Midbrain pathways for visual hypersensitivity in neurofibromatosis type 1

项目摘要/摘要 1型神经纤维瘤病(NF1)是一种常染色体显性遗传病，全世界每3500人中就有1人患病 由于NF1基因的突变失活。NF1的认知症状包括执行力受损 功能障碍、自闭症特征、言语和语言延迟、注意力缺陷、多动症和冲动。 疾病的表现是由于NF1的蛋白产物功能性神经纤维蛋白表达减少所致 这通过加速RAS-GTP的水解来抑制RAS-MAPK(RAS-Raf-MEK-ERK)信号的级联。使用 杂合基因敲除(NF1+/-)小鼠模型的NF1，我们先前发现NF1单倍体不足 引起对突出的视觉刺激的过敏，如隐约可见的视盘，它促进快速逃逸到 通过从上方模拟捕食者的接近来获得可用掩体。这些表型很可能是由 上丘(SC)，接受来自视网膜神经节细胞(RGC)和坐标的直接视觉输入 对迫在眉睫的视觉威胁的行为反应。最近，有研究表明，培养的NF1+/-RGC是 在体外更容易兴奋。这些结果提出了NF1单倍体不足可能增强了 SC-将RGC投射到光；然而，到目前为止，还没有研究检查RGC在完整的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 MAPK依赖的NF1+/-RGCs对光的敏感性增加产生视觉的假说 通过下游上丘的超敏反应表型。在目标1中，我们将直接衡量研资局 NF1模型小鼠对视觉刺激的体内外反应。在目标2中，我们将使用钙成像和 光遗传学以确定腹侧SC谷氨酸能神经元对表型表达的贡献。最后， 在特定的目标3中，我们将通过以下方式测试激活的MAPK信号在NF1相关表型中的作用 确定在Noonan综合征的新敲入小鼠模型中是否再现了视觉超敏反应。如果 成功后，这些实验将确定NF1中视网膜顶盖视觉处理回路的新角色，并可能 典型地改变了注意力和视觉空间缺陷在这种疾病中的概念化。

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.