Neuroimmune modulation of neuronal function during cocaine conditioning

可卡因调理过程中神经元功能的神经免疫调节

• 批准号: 10015251
• 负责人: Drew Kiraly
• 金额: $ 21.19万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10015251
• 关键词: Abstinence; Acute; Affect; Alcohol or Other Drugs use; Animals; Area; Behavior; Behavioral; Blood; Brain; Calcium; Calcium Signaling; Cells; Cocaine; Code; Corpus striatum structure; Cre driver; Cues; Data; Disease; Dopamine; Dose; Drug Controls; Equilibrium; Exposure to; Extinction (Psychology); FDA approved; FOS gene; Functional disorder; Glutamates; Granulocyte Colony-Stimulating Factor; Granulocyte Colony-Stimulating Factor Receptors; Image; Imaging technology; Immediate-Early Genes; Immune; Injections; Intake; Lead; LoxP-flanked allele; Maps; Mediating; Mediator of activation protein; Microglia; Microscope; Modeling; Morbidity - disease rate; Motivation; Mus; Nature; Neuroglia; Neuroimmune; Neurons; Nucleus Accumbens; Paper; Pathologic; Patients; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Play; Population; Positioning Attribute; Proteome; Public Health; Rewards; Role; Self Administration; Signal Pathway; Signal Transduction; Societies; Specificity; Stimulus; Structure; Substance Use Disorder; Sucrose; Synapses; Synaptic plasticity; Tamoxifen; Target Populations; Technology; Testing; Training; Transgenic Mice; Treatment Factor; Ventral Tegmental Area; addiction; behavior influence; behavior measurement; behavior test; behavioral plasticity; behavioral response; brain cell; burden of illness; cocaine exposure; conditioned place preference; conditioning; cost; cytokine; drug craving; drug development; drug of abuse; drug seeking behavior; enhancing factor; experimental study; in vivo calcium imaging; in vivo imaging; insight; mortality; mouse model; neural circuit; neural patterning; neuronal patterning; neuropsychiatric disorder; neurotrophic factor; novel; open source; psychostimulant; relating to nervous system; response; stimulant use disorder; therapeutic target; Abstinence; Acute; Affect; Alcohol or Other Drugs use; Animals; Area; Behavior; Behavioral; Blood; Brain; Calcium; Calcium Signaling; Cells; Cocaine; Code; Corpus striatum structure; Cre driver; Cues; Data; Disease; Dopamine; Dose; Drug Controls; Equilibrium; Exposure to; Extinction (Psychology); FDA approved; FOS gene; Functional disorder; Glutamates; Granulocyte Colony-Stimulating Factor; Granulocyte Colony-Stimulating Factor Receptors; Image; Imaging technology; Immediate-Early Genes; Immune; Injections; Intake; Lead; LoxP-flanked allele; Maps; Mediating; Mediator of activation protein; Microglia; Microscope; Modeling; Morbidity - disease rate; Motivation; Mus; Nature; Neuroglia; Neuroimmune; Neurons; Nucleus Accumbens; Paper; Pathologic; Patients; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Play; Population; Positioning Attribute; Proteome; Public Health; Rewards; Role; Self Administration; Signal Pathway; Signal Transduction; Societies; Specificity; Stimulus; Structure; Substance Use Disorder; Sucrose; Synapses; Synaptic plasticity; Tamoxifen; Target Populations; Technology; Testing; Training; Transgenic Mice; Treatment Factor; Ventral Tegmental Area; addiction; behavior influence; behavior measurement; behavior test; behavioral plasticity; behavioral response; brain cell; burden of illness; cocaine exposure; conditioned place preference; conditioning; cost; cytokine; drug craving; drug development; drug of abuse; drug seeking behavior; enhancing factor; experimental study; in vivo calcium imaging; in vivo imaging; insight; mortality; mouse model; neural circuit; neural patterning; neuronal patterning; neuropsychiatric disorder; neurotrophic factor; novel; open source; psychostimulant; relating to nervous system; response; stimulant use disorder; therapeutic target

Project Summary Pathological substance use disorders are a public health crisis leading to tremendous morbidity and mortality for afflicted patients and incalculable costs to society at large. Addiction to cocaine and other psychostimulants accounts for a significant proportion of this burden of disease, and treatment of these patients is currently limited by the lack of any FDA-approved pharmacotherapies. Despite significant advances in our understanding of the dopaminergic, glutamatergic, and intracellular signaling cascades altered in models of stimulant use disorders, efforts to develop medications aimed at treating stimulant use disorder have been unsuccessful. There is a growing appreciation for the role of neuroimmune interactions in normal brain function and plasticity as well as in the pathophysiology of neuropsychiatric diseases. Microglia, the resident immune cells of the CNS, interact with neurons, prune synapses, and produce neurotrophic factors that can alter synaptic plasticity and behavior. We have recently identified granulocyte-colony stimulating factor (G-CSF) as a cytokine that is increased in blood and brain following prolonged cocaine. Systemic injections of G-CSF enhance the formation of conditioned place preference and enhance motivation to self-administer cocaine. Additionally, G-CSF potentiates cocaine induction of the immediate early gene c-Fos and enhances dopamine release from the ventral tegmental area into the nucleus accumbens (NAc). Interestingly, the receptor for G- CSF is expressed exclusively on microglia in the NAc. In this proposal we will utilize cutting-edge in vivo imaging technology to directly visualize and interrogate the effects of this microglial modulator on patterns of neuronal activity that encode cocaine administration and seeking. In Aim 1 we will record calcium signals in D1 and D2 expressing medium spiny neurons in the NAc of animals treated with G-CSF or vehicle during active cocaine self-administration or during a drug seeking task. Given that the D1 and D2 expressing populations of neurons have been shown to have opposing effects on encoding rewarding stimuli, these experiments will provide crucial information as to how G-CSF is shifting the balance of patterns of neural activity between these two discrete cell populations. In Aim 2, we will test the causal nature of G-CSF signaling through microglia by using a transgenic mouse model that deletes the G-CSF receptor exclusively in microglia and measure behavioral and neural circuit changes. Together, these experiments will characterize the neural circuit changes induced by G-CSF signaling through microglia and elucidate the mechanisms by which microglial signaling controls cocaine-associated behavior.

项目摘要 病理药物使用障碍是一种公共卫生危机，导致了巨大的发病率和死亡率 对于受苦的患者和整个社会的不可估量的费用。对可卡因和其他心理刺激剂的成瘾 目前是这种疾病负担的很大比例，这些患者的治疗是 由于缺乏FDA批准的药物治疗而受到限制。尽管我们的进步取得了重大进展 了解多巴胺能，谷氨酸能和细胞内信号传导级联反应的了解 兴奋剂使用障碍，开发旨在治疗刺激使用障碍的药物的努力一直是 不成功。对神经免疫相互作用在正常脑功能中的作用越来越多 以及可塑性以及神经精神疾病的病理生理学。小胶质细胞，居民免疫 中枢神经系统的细胞与神经元相互作用，修剪突触并产生可以改变的神经营养因素 突触可塑性和行为。我们最近已经确定粒细胞 - 颜色刺激因子（G-CSF）为 长时间可卡因后血液和大脑增加的细胞因子。全身注射G-CSF 增强条件地点偏好的形成，并增强自我管理可卡因的动力。 此外，G-CSF增强了早期基因C-FOS的可卡因诱导并增强多巴胺 从腹侧对盖区域释放到伏隔核（NAC）。有趣的是，G-的受体 CSF仅在NAC中的小胶质细胞上表达。在此提案中，我们将利用尖端的体内 成像技术直接可视化和询问该小胶质调制器对模式的影响 编码可卡因给药和寻求的神经元活性。在AIM 1中，我们将在D1中记录钙信号 D2在活动过程中用G-CSF或媒介物处理的动物NAC表达培养基神经元 可卡因自我管理或在寻求毒品的任务中。鉴于D1和D2表达 已证明神经元对编码奖励刺激有相反的影响，这些实验将 提供有关G-CSF如何转移神经活动模式平衡的关键信息 两个离散的细胞群体。在AIM 2中，我们将通过小胶质细胞测试G-CSF信号的因果性质 使用仅在小胶质细胞中删除G-CSF受体并测量的转基因小鼠模型 行为和神经回路发生变化。这些实验共同表征了神经回路的变化 通过小胶质细胞引起的G-CSF信号传导并阐明了小胶质细胞传导的机制 控制可卡因相关的行为。