Ingqondo ye-hypocretins kunye ne-receptors: abalamli be-allostatic arousal (2009)

Curr Opin Pharmacol. Umbhalo-ngqangi wombhali; ifumaneka kwi-PMC 2013 Oct 7.

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Abstract

I-hypocretins (efinyeziweyo "i-Hcrts" -ekwabizwa ngokuba yi "orexins") zimbini ze-neuropeptides ezifihliweyo ngokukodwa ngabantu abancinci bee-neurons kwi-hypothalamus esecaleni. Ezi peptides zibophelela kwii-receptors ezimbini ezibekwe kuyo yonke ingqondo kwi-nuclei ehambelana nemisebenzi eyahlukeneyo yengqondo kunye neyomzimba. Ekuqaleni, inkqubo ye-Hcrt yobuchopho yafunyaniswa inendima enkulu ekulawuleni ukulala / ukuvuka kweenguqu. Uphononongo lwamva nje lubonisa ukuba ii-Hcrts zinokudlala indima kweminye imisebenzi yomzimba, kubandakanya nokutya, umlutha, kunye noxinzelelo. Zithatyathwe kunye, ezi zifundo zibonisa indima eqhelekileyo ye-Hcrts ekulamleni ukuvuswa, ngakumbi xa into ephilayo kufuneka iphendule kuxinzelelo olungalindelekanga kunye nemingeni kwindalo esingqongileyo.

intshayelelo

Sele ishumi leminyaka ukusukela oko kwafunyaniswa i-hypocretins (Hcrts), kwaye kule minyaka ilishumi idlulileyo siye safunda okuninzi malunga nokuthetha, ukwakheka kunye nokusebenza kwazo. Phantse ngokukhawuleza emva kokufunyanwa kwabo, indima ebalulekileyo ye-Hcrts ekugcineni ukuphaphama yaxelwa kwiintlobo ezininzi kuquka abantu [1-5]. Iminyaka elandelayo iqinise ubungqina bokuba ii-Hcrts zombini ziyimfuneko ukuze zigcinwe kwaye zanele ukuphembelela ukuphaphama, kwaye ngoku zijongwa njengeepeptides “zokukhuthaza ukuvusa” [6-7]. Kutshanje, ii-Hcrts ziye zabandakanyeka kwimisebenzi yomzimba kunye nokuziphatha ngaphandle kokuvuka. Kolu phononongo, sinika isishwankathelo se-Hcrts yobuchopho kunye ne-receptors zabo kwaye sivavanya izifundo zakutsha nje ezibandakanya indima ye-Hcrts kule misebenzi yahlukeneyo yomzimba. Ekuzameni ukudibanisa ezi zifundo, sicebisa ukuba imisebenzi emibini jikelele ye-Hcrts kukulamla ukuphaphama kunye ne-allostatic arousal.

Ii-hypocretins

I-Hcrts yafunyanwa ngokuzimeleyo ngamaqela amabini ekupheleni kweminyaka yoo-1990 [8,9]. Ziquka iperi yeepeptides ezifihlakeleyo, i-hypocretin-1 kunye ne-hypocretin-2 (i-Hcrt1 kunye ne-Hcrt2; eyaziwa nangokuthi "i-orexin A" kunye ne "orexin B", ngokulandelanayo). Ezi peptides zicutshungulwa kwi-precursor yemfuzo efanayo, "preprohypocretin" (ppHcrt) kwaye zibonakaliswa ngokukodwa kwi-perifornical lateral hypothalamic area of ​​the brain [8,9]. I-Hctrs kunye ne-receptors yazo ibonakaliswe kwi-periphery [10], kodwa kolu hlaziyo sigxininisa kwi-Hctrs yenkqubo ye-nervous central.

I-Brain Hcrt neurons ifumana uqikelelo olwahlukileyo oluvela kwiinuclei ezininzi kwi-hypothalamus, i-allocortex, i-claustrum, i-nucleus yebhedi ye-stria terminalis, i-periaqueductal grey, i-dorsal raphe nucleus, kunye ne-lateral parabrachial nucleus [11]. I-Hcrt neurons ifumana igalelo kwi-GABAergic, glutamatergic, kunye ne-cholinergic neurons [12]. Ngaphezu koko, in vitro Izifundo ze-electrophysiology zibonisa ezininzi ii-neurotransmitters/neuromodulators excite Hcrt neurons (kubandakanywa ne-corticotropin releasing factor, ghrelin, neurotensin, vasopressin, kunye ne-oxytocin) okanye inhibit neurons ye-Hcrt (kuquka i-serotonin, i-noradrenalin, i-dopamine, i-neuropeptide Y, kunye ne-leptin) [13].

Ngapha koko, iprojekthi ye-Hcrt neurons iya kwiindawo ezahlukeneyo zenkqubo yemithambo-luvo, kubandakanywa uqikelelo olubalaseleyo kwi-noradrenergic locus coeruleus (LC), i-histaminergic tuberomammilary nucleus (TMN), i-serotoninergic raphe nuclei, indawo ye-dopaminergic ventral tegmental (VTA), indawo ye-cholinergic pedunculopontine tegmental (PPT) kunye ne-laterodorsal tegmental area (LDT), kunye ne-galaninergic ventrolateral preoptic nucleus (VLPO) [14]. I-Hcrt neurons nayo iprojekthi ngokwahlukeneyo kuyo yonke i-cerebral cortex. I-Hcrts ziipeptides ezivuselelayo kwaye ke ngoko zinciphisa iithagethi zazo [8,9].

Zithathiwe kunye, ezi zifundo ze-anatomical kunye ne-electrophysiological zibonisa ukuba i-Hcrt neurons idibanisa iindidi ezahlukeneyo zeempawu ze-homeostatic ukusuka kwinkqubo ye-nervous central kunye ne-periphery, kunye neprojekthi kwiindawo ezininzi zobuchopho, ezininzi ezibonisa ezinye i-neuromodulators kwaye ziyakwazi ukulawula imisebenzi eyahlukeneyo yomzimba kunye nokuziphatha.Umzobo 1).

Umzobo 1 

Uqikelelo oludibeneyo lwe-hypocretin neurons kunye nokubonakaliswa kwe-hypocretin receptors

I-hypocretin receptors

Zombini i-peptides ye-Hcrt idibanisa kunye nobudlelwane obuhlukeneyo kwi-receptors ezimbini ze-Hcrt, i-hypocretin receptor 1 (i-Hcrtr-1-ebizwa ngokuba yi "OxR1") kunye ne-2 (Hcrtr-2-ebizwa ngokuba yi "OxR2") [8,9]. I-Hcrt-r1 ibopha i-Hcrt1 kunye nobudlelwane obuphezulu kwaye ibophe i-Hcrt2 kunye ne-100 ukuya kwi-1000-fold-fold in affinity esezantsi [9,15]. I-Hcrt-r2 inobudlelwane obuphezulu kuzo zombini i-Hcrt1 kunye ne-Hcrt2 (Umzobo 2).

Umzobo 2 

Ingqondo ye-hypocretins kunye ne-receptors yazo

I-Hcrt receptors ibekwe kwii-terminals ze-postsynaptic kwipatheni ehambelana ne-anterograde projections ye-hypocretin neurons echazwe ngasentla (Iimpawu ze1 kwaye Kunye ne2) 2) [6,8,9,14]. I-Hcrt-r1 mRNA ifunyenwe ngaphakathi kwe-hypothalamus, i-LC, i-cortex ye-cerebral, kunye ne-nuclei ye-brainstem nuclei. Ngokwahlukileyo, i-Hcrt-r2 mRNA ibonakaliswa kwi-nuclei ye-cholinergic kwi-brainstem, indawo ye-ventral tegmental, kunye ne-TMN, kunye nokugqithiswa kwentetho kunye ne-Hcrt-r1 kwi-hypothalamus. Ngokuyinxenye ngenxa yokunqongophala kwabachasi abathile (Ibhokisi 1), kuncinci okwaziwayo malunga nemisebenzi eyahlukileyo ye-Hcrt-r1 kunye ne-Hcrt-r2. Nangona kunjalo, izilwanyana ze-Hcrt-r2 ezinkqonkqozayo, kodwa kungekhona i-Hcrt-r1 iigundane, zibonisa i-narcolepsy, kwaye ngoko ke ixhasa indima eveleleyo yale receptor ekuzinzeni kokuvusa.

Ibhokisi 1

Ukuphazamiseka kwe-Pharmacological yenkqubo ye-Hcrt

Ngenxa yendima ebalulekileyo ye-Hcrts ebuthongweni kunye nezinye iingxaki ze-neurological, iinkampani ezininzi zamayeza zizame ukuphuhlisa ii-arhente ukujolisa inkqubo ye-Hcrt. kwi vivo [49]. Oyena mchasi we-Hcrt osetyenziswa rhoqo kuncwadi ngu-SB-334867 [50]. Lo mchasi unokutofwa ngokwenkqubo kwaye abuyisele umva ukubopha i-Hcrtr-1, nangona ingacacanga ukuba ichaphazela ukubopha kwe-Hcrtr-2 ngokunjalo. I-SB-334867 isetyenziswe kwiindawo ezininzi in vitro izifundo ze-Hcrt neurons kodwa nangaphezulu kwe-100+ kwi vivo izifundo, ukucacisa indima ye-Hcrts kwindlela ezininzi zokuziphatha kubandakanya ukutya, ukulala, uxinzelelo, kunye nokuba likhoboka.

Umchasi omtsha we-Hcrt receptor, ACT-078573 ("Almorexant") [51], inokulawulwa ngomlomo, inqumla ngokukhawuleza isithintelo segazi-ingqondo, kwaye ivimbela ngokuphindaphindiweyo zombini ii-receptors ze-Hcrt ezinobudlelwane obuphezulu. Mhlawumbi okona kubaluleke nangakumbi, kulingo lokuqala le khompawundi ayivezi cataplexy (nangona kunokuxelwa kwangaphambili ukusuka kumchasi osebenzayo kuzo zombini ii-receptors ze-Hcrt), iyenza ibe lithemba elivuyisayo lonyango lokuphuthelwa. Ke, i-ACT-078573 iya kuba ngumxholo wophononongo oluninzi lwexesha elizayo, zombini kwibhentshi yelebhu kunye naseklinikhi.

Okwangoku akukho zi-agonists ze-Hcrt ezinamandla ezinokusetyenziswa kwi vivo ngaphandle kweepeptides ezimbini zeHcrt ngokwazo. Kuphando lwezilwanyana, ezi peptides zihlala zitofwa ngokuthe ngqo kwimimandla yobuchopho okanye itofwe nge-intracerebroventricularly kwinkqubo ye-ventricle yengqondo. Nangona kunjalo, kubantu nakwizilwanyana, i-Hcrt peptides ayisebenzi xa itofwe ngokwenkqubo [52]. Ke ngoko, iimpawu ze-narcolepsy okanye i-cataplexy zihlala ziphathwa kusetyenziswa iikhompawundi ezijolise kwezinye iinkqubo zokuvuselela ingqondo. Ngokomzekelo, i-Modafinil ivunyiwe yi-FDA yonyango lwe-narcolepsy kunye nezinye iingxaki zokulala. Le khompawundi yokukhuthaza ukuvuka mhlawumbi inqanda umthuthi we-dopamine, kodwa eyona ndlela yokusebenza ayaziwa [52].

Ngenxa yeendima ezisandula ukufunyanwa zenkqubo ye-Hcrt ekutyeni, ekusetyenzweni komvuzo, uxinzelelo, ukuphaphama, kunye nokudakumba, kuyahenda ukucinga ukuba ukulawulwa kwenkqubo ye-Hcrt kunokuba luncedo kunyango lweziphazamiso ezinjengokutyeba, ukuba likhoboka leziyobisi, ixhala, ingqalelo-deficit disorder, okanye ukudakumba. Ubuncinci ezinye zezi zikhetho zonyango ezinokubakho ngoku zinokwenzeka, ngokunikezelwa kophuhliso lwe-Hcrt entsha kunye ne-Hcrt receptor antagonists echazwe ngasentla.

Indima ebalulekileyo ye-hypocretins ekuzinzeni kokuvusa

Ubungqina obuninzi bubonisa ukuba i-Hcrts ikhuthaza kwaye igcine ukuphaphama, njengoko kuchazwe ngokucokisekileyo kolunye uphononongo oluhle kakhulu [6-7,13]. Ubungqina obuninzi buvela ekufunyanisweni kwasekuqaleni ukuba ukonakala kwenkqubo ye-Hcrt kubangela ukuphazamiseka kokulala kwe-narcolepsy kwiimpuku, izinja kunye nabantu [1-5]. Uninzi lwe-narcoleptics yabantu luye lwehla amanqanaba e-Hcrt kulwelo lwe-cerebrospinal, kwaye uhlalutyo lwe-postmortem lubonisa ukuncitshiswa kwe-Hcrt neurons kwingqondo yomntu ye-narcoleptic [4,5]. Okubangel 'umdla kukuba, inkqubo ye-Hcrt nayo iyimfuneko ekuveleni okuqhelekileyo kwi-anesthesia jikelele [16]. Inaliti ye-Intracerebroventricular (icv) ye-Hcrt1 kunye/okanye i-Hcrt2 yonyusa ixesha elichithwe liphapheme kwaye linciphise ixesha elichithwe kwi-slow-wave kunye ne-REM yokulala kwiintlobo ngeentlobo ze-vertebrate [17-18]. Ngaphaya koko, ukuvuselela okwenziweyo kwe-Hcrt neurons kusetyenziswa isitishi se-cation esikhanyiselwe ukukhanya, i-channelrhodopsin-2, kwandisa amathuba okutshintsha ukusuka ebuthongweni ukuya ekuvukeni ngexesha lokulala okucothayo kunye nokulala kwe-REM.19]. Ke, ngoku kukho ubungqina obubambekayo bokuba ii-Hcrts ziyimfuneko ukuze zigcinwe kwaye zanele ukuphembelela ukuphaphama.

Eminye imisebenzi enokwenzeka yenkqubo ye-hypocretin

I-Hcrts ibandakanyeka kwimisebenzi emininzi yendalo ngaphandle kokugcina uphaphile. Umzekelo, elinye igama le-Hcrts, "i-orexins", latyunjwa ngenxa yokuba i-icv infusion ye-Hcrts yonyusa ukutya kwiimpuku [9]. Ezi ziphumo ngoku zithathwa njengempembelelo engathanga ngqo yeziphumo zokukhuthaza ukuvuka kwe-Hcrts, kodwa oku kuseyindawo esebenzayo yophando. I-Microinjection ye-Hcrts kwi-nucleus ye-arcuate ivuselela i-orexigenic GABAergic neurons kwaye inqanda i-anorexigenic ye-POMC-ebonisa i-neurons. I-Hcrts iphinda ithintele i-neurons kwi-hypothalamus ye-ventromedial, iziko le-satiety elisekiweyo [20]. Ke, ii-Hcrts zisebenza ngendlela ehambelanayo kwihomoni yokuhlutha i-leptin kwimimandla ebalulekileyo yamandla e-homeostatic ye-hypothalamus.

Kutshanje, indima enomdla ye-Hcrts isekiwe ekufuneni umvuzo kunye nokuba likhoboka. Ukusebenza kwe-Hcrt neurons kunxibelelene neempawu ezinxulumene neziyobisi kunye nomvuzo wokutya. Ukukhuthazwa kwe-Hcrt neurons okanye i-microinjection ye-Hcrt1 kwi-VTA okanye i-ventricles ibuyisela ukuziphatha okucinywayo kwangaphambili kokufuna iziyobisi, kwaye ezi ziphumo zivaliwe ngumchasi we-Hcrtr-1 [21,22]. Ezi zifundo zeseminal ziye zavusa iqumrhu elikhula ngokukhawuleza lophando eliqinisekisa ngokuphindaphindiweyo i-Hcrts imodareyitha ukusetyenzwa komvuzo [23].

Izivuseleli ezonyusa ukuvuswa / ukuphaphama nazo zihlala zonyusa uxinzelelo kunye noxinzelelo. Ke ngoko, amandla e-Hcrts okukhuthaza ukuphaphama acebisa ukuba ezi peptides zinokudlala indima ekwandiseni iimpawu zokuziphatha kunye neyomzimba yoxinzelelo. Ukuxhasa le ngqikelelo, inaliti ye-icv ye-Hcrt1 yenza uninzi lweendlela zokuziphatha ezinxulumene noxinzelelo [17,24]. Ukonyuka komsebenzi we-Hcrt kukwanxulunyaniswa neenkqubo ezahlukeneyo zokuzimela ezinxulumene noxinzelelo, ezinjengokunyuswa koxinzelelo lwegazi oluphakathi, izinga lentliziyo, ukusetyenziswa kweoksijini, kunye nobushushu bomzimba.25-27]. Ngaphezu koko, iprojekthi ye-Hcrt ye-fibers kwi-corticotropin ekhupha into (CRF) i-neurons ngaphakathi kwe-nucleus ye-paraventricular (PVN) [28-29], i-neurons eyenza i-hypothalamus-pituitary-adrenal (HPA) i-axis yempendulo ye-organism kuxinzelelo. Ukusetyenziswa kwebhafu ye-Hcrt1 kubangela ukuchithwa kwepolarization kunye nokwandisa i-spike frequencies kwezi seli zeCRF [28]. Obu bungqina bucebisa ukuba ii-Hcrts zinokusebenzisana neenkqubo zeCRF ezisembindini ukuze kusebenze i-axis ye-HPA kunye nezinye iinkqubo ezinxulumene noxinzelelo.

Ukongeza kokutya, umlutha, kunye noxinzelelo, ii-Hcrts ziye zabandakanyeka kwiimodeli zokuhoya [30] kunye nokuziphatha ngokwesondo kwamadoda [31]. Ii-Hcrts ziye zacingelwa ukuba zidlala indima kwiimpawu ze-Parkinson's Disease [32], schizophrenia [33-34], kunye nokudakumba [35-36]. Lilonke, izifundo zenkqubo ye-Hcrt ziqhubele phambili ngaphaya kokufunyanwa kokuqala kokubandakanyeka kwe-Hcrts ebuthongweni nasekuvukeni. Ezi zifundo zicela lo mbuzo: Ii-Hcrts zinokudlala njani indima kuluhlu olunje lweendlela zokuziphatha ukusuka ekuphaphameni ukuya ekutyeni, ukuba likhoboka, uxinzelelo, ukuphaphama, kunye nokuziphatha ngokwesondo? Ngezantsi, sinikezela ngempendulo yokuqala kulo mbuzo.

I-Hypocretins: abalawuli be-arousal kunye ne-allostasis

Indima yenkqubo ye-hypocretin ekukhuthazeni ukuphaphama idla ngokuchazwa njengendima “ekuvuseleleni inkanuko yesini.” Ukuvuswa okuqhelekileyo kuphawulwa kukonyuka kwentshukumo yemoto kunye nokusabela okuphakamileyo kwimvakalelo kunye nesivuseleli esinamandla ngokweemvakalelo [37-40]. Okungagxininiswa kaninzi, nangona kunjalo, kukuba iinkqubo zokuvuselela zibandakanyeka kakhulu kunokulawula nje imijikelo yokulala / yokuvuka, njengokuphaphama, ukuxhalaba, kunye neempawu zokuphazamiseka kwengqondo okuninzi [41]. Okubalulekileyo, izakhiwo zobuchopho ezibandakanyekayo ekuvukeni ngokubanzi, kubandakanywa ukubunjwa kwe-reticular ye-medulla kunye neepons, i-midbrain, kunye ne-paraventricular, i-dorsomedial, kunye ne-lateral hypothalamic nuclei [42], fumana uqikelelo kwi-Hcrt neurons. Sicebisa ukuba ukuba ii-Hcrts zinokumodareyitha le nethiwekhi yokuvuselela, ziyakwazi ukulungelelanisa izimilo ezicwangciswe yile nethiwekhi. Ngokuxabisa indima evuselelayo eyaziwayo njengedlalayo kwizinto ezinjalo zokuziphatha ezifundwe ngaphandle kwendawo yokulala, abaphandi banokukwazi ukwenza inoveli ekhulayo kodwa ingqikelelo ethile malunga nomsebenzi we-Hcrts ekuziphatheni okungalaliyo. Ngokomzekelo, iingxelo zamva nje ukuba i-Hcrts imodareyitha ukuziphatha kwiimodeli ze-murine zokudakumba [35-36] iyaqondakala kwaye ilindeleke kwiminyaka yophando lwengqondo ebonisa ukuba ukuvuselela ukuvuswa kuphazamisekile kubantu abanokudakumba [43].

Ii-Hctrs zibonakala zineempembelelo zazo ezinkulu xa kufuneka uvukelo ukulawula uxinzelelo olusisiseko lwe-homeostatic njengendlala, ixhala, okanye ukuqhubela phambili ngesondo. Ke ngoko, sicebisa ukuba ii-Hcrts zibaluleke kakhulu kwi-allostasis. Ngokwahlukileyo kwi-homeostasis, i-allostasis igcina uzinzo kumanqanaba angaphandle koluhlu oluqhelekileyo kwaye iphunyezwa ngokutshintsha imeko yangaphakathi ukuze ihambelane neemfuno eziqikelelwayo zokusingqongileyo.44,45]. Umzekelo, qwalasela uphononongo lwamva nje oluvavanya iziphumo zokuthintelwa kweekhalori kuxinzelelo kunye nokudakumba [46]. Umsebenzi odibanisa uxinzelelo kunye nokudakumba ubonisa ukuba iimpuku ze-preprohypocretin ezinkqonkqozayo kunye neempuku ze-Hcrt neuron-ablated zibonisa iimpendulo ezincitshisiweyo zoxinzelelo kuxinzelelo olubukhali kunye nolungapheliyo [47]. Nangona kunjalo, ezinye iimpendulo zoxinzelelo ziyagcinwa, zombini kuxinzelelo olunzima olubangelwa luvavanyo lokuqubha olunyanzelwayo kunye noxinzelelo olungapheliyo olubangelwa kukoyiswa okungapheliyo kwentlalo. Olu xinzelelo lubangela iimpawu zokudakumba [46]. Okubangel 'umdla, phantsi koxinzelelo lwe-allostatic, ii-Hcrts zinokunqanda iimpawu zokudakumba ezibangelwa kuxinzelelo, ukubuyisela ulawulo "lwe-homeostatic" lokuvusa ingqondo. Iimpuku ezinomlinganiselo wekhalori ziqhuba ngcono kuvavanyo lokuqubha ngenkani (ziba nexesha elide lokushukuma kunye nokungashukumi ngokupheleleyo) kwaye azibonakalisi ntsilelo kwintsebenziswano yoluntu xa kuthelekiswa no. ad adum-ezondliwe iimpuku. I-Hcrt null mice ayibonisi nanye kwezi zibonelelo zothintelo lwekhalori. Ngapha koko, inani le-c-Fos positive Hcrt neurons elenziwe sisithintelo sekhalori linxibelelana ngamandla nophuculo kuvavanyo lokusebenzisana kwentlalo [46]. Oku kuphakamisa ukuba i-Hcrt neurons idibanisa impendulo yoxinzelelo oluqhelekileyo lwe-allostatic kwisithintelo sekhalori esivumela isilwanyana ukuba soyise iimpawu zokudakumba ezibangelwa luxinzelelo olungapheliyo. Ngokufanayo, nangona ii-Hcrts zingakukhuthazi ukutya phantsi kweemeko eziqhelekileyo, kwiimeko zokuthintelwa kweekhalori, ii-Hcrts ziyimfuneko ekunyukeni okuguquguqukayo kwindlela yokuziphatha elindelekileyo.48]. Olu phononongo lubonisa ngakumbi ukuba i-Hcrt neurons idibanisa utshintsho lwe-allostatic kwindlela yokuziphatha, kule meko iqinisekisa ukuba izilwanyana ziya kuvuka kwaye zikhuthazeke ukuba zifumane ukutya ngexesha elilinganiselweyo elikhoyo. Nangona uphando olungakumbi lufunekayo ukuqonda imisebenzi ye-Hcrts kwiindidi ezahlukeneyo zemingeni yokusingqongileyo, le mizekelo ibonisa indlela imisebenzi ye-physiological ye-Hcrts iya kutyhilwa ngayo ngokupheleleyo xa sixabisa indima ye-Hctrs kwi-homeostasis kunye ne-allostasis.

izigqibo

Kwiminyaka elishumi emva kokufunyanwa kwabo, sifunde okuninzi malunga nenkqubo ye-Hcrt yobuchopho. Ewe, indima ye-Hcrts ekukhuthazeni ukuphaphama ayinakuphikiswa. Olu phononongo lucebisa isakhelo sokucinga malunga nendima eqhelekileyo ye-Hcrts kwezinye iindlela zokuziphatha ngokunjalo. Nangona uphando olongezelelweyo lufunekayo ukucacisa imisebenzi echanekileyo ye-Hcrts, mhlawumbi indima yenkqubo ye-Hcrt iya kuthakazelelwa ngokupheleleyo kumxholo we-homeostasis ye-organism kunye ne-allostasis. Ngomfanekiso omtsha ophucukileyo kunye nobuchwepheshe be-optogenetic, iminyaka elishumi ezayo ngokungathandabuzekiyo iya kuqulatha inkqubela phambili ekuqondeni kwethu le nkqubo inomdla yokuvuselela ingqondo.

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Ibhokisi 2

Imibuzo engaphendulwanga malunga nenkqubo ye-hypocretin

  • Ngaba kukho ulwahlulo olusebenzayo ngaphakathi kweenuclei zeHcrt? Kuye kwacetyiswa ukuba kukho ubuncinci abantu ababini abasebenzayo be-Hcrt neurons: abantu abasecaleni abadlala indima ekutyeni nasekukhobokeni, kunye nabemi abaphakathi abadlala indima ekuvuseleleni kunye noxinzelelo [53]. Izifundo zexesha elizayo ziyafuneka ukuvavanya le ngcamango.
  • Ngaba ii-receptors ezimbini ze-Hcrt zilawula ngokwahlukeneyo imisebenzi yomzimba kunye nokuziphatha? Ngaba zombini ziyimfuneko ekulawuleni ukuziphatha, okanye ngaba i-receptor enye yanele?
  • Ngaba i-Hcrt neurons ikhuthaza ukuphaphama ngokuqikelela iindawo ezininzi engqondweni, okanye nje iindawo ezimbalwa eziphambili zee-neurons? Iimodeli ezininzi zokulala/ukuvuka kokujikeleza, okufana neflip/flop imodeli yokulala, icebisa ukuba iHcrt iphucula imeko ephaphileyo ngokukrola kwamanye amaziko avuselelayo anjengeLC, TMN, kunye nedorsal raphe nuclei [7]. Nangona kunjalo, izilonda zale nuclei azikhokeleli kwi-phenotype eyomeleleyo kwaye ukuphaphama okuqhelekileyo kugcinwa, nangona zonke ezi nuclei zikhutshwe kwisilwanyana esinye [54]. Ke, iisayithi ze-postsynaptic eziyimfuneko ukulamla isenzo se-Hcrt neurotransmission ayikacaci.
  • Loluphi uxinzelelo lwe-allostatic oluyimfuneko okanye olwaneleyo ukuqhuba ukuvuswa kwe-Hcrt-mediated? Uxinzelelo lokusingqongileyo luguqulela njani ekubeni kusebenze inkqubo yeHcrt?

Imibulelo

I-MEC kunye ne-JSB zixhaswa ngamaBhaso oBudlelwane boPhando lweSidanga kwiNational Science Foundation. I-MEC ikwaxhaswa yiMbasa yeNkonzo yoPhando yeSizwe evela kumaZiko ezeMpilo eSizwe. I-LdL ixhaswa zizibonelelo ezivela kwiZiko leSizwe lokuSetyenziswa gwenxa kweZiyobisi, iDARPA kunye neNARSAD.

Ucaphulo

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