Maintenance and Neuroprotection

在许多神经精神和神经退行性疾病中，包括精神分裂症、帕金森氏病、注意力缺陷障碍、药物成瘾、抑郁和焦虑，中脑提升多巴胺系统的功能和/或结构破坏都很突出。全面了解导致成人大脑多巴胺系统维持的营养支持机制可能有助于开发治疗这些疾病的新策略。Sonic hedgehog基因Shh在成年小鼠大脑的中脑多巴胺能神经元中表达。Shh是一种形态因子，控制着个体发育的许多方面，协调一致的生长和模式，也参与许多组织中细胞存活的调节。我们通过表达由多巴胺转运蛋白（Dat）位点控制的重组酶Cre，实现了从多巴胺能神经元特异性地基因切除Shh，从而导致存活和活跃的动物。然而，在12周龄时，我们观察到运动活动的进行性缺陷和纹状体中多巴胺能（DA）神经元和胆碱能（ChAT）神经元数量的减少。本探索性项目的目的是确定多巴胺能神经元shh的消蚀是否(1)导致成年小鼠SNpc和/或纹状体的进行性功能和结构破坏(2)影响DA神经元对神经毒性损伤的恢复能力(3)影响DA神经元在神经毒性损伤后的再生能力。我们期望通过这项资助的工作将导致一种新的神经退行性疾病模型。PHS 398/2590 （09/04 Rev.）首席研究员/项目主管（最后，第一，中间）：Kottmann, Andreas H.叙述：上升的中脑多巴胺能系统的功能和/或结构腐败在许多神经精神和神经退行性疾病中都很突出，包括精神分裂症，帕金森病，注意力缺陷障碍，药物成瘾，抑郁和焦虑。我们通过表达由多巴胺转运蛋白（DAT）基因座控制的重组酶Cre实现了多巴胺能神经元特异性Shh的基因消蚀，导致12周龄时运动活性进行性缺陷，纹状体中致密黑质多巴胺能（DA）神经元和胆碱能（ChAT）神经元数量减少。通过这项拨款资助的工作旨在确定这种动物模式是否是一种新的神经退行性疾病模型。

Functional and/or structural corruption of the ascending, mesencephalic dopaminergic system is prominent in many neuropsychiatric and neurodegenerative disorders including schizophrenia, Parkinson's disease, attention deficit disorder, drug addiction, depression, and anxiety. A complete understanding of the trophic support mechanisms that lead to the maintenance of the dopamine system in the adult brain might aid in the development of novel strategies for the management of these diseases. Sonic hedgehog, Shh, is expressed in mesencephalic, dopaminergic neurons in the adult mouse brain. Shh, a morphogen, which controls many aspects of ontogeny, orchestrating congruent growth and patterning, also takes part in the regulation of cell survival in many tissues. The genetic ablation of Shh specifically from dopaminergic neurons, which we achieved through the expression of the recombinase Cre controlled by the dopamine transporter (Dat) locus, leads to viable and active animals. However, we observe a progressive deficit in locomotion activity and a reduction of the numbers of both, dopaminergic (DA) neurons in the substantia nigra pars compacta and cholinergic (ChAT) neurons in the striatum, at 12 weeks of age. The objective of this explorative project is to determine whether ablation of shh from dopaminergic neurons (1) leads to a progressive functional and structural corruption of the SNpc and/or striatum in the adult mouse (2) influences the resilience of DA neurons to neurotoxic insults (3) influences the regenerative capacity of DA neurons after neurotoxic insults We expect that work funded through this grant will lead to a novel neurodegenerative disease model. PHS 398/2590 (Rev. 09/04) Page Continuation Format Page Principal Investigator/Program Director (Last, First, Middle):Kottmann, Andreas H. Narrative: Functional and/or structural corruption of the ascending, mesencephalic dopaminergic system is prominent in many neuropsychiatric and neurodegenerative disorders including schizophrenia, Parkinson's disease, attention deficit disorder, drug addiction, depression, and anxiety. The genetic ablation of Shh specifically from dopaminergic neurons, which we achieved through the expression of the recombinase Cre controlled by the dopamine transporter (DAT) locus, leads to a progressive deficit in locomotion activity and a reduction of the numbers of both, dopaminergic (DA) neurons in the substantia nigra pars compacta and cholinergic (ChAT) neurons in the striatum, at 12 weeks of age. Work funded through this grant seeks to determine whether this animal paradigm is a novel neurodegenerative disease model.