COMMENTS: Eric Nestler ya ba da cikakken bayani game da DeltaFosB da buri. (Hasari an gano hakan.) A taƙaice, DeltaFosB ya tashi a cikin ladan sakamako saboda yawan shan kwayoyi na zagi da wasu lada na halitta. Manufarta ta juyin halitta shine don samun sa yayin samin mai kyau (abinci da jima'i) - ma'ana, wayar da kan cibiyar lada. Koyaya, sifofin al'ada na al'ada na ladabi na iya haifar da yawan amfani da tarin DeltaFosB… da canjin kwakwalwa wanda ke haifar da ƙarin sha'awa da ƙarin binging. Abin sha'awa, matasa suna samar da DeltaFosB fiye da manya, wanda shine dalili guda daya da yasa suka fi saurin kamuwa da jaraba.
10.1098 / rstb.2008.0067 Phil. Trans. R. Soc. B 12 Oktoba 2008 Vol. 363 ba. 1507 3245-3255
+ Mawallafin Aboki Ma'aikatar Neuroscience, Dutsen Sinai Sinai School of Medicine
New York, NY 10029, Amurka
Abstract
Dokar bayyana jinsi ana ɗaukarta a matsayin hanyar da za a iya amfani da ita don shan kwayar, saboda ba da daidaituwar halayen halayen da ke ba da ma'anar yanayin jaraba. Daga cikin abubuwanda aka rubuta da yawa waɗanda aka sani da tasirin tasirin jaraba, ɗayan mafi kyawun halin shine ΔFosB, wanda ke haifar da shi a cikin yankuna lada na ƙwaƙwalwa ta hanyar bayyanar da ci gaba ga kusan dukkanin magungunan zagi da kuma maganganun da aka ba da sanarwa game da tasirin magani. Tunda ΔFosB shine gina jiki mai gina jiki sosai, yana wakiltar wata hanyar da kwayoyi ke haifar da canje-canje a cikin jinsin bayanan bayan an gama amfani da miyagun ƙwayoyi. Binciken ya fara nazarin hanyoyin da kwayoyin halitta suka tsara ta hanyar da ΔFosB ke tsara jigilar kwayoyin halitta kuma ya haifar da tasirinsa. Muna gabatowa wannan tambaya ta amfani da bayanan DNA da aka hada tare da nazarin gyaran gyara na chromatin-canje-canje a cikin gyare-gyare na tarihi a masu amfani da kwayoyin halitta-don gano kwayoyin da aka sanya ta hanyar yin amfani da magunguna ta hanyar shigar da ΔFosB da kuma samun basira a cikin cikakkun hanyoyin da suka shafi kwayoyin halitta. Abubuwan da muka gano sun kafa tsarin gyaran chromatin a matsayin wani muhimmin mahimmancin tsari wanda ke haifar da fizikancin hali, da kuma alkawarinsa don bayyana sabon fahimta game da yadda ΔFosB ke taimakawa wajen farfadowa ta hanyar tsara tsarin ƙayyadaddun kwayoyin halitta a cikin hanyoyi na ladabi.
1. Gabatarwa
Binciken abubuwan da ake amfani da su akan jita-jita ya danganci ra'ayin cewa ka'idar furcin kalma wata hanya ce mai mahimmanci ta hanyar yin kwaskwarima ga miyagun ƙwayoyi wanda ke haifar da canje-canje a cikin kwakwalwa, wanda ke haifar da halayen halayen da ke ƙayyade yanayin jiji (Nestler 2001). Wani bayani game da wannan tsinkaya shi ne cewa canje-canje na kwayar cutar da aka yi a cikin kwakwalwa na wasu kwayoyin halitta neuronal a cikin kwakwalwa, wanda aka haɗu da wani mutum wanda ya kamu da shi, an sasanta shi a wani ɓangare ta hanyar canje-canje a fannin nunawa.
Aiki a cikin shekaru 15 da suka gabata ya ba da ƙarin shaida game da rawar nuna kwayar halitta a cikin jarabar shan kwayoyi, kamar yadda yawancin abubuwan rubuce-rubuce - sunadaran da ke ɗaure da takamaiman abubuwan amsa a cikin yankuna masu tallata kwayoyin halitta da kuma tsara maganganun kwayoyin - an shigar dasu cikin aikin magani. Misalai masu kyau sun hada da ΔFosB (Fos family protein), FAMP-mayar da martani mai gina jiki (CREB), CAMP mai saukewa na farko (ICER), kayan aiki na yin aiki (ATFs), farkon sunadarai masu amsawa (EGRs), 1 (NAC1) ), nukiliya factor κB (NFBB) da kuma glucocorticoid receptor (O'Donovan et al. 1999; Mackler et al. 2000; Ang et al. 2001; Deroche-Gamonet et al. 2003; Carlezon et al. 2005; Green et al. 2006, 2008). Wannan bita ya mayar da hankali kan ΔFosB, wanda ya bayyana yana taka muhimmiyar rawa a cikin tsarin jaraba, a matsayin wata hanya ta kwatanta nau'o'in gwajin gwaje-gwaje da aka yi amfani dasu don bincika abubuwan da ake amfani da su a cikin fassarar.
2. Rigar da ΔFosB a tsakiya ya kara da kwayoyi masu cin zarafi
ΔFosB an sanya shi ta hanyar fosB gene (siffar 1) da kuma haɗin kamfanoni tare da wasu dalilai na Fos na iyali, waɗanda suka hada da C-Fos, FosB, Fra1 da Fra2 (Morgan & Curran 1995). Wadannan sunadarai na iyali da suka hada da sunadaran iyali na Jun (c-Jun, JunB ko JunD) don samar da abubuwan da ke ɗaukar nauyin abubuwan da ke ɗaukar AP-1 (yarjejeniyar rikice-rikice: TGAC / GTCA) a cikin masu tallafawa wasu kwayoyin don tsara fassarar su. Wadannan sunadarai na Fos suna haifar da hanzari da sauri a wasu yankunan ƙwayoyin kwakwalwa bayan da aka yi amfani da magungunan magunguna da dama (siffar 2; Graybiel et al. 1990; Young et al. 1991; Fata da al. 1992). Wadannan martani ana ganin su ne mafi kyau a cikin ƙananan ƙwayoyin cuta da kuma dorsal striatum, waɗanda ke da mahimmanci masu jarrabawar aikin da ake yi da kuma aikin locomotor na kwayoyi. Dukkan wadannan sunadarai Fos na iyali, duk da haka, suna da karfin gaske kuma suna komawa matakan basal a cikin sa'o'i na gwamnatin miyagun ƙwayoyi.
Figure 1
Tushen biochemical na ΔFosB na musamman kwanciyar hankali: (a) FosB (338 aa, Mr kimanin. 38 kD) da (b) ΔFosB (237 aa, Mr kimanin. 26 kD) an tsara shi ta hanyar asalin fosB. GeneratedFosB ana samar dashi ta hanyar sauyawa dabam kuma bashi da amino acid C-terminal 101 wanda yake cikin FosB. Hanyoyi guda biyu sanannu ne don asusun ΔFosB. Na farko, ΔFosB ba shi da yanki guda biyu na degron da ke cikin C-terminus na cikakken FosB (kuma ana samun su a cikin sauran sauran sunadarai na Fos suma). Ofaya daga cikin waɗannan yankuna masu haɓaka suna ƙaddamar da FosB don yaduwa da lalacewa a cikin proteasome. Sauran yankin degron sunyi niyyar lalacewar FosB ta hanyar ubiquitin- da kuma tsari mai zaman kansa na proteasome. Abu na biyu, ΔFosB shine phosphorylated by casein kinase 2 (CK2) kuma mai yiwuwa wasu protein kinases (?) A N-terminus dinsa, wanda ya kara inganta protein din.
Figure 2
Tsarin da ke nuna jigilar ΔFosB a hankali tare da saurin haɓakawa da kuma cigaba da haifar da wasu sunadarai Fos na iyali saboda maganin magunguna. (a) Rukunin autoradiogram ya kwatanta bambancin shigarwa da sunadarai na Fos a cikin kwayar da ke ƙarfafawa ta hanyar ƙarfin zuciya (1-2 hours bayan an kwantar da shi daya daga cikin cocaine) tare da rawar jiki (1 ranar bayan an nuna shi a lokaci daya). (b) (i) Yawancin raƙuman ruwa na sunadarin Fos iyali (ciki har da C-Fos, FosB, ΔFosB (33 kD isoform), da kuma yiwu (?) Fra1, Fra2) ana haifar da su a cikin ƙananan ƙwayoyin cuta da kuma dorsal stronatal neurons ta hanyar kula da miyagun ƙwayoyi na zagi. Har ila yau an jawo shi a matsayin gyaran ƙaddara na ΔFosB (35-37 kD); an jawo su a ƙananan matakan ta hanyar gwamnatin miyagun ƙwayoyi, amma suna ci gaba da kwakwalwa saboda dogon lokaci saboda kwanciyar hankali. (ii) Tare da magungunan miyagun ƙwayoyi (misali sau biyu a kowace rana), duk wani karamin motsi yana haifar da matakin ƙananan ƙa'idodin ΔFosB. Ana nuna wannan ta hanyar ƙananan layi na layi waɗanda ke nuna cewa ΔFosB ya haifar da kowane abu mai mahimmanci. Sakamakon hakan shine karuwa a hankali a cikin jimlar ΔFosB tare da maimaita matsalolin yayin da ake kula da su. An nuna wannan ta hanyar layi mai zurfi a cikin zane.
Ana nuna bambancin ra'ayi daban-daban bayan da na ci gaba da yin amfani da kwayoyi na cin zarafi (siffar 2). Shirye-shiryen na ΔFosB (Mr 35-37 kD) suna tara a cikin ɗakunan kwakwalwa guda bayan an nuna magungunan miyagun ƙwayoyi, yayin da duk sauran iyalin Fos suna nuna haƙuri (watau rage yawan inuwa idan aka kwatanta da asibitoci na farko; Chen et al. 1995, 1997; Hiroi et al. 1997). Irin wannan jigilar ΔFosB an lura dashi kusan dukkanin magunguna na zalunci (Table 1; Fata da al. 1994; Nye et al. 1995; Moratalla et al. 1996; Nye & Nestler 1996; Pich et al. 1997; Muller & Unterwald 2005; McDaid et al. 2006b), kodayake kwayoyi daban-daban sun bambanta da wani abu a cikin matakan da aka gani a cikin ginshiƙan tsakiya da kuma dorsal striatum (Perrotti et al. 2008). Aƙalla ga wasu magungunan zalunci, shigar da ΔFosB ya nuna zaɓuɓɓuka don ɓangaren samfurori na dynorphin wanda ke da ƙananan igiyoyi waɗanda ke cikin sassan kwakwalwa (Nye et al. 1995; Moratalla et al. 1996; Muller & Unterwald 2005; Lee et al. 2006), ko da yake an bukaci ƙarin aiki don kafa wannan da tabbacin. Kayan tsari na 35-37 kD na ΔFosB sun cika yawanci tare da JunD don samar da matakan AP-1 mai aiki da dindindin a cikin waɗannan sassan kwakwalwa (Chen et al. 1997; Hiroi et al. 1998; Pérez-Otao et al. 1998). Kwayar maganin ΔFosB a cikin ƙananan ƙwayoyin cuta shine alama ce ga magungunan kwayoyin magungunan miyagun ƙwayoyi ta hanyar da ba su da dangantaka da ciwon magungunan ƙwayoyi, tun da dabbobin da ke kula da maganin sankarar jiki ko karɓar maganin miyagun kwayoyi sun nuna daidai ƙaddamar da wannan factor a cikin wannan kwakwalwa yankin (Perrotti et al. 2008).
Table 1
Magungunan ƙwayoyi da aka sani suna haifar da ΔFosB a cikin ƙananan ƙwayoyin cuta bayan ci gaba da mulki.
| opiatesa |
| hodar Iblisa |
| amphetamine |
| methamphetamine |
| nicotinea |
| ethanola |
| phencyclidine |
| cannabinoids |
· ↵wani Induction ya ruwaito game da miyagun ƙwayoyi da aka yi amfani da shi kai tsaye ga magungunan bincike. An gabatar da kwayar cutar ta ΔFosB a dukkanin berayen da mice, sai dai wadannan: linzamin kwamfuta kawai, cannabinoids; rat kawai, methamphetamine, phencyclidine.
T35-37 kD ΔFosB kamfanoni sun haɗu tare da maganin miyagun ƙwayoyi na yau da kullum saboda mummunan rayuka masu rai (Chen et al. 1997; Alibhai et al. 2007). Ya bambanta, babu wani shaida da nuna cewa ƴan ΔFosB ko kwanciyar hankali na mRNA an tsara ta ta hanyar miyagun ƙwayoyi. A sakamakon kwanciyar hankali, sabili da haka, furotin na ΔFosB yana ci gaba a cikin ƙananan hanyoyi don akalla makonni da yawa bayan mutuwar magunguna. Yanzu mun sani cewa wannan kwanciyar hankali ta kasance ne saboda dalilai biyu masu biyowa (siffar 1): (i) rashin wuri biyu na degron a cikin ΔFosB, wanda ke nan a C-finus na FosB cikakke da sauran sauran sunadaran Fos kuma sunyi amfani da wadannan sunadarai don raguwa da sauri kuma (ii) phosphorylation na ΔFosB a N-karshen by casein kinase 2 kuma watakila wasu sunadaran kinases (Ulery et al. 2006; Carle et al. 2007). Tyana da karfin kwancen kafa na ΔFosB yana samar da wani nau'i na kwayoyin halitta ta hanyar maye gurbin miyagun ƙwayoyi a fannin jinsin mutum zai iya ci gaba duk da tsawon lokaci na janyewar miyagun ƙwayoyi. Saboda haka, muna da shawarar cewa ayyuka na ΔFosB suna ci gaba da 'maye gurbin kwayoyin' wanda ke taimakawa wajen farawa sannan kuma ya kula da yanayin da ya kamu da shi (Nestler et al. 2001; McClung et al. 2004).
3. Matsayin ΔFosB a cikin tsakiya yana ci gaba da yin gyaran halayen halayyar maganganu na zalunci
Binciken cikin rawar da ΔFosB ke yi a maganin ƙwayar magungunan ƙwayoyi ya fito ne daga nazarin ƙwayoyin bitransgenic wanda za'a iya haifar da ΔFosB a cikin tsakiya da ƙananan dabbobi (dabbobi masu girma)Kelz et al. 1999). Mafi mahimmanci, waɗannan ƙuƙwan Mafi yawancin ΔFosB a cikin magungunan ƙwayoyin matsakaicin matsakaici na dynorphin, inda aka yi amfani da kwayoyi don haifar da sunadaran. Siffar kwaikwayon kwaikwayon na ΔFosB-overexpressing mice, wanda a wasu hanyoyi kama da dabbobin bayan m magani miyagun ƙwayoyi, an taƙaita a cikin Table 2. Mice nuna yawan haɓakar locomotor da aka yi don maganin cocaine bayan gwamnati mai tsanani da ci gaba (Kelz et al. 1999). Har ila yau, suna nuna yadda za a iya ingantaccen abin da ake samu na maganin cocaine da morphine a cikin gwajin yanayin da ake dashi.Kelz et al. 1999; Zachariou et al. 2006), da kuma kula da kai kan maganin maganin cocaine fiye da wadanda ba su da tsauri ΔFosB (Colby et al. 2003). Bugu da ƙari, ΔFosB overexpression a cikin tsakiya accumbens ƙara ƙaddamar da opiate jiki dogara da inganta na opiate analgesic haƙuri (Zachariou et al. 2006). Ya bambanta, ΔFosB-bayyana ƙuƙwanci na al'ada ne a wasu ƙananan yankuna, ciki har da ilmantarwa na sararin samaniya kamar yadda aka tantance a cikin mashin ruwa na Morris (Kelz et al. 1999).
Tsarin littattafai na jaraba: rawar ΔFosB
Table 2
Abubuwan da ke nunawa a kan ΔFosB shigarwa a dynorphin + neurons na tsakiya accumbens da dorsal striatuma.
| STIMULUS | PHENOTYPE |
| hodar Iblis | Yawan haɓaka locomotor masu girma ga gwamnati mai zurfi |
| Ƙara yawan haɗin locomotor zuwa gwamnati mai maimaitawa | |
| Ƙaunar da aka sanya a cikin ƙananan asara | |
| ƙara yawan karfin gwanin cocaine a ƙananan allurai | |
| Ƙara ƙarfafa motsa jiki a cikin tsari na ci gaba | |
| morphine | Ƙaramar wurin da aka ƙaddamar a yanayin ƙwayar magani |
| ƙãra karuwa na dogara da kuma janye jiki | |
| rage rahotannin farko na analgesic, haɓaka haƙuri | |
| barasa | ƙara yawan martani |
| ƙafafun yana gudana | Ƙara waƙa da ke gudana |
| sucrose | ƙara yawan ƙarfafawa ga tsarin sucrose a cikin tsari mai zurfi |
| babban mai | ƙara yawan maganganu kamar damuwar da aka yi kan janyewar abinci maras nauyi |
| jima'i | ƙara yawan halayen jima'i |
· ↵a Abubuwan da aka bayyana a cikin wannan tebur an kafa ne a kan rashin maganin ΔFosB a cikin micransgenic mice inda ake magana da ΔFosB zuwa dynorphin + ƙananan ƙananan ƙananan ƙwayoyin cuta da dorsal striatum; Ƙananan ƙananan ƙananan ΔFosB ana gani a hippocampus da kuma na gaba. A lokuta da dama, an gano siffar phenotype ta hanyar halayyar ΔFosB a cikin ƙananan ƙwayoyin cuta ta hanyar amfani da hanyar canzawa ta hanyar gwanin hoto.
Musamman mahimmanci na ΔFosB overexpression zuwa ƙananan ƙwayoyin cuta, ta amfani da hanyar canzawa ta hanyar sarrafawa ta kyamarar hoto, ya ba da cikakkiyar bayanai (Zachariou et al. 2006), wanda ke nuna cewa wannan yankin ƙwararren ƙwaƙwalwar zai iya lissafin samfurin phenotype da aka yi a cikin ƙwayoyin bitransgenic, inda aka bayyana ΔFosB a cikin dorsal striatum kuma zuwa ƙananan ƙwayar a wasu yankuna na kwakwalwa. Bugu da ƙari, da ke da ƙwayar magungunan ƙwararrun ƙwayoyi waɗanda ke dauke da ƙananan ƙwayoyin cuta a cikin ƙananan ƙwayoyin bitransgenic wadanda ba su nuna yawancin wadannan siffofi na al'ada, musamman sun hada da dynorphin + nucleus accumbens neurons a cikin wadannan abubuwa.
Ya bambanta da maganganu na ΔFosB, bayyanar da wani jinsin Yammacin mutun (ΔcJun ko ΔJunD) -nanan ayyuka a matsayin mai amfani da magungunan AP-1-wanda aka yi amfani dasu-ta hanyar amfani da ƙwayoyin bitransgenic ko hanyar sarrafawa ta hanyar bidiyo mai hoto yanayin halayen (Peakman et al. 2003; Zachariou et al. 2006). Tbayanan bayanan sun nuna cewa shigar da ΔFosB a cikin dynorphin dauke da matsakaiciyar ƙwayoyin cuta na ƙananan ƙwayoyin cuta yana ƙaruwa da ƙwarewar dabba ga hodar iblis da sauran magunguna na zagi, kuma yana iya wakiltar wata hanyar don ƙara tsinkayar fahimtar maganin.
Abubuwan ΔFosB zasu iya wucewa fiye da tsari na ƙwarewar miyagun ƙwayoyi ta hanyar yin halayyar al'amuran da suka shafi rikitarwa.. Mice da wahala mai tsanani ΔFosB aiki da wuya ga maganin cocaine kai tsaye a cikin raƙuman tsarin mulki na jiki, yana nuna cewa ΔFosB zai iya kula da dabbobin ga abin da ya dace da halayen cocaine kuma hakan zai haifar da haɓaka don sake dawowa bayan janyewar miyagun ƙwayoyi (Colby et al. 2003). ΔFosB-overexpressing mice kuma ya nuna inganta yanayin anxiolytic na barasa (Picetti et al. 2001), wani samfurin da aka hade tare da karuwa da barasa a cikin mutane. Tare, waɗannan binciken farko sun nuna cewa ΔFosB, baya ga karuwa da ƙwarewa ga magungunan zalunci, ya haifar da canje-canje na dabi'un da ke inganta halayyar miyagun ƙwayoyi, da kuma tallafawa ra'ayi, wanda aka bayyana a sama, cewa ΔFosB yana aiki ne a matsayin likitan kwayar cutar Jihar. Tambaya mai muhimmanci a cikin binciken yanzu shine idan ΔFosB haɗuwa a yayin yaduwar miyagun ƙwayoyi yana inganta dabi'un haɗin magungunan bayan an karbar lokaci, ko da bayan matakan ΔFosB sun sabawa (duba ƙasa).
4. Sakamakon ΔFosB a tsakiya ya kara da sakamakon lada
An yi amfani da ginshiƙan da aka yi amfani da shi a cikin al'ada ta hanyar yin gyaran amsoshin sakamakon ladabi, irin su abinci, abin sha, jima'i da zamantakewar zamantakewa. A sakamakon haka, akwai babban sha'awa ga wani rawar da ake ciki na wannan kwakwalwa a cikin abin da ake kira duniyar halitta (misali cin abincin jiki, caca, motsa jiki, da dai sauransu). Dabbobin dabbobin irin wannan yanayi suna iyakance; Duk da haka, mu da sauransu sun gano cewa matakan amfani da nau'o'in nau'o'in nau'o'in halitta yana haifar da haɗin ƙaddamarwa na 35-37 kD na ΔFosB a tsakiya na accumbens. An gani wannan bayan manyan matakan da ke motsi (Werme et al. 2002) da kuma bayan ci gaba da amfani da sucrose, abinci mai yawa ko jima'i (Teegarden & Bale 2007; Wallace et al. 2007; Teegarden et al. a latsa). A wasu lokuta, wannan shigarwa yana zaɓuɓɓuka don ragowar dynorphin + na ƙananan ƙwararren ƙwararru (Werme et al. 2002). Binciken da ba a iya haifarwa ba, bitransgenic mice da kuma hanyar canzawa ta hanyar kyamarar hoto sun nuna cewa rashin fahimta na ΔFosB a cikin ƙananan ƙwayoyin yana ƙara yawan kullun da kuma amfani da wadannan ladaran, yayin da rashin tsinkayar wani jinsin Yammacin Labaran ya yi aiki a gaban ketaret (Table 2; Werme et al. 2002; Olausson et al. 2006; Wallace et al. 2007). Wadannan binciken sun nuna cewa ΔFosB a cikin wannan kwakwalwa tana da hankali ga dabbobi ba kawai don ladan magani bane amma sakamakon ladabi, kuma zai iya taimakawa ga jihohi na buri.
5. Sakamakon ΔFosB a cikin tsakiya yana cike da damuwa mai tsanani
Idan aka ba da shaida mai zurfi cewa ΔFosB ya haifar da ciwon zuciya ta hanyar ci gaba da daukan kwayoyi da kuma ladabi, yana da ban sha'awa a lura cewa ΔFosB yana da karfi sosai a cikin wannan kwakwalwa bayan da wasu nau'i na matsaloli na yau da kullum, ciki har da damuwa da damuwa, damuwa marar damuwa da damuwa. zamantakewar al'umma (Perrotti et al. 2004; Vialou et al. 2007). Sabanin kwayoyi da sakamakon ladabi, duk da haka, ana ganin wannan shigarwa a cikin wannan kwakwalwar kwakwalwa saboda an lura da shi a cikin dynorphin + da kuma enkephalin + ragowar ƙananan maƙaurai. Shaidun farko sun nuna cewa wannan shigarwa na ΔFosB zai iya wakiltar wani amsa mai kyau, wanda zai taimakawa mutum ya dace da matsala. Wannan tsinkaya yana goyan bayan bayanan farko cewa rashin nuna bambanci na ΔFosB a cikin ƙananan ƙwayoyin cuta, ta hanyar amfani da inducible, mice bitransgenic ko canzawa ta hanyar sarrafawa ta hanyar hoto, yana yin maganin antidepressant kamar yadda ya kamata (misali cin nasarar zamantakewa, gwagwarmayar gwagwarmaya), yayin ΔcJun magana yana haifar da cututtuka-nau'i-nau'i-nau'i (Vialou et al. 2007). Bugu da ƙari, tsarin na yau da kullum na magungunan maganin antidepressant na yau da kullum yana da tasiri irin na damuwa da haɓaka ΔFosB a cikin wannan kwakwalwa. Yayin da ake buƙata aiki don tabbatar da waɗannan binciken, irin wannan tasirin zai dace da lura da hakan ΔFosB yana haɓaka ƙwarewar ladaran ladaran ƙwaƙwalwa kuma yana iya taimaka wa dabbobi shawo kan matsalolin damuwa. Abin sha'awa shine, wannan tasirin da ake yi na ΔFosB a tsakiya na accumbens yana kama da abin da aka nuna a kwanan nan don launin fata na periaqueductal wanda aka sanya ma'anar sakonnin ta hanyar danniya mai tsanani (Berton et al. 2007).
6. Kwayoyin da aka tsara don ΔFosB a cikin ƙananan accumbens
Tun da ΔFosB wani abu ne na ƙididdiga, zai yiwu ya samar da wannan siffar mai ban sha'awa mai ban sha'awa a cikin tsakiya ta hanyar ingantawa ko kuma maimaita bayanin maganganun sauran kwayoyin halitta. Kamar yadda aka nuna a siffar 1, ΔFosB wani samfuri ne mai ƙananan fosB wanda bai sami yawancin ƙungiyar kasuwanci na C-muni ba a cikin FosB mai cikakke amma yana riƙe da dimerization da DNA-daure yankuna. ΔFosB yana ɗaure ga iyalan gidan Yuni kuma sakamakon dimantaka yana ɗaukar shafukan AP-1 a cikin DNA. Wasu nazarin in vitro sun bayar da shawarar cewa saboda ΔFosB ba ta da yawancin ayyukan da ake gudanarwa, yana aiki ne a matsayin mai kula da aikin AP-1, yayin da wasu da dama sun nuna cewa ΔFosB zai iya kunna takardun karatu a shafukan AP-1 (Dobrazanski et al. 1991; Nakabeppu & Nathans 1991; Yen et al. 1991; Chen et al. 1997).
Amfani da maɓallinmu maras kyau, mice bitransgenic cewa ΔFosB ya fi tsauri ko magungunta na musamman ΔcJun, da kuma nazarin faɗar nunawa a kan kwakwalwan Abystrix, mun nuna cewa, a cikin ƙananan ƙwayoyin da ke cikin vivo, ΔFosB aiki na farko a matsayin mai aiki na ƙwaƙwalwa, yayin da yake aiki a matsayin repressor don ƙarami ƙarancin kwayoyin halitta (McClung & Nestler 2003). NiAbin takaici, wannan aikin daban na ΔFosB yana aiki ne na tsawon lokaci da digiri na magana na ΔFosB, tare da gajeren lokaci, ƙananan matakan da ke haifar da ƙarin danniya na danniya da kuma dogon lokaci, matakan da suka fi girma ya haifar da ƙarin kunnawa. Wannan ya dace da binciken cewa gajeren lokaci da kuma lokaci mai tsawo ΔFosB maganganu ya haifar da halayen kullun akan halayen: kalmar ΔFosB na ɗan gajeren lokaci, kamar maganganun ΔcJun, ya rage zafin zabi na cocaine, yayin da tsawon lokaci ΔFosB magana yana ƙara ƙin cocaine (McClung & Nestler 2003). Hanyar da ke da alhakin wannan matsawa a halin yanzu an gudanar da bincike; wani sabon abu mai yiwuwa, abin da ya kasance sananne, shine ΔFosB, a matakan da ya fi girma, na iya haifar da homodimers wanda ke kunna takardun AP-1 (Jorissen et al. 2007).
Yawancin jinsin ΔFosB an kafa su ta hanyar amfani da dan takara (Table 3). Ɗaya daga cikin gwargwadon rahoto shine GluR2, amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) mai karɓa mai sauƙi (Kelz et al. 1999). ΔFosB overexpression a cikin inducible bitransgenic mice Hakanan yana kara yawan fadin GluR2 a cikin ƙananan ƙwayoyin cuta, ba tare da an gani ba a kan wasu shafuka masu karɓa na AMAP glutamate subunits., yayin da ΔcJun magana ta kaddamar da ikon cocaine don daidaitawa GluR2 (Peakman et al. 2003). AP-1 ƙwayoyin da suka ƙunshi ΔFosB (kuma mafi mahimmanci JunD) sun ɗauka wani kamfani AP-1 da aka gabatar a cikin kamfanin GluR2. Bugu da ƙari kuma, GluR2 overexpression ta hanyar hanyar sarrafawa ta hanyar bidiyo mai hoto yana ƙara yawan sakamako na cocaine, kamar yadda aka yi tsawon lokaci ΔFosB overexpression (Kelz et al. 1999). Tun da tashoshin AMPA na GluR2 da ke dauke da tashoshi na AMPA suna da ƙananan haɗin kai idan aka kwatanta da tashoshin AMPA waɗanda ba su dauke da wannan ƙananan ba, haɗin cocaine- da kuma ΔFosB na GluR2 a cikin tsakiya na accumbens zai iya lissafi, akalla a wani ɓangare, don rage yawan abin da aka gani a glutamatergic wadannan ƙananan bayanan bayan sunadaran miyagun ƙwayoyi (Kauer & Malenka 2007; Table 3).
Misalan makasudin saiti na ΔFosB a cikin ƙananan haɓakaa.
| manufa | yankin kwakwalwa |
| ↑ GluR2 | rage hankali ga glutamate |
| ↓ dynorphinb | downregulation na k-opioid feedback madauki |
| ↑ Cdk5 | fadadawa na tsarin tafiyar dendritic |
| ↑ NFBB | faɗakarwa da tsarin tafiyar dendritic; tsari na hanyoyin rayuwa |
| ↓ c-Fos | Kwayoyin kwayoyin cutar daga dan kankanin sunadaran sunadaran iyali sun jawo hankalin ΔFosB lokaci-lokaci |
· ↵a Kodayake ΔFosB yana tsara maganganun halittu masu yawa a kwakwalwa (misali McClung & Nestler 2003), teburin yana lissafa ne kawai wadanda suke haduwa da a kalla uku daga cikin wadannan ka'idoji masu zuwa: (i) ya karu (↑) ko ya ragu (↓) bayyanawa akan ΔFosB wuce gona da iri, (ii) daidaito ko daidaitaccen tsari ta ΔcJun, babban mai hana mai hana rubuce-rubuce na AP-1, (iii) ΔFosB dauke da hadaddun AP-1 hade da shafukan AP-1 a yankin masu tallata kwayar halitta, kuma ( iv) ΔFosB yana haifar da irin wannan tasirin akan aikin mai tallata kwayar halitta a cikin vitro kamar yadda aka gani a cikin rayuwa.
· ↵b Duk da hujjar cewa ΔFosB ta kalli tsarin dynorphin a cikin miyagun ƙwayoyi (Zachariou et al. 2006), akwai wasu shaida cewa zai iya aiki don kunna jigilar kwayar halitta a wasu yanayi daban (duba Cenci 2002).
Table 3
Misalan makasudin saiti ga ΔFosB a cikin accumbensa tsakiya.
Wani nau'in ci gaba na dan ΔFosB wanda ke cike da dan takara shine da peptide opioid, dynorphin. Ka tuna cewa ΔFosB yana shawo kan ƙwayoyi masu cin zarafin musamman a cikin jinsunan halittar dynorphin a cikin wannan kwakwalwa. Magunguna na cin zarafi suna da tasiri masu tasiri a kan maganganun dynorphin, tare da ƙarawa ko ragewa gani dangane da yanayin da ake amfani dasu. Ƙungiyar dynorphin ta ƙunshi shafukan AP-1 kamar yadda suke, wanda zai iya ɗaukar ƙaddarar AP-1 mai suna ΔFosB. Bugu da ƙari, mun nuna cewa ƙaddamar da ΔFosB ya ɗauka furcin furcin dynorphin a cikin ƙwayar accumbens (Zachariou et al. 2006). Dynorphin ana tsammanin zai kunna masu karɓan masu amfani da v-opioid a kan VTA da kuma hana haɗin dopaminergic kuma don haka ya rage tsarin jayayya. (Shippenberg & Rea 1997). Hence, ΔFosB danniya game da maganganun dynorphin na iya ba da gudummawa ga haɓaka hanyoyin ladaran da aka haɗa ta wannan mahimmancin rubutun. Yanzu akwai hujja kai tsaye da ke tallafawa shigar da tasirin dynorphin danniya a cikin yanayin ΔFosB (Zachariou et al. 2006).
Shaidu na yanzu sun nuna cewa ΔFosB kuma ya kaddamar da nauyin c-fos wanda zai taimaka wajen haifar da kwayoyin halitta-daga shigar da wasu sunadaran iyali na Fos marasa gajeren lokaci bayan da aka nuna mummunar magani ga kamfanonin ΔFosB bayan an shawo kan miyagun ƙwayoyi-Cited a baya (Renthal et al. a latsa). Hanyoyin da ke da alhakin ΔFosB zubar da maganganun c-fos na da wuya kuma an rufe su a kasa.
Wata hanya da aka yi amfani dashi don gano nau'in kwayoyin halitta na ΔFosB ya auna yawan canjin da aka haifar da launin halitta wanda ya faru a kan rashin fahimta na ΔFosB (ko ΔcJun) a cikin ƙananan ƙwayoyin amfani da bayanan maganin DNA, kamar yadda aka bayyana a baya. Wannan tsarin ya haifar da gano yawan kwayoyin halittar da ΔFosB ya bayyana a cikin wannan kwakwalwa (Chen et al. 2000, 2003; Ang et al. 2001; McClung & Nestler 2003). TKu kwayoyin halittar da suka bayyana kamar za a haifar dasu ta hanyar ayyukan osFosB a matsayin mai rikodin rubutun sune kinase-5 (Cdk5) mai haɗin cyclin da mai haɗin P35 (Bibb et al. 2001; McClung & Nestler 2003). Cdk5 kuma ya haifar da cocaine na yau da kullum a cikin ƙananan ƙwayoyin cuta, wani tasiri ya kulle akan magana ta ΔcJun, kuma ΔFosB ya ɗauka kuma ya kunna ma'anar Cdk5 ta hanyar shafin AP-1 a cikin mai saka shi (Chen et al. 2000; Peakman et al. 2003). Cdk5 wani muhimmin manufa ne na ΔFosB tun lokacin da aka nuna magana ta hanyar haɗuwa da canje-canje a cikin tsarin phosphorylation da yawancin sunadaran synaptic ciki har da sassan mai karfin katako (Bibb et al. 2001), kazalika da ƙãrawa a cikin tsabar tsabar tsabar dindritic (Norrholm et al. 2003; Lee et al. 2006), a cikin ƙananan ƙwayoyin cuta, waɗanda suke haɗuwa da gwamnatin cocaine na yau da kullum (Robinson & Kolb 2004). Kwanan nan, tsarin da aka yi na Cdk5 a cikin mahaifa accumbens an danganta shi da nasaba da canje-canje a cikin halin halayen hawan cocaine (Taylor et al. 2007).
Wani ƙarin ΔFosB da aka gano ta hanyar amfani da microarrays shine NFBB. Wannan ƙididdigar motar ta haifar da shi ne a cikin ƙwayar cutar ta ΔFosB overexpression da cocaine na yau da kullum, an rufe shi ta hanyar ΔcJun magana (Ang et al. 2001; Peakman et al. 2003). Shaidun kwanan nan sun nuna cewa shigar da NFBB na iya taimakawa ga ikon hawan cocaine don haifar da ƙwayoyin dendritic a cikin ƙananan ƙwayoyin cuta (Russo et al. 2007). Bugu da ƙari, NFBB an saka shi a wasu cututtuka na methamphetamine a cikin yankuna masu sassaucin ra'ayi (Asanuma & Cadet 1998). Ganin cewa NFBB wani nau'i ne mai mahimmanci ga ΔFosB ya jaddada muhimmancin hanyoyin da ΔFosB ke ba da tasirin maganin cocaine a kan bayyanar nunawa. Saboda haka, baya ga kwayoyin da ΔFosB ya tsara ta hanyar via AP-1 shafukan yanar gizo a kan masu samar da jinsin, ΔFosB za a sa ran tsara wasu ƙarin kwayoyin ta hanyar canza tsarin NFBB da kuma yiwuwar sauran furotin na tsarin rubutu.s.
Hanyoyi na DNA sun samar da jerin ladaran wasu ƙarin kwayoyin halittar da ΔFosB zai iya niyya, kai tsaye ko kuma kai tsaye. Daga cikin wadannan kwayoyin akwai wasu masu karɓar sakonni, sunadarai da ke aiki a cikin ayyuka na farko da na postsynaptic, da dama na tashar tashoshi da magungunan sigina na intracellular, da sunadarin sunadarai na cytoskeleton neuronal da ci gaban kwayoyin halitta (McClung & Nestler 2003). Bugu da kari ana buƙatar aiki don tabbatar da dukkanin wadannan sunadarai masu yawa kamar yadda ake amfani da su ta hanyar ΔFosB da kuma tabbatar da muhimmancin rawar da kowace furotin ke takawa wajen yada labaran ƙwayoyin hankula da kuma halin halayen cocaine. Daga ƙarshe, ba shakka, zai zama mahimmanci don motsawa fiye da nazarin kwayoyin halittar kowane mutum zuwa ka'idojin kungiyoyi na kwayoyin halittar wanda aka tsara ka'idar da aka tsara don magance halin da ake ciki.
7. Ƙaddamar da ΔFosB a wasu sassan kwakwalwa
Tattaunawar har zuwa yanzu ya mayar da hankali ne kawai a kan ƙananan abubuwa. Duk da yake wannan babbar hanyar ladabi ce mai mahimmanci ga ayyukan hawan cocaine da sauran magungunan zalunci, wasu ƙananan ƙwayoyin kwakwalwa suna da mahimmanci a cikin ci gaba da kuma kula da jiha. Tambaya mai mahimmanci ita ce ko ΔFosB aiki a wasu sassan kwakwalwa fiye da ƙwayar ƙwayar cuta zai iya rinjayar magunguna. NiMista, yanzu akwai ƙarin shaida cewa shawo kan ƙwayoyin cuta da zubar da cututtuka suna haifar da ΔFosB a wurare da dama da ke cikin kwakwalwa wanda ke faruwa a bangarori daban-daban na masu shan magunguna.n (Nye et al. 1995; Perrotti et al. 2005, 2008; McDaid et al. 2006A,b; Liu et al. 2007).
Wani binciken da aka yi a kwanan nan yayi amfani dashi sosai idan aka kwatanta da ΔFosB a cikin wadannan sassa daban-daban na kwakwalwa a kan wasu magunguna daban-daban daban-daban na cin zarafi: cocaine; morphine; cannabinoids; da ethanol (Table 4; Perrotti et al. 2008). Dukkanin kwayoyi guda huɗu suna haifar da nau'in sakonnin da ke da nauyin haɓaka a cikin ƙananan ƙwayoyin cuta da ƙananan ƙwayoyin cuta da kuma a cikin ƙwayoyin cuta na farko, amygdala, hippocampus, tsakiya na tsakiya na stria terminalis da kuma tsakiya na tsakiya na ƙananan ƙafa na kwamandan baya. Cocaine da ethanol kadai suna jawo ΔFosB a cikin layi na waje, dukkanin kwayoyi sai dai don cannabinoids sukan haifar da ΔFosB a cikin launin fatar jiki na periaqueductal, kuma cocaine na da mahimmanci wajen haifar da ΔFosB a cikin kwayoyin cututtuka na gamma-aminobutyric acid (GABA) a cikin ƙananan ƙananan ƙananan kwakwalwa (Perrotti et al. 2005, 2008). Bugu da ƙari, an nuna morphine don jawo ΔFosB a cikin pallidum (McDaid et al. 2006A). A cikin waɗannan yankuna, ƙananan tsari ne na 35-37 kD na ΔFosB da suke tarawa tare da yaduwar miyagun ƙwayoyi na yau da kullum da kuma jurewa don dogon lokacin lokacin janyewa.
Table 4
Hada kwakwalwar yankuna masu kwakwalwa da ke nuna ΔFosB shigarwa bayan an daukaka kara zuwa magungunan wakilan magungunaa.
| hodar Iblis | morphine | ethanol | cannabinoids | |
| ƙananan accumbens | ||||
| core | + | + | + | + |
| harsashi | + | + | + | + |
| dorsal striatum | + | + | + | + |
| alamar pallidumb | n | + | n | n |
| kodin farkoc | + | + | + | + |
| labaran layi | + | - | + | - |
| medial septum | - | - | - | - |
| BNST | + | + | + | + |
| IPAC | + | + | + | + |
| hippocampus | ||||
| hakora hakora | + | + | - | + |
| CA1 | + | + | + | + |
| CA3 | + | + | + | + |
| amygdala | ||||
| tushe | + | + | + | + |
| Tsakiya | + | + | + | + |
| na tsakiya | + | + | + | + |
| periaqueductal launin toka | + | + | + | - |
| ƙananan yanki na yanki | + | - | - | - |
| nada janar | - | - | - | - |
· ↵Tebur ba ya nuna matakan dangin ΔFosB da wasu magunguna daban-daban. Dubi Perrotti et al. (2008) don wannan bayani.
· ↵b Ƙin sakamako na cocaine, ethanol da cannabinoids a kan ΔFosB shigarwa a cikin pralidum kwakwalwa ba a riga an yi nazarin ba, amma irin wannan shigarwa an lura da shi wajen amsa methamphetamine (McDaid et al. 2006b).
· ↵ΔFosB shigarwa ana gani a cikin wasu subregions na kodayake na farko, ciki har da infralimbic (na tsakiya na tsakiya) da kuma kobitofrontal cortex.
Babban manufar bincike na gaba shine gudanar da bincike, wanda ya kasance daidai da waɗanda aka bayyana a sama don ƙananan ƙwayoyin cuta, don yada siffofin da ke cikin kwakwalwa ta hanyar ΔFosB don kowane ɗayan kwakwalwa. Wannan yana wakiltar wani babban aiki, duk da haka yana da mahimmanci don fahimtar tasirin duniya na ΔFosB akan tsarin jaraba.
A kwanan nan mun yi wani mataki mai mahimmanci a wannan batun ta amfani da hanyar canzawa ta hanyar kyamarar kyamara don faɗakar da ayyukan ΔFosB a cikin wani canji na farfadowa na farko, watau, orbitofrontal cortex. Wannan yankin yana da karfi a cikin jaraba, musamman ma, don taimakawa ga impulsivity da compulsivity da ke nuna hali mai kamu (Kalivas & Volkow 2005). Abin sha'awa shine, ba kamar ginshiƙan ba ne wanda aka yi amfani da shi da kuma haɗin cocaine mai yalwata ya haifar da matakan da aka kwatanta da ΔFosB kamar yadda muka gani a baya, mun lura cewa mulkin mallaka na cocaine yana haifar da karuwar ΔFosB da yawa a cikin magungunan orbitofrontal cortex, yana nuna cewa wannan amsa zai iya kasancewa da alaka da abubuwan da ke tattare da gwamnatin miyagun ƙwayoyi. (Winstanley et al. 2007). Daga nan muka yi amfani da gwajin gwagwarmayar kula da hankali da kuma yanke shawara (misali lokutan sau biyar da gwajin gwagwarmaya) don sanin ko ΔFosB a cikin kodayyar orbitofrontal yana taimakawa wajen gyaran ƙwayoyin cuta a cikin cognition. Mun gano cewa maganin cocaine na kullum yana haifar da haɗin kai ga rashin tausayi wanda ya haifar da hawan cocaine. Cikakken maganin cutar ta hanyar hoto na ΔFosB a cikin wannan yanki ya haifar da lalacewar cocaine na yau da kullum, yayin da mummunar mummunan kwakwalwa mai cin gashin kai, ΔJunD, ya hana wannan karbar hali. Halittar DNA maganin ƙwaƙwalwar microarray sun gano matakan kwayoyin da dama wadanda ke haifar da wannan canji na hali, ciki har da haɓakar cocaine- da kuma ΔFosB a ƙididdigar karɓa mai karɓa na metabotrophic mutus na mGluR5 da GABAA mai karɓa da kuma abu P (Winstanley et al. 2007). Rashin rinjayar waɗannan da sauran makasudin ΔFosB na sakawa na bukatar ƙarin bincike.
Wadannan binciken sun nuna cewa ΔFosB yana taimakawa ga juriya don magance cocaine. Masu amfani da ke fama da haɗin kai ga cututtukan cocaine sun fi dacewa su zama kwakwalwa na cocaine, yayin da wadanda suka sami magungunan miyagun ƙwayoyi fiye da rikicewa a aikin ko makaranta ba su iya zama kamu ba. (Shaffer & Eber 2002). Tsayawa ga rushewar halayyar da cututtukan cocaine suke ciki a cikin cocaine-mutanen da ke jin dadi suna iya taimakawa wajen magance buri. Ta wannan hanyar, shigarwa ta ΔFosB a cikin asalin kobitofrontal zai iya inganta yanayin da ya kamu, kamar yadda ya yi a cikin ƙwayar da ake ciki a inda ΔFosB ke inganta jaraba ta hanyar inganta ƙwarewar sakamako da kuma motsa jiki na miyagun ƙwayoyi.
8. Tsarin halittu na ΔFosB
Har zuwa kwanan nan, duk nazarin ka'idojin rubutu a cikin kwakwalwa sun dogara da ma'aunin matakan mRNA mai ɗorewa. Misali, binciken esFosB kwayoyin halittar da suka hada da gano mRNA ta sama- ko gurguntawa akan ΔFosB ko verecJun wuce gona da iri, kamar yadda aka fada a baya. Wannan matakin bincike yana da matukar amfani wajen gano maƙasudin saiti don ΔFosB; Koyaya, yana da iyakantaccen asali don samar da haske game da hanyoyin da ke ciki. Maimakon haka, duk nazarin hanyoyin sun dogara da matakan in vitro kamar su ΔFosB haɗuwa da jerin masu gabatar da kwayar halitta a cikin gwajin canzawar gel ko tsarin ΔFosB na aikin mai gabatar da kwayar halitta a cikin kwayar halitta. Wannan ba shi da gamsuwa saboda tsarin tsarin rubutun ya nuna bambance-bambancen ban mamaki daga nau'in kwayar halitta zuwa nau'in kwayar halitta, ya bar shi kusan kwata-kwata ba a san yadda maganin zagi, ko ΔFosB, ke tsara takamaiman kwayoyin halittar sa a cikin kwakwalwa ba.
Nazarin ilimin halittar asalin halitta yana iya yiwuwa, a karo na farko, don matsawa ambulant mataki na gaba kuma kai tsaye a kan nazarin rubutun bayanan rubutu a cikin kwakwalwa na dabbobin dabba (Tsankova et al. 2007). Tarihi, lokaci ne epigenetics ya bayyana sassan da tsarin dabi'ar salula zai iya zama ba tare da canji a DNA ba. Mun yi amfani da wannan kalma mafi mahimmanci don haɗawa da 'daidaitaccen tsari na yankuna na chromosomal domin yin rajistar, sigina ko ci gaba da ayyukan da aka canza' (Bird 2007). Don haka, yanzu mun san cewa ayyukan ƙwayoyin halitta ana sarrafa su ta hanyar canjin yanayi (misali acetylation, methylation) na tarihi a cikin kusancin kwayoyin halittu da kuma ɗaukar nau'ikan kwaminis masu aiki dabam-dabam ko kuma masu kawo ƙarshen rubutun. Gwajin rigakafin Chromatin (ChIP) yana ba da damar yin amfani da wannan ƙwarewar ilimin ilimin halittar chromatin don ƙayyade yanayin kunna jinsi a cikin wani yankin kwakwalwa na dabba da aka yiwa magani da zagi.
Misalan yadda nazarin tsarin tsarin chromatin zai iya taimaka mana mu fahimci tsarin tsarin kwayoyin halitta na aikin cocaine kuma an bayar da ΔFosB a siffar 3. Kamar yadda aka bayyana a sama, ΔFosB zai iya aiki kamar yadda ya kamata a yi amfani da maƙalafi ko raguwa ta hanyar dogara da nau'in manufa da aka samu. Don samun fahimta a cikin waɗannan ayyukan, zamu bincika tsarin chromatin na jinsin wakilci guda biyu na ΔFosB, cdk5 wanda aka samo shi ta hanyar ΔFosB da c-fos wanda aka kaddamar a tsakiya. Tsare-tsaren kwarewa na Chromatin ya nuna cewa cocaine yana kunna hanyar cdk5 a cikin wannan kwakwalwa ta hanyar kwaskwarima: ΔFosB yana ɗaura zuwa kundin cdk5 sannan kuma ya sake samo histone acetyltransferase (HAT; wanda ya kasance acetylate a kusa da tarihi) da abubuwan SWI-SNF; dukkanin ayyuka suna inganta haruffa gizon (Kumar et al. 2005; Levine et al. 2005). Hawan cocaine na yau da kullum ya haɓaka histone acetylation ta hanyar phosphorylation da hanawa histocacetylases (HDAC; wanda ke da magunguna da kuma kare jini; Renthal et al. 2007). Ya bambanta, cocaine ta shafe kodin c-fos: lokacin da ΔFosB ke ɗaura zuwa wannan rukuni ya samarda HDAC da yiwuwar histone methyltransferase (HMT; wanda tarihi ne na methylate) kuma hakan ya hana kundin c-fos (siffar 3; Renthal et al. a latsa). Babban tambaya ita ce: menene ya tantance ko ΔFosB yana kunnawa ko kuma danniya da kwayar halittar jini lokacin da ya jingina ga mai gabatar da kwayar?
Figure 3
Tsarin halittu na ΔFosB. Wannan adadi ya kwatanta sakamakon da ya faru yayin da ΔFosB ke ɗaura zuwa wani nau'in da yake kunna (misali cdk5) a kan su (misali c-fos). (a) A mashaya na cdk5, ΔFosB recruits HAT da kuma SWI-SNF dalilai, wanda ya inganta karfin kunnawa. Har ila yau, akwai shaidun da ba za a cire HDACs ba (duba rubutun). (b) A bambanta, a mai gabatarwa na c-fos, ΔFosB recruits HDAC1 da kuma watakila HMTs wanda wakiltar bayyanar nunawa. A, P da M nuna tarihin acetylation, phosphorylation da methylation, bi da bi.
Wadannan nazarin farko na jinsin halittu na maganin ƙwayar maganin miyagun ƙwayoyi suna da ban sha'awa saboda sun yi alkawalin bayyana wani sabon bayani game da kwayoyin kwayoyin halitta wanda magungunan ƙwayoyi suke amfani da shi wajen tsara rikice-rikice na kwayoyin halitta a tsakiya da kuma sauran yankuna. Hada jigilar kalmomin DNA da ake kira ChIP a kan gwaji (inda canje-canje a tsarin tsarin chromatin ko takardun ƙididdiga da ke ɗaure za a iya nazarin gwargwadon tsari) zai haifar da ganewar kwayoyin magani da kuma ΔFosB da ƙari da yawa da ƙwarewa. Bugu da ƙari, ƙwayoyin halittu sune 'yan takara masu mahimmanci don yin jarrabawar tsakiyar tsinkar rayuwa a cikin yanayin kwari. Ta wannan hanyar, miyagun ƙwayoyi da kuma ΔFosB sun canza canje-canje na histone da gyaran asalin epigenetic suna samar da matakan yiwuwar wanda canjin canji zai iya jimre bayan da yaduwar miyagun ƙwayoyi ya ƙare kuma watakila ma bayan ΔFosB ya ɓata zuwa matakan al'ada.
9. Ƙarshe
Halin shigar da ΔFosB a cikin ƙwayoyin cuta yana ƙaruwa ta hanyar yawan ciwan kai ga lada na halitta, damuwa ko magungunan zagi yana haifar da kyakkyawan zato game da aikin yau da kullun na furotin a cikin wannan yankin kwakwalwa. Kamar yadda aka nuna a ciki siffar 2, akwai kyakkyawan matakin ΔFosB a cikin ƙananan ƙwayoyin cuta a ƙarƙashin yanayi na yau da kullun. Wannan na musamman ne ga yankuna masu ɗimbin yawa, kamar yadda ΔFosB ba shi da tabbas a wani wuri ko'ina cikin ƙwaƙwalwar ajiya. Muna tsammanin cewa matakan ΔFosB a cikin ƙananan ƙwayoyin cuta suna wakiltar karantawa daga bayyanar da mutum ga matsalolin motsin rai, na tabbatacce da mara kyau, haɗuwa akan ɗan lokaci mai tsawo wanda aka ba da kaddarorin na furotin. Bambancin bambance-bambance a cikin takamaiman salon salula na shigarwar ΔFosB ta hanyar bayar da lada tare da kauce wa rikicewa ba a fahimtarsu, kuma ana buƙatar ci gaba da aiki don haɓaka sakamakon aikin waɗannan bambancin. Muna kara tsammanin cewa yayin da matakan da suka fi ƙarfin motsa jiki suka haifar da ΔFosB a cikin ƙananan ƙwayoyin cuta, ana canza ayyukan jijiyoyin don su zama masu saurin lura da lada. Ta wannan hanyar, shigar da ΔFosB zai inganta ƙwaƙwalwar da ke da alaƙa (watau motsin rai) ta hanyar ayyuka masu ban sha'awa na ƙananan mahaifa. A karkashin yanayi na yau da kullun, shigar da matsakaiciyar matakan ΔFosB ta hanyar bada lada ko juya baya zai zama mai dacewa ta hanyar inganta dabbobin da suka dace da kalubalen muhalli. Koyaya, yawan shigar da ΔFosB da aka gani a ƙarƙashin yanayin cuta (misali yawan ci gaba da shan kwayoyi na zagi) zai haifar da ƙarancin fahimta na mahaɗan mahaɗan kuma yana taimakawa sosai ga halayen halayen cuta (misali neman ƙwayoyi masu tilastawa da shan su) hade da shan kwayoyi. ΔFosB shigar da shi a wasu yankuna na kwakwalwa zai yiwu ya ba da gudummawa ga fannoni daban-daban na halin maye, kamar yadda aka ba da shawara ta hanyar binciken kwanan nan na aikin osFosB a cikin kobitofrontal cortex.
Idan wannan tsinkaye daidai ne, yana nuna yiwuwar ban sha'awa cewa matakan ΔFosB a cikin ƙananan ƙwayoyin cuta ko wataƙila wasu yankuna na kwakwalwa ana iya amfani dasu azaman masanin kimiyyar halittu don kimanta yanayin kunna aikin lada na mutum, da kuma matakin da mutum yake yana 'kamu', duka yayin ci gaba da jaraba da raguwarta a hankali yayin tsawaita janyewa ko magani. Amfani da ΔFosB a matsayin alama ta yanayin jaraba an nuna a cikin samfurin dabbobi. Yaran dabbobi suna nuna yawancin shigarwa na ΔFosB idan aka kwatanta da dabbobi tsofaffi, daidai da matsananciyar damuwa ga jaraba (Ehrlich et al. 2002). Bugu da ƙari, ƙaddamar da sakamakon sakamako na nicotine tare da GABAB mai karɓar mai kwakwalwa mai haɗin gwiwa mai haɗin gwiwa yana hade da haɗuwa da nicotine shigarwa na ΔFosB a tsakiya acumbens (Mombereau et al. 2007). Ko da yake kwarewa sosai, yana tunanin cewa wani karamin kwayoyin PET ligand, tare da babban dangantaka da ΔFosB, za'a iya amfani dashi don taimakawa wajen gane zubar da hankali da kuma ci gaba a yayin jiyya.
A ƙarshe, ΔFosB kanta ko kowane ɗayan ƙwayoyin halittar da yake sarrafawa-wanda aka gano ta hanyar tsara maganganu na DNA ko ChIP akan gwajin gwaiwa-suna wakiltar maƙasudin maƙasudin ci gaban ƙwararrun magunguna na asali game da shan kwayoyi. Mun yi imanin cewa yana da mahimmanci a duba bayan magungunan gargajiya na gargajiya (misali masu karɓar siginar neurotransmitter da masu jigilar kayayyaki) don wakilan maganin magani don jaraba. Taswirar taswirar da ke cike da fasahar zamani wacce ke samar da kyakkyawar hanyar samar da irin wadannan sabbin abubuwan a cikin kokarin mu na mu'amala mafi kyau da kuma magance cutar jaraba.
Acknowledgments
Bayarwa. Marubucin ya ba da rahoto akan rikice-rikice na sha'awar shirya wannan bita.
Bayanan kalmomi
· Contributionaya daga cikin gudummawar 17 zuwa batun Tattaunawa game da batun 'Kwayar halittar jaraba: sabon vistas'.
· © 2008 Kamfanin Sarauta
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