Optical and fMRI Studies of Cocaine in the Rat Brain

描述(申请人提供)：这份申请描述了一个系统的5年培训计划和实验研究，将导致在翻译神经科学的独立职业生涯，重点是刺激剂，如可卡因对大脑的影响。定量光学荧光和光谱成像与高分辨率磁共振成像(9.4T)将在计划中的研究中使用。在之前的工作中，候选人开发了一种基于导管的光学扩散和荧光(ODF)仪器，该仪器已被验证可同时检测脑缺血期间脑血容量(CBV)、组织氧合(StO2)和细胞内钙离子([Ca++]i)的变化(Du等人)。脑部血流代谢杂志，2005(25)，1078-1092)。该系统已经获得了初步结果，在该系统中，在急性可卡因激发后，比较了未服用可卡因的大鼠和有可卡因自身给药史的大鼠。在药物幼稚的大鼠中，可卡因引起CBV和StO2轻度、短暂的下降，[Ca++]i逐渐增加10%。在慢性可卡因暴露的大鼠中，可卡因使[Ca++]i迅速增加20%，CBV和StO2显著、持续下降。此外，在药物幼稚的大鼠中，可卡因诱导的[Ca++]i增加不依赖于其对CBV和StO2的作用。可卡因诱导的过度[Ca++]i升高(如在自我注射可卡因的大鼠中观察到的)将使细胞更容易受到伤害，特别是当同时伴随着CBV和StO2的下降时(Du et a/.，提交给J·神经科学，2006年)。在这里，我们提出了一种策略，将可卡因对血管系统的直接影响与对皮质功能的直接影响分开。具体目标是：(1)描述急性可卡因对血流动力学和钙瞬变的影响；(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，以及功能磁共振成像(FMRI)测量刺激前爪刺激的影响，以确定是否对皮质功能有影响，(3)评估可卡因戒断对自我给药动物的影响，以此作为戒毒期间发生的生理变化的模型，以及(4)对ODF系统进行技术改进，将光学探针的尺寸(目前为3 mm)缩小至300？m。这第四个目标应可在未来的研究中测量大脑更深层的神经信号。PI正在寻求这一K25奖项，以进一步扩展她对大脑对滥用药物的急性和慢性给药反应的生理、生化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.