Inhibitory engrams in learning and memory consolidation

学习和记忆巩固中的抑制性印迹

• 批准号: MR/W01971X/1
• 负责人: Jill O'Reilly
• 金额: $ 127.35万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW01971X%2F1
• 关键词: Inhibitory; engrams; learning; memory; consolidation

The human brain is the most complex system in the known universe. Yet despite this complexity, and in contrast to other systems such as cars or computers, the brain does not need to be regularly serviced. Instead, the brain has a remarkable ability to undergo modification without compromising previously learned information. This reflects a finely tuned trade-off between plasticity and stability. Arguably this trade-off ensures we have the flexibility to meet the demands of an ever-changing environment (plasticity) while also protecting memories from interference (stability). This trade-off between plasticity and stability is thought to be set by homeostatic mechanisms. However, the details of these mechanisms remain poorly understood, particularly in relation to behavioural read-outs of learning. This is in part reflected in the performance of artificial neural networks, which typically forget past learning if trained on new tasks, giving rise to 'catastrophic forgetting' which has emerged as one of the main challenges facing artificial intelligence. Previous studies in both animals, humans and computational models suggest stability within the brain is restored after new learning by establishing a balance between excitatory and inhibitory activity. Specifically, while new learning is thought to first induce plasticity at excitatory connections, this leads to an increase in overall activity which must later be stabilized by matched changes in inhibitory connections. Here, we will investigate this homeostatic mechanism in the human brain. In our experiments, volunteers will acquire new memories by learning sets of associations between pictures and symbols. We will then measure changes in the inhibitory component of a memory using neuroimaging techniques that involve non-invasive Magnetic Resonance Imaging. First, we will investigate mechanisms that control the formation of matched inhibitory connections after new learning. Specifically, we will ask how brain activity during rest after a learning session serves to build matched inhibitory connections. Second, we will investigate the circumstances under which this homeostatic mechanism is disrupted, leading to instability and disturbance in memory. To this end, we will use a single-dose of a non-harmful drug to mimic natural changes in our brain chemistry under stress. Third, we will assess the adaptive advantage associated with having a transient window of memory instability immediately after new learning. We will test whether we can promote generalization of shared features across different memories when this window of instability is prolonged. Together these studies will reveal mechanistic insight into how the human brain regulates a finely tuned trade-off between plasticity and stability. In doing so, these studies will provide an important basis from which to establish how memory distortions arise in psychological and neurological disorders.

人脑是已知宇宙中最复杂的系统。然而，尽管如此复杂，并且与汽车或计算机等其他系统相比，大脑并不需要定期维护。相反，大脑具有非凡的能力，可以在不损害先前学到的信息的情况下进行修改。这反映了可塑性和稳定性之间的微妙权衡。可以说，这种权衡确保我们能够灵活地满足不断变化的环境的需求（可塑性），同时还能保护记忆免受干扰（稳定性）。可塑性和稳定性之间的这种权衡被认为是由稳态机制决定的。然而，人们对这些机制的细节仍然知之甚少，特别是与学习的行为读出相关的细节。这在一定程度上反映在人工神经网络的性能上，如果接受新任务的训练，人工神经网络通常会忘记过去的学习，从而导致“灾难性遗忘”，这已成为人工智能面临的主要挑战之一。先前对动物、人类和计算模型的研究表明，在新的学习之后，通过在兴奋性和抑制性活动之间建立平衡，大脑内的稳定性得以恢复。具体来说，虽然新的学习被认为首先会诱导兴奋性连接的可塑性，但这会导致整体活动的增加，而整体活动必须随后通过抑制性连接的匹配变化来稳定。在这里，我们将研究人脑中的这种稳态机制。在我们的实验中，志愿者将通过学习图片和符号之间的关联来获得新的记忆。然后，我们将使用涉及非侵入性磁共振成像的神经成像技术来测量记忆抑制成分的变化。首先，我们将研究新学习后控制匹配抑制连接形成的机制。具体来说，我们将询问学习课程后休息期间的大脑活动如何建立匹配的抑制连接。其次，我们将研究这种稳态机制被破坏的情况，从而导致记忆不稳定和紊乱。为此，我们将使用单剂量的无害药物来模拟压力下大脑化学物质的自然变化。第三，我们将评估新学习后立即出现短暂的记忆不稳定窗口所带来的适应性优势。我们将测试当这种不稳定窗口延长时，我们是否可以促进不同记忆之间共享特征的泛化。这些研究将共同​​揭示人类大脑如何调节可塑性和稳定性之间的精细权衡的机制。在此过程中，这些研究将为确定心理和神经疾病中记忆扭曲如何产生提供重要的基础。