Moriri o sebetsang oa hypocretin le li-neurons tsa LC-NE: moelelo oa ho tsosoa (2013)

inahaneloang

Ho robala le ho falimeha ke libaka tse peli tse ikhethileng tse arohaneng le linako tsa phepelo le lipoteng ho pholletsa le 'muso oa liphoofolo. Ho tsoha ke boemo boo ho bona phoofolo e ka bonang le ho sebelisana le tikoloho ea eona. Kamora nako e telele ea ho tsoha, khatello ea boroko ea eketseha 'me e lebisa ho ho qala ho robala ho khetholloang ka hore ke nako ea ho se sebetse ka ho lekana le boemo bo morao ba maikutlo.

Ho liphoofolo tse anyesang, boroko hangata bo arotsoe boroko bo tsamaeang butle (SWS, kapa NREM robala ho batho), le ho tsamaisa mahlo kapele (REM) ho robala (hape ho bitswa "boroko bo makatsang"). Ho robala ka ho tsoha, ho robala ha SWS le REM ke mefuta e ikhethang ea boitšoaro e ka hlalosoang ke likarolo tse nepahetseng tsa li-electroencephalographic (EEG) le li-electromyographic (EMG). Nakong ea tsoho, ho ba le maemo a tlase, ho kopanya hangata le linako tse sa tsoaneng. SWS e tšoauoa ka li-oscillations tse phahameng tsa boemo bo phahameng (0.5-4 Hz) eo boholo ba eona (joalo ka ha bo lekantsoe ke matla a matla a EEG) e bonts'a botebo ba boroko. Boroko ba REM ke boemo bo kopanetsoeng ba boits'oaro, bo khetholloang ka ho panya ha leihlo, bo kopaneng, bohareng moo "li-oscillations" tsa 5-10 Hz) li busang ka litoeba, li tsamaisana le mesifa ea mokokotlo, hammoho le phallo ea pelo le litheko tsa ho hema.

Le ha maemo a boroko le ho tsoha a le bonolo ka mokhoa o hlakileng ebile ho le bonolo ho a khetholla, ho a makatsa ho hlalosa se boleloang ke "ho tsosa." Hangata poleloana ea ho tsosa takatso e bolela boemo ba ho falimeha le ho falimeha nakong ea ho tsoha, ho bonahatsa ho eketsa ts'ebetso ea makoloi ho kenya litlatsetso tsa maikutlo, ho fetoha ha maikutlo le ts'ebetso e ntlafalitsoeng ea kelello.

Mekhatlo ea boko e hlophisang motsamao oa potoloho ea ho robala le maemo a tloaelehileng a borumuoa a lula a sa hlake ebile lithuto tse ngata tsa khale li bontsitse palo e mengata ea li-neuron tseo ts'ebetso ea eona e lumellanang le linaha tsa boitšoaro bo ikhethileng. Pele ho ne ho nahanoa hore li-neurons tse sebetsang pele ho liphetoho tsa boitsoaro (ke hore, li-neurons tse sebetsang pele ho phetoho ea boroko-ho-wake) Khothalletsa boemo bo tlang, ha li-neuron tse sebetsang nakong ea boemo bo itseng (ho tsoha kapa ho robala) li bohlokoa ho boloka eona. Pono ena e thatafatsoa le ho feta ke kutlwisiso ea hore li-neurons tse marang-rang li ka bonts'a mesebetsi e amanang le meeli ka lebaka la ho hokahana le tse ling, li-neuron tsa causal ntle le ho ikarabella ka kotloloho phetohong ea mmuso. Leha ho le joalo, ka kakaretso ho na le tšusumetso ea hore ho na le baahi ba neural ba etsang karolo ea bohlasoa ho boroko le / kapa libakeng tse tsosang takatso. Baahi bao ho nahanoang hore ba hlohlelletsa thabo e kenyelletsa: hypocretin (hcrt - eo hape e bitsoang "orexins") - e hlalosang li-neurons ho latela li-hypothalamus tsa morao-rao, Noradrenergic locus coeruleus (LC) - e hlalosang li-neuron tsamaisong ea methapo ea kutlo, serotoninergic dorsal raphe nuclei (DRN) bokong ba kelello, histaminergic tuberomammilary nucleus (TMN) ho posterior hypothalamus, cholinergic pedunculopontine (PPT) le laterodorsal tegmental (LDT) nuclei bohareng ba mokokotlo, hammoho le li-neuron tsa cholinergic tse bokamoreng ba basal (Jones, 2003). Ka lehlakoreng le leng, li-neurons tsa inhibitory tse tsoang mehahong ea anterior hypothalamic li sebetsa nakong ea SWS, ha Melanin-Concentrating Hormone (MCH) neurons e tsoang ho hypothalamus ea morao-rao, hammoho le glutamatergic le Gabaergic neurons tse tsoang bokong ba methapo li sebetsa nakong ea ho robala ha REM (Fort et al., 2009).

Lilemong tsa morao tjena, rona le ba bang re se re qalile ho sebelisa theknoloji ea optogenetic ka mefuta e fapaneng ea mouse ho araba lipotso tse kang Litsamaiso tse hlasimollang li laola joang ho tsoha le ho tsosa? Ba sebetsa 'moho joang ho khothatsa, ho boloka kapa ho pharalatsa maikutlo maemong a itseng? Lithutong tsa rona tsa morao-rao, re khahliloe haholo ke li-neurons tse hlalosang hcrt (de Lecea et al., 1998; Sakurai et al., 1998). Li-hcrt ke li-peptide tse peli tse khahlisang (ne Lecea et al., 1998; Sakurai et al., 1998) e hlahisitsoeng ka ~ 3200 neurons ho toeba ea lateral hypothalamus (~ 6700 le 50,000-80,000 ho rat le bokong ba motho, ka tatellano) (de Lecea le Sutcliffe, 2005; Modirrousta et al., 2005). Li-neuron tsena li fumana lipehelo tse sebetsang tse tsoang lits'ebetsong tse ngata tse abeloang ka cortex, system ea limbic, libakeng tse ka tlase ho cortical ho kenyeletsa hypothalamus ka boeona, thalamus, le likhakanyo tse nyolohang ho tsoa ho brainstem cholinergic nuclei, the reticular form, midbrain raphe nuclei, and griaqueductal grey. Ka lehlakoreng le leng, li-neuron tsena li etsa projeke ho ts'ebetso ea methapo e bohareng, ho kenyelletsa le litsing tsa boko le meputso, ho li-neuron tse hlalosang li-receptors tsa hcrt (OX1R le OX2R). Maiketsetso a amanang le ho sebetsa hantle ha li-neuron tsa hcrt a fana ka maikutlo a hore ba bapala karolo ea mesebetsi e mengata ea hypothalamic ho kenyelletsa taolo ea mokokotlo oa ho robala / ho tsoha le boits'oaro bo nang le sepheo. Ho khahlisang, re fumane hore projeke e ikhethang ea ho qala ho sebetsa ho tloha ho li-neuron tsa hcrt ho ea ho noradrenergic LC neurons e fetoha phetoho ea boroko-ho-wake mme mohlomong le likarolo tse akaretsang tsa boroko.

Mona, re akaretsa liteko tsa morao-rao tsa optogenetic tse lekang ts'ebetso ea kelello eo hcrt le LC neurons li bakang liphetoho le maemo a bophelo ba arousal (Adamantidis et al., 2007; Carter et al., 2009, 2010, 2012). Taba ea mantlha, re hlakisa le ho khutsufatsa litlaleho tsa pejana mabapi le litsamaiso tsena re sebelisa mekhoa ea setso ea liphatsa tsa lefutso le meriana. Ka mor'a moo, re hokahanya liphumano tsa rona re sebelisa li-optogenetic probes ho khothaletsa kapa ho thibela lits'ebetso tsena ka litoeba tse tsamaeang ka bolokolohi. Kamora nako, re buisana ka lipotso tse sa rarolloang ebe re nahana ka likarohano tsa moseho oa li-anatomical le tšebetso mabapi le lipotoloho tse khahlisang.

Hypocretins, wakeever le narcolepsy

Li-neurons tsa hcrt hangata ha li khutse nakong ea ho phomola ho khutsitseng, SWS, le ho robala ha REM empa li bonts'a litheko tse phahameng nakong ea ts'ebetso le liphetoho tsa boroko ba ho robala (Lee et al., 2005; Mileykovskiy et al., 2005; Takahashi et al., 2008; Hassani et al., 2009). Ntle le moo, ba bonts'a litheko tse phahameng nakong ea ha ba tsosa tjantjello ke susumetso ea tikoloho (mohlala, khothalletso ea tlhaiso) (Takahashi et al., 2008) le boits'oaro bo nang le sepheo (Mileykovskiy et al., 2005; Takahashi et al., 2008). Lithuto tsena li fana ka maikutlo a hore li-neurons tsa hcrt li nka karolo ho fetoleng boroko-ho-ho-ea, hammoho le tlhokomelong e eketsehileng ea tlhokomeliso nakong ea boits'oaro bo fapaneng ba sepheo sa sepheo.

Ho thibela kapa ho hatella ha lets'oao la hcrt ho bonts'a tlhokahalo ea hcrt bakeng sa ho ts'epahala hoa linaha tsa boitshwaro ho litoeba, likhoto, lintja, batho, mohlomong le liqoaha (Sakurai, 2007; Yokogawa et al., 2007). Ho joalo, bopaki bo qobellang ho lahleheloa ke mosebetsi bo tsoa khokahanong lipakeng tsa khaello ea hcrt le matšoao a narcolepsy (Peyron et al., 2000; Saper et al., 2010). Bakuli ba narcoleptic ba nang le cataplexy ha ba na ho hang hcrt phetisetso ea liphatsa tsa lefutso ho hypothalamus hammoho le maemo a sa bonahaleng kapa a sa bonahaleng a hcrt ho mokelikeli oa "cerebrospinal fluid" (Thannickal et al., 2000; Sakurai, 2007; Yokogawa et al., 2007). Lintja tsa Doberman narcoleptic li na le phetoho ho OX2R, le litoeba tsohle tse entsoeng ka liphatsa tsa lefutso ka ho tlosoa hoa hcrt, OX2R, kapa lisele tsa hcrt li hlahisa ho ts'oaroa hoa boits'oaro bo tšoanang le cataplexy, letšoao le hlakileng la narcolepsy (Jones, 2003; Sakurai, 2007; Sehgal le Mignot, 2011). Ho bohlokoa, pholoso ea liphatsa tsa lefutso hcrt polelo ea gene e felisang matšoao a narcolepsy ho litoeba (Liu et al., 2011; Blanco-Centurion et al., 2013).

Intracerebroventricular (icv) infusion ea hcrt peptides kapa hcrt agonists e baka keketseho ea nako e sebelisitsoeng e falimehile le ho fokotseha ha boroko ba SWS le REM [tlhahlobo ho Sakurai (2007)]. Stereotactic ente ea peptide ho LC, LDT, basal forebrain, kapa hypothalamus ea morao-rao e eketsehang ea ts'ebetso le ts'ebetso ea locomotor hangata e amanang le phokotso e tšoaeang ho robala ha SWS le REM (Hagan et al., 1999). Haufinyane tjena, liphatsa tsa lefutso tse thibelang li-neuron tsa hcrt tse sebelisang mofuta o mong oa ho tlosa GABA-B receptor gene feela maemong a hcrt li kentse karohano e matla ea boroko / ho khutla nakong ea leseli le linako tse lefifi ntle le ho bonts'a ho sa lekana ka ho robala ka botlalo / ho tsosa kapa matšoao. of cataplexy (Matsuki et al., 2009). Ka kopanelo, lintlha tsena li fana ka maikutlo a hore li-peptide tsa hcrt li bohlokoa ho hlalosa meeli lipakeng tsa boroko le ho tsoha, joalo ka ha ho bonts'itsoe ke karohano ea boroko le boemo ba liphoofotsoana tsa liphoofolo tsa narcolepsy.

Le ha ho tlalehiloe ka bongata hore ts'ebetso ea likokoana-hloko ea li-peptide tsa hcrt ea hlokahala ho boloka tsoho le boroko bo loketseng, ho ntse ho sa tsejoe hore na ke liofising tse peli tsa hcrt, OX1R, kapa OX2R, e ikarabellang ho tsa tlhaho litlamorao tsa hcrt mabapi le tsoho, hammoho le botsitso ba boroko le taolo ea molumo oa mesifa. OX1R mRNA e hlahisoa libakeng tse ngata tsa boko, haholo LC, raphe nuclei, LDT ha e ntse e le OX2R mRNA e bonts'a mokhoa o tlatselletsang oa polelo ho cortex ea "cerebral cortex", "raphe nuclei", le dorsomedial le posterior (ho tuberomammillary nucleus) hypothalamus (Trivesi et al., 1998; Marcus et al., 2001; Mieda et al., 2011). Kahoo, ho bile le tlhahiso ea hore taolo ea ho tsoha le ho robala ka NREM e itšetlehile haholo ka OX2R (Mochizuki et al., 2011) ha ts'ebetso ea boroko ea REM (e ikhethang ho narcolepsy-cataplexy) e bakoa ke tahlehelo ea ho saena ka bobeli ba OX1R le OX2R (Mieda et al., 2011). Leha ho le joalo, seo ba se bolelang molemong oa narcolepsy, haholo-holo tlhaselo ea bohloeki le tlhaselo ea boroko, e ntse e sa hlaka. Ntja tse nang le lefu la ho hlaba ka mokhoa o hlasimollang li na le phetoho e ntle liphatseng tsa OX2R gene (Lin et al., 1999) le mofuta o tšoanang oa toeba, OX2R Litoeba tsa KO, li bonts'a matšoao a fokolang ho feta lintja (Willie et al., 2003). Leha OX1R e nka karolo ho fetiseng melao ea lihlahisoa tsa bohloeki (Mieda et al., 2011), tlatsetso ea eona matšoao a lefu la narcolepsy e ntse e tlameha ho bonahala.

Taba ea bohlokoa ke hore ts'ebetso lits'ebetsong tse ling tsa mahlahahlaha e ba le tšusumetso e matla nakong ea sehloho. LC methapo ea kutlo e khaotsa ho tsoa (Gulyani et al., 1999) le li-neuron tsa serotoninergic li fokotsa haholo tšebetso ea tsona (Wu, 2004), ha lisele li le Amygdala (Gulyani et al., 2002) mme TMN e bontšitse boemo bo eketsehileng ba ho thunya (John et al., 2004). Mokhatlo ona o fana ka maikutlo a hore bobeli ba OX1R (LC, raphe), le OX2R (TMN, raphe) ba kentse letsoho ho boloka molumo o loketseng oa mesifa. Boithuto ba morao-rao bo boetse bo totobalitse karolo ea li-system tse fetotsoeng tsa cholinergic ho tsitsitseng cataplexy ho litoeba tsa narcoleptic (Kalogiannis et al., 2011, 2010). Ka hona, sepheo sa bohlokoa, se sa rarolloang ke ho khetholla wiring e sebetsang ea li-neurons, hammoho le matla a matla a ho lokolloa ha synaptic ho tsoa litsing tsa hcrt ho hlakola merero e hlakileng ea metsi (de Lecea et al., 2012) taolo e laolang ho tsosa, ho robala, molumo oa mesifa le boits'oaro bo nang le sepheo.

The locus coeruleus, norepinephrine, le tsoho

LC e haufi le 4^th ventricle bokong 'me e na le methapo ea kutlo e etsang monoamine norepinephrine (NE). Leha lipalo tse ling tse 'ne tsa sele li boetse li hlahisa NE (A1, A2, A5, le A7 lihlopha tsa sele), LC e hlahisa ~ 50% ea kakaretso ea boko ea NE mme ke ona feela mohloli oa cortex. Ho na le li-receptor tse ngata tse sebetsang tsa NE tse fumanehang bokong bohle, 'me li-receptor tsa α1 le usually hangata li baka menyetla e khahlisang ea li-postynaptic mme li-receptor tsa α2 hangata li baka menyetla ea thibelo ea postynaptic. Li-receptors tsa α2 li fumanoa li le li-neuron tsa LC (Berridge le Waterhouse, 2003) Ka bo bona ba sebetsa e le li-inhibitory autoreceptors ho hatella tšebetso ea methapo.

Rekoto liphoofolong tse etsang hore liphoofolo li tsohe, e bonts'a hore LC li-neurons li tuka hampe ka nako ea 1-3 Hz nakong ea mebuso e sa tsoheng, mollo o fokolang nakong ea boroko ba SWS, mme o khutsitse nakong ea boroko ba REM (Aston-Jones le Bloom, 1981; Jones, 2003; Saper et al., 2010). LC e boetse e chesa ka mokhoa o pharalletseng oa li-8-10 Hz nakong ea tlhahiso ea maikutlo a ikhethang a ka eketsang nako ea ho tsoha. Joalo ka li-neurons tsa hcrt, liphetoho tse bang teng maemong a thibelo ea bokhachane li etella pele liphetoho phetohong ea boroko-ho-wake (Aston-Jones le Bloom, 1981), ho fana ka maikutlo a hore lisele tsena li bohlokoa bakeng sa phetoho ho tsosetsong kapa tlhokomelong.

Ho khahlisang ke hore, liso tsa 'mele tsa LC ha li hlahise liphetoho tse sa fetoheng ho cortical EEG kapa boits'oarong ba boits'oaro ba bohloeki (Lidbrink, 1974; Blanco-Centurion et al., 2007). Tlatsetso ea liphatsa tsa lefutso ea dopamine beta-hydroxylase, enzyme e hlokahalang bakeng sa mofuta oa NE, le eona ha e ferekanye libaka tsa boroko (Hunsley et al., 2006). Sena se supa boteng ba redundant neural circry, kantle ho sebopeho sa LC, ho ts'ehetsa ts'ebetso ea cortical le mekhoa e ntlafalitsoeng ea nts'etsopele, ka ho latellana. Leha ho le joalo, liente tsa bohareng ba bahanyetsi ba meriana ea í1 le β noradrenergic receptors (Berridge le España, 2000) kapa agonists of inhibitory α2 li-autoreceptors (De Sarro et al., 1987) ba le litlamorao tse kholo tsa ho susumetsa. Tsamaiso e bohareng ea NE ka kotloloho kahare ho li-ventricles kapa bokapele ba sefahleho bo khothaletsa tsoho (Segal le Mandell, 1970; Flicker le Geyer, 1982). Ho hlohlelletsa li-neuron ho LC ho sebelisa li-microinjections tsa lehae tsa cholinergic (bethanechol) ho hlahisa ts'ebetso ea kapele ea EBG ka litšoelesa tse sa sebetseng (Berridge le Foote, 1991). Haufinyane, sistimi ea LC-NE e bonts'itsoe e le ea bohlokoa bakeng sa ho boloka bokhoni bo eketsehang ba membrane ba li-cortical neurons ka ho tsoha bo bapisoa le libaka tsa ho robala (Constantinople le Bruno, 2011). Ha li kopantsoe hammoho, liphuputso tsena li fana ka maikutlo a hore sistimi ea LC-NE e etsa mosebetsi oa cortical hape e eketsa le monyetla oa ho ruruha.

Distogenetic dispar ea hcrt le LC-NE taolo ea arousal

Ketsahalo ea hcrt le LC-NE neurons e lumellana le phetoho ea boroko-ho-wake, leha ho le joalo, ho bile thata ho khetha ka mokhoa o ikhethileng kapa ho thibela li-hcrt tse ikhethang le lipalo tsa LC-NE tse nang le tharollo ea nakoana e amanang le likarolo tsa boroko kapa tsa ho tsoha, le ho fihlella boikhethelo ba sebaka sa ho etsa lipatlisiso tsa lisele tsena ntle le ho ama lisele tse potileng kapa likhoele tse potileng. Boitekong ba ho utloisisa hamolemo matla a nakoana a ho potoloha ha methapo ea kutlo, re sa tsoa sebelisa li-optogenetics ho fetola ka mokhoa o ikhethileng le ka mokhoa o khethang mosebetsi oa li-neurons tsa hcrt le LC ho liphoofolo tse tsamaeang ka bolokolohi (Adamantidis et al., 2007; Carter et al., 2009, 2010, 2012). Optogenetics e sebelisa li-molecule tsa "activator opsin" (mohlala, Channelrhodopsin-2 (ChR2) kapa halorhodopsin-NpHR) ho khetha ka mokhoa o ikhethileng kapa ho khutsisa lisele tse lebisitsoeng ho liphatsa tsa lefutso, ka tatellano, ka khanya ea khanya ka mokhoa o khethehileng oa wavelength (Boyden et al., 2005). Tlhahisoleseling e eketsehileng ka theknoloji ea optogenetic e ka fumanoa litlhahlobisong tse ling tse ngata tse ntle (Zhang et al., 2006; Miesenbock, 2009; Scanziani le Häusser, 2009; Yizhar et al., 2011; Deisseroth, 2012).

Ho nehelana ka li-activator tsena ho hcrt kapa LC neurons, re sebelisitse lisebelisoa tsa mofuta oa li-lentiviral le tse itšetlehileng ka mofuta oa tlatsetso, ka tlasa taolo ea barekisi ba khethehileng ba mofuta oa cell (Adamantidis et al., 2007). Ho fana ka leseli ho hcrt kapa lebaleng la LC, re qapile li-interface tsa mahlo-a-neural tseo ho tsona likhoele tsa mahlo li neng li kentsoe ka mokhoa o sa tsitsang ka lehata la mouse, joalo ka ha ho hlalositsoe kae kapa kae (Adamantidis et al., 2005, 2007; Aravanis et al., 2007; Zhang et al., 2010). Re sebelisa leano lena, re ile ra khona ho laola tšebetso ea hcrt neural ka bobeli a vitro 'me Ka vivo ka tšusumetso ea millisecond e nepahetseng e nepahetseng (Adamantidis et al., 2007). Tekanyo e phahameng ea nakoana ea moea le sebaka sa ts'usumetso e re lumelletse ho etsisa maemo a fapaneng a mmele a hypocretin neuron discharge (1-30 Hz) (Hassani et al., 2009). Ho joalo, re sebelisitse literene tse bobebe tsa matla a rona bakeng sa ts'usumetso ea optogenetic e neng e thehiloe ho parameta ho tlhahlobo ea maqhubu a li-neurons tsa hcrt Ka vivo (ho joalo hape bakeng sa taolo ea optogenetic ea LC-NE neurons e hlalositsoeng ka tlase). Re fumane hore ts'usumetso e ikhethileng ea li-neuron tsa mahlo a tobileng a eketsang monyetla oa phetoho ho tsoha ho tloha ho SWS kapa ho robala ha REM (Setšoantšo. (Figure1A) .1A). Ho khahlisang ke hore maqhubu a phahameng a sefahleho (5-30 Hz literene tse bobebe tsa terene) a theolitse morao hore a se ke a tsoha, athe literene tsa 1 Hz ha lia ka tsa fana ka maikutlo a hore ho lokolloa ha li-synaptic tse itšetlehileng hangata ka li-neurotransmitter (glutamate) le li-neuromodulator, ho kenyeletsoa hcrt kapa dynorphin ho tsoa litsing. Re boetse re bonts'a hore litlamorao tsa ho hlasimolla li-neurons tsa hcrt li ka koaloa ka ente ea mohanyetsi oa OX1R kapa ka ho tlosoa hoa liphatsa tsa lefutso tsa hcrt, ra fana ka maikutlo a hore hcrt peptides mediate, bonyane ka karolo, optogenetically-ikiwa. Liphetho tsena li bonts'a hore ho lokolloa ha hcrt ho tsoa ho li-neuron tse hlahisang hcrt hoa hlokahala bakeng sa thepa e khothatsang ea li-neuron tsena. Habohlokoa, liphetho tsena li bonts'a khokahano pakeng tsa ts'ebetso ea ts'ebetso ea methapo ea hcrt le liphetoho tsa ho robala ho tsoha, li lumellana le lithuto tsa pele tse amanang. Sena se ile sa ts'ehetsoa hape ke taba ea hore ho khutsisa ha li-neurons tsa hcrt ho khothaletsa SWS (Tsunematsu et al., 2011).

 

Setšoantšo sa 1

Distogenetic disgment tsa argesal circuits tsa boko. (A) Ho hlohlelletsa li-neurons tsa hcrt tse nang le ChR2 ho baka ho fokotseha hoa ho robala ha boroko ho 10 Hz empa eseng 1 Hz (data e tsoang ho Adamantidis et al., 2007). (B) Ho hlohlelletsa li-neuron tsa LC tse nang le ChR2 ho baka kapele ...

Liphetho tsena li sa tsoa netefatsoa ke Sasaki le bathusi (Sasaki et al., 2011), ea sebelisang mokhoa oa ho rekisa oa litlama o bitsoang Designer Receptors Exclusively activated by Designer D drug (DREADDs) ho kenya letsoho le ho hatella tšebetso ea hcrt neural. Mahlale a DREADD a lumella phetisetso ea bimodal ea tšebetso ea neural ka tharollo ea nakoana ea lihora tse 'maloa (Dong et al., 2010). Ba fumane hore ts'ebetso ea ts'ebetso ea hcrt neural e eketseha ha a ntse a hatella tšebetso ea hcrt e khothaletsa SWS.

Thutong ea bobeli (Carter et al., 2009), re bontšitse hore taolo ea hcrt ea liphetoho tsa boroko tse tlasa ts'ebetso ea ts'ebetso ea homeostasis kaha liphetoho tsa boroko tsa ho robala li koetsoe ke khatello e matla ea ho robala (e bakoang ke ho hloka boroko). Leha ho le joalo, phello ea ts'usumetso ea optogenetic ea hcrt e ile ea phehella ho litoeba tsa histamine decarboxylase knockout (litoeba tse sa khoneng ho kopanya histamine) e fana ka maikutlo a hore pakane e 'ngoe eo tsamaiso ea histaminergic e ikarabellang ho eona ke phello ea hcrt. Kamora moo, re bonts'a hore litsi tse tlase tsa noka tse kang li-neuron tsa LC ka bobeli li matlafalitse tšebetso ea tsona (joalo ka ha ho lekantsoe ke polelo ea c-Fos) ho arabela ka ho ts'oaroa ha hcrt optogenetic. Hobane mosebetsi o fetileng o bontšitse phello e thabisang ea hcrt ho LC NE neurons (Bourgin et al., 2000), re fuputse khokahano ea hcrt-LC mme ra tsepamisa lipatlisiso tsa rona tsa liteko ho Noradrenergic LC e le sepheo se secha sa ho laola mashano a optogenetic.

Thutong ea boraro (Carter et al., 2010), re lebisitse ho liphatsa tsa lefutso tsa LC-NE ka liphatsa tsa lefutso ka ente e tsoang ho kokoana-hloko e amanang le ad receptinase-adenti e amanang le mofuta oa "Creve" ho litoeba tse kenang ka mokhoa o ikhethileng o hlalosang Cre ka tyrosine hydroxylase (TH) neurons (Atasoy et al., 2008; Tsai et al., 2009). Re fumane hore bobeli ba NpHR le ChR2 li ne li sebetsa ebile li ka thibela le ho kenya tšebetsong, ka tatellano, li-neuron tsa LC-NE ka bobeli a vitro 'me Ka vivo (Setšoantšo (Figure1B) .1B). Re fumane hore tšusumetso ea "li-optogenetic low frequency" (1-10 Hz) e bakang phetoho ea ho robala ka morao ho nako e ka tlase ho 5 s ho tsoa boroko ka bobeli ba SWS le REM. Ho hlohlelletsa li-neuron tsa LC nakong ea ho tsoha ho eketsa ts'ebetso ea locomotor le nako eohle e sebelisitsoeng e falimehile, e netefatsang phello e matla ea thabo. Ka lehlakoreng le leng, ho khutsisa ho pakeng tsa NpHR ka li-neuron tsa LC-NE ho fokotsitse nako ea liketsahalo tsa tsoho empa ha hoa ka ha thibela phetisetso ea ho robala ho ea ha liphoofolo li ne li robetse. Ha ho kopanngoa hammoho, thuto ena e bonts'itse hore ts'ebetso ea li-neuron tsa LC-NE ea hlokahala bakeng sa ho boloka linako tse tloaelehileng tsa ho falimeha (teko ea NpHR), 'me e lekane ho susumetsa phetoho ea boroko hang-hang, ho tsosa tsoelo-pele, le ho tsosa mofere-fere. Kahoo, re khothalelitse hore LC-NE neurons e sebetse e le sistimi e potlakileng ea ho khothaletsa phetoho ea boroko le ho tsosa ka kakaretso. Ho khahlisang, re fumane hore ts'ebetso e tsitsitseng ea ts'ebetso ea li-neuron tsa LC-NE e etsa hore locomotor e tšoaroe (Carter et al., 2010). Boitšoaro bo joalo ba boits'oaro bo arolelana matšoao a tloaelehileng le cataplexy, catatonia kapa boits'oaro bo botle ba boitšoaro ka mefuta ea liphoofolo le bakuli ba batho (Scammell et al., 2009). Mechine e ka bang teng e ka kenyelletsa ho putlama ha NE ho tsoa litsing tsa LC-NE synapse kapa LC-NE ovexcitation ea brainstem motor nuclei e ka lebisang ho shoeleng litho. Phuputso e eketsehileng ea hlokahala ho sibolla mekhoa e ka tlase.

Thutong ea rona ea morao-rao (Carter et al., 2012), re lekile khopolo-taba ea hore liheke tsa tšebetso tsa LC li ama litlamorao tsa liphetoho tsa boroko le boroko. Hobane palo ea batho ba hcrt le LC ba fumanehang libakeng tse fapaneng tsa boko, ho a khonahala ho fihlella meaho ka bobeli ka nako e le 'ngoe phoofolo e le' ngoe. Ka hona re nkile mokhoa o habeli oa optogenetic ho matlafatsa li-hcrt neurons ha re ntse re thibela ka mokhoa o ts'oanang kapa re susumetsa li-neuron tsa LC tsa noradrenergic nakong ea boroko ba SWS. Re fumane hore ho khutsisa li-neuron tsa LC nakong ea ts'usumetso ea hcrt ho thibetse liphetoho tsa boroko ho tsoha tsa hcrt (Setšoantšo) (Figure1C) .1C). Ho fapana le hoo, re fumane hore ho eketsa thabo ea "li-neuron tsa LC" ka ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso-e leng keketseho ea lisele tse lebisitsoeng (Berndt et al., 2009) - - ho eketsa ts'usumetso ea hcrt (ho sebelisa protocol ea ts'usumetso ea LC eo ka boyona e sa eketseng phetoho ea boroko-ho-tsoha) ntlafatso e ntlafalitsoeng ea ho robala le ho tsosa (setšoantšo) (Figure1D) .1D). Ha re kopantsoe hammoho, liphetho tsa rona li bonts'a hore LC e sebetsa e le sephetho se hlokahalang le se lekaneng sa pheletso ea phetoho ea hcrt-Mediated SWS-to-wake nakong e sa sebetseng.

hcrt le LC-NE tsamaiso ea methapo

Nako le nako lithutong tsa rona tsa liteko, re hlokometse hore ho qhekelloa ha li-optogenetic tsa hcrt le li-neuron tsa LC-NE ho ama phetoho ea boroko-ho tsosa ka liphetoho tse fapaneng tsa matla a nakoana (Adamantidis et al., 2007; Carter et al., 2009, 2010, 2012). Ho kenella ka matla ha li-neurons tsa hcrt ho baka ho fetoha ha boroko ka nako e telele ea 10-30 s, ha ho tsosoa ha li-neuron tsa LC ho baka ho fetoha ha boroko ka nako e ka tlase ho 5 s. Tlhaloso e le 'ngoe ke hore li-neurons tsa hcrt li ka sebetsa e le setsi se hloahloa sa ho nyatsa nakong ea mesebetsi e amanang le hypothalamic ha tsamaiso ea LC-NE e sebetsa e le tšusumetso ea mantlha ea ho tsosa moferefere, khatello ea maikutlo le tlhokomelo. Le ha ho le joalo, lits'ebetso tsa "neuronal effector" ha li na thuso ebile li susumetsoa ke lipehelo tse fapaneng. Ka hona, re ke ke ra fana ka taelo ea hore ho thibela lits'ebetso tse ling tse khahlisang, joalo ka litsamaiso tse bohareng tsa histaminergic le cholinergic, ho ka ama hampe liphetoho tsa maemo a ts'usumetso ea maemo a hcrt tse hlohlellelitsoeng maemong a mang a liteko.

Ntle le litlamorao tsa nako e khuts'oane, ho boetse hoa khahlisa hore liteko tsa lifilimi tsa ~ 1-4 h tsa "hcrt" tsa "hcrt" li ekelitse liphetoho tsa ho robala li sa fetole nako eohle ea ho tsoha, ha nako e telele Photostimulation ea LC-NE li-neurons li eketsehile haholo nako ea ho tsoha. Liphetho tsena li fana ka maikutlo a hore ts'ebetso ea hcrt e ka laola meeli ea ho robala ha LC-NE e ka laola taolo ea nako ka ho eketsa bokhoni ba karolo ea cortical membrane ea eona le ho etsa hore ho be thata ho ts'oara EEG.

Hypothalamic ea lehae ea li-neurons ea hcrt e bolela hore lisele tsena li na le karolo e hlahelletseng ea nyakallo nakong ea ts'ebetso ea homeostatic, ho kenyelletsa boitšoaro ba thobalano, lijo tse qalang, karabelo ea khatello ea maikutlo le tšusumetso. Ntle le taolo ea bona ea ho phaphama, lits'ebetso tse hlasimolohileng li boetse li nka karolo liketsong tsa ho batla moputso, liketso tsa thobalano, likarabo tsa sefofane kapa ntoa ea ntoa, jj. pholoha. Mohlala, ts'ebetso ea ts'ebetso ea LC-NE e eketsa nyakallo mme e baka boits'oaro bo kang ba ho tšoenyeha (Itoi le Sugimoto, 2010). Ka lehlakoreng le leng, tsamaiso ea neuropeptide S (NPS), peptide e hlahisoang ke "neuronal" ea palo ea batho ba kenang kahare ho LC, le eona e eketsa nyakallo. ea fokotseha ho tšoenyeha (Pape et al., 2010). Kahoo, ho ts'ehetsa mesebetsi e fapaneng ea boits'oaro, lipotoloho tse khahlisang li tlameha hore li fihle maemong a hloahloa, mohlomong ka ho khetha likarolo tse ikhethileng tsa khokahano ea tsona tse kopanetsoeng le tse sebetsang, li-transmitter / modulators li khona ho lokolla bokhoni ba tsona le ts'ebetso e kopanetsoeng le batho ba bang ba mekoloko e metle.

Sepheo

Lilemong tse hlano tse fetileng, motsoako oa li-optogenetics, mefuta ea likhoto tse entsoeng ka liphatsa tsa lefutso, le tlhahlobo ea boroko ea EEG / EMG e fane ka lisebelisoa tse ikhethileng le tse matla tsa ho ntšetsa pele kutloisiso ea menehelo ea litsamaiso tsa hcrt le LC ho tsosa, hammoho le mefuta e meng ea li-neuron tse laolang boroko le ho tsoha. Ho shebana le li-probogenetic ho lipalo tse ling tsa methapo ea kutlo bokong ho tla lekanya likarolo tsa bona ka bomong le tse kopaneng meeling ea boroko / tsoha. Ntle le moo, lisebelisoa tsena li tla re lumella ho tseba mochini oa boko o ipapisang le linaha tse ipapisitseng le 'mele ho latela likhakanyo tsa anatomical, synaptic neurotransmission le matla a phetiso ea transmitter. Bokhoni ba ho supa le ho khetha lipotoloho tsena ka nepo e phahameng ea nakoana (<1 s) li lumella monyetla oa ho fuputsa karolo ea bona maemong a fapaneng a boits'oaro joalo ka ho ja lijo, ho lemalla, khatello ea maikutlo, ho tsepamisa maikutlo le ho tsosa takatso ea thobalano. Qetellong, lithuto tsena li ka senola mekhoa ea mafu a kelello e kang ho tšoenyeha ho sa feleng, bokhoba ba tahi, khaello ea tlhokomelo le khatello ea maikutlo.

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References