Neurodevelopmental function of Beta1-integrin-mediated signaling events in the prefrontal cortex

前额皮质 Beta1 整合素介导的信号事件的神经发育功能

基本信息

批准号：
9918761
负责人：
Henry W. Kietzman
金额：
$ 5.05万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918761
关键词：
3-Dimensional Actins Adolescence Adolescent Adult Behavior Behavioral Brain Brain region CD29 Antigen Cell Adhesion Cellular Structures Complex Cytoskeleton DISC1 gene Decision Making Dendrites Dendritic Spines Development Disease EMS1 gene Embryo Environment Etiology Event Extracellular Matrix Proteins Fluorescence Genes Goals Hippocampus (Brain)Human Image Impairment Infusion procedures Integrins Interleukins Lead Ligand Binding Light Long-Term Potentiation Medial Mediating Mental disorders Mus Mutant Strains Mice Neurodevelopmental Disorder Neurons Pharmacology Phosphotransferases Prefrontal Cortex Process Proteins Receptor Cell Reversal Learning Rewards Risk-Taking Role Schizophrenia Signal Transduction Site Social Interaction Stimulus Stress Structure Synapses Testing Time Viral Vector base cell type clinically relevant cognitive function critical period density early adolescence excitatory neuron extracellular genome wide association study in vivo insight knock-down mood regulation neonatal period neurobehavioral neurodevelopment neuropsychiatric disorder novel novel therapeutic intervention novel therapeutics object recognition polymerization postnatal preadolescence reconstruction resilience synaptic pruning

项目摘要

PROJECT SUMMARY: Adolescence is characterized by massive synaptic pruning and structural stabilization in the prefrontal cortex (PFC). Given that ~50% of “adult” mental health disorders initially present during adolescence, investigating factors mediating this dramatic structural change could inform disease vulnerabilities or etiologies. Genome-wide association studies implicate ITGB1, the gene encoding β1-integrin, in disorders such as schizophrenia. In hippocampal CA1, stimulation of β1-integrin by extracellular matrix proteins stabilizes dendrites and synapses starting in adolescence. We recently observed that selective reduction of Itgb1 in the medial PFC (mPFC) has developmentally-selective consequences also, with adolescent-onset knockdown causing anhedonic-like and risk-taking behaviors. Meanwhile, adult-onset knockdown has no such effects. Given that the mPFC undergoes structural remodeling during adolescence – and is dysregulated in psychiatric illnesses – clarifying the role of β1-integrin in mPFC development may provide insight into disease etiology. I hypothesize that β1-integrin is necessary for the structural stabilization – referring here to the process by which dendritic spines are retained and escape pruning – of excitatory mPFC neurons throughout adolescence, and that this stability is necessary for the proper development of mPFC-regulated behaviors. My first aim investigates the impact of β1-integrin on mPFC neurodevelopment and function. I will selectively reduce neuronal Itgb1 in the mPFC (prelimbic subregion) of pre-adolescent mice. I will then image layer V neurons – which receive input from subcortical regions involved in mPFC-dependent decision making and mood regulation – throughout adolescence and reconstruct dendritic spines in 3D to delineate developmental trajectories. I will next selectively reduce Itgb1 in layer V neurons and identify consequences in sensorimotor gating, social interaction and recognition, and goal-directed decision making. I hypothesize that Itgb1 deficiency will cause dendritic spine loss on layer V neurons, triggering behavioral abnormalities. Neuronal β1-integrin signaling partners include Abl2/Arg kinase, cortactin, and ROCK2, which regulate actin polymerization. In my second aim, I will pharmacologically stimulate or inhibit (as appropriate) each of these factors during a key period of mPFC development, vs. when dendritic spine densities are relatively stable by comparison. I hypothesize that some or all of these pharmacomanipulations, when administered during this key period, will correct the behavioral abnormalities observed in Itgb1-deficient mice. Impact: The function of β1-integrin in the mPFC is unknown, despite β1-integrin linkage with neuropsychiatric disease and neurodevelopmental processes in other brain regions. Understanding the neurobehavioral functions of β1-integrin in the adolescent mPFC may provide insight into novel therapeutic approaches to neurodevelopmental disorders and reveal periods during which resiliencies can be conferred.

项目摘要：青春期的特征是前额叶大量的突触修剪和结构稳定皮质（PFC）。鉴于最初在青少年时期出现的“成人”心理健康障碍中约有50％调查介导这种戏剧性结构变化的因素可以为疾病脆弱性或病因提供依据。全基因组关联研究暗示ITGB1是编码β1-整合蛋白的基因，例如精神分裂症。在海马CA1中，细胞外基质蛋白刺激β1-整合蛋白稳定树突和突触从青春期开始。我们最近观察到选择性减少ITGB1 内侧PFC（MPFC）也具有发展性选择性的后果引起类似于Anhedonic的行为。同时，成人发作的敲除没有这种影响。鉴于MPFC在青少年期间经历结构重塑 - 并且在精神病学中失调疾病 - 阐明β1-整合素在MPFC发育中的作用可能会洞悉疾病病因。我假设β1-整合蛋白对于结构稳定是必要的 - 请参见此过程保留树突状刺并逃脱修剪 - 兴奋性MPFC神经元青少年，这种稳定性对于适当的MPFC调节是必要的行为。我的第一个目标研究了β1-整合素对MPFC神经发育和功能的影响。我会在青春期前小鼠的MPFC（初步子区域）中有选择地减少神经元ITGB1。然后我会形象 V层神经元 - 从涉及MPFC依赖性决策的皮层下区域接收输入和情绪调节 - 在整个青少年和重建3D中的树突状棘以描绘的树突状刺发展轨迹。接下来，我将在V层神经元中有选择地减少ITGB1，并确定后果感觉运动门控，社会互动和认可以及目标指导的决策。我假设这一点 ITGB1缺乏会导致V层神经元上的树突状脊柱丧失，从而触发行为异常。神经元β1-整合蛋白信号伴侣包括调节的ABL2/ARG激酶，Cortactin和Rock2 肌动蛋白聚合。在我的第二个目标中，我将身体刺激或抑制（适当）这些因素在MPFC开发的关键时期，与树突状棘密度相对稳定时相比之下。我假设在此期间进行管理时，某些或全部这些药房关键时期将纠正ITGB1缺陷小鼠中观察到的行为异常。影响：MPFC中β1-紧密蛋白的功能未知，dospiteβ1-整合蛋白与其他大脑区域的神经精神病和神经发育过程。了解 β1-整合蛋白在青少年MPFC中的神经行为功能可能会洞悉新型治疗神经发育障碍的方法和揭示了可以赋予弹性的时期。