Mechanisms underlying reward-related synaptogenesis

奖励相关突触发生的机制

• 批准号: 6671277
• 负责人: Gloria E. Meredith
• 金额: $ 27.05万
• 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 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6671277
• 关键词: AMPA receptors; NMDA receptors; amphetamines; amygdala; brain derived neurotrophic factor; conditioning; electron microscopy; electrophysiology; glutamate receptor; laboratory rat; memory; neural plasticity; neural transmission; reinforcer; synaptogenesis

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.

描述（由申请人提供）：成瘾药物对大脑有多种影响，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。本提案中概述的研究探讨了安非他明诱导调节过程中这些过程的潜在机制。由于杏仁核对于情绪学习很重要，因此条件行为的表达可能需要位于此处的电路的结构变化。这些改变可能表现为突触增加或重塑，我们的初步研究表明，反复接触安非他明与杏仁核基底外侧（BL）核中突触素和血清素免疫反应末端密度的增加有关。我们还证明了神经营养素、BDNF 及其酪氨酸激酶 B 受体的表达和产生的持久变化。这种增强的 BDNF 信号传导可能会导致突触强化。如其他地方所示，该核中的中间神经元受到锥体细胞和血清素能末梢的侧支神经支配，因此我们假设精神兴奋剂增强 BL 输出途径的兴奋会导致投射神经元的抑制调节发生补偿性变化，重置其放电同步性，适应可能是条件反应的基础。该应用将重点关注 BDNF 和 trkB 在改变突触结构和重置 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。我们将进一步探讨突触覆盖增加的生理后果。这项工作是围绕三个目标设计的。 具体来说，在目标 1 中，我们将测试 BL 安非他明诱导的调节是否与突触发生和神经元兴奋性增强有关。这项工作将涉及突触组织的无偏立体学测量以及安非他明调理后 FOS 诱导的分析。在目标 2 中，我们将通过研究 BL 中的 AMPA 和 NMDA 受体表达和功能，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 因子并研究生理和解剖学突触反应来检查 BDNF 对 BL 突触强度的影响。