlobo lwe-cocaine self-management kungahle kuchaze imiphumela ephikisayo ebonwa kulezi zifundo.

Ngaphezu kokubandakanyeka ekubuyeleni emuva ekufuneni izidakamizwa, indlela ye-mPFC-NAc ifakwe umfutho ophoqelelayo wokuphuza utshwala obungaqediwe. I-Photoinhibition ye-dmPFC-NAc core projection inciphise ukuphuza utshwala okubhanqazwe ngesisusa esibuhlungu semodi yokuzwa ehlukahlukene nezindlela ezihlukile zokudla (uSeif et al., 2013). Ukuphuza utshwala akubange kuthintwe yi-photoinhibition lapho bekungabanjwanga ngomphumela omubi, kuphakamisa ukuthi le ndlela ihamba phambili ekuhleleni izici eziphikisayo, eziphoqayo zokuphuza utshwala, lapho ukuphuza kuvame ukuhambisana nokungqubuzana noma inselelo (Tiffany and Conklin, 2000). Kodwa-ke, le miphumela iyangqubuzana nokutholwa kokuthi i-photoinhibition ye-PLC ithuthukisa ukudla okungafanele ukumelana ne-cocaine (Chen et al., 2013), kuphakamisa ukuthi i-PLC ingahle ilawule ngokwahlukeka kotshwala obucindezelayo kanye ne-cocaine.

Ukubandakanyeka kwendlela ye-mPFC-NAc ekutholeni umvuzo kanye nokuzilawula kwezidakamizwa nakho sekutholakele ngezindlela ze-optogenetic. Stuber et al. (2011) ithole ukuthi ukwenziwa kwe-activation kwe-mPFC-NAc igobolondo le-(20 Hz) ayikwesekanga ukutholwa kokuziphatha kokuzivuselela kokusebenza (izimpendulo ezisebenzayo zibangele ukukhishwa okukhanyayo okulethwa ezikhungweni zezempilo ze-mPFC ze-NAc), naphezu kweqiniso lokuthi ukwenziwa kwamehlo kusebenze ukuqagelwa kwe-mPFC kwaveza ama-EPSC kwi-NAc. Ucwaningo olulandelayo lubonise ukuthi izilwane zizitholela ngokwazo indlela yokuvuselela indlela ye-mPFC-NAc lapho imvamisa yokukhuthaza inyuka iye kwi-30 Hz (Britt et al., 2012). Ngakho-ke, ukuqagela kwe-glutamatergic kusuka ku-mPFC kuya ku-NAc kungahle kukhiphe i-spiking yama-MSNs futhi kuqinise nokuziphatha kusebenze ngokuqinile kwe-mPFC noma lapho amazinga e-DA kwi-NAc ephakanyiswa ngokufana. Indawo ngqo yokwenyusa ngaphakathi kwe-mPFC ingahle ibaluleke kakhulu ukufeza lo mphumela, uma kucatshangelwa ukuthi i-ILC icatshangelwa ukuthi inamandla amakhulu okuqagela egobolondweni le-NAc kune-PLC (Voorn et al., 2004). Njengasezifundweni ezishiwo ngenhla i-ChR2 expression ayibhekanga ngqo ku-PLC noma i-ILC, kusalokhu kunqunywa ukuthi ngabe umehluko ukhona yini ekuthambekeni kwalezi zindlela zombili zokukhipha i-spiking kuma-NAc shell MSNs nasekuqiniseni indlela yokuziphatha yokufuna umvuzo.

Ngokuhambisana namasu wokungenelela kwendabuko, ukusetshenziswa kwe-optogenetic kumjikelezo we-mPFC kumamodeli wokulutha ngokugqamile kuqinisekisile ukubandakanyeka okubucayi kwalesi sifunda ngokulawula ukuthathwa kwezidakamizwa nokuziphatha kwezidakamizwa futhi kubuye kuxhaswe ukuhlukaniswa okusebenzayo eceleni kwe-dorsal-ventral axis ye-mPFC. Ngaphezu kwalokho, indlela yokushintshwa kwendlela ethile inikeze ukuqonda okusha ngendima ye-BLA-PLC kanye ne-mPFC-NAc. Ikakhulu, ukugqugquzelwa kwe-optic ye-PLC ne-ILC axonal terminals ku-acute aclicic silices ukulungiswa komgogodla we-NAc kanye negobolondo kubonise ama-neuroadaptations we-cocaine afakwe i-cocaine angabuyiselwa emuva kusetshenziswa amachaphaza we-photoactivation echaziwe (Pascoli et al., 2012, 2014; Ma et al., 2014). Lokhu kunganikeza amathuba wokubuyiselwa okuphakathi kwezilingo kwe-DBS kwe-neuroadaptations ebangelwa izidakamizwa. Kodwa-ke, njengoba ukushukunyiswa kukagesi kuthinta ukusebenza kwe-neuronal ngendlela engakhethi, ukusebenza ngokuhumelelayo ku-DBS kusamele kusondele ngokuqapha futhi kudinga ezinye izifundo.

UMariana R. Matos uxhaswa yi-EU MSCA-ITN CognitionNet (FP7-People-2013-ITN 607508). U-Agasti B. Smit, uSabine Spijker uxhaswa ingxenye ethile yesibonelelo esinikezwe i-NeuroBasic Pharmaphenomics Consortium. UDanai Riga uxhaswe ingxenye yesikhwama se-NCA proof-of-umqondo fund (iSabine Spijker). UMichel C. Van den Oever uxhaswa isibonelelo sikaZonMw VENI (916.12.034) kanye neHersenstichting Nederland (KS 2012 (1) -162).

• I-Airan RD, Thompson KR, Fenno LE, Bernstein H., Deisseroth K. (2009). Ukunemba okwesikhashana ngokulawulwa kwe-vivo kokusayina kwe-intracellular. Imvelo 458, 1025-1029. I-10.1038 / nature07926 [I-PubMed] [Isiphambano Ref]
• U-Albert PR (2014). Khanyisa impilo yakho: optogenetics yokudangala? J. Psychiatry Neurosci. I-39, 3-5. 10.1503 / jpn.130267 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• U-Albert PR, uVahid-Ansari F., uLuckhart C. (2014). I-Serotonin-prefrontal cortical circry in ukukhathazeka nokucabanga kwama-phenotypes: indima ebaluleke kakhulu yesisho se-pre-and post-synaptic 5-HT1A receptor expression. Phambili. Behav. I-Neurosci. I-8: 199. 10.3389 / fnbeh.2014.00199 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• I-Alitto HJ, Usrey WM (2003). Impendulo yeCorticothalamic kanye nokusebenza kwezinzwa. UCrr. Opin. I-Neurobiol. I-13, 440-445. I-10.1016 / s0959-4388 (03) 00096-5 [I-PubMed] [Isiphambano Ref]
• I-Allsop SA, Vander Weele CM, Wichmann R., Tye KM (2014). Ukuqonda kwe-optogenetic ebuhlotsheni obuphakathi kokuziphatha okuhlobene nokukhathazeka nokushoda kwezenhlalo. Phambili. Behav. I-Neurosci. I-8: 241. 10.3389 / fnbeh.2014.00241 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• U-Amat J., Baratta MV, Paul E., Bland ST, Watkins LR, Maier SF (2005). I-cortex ye-medial predomal inquma ukuthi i-controrability controllability ikuthinta kanjani ukuziphatha kanye ne-dorsal raphe nucleus. Nat. I-Neurosci. I-8, 365-371. I-10.1038 / nn1399 [I-PubMed] [Isiphambano Ref]
• I-American Psychiatric Association (2013). I-Diagnostic kanye ne-Statistical Manual Yokuphazamiseka Kwengqondo. I-Arlington, VA: I-American Psychiatric Publishing.
• I-Arnsten AF (2009). Izindlela zokubonisa ukucindezela ezithikameza isakhiwo sangaphambili se-cortex nomsebenzi. Nat. UMfu Neurosci. I-10, 410-422. I-10.1038 / nrn2648 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• I-Arnsten AF, i-Wang MJ, iCaspalas CD (2012). I-Neuromodulation yomcabango: ukuguquguquka nobuthakathaka ekuvumelaneni kwenethiwekhi yangaphambi kwecortical. Neuron 76, 223-239. I-10.1016 / j.neuron.2012.08.038 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• Ascoli GA, Alonso-Nanclares L., Anderson SA, Barrionuevo G., Benavides-Piccione R., Burkhalter A., ​​et al. . (2008). Isigama sePetilla: igama lokuqanjwa kwezici ze-GABAergic interneurons ze-cortex yamandla okuzala. Nat. UMfu Neurosci. I-9, 557-568. I-10.1038 / nrn2402 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UBaddeley A. (1992). Ukusebenza kwememori. Isayensi 255, 556-559. I-10.1126 / isayensi.1736359 [I-PubMed] [Isiphambano Ref]
• Beasley CL, Reynolds GP (1997). Ama-neuron we-Parvalbumin-immunoreactive ancishiswa ku-cortex yokuqala ye-schizophrenics. Isazi. Res. I-24, 349-355. I-10.1016 / s0920-9964 (96) 00122-3 [I-PubMed] [Isiphambano Ref]
• I-Beaulieu JM, Gainetdinov RR (2011). I-physiology, isignesha kanye ne-chemacology ye-dopamine receptors. I-Pharmacol. IsAm. 63, 182-217. I-10.1124 / pr.110.002642 [I-PubMed] [Isiphambano Ref]
• Beevers CG, Clasen P., Stice E., Schnyer D. (2010). Izimpawu zokucindezelwa kanye nokulawulwa kokuqonda kwezimpawu zezimo zomoya: isifundo sokucabanga se-magnetic resonance esisebenzayo. I-Neuroscience 167, 97-103. I-10.1016 / j.neuroscience.2010.01.047 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• Belzung C., Turiault M., Griebel G. (2014). Ama-Optogenetics wokutadisha amasekhethi wokuziphatha okuphathelene nokwesaba nokudangala-okufana nokuhlaziywa: ukuhlaziya okubucayi. I-Pharmacol. I-Biochem. Behav. I-122, 144-157. 10.1016 / j.pbb.2014.04.002 [I-PubMed] [Isiphambano Ref]
• IBerridge CW (2008). Ukuguqulwa kwe-Noradrenergic ye-arousal. Brain Res. IsAm. 58, 1-17. I-10.1016 / j.brainresrev.2007.10.013 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UBossert JM, uStern AL, Theberge FR, Mashiant NJ, Wang HL, Morales M., et al. . (2012). Indima yokuqagela kusuka ku-cortex ye-ventral medial predomal cortex kuya ku-nucleus iqoqeka igobolondo ekubuyiselweni kwengqondo-okuyisisekelo kokufuna kwe-heroin. J. Neurosci. I-32, 4982-4991. I-10.1523 / JNEUROSCI.0005-12.2012 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UBoyden ES, uZhang F., uBamberg E., uNagel G., Deisseroth K. (2005). I-Millisecond-timescale, ukulawulwa komoya okuqondiswe ngofuzo komsebenzi we-neural. Nat. I-Neurosci. I-8, 1263-1268. I-10.1038 / nn1525 [I-PubMed] [Isiphambano Ref]
• UBrisch R., Saniotis A., Wolf R., Bielau H., Bernstein HG, Steiner J., et al. . (2014). Indima ye-dopamine ku-schizophrenia kusuka embonweni we-neurobiological and change: umbono wakudala, kepha namanje osesimweni esinamandla. Phambili. I-Psychiatry 5: 47. I-10.3389 / fpsyt.2014.00047 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• Britt JP, Benaliouad F., McDevitt RA, Stuber GD, Wise RA, Bonci A. (2012). Iphrofayili ye-Synaptic kanye nokuziphatha kokufakwayo okuningi kwe-glutamatergic kuma-nucleus accumbens. Neuron 76, 790-803. I-10.1016 / j.neuron.2012.09.040 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UCalu DJ, Kawa AB, Mashiant NJ, Navarre BM, Henderson MJ, Chen B., et al. . (2013). I-Optogenetic inhibition ye-dorsal medial prelineal cortex ifaka ukubuyiselwa kwengcindezi kokudla okuthandekayo kokudla kwamagundwane abesifazane. J. Neurosci. I-33, 214-226. I-10.1523 / JNEUROSCI.2016-12.2013 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UCardin JA, Carlén M., Meletis K., Knoblich U., Zhang F., Deisseroth K., et al. . (2009). Ukushayela kwamaseli okushesha kudonsa isigqi se-gamma futhi kulawula izimpendulo zemizwa. Imvelo 459, 663-667. I-10.1038 / nature08002 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• Carlén M., Meletis K., Siegle JH, Cardin JA, Futai K., Vierling-Claassen D., et al. . (2012). Indima ebucayi yama-receptors e-NMDA kuma-interneurons we-parvalbumin wokuqanjwa kwesigqi se-gamma nokuziphatha. Mol. I-Psychiatry 17, 537-548. 10.1038 / mp.2011.31 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UCarter ME, uYizhar O., Chikahisa S., Nguyen H., Adamantidis A., Nishino S., et al. . (2010). I-Tuning evousal module ye-optogenetic ye-locus coeruleus neurons. Nat. I-Neurosci. I-13, 1526-1533. I-10.1038 / nn.2682 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UCavanaugh J., Monosov IE, McAlonan K., Berman R., Smith MK, Cao V., et al. . (2012). I-optogenetic inactivation iguqula indlela yokuziphatha kwe-monkey visuomotor. Neuron 76, 901-907. I-10.1016 / j.neuron.2012.10.016 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UChallis C., Beck SG, uBerton O. (2014). Ukuguqulwa kwe-optogenetic kokwehla okokufaka kokukhethayo ku-dorsal raphe bidirectionally bias socialoaffective ukukhetha ngemuva kokwehlulwa komphakathi. Phambili. Behav. I-Neurosci. I-8: 43. 10.3389 / fnbeh.2014.00043 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• I-Chang CH, i-Chen MC, i-Qiu MH, uLu J. (2014). I-Ventromedial preortal cortex ilawula indlela yokuziphatha ecindezelayo efana nokuhamba kwamehlo okulala ku-rat. I-Neuropharmacology 86C, 125-132. I-10.1016 / j.neuropharm.2014.07.005 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UChaudhury D., uWalsh JJ, uFriedman AK, uJuarez B., uKu SM, uKoo JW, et al. . (2013). Ukulawulwa okusheshayo kokuziphatha okuhlobene nokucindezelwa ngokulawulwa kwama-midbrain dopamine neurons. Imvelo 493, 532-536. I-10.1038 / nature11713 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• I-Chen BT, i-Yau HJ, i-Hatch C., i-Kusumoto-Yoshida I., i-Cho SL, iHopf FW, et al. . (2013). Ukuhlenga i-cocaine ecijiswe ngaphambili kwe-cortex hypoactivity kuvimbela ukufuna okuphoqelekile kwe-cocaine. Imvelo 496, 359-362. I-10.1038 / nature12024 [I-PubMed] [Isiphambano Ref]
• I-Cho JH, iDeisseroth K., iBolshakov VY (2013). I-Synaptic encoding yokusaba ukuqothuka kumasekethe we-mPFC-amygdala. Neuron 80, 1491-1507. I-10.1016 / j.neuron.2013.09.025 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• I-Cho KK, i-Sohal VS (2014). Izindlela ze-optogenetic zokuphenya izindlela ze-neural zifakwe ku-schizophrenia nokuphazamiseka okuhlobene. Hum. Mol. Uhlobo. I-23, R64-R68. I-10.1093 / hmg / ddu225 [I-PubMed] [Isiphambano Ref]
• UChristophe E., Roebuck A., Staiger JF, Lavery DJ, Charpak S., Audinat E. (2002). Izinhlobo ezimbili ze-nicotinic receptors zidingida i-excitation ye-neocortical ungqimba I interneurons. J. Neurophysiol. I-88, 1318-1327. I-10.1152 / jn.00199.2002 [I-PubMed] [Isiphambano Ref]
• UChudasama Y., Diking JW, Nathwani F., Bouger P., Robbins TW (2004). Ukushintshwa kwe-Cholinergic ukunakwa kokubukwa nememori yokusebenza: imiphumela ehlukanisayo ye-basal forebrain 192-IgG-saporin izilonda kanye ne-infraprefrontal infusions ye-scopolamine. Funda. Mem. I-11, 78-86. 10.1101 / lm.70904 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UClark L., uChamberlain SR, uSahakian BJ (2009). Izindlela ze-Neurocognitive ekucindezelekeni: imiphumela yokwelashwa. Annu. UMfu Neurosci. I-32, 57-74. I-10.1146 / annurev.neuro.31.060407.125618 [I-PubMed] [Isiphambano Ref]
• UCortin J., Bienvenu TC, Einarsson EO, Herry C. (2013). Imibuthano ye-neuronal preortal cortex neuronal ekuziphatheni ngokwesaba. I-Neuroscience 240, 219-242. I-10.1016 / j.neuroscience.2013.03.001 [I-PubMed] [Isiphambano Ref]
• UCortin J., Chaudun F., Rozeske RR, Karalis N., Gonzalez-Campo C., Wurtz H., et al. . (2014). Ingaphambili le-parvalbumin interneurons lenza umsebenzi we-neuronal ukushayela ukuveza ukwesaba. Imvelo 505, 92-96. I-10.1038 / nature12755 [I-PubMed] [Isiphambano Ref]
• UCoutureau E., Killcross S. (2003). Ukuqanjwa kwe-infralimbic preortal cortex kuqinisa ukuphendula okuqondiswe kumgomo kumagundane okweqile. Behav. Brain Res. I-146, 167-174. I-10.1016 / j.bbr.2003.09.025 [I-PubMed] [Isiphambano Ref]
• UCovington HE, 3rd, uLebo MK, uMaze I., uVialou V., uHyman JM, uZaman S., et al. . (2010). Umphumela we-antidepressant wokukhuthaza i-optogenetic we-medial prefrontal cortex. J. Neurosci. I-30, 16082-16090. I-10.1523 / JNEUROSCI.1731-10.2010 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UCruikshank SJ, u-Ahmed OJ, uStevens TR, uPatrick SL, uGonzalez AN, u-Elmaleh M., et al. . (2012). Ukulawulwa kwe-Thalamic kokujikeleza kwe-1 yesendlalelo ku-cortex yangaphambili. J. Neurosci. I-32, 17813-17823. I-10.1523 / JNEUROSCI.3231-12.2012 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• Cruwys T., Haslam SA, Dingle GA, Haslam C., Jetten J. (2014). Ukudana komoya kanye nobunikazi bezenhlalo: isibuyekezo esihlanganayo. Pers. Umphakathi Psychol. IsAm. [Epub ngaphambi kokuphrinta]. I-18, 215-238. I-10.1177 / 1088868314523839 [I-PubMed] [Isiphambano Ref]
• Cruz FC, Koya E., Guez-Barber DH, Bossert JM, Lupica CR, Shaham Y., et al. . (2013). Ubuchwepheshe obusha bokuhlola iqhaza lama-envirles we-neuronal ekuluthweni kwezidakamizwa nokwesaba. Nat. UMfu Neurosci. I-14, 743-754. I-10.1038 / nrn3597 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UCzéh B., Müller-Keuker JI, Rygula R., Abumaria N., Hiemke C., Domenici E., et al. . (2007). Ukucindezelwa okungapheli kwezenhlalo kuvimbela ukwanda kweseli ku-cortex yabantu abadala medical prefrontal: i-hemispheric asymmetry kanye nokubuyela emuva ngokwelashwa kwe-fluoxetine. I-Neuropsychopharmacology 32, 1490-1503. 10.1038 / sj.npp.1301275 [I-PubMed] [Isiphambano Ref]
• UDeFelipe J., López-Cruz PL, Benavides-Piccione R., Bielza C., Larrañaga P., Anderson S., et al. . (2013). Ukuqonda okusha ekuhlukaniseni namagama we-cortical GABAergic interneurons. Nat. UMfu Neurosci. I-14, 202-216. I-10.1038 / nrn3444 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UDeisseroth K. (2010). Ukulawula ubuchopho ngokukhanya. Isayensi Am. I-303, 48-55. I-10.1038 / scienceamerican1110-48 [I-PubMed] [Isiphambano Ref]
• Dembrow N., Johnston D. (2014). I-subcircuit eqondene ne-neuromodulation ku-cortex yangaphambili. Phambili. Amasekethe we-Neural Circuits 8: 54. I-10.3389 / fncir.2014.00054 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UDerntl B., uSeidel EM, u-Eickhoff SB, uKellermann T., uGur RC, uSchneider F., et al. . (2011). Izixhumanisi ze-Neural zendlela yokuxhumana nabantu nokuhoxa ezigulini ezinokudangala okukhulu. Umphakathi I-Neurosci. I-6, 482-501. I-10.1080 / 17470919.2011.579800 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• Dias-Ferreira E., Sousa JC, Melo I., Morgado P., Mesquita AR, Cerqueira JJ, et al. . (2009). Ukucindezeleka okungapheli kubangela ukuhlelwa kabusha kwe-frontostriatal futhi kuthinta izinqumo. Isayensi 325, 621-625. I-10.1126 / isayensi.1171203 [I-PubMed] [Isiphambano Ref]
• UDiester I., Kaufman MT, Mogri M., Pashaie R., Goo W., Yizhar O., et al. . (2011). Ibhokisi lamathuluzi le-optogenetic lenzelwe izinyoni. Nat. I-Neurosci. I-14, 387-397. I-10.1038 / nn.2749 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• I-Disner SG, i-Beevers CG, i-Haigh EA, i-Beck AT (2011). Amasu wokusebenzisa imodeli wokucindezelwa kwengqondo. Nat. UMfu Neurosci. I-12, 467-477. I-10.1038 / nrn3027 [I-PubMed] [Isiphambano Ref]
• UDouglas RJ, uMartin KA (2004). Ukujikeleza kwe-Neuronal kwe-neocortex. Annu. UMfu Neurosci. I-27, 419-451. I-10.1146 / annurev.neuro.27.070203.144152 [I-PubMed] [Isiphambano Ref]
• UDrew MR, Fairhurst S., Malapani C., Horvitz JC, Balsam PD (2003). Imiphumela yabaphikisi be-dopamine ngesikhathi sezikhathi ezimbili. I-Pharmacol. I-Biochem. Behav. I-75, 9-15. I-10.1016 / s0091-3057 (03) 00036-4 [I-PubMed] [Isiphambano Ref]
• UDunnett SB, Nathwani F., Brasted PJ (1999). Izilonda zangaphambi kwangaphambi kokukhubazeka nezindondo zaphazamisa ukusebenza komsebenzi obambezelekile we-alternation kumagundane. Behav. Brain Res. I-106, 13-28. I-10.1016 / s0166-4328 (99) 00076-5 [I-PubMed] [Isiphambano Ref]
• UDurstewitz D., amaSeamans JK (2008). Umbono we-dopamine dual-state of preortal cortex dopamine usebenza ngokuhambisana ne-catechol-o-methyltransferase genotypes kanye ne-schizophrenia. Biol. I-Psychiatry 64, 739-749. 10.1016 / j.biopsych.2008.05.015 [I-PubMed] [Isiphambano Ref]
• U-Euston DR, Gruber AJ, McNaughton BL (2012). Indima ye-cialex yangaphambi kokukhumbula kwimemori nokwenza izinqumo. Neuron 76, 1057-1070. I-10.1016 / j.neuron.2012.12.002 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• Fales CL, Barch DM, Rundle MM, Mintun MA, Snyder AZ, Cohen JD, et al. . (2008). Ukushintshwa kokuphazanyiswa kwemizwa okushintshiwe ekuhambisaneni nobuchopho nokulawulwa kwengqondo ekucindezelekeni okukhulu. Biol. I-Psychiatry 63, 377-384. 10.1016 / j.biopsych.2007.06.012 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UFriedman AK, Walsh JJ, Juarez B., Ku SM, Chaudhury D., Wang J., et al. . (2014). Ukwandisa izindlela zokucindezeleka ku-midbrain dopamine neurons kufinyelela ukuqina kokuqina kwe-homeostatic. Isayensi 344, 313-319. I-10.1126 / isayensi.1249240 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• IGabret Pl, iWarner TA, iJays PR, iSalway P., iBusby SJ (2005). I-cortex yangaphambili kuleligundwane: ukuqagela ezikhungweni ezizimele ezizimele, ezimotweni nasezimilenzeni. J. Comp. INeurol. I-492, 145-177. I-10.1002 / cne.20738 [I-PubMed] [Isiphambano Ref]
• UGee S., Ellwood I., Patel T., Luongo F., Deisseroth K., Sohal VS (2012). Umsebenzi we-Synaptic unmasks dopamine D2 receptor module yesigaba esithile sosendlalelo lwe-V pyramidal neurons ku-cortex yangaphambili. J. Neurosci. I-32, 4959-4971. I-10.1523 / JNEUROSCI.5835-11.2012 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UGerits A., Farivar R., Rosen BR, Wald LL, Boyden ES, Vanduffel W. (2012). Izinguquko zenethiwekhi ezenziwa ngokusetshenzisanayo nezisebenzayo ezinhlanganweni. UCrr. Biol. I-22, 1722-1726. I-10.1016 / j.cub.2012.07.023 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UGilmartin MR, Helmstetter FJ (2010). Ukulandela ngomkhondo kanye nesimo sokwesaba sokuqukethwe kudinga umsebenzi we-neural kanye nokuhanjiswa okuncike kwe-NMDA ku-cortex ye-medial. Funda. Mem. I-17, 289-296. 10.1101 / lm.1597410 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UGilmartin MR, McEchron MD (2005). Ama-neurons awodwa ku-cialex ye-medial prefrontal ye-rat ekhombisa i-tonic kanye ne-phasic coding ngesikhathi sokulandela isimo sokusaba. Behav. I-Neurosci. I-119, 1496-1510. I-10.1037 / 0735-7044.119.6.1496 [I-PubMed] [Isiphambano Ref]
• UGilmartin MR, Miyawaki H., Helmstetter FJ, Diba K. (2013). Umsebenzi ongaphambili uhlanganisa izehlakalo zokungakwazi ukukhumbula kwimemori. J. Neurosci. I-33, 10910-10914. I-10.1523 / JNEUROSCI.0144-13.2013 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• IGoldstein RZ, Volkow ND (2011). Ukungasebenzi kwe-cortex yokuqala ekumlutha: okutholakele kwe-neuroimaging kanye nemiphumela yomtholampilo. Nat. UMfu Neurosci. I-12, 652-669. I-10.1038 / nrn3119 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UGotlib IH, uJoormann J., uMncane KL, uHallmayer J. (2008). Ukuvuselelwa kwe-axis kwe-HPA: indlela esekela izinhlangano phakathi kwe-5-HTTLPR, ukucindezela kanye nokudangala. Biol. I-Psychiatry 63, 847-851. 10.1016 / j.biopsych.2007.10.008 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UGradinaru V., Thompson KR, Zhang F., Mogri M., Kay K., Schneider MB, et al. . (2007). Amasu wokuqondisa nokufunda ngokuqhamuka okulawula okusheshayo kwe-neural ku-vitro naku-vivo. J. Neurosci. I-27, 14231-14238. I-10.1523 / jneurosci.3578-07.2007 [I-PubMed] [Isiphambano Ref]
• IGroenewegen HJ, iWight CI, i-Uylings HB (1997). Ubudlelwano be-anatomical be-cortex yangaphambili enezakhiwo ze-limbic kanye ne-basal ganglia. J. Psychopharmacol. I-11, 99-106. I-10.1177 / 026988119701100202 [I-PubMed] [Isiphambano Ref]
• UGunaydin LA, Grosenick L., Finkelstein JC, Kauvar IV, Fenno LE, Adhikari A., et al. . (2014). Amandla wokuqagela wemvelo we-neural angaphansi kokuziphatha komphakathi Iseli 157, 1535-1551. I-10.1016 / j.cell.2014.05.017 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UHamani C., Diwan M., Isabella S., Lozano AM, Nobrega JN (2010a). Imiphumela yamapharamitha wokukhuthaza ahlukile ekuphenduleni okubangelwa yizinhlungu zokuphakanyiswa kobuchopho kwe-medial prefrontal cortex ekujuleni kwamagundane. J. Psychiatr. Res. I-44, 683-687. I-10.1016 / j.jpsychires.2009.12.010 [I-PubMed] [Isiphambano Ref]
• UHamani C., Diwan M., waseMarto CE, uBrandão ML, uShumake J., Gonzalez-Lima F., et al. . (2010b). Imiphumela elwa ne-antidepressant efana nokukhuthaza ubuchopho be-medial prefrontal cortex ekujuleni kwamagundane. Biol. I-Psychiatry 67, 117-124. 10.1016 / j.biopsych.2009.08.025 [I-PubMed] [Isiphambano Ref]
• UHamani C., iMachado DC, i-Hipólide DC, iDubiela FP, iSuchecki D., iMiteo CE, et al. . (2012). Ukugqugquzela ubuchopho obujulile kubuyisela emuva ukufana nokuziphatha kwe-anhedonic kwimodeli engapheli yokudangala: indima ye-serotonin nengqondo ethathwe yi-neurotrophic factor. Biol. I-Psychiatry 71, 30-35. 10.1016 / j.biopsych.2011.08.025 [I-PubMed] [Isiphambano Ref]
• UHan X., Chow BY, uZhou H., uKlapoetke NC, uChuong A., uRajimehr R., et al. . (2011). Ukuzwela okuphezulu kokukhanya okukhulu kwe-neural silencer: ukuthuthukiswa kanye nokusetshenziswa kokulawulwa kwe-optogenetic ye-cortex engeyona eyabantu. Phambili. ISyst. I-Neurosci. I-5: 18. I-10.3389 / fnsys.2011.00018 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• IHan X., Qian X., Bernstein JG, Zhou HH, Franzesi GT, Stern P., et al. . (2009). Ukulawulwa kokukhanya kwe-Millisecond-timescale kwe-neural dynamics ebuchosheni obungeyona eyabantu. Neuron 62, 191-198. I-10.1016 / j.neuron.2009.03.011 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• Uzwa uMc, uZink AN, uWickman K. (2012). Ukulungiswa okwenziwe nge-cocaine kusignali ye-metabotropic inhibitory kuhlelo lwe-mesocorticolimbic. UMfu Neurosci. I-23, 325-351. I-10.1515 / revneuro-2012-0045 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• I-Heidbreder CA, Groenewegen HJ (2003). I-cialex ye-medial pre mapemaal ku-rat: ubufakazi bokwehlukaniswa kwe-dorso-ventral ngokusekelwe kwizimpawu zokusebenza nokusebenzayo. I-Neurosci. I-Biobehav. IsAm. 27, 555-579. 10.1016 / j.neubiorev.2003.09.003 [I-PubMed] [Isiphambano Ref]
• IHogarth L., i-Balleine BW, iCorbit LH, iKillcross S. (2013). Izinqubo zokufunda ezihlangene ezisekela ushintsho kusuka ekusetshenzisweni kwezidakamizwa zokuzijabulisa kuya kumlutha. U-Ann. I-NY Acad. Isayensi I-1282, 12-24. I-10.1111 / j.1749-6632.2012.06768.x [I-PubMed] [Isiphambano Ref]
• IHoover WB, iVertes RP (2007). Ukuhlaziywa kwe-anatomical of provent proionnt to the Cialex preialal cortex ku-rat. Isakhiwo sobuchopho. Funct. I-212, 149-179. I-10.1007 / s00429-007-0150-4 [I-PubMed] [Isiphambano Ref]
• UHübner C., Bosch D., Gall A., Lüthi A., Ehrlich I. (2014). I-Ex vivo disgment of optergenetically activated mPFC kanye ne-hippocampal okokufaka kuma-neuron ku-basolateral amygdala: imiphumela yokwesaba nememori engokomzwelo. Phambili. Behav. I-Neurosci. I-8: 64. 10.3389 / fnbeh.2014.00064 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UHumeau Y., Herry C., Kemp N., Shaban H., Fourcaudot E., Bissiere S., et al. . (2005). I-dendritic spine heterogeneity inquma ukuhlangana kwe-Hebrew ethize e-Amygdala. Neuron 45, 119-131. I-10.1016 / j.neuron.2004.12.019 [I-PubMed] [Isiphambano Ref]
• I-Hyman SE (2005). Umlutha: isifo sokufunda nenkumbulo. Am. J. Psychiatry 162, 1414-1422. I-10.1176 / appi.ajp.162.8.1414 [I-PubMed] [Isiphambano Ref]
• IHyman SE, iMalenka RC, iNestler EJ (2006). Izindlela zokusebenzisa umlutha: iqhaza lokufunda nememori elihlobene nomvuzo. Annu. UMfu Neurosci. I-29, 565-598. I-10.1146 / annurev.neuro.29.051605.113009 [I-PubMed] [Isiphambano Ref]
• U-Isaac JT, Ashby M., McBain CJ (2007). Indima ye-GluR2 subunit ekusebenzeni kwe-AMPA receptor kanye ne-synaptic plasticity. Neuron 54, 859-871. I-10.1016 / j.neuron.2007.06.001 [I-PubMed] [Isiphambano Ref]
• Jazayeri M., Lindbloom-Brown Z., Horwitz GD (2012). Ukunyakaza kwamehlo kwe-Saccadic kudalwe ukusebenza kwe-optogenetic ye-V1 yasesikhathini. Nat. I-Neurosci. I-15, 1368-1370. I-10.1038 / nn.3210 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• Ji G., Neugebauer V. (2012). Ukushintshwa kokuguqulwa komsebenzi we-medical preortal cortical usebenzisa ukuqoshwa kwe-vivo nama-optogenetics. Mol. Brain 5: 36. I-10.1186 / 1756-6606-5-36 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UJohn ER (2002). Ama-neurophysics ofokwazi. Brain Res. Brain Res. IsAm. 39, 1-28. I-10.1016 / s0165-0173 (02) 00142-x [I-PubMed] [Isiphambano Ref]
• I-Kalivas PW (2009). I-glutamate homeostasis hypothesis yomlutha. Nat. UMfu Neurosci. I-10, 561-572. I-10.1038 / nrn2515 [I-PubMed] [Isiphambano Ref]
• I-Kalivas PW, i-O'Brien C. (2008). Umlutha wezidakamizwa njenge-pathology ye-neuroplasticity ehleliwe. I-Neuropsychopharmacology 33, 166-180. 10.1038 / sj.npp.1301564 [I-PubMed] [Isiphambano Ref]
• I-Kalivas PW, iVolkow ND (2005). Isisekelo se-neural sokulutha: indlela yokugqugquzela nokukhetha. Am. J. Psychiatry 162, 1403-1413. I-10.1176 / appi.ajp.162.8.1403 [I-PubMed] [Isiphambano Ref]
• IKalivas PW, Volkow N., Seamans J. (2005). Isisusa esingenakulawuleka kumlutha: i-pathology ekudluliseleni kwe-glutamate kwangaphambili. Neuron 45, 647-650. I-10.1016 / j.neuron.2005.02.005 [I-PubMed] [Isiphambano Ref]
• Killcross S., Coutureau E. (2003). Ukudidiyelwa kwezenzo nemikhuba ku-cortex yama-medical predomal yamagundane. UCerebi. ICortex 13, 400-408. I-10.1093 / cercor / 13.4.400 [I-PubMed] [Isiphambano Ref]
• UKim J., Ghim JW, Lee JH, Jung MW (2013). Izixhumanisi ze-Neural zesikhathi sokuphumula ku-centex yangaphambili ye-rodent. J. Neurosci. I-33, 13834-13847. I-10.1523 / JNEUROSCI.1443-13.2013 [I-PubMed] [Isiphambano Ref]
• UKlein J., Ubusika C., uCoquery N., uHeinz A., uMorgenstern R., uKupsch A., et al. . (2010). I-Lesion ye-cialex ye-medial predomal cortex ne-subthalamic nucleus ngokukhethekile ithinta ekuziphatheni okufana nokudangala kumagundane. Behav. Brain Res. I-213, 73-81. I-10.1016 / j.bbr.2010.04.036 [I-PubMed] [Isiphambano Ref]
• U-Koenigs M., uGrafman J. (2009). I-neuroanatomy esebenzayo yokudangala: izindima ezihlukile ze-cortex ye-ventromedial ne-dorsolateral preortal cortex. Behav. Brain Res. I-201, 239-243. I-10.1016 / j.bbr.2009.03.004 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UKoya E., Uejima JL, Wihbey KA, uBossert JM, Ithemba BT, Shaham Y. (2009). Iqhaza le-cortex ye-ventral medial pre kuqalaal cortex ekufakweni kokufisa kwe-cocaine. I-Neuropharmacology 56 (Suppl. 1), 177-185. I-10.1016 / j.neuropharm.2008.04.022 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• Kumar S., Black SJ, Hultman R., Szabo ST, Demaio KD, Du J., et al. . (2013). Ukulawulwa kwe-cortical kwamanethiwekhi ahambisanayo. J. Neurosci. I-33, 1116-1129. I-10.1523 / JNEUROSCI.0092-12.2013 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UKvitsiani D., Ranade S., Hangya B., Taniguchi H., Huang JZ, Kepecs A. (2013). Hlukanisa okuphathelene nokuziphatha nenethiwekhi yezinhlobo ezimbili ze-interneuron ku-cortex yangaphambili. Imvelo 498, 363-366. I-10.1038 / nature12176 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• I-LaLumiere RT, i-Kalivas PW (2008). Ukukhishwa kwe-Glutamate emgogodleni we-nucleus accumbens kuyadingeka ekufuneni i-heroin. J. Neurosci. I-28, 3170-3177. I-10.1523 / JNEUROSCI.5129-07.2008 [I-PubMed] [Isiphambano Ref]
• I-LaLumiere RT, i-Niehoff KE, i-Kalivas PW (2010). I-cortex ye-infralimbic ilawula ukuhlanganiswa kokuqothulwa ngemuva kokuzibusa kwe-cocaine. Funda. Mem. I-17, 168-175. 10.1101 / lm.1576810 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• Lammel S., Tye KM, Warden MR (2014). Inqubekela phambili ekuqondeni ukuphazamiseka kwemizwa: i-optogenetic dissection yemijikelezo ye-neural. Uhlobo Brain Behav. I-13, 38-51. 10.1111 / gbb.12049 [I-PubMed] [Isiphambano Ref]
• Umhlaba BB, Narayanan NS, Liu RJ, Gianessi CA, Brayton CE, Grimaldi DM, et al. . (2014). Ama-dopamine neuron angaphambili e-Medial alawula ukungena kokudla. Nat. I-Neurosci. I-1, 17-248. I-253 / nn.10.1038 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• I-LeDoux JE (2000). Ukujikeleza kwemizwelo ebuchosheni. Annu. UMfu Neurosci. I-23, 155-184. I-10.1146 / annurev.neuro.23.1.155 [I-PubMed] [Isiphambano Ref]
• U-Lee AT, uGee SM, Vogt D., Patel T., Rubenstein JL, Sohal VS (2014a). Ama-neuron we-Pyramidal ku-cortex yangaphambili athola izinhlobo ezicashile zokwexwaya nokuvinjwa. Neuron 81, 61-68. I-10.1016 / j.neuron.2013.10.031 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• U-Lee HM, uGiguere PM, uRoth BL (2014b). Ama-DREADDs: Amathuluzi enoveli okutholakele izidakamizwa kanye nentuthuko. I-Drug Discov. Namuhla i-19, 469-473. I-10.1016 / j.drudis.2013.10.018 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• U-Lee AT, Vogt D., Rubenstein JL, Sohal VS (2014c). Isigaba se-GABAergic neurons ku-preortalal cortex sithumela ukuqagela kobude obude kuma-nucleus accumbens kanye nokubuyisa indlela yokuziphatha yokugwema kakhulu. J. Neurosci. I-34, 11519-11525. I-10.1523 / JNEUROSCI.1157-14.2014 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• Lewis DA, Hashimoto T., Volk DW (2005). I-Cortical inhibitory neurons ne-schizophrenia. Nat. UMfu Neurosci. I-6, 312-324. I-10.1038 / nrn1648 [I-PubMed] [Isiphambano Ref]
• Lisman J. (2012). Ukudabukisa, ukuvimbela, ama-oscillations wendawo, noma izihibe ezinkulu: yini ebangela izimpawu ze-schizophrenia? UCrr. Opin. I-Neurobiol. I-22, 537-544. I-10.1016 / j.conb.2011.10.018 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• Little JP, Carter AG (2012). Ukuxhunyaniswa kwe-subcellular synaptic kwengqimba ye-2 pyramidal neurons ku-cortex ye-medial prefrontal. J. Neurosci. I-32, 12808-12819. I-10.1523 / JNEUROSCI.1616-12.2012 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• Little JP, Carter AG (2013). Amasu we-Synaptic angaphansi kokuxhuma okuqinile kokubuyisela phakathi kwe-cortex yangaphambi kwangaphambi kwe-cortex ne-basolateral amygdala. J. Neurosci. I-33, 15333-15342. I-10.1523 / JNEUROSCI.2385-13.2013 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• Liu X., Ramirez S., Pang PT, Puryear CB, Govindarajan A., Deisseroth K., et al. . (2012). Ukugqugquzelwa kwe-optogenetic ye-hramocampal engram kusebenze ukukhumbula ukukhumbula. Imvelo 484, 381-385. I-10.1038 / nature11028 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• ULebo MK, uCovington HE, u-3rd, uChaudhury D., uFriedman AK, uLanga H., uDamez-Werno D., et al. . (2010). Ukulahleka kohlobo oluthile lweseli kwe-BDNF signaling mimics optogenetic yokulawulwa komvuzo we-cocaine. Isayensi 330, 385-390. I-10.1126 / isayensi.1188472 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• ULebo MK, uKarsten SL, uGrey M., Geschwind DH, uYang XW (2006). I-FACS-profiling profiling ye-striatal provenion proon subtypes ebuchosheni bezinsana nabadala begundane. Nat. I-Neurosci. I-9, 443-452. I-10.1038 / nn1654 [I-PubMed] [Isiphambano Ref]
• Lobo MK, Nestler EJ, Covington HE, 3rd (2012). Ukusetshenziswa okungenzeka kwama-optogenetics ocwaningweni lokudangala. Biol. I-Psychiatry 71, 1068-1074. 10.1016 / j.biopsych.2011.12.026 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• Lobo MK, Zaman S., Damez-Werno DM, Koo JW, Bagot RC, DiNieri JA, et al. . (2013). Ukungeniswa kwe-ΔFosB kuma-striatal medium spiny neuron subtypes ekuphenduleni kwe-stimuli ye-pharmacological, yokomzwelo neye-optogenetic. J. Neurosci. I-33, 18381-18395. I-10.1523 / JNEUROSCI.1875-13.2013 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• Ama-Lubers BR, van Mourik Y., Schetters D., Smit AB, De Vries TJ, Spijker S. (2014). Uhlobo lwangaphambi kwe-gamma-aminobutyric acid uhlobo lokufakelwa kwe-receptor lulawula ukubuyela emuva kwe-cue-eyenziwe ekufuneni i-nicotine. Biol. I-Psychiatry 76, 750-758. 10.1016 / j.biopsych.2014.02.001 [I-PubMed] [Isiphambano Ref]
• Luján R., Marron Fernandez de Velasco E., Aguado C., Wickman K. (2014). Ukuqonda okusha emandleni okwelapha eziteshi ze-Girk. Ithrend Neurosci. I-37, 20-29. I-10.1016 / j.tins.2013.10.006 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• Lüscher C., Huber KM (2010). Ukudangala kwesikhathi eside kweqembu 1 mGluR-based synaptic yesikhathi eside: izindlela kanye nemithelela yokujikeleza nezifo. Neuron 65, 445-459. I-10.1016 / j.neuron.2010.01.016 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UMa YY, u-Lee BR, u-Wang X., uGuo C., uLiu L., uCui R., et al. . (2014). Ukuguqulwa kwesimo seBidirectional of incubation of cocaine craine ngokulungisa kabusha okususelwa kusisekelo se-cortex ye-cortex ukuze kuqoqwe ukuqagelwa. Neuron 83, 1453-1467. I-10.1016 / j.neuron.2014.08.023 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• Mahar I., Bambico FR, Mechawar N., Nobrega JN (2014). Ukucindezelwa, i-serotonin ne-huroocis ye-hippocampal maqondana nokudangala kanye nemiphumela yokuphikisa. I-Neurosci. I-Biobehav. IsAm. 38, 173-192. 10.1016 / j.neubiorev.2013.11.009 [I-PubMed] [Isiphambano Ref]
• UMaren S., Phan KL, Liberzon I. (2013). Ubuchopho bokuqukethwe: imiphumela yokushaywa kovalo, ukuqothuka kanye ne-psychopathology. Nat. UMfu Neurosci. I-14, 417-428. I-10.1038 / nrn3492 [I-PubMed] [Isiphambano Ref]
• UMartín-García E., uCourtin J., uRenault P., uFiancette JF, uWurtz H., uSimonnet A., et al. . (2014). Imvamisa ye-cocaine self-management ithonya ekufuneni izidakamizwa ku-rat: ubufakazi be-optogenetic bendima ye-cortex ye-prelimbic. I-Neuropsychopharmacology 39, 2317-2330. 10.1038 / npp.2014.66 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UMatis J., Tye KM, Ferenczi EA, Ramakrishnan C., O'Shea DJ, Prakash R., et al. . (2012). Izimiso zokusebenzisa amathuluzi we-optogenetic asuselwa ekuqhathaniseni ngokuthe ngqo kokuqhathanisa kwama-opsins amancane. Nat. Izindlela 9, 159-172. I-10.1038 / nmeth.1808 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UMayberg HS, uLozano AM, uVoon V., McNeely HE, uSeminowicz D., uHamani C., et al. . (2005). Ukugqugquzela kobuchopho obujulile bokucindezelwa okungazweli ekwelashweni. Neuron 45, 651-660. I-10.1016 / j.neuron.2005.02.014 [I-PubMed] [Isiphambano Ref]
• McFarland K., Lapish CC, Kalivas PW (2003). Ukukhishwa kwe-glutamate yangaphambili engxenyeni engaphakathi ye-nucleus accumbens mediates ukubuyiselwa kwe-cocaine okuvuselelekile ekuziphatheni okuphathelene nezidakamizwa. J. Neurosci. I-23, 3531-3537. [I-PubMed]
• McLaughlin J., Bona i-RE (2003). Inactivation ekhethiwe ye-dorsomedial prefrontal cortex kanye ne-basolateral amygdala attenuates conditioned-cued reseatat of extinguated cocaine-beha behaviour in rats. I-Psychopharmacology (Berl) 168, 57-65. I-10.1007 / s00213-002-1196-x [I-PubMed] [Isiphambano Ref]
• Meyer-Lindenberg A. (2010). Ukusuka kumamephu kuya kwizixhobo ngokusebenzisa i-neuroimaging ye-schizophrenia. Imvelo 468, 194-202. I-10.1038 / nature09569 [I-PubMed] [Isiphambano Ref]
• I-Milad MR, i-Quirk GJ (2002). Ama-Neurons kwimemori yesiginali ye-medial prefrontal cortex yokuqothuka kwesaba. Imvelo 420, 70-74. I-10.1038 / nature01138 [I-PubMed] [Isiphambano Ref]
• I-Milad MR, i-Quirk GJ (2012). Ukwesaba ukuqothulwa njengemodeli yokuhumusha i-neuroscience: iminyaka eyishumi yenqubekela phambili. Annu. IsAm Psychol. I-63, 129-151. I-10.1146 / annurev.psych.121208.131631 [I-PubMed] [Isiphambano Ref]
• Miller EK, Cohen JD (2001). Umbono wokuhlanganisa we-preortal cortex function. Annu. UMfu Neurosci. I-24, 167-202. I-10.1146 / annurev.neuro.24.1.167 [I-PubMed] [Isiphambano Ref]
• Morgan Morgan, LeDoux JE (1995). Umthelela ohlukile we-dorsal ne-ventral medial preortal cortex yokutholwa kanye nokuqothulwa kokwesaba okunesimo kumagundane. Behav. I-Neurosci. I-109, 681-688. I-10.1037 // 0735-7044.109.4.681 [I-PubMed] [Isiphambano Ref]
• UMurrough JW, u-Iacoviello B., uNeumeister A., ​​uCharney DS, u-Iosifescu DV (2011). Ukungasebenzi kahle kwengqondo ekucindezelekeni: amasu we-neurocircuitry namasu amasha okwelapha. I-Neurobiol. Funda. Mem. I-96, 553-563. 10.1016 / j.nlm.2011.06.006 [I-PubMed] [Isiphambano Ref]
• I-Narayanan NS, i-Land BB, iSolder JE, iDeisseroth K., i-DiLeone RJ (2012). Isiginali ye-dopamine yokuqala ye-D1 iyadingeka ukulawula okwesikhashana. I-Proc. Natl. I-Acad. Isayensi I-USA 109, 20726-20731. I-10.1073 / pnas.1211258109 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• I-Nestler EJ, iHyman SE (2010). Izinhlobo zezilwane zokuphazamiseka kwe-neuropsychiatric. Nat. I-Neurosci. I-13, 1161-1169. I-10.1038 / nn.2647 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UPascoli V., uTerrier J., u-Espongegues J., uValjent E., O'Connor EC, uLüscher C. (2014). Izinhlobo ezihlukanisayo zezingxenye zokulawulwa kwe-cocaine-evoke plasticity zokubuyela emuva. Imvelo 509, 459-464. I-10.1038 / nature13257 [I-PubMed] [Isiphambano Ref]
• Pascoli V., Turiault M., Lüscher C. (2012). Ukubuyela emuva kwe-cocaine-evoke synaptic potentiation kusetha kabusha ukusebenza kokuzibandakanya kokusebenzisa izidakamizwa. Imvelo 481, 71-75. I-10.1038 / nature10709 [I-PubMed] [Isiphambano Ref]
• UPeled A. (2011). Ukulawulwa kwe-optogenetic neuronal ku-schizophrenia. UMedi. I-Hypotheses 76, 914-921. I-10.1016 / j.mehy.2011.03.009 [I-PubMed] [Isiphambano Ref]
• UPeter J., Kalivas PW, Quirk GJ (2009). Imibuthano yokuqothula ukwesaba nomlutha ogqagqene ku-cortex yangaphambili. Funda. Mem. I-16, 279-288. 10.1101 / lm.1041309 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UPeter J., LaLumiere RT, Kalivas PW (2008). I-infralimbic preortal cortex ibhekele ukuvimbela ukufuna kwe-cocaine ekucimeni amagundane. J. Neurosci. I-28, 6046-6053. I-10.1523 / JNEUROSCI.1045-08.2008 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UPeter J., Pattij T., De Vries TJ (2013). Ukuhlwaya izinkumbulo ze-cocaine kanye ne-heroin: izindima eziphambukayo ngaphakathi kwe-cortex ye-ventromedial prefrontal. Amathrenda Pharmacol. Isayensi I-34, 689-695. I-10.1016 / j.tips.2013.10.004 [I-PubMed] [Isiphambano Ref]
• UPetreanu L., uHuber D., uSobczyk A., Svoboda K. (2007). Imephu yesekethe ye-Channelrhodopsin-2-esiza izigaba zokubonisa ukubonwa okude. Nat. I-Neurosci. I-10, 663-668. I-10.1038 / nn1891 [I-PubMed] [Isiphambano Ref]
• URalph RJ, uVarty GB, uKelly MA, uLang YM, uCaron MG, uRubinstein M., et al. . (1999). I-dopamine D2, kepha hhayi i-D3 noma i-D4, i-receptor subtype ibalulekile ukuze iphazamise ukunqotshwa kokuvimbela okukhiqizwe yi-amphetamine kumagundane. J. Neurosci. I-19, 4627-4633. [I-PubMed]
• URamos BP, uStark D., uVerduzco L., uVan Dyck CH, u-Arnsten AF (2006). Isisusa se-Alpha2A-adrenoceptor sithuthukisa ukulawulwa kokuziphatha kwangaphambi kokucabanga kokuziphatha ngokuvimbela ukusayina kwe-cAMP ezilwaneni ezigugayo. Funda. Mem. I-13, 770-776. 10.1101 / lm.298006 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• Robbins TW, Roberts AC (2007). Ukulawulwa okungafani kokusebenza kwe-fronto-Executive yi-monoamines ne-acetylcholine. UCerebi. ICortex 17 (Suppl. 1), i151-i160. I-10.1093 / cercor / bhm066 [I-PubMed] [Isiphambano Ref]
• Robinson TE, Berridge KC (1993). Isisekelo se-neural sokufisa izidakamizwa: umbono wokukhuthaza ukuthambekela. Brain Res. Brain Res. IsAm. 18, 247-291. I-10.1016 / 0165-0173 (93) 90013-p [I-PubMed] [Isiphambano Ref]
• Ro Roje JL, Ghee S., Bona RE (2008). Ukujikeleza kwe-neural okuyisisekelo sokubuyiselwa kokuziphatha okufuna i-heroin kumodeli yezilwane yokuphinda ubuye. I-Neuroscience 151, 579-588. I-10.1016 / j.neuroscience.2007.10.012 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• I-Romanki LM, iTian B., uFritz J., iMishkin M., uGoldman-Rakic ​​PS, uRauschecker JP (1999). Ukusakaza okumbaxambili kwezivumelwano zokuhlolisisa kuqondiswa kuzizinda eziningi ku-cortex yangaphambili yangaphambili. Nat. I-Neurosci. I-2, 1131-1136. I-10.1038 / 16056 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• I-Ross CA, iMargolis RL, i-Read SA, uPletnikov M., uCoyle JT (2006). I-Neurobiology ye-schizophrenia. Neuron 52, 139-153. I-10.1016 / j.neuron.2006.09.015 [I-PubMed] [Isiphambano Ref]
• Rossetti ZL, Carboni S. (2005). Ukuphakanyiswa kweNoradrenaline ne-dopamine kukhokho wangaphambili wegundane kwimemori yokusebenza kwendawo. J. Neurosci. I-25, 2322-2329. I-10.1523 / jneurosci.3038-04.2005 [I-PubMed] [Isiphambano Ref]
• URossi MA, uHayrapetyan VY, uMaimon B., uMake K., uJe HS, uYin HH (2012). Izindlela zokuqala zangaphambi kokushintshana kokubambezeleka kokubambezeleka kumagundane. J. Neurophysiol. I-108, 1211-1222. I-10.1152 / jn.01060.2011 [I-PubMed] [Isiphambano Ref]
• USartorius A., Kiening KL, Kirsch P., Von Gall CC, Haberkorn U., Unterberg AW, et al. . (2010). Ukuxoshwa kokuxineka okukhulu ngaphansi kokuvuselelwa kobuchopho obujulile kwe-habenula ye-lateral esigulini esivumelanisa nokwelashwa. Biol. I-Psychiatry 67, e9-e11. 10.1016 / j.biopsych.2009.08.027 [I-PubMed] [Isiphambano Ref]
• Ama-Seamans JK, uYang CR (2004). Izici eziyinhloko nezindlela zokuguqulwa kwe-dopamine module ku-cortex yangaphambili. Inqubekela phambili. I-Neurobiol. I-74, 1-58. 10.1016 / j.pneurobio.2004.05.006 [I-PubMed] [Isiphambano Ref]
• USeeman P., Kapur S. (2000). I-Schizophrenia: ama-dopamine amaningi, ama-receptors e-D2 ngaphezulu. I-Proc. Natl. I-Acad. Isayensi I-USA 97, 7673-7675. I-10.1073 / pnas.97.14.7673 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• USeif T., Chang SJ, uSimms JA, uGibb SL, uBabagar J., Chen BT, et al. . (2013). I-Cortical activation ye-NABDARs esebenzayo ye-accumbens isebenzisa ukuphuza ukuphuza utshwala obungahlangani. Nat. I-Neurosci. I-16, 1094-1100. I-10.1038 / nn.3445 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• I-Sesack SR, i-Deutch AY, i-Roth RH, iBunney BS (1989). Inhlangano ye-topographical yokuqagela okuhle kwe-cialex yangaphambi kokukhipha ku-rat: isifundo se-anterograde traching traching ne-Phaseolus vulgaris leucoagglutinin. J. Comp. INeurol. I-290, 213-242. I-10.1002 / cne.902900205 [I-PubMed] [Isiphambano Ref]
• Sheline YI, Intengo JL, Yan Z., Mintun MA (2010). I-MRI esebenza ngokusebenza kwesimo ekucindezelekeni okungenasisekelo ikhuphule ukuxhumana phakathi kwamanethiwekhi nge-dorsal nexus. I-Proc. Natl. I-Acad. Isayensi I-USA 107, 11020-11025. I-10.1073 / pnas.1000446107 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• IShenhav A., Botvinick MM (2013). Isenzo esishukumiselekile: ukukhanya okusha kumasekethe angaphambili-e-neuromodulatory. UCrr. Biol. I-23, R161-R163. I-10.1016 / j.cub.2012.12.028 [I-PubMed] [Isiphambano Ref]
• ISer--Mercado D., uPadilla-Coreano N., i-Quirk GJ (2011). Izindima ezihlukanisayo ze-cortices zangaphambi kokuqala kanye ne-infralimbic, i-hralocampus ye-ventral kanye ne-basolateral amygdala enkulumweni nasekuqothulweni kokwesaba okunesimo. I-Neuropsychopharmacology 36, 529-538. 10.1038 / npp.2010.184 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• I-Slattery DA, i-ID yeNeumann, uCryan JF (2011). Ukuqalwa kwesikhashana kwe-infralimbic cortex kubangela imiphumela efana ne-antidepressant ku-rat. J. Psychopharmacol. I-25, 1295-1303. I-10.1177 / 0269881110368873 [I-PubMed] [Isiphambano Ref]
• USmith KS, uGraybiel AM (2013). Umbono opharetha ombaxambili wokuziphatha okujwayelekile okubonisa amandla we-cortical and striatal. Neuron 79, 361-374. I-10.1016 / j.neuron.2013.07.032 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• Smith KS, Virkud A., Deisseroth K., Greybiel AM (2012). Ukulawulwa okuguqukayo kwe-inthanethi kokuziphatha okujwayelekile ngokwe-optogenetic perturbation of cortex yangaphambi kwangaphambi kwekhaya. I-Proc. Natl. I-Acad. Isayensi I-USA 109, 18932-18937. I-10.1073 / pnas.1216264109 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• I-Sohal VS (2012). Ukuqonda kuma-oscillations we-cortical avela ezifundweni ze-optogenetic. Biol. I-Psychiatry 71, 1039-1045. 10.1016 / j.biopsych.2012.01.024 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• USohal VS, uZhang F., uYizhar O., uDeisseroth K. (2009). Ama-neuron we-Parvalbumin nemigqi ye-gamma kuthuthukisa ukusebenza kwesekethe cortical. Imvelo 459, 698-702. I-10.1038 / nature07991 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• ISouthwick SM, iVythilingam M., uCharney DS (2005). I-psychobiology yokudangala nokuqina kokuxineka: imiphumela yokuvimbela nokwelashwa. Annu. UMfu Clin. Psychol. I-1, 255-291. I-10.1146 / annurev.clinpsy.1.102803.143948 [I-PubMed] [Isiphambano Ref]
• Sparta DR, Hovelsø N., Mason AO, Kantak PA, Ung RL, Decot HK, et al. . (2014). Ukwenza kusebenze kwe-preortal cortical parvalbumin interneurons kusiza ukuqothulwa kokuziphatha okufuna umvuzo. J. Neurosci. I-34, 3699-3705. I-10.1523 / jneurosci.0235-13.2014 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• ISparta DR, iStamatakis AM, uPhillips JL, uHovelso N., uVan Zessen R., uStuber GD (2012). Ukwakhiwa kwezicucu ze-optical ezifakelwayo zesikhathi eside zokuxhaphaza i-optogenetic yemijikelezo ye-neural. Nat. I-Protoc. I-7, 12-23. I-10.1038 / nprot.2011.413 [I-PubMed] [Isiphambano Ref]
• UStefanik MT, Kalivas PW (2013). Ukuhlukaniswa kwe-optogenetic kokuqagela kwe-basolateral amygdala ngesikhathi sokubuyiselwa kwe-cueine okuyisisekelo sokufuna i-cocaine. Phambili. Behav. I-Neurosci. I-7: 213. 10.3389 / fnbeh.2013.00213 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• Stefanik MT, Moussawi K., Kupchik YM, Smith KC, Miller RL, Huff ML, et al. . (2013). I-Optogenetic inhibition yokufuna i-cocaine kumagundane. Umlutha. Biol. I-18, 50-53. I-10.1111 / j.1369-1600.2012.00479.x [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• Steinberg EE, Christoffel DJ, Deisseroth K., Malenka RC (2014). Ukukhanyisa ukujikeleza okuhlobene nokuphazamiseka kwengqondo ngama-optogenetics. UCrr. Opin. I-Neurobiol. I-30C, 9-16. I-10.1016 / j.conb.2014.08.004 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• I-Sternson SM, i-Roth BL (2014). Amathuluzi e-Chemogenetic okuhlolisisa imisebenzi yobuchopho. Annu. UMfu Neurosci. I-37, 387-407. I-10.1146 / annurev-neuro-071013-014048 [I-PubMed] [Isiphambano Ref]
• IStuber GD, iSparta DR, iStamatakis AM, uVan Leeuwen WA, iHardjoprajitno JE, i-Cho S., et al. . (2011). Ukudluliselwa okujabulisayo kusuka ku-amygdala kuya kuma-nucleus accumbens kusiza ukufuna umvuzo. Imvelo 475, 377-380. I-10.1038 / nature10194 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• USuska A., uLee BR, uHuang YH, uDong Y., uSchlüter OM (2013). Ukuthuthuka okukhethekile kokugcina komugqa wokuqala we-cortex kuya ku-nucleus accumbens indlela nge-cocaine. I-Proc. Natl. I-Acad. Isayensi I-USA 110, 713-718. I-10.1073 / pnas.1206287110 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UTiffany ST, Conklin CA (2000). Imodeli yokucubungula ingqondo yokuphuza utshwala nokusebenzisa utshwala ngokuphoqelela. Umlutha 95 (Suppl. 2), S145-S153. I-10.1046 / j.1360-0443.95.8s2.3.x [I-PubMed] [Isiphambano Ref]
• I-Touriño C., Eban-Rothschild A., de Lecea L. (2013). Ama-optogenetics ezifweni zezifo zengqondo. UCrr. Opin. I-Neurobiol. I-23, 430-435. I-10.1016 / j.conb.2013.03.007 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• I-Treadway MT, Buckholtz JW, Zald DH (2013). Ukuxineka okutholakele kubikezela ukuguqulwa komvuzo kanye nokulahleka kokuphendula ngempendulo ku-cortex yokwelashwa kwangaphambili. Phambili. Hum. I-Neurosci. I-7: 180. I-10.3389 / fnhum.2013.00180 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• I-Treadway MT, Zald DH (2011). Ukucabanga kabusha kwe-anhedonia ekucindezelekeni: izifundo ezivela ku-neuroscience yokuhumusha. I-Neurosci. I-Biobehav. IsAm. 35, 537-555. 10.1016 / j.neubiorev.2010.06.006 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UTye KM, uDeisseroth K. (2012). Uphenyo lwe-optogenetic yemijikelezo ye-neural engaphansi kwezifo zobuchopho kumamodeli ezilwane. Nat. UMfu Neurosci. I-13, 251-266. I-10.1038 / nrn3171 [I-PubMed] [Isiphambano Ref]
• I-Tzschentke TM (2001). I-Pharmacology kanye ne-pharmacology yokuziphatha ye-mesocortical dopamine system. Inqubekela phambili. I-Neurobiol. I-63, 241-320. I-10.1016 / s0301-0082 (00) 00033-2 [I-PubMed] [Isiphambano Ref]
• Uhlhaas PJ, Singer W. (2006). I-synchrony ye-Neural ekuphazamisekeni kobuchopho: ukuhambisana kokungasebenzi kahle kwengqondo kanye ne-pathophysiology. Neuron 52, 155-168. I-10.1016 / j.neuron.2006.09.020 [I-PubMed] [Isiphambano Ref]
• Uhlhaas PJ, Singer W. (2010). I-oscillations engajwayelekile ye-neural ne-synchrony ku-schizophrenia. Nat. UMfu Neurosci. I-11, 100-113. I-10.1038 / nrn2774 [I-PubMed] [Isiphambano Ref]
• Uhlhaas PJ, Haenschel C., Nikolić D., Singer W. (2008). Indima ye-oscillations ne-synchrony kumanethiwekhi e-cortical kanye nokuhambisana kwawo okubalulekile kwe-pathophysiology ye-schizophrenia. Isazi. Bull. I-34, 927-943. I-10.1093 / schbul / sbn062 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• Uylings HB, Groenewegen HJ, Kolb B. (2003). Ingabe amagundane ane-cortex yokuqala? Behav. Brain Res. I-146, 3-17. I-10.1016 / j.bbr.2003.09.028 [I-PubMed] [Isiphambano Ref]
• UVan den Oever MC, Rotaru DC, Heinsbroek JA, Gouwenberg Y., Deisseroth K., Stuber GD, et al. . (2013). Amaseli we-pentex we-pentex prelineal cortex preaphaladi anendawo yesikhashana ekhumbulekayo nasekuqothulweni kwememori ehlobene ne-cocaine. J. Neurosci. I-33, 18225-18233. I-10.1523 / jneurosci.2412-13.2013 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UVan den Oever MC, uSpijker S., uSmit AB, uDe Vries TJ (2010). Izindlela zangaphambili zekhampasi ye-cortex ekusebenzeni kwezidakamizwa nokubuyela emuva. I-Neurosci. I-Biobehav. IsAm. 35, 276-284. 10.1016 / j.neubiorev.2009.11.016 [I-PubMed] [Isiphambano Ref]
• UVeerakumar A., ​​uChallis C., uGupta P., uDa J., u-Upadhyay A., Beck SG, et al. . (2014). Imiphumela efana ne-antidepressant efana nokukhuthaza ubuchopho be-cortical ejulile ihlangana nezimo ezihambelana ne-pro-neuroplastic ye-serotonin system. Biol. I-Psychiatry 76, 203-212. 10.1016 / j.biopsych.2013.12.009 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• I-Vertes RP (2004). Ukuqagela okwehlukile kwe-infralimbic ne-prelimbic cortex ku-rat. I-Synapse 51, 32-58. I-10.1002 / syn.10279 [I-PubMed] [Isiphambano Ref]
• I-Vertes RP (2006). Ukuxhumana phakathi kwe-cortex ye-medial predomal cortex, i-hippocampus ne-midline thalamus ekusebenzeni okungokomzwelo nokuqondayo ku-rat. I-Neuroscience 142, 1-20. I-10.1016 / j.neuroscience.2006.06.027 [I-PubMed] [Isiphambano Ref]
• IVialou V., iBagot RC, uCahill ME, uFerguson D., Robison AJ, Dietz DM, et al. . (2014). Isiphalaphala sangaphambi kwecortical yokucindezelwa- nokuziphatha okuhlobene nokukhathazeka okulawulwa yi-cholecystokinin: indima ye-ΔFosB. J. Neurosci. I-34, 3878-3887. I-10.1523 / jneurosci.1787-13.2014 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• Volman I., Roelofs K., Koch S., Verhagen L., Toni I. (2011). Ukuvinjwa kokukhubazeka kwe-preerioral cortex kulawula izenzo zokomoya zomphakathi. UCrr. Biol. I-21, 1766-1770. I-10.1016 / j.cub.2011.08.050 [I-PubMed] [Isiphambano Ref]
• UVoorn P., Vanderschuren LJ, Groenewegen HJ, Robbins TW, Pennartz CM (2004). Ukubeka i-spin ekuhlukaniseni kwe-dorsal-ventral ye-striatum. Ithrend Neurosci. I-27, 468-474. I-10.1016 / j.tins.2004.06.006 [I-PubMed] [Isiphambano Ref]
• Wang X., Carlén M. (2012). Ukuhlukaniswa kwe-optogenetic kokukhanya kwemininingwane ye-cortical processing-ecwebezelayo ku-schizophrenia. Brain Res. I-1476, 31-37. I-10.1016 / j.brainres.2012.04.015 [I-PubMed] [Isiphambano Ref]
• UWarden MR, uSelimbeyoglu A., Mirzabekov JJ, Lo M., Thompson KR, Kim SY, et al. . (2012). Ukuqagela kwe-cortex-brainstem neuronal eyaphambili elawula impendulo enseleleni yokuziphatha. Imvelo 492, 428-432. I-10.1038 / nature11617 [I-PubMed] [Isiphambano Ref]
• I-Willcocks AL, McNally GP (2013). Indima ye-cortex yangaphambi kokucwaswa kokuqothulwa kanye nokubuyiselwa kokufuna utshwala kumagundane. I-Euro. J. Neurosci. I-37, 259-268. I-10.1111 / ejn.12031 [I-PubMed] [Isiphambano Ref]
• UWillner P., Scheel-Kruger J., Belzung C. (2013). I-neurobiology yokudangala kanye nesenzo sokulwa nokucindezela. I-Neurosci. I-Biobehav. IsAm. 37, 2331-2371. 10.1016 / j.neubiorev.2012.12.007 [I-PubMed] [Isiphambano Ref]
• Inhlangano Yezempilo Yomhlaba (2012). Ishidi Fact Sheet No. 290. Kutholakala online ku: http://www.who.int/mediacentre/factsheets/fs369/en/. Kutholwe ngo-Agasti 21, 2014.
• I-Yizhar O. (2012). Ukuqonda kwe-optogenetic ekusebenzeni kokuziphatha komphakathi. Biol. I-Psychiatry 71, 1075-1080. 10.1016 / j.biopsych.2011.12.029 [I-PubMed] [Isiphambano Ref]
• U-Yizhar O., Fenno LE, Davidson TJ, Mogri M., Deisseroth K. (2011a). Ama-optogenetics ezinhlelweni ze-neural. Neuron 71, 9-34. I-10.1016 / j.neuron.2011.06.004 [I-PubMed] [Isiphambano Ref]
• U-Yizhar O., Fenno LE, Prigge M., Schneider F., Davidson TJ, O'shea DJ, et al. . (2011b). I-Neocortical ukucaphuna / ibhalansi yokuvinjwa ekusebenzeni kolwazi kanye nokungasebenzi kahle kwezenhlalo. Imvelo 477, 171-178. I-10.1038 / nature10360 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UZhang Z., uCordeiro Matos S., Jego S., Adamantidis A., Seguela P. (2013). I-Norepinephrine ushayela umsebenzi ophikelelayo ku-cortex yangaphambili nge-alnerXistic alpha1 kanye ne-alpha2 adrenoceptors. I-PloS One 8: e66122. I-10.1371 / journal.pone.0066122 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]
• UZhang F., Gradinaru V., Adamantidis AR, Durand R., Airan RD, de Lecea L., et al. . (2010). Ukuphenywa kwe-optogenetic yemijikelezo ye-neural: ubuchwepheshe bokuhlola ukwakheka kobuchopho be-mammalian. Nat. I-Protoc. I-5, 439-456. I-10.1038 / nprot.2009.226 [Isihloko samahhala se-PMC] [I-PubMed] [Isiphambano Ref]