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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.

对可卡因等精神兴奋剂的成瘾是一个严重的公共卫生问题财务和社会成本。尽管如此，精神兴奋剂使用障碍仍然是一种顽固性疾病，没有任何影响目前 FDA 批准了用于治疗的药物。在精神病学研究的许多领域中，大脑和免疫系统已被广泛研究作为确定病理生理学并发现新的治疗方法。虽然众所周知，可卡因可以改变先天性和适应性的功能免疫系统，这些免疫变化与适应不良的吸毒和寻求行为之间的联系仍然处于最低限度的探索之中。在一系列初步实验中，我们研究了实验者或自我如何施用可卡因改变了 32 种细胞因子的血清特征。其中，我们发现粒细胞集落可卡因会增加刺激因子 (G-CSF)，并且血清水平与可卡因呈线性相关对可卡因的行为反应。在行为上，注射 G-CSF 会改变可卡因的剂量反应曲线地点偏好，促进可卡因灭绝并减少可卡因寻求的恢复。综合起来，这些初步研究表明，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戒断的潜在治疗目标。在指导下博士的。 Eric Nestler 和 Yasmin Hurd 我将寻求进一步阐明 G-CSF 在成瘾中的作用，同时获得额外的培训让我能够过渡到独立。在本提案的目标 1 中，我将询问通过使用病毒载体敲击，以细胞类型特异性方式检测 G-CSF 在伏核 (NAc) 中的作用在可卡因自我作用之前，D1 和 D2 阳性中型多刺神经元群体中的 G-CSF 受体下降管理、灭绝和恢复。这些实验将提供对微电路的深入了解 G-CSF 行为效应的基础，将为我提供自我管理和治疗方面的重要培训有针对性地操纵基因表达。在目标 2 中，我将寻求鉴定 NAc 中的 G-CSF 反应基因，解释其行为效应。我将对自我给药的动物的 NAc 进行 mRNA 测序可卡因，然后进行差异表达和通路分析。高度监管的行为影响在可卡因自我给药之前，基因和途径将通过病毒基因操作进行询问，灭绝和恢复。这些实验将为我提供创作、分析方面的重要指导以及大型测序数据集的利用，同时还提供有关 G-CSF 如何影响的详细信息可卡因相关的行为可塑性。总之，该奖项提出的研究将阐明神经网络以及与翻译相关的治疗目标的分子机制，同时为我提供了足够的信息指导过渡为独立调查员。