The masking, unmasking, and re-masking of food memories: neuronal ensemble mechanisms

令人震惊的估计表明，三分之二的英国成年人由于暴饮暴食而超重或肥胖，患糖尿病等疾病的风险增加。暴露在与食物有关的感官刺激或暗示(例如，看到食物)中会恢复对食物的“兴奋性”记忆，并可能引发对食物的渴望，这会导致某些人暴饮暴食。有趣的是，线索暴露疗法(CET)降低了这种进食欲望。它借用了巴甫洛夫近100年前在他著名的经典条件反射实验中研究的灭绝学习中成熟而优雅的概念。他注意到，拿到与食物有关的铃声的狗会流口水，但当铃声反复出现而没有任何食物时，流口水的反应就会停止或消失。同样，在大学英语四级考试中，没有食物的情况下，食物线索会被反复呈现，并通过建立新的“抑制性”记忆来降低食欲。然而，CET的成功是有限的，对食物线索的反应最终会自行恢复或显示出“自发恢复”，因为关于灭绝学习的记忆没有得到适当的提取。令人振奋的是，我们和其他人的动物研究显示，与消退学习相关的提醒或“提取线索”，如闪光，有助于找回抑制性消退记忆，抑制自发恢复。到目前为止，人们对自发恢复的大脑机制以及它是如何被抑制的知之甚少。然而，我们最近在小鼠身上的研究表明，当小鼠接触到食物提示并表现出觅食行为时，特殊的被激活的神经元组--神经元组--有助于恢复关于食物奖励的兴奋性记忆。此外，我们和其他人已经证明，在灭绝学习之后，食物线索激活了较小的神经元群，神经元的电特性和神经元之间的连接也有生理变化，称为突触，突触会重新连接大脑电路。因此，能否通过逆转这些与灭绝相关的神经元活动模式和生理特性的变化来实现自发恢复？而灭绝恢复线索能将这些特性恢复到灭绝学习时看到的样子吗？为了回答这些重要的问题，我们将分别研究小鼠在食物线索和灭绝提取线索触发的觅食自发恢复的出现和抑制过程中神经丛的活动。我们将重点关注伏隔核，这是大脑中控制进食等奖赏行为的区域。我们将首先使用可以探测单个神经元的电和突触属性的设备，并揭示为什么这些神经元在自发恢复及其抑制期间表现出特定的活动模式。接下来，我们将使用生化方法来确定哪些特定神经元在自发恢复过程中被激活，以及消退恢复线索是否会关闭这些神经元。在另一项实验中，我们将用一种名为GCaMP的特殊化学活动传感器来标记或标记在觅食和灭绝过程中激活的神经元，然后使用一种名为“纤维光度法”的技术来现场记录它们在出现和抑制自发恢复期间的快速神经元活动。使用这个工具，我们将神经活动与老鼠对与觅食和灭绝经历相关的线索做出反应的行为联系起来。最后，我们将使用一种名为“光遗传学”的基于光的方法来快速控制这些神经元的活动，看看它们是否真的控制了自发恢复及其抑制。综上所述，我们的研究将帮助我们更好地理解如何通过加强抑制性消退记忆来更好地抑制我们对食物提示的反应，从而使CET更加健壮和持久。

Alarming estimates indicate that 2 out of 3 UK adults are overweight or obese, as a result of overeating, with an increased risk for diseases such as diabetes. Exposure to sensory stimuli or cues (e.g., the sight of food) linked with food recovers 'excitatory' memories about food and can elicit food cravings, which leads to excessive eating in certain individuals. Interestingly, cue exposure therapy (CET) reduces such desires to eat. It borrows well-established and elegant concepts from 'extinction learning' that Pavlov examined in his famous classical conditioning experiment nearly 100 years ago. He noticed that a dog presented with a bell associated with food would salivate, but when the bell was repeatedly presented without any food, the salivation response stopped or went 'extinct'. Likewise, in CET a food cue is repeatedly presented without food and reduces the desire to eat by creating a new 'inhibitory' memory. However, CET's success is limited and responses to food cues eventually return on their own or show 'spontaneous recovery', as memories about extinction learning are not properly retrieved. Promisingly, animal studies from we and others have revealed that reminders or 'retrieval cues', such as a flashing light, associated with extinction learning help retrieve inhibitory extinction memories and dampen spontaneous recovery. To date, the brain mechanisms of spontaneous recovery and how it is suppressed are poorly understood. However, our recent studies in mice show that specialised groups of activated neurons called 'neuronal ensembles' help retrieve excitatory memories about food rewards when they are exposed to food cues and show food seeking behaviours. Moreover, we and others have shown that following extinction learning, food cues activate smaller neuronal ensembles and there are also physiological changes in the electrical properties of neurons and connections between neurons called synapses, which 'rewire' brain circuits. As such, might spontaneous recovery occur by reversing these changes in activity patterns and physiological properties of neurons related to extinction? And could extinction retrieval cues restore these properties back to what was seen during extinction learning? To answer these important questions, we will investigate the activity of neuronal ensembles in mice during the emergence and suppression of spontaneous recovery of food seeking that is triggered by food cues and extinction retrieval cues, respectively. We will focus on the nucleus accumbens, a brain area that controls rewarding actions such as eating. We will first use devices that can probe the electrical and synaptic properties of individual neurons and reveal why these neurons show certain activity patterns during spontaneous recovery and its suppression. Next, we will use biochemical approaches to determine which specific neurons are activated during spontaneous recovery and whether extinction retrieval cues will switch off these neurons. In another experiment, we will label or 'tag' neurons that are activated during food seeking and extinction with a special chemical activity sensor called 'GCaMP', and then live record their fast neuronal activity during the emergence and suppression of spontaneous recovery using a technique called 'fibre photometry'. Using this tool, we link the neural activity with the behaviour of the mice in response to cues associated with food seeking and extinction experiences. Finally, we will rapidly manipulate the activity of these neurons using a light-based approach called 'optogenetics' to see if they actually control spontaneous recovery and its suppression. Taken together, our studies will help us better understand how to make CET more robust and long-lasting by strengthening inhibitory extinction memories that will better suppress our reactions to food cues.