Neuroimmune modulation of neuronal function during cocaine conditioning

项目摘要 病理性物质使用障碍是一种公共卫生危机，导致巨大的发病率和死亡率 以及整个社会的不可估量的成本。可卡因和其他精神兴奋剂成瘾 占这种疾病负担的很大比例，目前对这些患者的治疗 由于缺乏FDA批准的药物治疗而受到限制。尽管我们在这方面取得了重大进展， 了解多巴胺能、多巴胺能和细胞内信号级联在模型中的改变， 尽管存在刺激物使用障碍，但开发旨在治疗刺激物使用障碍的药物的努力已经 不成功。人们越来越重视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 中枢神经系统的细胞，与神经元相互作用，修剪突触，并产生神经营养因子， 突触可塑性和行为。我们最近发现粒细胞集落刺激因子（G-CSF）是 长期服用可卡因后血液和大脑中增加的细胞因子。全身注射G-CSF 增强条件性位置偏好的形成，增强自我服用可卡因的动机。 此外，G-CSF增强可卡因对即刻早期基因c-Fos的诱导，并增强多巴胺 从腹侧被盖区释放到延髓核（NAc）。有趣的是，G- CSF仅在NAc中的小胶质细胞上表达。在这项提案中，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 在活动期用G-CSF或载体处理的动物的NAc中表达D2和D2的中型多刺神经元 自我服用可卡因或在寻找毒品的任务期间。考虑到D1和D2表达群体 神经元在编码奖励刺激时具有相反的作用，这些实验将 提供了关于G-CSF如何改变这些神经活动模式之间平衡的关键信息。 两个离散的细胞群。在目标2中，我们将通过以下方式测试G-CSF信号通过小胶质细胞的因果性质： 使用转基因小鼠模型，该模型仅在小胶质细胞中缺失G-CSF受体， 行为和神经回路的变化总之，这些实验将描述神经回路的变化， 诱导的G-CSF信号通过小胶质细胞和阐明的机制， 控制可卡因相关的行为

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.