Adolescent sugar overconsumption programs food choices via altered dopamine signalling

根据NHS 2022的调查，超过60%的英国成年人口超重或肥胖，这使得肥胖和糖尿病等相关疾病成为最重要的健康问题之一。肥胖发病率在儿童和青少年中增长尤其迅速，他们在生命早期就患上了心血管疾病或2型糖尿病。这些非传染性疾病的主要原因之一是过度食用美味的富含能量的食物。最近，这促使英国政府对含糖食品征收“糖税”，并启动了“儿童肥胖行动计划”，以减少糖的摄入量。尽管许多关于成人和发育期间过量摄入糖对代谢影响的研究，但对大脑和行为的长期影响，特别是对控制摄食和食物选择的影响，仍未得到充分研究。青春期似乎是一个关键的脆弱窗口，因为参与这些过程的几个大脑区域仍在开发中。在这里，我们将确定青少年糖过量摄入如何影响大脑功能，并导致成年后对喂养的控制发生变化。神经调节剂多巴胺是这些影响的完美候选者。它在控制多种与食物有关的行为方面发挥着核心作用，包括对食物提示(如食物气味/视觉、食物广告)的偏好和反应，这些提示可能会对食物选择产生偏见。我们之前已经证明，多巴胺系统直到成年才完全发育，这使得它很容易受到外部侮辱，如不平衡的饮食习惯。这个项目试图回答的主要问题是：i)青春期过度摄糖如何影响与摄食控制有关的多巴胺信号；ii)是否有可能通过操纵多巴胺系统恢复对摄食的适应性控制；iii)成年期摄食行为的改变直接由青春期不发达的多巴胺系统过度刺激引起。为了回答这些问题，我们将通过观察两种行为来研究青春期过度摄糖对小鼠的影响：1)与标准的平衡食物相比，它们选择了多少富含脂肪和糖的可口食物，2)食物暗示(例如，声音总是与食物配对)是如何引发寻找食物和进食的。根据我们的初步工作，我们预测糖暴露的小鼠将表现出更高的可口食物摄入量，也将表现出更高的寻找/进食反应，由食物提示触发。我们将首先使用一种名为纤维光度法的复杂技术，通过这种技术，我们可以使用荧光传感器实时记录动物行为中的多巴胺释放，以确定这些控制摄食的变化是否与多巴胺释放的变化有关。我们将专注于大脑伏隔核的一个区域，该区域接收高水平的多巴胺，并已知控制动机行为。接下来，我们将使用一种名为化学遗传学的技术来操控成年后的多巴胺神经元的活动，看看我们是否可以逆转青少年过度摄入糖导致的摄食控制的变化。最后，我们将在青春期小鼠身上使用相同的技术来证明，成人在控制进食方面的缺陷与青春期糖刺激这些多巴胺神经元直接相关。通过结合最先进的技术来定位、记录和操纵特定的大脑回路，这个项目将对青春期含糖食物和饮料对大脑功能的影响提供基本的见解，为更好地理解现代生活方式对进食行为和健康的影响铺平道路。

According to the NHS 2022 survey, more than 60% of the UK adult population is overweight or obese, making obesity and associated diseases like diabetes one of the most important health issues. Obesity incidence is especially growing fast in children and teens who end up developing cardiovascular diseases or type 2 diabetes early in life. One of the main causes of these non-communicable diseases is the overconsumption of highly palatable energy-rich foods. This recently prompted the UK government to introduce a 'sugar tax' on sweetened foods and to launch the 'Childhood obesity action plan' to reduce sugar consumption. Despite numerous studies on metabolic effects of sugar overconsumption in adults and during development, the long-term impact on brain and behaviour, especially on the control of feeding and food choice, remains understudied. Adolescence appears to be a crucial vulnerability window as several brain regions involved in these processes are still under development. Here we will determine how adolescent sugar overconsumption impacts brain functioning and leads to altered control of feeding at adulthood.The neuromodulator dopamine is the perfect candidate for these effects. It plays a central role in controlling multiple food-related behaviours including preference and response to food cues (e.g. food smell/sight, food advertisements) which may bias food choice. We have previously shown that the dopamine system is not fully developed until adulthood, leaving it vulnerable to external insults such as unbalanced dietary habits. The main questions that this project seeks to answer are i) how does sugar overconsumption during adolescence impact dopamine signalling in relation to the control of feeding, ii) is it possible to restore adaptive control of feeding by manipulating the dopamine system, and iii) are alterations of feeding behaviours at adulthood directly caused by the overstimulation of the underdeveloped dopamine system during adolescence.To answer these questions, we will investigate in mice the effect of sugar overconsumption during adolescence by looking at two kinds of behaviour: 1) how much they choose a very palatable food enriched in fat and sugar compared to standard balanced food, and 2) how food cues (e.g. sound always paired with food) can trigger food-seeking and eating. Based on our preliminary work, we predict that sugar-exposed mice will exhibit a higher intake of the palatable food and will also express higher seeking/eating responses triggered by food cues. We will first use a sophisticated technique called fibre photometry with which we can record dopamine release in real time in behaving animal using fluorescent sensors to determine if these changes in the control of feeding are associated with changes in dopamine release. We will focus on a brain region called the nucleus accumbens, receiving high levels of dopamine and known to control motivated behaviours. Next, we will manipulate the activity of dopamine neurons at adulthood using a technique called chemogenetics to see if we can reverse the changes in the control of feeding cause by adolescent sugar overconsumption. Finally, we will use the same technique in adolescent mice to demonstrate that adult deficits in the control of feeding is directly linked to the stimulation of these dopamine neurons by sugar during adolescence.By combining state-of-the-art techniques to target, record and manipulate specific brain circuits, this project will give fundamental insights into the impact of sugary foods and drinks during adolescence on brain functioning, paving the way to a better understanding of the effect of the modern lifestyle on feeding behaviours and health.