Defining the role of glucocorticoid-related dendritic spine plasticity in cocaine-induced habits

定义糖皮质激素相关的树突棘可塑性在可卡因诱发的习惯中的作用

基本信息

批准号：
10203832
负责人：
Michelle Kathryn Sequeira
金额：
$ 4.6万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-09 至 2023-06-08
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10203832
关键词：
Actins Address Adrenal Glands Affect Affinity Agonist Astrocytes Behavior Behavioral Binding Brain Characteristics Chronic Cocaine Complex Corticosterone Cytoskeleton Decision Making Dendritic Spines Disease Enterobacteria phage P1 Cre recombinase Equilibrium F-Actin Failure Gene Silencing Glial Fibrillary Acidic Protein Glucocorticoid Receptor Glucocorticoids Goals Habits Health Hormones Human Hydrocortisone Hypothalamic structure Impairment Infusion procedures Link LoxP-flanked allele Mediating Morphology Mus NR3C1 gene Neurons Obsessive-Compulsive Disorder Organism Outcome Pattern Pharmaceutical Preparations Pharmacology Pharmacotherapy Phosphotransferases Pituitary Gland Primates Proteins Publishing Receptor Activation Regulation Reporting Research Research Personnel Rodent Role Shapes Site Stimulus Stress Structure Substance Use Disorder Techniques Testing Training Transgenic Mice Vertebral column Viral Viral Vector Work addiction alpha Actin alpha Tropomyosin base career cocaine exposure cocaine use density drug of abuse excitatory neuron experimental study hippocampal pyramidal neuron improved in vivo inhibitor/antagonist latrunculin A neurobiological mechanism neuron loss neuropsychiatric disorder neurotoxicity novel strategies polymerization preservation prevent promoter psychostimulant receptor receptor binding recombinase response skills stressor

项目摘要

Project Summary Goal-directed action refers to the ability to select an action based on a desired outcome. In contrast to goal- directed actions, habits are stimulus-elicited and insensitive to goals. Both goal-directed action and habits are important for survival, but habits can be maladaptive and are characteristic of many neuropsychiatric diseases including cocaine use disorder (CUD). The first report that cocaine causes a bias towards habits at the expense of goal-directed action in rodents was published ~15 years ago, but the underlying mechanisms remain unclear. Cocaine causes the release of stress hormones, and both cocaine and stress hormone exposure cause the destabilization of dendritic spines in the orbitofrontal cortex (OFC). Research in rodents also indicates that local infusion of drugs that destabilize dendritic spines in the OFC disrupts goal-directed action, causing a bias towards habitual behavior. The investigator will test the hypothesis that chronic cocaine exposure causes habit biases by increasing levels of circulating stress hormones, activating glucocorticoid receptors (GR), leading to dendritic spine loss in the OFC. The investigator will thus identify mechanisms by which cocaine induces habit biases. In Aim 1, the investigator will use in vivo viral-mediated gene silencing and a task termed “instrumental contingency degradation”, which tests the ability of mice to associate a trained response with its likely outcome. The investigator will thereby determine whether cocaine degrades goal-directed action (causing habit biases) via prolonged stimulation of GRs in the OFC. The investigator hypothesizes that prolonged cocaine exposure induces habits by triggering CORT release, causing chronic activation of GRs in the OFC. Thus, reducing GR levels in the OFC will protect against cocaine-induced habitual behavior. In Aim 2, the investigator will use pharmacological techniques to directly manipulate the actin cytoskeleton selectively within the OFC to determine the role of cytoskeletal stability in OFC-dependent goal-directed action. The investigator hypothesizes that stimulating dendritic spinogenesis will promote goal-directed action in cocaine-exposed mice, while destabilizing dendritic spines will block this effect. It is widely accepted that psychostimulants and stress modify dendrite and dendritic spine densities and morphologies, yet causal relationships with the behavioral effects of drugs of abuse or stressors are largely not verified. Thus, by carrying out this proposed work, the investigator will address fundamental unanswered questions regarding how stress hormones and dendritic spine plasticity influence the manner in which cocaine alters complex decision making. This research is highly translational and could reveal new approaches to treating CUD, for which no pharmacotherapies currently exist, while also equipping the investigator with the skills necessary for a successful scientific career.

项目概要目标导向的行动是指根据期望的结果选择行动的能力。目标导向的行动和习惯都是由刺激引起的，并且对目标不敏感。对生存很重要，但习惯可能会导致适应不良，并且是许多神经精神疾病的特征包括可卡因使用障碍 (CUD) 的第一份报告表明可卡因会导致人们对习惯的偏见。大约 15 年前发表了针对啮齿动物的目标导向行动的研究，但其潜在机制仍不清楚。可卡因会导致应激激素的释放，而可卡因和应激激素的暴露都会导致对啮齿类动物的研究也表明，眶额皮质（OFC）中的树突棘不稳定。输注破坏 OFC 树突棘稳定的药物会扰乱目标导向的行动，导致偏向调查员将检验长期接触可卡因导致习惯的假设。通过增加循环应激激素水平、激活糖皮质激素受体（GR）、导致 OFC 树突棘损失的研究人员将因此确定可卡因的机制。诱发习惯偏差。在目标 1 中，研究人员将使用体内病毒介导的基因沉默和一项名为“仪器分析”的任务意外退化”，它测试小鼠将经过训练的反应与其可能结果联系起来的能力。因此，调查人员将确定可卡因是否会降低目标导向的行动（导致习惯偏差）研究人员通过长时间刺激 OFC 中的 GR 来延长可卡因暴露时间。通过触发 CORT 释放来诱发习惯，导致 OFC 中 GR 的慢性激活，从而减少 GR。 OFC 中的水平将防止可卡因引起的习惯性行为。在目标 2 中，研究者将使用药理学技术直接操纵肌动蛋白细胞骨架在 OFC 内选择性地确定细胞骨架稳定性在 OFC 依赖性目标导向行动中的作用。研究人员正在研究刺激树突棘发生将促进目标导向的行动暴露于可卡因的小鼠，而不稳定的树突棘会阻止这种效应。人们普遍认为精神兴奋剂和压力会改变树突和树突棘的密度，形态学，但与滥用药物或压力源的行为影响之间的因果关系基本上不存在因此，通过开展这项拟议的工作，研究者将解决根本性的未解答问题。关于应激激素和树突棘可塑性如何影响可卡因的方式的问题这项研究具有高度转化性，可以揭示新的治疗方法。 CUD，目前尚无药物疗法，同时也为研究者配备了技能成功的科学事业所必需的。