Mechanisms underlying reward-related synaptogenesis

奖励相关突触发生的机制

• 批准号: 7741980
• 负责人: Gloria E. Meredith
• 金额: $ 30.8万
• 依托单位: ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7741980
• 关键词: Amphetamines; Amygdaloid structure; Animals; Association Learning; Behavior; Biological; Brain region; Burn injury; Cells; Clinical; Complement; Complex; Cues; Data; Dendritic Spines; Electron Microscopy; Electrophysiology (science); Environment; Excitatory Synapse; Goals; Hippocampal Formation; Home environment; Human; In Vitro; Individual; Judgment; Knowledge; Learning; Length; Light; Measures; Mediating; Medical; Memory; Modeling; Modification; Morphogenesis; Neurons; Pharmaceutical Preparations; Physiological; Process; Pyramidal Cells; Rattus; Research; Rewards; Saline; Sensory; Shapes; Signal Transduction; Social Problems; Stimulus; Structure; Symptoms; Synapses; Synaptic plasticity; Techniques; Translational Research; Work; base; classical conditioning; conditioned fear; drug craving; drug seeking behavior; effective therapy; experience; hippocampal pyramidal neuron; immunocytochemistry; in vivo; innovation; memory retrieval; neural circuit; novel therapeutics; preference; presynaptic; psychologic; research study; response; stimulant abuse; synaptogenesis

When amphetamine is repeatedly associated with the same environmental context, the environment becomes a powerful stimulus to elicit memories of the drug experience. These memories bring out a strong, physiological response, even in the absence of drug. Such associative learning is maladaptive and contributes to the poor judgment of individuals who crave the drug. However, we know surprisingly little of the synaptic modifications that shape drug-related memories, even though memory retrieval appears critical for the persistence of drug-seeking behavior. Conditioned place preference (CPP) is a model of cue-elicited drug seeking. When amphetamine is repeatedly paired with the same environment, rats learn to associate the rewarding effects of the drug with the cues provided by the environment. Our work has shown that the neural circuitry underlying this behavior could involve synaptic interactions between the hippocampal formation and basolateral amygdala (BLA). We have shown that amphetamine-induced CPP (AM PH CPP) is accompanied by increased synapses and a significant elevation in synaptic drive from the hippocampal formation. We believe that drug-seeking behavior therefore requires both structural and functional plasticity of BLA pyramidal cells to consolidate the learned association of drug and environment. We hypothesize further that this plasticity is mediated by the hippocampal formation. Through experiments outlined herein, we have set 2 specific aims: (1) The first will determine how AMPH CPP rewires BLA pyramidal neurons. The goal is to examine how CPP alters the eXCitatory and inhibitory synaptic complements of pyramidal neurons, using light and electron microscopy, immunocytochemistry and stereology. (2) In the scond, we will determine if AM PH CPP causes enhanced eXCitatory synaptic drive of BLA pyramidal neurons. The goals are to determine, using in vivo intracellular electrophysiological recordings, if BLA pyramidal neurons are subjected to abnormal excitatory drive, and if the hippocampal formation contributes to the excitation. The neuronal structure (dendrites and spines) of recorded BLA neurons will be studied to establish whether morphogenesis (increased spines, dendritic length and branching) is indicative of the strong increases in synaptic drive.

当苯丙胺反复与相同的环境背景联系在一起时，环境就会成为一种强大的刺激，以唤起人们对毒品经历的记忆。这些记忆会带来强烈的生理反应，即使在没有药物的情况下也是如此。这种联想学习是不适应的，并导致渴望吸毒的人判断力不佳。然而，令人惊讶的是，我们对形成毒品相关记忆的突触修饰知之甚少，尽管记忆提取似乎对毒品寻找行为的持久性至关重要。条件性位置偏好(CPP)是一种线索诱导型药物寻找模型。当苯丙胺反复与相同的环境配对时，大鼠学会将药物的有益效果与环境提供的线索联系起来。我们的工作表明，这种行为背后的神经回路可能涉及到海马结构和杏仁基底外侧核(BLA)之间的突触相互作用。我们已经证明，苯丙胺诱导的CPP(AM、PH、CPP)伴随着突触的增加和来自海马结构的突触驱动的显著增加。因此，我们认为，寻找药物的行为需要BLA锥体细胞的结构和功能的可塑性，以巩固药物和环境之间的习得联系。我们进一步假设，这种可塑性是由海马体结构介导的。通过本文概述的实验，我们设定了两个具体目标：(1)第一个目标将确定amph CPP如何重新连接BLA锥体神经元。目的是研究CPP如何改变锥体神经元的兴奋性和抑制性突触补体，使用光学和电子显微镜、免疫细胞化学和体视学。(2)在第二部分中，我们将确定AM PH CPP是否引起BLA锥体神经元兴奋性突触驱动的增强。我们的目标是利用活体细胞内的电生理记录来确定BLA锥体神经元是否受到异常的兴奋性驱动，以及海马结构是否参与了兴奋。将对记录的BLA神经元的神经元结构(树突和棘突)进行研究，以确定形态发生(棘突增加、树突长度和分支)是否表明突触驱动的强劲增加。