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: 8434945
• 负责人: Linda E Wilbrecht
• 金额: $ 2.9万
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8434945
• 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.

描述（由申请人提供）：青少年接触可卡因等兴奋剂，可能会永久影响突触，电路和行为水平下额叶皮层的协调发展。额叶皮层的发展发生在儿童晚期和青春期，这是用于吸毒的开发的关键时刻（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，人类的额叶皮质发育在青春期是高度动态的（Lewis等，1997; 2008; Paus等，2008）。这一时期的波动可能会造成成瘾和严重心理健康问题的发展脆弱性。反复的刺激性暴露始终增强成年啮齿动物内侧前额叶皮质的顶端树突中的脊柱密度（Robinson and Kolb，2004）。目前尚不清楚这种影响是否是由于在脊柱周转的动态过程中丢失或更多的突触引起的，而脊柱周转的过程一直持续到成年（Holtmaat et al。，2005）。还不清楚这些额外的棘突是否代表了杏仁核，丘脑或其他支配额叶树突的区域的更大连通性。需要进行进一步的工作，以了解刺激性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挥发性期间。我们的理解还需要完善，以便我们更好地了解这些突触变化的机制和对特定电路的特异性。我们使用多光子成像技术来确定早期和晚期的狂饮可卡因暴露对体内脊柱结构动力学（脊柱生长和损失，AIM1）和光遗传学技术的影响，以测量从特定的，孤立的，远距离的传入中的投入平衡，这些传入驱动前层frontal cortex（AIM 2）。我们补充了通过行为分析的突触的解剖学和功能研究，以评估在青春期和盐水控制阶段早期和晚期暴露于可卡因的小鼠中额叶皮层的功能（AIM 3）。我们将比较青少年和成年小鼠中可卡因暴露对脊柱动力学，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，使青少年成为使用物质使用问题的高风险时期，并将为临床医生和兴奋的使用者告知使用对特定额叶电路突触在不同发育阶段的特定额叶电路突触的可能负面影响。通过识别受刺激性暴露破坏的特定电路，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，以改善青少年刺激性刺激性暴露对成人大脑特定神经电路的负面影响。