Ho hopola le ho lemalla ho arolelana neural circuitry le mekhoa ea limolek'hule. (2004)

Maikutlo: Joalokaha thuto e bolela, ho lemalla joala ho kenyelletsa liphetoho tsamaisong e tloaelehileng ea boko. Ke ka lebaka leo bokhoba ba lithethefatsi le boits'oaro bo lebisang liphetohong tse tšoanang tse kholo ho potoloho e le 'ngoe (sesepa sa forebrain medial).

Neuron. 2004 Sep 30; 44 (1): 161-79.

Kelley AE.

mohloli o moholo

Lefapha la Psychiatry le Neuroscience Training Program, Univesithi ea Wisconsin-Madison Medical School, 6001 Research Park Boulevard, Madison, WI 53719, USA. [imeile e sirelelitsoe]

inahaneloang

Tsoelo-pele ea bohlokoa mohopolong lilemong tse leshome tse fetileng e bile kutloisiso ea hore ts'ebetso ea ts'ebeliso ea lithethefatsi e arolelana litaba tse tloaelehileng le neural plasticity e amanang le ho ithuta le ho hopola ka tlhaho. Mekhoa ea mantlha e kenyelletsang dopamine, glutamate, le liphiri tsa eona tse kahare le tsa genomic e 'nile ea tsepamisa maikutlo sebakeng sena sa lipatlisiso. Ts'ebetso tsena tse peli tsa methapo ea kutlo, tse ajoang haholo libakeng tse ngata tsa cortex, system ea limbic, le basal ganglia, li bonahala li bapala karolo ea bohlokoa ho susumetseng, ho ithuteng, le ho hopoleng, ka hona ho fetolela boits'oaro bo feto-fetohang. Leha ho le joalo, lithethefatsi tse ngata tsa tlhekefetso li sebelisa litlamorao tsa tsona hantle lits'ebetsong tsena mme li khona ho etsa liphetoho tsa cellular ho li-network tsa khothalletso, ka hona li lebisa boits'oarong bo bobe. Likhopolo tsa morao-rao le lipatlisiso mabapi le sehlooho sena li hlahlojoa ho tsoa ho pono ea litsamaiso, ka ho totobatsa ho ikhethang liseleng, limolek'hule, le boits'oaro ba dopamine D-1 le glutamate NMDA ho saena, ho ithuta ka matla, le maemo a cue lithethefatsi.

Sengoloa sa sehlooho

Selelekela

Ka nako e 'ngoe nalaneng ea rona ea ho iphetola ha lintho, batho ba ile ba qala ho sebelisa lithethefatsi tsa kelello. Ts'ebeliso ea semela sa coca e kanna ea qaloa morao lilemong tse ka bang 7000, mme ho na le bopaki ba nalane ea hore "betal nut" (e nang le arecoline, agonist ea muscarinic) e hlafuniloe lilemong tsa 11,000 tse fetileng Thailand le 13,000 lilemong tse fetileng ho Timor (Sullivan le Hagen, 2002). Ho joalo, ho na le kamano e haufi ea ho iphetola ha lintho pakeng tsa limela le li-neurotransmitters tsa boko; Tsamaiso ea methapo ea methapo ea kutlo le li-invertebrates e na le li-transmitter tsa lik'hemik'hale le li-receptor tse tšoanang hantle le sebopeho sa lintho tse entsoeng ka litlhare tse entsoeng ke semela. Cannabinoids, nicotine, cocaine le opiates li sebetsa ka liprotheine tsa boko tse tsamaisang likarolo tsena ka kotloloho; joala le bona bo ama likarolo tse sa tsamaelaneng. Ho batho, lithethefatsi tsena le tse ling tsa tlhekefetso li khona ho tsosa maikutlo a monate kapa thabo le ho imolla maikutlo a mabe a kang ho tšoenyeha le khatello ea maikutlo. (Nesse le Berridge, 1997). Leha ho le joalo, bathong ba tlokotsing, ts'ebeliso e sa khaotseng ea lithethefatsi tse nang le kelello e na le kotsi ea ho itšepa le ho lemalla, e khethiloeng ke tahlehelo ea taolo holim'a boitšoaro bo batlang lithethefatsi le litlamorao tse mpe tse mpe Koob et al. 2004 'me Volkow le Fowler 2000. Papali ea bokhoba ba tahi e hapile tlhokomelo ea lingaka, litsebi tsa kelello le litsebi tsa meriana ka mashome a lilemo-lemo empa ke lilemong tsa morao tjena moo tsoelopele e kholo litabeng tsa limolek'hule, kelello le boits'oaro li faneng ka sebopeho se kopanyang sa ho rarolla bothata bona.

Mohlomong tšibollo ea bohlokoa ka ho fetesisa e kenyelletsa kutloisiso e ntseng e hola ea hore ts'ebetso ea bokhoba ba litaba e arolelana lintho tse ts'oanang le polasetiki ea neural e amanang le ho ithuta le moputso oa tlhaho. Ka ho khetheha, mekhoa ea mantlha ea cellular e kenyeletsang dopamine, glutamate, le litekanyetso tsa bona tse ikhethileng le genomic e bile sepheo sa lipatlisiso tse matla likarolong ka bobeli tsa thuto e amanang le moputso le bokhoba. Ts'ebetso tsena tse peli tsa methapo ea kutlo, tse ajoang haholo libakeng tse ngata tsa cortex, limbic system, le basal ganglia, li bonahala li bapala karolo ea bohlokoa ho susumetseng, ho ithuteng, le ho hopoleng. Hajoale ho lumeloa hore ho tsamaisoa ha limolek'hule tse amanang le litsamaiso tsa dopaminergic le glutamatergic, haholo-holo ka dopamine D-1 le glutamate N-methyl-D-aspartate (NMDA) le α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors, ke ketsahalo e bohlokoa ho kenyelisong ea li-transceptular tse ngotsoeng le tse fetoletsoeng, tse lebisang ho liphetoho tse feto-fetohang polelo ea gene le polasetiki ea synaptic, ho kopanya hape marang-rang a neural, 'me qetellong boits'oaro. Ka tloaelo, boko bo sebelisa mekhoa ena ho ntlafatsa likarabo ho libopuoa tse ntlafatsang ho phela; ho hlakile hore ho fetoha ka mokhoa o hlakileng ho ithuta hore na lijo li fumanoa kae kapa tlasa maemo afe kapa afe le ho fetola liketso tsa boitšoaro ka nepo. Lithethefatsi tse ngata tsa tlhekefetso li hlahisa litlamorao tsa tsona hantle litseleng tsena mme ho bonahala li khona ho tlisa liphetoho tsa nako e telele haholo, mohlomong ebile li tšoarella, 'me li lebise boits'oarong bo bobe. Berke le Hyman 2000, Hyman le Malenka 2001, Kelley le Berridge 2002 'me Koob le Le Moal 1997.

Thutong ena, ke ikemiselitse ho shebisisa haholo marang-rang a dopaminergic le glutamatergic neuronal le ho sebelisana ha bona. Ke qala ka ho nahana ka bothata ba tlhaho le tšusumetso ea eona ea tlhaho, e totobatsang kholo ea pele ea phylogenetic ea li-system tsa limolek'hule tse loketseng polasetiki. Patlisiso ea hajoale mabapi le li-dopamine le li-glutamate-coded system tse amanang le polasetiki ea synaptic le ho ithuta ka motor e lumellanang e ea hlahlojoa hape. Kamora nako ke leka ho hokahanya liphumano tsena le mosebetsi o amanang le lithethefatsi tsa tlhekefetso, o etsa lintho tse tšoanang mabapi le mekhoa e arolelanoang lipakeng tsa memori le ho lemalla. Ntle le ho bonesa mekhoa ea mantlha, ho sebetsa ka polasetiki ka har'a litabatabelo tsa takatso ea takatso ho na le litlamorao tsa bohlokoa bakeng sa bophelo ba motho. Ts'ebeliso e mpe ea lithethefatsi (tšebeliso ea lithethefatsi) le moputso oa rona oa tlhaho oa bohlokoa ka ho fetisisa, lijo (botenya), leha li sa amane ka ho hlaka mabapi le thuto ea kelello, leha ho le joalo hammoho li etsa mathata a bohlokoa haholo a bophelo bo botle ba sechaba a tobaneng le sechaba sa ntlafatso sa lekholong la 21st.

Moralo oa ho iphetola ha lintho oa Plasticity in System Motivational Systems

Bakeng sa ho utloisisa kamano lipakeng tsa ho hopola le ho lemalla, ho bohlokoa haholo ho nahana ka tšebeliso ea lithethefatsi le lits'ebetso tseo ba etsang lintho ho tsona ka pono e pharalletseng ea ho iphetola ha lintho. Joalokaha ho boletsoe ka holimo, ka nako e 'ngoe kholisong ea khopolo ea ho iphetola ha lintho Homo sapiens, batho ka bomong le litso tse fapaneng ba ile ba qala ho kenyelletsa tšebeliso ea lithethefatsi le joala bophelong ba letsatsi le letsatsi. Boitšoaro bona bo kanna ba ba ba hlaha ka tšohanyetso ho pepesetsoa likhakanyo lijalo tsa limela tsa hlaha ha ba ntse ba theola. Mohlala, bopaki ba baepolli ba lintho tsa khale bo fana ka maikutlo a hore bo-aborigine hohle Australia ba ile ba sebelisa limela tsa tlhaho tsa nicotine tse nang le lilemo tse mashome a likete pele ho likolone (Sullivan le Hagen, 2002), mme e thehiloe hantle hore batho ba matsoalloa a tikolohong ea Andean Amerika Boroa ba ile ba tlatlapa semela sa coca hantle pele se lengoa lilemong tsa 7000 tse fetileng (Schultes, 1987). Li-vertebrates tsa Fructivore li qetile ho ja joala bo tlase ka lilemo tse limilione, ka litholoana tse butsoitseng tse jeoang ke linonyana le liphoofolo tse anyesang, 'me joala bo khothatsang bo' nile ba lengoa ke mekhatlo ea batho ka lilemo tse fetang 6000 (Dudley, 2002). Ka ho hlakileng, hore na o kopane le ho qala kapa ho hlahisoa ka mokhoa o hlophisitsoeng, lithethefatsi tse matlafatsang ke ka ho tiisa, ka hore boits'oaro bo tla phetoa ho fumana lintho tsena. Lithethefatsi tse sebelisang matlafatsang ha se ntho e ikhethileng ea batho. Mefuta e mengata, joalo ka likhoto, litoeba le litoeba tse se nang botho, e tla sebelisa lithethefatsi tse ngata tse sebelisoang kapa tse hlekefelitsoeng ke batho joalo ka joala, heroin le opiate tse ling, li-cannabinoids, nikotine, cocaine, amphetamine le caffeine. Liphoofolo li tla etsa karabelo e sebetsang ka mohlala, ho hatella lere-bakeng sa ho kenya motsoako o kenang ka har'a metsoako ena, 'me maemong a mang (joalo ka koae) e tla tsamaisa lithethefatsi ho isa lefung, li hlokomolohe meputso e meng ea bohlokoa joalo ka lijo le metsi Aigner le Balster 1978 'me Bozarth le Wise 1985. Hoa makatsa hore malinyane a matsatsi a 5 a lilemo li ithuta ho rata monko o amanang le morphine (Kehoe le Blass, 1986); esita le crayfish e bonts'a libaka tse ntle tsa li-psychostimulants (Panksepp le Huber, 2004). Hlokomela hore mehlaleng ena kaofela, ho ithuta se etsahetse — mmele o bonts'a tloaelo ea boitšoaro e bonts'ang boleng bo itseng ba boleng ba moputso, kapa hantle haholo, boleng ba mmuso boo o bo etsang. Liphumano tsena tsa boits'oaro ha li supe feela hore ho na le likarolo tse tloaelehileng tsa lik'hemik'hale le tsa limolek'hule tse fanang ka litheko tse fumanehang ho phyla empa hape hore karolo ea bohlokoa ea ts'ebelisano ea setho sa lithethefatsi ke polasetiki. Hobaneng ho le joalo?

Pele u nahana ka hore na liketsahalo kapa litlhare li fetola bophelo ba hau bokong joang, ho bohlokoa ho qala ka likarolo tse peli tsa bohlokoa. Taba ea pele, e bile e na le mekhoa ea khale ea ho susumetsa ea khale e teng bokong mme e bile teng ka lilemo tse limilione tsa thuto ea ho iphetola ha lintho ho netefatsa hore li ikamahanya le maemo le ho phela. Motso oa khale oa tšusumetso o ka bonoa le ho libaktheria, e leng mofuta oa pele oa bophelo lefatšeng. Ka mohlala, E. coli Libaktheria li na le mochine o rarahaneng oa liphatsa tsa lefutso o li qhekellang ho limatlafatsi tse kang tsoekere le hole le lintho tse hohelang le tse chefo Adler 1966 'me Qi le Adler 1989. Taba ea bobeli ke hore, lits'ebetso tsena li etsoa ke maikutlo a susumetsang tikoloho, ke hore, tlhaiso-leseling, 'me ha ba kenelletse joalo, ba hlahisa linaha tse ikemetseng (maikutlo a monate kapa a fosahetseng) tseo e leng bakhanni ba nakoana, ba matla le / kapa batšehetsi ba boitšoaro. Maikutlo a monate ka kakaretso a sebeletsa ho kopanya setho le lisebelisoa tse ka bang molemo - lijo, metsi, tšimo, ho hola kapa menyetla e meng ea boithabiso. Maikutlo a fosahetseng a sebeletsa ho sireletsa setho sa tlhaho kotsing - haholoholo ho netefatsa likarabo tsa ho loana kapa ho fofa kapa maano a mang a ts'ireletso, joalo ka boits'oaro bo ikokobelitseng kapa ho ikhula, ts'ireletso ea sebaka kapa setho, le ho qoba bohloko. Sistimi ea bono e hlokomela lefatše le kantle le kahare ('mele) bakeng sa lipontšo le ho laola ho theoha ha maikutlo ana. Ho feta moo, lets'oao la lik'hemik'hale le molek'hule molemong oa liphatlalatso tse matlafatsang le ho qalisoa ha polasetiki (mohlala, li-monoamine, li-protein tsa "protein" tse nang le protheine, proteni kinases, CREB) ke karolo e bolokiloeng haholo ho pholletsa le kholo (Kelley, 2004a).

Mekhoa e Khethehileng ea Morero oa Motheo

Mabapi le semolao sa pele, boko ba vertebrate bo na le litsamaiso tse fapaneng tse ikhethileng tse fetoletsoeng merero e ikhethileng, joalo ka ho ruruha, puisano ea sechaba le ho kenella. Lisebelisoa tse tsamaellanang li teng bokong ba invertebrate. Moralo oa neuroanatomical bakeng sa tlhophiso ea litsamaiso tse susumetsang o sa tsoa ntlafatsoa haholo, o shebane le se bitsoang "likholomo tsa boitšoaro tsa boitšoaro" (Swanson, 2000). Swanson e fana ka maikutlo a hore mekhoa e hlalositsoeng hantle haholo ebile e hokahane haholo ea ts'ebetso ea kelello ho hypothalamus le ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso li ikemiselitse ho boloka tsebo le boitšoaro bo ikhethang bo hlokahalang bakeng sa ho pholoha: boits'oaro bo potlakileng ba tšireletso, le boits'oaro, boits'ireletso, le bohlola. Liphoofolo tse nang le mekhoa e sa foleng eo ho eona hypothalamus e sa bolokoang e ka ja kapa ea ja hanyane, ea e-ja, ea ikatisa hape ea bonts'a boits'oaro bo itšireletsang - athe kelello e ts'oarehile ka tlase ho hypothalamus, phoofolo e bonts'a likotoana tsa boits'oaro bona feela, bo thusitsoeng ke jenereithara ea mohlala. bokong ba kelello. Lits'ebetso tse ngata tse rarahaneng tsa "neurochemically", "anatomically" le "li-coded" li teng ho ntlafatsa bophelo ba motho ka boeena le mefuta ea tsona, ho tloha ho li-opioids tse fanang ka maikutlo a khatello ea maikutlo malulong a ratoa le 'm'a bona ho ea ho li-steroid tsa bong bo laolang karohano ea thobalano le boits'oaro. Kahoo, tlala, lenyora, thobalano, mabifi, le tlhoko ea moea, metsi le sebaka sa bolulo kapa sebaka ke tse ling tsa lintho tse susumetsang tse teng ho phehella setho ho batla mohopolo o tla sebetsana le ho phela ha ona oa mantlha.

Litsamaiso tse susumetsang li sebetsa ke Salient Stimuli, E Fumanehang le linaheng tse amehang

Leha ho le joalo, linaha tsena ha li sebetse ka linako tsohle (ntle le ho phefumoloha); feela ha ho arabeloa maemo, maemo kapa litlhoko tse itseng ho tla sebelisoa li-circuits tsa sepheo, ho lebisang mohlaleng oa bobeli-hore litsela tsena li hlahisoa ke maemo a susumetsang a tlhaho kapa a kantle a maikutlo le a ntlafalitsoeng le ho matlafatsoa ke e ama or Maikutlo. Ho hatisitsoe hore khothatso ke "'nang"Bakeng sa boits'oaro bo thehiloeng tsamaisong ea taolo ea boitšoaro (Buck, 1999). Maikutlo kapa linaha tse amehang ke bala haholo ea litsamaiso tsena tse ikhethang tsa morero ha o kengoa tšebetsong, ke hore pontšo ya bokgoni. Mohlala, lintho tsohle tse phelang li na le mekhoa ea tlhaho ea ho itšireletsa ha o ts'osa kapa o kotsing; ha ts'okelo e le teng, lits'ebetso li qala ho sebetsoa le mekhoa ea ts'ireletso ea mefuta-futa e qala. Kahoo, litsamaiso tsa neural le tsa lik'hemik'hale li teng bakeng sa ho kenella, ho ba mabifi le ho itšireletsa, empa hangata tsena li bonahala, kapa li “tsamaee” (motso oa lentsoe la Latin), tlasa maemo a nepahetseng. Sebaka sena se bohlokoa bakeng sa temohisiso ea ho lemalla, hobane lithethefatsi tsa tlhekefetso li fana ka litlamorao tsa nakoana maikutlong (mohlala, heroin kapa cocaine e susumetsang euphoria, joala kapa benzodiazepines e kokobetsa ho tšoenyeha, tlhokomeliso ea nicotine) boemo ba phomolo ba litsamaiso tsa mantlha tsa susumetso le maikutlo a bona a ho chorisa. Pono e reriloeng ea mehopolo ena, e boetse e tšohloa ke Nesse le Berridge (1997) e bontšoa ka Setšoantšo sa 1.

Balk Circuitry E Akarelletsa mohopolong le ho lemalla

Tlaleho e boletsoeng esale pele e fana ka maikutlo a hore ho na le likhokahano tse ikhethang tsa boko tse fanang ka tšusumetso le maikutlo le hore tšebetso le ho ikamahanya le maemo (polasetiki) ka har'a marang-rang ana li lumelloa ke ho saena le ho etsahalla limolek'hule. Lilemong tse mashome a morao tjena, tsebo mabapi le marang-rang ana e hatetse pele ka lebelo le utloisisehang ka botlalo ka tšebetso ea mokhatlo, ho hokahana, ts'ebetso ea methapo le kutloano, biology ea molek'hule, le karolo mohlaleng oa boitsoaro le boits'oaro. Morero oa karolo ena ke ho fana ka setšoantšo se akaretsang sa lintlha tsa bohlokoa le tlhophiso ea mantlha ea marangrang ana, ka ho shebana haholo le libaka tsa boko le litsela tse atisang ho ba le takatso ea ho ithuta le ho lemalla lithethefatsi. Litlhahlobo tse ngata tse tebileng tsa sebopeho sa "anatomy" tse amanang le boits'oaro bo susumetsang li teng, tseo 'mali a li romelletsoeng bakeng sa tlhaiso-leseling e qaqileng hammoho le litlamorao tsa ho hlaka ha boko Risold et al. 1997 'me Swanson 2000. Moko-motheo oa taba ke hore, ka ho iphetola ha lintho, ho rarahana ho tsoelang pele ha tlhaho le lisele tsa corticothalamostriatal circry ho thusitse taolo e kholo le tšebelisano e rarahaneng ka li-circuits tse thata tsa "hypothalamic-brainstem" ("li-collans tsa boitšoaro," kapa lits'ebetso tse ikhethang). Ka lebaka la polasetiki e ngata ea cortex le libaka tse amanang le tsona tse kang striatum, liphoofolo tse anyesang li khona ho fetoha ka mokhoa o fetelletseng oa ts'ebetso mme, joalo ka tšusumetso ea ts'ebetso ea ts'ebetso, joalo ka ha e le hantle, li ts'oaroa haholo ho lithethefatsi tse sebelisang litsamaiso tsena. Setšoantšo sa 2 e fana ka setšoantšo sa lits'ebetso tsena tse loketseng tsa neural.

Puisano ea Puseletso pakeng tsa Tsamaiso ea Morero o Ikhethileng oa Morero le Neocortex e Atolositsoeng

Khubu ea mofuta ona oa motheo oa boits'oaro bo susumetsoang ke kananelo ea likenyelletso tse kholo ho li-system tsena tsa hypothalamic, likarolo tsa mokhatlo oa eona mabapi le libaka tse ling tse kholo tsa boko, le sepheo sa bona (bona Setšoantšo sa 2). Joalokaha ho hlalositsoe kaholimo, lits'ebetso tse susumetsang maikutlo li susumetsoa ke matšoao a itseng — khaello ea matla, ho se leka-lekane ha lintho tse sa bonahaleng, litekanyetso tsa bophelo bo bobe, tšusumetso ea ts'usumetso - e lebisang ts'ebetsong le ho qala (hammoho le ho khaotsa) ts'ebetso litseleng tse ikhethang tsa boko, ka hona likarabo tse hlahisang. . Ho lipopae tse phahameng, matšoao a neural le a lik'hemik'hale a tsoang lits'ebetsong tsa maikutlo a fihla moleng oa taolo ea boitšoaro ka mekhoa e mengata, ka mekhoa ea anatomical le neuroendocrine. Leha ho le joalo, karolo ea bobeli ea bohlokoa ka ho hlakileng khokahanong ea taolo ea boits'oaro e tsoa ho cortex ea likhoerekhoere, ho kenyelletsa le barekisi ba maholo ba ka kotloloho le ba sa tobang ho tsoa libakeng tse kang hippocampus, amygdala, preortalal cortex, striatum le pallidum. Ka lebaka la lipehelo tsena, mantlha a susumetsang a khona ho fihlella bokhoni bo rarahaneng ba ho rarahana, ho lemoha, le ho hloaea ba "cortex ea" cerebral cortex. Mohlala, hippocampus ke sebopeho sa boko se phethang karolo ea bohlokoa khokahanong ea memori e amanang, ho kenyeletsa le ho kopanya leseli la tikoloho le ho ithuta tlhaiso-leseling e amanang lipakeng tsa susumetso ea tikoloho. (Morris et al., 2003). Litlatsetso tsa Hippocampal tse tsoang subiculum innervate karolo ea caudal ea kholomo e kentsoeng ho etseng le ho fana ka tlhahisoleseling ea bohlokoa ea sebaka ho laola maano a ho tsamaea; lisele tsa sebaka li fumanoa libakeng tsa 'mele ea liphoofolo tse anyesang hammoho le hippocampus, anterior thalamus, le striatum Blair et al. 1998 'me Ragozzino et al. 2001. Karolo ea amygdala ho boleng ba moputso le ho ithuta Mok'hadinale et al. 2002 'me Schoenbaum et al. 2000, haholoholo likarolong tsa eona tsa morao-rao le tsa basolatal (tse amanang haufi-ufi le cortex ea frontotemporal) li ka susumetsa hypothalamus ea morao, moputso oa bohlokoa le sebaka se kopaneng sa hypothalamus. Ka sebele, lithuto tsa morao-rao li tšehelitse khopolo ena; disconnection of the amygdalo-lateral hypothalamic pathway ha e felise lijo tse nang le karolo e le 'ngoe, empa tlhahlobo e poteletseng ea boleng bo bapisoang ba lijo tse thehiloeng ho ithuteng kapa lithahasellong tsa maikutlo (Petrovich et al., 2002). Mosebetsing o mong oa rona oa morao-rao, ho inactivation ea amygdala ho thibela ho bua ha boits'oaro bo kenang bo kopantsoeng le "striatal-hypothalamic circry" (E tla latela al., 2004). Cortex ea pele le eona ke karolo e bohlokoa ea marang-rang a tšusumetso, ts'ebetso ea ts'ebetso ea botsamaisi, mohopolo oa ho sebetsa, le tataiso ea karabelo; Ntle le khokahano e kholo ea ho iphetetsa le libaka tse ling tse ngata tsa cortical, le eona e sebetsa haholo ho hypothalamus (Floyd et al., 2001). Ntle le tšusumetso ea li-hypothalamo-brainstem pathways, libaka tsena kaofela tse bohlokoa tsa cortical — hippocampus, amygdala, le cortex ea pele-li etsa morero o moholo ho striatum, li sebelisa glutamate e le "neurotransmitter" ea mantlha Setšoantšo sa 2). The thalamus e boetse e romella likhakanyo tse matla tsa glutamate-coded tsohle tsa neocortex le striatum. Likarolo tsena kaofela li na le li-receptor tse ka sehloohong tsa li-glutamate receptors — NMDA, AMPA / kainate, le li-receptor tsa metabotropic. Kaha ts'ebetso e itšetlehileng ka tšebetso, glutamate-coded synaptic ke mohlala oa mantlha oa polasetiki ea nako e telele tsamaisong ea methapo (Malenka le Nicoll, 1999), ha ho makatse hore ts'ebetso ea glutamatergic ho li-network tsena tse rarahaneng e ka fetola haholo ts'ebetso ea marang-rang le ea sebopuoa, joalo ka ha ho tla hlalosoa ka tlase.

Karolo e 'ngoe ea bohlokoa ho polasetiki e fumanehang lipotolohong tsena ke dopamine (DA). Dopaminergic neurons li fumaneha bohareng ba mokokotlo, kahare ho sebaka sa karoloana ea sekhahla le substantia nigra. Ba romela li-axon tsa bona ka har'a mokotla o ka pele oa boko le libaka tse pharalletseng ka har'a sistimi e hlalositsoeng kaholimo-haholo-holo striatum, preortal cortex, amygdala le hippocampus. Kamohelo ea Dopaminergic le tšusumetso ea li-intracellular tsa ho saena ha DA li buelloa ka mefuta e 'meli e meholo ea li-receptor tsa G tse kopantseng liprotheine tsa G, lelapa la D-1 (D-1 le D-5) le lelapa la D-2 (D-2/3 le D-4). Li-amine tse ling, joalo ka serotonin le norepinephrine, tse bolokang libaka tsena tsa boko bo ka pele le tsona li na le karolo ea bohlokoa ho polasetiki ea synaptic; Leha ho le joalo, ho tloha ha nts'etsopele ea likhopolo tse kholo tsa bokhoba le ts'usumetso e thehiloe holima karolo ea dopamine, puisano ea hajoale e tla fokotsoa ts'ebelisanong ea sistimi le glutamate. Karolo e 'ngoe ea bohlokoa ea sebopeho se amanang le ngangisano ea hajoale ke ho hlophisa li-terminals tsa dopaminergic le glutamatergic haufi haholo le methapo e tšoanang ea dendritic Sesack le Pickel 1990, Smith le Bolam 1990 'me Totterdell le Smith 1989. Mohlala oa tokisetso ena ho "striatal medium spiny neuron" e bonts'oa Setšoantšo sa 3.

Monyetla oa polasetiki ea cellular libakeng tsa cortical le striatal o atolosoa haholo ha o bapisoa le li-system tsa brainstem le hypothalamic. Ho joalo, mekhoa ea liphatsa tsa lefutso e ka senola keketseho ena kholisong ea ho iphetola ha lintho. Mefuta e amanang le polasetiki, joalo ka li-protheine tsa protheine, CREB, liphatsa tsa lefutso tsa kapele, le liprotheine tsa dysity tsa poso, li matlafalitsoe makaleng a corticostriatal. Mohlala o tsoang linthong tsa rona, o bonts'itsoeng Setšoantšo sa 4, e bontša hore cortex le striatum, bapisoa le meetso ea diencephalic, li na le sehlahisoa sa protheine ea mofuta oa liphatsa tsa lefutso. zif268 (Eo hape a tsejoa e le NGFI-A), ntlha ea ho ngoloa e ka amehang ho glutamate- le dopamine-Mediated polasetiki Keefe le Gerfen 1996 'me Wang le McGinty 1996. Ka hona, phylogenetically morao-rao e ntlafalitsoeng le ho hola ha boko (neocortex) e na le mohala o matla oa ho buisana le ho susumetsa likholomo tsa boitšoaro tsa baholo-holo mme o khona ho etsa cellular e rarahaneng e thehiloeng boiphihlelo.

Joalo ka ha tšimoloho ea lentsoe e ka fana ka maikutlo, sepheo se tlameha ho qetella se hlahisitse liketso tsa boitšoaro. Ketso e etsahala ha sepheo sa ts'ebetso ea lits'ebetso tsena se saennoe-ekaba ka ho tsoa ha autonomic (sekhahla sa pelo, khatello ea mali), tlhahiso ea visceroendocrine (cortisol, adrenaline, tokollo ea lihormone tsa thobalano), kapa tlhahiso ea somatomotor (mohlala, pina ea boitšoaro, sebopeho sa sebini, sefahleho / likarabo tse fanoang ka molomo, litšireletso tse sireletsang kapa tse holofatsang). Nakong ea puisano e kopanetsoeng ea litloaelo tse susumetsoang tse itšetlehileng ka moelelo oa taba, ho sebelisoa mekhoa e fapaneng ea lits'ebetso tsena tsa motlakase. Ehlile, lits'ebetso tsohle tsa taolo ea boits'oaro li sebetsa ka kotlolloho ho litsela tsena tse tsamaeang ka motlakase (bona Setšoantšo sa 2). Leha ho le joalo, ho liphoofolo tse anyesang, taolo e etsoang ka boithaopo le e etsoang ka boithaopo e boetse e matlafatsoa ke ts'ebetso e kholo ea lits'ebetso tsa cortical ho marang-rang a mantlha a matla a maikutlo. Ho feta moo, ho na le puisano e pharalletseng pakeng tsa methapo ea methapo ea kutlo le likhokahano tsa motlakase tsa motlakase. Molao-motheo o mong o moholo bakeng sa tlhophiso ea likholomo tsa taolo ea boitšoaro ke hore li sebetsa hantle haholo morao ho tsamaiso ea methapo ea kelello / tsamaiso ea boithaopo ka kotloloho kapa ka kotloloho ka dorsal thalamus, joalo ka ha ho bonts'itsoe ho Setšoantšo sa 2 Risold et al. 1997 'me Swanson 2000. Mohlala, hoo e batlang e le merero eohle ea hypothalamus e eang ho dorsal thalamus, eo ka eona merero e sebetsang libakeng tse atileng tsa neocortex. Ho feta moo, lits'ebetso tsa morao-rao tse nang le li-neuropeptide-coded tse sa tsoa supa li senotse hore orexin / hypocretin- le melanin e tsepamisang lisele tse nang le lisele tse kahare ho hypothalamus ea morao-rao (eo ka boeona e nang le phihlello e haufi ea proocrine, matla a lekanang, le libaka tsa autonomic) ka kotlolloho libakeng tse pharalletseng ka har'a neocortex, amygdala, hippocampus, le ventral striatum 'me e ka ba tsa bohlokoa haholo bakeng sa melao ea boits'oaro ba mmuso le ho tsosa Baldo et al. 2003, Espana et al. 2001 'me Peyron et al. 1998. Setšoantšo sa 5 e bonts'a mehlala ea libaka tse reretsoeng ho ba le tšenyo ea maikutlo li tsoang mosebetsing oa rona (Baldo et al., 2003). Morero ona oa phepelo ea lijo tse matlafatsang 'meleng ke taba ea bohlokoa haholo ea ho utloisisa likhopolo tse hlalositsoeng ka holimo, hore phihlello ea libaka tse hokahaneng le tsebiso ho li-network tsa mantlha tsa ts'usumetso li thusa ho hlahisa maikutlo kapa ponahatso ea "matla a susumetsang." bokong ba morao-rao, tšebelisano ena e matla ea lipuisano lipakeng tsa methapo ea khale ea taolo ea boitsoaro bo ntlafalitsoeng le li-cortex tse ntlafalitsoeng haufinyane tse fanang ka ts'ebetso ea taolo e phahameng joalo ka puo le tlhalohanyo e nolofalelitse tsela ea libaka tse peli bakeng sa taolo ea linaha tse susumetsang. Ha se feela hore lipotoloho tse laolang liketso tsa boithaopo tsa boithaopo, ho nka liqeto, le tšebetso ea botsamaisi li ka susumetsa le ho tsamaisa lits'oants'o tsa mantlha, empa ts'ebetso ka har'a marangrang a mantlha a tšusumetso e ka fetisa mebala ea maikutlo lits'ebetsong tse hlokolosi mme ea li ts'oara ka mekhoa e sa fihleheng habonolo kelellong. Mohopolo ona, o thehiloe khopolong ea likhopolo tsa tlhekefetso tse totobatsang tloaelo le mekhoa e ikemetseng (mohlala, E-et-et al. 2001 'me Tiffany le Conklin 2000), e ka ba senotlolo sa ho utloisisa lits'oants'o tsa batho tse susumetsang, ho kenyelletsa le tse amanang le bokhoba.

Dopamine- le Glutamate-Initiated Plasticity: Ho tloha Seleng ho ea ho Behavior

Hona joale ho na le bopaki bo bongata ba hore ho kopants'oa ha matšoao a dopamine le likhakanyo tsa "glutamate-level" liseleng le limolek'hule ke ketsahalo ea bohlokoa e tlisoang ke polasetiki ea nako e telele le thuto e amanang le moputso marangrang a corticostriatal. Ho joalo, mohlala o ka sehloohong oa hona joale o supa hore lisele tse emeng lipontšo tsa dopaminergic le glutamatergic (mohlala, li-spiny neurons tse bohareng kahare ho striatum, kapa lisele tse nang le "pyramidal" ka hare ho cortex) li sebetsa joalo ka lintho tse etsahallang thuto e amanang le ho ithuta. Berke le Hyman 2000, Horvitz 2002, Kelley et al. 2003, Reynolds le Wickens 2002 'me Sutton le Beninger 1999. Kahoo, glutamate e kenyelletsa leseli le ikhethileng la sensory, motor, le mnemonic ho lits'ebetso tsa cortico-cortical, corticostriatal, le thalamocortical, ha ho nahanoa hore dopamine neurons e arabela ka kutloisiso ea lefats'e ho liketsahalo tse sa reroang, tsa moputso, kapa tse ikhethang tikolohong. Horvitz 2000 'me Schultz 2002. Letšoao le hokahaneng la litsamaiso tsena ka bobeli le bapala karolo ea bohlokoa ho fetoleng kemiso ea methapo ea kutlo le ho fetoleng tšebetso ea li-enuralles.

Bopaki ba Cellular

Mits'ebetsong ea mohlala e ithutoang, haholo-holo dorsal le ventral striatum le preortal cortex, ho na le bopaki bo fetolelang ba hore phepelo ea dopamine, haholo-holo ho susumetsa ha li-receptor tsa D-1, li fetola haholo thabo ea neuronal, membrane ea li-oscillations tse ka khonehang, le khethollo ea lipontšo tse tlang tsa nyakallo. Li-neurons tsa pyramidal le tse bohareng li bontša liphetoho tse sa tloaelehang, tse sa amaneng le maemo; hangata e ts'oaroang e se ke ea khutsisoa ke "membrane" e seng thata haholo ea ho phomola⁺ maqhubu ("tlase mmuso"), nako le nako a fetohela boemong bo nyarosang haholo moo a ka hlahisang menyetla ea ts'ebetso (Wilson le Kawaguchi, 1996). Libaka tsena, tse hlokahalang bakeng sa ho thunngoa ha sele le ho fetisetsoa hoa matšoao a kopaneng libakeng tsa sephetho sa makoloi, li its'etleha ho se kenyelletsoang ho tsoa ho "cortex" ea "cerebral" le "thalamus" O'Donnell le Grace 1995 'me Wilson 1995. Liphetoho tsena li kanna tsa hloka botsitso ba sistimi le tšitiso ea phallo ea tlhaiso-leseling; tlatsetso e kholo ea thabo e tsoang cortex e ne e ka ba chefo ntle le matla a kahare a ntlafatsang maqhubu a potasiamo; Leha ho le joalo ts'oarello ea lipontšo tse ikhethang, tse ikhethang tsa tumello li lumella khetho ea litlatsetso tse itseng tse loketseng haholo hajoale. Ka ho sebelisana ka mokhoa o fapaneng le maqhubu a khahlisang AMPA- le NMDA-Mediated, dopamine e hlophisa ts'ebetso ena ea khetho, 'me litlamorao tsa eona tsa postynaptic li itšetleha haholo ka bokhoni ba membrane ba hona joale. Mohlala, ts'ebetso ea li-receptor ea D-1 e bonahala e na le litlamorao tse peli tsa mantlha tsa postynaptic mme e boetse e bonahala e hlokahala bakeng sa polasetiki ea cellular mme qetellong bakeng sa matlafatso ea enlectle e khethiloeng ea corticostriatal le ho phahamisa boitšoaro bo bocha ba ho fetohela. See se etsahala joang?

Taba ea pele, ts'ebetso ea li-receptor ea D-1 e na le tšebelisano ea bohlokoa le bobeli ba K⁺ liteishene le mofuta oa L-Ca²⁺ dikanale. D-1 ts'ebetso e ntlafatsa K⁺ maqhubu a haufi le bokhoni ba ho phomola, a phahamisa khatello ea thabo (Pacheco-Cano et al., 1996). Leha ho le joalo, haufi le libaka tse senyehileng haholoanyane, ho hlohlelletsoa ha D-1 ho na le litlamorao tse fapaneng; eona ea eketseha thabo ka ntlafatso ea mofuta oa mofuta oa L²⁺ maqhubu (Hernandez-Lopez et al., 1997). Lithuto tse 'maloa ho striatum le cortex li bonts'a hore ts'ebetso ea dopamine D-1 activation e ntlafatsa thabo e hlahisitsoeng ke NMDA Cepeda et al. 1993, Cepeda et al. 1998, Harvey le Lacey 1997 'me Wang le O'Donnell 2001. Phuputsong e entsoeng ka pele ho cortex (PFC), Ma-Seaman le basebetsi-mmoho ba bonts'itse hore li-agonists tsa D-1 li khetha ka mokhoa o ikhethileng likarolo tsa "NMDA-mediated" tsa li-posynaptic tsa hona joale; ba etsa tlhahiso ea hore mochine ona oa neuromodulatory e ka ba oa bohlokoa ho bolokang lipehelo tsa mesebetsi tse bohlokoa molemong oa ho hopola (Seamans et al., 2001). Ho na le bopaki bo bong ba hore lipontšo tsa DA li bapala karolo ea bohlokoa ho nolofatseng le ho boloka linaha. Mohlala, phetoho lipakeng tsa li-neuron tsa pele pele li koetsoe ke ts'ebeliso ea mohanyetsi oa D-1 (Lewis le O'Donnell, 2000); sephetho se tšoanang se ile sa bonoa ho li-neuron tsa striatal (Bophirima le Mohau, 2002).

Ho kenyelletsoa ha mokhoa oa lits'ebetso tse nang le mekhoa ea elektronike, mesebetsing le linthong tsa vivo, ho senotse ho hongata ka polokeho ea leqhubu litseleng tse fanang ka tšusumetso le ho ithuta ka moputso. Ho na le bopaki bo ka bang teng ho tloha lilemong tse leshome tse fetileng tsa hore ho hlohlona ha liponche tsa cortical ho lisele tse khutsitseng ho ka ts'oara LTP kapa LTD, ho latela maemo a susumetsang, sebaka sa striatal, le maemo a fapaneng a synaptic Pennartz et al. 1993, Centonze et al. 2003, Lovinger et al. 2003, Nicola et al. 2000 'me Reynolds le Wickens 2002. Mohlala, LTP maemong a boreleli e ipapisitse le ts'ebelisano ea nakoana ea tlatsetso ea nyakallo ka ts'ebetso ea dopamine D-1 Kerr le Wickens 2001 'me Wickens et al. 1996. Khothatso ea li-hippocampal kapa li-amygdala tse amanang le li-ventral striatum induces tsa nako e telele tsa polasetiki (Mulder et al., 1997), 'me ho na le bopaki ba tšebelisano ea bohlokoa kapa ho soetseha pakeng tsa maiketsetso ana (Mulder et al., 1998). Floresco le basebetsi-mmoho ba bonts'itse hore D-1 le li-receptors tsa NMDA li nka karolo ts'ebetsong ena Floresco et al. 2001a 'me Floresco et al. 2001b. Mosebetsi oa Jay le basebetsi-mmoho o totobatsa karolo ea D-1 le ho saena le ho tsamaellana le liketsahalo tsa intracellular tse amanang le lits'ebetso tsa polasetiki; mohlala, ts'ebetso ea nako e telele ho li-hippocampal-prefrontal synapses e ipapisitse le ho kopanngoa ha DA D-1 le li-receptor tsa NMDA hammoho le likhase tse kenelletseng tse kenyelletsang PKA Gurden et al. 1999, Gurden et al. 2000, Jay et al. 1995 'me Jay et al. 1998. Ho joalo, hippocampus e kanna ea ba sebaka sa bohlokoahali bakeng sa ho khetholla kopanyo ea synaptic kahare ho ventral striatum, hobane e bonahala e le bohlokoa bakeng sa ho boloka linaha (ka hona ho thunya ho hoholo) ho li-neuron tsa pelehi tse kenang. Goto le O'Donnell ba tlaleha hore ts'ebetso e lumellanang e bonoa lipakeng tsa hippocampus ea ventral le ventral striatum (Goto le O'Donnell, 2001) le hore tlhahlobo ea mokhatlo oa nakoana oa ho kopana ha li-synaptic pakeng tsa pele le tse ling tse limbic (mohlala, lipalo tsa li-amygdala, hippocampus, paraventricular thalamus) li fana ka bopaki bakeng sa khetho ea ho kenya le ho bonts'a liketsahalo tsa tšohanyetso. (Goto le O'Donnell, 2002). Ha re e kopantsoe hammoho, lethathamo lena le tsotehang la lintlha tsa methapo ea kutlo li fana ka tšehetso e matla bakeng sa mohopolo oa hore ho kopantsoe matšoao a kopaneng a DA- le matšoao a glutamate, libakeng tse ngata tsa marang-rang a corticothalamic striatal, a nka karolo ho fetoleng mekhoa ea ts'ebetso ea neural e ka bonts'ang thuto e ncha.

Mekhoa ea molek'hule le Genomic

Haeba tšebelisano ea 'mele ea nakoana ea DA le ho tšoaetsoa ke glutamate li lumella ho nchafatsoa hoa marang-rang a neural, ho tšoaea hona ho tlameha ho bonts'oa ts'ebetsong ea limolek'hule tsa phetoho ea lipontšo tsa methapo, joalo ka cyclic AMP le kinases ea protheine, taolong ea liphatsa tse ling tsa lefutso le liprotheine tse ncha ho lumellana. Ketsahalo e joalo e tsejoa e le motheo oa ho ithuta le ho hopola, 'me lilemong tsa morao tjena ho fanoa ka kakaretso e ntle haholo (mohlala, Abel le Lattal 2001, Kandel 2001 'me Morris et al. 2003). Mona, ke rata ho sheba haholo mehlala ea liphetoho tse lipakeng tsa DA- le glutamate-Mediated ho transcript le phetolelo tse ka bang le bohlokoa bo ikhethileng litloaelisong tsa marang-rang a corticostriatal. Li-dendritic spines tsa lisele tsa pyramidal ho cortex le li-spiny neurons ka har'a ventral le dorsal striatum ho nahanoa hore ke sebaka sa mantlha sa phetoho ea synaptic (lebisa tlhokomelo ho Setšoantšo sa 3). Joalokaha ho hlokometsoe pejana, li-axon tsa dopaminergic le glutamatergic li kopana le methapo e tšoanang ea dendritic, li atamelana haufi. Sesack le Pickel 1990, Smith le Bolam 1990 'me Totterdell le Smith 1989. Mekhoa e meholo ea "biochemical" e ka hare e arabisang e arabisang e etsang hore ho be le nako e telele ea plastiki e sebetse hantle. Ts'ebetso ho glutamate synapse e kenyelletsa ts'ebetso ea li-receptor tsa AMPA le li-receptor tsa NMDA tse itšetlehileng ka motlakase, tse hlahisang tšusumetso e kholo ea khalsiamo ka liteishene tsa NMDA. Dopamine e laola tlhahiso ea cAMP ka ho sebelisana le D-1 le D-2 (G protein coupled) receptors. Man messengersosa ana a fapaneng a bobeli a kenya tšebetsong libaka tse ngata tsa kinase, ho kenyelletsa PKA, PKC, CaMK, le ERK / MAP / RSK kinases, tse sebetsanang, ho laola phallo ea khalsiamo, le ho fetohela linthong tsa bohlokoa tse hatisang tse kang CREB. Phosphorylation ea CREB e etsa hore CREB e hokahane le likarolo tse ngata tsa karabelo liphatseng tsa lefutso tse ngata, ka hona e lebisa ho kenelleng ha polelo ea gene le syntheine ea liprotheine tse ngata tsa synaptic, tseo tse ling tsa tsona li tšohliloeng ka tlase. CREB ke khetho e khahlisang bakeng sa setsi sa tlhaho se kenelletseng ho ithuteng ho kopaneng, kaha se laoloa ke calcium le PKA e fetotsang matšoao a glutamate le dopamine ka ho latellana (Silva et al., 1998). Protheine ea intracellular DARPP-32 le e 'ngoe ea lipehelo tsa eona tse kholo, protein phosphatase-1 (PP-1), le eona ke molaoli oa bohlokoa oa boemo ba phosphorylation ba li-processor tse ngata tse kenang kahare (Greengard et al., 1998). Ketsahalo ea pele ho polasetiki ea synaptic ke ho qaptjoa hoa mefuta e mengata ea pele le lintlha tse tsoang, tse fetisoang ka mokhoa o atileng empa haholo li ruisetsoa meaho ea corticostriatal, joalo ka c-fos, c-Jun, NGFI-B, homer1A, ania 3, Arc, 'me zif268 (NGFI-A, krox-24). Ho hlahisoa ha mefuta e mengata ea mofuta ona ho bontšitsoe hore ke NMDA le / kapa DA D-1. Mohlala, phosphorylation ea CREB le ho kenella hoa mefuta ea karabelo ea pele ho thibetsoe ke NMDA le / kapa bahanyetsi ba D-1 Das et al. 1997, Konradi et al. 1996, Lenane et al. 1997, Steiner le Kitai 2000, Steward le Worley 2001b 'me Wang et al. 1994. Kahoo, lintlha tse ngata tsa dopaminergic le glutamate-regulated biochemical pathways li hlakisitsoe (joalo ka ha li akaretsoa ho Setšoantšo sa 3), leha e le hore na mekhoa ena e fetolela joang ho fetoheng le liphetoho tse teng ka har'a boitšoaro e ntse e sa tsejoe.

Liphumano tse ncha tse thabisang li fana ka lintlha tse ncha tsa ho etsa lipatlisiso mabapi le ho koala likheo tsena tse thata. Tse ling tsa tsena li shebana le tšebelisano ea lipale lipakeng tsa glutamate le D-1 receptors. Mohlala, ho kenyelletsa matšoao a converter kahare ho neuron, ho bonahala ho na le tšebelisano e tobileng ea 'mele pakeng tsa D-1 le li-receptors tsa NMDA. Patlisiso ea morao-rao mabapi le litšebelisano tsa "hippocampal tis" e bonts'a tšebelisano e fapaneng ea liprotheine le protheine e laolang tšebetso ea li-receptor tsa NMDA, ka libaka tse ikhethang mohatleng oa carboxyl oa D-1 receptor e sebelisanang le NR1-1a le NR2A subunits ea NMDA receptor Lee et al. 2002 'me Pei et al. 2004. Tšebelisano ena e lumella ho kenngoa ha membrane ea plasma ea li-receptor tsa D-1, e fana ka motheo o ka eketsang polasetiki ka tokollo ea DA. Ho latela mohopolo ona, ho tlalehoa hore, ts'ebetsong ea li-receptor tsa NMDA tse bitsitsoeng, li baka phetisetso ea D-1 (empa eseng D-2) ho tloha kahare ea sele ho ea ho karolo ea plasma ea li-spendritic spines, hape ho fella ka keketseho e sebetsang ea tšebetso ea cymbase ea adenylate (Scott et al., 2002). Ho makatsang ke hore, moqoqo o ka ba 'nete, bonyane bakeng sa li-receptors tsa AMPA; ts'usumetso ea li-receptor tsa D1 ho li-nucleus tse cultured li-neurons li ntlafatsa sebaka sa AMPA (gluR1) polelo ea li-receptor (Chao et al., 2002), ke ts'ebetso e itšetlehileng ka PKA (Mangiavacchi le Wolf, 2004).

Kutloisiso e ngoe hape mabapi le liphetoho tsa phetolelo e hlahisitsoeng ke ts'ebelisano ea NMDA-D-1 e ka fanoa ke mosebetsi ka protheine synthetic libakeng tsa dendritic synaptic le mokhatlo oa liprotheine tsa dysity density. Ho na le mosebetsi o mongata o thabisang o entsoeng ho li-mRNA tse lebisitsoeng ka mokhoa o sa tsotelleng joalo ka Arc (protein-cytoskeletal protein) le CaMKII (Steward le Schuman, 2001). selikalikoe ke mofuta oa karabelo ea pele-pele eo mRNA ea eona e khethiloeng ka mokhoa o ikhethileng ho li-site tsa synaptic tse sa tsoa etsoa, ​​moo e fetoleloang le ho kenyelletsoa sebakeng sa "postynaptic density" (Steward le Worley, 2001a). Ts'ebetso ena e ikhethileng le ho shebisoa e thibetsoe ke ts'usumetso ea lehae ea bahanyetsi ba NMDA receptors (Steward le Worley, 2001b). Arc ka hona e bonahala e le e 'ngoe ea liprotheine tse ngata (mohlala, PSD-95, Shank, Homer, ho bolela tse' maloa feela) tse hokahaneng le NMDA receptor mme li kenya letsoho tšebetsong le mesebetsing ea li-synapses tse nchafalitsoeng ka taolo ea mokokotlo oa dendritic. sebopeho (Sheng le Lee, 2000).

Ho Etsa Lintho Tse U Khahlisang, Ho Ithuta le Meputso: Ho tloha ho Ba Ikanyetsang ho ea ho Liqeto

Potso e latelang e shebisisa hore na liketsahalo tse joalo tsa lisele le limolek'hule tse tsamaeang le "glutamate-dopamine" li ka etsa hore ho feto-fetoha le maemo ho teng liketsong tsa boitšoaro tse bonts'ang ho ithuta. Leha ho na le sengoloa se seholo ka har'a mehala ea mefuta e fapaneng ea ho ithuta le ho hopola, molemong oa puisano ena, ke tla tsepamisa maikutlo ho ithuteng moelelo o sebetsang o tataisoang ke sepheo. Ho ithuta ka lisebelisoa, moo setho se ithutang karabo e ncha ea makoloi ho fumana sephetho se nepahetseng (theko ea lijo nakong ea tlala, ho qoba kotsi kapa bohloko), ke e 'ngoe ea mekhoa ea mantlha ea boits'oaro. Dickinson le Balleine 1994 'me Rescorla 1991. Ehlile, esita Aplysia a ka koetlisetsoa ho etsa karolo e itseng ea ho ithuta e hlokahalang; ka mokhoa o makatsang, dopamine e kenya letsoho ho thehoeng ha karabelo ena (Brembs et al., 2002). Ho ithuta ka karabelo ho kopants'oa le nts'etsopele ea tsebo (kapa pontšo ea kelello) ea tšohanyetso lipakeng tsa ketso le sephetho kapa sepheo ("moputso"). Mosebetsi o mongata oa maiketsetso o ts'ehetsa mohopolo oa hore liphoofolo li etsa tsebo mabapi le maemo a ts'ohanyetso mme li ela hloko liphetoho maemong a tšohanyetso, linaha tse khothatsang, boleng ba hona joale le bo fetileng ba thekiso, joalo-joalo Colwill le Rescorla 1990 'me Dickinson le Balleine 1994. Litloaelo tsa Pavlovian, mehopolo, kapa maemo a amanang le moputso le tsona li na le tšusumetso e matla lithutong tse matla tsa ho ithuta Mok'hadinale et al. 2002 'me Rescorla 1991. Rescorla e fana ka maikutlo a hore lintlha tsa bohlokoa tse tharo tse teng nakong ea ho ithuta ka matla, karabelo kapa ketso, sephetho kapa moputso, le tšusumetso, kapa mohopolo o amanang le moputso, kaofela li arolelana mekhatlo ea binary le e mong. Mekhatlo ea likamano tsa khoebo e kanna ea hlalosoa ka mokhoa o rarahaneng oa litekanyetso tse ntlafatsang moo ho khothalletsang kamano e amanang le kamano ea sephetho sa karabelo (bona Setšoantšo sa 6).

Ho ithuta ho joalo ho ka hloka mokhoa oo ka mokhoa o ikhethileng o etsang boits'oaro bo hlahisoang ke ts'ebetso ea mantlha; boleng bo fetohang ba liketso bo tlameha ho matlafatsoa ke liphetoho tse feto-fetohang lipotolohong tse amanang le boits'oaro boo. [Friston et al., 1994]). Khopolo-taba ea Neural network le mohlala oa khomphutha li rarolle bothata bona ba ho ithuta ka matlafatso. Sistimi ea matlafatso ea thuto ea maiketsetso (RL) e lokisa boitšoaro ba eona ka sepheo sa ho ntlafatsa ketsahalo ea ho tiisa liketsahalo ha nako e ntse e ea Barto 1995 'me Sutton le Barto 1981. Meetso ea RL e sebelisa maikutlo a itšetlehileng ka karabelo a lekolang sephetho mme a nolofalletsa moithuti ho fetola ts'ebetso ho eketsa "molemo" oa boits'oaro. Barto o hlokomela hore sistimi e joalo e tla hloka ho lekola litlamorao tse liehang le litlamorao mme e "sebetsane le likhoele tsa ts'ebetso le litlamorao tsa tsona tse etsahalang ha nako e ntse e tsamaea." Sena se bitsoa "bothata ba kabelo ea mokoloto ea nakoana." Ho seo ho thoeng ke "sebapali-mohlahlobisisi" moahong oa marang-rang, "mohlahlobisisi" (ea nang le phihlello ea maemo le maemo a susumetsang) o fa "motšoantšisi" maikutlo mabapi le tlhahiso ea boits'oaro mme o fana ka litekanyo ho sebapali hang-hang liketso tse etsahetseng. E amanang haufi le khopolo ena ke mehlala ea lipalo e sebelisang algorithm ea nakoana ea thuto e matlafatsang. (Sutton le Barto, 1998). Mohlaleng ona, ho etsoa tlhahiso ea ho ikarabella bakeng sa boits'oaro ba dopaminergic neurons nakong ea thuto ea liphoofolo Schultz 2002 'me Schultz et al. 1997, ho ithuta ho ipapisitse le tekanyo ea ho se ikemisetse ha ba matlafatsang ba mantlha. Mananeo a marang-rang a kenyelletsa "phoso ea ho bolela esale pele" ka nako ea 'nete, e thehiloeng ho phapano lipakeng tsa ho hlaha hoa motho ea matla le ho bolela esale pele; ha ho sa na ho ithuta ho etsahalang ha ketsahalo e boletsoe esale pele 'me polelo ea phoso e le zero. Moetso ona o sebelisoa ho lithuto tsa Pavlovian le tsa ho ithuta ka boitšoaro kapa ka boitšoaro (Schultz le Dickinson, 2000). Maemong a morao-rao, liketso tsa boits'oaro li hlahlojoa ho latela liketsahalo tse sa lebelloang (mohlala, mochine oa khatiso o sa reroang le pellet ea lijo e sa lebelloang), mme phoso ea ho bolela esale pele e kopantsoe ebe e fetole maemo a boletsoeng esale pele le ts'ebetso. Khokahano e lumellanang le thuto ea matlafatso e tla hloka le mokhoa oa ho feto-fetola mantsoe ka tsela e tšoarellang, ho sebelisa mochine oa ho ithuta oa Seheberia, oo ts'ebetso ea pele le ea postynaptic e kopaneng ho susumetsa liphetoho tsa nako e telele mesebetsing ea mahlale. Mefuta e mengata ea likhomphutha e kentse karolo ea "glutamatergic presynaptic" lipakeng tsa "striatal medium spiny neurons", "nyoloha" ea "calcium" le nako e nepahetseng ea lets'oao la dopamine e le motheo oa li-synapses tse kenelletseng ka har'a marang-rang a corticostriatal. Kotter 1994, Pennartz 1997 'me Wickens le Kötter 1995.

Corticostriatal network e etselitsoe hantle ho sebetsana le litlhoko tsa ho ithuta ka koloi tse hlophisitsoeng kaholimo, ka bobeli ho latela boqapi ba tsona ba sebopeho sa limolek'hule le limolek'hule. Ho joalo, ho na le bopaki bo bongata ba liteko ba hore lits'ebetso tse kenyelletsang cortex ea pele, striatum, amygdala le dorsal le ventral striatum li nka karolo ho ithuteng ka matla. Re bontšitse hore ho saena lipakeng tsa glutamate le dopamine ho tse ngata tsa libaka tsena ho bohlokoa bakeng sa liphetoho tse hlokahalang bakeng sa ho ithuta makoloi a macha. Mohlaleng oo re o sebelisang, liphoofolo tse lapileng li tlameha ho ithuta mochini o bonolo oa tobetsa hore li fumane li-pente tse ntle Andrzejewski et al. 2004 'me Pratt le Kelley 2004. Re khahloa haholo ke nako ea ho ithuta ea pele, ha phoofolo e kenella ts'ebetsong e kholo ka phapusing ea motho ea sebetsang (molemong oa rona oa mosebetsi ona, e se e bile le boiphihlelo bo itseng ka kamoreng ena e nang le pellets ea sucrose e sa lebelloang ho hlahisoa). Nakong ena, Rat e sebetsa ka mokhoa o susumetsang le ka mokhoa o sebetsang (lits'oants'o, marang-rang, li-ambulense, likompong, joalo ka "li-furu") ka lebaka la boemo ba eona ba ho se amohehe le lits'usumetso tsa moputso o itseng. Mochine oa khatiso o sa sebetseng o hlahisa sephetho sa moputso; Kamora tse 'maloa tsa lipara tsena tse sa sebetseng, likhoto li qala ho pheta mochine oa khatiso. Leha ho le joalo ka tekanyo e le 'ngoe moemeli oa maemo a tšohanyetso a hlaha ka potlako (ha sena se ka nka matsatsi a' maloa a boikoetliso), lebelo le katleho ea boits'oaro bo fumanoa butle butle; ka matsatsi a mangata, phoofolo e ntlafatsa ts'ebetso ea eona mme e hatella ka sekhahla se phahameng haholo (bona Setšoantšo sa 7).

Re fumane hore infusion ea mohanyetsi ea khethiloeng oa NMDA AP-5 libakeng tse ling tsa corticolimbic (ho kenyelletsa le nucleus accumbens mantlha, basolateral amygdala, le medial prefrontal cortex) nakong ena ea ho ithuta ea pele e sitisa kapa e hlakola bokhoni ba likhoto ho ithuta maemo a phello ea karabelo. Kelley 2004b 'me Kelley et al. 2003. Ka mokhoa o makatsang, infusions e joalo ho litoeba tse tšoanang, hang ha ba ithutile mosebetsi (oo kaofela ba o etsang ha ba koetlisoa ntle le kalafo ea lithethefatsi), ha ba na tšusumetso ea boitšoaro (libakeng tse ngata). Boitšoaro ba sepakapaka le ho ithuta ho pheta-pheta ho boetse ho kenyelletsa ts'ebetso ea glutamate receptor kahare ho li-nucleus accumbens De Leonibus et al. 2003, Roullet et al. 2001 'me Smith-Roe et al. 1999. Ho fumaneha ha boits'oaro ba lisebelisoa ho boetse ho its'etleha ho ts'ebetsong ea li-receptor tsa DA D-1, 'me tlhaiso-leseling e fana ka maikutlo a hore ho fumanoa ka tšohanyetso ha D-1 le ts'ebetso ea li-receptor tsa NMDA, sebakeng sa bokello ba li-cortex, mohlomong le libaka tse ling. Baldwin et al. 2002b 'me Smith-Roe le Kelley 2000. Lithethefatsi tse kenang le ts'ebetso ea AMPA le muscarinic receptor le tsona li sitisa ho ithuta, li fana ka maikutlo a hore matšoao a mangata a rarahaneng a sebelisana ho laola polasetiki (PJ Hernandez et al., E rometsoe; Pratt le Kelley, 2004a). Mabapi le ho saena ho sa tsotelleng, data ea morao-rao e boetse e fana ka maikutlo a karolo bakeng sa PKA le devovo synthesis ea li-nucleus Baldwin et al. 2002a 'me Hernandez et al. 2002. Hoa thahasellisa ho tseba hore blockade of synthesis protein in the motor cortex ha e na thuso ho thuto ea maemo a tšohanyetso, empa e sitisa ntlafatso ea boiphihlelo ba motlakase oa koloi bakeng sa lithuto (Luft et al., 2004). Le ha ts'ebetso e kopanetsoeng ea dopamine le lits'ebetso tsa glutamate li ka bapala likarolo tse fapaneng libakeng tsena tse fapaneng tsa forebrain (mohlala, amygdala e kanna ea sebetsa mefuta e fapaneng ea tlhahisoleseling ho feta hippocampus kapa accumbens konokono), lintlha tse khahlisang li khothalelitsoe lipatlisisong tsa morao tjena. Mohlala, litloaelo tsa tikoloho tsa Pavlovian tse amanang le moputso li na le tšusumetso e matla ho ts'ebetsong le ho laola boitšoaro bo tsoelang pele Corbit et al. 2001, Dayan le Balleine 2002 'me Dickinson le Balleine 1994. NMDA receptor blockade bokong bo thibela ho fumana boitšoaro ba mokhoa oa Pavlovian (Di Ciano et al., 2001), e fana ka tlhahiso ea hore ts'ebetso ea li-receptor tsa NMDA sebakeng sena e ea hlokahala bakeng sa litšitiso tse ikhethang ho fumana taolo holim'a likarabo tsa mokhoa. Ho khahlisang, thutong eo, mohanyetsi oa DA le eena o ile a sitisa ho ithuta ka mokhoa oo, mme mohanyetsi oa AMPA o amme ts'ebetso ea karabelo e ithutileng. Manonyeletso le litlatsetso tsa dopamine ka har'a li-drabens le tsona li felisa boitšoaro ba mokhoa oa ho ithuta Parkinson et al. 1999 'me Parkinson et al. 2002. Mosebetsi ona o fana ka maikutlo a hore mekhatlo ea pele-pele ea khothalletso ea (susumetso) (susumetso) e susumetsa tlhahiso ea likarabo tsa lisebelisoa tse ka lebisang liphellong tse ntle tsa morao-rao le hore tšusumetso ena e hloka tšebetso ea DA le glutamate tseleng ea amygdalo-accumbens (Cardinal et al., 2002).

Tlhahlobo ea rona ea micostructure ea boitšoaro ka kamoreng ea opereishene e boetse e fana ka leseli mechineng ea boitšoaro e nang le litšitiso tse tebileng tsa ho ithuta tse susumetsoang ke bahanyetsi ba glutamate kapa dopamine (PJ Hernandez et al., E romelletsoe; PJ Hernandez et al., 2003, Soc. Neurosci. , abstract, Moqolo 29). Ntle le ho lekanya khatello ea matla nakong ea thupelo ea lipalo, re boetse re hatisa linkho ka mokotleng oa lijo — karabelo e sa reroang e hlile e hlokahala bakeng sa ho fumana lijo empa hape e eketsehile haholo tlasa maemo a phahameng kapa a "meputso e sa tloaelehang". Re ile ra hlahloba likarabo tsena kahar'a likarolo tse 'maloa tsa pele tsa mosebetsi,' me ra sebelisa lenaneo la komporo leo le hatisang tatellano ea liketsahalo le kamano ea nakoana ea liketsahalo (nosetso-koano, khatello ea loto, tlhahiso ea meputso). Ho tloha (litekong tsa moraorao tjena, mohlala, Pratt le Kelley, 2004) re rala mosebetsi o tla etsa hore liphoofolo tsohle li be le “mahala,” li tsamaisoa ka mokhoa o sa reroang matsatsing ana a 2 a pele mme kaha liphoofolo tse ngata ha li e-so ithute ho hatisa, likarolo tsena li fana ka monyetla oa ho lekanya mokhatlo oa nakoana oa boits'oaro bo atamelaneng le phano ea meputso. , pele kapa nakong ea thuto ea pele ea pele. Joalokaha ho ka bonoa ho Setšoantšo sa 8, liphoofolo tse tlas'a tšusumetso ea AP-5 li bontsitse maemo a tlase a liphokotso tsa nosetso, leha litekanyetso tsa matlafatso li lekantsoe lipakeng tsa lihlopha tsa lithethefatsi le taolo. Ntle le moo, haeba sekhahla pakeng tsa ho tsamaisoa ka matla le nko-poke e lekantsoe, hammoho le monyetla oa ho hlaha ha nko ka lebaka la hore matlafatso a sa tsoa tlisoa, re fumana phapang e teng boits'oarong ba liphoofolo tse nang le li-accumbens NMDA receptor blockade. Likhoto tsena li batlile li kopitsa habeli ho khutlisa li-pellets li bile li theotse monyetla oa hore nko ea nko e ka hlaha kamora ho fana ka matla. Leha ho le joalo, lithuto tsa rona tse ling ha li na phello mesebetsing e meng ea makoloi maemong a sa hlokeng temoso, kapa litheko tsa lijo kapa karolo efe kapa efe ea boits'oaro ba ho ja. Kelley et al. 1997 'me Smith-Roe et al. 1999, le likhoto tse sebelisitsoeng ke lithethefatsi li sebelisa pellet hang ha li e fumana. Ka hona, liphokotso tse akaretsang tsa ts'usumetso kapa tsa koloi ha li na ho baka profil ena. Mohanyetsi oa DA D-1 le eena o fokotse marokho a nko, empa a le tlase haholo, mme a sena tšusumetso ho li-latitude kapa menyetla (ya data e sa bontsitsoeng). Boemo bona bo fana ka maikutlo a hore matšoao a glutamate a sebetsang ho li-receptor tsa NMDA ho li-accumbens e ka ba a bohlokoa bakeng sa ho eketsa tlhahiso le lebelo la likarabo tsa ho epa liqeto. tlasa maemo a itseng a susumetsang le a maemo. Ha tlhahiso ea likarabo tsena e phahame ho feta fensetere e behiloeng, monyetla oa hore mechini e hatellang e sa sebetseng e hlahisang moputso e tla ba kholo. Tlas'a tšusumetso ea AP-5, likhoto li bonahala li etsa boiteko bo fokolang ba ho tobetsa kapa ho phunya nko, leha ho hlahisoa lipelete tse matlafatsang lijo. Le ha mekhoa e nepahetseng e e-s'o hlake, ka tsela e itseng AP-5 e thibela ho ba teng ha lits'ebetso tse kopaneng lipakeng tsa phumants'o ea moputso le liketso tsa phoofolo. E kanna eaba methapo ea kutlo e hlaselang e tlameha ho fetela mmusong o kopaneng oa NMDA bakeng sa tlhahiso ea boemo bo boima ba likarabo tsa ho iphelisa, ka hona, karabelo ea karabelo ea moputso. DA (e lokolloang ka phasically le moputso o mong le o mong o neng o sa lebelloa) le eona ntle le pelaelo e kentse letsoho nakong ena ea pele ea ho hapa; Ntle le tlhaiso-leseling ea rona, Wickens le basebetsi-mmoho ba fumane hore ho fumana karabelo ea boralitaba bakeng sa tšusumetso ea kelello ea motlakase e hokahana haufi-ufi le ts'oaetso e susumetsoang ke DA ea li-synapses tsa cortiocostriatal, mme ba sisinya hore mochini o joalo ke senotlolo sa kopanyo ea moputso le maemo a karabelo e itšetlehileng ka maemo le leeme la liketso tsa boits'oaro Reynolds et al. 2001 'me Wickens et al. 2003.

Rona le ba bang re sa tsoa qala ho hlahloba hore na ke liprotheine tsa khale tsa karabelo kapa liprotheine tsa khatello ea methapo tse ka amehang mehatong ea pele ea ho ithuta ka moputso. Mohlala, Kelly le Deadwyler ba bonts'a seo Arc e kenelletse ka matla marangrang a corticolimbic nakong ea ho fumana mosebetsi oa bohlokoa o tšoanang le oa rona Kelly le Deadwyler 2002 'me Kelly le Deadwyler 2003, mme le rona re fumana seo Arc, homer1A, 'me zif26 (NGFI-A) li ts'oarelitsoe libakeng tsa cortical le tsa striatal mohato oa pele oa ho ithuta ka matla (PJ Hernandez et al., 2004, Soc. Neurosci., abstract, Buka 30) (mehlala ea data e bontšitsoeng ho Setšoantšo sa 8). Bopaki bo tšehetsang bakeng sa mefuta e amanang haufi-ufi ea ho ithuta bo fanoa ke mosebetsi oa Everitt le basebetsi mmoho, ba bonts'ang tlhahiso ea zif268 marang-rang a corticolimbic-striatal maemong a amehang a susumetsang Hall et al. 2001, Thomas et al. 2002 'me Thomas et al. 2003. Tumellanong le maikutlo a makatsang a makatsang, liketsahalo tse sa tloaelehang, kapa liketsahalo tse sa lebelloang li theha motheo oa thuto e ncha, Arc 'me homer1A li fumanoe li ntlafalitsoe ka matla ho li-hippocampus le li-network tsa cortical kamora ho phenyekolla tikoloho e ncha (Vazdarjanova et al., 2002), e ka hlalosang hore na hobaneng re fumana mefuta ena e entsoe ke liphoofolo tse seng li sa ithute ho hatisa empa li e-na le tšebeliso ea lijo tse ikhethileng 'me li fana ka likarabo tse matla. Hoba polelo e susumetsoang ke ts'ebetso boholo ba mefuta ena e bontšitsoe hore e itšetlehile ka ts'ebetso ea NMDA Sato et al. 2001, Steward le Worley 2001b 'me Wang et al. 1994, liphumano tsena li fana ka maikutlo a hore, joalo ka mefuta e meng ea ho ithuta, sebopeho sa mohopolo oa mohopolo se hloka ts'ebetso e its'epahang hang-hang mabapi le liphatsa tsa lefutso likarolong tse ngata tsa boko, tseo ka nako ena li ka fetolang phetoho ea li-synaptic le netweke.

Dopamine- le Glutamate-Initiated Plasticity: Lithethefatsi le ho lemalla

Tlaleho e kaholimo e fana ka maikutlo a hore litšebelisano tsa glutamate-dopamine ka har'a marang-rang a corticolimbic-striatal le litlamorao tsa ho kenella le limolek'hule tsa lipuisano tsena li bapala karolo ea bohlokoa thutong e matla ea ho ithuta. Bopaki bo bongata bo eketsehile lilemong tse leshome tse fetileng ho ts'ehetsa maikutlo ana. Katoloso ea tšibollo ena mabapi le bokhoba ba lithethefatsi ke hore lithethefatsi tse nang le matla a ho lemalla li ka hlahisa litholoana tsa tsona ka litselana tse ts'oanang le tšebetso tse bohlokoa ho matlafatsong ea ho ithuta le hore thepa ena e bohlokoa boikutlong ba bona ba ho theha boits'oaro bo bobebe. Libaka tsena tse peli tsa ho botsa, neurobiology ea ho ithuta le ho hopola le ts'ebetso ea ts'ebetso ea ts'oaetso, li ruile molemo o moholo tsoelo-peleng e 'ngoe le e' ngoe e tsebisang e ngoe. Lilemong tsa morao tjena, ho bile le litlhahlobo tse 'maloa tse ntle mabapi le ts'ebeliso ea tahi ka tsepamiso ena (mohlala, Berke le Hyman 2000, Mok'hadinale le Everitt 2004, Di Chiara 1998, Hyman le Malenka 2001 'me White 1996). Bakeng sa tlhahlobo ea hona joale, ke lakatsa ho tsepamisa mehlala ea lintho tse sibolotsoeng haufinyane le ho li hokela le mehopolo e meng e boletsoeng pejana pampiring.

Mekhoa ea Cellular le Molek'hule

Ho na le bopaki bo kholisang ba hore lithethefatsi tsa tlhekefetso li na le litlamorao tse matla ho lets'oao la glutamate le dopamine. Boholo ba tsepamiso ena e bile ka li-nucleus accumbens, pele ho cortex, le sebaka sa likarolo tsa harese, libaka tse ka sehloohong li hlahisoang ke liphetoho tsa neural tse amanang le tšebeliso ea lithethefatsi, leha libaka tse ling li ntse li etsoa lipatlisiso, joalo ka amygdala le hippocampus E-et-et al. 1999 'me Vorel et al. 2001. Ho na le palo e kholo ea lithuto tse bonts'ang hore ho pepeseha khafetsa kapa khafetsa ho lithethefatsi tsa tlhekefetso ho fetola haholo liprotheine tsa synaptic tse amanang le li-synapses tsa dopaminergic le glutamatergic; ho tla fanoa ka mehlala e fokolang feela mona. Ho netefalitsoe hore lithethefatsi tsa tlhekefetso li na le litlamorao ho lets'oao la liprotheine la G mme ka tsela ena e ka fetola karabelo ea methapo ea kutlo linthong tse ngata tse kantle ho sele. (Hyman, 1996). Phuputso ea morao-rao e entsoeng ke Bowers et al. e bonts'a hore motho ea buellang protheine ea G e saenneng, AGS3, o ntse a eketseha ka mokhoa o phehellang kalafong ea cortex le li-nucleus ka mor'a ho khaotsa kalafo e sa foleng ea koae (Bowers et al., 2004). Ho makatsang ke hore liphetoho tsena li ile tsa nka likhoeli tsa 2 ho cortex ea pele ho kamora ho khaotsa kalafo ea koae. Ba boetse ba fumane hore antisense ho AGS3 e kentsoeng ho PFC e thibetse ho ts'oaroa ha cococaine priming-e susumetsang ea boits'oaro ba koae. Liphetoho lelapeng le eketsehileng la balaoli ba liprotheine tsa G, RGS, le tsona li bontšitsoe cocaine Bishop et al. 2002 'me Rahman et al. 2003. Boithuto bona bo fana ka maikutlo a hore lithethefatsi tsa tlhekefetso li fetola limolek'hule tse methating ea pele ea ho saena kapa "babulisi ba liheke" ba li-cascade tse theohileng. Liphetho tse ling tsa nako e telele tsa kalafo e sa foleng tsa kalafo li kenyelletsa liphetoho ho deltaFosB le sepheo sa eona se tlase sa CdK5 Bibb et al. 2001 'me Nestler et al. 1999. Ho bontšitsoe hape hore liprotheine tsa Homer1, tse boletsoeng pejana e le tsa bohlokoa bakeng sa khatello ea methapo ea "postynaptic" le tsona li fetotsoe ke cocaine (Ghasemzadeh et al., 2003). Mohopolo o makatsang ke hore ho etsoa tlhahiso ea liprotheine tsa Homer ho "theola" botebo ba lets'oao la calcium ho li-protein tse kopantsoeng tsa G le ho laola sekhahla sa Ca²⁺ oscillations ka liprotheine tsa RGS (Shin et al., 2003). Phuputso e 'ngoe e ntle e bonts'itse hore ho fokotseha ho tsoelang pele ha PSD-95, protheine ea scaptold e thata, e fumanoe litoeba tse phekotsoeng hampe le koae-esita le ho isa likhoeling tsa 2 kamora ho felisoa ha kalafo (Yao et al., 2004). Ho litoeba tsena, li-synaptic plasticity (LTP) li-synapsic glutamatergic synapses lia ntlafatsoa, ​​li fana ka maikutlo a hore ho fokotseha ho sa feleng ha PSD-95 ho kanna ha tlatsetsa ho liphetoho tsa nako e telele tse bonoang temeng. Hoa makatsa hore esita le ho pepesehela lithethefatsi ho ka ba le phello e tšoarellang; ponts'o e le 'ngoe ea koae, cofine, amphetamine, nicotine, morphine, kapa ethanol (hammoho le ho pepesetsoa khatello e le' ngoe ea khatello ea maikutlo) e bakile tšebeliso ea nako e telele ea liqhubu tsa AMPA liseleng tsa dopamine Saal et al. 2003 'me Ungless et al. 2001, ha khatello ea maikutlo ea nako e telele e ne e bonoa ho GABAergic synapses ho VTA, kamora ho pepeseha ho le leng la ethanol (Melis et al., 2002). Li-Accumbens le hippocampal synaptic polasetiki li fetotsoe ke ho pepeseha ho le 'ngoe ho THC (Mato et al., 2004). Ha ho kopanngoa hammoho, sehlopha sena sa lithuto (se emelang khetho e nyane) se fana ka maikutlo a hore liprotheine tse ngata tse bonts'ang kahare ho sethala sa postynaptic libakeng tse bohlokoa bakeng sa ho susumetsa le ho ithuta li fetoloa ka mokhoa o ts'oanang, ka nako e telele, ka ho pepeseha ho sa feleng (kapa esita le ho hlobaetsang). ho lithethefatsi. Bongata ba liprotheine tsena li se li qaliloe e le tsa bohlokoa mefuteng ea memori le li-memory tsa eona, joalo ka ha ho boletsoe pejana.

Ho feto-fetoha ha maemo libakeng tsa bokong ho bohlokoa bakeng sa ho ithuta le ho susumetsa ho ka fana ka maikutlo a hore karolo ea mantlha ea bokhoba e fetotsoe kapa ho ithuta bocha ho arabela ho itaola hangata ha ntho maemong kapa maemong a teng (maikutlong le tikolohong). Ho joalo, litlaleho tse kholo tsa thuto ea bokhoba ba lithethefatsi li hlahisa hore mekhoa ea ho ithuta le "e sentse e le ntho e ngoe" le hore phetoho ena e baka mekhoa e qobelloang eo ho leng thata ho e laola. (Everitt et al., 2001) kapa hore lits'ebetso tse joalo li nkoe ka mokhoa o sa tloaelehang, li lebisa ho sengoeng kapa ho bohlokoa haholo ho lithahasello tse fapaneng tse amanang le lithethefatsi kapa linaha tsa maikutlo (Robinson le Berridge, 2001). Le ha sesosa kapa tlhaloso ea bokhoba ba tahi ntle ho pelaelo e tla paka lintho tse ngata tse thata ebile li le ngata, lintlha tse ngata tsa morao-rao tse sebelisang lipapatso tse batlang lithethefatsi kapa tse tlisang lithethefatsi li ts'ehetsa ka matla mehopolo ena ka kakaretso. Tsoelo-pele ea bohlokoa ntlheng ena e bile tšebeliso ea mefuta e batlang lithethefatsi e sebelisang lithethefatsi, moo litheko tse amanang le lithethefatsi, khatello ea maikutlo, kapa sethethefatsi ka boeona se sebelisoa ho "kopanya" ho arabela liphoofolong tseo ho arabela ho seng ho felisitsoe ka lebaka la ho tlosoa. matlafatso (Shaham et al., 2003). Paradigm ena e khothalletsoa ho khutlisetsa morao ka mor'a nako ea ho tlohela lithethefatsi. Ho lokolloa ha Glutamate (le dopamine) ka har'a bokellane ba nyutlelie ho eketseha nakong ea boitšoaro bo batlang lithethefatsi, 'me bahanyetsi ba glutamate ba kenelletseng sebakeng sena sa blockchain ea ho sebelisa koae ba ntse ba khutlisetsa lithethefatsi. (Cornish and Kalivas, 2000). Bonyane mohloli o le mong oa keketseho ea liqoqiso tsa extracellular nakong ea ho batla lithethefatsi e kanna ea ba cortex ea pele. (McFarland et al., 2003). Ho feta moo, koae e phetoang hangata e baka maemo a phahameng a glutamate mokokotlong oa rubber o kopaneng le maikutlo a boitšoaro (Pierce et al., 1996). Wolf le basebetsi-mmoho ba fumane hore tšusumetso e hlophisitsoeng e kopantsoeng le koae (empa eseng e sa lefelloeng) e phahamisa maemo a glutamate ho li-nucleus (Hotsenpiller et al., 2001). Karolo ea dopamine le haholo-holo li-D-1 receptors le eona e khothalelitsoe. Mohlala, tlhahiso ea mekhoa e amanang le lithethefatsi e ka etsa hore phello ea ho araba (ho batla lithethefatsi) ho liphoofolo e felisitseng karabelo; ho khutlisetsoa hona ho itšetlehile ka ts'ebetso ea li-receptor tsa D-1 Alleweireldt et al. 2002, Ciccocioppo et al. 2001 'me Khroyan et al. 2003. Litlhaselo tsa bahanyetsi ka har'a khetla ea "ana" kapa "polgineal" e boetse e fokotsa kapa ho felisa ho ts'oara koae. Anderson et al. 2003 'me et al. 2001, mme lipatlisiso tsa morao-rao li bonts'a ka mokhoa o hlakileng hore ts'ebetso e ts'oanang ea li-receptor tsa DA kahare ho amygdala ea basolateral le li-receptor tsa AMPA tse nang le konokono ea accumbens lia hlokahala bakeng sa ho batla koae ka taolo ea taolo e amanang le lithethefatsi. (Di Ciano le Everitt, 2004). Lintlha tse ling tsa morao-rao tse khahlisang tse sebelisang mokhoa o fumanehang ka potlako oa "cyclic voltammetry" o ka sebelisang sampole ea DA maemong a 100 o bonts'a bopaki bo tobileng ba ho lokolloa ha dopamine nakong ea ho tsuba koae. Likhokahano tse amanang le cocoaine le tsona li bakile kholo ea DA ea liphoofolo tse tsoang kantle ho naha moo likhoele li neng li entsoe ka phumants'o ea koae, empa eseng liphoofolong moo likotsi li neng li sa koaheloa. (Phillips et al., 2003). Sehlopha sena se boetse se bontšitse boemo bo tšoanang haholo ba ho lokolloa ha subopond dopamine mabapi le moputso oa tlhaho (sucrose); mekhoa e amanang le sucrose le eona e ile ea baka tokollo e potlakileng (Roitman et al., 2004). Liphuputso tsena li fana ka maikutlo a ho tšoana ho eketsehileng lipakeng tsa liphetoho tsa polasetiki tse tlisang meputso ea tlholeho le lithethefatsi. Kamora nako, ho sebetsa ka meetso ea sensitization ho bonts'a hore ho pepesehela li-stimulants pele ho nako e telele ho eketsa boikemisetso ba likhoto ba ho sebeletsa ho intša lithethefatsi (Vezina et al., 2002), e fana ka maikutlo a hore liphetoho tsa nako e telele tsa limolek'hule le tsa cellular li hlile li fetola tšusumetso ea lithethefatsi le (maemong a mang) khothatso ea meputso ea tlhaho (Fiorino le Phillips, 1999).

Le ha puisano e kaholimo e bua haholo ka mehlala e nang le litlatsetso, ho bohlokoa ho hopola hore lithethefatsi tse ling tsa tlhekefetso, joalo ka joala, nicotine le opioids, le tsona li na le litlamorao tse hlakileng tsa mobile ho li-system tsa DA le glutamatergic. Ho na le bopaki ba hore litsamaiso tsa "glutamate" le "dopamine" li nka karolo litlamorao tse mpe tsa nako e telele le tsa nako e telele tsa nicotine Dani et al. 2001, Kenny et al. 2003, Mansvelder le McGehee 2000 'me Pontieri et al. 1996 le joala Brancucci et al. 2004, Koob et al. 1998, Lovinger et al. 2003 'me Maldve et al. 2002.

Boemo ba maemo, Khopotso ea Lithethefatsi, le Moputso

Lilemong tse leshome tse fetileng, ho ile ha lebisoa tlhokomelo haholo mefuteng ea boemo ba lithethefatsi le tlhahlobo ea motheo ea neural ea mekhoa ea boemo ba Pavlovia e laolang maemo a lithethefatsi. Sebaka sena se holile ho tloha ponong ea bongaka ea pele eo ho lemaletseng lithethefatsi ho neng ho bonahala eka e arabela ka mokhoa o sa tloaelehang litabeng tse amanang le lithethefatsi tse amanang le lithethefatsi. O'Brien et al. 1992 'me Wikler 1973. Lits'oants'o tsa tikoloho tse neng li amana le boemo ba lithethefatsi e ka ba liqeto tse matla tsa ho khutla hape (Stewart et al., 1984). Ka sebele, lipatlisiso mabapi le ho hlaphoheloa lithethefatsi tsa opioid le lithethefatsi tsa koae li fana ka maikutlo a hore maemo a feto-fetohang maikutlong a amanang le 'mele a ka khothatsoa ke lintlha tse amanang le lithethefatsi. Mohlala, ho fumanoe hore litloaelo tse amanang le lithethefatsi (livideo tsa heroin paraphernalia, "pheha" litšebeletso, ho reka le ho rekisa) li ka etsa hore likarabo tsa boikemelo tse kang ho eketseha ha sekhahla sa pelo le khatello ea mali le maikutlo a ho lakatsa Ngaka ea bana et al. 1986 'me Sideroff le Jarvik 1980. Likarabo tse nang le maemo a ikemetseng tsa ts'ebetso le tsona li ngotsoe ka ts'ebeliso ea nicotine le joala Kaplan et al. 1985, Ludwig et al. 1974 'me Droungas et al. 1995. Lilemong tsa morao tjena, lithuto tsa neuroimaging li senotse mekhoa ea bohlokoa ea ts'ebetso ea boko ha lithethefatsi li pepesetsoa litloaelo tse amanang le lithethefatsi; boholo ba lithuto li fana ka maikutlo a karolo ea bohlokoa bakeng sa cortex ea pele le li-circry tse amanang le eona tse kang amygdala (bakeng sa litlhahlobo, bona Goldstein le Volkow 2002, Jentsch le Taylor 1999 'me London et al. 2000). Mohlala, lipatlisiso tsa MRI tse sebetsang li tlaleha hore ho pepesetsoa hoa batho ba sebelisang koae ka koae ho bakile takatso ea matla le ts'ebetso ea libaka tsa amygdala le pele ho kotlo ea cortical. (Bonson et al., 2002) le boithuto bo ts'oanang bo sebelisang phallo ea mali a khoerese ea tikoloho bo bontšitse ts'ebetso ho amygdala le cingrate cortex Ngaka ea bana et al. 1999 'me Kilts et al. 2001. Boithuto bo joalo bo senola hore, ho batho, lits'ebetso tse amanang le ts'usumetso le ts'usumetso e susumetsang ea linaha tse itseng tse susumetsang tse bonts'ang takatso ea lithethefatsi kapa ho batla ke likarolo tsa mantlha tsa ts'ebetso ea bokhoba.

Mosebetsi oa morao-rao o sebelisa mefuta ea liphoofolo o boetse o arabetse potso ea hore na joala bo kopanang ba lithethefatsi le tikoloho bo fetohang lipotoloho tsa ubongo tse bohlokoa bakeng sa ho susumetsa le ho ithuta. Robinson le basebetsi-mmoho ba bonts'itse litlamorao tse matla tsa bonohe ba tikoloho le maemo mabapi le boits'oaro bo bobe ba boits'oaro le molek'hule. Anagnostaras le Robinson 1996, Badiani et al. 1997 'me Badiani et al. 1998. Sehlopha sena se sa tsoa supa hore amphetamine induces Arc polelo kahara sebopeho sa striatum le pele ho boemo bo boholo tikolohong e nyane haholo ha e bapisoa le ntlo ea lapeng (Klebaur et al., 2002). Mofuta ona, o tšohliloeng pejana mabapi le polasetiki le liphetoho lipakeng tsa postynaptic, e kanna ea kenya letsoho liphetoho tse tlisoang ke lithethefatsi ho theheng ha lesapo la mokokotlo ka pele ho cortex le striatum, e fetang likhoeli tsa 3 kamora ho khaotsa kalafo ea lithethefatsi (Li et al., 2003).

Mosebetsi oa rona o tsepamisitse maikutlo phetohong e amanang le maemo a amanang le karabelo ea pele-le liphatsa tsa lefutso tse amanang le polasetiki lipotolohong tsa corticolimbic. R and ona le ba bang re bonts'itse hore ho pepesetsoa likhoto libakeng tse kentsoeng lithethefatsi ho kenya c-fos polelo likarolong tsena tsa boko. Mohlala, likotsi tse tsamaeang ka morphine (tseo hape li bakang ts'ebetso ea ts'ebetso ea locomotor) li susumetsa polelo ea "protheine" ea Fos ka mokhoa o matla ho pele ho methapo ea methapo ea methapo, "ventrolateral orbital" le "cingex" ea cortex; tlhahiso ena ke taba e ikhethang molemong oa hore liphoofolo tse fuoeng kalafo e tšoanang ea morphine le tse pepesitsoeng moelelo o sa reroang ha li bonts'e polelo e eketsehileng ea fos Schroeder et al. 2000 'me Schroeder le Kelley 2002. Mohopolo-cfos Ho qala ka kotlolloho libakeng tsa pele ho moo ho bontšitsoe cocaine, amphetamine, nikotine, biri le lijo tse fumanehang habonolo. Franklin le Druhan 2000a, Hotsenpiller et al. 2002, Neisewander et al. 2000, Schroeder et al. 2001 'me Topple et al. 1998. Haufinyane tjena, re se re qalile ho etsa lipatlisiso ka taba ena ka botlalo le tsamaiso ea nicotine ka litoeba, re hlahloba karabelo ea mefuta e kang Arc (CA Schiltz et al., E romelletsoe; CA Schiltz et al., 2003, Soc. Neurosci., Abstract, Moqolo 29). Likhoto tsohle li ile tsa fuoa nikotine le letsoai libakeng tse fapaneng. Leha ho le joalo ka letsatsi la liteko, halofo ea liphoofolo e ile ea ea tikolohong ea tsona e nchocho ka nicotine le halofo ea bona e le tikolohong ea bona e nang le letsoai. Lits'oants'o tse amanang le Nicotine li matlafalitsoe haholo Arc polelo ha e bue feela ka cortex ea pele empa hape le libakeng tse atileng tsa sensorimotor cortical (bona Setšoantšo sa 9). Ho latela mohopolo oa hore PFC e bohlokoa bakeng sa tšusumetso ea mekhoa e amanang le lithethefatsi mabapi le boits'oaro, ts'ebetso ea lehae ea PFC ea semmuso e thibela ka botlalo ts'ebetso ea ts'ebetso ea cocaine cue-e susumetsang (Franklin le Druhan, 2000b).

Boemo bona ba tlhahiso ea pele ea gene bo fana ka maikutlo a hore likhokahanyo tsa cortical tseo hangata li bohlokoa bakeng sa tšebetso ea polasetiki le kopanyo li fetoloa ke likoto tse atisang ho buuoa ka lithethefatsi. Ha ho hlake hore na ts'ebetso ea gene e emelang ho liphoofolo, empa ts'ebetso ea neural activate ea liteko tsa liteko tsa batho hangata e amahanngoa le litakatso kapa menahano e amanang le lithethefatsi. Mohlomong ts'ebetso ena ea liphatsa tsa lefutso e emela "ho se sebetse hantle" ketsahalo e sa lebelloang eo ho eona moputso o reng moputso (lithethefatsi, lijo) o teng, empa moputso oa mantlha ha o latele. Ho oela hape ho ka etsahala likhoeli kapa esita le lilemo kamora ho khaotsa ho sebelisa lithethefatsi le ho qeta nako e telele ho sa tsilatsile, ho fana ka maikutlo a hore ho tsitsitse haholo, mohlomong le liphetoho tse sa feleng kelellong li ka tlatsetsa tlokotsing ena. Kaha preortal cortex e bohlokoa mesebetsing e mengata ea kelello e kenyeletsang taolo ea thibelo, ho nka liqeto le taolo ea maikutlo, ba bangata ba boletse hore liphetoho tsa methapo ea kutlo sebakeng sena sa boko li ka ba karolo ea tahlehelo ea taolo e tsamaeang le linaha tse tsoetseng pele tsa bokhoba. Jentsch le Taylor 1999, London et al. 2000 'me Volkow le Fowler 2000. Ka ho oela hape, batho ka bomong ba hloleha ho etsa khetho e hlakileng, leha ba ne ba ikemiselitse pele ebile ba tsebahala ka litholoana tse bohloko tsa nako e tlang. Ha ba khahlisoa ke lithahasello tsa kantle tse sebetsang e le "likhopotso tsa lithethefatsi," batho ba joalo ba ka ba le likarabelo tse ikhethileng tsa boits'oaro le litakatso tse matla. Haeba ts'ebetso ea pele-pele ea cortical e songoa ke lits'oants'o tse bobebe tsa selefounung le limolek'hule, tekanyo ea taolo ea boithaopo eo taba e nang le eona ka maikutlo ana e ka fokola haholo. Ho joalo, mohlala oa bohlokoa oa ho lemalla o lematsa hore mehopolo le boits'oaro bo amanang le ho ts'oara lithethefatsi li fetoha tse iketsahallang le tse kang tloaelo le ts'ebetso ea bona e le tlasa taolo e fokolang ea boithaopo. (Tiffany le Conklin, 2000).

Khopolo-taba le sephetho

Thutong ena, mekhoa ea mantlha e arolelanoang ke lits'ebetso tsa ho ithuta ka moputso oa tlhaho le lithethefatsi tsa tlhekefetso li se li nkuoe ka har'a moralo oa li-system tsa neural tse sebetsang. Li-circuits tsa boko tse nang le li-codedically tse nang le li -cocodically li bile teng e le likarolo tse ling tsa bohlokoa ho tataiseng boits'oaro bo ntlafatsang le ho matlafala le ho phela. Nts'etsopele ea litsamaiso tse susumetsang maikutlo molemong oa liphoofolo tse anyesang e na le metso ea limolek'hule boits'oarong ba lintho tse limilione esita le limilione tse likete tse fetileng. Lits'ebetso tsena li thusa liphoofolo ho batla ts'usumetso e matlafatsang ho fumaneha hoa lisebelisoa (lijo, menyetla ea mating, polokeho, tšireletso) le ho qoba kotsi kapa ho itšireletsa khahlanong le libatana. Karolo e kholo ea "potry" ena, bonyane bokong ba mammary, ke maano a kopanyang le a ferekanyang lipakeng tsa methapo ea methapo e matla kahare ho hypothalamus le brainstem le li-corticostriatal tse phahameng le tse hlophisehileng haholoanyane. Puisano ena e pakeng tsa marang-rang a cortical le subcortical e thusa puisano e haufi pakeng tsa likarolo tse ncha tsa boko ba phylogenetic, e fanang ka kutloisiso e rarahaneng, ho ithuta, le polasetiki, ka lits'ebetso tsa motheo tse teng ho khothaletsa boits'oaro bo pholohileng. Li-coding tsa Neurochemical le intracellular li kenya tekanyo e sa tloaelehang ea ho hlaka, ho fetoha le maemo le polasetiki ka har'a marang-rang ana. Plasticity ka hare ho lipotoloho tsena e arolelanoa, bonyane karolo e itseng, ka ho khetholla ka ho hlaka hoa lets'oao la glutamate- le dopamine-Mediated le litlamorao tsa eona tse kahare le tsa genomic. Le ha lits'ebetso tse susumetsang maikutlo li susumetsa karolo e sebetsang haholo 'me e fetoha ea boitšoaro le ho ithuta, li ka ameha ka mekhoa e mebe maemong a ho lemalla. Ha ho pelaelo hore lipatlisiso tsa nako e tlang li tla fana ka leseli le tebileng haholoanyane ka ts'ebeliso ea lik'hemik'hale, liphatsa tsa lefutso, le tlhophiso ea moputso oa boko le ho fetoha hoa tsona ke tšebeliso ea lithethefatsi.

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