Ayyukan Abinci na Intravascular (2010)

PLoS One. 2011; 6 (9) : e24992.

An buga a kan layi na 2011 Satumba 27. doi: 10.1371 / journal.pone.0024992

PMCID: PMC3181252

Albino J. Oliveira-Maia,^1,^*^¤a^¤b Craig D. Roberts,¹ Q. David Walker,² Brooke Luo,¹ Cynthia Kuhn,² Sidney A. Simon,^1,^3,⁵ da kuma Miguel AL Nicolelis^1,^3,^4,^5,⁶

Xiaoxi Zhuang, Edita

Bayanin marubucin} Mataki na asali ► Bayanin Copyright da Bayanin lasisi ►

Wannan labarin ya kasance wanda aka ambata wasu articles a PMC.

Abstract

Yin amfani da sukari mai ɗauke da kalori yana haifar da martanin halaye na ci da sakin dopamine a cikin ventral striatum, ko da in babu injin sarrafa ɗanɗano mai daɗi. Koyaya, ba a sani ba idan irin waɗannan tasirin sakamako masu alaƙa da lada suna nuna abubuwan da suka faru na preabsorptive ko postabsorptive. Don goyan bayan mahimmancin ganowar glucose na postabsorptive, mun gano cewa, a cikin gwaje-gwajen halayen bera, babban maganin glucose mai yawa da aka gudanar a cikin jijiya jugular sun isa don yanayin rashin son kai. Bugu da ƙari, ƙananan maganin glucose na maida hankali yana haifar da ingantacciyar amsawar ɗabi'a lokacin da aka gudanar a cikin hanta-portal, amma ba jijiya jugular ba. Bugu da ƙari, gudanar da shigar da glucose a cikin maida hankali wanda ya isa ya haifar da yanayin yanayi ya haifar da bayanin martabar glycemic kwatankwacin abin da aka lura bayan gudanar da ƙaramin taro na glucose a cikin hepatic-portal, amma ba jijiya jugular ba. A ƙarshe ta yin amfani da saurin-scan cyclic voltammetry mun gano cewa, daidai da binciken ɗabi'a, ƙaramin maganin glucose mai hankali ya haifar da haɓaka abubuwan sakin dopamine na kwatsam a cikin ƙwayar ƙwayar ƙwayar cuta lokacin da aka gudanar a cikin hanta-portal, amma ba jijiya jugular ba. Waɗannan binciken sun nuna cewa sakamakon postabsorptive na glucose sun isa don haɓaka halayen haɓakawa da martanin sakamako na dopaminergic waɗanda ke haifar da cin sukari. Bugu da ƙari kuma, matakan glycemia a cikin hanta-portal venous tsarin suna ba da gudummawa sosai ga wannan sakamako fiye da tsarin glycemia, suna jayayya don sa hannu na firikwensin visceral na ciki na ciki don glucose.

Ka tafi zuwa ga:

Gabatarwa

Sakamakon da ya dace bayan cin abinci yana da matuƙar muhimmanci wajen tantance ɗabi'ar ciyarwa [1] . A gaskiya ma, kwanan nan mun gano cewa a cikin yanayin ɗabi'a mai kwalba biyu, har ma a cikin dabbobi waɗanda hanyoyin motsa jiki masu daɗi ba su nan, shan sucrose ta baki (saccharide mai ɗauke da kalori), amma ba sucralose ba (mai zaki mara kalori), ya isa ga daidaita fifikon gefe [2] . Bugu da ƙari, lokacin da irin waɗannan dabbobin suka cinye sucrose, an sami ƙaruwar sakin dopamine da kunna neuronal a cikin nucleus accumbens (NAcc). An kuma ba da shawarar ƙarfafa tsarin dopamine bayan cin abinci a cikin wani nazarin hoton aiki na ɗan adam, inda aka gabatar da sucralose da sucrose a cikin yawan haɗuwa da ɗanɗano, kuma na ƙarshe ne kawai aka kunna dopaminergic midbrain [3] . An tabbatar da mahimmancin kunna dopaminergic don koyo mai dogara da postestive a cikin gwaje-gwajen da aka gudanar a cikin beraye, inda adawar mai karɓar dopamine a cikin NAcc ta hana ci gaban alaƙa tsakanin dandanon da ba na kalori ba da glucose da aka allura kai tsaye cikin duodenum [4].

Dangane da hanyoyin da ke haifar da tasirin sakamako na ɗabi'a na ƙarfafawa bayan haihuwa ta hanyar sukari kamar sucrose, bayanan da ake da su ba su da daidaito gaba ɗaya. Wani bincike ya nuna cewa ana buƙatar ƙarfafawa kai tsaye na mucosa na hanji [5] , yayin da wasu suka nuna mahimmancin tasirin bayan haihuwa ta hanyar allurar abinci mai gina jiki ta hanyar jijiya [6] , [7] . Kwanan nan an kuma ba da shawarar cewa, ba tare da ɗanɗano ba, amfani da glucose na nama yana da mahimmanci don amfani da glucose don haifar da sakin dopamine a cikin striatum [8] . A kowane hali, hanyoyin siginar postecious da ke haifar da yanayin hali da sakin dopamine har yanzu suna da ce-ce-ku-ce.

Anan muna da sha'awar fayyace sa hannu na hanyoyin preabsorptive da postabsorptive a cikin tasirin sakamako masu alaƙa da sukari mai ɗauke da kalori, ba tare da ɗanɗanonsa ba. Don wannan tasirin, mun yi amfani da berayen don gwada halayen halayen dopaminergic ga gudanarwar glucose na jini a cikin jijiya jugular (JV) da jijiyoyin hanta-portal (HPV). Da farko mun gwada ko nau'ikan glucose daban-daban (5%, 22.5% da 50%), waɗanda aka gudanar a cikin JV, sun wadatar don daidaita son zuciya a cikin gwajin zaɓin kwalba biyu. A cikin wannan gwaji, an yi amfani da saccharin azaman sarrafawa don yuwuwar haɓakar ɗanɗanon intravascular. A cikin wani gwaji, da aka ba da tasirin glycemic na daban-daban na motsa jiki na glucose da aka gudanar a cikin JV, an gwada tasirin 5% glucose da aka gudanar a cikin HPV a cikin yanayin ɗabi'a iri ɗaya. A cikin wannan gwajin, an yi amfani da mannitol azaman sarrafawa don tasirin osmotic. Bayan haka, an auna tasirin glycemic na daban-daban na motsa jiki na glucose da aka yi amfani da su a cikin waɗannan gwaje-gwajen lokaci guda a cikin wutsiya da jinin HPV, don tantance ma'anar canje-canje a kowane ɗayan waɗannan wurare don tasirin halayen da aka gani a baya. A ƙarshe, ta amfani da voltammetry na cyclic, an auna mitar dopamine a cikin NAcc kuma an gwada tasirin HPV da JV na maganin glucose na 5%.

Ka tafi zuwa ga:

results

Domin fayyace yadda ƙwayoyin cuta (na hanji) da na bayan shan ruwa ke shiga cikin yanayin da ba ya dogara da ɗanɗano ta hanyar tasirin bayan shan ruwa a cikin beraye, mun gudanar da gwaje-gwaje don gwada juyawar bambancin gefen a cikin yanayin halayen kwalba biyu [2] . A takaice, an gwada dabbobi don bambancin gefen a cikin gwajin ruwan kwalba biyu da ruwa a ƙarƙashin ruwa da ɗan takaitaccen abinci. Don magance bambancin gefen, an fallasa dabbobi ga tsarin gyaran jiki na kwanaki 4 tare da samun damar shiga ruwa kyauta kowace rana a wasu ɓangarorin akwatin ɗabi'a. A cikin kwanaki 2 da aka fallasa dabbobi zuwa gefen da ke akasin bambancin asalin, an ba da maganin glucose 3 mL a lokaci guda don shan ruwa da kuma dangane da halayen lasar ruwa (3 µL/lasar na farko 1000 na lasar ruwa). A cikin sauran kwanaki 2, lokacin da aka fallasa dabbobi zuwa gefen ainihin bambancin, an ba da abin hawa a ƙarƙashin irin wannan yanayi. A wasu dabbobi, waɗanda aka dasa a baya da catheters na jijiyoyin jini, an saka abubuwan ƙarfafawa (glucose ko abin hawa) ta hanyar jijiya, yayin da a wasu kuma an ba su ta baki ta hanyar allurar da ke da zaman kanta a cikin bututun shan ruwa da ake amfani da shi don isar da ruwa (duba Hanyoyi). A ranar gwaji ta ƙarshe, an gwada juyawar gefe ga dukkan dabbobi ta amfani da gwajin ruwa mai kwalba biyu da ruwa (duba Hanyoyi da Tebur 1 don cikakkun bayanai).

Table 1

Hanyoyi don Canjawa zuwa Tasirin Bugawa.

Rukunin dabbobi biyu an daidaita su ta amfani da ko dai 5% (n=6) ko 15% (n=5) Maganin glucose da ake bayarwa da baki. Gabaɗaya, dabbobin da ke cikin waɗannan ƙungiyoyin suna da matakan amfani da yawa yayin zaman motsa jiki na abin hawa fiye da lokacin zaman glucose, tasirin da zai iya zama saboda sakamakon satiating na gudanarwar glucose ko kuma yin amfani da manyan matakan rashin ruwa.Hoton S1A). An gwada jujjuyawar gefe-gefe ta hanyar kwatanta fifiko ga gefen kishiyar kowace dabba ta asali a cikin zaman kwalabe biyu kafin da bayan sanyaya. Mun sami tasiri mai mahimmanci don kwantar da hankali (5% vs. 15%, F=9.3, p=0.014) da zaman gwaji (pre vs. post-conditioning, F=7.9, p=0.021), kuma kusa da muhimmiyar hulɗar tsakanin abubuwan biyu (F=4.2, p=0.071; maimaita-matakan ANOVA biyu). Koyaya, babban haɓakawa a cikin fifikon pre vs. post-conditioning fifiko ga gefen da ke da alaƙa da isar da glucose an samo shi ne kawai a cikin dabbobi masu sharadi 15% glucose (0.11 ± 0.06 vs. 0.8 ± 0.2, t=3.3, p<0.05), amma ba waɗanda ke da sharadi na 5% glucose (0.07 ± 0.04 vs. 0.18 ± 0.15, t=0.6, p>0.05; post-hoc Bonferroni t-gwajin; Fig. 1A).

Figure 1

Gudanar da jijiyar jugular na glucose ya isa don yanayin jujjuyawar gefe.

Yin amfani da ƙa'idar ɗabi'a iri ɗaya, mun gwada tasirin jiko na JV na ƙananan (5%, n=10), matsakaici (22.5%, n=7) kuma babba (50%, n=11) maganin glucose. Sodium saccharin (NaSacc; 3.16%, wanda aka nuna a baya don zama mafi kyawun maida hankali don haɓakar intravascular na ɗanɗano mai daɗi). [9]) an yi amfani dashi azaman sarrafawa don yuwuwar haɓakar ɗanɗanon intravascular (n=5). Hakazalika ga abin da aka samo a cikin dabbobin da aka kwantar da su a baki, gabaɗaya waɗannan berayen suna da matakan amfani da su yayin lokutan gyaran abin hawa fiye da lokacin zaman glucose ko saccharin (Hoton S1B). Game da juye-juye na gefe, mun sami tasiri mai mahimmanci don daidaita yanayin motsa jiki (ƙananan vs. matsakaici vs. high glucose vs. NaSacc, F=7.8, p<0.001), zaman gwaji (pre vs. post-conditioning, F=45.3, p<0.001) da kuma hulɗar tsakanin waɗannan abubuwan (F=15.8, p<0.001; maimaita-matakan ANOVA biyu). An sami juzu'i na gefe-bias a cikin dabbobi masu sharadi tare da JV infusions na 22.5% (0.18 ± 0.05 vs. 0.63 ± 0.10, t=4.7, p<0.001) da 50% glucose (0.13± 0.05 vs. 0.82± 0.07, t=9.1, p<0.001), amma ba waɗanda ke da sharadi na 5% glucose (0.14 ± 0.05 vs. 0.12 ± 0.05, t=0.3, p>0.05) ko NaSacc (0.19± 0.09 vs. 0.3± 0.19, t=1, p>0.05; post-hoc Bonferroni t-gwajin; Fig. 1B). A taƙaice, yayin da mafi girman matakan glucose na maida hankali biyu suka haifar da juzu'i na gefe-gefe, ba a sami wani tasiri ga NaSacc ba, don haka kawar da ɗanɗanon intravascular azaman alamar waɗannan canje-canjen halayen.

Don ƙarin fahimtar tasirin glycemic na abubuwan motsa jiki daban-daban, an ba da izinin ƙungiyoyin dabbobi daban-daban damar samun ruwa kyauta a cikin zaman ɗabi'a na tsawon mintuna 10 yayin da 3 ml na kowane maganin glucose da aka yi amfani da shi don daidaitawa ana gudanar da su lokaci guda don amfani da ruwa da ƙari. lasa (3 µL/lasa na farko na 1000 na ruwa; 5% na baka, n=3; 15% na baka, n=4; 5% JV, n=6; 22.5% JV, n=4; 50% JV, n=6). An auna glycemia daga jinin wutsiya kafin (tushe) kuma a lokuta da yawa bayan gudanarwar glucose (0'-40'). Ban da glucose na baki 5%, duk abubuwan motsa jiki sun haifar da ƙaruwa mai yawa na glycemia na gefe.Fig. 2A, gani S1 Table don data). Hakanan an tabbatar da wannan tasirin don glucose na JV 5%, wanda bai daidaita juzu'i na gefe-gefe ba, yana nuna cewa haɓakar glycemia na gefe bai isa ya haifar da canje-canje na gefe ba. Don ƙarin fayyace bayanin martabar glycemic na kowane abin ƙarfafawa, duka cikakke (mg/dL) da ma'aunin dangi (% tushe) na glycemia an bincikar su cikin ma'ana da kololuwar glycemia. A cikin dabbobin da aka gudanar da glucose a cikin baki, ba a sami bambance-bambance ba don glycemia dangi mafi girma (% tushe) bayan bayyanar 5% da 15% glucose (117 ± 8 vs. 131 ± 9, bi da bi, t)=1.1, p=0.33, t-gwajin da ba a haɗa ba; Fig. 2B). Lokacin da glycemia bayan 15% glucose na baki, wanda ke da tasiri a yanayin jujjuyawar gefe-bias, an kwatanta shi da waɗanda sakamakon JV na glucose, an sami babban tasiri (F).=37.7, p<0.0001, ANOVA hanya ɗaya). Kwatancen hikimar bi-biyu sun nuna bambance-bambance dangane da JV 22.5% (428 ± 34, t=5.8, p <0.001) da 50% glucose (536 ± 48, t=8.6, p <0.001), amma ba dangi zuwa 5% glucose (170± 10, t)=0.8, p>0.05; post-hoc Bonferroni t-gwajin; Fig. 2C). An samo irin wannan sakamakon don kololuwa da ma'anar cikakken glycemia (Figs. S2A, B, D da E) kuma yana nufin dangi glycemia (Figs. S3A da B).

Figure 2

Jikowar jijiya na motsa jiki na glucose wanda yanayin jujjuyawar gefe-bangare shima yana haifar da hyperglycemia mai tsananin wutsiya.

Abubuwan da muka gano sun nuna cewa, yayin da glucose na cikin jini ya isa don yanayin jujjuyawar gefe-gefe a cikin gwajin ruwa na kwalba biyu da gwajin ruwa, wannan yana yiwuwa ne kawai lokacin da matakan glycemia ya fi girma fiye da waɗanda ke haifar da glucose na baki. Don haka muka yi hasashen cewa hyperglycemia na tsarin jiki daga gudanarwar glucose na JV ya zama dole don fitar da firikwensin firikwensin da ke aiki bayan gudanarwar glucose na ciki. TTsarin HPV yana da mafi kyawun wuri don irin wannan firikwensin, tun da yake yana ɗaukar mafi yawan jini mai wadatar abinci daga tsarin gastrointestinal, kafin a sake shi a cikin wurare dabam dabam.. Don gwada wannan hasashe, an yi ƙa'idar daidaitawa iri ɗaya tare da 5% glucose wanda aka gudanar ta hanyar catheters HPV (n.=10), maimakon baki ko ta hanyar JV. A matsayin iko na osmotic, wani (dandana mai dadi) monosaccharide (5% mannitol [10]) an yi amfani da shi azaman abin motsa jiki a cikin madadin rukunin dabbobi (n=5 Hoton S1C). A cikin wannan gwajin ba a sami bambance-bambance a cikin amfani ba yayin abin hawa vs. glucose ko zaman sanyaya mannitol. Madadin haka, dabbobi masu sharadi tare da glucose gabaɗaya suna da matakan amfani da su sama da waɗanda ke da mannitol.Hoton S1C). Lokacin yin la'akari da illolin ɗabi'a a cikin wasu lokutan yanayin sanyi (Figs. S1A da S1B) wannan yana nuna cewa, a ƙarƙashin waɗannan sharuɗɗan, mannitol ya haifar da wani sakamako mai banƙyama wanda ya haɗa da zaman abin hawa. Game da juye-juye na gefe, an sami sakamako mai mahimmanci don daidaita yanayin motsa jiki (glucose vs. mannitol, F).=10.2, p=0.007), zaman gwaji (pre vs. post-conditioning, F=5.2, p=0.04) da kuma hulɗar tsakanin waɗannan abubuwan (F=9.5, p=0.009; maimaita-matakan ANOVA biyu). Bugu da ƙari kuma, a cikin goyon bayan tunanin mu, an sami karuwa mai yawa a cikin pre vs. bayan-kwance fifiko ga gefen da ke hade da glucose (0.17 ± 0.05 vs. 0.69 ± 0.12, t=4.7, p <0.001), amma ba jiko na mannitol a lokacin kwandishan (0.14 ± 0.04 vs. 0.06 ± 0.06, t=0.5, p>0.05; gwajin gwajin Bonferroni bayan hoc, Fig. 3A). Don haka, 5% glucose yana da tasiri a cikin yanayin jujjuyawar gefe-bias lokacin gudanar da shi a cikin HPV (Fig. 3Aamma ba JV ba (Fig. 1B). Wannan bambance-bambance a cikin tasirin halayen glucose na 5% bai haifar da bambance-bambance a cikin tsarin glycemia ba dangane da wurin gudanarwa, tunda glycemia na jini mafi girma (% tushe) bayan HPV (171 ± 13) da gwamnatin JV.Fig. 1D) ba su bambanta sosai ba (t=0.07, p=0.9, t-gwajin da ba a haɗa ba; Fig. 3B; duba tebur S1 don data). Hakanan ba a sami bambance-bambance ga kololuwa ba kuma yana nufin cikakkiyar glycemia (Figs. S2C da Fda kuma ma'ana dangi glycemia (Hoton S3D).

Figure 3

Gudanar da jijiyoyin hanta-portal na yanayin glucose na gefe-bangare koma baya a ƙananan yawa fiye da waɗanda ake buƙata tare da sarrafa jijiya jugular.

Gabaɗaya, waɗannan binciken suna nuna ƙarfi sosai cewa haɓakar glycemia na HPV, maimakon tsarin glycemia, wani abu ne mai mahimmanci wanda ke haifar da juzu'i mai cin gashin kai na gefe-bangare. Don ƙarin gwada wannan hasashe, ƙungiyoyi daban-daban na dabbobin da aka saƙa an yi musu allura da abin hawa ko nau'ikan maganin glucose daban-daban da aka yi amfani da su don daidaitawa, ta hanyar sanya catheters a cikin duodenum (ruwa, n.=5; 5% glucose, n=4; 15% glucose, n=6), JV (saline, n=5; 5% glucose, n=6; 22.5% glucose, n=4; 50% glucose, n=4) ko HPV (saline, n=4; 5% glucose, n=7). An auna glycemia daga duka wutsiya da jini na HPV a farkon (tushe) da kuma ƙarshen (0′) na perfusion na motsa jiki, kuma kowane minti 10 bayan haka (10′-50′). An binciko bayanan danyen daban don abin hawa da allurar glucose da wutsiya da glycemia na jini na HPV (Siffa 4, gani S2 Table don data). Kamar yadda aka yi bayani game da glycemia a cikin dabbobi masu tasowa, an kwatanta ƙimar glycemia kololuwa da ma'ana (duba bayanai a ciki). Tables S3 da kuma S4). Don kololuwar dangi glycemia (% na asali), an sami muhimmiyar hulɗa tsakanin abin ƙarfafawa (JV vs. HPV vs. duodenal 5% glucose vs. duodenal 15% glucose vs. JV 22.5% glucose vs. JV 50% glucose vs. abin hawa) da wurin samfurin jini (wutsiya vs. HPV; F=11.4, p <0.001), ba da damar yin nazari daban-daban na wutsiya da glycemia na HPV (duba S4 Table don ƙarin bayani). A kowane hali, glycemia bayan JV 5% glucose, wanda aka yi la'akari da shi azaman abin ƙarfafawa wanda bai dace da jujjuyawar gefe ba (duba. Fig. 1B), an kwatanta shi da abin da aka lura bayan sauran abubuwan motsa jiki. Fko ma'aunin jini na wutsiya, kawai JV 22.5% da 50% glucose da abin hawa, amma ba HPV 5% da duodenal 5% da 15% glucose ba, sun bambanta sosai da JV 5% glucose. (Fig. 4C). Don ma'aunin jini na HPV, duk da haka, duodenal 5% glucose, kawai sauran abubuwan motsa jiki waɗanda ba su daidaita juzu'i na gefe ba (duba. Fig. 1A), kuma shine kawai abin ƙarfafawa wanda bai bambanta sosai da glucose na JV 5% ba (Fig. 4D). Don haka, daidai da bincikenmu na baya, HPV, amma ba tsarin glycemia ba, kamar yadda aka auna a cikin berayen da ba su da lafiya, daidai yana nuna jujjuyawar gefe-gefe da aka lura bayan daidaitawa a cikin dabbobin farke. Wannan kamance tsakanin tasirin halayya da amsawar glycemic mafi girman HPV ba a samo shi ba don ma'anar glycemia (S4 Table), yana ba da shawarar cewa halayen halayen da suka dace na gudanarwar glucose suna haifar da sakamako mai girma na glycemia maimakon tasirin ci gaba da canje-canjen glycemia. An samo irin wannan sakamakon lokacin da aka kwatanta cikakken matakan glycemia (mg/dL). (S3 Table).

Figure 4

Haɓakawa a cikin hanta-portal jijiyar jini glycemia yayi daidai da iyawar abubuwan motsa jiki zuwa yanayin jujjuyawar gefe-bias.

Nazarin da aka yi a baya sun nuna cewa za a iya fitar da sakin dopamine a cikin ƙananan ƙwayoyin cuta, don mayar da martani ga isar da sukari na gastrointestinal, ba tare da dandano ba. [2], [4], [11]. Don haka muna da sha'awar fahimtar idan sakin dopamine a cikin wannan yanki zai bambanta ta hanyar JV da gwamnatin HPV na 5% glucose. FAn yi amfani da ast-scan cyclic voltammetry don gano abubuwan sakin dopamine na kwatsam ko "masu wucewa" [12], [13], [14], [15] a cikin tsakiya yana tara harsashi na berayen da aka anesthetize (n=12) (duba hanyoyin). Bayan samun rikodin asali na mintuna 6 zuwa 8, an saka berayen a cikin jijiya ta JV tare da glucose 5% ko a cikin HPV tare da ko dai 5% glucose ko abin hawa. Matsakaicin matsakaicin matsakaici (3.4 ± 0.7 transients / min), tsawon lokaci (520 ± 68 msec) da amplitude (30 ± 3 nM) sun yi kama da abin da aka kwatanta a cikin dabbobin farke. [12], [14], [15] (duba Fig. 5A da B don wakilcin rikodin). Bugu da ƙari kuma, da zarar an auna canje-canjen glucose, an yi amfani da hodar iblis (15 mg / kg) ga duk dabbobi don nuna tasirin hanawar dopamine a ƙarƙashin waɗannan yanayi. Mun gano cewa hodar Iblis ya karu da mitar lokaci da tsawon lokaci, ba tare da rinjayar girman ba (Fig. S5).

Figure 5

Nucleus yana haɓaka mitar dopamine na wucin gadi yana ƙaruwa bayan allurar glucose a cikin jijiyoyin hanta-portal.

Game da canje-canje a cikin mitar mai wucewa bayan gudanar da glucose, maimaita-matakan hanyoyi biyu na ANOVA ya bayyana babban tasiri na lokaci (baseline vs. 1-5 min vs. 6-10 min vs. 11-15 min vs. 16-). 20 min; F=2.7, p=0.044) amma ba don ƙungiyar jiyya ba (JV glucose vs. HPV glucose vs. HPV saline; F=1.6, p=0.26), da muhimmiyar hulɗar tsakanin abubuwa (F=2.4, p=0.036, Fig. 5C). Ganin mahimmancin hulɗar tsakanin abubuwa, ƙarin kwatancen don tasirin lokaci an yi su daban don kowane rukunin jiyya. Ga saline na HPV da ƙungiyoyin glucose na JV, tasirin lokaci ba shi da mahimmanci (F=0.5, p=0.75 da F=0.61, p=0.66 bi da bi) da kuma kwatanta a kowane lokaci na lokaci dangane da ma'auni na asali kuma ba su da mahimmanci (t<1.1 da t <1.5 bi da bi, p>0.05 ga kowa). Koyaya, ga rukunin glucose na HPV, an sami gagarumin tasirin lokaci (F=3.9, p=0.031; maimaita-matakan ANOVA guda ɗaya) kuma, idan aka kwatanta da tushe, mitar mai wucewa ta kasance mafi girma na mintuna 5 na farko bayan fara jiko (t).=3, p<0.05) amma ba a cikin sauran lokutan lokaci ba (t<1.7, p>0.05 ga duka; gwajin gwajin Bonferroni bayan-hoc; duba S5 Table don ƙarin bayani). Babu wani tasiri da aka samu na lokaci, ƙungiyar jiyya ko hulɗar su dangane da tsawon lokaci ko girma (Fig. S4). A cikin waɗannan dabbobin, an ƙaddara glycemia na wutsiya a gabanin da mintuna 20 bayan farawar JV ko infusions na HPV, yana nuna, kamar yadda aka zata, cewa bambance-bambancen da aka lura a cikin mitar mai wucewa bayan jikowar glucose ba saboda bambance-bambance a cikin tsarin glycemia ba.Fig. 5D). Don haka, daidai da bayanan halayen da aka gabatar da bayanan glycemia, a ƙaramin maida hankali (5%), glucose yana ƙaruwa da yawa na ɗan lokaci na dopamine lokacin shigar da shi cikin HPV, amma ba JV ba.

Ka tafi zuwa ga:

tattaunawa

A cikin wannan binciken mun nuna cewa hanyoyin bayan shan glucose suna shiga cikin tasirin sakamako mai alaƙa da ɗabi'a da dopaminergic na glucose, ba tare da la'akari da kyawawan halayensa na ɗanɗano ba. Da farko mun gano cewa, a cikin beraye, yawan glucose da aka bayar a cikin JV ya isa ya daidaita rashin jin daɗi ( Hoto na 1B ). Duk da haka, wannan ya yiwu ne kawai a yawan glucose wanda ya haifar da glycemia mafi girma fiye da wanda ya samo asali daga shan glucose ta baki, a yawan da ya isa ya daidaita rashin jin daɗi ( Hoto na 2 ). Don fayyace wannan rashin jin daɗi, an gudanar da ƙarin gwaje-gwaje don kwatanta tasirin glucose da aka bayar a cikin JV da HPV, tunda na ƙarshen shine wurin farko na tarin glucose bayan sha a cikin hanji [16] . A wannan batun, mun gano cewa, a ƙaramin yawan, maganin glucose yana da ƙarfi rashin jin daɗi lokacin da aka ba da shi a cikin HPV, amma ba JV ba ( Hoto na 3A ). Don tallafawa wannan binciken, gudanar da glucose a cikin jiki a cikin wani taro wanda ya isa ya haifar da yanayin hali ( Hoto na 1A ) ya haifar da bayanin glycemic irin wanda aka gani bayan gudanar da ƙaramin maganin glucose a cikin HPV, amma ba JV ba ( Hoto na 4 ). A ƙarshe, gudanar da ƙaramin maganin glucose a cikin HPV, amma ba JV ba, ya haifar da ƙaruwa a cikin yawan dopamine transients a cikin harsashi na nucleus accumbens, kamar yadda aka auna ta hanyar saurin duba cyclic voltammetry ( Hoto na 5 ). Gabaɗaya, waɗannan binciken suna goyan bayan cewa tasirin glucose bayan sha ya isa ga martanin da suka shafi ɗabi'a da dopaminergic sakamakon shan sukari, da matakan glycemia a cikin tsarin HPV suna ba da gudummawa sosai ga wannan tasirin fiye da glycemia na tsari.

Bambance-bambancen abubuwan da ke faruwa na baka da na baya a cikin sarrafa halayen ciyarwa sun kasance da kyau [1]. Abubuwan sarrafa abubuwan da ake amfani da su na cin abinci galibi an san su azaman tasirin hanawa (watau satiation) amma ƙarancin bincike an sadaukar da shi ga ingantaccen tasirin abinci. [17]. Yayin da yawancin marubutan farko suka nuna cewa allurar abinci mai gina jiki na cikin ciki na iya zama isasshiyar ƙarfafa ɗabi'a [18], [19], wannan binciken ya kasance mai rikitarwa kuma an danganta shi da leaks a cikin tsarin cannulation na ciki [1], [20]. A zahiri, yawancin marubutan sun haɓaka aikin da ke nuna cewa abubuwan gina jiki da aka allura kai tsaye cikin ciki za su ba da fifiko ga dandano mai alaƙa [20], [21], [22], [23], [24], [25], kuma kwanan nan ne muka gano cewa, a cikin mice ba tare da aikin aikin ɗanɗano mai daɗi a cikin sel masu karɓar dandano ba, cin sucrose na baki ya wadatar don daidaita abubuwan zaɓin gefe mai ƙarfi, ba tare da kowane alamun baka ba. [2]. Anan, tsarin ɗabi'a ya haɓaka a baya a cikin beraye [2] An daidaita shi don amfani a cikin bera, kuma mun nuna cewa za a iya amfani da shi don auna yanayin yanayin da ya haifar da amfani da glucose (glucose).Fig. 1A).

Duk da cewa wallafe-wallafen da ke kan ingantaccen tsarin kula da abinci bayan an ci abinci yanzu ya kusan shekaru 60, siginar da ke ƙarƙashin waɗannan tasirin, musamman na glucose, har yanzu suna da ce-ce-ku-ce [5] . Gwaje-gwajen da aka yi game da allurar glucose a cikin berayen ko zomaye, don gwada tasirinsa a matsayin alama don ingantaccen tsarin kula da abinci bayan an ci, sun sami sakamako masu kyau [7] , [26] , [27] , [28] , [29] da sakamako mara kyau [30] , [31] , [32] . A nan mun nuna tasirin amsawar allurai a cikin ikon glucose don daidaita hali, lokacin da aka ba da shi a cikin JV ( Hoto na 1B ). Waɗannan sakamakon suna ba da bayani mai ma'ana game da bambance-bambancen da suka gabata tare da gudanar da glucose na JV, tunda an sami sakamako masu kyau tare da yawan glucose mafi girma (30%) [7] fiye da waɗanda aka yi amfani da su a gwaje-gwajen da suka sami sakamako mara kyau (10%) [31] , [32].

A cikin beraye, an gabatar da HPV a matsayin muhimmin wuri don gano alamun bayan shan ruwa waɗanda ke tallafawa yanayin ci bayan abinci [6] . A wani bincike da aka yi daga baya a cikin berayen da ba su da abinci, ba a gano allurar glucose ta HPV don daidaita dandano ba, wanda ya haifar da shawarar cewa ƙarfafa hanji ta hanyar abubuwan gina jiki yana da mahimmanci don allurar HPV don daidaita hali [5] . A nan mun gano cewa, ko da a cikin berayen da ba su da abinci, allurar glucose ta HPV ta isa ta daidaita bambanci ( Hoto na 3A ). Idan aka kwatanta da gwaje-gwajen da aka ambata a sama [5] , ba za a iya bayyana waɗannan sakamakon ta hanyar amfani da yawan glucose mai yawa ba (5% da aka yi amfani da su a nan idan aka kwatanta da 10%), amma yana iya zama sakamakon bambance-bambance a cikin yawan jiko (ba kasa da 0.3 mL/min a nan idan aka kwatanta da 0.083 mL/min). Bugu da ƙari, bisa ga binciken da aka yi a baya [6] , jiko na irin wannan yawan glucose a cikin JV ba shi da irin wannan tasirin ( Hoto na 1B ). Saboda haka, yayin da bayananmu ba za su iya ware mahimmancin motsa jiki na abinci mai gina jiki na hanji don yanayin ci bayan ci ba, sun nuna a fili cewa ba lallai ba ne, kuma abubuwan da ke haifar da sha bayan sha, waɗanda ke aiki a gefe a cikin tsarin HPV, sun isa ga irin waɗannan tasirin halayen.

Yana da mahimmanci a lura cewa glucose da sauran abubuwan gina jiki da ke cikin hanji za su sha, wanda zai haifar da karuwa mai yawa a cikin matakan sinadarai na jini a cikin HPV fiye da tsarin kewayawa. [16]. Wannan tasirin zai yuwu ya zama ƙari ga na allurar abinci mai gina jiki a cikin HPV, yana ba da bayani mai ma'ana ga ƙungiyar da aka ambata a baya tsakanin kasancewar abubuwan gina jiki a cikin hanji da ƙarfin infusions na HPV zuwa yanayin yanayin yanayi. [5], [6]. Don haka, lokacin da aka kwatanta halayen halayen shigar, JV da / ko infusions na gina jiki na HPV, yana da mahimmanci don auna matakan sinadirai na jini kai tsaye daga waɗannan infusions. Koyaya, kaɗan ne kawai daga cikin binciken da ke bincika ingantattun tasirin yanayin yanayin sarrafa glucose na cikin jini sun haɗa da ma'aunin glycemia na tsarin jini, tare da gaurayawan sakamako. [27], [31], [33], kuma babu wanda ya haɗa waɗannan ma'auni a cikin jinin HPV. Anan mun nuna, duka a farke da berayen da aka kwantar da su, cewa ma'aunin glycemia na wutsiya bai yi cikakken bayani game da bambance-bambancen halayen halayen enteric, JV da infusions na glucose na HPV ba.Fig. 2, , 3B, 3B, 4A, 4C, S2 da kuma S3; Tables S1, S2, S3 da kuma S4). Koyaya, lokacin da aka yi ma'auni a cikin jinin HPV na dabbobin da aka anesthetize, an gano kololuwar glycemia yana da alaƙa mai kyau na iyawar maganin glucose zuwa yanayin rashin son rai.Figs. 4B da 4D; Tables S2, S3 da kuma S4). Wannan ba gaskiya ba ne ga ma'anar glycemia, yana nuna gaskiyar cewa allurar glucose na cikin jini ba ta haifar da cikakken bayanin martabar glycemia ba, kuma yana ba da shawarar cewa tasirin halayen halayen glucose na jini sun dogara da mafi girman matakan glycemia fiye da ci gaba da glycemia. tsayin daka. A kowane hali, waɗannan binciken sun ƙara goyan bayan mahimmancin nauyin glucose na postabsorptive a cikin HPV don yanayin yanayin motsa jiki yana nunawa, mahimmanci, cewa wannan gaskiya ne ko da lokacin da ake sarrafa kayan abinci a cikin gut, maimakon kai tsaye a cikin JV ko HPV.

An kuma gudanar da gwaje-gwajen da aka gudanar don bincika mummunan tasirin (watau, mai gamsarwa) na abubuwan gina jiki da aka saka a cikin HPV a cikin nau'ikan halittu da dama. Kamar yadda aka bayyana don yanayin lafiya mai kyau, an lura da sakamakon da bai dace ba, (duba [6] , [34] don sake dubawa). Dalilin waɗannan bambance-bambancen an danganta su daban-daban ga yanayin abinci mai gina jiki na dabbar, tsarin da aka yi don jiko na HPV da kuma nau'ikan gwaji daban-daban [34] . A gaskiya ma, yawancin waɗannan abubuwan za su iya shafar matakin sinadari a cikin HPV, yana nuna cewa wannan abu zai iya zama tushen tasirin jiko na abinci mai gina jiki a cikin jijiyoyi, kamar yadda aka bayyana a nan don yanayin hali mai kyau.

A cikin gwaje-gwajen halayya tare da jiko na glucose a cikin JV ko HPV, an kuma yi amfani da hanyoyin sarrafawa, don bambance tsakanin tasirin da ke tattare da yanayin abinci mai gina jiki na glucose, daga waɗanda za su iya haifar da ƙarfafa ɗanɗano ko canje-canje a cikin osmolality. Ga gwaje-gwajen jiko na JV, an yi amfani da maganin sodium saccharin, a cikin taro wanda a baya aka nuna cewa ya fi kyau don ƙarfafa ɗanɗano mai daɗi a cikin jijiyoyin jini [9] . Ga jiko na HPV, an yi amfani da mannitol tunda, a daidai adadin glucose, wannan monosaccharide mai ɗanɗano mai daɗi yana haifar da canje-canje iri ɗaya a cikin osmolality na plasma, amma yana da ƙarancin tasirin rayuwa [10] . Sabanin glucose, saccharin da mannitol ba su daidaita canje-canjen gefe bayan jiko a cikin JV ko HPV bi da bi ba, suna kawar da ɗanɗano da osmolality na plasma a matsayin hanyar da ke ƙarƙashin waɗannan tasirin halayen ( Figures. 1B da da3A).3A ). Waɗannan muhimman abubuwan sarrafawa sun goyi bayan bincikenmu na baya game da yanayin ɗabi'a mara ɗanɗano tare da sucrose a cikin beraye [2] , da kuma rahotannin farko na yanayin kayan aiki da fifikon wuri wanda ya samo asali daga allurar abinci mai gina jiki a cikin ciki da kuma ta hanyar jijiya, idan babu alamun jin daɗi ko ƙamshi [18] , [19] , [26] , [27].

Matsayin dopamine a cikin tsaka-tsakin halayen abinci na abinci an riga an kafa shi da kyau [35]. Haɓaka matakan dopamine a cikin ƙwayar ƙwayar ƙwayar cuta (NAcc) yana faruwa ne akan cin sukari mai ɗauke da kalori kamar sucrose. [36], [37], kuma duka dandano mai dadi da haɓakawa na posting sun nuna sun isa ga wannan sakamako [2], [38], [39]. Koyaya, hanyoyin sakawa waɗanda ke haifar da sakin dopamine a cikin NAcc bayan cin sukari, har yanzu ba a sani ba. Yin jayayya game da mahimmancin haɓakawa na preabsorptive, an nuna hormone ghrelin da aka samu daga gut don ƙarfafa sakin mesoaccumbens dopamine. [40]. An kuma gabatar da hujjoji don sarrafa abubuwan da suka biyo baya na sakin dopamine striatal, amma binciken da aka ruwaito yana da ɗan daidaita. [8], [41], [42]. Mahimmanci, tasirin glycemia akan striatal dopamine homeostasis an danganta shi da glucosensing neurons a cikin kwakwalwa. [41], musamman tun da karuwa a cikin dorsal striatum dopamine matakan an gano yana faruwa lokacin da aka shigar da glucose kai tsaye a cikin substantia nigra. [43]. Anan, ta amfani da voltammetry na cyclic, mun gano cewa 5% glucose an saka shi a cikin HPV, amma ba JV ba, ya haifar da haɓakar abubuwan da suka faru na wucin gadi na dopamine.Figs. 5A-C), yayin da yake haifar da haɓaka mai kama da physiologically a cikin glycemia na gefe a cikin lokuta biyu.Figs. 3B, 4A, 4C da kuma da 5D).5D). Wannan binciken ya tabbatar da cewa alamun glucose na postabsorptive sun isa don haifar da sakin dopamine a cikin NAcc, kuma yana nuna, ga iliminmu a karon farko, cewa waɗannan tasirin postabsorptive sun dogara da haɓakar glycemia a cikin HPV, maimakon daga gano kai tsaye a cikin kwakwalwa ko wasu hanyoyin daban-daban, kamar dandano na intravascular. Bambance-bambancen tasirin dopaminergic na 5% glucose da aka gudanar a cikin JV da HPV sun dace musamman idan aka yi la'akari da bambancin tasirin waɗannan jiyya akan hali (Figs. 1B da kuma da 3A) 3A(HPV glycemia)Figs. 4B da 4D), yana ba da shawarar cewa na ƙarshe na iya zama tushen bayanin abubuwan da ke tattare da halayen halayen halayen da neurochemical na gudanarwar glucose.

Ko da yake an ba da rahoton masu wuce gona da iri na dopamine a cikin berayen farke [44], [45], mun lura cewa, a iya saninmu, wannan shine rahoto na farko a cikin berayen da ba su da lahani (Hoto na 5A da 5B). Duk da haka, mun gano cewa duk halaye guda uku da aka yi amfani da su don bayyana masu wucewa (yawanci, tsawon lokaci da girma) sun yi kama da waɗanda aka ruwaito a cikin berayen farke. [14], [15], [44], [46], [47]. Bugu da ƙari, ko da a cikin berayen da ba su da lafiya, mitar mai wucewa ta kasance mai amsawa ga jikowar glucose a cikin HPV (Fig. 5C) da kuma sarrafa ip na cocaine (Hoton S5A). Gwaje-gwajen da suka gabata ta amfani da voltammetry na cyclic sun bayyana martanin NAcc dopaminergic ga sucrose na baka. [47] ko saccharin [39] jiko. Idan aka kwatanta da waɗannan karatun voltammetric na baya, muna ba da rahoton ci gaba da ƙaruwa a cikin mitar mai wucewa a cikin mintuna kaɗan bayan jikowar glucose ta cikin jijiya, maimakon martanin da ke cikin 'yan daƙiƙai waɗanda ke faruwa bayan gabatar da abubuwan motsa jiki na baki. [46], [48]. Hakazalika ga abin da aka bayyana a baya don nomifensine [15] da kuma cocaine [45] gwamnati, mun kuma gano cewa allurar 15 mg / kg cocaine ya haifar da haɓakar mitar NAcc dopamine na wucin gadi (Hoton S5A) da kuma tsawon lokaci (Hoton S5B). Duk da haka, ba mu sami wani tasiri ga girman girman lokaci ba (Hoton S5C). Don haka, tasirin psychostimulants iri ɗaya ne a farke da berayen da aka saƙa. Tasirin bincike akan masu wucewa a cikin rodents ɗin da ba a safai ba na iya zama mafi dacewa a cikin mahallin da mahalli da yanayin yanayin ruɗani maras so.

NAcc, inda muka auna canjin dopamine, ba tsari ne mai kama da juna ba. Akwai manyan sassa guda biyu, wato Nacc core da Nacc shell, waɗanda aka ruwaito bambance-bambancen aiki a cikin sarrafa lada da kuma sakin dopamine release kinetics [49] , [50] . An auna bayanan voltammetry da aka ruwaito a nan da electrodes da aka dasa a cikin yankin harsashi. A zahiri, tasirin da muka lura bayan allurar cocaine ( Hoto na S5A ) sun yi daidai da binciken da aka yi a baya, suna nuna cewa cocaine yana ƙara yawan lokaci a cikin wannan yanki, amma ba NAcc core ba [51] . An gabatar da shawarar watsa dopamine a cikin harsashin NAcc don shiga cikin babban aikin lada don mayar da martani ga duka abubuwan motsa jiki na psychostimulants [49] , [51] da kuma abubuwan da ke haifar da cin abinci ta baki [39] , yayin da ake tsammanin sakin dopamine a cikin NAcc core yana da takamaiman rawa a cikin martani ga alamun da ke hasashen lada a cikin mahallin ƙungiyoyin da aka koya [39] , [49] . Yanzu mun nuna cewa jiko na glucose na HPV yana haifar da ƙaruwar mizanin dopamine na ɗan lokaci a cikin harsashin NAcc, wani tasiri wanda, kamar yadda aka nuna daga tasirin adawar mai karɓar dopamine a wannan yanki, na iya zama mai dacewa ga koyon fifikon ɗanɗano wanda sakamakon carbohydrates bayan baki ya haifar [4] . A kowane hali, ana buƙatar ƙarin bincike don bincika halartar NAcc core a cikin martanin bayan shaye-shaye ga sukari.

Binciken da aka yi a baya ya ba da shawarar cewa hanyoyin gano zaƙi da kuma jujjuyawar da ake samu akan ƙwayoyin ɗanɗano a cikin harshe, suma suna cikin hanji, kuma suna da mahimmancin saka idanu akan sha'awar sukari. [52]. Duk da haka, mu da wasu sun nuna cewa masu zaƙi marasa gina jiki, waɗanda kuma za su kunna waɗannan hanyoyin [52], ba sharadi gefe [2] ko dandano [53] abubuwan da ake so. Bugu da ƙari kuma, ko da yake gano-kamar dandano da hanyoyin sarrafawa suna da lahani, duka Trpm5 KO [2] da T1R3 KO [53] beraye za su ci gaba da abubuwan da aka zaɓa ta hanyar sukari masu gina jiki. Sakamakon da aka bayyana a nan yana goyan bayan cewa wani abu na postabsorptive, ya dogara da canje-canjen glycemic a cikin HPV, maimakon tsarin tsari, yana ba da gudummawa ga ingantattun halayen halayya da tasirin NAcc dopaminergic sakamakon cin sukari. Duk da yake waɗannan sakamakon suna jayayya da babban rawar da ake takawa don shigar da kayan aikin preabsorptive, irin wannan tsarin ba za a iya cire shi ba, kuma, a gaskiya ma, akwai shaida cewa mucosal da abubuwan da suka shafi postabsorptive zasu iya yin aiki tare a cikin yanayin kwantar da hankali. [5]. A kowane hali, har yanzu ana iya tantance yanayin abubuwan da suka dogara da glucose na HPV. Wata yuwuwar ita ce shigar da insulin, musamman tunda an nuna wannan hormone yana dacewa da martanin dopaminergic ga hyperglycemia [41]. Wani hanyar shiga tsakani na ɗan takara shine ɗaukar glucose na hanta, tunda ya dogara da matakan insulin [54] kuma yana ƙaruwa lokacin da aka isar da glucose a cikin HPV, idan aka kwatanta da jiko na gefe [55]. Dangantaka tsakanin matsayin makamashi na hanta, wanda aka auna dangane da maida hankali na ATP na hepatocyte, da cin abinci kuma an nuna. [56]. A ƙarshe, waɗannan abubuwan zasu iya yin bayanin binciken kwanan nan, yana nuna cewa amfani da glucose yana da mahimmanci don yanayin yanayin yanayi da tasirin dopaminergic na amfani da glucose. [8]. Hanyar watsa sigina daga hanta zuwa kwakwalwa shima ba a sani ba. Hasashe ɗaya shine watsa jijiya, mai yiyuwa ta hanyar jijiyoyi masu raɗaɗi na vagal afferent na glucose [57]. Duk da haka, ba a nuna raunin vagal na ciki da na jijiyoyi marasa vagal don toshe zaɓin dandano wanda aka tsara ta hanyar shigar da ƙwayoyin glucose. [58], [59], [60]. Wani madadin, wanda ba a bincika ba [61], shine abubuwan ban dariya, mai yiwuwa hanta da / ko pancreas ke samarwa, ana fitar da su a cikin jini kuma suna aiki kai tsaye a cikin kwakwalwa don daidaita cin abinci. [62].

A taƙaice, waɗannan binciken sun goyi bayan da'awar cewa tasirin glucose bayan shan ruwa ya isa ya haifar da martanin ɗabi'a ga cin sukari, kuma matakan glycemia a cikin tsarin HPV suna ba da gudummawa sosai ga wannan tasirin fiye da glycemia na tsari. Bugu da ƙari, waɗannan tasirin suna faruwa ba tare da la'akari da ɗanɗano ba, motsawar mucosal bayan an yi amfani da su, da kuma osmolality na plasma. Bugu da ƙari, wannan shine gwaji na farko, cewa gudanar da glucose na HPV ya isa ya haifar da transients na dopamine na striatal, wani tasiri wanda zai iya haifar da tasirin halayen wannan magani mai kyau. Ganin tasirin halayen tiyata na gastrointestinal bypass don rage nauyi [63] , [64] , tare da yuwuwar tasiri akan matakan gina jiki na HPV, mun yi imanin cewa hanyoyin da aka bayyana a nan na iya taka rawa a cikin asalin da maganin kiba na ɗan adam, don haka ya cancanci ƙarin bincike mai zurfi a cikin samfuran dabbobi da na ɗan adam.

Ka tafi zuwa ga:

Kaya da matakai

Bayanan Haɓaka

An aiwatar da duk hanyoyin bisa ƙa'idodin da Kwamitin Kula da Dabbobi na Jami'ar Duke ya amince da su (lambar yarjejeniya A329-07-12).

batutuwa

An samo beraye maza 144 na Long-Evans da beraye maza 12 na Sprague-Dawley daga Charles Rivers Laboratories (Raleigh, NC) kuma an ajiye su daban-daban a cikin keji na Plexiglas. An kula da dukkan dabbobin a cikin jadawalin haske/duhu na awanni 12 kuma an gudanar da gwaje-gwaje a cikin ɓangaren haske na zagayowar. A lokacin kowace gwaji, dabbobin suna da watanni 3 zuwa 6 kuma ba su da masaniya game da abubuwan da ke motsa su. Gwaje-gwajen farko sun nuna cewa, a ƙarƙashin yanayin da ake buƙata don gudanar da gwaje-gwaje tare da allurar jijiya, ana iya samun isasshen lasa ne kawai lokacin da aka takaita samun ruwa ta baki ga zaman ɗabi'a. Don haka, ana samun ruwan da beraye na Purina ad libitum , sai dai tsawon lokacin gwajin ɗabi'a, lokacin da aka hana dabbobi abinci dare ɗaya kuma suna da damar samun ruwa kawai a lokacin aikin ɗabi'a. A cikin gwaje-gwajen da aka gudanar a cikin dabbobin da aka yi wa sa barci, an takaita abinci da ruwa kimanin awanni 24 kafin gwajin. A cikin waɗannan dabbobin da nauyin jikinsu ya faɗi ƙasa da kashi 85% na asali, an dakatar da ƙuntatawa abinci da ruwa kuma an cire dabbobin daga gwajin.

Sakamakon

Duk hanyoyin da aka haɗa (d-glucose - 5%, 15%, 22.5% da 50%; d-mannitol - 5%; sodium saccharin - 3.16%) an shirya su yau da kullum a cikin ruwa mai tsabta ko 0.9% NaCl kuma ana kiyaye su a cikin dakin da zafin jiki. An kuma yi amfani da ruwan da aka cire da kuma maganin 0.9% NaCl kuma an sanya su azaman 'motoci'. An kuma isar da ruwan da aka zubar da baki, kamar yadda, a cikin wani gwajin gwaji, 5% da 15% na maganin glucose da aka shirya a cikin ruwan da ba a daɗe ba. d-glucose, d-mannitol, sodium saccharin, deionized ruwa da NaCl ana kiran su a cikin takarda kamar glucose, mannitol, saccharin, ruwa da saline bi da bi. An samo dukkan sinadarai daga Sigma-Aldrich (St. Louis, MO) kuma sun kasance-reagent-grade.

Jugular da Hepatic Portal Vein (HPV) Catheterization

Polyurethane catheters (Strategic Applications, Inc., Libertyville, IL), an dasa su a cikin jijiyar jugular dama a cikin berayen 75 kuma a cikin jijiya ta hanyar hanta a cikin berayen 35. Wasu dabbobin an sanya su a waje (Charles Rivers Laboratories, Wilmington, MA) yayin da wasu aka sanya su a cikin gida ta hanyar amfani da wannan hanya. A taƙaice, an yi amfani da dabbobi ta hanyar amfani da 5% halothane tare da intraperitoneal ko allurar intramuscular na xylazine (5-20 mg / kg) da ketamine (75-100 mg / kg). An ba da ƙarin allurai a duk lokacin da ya cancanta. Don catheterization na jugular, an yi ɗan ƙarami don fallasa jijiyar jugular dama. An haɗa ƙarshen cranial na jijiya kuma an sanya ligature maras kyau don ware wani yanki na 5 mm na jirgin ruwa. Don catheterization na portal, an yanke tsakiyar layi na ciki, an ciro cecum kuma an gano jijiya mesenteric. Hakazalika, an haɗa ƙarshen ƙarshen jijiya kuma an sanya ligature maras kyau a kusa don ware wani yanki na jirgin ruwa. A kowane hali, an shigar da catheter a cikin wani yanki da aka yi a tsakanin ligatures kuma an kiyaye shi ta wurin ɗaure ligature maras kyau a kusa da jirgin ruwa. Sannan an yi ɗan ƙaramin yanki a cikin yanki na scapular kuma an gyara catheter a cikin ƙasa kuma an fitar da shi waje ta wannan tsinkayar. An gwada rashin lafiya kuma an cika catheter da 'maganin kullewa' (500 IU/ml heparin a cikin 50% glucose) kuma an rufe shi da filogi. An yi wani aljihun fata mai ƙwanƙwasa ƙwanƙwasa kuma an saka mafi tsayin catheter a cikin aljihun. A ƙarshe, an rufe wurin katsewar jirgin ruwa da ɓangarorin fata na scapular tare da shirye-shiryen raunin rauni. An bar dabbobi su murmure har tsawon kwanaki 3 zuwa 5 bayan tiyata kafin fara wasu hanyoyin gwaji. Kafin waɗannan hanyoyin, an maye gurbin maganin kulle catheter da 50 IU/ml heparin a cikin 0.9% NaCl bayani, wanda kuma aka yi amfani da shi don kula da patency a cikin gwaje-gwajen halayen da aka gudanar a cikin kwanaki da yawa.

Saita Hali

An gudanar da dukkan gwaje-gwajen ɗabi'a a cikin akwatunan ɗabi'a na Med Associates (Med Associates Inc., St. Albans, VT), kowannensu a cikin ɗaki mai iska da rage sauti, kamar yadda aka bayyana a baya [65] . A takaice, an sanya ɗakuna da ramuka biyu don bututun sipper a ɗaya daga cikin bangon. Ana iya toshe hanyoyin shiga bututun sipper ta hanyar ƙofofi masu sarrafa kwamfuta kuma an sanya ramukan sipper da na'urorin lickometers da ake amfani da su don gano lasa (Med Associates Inc., St. Albans, VT). Kowace bututun sipper ta ƙunshi cannulae guda biyu masu ma'auni 20 waɗanda aka haɗa su da ginshiƙan chromatography na 50-ml (Kontes Flex-Columns; Fisher Scientific, Hampton, NH) inda aka ƙunshi hanyoyin ƙarfafawa. An sanya kwantena na maganin a wajen ɗakunan da ke rage sauti kuma an ajiye su a wuri mai tsayi don haɓaka kwararar ruwa ta hanyar nauyi. Na'urorin solenoids masu sarrafa kwamfuta (Parker Hannifin Corporation, Fairfield, NJ) sun daidaita kwararar ruwa ta yadda cikin mintuna 10 bayan an gano lasa, ɗaya daga cikin bawuloli ya buɗe ya kuma isar da kimanin µL na ruwa. An yi amfani da famfon sirinji (Med Associates Inc., St. Albans, VT) don ba da damar allurar mafita a cikin jijiyoyin jini yayin ayyukan ɗabi'a. An kunna famfon bayan mintuna 10 bayan an gano lasa, wanda ya haifar da allurar kusan µL na duk wani maganin da ke cikin sirinji da aka haɗa da famfon. Don haka, ƙimar jiko ta daidaita da ƙimar lasa (∼7 Hz) kuma yawan ruwan da aka sha ya yi daidai da adadin da aka saka.

Yanayi zuwa Tasirin Bugawa

Janar Protocol

Don gwada idan berayen sun ci gaba da nuna son kai ta hanyar glucose a cikin tsarin kwalba biyu, dabbobi 72 an fallasa su zuwa ka'idar sanyaya kwatankwacin abin da muka yi amfani da su a baya a cikin berayen. [2]. Ga kowane dabba, an ƙaddara son zuciya a cikin a Tsawon minti 10 gwada da ruwa da aka kawo a bangarorin biyu na akwatin ɗabi'a (ruwan kwalba biyu vs. gwajin ruwa). Da zarar an kafa nuna bambanci na gefe, an fallasa dabbobin na tsawon kwanaki 4 zuwa Tsawon minti 30 zaman samun damar samun ruwa kyauta wanda aka gabatar yau da kullum a wasu bangarori daban-daban na akwatin (zaman horo na tilasta zabin kwalba daya). A rana ta farko da ta uku, an gabatar da ruwa a gefe da ke gaban gaba da son zuciya na farko kuma an isar da 3 ml na abin motsa jiki lokaci guda zuwa ruwa don lasa 1000 na farko (watau 1000 × 3 µL).=ml 3). A kwana na biyu da na hudu, an gabatar da ruwa a kan gefen farko-bias da 3 mL na abin hawa (saline ko ruwa, duba ƙasa don cikakkun bayanai) an ba da shi lokaci guda zuwa ruwa don 1000 na farko. Yawanci, latsa 1000 na farko sun faru a cikin mintuna 8. Bayan horo, an gwada juyar da son zuciya a ciki Tsawon minti 10 ruwan kwalba biyu vs gwajin ruwa. A cikin waɗannan gwaje-gwajen, dabbobi 8 ba su kammala ka'idar kwantar da hankali ba saboda cuta ko asarar nauyi mai yawa kuma a cikin wasu 5 an sami kuskure a cikin ka'idar kwantar da hankali. Bayanai daga waɗannan dabbobi 13 an cire su daga bincike.

Ƙarfafa Ƙarfafawa

A cikin dabbobi 11, an yi gyaran jiki ta hanyar amfani da ruwan da ke cikin mota (ruwa) da kuma maganin glucose (beraye 6 da kashi 5% da kuma beraye 5 da kashi 15%), ana ba su ta baki yayin lasar ruwa. A cikin dabbobi 33, an yi gyaran jiki ta hanyar amfani da jiko na abin hawa (ruwa ko gishiri - babu wani bambanci da aka samu bisa ga nau'in abin hawa, bayanai ba a nuna ba) da kuma saccharin (beraye 5) ko kuma maganin glucose (beraye 10 da kashi 5%, beraye 7 da kashi 22.5% da kuma beraye 11 da kashi 50%) da aka bayar ta hanyar jiko na jijiya na jugular . A cikin dabbobi 15, an yi gyaran jiki ta hanyar amfani da jiko na mannitol 5% (beraye 5) ko kuma 5% glucose (beraye 10) da aka bayar ta hanyar jiko na jijiya na portal . A cikin waɗannan dabbobin da aka yi gyaran jiki ta amfani da jiko na jijiya, kafin a yi gwaji da kuma zaman gyaran jiki, an yi wa dabbar maganin sa barci ta amfani da isoflurane 5% kuma an haɗa jiko na jiko da sirinji da aka sanya a kan famfon jiko.

Ma'aunin Glucose na Jini

Wayyo Dabbobi

An horar da berayen da farko su sha a cikin tsawon mintuna 10 na yau da kullun na samun ruwa kyauta. Da zarar an sami daidaiton matakan amfani, an gudanar da zaman gwaji inda, don lasa na farko na 1000 na ruwa, an ba da wani abin ƙarfafawa (~ 3 mL) a baki ko kuma an saka shi, lokaci guda don lasa. A cikin maganin glucose na dabbobi 7 (berayen 3 tare da 5% da berayen 4 tare da 15%) an ba da su ta baki. A cikin dabbobi 20 maganin glucose an ba da su ta hanyar catheters jugular vein catheters (berayen 6 tare da 5%, berayen 4 tare da 22.5% da berayen 6 tare da 50%) ko catheters portal vein catheters (4 berayen tare da 5%). A ranar gwajin, an tattara jinin wutsiya don tantance glycemia duka kafin da kuma nan da nan bayan fallasa zuwa ɗakin gwaji (bi da bi na asali da 0′), da kuma a cikin mintuna 10 bayan an dawo da dabbar zuwa kejin gidansa (10′). , 20', 30', 40'). An auna Glycemia ta amfani da glucometer na hannu (Precision Xtra, Abbott Laboratories, Abbott Park, IL, Amurka; matsakaicin matakin gano 500 mg/dL).

Dabbobi masu saƙa

An yi amfani da berayen marasa ƙarfi ta hanyar amfani da 5% halothane sannan kuma allurar intramuscular na 50 mg/kg pentobarbital, wanda aka nuna yana ɗaya daga cikin dabarun maganin sa barci tare da ƙananan tasiri akan glycemia. [66]. An ba da ƙarin allurai a duk lokacin da ya cancanta. An yi wani yanki na tsakiya na ciki. A cikin berayen 15, waɗanda ba a yi musu tiyata a baya ba, an huda bangon ciki kuma an saka catheter polyethylene kamar yadda ƙarshensa ya kasance a cikin duodenum, kusan 2 cm daga pylorus. Sauran berayen 30 an riga an dasa su tare da catheters na jugular ko portal vein catheters. An auna matakan glucose na wutsiya a cikin tazara na mintuna 5 zuwa 10. Da zarar jinin glycemia na wutsiya ya daidaita, an yi rikodin ma'aunin glycemia na asali (0′) don duka wutsiya da jinin jijiya. Don tarin jinin portal, an gano jijiya ta hanta kusa da hilus hepatic kuma an yi amfani da allurar ma'auni 31 don tattara 0.05 zuwa 0.1 ml na jini. Sannan an yi allurar 3 ml na wani abin ƙarfafawa akai-akai a cikin mintuna 8 ta amfani da famfon sirinji (Med Associates Inc., St. Albans, VT), don yin koyi da yanayi yayin zaman horon ɗabi'a. Daga cikin dabbobin da ke da catheters duodenal, an yi wa berayen 5 allura da abin hawa (ruwa), 4 tare da 5% glucose da 6 tare da 15% glucose. A cikin berayen 11 tare da catheters portal vein ko dai abin hawa (saline; n=4) ko 5% glucose an gudanar da shi (n=7). Ragowar berayen 19 suna da catheters jugular vein catheters kuma sun sami ko wanne abin hawa (saline; n=5) ko maganin glucose (5%, n=6; 22.5%, n=4; 50%, n=4). An tattara jinin wutsiya da jinin jijiya na portal daga baya a tazara na mintuna 10 har zuwa awa 1, farawa minti 10 bayan ƙaddamar da infusions (10′, 20′, 30′, 40′, 50′ da 60′). An auna Glycemia a cikin wutsiya da jini na portal kamar yadda aka bayyana a sama.

Saurin motsa jiki mai saurin motsa jiki

Ƙirarradi

An shirya ƙananan electrodes na carbon-fiber daga zaruruwan carbon T-300 masu diamita 7 µm (Amoco, Greenville, SC) kamar yadda aka bayyana a baya [67] . Idan ya zama dole, an ƙara epoxy a cikin haɗin gilashi/fiber don inganta hatimin. An bar kusan µm na zare a bayan hatimin gilashi/carbon. An jiƙa duk electrodes a cikin 2-propanol tare da gawayi Norit-A da aka kunna na akalla minti 10 kafin amfani. Bayan an rage zuwa zurfin farawa a cikin ƙwayoyin nucleus, an daidaita electrodes ta hanyar yin keke na tsawon mintuna 15 a 60 Hz tare da siffar waveform alwatika (−0.4 V zuwa 1.3 V vs Ag/AgCl a 400 V/sec) sannan kuma na tsawon mintuna 15 a mitar da aka yi amfani da ita don tattara bayanai, 10 Hz [68] . An yi amfani da wayoyin azurfa da aka yi da chlorid a matsayin electrodes na tunani kuma an bayar da rahoton duk ƙarfin da aka samu idan aka kwatanta da Ag/AgCl.

Lantarki

Don saurin-scan cyclic voltammetry (FSCV) mun yi amfani da kayan aikin lantarki na UEI (Jami'ar North Carolina Department of Chemistry Electronics Facility, Chapel Hill, NC). An yi amfani da allunan Instruments na ƙasa (PCI-6052 da PCI-6711E) da software na TH-1 (ESA, Chelmsford, MA) don haɓakar motsi, tattara bayanai, tace dijital da ganowa da bincike na wucin gadi na dopamine. Don gano dopamine na extracellular an yi amfani da nau'in igiyar alwatika (-0.4 V zuwa 1.3 V vs Ag/AgCl a 400 V/sec) zuwa microelectrode na carbon-fiber a 10 Hz. Canje-canje a cikin dopamine na waje an ƙaddara ta hanyar saka idanu na yanzu akan taga 100 mV a mafi girman yuwuwar iskar oxygenation na dopamine (kimanin 0.65 V). Dopamine igiyoyin ruwa a vivo an canza su zuwa adadin dopamine ta hanyar daidaita na'urorin lantarki bayan amfani da gwaji tare da daidaitattun hanyoyin maganin dopamine guda biyu a cikin tsarin allurar kwarara. Abun da ke cikin buffer da aka yi amfani da shi don daidaitawa shine (a cikin mM): 126 NaCl, 2.5 KCl, 2.4 CaCl₂, 1.2 MgCl₂, 2.0 Na₂SO₄, 1.2 NaH₂PO₄, 15 TRIS HCl, pH=7.4.

Hanyoyin In-vivo

An ba beraye goma sha biyu damar murmurewa daga dashen catheter na akalla kwanaki 3 kafin abinci da rashin ruwa na dare. Da safe bayan rashi, an sanya berayen da urethane (1.5 g/kg ip) kuma an sanya su a cikin na'urar stereotaxic (David Kopf Instruments, Tujunga, CA). An kiyaye zafin jiki a 37°C tare da Deltaphase Isothermal Pad (Braintree Scientific, Braintree, MA). An sake gyara gashin kai da abin da ke ciki kuma an tona ramuka don aiki, ƙarfafawa da na'urorin lantarki. Ana ba da haɗin gwiwar stereotactic a mm anteroposterior (AP) da matsakaici (ML) daga bregma, da dorsoventral (DV) daga dura. An sanya na'urar lantarki mai motsa jiki ta bipolar (Plastics One Inc., Roanoke, VA) a cikin yanki na ventral tegmental (VTA): -5.2 AP, +1.0 ML, -7.5 to -9.0 DV. An sanya microelectrode na carbon-fiber a cikin ƙwayar ƙwayar ƙwayar cuta ta ipsilateral (+1.7 AP, 0.8 ML, -6.4 to -7.4 DV). An sanya waya mai magana ta Ag/AgCl a cikin cortex mai cin karo da juna. Extracellular dopamine taro sakamakon 24 bugun jini 60 Hz motsa jiki jiragen kasa (biphasic, 2 ms kowane lokaci da 130 µA) na VTA aka yi rikodin. Wuraren da ke daɗa kuzari da na'urori masu aiki an inganta su don nemo rukunin yanar gizon da ke goyan bayan sakin dopamine mai kuzari da lantarki da kuma wuce gona da iri na dopamine. Samfuran Dopamine don ganowa na ɗan lokaci na gaba an yi su daga nau'ikan voltammogram na cyclic da aka samu daga haɓakar sakin. Duk rukunin yanar gizon da aka zaɓa don bincike na wucin gadi suna tallafawa sakin dopamine mai kuzari tare da siginar amo na 30 ko fiye. An ƙaddara glycemia na jini na wutsiya, kamar yadda aka bayyana a sama, kuma an rubuta bayanan asali na tsawon mintuna 6 zuwa 10 ba tare da ƙarin kuzari ba. Nan da nan bayan tattara bayanan tushe na ƙarshe, an kunna famfo jiko. An saka glucose (5% a cikin saline) (3 ml/5 min) a ko dai ta hanyar hanta ko jijiya. Don ƙungiyar kulawa, an shigar da saline a cikin jijiya ta portal. An yi rikodin fayilolin minti ɗaya ci gaba har tsawon mintuna 20, bayan haka an sake ƙaddara glycemia na jini na wutsiya kuma an tabbatar da tabbatar da sakin kuzari. Ba za a iya auna glycemia a cikin dabbobi guda 2 ba, saboda rashin aikin glucometer. Don sanin ko rukunin sakin dopamine da aka yi rikodin ya kasance mai amsawa ga hanawar dopamine, an ba da allurar intraperitoneal na 15 mg/kg cocaine awa daya bayan jiko. An yi rikodin bayanai na mintuna 25 bayan hodar Iblis kuma an sake duba sakin kuzari. A cikin dabbobin 4, mitar mai wucewa ta ragu ko kuma ta kasance mara ƙarfi a lokacin da ake sarrafa hodar iblis.

data Analysis

An bayyana sakamakon binciken bayanai a matsayin matsakaicin ± kuskuren daidaito na matsakaicin kuma 'n' shine adadin beraye. An yi nazarin tare da GraphPad Prism (GraphPad Software, Inc., San Diego, California) ko software na NCSS 2000 (NCSS, Kaysville, UT), kuma an yi amfani da ANOVAs masu hanya biyu ko hanya ɗaya (tare da gwaje-gwajen post-hoc na Bonferroni) da gwaje-gwajen t-samfuri biyu ko samfurin ɗaya. An yi gyaran Bonferroni mai jere don kwatantawa da yawa tare da hanyar Holm [69] duk lokacin da aka yi amfani da gwaje-gwajen t-mai zaman kanta da yawa a cikin saitin bayanai iri ɗaya.

Matakan Zaɓin Halaye

An tantance gwajin zaɓin kwalba biyu ta hanyar ƙididdige ƙimar fifiko kamar

inda n (.) ke nuna jimlar adadin lasa da aka gano a wani sipper na musamman yayin zaman. Mahimman gwaje-gwajen sun dogara ne akan gwajin-t-samfuri guda ɗaya akan 0.5, wanda shine ma'anar ƙimar ma'anar rashin kulawa game da kowane sipper.

Matakan Glycemia na Jini

Danna nan don ƙarin fayil din bayanai.^{(57K, doc)}

S5 Table

Dopamine na wucin gadi na wucin gadi a cikin tsakiya na tarin berayen da ba a sa su ba, bayan glucose ko sarrafa abin hawa a cikin hepatic-portal ko jugular vein. An yi amfani da saurin-scan cyclic voltammetry don gano abubuwan sakin dopamine na kwatsam ko "masu wucewa" a cikin ƙwayar ƙwayar ƙwayar ƙwayar cuta ta berayen da aka saƙa. An gudanar da ma'auni na tsawon lokaci, da kuma lokacin da kuma bayan jiko na 5% glucose a cikin JV (n)=4) ko HPV (n=4), ko abin hawa a karshen (n=4). Jikowar glucose a cikin HPV, amma ba JV ba, an nuna yana haifar da haɓakar mitar dopamine na wucin gadi, idan aka kwatanta da tasirin jiko na abin hawa a cikin HPV da kuma ma'auni na asali (kuma duba). Siffa 5). Ana jaddada mahimmin kwatance a matsayin rubutu mai ƙarfi. (salin-salin).

(DOC)

Danna nan don ƙarin fayil din bayanai.^{(45K, doc)}

Ka tafi zuwa ga:

Acknowledgments

Mun gode wa Teresa Maia, Jim Meloy da Gary Lehew don goyon bayan fasaha, da Susan Halkiotis don nazarin rubutun.

Ka tafi zuwa ga:

Bayanan kalmomi

Abubuwan da ke Gogayya: Marubutan sun bayyana cewa babu wani abin da ke gogayya da juna.

Tallafi: An tallafa wa wannan aikin ta hanyar lambar Tallafi ta R01DC001065 ga Sidney Simon daga Cibiyar Kula da Kurame da Sauran Matsalolin Sadarwa ta Ƙasa (NIDCD). Masu ba da tallafin ba su da wani tasiri a cikin tsara nazari, tattara bayanai da nazarin su, yanke shawarar bugawa, ko shirya rubutun. Abubuwan da ke ciki alhakin marubuta ne kawai kuma ba lallai bane su wakilci ra'ayoyin hukuma na NIDCD ko Cibiyoyin Lafiya na Ƙasa.

Ka tafi zuwa ga:

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Abstract

Gabatarwa

results

tattaunawa

Kaya da matakai

Bayanan Haɓaka

batutuwa

Sakamakon

Jugular da Hepatic Portal Vein (HPV) Catheterization

Saita Hali

Yanayi zuwa Tasirin Bugawa

Janar Protocol

Ƙarfafa Ƙarfafawa

Ma'aunin Glucose na Jini

Wayyo Dabbobi

Dabbobi masu saƙa

Saurin motsa jiki mai saurin motsa jiki

Ƙirarradi

Lantarki

Hanyoyin In-vivo

data Analysis

Matakan Zaɓin Halaye

Matakan Glycemia na Jini

Dopamine Transients

Goyan bayan Bayanan

S1

S2

S3

S4

S5

S1 Table

S2 Table

S3 Table

S4 Table

S5 Table

Acknowledgments

Bayanan kalmomi

References

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