Mechanisms underlying reward-related synaptogenesis

描述(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助记过程的强大影响。本提案中概述的研究探索了苯丙胺诱导的条件反射过程中潜在的机制。由于杏仁核对情绪学习很重要，条件性行为的表达可能需要在这里的回路中发生结构变化。这些改变可能以突触增加或重塑的形式出现，我们的初步研究表明，反复暴露苯丙胺与杏仁核基底外侧核中突触素和5-羟色胺能免疫反应终末密度增加有关。我们还展示了神经营养因子、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信号可能导致突触的加强。如其他地方所示，该核团中的中间神经元由锥体细胞和5-羟色胺能终末的侧支支配，因此我们假设，精神刺激剂增强的对BL输出通路的兴奋导致了投射神经元的抑制调节的代偿性改变，该抑制调节重置其放电同步性，这一适应可能是条件性反应的基础。本文将重点介绍BDNF和TrkB在改变突触结构和重新定位BL神经元功能中的作用。我们将使用条件性位置偏好范式，并确定突触变化是否由BDNF通过其trk B受体作用的表达变化引起。我们将进一步探索增加突触覆盖的生理后果。这项工作围绕三个目标进行设计。具体地说，在目标1中，我们将测试在BL中苯丙胺诱导的条件反射是否与突触发生和增强的神经元兴奋性有关。这项工作将包括对突触组织的无偏向体视学测量和苯丙胺条件作用后FOS诱导的分析。在目标2中，我们将通过研究AMPA和NMDA受体在BL中的表达和功能，进一步验证突触增强是否是谷氨酸受体介导的。最后，在目标3中，我们将通过慢性注入BDNF因子并研究其生理和解剖突触反应，来检验BDNF对BL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.