Molecular and cellular mechanisms underlying catecholaminergic regulation of higher brain functions

儿茶酚胺(多巴胺和去甲肾上腺素)神经传递在多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和神经精神疾病的发病密切相关，如帕金森氏病和精神分裂症。然而，人们对儿茶酚胺控制大脑功能的确切机制知之甚少。在这项研究中，我们用小鼠的基因操作方法进行了分子和细胞研究，重点是儿茶酚胺介导的运动控制和学习/记忆。首先，我们证明了遗传证据表明，多巴胺对出生后发育过程中的运动控制和情绪学习是必不可少的，去甲肾上腺素是巩固和回忆条件性学习范例的长期记忆所必需的。第二，我们发现双侧丘脑投射神经元依赖于…双向控制基底节的功能更多关于纹状体中含有多巴胺D2受体的神经元的遗传消融对多巴胺传递状态的影响。使用类似的方法，我们选择性地消融了直立的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精神运动兴奋剂依赖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。该方法的一个结果是，孤儿核受体Nurr1的一个成员是酪氨酸羟化酶基因启动子的直接激活子。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，以显示活的多巴胺能神经元。利用带有内部核糖体进入位点的双顺反子基因表达系统，提高了免疫毒素介导的细胞靶向性。利用Cre-loxP位点特异性基因重组系统建立儿茶酚胺能神经元特异性基因打靶方法。这些实验系统为阐明分子和细胞机制提供了有用的技术，这些机制依赖于未来的儿茶酚胺神经传递来控制更高的大脑功能。较少

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