Molecular and cellular mechanisms underlying catecholaminergic regulation of higher brain functions
儿茶酚胺能调节高级脑功能的分子和细胞机制
基本信息
- 批准号:11480231
- 负责人:
- 金额:$ 9.79万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (B)
- 财政年份:1999
- 资助国家:日本
- 起止时间:1999 至 2001
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Catecholamine (dopamine and noradrenaline) neurotransmission plays an important role in a variety of higher brain functions and their functional development. Dysfunction in these neurotransmission systems is closely linked to pathogenesis of some neurological and neuropsychiatric disorders, such as Parkinson's disease and schizophrenia. However, little is known about the precise mechanisms by which catecholamines control brain functions. In the present study, we performed molecular and cellular studies with mouse gene manipulation approaches focusing on motor control and learning/memory mediated by catecholamines. First, we demonstrated genetic evidence that dopamine is essential for motor control and emotional learning during postnatal development and that noradrenaline is required for consolidation and recall in long-term memory of conditioned learning paradigms. Second, we indicated that the stiatopallidal projection neurons bidirectionally control basal ganglia functions depending … More on the state of dopamine transmission by genetic ablation of the striatal dopamine D2 receptor-containing neurons. Using the similar approach, we performed a selective ablation of the straital GABAergic interneuron subtypes to elucidate functional diversity of these interneurons. Knockout of dopamine D4 receptor gene showed an important role of this receptor subtype in behavioral adaptation depending on the psychomotor stimulants. Third, we sought to find possible factors that regulate dopamine neuron functions. One result obtained from this approach was that a member of orphan nuclear receptor Nurrl is a direct activator of tyrosine hydroxylase gene promoter. Finally, we developed three novel approaches with mouse gene manipulation. Transgenic mouse lines that express green fluorescent protein were established to visualize live dopaminergic neurons. Immunotoxin-mediated cell targeting was improved by utilizing the bicistronic gene expression system with an internal ribosome entry site. Catecholaminergic neuron-specific gene targeting approach was established by the Cre-loxP site-specific gene recombination system. These experimental systems provide a useful technology to elucidate molecular and cellular mechanisms that control higher brain functions depending on catecholamine neurotransmission in the future. Less
儿茶酚胺(多巴胺和去甲肾上腺素)神经传递在各种高级脑功能及其功能发育中起着重要作用。这些神经传递系统的功能障碍与一些神经系统和神经精神疾病的发病机制密切相关,如帕金森病和精神分裂症。然而,人们对儿茶酚胺控制大脑功能的确切机制知之甚少。在本研究中,我们进行了分子和细胞研究与小鼠基因操作的方法,重点是运动控制和学习/记忆的儿茶酚胺介导的。首先,我们证明了遗传学证据表明,多巴胺是必不可少的运动控制和情绪学习在出生后的发展和去甲肾上腺素是必要的巩固和回忆的条件学习范式的长期记忆。第二,我们指出,stiatopallidal投射神经元双向控制基底神经节的功能, ...更多信息 通过基因消融纹状体含多巴胺D2受体的神经元来研究多巴胺传递的状态。使用类似的方法,我们进行了选择性消融的纹状体GABA能中间神经元亚型,以阐明这些中间神经元的功能多样性。多巴胺D4受体基因的敲除表明该受体亚型在依赖精神兴奋剂的行为适应中起重要作用。第三,我们试图找到调节多巴胺神经元功能的可能因素。从该方法获得的一个结果是孤儿核受体Nurrl的成员是酪氨酸羟化酶基因启动子的直接激活剂。最后,我们开发了三种新的小鼠基因操作方法。建立了表达绿色荧光蛋白的转基因小鼠系,以可视化活的多巴胺能神经元。免疫毒素介导的细胞靶向通过利用具有内部核糖体进入位点的双顺反子基因表达系统来改进。利用Cre-loxP位点特异性基因重组系统建立了儿茶酚胺能神经元特异性基因打靶方法。这些实验系统提供了一个有用的技术,阐明分子和细胞机制,控制更高的脑功能依赖于儿茶酚胺神经传递的未来。少
项目成果
期刊论文数量(103)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Iwawaki, T.et al.: "Identification of a potential Nurr1 response element that activates the tyrosine hydroxylase gene promoter in cultured cells"Biochem.Biophys.Res.Commun.. 274・3. 590-595 (2000)
Iwawaki, T. 等:“在培养细胞中激活酪氨酸羟化酶基因启动子的潜在 Nurr1 反应元件的鉴定”Biochem.Biophys.Res.Commun. 274・3 (2000)。
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Usukiura, J.et al.: "Direct imaging of phosphorylation-dependent conformational change and DNA binding of CREB by electron microscopy"Genes to Cells. 5・6. 515-522 (2000)
Usukiura, J.et al.:“通过电子显微镜直接成像 CREB 的磷酸化依赖性构象变化和 DNA 结合”Genes to Cells 5·6 (2000)。
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Kobayashi, K.: "Role of catecholamine signaling in brain and nervous system functions: new insights from mouse molecular genetic study"J. Invest. Dermatol. 6(1). 117-121 (2001)
Kobayashi, K.:“儿茶酚胺信号传导在大脑和神经系统功能中的作用:小鼠分子遗传学研究的新见解”J.
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Kobaydshi, K. and Kobayashi. T.: "Genetic evidence for noradrenergic control of long-term memory consolidation"Brain Dev. 23(1). 16-23 (2001)
Kobaydshi,K.和小林。
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Kobayashi, K.et al.: "Modest neuropsychological deficits caused by reduced noradrenaline metabolism in mice heterozygous for a mutated tyrosine hydroxvlase gene"J.Neurosci.. 20・6. 2418-2426 (2000)
Kobayashi, K.等:“突变酪氨酸羟化酶基因杂合的小鼠中去甲肾上腺素代谢减少导致的适度神经心理缺陷”J.Neurosci.. 20・6 (2000)。
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KOBAYASHI Kazuto其他文献
KOBAYASHI Kazuto的其他文献
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{{ truncateString('KOBAYASHI Kazuto', 18)}}的其他基金
The roles of CREBH in non-alcoholic fatty liver
CREBH在非酒精性脂肪肝中的作用
- 批准号:
26500001 - 财政年份:2014
- 资助金额:
$ 9.79万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Development of genetic manipulation technology for excitatory and inhibitory control of the target neuron activity
开发用于靶神经元活动的兴奋性和抑制性控制的基因操纵技术
- 批准号:
22650065 - 财政年份:2010
- 资助金额:
$ 9.79万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
The autoloop pathogenic mechanism of diabetic complication by SREBP-1c
SREBP-1c研究糖尿病并发症的autoloop致病机制
- 批准号:
20591043 - 财政年份:2008
- 资助金额:
$ 9.79万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Neural circuit mechanisms of behavioral control through striatal projection pathways
通过纹状体投射途径进行行为控制的神经回路机制
- 批准号:
19300109 - 财政年份:2007
- 资助金额:
$ 9.79万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Behavioral and physiological roles of the striatal GABAergic interneuronal types
纹状体 GABA 能中间神经元类型的行为和生理作用
- 批准号:
16300102 - 财政年份:2004
- 资助金额:
$ 9.79万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Mouse genetic studies on the functions of the mammalian catecholaminergic nervous system
哺乳动物儿茶酚胺能神经系统功能的小鼠遗传学研究
- 批准号:
06454182 - 财政年份:1994
- 资助金额:
$ 9.79万 - 项目类别:
Grant-in-Aid for General Scientific Research (B)