How does the mammalian neocortex sense and adapt to metabolic state in health and disease?

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Our brain requires substantial amounts of energy to function. Indeed, despite only weighing 2% of our body's mass, our brain consumes 20% of our caloric intake. It is of little surprise then that the brain is very sensitive to changes in our diet, with extreme deviations in our calorie intake greatly affecting our cognitive function. Of particular importance to global health are the calorie-rich, high-fat diets of the modern world, which contribute to alarming rates of obesity and type 2 diabetes. While it is known that these diets impair cognitive function, it remains unclear how they do so. Understanding this is of critical importance for developing therapies and interventions to preserve life-long cognitive function and improve quality of life.How does our brain sense what we eat? I will test the hypothesis that the brain directly senses our diet by detecting levels of two hormones in our blood: 1) leptin, which relays how much fat we have, and 2) insulin, which increases with blood sugar levels after a meal. With nutritious diets, I predict healthy levels of these hormones in the blood signal to the brain that there is plenty of energy available for it to use, and therefore promote healthy brain function. However, I predict that with prolonged consumption of a high-fat diet, the brain loses its ability to properly detect these hormones, leading to dysfunction. I will test these hypotheses in mice. I will manipulate their diets, feeding them either normal, healthy diets or calorie-rich, high-fat diets and examine the consequence of this on their brain function. I will assess brain function by recording the brain's electrical activity and energy use, and by examining how well mice perform behavioral tasks. I will also measure and manipulate leptin and insulin signalling to see how this impacts brain function. Finally, I will examine what effect diet has in humans. I will give participants either a high-fat diet or a calorie-restricted diet for 4 weeks and examine how this impacts brain function using functional MRI, which is a non-invasive form of measuring brain activity. Overall, my research will provide critical insight into how diet impacts the function of the brain, with direct relevance for humans. This work is critical for developing dietary and pharmacological strategies to preserve life-long cognitive function and improve quality of life. For example, knowing the mechanisms by which diet can alter brain function and energy use, enables the development of drugs that can interact with these mechanisms to improve cognitive function. Such interventions would benefit those suffering from obesity and type 2 diabetes, and more generally, is of potential benefit for those suffering with cognitive impairment or age-related cognitive decline.