Molecular and cellular mechanisms underlying catecholaminergic regulation of higher brain functions

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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