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.
