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

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.

项目概要 病理性物质使用障碍是一场公共卫生危机，导致巨大的发病率和死亡率 给受苦的患者和整个社会带来难以估量的损失。可卡因和其他精神兴奋剂成瘾 占这种疾病负担的很大一部分，目前正在对这些患者进行治疗 由于缺乏 FDA 批准的药物疗法而受到限制。尽管我们的技术取得了重大进展 对多巴胺能、谷氨酸能和细胞内信号级联在模型中改变的理解 兴奋剂使用障碍，致力于开发旨在治疗兴奋剂使用障碍的药物 不成功。人们越来越认识到神经免疫相互作用在正常大脑功能中的作用 和可塑性以及神经精神疾病的病理生理学。小胶质细胞，常驻免疫细胞 中枢神经系统细胞，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子 突触可塑性和行为。我们最近将粒细胞集落刺激因子（G-CSF）确定为 长期服用可卡因后血液和大脑中的细胞因子会增加。 G-CSF 全身注射 增强条件性位置偏好的形成并增强自我服用可卡因的动机。 此外，G-CSF 增强可卡因对立即早期基因 c-Fos 的诱导并增强多巴胺 从腹侧被盖区释放到伏隔核（NAc）。有趣的是，G-的受体 CSF 仅在 NAc 中的小胶质细胞上表达。在这个提案中，我们将利用最先进的体内 成像技术直接可视化和询问这种小胶质细胞调节剂对模式的影响 编码可卡因给药和寻找的神经元活动。在目标 1 中，我们将记录 D1 中的钙信号 在活动期间用 G-CSF 或媒介物处理的动物的 NAc 中表达中型多棘神经元和 D2 自我施用可卡因或在寻找毒品的任务期间。鉴于 D1 和 D2 表达群体 神经元已被证明对编码奖励刺激具有相反的作用，这些实验将 提供关于 G-CSF 如何改变这些神经活动模式之间的平衡的重要信息 两个离散的细胞群。在目标 2 中，我们将通过小胶质细胞测试 G-CSF 信号传导的因果性质： 使用仅删除小胶质细胞中的 G-CSF 受体的转基因小鼠模型并测量 行为和神经回路的变化。这些实验将共同描述神经回路的变化 通过小胶质细胞诱导 G-CSF 信号传导，并阐明小胶质细胞信号传导的机制 控制与可卡因相关的行为。