伏隔核中型多棘神经元兴奋性及海马长时程增强在抑郁症发病中的作用
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摘要
抑郁症是现今世界上最流行的精神疾病，在中国有超过2600万人患有抑郁症，具有高发病率及低诊断率的特点，对当今社会带来了严重的影响。同时，抑郁症的产生原因复杂，遗传和环境因素兼而有之，而且在病理上不易显现出可检测的实质性病变特征，因此对人们研究抑郁症的发病机制造成了极大的困扰，直接影响到抗抑郁药物的开发。因此阐明抑郁症的发病机制，为抑郁症的临床治疗提供有效的思路与方法是当今中国乃至世界精神疾病研究领域亟待解决的科学问题之一。近年来负责奖赏及成瘾机制的重要脑区——伏隔核（Nuclear accumbens, NAc）在抑郁发病和抗抑郁药物治疗中的作用受到越来越多的关注。NAc是基底核区域的一个信息整合核团，主要接受来自中脑腹侧背盖区（ventraltegmental area, VTA）的多巴胺能神经投射，参与与情绪调节相关的神经环路。同时，抑郁症发病假说之一的单胺类假说认为多巴胺在抑郁症发病及抗抑郁治疗中有着不可忽视的作用，但是多巴胺对脑内相关脑区神经活动的影响仍不明了，因此如果能够从电生理学的角度，对NAc的神经元放电特点进行研究，并结合行为学和生化学的研究，则能够帮助我们更加全面深入的了解脑内多巴胺系统中的NAc神经元活性在抑郁症的发病过程中的作用及变化情况。另外，我们也对来自于郭熙志教授实验室的一种干细胞因子（stem cell factor, SCF）及其酪氨酸激酶受体c-Kit通路功能受损的基因突变小鼠进行了电生理学的研究。这种基因突变小鼠具有显著的抑郁样行为表现，并且伴随着学习与记忆功能的缺陷和海马区域的神经元再生障碍。因此通过对其海马区突触可塑性的研究，能够帮助我们了解这种基因突变对海马的突触传递及其可塑性的影响，从电生理学的角度解释这种抑郁小鼠在学习与记忆方面出现缺陷的原因。
在本研究中，我们选取了两种抑郁症模型鼠Wistar Kyoto (WKY)大鼠和c-KitV922G/+杂合突变小鼠，在进行行为学检测验证抑郁样行为的基础上，1）研究幼年期WKY大鼠在抑郁发生及药物治疗过程中，多巴胺NAc的中型多棘神经元（Medium spiny neurons, MSNs）兴奋性的变化；2）研究成年c-KitV922G/+杂合突变小鼠海马（hippocampus, HP）的CA1区及CA3区突触传递及长时程增强（long-term potentiation, LTP）形成的变化。通过以上检测，我们探讨了NAc的MSNs放电特点及海马神经环路的信号传导变化在抑郁症发病中的作用。
主要的方法及结果：
1检测幼年期WKY大鼠在抑郁发生及药物治疗过程中，多巴胺D2类受体（dopamine D2-like receptor）介导的NAc MSNs膜兴奋性的变化。
（1）制作4~5周健康雄性WKY大鼠和其正常对照组Wistar大鼠的大脑冠状切片（含有NAc），切片厚度300μm。
（2）通过可视化全细胞膜片钳的方法，记录并分析在给予多巴胺D2类受体激动剂喹吡罗（quinpirole）前后，NAc中心核（core）区域的MSNs动作电位的发放情况。在记录过程中，始终在灌流液中加入伽马氨基丁酸A（GABAA）受体阻断剂木防己苦毒素（picrotoxin, PTX）和兴奋性谷氨酸受体阻断剂犬尿喹啉酸（kynurenic acid）。在电流钳模式下给予细胞膜间隔20sec、强度呈步进递增形式的电流刺激，电流强度范围为0-500pA，步幅为50pA，记录其诱发的动作电位数量及产生阈值。结果发现在幼年期WKY大鼠中，多巴胺D2类受体介导的信号通路对NAc core区域的MSNs膜兴奋性的抑制作用缺失；
（3）给予幼年期WKY大鼠持续12天的诺米芬新（nomifensine，一种多巴胺和去甲肾上腺素重摄取抑制剂）治疗，通过一系列的行为学检测发现治疗前的WKY大鼠在糖水偏好、开场实验和强迫游泳的行为学实验中均表现出显著的抑郁样行为，而nomifensine治疗后其在糖水偏好和强迫游泳实验中的抑郁样行为显著减少。
（4）对治疗后的WKY大鼠NAc core区域的MSNs进行电生理学检测，并与未治疗组的WKY大鼠以及正常对照组Wistar大鼠比较，结果发现在接受nomifensine治疗后WKY大鼠NAc core区域的MSNs膜兴奋性减弱。
2检测成年c-KitV922G/+杂合突变小鼠在抑郁发生过程中，Mossyfiber-CA3(MF-CA3)和Schaffer collateral-commissural fiber-CA1(Sch-CA1)通路上高频刺激诱导的LTP形成情况。
（1）制作2~3月龄的健康雄性c-KitV922G/+杂合突变小鼠和其野生型对照小鼠的急性海马切片，切片厚度400μm。
（2）在场电位模式下给予海马切片MF-CA3通路100Hz/1sec两次，以及Sch-CA1通路100Hz/1sec1次的高频刺激，观察LTP的形成情况。实验结束后灌流含有0.1μM DCG IV的人工脑脊液（artificialcerebrospinal fluid, ACSF)，观察突触反应的被抑制情况，以验证所记录的通路确实为MF-CA3。结果发现c-KitV922G/+杂合突变小鼠的MF-CA3通路的LTP形成受损，而Sch-CA1通路的LTP形成未受影响。主要结论：
（1）Nomifensine能够改善幼年期WKY大鼠的抑郁样行为；
（2）多巴胺D2类受体介导的对MSNs兴奋性的抑制的缺失可能参与幼年期WKY大鼠抑郁样行为的发生。
（3）Nomifensine可能通过影响幼年期WKY大鼠海马和纹状体区域的DRD2发挥抗抑郁作用。
（4）成年小鼠海马的SCF/c-Kit通路异常对MF-CA3通路LTP形成的抑制，可能参与其学习与记忆的形成障碍。
Depression is the most popular mental illness in the world today. InChina, there are about over26million people suffering from depression withhigh morbidity and low diagnostic rate, which causes severe impact onChina's economic, cultural and social development. Meanwhile, thecomplex pathogenic mechanisms of depression, including genetic andenvironmental factors, and less of detectable changes in the pathologicalaspect bring great obstacles to the investigation of pathogenic mechanismsof depression and the development of antidepressant. Therefore, theclarification of the pathological mechanism, and providing effective ideasand methods for the clinical treatment are important topics and urgentscientific issues in the world’s mental illness area. Nowadays, nuclear accumbens (NAc), which responsible for the mechanism of reward andaddiction attracted more and more attentions in the field of depression andantidepressant studies. NAc, located in the basal ganglia area, areresponsible for information integration which mainly receives thedopaminergic neural projections that send from ventral tegmental area(VTA), participates in neurological circuits that relevant to the emotionregulation. Meanwhile, based on the hypothesis of pathogenesis, it wasconsidered that dopamine plays a not negligible role in pathogenesis ofdepression. However, the functions of dopamine system that regulate theactivities of neural transmission among several related brain areas are stillunclear. Therefore, it would be helpful for us to deeply understand theneuronal activity in NAc in the pathogenesis of depression, by studying thecharacteristics of neural signals. On the other hand, we also studied themutant mice which had impaired stem cell factor (SCF)/c-Kit signalingpathway in hippocampus by electrophysiology. The mutant mice exhibitsignificant depression-like behaviors and impairment of memory formationand neuronal regeneration in hippocampus. Therefore, it would be helpfulfor us to understand the effects of gene mutant on synaptic transmission andplasticity in hippocampus and the reasons for the defects of learning andmemory were analyzed.
In the present study, we selected two kinds of depression model rats:Wistar Kyoto (WKY) rats and c-KitV922G/+heterozygous mutant mouse.Based on the behavioral studies,1) we studied the changes of excitability ofmedium spiny neurons (MSNs) in the pathogenesis of depression inchildhood WKY rats;2) we also studied the LTP induction in thehippocampus of adult c-KitV922G/+heterozygous mutant mice. Depending onall above studies and experiments, we discussed the characteristics of NAcMSNs’ firing pattern and the changes of synaptic plasticity in hippocampusduring the pathogenesis of depression.
Main methods and results:
1. The membrane excitability changes of MSNs in NAc core region inthe process of depression and its improvement in childhood WKY rats.
1) Prepared coronal brain acute slices (300μM, contained NAc region)from healthy WKY and Wistar rats (4-5weeks old, male).
2) Through visually guided whole-cell patch clamp recording, wecalculated the membrane excitability of MSNs in the core of NAc of WKYrats. Under the current clamp mode, the stimulation was applied to MSNs byincreasing current intensity from0pA to500pA, with50pA increment.During the process of experimental recording, picrotoxin and kynurenic acid were applied to block the inhibition GABAAreceptors and the excitatoryglutamate receptors respectively. The results showed that the inhibition ofMSNs membrane excitability by dopamine D2-like receptor-mediatedsignaling was attenuated.
3) Treated childhood WKY rats with nomifensine for12day(nomifensine, a dopamine and norepinephrine reuptake inhibitor), and toexamine the depression-like behavior through open field test and forcedswimming test. Childhood WKY rats have shown significant depressivebehaviors in sucrose preference test, open field test, and forced swimmingtest, while accepted the nomifensine treatment, childhood WKY ratsexhibited decreased the depressive behaviors in sucrose preference andforced swimming test.
4) Compared the membrane excitability of MSNs to control WKYrats and normal wistar rats, the excitability of MSNs in NAc core region oftreated WKY rats was suppressed.
2. The formation of long-term potentiation (LTP) in Mossy fiber-CA3(MF-CA3) and Schaffer collateral-commissural fiber-CA1(Sch-CA1)pathway in c-KitV922G/+heterozygous mutant mouse.
1) Prepared hippocampal acute slices (400μm) from c-KitV922G/+heterozygous mutant mouse and the wild control mouse (2~3months old, healthy, male).
2) By using field potential recording technique, HFS (100Hz/1sec)twice, was delivered to MF-CA3pathway or Sch-CA1pathway respectivelyto induce LTP. At the end of experiments, ACSF containing DCG IV wasapplying to block EPSP response to verification the MF-CA3pathway. Theresults showed that LTP induction was impaired in MF-CA3but not inSch-CA1pathway in c-KitV922G/+heterozygous mutant mice.
Main conclusions:
1) Nomifensine treatment could improve depressive-like behavior ofWKY rat.
2) The impairment of inhibition on MSNs membrane excitability whichmediated by dopamine D2-like receptor may be involved in the formation ofdepression-like behavior in childhood WKY rats.
3) Nomifensine may act on WKY rats via modulation of DRD2expression in hippocampus and striatum, but not in NAc.
4) The disturbed function of SCF/c-Kit pathway could inhibit the LTPinduction, which possibly participates in the impairement of learning andmemory in mutant mice.
在本研究中，我们选取了两种抑郁症模型鼠Wistar Kyoto (WKY)大鼠和c-KitV922G/+杂合突变小鼠，在进行行为学检测验证抑郁样行为的基础上，1）研究幼年期WKY大鼠在抑郁发生及药物治疗过程中，多巴胺NAc的中型多棘神经元（Medium spiny neurons, MSNs）兴奋性的变化；2）研究成年c-KitV922G/+杂合突变小鼠海马（hippocampus, HP）的CA1区及CA3区突触传递及长时程增强（long-term potentiation, LTP）形成的变化。通过以上检测，我们探讨了NAc的MSNs放电特点及海马神经环路的信号传导变化在抑郁症发病中的作用。
主要的方法及结果：
1检测幼年期WKY大鼠在抑郁发生及药物治疗过程中，多巴胺D2类受体（dopamine D2-like receptor）介导的NAc MSNs膜兴奋性的变化。
（1）制作4~5周健康雄性WKY大鼠和其正常对照组Wistar大鼠的大脑冠状切片（含有NAc），切片厚度300μm。
（2）通过可视化全细胞膜片钳的方法，记录并分析在给予多巴胺D2类受体激动剂喹吡罗（quinpirole）前后，NAc中心核（core）区域的MSNs动作电位的发放情况。在记录过程中，始终在灌流液中加入伽马氨基丁酸A（GABAA）受体阻断剂木防己苦毒素（picrotoxin, PTX）和兴奋性谷氨酸受体阻断剂犬尿喹啉酸（kynurenic acid）。在电流钳模式下给予细胞膜间隔20sec、强度呈步进递增形式的电流刺激，电流强度范围为0-500pA，步幅为50pA，记录其诱发的动作电位数量及产生阈值。结果发现在幼年期WKY大鼠中，多巴胺D2类受体介导的信号通路对NAc core区域的MSNs膜兴奋性的抑制作用缺失；
（3）给予幼年期WKY大鼠持续12天的诺米芬新（nomifensine，一种多巴胺和去甲肾上腺素重摄取抑制剂）治疗，通过一系列的行为学检测发现治疗前的WKY大鼠在糖水偏好、开场实验和强迫游泳的行为学实验中均表现出显著的抑郁样行为，而nomifensine治疗后其在糖水偏好和强迫游泳实验中的抑郁样行为显著减少。
（4）对治疗后的WKY大鼠NAc core区域的MSNs进行电生理学检测，并与未治疗组的WKY大鼠以及正常对照组Wistar大鼠比较，结果发现在接受nomifensine治疗后WKY大鼠NAc core区域的MSNs膜兴奋性减弱。
2检测成年c-KitV922G/+杂合突变小鼠在抑郁发生过程中，Mossyfiber-CA3(MF-CA3)和Schaffer collateral-commissural fiber-CA1(Sch-CA1)通路上高频刺激诱导的LTP形成情况。
（1）制作2~3月龄的健康雄性c-KitV922G/+杂合突变小鼠和其野生型对照小鼠的急性海马切片，切片厚度400μm。
（2）在场电位模式下给予海马切片MF-CA3通路100Hz/1sec两次，以及Sch-CA1通路100Hz/1sec1次的高频刺激，观察LTP的形成情况。实验结束后灌流含有0.1μM DCG IV的人工脑脊液（artificialcerebrospinal fluid, ACSF)，观察突触反应的被抑制情况，以验证所记录的通路确实为MF-CA3。结果发现c-KitV922G/+杂合突变小鼠的MF-CA3通路的LTP形成受损，而Sch-CA1通路的LTP形成未受影响。主要结论：
（1）Nomifensine能够改善幼年期WKY大鼠的抑郁样行为；
（2）多巴胺D2类受体介导的对MSNs兴奋性的抑制的缺失可能参与幼年期WKY大鼠抑郁样行为的发生。
（3）Nomifensine可能通过影响幼年期WKY大鼠海马和纹状体区域的DRD2发挥抗抑郁作用。
（4）成年小鼠海马的SCF/c-Kit通路异常对MF-CA3通路LTP形成的抑制，可能参与其学习与记忆的形成障碍。
Depression is the most popular mental illness in the world today. InChina, there are about over26million people suffering from depression withhigh morbidity and low diagnostic rate, which causes severe impact onChina's economic, cultural and social development. Meanwhile, thecomplex pathogenic mechanisms of depression, including genetic andenvironmental factors, and less of detectable changes in the pathologicalaspect bring great obstacles to the investigation of pathogenic mechanismsof depression and the development of antidepressant. Therefore, theclarification of the pathological mechanism, and providing effective ideasand methods for the clinical treatment are important topics and urgentscientific issues in the world’s mental illness area. Nowadays, nuclear accumbens (NAc), which responsible for the mechanism of reward andaddiction attracted more and more attentions in the field of depression andantidepressant studies. NAc, located in the basal ganglia area, areresponsible for information integration which mainly receives thedopaminergic neural projections that send from ventral tegmental area(VTA), participates in neurological circuits that relevant to the emotionregulation. Meanwhile, based on the hypothesis of pathogenesis, it wasconsidered that dopamine plays a not negligible role in pathogenesis ofdepression. However, the functions of dopamine system that regulate theactivities of neural transmission among several related brain areas are stillunclear. Therefore, it would be helpful for us to deeply understand theneuronal activity in NAc in the pathogenesis of depression, by studying thecharacteristics of neural signals. On the other hand, we also studied themutant mice which had impaired stem cell factor (SCF)/c-Kit signalingpathway in hippocampus by electrophysiology. The mutant mice exhibitsignificant depression-like behaviors and impairment of memory formationand neuronal regeneration in hippocampus. Therefore, it would be helpfulfor us to understand the effects of gene mutant on synaptic transmission andplasticity in hippocampus and the reasons for the defects of learning andmemory were analyzed.
In the present study, we selected two kinds of depression model rats:Wistar Kyoto (WKY) rats and c-KitV922G/+heterozygous mutant mouse.Based on the behavioral studies,1) we studied the changes of excitability ofmedium spiny neurons (MSNs) in the pathogenesis of depression inchildhood WKY rats;2) we also studied the LTP induction in thehippocampus of adult c-KitV922G/+heterozygous mutant mice. Depending onall above studies and experiments, we discussed the characteristics of NAcMSNs’ firing pattern and the changes of synaptic plasticity in hippocampusduring the pathogenesis of depression.
Main methods and results:
1. The membrane excitability changes of MSNs in NAc core region inthe process of depression and its improvement in childhood WKY rats.
1) Prepared coronal brain acute slices (300μM, contained NAc region)from healthy WKY and Wistar rats (4-5weeks old, male).
2) Through visually guided whole-cell patch clamp recording, wecalculated the membrane excitability of MSNs in the core of NAc of WKYrats. Under the current clamp mode, the stimulation was applied to MSNs byincreasing current intensity from0pA to500pA, with50pA increment.During the process of experimental recording, picrotoxin and kynurenic acid were applied to block the inhibition GABAAreceptors and the excitatoryglutamate receptors respectively. The results showed that the inhibition ofMSNs membrane excitability by dopamine D2-like receptor-mediatedsignaling was attenuated.
3) Treated childhood WKY rats with nomifensine for12day(nomifensine, a dopamine and norepinephrine reuptake inhibitor), and toexamine the depression-like behavior through open field test and forcedswimming test. Childhood WKY rats have shown significant depressivebehaviors in sucrose preference test, open field test, and forced swimmingtest, while accepted the nomifensine treatment, childhood WKY ratsexhibited decreased the depressive behaviors in sucrose preference andforced swimming test.
4) Compared the membrane excitability of MSNs to control WKYrats and normal wistar rats, the excitability of MSNs in NAc core region oftreated WKY rats was suppressed.
2. The formation of long-term potentiation (LTP) in Mossy fiber-CA3(MF-CA3) and Schaffer collateral-commissural fiber-CA1(Sch-CA1)pathway in c-KitV922G/+heterozygous mutant mouse.
1) Prepared hippocampal acute slices (400μm) from c-KitV922G/+heterozygous mutant mouse and the wild control mouse (2~3months old, healthy, male).
2) By using field potential recording technique, HFS (100Hz/1sec)twice, was delivered to MF-CA3pathway or Sch-CA1pathway respectivelyto induce LTP. At the end of experiments, ACSF containing DCG IV wasapplying to block EPSP response to verification the MF-CA3pathway. Theresults showed that LTP induction was impaired in MF-CA3but not inSch-CA1pathway in c-KitV922G/+heterozygous mutant mice.
Main conclusions:
1) Nomifensine treatment could improve depressive-like behavior ofWKY rat.
2) The impairment of inhibition on MSNs membrane excitability whichmediated by dopamine D2-like receptor may be involved in the formation ofdepression-like behavior in childhood WKY rats.
3) Nomifensine may act on WKY rats via modulation of DRD2expression in hippocampus and striatum, but not in NAc.
4) The disturbed function of SCF/c-Kit pathway could inhibit the LTPinduction, which possibly participates in the impairement of learning andmemory in mutant mice.
引文
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