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

食物记忆的掩蔽、揭露和重新掩蔽：神经元集成机制

• 批准号: BB/X000427/1
• 负责人: Eisuke Koya
• 金额: $ 76.85万
• 依托单位: University of Sussex
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX000427%2F1
• 关键词: masking; unmasking; re; food; memories

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.

令人震惊的估计表明，由于暴饮暴食，三分之二的英国成年人超重或肥胖，患糖尿病等疾病的风险增加。暴露于感官刺激或线索（例如，与食物有关的视觉（即看到食物）会恢复关于食物的“兴奋性”记忆，并会引起对食物的渴望，这会导致某些人过度进食。有趣的是，线索暴露疗法（CET）减少了这种进食欲望。它借用了巴甫洛夫在近100年前著名的经典条件反射实验中检验的“消退学习”中成熟而优雅的概念。他注意到，一只狗看到与食物有关的铃铛时会分泌唾液，但当铃铛反复出现而没有任何食物时，唾液分泌反应停止或“停止”。同样，在CET中，食物提示在没有食物的情况下反复出现，并通过创建新的“抑制性”记忆来减少进食欲望。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“自发恢复”，因为关于灭绝学习的记忆没有被正确检索。令人鼓舞的是，我们和其他人的动物研究表明，与灭绝学习相关的提醒或“检索线索”，如闪光，有助于检索抑制性灭绝记忆并抑制自发恢复。到目前为止，自发恢复的大脑机制以及它是如何被抑制的还知之甚少。然而，我们最近对小鼠的研究表明，被称为“神经元集合”的激活神经元的专门群体在暴露于食物线索并表现出寻找食物的行为时，有助于恢复关于食物奖励的兴奋性记忆。此外，我们和其他人已经表明，在灭绝学习之后，食物线索激活了较小的神经元集合，神经元的电特性和神经元之间的连接也发生了生理变化，称为突触，“重新连接”大脑电路。因此，通过逆转与灭绝相关的神经元的活动模式和生理特性的变化，是否会发生自发恢复？灭绝恢复线索是否可以将这些特性恢复到灭绝学习过程中所看到的？为了回答这些重要的问题，我们将研究小鼠神经元集合的活动，在食物线索和灭绝检索线索分别触发的自发恢复觅食的出现和抑制。我们将重点关注脑桥核，这是一个控制奖励行为（如进食）的大脑区域。我们将首先使用可以探测单个神经元的电特性和突触特性的设备，并揭示为什么这些神经元在自发恢复及其抑制过程中表现出某些活动模式。接下来，我们将使用生物化学方法来确定哪些特定的神经元在自发恢复过程中被激活，以及灭绝恢复线索是否会关闭这些神经元。在另一个实验中，我们将用一种名为“GCaMP”的特殊化学活性传感器标记或“标记”在寻找食物和灭绝过程中被激活的神经元，然后使用一种名为“纤维光度计”的技术实时记录它们在自发恢复出现和抑制过程中的快速神经元活动。使用这个工具，我们将神经活动与小鼠的行为联系起来，以响应与觅食和灭绝经历相关的线索。最后，我们将使用一种称为“光遗传学”的基于光的方法快速操纵这些神经元的活动，看看它们是否真正控制自发恢复及其抑制。总之，我们的研究将帮助我们更好地了解如何通过加强抑制性消退记忆来使CET更加强大和持久，这将更好地抑制我们对食物线索的反应。

项目成果

Microglia: The new player orchestrating cocaine-induced expression of calcium-permeable AMPA receptors.

小胶质细胞：协调可卡因诱导的钙渗透性 AMPA 受体表达的新参与者。

• DOI: 10.1016/j.bbi.2023.11.032
• 发表时间: 2023
• 期刊: Brain, behavior, and immunity
• 作者: Koya E