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

项目概要/摘要： 通过在结肠直肠癌中缺失的netrin受体（Dcc）的netrin-1信号传导在神经细胞凋亡中起关键作用。 通过促进生长锥运动性、轴突分支和突触发生来促进回路发育。新兴 现在有证据表明，分泌的netrins在维持兴奋性突触连接中起着额外的作用。 成人大脑虽然netrin-1在神经发育过程中高度表达，但这种表达在整体上减少。 中枢神经系统（CNS）形成后。有趣的是，腹侧被盖区（VTA）的神经元 在成年小鼠中维持Netrin-1和Dcc的高表达。迄今为止，netrin-1和netrin的功能 成年CNS的VTA神经元中的受体仍然未知。我假设Netrin-1在 在调节成人腹侧被盖区突触连接中的作用，以及Ntn1基因表达水平的改变 将导致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验证这一点，我建议1）评估Netrin-1在VTA中的突触贡献 和2）Ntn1的细胞类型特异性遗传破坏的行为影响。确定Netrin的功能- 1在成年神经元中的表达不仅将阐明负责调节兴奋性和 抑制性突触连接在中脑多巴胺系统，并将有助于我们了解如何 多巴胺回路的改变可能导致精神功能障碍。

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.