Myosin II regulation of actin dynamics and the selective vulnerability of methamphetamine- and opioid-associated memory

肌球蛋白 II 调节肌动蛋白动力学以及甲基苯丙胺和阿片类药物相关记忆的选择性脆弱性

• 批准号: 10533792
• 负责人: Courtney A Miller
• 金额: $ 72.16万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10533792
• 关键词: AODD relapse; Actins; Address; Amphetamines; Amygdaloid structure; Association Learning; Behavior; Behavior Therapy; Brain; Brain region; Cell Culture Techniques; Clinical; Cocaine; Cytoskeletal Modeling; Cytoskeleton; Data; Dendritic Spines; Development; Dopamine; Drug usage; Food; Funding; Genetic; Heroin; Hippocampus; Image; Individual; Investigation; Knowledge; Learning; Literature; Memory; Memory impairment; Mental disorders; Methamphetamine; Methamphetamine use disorder; Mission; Morphine; Motivation; Myosin ATPase; Myosin Type II; National Institute of Drug Abuse; National Institute of Mental Health; Nature; Neuromodulator; Neuromodulator Receptors; Neurons; Nicotine; Opioid; Pharmaceutical Preparations; Pharmacotherapy; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Polymers; Population; Post-Traumatic Stress Disorders; Predisposition; Preparation; Proteins; Regulation; Relapse; Research; Retrieval; Rewards; Risk Factors; Role; Self Administration; Signal Transduction; Slice; Smoke; Specificity; Stimulant; Structure; Synapses; Synaptic plasticity; Therapeutic; Time; Tissues; Training; United States National Institutes of Health; Vertebral column; Work; cell cortex; cell motility; depolymerization; drug abuse vulnerability; drug of abuse; fear memory; in vivo; inhibitor; innovation; methamphetamine effect; methamphetamine user; neural circuit; new therapeutic target; non-muscle myosin; novel therapeutics; opioid use; pharmacologic; polymerization; polysubstance use; postsynaptic; prevent; public health relevance; recruit; relapse risk; response; stimulant abuse; substance abuse prevention; therapeutic target; two-photon

PROJECT SUMMARY  There are no pharmacotherapies for stimulant abuse, including methamphetamine (METH) and relapse rates  are high. Relapse triggered by reminders of drug use is a particular challenge to prevent, as the underlying  memories exert a powerful motivational influence over behavior and represent a lifelong relapse risk factor.  Learning is supported by structural plasticity in dendritic spines, driven by training-­induced actin polymer-­ ization. Memory stability is subsequently achieved by arresting actin dynamics, stabilizing the cytoskeleton. As  a result, memory is impervious to actin depolymerization within minutes of learning. However, prior work in the  lab discovered that the actin cytoskeleton supporting METH memories remains uniquely dynamic in the  amygdala long after training. This enables selective, retrieval-­independent disruption of METH-­associated  memories and drug seeking with a single administration of an actin depolymerizer. Because actin’s critical  roles in the body limit its therapeutic potential, focus shifted to nonmuscle myosin II (NMII), a direct driver of  learning-­stimulated actin polymerization in spines. The effect of NMII inhibition is specific to the amygdala and  METH. Indeed, NMII inhibition has no effect on METH memories when other regions of the drug-­memory  neural circuit are targeted and there is no similar retrieval-­independent effect on memories for fear, food  reward or other drugs of abuse, including opioids. Genetic and pharmacologic targeting of NMII established it  is a viable therapeutic target and an NIH-­funded medication development project for a clinically safe NMII  inhibitor is underway (UH3 NS096833). However, fundamental knowledge needed to understand and further  leverage this specificity is lacking. This will be addressed through the central hypothesis in this new project:  that METH-­associated memories are uniquely supported in the amygdala by NMII, leaving those memories  selectively vulnerable to disruption long after learning, even when other associative learning is introduced. The  focus of this application is two-­fold: (1) The key mechanistic question regarding the specific requirement of  the amgydala, actin-­NMII and METH for selective memory storage disruption will be addressed. For this, the  impact of METH-­related neuromodulators (Aim 1), as well as NMII phosphorylation and interacting partners  (Aim 2) will be studied on NMII-­dependent BLA synaptic actin dynamics and METH-­associated memory, with a  focus on factors that are unique to METH and the BLA. Once identified, the mechanism(s) responsible could  be harnessed to render relapse-­inducing memories for other drugs of abuse vulnerable to disruption. (2)  Because most individuals with METH use disorder use multiple substances, including opioids, it is necessary  to determine the impact of polydrug administration on METH memory susceptibility to NMII inhibition.  Preliminary data indicate that METH confers susceptibility to previously impervious opioid associations.  Technically innovative approaches will be employed throughout the project, spanning from single synapse  manipulations in live tissue slices to memory-­based self-­administration studies.

项目总结