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

项目概要： 青春期的特点是大量的突触修剪和结构稳定的前额叶 皮质（PFC）。鉴于约50%的“成人”心理健康障碍最初出现在青春期， 调查介导这一巨大结构变化的因素可以为疾病脆弱性或病因提供信息。 全基因组关联研究表明，编码β1-整联蛋白的基因ITGB 1与以下疾病有关， 精神分裂症在海马CA 1区，细胞外基质蛋白刺激β1-整合素稳定 树突和突触在青春期开始。我们最近观察到，Itgb 1在细胞中的选择性还原， 内侧PFC（mPFC）也具有发育选择性后果， 从而导致快感缺失和冒险行为。而成年期的击倒则没有这样的影响。 鉴于mPFC在青春期经历结构重塑，并且在精神病患者中失调， 疾病-阐明β1-整合素在mPFC发展中的作用可能有助于了解疾病的病因。我 假设β1-整联蛋白是结构稳定所必需的-这里指的是该过程 通过这种方式，树突棘得以保留，并在整个过程中逃避兴奋性mPFC神经元的修剪。 青春期，这种稳定性是必要的适当发展mPFC调节 行为。 我的第一个目标是研究β1-整合素对mPFC神经发育和功能的影响。我会 选择性减少青春期前小鼠mPFC（边缘前亚区）中的神经元Itgb 1。我会想象 第五层神经元--接受来自皮层下区域的输入，这些区域参与mPFC依赖性决策 和情绪调节-在整个青春期，并重建树突棘在3D描绘 发展轨迹接下来，我将选择性地减少第V层神经元中的Itgb 1，并确定其在 感觉运动门控、社会互动和识别以及目标导向决策。我假设 itgb 1缺乏会导致V层神经元树突棘缺失，引发行为异常。 神经元β1-整联蛋白信号传导伙伴包括β 2/Arg激酶、corneum和ROCK 2，它们调节 肌动蛋白聚合在我的第二个目标中，我将适当地刺激或抑制每一个 这些因素是在mPFC发育的关键时期，而不是在树突棘密度相对稳定时 相比之下。我假设，当在此期间给予某些或所有这些药物操作时， 关键时期，将纠正在Itgb 1缺陷小鼠中观察到的行为异常。 影响：β1-整合素在mPFC中的功能尚不清楚，尽管β1-整合素与 神经精神疾病和其他大脑区域的神经发育过程。了解 β1-整合素在青少年mPFC中的神经行为功能可能为新的治疗方法提供新的见解。 研究神经发育障碍的方法，并揭示了可以赋予神经发育障碍的时期。

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.