The role of axonal guidance genes in the regulation of dopamine-mediated behaviors and synaptic connectivity

项目摘要/摘要： Netrin-1信号通过Netrin受体缺失在结直肠癌(DCC)的神经中起关键作用 通过促进生长锥运动、轴突分支和突触发生来促进回路的发育。新兴 现在有证据表明，分泌的netrins在维持兴奋性突触连接方面起着额外的作用。 成人的大脑。虽然netrin-1在神经发育过程中高度表达，但这种表达在全球范围内呈下降趋势 中枢神经系统(CNS)形成后。有趣的是，腹侧被盖区(VTA)的神经元 在成年小鼠体内维持Netrin-1和DCC的高表达。到目前为止，netrin-1和netrin的功能 成年中枢神经系统VTA神经元上的受体尚不清楚。我假设Netrin-1是一种基本的 成年VTA中突触连接的调节作用及Ntn1基因表达水平的变化 将导致与疾病相关的多巴胺能神经元连接失调和可测量的变化 多巴胺介导的行为。为了测试这一点，我建议1)评估Netrin-1在VTA中的突触贡献 2)Ntn1细胞类型特异性基因突变对行为学的影响。确定Netrin的功能- 将不仅阐明负责调节兴奋性和兴奋性的分子机制 中脑多巴胺系统中的抑制性突触连接，将有助于我们理解 多巴胺回路的改变可能会导致精神功能障碍。

Project Summary/Abstract: Netrin-1 signaling through the netrin receptor deleted in colorectal cancer (Dcc) serves a critical role in neural circuit development by promoting growth cone motility, axonal branching, and synaptogenesis. Emerging evidence now suggests secreted netrins play an additional role in maintaining excitatory synaptic connections in the adult brain. While netrin-1 is highly expressed during neurodevelopment, this expression decreases globally after central nervous system (CNS) formation. Interestingly, neurons of the ventral tegmental area (VTA) maintain high expression of both Netrin-1 and Dcc in adult mice. To date, the function of netrin-1 and netrin receptors in VTA neurons of the adult CNS remains unknown. I hypothesize that Netrin-1 plays a fundamental role in regulating synaptic connectivity in the adult VTA, and alterations in the expression levels of the Ntn1 gene will result in disease relevant dysregulation of dopaminergic neuron connectivity and measurable changes in dopamine-mediated behaviors. To test this, I propose to 1) assess synaptic contribution of Netrin-1 in the VTA and 2) the behavioral impact of cell-type specific genetic disruption of Ntn1. Determining the function of Netrin- 1 in adult neurons will not only shed light on the molecular mechanisms responsible for regulating excitatory and inhibitory synaptic connectivity in the midbrain dopamine system, and will contribute to our understanding of how alterations in dopamine circuitry may contribute to psychiatric dysfunction.