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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：
10407634
负责人：
Michelle Kathryn Sequeira
金额：
$ 3.49万
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 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10407634
关键词：
Actins Address Adrenal Glands Affect Affinity Agonist Astrocytes Behavior Behavioral Binding Brain Characteristics Chronic Cocaine Cocaine misuse Cocaine use disorder Complex Corticosterone Cytoskeleton Decision Making Dendritic Spines 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 Stimulant 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 density drug of abuse excitatory neuron experimental study hippocampal pyramidal neuron improved in vivo inhibitor 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.

项目总结