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

描述（由申请人提供）：临床医生对精神兴奋剂成瘾的人几乎没有希望。与先前吸毒和奖励相关的情境记忆所引发的动机和杏仁核激活会驱使成瘾者复吸。几十年来的研究主要集中在神经递质系统上，但未能产生有效的药物治疗成瘾，这表明需要研究新的机制。这项研究中强有力的初步数据表明，破坏杏仁核内的肌动蛋白聚合（树突棘结构的关键调节因子）或肌球蛋白II（促进聚合的马达），会产生由情境记忆引起的药物寻找的持久破坏，而不会改变其他巩固的杏仁核依赖的记忆。重要的是，这种破坏可以在训练后几天发生，那时记忆已经储存起来了。因此，了解这些记忆脆弱性背后的细胞和分子机制可能有一天会导致一种新的治疗方法来治疗复发，同时也会促进对记忆神经生物学的理解。推动这一提议的核心假设是，杏仁核的结构和功能可塑性支持药物与环境的关联。此外，突触杏仁核肌动蛋白动力学可能会随着药物-环境配对而不断循环，由于循环的肌动蛋白本身是稳定的，因此产生的记忆非常容易被破坏。不幸的是，该领域对肌动蛋白动力学如何影响杏仁核的结构和功能可塑性知之甚少，

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.