Molecular Genetics of Visual Circuit Assembly in the Developing Superior Colliculus

发育中丘视觉电路组装的分子遗传学

• 批准号: 10028580
• 负责人: In-Jung Kim
• 金额: $ 43.36万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10028580
• 关键词: Affect; Area; Axon; Behavior; Behavioral; Binding; Brain; Candidate Disease Gene; Cells; Cues; Development; Dorsal; ETV1 gene; Event; Fright; Functional disorder; Genes; Goals; Knock-out; Label; Lateral Geniculate Body; Lateral posterior nucleus of thalamus; Maintenance; Mediating; Midbrain structure; Molecular; Molecular Genetics; Motor; Mus; Mutant Strains Mice; Neurologic; Neurons; Neurophysiology - biologic function; Orphan; Output; Pathway interactions; Pattern; Phenocopy; Phenotype; Play; Reaction; Regulation; Reporting; Retina; Retinoids; Role; Sensory; Stimulus; Structure; Testing; Thalamic Nuclei; Thalamic structure; Time; Visual; Visual impairment; Wild Type Mouse; base; behavioral response; brain circuitry; cadherin-6; contactin; experience; experimental study; genetic approach; improved; innovation; insight; loss of function; mutant; nervous system disorder; neural circuit; novel; overexpression; receptor; response; screening; sensory input; success; superior colliculus Corpora quadrigemina; transcription factor; transcriptome sequencing; visual stimulus

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.

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和修改的 根据经验，并根据神经系统状况而改变。该提案的目标是研究以下机制： 调节上丘（SC）和特定区域之间的远程神经元连接的形成 皮质下大脑区域。我们选择关注 SC 的表层 (sSC) 和 丘脑。 SC 是中脑中心，在感觉和运动处理中发挥重要作用。 sSC 接收来自视网膜和皮质的视觉输入，并且已知 sSC-丘脑连接可以调节 对威胁性视觉刺激的防御反应。由于大多数传统研究都调查了组织 sSC 的感觉输入，但对于调节 sSC 输出途径发育的机制知之甚少。 此外，还没有研究描述视觉驱动下的 sSC-丘脑回路的发育调节。 行为反应。在筛选 sSC 神经元子集的标记物时，我们发现了几个 可能控制 sSC 神经元发育的基因。现在，我们建议调查这些角色的作用 sSC 输出电路组件中的分子。我们已经证明，转录因子视黄醇相关孤儿受体 β (Rorβ) 可调节 sSC 神经元向特定丘脑核的投射。在这里，我们计划 通过功能获得和丧失的方法检查 Rorβ 依赖性调节的下游机制。 我们还将研究另一种转录因子 Brn3b 在不同 sSC 发育中的作用 电路并识别 Brn3b 的下游效应器。鉴于 sSC 神经元仅限于特定 亚层，选择性地将轴突投射到不同的丘脑核，并且 Brn3b 和 Rorβ 在 sSC 的不同亚层，我们假设 Brn3b 通过 Rorβ 独立调节轴突投射 机制。 Rorβ 和 Brn3b 表达的操纵产生不同模式的轴突改变 丘脑核的投射，已知控制视觉提示触发的行为。基于这些发现， 我们将测试 Rorβ 和 Brn3b 依赖性电路组装机制是否需要适当的 对视觉威胁的行为反应。拟议项目的成功将加深我们对 建立 sSC 和丘脑区域之间的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组装提供新颖的机制见解 对威胁性刺激的反应。