Molecular specification of dopaminergic neuron diversity

项目摘要 多巴胺是由眼睛和大脑中一小部分但有影响力的神经元产生的。因为这 神经调质在许多精神疾病中起着关键作用，了解它是如何起作用的至关重要。 建立并维持多巴胺神经元亚群。我们的初步数据显示， 激酶LKB 1是限制视网膜中多巴胺能神经元数量所必需的。此外，我们还发现， 新的多巴胺能细胞亚群，并表明LKB 1是细胞内在所需的抑制性中间神经元， 使用分子和神经遗传学方法调节多巴胺神经元多样性。这是一个引人注目的结果 因为控制产生多巴胺的神经元的数量和类型的因素仍然难以捉摸。 为了了解LKB 1如何调节多巴胺神经元多样性，我们设计了一种策略， 神经身份和连接映射，细胞类型特异性交叉遗传和病毒策略，分子 生物化学研究和功能分析。我们提出三个目标。在目标1中，我们问LKB 1是否是 在空间上和时间上足以通过在特异性地调节这种激酶来指导多巴胺神经元多样性， 地点和特定时间。在目标2中，我们确定了LKB 1发挥作用的机制，并测试了 LKB 1-AMPK信号通路在其中起关键作用的假说。在目标3中，我们将分析扩展到中脑 为了测试LKB 1是否在这个与疾病相关的大脑区域中同样需要，以限制多巴胺神经元 多样性确定一种精确控制多巴胺神经元多样性的激酶通路是令人惊讶的， 完成这些目标将显著推进我们对多巴胺能神经元是如何被赋予的理解。 它们独特的特性。此外，这些结果将为恢复 疾病背景下的多巴胺产生。

PROJECT SUMMARY Dopamine is produced by a small but impactful subset of neurons in the eye and brain. Because this neuromodulator plays a critical role in a host of mental illnesses and diseases, it is vital to understand how dopamine neuron subsets are established and maintained. Our preliminary data show that the serine-threonine kinase LKB1 is required to restrict the number of dopaminergic neurons in the retina. In addition, we identify new dopaminergic cell subsets and show that LKB1 is cell-intrinsically required in inhibitory interneurons to modulate dopamine neuron diversity using molecular and neurogenetic approaches. This is a compelling result because factors that control the number and type of neurons that produce dopamine have remained elusive. To understand how LKB1 regulates dopamine neuron diversity, we have devised a strategy encompassing neural identity and connectivity mapping, cell-type specific intersectional genetic and viral strategies, molecular and biochemical studies, and functional analysis. We propose three aims. In Aim 1, we ask whether LKB1 is spatially and temporally sufficient to instruct dopamine neuron diversity by modulating this kinase in specific locations and at particular times. In Aim 2, we identify the mechanism through which LKB1 functions and test the hypothesis that LKB1-AMPK signaling plays a critical role. In Aim 3, we extend our analysis to the midbrain to test whether LKB1 is similarly required in this disease-relevant brain region to limit dopamine neuron diversity. Identifying a kinase pathway that precisely controls dopamine neuron diversity is surprising, so completing these aims will markedly advance our understanding of how dopaminergic neurons are endowed with their unique properties. In addition, these results will provide new therapeutic avenues for restoring dopamine production in the context of disease.