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：
9370396
负责人：
Drew Kiraly
金额：
$ 19.14万
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/9370396
关键词：
Abstinence Adaptive Immune System Affect Alpha Cell 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 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 Injection of therapeutic agent Investigation Lead Link Measures Mediating Mental disorders Mentors Mentorship Messenger RNA 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 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 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.

对可卡因等心理刺激剂的成瘾代表了一个重大的公共卫生问题财务和社会成本。尽管如此，精神刺激使用障碍仍然是顽固疾病目前，FDA批准的药物用于治疗。在许多精神研究领域，大脑和免疫系统已被大量研究，以确定病理生理学并找到新的治疗方法。众所周知，可卡因可以改变先天和自适应的功能免疫系统，这些免疫变化与适应不良药物服用和外观行为之间的联系保持最低限度的探索。在一系列初始实验中，我们研究了实验者或自我施用的可卡因改变了32个细胞因子的血清谱。其中，我们发现粒细胞粘合剂可卡因增加了刺激因子（G-CSF），而血清水平与线性相关对可卡因的行为反应。在行为上，注射G-CSF改变了可卡因的剂量反应曲线放置偏好，并促进扩展并减少可卡因外观的恢复。这些也是如此初步研究表明，G-CSF是可卡因诱导的行为可塑性的有效调节剂，并且可能是延长可卡因使用障碍禁欲的潜在治疗靶标。在心态下博士。 Eric Nestler和Yasmin Hurd，我将看到进一步阐明G-CSF的作用。额外的培训使我可以过渡到独立。在本提案的目标1中，我将审问 G-CSF在细胞类型的特异性方式中通过使用病毒载体敲击的效果以细胞类型的方式敲击在可卡因自我的D1和D2阳性培养基神经元种群中的G-CSF受体下降管理，扩展和恢复原状。这些实验将为微电路提供洞察力 G-CSF的行为效应的根本，将为我提供自我管理和靶向基因表达的操纵。在AIM 2中，我将看到NAC中的G-CSF响应性基因解释其行为效应。我将对自我管理的动物进行NAC进行mRNA测序可卡因，然后进行差异表达和途径分析。高度调节的行为效应在可卡因自我给药之前，基因和途径将通过病毒基因操纵来询问，扩展和恢复原状。这些实验将使我在创建中给予至关重要的心理，分析并利用大型测序数据集，同时还提供有关G-CSF如何影响的详细信息与可卡因相关的行为可塑性。总而言之，该奖项提出的研究将阐明神经和与翻译相关的治疗靶标的分子机制，同时为我提供足够的过渡到独立调查员的精神制。