Synaptic actin dynamics and the selective vulnerability of drug-associated memory

突触肌动蛋白动力学和药物相关记忆的选择性脆弱性

• 批准号: 8599450
• 负责人: Courtney A Miller
• 金额: $ 42.53万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8599450
• 关键词: AODD relapse; Actins; Address; Amygdaloid structure; Automobile Driving; Behavior; Biochemical; Biology; Brain region; Cells; Complex; Cytoskeleton; Data; Dendritic Spines; Dependence; Drug usage; Employee Strikes; Food; Goals; Housing; Image; Individual; Laboratories; Lateral; Learning; Link; Measurement; Measures; Mediating; Memory; Methamphetamine; Mission; Molecular; Motivation; Motor; Myosin Type II; National Institute of Drug Abuse; National Institute of Mental Health; Nature; Neurobiology; Neurotransmitters; Outcome; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Post-Traumatic Stress Disorders; Prevention; Property; Prosencephalon; Relapse; Research; Rewards; Role; Self Administration; Structure; Sucrose; Synapses; Synaptic plasticity; System; Testing; Therapeutic; Time; Training; Ursidae Family; Vertebral column; Work; addiction; base; density; drug of abuse; drug reward; drug seeking behavior; inhibitor/antagonist; innovation; new therapeutic target; novel; novel strategies; novel therapeutic intervention; polymerization; prevent; psychostimulant; public health relevance; research study; response; small molecule; synaptic function

DESCRIPTION (provided by applicant): Clinicians can offer little hope to people addicted to psychostimulants. Recovering addicts are driven to relapse by the motivation and amygdala activation elicited by contextual memory associated with previous drug use and reward. Decades of research largely focused on neurotransmitter systems have failed to yield an effective pharmacotherapy for the treatment of addiction, suggesting the need to investigate novel mechanisms. Strong preliminary data in this proposal indicates that disrupting actin polymerization, the critical regulator of dendritic spine structure, or myosin II, the motor that promotes polymerization, within the amygdala produces a long- lasting disruption of drug seeking induced by contextual memory, without altering other consolidated amygdala-dependent memories. Importantly, this disruption can be made days after training, when the memory has already been stored. Thus, understanding the cell and molecular mechanisms that underlie the vulnerability of these memories may one day result in a novel therapeutic approach to treat relapse, while also advancing understanding of the neurobiology of memory. The central hypothesis driving this proposal is that drug-context associations are supported by structural and functional plasticity in the amygdala. Further, synaptic amygdala actin dynamics may perpetually cycle in response to drug-context pairing, rendering the resulting memories uniquely susceptible to disruption, as cycling actin is inherently stable. Unfortunately, the field knows vey little about how actin dynamics contribute to structural and functional plasticity in the amygdala, or how this is altered by drugs of abuse. This proposal details an innovative approach to understanding how amygdala actin dynamics alter structural and functional plasticity and control drug seeking behavior. A top-down approach will be used to test the hypothesis; moving from manipulations of drug seeking behavior driven by established drug-context associations during self-administration, down to the mechanisms governing plasticity at single dendritic spines in the amygdala (e.g. multiphoton imaging of actin dynamics and structural and functional changes in individual amygdala spines). Importantly, the mechanisms supporting drug-context memories will be compared to those supporting similar contextual memories for food reward. The goals of this project are 3- fold: (1) To determine when context-associated self-administration triggers a shift in amygdala actin dynamics. (2) To determine the impact of spine actin dynamics on amygdala structural and functional plasticity. (3) To determine the relationship between amygdala synaptic plasticity and the stability of a drug-associated memory. It is expected that determining the mechanisms responsible for this striking actin-based disruption of drug seeking will inform the approach to developing novel strategies for substance abuse relapse and the fundamental understanding of amygdala-dependent memory mechanisms, both of which are long-term goals of the laboratory.

描述（由申请人提供）：临床医生几乎无法给沉迷于心理刺激物的人提供希望。恢复成瘾者的驱动是通过与先前的药物使用和奖励相关的上下文记忆引起的动机和杏仁核激活的复发。数十年的研究主要集中在神经递质系统上，无法产生有效的药物治疗成瘾的药物疗法，这表明需要研究新型机制。该提案中的强大初步数据表明，在杏仁核内破坏肌动蛋白聚合，树突状脊柱结构的关键调节剂或肌球蛋白II，促进聚合的电动机，促进聚合的电动机会产生持续的持久毒品中断，从而在不改变其他综合amyygdala依赖性的依赖性依赖性的依赖性的伴奏记忆引起的药物寻求中。重要的是，这种干扰可以在训练后的几天内（存储记忆存储）造成。因此，了解这些记忆脆弱性的基础的细胞和分子机制可能有一天会导致一种新型的治疗方法来治疗复发，同时也促进了对记忆神经生物学的理解。推动该提议的中心假设是杏仁核中的结构和功能可塑性支持药物秘密关联。此外，突触杏仁核肌动蛋白动力学可能会永久循环响应药物膜的配对，从而使所产生的记忆易于破坏，因为循环肌动蛋白本质上是稳定的。不幸的是，该领域对肌动蛋白动力学如何促进杏仁核的结构和功能可塑性，对此一无所知。 或如何通过滥用药物来改变这种情况。该建议详细介绍了一种创新的方法，用于了解杏仁核肌动蛋白动力学如何改变结构和功能性可塑性以及控制药物寻求行为。自上而下的方法将用于检验假设。从自我管理过程中既定的药物秘密关联所驱动的对药物寻求行为的操纵，一直到杏仁核中单个树突状棘的可塑性的机制（例如，肌动蛋白动力学的多光图像以及单个amyygdala spine的肌动蛋白动力学以及结构和功能变化）。重要的是，将支持毒品秘密记忆的机制与支持类似上下文记忆以获得食物奖励的机制。该项目的目标是3倍：（1）确定何时与上下文相关的自我管理会触发杏仁核肌动蛋白动力学的转变。 （2）确定脊柱肌动蛋白动力学对杏仁核结构和功能可塑性的影响。 （3）确定杏仁核突触可塑性与药物相关记忆的稳定性之间的关系。可以预期，确定负责这种基于肌动蛋白的药物的破坏的机制将为制定新颖的滥用药物滥用策略复发和对依赖杏仁核依赖性记忆机制的基本理解的方法，这都是实验室的长期目标。