Functional magnetic resonance imaging and c-Fos mapping in rats following a glucoprivic dose of 2-deoxy-D-glucose

The glucose analogue, 2-deoxy-D-glucose (2-DG) is an inhibitor of glycolysis and, when administered systemically or centrally, induces glucoprivation leading to counter-regulatory responses, including increased feeding behaviour. Investigations into how the brain responds to glucoprivation could have important therapeutic potential, as disruptions or defects in the defence of the brain s glucostatic circuitry may be partly responsible for pathological conditions resulting from diabetes and obesity. To define the glucostat brain circuitry further we have combined blood-oxygen-level-dependent 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; subcutaneous (s.c.)]. For phMRI, rats were imaged using a T(2)*-weighted gradient echo in a 7T magnet for 60 min under alpha-chloralose anaesthesia, whereas animals for immunohistochemistry were unanaesthetised and freely behaving. These complementary methods demonstrated functional brain activity in a number of previously characterised glucose-sensing brain regions such as those in the hypothalamus and brainstem following administration of 2-DG compared with vehicle. As the study mapped whole-brain functional responses, it also identified the orbitofrontal cortex and striatum (nucleus accumbens and ventral pallidum) as novel 2-DG-responsive brain regions. These regions make up a corticostriatal connection with the hypothalamus, by which aspects of motivation, salience and reward can impinge on the hypothalamic control of feeding behaviour. This study, therefore, provides further evidence for a common integrated circuit involved in the induction of feeding behaviour, and illustrates the valuable potential of phMRI in investigating central pharmacological actions.