Midbrain pathways for visual hypersensitivity in neurofibromatosis type 1

1 型神经纤维瘤病视觉超敏反应的中脑通路

基本信息

批准号：
10733781
负责人：
John Elliott Robinson
金额：
$ 40.97万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-15 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10733781
关键词：
Acceleration Address Affect Attention Attention deficit hyperactivity disorder Attentional deficit Axon Behavioral Brain Brain region Calcium Cognitive deficits Corpus striatum structure Cues Data Dependence Disease Dopamine Electrophysiology (science)Executive Dysfunction Exhibits FRAP1 gene Fiber Functional disorder Glutamates Guanosine Triphosphate Heterozygote Hydrolysis Hyperactivity Hypersensitivity Image Impulsivity In Situ In Vitro Incidence Individual Intervention Knock-in Mouse Knock-out Knockout Mice Knowledge Language Delays Light MAPK1 gene MEKs Measures Midbrain structure Mitogen-Activated Protein Kinases Modeling Mus Mutation NF1 gene Neurobehavioral Manifestations Neurobiology Neurofibromatoses Neurofibromatosis 1 Neurons Noonan Syndrome Nucleus Accumbens Optics PIK3CG gene Pathway interactions Patients Phenotype Phosphotransferases Photometry Preparation Proteins Proto-Oncogene Proteins c-akt Publications RAS inhibition Ras/Raf Research Proposals Retina Retinal Ganglion Cells Role Shelter facility Signal Transduction Speech Delay Stimulus Symptoms Testing Transgenic Mice Up-Regulation Ventral Tegmental Area Visual Visual Pathways Visuospatial autistic autosome behavioral response calcium indicator conditional knockout defined contribution dopaminergic neuron executive function experimental study gain of function gain of function mutation in vivo interdisciplinary approach motivated behavior mouse model mutant mouse model novel optogenetics patch clamp response retinotectal sensor superior colliculus Corpora quadrigemina therapeutic target tumor visual information visual processing visual stimulus

项目摘要

PROJECT SUMMARY/ABSTRACT Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder affecting 1 in 3500 individuals worldwide due to inactivating mutations in the NF1 gene. Cognitive symptoms in NF1 include impaired executive functioning, autistic features, speech and language delays, attention deficits, hyperactivity, and impulsivity. Disease manifestations are due to reduced expression of functional neurofibromin, the protein product of NF1 that inhibits Ras-MAPK (Ras-Raf-MEK-ERK) signaling cascades by accelerating Ras-GTP hydrolysis. Using a heterozygous knockout (Nf1+/-) mouse model of NF1, we previously discovered that Nf1 haploinsufficiency causes hypersensitivity to salient visual stimuli, such as a looming disc that promotes rapid escape to an available shelter by simulating predator approach from above. These phenotypes are likely controlled by the superior colliculus (SC), which receives direct visual input from retinal ganglion cells (RGCs) and coordinates behavioral responses to looming visual threats. Recently, it has been shown that cultured Nf1+/- RGCs are more excitable in vitro. These results raise the possibility that Nf1 haploinsufficiency enhances the sensitivity of SC-projecting RGCs to light; however, no study to date has examined RGC firing in an intact Nf1+/- retina or recorded neuronal responses in the superior colliculus in Nf1+/- mice. In this proposal we will test the hypothesis that a MAPK-dependent increase in the sensitivity of Nf1+/- RGCs to light produces visual hypersensitivity phenotypes via the downstream superior colliculus. In Aim 1, we will directly measure RGC responses to visual stimuli ex vivo and in vivo in NF1 model mice. In Aim 2, we will use calcium imaging and optogenetics to define the contribution of ventral SC glutamatergic neurons to phenotypic expression. Finally, in Specific Aim 3, we will test the role of activated MAPK signaling in NF1-associated phenotypes by determining if visual hypersensitivity is recapitulated in a novel knock-in mouse model of Noonan syndrome. If successful, these experiments will identify a new role for retinotectal visual processing circuits in NF1 and may paradigmatically shift how attentional and visuospatial deficits are conceptualized in this disease.

项目概要/摘要 1 型神经纤维瘤病 (NF1) 是一种常染色体显性遗传疾病，全世界每 3500 人中就有 1 人受到影响由于 NF1 基因失活突变。 NF1 的认知症状包括执行能力受损功能、自闭症特征、言语和语言发育迟缓、注意力缺陷、多动和冲动。疾病表现是由于功能性神经纤维蛋白（NF1 的蛋白质产物）表达减少所致通过加速 Ras-GTP 水解来抑制 Ras-MAPK (Ras-Raf-MEK-ERK) 信号级联反应。使用 NF1杂合敲除（Nf1+/-）小鼠模型，我们之前发现Nf1单倍体不足引起对显着视觉刺激的过敏，例如隐现的椎间盘，促进快速逃逸通过模拟捕食者从上方接近来提供可用的庇护所。这些表型可能是由上丘 (SC)，接收来自视网膜神经节细胞 (RGC) 的直接视觉输入和坐标对迫在眉睫的视觉威胁的行为反应。最近，研究表明培养的 Nf1+/- RGCs 体外更兴奋。这些结果提出了 Nf1 单倍体不足增强敏感性的可能性 SC-将 RGC 投射到光上；然而，迄今为止还没有研究检查完整的 Nf1+/- 视网膜或记录 Nf1+/- 小鼠上丘的神经元反应。在本提案中，我们将测试假设 Nf1+/- RGC 对光的敏感性依赖于 MAPK 增加，从而产生视觉通过下游上丘的超敏反应表型。在目标 1 中，我们将直接测量 RGC NF1 模型小鼠对离体和体内视觉刺激的反应。在目标 2 中，我们将使用钙成像和光遗传学来定义腹侧 SC 谷氨酸能神经元对表型表达的贡献。最后，在具体目标 3 中，我们将测试激活的 MAPK 信号在 NF1 相关表型中的作用：确定视觉超敏反应是否在努南综合征的新型敲入小鼠模型中重现。如果如果成功的话，这些实验将确定视网膜顶盖视觉处理回路在 NF1 中的新作用，并可能范式改变了这种疾病中注意力和视觉空间缺陷的概念。