Mechanisms Regulating Cocaine Memory Strength

调节可卡因记忆强度的机制

基本信息

批准号：
9919523
负责人：
Mary M Torregrossa
金额：
$ 34.65万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9919523
关键词：
Address Amygdaloid structure Behavior Behavioral Behavioral Mechanisms Calcineurin Calmodulin Chemosensitization Clinical Cocaine Cues Data Electrophysiology (science)Equilibrium Event Extinction (Psychology)Female Goals Homosynaptic Depression Individual Learning Maintenance Measures Mediating Memory Methods Modeling Molecular Neuronal Plasticity Pathway interactions Pattern Pharmaceutical Preparations Phosphopeptides Phosphoric Monoester Hydrolases Phosphorylation Phosphoserine Phosphotransferases Physiological Process Protein Analysis Protein Dephosphorylation Proteomics Rattus Regulation Relapse Reporting Research Research Personnel Role Self Administration Serine Sex Differences Signal Pathway Signal Transduction Societies Synapses Testing Time Tissues Training Viral addiction base calcineurin phosphatase calmodulin-dependent protein kinase II cohort conditioned fear craving cue reactivity disorder later incidence prevention drug of abuse effective therapy experimental study fear memory follow-up improved male memory process mimetics mutant non-drug novel phosphoproteomics pre-clinical prevent therapy development

项目摘要

Project Summary/Abstract Addictive disorders are a huge burden on both the individual and on society. Unfortunately, there are few effective treatments, partially due to the persistence of drug-associated memories that drive craving and relapse. Therefore, recent research has focused on finding ways to reduce the strength of drug-associated memories to prevent relapse. Memory strength can be reduced by either disrupting the association between a cue and a drug via extinction or by inhibiting the reconsolidation of the memory after a reminder event. Both strategies have been effective in preclinical and clinical models, but in some cases, a memory meant to be weakened, is instead strengthened due to unintentional enhancement of reconsolidation or inhibition of extinction. In order to address this problem, we have analyzed changes in protein phosphorylation after a memory undergoes extinction vs. reconsolidation to identify signaling cascades that are selective to either memory process, or that ideally regulate the two processes in opposite directions. Identification of opposing signaling events could allow the development of treatments that both enhance extinction and inhibit reconsolidation, reducing the strength of the drug-associated memories that drive relapse. Our preliminary data strongly suggest that opposing Ca2+-related signaling events in the basolateral amygdala (BLA) mediate the reconsolidation vs. extinction of a memory associated with self-administered cocaine. We will expand our identification of opposing signaling events in Aim 1 of the proposed studies, including increasing the number of proteins analyzed, expansion of the time course of analysis, and extending the analysis to females. Moreover, we will follow-up on the exciting findings from our initial study, which include 1) identification of a novel phosphorylation event on Ca2+ -calmodulin-dependent kinase 2 alpha (CaMKIIα, phospho-serine 331) induced by extinction and reduced during reconsolidation that functions to inhibit kinase activity, and 2) a general decrease in protein phosphorylation after extinction, implicating activation of a phosphatase, such as calcineurin. Our data led us to hypothesize that extinction training, in addition to involving new learning mechanisms, can also oppose normal reconsolidation processes. We propose that this occurs within the same circuits via Ca2+-regulated synaptic depotentiation mechanisms. Extinction-induced synaptic depotentiation and differences in CaMKII and calcineurin signaling have been reported for conditioned fear memories, but have not been examined for cocaine-associated memories. Thus, using a combination of approaches in Aims 2 & 3, we will determine if CaMKIIα inhibition via S331 phosphorylation, and activation of calcineurin phosphatase, can reduce cocaine memory strength to decrease cue-induced reinstatement via enhancement of extinction AND inhibition of reconsolidation. We will also determine if these signaling pathways directly regulate each other and synaptic strength in the same or different pathways. Determination of the mechanisms regulating cocaine memories will lead to novel targets for relapse prevention treatment development.

项目摘要/摘要上瘾的疾病是个人和社会的巨大负担。有效的治疗，部分是由于吸毒的记忆的持续存在，这些记忆使人们渴望渴望和因此，最近的研究重点是寻找与药物相关的强度回忆以防止亲戚。通过灭绝或在提醒事件后抑制记忆的重构。策略在临床前和临床模型中具有效果，但在某些情况下是记忆的心理削弱，而是由于不明确的重新识别的重新识别，强度强度强度强度为了解决这个问题，我们已经分析了蛋白质磷酸化的变化内存进行灭绝与重新构造，以识别选择性的信号级联对立的识别。信号事件可能会开发增强灭绝和抑制的处理重新解决，减少，驱动我们的预后数据的药物相关记忆的强度强烈建议基底外侧杏仁核（BLA）中相对的Ca2+相关信号事件使您介导您与高级可卡因相关的记忆的重新构造与灭绝。在AIM 1中识别支撑研究的AIM 1中的相对信号事件，使数量增加分析的蛋白质，分析时间过程的扩展，并将分析扩展到女性。我们将跟进我们最初研究的兴奋，其中包括1）识别新颖的 Ca2+ -calmodulin-Depenpentenase 2 alpha（CaMKIIα，磷酸 - 丝氨酸331）上的磷酸化事件通过灭绝并减少在重新构液中起作用以抑制激酶作用的作用，2）一般消灭后蛋白质磷酸化的降低，暗示激活钙调神经酶。机制也可以反对正常的重新固定过程。通过CA2+调节的突触繁殖机制的电路据报道有条件的恐惧记忆，CAMKII和钙调神经蛋白信号的差异已有报道，但是尚未检查可卡因相关的记忆。 2＆3，我们将确定CAMKIIα是否通过S331磷酸化和钙调蛋白的激活是否抑制磷酸酶，可以降低可卡因记忆强度，从而通过增强来降低提示诱导的恢复原状灭绝和抑制重新构造。相互调节，并在相同或不同的途径中进行突触强度。调节可卡因的记忆将导致新的目标，以防止发育。