Mechanisms underlying reward-related synaptogenesis

当安非他明反复与相同的环境背景联系在一起时，环境就成为一种强大的刺激，引发对毒品经历的记忆。即使没有药物，这些记忆也会引起强烈的生理反应。这种联想学习是不适应的，会导致渴望药物的人判断力差。然而，令人惊讶的是，我们对形成药物相关记忆的突触修饰知之甚少，尽管记忆提取似乎对药物寻求行为的持续性至关重要。条件性位置偏爱（CPP）是一种线索诱导的药物寻求模型。当安非他明与相同的环境反复配对时，老鼠学会了将药物的奖励效应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海马结构和基底外侧杏仁核（BLA）之间的突触相互作用。我们已经证明，安非他明诱导的CPP（AM PH CPP）伴随着突触增加和海马结构突触驱动的显着升高。因此，我们认为，觅药行为需要BLA锥体细胞的结构和功能可塑性，以巩固药物和环境的学习关联。我们进一步假设这种可塑性是由海马结构介导的。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)第二，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增强。目标是确定，使用在体内细胞内电生理记录，如果BLA锥体神经元受到异常兴奋性驱动，如果海马结构有助于兴奋。将研究记录的BLA神经元的神经元结构（树突和棘），以确定形态发生（棘增加、树突长度和分支）是否指示突触驱动的强烈增加。

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.