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: 10225346
• 负责人: In-Jung Kim
• 金额: $ 40.42万
• 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/10225346
• 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下的神经回路是如何形成、修改 通过经验，并在神经条件下改变。这项建议的目的是审查各种机制， 调节上级丘（SC）和特定的神经元之间的长距离神经元连接的形成 大脑皮层下区域我们选择专注于SC的表面层（sSC）和 丘脑SC是中脑中枢，在感觉和运动处理中起重要作用。的sSC 接收来自视网膜和皮质的视觉输入，已知sSC-丘脑连接介导 对威胁性视觉刺激的防御反应传统的研究大多是从组织学的角度来研究组织的， 感觉输入到sSC，很少有人知道的机制调节sSC输出途径的发展。 此外，还没有研究描述了视觉驱动下的sSC-丘脑回路的发育调节。 行为反应在筛选标记sSC神经元亚群的标记物时，我们已经鉴定了几种 可能控制sSC神经元发育的基因。现在，我们建议调查那些 sSC输出电路组件中的分子。我们已经证明，一种转录因子，维甲酸相关孤儿受体β（Rorβ），调节sSC神经元投射到特定的丘脑核。在这里，我们计划 通过功能获得和功能丧失方法检查Rorβ依赖性调节的下游机制。 我们还将研究另一种转录因子Brn 3b在不同sSC发育中的作用。 电路和识别Brn 3b的下游效应器。鉴于sSC神经元，仅限于特定的 亚层，选择性地将轴突投射到不同的丘脑核，并且Brn 3b和Rorβ在 sSC的不同亚层，我们假设Brn 3b通过Rorβ非依赖性调节轴突投射， 机制等Rorβ和Brn 3b表达的操纵产生不同模式的改变的轴突 投射到丘脑核，已知支配视觉线索触发的行为。根据这些发现， 我们将测试Rorβ和Brn 3b依赖的电路组装机制是否需要适当的 对视觉威胁的行为反应该项目的成功将使我们更好地了解 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了新的机制见解 对威胁性刺激的反应。