Molecular Genetics of Visual Circuit Assembly in the Developing Superior Colliculus

我的长期目标是了解特定大脑功能背后的神经回路是如何形成、修改的 通过经验，并在神经条件下改变。这项提案的目标是审查 调节上丘(SC)和特异体神经元之间的远程神经元联系的形成 大脑皮层下区域。我们选择关注SC的表层(SSC)和 丘脑。SC是一个中脑中心，在感觉和运动处理中发挥着重要作用。SSC 接受来自视网膜和皮质的视觉输入，SSC-丘脑连接被认为是中介 对威胁性视觉刺激的防御反应。由于大多数传统研究都是对组织结构进行调查 对于SSC的感觉输入，对SSC输出通路的调控机制知之甚少。 此外，还没有研究描述视觉驱动下SSc-丘脑回路的发育规律 行为反应。在对标记SSc神经元亚集的标记的筛选中，我们已经识别了几个 可能控制SSC神经元发育的基因。现在，我们建议调查这些人的作用 分子在SSC输出电路中组装。我们已经证明了一种转录因子，视黄醇相关孤儿受体β(Rorβ)，调节SSc神经元向特定丘脑核团的投射。在这里，我们计划 通过功能增益法和功能损失法研究RORβ依赖调控的下游机制。 我们还将研究另一种转录因子Brn3b在不同SSC发展中的作用 电路，并确定Brn3b的下游效应器。鉴于SSC神经元，局限于特定的 亚层，选择性地将轴突投射到不同的丘脑核团，Brn3b和RoRβ在 不同的SSc亚层，我们假设Brn3b通过不依赖于RoRβ来调节轴突投射 机械装置。操纵RoRβ和Brn3b表达产生不同模式的轴突改变 投射到丘脑核团，已知控制视觉线索触发的行为。基于这些发现， 我们将测试是否需要依赖于RoRβ和Brn3b的电路组装机制 对视觉威胁的行为反应。拟议项目的成功将提高我们对 在SSc和丘脑区之间建立远程连接的分子基础。它还将 为皮层下视觉回路调节的发育可评价性提供新的机制见解 对威胁刺激的反应。

My long-term goal is to understand how neural circuits underlying specific brain functions are formed, modified by experience, and altered in neurological conditions. The goal of this proposal is to examine mechanisms that regulate formation of the long-range neuronal connections between the superior colliculus (SC) and specific subcortical brain areas. We chose to focus on the connections between superficial layer of SC (sSC) and the thalamus. The SC is a midbrain center that plays an important role in sensory and motor processing. The sSC receives visual inputs from the retina and cortex, and sSC-thalamic connections are known to mediate defensive responses to threating visual stimuli. As most of traditional studies have investigated organization of sensory inputs to sSC, little is known about mechanisms regulating development of sSC output pathways. Moreover, no study has described developmental regulation of sSC-thalamic circuits underlying visually-driven behavioral responses. In a screen for the markers labeling subsets of sSC neurons, we have identified several genes that are likely to control development of sSC neurons. Now, we propose to investigate the role of those molecules in sSC output circuit assembly. We have already demonstrated that a transcriptional factor, retinoid-related orphan receptor β (Rorβ), regulates sSC neuronal projections to specific thalamic nuclei. Here, we plan to examine downstream mechanisms of Rorβ-dependent regulation by gain- and loss-of-function approaches. We will also investigate the role of another transcription factor, Brn3b, in the development of distinct sSC circuits and identify the downstream effectors of Brn3b. Given that sSC neurons, confined to specific sublayers, selectively project axons to distinct thalamic nuclei, and that Brn3b and Rorβ are expressed in different sublayers of sSC, we hypothesize that Brn3b regulates axonal projections via Rorβ-independent mechanisms. Manipulations of Rorβ and Brn3b expression produce different patterns of altered axonal projections to the thalamic nucleus, known to govern visual-cue triggered behaviors. Based on these findings, we will test if Rorβ- and Brn3b-dependent mechanisms of circuit assembly are required for appropriate behavioral responses to visual threat. The success of the proposed project will improve our understanding of the molecular basis for establishing the long-range connections between sSC and thalamic areas. It will also provide novel mechanistic insights into developmental assmebly of subcortical visual circuits regulating responses to the threatening stimuli.