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。中枢神经元 人口编码不同方面的显着经验，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 VTA-DA神经元在在线编码显着性中的作用是公认的，无论VTA-DA神经元是否以及如何 离线时将这些经历整合成长期记忆的过程中所涉及到的知识却少得多。 特别是，尽管有药理学证据表明，睡眠期间的多巴胺能活动是记忆所必需的， 形成，和生理学证据表明，食物刺激的VTA表征可以显示一种形式的再激活， 关于VTA-DA神经元活动的经验依赖性， 睡眠，VTA-DA活性与海马（HC）依赖性记忆巩固过程的整合， 腹侧被盖区-多巴胺神经元活动在记忆巩固和相关神经回路中的因果作用。 我们的总体假设是，睡眠期间VTA-DA活动与以下巩固密切相关： 通过唤醒清醒经验的显著方面，将近期的显著经验转化为长期记忆， 与HC的双向通信和下游靶结构中多巴胺释放的调节。 我们将使用神经活动和闭环的光学和电生理记录来验证这一假设。 在自由行为、学习和睡眠的小鼠中的特定神经回路的光遗传学操纵。指导 强有力的初步数据，我们将首先测试哪些方面的清醒经验是由腹侧被盖区-DA神经元重新激活 在睡眠期间，以及如何以及何时这种重新激活在群体，整体和单细胞水平上表现出来。 接下来，我们将确定腹侧被盖区DA神经元活动和HC尖波波纹之间的因果关系 在睡眠中。最后，我们将确定多巴胺释放在主要目标区域的记忆功能 在睡眠期间，使用记录和失活范例。 这些实验将提供关于腹侧被盖区-多巴胺能神经元在巩固中的作用的基本新见解。 突出的经验。这些发现将揭示一个关键的认知神经机制， 功能，并可以促进各种精神疾病的新治疗方法的发展 与多巴胺信号失调和记忆受损有关。

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.