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

青少年可卡因对额叶脊柱周转、突触和行为的影响

• 批准号: 8265876
• 负责人: Linda E Wilbrecht
• 金额: $ 36.4万
• 依托单位: ERNEST GALLO CLINIC AND RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8265876
• 关键词: AMPA Receptors; Acute; Adolescence; Adolescent; Adolescent Development; Adult; Affect; Age; Alcohol or Other Drugs use; Amygdaloid structure; Apical; Axon; Behavior; Behavioral; Brain; Cells; Childhood; Chronic; Cocaine; Cognitive; Cognitive Therapy; Data; Dendrites; Development; Dopamine; Dorsal; Equilibrium; Exposure to; Future; Growth; Human; Image; Imaging technology; Interneurons; Lead; Life; Long-Term Effects; Measures; Medial; Mental Health; Mus; N-Methyl-D-Aspartate Receptors; Pathway interactions; Performance; Pharmacotherapy; Plastics; Play; Prefrontal Cortex; Process; Property; Relative (related person); Research; Reversal Learning; Rodent; Role; Saline; Specificity; Staging; Synapses; Synaptic plasticity; Technology; Testing; Thalamic structure; Training; Vertebral column; Work; addiction; cocaine exposure; density; drug of abuse; excitatory neuron; experience; frontal lobe; high risk; in vivo; inhibitory neuron; mouse model; multi-photon; neural circuit; new technology; optogenetics; peer; public health relevance; relating to nervous system; repaired; response; skills

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.

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、回路和行为层面的协调发育。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，2007；Chambers 等，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，人类额叶皮层发育在青春期是高度动态的（Lewis等，1997；2008；Paus等，2008）。这段时期的波动可能会导致成瘾和严重心理健康问题的脆弱性。反复接触刺激物会持续增强成年啮齿动物内侧前额叶皮层顶端树突的脊柱密度（Robinson 和 Kolb，2004）。目前还不清楚这种效应是否是由于在整个成年期皮质中持续的脊柱更新动态过程中丢失的突触减少或获得的突触增加所致（Holtmaat et al., 2005）。目前还不清楚这些额外的刺是否代表了杏仁核、丘脑或其他支配额叶树突的区域的更大连通性。需要做进一步的工作来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不稳定时期。我们的理解也需要完善，以便我们更好地理解这些突触变化的机制和特定电路的特异性。我们正在使用多光子成像技术来确定青少年早期和晚期暴饮可卡因暴露对体内脊柱结构动力学（脊柱生长和损失，Aim1）的影响，并使用光遗传学技术来测量来自特定的、孤立的、长期的输入的平衡。驱动额叶皮层的范围传入神经（目标 2）。我们通过行为分析补充这些突触的解剖和功能研究，以评估青春期早期和晚期接触可卡因的小鼠和盐水对照小鼠额叶皮层的功能（目标 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性突触和回路机制，这些机制使青春期成为物质使用问题发展的高风险期，并将告知临床医生和兴奋剂使用者在不同发育阶段使用对特定额叶回路突触可能产生的负面影响。通过识别因兴奋剂暴露而破坏的特定回路、突触和突触可塑性机制，我们的数据还将作为未来药物和认知疗法的选择和测试的指南，以改善青少年兴奋剂暴露对特定神经回路的负面影响。成人的大脑。 公共健康相关性：青少年接触可卡因等兴奋剂可能会永久影响额叶皮层突触、回路和行为水平的协调发育。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回路、突触和突触可塑性机制，我们的数据还将作为选择和测试未来药物和认知疗法的指南，以修复青少年兴奋剂暴露对成人神经回路的负面影响。