Calcium-related neurotoxicity of cocaine

可卡因与钙相关的神经毒性

• 批准号: 9886788
• 负责人: Congwu Du
• 金额: $ 42.87万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9886788
• 关键词: 3-Dimensional; Acute; Affect; Angiography; Animal Model; Animals; Astrocytes; Behavioral; Blood Vessels; Brain; Brain Diseases; Calcium; Caliber; Cerebrovascular Circulation; Cerebrovascular system; Chronic; Cocaine; Cocaine Dependence; Complement; Consumption; Development; Doppler tomography; Fluorescence; Functional disorder; Glial Fibrillary Acidic Protein; Hemoglobin; Human; Image; Imaging Techniques; Impairment; Individual; Intake; Intervention; Ischemia; Knowledge; Measures; Mediating; Modality; Multi-modal optical imaging; Mus; Neuroglia; Neurons; Optics; Paralysed; Pharmaceutical Preparations; Pilot Projects; Play; Prefrontal Cortex; Reporting; Resolution; Role; Self Administration; Severities; Techniques; Transient Ischemic Attack; addiction; cerebral hemodynamics; cocaine use; designer receptors exclusively activated by designer drugs; efficacy testing; fluorescence imaging; imaging platform; imaging study; improved; in vivo; insight; neuroimaging; neurotoxic; neurotoxicity; neurovascular; neurovascular coupling; novel; novel imaging technique; prevent; quantitative imaging; response; vasoconstriction

Disfunction of the prefrontal cortex (PFC), plays a crucial role in compulsive cocaine use and addiction. The role of glia in addition to that of neurons and vascular networks in cocaine-induced PFC dysfunction remains elusive. In the completing R01, we showed that the neurotoxic effects of cocaine were associated with persistent decreases in cerebral blood flow (CBF) and an elevation in intracellular calcium in cortex; however, we did not assess the role of glia versus that of neurons on the CBF decreases. This renewal application, "Calcium-related neurotoxicity of cocaine", will assess the effects of acute and chronic cocaine on astrocytic Ca2+ and its role on the CBF deficits and neuronal Ca2+ increases in PFC and their association with cocaine intake in an animal model of compulsive-like cocaine self-administration. Specifically, we will apply multimodality optical imaging (MOI) in combination with genetically-encoded Ca2+ indicators to capture activities in neurons (jRGECO1a) and astrocytes (GCaMP6f) and ultrahigh- resolution optical coherence angiography and Doppler tomography (µODT) for quantitative imaging of 3D CBF networks in PFC of GFAP cre mice (Aim 1). We will apply chemogenetics with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to manipulate astrocytic Ca2+ accumulation while assessing its consequences on acute and chronic cocaine’s vascular and neuronal effects and cocaine intake (Aim 2, Aim 3). These studies will be valuable for understanding how astrocyte and neuronal networks in the PFC interact and mediate the associated local neurovascular responses to cocaine and how they contribute to compulsive-like drug consumption, providing knowledge to guide development of novel addiction interventions.

前额皮质（PFC）功能障碍在可卡因强迫使用和成瘾中起着至关重要的作用。 神经胶质细胞以及神经元和血管网络在可卡因诱导的 PFC 功能障碍中的作用 仍然难以捉摸。在完成的 R01 中，我们表明可卡因的神经毒性作用与 脑血流量（CBF）持续减少，皮质细胞内钙升高； 然而，我们没有评估神经胶质细胞与神经元对 CBF 降低的作用。此次续订 申请“可卡因与钙相关的神经毒性”将评估急性和慢性可卡因的影响 星形细胞 Ca2+ 及其对 PFC 中 CBF 缺乏和神经元 Ca2+ 增加的作用及其关联 在强迫性可卡因自我给药的动物模型中摄入可卡因。 具体来说，我们将结合基因编码应用多模态光学成像（MOI） 用于捕获神经元 (jRGECO1a) 和星形胶质细胞 (GCaMP6f) 以及超高活性的 Ca2+ 指示剂 用于 3D 定量成像的高分辨率光学相干血管造影和多普勒断层扫描 (µODT) GFAP cre 小鼠 PFC 中的 CBF 网络（目标 1）。我们将应用化学遗传学与设计受体 由设计药物 (DREADD) 独家激活，可操纵星形细胞 Ca2+ 积累，同时 评估其对急性和慢性可卡因血管和神经元影响以及可卡因的影响 摄入量（目标 2、目标 3）。 这些研究对于了解 PFC 中的星形胶质细胞和神经元网络如何发挥作用非常有价值 相互作用并介导与可卡因相关的局部神经血管反应以及它们如何促进 类似强迫性的药物消费，提供知识来指导新型成瘾的发展 干预措施。