Psy Psychology. 2013; 4: 68.
E hatisitsoe Inthaneteng 2013 Aug 1. doi: 10.3389 / fpsyt.2013.00068
PMCID: PMC3730062
Sehlooho sena se bile teng e boletsoeng ke lihlooho tse ling ho PMC.
inahaneloang
Ho na le bopaki bo hlahang ba hore batho ka bomong ba na le bokhoni ba ho ithuta ho phela ka ho its'ireletsa ka mekhoa e ba sirelletsang likhatellong tse mpe tse bakang khatello ea maikutlo. Lekala le hlahang la methapo ea methapo ea kutlo le se le qalile ho pepolla liserekisi le limolek'hule tse sirelletsang khahlanong le mafu a amanang le khatello ea kelello, joalo ka ho lemalla. Glucocorticoids (GCs) ke li-regostra tsa bohlokoa tsa homeostasis tse amanang le khatello ea maikutlo linthong tsohle tse phahameng mme li susumetsa mefuta e mengata e fapaneng ea litho tsohle le lisele tse ling. Ka hona, li-GC li sebakeng se loketseng ho khothaletsa kapa ho thibela ho ikamahanya le maemo ha khatello ea maikutlo. Thutong ena, re tla shebisisa karolo ea li-GCs maemong a hypothalamic-pituitary adrenocortical axis le libaka tse eketsehileng tsa hypothalamic ho laola likarabo tsa basal le khatello ea maikutlo tse sa foleng. Li-GC li sebetsana le palo e kholo ea methapo ea neurotransmitter le neuropeptide e amanang le nts'etsopele ea bokhoba ba tahi. Ho feta moo, tlhahlobo e tla shebisisa litsela tsa orexinergic le cholinergic mme e totobatse karolo ea bona khatellong le bokhobeng. Li-GC li bapala karolo ea bohlokoa ho nts'etsapele nts'etsopele ea bofokoli kapa pherekano mme li emela lipheo tsa bohlokoa tsa meriana e ka fokotsang phello ea tsamaiso e sa nepahalang ea khatello ea maikutlo bakeng sa kalafo ea ho lemalla khatello ea maikutlo.
Selelekela
Boiketsi ba ho theha temallo bo laoloa ke liphatsa tsa lefutso le ho fetoloa ke boiphihlelo le tikoloho. Khatello ea maikutlo e bapala karolo ea bohlokoa ho eketsang monyetla oa ho lemalla. McEwen o ngotse ka mokhoa o hlakileng hore, "liphihlelo tsa bophelo ba motho li na le tšusumetso e kholo bokong, joalo ka sepheo sa khatello ea maikutlo le khatello e kholo ea maikutlo le mokhoa oa karabelo ea 'mele le boits'oaro ho khatello ea maikutlo" (1). Bokhoni ba ho sebetsana le khatello ea maikutlo kapa boikoetliso (bokhoni ba ho khutlela morao ka mor'a litsietsi) bo bolela esale pele hore na hamorao motho o tla hlaolela lefu le amanang le khatello ea maikutlo le amanang le khatello ea maikutlo joalo ka ho tšoenyeha, khatello ea maikutlo le ts'ebeliso ea maikutlo [e lekantsoe ho (2)]. Bongata bo boholo bo bile le ketsahalo e bohloko nakong ea bophelo ba bona. Leha ho le joalo, ke liperesente tse nyane feela tse tla latela khatello ea maikutlo e tlang ho lebisa ho ho sithabeha hoa khatello ea maikutlo (PTSD) kapa bokhoba ba joala kapa lithethefatsi tse ling (3). Maemong a mangata, batho ba khona ho mamella 'me ha ba na bokuli kapa bokuli kamora ho pepesetsoa khatello ea maikutlo. Lekala le hlahang la ts'ebetso ea methapo ea kutlo le ho senola li-circuits tse ncha le limolek'hule tse sebeletsang ho sireletsa khahlanong le mafu a amanang le khatello ea kelello.
Hangata ho nahanoa hore matlafatso ke mochini o kahare kapa o sa fetoleng letho o ke keng oa fetoloa. Leha ho le joalo, lipatlisiso tsa liphoofolo le batho li bontša hore ho nts'etsapele matla e ka ba boitšoaro bo ithutoang (2). Batho ka bomong ba na le bokhoni ba ho ithuta ho ba le botsitso ka ho theha mekhoa e sirelletsang liphellong tse mpe tsa khatello ea maikutlo. Glucocorticoids (GCs), cortisol bathong, kapa corticosterone ka litoeba ke batsamaisi ba bohlokoa ba homeostasis e amanang le khatello ea maikutlo mme ba bontšitsoe ho feto-fetoha mefuta e mengata ea liphatsa tsa litho tsa 'mele le lisele tse ngata (4-,6). Kahoo, li-GC li behiloe ka mokhoa o loketseng ho laola litsela tse ngata tse tšoaeang tsela tse sebetsanang le khatello ea maikutlo le bokhoba ba tahi. Thutong ena, re tla shebisisa karolo ea li-GCs maikutlong a hypothalamic-pituitary adrenocortical (HPA) ho laola likarabo tsa basal le khatello ea maikutlo e sa foleng. Ntle le moo, re tla shebana le litsamaiso tse peli, e leng lits'ebetso tsa orexinergic le cholinergic le karolo ea bona ho arolelanang khatello le bokhoba. Re tla boela re tšohla tšebelisano e ntseng e hlaha lipakeng tsa litsamaiso tsena le li-GC le taolong ea khatello ea maikutlo. Qetellong, ha li-GC li bapala karolo ea bohlokoa ho holiseng botsitso kapa ho imeloa kelellong, re tla hlahloba menyetla ea litlhare e lebisang li-GC bakeng sa kalafo ea tlhekefetso e tlisoang ke khatello ea maikutlo.
Karolo ea HPA Axis le Glucocorticoids ho Neurobiology ea Resilience to Stress
Mekhoa e laolang bokhoni ba setho ba ho sebetsana le khatello ea maikutlo e hlalositsoe hantle mefuteng ea likokoana-hloko tse ikhethang, tse bitsoang li-stressosomes, tse laolang karohano e ngata ea nyeliso ea mmele le tikoloho (7, 8). Stressosome ke sebopeho se ikhethileng ka har'a microorganism e hlophisehang hantle mochine oa limolek'hule o hlophisang boholo ba karabelo ho khatello ea maikutlo. The khatello ea maikutlo qetellong e etsa bonnete ba ho pholoha ha sele ka lebaka la mefuta e mengata e fapaneng ea khatello ea lik'hemik'hale le ea 'mele (7, 8). "Mamina" a "stressosome" ke "axis" ea HMA, kaha e fana ka karabelo e kopanetsoeng ea khatello ea maikutlo e matla (9). Likarolo tsa motheo tsa HPA axis e bohareng li tsejoa hantle 'me li kenyelletsa li-corticotropin-releasing hormone (CRH) tse matlafatsang li-neurons tsa "patventricular nucleus" tsa hypothalamus (PVN) (10) e tsosang pituitary adrenocorticotropic hormone (ACTH) le secretion ea adrenal corticosterone (CORT) (11).
Li-Glucocorticoids ke lihormone tsa li-steroid tse patiloeng ke litšoelesa tsa adrenal mme ke batsamaisi ba bohlokoa ba homeostasis maemong a basal le a sithabetsang. Li-GC li fana ka tšusumetso ea tsona ka mefuta e 'meli ea li-intracellular receptor mofuta I mineralocorticoid receptor le mofuta II glucocorticoid receptor. Li-receptor tsena ka bobeli li hlahisoa ho pholletsa le 'mele le litla-morao tsa tsamaiso. Ka bokong, mofuta o phahameng oa kopanelo I mineralocorticoid receptor (eo hape o bitsoang aldosterone receptor ka liphio), o hlahisoa ka mokhoa o ikhethang kahare ho sebopeho sa hippocampal le polelo e lekanyelitsoeng e fumanoa ho preortal cortex (PFC) le amygdala (12-,14). Mofuta o tlase oa mofuta oa II GR o bonts'oa hohle bokong ka polelo e phahameng ka ho fetisisa ho PVN le hippocampus mme ka lebaka la kamano ea eona e tlase ho cortisol e bapala karolo ea bohlokoa ho homeostasis e amanang le khatello ea maikutlo ha maemo a potoloho ea cortisol a phahame (14-,17). Li-GRs le li-MRs receptors li lula ho cytoplasm le ho nka bohato ba genomic genital ka li-GC ka ho sebetsa joalo ka li-activator tse hatisang lingoliloeng tsa nyutlelie le ba hatellang (14, 18) le li-GRs tse tlameletsoeng membrane li kopanya liketso tse potlakileng tsa li-GC (19, 20). Li-GC li na le sebaka se loketseng sa ho fetolela likarabo tsa khatello ea maikutlo le ho kenngoa ts'ebetsong bokong nakong ea maemo a phetseng hantle, kamora khatello ea maikutlo le nakong ea likarabelo tsa khatello ea maikutlo e sa foleng.4, 5, 21).
Glucocorticoids e fana ka likarabo tsa thibelo ea maikutlo nakong e potlakileng (metsotsoana ho isa metsotso) le nako e telele (lihora ho isa matsatsing) timescales (4, 18, 22-,24). Litlamorao tse potlakileng li kenyelletsa ho fokotseha khafetsa hoa melatsoana ea EPSC khafetsa ts'ebelisong ea corticosterone kapa dexamethasone (synthetic GC) ho PVN (25), le ho fokotsa maemo a ACTH le corticosterone, phello e sa bonoeng ha "membrane impermeable dexamethasone" e sebelisoa, e bonts'ang karabo ea kapele ea karabo (26). Liphetoho tse tšoanang tse potlakileng tsa corticosterone ho mEPSC ho hippocampus li hlokometsoe (27, 28). Kahoo liketso tse khutšoane tsa nako e khuts'oane (mohlomong tseo e seng tsa genomic) le nako e telele (genomic) tsa GC mmoho li laola taolo ea karabo ea inhibitory. Mekhoa ea limolek'hule le methapo ea kutlo e tšehetsang boikemisetso bo matla le bo sebetsang e ntse e hlahlojoa mme ba khethiloeng ke batsamaisi ba axel ea HPA, limolek'hule tse kenyelletsoeng moahong oa molek'hule le ho bonts'a limolek'hule tse amanang le polasetiki ea neural [e hlahlojoe ke (2)]. Li-GC li bonts'a sehlahisoa sa pheletso sa selepe sa HPA mme se susumetsa mesebetsi e mengata ea methapo e kholo ea methapo, joalo ka ho tsosa takatso ea motho, kelello, moea, boroko, metabolism, le molumo oa pelo, boits'ireletso ba mmele le ts'oaetso ea ts'oaetso (Setšoantšo. (Figure11).
Liketsahalo tse phetoang khafetsa li baka liphetoho tse telele tsa boitsoaro bo amang boits'oaro, maikutlo le boits'oaro bo qetellang bo fana ka ts'ireletso ea setho kapa ho pholoha. Bokhoni ba ho sebetsana le khatello ea maikutlo bo ka itšetleha ka karabelo ea motho ea mahlaba ea HPA eo ka nako e 'ngoe e ka bolelang monyetla oa ho ba le mathata a amanang le ho ruruha ha kelello joalo ka ho lemalla. Leha ho le joalo, tlasa khatello ea maikutlo e sa feleng khatello ena e fetoha e sa sebetseng e lebisang ho mefuta e fapaneng ea litla-morao tsa lefu le tšoaetsanoang, joalo ka matšoenyeho le mefuta e fapaneng ea mafu a sithabetsang (1, 5, 29-,33) le bokhoba ba ho lemalla joala,34). Ho bontšitsoe hore tšebeliso ea khatello ea kelello ea HPA ka khatello e sa feleng le e sa laoleheng e lebisa ho secretion ea GC e sa sebetseng (35, 36). Li-GRs li nka bohato ba ho ikamahanya le khatello ea maikutlo le ho laola ho felisoa ha karabelo ea khatello ka maikutlo a fosahetseng boemong ba axis ea HPA (30-,32). Li-GC li ka laola ka matla kutloisiso ea mesifa ka mokhoa oa stochastic (5) le ho laola karabelo ea khatello ea maikutlo e sa foleng. Li-GC li laola methapo ea kutlo ea litho le litho ka ho fetolela ho tšoaetsoa ha GRs, ho fumaneha ha ligand, polelo ea li-receptor isoform, ho potoloha ka bongata, le mokhatlo oa papatso (30-,32).
Li-Receptors tsa Glucocorticoid ho Karabelo tsa Khatello ea Kelello: Bohlokoa ba Liphetoho ho Plasticity ho Amygdala
Amygdala ke sebaka sa bohlokoa sa boko se kenyelletsoang ho sebetsana le khatello ea maikutlo, tšabo le boemo ba pavlovia, mme ke sebaka seo lipontšo tsa neuroendocrine li susumetsoang ke tšabo le khatello ea maikutlo. Ho bile le tlhahiso ea hore ho leka-lekana pakeng tsa ho ithuta ka hippocampal le amygdalar ho bohlokoa bakeng sa ho khetha likhetho tsa khatello ea maikutlo mabapi le ho sebetsana le khatello ea maikutlo. Ho imeloa kelellong ho sa feleng ho eketsa kholo ea dendritic le letsoalo la mokokotlo ho basolateral amygdala (BLA) mme ho fapana le karolo ea eona ho hippocampus. Liphetoho ho hippocampus li khutlela ho motheo nakong ea ho hlaphoheloa, athe li-amygdala ke tsa nako e telele (37). Lintlha tsa Neurotrophic tse kang BDNF li nka bohato bo pakeng tsa khatello ea maikutlo libakeng tsena tsa kelello. Phuputso ea morao-rao e bonts'itse hore maemo a eketsehang a BDNF a fumanoa ho arabela khatello ea maikutlo ho BLA, athe litekanyetso tse fokotsehileng li ile tsa bonoa hippocampus (38). Liphoofolo tse phonyohang litšebelisanong tse mabifi li bonahala li na le profilse ea bonono ea BDNF hippocampus le tlase ho amygdala, athe boitšoaro bo fapaneng (ba ho lula le ho tobana le mohanyetsi) bo na le litlamorao tse fapaneng (39). Kahoo khatello ea kelello e kenya tšebetsong lintlha tsa neurotrophic libakeng tse fapaneng tsa boko mme ho nahanoa hore e tsamaisana le tsamaiso ea GR. Lintsu tse nang le sepheo sa ho tlosa mofuta oa mofuta oa GR ka ho hlaka, ka ho khetheha karolong e bohareng ea amygdala (CeA) empa e seng phatleng e fokolitse likarabo tsa maemo a tšabo (40). Ho fapana le hoo, ho senyeha ha tšenyo ea nako ea pele ea li-GR, ntle le CeA, ha ho joalo. Hoa tsebahala hore li-GRs ho BLA li kentse letsoho ho kopaneng maikutlong le maikutlong a sithabetsang maikutlong le bathong ka ho sebelisana le noradrenaline. Lithuto tsa batho li bontšitse hore tšebelisano lipakeng tsa ts'ebetso ea noradrenergic le lihormone tsa khatello ea glucocorticoid li ka baka tsitsipano mokhoeng oa neural oa ketso o lebisitsoeng ho thuto e tloahelehileng ea karabelo (41). Haufinyane, ho ile ha bonts'oa hore ho latela khatello ea maikutlo e matla, ho kenella kahare ho LTP ho nolofalletsoa BLA ke ts'ebetso ea β-adrenergic le GRs ka bobeli.42). Ha ho kopantsoe hammoho, ho na le liphetoho tse ikhethang tse potolohileng ho ithuta nakong ea maemo a sithabetsang, liphoofolo tse ts'oaroang ke khatello ea maikutlo li na le keketseho e kholo ea ts'ebetso ea synaptic makaleng a amanang le tšabo joalo ka amygdala ha a bapisoa le liphoofolo tse mamellang khatello ea maikutlo.
Liphetoho tsa Glucocorticoids Drive in Plasticity ho Hippocampus le libaka tsa Cortical ho arabela khatello ea maikutlo
Li-receptor tsa Glucocorticoid ho hippocampus control homeostasis nakong ea maemo a phetseng hantle ebe li bapala karolo ea ho khanna liphetoho lipolasetiking ho latela maemo a sithabetsang (43, 44). Liphihlelo tsa bophelo ba pejana tse qetellang li laolang karabelo ea HPA ea motho maikutlong a sithabetsang li fetoloa ke polelo ea GR gen ho hippocampus le frontal cortex (45). Hippocampal GRs e bapala karolo ea ho theha mohopolo oa nako e telele oa thibelo ea lithibelo ho likhoto ka ho kenya mekhoa ea polasetiki ea CaMKIIcy-BDNF-CREB e tsamaeang le neural.46). Phuputsong e arohaneng, ho pepesetsoa ho corticosterone e sa foleng ho felletse ka bokhoni ba ho se khone ho ithuta sephetho sa karabelo (47). Ho kopanya Memori ho nahanoa hore e kopantsoe ke GR, ha tlhahlobo ea maikutlo le likarabo tsa tlhaiso-leseling e ncha li sebetsoa ke MR. Boithuto ba batho le litoeba li supa hore tlasa maemo a sithabetsang ho na le phetoho e tsoang memong ea kelello e kopantsoeng le hippocampus ho tloaela mohopolo o kopantsoeng ke "caudate nucleus"48, 49). Ebile, litheko tse fokolang tsa li-receptor tsa MR li senyehile memori ea lehae, leha ho le joalo li ile tsa pholosoa ho senyeha ho feta ka ho hopoloa ha karabelo ea ts'usumetso kamora khatello ea maikutlo (50). Ka mokhoa o ts'oanang, kamora khatello ea maikutlo e matla, li-GR li hlahisoa le ho kenya polasetiki ea synaptic ho PFC ka ho eketsa ho ts'oaroa le ts'ebetso ea li-NMDAR le AMPAR (51). Ntle le moo, ha MR e ne e phahame haholo ponong ea litoeba e sebelisa polelo ea sepheo sa CAMkIIa se buelloang ke MR cDNA ea motho ea nang le tagi, litoeba li supile memori e ntlafalitsoeng ea maemo, ea fokotsa ho tšoenyeha ntle le phetoho ho likarabo tsa khatello ea maikutlo tsa HPA (52). Ho na le bopaki bo ntseng bo eketseha ba hore li-GC li nka karolo ho etseng mehopolo mekotleng e itseng e laolang likarabo tsa khatello ea maikutlo le ho arabela ka mokhoa o felletseng linthong tsa tlhekefetso le joala.
Glucocorticoids ho Nts'etsopele ea Tlatsetso ea Tlatsetso
Ho pepesehela khatello ea kelello ho sa feleng ho lebisa ho liphetoho mats'ebetsong a homeostatic a GCs (29). Ntle le moo, ho na le phokotso e kholo ea khaba ea HPA kamora ho ts'epa joala. Ho bontšitsoe hore ho itaola ho matla ha ethanol ka boithaopo ho eketsa maemo a corticosterone, ka lehlakoreng le leng, ho pepesoa ha ethanol ka nako e telele ho litoeba ho etsa hore karabelo e sa utloahaleng e bonts'ang hore ho ts'epa joala ho lebisa ho ho tsitsinyeheng ha molala oa HPA (53). Ho qeta nako le nako ha u senya nako ea GR ho liphoofolo tse nyane hoa hlokahala ebile ho lekane ho tlisa liphetoho tse kholo ho transcriptome libakeng tse ikhethang tsa boko tse lebisang keketseho ea bophelo bohle kotsing ea ho tšoenyeha le lithethefatsi tsa tlhekefetso (54). Lingoloa tse fetotsoeng li bile le tšusumetso ho tataiso ea GR le axonal signature in dentate gyrus le dopamine receptor signaling in nucleus accumbens (NAc) (54). Ntle le moo, bathong ba bang, kamora ho pepesetsoa khatello ea maikutlo le khatello ea maikutlo, li-GC li ka khothaletsa boitšoaro bo bobe ba ho sebelisa lithethefatsi le ho tsitsisa mohopolo oa HPA o theotsoeng. Li-GC li ka thellelisana ka litlamorao tse matlafatsang tsa lithethefatsi phetisong ea dopamine kahare ho moputso oa mesolimbic dopamine / potoloho ea matlafatso (55) le ho eketsa menyetla ea ho ba le boits'oaro bo bobebe (56-,58) ka ho eketsa matla a synaptic a dopaminergic synapses (59). Habohlokoa le ho feta, likarabo tsa dopamine karolong ea mantlha ea NAc, empa eseng likhetla, li bonts'itsoe ho arabela maemong a fetohang a li-GCs (60). Khaello ea gene ea GR ka litoeba ka ho khetheha ho li-dopaminergic neurons tse hlalosang li-receptor tsa dopamine D1 tse fumanang ho kenngoa ha dopaminergic li ne li fokotse ho ikarola ha cocaine le ho ts'oaroa ha sele ka dopamine (61). Ho pepeseha ka mokhoa o hlobaetsang kapa ho itlopa joala joaloka ethanol phetoho ea maemo a GC le ho khothaletsa polelo ea mofuta oa PFC e laoloang ke GC (62) le neurodegeneration e itšetlehileng ka mofuta oa II GRs (63). Li-GC li kenya ethanol e tsamaellanang le polasetiki ea li-glutamatergic synapses tse boletsoeng hore li theole nts'etsopele ea ts'epahalo ea ethanol, e hlahlojoang ho (64).
Ho bontšitsoe hore ho na le khokahano lipakeng tsa ho tlosoa hoa joala bo hlobaetsang le ho fokotseha ho matla ha GR mRNA ho PFC, NAc, le mohatla oa bethe oa stria terminalis (BNST), ha protocol e senotsoeng ea joala e hokahantsoeng le GRRR ea MRNA e ka sehlohlolong sa NAc, ventral. BNST, le CeA (65, 66), e lekantsoe ho (67). Phetoho ho tloha tšebeliso ea lithethefatsi ea boithaopo ea tšebeliso ea lithethefatsi ho ea ho tse latelang e hlahisitsoe ho bontša phetoho e tlohang ho sepheo e lebisitsoeng ho sepheo se laoloang ketso ea liketso (68). Bafuputsi ba etsa tlhahiso ea hore khatello ea maikutlo e matla e khutlisetse ho arabela litloaelong tse amanang le lithethefatsi le khatello ea maikutlo khafetsa ho ka khothaletsa phetoho ho tloha ka boithaopo ho isa ts'ebetsong e qobelloang ea tšebeliso ea lithethefatsi. Li-GC li maemong a loketseng a ho hlophisa mefuta e fapaneng ea litsamaiso tse ntlafatsang tlhabollo ea bokhoba. Likarolong tse latelang, re lekola puisano pakeng tsa GC le litsamaiso tsa orexinergic le cholinergic.
Sistimi ea Orexinergic
Mesebetsi e ithutoang haholo ea bioloji ea li-orexins / hypocretins e maemong a mantlha a ho fepa, ho robala, homeostasis ea matla le ho batla moputso. Orexin-A le Orexin-B (e boetse e bitsoa hypocretin-1 le -2) e sebetsana le li-subtypes tse peli tsa orexin / hypocretin receptor, Orexin1 Receptor (OX1R) le Orexin2 Receptor (OX2R) e tlama ho orexin-A kapa orexin-B (69, 70). Ho sibolloa ha mantlha mabapi le karolo ea li-orexin ho bile teng ka ho tsebahatsa mefokolo ho liphatsa tsa lefutso tse kenyelletsang orexin kapa sethala sa OX2R se bakang tšenyo ea kelello, ho beha karolo ea Sisteme ea ORX / Hcrt taolong ea boroko le ho tsosa71, 72). Orexin-A le orexin-B li bontšitsoe ho eketsa tšebeliso ea lijo e thibetsoeng ke bahanyetsi ba ikhethileng (73, 74). Ntle le moo, li-fibre tsa orexinergic li hlokomela likarolo tse fapaneng tsa boko tse kenyelletsang ho homeostasis ea matla, joalo ka khubung ea moea ea "hemocalate", "arcuate", le PVN ea hypothalamus (75). Li-Orexins li laola mesebetsi ea boikemelo, joalo ka taolo ea khatello ea mali le sekhahla sa pelo (76). Kahoo li-neuropeptide tsena li boemong bo ikhethileng ba ho arabela khatello ea maikutlo.
Karolo ea Li-Orexins Khatellong ea Kelello le ts'ebetso ea HPA Axis
Arousal ke karolo ea bohlokoa ea karabelo ea khatello ea maikutlo 'me tsamaiso ea orexin ke karolo ea bohlokoa ea karabelo ea khatello ea maikutlo. Menahano e tsoang molemong oa phello ea matla a phahameng a phello le dorsomedial nucleus ea hypothalamus le tsona li na le tšusumetso mekhoeng ea boits'oaro, leha ho le joalo karolo ea bona khatellong e makatsang le e kopaneng e bile eona sepheo se ka sehloohong (77). Li-Orexins li feto-fetola molala oa HPA ho araba maikutlo a fapaneng a sithabetsang. Polelo ea Prepro-orexin mRNA e ile ea eketseha ho "hypothalamus" (LH) ea morao ho likhoto tse nyane tse latelang khatello ea maikutlo le likotong tsa batho ba baholo ka mor'a khatello ea maikutlo78). OX-A e kenya tshebetsong axis ea HPA e hlohlelletsang secretion ea ACTH le corticosterone (79). OX-A, empa eseng OX-B, e eketsa secretion ea glucocorticoid ho tsoa ho rat le ho cortices ea motho ea adrenal ka ho susumetsa ka ho toba ha lisele tsa adrenocortical ka OX1R e kopantsoeng le papali ea papali ea adenylate cyclase.79) (Setšoantšo (Figure1) .1). Tsamaiso ea Intracerebroventricular (ICV) ea OX-A e ntlafalitsoeng ea ACTH le tokollo ea corticosterone (80-,82). Ho reriloe hore li-neuron tsa orexin li bapala karolo ea bohlokoa e hokahanyang likarabo tsa boikemelo le / kapa ho falimeha nakong ea karabelo ea ho loana kapa ea sefofane (83) (Setšoantšo (Figure22).
Karolo ea li-Orexins ka ho lemalla
Hammoho le mesebetsi e mengata e etsoang ke li-orexin, e khahlang haholo ke karolo ea bona tsamaisong ea moputso. Morero oa "Orexin" o nang le "neurons projeke" ho tloha ho LH ho ea sebakeng sa ventral tegmental (VTA) le NAc, likarolo tsa bokong tse nang le "tsela ea moputso" ea mesolimbic (84-,86). Li-OXR haufinyane li kentsoe ts'ebetsong ea khothalletso ea lintho tse lemalloang joalo ka morphine, cocaine (87-,91), le joala (92-,97). OX1R e bapala karolo e ikhethileng ea taolo ea ethanol, cue, le khatello ea maikutlo e khutlisetsang maikutlo, e hlahlojoang ho (98) le karolo e lekanyelitsoeng bakeng sa ho bontšoa ha OX2R (99). Sisteme ea orexin le eona e bile le tšusumetso ho khutlisong ea ts'ebeliso ea lithethefatsi. OX1R e bapala karolo ea ts'ebetso ea khatello ea kelello ea maoto le ts'isinyeho ea cococaine (100, 101) cue le yohimbine tse ileng tsa khutlisetsoa hoa ho batla ethanol (94, 96, 102).
Merero e bohareng ea amygdaloid e laola axis ea HPA le li-orexin tsa kahare tse nang le li-neuron ho hypothalamus ea morao. Amygdala e atolositsoeng e kenyelletsang CeA, BNST, le NAc ke libaka tsa bohlokoa tsa boko tse sebetsanang le boits'oaro bo kang ho tšoenyeha, tšabo, khatello ea maikutlo le ts'ebeliso ea lithethefatsi. Haholo-holo, CeA le BNST li bontšitsoe li bapala karolo ea bohlokoa boits'oarong bo amanang le ho tšoenyeha le tšebeliso ea boithaopo ea ethanol (103). Amygdala e atolositsoeng, ho kenyelletsa le CeA, e bontšitsoe e bapala karolo ea bohlokoa boits'ebetsong ba ho khutlisetsa lithethefatsi tsa tlhekefetso. Ho qaptjoa hoa CeA, empa eseng BLA, ho thibela ho ts'oaroa hoa tšabo ka maoto le ho ts'oaroa ha motho ea batlang k'hok'heine (104). Dense orexinergic innervation e boetse e bonoa libakeng tsena tsohle tsa boko (76, 105, 106). Libaka tsena tsa boko li boetse li bontša li-peptide tsa khatello ea kelello tse kang corticotrophin releasing factor (CRF) le li-peptide tse loantšang khatello ea maikutlo tse kang neuropeptide Y (NPY). Li-neuropeptide ka bobeli li na le liketso tse hanyetsanang ho CeA mme li laola ts'ebeliso ea ethanol. Li-infusions tsa OX-BNB li hlahisa matšoenyeho a joalo ka likarabo joalo ka ha li lekantsoe ke liteko tsa tšebelisano ea sechaba le tlhahlobo e phahameng ea maze mme phello e kopantsoe ke li-receptors tsa NMDA (107). Phuputso ea morao-rao e boetse e bonts'a hore yohimbine e kenya likarabo tsa orexinergic, empa eseng ts'ebetso ea adrenergic receptor, le khatello ea maikutlo e nyarosang ho BNST e kentseng letsoho ho khutlisetsong ha CPP e felisitsoeng ea cocaine (108). Kahoo tsamaiso ea orexinergic e kenella ho aroleng boits'oaro bo khothalletsang lithethefatsi ha e ntse e hira libaka tse ngata tsa boko tse kenyelletsang ts'ebetsong ea khatello e matla le boits'oaro bo lematsang. Ho bohlokoa ho utloisisa tlatsetso ea li-orexin lipakeng tsa khatello ea maikutlo le lits'ebetso tsa moputso. Ho khetholla mekotla e arolelanang khatello e tlisoang ke ts'ebeliso e mpe ea lithethefatsi ho tla hlokahala bakeng sa ho nts'etsapele mekhoa ea ho rekisa meriana e amanang le khatello ea maikutlo e bakang khatello ea maikutlo. The orexin receptor antagonist e bitsoang suvorexant (109) e phethile ka katleho liteko tsa bongaka tsa karolo ea boraro kalafong ea ho phekola ho hloka boroko mme hajoale e ntse e le tlhatlhobo ea FDA. Haeba e amohetsoe, hona e tla ba mohanyetsi oa pele oa FDA orexin ea fumanehang bakeng sa ho phekola mathata a ho robala mme o na le monyetla oa ho rekolleloa ka ts'ebeliso ea ona e sebetsang ho phekola khatello ea maikutlo le mathata a ho lemalla.
Tšebelisano lipakeng tsa Cholinergic System le HPA Axis
Allostasis, ke ts'ebetso eo homeostasis e fumanang hape kamora khatello ea maikutlo, e etsahala ka tšebelisano lipakeng tsa PFC, amygdala, le hippocampus ka axis ea HPA (110-,113). Ts'ebetsong ena li-neurotransmitters le li-neuromodulator tse kang acetylcholine, glutamate le GABA, li bontšitsoe hore li fetoloa ka mokhoa o fapaneng. Mona, re shebisisa ho kenya letsoho ha likarolo tsa tsela ea cholinergic ho arabela, ho matlafatsa, esita le ho hatella khatello ea maikutlo.
Likarolo tsa tsela ea cholinergic ke - ligand, acetylcholine (ACh); enzyme e ikarabellang bakeng sa ho phatloha ha acetylcholine, acetylcholinesterase (AChE); enzyme e amehang ho kopaneng ACh, choline acetyltransferase (ChAT); , le li-receptor tsa acetylcholine, li-nicotinic acetylcholine receptor (nAChR), le muscarinic acetylcholine receptor (mAChR). Re tsepamisitse maikutlo ho nicotinic receptor - nAChR - mabapi le karabelo ea cholinergic khatello ea maikutlo. Ka ho tsepamisa maikutlo ho tsela ea nachR-cholinergic, ha se sepheo sa rona ho fana ka maikutlo a hore nAChR ke eena feela sebapali sa bohlokoa se arabelang karabong ea khatello ea maikutlo. Ho fapana le moo, ho reretsoe hore tlhahlobo ena e totobatse tšebelisano ea tsela ea glucocorticoid (e kopantsoeng ka HPA) le tsela ea nachR-cholinergic mabapi le khatello ea maikutlo.
Hoa tsebahala hore li-nAChR li kenya letsoho ho ithuteng le ho hopoleng (114, 115). Ho feta moo, litlamorao tse mpe tsa khatello ea maikutlo e sa feleng mohopolong le tsona li thehiloe hantle (116, 117). Ehlile, pele ho 1968, hippocampus e ile ea amoheloa e le sebopeho se etselitsoeng li-hormone tsa khatello (118) ka ho bona hore acetylcholine e lokolla hippocampus (119, 120) e eketsehile tlasa mefuta e fapaneng ea khatello ea maikutlo (121). Meetso ea "Transgenic mouse-Out-kunja" e bontšitse bohlokoa ba α4 (122), β3 (123), le β4 (124) NAChR e ipeha maemong a ho ferekanya litlamorao tsa khatello ea maikutlo. Ho feta moo, litoeba tsa α5 le β4 li sa utloe ho na le nicotine (125, 126), moemeli ea nang le matla oa ho tšoenyeha (127-,129) ka tekanyetso e tlase (130). Ho joalo, li-ncyhine tsa α7 le α4β2, tseo e leng sepheo sa mantlha sa nicotine, li bonts'itsoe ho fana ka phello ea methapo ea methapo ea methapo molemong oa khatello ea maikutlo e tlisoang ke khatello ea maikutlo ea hippocampus (131). The hippocampus e bontšitsoe ho fana ka phello ea thibelo ho molala oa HPA (132-,136), ka tsela eo, fokotsa khatello ea maikutlo. Ha e kopantsoe hammoho, NAChR e bonahala e arabana ka tsela e fapaneng ho arabela likarolong tsa khatello ea maikutlo ka mananeo a eona a fapaneng.
Ts'ebetso ea karabelo ea khatello ea maikutlo e bakoa ke bohlasoa bo felisang CRH, ACTH le cortisol. Nicotine, ligt ligand e nang le matla ho li-NAChR, ka tekanyetso e phahameng (2.5-5.0 μg / kg) e bonts'itsoe ho hlahisa keketseho e thehiloeng ho litekanyetso ho ACTH (137), mme mohanyetsi oa eona, mecamylamine, o bontšitsoe ho thibela tokollo ea nicotine e susumetsoang ke ACTH (137, 138). Ka bokong, sebaka se ikarabellang bakeng sa tokollo ea CRH-mediated ACTH ke sebaka sa parvocellular sa PVN (pcPVN) sa hypothalamus (139, 140). Leha ho le joalo, ho bontšitsoe hore nicotine mediates ACTH e lokolla ka tsela e sa tobang, ka li-receptor tsa nicotinic tse ho nucleus treususitarius (NTS) (141, 142). NTS hamorao e hokahanya menyetla ea ts'ebetso ka liphatlalatso tse fapaneng ho pcPVN (143, 144). NAChR ho NTS e fumaneha pele ho nako ho latela likhakanyo tsa glutamatergic ho pcPVN (145, 146). Ho feta moo, nachR e fana ka sepheo se matla litlamorao tse kopaneng tsa ACTH tseleng ena ke "β"4-Ko na le li-nAChRs (tse ngata tse ka angoang3β4*) empa eseng α4β2 joalo ka ha ho khethoa ka litekanyo tsa li-mEPSCs ka pel'a boteng ba DHαE, α e matla4β2 inhibitor kapa cytisine, e leng matla β4*-NAChR agonist (146). Ka hona, ha e le α4β2 le α7 NAChR e tsamaisa likarolo tse fetoletsoeng tsa nicotine libakeng tse ling (131), ho NTS ke subtype e fapaneng (146), e supa hape modulong oa karohano o thehiloeng ho nachR (Setšoantšo (Figure11).
Ho sebelisana le Glucocorticoid le Sistimi ea Cholinergic
Li-Glucocorticoids li bontšitsoe ho thibela ka kotloloho mosebetsi oa nAChR (147-,149). Sena se ts'ehetsoa ke taba ea hore khatello ea maikutlo e baka taolo e tlase ea nachR ho cortex ea creex ea lig le "150). Ntle le moo, bahanyetsi ba steroid ba bontšitsoe ho nyolla polelo ea nAChR (151). Hore li-GC li ka ama ka kotloloho ts'ebetso ea NAChR ka li-receptor binding kapa liphetoho tsa maemo a polelo li ka hlalosoa ke boteng ba likarolo tsa karabelo ea glucocorticoid (GRE) ka liphatsa tsa lefutso tse hatisang α7 subunit of the NAChR - CHRNA7 (152). Ka sebele, li-GREs li boetse li fumanoe ka mefuta ea ChAT (153) le AChE (154), likarolo tsa tsela ea cholinergic. Patlisiso e 'ngoe e hlokahala ho ithuta ka litlamorao tse hlakileng tsa li-GREs tseleng ena hammoho le ho etsa lipatlisiso haeba li-GRE tsena li le teng ka mefuta e meng ea nachR.
Likarolo tse ling tsa tsela ea cholinergic le tsona li bontšitsoe hore li angoa ke khatello ea maikutlo. AChE, e ikarabellang bakeng sa tšilafalo ea nako ea ACh, e bonts'itsoe hore e laoloa ka mokhoa o mong oa ho qhekella ka mokhoa ona o fetolang methapo ea kutlo (155). Kannete, phetolo ea morao-rao ea transcriptal ea AChE ho tloha ho e tloaelehileng ea eona ea AChE-S ho ea ho sebopeho sa AChE-R alters cholinergic transmission (156). Ntle le moo, phetolo ea morao-rao ea mongolo oa AChE, hape ka miRNA, e baka bofokoli bo amang kelello ba hippocampal (157). Joalokaha ho boletsoe pejana, polelo ea AChE e laoloa maemong a genomic ka GRE (154joalo ka ChAT (153). Hape, maemo a liproteine tsa ChAT a bontšitsoe hore a fokotseha ka lebaka la khatello ea maikutlo e sa foleng (158). Boemong ba epigenetic, ho na le khatello ea maikutlo e hatisitsoeng ea epigenetic e hatisitsoeng ea AChE ka HDAC4 (159). Ho khahlisang ke hore thutong ena GRE e ile ea tsebahatsoa hape ho HDAC4 (159), ho fana ka maikutlo a phello e tobileng ea epigenetic ea khatello ea maikutlo ho AChE. Liphetho tsena kaofela li supa mochine o nang le likarolo tse ngata moo karabelo ea khatello ea khatello ea maikutlo e laoloang ntle le ho buuoa ka karabelo ea eona ntle le pelaelo e ka lebisang ho li-neuropathologies tse fapaneng tse amanang le khatello ea maikutlo tse kang PTSD (160, 161), bokhoba ba joala (162, 163), le bokhoba ba lintho tse ling tsa tlhekefetso (164, 165).
Ka kakaretso, ho kenella ha li-subtypes tse fapaneng tsa nachR libakeng tse fapaneng tsa boko hammoho le ho feto-fetoha ha tsela ea cholinergic maemong a fapaneng joalo ka phetisetso, phetisetso ea morao-rao le epigenetic, li supa tsamaisong e hlophisitsoeng hantle ka nako le ka nako. e lumellanang ho arabela likhatellong tse fapaneng tseo re tobanang le tsona bophelong ba rona ba letsatsi le letsatsi. Qetellong, ha tlhahlobo ena e tsepamisitse maikutlo ho nachR le tseleng ea cholinergic, ho nka karolo ha sethethefatsi sa muscarinic le li-circuits tse ling tse ngata tsa neural li ke ke tsa hatelloa. Ehlile sepheo sa mantlha sa lefapha lena la lipatlisiso ke ho utloisisa ka nepo lipina tse rarahaneng lipakeng tsa litsela tse fapaneng le lipotoloho tsa neural tseo qetellong li tla etsa hore phokotso ea khatello ea maikutlo e bakoang ke khatello ea maikutlo le nts'etsopele ea maano a atlehang haholo a litlhare khahlanong le khatello ea maikutlo.
Mekhoa ea Mahlale a Litaba tsa Pharmacotherapeutic
Bopaki bo bongata bo teng ho bonts'a hore mofuta oa II GRs ke lipheo tsa bohlokoa tsa kalafo bakeng sa kalafo ea mafu a bakoang ke likarabo tsa khatello ea maikutlo. Mifepristone, e tsejoang hape e le RU486, e tsoa ho 19-norprogestin norethindrone mme e ka tlholisana le mofuta oa II GRs le li-progesterone receptors (PRs). Mifepristone e bontšitsoe hore e fokotsa ho khutlisetsoa hoa ho ts'oaroa hoa ho batla hoa ethanol le ho ata ha mefuta e 'meli e fapaneng ea liphoofolo.66, 166). Ho feta moo, mifepristone e bontšitsoe hore e sebetsa hantle ho fokotsa tsamaiso ea amphetamine (167), cocaine (168, 169), morphine (170), le ethanol57, 66, 162, 166, 171-,175). Phuputso ea morao-rao e boetse e bonts'a katleho ea mifepristone ho fokotsa matšoao a botahoa.176). Ts'ebetso ea anti-glucocorticoid ea mifepristone e e entse kalafo e ka bang teng bakeng sa lefu la Cushing's (177) le mathata a methapo ea kelello le kelello (178-,183). Mifepristone e fana ka mokhoa o ts'episang oa ho khutlisa mokhoa oa ho arabela khatello ka nakoana o seng o le hantle ka lebaka la ts'ebeliso e mpe ea joala ea nako e telele.
fihlela qeto e
Ho ithuta ho sebetsana ka katleho le bophelo le / kapa khatello ea maikutlo kapa ho ithuta ho ba le khatello ea maikutlo ho kenyelletsa taolo e matla ea polasetiki lipotolohong tsa kelello tse laolang tsela ea karabelo ea khatello ea maikutlo. Ha boko bo ka nchafatsoa ke boiphihlelo 'me lipotoloho tsa neural li fetoha le maemo, li fana ka maikutlo a hore ho na le monyetla oa ho fetola kelello kapa ho ithuta ho sebetsana le khatello ea maikutlo le ho hlola temallo le ho ithuta ho tenyetseha le ho feta. Litsela tsa limolek'hule le lipotoloho tse tsamaisang botsitso li senoloa butle-butle 'me sena se tla fana ka menyetla ea ho khetholla maano a boloi a hlolang tšusumetso ea bokhoba bokong a kopantsoe le maano a litlatsetso a lipale tse shebaneng le litsela tsa pro-resilience. Thutong ena, re shebile karolo ea lihormone tsa glucocorticoid, kaha li na le bokhoni ba ho fana ka maikutlo ka kakaretso nakong ea khatello e matla le e sa foleng mme re fane ka tsela ea ho ea botsa lipotso le ho lokisa marang-rang a boko. Ho utloisisa methapo ea limolek'hule e laolang methapo eo boko bo e sebelisang ho itšireletsa liphellong tse bakang khatello ea maikutlo ho tla fana ka mekhoa e mecha e khahlisang ea methapo ea kutlo.
Tlhōlisano ea Tlhaloso
Bangoli ba bolela hore lipatlisiso li ne li etsoa ka ho se be le likamano leha e le life tsa khoebo kapa tsa lichelete tse ka nkoang e le khohlano e ka 'nang ea e-ba le thahasello.
lumela hore baa fokola
Mosebetsi ona o ne o tšehelitsoe ka chelete e tsoang ho ARC Bokamoso ba Fitness (Selena E. Bartlett).
References