Mechanisms underlying reward-related synaptogenesis

描述（由申请人提供）：成瘾药物对大脑有许多影响，但其中最重要的是与药物相关的刺激对记忆过程的强大影响。本研究的建议中概述的机制探讨这些过程中苯丙胺诱导的条件反射。由于杏仁核对情绪学习很重要，条件反射行为的表达可能需要位于这里的回路的结构变化。这些改变可能采取增加或重塑突触的形式，我们的初步研究表明，反复安非他明暴露与杏仁核基底外侧（BL）核中突触素和突触素能免疫反应性终末密度增加有关。我们还证实了神经营养因子、BDNF及其酪氨酸激酶B受体的表达和产生的长期变化。这种增强的BDNF信号传导可能导致突触强化。如其他地方所示，这个核中的中间神经元由锥体细胞和神经元末梢的侧枝支配，因此我们假设，精神兴奋剂增强BL输出通路的兴奋导致投射神经元重置其放电同步性的抑制性调节的补偿性变化，这种适应可能是条件反应的基础。本申请将集中于BDNF和trkB在改变突触结构和BL神经元功能重置中的作用。我们将使用条件性位置偏爱范例，并确定是否突触变化是由BDNF通过其trk B受体作用的表达改变引起的。我们将进一步探讨增加突触覆盖的生理后果。这项工作是围绕三个目标。 具体来说，在目标1，我们将测试是否在BL安非他明诱导的条件反射与突触和增强神经元兴奋性。这项工作将涉及无偏见的突触组织的体视学测量和安非他明条件反射后FOS诱导的分析。在目的2中，我们将通过研究BL中AMPA和NMDA受体的表达和功能，进一步测试突触强化是否是谷氨酸受体介导的。最后，在目标3中，我们将通过长期注入BDNF并研究生理和解剖突触反应来检查BDNF对BL中突触强度的影响。

DESCRIPTION (provided by applicant): Addictive drugs have numerous effects on the brain but among the most significant is the powerful effect of drug-related stimuli on mnemonic processes. The research outlined in present proposal explores the mechanisms underlying these processes during amphetamine-induced conditioning. Since the amygdala is important for emotional learning, the expression of conditioned behavior may require structural changes in circuits located here. These alterations could take the form of increased or remodeled synapses, and our preliminary studies show that repeated amphetamine exposure is associated with increased density of synaptophysin- and serotonergic- immunoreactive terminals in the basolateral (BL) nucleus of the amygdala. We have also demonstrated long-lasting changes in the expression and production of the neurotrophin, BDNF and its tyrosine kinase B receptor. This enhanced BDNF signaling could lead to the synaptic strengthening. As shown elsewhere, interneurons in this nucleus are innervated by collaterals of pyramidal cells and serotonergic terminals, and so we postulate that psychostimulant-enhanced excitation of BL output pathways results in compensatory changes in the inhibitory regulation of the projection neurons resetting their firing synchrony, an adaptation that may be fundamental to the conditioned response. This application will focus on the role of BDNF and trkB in changing synaptic structure and the resetting of BL neuron function. We will use a conditioned place preference paradigm and determine whether synaptic changes are precipitated by altered expression of BDNF acting through its trk B receptors. We will further explore the physiological consequences of an increased synaptic covering. The work is designed around three aims. Specifically, in Aim 1, we will test whether in BL amphetamine-induced conditioning is associated with synaptogenesis and enhanced neuronal excitability. This work will involve unbiased stereological measurement of synaptic organization and an analysis of FOS induction after amphetamine conditioning. In Aim 2, we will further test whether synaptic strengthening is glutamate receptor-mediated, by studying AMPA and NMDA receptor expression and function in BL. Finally, in Aim 3, we will examine the influence of BDNF on synaptic strength in BL by chronically infusing this factor and studying the physiological and anatomical synaptic responses.