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

目前，英国每四个人中就有一个人肥胖，英国国民健康保险制度最近的数据显示，约61亿英镑用于治疗超重和肥胖相关的健康问题。肥胖可能是由于暴饮暴食造成的，并增加了罹患致衰性疾病(如癌症)的风险。被称为“暗示”的刺激(例如食物的视觉/气味、食物广告)会激发我们渴望、寻找和食用食物。因此，我们需要确定如何提高我们对食物暗示的这些影响的适应能力，以更好地管理与饮食相关的行为。尽管许多研究揭示了线索是如何在大脑中引发食欲的，但关于它是如何产生抗食欲的效果却知之甚少。有趣的是，短暂的身体和认知刺激(如散步、玩俄罗斯方块)可以减少食欲和食物线索的吸引力。同样，在实验动物中，通过短暂接触运动轮和玩具等被称为环境丰富(EE)的物品进行的这种刺激，可以有效地减少由食物提示引发的觅食。因此，EE是一种有用的方法来研究对暗示和渴望的反应的弹性增加。前额叶皮质与抑制冲动和调节食物渴望有关，而肥胖患者的这两项功能都受到了损害。在动物中，食物提示会动员或“招募”特定的神经元群体或“整体”，以抑制或促进这一大脑区域的觅食行为。此外，当寻找食物的水平发生变化时，合奏也会改变它们的“电”特性。反过来，这又控制着神经元的快速“活动”，它解释有关线索的信息。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，短暂的EE暴露显著减少了饥饿小鼠由食物线索引发的前额叶皮质的觅食和整体招募。但是，在EE之后，这个动态调节的合奏的确切身份是什么？我们的目的是揭示EE是如何通过两种可能的前额叶皮质动作来抑制由食物线索引发的食物寻找的：i)调整“现有”食物寻找群体的招募、兴奋性或快速活动属性；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属性的“新”群体。我们将研究EE前后寻找食物所激活的前额叶皮质的特性。值得注意的是，由于这一大脑深层区域很难成像，我们将利用玻璃“微棱镜”来成像整体是如何被招募和快速激活的。我们还将有选择地激活一个合奏，并确定合奏活动和抑制觅食之间的因果联系。此外，我们将使用电生理学来表征系综的电状态变化。我们将揭示生理特性改变的特定神经元组如何减少对食物提示的反应。这些知识将为开发新的治疗策略提供关键的基础，这些策略利用抗欲机制来对抗肥胖。

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.