The functions of dopamine signaling during sleep in memory

项目摘要 在所有的日常经历中，突出的经历最有可能留下持久的记忆。一种中枢神经元 编码显著体验的不同方面的群体，包括奖励和厌恶刺激，奖励- 预测线索和行为选择，是腹侧被盖区多巴胺(VTA-DA)神经元。而当 VTA-DA神经元在在线编码显著中的作用是公认的，VTA-DA神经元是否以及如何 在离线情况下将这些经历整合到长期记忆中，人们对此知之甚少。 特别是，尽管有药理学证据表明睡眠中的多巴胺能活动是记忆所必需的 形成和生理证据表明，食物刺激的VTA表征可以表现出一种重新激活的形式， 关于VTA-DA神经元活动的经验依赖性，目前还存在很大的知识差距 睡眠，VTA-DA活动与依赖于海马(HC)的记忆巩固过程的整合， VTA-DA神经元活动在记忆巩固中的因果作用及其涉及的神经回路。 我们的主要假设是，睡眠中的VTA-DA活动关键地参与了 近期的显著体验通过重新激活清醒体验的显著方面转变为长期记忆， 与HC的双向通信和下游靶结构中多巴胺释放的调制。 我们将使用神经活动和闭环系统的光和电生理记录来验证这一假设 自由行为、学习和睡眠小鼠特定神经回路的光遗传操作。指导原则 强大的初步数据，我们将首先测试VTA-DA神经元重新激活清醒体验的哪些方面 在睡眠期间，这种重新激活的方式和时间在群体、群体和单细胞水平上表现出来。 接下来，我们将确定VTA-DA神经元活动与HC尖波波动之间的因果关系 在睡觉的时候。最后，我们将确定主要靶区多巴胺释放的记忆功能 在睡眠期间，使用记录和失活范例。 这些实验将为了解VTA-DA神经元在巩固中的作用提供根本的新见解 突出的体验。这些发现将阐明关键认知能力背后的神经机制。 功能，并可促进开发各种精神障碍的新治疗方法 这与多巴胺信号失控和记忆力受损有关。

Project Summary Out of all daily experiences, salient ones are likeliest to leave long-lasting memories. A central neuronal population encoding different aspects of salient experiences, including rewarding and aversive stimuli, reward- predictive cues and behavioral choices, is the ventral tegmental area dopamine (VTA-DA) neurons. While the role of VTA-DA neurons in online coding of salience is well-established, whether and how VTA-DA neurons are involved in offline consolidation of these experiences into long-term memory is considerably less understood. In particular, despite pharmacological evidence that dopaminergic activity during sleep is required for memory formation, and physiological evidence that VTA representations of food stimuli can show a form of reactivation, there are still large knowledge gaps regarding the experience dependence of VTA-DA neuronal activity during sleep, the integration of VTA-DA activity with hippocampal (HC)-dependent memory consolidation processes, the causal role of VTA-DA neuronal activity in memory consolidation and the neural circuitry involved. Our overarching hypothesis is that VTA-DA activity during sleep is critically involved in the consolidation of recent salient experiences into long-term memories via reactivation of salient facets of waking experience, bidirectional communication with the HC and modulation of dopamine release in downstream target structures. We will test this hypothesis using optical and electrophysiological recordings of neural activity and closed-loop optogenetic manipulations of specific neural circuits in freely behaving, learning and sleeping mice. Guided by strong preliminary data, we will first test which facets of waking experience are reactivated by VTA-DA neurons during sleep and how and when this reactivation manifests at the population, ensemble and single-cell levels. Next, we will determine the causal relationship between VTA-DA neuronal activity and HC sharp-wave ripples during sleep. Finally, we will determine the memory function of dopamine release at major target regions during sleep, using recording and inactivation paradigms. These experiments will provide fundamental new insight regarding the role of VTA-DA neurons in consolidation of salient experiences. These findings will shed light on the neural mechanisms underlying a key cognitive function, and could promote the development of new therapeutic approaches for various psychiatric disorders that are associated with a combination of dysregulated dopamine signaling and impaired memory.