Functional magnetic resonance imaging and c-Fos mapping in rats following an orexigenic dose of 2-Deoxy-D-Glucose

Garron Dodd, Steve Williams, Simon Luckman. The University of Manchester, Manchester, United Kingdom.

Glucose homeostasis is of major importance in order to maintain optimum physiological function. Many studies investigating glucose homeostasis have used the glucose anti-metabolite, 2-deoxy-D-glucose (2-DG), to induce glucoprivation. Administration of 2-DG blocks intracellular metabolism of glucose, thus inducing the perception that glucose levels are low. In an attempt to reassert energy homeostasis, the brain produces counter-regulatory responses to increase feeding behaviour, glucagon secretion and release of glucose from the liver. It is thought that disruptions or defects in the defence of the brains “glucostatic” set point may be partly responsible for pathological conditions such as diabetes and obesity, thus further understanding of how the brain responds to glucoprivation could have important therapeutic potential. To define the “glucostat” brain circuitry we have combined blood-oxygen-level-dependant (BOLD) pharmacological-challenge magnetic resonance imaging (phMRI) with whole brain c-Fos functional activity mapping to characterise brain regions responsive to an orexigenic dose of 2-DG (200 mg/kg; s.c.). For fMRI, rats were imaged using a T2*-weighted gradient echo in a 7T magnet for 60 minutes under α–chloralose anaesthesia, while those for immunohistochemistry were unanaesthetised and freely behaving. These complementary methods demonstrated functional brain activity in the nucleus accumbens, amygdala, ventral pallidum, medial hypothalamus, lateral hypothalamus and periaqueductal grey following administration of 2-DG compared with vehicle injection. This study provides insight into how the “whole” brain responds to 2-DG in order to co-ordinate a complex counter-regulatory response, and further illustrates the valuable potential of phMRI in investigating central pharmacological action.