Resilience against food cravings via environmental enrichment (EE): neuronal ensemble mechanisms

在英国，四分之一的人现在肥胖，最近的NHS数据显示，约61亿英镑用于治疗超重和肥胖相关的疾病。肥胖可能是由于过量进食而导致的，并会增加患上使人衰弱的疾病（如癌症）的风险。被称为“线索”的刺激（例如食物的视觉/气味，食品广告）触发我们渴望，寻找和吃食物。因此，我们需要确定如何提高我们对食物线索影响的适应力，以更好地管理与饮食相关的行为。尽管许多研究已经揭示了暗示是如何在大脑中引发渴望的，但人们对它如何产生“反渴望”效果却知之甚少。有趣的是，短暂的身体和认知刺激体验（例如散步，玩俄罗斯方块）会减少渴望和食物暗示的吸引力。类似地，在实验室动物中，通过短暂暴露于运动轮和玩具等被称为“环境富集”（EE）的物品来进行这种刺激，可以有效减少由食物线索引发的食物寻求。因此，EE是一种有用的方法来研究增加对线索和渴望的反应的弹性。前额叶皮层与抑制冲动和调节食物渴望有关，这在肥胖患者中受到损害。在动物中，食物线索动员或“招募”特定的神经元群体或“集合体”，以抑制或促进该大脑区域的食物寻求。此外，当寻找食物的水平改变时，合奏会改变它们的“电”属性。反过来，这控制了神经元的快速“活动”，这些神经元解释了有关线索的信息。这些特性由离子通道调节，离子通道被视为各种疾病的重要治疗靶点。我们最近发现，在饥饿的小鼠中，短暂的EE暴露强烈地减少了由食物线索触发的前额叶皮层的食物寻求和整体招募。但是，这个动态调节的合奏后EE的确切身份是什么？我们的目的是揭示EE如何通过两种可能的前额叶皮层动作来抑制食物线索触发的食物寻求：i）调整“现有”食物寻求集合的招募、兴奋性或快速活动特性;和/或ii）在线索暴露期间积极招募具有独特兴奋性或快速活动特性的“新”集合。我们将研究前额叶皮层合奏激活的食物寻求之前和之后EE的属性。值得注意的是，由于这个脑深部区域是难以成像，我们将利用玻璃“微棱镜”的图像合奏是如何招募和快速激活。我们还将选择性地激活一个集合，并确定集合活动和抑制食物寻求之间的因果关系。此外，我们将使用电生理学来观察电状态的变化。我们将揭示具有改变的生理特性的特定神经元群如何减少对食物线索的反应。这些知识将为开发新的治疗策略提供关键的基石，这些策略将利用反渴望机制来对抗肥胖。

1 in 4 people in the UK are now obese and recent NHS figures indicate ~£6.1 billion is spent on treatment of overweight and obesity-related ill-health. Obesity may result from excessive eating and increases the risk of debilitating diseases (e.g. cancer). Stimuli called 'cues' (e.g. the sights/smells of food, food advertisements) trigger us to crave, seek, and eat foods. Thus, we need to identify how we can increase our resilience against these effects of food cues to better manage eating-related behaviours. Although many studies have revealed how cues trigger cravings in the brain, little is known about how it produces 'anti-craving' effects.Interestingly, a brief experience of physical and cognitive stimulation (e.g. walking, playing Tetris) reduces cravings and the attractiveness of food cues. Similarly, in laboratory animals such stimulation via brief exposure to items such as exercise wheels and toys called 'environmental enrichment' (EE) powerfully reduces food seeking triggered by food cues. As such, EE is a useful approach to investigate increased resilience against reactions to cues and cravings. The prefrontal cortex is implicated in suppressing urges and regulating food cravings, which are impaired in obese patients. In animals, food cues mobilise or 'recruit' specific groups or 'ensembles' of neurons to suppress or promote food seeking in this brain area. Also, when food seeking levels change, ensembles change their 'electrical' properties. In turn, this controls the rapid 'activity' of neurons which interprets information about cues. These properties are regulated by ion channels, which are viewed as important therapeutic targets for various diseases. We recently found that brief EE exposure robustly reduced food seeking and ensemble recruitment in the prefrontal cortex triggered by food cues in hungry mice. But what is the precise identity of this dynamically regulated ensemble following EE? Our aim here is to reveal how EE suppresses food seeking triggered by food cues through two possible prefrontal cortex actions by: i) adjusting the recruitment, excitability, or rapid activity properties of an 'existing' food seeking ensemble; and/or ii) actively recruiting a 'new' ensemble during cue exposure with unique excitability or rapid activity properties. We will examine the properties of prefrontal cortex ensembles activated by food seeking before and after EE. Notably, since this deep brain area is difficult to image, we will take advantage of a glass 'microprism' to image how ensembles are recruited and rapidly activated. We will also selectively activate an ensemble and determine the causal link between ensemble activity and suppression of food seeking. Furthermore, we will use electrophysiology to characterise electrical state alterations of ensembles. We will reveal how specific groups of neurons with altered physiological properties reduce reactions to food cues. Such knowledge will provide the crucial building blocks to develop novel therapeutic strategies that engage anti-craving mechanisms to combat obesity.