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

我们的大脑需要大量的能量来运作。事实上，尽管我们的体重只占我们体重的2%，但我们的大脑消耗了我们摄入的20%的热量。因此，大脑对我们饮食的变化非常敏感就不足为奇了，我们卡路里摄入量的极端偏差会极大地影响我们的认知功能。对全球健康特别重要的是现代世界高热量、高脂肪的饮食，这导致了惊人的肥胖率和2型糖尿病。虽然已知这些饮食会损害认知功能，但尚不清楚它们是如何造成的。了解这一点对于开发治疗和干预措施以保持终身认知功能和提高生活质量至关重要。我们的大脑是如何感知我们吃的东西的？我将测试大脑通过检测血液中两种激素的水平来直接感知我们的饮食的假设：1)瘦素，它传递我们有多少脂肪；2)胰岛素，它在饭后随着血糖水平的增加而增加。通过营养饮食，我预测血液中这些激素的健康水平会向大脑发出信号，表明有足够的能量可供大脑使用，从而促进大脑的健康功能。然而，我预测，随着长时间摄入高脂肪饮食，大脑会失去正确检测这些激素的能力，从而导致功能障碍。我将在老鼠身上验证这些假设。我将控制他们的饮食，给他们喂食正常、健康的饮食或高热量、高脂肪的饮食，并检查这对他们大脑功能的影响。我将通过记录大脑的电活动和能量使用，以及检查老鼠执行行为任务的表现来评估大脑功能。我还将测量和控制瘦素和胰岛素信号，看看它们是如何影响大脑功能的。最后，我将研究饮食对人类的影响。我将给参与者提供为期四周的高脂肪饮食或卡路里限制饮食，并使用功能性核磁共振检查这对大脑功能的影响，这是一种非侵入性的测量大脑活动的方式。总的来说，我的研究将为饮食如何影响大脑功能提供关键的见解，与人类直接相关。这项工作对于制定饮食和药理策略以保持终身认知功能和提高生活质量至关重要。例如，了解饮食改变大脑功能和能量使用的机制，可以开发出与这些机制相互作用的药物，以改善认知功能。这些干预措施将有利于那些患有肥胖和2型糖尿病的人，更普遍地说，对那些患有认知障碍或与年龄相关的认知衰退的人有潜在的好处。

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.