The functions of dopamine signaling during sleep in memory

睡眠期间多巴胺信号在记忆中的作用

• 批准号: 10649893
• 负责人: Ada Eban-Rothschild
• 金额: $ 50.09万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649893
• 关键词: Amygdaloid structure; Anatomy; Aversive Stimulus; Axon; Behavioral; Binding; Brain region; Cells; Code; Communication; Computer Analysis; Cues; Data; Data Reporting; Dependence; Development; Dopamine; Electrophysiology (science); Event; Fiber; Food; Fright; Head; Hippocampus; Knowledge; Learning; Memory; Memory impairment; Mental disorders; Microscope; Molecular; Mus; Nature; Negative Valence; Neurons; Nucleus Accumbens; Optics; Photometry; Physiological; Population; Positive Valence; Process; Reporting; Research; Resolution; Rewards; Role; Sensory; Signal Transduction; Sleep; Stimulus; Structure; Testing; Ventral Tegmental Area; cell type; cognitive function; dopaminergic neuron; experience; experimental study; insight; long term memory; memory consolidation; memory recall; neural; neural circuit; neuromechanism; novel therapeutic intervention; optogenetics; pharmacologic

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.

项目概要 在所有日常经历中，突出的经历最有可能留下持久的记忆。一个中枢神经元 编码显着经历的不同方面的人群，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。虽然 VTA-DA 神经元在显着性在线编码中的作用已经明确，VTA-DA 神经元是否以及如何 人们对将这些经历离线整合到长期记忆中的过程知之甚少。 特别是，尽管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，以及食物刺激的 VTA 表征可以表现出某种形式的重新激活的生理证据， 关于 VTA-DA 神经元活动的经验依赖性，仍然存在很大的知识差距 睡眠，VTA-DA 活动与海马 (HC) 依赖的记忆巩固过程的整合， VTA-DA 神经元活动在记忆巩固和相关神经回路中的因果作用。 我们的首要假设是，睡眠期间的 VTA-DA 活动对于巩固 通过重新激活清醒经历的显着方面，将最近的显着经历转化为长期记忆， 与 HC 双向通信并调节下游目标结构中的多巴胺释放。 我们将使用神经活动的光学和电生理记录以及闭环来测试这一假设 对自由行为、学习和睡眠小鼠的特定神经回路进行光遗传学操作。指导者 强有力的初步数据，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 睡眠期间以及这种重新激活如何以及何时在群体、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尖波波纹之间的因果关系 睡眠期间。最后，我们将确定主要目标区域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 VTA-DA 神经元在巩固中的作用提供基本的新见解 的突出经历。这些发现将揭示关键认知背后的神经机制 功能，并可以促进各种精神疾病新治疗方法的开发 与多巴胺信号失调和记忆受损的组合有关。