本文選題：MGE + nNOS��； 參考：《南京醫(yī)科大學》2017年碩士論文

【摘要】：皮層與海馬的信息處理依賴于谷氨酸能興奮性投射神經元與γ-氨基丁酸(GABA)能抑制性神經元之間復雜的相互作用。兩種神經元之間協(xié)調的相互作用對于維持大腦興奮與抑制信號之間微妙的平衡關系至關重要,這種平衡受到很多神經調節(jié)物質如不同的神經肽、一氧化氮(NO)等的動態(tài)調節(jié)。平衡的破壞會導致很多病理性的障礙如癲癇、自閉癥、精神分裂癥等。NO參與了神經傳遞、突觸可塑性、血管舒張、炎癥等很多生理過程,是一個非常重要的信號分子,NO產生或釋放功能的缺陷會導致神經元死亡以及癲癇等疾病。NO由一氧化氮合酶(NOS)合成,根據最初被發(fā)現(xiàn)時所在的部位,NOS又可分為內皮型一氧化氮合酶(eNOS)、神經元型一氧化氮合酶(nNOS)以及可誘導型一氧化氮合酶(iNOS)。在神經元中NO主要由nNOS合成,在幼稚和成熟的海馬與皮層中nNOS主要表達在GABA能中間神經元上。GABA能中間神經元主要來源于三個不同部位:中間神經節(jié)隆起(MGE)、外側/尾部神經節(jié)隆起(LGE/CGE)以及視前區(qū)(POA),每個神經上皮前體細胞部位都會產生不同的中間神經元亞型。通過在轉基因鼠上運用遺傳譜系追蹤技術發(fā)現(xiàn),皮層I型nNOS主要來源于MGE,II型nNOS則是MGE、LGE/CGE以及POA的混合來源,也就意味著皮層大部分的nNOS來源于MGE。MGE細胞移植到成年鼠的腦內可以擴散、遷移并且分化成GABA—主要的抑制性神經遞質。很多假說認為移植MGE的前體細胞可以增加局部的抑制,運用于臨床治療具有非常重要的意義。近幾年來分離、移植MGE來源的中間神經元前體細胞方面研究有很多,皮質中間神經元的前體細胞移植到一系列的中樞神經系統(tǒng)組織后可以廣泛的遷移并且與宿主神經元網絡形成突觸聯(lián)系。MGE細胞移植后可以進行整合的能力被廣泛運用到細胞療法上,從而治療一系列中樞神經系統(tǒng)疾病:癲癇、神經性疼痛、帕金森以及阿爾茲海默病等。因此運用MGE前體細胞進行的細胞移植在治療神經和精神疾病中是一個非常有潛能的臨床途徑�？謶质且环N與適應能力相關的基本情緒,是面對外界可知或不可知的威脅時激發(fā)的學習能力。適度的恐懼反應能警示動物面對類似于先前經歷的有害環(huán)境,及時評估潛在的危險并做出保護反應,而病理性恐懼記憶的產生將會導致創(chuàng)傷后應激綜合征(posttraumatic stress disorder,PTSD)、驚恐障礙(panic disorder)、恐懼癥(phobia)等恐懼相關疾病�；诎透β宸驐l件反射原理建立的經典的條件性恐懼(Cued-fear conditioning)以及在此基礎上發(fā)展出的背景關聯(lián)恐懼(Contextual fear conditioning)是最常見研究恐懼相關疾病的動物模型,廣泛應用于恐懼學習和記憶的神經、分子機制研究。海馬是大腦邊緣系統(tǒng)結構之一,在情感和認知功能中具有重要作用。既往研究表明,海馬與PTSD發(fā)生、發(fā)展及治療密切相關,海馬DG區(qū)是認知功能和情緒調控的神經基礎,包含DG區(qū)的海馬三突觸通路對于背景關聯(lián)型恐懼記憶至關重要。由于目前對于nNOS前體細胞來源鮮有報道,且大部分研究著眼于皮層nNOS細胞。因此,我們希望能通過培養(yǎng)MGE細胞來研究nNOS。本課題設計研究三部分內容:1)通過培養(yǎng)不同部位前體細胞來確證nNOS細胞最主要的胚胎來源是MGE,并改進獲取MGE的方法,從而獲得狀態(tài)較好的nNOS細胞;2)對nNOS細胞進行體外培養(yǎng)與鑒定,并嘗試多種方法來提高其中nNOS細胞的比例;3)將較高nNOS比例的MGE前體細胞體外培養(yǎng)成神經球,并移植到海馬DG區(qū),研究nNOS細胞以及GABA能中間神經元在小鼠恐懼記憶獲得中發(fā)揮的作用。第一部分為了探究nNOS的胚胎來源,結合已有的文獻報導以及對不同時間點nNOS陽性率的研究,我們選取了 E12.5的胎仔,在體視顯微鏡下取其整腦,并于多聚甲醛中固定24h,隨后蔗糖梯度脫水6天后進行冠狀冰凍切片,并于載玻片上貼片免疫組化,用免疫標記物PAX6、FOXG-1、Meis-2、Nkx2.1分別標記皮層、前腦、LGE和MGE,對E12.5天胚胎各個部位的形態(tài)及范圍有個確切的認識。此后,我們就進行E12.5天胎仔的原代培養(yǎng),在體視顯微鏡下,分離出同一只胎仔的皮層、POA、CGE、LGE和MGE,體外培養(yǎng)10天后,通過細胞免疫組化鑒定其中nNOS細胞的比例,發(fā)現(xiàn)MGE部位nNOS細胞比例最高,即確證了 MGE是nNOS細胞主要的胚胎來源。由于MGE細胞獲取方法以及分離的時間長短均會影響原代培養(yǎng)后細胞的狀態(tài),因此我們希望能夠通過改進現(xiàn)有的MGE獲取方法,使得原代培養(yǎng)后的細胞狀態(tài)更好。綜合對比多種方法后,我們嘗試了瓊脂糖凝膠包埋整腦后Chopper冠狀切片、緩沖液中分離MGE的方法以及體視顯微鏡下于緩沖液中直接分離MGE的方法,后者無論是操作時長、細胞狀態(tài)以及nNOS細胞陽性率均優(yōu)于前者。因此第一部分的實驗,我們確定了 MGE是nNOS細胞主要的胚胎來源,并通過對比改進了 MGE獲取的方法,便于之后的研究。第二部分為了了解MGE來源的nNOS細胞的形態(tài)和性質,我們進行了E12.5天胎仔的原代培養(yǎng),10天后通過免疫組化進行了 nNOS細胞鑒定。發(fā)現(xiàn)培養(yǎng)的MGE細胞中90%為GAD67+細胞,99.97%為Tuj-1+細胞,大部分的nNOS細胞可以與GAD67共標,但也有部分nNOS細胞是GAD67陰性的。由于MGE細胞大部分是GABA能中間神經元,且在體能分化形成各種亞型,鑒于體外培養(yǎng),因此我們也進行了其它亞型的鑒定,發(fā)現(xiàn)體外培養(yǎng)的MGE細胞中確實有表達生長抑素(somatostatin,SST)、小清蛋白(parvalbumin,PV)、鈣結合蛋白(Calbindin,CB)、鈣網膜蛋白(Calretinin,CR)等其它亞型的中間神經元。體外培養(yǎng)的nNOS細胞形態(tài)多樣,大小不一,且同一玻片上免疫組化的熒光強度也有所差別。由于體外培養(yǎng)的nNOS細胞陽性率較低,因此我們嘗試了多種方法來提高其中nNOS的比例。結果表明選取MGE不同部位以及神經營養(yǎng)因子(NGF)的誘導并不能提高nNOS細胞的陽性率。而在不同胚胎期(E11.5-E14)分離MGE,胚胎以及MGE的大小和形態(tài)有很大的差別。其中nNOS比例確有差異,E12.5天陽性率最高,其次是E13天。結果表明MGE來源的nNOS經過體外培養(yǎng),其細胞形態(tài)以及性質與體內培養(yǎng)差異不大,且E12.5天獲取的MGE細胞nNOS比例最高。第三部分為了進一步探索MGE來源的nNOS在小鼠背景關聯(lián)型近期恐懼記憶獲得中所扮演的角色,我們首先將體外培養(yǎng)3天成神經球的GFP鼠的MGE細胞濃縮,并通過玻璃導管注射到野生型鼠海馬DG區(qū),移植2個月后與注射GFP鼠的MGE死細胞相比較,發(fā)現(xiàn)野生型鼠中移植MGE細胞并沒有恐懼記憶獲得值的改變。接下來,我們又將GFP鼠MGE神經球移植到nNOS--鼠海馬DG區(qū),與注射死細胞相比,發(fā)現(xiàn)nNOS--鼠移植GFP+MGE細胞后,其背景關聯(lián)型近期恐懼記憶獲得顯著提高,且nNOS-/-鼠不論雌雄。以上結果表明,野生型鼠海馬DG區(qū)移植MGE細胞,背景關聯(lián)型近期恐懼記憶造模后,其恐懼獲得的學習能力無改善,而nNOS-/-鼠海馬DG區(qū)移植MGE細胞,造模后,不論雌雄,其獲得恐懼記憶的學習能力提高。為了進一步探究MGE細胞對nNOS-/-鼠行為學的改善作用是否由MGE來源的nNOS細胞主導。我們取B6或nNOS-/-鼠的MGE細胞,體外培養(yǎng)3天成球后濃縮液轉染GFP病毒1.5小時,然后懸瓶培養(yǎng)4-6天后,將神經球移植到nNOS-/-鼠海馬DG區(qū)。2個月后,發(fā)現(xiàn)移植B6和nNOS--鼠的MGE對比,nNOS-/-鼠恐懼記憶獲得值沒有改變,且與宿主的性別無關。為了確證,我們又選取了雌性nNOS-/-鼠進行分析,結果表明nNOS-/-鼠移植B6鼠的MGE與移植死細胞相比,獲得值增加,nNOS--鼠移植nNOS-/-鼠的MGE與移植死細胞相比,獲得值也增加,但nNOS-/-鼠移植B6或nNOS-/-鼠的MGE細胞之間無差異。以上結果表明nNOS-/-鼠移植MGE后恐懼記憶學習能力的提高源于MGE細胞中非nNOS的其它GABA能中間神經元。結論:(1)MGE是nNOS細胞主要的胚胎來源,并通過對比改進了 MGE獲取的方法,便于之后的研究(2)MGE來源的nNOS經過體外培養(yǎng),其細胞形態(tài)以及性質與體內細胞差異不大,且E12.5天獲取的MGE細胞nNOS比例最高。(3)野生型鼠海馬DG區(qū)移植MGE細胞,背景關聯(lián)型近期恐懼記憶造模后,其恐懼獲得的學習能力無改善,而nNOS-/-鼠海馬DG區(qū)移植MGE細胞,造模后,不論雌雄,其獲得恐懼記憶的學習能力提高。nNOS-/-鼠移植MGE后恐懼記憶學習能力的提高源于MGE細胞中非nNOS的其它GABA能中間神經元。
[Abstract]:The information processing of the cortex and hippocampus depends on the complex interaction between glutamate excitatory and gamma aminobutyric acid (GABA) suppressor neurons. The coordinated interaction between the two neurons is essential to maintain a delicate balance between the brain's excitatory and inhibitory signals, which is affected by many nerves. Regulatory substances such as different neuropeptides, nitric oxide (NO) and other dynamic regulation. Balance damage can lead to many pathological disorders such as epilepsy, autism, schizophrenia, etc..NO participates in many physiological processes, such as neurotransmission, synaptic plasticity, vasodilatation, and inflammation, is a very important signal molecule, NO production or release function. Defects, such as neuronal death and epilepsy, are synthesized by nitric oxide synthase (NOS), and NOS can be divided into endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS), according to the site where it was originally found. In neurons, NO is synthesized mainly by nNOS in the neuron. In the neuron, the.NO is synthesized in the neuron. The immature and mature hippocampal and cortex nNOS are mainly expressed in the middle neurons of the GABA energy intermediate neurons mainly from three different sites: the middle ganglion bulge (MGE), the lateral / tail ganglion bulge (LGE/CGE) and the preoptic region (POA), and each of the neurons of the preoptic nerve progenitor cells produce different intermediate neurons. By using genetic lineage tracking technique on transgenic mice, the cortical I type nNOS is mainly derived from MGE, and II nNOS is a mixed source of MGE, LGE/CGE, and POA, which means that the majority of the nNOS originates from the transplantation of MGE.MGE cells to the brain of adult mice, and migrates and differentiates into GABA major inhibitory gods. There are many hypotheses that transplantation of MGE's precursor cells can increase local inhibition and is of great significance in clinical treatment. In recent years, there have been many studies on the transplanting of MGE derived intermediate neurons in the precursor cells, and the precursor cells of the cortical neurons were transplanted into a series of central nervous system tissues. The ability to undergo extensive migration and to form synaptic connections with the host network of.MGE cells can be widely applied to cell therapy to treat a series of central nervous system diseases: epilepsy, neuropathic pain, Parkinson and Alzheimer's disease, and so on the use of MGE precursor cells Transplantation is a very potential clinical pathway in the treatment of neurological and mental diseases. Fear is a basic emotion associated with adaptation. It is a learning ability that is stimulated in the face of an outside known or unknowable threat. A moderate fear response can warn the animal to face the harmful environment similar to the previous experience and assess the potential in time. Dangerous and protective reactions, and the formation of pathological fear memory will cause posttraumatic stress disorder (PTSD), panic disorder (panic disorder), phobia (phobia) and other phobia related diseases. The classical conditioned fear based on Pavlov conditioned reflex (Cued-fear conditioning) is based on the classical conditioned fear (Cued-fear conditioning). Contextual fear conditioning, developed on this basis, is the most common animal model for studying fear related diseases. It is widely used in the study of nervous and molecular mechanisms of fear learning and memory. The hippocampus is one of the structure of the cerebral marginal system and plays an important role in emotional and cognitive functions. Previous studies have shown that The hippocampus is closely related to the occurrence, development and treatment of PTSD. The hippocampal DG area is a neural basis for cognitive and emotional regulation. The hippocampal three synaptic pathway, including the DG region, is essential for the background associated fear memory. Since there are few reports on the source of nNOS precursor cells, and most of the studies focus on the cortical nNOS cells. We hope to study the three parts of the design and research of nNOS. based on the cultivation of MGE cells: 1) to confirm that the most important embryonic source of nNOS cells by cultivating different parts of the precursor cells is MGE, and improves the method of obtaining MGE to obtain the better nNOS cells; 2) to culture and identify the nNOS cells in vitro, and to try a variety of methods. To improve the proportion of nNOS cells; 3) the MGE precursor cells of higher nNOS ratio were cultured into nerve spheres in vitro and transplanted into the hippocampal DG region to study the role of nNOS cells and GABA intermediate neurons in the acquisition of fear memory in mice. The first part was to explore the embryonic fetal origin of nNOS, combined with the existing literature and the difference. In the study of the time point nNOS positive rate, we selected the E12.5 fetus, took the whole brain under the stereoscopic microscope, and fixed the 24h in the paraformaldehyde, then the coronary frozen section was followed by 6 days after the sucrose gradient dehydration, and the patch was immunohistochemistry on the slides. The immune markers, PAX6, FOXG-1, Meis-2, and Nkx2.1 were used to mark the cortex, the forebrain, LGE and MGE respectively. There is a definite understanding of the morphology and scope of each part of the E12.5 day embryo. After that, we carried out the primary culture of the E12.5 day fetus. Under the stereoscopic microscope, we isolated the same fetus' cortex, POA, CGE, LGE and MGE. After 10 days in vitro culture, the proportion of nNOS cells was identified by cellular immunization, and nNOS cells in MGE site were found. The highest proportion, that is, confirmed that MGE is the main source of nNOS cells. Because the method of obtaining MGE cells and the length of separation will affect the state of the cells after primary culture, we hope that we can improve the existing MGE methods to make the cells in the primary culture better. The Chopper coronal section of the whole brain after the agarose gel was embedded in the agarose gel, the method of separating MGE in the buffer solution and the method of direct separation of MGE under the stereoscopic microscope in the buffer solution were tried. The latter was superior to the former in the length of operation, the cell state and the positive rate of the nNOS cells. Therefore, the first part of the experiment confirmed that MGE was the main nNOS cell master. In order to understand the morphology and properties of nNOS cells from MGE sources, the second part, in order to understand the morphology and properties of nNOS cells from MGE sources, carried out the primary culture of E12.5 day fetus and identified the nNOS cells by immunohistochemistry. 90% of the cultured MGE cells were GAD67+ cells, 99.97 were found to be GAD67+ cells, and 99.97 were found to be GAD67+ cells. % of Tuj-1+ cells, most of the nNOS cells can be co labeled with GAD67, but also some of the nNOS cells are GAD67 negative. Since most of the MGE cells are GABA in the intermediate neurons, and in the physical differentiation to form a variety of subtypes, in vitro culture, we have also conducted other subtypes of identification, found in the culture of MGE cells in vitro indeed. Expression of somatostatin (SST), parvalbumin (PV), calcium binding protein (Calbindin, CB), calcalum (Calretinin, CR) and other subtypes of intermediate neurons. The morphology of nNOS cells in vitro is diverse and different in size, and the fluorescence intensity of the same slide is also different. In vitro culture of nNOS. The positive rate of cells was low, so we tried a variety of methods to improve the proportion of nNOS. The results showed that the selection of different parts of MGE and the induction of neurotrophic factor (NGF) did not improve the positive rate of nNOS cells. And there was a great difference between the size and morphology of the embryo and MGE in the different embryo period (E11.5-E14) and the size and morphology of MGE. The positive rate of E12.5 days was the highest, followed by E13 days. The results showed that the MGE source nNOS had little difference in cell morphology and nature from the body culture in vitro, and the nNOS ratio of MGE cells obtained on E12.5 days was the highest. The third part was to further explore the short-term fear memory of MGE derived nNOS in mouse background associated type. In order to get the role, we first concentrated the MGE cells of the GFP rat of the 3 day adult nerve bulb in vitro, and injected it into the hippocampal DG area of the wild rat through a glass catheter. After 2 months, we compared the MGE dead cells of the GFP mice. We found that the transplanted MGE cells in the wild mice did not have a change of fear memory. We also transplanted the GFP rat MGE nerve ball into the DG region of the hippocampus of nNOS-- mice. Compared with the injected dead cells, it was found that after the nNOS-- mice transplanted to GFP+MGE cells, the background associated type of fear memory was significantly improved, and the nNOS-/- mice were male and female. The results showed that the MGE cells in the hippocampal DG area of the wild rat were transplanted and the background associated model of the short-term fear memory model was built. The learning ability of the hippocampal DG region of nNOS-/- rats was not improved, and the transplantation of MGE cells in the DG region of the hippocampus of the rat was improved. To further explore whether the effect of MGE cells on the behavioral learning of nNOS-/- rats was dominated by nNOS cells from MGE sources, we took B6 or nNOS-/- mouse MGE cells in vitro. After 3 days of culture, the concentration solution was transfected to GFP virus for 1.5 hours, and then cultured for 4-6 days after suspension bottle culture, after transplantation of the nerve ball to the nNOS-/- rat hippocampus DG area for.2 months, the MGE contrast between the transplanted B6 and nNOS-- mice was found to be unchanged, and it was not related to the sex of the host. In order to confirm, we also selected female nNOS-/- mice. The results showed that the MGE of the transplanted B6 mice of the nNOS-/- mice increased in comparison with the transplanted dead cells. The MGE of the nNOS-- mice transplanted to the nNOS-/- mice increased as compared with the transplanted dead cells, but there was no difference between the nNOS-/- mice and the MGE cells of the B6 or nNOS-/- mice. The above results showed that the learning ability of fear memory in nNOS-/- mice after the transplant MGE was improved. It is derived from other GABA intermediate neurons of non nNOS in MGE cells. Conclusion: (1) MGE is the main embryonic source of nNOS cells, and the method of MGE obtained by comparison is improved to facilitate the subsequent study (2) the nNOS of MGE source is cultured in vitro, and its cell morphology and properties are not very different from the cells in the body, and the nNOS ratio of MGE cells obtained by E12.5 days is obtained. (3) (3) the transplantation of MGE cells in the hippocampal DG region of the wild rat, the learning ability of fear acquisition was not improved after the background related recent fear memory model, and the transplantation of MGE cells in the DG region of the nNOS-/- rat hippocampus, regardless of the male and female, obtained the learning ability of the fear memory to raise the source of the learning ability of the fear memory learning after the.NNOS-/- mice transplanted to MGE. In MGE cells, non nNOS other GABA interneurons.

【學位授予單位】：南京醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R749

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3 宋志宇;盧宏;孫玉華;魏建科;譚巖;方艷秋;;血管性癡呆大鼠腦內超微結構變化及生長抑素和nNOS的表達[J];中國老年學雜志;2009年18期

4 趙昱,李莉,馬洪駿,羅波,李陳莉,王慧娟;大鼠局灶性腦缺血再灌注中nNOS來源的NO對細胞凋亡的影響[J];中國組織化學與細胞化學雜志;2005年04期

5 余菁;沈偉哉;郭國慶;;自發(fā)性高血壓大鼠中腦導水管周圍灰質nNOS陽性神經元的變化[J];解剖學研究;2009年05期

6 穆長征;王小梅;劉霞;包翠芬;;胚胎小鼠腎發(fā)育過程中nNOS的表達[J];中國體視學與圖像分析;2011年02期

7 ;Alterations in nNOS-containing nerve fibers in corpus cavernosum of spontaneous hypertension rats[J];Asian Journal of Andrology;2003年02期

8 胡向陽;;醒腦合劑對急性CO中毒模型小鼠海馬nNOS蛋白表達的影響[J];河南中醫(yī)學院學報;2006年01期

9 南娟;劉慧慧;杜艷霞;邢偉;蔡葵;蔡原;劉鵬;劉玉麗;時利德;;出生前后鋁暴露對大鼠學習記憶及海馬NO、nNOS的影響[J];中國藥理學通報;2007年09期

10 閆蓓,李積勝,汪超,張玉和,何煒;染鉛早期大鼠海馬各區(qū)NOS和nNOS陽性神經元的變化[J];衛(wèi)生研究;2002年06期

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1 ;Down Regulation of nNOS Activity by PMCA4 via PDZ Domain-dependent Protein-protein Interactions[A];第十一次中國生物物理學術大會暨第九屆全國會員代表大會摘要集[C];2009年

2 胡向陽;鄭紹周;;醒腦合劑對急性CO中毒模型小鼠海馬nNOS蛋白表達的影響[A];第八次全國中西醫(yī)結合虛證與老年醫(yī)學學術研討會論文集[C];2005年

3 康定鑫;曾因明;;M_5受體參與激活腹側背蓋區(qū)和伏隔核nNOS表達[A];2004年浙江省麻醉學學術年會論文匯編[C];2004年

4 李梅;王林;程驍;周麗華;;nNOS基因調控發(fā)育期小腦顆粒細胞神經元生長的體外研究[A];2008年神經內分泌暨神經免疫內分泌學術研討會論文摘要匯編[C];2008年

5 ;The expression of postsynaptic density-95 after spinal cord and sciatic nerve injury in rats[A];Proceedings of the 7th Biennial Meeting and the 5th Congress of the Chinese Society for Neuroscience[C];2007年

6 李英慧;趙彥艷;;p300催化的NF-kB乙�；趎NOS基因轉錄調控中的作用[A];第八次全國醫(yī)學遺傳學學術會議(中華醫(yī)學會2009年醫(yī)學遺傳學年會)論文摘要匯編[C];2009年

7 ;Developmental regulation of PSD-95 and nNOS expression in lumbar spinal cord of rats[A];Proceedings of the 8th Biennial Conference of the Chinese Society for Neuroscience[C];2009年

8 Qi-Gang Zhou;Yao Hu;Jing Zhang;Li-Juan Zhu;Chen Chen;Dan-Lian Wu;Chun-Xia Luo;Dong-Ya Zhu;;Hippocampal nNOS and depression/anxiety behaviors[A];中國神經科學學會第十屆全國學術會議論文摘要集[C];2013年

9 李自成;李麗;嚴亨秀;呼海燕;張奇蘭;孫學川;鄭煜;;川芎嗪對缺氧所致大鼠呼吸效應和腦干nNOS表達的影響[A];中國生理學會第五屆全國心血管、呼吸和腎臟生理學學術會議論文摘要匯編[C];2005年

10 關云謙;孫明;徐超;;腦缺血/再灌注時Calpain對nNOS表達的影響[A];中國藥理學會第十屆全國神經學術會議暨浙江省藥理學會2002年年會論文摘要集[C];2002年

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2 周其岡;nNOS調控神經元再生與抑郁癥[D];南京醫(yī)科大學;2009年

3 張觀坡;谷氨酸興奮毒性在糖尿病大鼠選擇性nNOS神經元減少及胃輕癱中的作用[D];第二軍醫(yī)大學;2014年

4 李英慧;核因子（NF）-κB乙�；瘜ι窠浶鸵谎趸厦福╪NOS）基因表達的調控[D];中國醫(yī)科大學;2007年

5 胡英華;基于nNOS表達的攢竹透睛明針刺治療弱視作用機制研究[D];長春中醫(yī)藥大學;2014年

6 朱新建;nNOS調控成年海馬齒狀回神經元再生及其分子機制研究[D];南京醫(yī)科大學;2006年

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1 劉麗霞;α7nAChR和nNOS在Aβ誘導的認知障礙大鼠中樞表達的變化及其對學習記憶功能的影響[D];山西醫(yī)科大學;2015年

2 沈良華;不同張力擴張子宮頸誘導大鼠延髓內臟帶Fos及nNOS的表達變化[D];浙江大學;2015年

3 饒云;Tat-LK15介導siRNA抑制nNOS表達治療神經病理性疼痛的實驗研究[D];南方醫(yī)科大學;2015年

4 周恬恬;基于“Src-NR2-nNOS”信號通路的芍藥甘草配伍調控“GABA-Glu”平衡的神經保護作用[D];北京中醫(yī)藥大學;2016年

5 肖容容;nNOS通過改善線粒體功能參與缺血后適應心肌保護作用[D];南京醫(yī)科大學;2014年

6 宋奕辰;nNOS通過改善肌漿網功能參與心肌缺血后適應保護作用[D];南京醫(yī)科大學;2014年

7 張文tD;邊緣型人格障礙及其心理相關因素與nNOS、TPH1某因多態(tài)性的關聯(lián)研究[D];南京醫(yī)科大學;2016年

8 曾娟;MrgC和腎上腺髓質素受體對DRG中IL-1β、nNOS或pERK表達的作用研究[D];福建師范大學;2016年

9 周露;nNOS參與缺血后適應改善Ca~(2+)循環(huán)的心肌保護作用[D];南京醫(yī)科大學;2015年

10 郝茂娟;心肌缺血后適應通過nNOS/AMPK/mTOR通路增強自噬活性減輕缺血再灌注損傷[D];南京醫(yī)科大學;2017年

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