Nogo-A及受體NgR對大鼠視皮層可塑性調(diào)控作用的研究
發(fā)布時間：2018-09-19 18:34
【摘要】：第一章Nogo-A及受體NgR在正常發(fā)育及單眼剝奪模型大鼠視皮層中表達(dá)的動態(tài)變化 目的探討正常發(fā)育過程及單眼剝奪模型大鼠視皮層中Nogo-A及受體NgR的mRNA和蛋白質(zhì)表達(dá)的動態(tài)變化及意義。 方法84只新生SD大鼠隨機(jī)分為6組：0日齡正常組(NorPO,12只)、14日齡正常組(NorP14,12只)、28日齡正常組(NorP28,12只)、60日齡正常組(NorP60,18只)、28日齡模型組(MDP28,12只)以及60日齡模型組(MDP60,18只),模型組大鼠于出生后21天縫合右側(cè)眼瞼建立單眼形覺剝奪模型。各組動物均依照實驗設(shè)計的時間點處死并取左側(cè)視皮層組織,提取總RNA及蛋白質(zhì),采用RT-PCR及免疫印跡Western blot方法檢測視皮層中Nogo-A及NgR的表達(dá),了解正常發(fā)育及單眼剝奪模型大鼠視皮層中Nogo-A及NgR的動態(tài)表達(dá)趨勢,同時通過免疫熒光組織化學(xué)方法檢測早期單眼剝奪對Nogo-A及NgR蛋白表達(dá)影響的層特異性。 結(jié)果正常新生大鼠(NorPO)視皮層中即有Nogo-A/NgR mRNA及蛋白質(zhì)的表達(dá),其表達(dá)量隨年齡增長而明顯上調(diào)。其中Nogo-A mRNA及蛋白質(zhì)于出生后28天(NorP28)到達(dá)高峰并持續(xù)至成年期(NorP60); NgR mRNA于出生后14天(NorP14)到達(dá)高峰并持續(xù)至成年期(NorP60),而NgR蛋白質(zhì)表達(dá)上調(diào)則較mRNA滯后,于出生后28天(NorP28)到達(dá)高峰并持續(xù)至成年期(NorP60)。早期單眼剝奪后,模型組(MDP28、MDP60)大鼠剝奪眼對側(cè)視皮層中Nogo-A/NgR mRNA及蛋白質(zhì)表達(dá)較同日齡正常組(NorP28、NorP60)輕度減少,差異均無統(tǒng)計學(xué)意義(P0.05)。此外,MDP28組與MDP60組大鼠比較剝奪眼對側(cè)視皮層中Nogo-A/NgR mRNA及蛋白質(zhì)表達(dá)水平差異無統(tǒng)計學(xué)意義(P0.05)。免疫熒光組織化學(xué)方法檢測顯示Nogo-A及NgR蛋白在NorP60組及MDP60組大鼠視皮層Ⅱ-Ⅲ層,Ⅳ層,Ⅴ層,Ⅵ層中均有表達(dá),早期單眼剝奪可使MDP60組大鼠剝奪眼對側(cè)視皮層中第Ⅱ-Ⅲ層、Ⅳ層Nogo-A及NgR免疫陽性細(xì)胞密度較NorP60組明顯下調(diào)。 結(jié)論大鼠Nogo-A/NgR mRNA及蛋白質(zhì)自出生到成年期在視皮層中持續(xù)表達(dá),且在視覺發(fā)育關(guān)鍵期后期達(dá)高峰,視覺發(fā)育早期單眼剝奪可致其表達(dá)下調(diào),呈現(xiàn)出一定的視覺經(jīng)驗依賴性。因此,Nogo-A/NgR在視覺發(fā)育早期可能主要參與軸突生長及導(dǎo)向；同時調(diào)控視皮層可塑性關(guān)鍵期的終止,并對成年視皮層可塑性發(fā)揮一定的抑制作用。 第二章NgR拮抗劑NEP1-40對成年單眼剝奪模型大鼠視皮層可塑性的再激活作用 目的觀察NgR拮抗劑NEP1-40對成年單眼剝奪模型大鼠剝奪眼對側(cè)視皮層結(jié)構(gòu)及功能可塑性再激活的影響,進(jìn)一步闡明Nogo-A/NgR信號系統(tǒng)對成年視皮層可塑性的調(diào)控作用。 方法將120只新生SD大鼠隨機(jī)分為兩大組即正常組和單眼剝奪模型組。按給藥方式不同,正常組又分為正常對照組(Nor)、正常+PBS治療組(Nor+PBS)、正常+NEP1-40治療組(Nor+NEP);單眼剝奪模型組又分為模型對照組(MD)、模型+PBS治療組(MD+PBS)以及模型+NEP1-40治療組(MD+NEP),每組各20只。模型組大鼠于出生后21天縫合右側(cè)眼瞼建立單眼形覺剝奪模型,于45日齡時打開剝奪眼,對各組大鼠行閃光視覺誘發(fā)電位(F-VEP)檢測,確定單眼剝奪模型建立成功后,對需給藥的各組大鼠按組別給予0.02mg/μl的NEP1-40或0.01M的PBS側(cè)腦室注藥治療,每天1次,每次10μl,持續(xù)7天。于52日齡時對各組大鼠再次行F-VEP檢測后處死動物,取側(cè)腦室組織行尼氏染色明確給藥部位,取左側(cè)視皮層組織進(jìn)行尼氏染色觀察神經(jīng)元形態(tài)及數(shù)量、高爾基染色觀察樹突棘密度、透射電鏡觀察突觸超微結(jié)構(gòu)變化。 結(jié)果(1)尼氏染色觀察側(cè)腦室及視皮層組織結(jié)構(gòu)：未接受側(cè)腦室注藥治療的MD組大鼠,大腦皮層組織結(jié)構(gòu)完整,未見注射針頭的痕跡；接受過側(cè)腦室注藥治療的MD+PBS組及MD+NEP組大鼠,可見注射針頭經(jīng)大腦皮層向側(cè)腦室方向穿過的痕跡。此外,接受過側(cè)腦室注藥治療的MD+PBS組及MD+NEP組大鼠剝奪眼對側(cè)視皮層層次分明,結(jié)構(gòu)清晰,神經(jīng)細(xì)胞數(shù)量及形態(tài)較MD組無明顯差異。 (2)高爾基染色觀察視皮層神經(jīng)元樹突棘密度：MD組大鼠剝奪眼對側(cè)視皮層神經(jīng)元樹突棘密度較Nor組顯著降低(P0.05)。Nor+PBS組及Nor+NEP組大鼠視皮層神經(jīng)元樹突棘密度與Nor組比較差異均無統(tǒng)計學(xué)意義(P0.05); MD+NEP組大鼠剝奪眼對側(cè)視皮層樹突棘密度較MD組及MD+PBS組明顯增加(P0.05),且與Nor組比較差異無統(tǒng)計學(xué)意義(P0.05)；MD+PBS組與MD組大鼠剝奪眼對側(cè)視皮層神經(jīng)元樹突棘密度比較差異無統(tǒng)計學(xué)意義(P0.05),而與Nor組比較差異有統(tǒng)計學(xué)意義(P0.05)。 (3)透射電鏡觀察視皮層神經(jīng)元突觸界面結(jié)構(gòu)參數(shù)：與Nor組比較,MD組大鼠剝奪眼對側(cè)視皮層神經(jīng)元突觸間隙增大,突觸活性區(qū)長度縮短,突觸界面曲率減小,突觸后致密物厚度變薄(P0.05)。Nor+PBS組及Nor+NEP組大鼠視皮層神經(jīng)元突觸界面結(jié)構(gòu)參數(shù)的各項指標(biāo)與Nor組比較差異均無統(tǒng)計學(xué)意義(P0.05)；MD+NEP組大鼠剝奪眼對側(cè)視皮層神經(jīng)元突觸界面結(jié)構(gòu)參數(shù)的各項指標(biāo)均較MD組、MD+PBS組明顯改善(P0.05),與Nor組相比除突觸間隙外(P0.05),其余各項參數(shù)差異無統(tǒng)計學(xué)意義(P0.05)。MD+PBS組與MD組大鼠比較剝奪眼對側(cè)視皮層神經(jīng)元突觸界面結(jié)構(gòu)參數(shù)的各項指標(biāo)差異均無統(tǒng)計學(xué)意義(P0.05),而與Nor組比較差異有統(tǒng)計學(xué)意義(P0.05)。 (4)閃光視覺誘發(fā)電位評估大鼠客觀視功能：45日齡時F-VEP檢測示,MD組、MD+PBS組及MD+NEP組與Nor組比較,P波潛伏期延長,波幅降低(P0.05)；而Nor+PBS組及Nor+NEP組大鼠P波的潛伏期及波幅與Nor組比較差異均無統(tǒng)計學(xué)意義(P0.05)。52日齡時F-VEP檢測示,MD組與Nor組比較大鼠右眼F-VEP的P波潛伏期延長,波幅降低(P0.05)。Nor+PBS組及Nor+NEP組大鼠右眼F-VEP的P波潛伏期及波幅與Nor組比較差異均無統(tǒng)計學(xué)意義(P0.05); MD+NEP組與MD組、MD+PBS組大鼠比較右眼F-VEP的P波潛伏期及波幅差異有統(tǒng)計學(xué)意義(P0.05),而與Nor組比較差異無統(tǒng)計學(xué)意義(P0.05); MD+PBS組與MD組大鼠比較,右眼F-VEP的P波潛伏期及波幅差異無統(tǒng)計學(xué)意義(P0.05),而與Nor組比較差異有統(tǒng)計學(xué)意義(P0.05)。 結(jié)論NgR拮抗劑NEP1-40可使成年單眼剝奪模型大鼠剝奪眼對側(cè)視皮層神經(jīng)元的樹突棘密度、突觸界面結(jié)構(gòu)參數(shù)得以恢復(fù),F-VEP的P波潛伏期及波幅恢復(fù)至正常水平,重新“激活”被抑制的視皮層結(jié)構(gòu)及功能可塑性。這一研究結(jié)果為Nogo-A/NgR系統(tǒng)參與視皮層可塑性的調(diào)控提供了直接證據(jù),同時為成年弱視患者提供新的治療途徑奠定了理論基礎(chǔ)。
[Abstract]:Chapter 1 Dynamic Changes of Nogo-A and NgR Expression in the Visual Cortex of Normal Developmental and Monocular Deprivation Rats
Objective To investigate the dynamic changes and significance of Nogo-A and NgR mRNA and protein expression in visual cortex of normal development and monocular deprivation rats.
Methods 84 neonatal SD rats were randomly divided into 6 groups: normal group (NorPO, 12 rats), normal group (NorP14, 12 rats), normal group (NorP28, 12 rats), normal group (NorP60, 18 rats), model group (MDP28, 12 rats) and model group (MDP60, 18 rats) at the age of 20 days after birth. Form deprivation model.Each group of animals was executed according to the experimental design time point and the left visual cortex was taken out to extract total RNA and protein.The expression of Nogo-A and NgR in visual cortex was detected by RT-PCR and Western blot. Immunofluorescence histochemistry was used to detect the layer specificity of the effect of early monocular deprivation on the expression of Nogo-A and NgR proteins.
Results The expression of Nogo-A/NgR mRNA and protein in visual cortex of normal neonatal rats (NorPO) was up-regulated with age. Nogo-A mRNA and protein peaked at 28 days after birth (NorP28) and lasted until adulthood (NorP60); NgR mRNA peaked at 14 days after birth (NorP14) and lasted until adulthood (NorP60). However, the up-regulation of NgR protein expression was lagged behind that of mRNA, reaching its peak at 28 days after birth (NorP28) and continuing to adulthood (NorP60). After early monocular deprivation, the expression of Nogo-A/NgR mRNA and protein in the contralateral visual cortex of the deprived rats in the model group (MDP28, MDP60) was slightly lower than that in the normal control group (NorP28, NorP60). In addition, there was no significant difference in the expression of Nogo-A/NgR mRNA and protein between MDP 28 and MDP 60 deprived rats (P 0.05). Immunofluorescence histochemistry showed that Nogo-A and NgR proteins were expressed in layers II-III, IV, V and VI of the visual cortex of NorP 60 and MDP 60 rats. The densities of Nogo-A and NgR immunoreactive cells in the contralateral visual cortex of MDP60 rats were significantly lower than those in NorP60 rats.
Conclusion Nogo-A/NgR mRNA and protein are continuously expressed in the visual cortex from birth to adulthood, and reach a peak at the late critical stage of visual development. Monocular deprivation in early visual development can lead to down-regulation of Nogo-A/NgR expression, showing a certain degree of visual experience dependence. At the same time, it regulates the termination of the critical period of visual cortex plasticity and inhibits the adult visual cortex plasticity.
The second chapter is about the reactivation of NgR antagonist NEP1-40 on the plasticity of visual cortex in adult monocular deprivation rats.
Objective To observe the effects of NgR antagonist NEP1-40 on the structural and functional plasticity reactivation of the contralateral visual cortex in adult monocular deprivation rats, and further elucidate the regulatory role of the Nogo-A/NgR signaling system on the plasticity of the adult visual cortex.
Methods 120 neonatal SD rats were randomly divided into two groups: normal group and monocular deprivation model group. According to different administration methods, the normal group was divided into normal control group (Nor), normal + PBS treatment group (Nor + PBS), normal + NEP1-40 treatment group (Nor + NEP), monocular deprivation model group was divided into model control group (MD), model + PBS treatment group (MD + PBS) and model. The model group was established by suturing the right eyelid 21 days after birth. The deprived eyes were opened at 45 days of age. The flash visual evoked potential (F-VEP) was detected in each group. After the successful establishment of the deprived model, the rats in each group were given 0.02mg/mu according to the group. L NEP 1-40 or 0.01M PBS were injected into the lateral ventricle once a day, 10 ml each time for 7 days. At the age of 52, the rats in each group were sacrificed after F-VEP test again. The lateral ventricle tissues were taken for Nissl staining to determine the site of administration. The left visual cortex tissues were taken for Nissl staining to observe the morphology and number of neurons. The dendrites were observed by Golgi staining. The ultrastructure of synapses was observed by transmission electron microscope.
Results (1) Nissl staining was used to observe the structure of the lateral ventricle and visual cortex: The cortex of MD rats without the treatment of lateral ventricle injection was intact, and there was no evidence of needle penetration; MD+PBS rats and MD+NEP rats with the treatment of lateral ventricle injection showed that the needle penetrated the lateral ventricle through the cerebral cortex. In addition, MD+PBS group and MD+NEP group, which had been treated by intraventricular injection, had distinct layers and clear structures of contralateral visual cortex. There was no significant difference in the number and morphology of nerve cells between MD+PBS group and MD+NEP group.
(2) Golgi staining to observe dendritic spine density of optic cortex neurons: The dendritic spine density of deprived contralateral optic cortex neurons in MD group was significantly lower than that in Nor group (P 0.05). The dendritic spine density of optic cortex neurons in Nor+PBS group and Nor+NEP group was not significantly different from that in Nor group (P 0.05). Compared with MD group and MD+PBS group, the density of dendritic spines in MD+PBS group increased significantly (P 0.05), and there was no significant difference between MD+PBS group and Nor group (P 0.05); there was no significant difference between MD+PBS group and MD group in dendritic spines density of deprived contralateral visual cortex neurons (P 0.05), but there was significant difference between MD+PBS group and Nor group (P 0.05).
(3) Observation of synaptic interface parameters by transmission electron microscopy: Compared with Nor group, the synaptic gap of deprived contralateral visual cortex neurons in MD group increased, the length of synaptic active area shortened, the curvature of synaptic interface decreased, and the thickness of postsynaptic dense substance thinned (P 0.05). There was no significant difference in the parameters of synaptic interface between MD + NEP group and Nor group (P 0.05). The parameters of synaptic interface of deprived contralateral visual cortex neurons in MD + NEP group were significantly improved compared with MD group and MD + PBS group (P 0.05). There was no significant difference in the parameters of synaptic interface between BS group and MD group (P 0.05), but there was significant difference between BS group and Nor group (P 0.05).
(4) Flash Visual Evoked Potentials Assessment of Objective Visual Function in Rats: At 45 days of age, F-VEP detection showed that compared with Nor group, MD+PBS group, MD+NEP group and MD+PBS group, P wave latency was prolonged and amplitude was decreased (P 0.05), but there was no significant difference between Nor+PBS group and Nor+NEP group in P wave latency and amplitude (P 0.05). The results showed that the P wave latency and amplitude of F-VE P in the right eye of MD group and Nor group were prolonged and decreased (P 0.05). There was no significant difference between Nor+PBS group and Nor+NEP group in the P wave latency and amplitude of F-VE P in the right eye (P 0.05). There was no significant difference in P wave latency and amplitude between MD+PBS group and MD group (P 0.05), but there was significant difference between MD+PBS group and Nor group (P 0.05).
Conclusion NgR antagonist NEP1-40 can restore the dendritic spine density, synaptic interface structure parameters, F-VE P latency and amplitude to normal level, and re-activate the inhibited visual cortex structure and functional plasticity in adult monocular deprivation rats. Systematic involvement in the regulation of visual cortex plasticity provides direct evidence, and provides a theoretical basis for the treatment of adult amblyopia.
【學(xué)位授予單位】：中南大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2011
【分類號】：R77
本文編號：2250974
[Abstract]:Chapter 1 Dynamic Changes of Nogo-A and NgR Expression in the Visual Cortex of Normal Developmental and Monocular Deprivation Rats
Objective To investigate the dynamic changes and significance of Nogo-A and NgR mRNA and protein expression in visual cortex of normal development and monocular deprivation rats.
Methods 84 neonatal SD rats were randomly divided into 6 groups: normal group (NorPO, 12 rats), normal group (NorP14, 12 rats), normal group (NorP28, 12 rats), normal group (NorP60, 18 rats), model group (MDP28, 12 rats) and model group (MDP60, 18 rats) at the age of 20 days after birth. Form deprivation model.Each group of animals was executed according to the experimental design time point and the left visual cortex was taken out to extract total RNA and protein.The expression of Nogo-A and NgR in visual cortex was detected by RT-PCR and Western blot. Immunofluorescence histochemistry was used to detect the layer specificity of the effect of early monocular deprivation on the expression of Nogo-A and NgR proteins.
Results The expression of Nogo-A/NgR mRNA and protein in visual cortex of normal neonatal rats (NorPO) was up-regulated with age. Nogo-A mRNA and protein peaked at 28 days after birth (NorP28) and lasted until adulthood (NorP60); NgR mRNA peaked at 14 days after birth (NorP14) and lasted until adulthood (NorP60). However, the up-regulation of NgR protein expression was lagged behind that of mRNA, reaching its peak at 28 days after birth (NorP28) and continuing to adulthood (NorP60). After early monocular deprivation, the expression of Nogo-A/NgR mRNA and protein in the contralateral visual cortex of the deprived rats in the model group (MDP28, MDP60) was slightly lower than that in the normal control group (NorP28, NorP60). In addition, there was no significant difference in the expression of Nogo-A/NgR mRNA and protein between MDP 28 and MDP 60 deprived rats (P 0.05). Immunofluorescence histochemistry showed that Nogo-A and NgR proteins were expressed in layers II-III, IV, V and VI of the visual cortex of NorP 60 and MDP 60 rats. The densities of Nogo-A and NgR immunoreactive cells in the contralateral visual cortex of MDP60 rats were significantly lower than those in NorP60 rats.
Conclusion Nogo-A/NgR mRNA and protein are continuously expressed in the visual cortex from birth to adulthood, and reach a peak at the late critical stage of visual development. Monocular deprivation in early visual development can lead to down-regulation of Nogo-A/NgR expression, showing a certain degree of visual experience dependence. At the same time, it regulates the termination of the critical period of visual cortex plasticity and inhibits the adult visual cortex plasticity.
The second chapter is about the reactivation of NgR antagonist NEP1-40 on the plasticity of visual cortex in adult monocular deprivation rats.
Objective To observe the effects of NgR antagonist NEP1-40 on the structural and functional plasticity reactivation of the contralateral visual cortex in adult monocular deprivation rats, and further elucidate the regulatory role of the Nogo-A/NgR signaling system on the plasticity of the adult visual cortex.
Methods 120 neonatal SD rats were randomly divided into two groups: normal group and monocular deprivation model group. According to different administration methods, the normal group was divided into normal control group (Nor), normal + PBS treatment group (Nor + PBS), normal + NEP1-40 treatment group (Nor + NEP), monocular deprivation model group was divided into model control group (MD), model + PBS treatment group (MD + PBS) and model. The model group was established by suturing the right eyelid 21 days after birth. The deprived eyes were opened at 45 days of age. The flash visual evoked potential (F-VEP) was detected in each group. After the successful establishment of the deprived model, the rats in each group were given 0.02mg/mu according to the group. L NEP 1-40 or 0.01M PBS were injected into the lateral ventricle once a day, 10 ml each time for 7 days. At the age of 52, the rats in each group were sacrificed after F-VEP test again. The lateral ventricle tissues were taken for Nissl staining to determine the site of administration. The left visual cortex tissues were taken for Nissl staining to observe the morphology and number of neurons. The dendrites were observed by Golgi staining. The ultrastructure of synapses was observed by transmission electron microscope.
Results (1) Nissl staining was used to observe the structure of the lateral ventricle and visual cortex: The cortex of MD rats without the treatment of lateral ventricle injection was intact, and there was no evidence of needle penetration; MD+PBS rats and MD+NEP rats with the treatment of lateral ventricle injection showed that the needle penetrated the lateral ventricle through the cerebral cortex. In addition, MD+PBS group and MD+NEP group, which had been treated by intraventricular injection, had distinct layers and clear structures of contralateral visual cortex. There was no significant difference in the number and morphology of nerve cells between MD+PBS group and MD+NEP group.
(2) Golgi staining to observe dendritic spine density of optic cortex neurons: The dendritic spine density of deprived contralateral optic cortex neurons in MD group was significantly lower than that in Nor group (P 0.05). The dendritic spine density of optic cortex neurons in Nor+PBS group and Nor+NEP group was not significantly different from that in Nor group (P 0.05). Compared with MD group and MD+PBS group, the density of dendritic spines in MD+PBS group increased significantly (P 0.05), and there was no significant difference between MD+PBS group and Nor group (P 0.05); there was no significant difference between MD+PBS group and MD group in dendritic spines density of deprived contralateral visual cortex neurons (P 0.05), but there was significant difference between MD+PBS group and Nor group (P 0.05).
(3) Observation of synaptic interface parameters by transmission electron microscopy: Compared with Nor group, the synaptic gap of deprived contralateral visual cortex neurons in MD group increased, the length of synaptic active area shortened, the curvature of synaptic interface decreased, and the thickness of postsynaptic dense substance thinned (P 0.05). There was no significant difference in the parameters of synaptic interface between MD + NEP group and Nor group (P 0.05). The parameters of synaptic interface of deprived contralateral visual cortex neurons in MD + NEP group were significantly improved compared with MD group and MD + PBS group (P 0.05). There was no significant difference in the parameters of synaptic interface between BS group and MD group (P 0.05), but there was significant difference between BS group and Nor group (P 0.05).
(4) Flash Visual Evoked Potentials Assessment of Objective Visual Function in Rats: At 45 days of age, F-VEP detection showed that compared with Nor group, MD+PBS group, MD+NEP group and MD+PBS group, P wave latency was prolonged and amplitude was decreased (P 0.05), but there was no significant difference between Nor+PBS group and Nor+NEP group in P wave latency and amplitude (P 0.05). The results showed that the P wave latency and amplitude of F-VE P in the right eye of MD group and Nor group were prolonged and decreased (P 0.05). There was no significant difference between Nor+PBS group and Nor+NEP group in the P wave latency and amplitude of F-VE P in the right eye (P 0.05). There was no significant difference in P wave latency and amplitude between MD+PBS group and MD group (P 0.05), but there was significant difference between MD+PBS group and Nor group (P 0.05).
Conclusion NgR antagonist NEP1-40 can restore the dendritic spine density, synaptic interface structure parameters, F-VE P latency and amplitude to normal level, and re-activate the inhibited visual cortex structure and functional plasticity in adult monocular deprivation rats. Systematic involvement in the regulation of visual cortex plasticity provides direct evidence, and provides a theoretical basis for the treatment of adult amblyopia.
【學(xué)位授予單位】：中南大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2011
【分類號】：R77
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