Effects of adolescent cocaine on frontal spine turnover, synapses and behavior

描述（由申请人提供）：青少年接触兴奋剂，如可卡因，可能会永久影响额叶皮层在突触，回路和行为水平的协调发展。额叶皮层的发育发生在儿童晚期和青春期，这是物质使用发展的关键时刻（Paus等人，2007; Chambers等人，2003; Spear，2000）。经典的组织学分析和最近的纵向解剖结构成像研究表明，人类额叶皮质发育在青春期是高度动态的（刘易斯等人，1997;2008; Paus等人，2008年）。这一时期的波动可能会导致成瘾和严重的心理健康问题的发展。反复暴露于刺激物可持续增强成年啮齿动物内侧前额叶皮质顶端树突的棘密度（罗宾逊和Kolb，2004）。目前尚不清楚这种效应是由于在脊髓更新的动态过程中丢失的突触较少还是获得的突触较多，该过程在皮质中持续到成年（Holtmaat等人，2005年）。同样不清楚的是，这些额外的棘是否代表了来自杏仁核、丘脑或其他支配额树突的区域的更大的连通性。需要做进一步的工作，以了解刺激物暴露如何影响脊柱可塑性和突触特性，特别是在青少年成熟的动荡时期。我们的理解也需要改进，以便我们更好地理解这些突触变化的机制和特定回路的特异性。我们正在使用多光子成像技术来确定早期和晚期青少年狂欢可卡因暴露对体内脊柱结构动力学的影响（脊柱生长和损失，Aim 1）和光遗传学技术来测量来自特定的，孤立的，驱动额叶皮层的长距离传入的输入平衡（Aim 2）。我们用行为分析来补充这些突触的解剖学和功能研究，以评估在青春期早期和晚期暴露于可卡因的小鼠和生理盐水对照组的额叶皮质的功能（目的3）。我们将比较可卡因暴露对青少年和成年小鼠脊柱动力学、突触和行为的短期和长期影响。我们的研究将阐明发育突触和电路机制，使青春期的高风险时期的发展物质使用问题，并将告知临床医生和兴奋剂使用者可能的负面影响，使用特定的额叶回路突触在不同的发展阶段。通过识别特定的电路，突触和突触可塑性机制，被破坏的兴奋剂暴露，我们的数据也将作为一个指导选择和测试未来的药物和认知疗法，以改善青少年兴奋剂暴露对特定的神经回路的负面影响在成年人的大脑。 公共卫生相关性：青少年接触兴奋剂，如可卡因，可能会永久影响额叶皮层在突触，回路和行为水平上的协调发展。我们将在青少年和成年小鼠模型中测量可卡因暴露对体内脊柱动力学、突触和行为的影响。通过识别被破坏的特定电路，突触和突触可塑性机制，我们的数据也将作为未来药物和认知疗法的选择和测试的指导，以修复青少年兴奋剂暴露对成人神经电路的负面影响。

DESCRIPTION (provided by applicant): Adolescent exposure to stimulants, such as cocaine, may permanently affect the coordinated development of the frontal cortex at the synaptic, circuit and behavioral level. The development of the frontal cortex takes place during late childhood and adolescence, a critical moment for the development for substance use (Paus et al., 2007; Chambers et al., 2003; Spear, 2000). Classic histological analysis and recent longitudinal anatomical structural imaging studies have shown that human frontal cortical development is highly dynamic during adolescence (Lewis et al.,1997;2008; Paus et al., 2008). Volatility of this period may create vulnerability to the development of addiction and serious mental health issues. Repeated stimulant exposure consistently enhances spine density in the apical dendrites of the medial prefrontal cortex in adult rodents (Robinson and Kolb, 2004). It is unclear if this effect is due to fewer synapses lost or more gained in the dynamic process of spine turnover which continues in the cortex through adulthood (Holtmaat et al., 2005). It is also unclear if these extra spines represent greater connectivity from the amygdala, the thalamus, or other regions that innervate frontal dendrites. Further work needs to be done to understand how stimulant exposure affects spine plasticity and synapse properties specifically during the volatile period of adolescent maturation. Our understanding also needs to be refined, so that we better understand the mechanisms of these synaptic changes and specificity to particular circuits. We are using multi-photon imaging technology to determine the effect of early and late adolescent binge cocaine exposure on spine structural dynamics in vivo (spine growth and loss, Aim1 ) and optogenetic technology to measure the balance of input from specific, isolated, long-range afferents that drive frontal cortex (Aim 2). We supplement these anatomical and functional studies of synapses with behavioral analysis to assess the function of the frontal cortex in mice exposed to cocaine at early and late stages of adolescence and saline controls (Aim 3). We will compare the short and long term effects of cocaine exposure on spine dynamics, synapses and behavior in both adolescent and adult mice. Our studies will illuminate the developmental synaptic and circuit mechanisms that make adolescence a high risk period for the development of substance use problems and will inform clinicians and stimulant users of possible negative impacts of use on specific frontal circuit synapses at different stages of development. By identifying specific circuits, synapses, and synaptic plasticity mechanisms that are disrupted by stimulant exposure, our data will also serve as a guide for selection and testing of future drug and cognitive therapies to ameliorate the negative effects of adolescent stimulant exposure on specific neural circuits in adult brains. PUBLIC HEALTH RELEVANCE: Adolescent exposure to stimulants, such as cocaine, may permanently affect the coordinated development of the frontal cortex at the synaptic, circuit and behavioral level. We will measure the effect of cocaine exposure on in vivo spine dynamics, synapses and behavior in both adolescent and adult mouse models. By identifying specific circuits, synapses, and synaptic plasticity mechanisms that are disrupted, our data will also serve as a guide for selection and testing of future drug and cognitive therapies to repair the negative effects of adolescent stimulant exposure on adult neural circuits.