权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Dissecting the role of granulocyte-colony stimulating factor in cocaine-mediated behavioral plasticity

剖析粒细胞集落刺激因子在可卡因介导的行为可塑性中的作用

基本信息

批准号：
9492785
负责人：
Drew Kiraly
金额：
$ 18.84万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9492785
关键词：
Abstinence Adaptive Immune System Affect Animals Attenuated Award Behavior Behavioral Brain Cocaine Cocaine Abuse Colony-Stimulating Factor Receptors Cues DRD2 gene Data Data Set Development Disease Dose Economics Enterobacteria phage P1 Cre recombinase Exposure to Extinction (Psychology)FDA approved FOS gene Family Functional disorder Gene Expression Genes Goals Granulocyte Colony-Stimulating Factor Granulocyte Colony-Stimulating Factor Receptors Growth Factor Immune Immune system Infusion procedures Injections Investigation Lead Link Measures Mediating Mental disorders Mentors Mentorship Methods MicroRNAs Molecular Morbidity - disease rate Motivation Mus Neuroimmune Neuronal Plasticity Neurons Nucleus Accumbens Pathologic Pathway Analysis Pathway interactions Patients Pattern Peripheral Pharmaceutical Preparations Pharmacotherapy Phase Play Population Process Production Psychiatric therapeutic procedure Public Health Randomized Rattus Regulation Relapse Reporting Research Research Personnel Rewards Role Saline Second Messenger Systems Self Administration Self-Administered Series Serum Signal Pathway Signal Transduction Societies Therapeutic Training Transgenic Animals Treatment Factor Up-Regulation Viral Genes Viral Vector Yasmin addiction base behavioral plasticity behavioral response brain reward regions cell type chemokine cocaine use cost cytokine differential expression effective therapy experimental study illicit drug use immune function immune system function inhibitor/antagonist innate immune function insight knock-down mRNA sequencing molecular targeted therapies neuronal circuitry novel preference psychostimulant relating to nervous system response social stimulant abuse therapeutic target transcriptome

项目摘要

Addiction to psychostimulants such as cocaine represents a major public health issue exacting tremendous financial and social costs. Despite this, psychostimulant use disorder remains a recalcitrant condition with no currently FDA-approved medications for its treatment. In many fields of psychiatric research, the link between the brain and the immune system has been heavily studied as a way to determine pathophysiology and to find new methods of treatment. While it is known that cocaine can alter the function of both the innate and adaptive immune systems, the link between these immune changes and maladaptive drug taking and seeking behaviors remains minimally explored. In a series of initial experiments, we examined how experimenter or self- administered cocaine altered the serum profile of 32 cytokines. Of these, we found that granulocyte-colony stimulating factor (G-CSF) was increased by cocaine, and the serum levels showed linear correlation with behavioral response to cocaine. Behaviorally, injections of G-CSF alter the dose-response curve for cocaine place preference, and facilitate extinction and reduce reinstatement of cocaine seeking. Taken together, these preliminary studies demonstrate that G-CSF is a potent modulator of cocaine-induced behavioral plasticity, and may be a potential therapeutic target for prolonging abstinence in cocaine use disorder. Under the mentorship of Drs. Eric Nestler and Yasmin Hurd I will seek to further clarify the role of G-CSF in addiction while gaining additional training to allow me to transition to independence. In Aim 1 of this proposal I will interrogate the effects of G-CSF in the nucleus accumbens (NAc) in a cell-type specific manner by using viral vectors to knock down the G-CSF receptor in populations of D1 and D2 positive medium spiny neurons prior to cocaine self- administration, extinction and reinstatement. These experiments will provide insight into the microcircuitry underlying the behavioral effect of G-CSF, and will provide me crucial training in self-administration and targeted manipulation of gene expression. In Aim 2, I will seek to identify G-CSF responsive genes in NAc that account for its behavioral effect. I will perform mRNA sequencing of the NAc from animals self-administering cocaine, followed by differential expression and pathway analysis. The behavioral effect of highly regulated genes and pathways will be interrogated by viral gene manipulation prior to cocaine self-administration, extinction and reinstatement. These experiments will provide me with crucial mentoring in creation, analysis and utilization of large sequencing datasets, while also providing detailed information as to how G-CSF affects cocaine-related behavioral plasticity. In summary, the research proposed in this award will elucidate the neural and molecular mechanisms of a translationally-relevant treatment target, while providing me with sufficient mentorship to transition into an independent investigator.

可卡因等精神兴奋剂成瘾是一个严重的公共卫生问题