Development of fMRI Methods for Neurpharmacology

描述（由申请人提供）：本提案是对NIBIB RFA EB-03-002“小动物成像系统和方法”的回应。我们将重点发展大鼠神经药理学的功能磁共振成像（fMRI）方法。主要目的是将功能磁共振成像技术应用于神经药理学。提出了四个具体目标。在Specific Aim 1中，我们将确定并表征麻醉剂和自主药物对前脚刺激大鼠大脑fMRI血氧水平依赖性（BOLD）反应的系统性心血管效应。a)确定氟烷、异氟烷、-氯氯醛和氨基甲酸乙酯四种麻醉剂对功能性BOLD反应的剂量效应。b)甲氧沙明是一种对脑血管没有直接作用的α -1受体激动剂，将用于确定平均动脉血压在脑血流自动调节的生理范围内或之外的急性升高是否会影响大鼠脑内的功能性BOLD反应。具体目标2是在3T扫描仪上开发定制的fMRI脉冲序列，以克服存在于空气-脑组织边界的敏感性伪影，以检测大鼠大脑中的BOLD信号。在Specific Aim 3中，我们将验证fMRI技术是一种有效的方法，通过使用一类药理功能已被很好地表征的药物来绘制大鼠大脑中药物诱导的活动。我们将测试在使用激动剂后的假设，fMRI方法可以检测来自激动剂-受体相互作用的神经事件的BOLD信号。此外，我们将验证这样的假设，即这些神经事件可以通过预处理阻止或通过特定受体拮抗剂的后处理逆转。将fMRI技术应用于神经药理学的最大挑战是如何解释药物诱导的BOLD信号的神经机制。在Specific Aim 4中，我们将建立一个生物物理模型来计算脑代谢耗氧量（cro2），并解释药物引起的BOLD信号变化。我们还将进行激光多普勒血流仪和脑电图实验来验证该生物物理模型。

DESCRIPTION (provided by applicant): This proposal is in response to NIBIB RFA EB-03-002, "Systems and Methods for Small Animal Imaging." We will focus on development of functional MRI (fMRI) methods for neuropharmacology in rats. The main goal is to extend application of fMRI method to neuropharmacology. Four specific aims are proposed. For Specific Aim 1, we will determine and characterize the systemic cardiovascular effects induced by anesthetic and autonomic agents on the fMRI blood oxygenation level dependent (BOLD) response in the rat brain produced by forepaw stimulation, a) Determine the dose effects of four anesthetic agents, halothane, isoflurane, alpha-chloralose and urethane, on the functional BOLD response. b) Methoxamine, an alpha-1 receptor agonist that has no direct cerebrovascular effect, will be used to determine if acute increases in mean arterial blood pressure, either within or outside of the physiological range of cerebral blood flow autoregulation, affect the functional BOLD response in the rat brain. Specific Aim 2 is to develop a tailored fMRI pulse sequence on the 3T scanner for overcoming susceptibility artifacts present in air-brain tissue boundaries, to detect BOLD signals in the rat brain. In Specific Aim 3, we will test the hypothesis that fMRI technology is a valid method to map drug-induced activities in the rat brain by using a class of drugs whose pharmacological functions are well characterized. We will test the hypothesis that upon administration of an agonist, fMRI methods can detect BOLD signals originating from the neural events of the agonist-receptor interaction. Further, we will test the hypothesis that such neural events can be blocked by pretreatment or reversed by post treatment with a particular receptor's antagonist. The biggest challenge in extending applications of fMRI technology to neuropharmacology is to interpret the neural mechanisms of the BOLD signals induced by drug administration. In Specific Aim 4, we will develop a biophysical model to calculate cerebral metabolic rate of oxygen consumption (CMRO2) and interpret the BOLD signal changes induced by drugs. We will also conduct Laser Doppler Flowmetry and EEG experiments to validate this biophysical model.