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，可能会永久性地影响额叶皮层在突触、回路和行为层面的协调发展。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 et al., 2007; Chambers et al., 2003; Spear, 2000）。经典组织学分析和最近的纵向解剖结构成像研究表明，人类额叶皮层的发育在青春期是高度动态的（Lewis et al.,1997;2008; Paus et al., 2008）。这一时期的不稳定可能造成成瘾和严重精神健康问题的脆弱性。在成年啮齿类动物中，反复接触兴奋剂会持续增强内侧前额叶皮层顶端树突的脊柱密度（Robinson and Kolb, 2004）。目前尚不清楚这种影响是由于在脊柱更新的动态过程中丢失的突触较少还是增加的突触较多，该过程在成年期继续在皮质中进行（Holtmaat et al., 2005）。同样不清楚的是，这些额外的脊椎是否代表了与杏仁核、丘脑或其他支配额叶树突的区域之间更大的连接。进一步的工作需要做，以了解兴奋剂暴露如何影响脊柱可塑性和突触特性，特别是在青春期成熟的不稳定时期。我们的理解也需要改进，这样我们才能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青少年早期和晚期可卡因暴露对体内脊柱结构动力学的影响（脊柱生长和丧失，Aim1）和光遗传学技术来测量驱动额叶皮层的特定的、孤立的、远程传入神经的输入平衡（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和生理盐水对照的小鼠额叶皮质的功能（目的3）。我们将比较可卡因暴露对青春期和成年小鼠脊柱动力学、突触和行为的短期和长期影响。我们的研究将阐明使青少年成为物质使用问题发展的高风险时期的发育突触和回路机制，并将告知临床医生和兴奋剂使用者使用在不同发展阶段对特定额叶回路突触可能产生的负面影响。通过识别被兴奋剂暴露破坏的特定回路、突触和突触可塑性机制，我们的数据也将为未来药物和认知疗法的选择和测试提供指导，以改善青少年兴奋剂暴露对成人大脑特定神经回路的负面影响。

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.