Mokhoa oa ho hopola lithethefatsi (2013)

Dialogues Clin Neurosci. 2013 Dec;15(4):431-43.

Eric J. Nestler, MD, PhD*

inahaneloang

Leha ho na le bohlokoa ba lintlha tse ngata tsa kelello, bokaholimo ba ts'ebeliso ea lithethefatsi e kenyelletsa ts'ebetso ea tlhaho: bokhoni ba ho pepesehela ts'ebeliso e mpe ea lithethefatsi ho etsa liphetoho kelellong e sa sireletsehang e khannang ho batla le ho ts'oara ha lithethefatsi, le tahlehelo ea taolo. ka ts'ebeliso ea lithethefatsi, e hlalosang boemo ba ho lemalla. Mona, re hlahloba mefuta ea liphetoho tsa limolek'hule le tsa cellular tse etsahalang libakeng tse ikhethang tsa boko ho thusa ho hokahana le tlhekefetso e amanang le tlhekefetso. Tsena li kenyelletsa liphetoho lipuong tsa mofuta oa liphatsa tsa lefutso tse fumanehang karolong e itseng ka methapo ea epigenetic, tšebetso ea polasetiki tšebetsong ea methapo ea kutlo le li-synapsic, le polasetiki e amanang le methapo ea kutlo le karohano ea methapo e arolelanoang ka karolo ka ho fetoloa hoa molaetsa oa neurotrophic factor. E 'ngoe le e' ngoe ea mefuta ena e fetotsoeng ke lithethefatsi e ka bonoa e le mokhoa oa "melaetsa ea sele kapa ea molek'hule." Ho feta moo, ho a makatsa hore mefuta e mengata e amanang le bokhoba ea polasetiki e ts'oana le mefuta ea botlolo eo e amanang le mefuta e mengata ea "boits'oaro ba boits'oaro," mohlomong e bonts'a phetoho e ntle ea mekhoa e sebetsang e fumanehang ho li-neurons ha e tobane le tikoloho. mathata. Kamora nako, liphetoho tse amanang le bokhoba le liselefshoa li kenyelletsa likarolo tse ngata tsa boko tse tšoanang tse hopolang mefuta e fapaneng ea memori, e lumellanang le maikutlo a hore mehopolo e sa tloaelehang ke bahlahisi ba bohlokoa ba li-syndromes tsa bokhoba. Morero oa lithuto tsena tse ikemiselitseng ho hlakisa molek'hule le liphatlalatso tsa bokhoba ba lithethefatsi ke ho hlahisa litlhahlobo tsa tlhahlobo ea tlhaho, hammoho le kalafo e sebetsang bakeng sa mathata a ho lemalla.

Keywords: sengoloa sa gene, epigenetics, TREEPO, DFFB, polasetiki ea synaptic, polasetiki eohle ea sele, nucleus accumbens, sebaka sa ventral tegmental, dintritic spines

Selelekela

Bokhoba ba lithethefatsi, bo ka hlalosoang e le ho batla le ho ts'oara lithethefatsi ntle le litlamorao tse nyarosang kapa tahlehelo ea taolo ea ts'ebeliso ea lithethefatsi, bo bakoa ke liphetoho tse bakiloeng ke lithethefatsi tsa nako e telele tse etsahalang libakeng tse ling tsa boko.1 Ke batho ba bang feela, leha ho le joalo, ba inehelang bokhobeng ba ho lemalla lithethefatsi khafetsa, ha ba bang ba khona ho sebelisa lithethefatsi hampe le ho baleha temallo ea ho lemalla. Lintho tsa liphatsa tsa lefutso li ikarabella bakeng sa 50 e batlang e le tlokotsing ea tlhekefetso ea lithethefatsi, mme boemo bona ba phepo e nepahetseng bakeng sa litlelase tsohle tse kholo tsa litlhare tse lemalloang, ho kenyeletsoa le tse matlafatsang, joala, nicotine le cannabinoids..2 Ha ho e-so khonehe ho khetholla boholo ba liphatsa tsa lefutso tse ka bang le monyetla oa ho ameha mohlomong ka mefuta e makholo ea liphatsa tsa lefutso e akaretsang ho motho a le mong ho fana ka ts'oaetso ea ho lemalla (kapa, ho batho ba bang, ho hanyetsa).

Karolo e 'ngoe ea 50% ea kotsi ea ho lemalla joala e bakoa ke mabaka a mangata a tikoloho, a etsahalang nakong eohle ea bophelo, a sebelisanang le sebopeho sa motho ho mo fa monyetla oa ho lemalla joala hanyane kapa hanyane. Mefuta e 'maloa ea maemo a tikoloho e' nile ea ameha bokhobeng, ho kenyeletsoa khatello ea maikutlo le kelello, empa lebaka le matla ka ho fetisisa ke ho pepesehela sethethefatsi sa tlhekefetso ka bo eona. Lithethefatsi tse ling tsa "heke", haholo-holo, nicotine, li bonts'itsoe ho eketsa ts'oaetso ea motho ea ho lemalla lithethefatsi tse ling.3 Ho feta moo, ho na le bopaki bo ntseng bo eketseha ba hore, ho sa na le likotsi tse ngata tsa liphatsa tsa lefutso bakeng sa ho lemalla batho bohle, ho pepesetsoa litekanyetso tse phahameng tsa lithethefatsi ka nako e telele ho ka fetola motho ea nang le liphatsa tsa lefutso tse tlase joalo ka ho lemalla..4

Tswelopele e kholo e se e entsoe lilemong tse mashome a mabeli tse fetileng ho tsebahatsa likarolo tse peli tsa boko tse bohlokoa ho hokahaneng le litekanyetso tsa tlhekefetso, hammoho le mefuta ea liphetoho maemong a limolek'hule le li-cellular tseo lithethefatsi li li tlisetsang libakeng tsena ho latela lintlha tsa bohlokoa. ya bokhoba.1,5 Potoloho e amohetseng tlhokomelo e kholo e bitsoa sisteme ea mesolimbic dopamine, e kenyang li-dopamine neurons sebakeng sa ventral tegmental area (VTA) ea methapo ea methapo ea methapo e ka hare ea methapo ea methapo ho li-nucleus accumbens (NAc, karolo ea ventral striatum). Li-neurons tsena tsa VTA le tsona li lula li le libakeng tse ling tse ngata tsa 'mele oa letlalo, ho kenyeletsoa hippocampus, amygdala, le preortalal cortex (PFC).

Hoa utloahala ho nahana ka mekhoa ena e khothalletsoang ea lithethefatsi bukeng ena mohopolong ka mabaka a mararo a manehileng.6

  1. Taba ea mantlha, liphetoho tsohle tse susumetsoang ke lithethefatsi li ka bonoa e le mefuta ea "limolek'hule kapa memori ea selula:" sele ea methapo e tlisoang ke liphetoho tse joalo e fapane ka lebaka la ts'ebeliso ea lithethefatsi 'me ka hona e arabela ka mokhoa o fapaneng le ts'ebeliso ea lithethefatsi tse tšoanang. ho lithethefatsi tse ling, kapa lintlafatso tse ling ka lebaka leo.
  2. Taba ea bobeli, hoa thabisa hore, mohlomong, boholo ba mefuta ea liphetoho tse amanang le boemo ba bokhoba (mohlala, transcript ea gene e fetotsoeng, epigenetics, synaptic le cellity eohle, le neuronal morphology le methapo ea methapo ea kutlo) hape e kenelletse ka mefuta ea "memori ea boits'oaro" e kang ho hopola maemo a sebaka, boemo ba tšabo, le maemo a sebetsang, hara ba bang.
  3. Taba ea boraro, hara likarolo tsa boko tse anngoeng ke lithethefatsi tsa tlhekefetso ke tseo e leng likarolo tsa bohlokoa tsa neural bakeng sa mohopolo oa boitšoaro, ho kenyeletsoa hippocampus, amygdala, le PFC. Sena se tsamaisana le ts'ebetso e ntseng e eketseha ea hore tse ling tsa likarolo tsa bohlokoahali tsa bokhoba ba bonohe ka bongaka (mohlala, litakatso tsa lithethefatsi le ho oela hape) li bonts'a lits'oants'o tse liphatlalatsong tsa moetlo tsa setso, tse hopotsang nako e telele tsa boiphihlelo ba lithethefatsi tse sebelisoang joalo ka bakhanni ba matla ba tšibollo ea lithethefatsi.4,7,8 Ka lehlakoreng le leng, libaka tsa moputso oa boko (mohlala, VTA le NAc) li ka susumetsa mohopolo oa boitšoaro.

Sengoliloeng sena se fana ka kakaretso ea mefuta ea mantlha ea liphetoho tsa limolek'hule le tsa cellular tse etsahalang libakeng tse 'maloa tsa boko mehlaleng ea liphoofolo, e tsepamisitse maikutlo ho seo ho fumanehang tlhahisoleseling ho sona. Habohlokoa le ho feta, e bile le monyetla o eketsehileng oa ho netefatsa tse ling tsa liphetoho tsena ho litlolo tsa batho tse thehiloeng boithuto ba kelello ba postmortem. Leha taba ea hore lithethefatsi tsa tlhekefetso li na le lits'ebetso tse fapaneng tsa lik'hemik'hale 'me li sebetsa ka lipehelo tse ikhethang tsa protheine, hoa makatsa hore litloaelo tse ngata tse tummeng tse amanang le bokhoba li tloaelehile ho ba bangata,' me maemong a mang kaofela, lithethefatsi tsa tlhekefetso ebile li ka kenya letsoho likarolong tse arolelanoang tsa tlhekefetso ea ho lemalla.4,9 Ka lehlakoreng le leng, litloaelo tse ling tse ngata tse susumetsoang ke lithethefatsi li tobile ho moriana o fanoeng mme li ka kopanya likarolo tse ikhethileng tsa bokhoba bo fanoeng. Mona re shebana le lithethefatsi tse matlafatsang le tse opangate tsa tlhekefetso, tse hlahisang litlamorao tse matla mefuteng ea liphoofolo ha li bapisoa le lithethefatsi tse ling. Re boetse re totobatsa libaka tsa bohlokoa bakeng sa lipatlisiso tsa nako e tlang tse tla eketsa tsebo ea rona ea li-syndromes tsa bokhoba le ho fetolela tsoelo-pele ena litekong tse ntlafalitsoeng tsa tlhahlobo le kalafo.

Mekhoa ea ho ngola le epigenetic

Tsebo eo e lemaletseng bokhoba ba eona e ka lula e le kotsing e kholo ea ho o tlohela hape le hoja e le lilemo tse ngata tsa ho tlohela mosebetsi, e bolela hore tlhekefetso e kenyelletsa liphetoho tse tlisoang ke lithethefatsi bokong tse ka tsitsitseng. Sena se entse hore lihlopha tse 'maloa li nahane ka liphetoho lipuong tsa mofuta oa tsona e le karolo ea bohlokoa ea ts'ebetso ea bokhoba (Setšoantšo sa 1). Ka hona, liphuputso tsa liphatsa tsa lefutso tse amanang le mofuta oa lipatlisiso tsa lefutso tse amanang le li-Microbine tsa DNA le RNA-seq (tatellano e kholo ea tatellano ea li-RNAs tse hlahisitsoeng) e thathamisitse mefuta e mengata eo polelo ea eona e fetotsoeng sebakeng sa boko bo fapaneng le mefuteng ea khale ea ho lemalla le bokhobeng ba batho. (mohlala, Ref. 10-17). Mehlala ea mefuta e joalo e tšohloa likarolong tse latelang tsa tlhahlobo ena.

Mekhoa ea melaoana ea ho hatisa le epigenetic ke lithethefatsi tsa tlhekefetso. Liseleng tsa eukaryotic, DNA e hlophisitsoe ka ho koaheloa ke li-octomers tse potolohileng historio, ebe li hlophisetsoa hape ho ntlafatsoa ho etsa li-chromosomes (karolo e ka letsohong le letšehali). Ke feela ka ho notlolla ka nakoana chompatin e kopantsoeng e ka etsang hore DNA ea mofuta o itseng e khonehe ho fihlella mochine o hatisang. Lithethefatsi tsa tlhekefetso li sebetsa ka lipehelo tsa "synaptic" tse kang li-reuptake mechanisms, li-ion channels, le li-receptor tsa neurotransmitter (NT) ho fetola li-Cascade tsa "intracellular signaling" (karolo e ka letsohong le letona). Sena se lebisa ts'ebetsong kapa ho thibelo ea lintlha tse hatisitsoeng (TFs) le lipakaneng tse ling tse ngata tsa nyutlelie, ho kenyelletsa liprotheine tse laoloang ke chromatin (e bontšitsoeng ke metsu e teteaneng); Mekhoa e qaqileng ea ho kenyelletsa protheine ea taolo ea chromatin e lula e sa utloisisoe hantle. Ts'ebetso tsena li qetella li hlahisitse kapa ho hatella mefuta ea mofuta o itseng, ho kenyelletsa le ea li-RNA tse sa hlophiseng lintlha tse kang li-MicroRNA; Polelo e fetotsoeng ea a mang a mefuta ena ea lefutso e ka laola ho fetisoa ha liphatsa tsa lefutso. Ho khothalletsoa hore tse ling tsa liphetoho tsena tse susumetsoang ke lithethefatsi maemong a chromatin li tsitsitse haholo mme ka hona li ka tlasa boitšoaro bo tšoarellang bo hlalosang bokhoba. CREB, protheine ea cyclic e arabelang ka cyclic; DNMTs, li-methyltransferase tsa DNA; HAT, histone acetyltransferases; HDAC, li-deacetylase tsa histone; Li-HDM, li-demethylase tsa histone; HMTs, histonetrylferansase; MEF2, myocyte-e khethehileng e ntlafatsang factor 2; NF-kB, ntlha ea nyutlelie; pol II, RNA polymerase II. E hlahisitsoe hape ho Ref 44: Robison AJ, Nestler EJ. Mekhoa ea ho ngola le epigenetic. Nat Rev Neurosci. 2011; 12: 623-637.

Ka mokhoa o ts'oanang, mefuta e mengata ea lintho tse ngotsoeng — liprotheine tse tsamaeang le liphatsa tsa lefutso mme ka hona li eketsa kapa li fokotsa ho fetisoa ha liphatsa tsa lefutso tseo — li ​​bile le tšusumetso ho hola litlamorao tsa nako e telele tsa lithethefatsi tsa tlhekefetso ho polelo ea lefutso bokong. Mehlala e hlahelletseng e kenyelletsa CREB (proteni ea karabo ea cAMP e tlamang), ΔFosB (ntlha e ngotsoeng ea lelapa la Fos), NFkB (nyutlelie ntlha kB), MEF2 (myocyte e ntlafatsang factor-2), le li-receptors tsa glucocorticoid, hara tse ling tse 'maloa.5,10,18-22 Ho 'nile ha e-ba bonolo ho utloisisa mekhoa ea ho tšoaea lisele tsa cellular eo ka eona lithethefatsi tsa tlhekefetso li kenyang sengoloa se fanoeng bokong le ho hokahanya ts'ebetso e joalo le liphatsa tsa lefutso tsa sengoloa le likarolo tse itseng tsa boits'oaro (bona Setšoantšo sa 1). Khatelo-pele ena e bontšoa ke ho hlahloba CREB le ΔFosB, e leng lintlha tse ithutoang haholo tsa mongolo ka mefuta ea bokhoba.

cAMP Karabelo ea karolo e tlamang protheine

Lithethefatsi tse matlafatsang le tse opangate tsa tlhekefetso lia qala TREEPO libakeng tse 'maloa tsa boko tse bohlokoa bakeng sa bokhoba, ho kenyeletsoa haholo ho NAc.23,24 CREB e tsejoa ho kenya ts'ebetsong lits'ebetsong tse ling ka cAMP, Ca2+Litsela tsa kholo,25 mme ha e e-so tsejoe hore na ke efe ho tsena e kopanyeletsang ts'ebetso ea eona ho NAc ka lithethefatsi tsa tlhekefetso. Ts'ebetso ea lithethefatsi ea CREB ho NAc e bontšitsoe ho emela mokhoa oa khale oa ho se arabe, eo ka eona CREB e sebeletsang ho fokotsa kutlo ea phoofolo litlamorao tse khahlisang tsa lithethefatsi tsena (mamello) le ho sebetsana le maemo a mabe a maikutlo nakong ea ho tlohela lithethefatsi (ts'epahalo).18,26,27 Litlamorao tsena li bontšitsoe haufinyane ho khanna ho itaola hoa lithethefatsi le ho khutla hape, hangata ka ts'ebetso ea ho matlafatsa hampe.28 Ketso ena ea CREB e bonahala e kenyelletsa subtypes e kholo ea li-neurc tsa spiny neurons tse mahareng, tse bonts'ang haholo D1 bapisa D2 dopamine li-receptors.24 IHo thabisang, sehlopha se seholo sa lingoliloeng se bonts'itse hore CREB, e sebelisang hippocampus le amygdala, ke molek'hule ea bohlokoa mohopolong oa boitšoaro.29-31 Karolo ena e pharaletseng ea bokhoba ba ho lemalla le ho ba le boits'oaro e kanna ea bonts'a 'nete ea hore li-neurons li na le palo e lekantsoeng ea methapo ea limolek'hule ea ho ikamahanya le tikoloho e lulang e fetoha.

Mefuta e lebelletsoeng ea CREB e arolelanang mokhoa ona oa boitšoaro e fumanoe ka lipalo tsa tlhaho le ka boiteko bo khethiloeng.10,18,32 Mohlala o mong ke opioid peptide dynorphin: tlhahiso e matlafatsang ea polelo ea dynorphin ho li-neuron tsa NAc, tse kopaneng ka CREB, e eketsa ts'ebetso ea dynorphin ea li-receptor tsa k opioid ho li-neurons tsa VTA dopamine ebe ka tsela eo e hatella phetiso ea dopaminergic ho NAc mme o sitisa moputso.18 Lipheo tse ling tsa CREB tse ngata li bonts'itsoe li le bohlokoa bakeng sa polasetiki e kopantsoeng le lithethefatsi, joalo ka ha ho hlalositsoe ka tlase. Ha CREB e boetse e kenngoa tšebetsong likarolong tse ling tse 'maloa tsa boko ka li-activators le opiates,23,24 ha ho tsejoe hakaalo ka litlamorao tsa boits'oaro ba sena le liphatsa tsa lefutso tseo li hlahang ka tsona. Ka mokhoa o ts'oanang, ha ho tsejoe hanyane ka karolo eo CREB e nang le eona ho fapakaneng liketso tsa lithethefatsi tse ling tsa tlhekefetso.19

DFFB

Ho pepesetsoa ka mokhoa o nepahetseng hoo e batlang e le lithethefatsi life kapa life tsa tlhekefetso ho etsa hore ho be le lintlha tsohle tse ngotsoeng tsa Fos ho malapa le Na le likarolo tse ling tsa boko. Ho kenella hona ka potlako ho potlakile hape ho nka nako e telele haholo, ha maemo a liprotheine tsa Fos a khutlela ho tloaelehileng nakong ea lihora tsa 8 ho isa lihora tsa 12. E ikhethang har'a protheine ena ea lelapa ea Fos ke ΔFosB, sehlahisoa se qotsitsoeng sa mofuta oa FosB, eo ka lebaka la botsitso ba eona bo sa tloaelehang, butle-butle e bokellang nakong ea ho pepesetsoa lithethefatsi khafetsa mme e ba protheine e kholo ea Fos e hlahisitsoeng tlasa maemo ana.22,33 Ho feta moo, ka lebaka la botsitso bona, maemo a ΔFosB a phehella libeke kamora ho tloheloa hoa lithethefatsi. Ho kenella ho joalo ka nako ea ΔFosB ho bontšitsoe hoo e batlang e le lithethefatsi tsohle tsa tlhekefetso34 , bakeng sa lithethefatsi tse ngata, e khetha li-neuron tsa Dl-NAc.34,35 E boetse e bile teng e bonts'itsoeng bokhobeng ba batho.35 Sehlopha se seholo sa lingoliloeng se bonts'itse hore tlhahiso ea ΔFosB e joalo ka D1-mofuta oa NAc neurons o eketsa kutloisiso ea phoofolo ho lithethefatsi le meputso ea tlhaho mme e khothaletsa boits'oaro ba lithethefatsi, mohlomong ka ts'ebetso ea ho matlafatsa (bona Refs 34 ho 38). Ho khahlisang, tšebeliso ea lithethefatsi ea ΔFosB ho NAc e atile haholo ho liphoofolo tsa bocha, nako ea ho ba tlokotsing ea ho lemalla joala ho feta tekano,39 'me ho hlahisoa ha eona ke nikotine ho bonts'itsoe ho buella tsela ea nicotine e ntlafatsang tsela ea moputso oa k'hok'heine.40

Ha e le CREB, mefuta e mengata ea sepheo sa ΔFosB e khethiloe ho NAc ka ts'ebeliso ea mefuta ea khetho le mofuta oa liphatsa tsa lefutso.10,32 Ha CREB e hlahisa dynorphin, ΔFosB ee hatella, e leng se tlatsetsang liphellong tsa pro-moputso tsa ΔFosB.38 Morero o mong oa ΔFosB ke li-cFos: ha ΔFosB e bokellana ka ho pepesetsoa lithethefatsi khafetsa e hatella c-Fos mme e kenya letsoho phetohong ea molek'hule moo ΔFosB e kenelletseng ka mokhoa o ikhethileng maemong a sa foleng a sebelisoang ke lithethefatsi..41 Lipheo tse ling tse ngata tsa ΔFosB li bonts'itsoe ho sebetsana le bokhoni ba lithethefatsi tse ling tsa tlhekefetso ho kenya li-synaptic polasetiki ho NAc le liphetoho tse amanang le ho fetoha ha meritritic arborization ea NAc medium spiny neurons, joalo ka ha ho tla tšohloa ka tlase.

Liphetho tse sebetsang tsa uctionFosB induction libakeng tse ling tsa boko ha li utloisisehe hantle, leha e le hore tšenolo ea eona ho orbitofrontal cortex (OFC) e ithutoe ka botlalo. Mona, ΔFosB e sebelisana le mamello e bang teng litlamorao tse amang kelello tsa koae nakong ea ho pepeseha ho sa feleng, 'me phetoho ena e tsamaisana le taolo e eketsehileng ea koae..42,43

Lipalo-palo tse pharalletseng li hlahisitse liphatsa tsa 'mele tse fumanehang tse hlahisang litlamorao.42 Leha e na le thepa e ikhethileng ea nakoana ea ΔFosB, le tsebo ea hore e kentsoe lipotolohong tsa moetlo (mohlala, hippocampus), ha ho so be le phuputso ea karolo ea ΔFosB mohopolong oa boits'oaro, taba e khahlisang bakeng sa lipatlisiso tsa nako e tlang.

Mekhoa ea epigenetic

Lilemong tsa morao tjena, lithuto tsa sengoloa li hatisitsoe mohato o le mong ho epigenetics44 (bona Setšoantšo sa 1), e ka hlalosoang ka botlalo e le phetoho ea polelo ea liphatsa tsa lefutso e etsahalang ntle le phetoho ea tatellano ea DNA. Mechine ea Epigenetic e laola ho kenngoa ha DNA ka har'a seleng ea sele ka ho sebelisana ha eona le histones le mefuta e meng e mengata ea protheine ea nyutlelie e kopaneng chromatin. Polelo ea Gene e laoloa ke boemo ba sephutheloana sena ka phetoho e kopaneng ea li-histones, liprotheine tse ling, le DNA ka boeona. Joalo feela mehlala e meng, acetylation ea histones e sekamela ho ntšetsa pele ts'ebetso ea liphatsa tsa lefutso, methylation ea li-histones e ka khothaletsa ts'ebetso ea gene kapa khatello ea maikutlo ho latela masala a Lys a tlisoang ke phetoho ena, mme methylation ea DNA ka kakaretso e amana le khatello ea gene leha mefuta e meng e fapaneng ea methylation ( mohlala, 5-hydroxymethylation) e kanna ea amahanngoa le ts'ebetso ea gene.

Epigenetics ke mokhoa o ipiletsang hobane, lits'ebetsong tse ling, ka mohlala, biology ea nts'etsopele le mofets'e, liphetoho tse itseng tsa epigenetic li ka ba tsa ka ho sa feleng. Ka lebaka lena, li-epigenetics li lelekiloe ka bobeli lithutong tsa ho ithuta le tsa ho hopola (mohlala, refs 45-48) hammoho le bokhoba ba tahi;44,49 ka har'a litsamaiso tsena ka bobeli phetoho e kholo e tlalehiloe histone acetylation le methylation le ho DNA methylation. E le mohlala o le mong feela, histonetrylferosase, G9a, e bohlokoa mohopolong ka bobeli50 le bokhoba ba ho lemalla.51,52 Mefuteng ea ho lemalla, Polelo ea G9a ha e theotsoe ho NAc ho arabela lithethefatsi tse hlasimollang kapa tse opangate tsa tlhekefetso le tea hae e bontšitsoe ho matlafatsa melemo e tlisoang ke lithethefatsi tsena.51,52 Ho khahlisang, khatello ea cocaine ea G9a e kenelletsoe ke ΔFosB. G9a e ruta ho qaptjoa ha Lys9 ea histone H3 (H3K9me2), mokena-lipakeng oa khatello ea mofuta oa gene. ChIP-chip kapa ChIP-seq (chromatin immunoprecipitation e lateloang, ka ho latellana, ka lipapatso tsa papatso kapa tatellano e phahameng) e sebelisitsoe ho fumana limmapa tse pharalletseng tsa mofuta oa mofuta oa NAc tse bonts'ang phetoho ea H3K9me2 kamora ho pepeseha kapa ho hlahisa mahlo.32,52,53 Ka ho fetisa lethathamo lena la liphatsa tsa lefutso le lethathamo la mefuta ea phetoho ea liphatsa tsa lefutso, le limmapa tse pharalletseng tsa mefuta e meng e mengata ea phetoho ea epigenetic (mohlala, ΔFosB binding, CREB binding, liphetoho tse ling tsa histone, jj)32,53 e lokela ho khona ho khetholla mofuta o felletseng oa mefuta ea tlhaho e laoloang ke lithethefatsi tsa tlhekefetso le ho utloisisa mekhoa e ikhethileng ea epigenetic.

Mofuta o mong oa taolo ea epigenetic e kenelletseng mohopolong le ho lemeng ke moloko oa li-microRNA. Li-RNA tsena tse nyane, tse sa kopaneng li tlama likarolo tse tlatselletsang tsa li-mRNA mme ka hona li hatella phetolelo ea tsona kapa ho etsa hore ho hle ebe lihlong tsa tsona. Tloso ea Argonaut, protheine ea bohlokoa bakeng sa ts'ebetso ea li-miRNA, liphetoho tsa boitšoaro ho cocaine, tse nang le litlamorao tse hlakileng tsa D1- bapisoa le D2-mofuta oa spiny neurons oa bohareng.54 LiRNA tse 'maloa tse ikhethileng le tsona li bontšitsoe hore li laoloa ke ho pepesetsoa hoa lithethefatsi, hape, ho susumetsa karabelo ea boitšoaro ho lithethefatsi (mohlala, refs 55,56). E tla ba ho thabisang lithutong tsa nako e tlang ho tseba sepheo sa mRNA tsa li-miRNA tsena le ho bontša kamoo li amang ts'ebetso ea bokhoba ka teng.

Synaptic polasetiki

Mefuta e ts'oanang e akaretsang ea liphetoho tsa synaptic ho li-glutamatergic synapses, tse kentsoeng hippocampus le amygdala mohopolong oa boits'oaro (bona lingoloa tse ling makasineng ena), le tsona li bontšitsoe li hlaha libakeng tsa moputso oa boko mekhoeng ea ho lemalla le ho ba bohlokoa ho buisanang. ketso ea ho lemalla.57,58 Ts'oarello ea mofuta ona oa "synaptic" e hlahisitsoeng ke lithethefatsi e hlalositsoe libakeng tse 'maloa tsa boko, leha ho le joalo, re tsepamisa maikutlo mona ho NAc moo lipatlisiso tse ngata li shebileng ho fihlela joale (Setšoantšo sa 2).

Model ea li-synaptic tse amanang le bokhoba le polasetiki ka har'a li-nucleus accumbens (NAc). Ho pepeseha ho sa feleng ha cocaine ho etsa hore ho be le nako le nako ea ho hlophisa bocha sebaka sa α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) le N-methyl-D-aspartic acid (NMDA). spiny neuron (MSN) synapses, hammoho le liphetoho tsa sebopeho hloohong ea mokokotlo oa li-NAc MSN tse lumellanang le mefuta e ikhethileng ea polasetiki ea synaptic. Mohlala, cocaine e sa foleng e etsa hore e bue ka li-receptor tsa NMDA, sebopeho se khutsitseng sa syloc le khatello ea maikutlo ea nako e telele (LTD) nakong ea pele ea nako ea ho tlohela. Nakong ea ho tlosoa ha nako e telele, wd, liphetoho tsena tsa synaptic li khutla hape ka lebaka la ho ba polelo e eketsang ea li-receptor tsa AMPA, kopanyo ea sehokelo se fetoha lesapo la mokokotlo le nang le sebopeho sa nako e telele (LTP). Litlamorao tsena li khutlela bothateng bo boholo hang ha motho a pepesetsoa tekanyetso ea cocaine e lebisang phetong ea lesapo la mokokotlo hore e be mesifa e tšesaane le khatello ea maikutlo.

Liteko tsa pele li bonts'itse hore ho pepesetsoa khafetsa ho lithethefatsi tse susumetsang tsa tlhekefetso ho hohela LTD (boemo ba maikutlo a nako e telele)-mmuso o kang oa glutamatergic synapses ho NAc.59 Leha ho le joalo, mosebetsi o mongata oa morao tjena o bonts'itse polasetiki e joalo e ts'epa nako haholo, 'me LTD e etsahetse kamora ho pepesoa koae ea ho qetela e fetoha karolo ea LTP (nako e telele ea ts'ebeliso ea nako e telele) kamora nako ea ho tlohela nako e telele.60,61 Mosebetsi ona, oo ho fihlela joale o seng o ntse o etsoa haholo ho sebelisoa lipatlisiso tse tsamaisitsoeng — ho fapana le meriana e laoloang ka boeona, o hlalositse tlhoko ea lipatlisiso tse hlophisehileng haholoanyane mehlaleng ea ho itaola e latelang mefuta ea polasetiki ea synaptic e etsahalang ho li-synapsic synapses ho NAc holim 'a nako e qaqileng ea nako ho tloha ho nkeng tsamaiso ea boithati ho e boloka, ho fihlela ka linako tse fapaneng tsa ho khaotsa le ho felisoa, le ka karabelo ea ho khutlisa hape. Ho sebetsa ho fihlela joale e boetse e hlalositse mekhoa e meng ea limolek'hule e kenyang letsoho polokelong ena e kopantsoeng le lithethefatsi, ho kenyeletsoa le ho ts'oaroa ha li-receptor tsa AMPA ho synapse mohlomong e le karolo e bohareng ka CaMKII (Ca2+/ utulivu wa protheine e tsamaeang le protheine kinase II) phosphorylation ea li-receptor tse itseng tsa AMPA le polelo e fetotsoeng ea li-subcom tsa AMPA receptor (mohlala, 60,62-65, Litšoantšo 2 le 3). Karolo ea CREB le ΔFosB e kentsoe tšebetsong tsena, hammoho le liphetoho tse amanang le morphology ea glutamatergic synapses (bona ka tlase). Mohlala, GluAl ke sepheo sa CREB ho NAc, moo GluA2 le CaMKII ka bobeli e leng liphofu tsa ΔFosB, sebakeng sena sa boko .35,36,66,67 Ha o tsoela pele, ho tla ba bohlokoa ho hokahanya liphetoho tse ikhethileng tsa nako le phetoho ea nako ea ts'ebetso ea synaptic le likarolo tsa boits'oaro ba bokhoba.   

Mekhoa ea limolek'hule e hlahisang k'hok'heine ea ho qhekelloa ha methapo ea dendritic ho li-nucleus accumbens (NAc) li-spiny neurons tse mahareng. A) e bonts'a keketseho e bakoang ke k'hok'heine ea nomoro ea mokokotlo ea dendritic e ka thibeloang ke khatello e fetelletseng ea vaerase ea G9a kapa JunD (mohanyetsi oa phetisetso ea AP1), kapa e etsisoang ke khatello e fetelletseng ea FosB. B) Taolo ea thekiso ea AMPA receptor (AMPAR) le ea actin cytoskeleton (ka ho le letšehali), hammoho le taolo ea phetisetso ea li-receptor tsa glutamate le liprotheine tse laoloang tsa actin (mohlala, joalo ka ha li buelloa ka ΔFosB, ka ho le letona) li bontšitsoe li bapala karolo ea bohlokoa khokahanong ea taolo ea k'hok'heine ea NAc dendritic spine density. UMK, LIM domain kinase; RAC, substrate e nang le chefo ea C3 ea botulinum e amanang le Ras.

Lisebelisoa tse ncha tsa liteko li etsa hore ho be le nako ea pele ea ho hlalosa ka ho nepahala ho eketsehileng hore na ke lipotoloho life tse bontšang mefuta ena ea polasetiki ea synaptic le hore na ke boits'oaro bofe bo bohareng bo bo kopanyang. Mohlala, to ile a theola le ho ngola likarolo tsa mantlha tsa NAc ho bontša phapang ea polasetiki e kentsoeng ke lithethefatsi, joalo ka D1- bapisa le D2-mofuta oa li-spiny neurons tsa methapo e bohareng kahare ho mofuta o mong le o mong.60,63,64,67 Ka mokhoa o tšoanang, liteko tsa optogenetic li fane ka leseli la lipale mabapi le monehelo oa mofuta o itseng oa synaptic plasticity (mohlala, LTD) libakeng tse ikhethang tsa li-synapses tsa glutamatergic ho NAc, ka mohlala, tse hlahang ho medial PFC khahlanong le basolateral amygdala kgahlano le subralulum (tlhahiso e kholo of hippocampus).68-70 Qetellong, ho tla hlokahala hore ho koaheloe limolek'hule tse bakoang ke lithethefatsi ho e 'ngoe le e' ngoe ea li-neuron tsena tse nang le li-synapse tse ikhethileng tse hlahang ho li-postynaptic dendrites ho bokella kutloisiso e felletseng ea kamoo lithethefatsi tsa tlhekefetso li fetolang potoloho ea boko ho tsamaisa likarolo tse itseng tsa lemaletse. Boiteko bona bo tla hloka kananelo e kholo ea polasetiki e bakoang ke lithethefatsi ho li-synapses tse thibelang likarolo tse tšoanang tsa libaka tsa boko, sebaka se sa tsotelloang haholo ho fihlela joale.65

Eona polasetiki eohle

Le ha lipatlisiso tse ngata tse kenyelletsang liphetoho tsa methapo ea kutlo li-neurons maemong a tlhekefetso ea lithethefatsi, joalo ka ho ithuta le ho hopola liketsahalo, li shebile polasetiki ea synaptic, ho na le bopaki bo ntseng bo eketseha ba bohlokoa ba polasetiki ea sele kaofela. Plastiki eohle, e boetse e bitsoa polasetiki ea homeostatic,71 e kenyelletsa liphetoho lipakeng tsa seleng ea methapo eohle ka tsela eo e sa ikhethang ka kotloloho. Ka lebaka la hore likarolo tse ling tsa ts'ebeliso ea lithethefatsi li kenyelletsa matla a ntlafatsang kapa a fokotsehileng a maikutlo a lithethefatsi, hoa utloahala hore ho ntlafatsa kapa ho fokotsa thabo ea motlakase oa lisele tse itseng tsa methapo ho tlatsetsa ho tloaelo ena ea boits'oaro.5

The Mohlala o motle oa polasetiki ea sele eohle ho sethethefatsi sa tlhekefetso ke bokhoni ba opiates bo sa foleng ho eketsa thabo e kholo ea li-neuradrenergic neurons tsa locus coeruleus (LC).72 Monate ona o eketsehileng o kopantsoe ka CREB le ho kenella hoa isoforms e itseng ea cymbase ea adenylyl, e khannang ho thunya ho hoholo ha li-neuron tsa LC mohlomong ka ho kenella lits'ebetsong tsa Na +.72-75 Hyperexcitabidence ea LC neurons e bontša mokhoa oa khale oa ho mamellana le ho ts'epahalla ebe o khanna matšoao le matšoao a ho khaohana ha opiate. Ho khahlisang, CREB e sebelisana le mofuta o tšoanang oa polasetiki ea cell cell le li-neuron tsa spiny tse khutšoaneng, tseo hape li fetoleloang ka hore ke hyprexcable ka ho pepesehela lithethefatsi tsa tlhekefetso ka CREB.76 Kahoo ho tla ba bohlokoa lipatlisisong tsa nakong e tlang ho utloisisa hore na CREB -ediedi e kopantsoeng le polasetiki ea li-glutamatergic synapses ho NAc medium spiny neurons65,66 e akaretsa ka CREB-Mediated intrinsic hyperexcitability ea li-neuron tsena76 ho laola likarolo tsa boits'oaro ba bokhoba.

Mohlala o mong oa polasetiki ea sele eohle mefuteng ea ho lemalla ke hyperexcitability ea VTA dopamine neurons e hlahang kamora ho pepeseha ho sa feleng ha lithethefatsi tsa opusate tsa tlhekefetso.e (Setšoantšo sa 4).77,78 Phetoho ena, e kopantsoeng le liphetoho tsa morphological liseleng tsena tsa methapo (bona karolo e latelang), ha e aroloe ke CREB empa e fihlelletsoe ka molao oa likhakanyo tsa molao tsa neurotrophic, joalo ka ha ho hlalositsoe ka tlase.   

Mohlala oa ho sebetsa oa litloaelo tse sa feleng tsa morphine tse susumetsoang sebakeng sa dopamine neuropathy sebakeng se bitsoang (transpar tegmental area (VTA)). Morphine e sa foleng e fokotseha boholo ba soma ea VTA dopamine (DA) leha ho le joalo e eketsa thabo ea neuronal, ha phetisetso ea dopamine ho li-nucleus accumbens e fokotseha. Litlamorao tsa morphine ke tsela e sa arabeloang haholo ea moputso, e leng, mamello ea moputso. Phokotso ea IRS2-AKT ho supa ho VTA e kenyelletsa litlamorao tsa morphine o sa foleng ka boholo ba soma le thabo ea motlakase; phello ea thabo e tšehelitsoe ka ho fokotsa γ-aminobutyric acid (GABA) maqhubu le khatello ea polelo ea K 'channel. Morphine-ikiwa e theotsoeng tlase molemong oa ts'ebetso ea mTORC2 ho VTA e bohlokoa bakeng sa liphetoho tsena tsa morphine le morphological le mmele hammoho le mamello ea moputso. Ho fapana le mT0RC2, morphine e sa foleng e eketsa tšebetso ea mTORCI, e sa susumetseng liphetoho tsena tse susumetsoang ke morphine. BDNF, neurotrophic factor e tsoang bokong; IRS, ntho ea "insulin" receptor; mTORC, mochini oa mTOR; AKT, protheine kinase B E hlahisoa hape ho RefXNNX

Morphological polasetiki le methapo ea methapo ea kutlo

Bopaki bo ntseng bo eketseha, boholo ba eona bo tsoa lipatlisisong tsa hippocampal le cortical neurons, bo bonts'itse hore liphetoho lipolotiking tsa synaptic li amana le liphetoho tsa morphological ho li-synapses. Mohlala, LTD le moloko oa li-synapses tse khutsitseng li amahanngoa le ho etsoa ha methapo e menyenyane kapa e boreleli ea dendritic, athe LTP e amahanngoa le mehala e meholo, e nang le sebopeho sa li-mushroom.79,80 Ho a khahlisa ka hona hore lefapha la ts'ebeliso e mpe ea lithethefatsi le shebane le liphetoho tse bakoang ke lithethefatsi mokhoeng oa dendritic bakeng sa lilemo tse 15. Ho pepeseha ho sa feleng ho lithethefatsi tse matlafatsang tsa tlhekefetso li eketsa letsoalo la mokokotlo oa methapo ea methapo e bohareng ea NAc, e leng phetoho e tlang pele ho li-neuron tsa mofuta oa Dl.67,81,82 Ho hlahisoa ha masapo a mokokotlo ho amahanngoa le karolo e kholo le likarabelo tsa maikutlo tse amanang le lithethefatsi tsena, leha bopaki bo bong bo hanana le pono ena.

Joalo ka lipatlisiso tsa polasetiki ea synaptic, leha ho le joalo, ho hlokahala mosebetsi o mongata haholo ho hlalosa liphetoho lits'ebetsong tsa dendritic tse etsahalang nakong ea boits'oaro ba lithethefatsi, ho ikhula le ho oela hape. SMatsoalo ho tla fihlela joale, ho kenyelletsa lipatlisiso tsa ngaka le lithethefatsi tse tsamaeang ka boeona, li fana ka maikutlo a liphetoho tse fapaneng haholo tsa lesapo la mokokotlo tse etsahalang libakeng tse fapaneng tsa ho tlosoa le ho NAc shell Khahlano le litlhaloso tsa mantlha.83-86 Hape ho tla ba bohlokoa ho hlalosa mekhoa e nepahetseng ea limolek'hule eo k'hemik'hale kapa mofuta o mong oa tlhahiso o hlahisang litla-morao tsena tse amanang le nako le lisele. ΔFosB e bontšitsoe hore e ea hlokahala ebile e lekane bakeng sa ho kenyelletsa methapo ea bongoana ho li-neuron tsa Dl-NAc.35,51,67 Taolo e joalo e etsahala moketjaneng oa "cocaine" le "osFosB" oa liprotheine tse ngata tse tsejoang ho laola ho hlophisoa bocha ha actin cytoskeleton. Joalo ka mohlala o le mong feela, melaoana ea ho ngola ea lintlha tse 'maloa tsa phapanyetsano ea li-guanine nucleotide le GTPase e sebetsang ea liprotheine e hlahisa Rac1, GTPase e nyane, bakeng sa nakoana e fokotsehang ts'ebetsong ho arabela tlhahiso e' ngoe le e 'ngoe ea k'hok'heine,' me ho fokotseha ho joalo ha ts'ebetso ea Rac1, ho sebelisoa optogenetic control ea Rac1, ho kenyelletsa ho kenyelletsa mele e sa sebetseng.87 Litlamorao tsena tsa Racl mohlomong li hlaha ka taolo ea eona ea cofilin le liprotheine tse ling tsa molao tsa actin, tseo le tsona li bonts'itsoeng ho laola taolo ea koae ka ho hola ha lesapo la mokokotlo.87,88 Leha ho le joalo, ho bohlokoa ho totobatsa hore ena ke tsela e le 'ngoe feela e amehang taolong ea k'hok'heine ea likhahla tse sa tsoaneng, hobane liprotheine tse ling tse' maloa le tsona li bontšitse karolo ea bohlokoa, ho kenyeletsoa CDK5 (cyclin-dependent kinase-5), CaMKII, NFkB , MEF2, CREB, G9a, le DNMT3 (DNA methyltransf e hlakola 3a), ha re bolela tse seng kae.20,21,35,51,67,89,90 Ho khahlisang, molao oa koae oa mefuta e 'maloa ea mefuta ena, ho kenyelletsa induction ea CDK5, CaMKII, le NFkB, le khatello ea G9a, le eona e kenelletse ka ΔFosB.20,35,51,91

Ho makatsang ke hore, lithethefatsi tsa opiate tsa tlhekefetso li na le litlamorao tse fapaneng le ho fokotsa khatello ea methapo ea mokokotlo oa mokokotlo oa mokokotlo oa mokokotlo oa NAc.81 Ha ho tsejoehale ka litlamorao tsa boits'oaro ba tloaelo ena le mekhoa e bakoang ke limolek'hule tse amehang. Taba ena ke, leha ho le joalo, ho a makatsa, ha ho nahanoa hore CREB le ΔFosB li susumetsoa ke lintho tse susumetsang le tse mpe 'me ka bobeli li na le tšusumetso molemong oa ho kenella bohareng ba NAc dendritic spine density. Sena se hlahisa potso ea hore na opiates e hatella joang le lesapo la mokokotlo la NAc leha ba bile le lintlha tsena.

Mokhoa o mong o moholo oa polasetiki ea morphological o bonoang mehlaleng ea tlhekefetso ea lithethefatsi ke phokotso ea 'mele ka boholo ba lisele tsa VTA dopamine neurons tse hlahisoang ke tsamaiso ea opiate e sa foleng..77,92,93 Ho feto-fetoha ha maemo ho tšoanang ho etsahala ka lebaka la li-cannabinoids.94 Shrinkage ena ea li-dopamine neurons tsa VTA, e etsahalang ka ho itaola ha opiate93 mme e tlaleha ho lithethefatsi tsa boloi ba batho ba hlahlobang postmortem,77 ho bonahala e le ho buisana ka mamello ea moputso mme e amana le ho fokotseha ha dopamine ho NAc. Bopaki bo nahanang hona joale bo supa hore phokotso ena ea boholo ba soma ea sele e kenngoe ke khatello ea opiate ea polelo e tsoang ho neurotrophic factor (BDNF) ka har'a methapo ena ea kutlo. Re hokahane ka kotloloho le ho tlosoa hoa ts'ebetso ea BDNF, le VTA neuron shrinkage, ho fokotsa ts'ebetso ea ho theoha ha BDNF ho supa li-cascades ho VTA dopamine neurons, ka ho khetheha ho fokotsa mosebetsi oa IRS2 (insulin receptor substrate-2), AKT (serine-threonine kinase), le TORC2 (sepheo sa rapamycin-2, se sa nahaneleng rapamycin).77,93 Re boetse re hokahanya ho theoha hona ha BDNF ho supa ka kotlolloho ho thabo e kholo eo morphine e e bakang methapong ena ea kutlo, joalo ka ha ho boletsoe pejana.77,78 Ho joalo, boholo bo fokotsehileng ba soma le ho eketseha ha thabo li hokahane ka thata, kaha ho kenella ho tse ling ho lebisa ho tse ling le ho fapana. Taolo ena mabapi le thabo ea seleng e kenyelletsa khatello ea K+ liteishene le tsa GABAA hona joale litsing tsena tsa methapo.

Karolo ena ea BDNF ho laola likarabo tsa morphine maemong a VTA e bapisoa le ho kenya letsoho ha eona ho fapaneng liketsong tsa koae le tse ling tse matlafatsang. Stimulants e etsa hore BDNF e supe ho NAc, sephetho ka lebaka la keketseho ea lehae ea BDNF hammoho le tokollo e eketsehang e tsoang libakeng tse fapaneng.95 Ntle le moo, ho saena BDNF ho ata ho NAc, empa eseng ho VTA, ho bontšitsoe ho khothaletsa litlamorao tsa boits'oaro ba lithethefatsi tsena ho kenyelletsa le boits'ebetso ba tsona.95,96 Molaoana o fapaneng oa ho saena ha BDNF tseleng ea VTA-NAc ka li-opiate le li-stimulants e phahamisa monyetla oa hore liphapang tse joalo li buelle taolo e fapaneng ea lithethefatsi ea li-NAc dendritic spines, monyetla o ntseng o etsoa lipatlisisong.

Litsela tsa nakong e tlang

Tlaleho e kaholimo e totobatsa tsoelo-pele e kholo e entsoeng ho utloisisa liphetoho tsa limolek'hule le tsa cellular tse etsahalang libakeng tsa moputso oa boko ho arabela khafetsa ho lithethefatsi tsa tlhekefetso, le mabapi le ho ikamahanya le maemo ka boits'oaro ho likarolo tse itseng tsa boits'oaro ba litumelo tsa mefuta ea liphoofolo. . Leha ho le tsoelo-pele ena, lipotso tse kholo li ntse li le teng. Boholo ba tsebo ea rona e teng bo shebane le VTA le NAc, le tlhaiso-leseling e fokolang e fumanehang ka libaka tse ling tsa bohlokoa tsa boko le tsona li bohlokoa bakeng sa ts'ebeliso ea lithethefatsi. Ntle le moo, lipontšo tsohle tsa liteko tsa karolo ea causal ea limolek'hule tsa boitšoaro bo amanang le lithethefatsi li thetsitse liphetoho tsa motho ka bonngoe. Ho theola liphetoho tse ngata ka nako e le 'ngoe ho hlakile hore ho thata le ho feta, empa ho bohlokoa hape, kaha rea ​​tseba hore lithethefatsi li hlahisa mefuta e mengata e fapaneng ea liphetoho le har'a li-neuron ka bomong, tse ka' nang tsa akaretsa ka tsela e rarahaneng ea ho susumetsa boitšoaro. Mokhoa o joalo oa biology o tla ba bohlokoa hore qetellong o tle o tsebe ho bala le ho feta tlholeho. Kamora nako, boiteko ba ho utloisisa mekhahlelo ea limolek'hule tsa memori tse amanang le bokhoba bo iphumana bo le makhatheng a ho feta moo liteko tsohle tse ling tsa ho utloisisa motheo oa boits'oaro ba kelello li loantšanang: bokhoni ba rona ba ho hokahanya liketsahalo tsa tlhaho le mohopolo o rarahaneng oa boits'oaro bo lula bo le thata haholo. Ho hlola karohano ena ho supa phephetso e kholo ho fetisisa ea li-neuroscience.

lumela hore baa fokola

Mosebetsi ona o ne o tšehelitsoe ke lithuso tse tsoang Setsing sa Naha sa Ts'ebeliso e Mpe ea Lithethefatsi.

Likarolo tse khethiloeng le litlhaloso

  • Nac
  • nucleus accumbens
  • TREEPO
  • Karolo ea karabelo ea cAMP
  • DFFB
  • Sekhao sa ho ngola sa lelapa sa Fos
  • VTA
  • sebaka sa ventral tegmental
  • AMPA
  • α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
  • LTD
  • khatello ea maikutlo ea nako e telele
  • LTP
  • pontsho ya nako e telele
  • BDNF
  • boko-derived neurotrophic factor
  • NKkB
  • Ntho ea nyutlelie kB

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