Effects of PDE4B inhibition on excessive weight gain-induced impairment in cognitive function in laboratory mice

In humans, obesity impairs cognition and produces atrophy of brain regions associated with learning and memory. Individual cognitive performance declines with increases in body mass and energy consumption. These deficits can be observed throughout life, from childhood to late adulthood. Our lab has generated mice that have a catalytic mutant form of PDE4B (Y358C) with a decreased ability to hydrolyse cAMP. We previously found that these mice show enhanced learning and memory; enhanced long-term potentiation and less synaptic depression in hippocampal slices; increased dendritic spine density in the hippocampus and amygdala; and enhanced neurogenesis in the adult dentate gyrus (McGirr et al. 2016 Neuropsychopharmacology 41:1080-92). In this PhD project, you will explore the cellular and biochemical mechanisms that might underlie obesity-induced changes in brain volume and cognitive function. Specifically, you will use behavioural, electrophysiological, biochemical and histological techniques to investigate the effects of high-fat diet-induced obesity on cognitive function in wild-type mice compared with mice with the PDE4B¬Y358C mutation that was previously shown to cause cognitive enhancement in lean mice fed a standard rodent diet. These experiments will increase understanding of the cellular processes underlying cognitive decline in obesity and the effects of inhibition of PDE4B upon this phenomenon