Optical and fMRI Studies of Cocaine in the Rat Brain

描述（由申请人提供）：本申请描述了一个系统的5年培训计划和实验研究，将导致转化神经科学的独立职业生涯，重点是兴奋剂如可卡因对大脑的影响。计划研究将采用定量光学荧光和光谱成像结合高分辨率磁共振成像（9.4T）。在之前的工作中，该候选人开发了一种基于导管的光学扩散和荧光（ODF）仪器，该仪器已被验证可以同时检测缺血期间脑血容量（CBV）、组织氧合（StO2）和细胞内钙[ca++]i]的变化（Du等）。[J]脑血流机制。生态学报，2005(25),1078- 1092。该系统的初步结果已经获得，在可卡因未接触的大鼠和有自我给药史的大鼠中，在急性可卡因刺激后进行比较。在未给药的大鼠中，可卡因诱导CBV和StO2轻度、短暂性下降，[ca++]i逐渐增加10%。在长期暴露于可卡因的大鼠中，可卡因使[ca++]i迅速增加20%，CBV和StO2持续显著下降。此外，在未给药的大鼠中，可卡因诱导的[Ca++]i的增加独立于其对CBV和StO2的作用。可卡因诱导的过量[Ca++]i增加（在自我服用可卡因的大鼠中观察到）会使细胞更容易受到损伤，特别是在CBV和StO2同时降低的情况下（Du et a/）。，提交给J. Neuroscience, 2006)。在这里，我们提出了一种策略来分离可卡因对血管系统的直接影响和对皮质功能的直接影响。具体目的是：(1)表征急性可卡因对血流动力学和钙瞬态的影响；(2)测量可卡因对MRI表观扩散系数的影响，以确定是否存在细胞损伤；fMRI测量可卡因自我给药和可卡因初吸大鼠前爪刺激的影响，以确定是否对皮质功能有影响；(3)评估戒断可卡因对自我给药动物的影响，作为戒断期间发生的生理变化的模型；(4)对ODF系统进行技术改进，将光学探头的尺寸（目前为3毫米）减小到300米。第四个目标应该允许在未来的研究中测量来自更深大脑区域的神经信号。PI正在寻求获得K25奖，以进一步扩展她在大脑对急性和慢性滥用药物反应的生理学，生物化学和药理学方面的知识。

DESCRIPTION (provided by applicant): This application describes a systematic 5-year training plan and experimental studies that will lead to an independent career in translational neuroscience with a focus on the effects of stimulants such as cocaine on the brain. Quantitative optical fluorescence and spectroscopic imaging combined with high-resolution magnetic resonance imaging (9.4T) will be used in the planned research. In previous work, the candidate has developed a catheter-based optical diffusion and fluorescence (ODF) instrument, which has been validated for simultaneously detecting changes in cerebral blood volume (CBV), tissue oxygenation (StO2) and intracellular calcium [Ca++]i) during ischemia (Du et al. J Cereb Blood Flow Metab., 2005(25), 1078- 1092). Preliminary results with this system have been obtained in which cocaine-naive rats, and rats with a history of self-administration of cocaine, are compared after an acute cocaine challenge. In drug-naive rats cocaine induced a mild, transient decrease in CBV and StO2 and a gradual 10% increase in [Ca++]i. In chronically cocaine exposed rats, cocaine produced a rapid >20% increase in [Ca++]i and significant, persistent decreases in CBV and StO2. Furthermore in drug naive rats have cocaine-induced increases in [Ca++]i occur independent of its actions on CBV and StO2. Cocaine-induced excessive [Ca++]i increases (as observed in rats self-administering cocaine) would make cells more vulnerable to injury particularly when simultaneously coupled with decreases in CBV and StO2 (Du et a/., submitted to J. Neuroscience, 2006). Here we propose a strategy to separate out direct effects of cocaine on the vasculature from direct effects on cortical function. Specific aims are: (1) characterization of the effects of acute cocaine on hemodynamics and calcium transients; (2) measurement of cocaine's effect on the MRI apparent diffusion coefficient to determine if there is cellular damage and fMRI measurements of effects of forepaw stimulation in cocaine self-administering and cocaine-naive rats to determine if there are effects on cortical functioning, (3) evaluation of the effects of abstinence from cocaine on self-administering animals as a model for the physiological changes that occur during drug withdrawal, and (4) making technical improvements on the ODF system to reduce the size of the optical probe (currently 3mm) to 300¿m. This fourth aim should permit measurements of neural signals from deeper brain regions in future studies. The PI is seeking this K25 award to further extend her knowledge of the physiology, biochemistry and pharmacology underlying the brain's responses to acute and chronic administration of abused drugs.