Imaging PTEN-induced changes in adult cortical structure and function in vivo

对 PTEN 诱导的成人皮质结构和功能的体内变化进行成像

基本信息

批准号：
8054250
负责人：
Joshua Trachtenberg
金额：
$ 30.03万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8054250
关键词：
1-Phosphatidylinositol 3-Kinase Action Potentials Adult Age Anxiety Apical Architecture Area Autistic Disorder Behavior Birth Cells Characteristics Child Chronic Data Set Dendrites Dendritic Cells Dendritic Spines Development Electric Capacitance Excision Exhibits Frequencies Gene Deletion Genes Genetic Goals Growth Human Hyperactive behavior Image Impairment Injection of therapeutic agent Interneurons Knock-out Knockout Mice Laser Scanning Microscopy Lead Learning Macrocephaly Measurement Measures Mediating Membrane Mental Retardation Mitotic Monozygotic Twinning Monozygotic twins Mus Mutation Neurodevelopmental Disorder Neurofibromatoses Neurons Oncogenes Oregon Output PTEN gene Pathway interactions Phosphoric Monoester Hydrolases Photic Stimulation Photons Physiology Population Predisposition Property Research Resistance Rest Role Sensory Physiology Sensory Process Shapes Signal Pathway Sirolimus Social Interaction Structure Syndrome TSC1/2 gene Testing Therapeutic Training Trees Tuberous Sclerosis Twin Multiple Birth Visual Cortex Visual Motion Width area striata autism spectrum disorder base calcium indicator cell type experience hippocampal pyramidal neuron human FRAP1 protein in vivo information processing mTOR Inhibitor neural circuit patch clamp postnatal preference programs public health relevance receptive field relating to nervous system research study response social social communication tensin

项目摘要

DESCRIPTION (provided by applicant): Autism is a severe neurodevelopmental disorder characterized by impairments in social interaction and communication. Rates of autism have exploded over the past decade and it is now estimated that 1 out of every 166 children exhibit some form of autism. The neuropathological cause of autism remains elusive, though a strong genetic contribution is evident from the 60%-92% concordance between monozygotic twins versus 0-10% in dizogtic twins. Research in human populations indicates that the number of loci associated with autism exceeds 15. Of specific relevance to this proposal is the phosphatase and tensin homologe (Pten). This oncogene regulates the growth of post-mitotic neurons. The PTEN signaling pathway is emerging as one of two major pathways that regulate the susceptibility to autism spectrum disorders. Mice with a cortical Pten deletion exhibit many of the characteristics associated with autism, including macrocephaly, deficits in social interactions, impaired social learning, hyperactivity, and increased anxiety-like behavior. Many of these deficits are reversible with chronic treatment of the mTOR inhibitor, rapamycin. In this proposal, we employ mice in which the Pten gene is deleted specifically from the cortex by CRE-mediated excision beginning some 6-8 weeks after birth. We recently demonstrated that cortical layer 2/3 pyramidal neurons experience a unique growth of their apical dendrites following PTEN deletion. This growth expands the apical dendritic tree by upwards of 1mm and adds hundreds of new dendritic spines. Our goal is to fully characterize any changes in basic physiology and sensory information processing in these growing neurons. To this end we use 2-photon laser scanning microscopy to guide the placement of in vivo whole cell patch recordings from growing neurons in the mouse primary visual cortex. We also use 2-photon imaging to image network activity in the cortex of knockout and wildtype mice. Results from these studies may provide targets for the development of rationally based therapeutics for autism spectrum disorders. PUBLIC HEALTH RELEVANCE: The PTEN signaling pathway is emerging as one of two major pathways that regulate the susceptibility to autism spectrum disorders. We earlier characterized robust changes in dendritic structure in conditional knockout mice. Here we measure changes in physiology and sensory processing in these growing neurons using in vivo whole cell patch recordings and 2-photon in vivo imaging of network activity.

描述（由申请人提供）：自闭症是一种严重的神经发育障碍，其特征是社会互动和沟通中的障碍。自闭症发生率在过去十年中爆发了，现在估计每166名儿童中有1个表现出某种形式的自闭症。自闭症的神经病理学原因仍然难以捉摸，尽管从单卵双胞胎之间的60％-92％的一致性中可以明显看出强有力的遗传贡献，而在双胞胎双胞胎中的遗传贡献是0-10％。人口的研究表明，与自闭症相关的基因座数量超过15。这种癌基因调节有灾后神经元的生长。 PTEN信号通路正在成为调节自闭症谱系易感性的两种主要途径之一。具有皮质PTEN缺失的小鼠表现出与自闭症相关的许多特征，包括脑畸形，社交互动的缺陷，社交学习障碍，活动过度和焦虑症的行为增加。这些缺陷中的许多缺陷可通过长期治疗MTOR抑制剂雷帕霉素进行可逆。在此提案中，我们采用了小鼠，其中PTEN基因从出生后约6-8周开始通过CRE介导的切除特异性从皮层中删除。我们最近证明，PTEN缺失后，皮质层2/3锥体神经元经历了其顶端树突的独特生长。这种生长将顶端树突树扩大了1mm，并增加了数百个新的树突状刺。我们的目标是充分表征这些成长神经元中基本生理学和感觉信息处理的任何变化。为此，我们使用2光子激光扫描显微镜指导体内的整个细胞斑块记录来自小鼠初级视觉皮层中生长的神经元的放置。我们还使用2光子成像来图像敲除和野生型小鼠皮质中的网络活动。这些研究的结果可能为开发自闭症谱系障碍的基于理性的治疗剂提供目标。公共卫生相关性：PTEN信号通路正在成为调节自闭症谱系易感性易感性的两种主要途径之一。我们较早地表征了条件敲除小鼠中树突结构的强大变化。在这里，我们使用体内整个细胞斑块记录和2片网络活动的体内成像来衡量这些成长神经元中的生理和感觉处理的变化。