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

• 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
• 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

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.

项目总结/摘要 1型神经纤维瘤病（NF 1）是一种常染色体显性遗传疾病，全世界每3500人中就有1人患病 是由于NF 1基因的失活突变。NF 1的认知症状包括执行功能受损 功能，自闭症特征，言语和语言延迟，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（NF 1的蛋白产物）表达减少所致 其通过加速Ras-GTP水解来抑制Ras-MAPK（Ras-Raf-MEK-ERK）信号级联。使用 Nf 1杂合敲除（Nf 1 +/-）小鼠模型，我们先前发现Nf 1单倍不足 引起对显著视觉刺激的超敏反应，如隐约可见的椎间盘，促进快速逃避到 通过模拟捕食者从上方接近可用的庇护所。这些表型很可能是由 上级丘（SC），其接收来自视网膜神经节细胞（RGC）的直接视觉输入并协调 对迫近的视觉威胁的行为反应最近，已经表明培养的Nf 1 +/- RGCs是 在体外更容易兴奋这些结果提高了Nf 1单倍不足增强了免疫反应敏感性的可能性。 SC投射RGC到光;然而，迄今为止还没有研究在完整的Nf 1 +/-视网膜中检查RGC放电， 记录Nf 1 +/-小鼠的上级丘中的神经元反应。在本提案中，我们将测试 Nf 1 +/- RGCs对光的敏感性的MAPK依赖性增加产生视觉刺激的假说， 通过下游上级丘的超敏反应表型。在目标1中，我们将直接测量RGC 在NF 1模型小鼠中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， 光遗传学来定义腹侧SC神经元对表型表达的贡献。最后， 在具体目标3中，我们将测试活化的MAPK信号传导在NF 1相关表型中的作用， 确定在努南综合征的新基因敲入小鼠模型中是否再现视觉超敏反应。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NF 1中的新作用， 范式转移注意力和视觉空间缺陷是如何概念化的这种疾病。