Revealing the causal role of hippocampal dopamine signaling in spatial learning

 描述（由申请人提供）：海马结构损伤导致近期记忆丧失，无法形成和维持新的长期记忆。因此，人们一致认为，海马结构在记忆巩固中起着至关重要的作用，通过这个过程，“不稳定”的记忆痕迹从海马网络转移到永久的皮层存储数周或数月。理解动机显著记忆痕迹被选择用于巩固的机制是系统水平神经科学研究的主要目标。多巴胺（DA）是维持海马网络长时程增强所必需的。腹侧被盖区（VTA）DA信号传导到海马的中断导致长期记忆形成的缺陷。腹侧被盖区也是DA能神经投射到大脑区域的主要来源，这些大脑区域起着重要的动机作用，如延髓核和内侧前额叶皮层。由于这些原因，人们普遍认为腹侧被盖区DA信号可以作为重要的大脑皮层依赖记忆的“显著标签”，将它们从长期存储中指定出来。我们实验室最近的工作揭示了不同形式的腹侧被盖区海马活动协调主动空间探索相比，海马'重放'以前的经验，发生在安静清醒。这表明VTA DA信号在空间学习中的作用可能会根据行为和/或神经状态迅速切换。然而，VTA-海马活动协调在空间记忆中的因果作用尚未建立。在这里提出的工作中，VTA DA神经元将被光遗传学抑制，这取决于主动探索行为或在安静清醒期间检测到记忆痕迹再激活。这种闭环方法将允许VTA-海马协调的选择性、状态依赖性破坏。空间学习的联想效应可以直接归因于在主动探索或先前经验的心理状态期间DA信号的存在或不存在。对理解记忆巩固的机制基础的强烈科学兴趣是其深远的临床意义的结果。对海马结构的损伤可由于多种原因而发生，包括创伤性脑损伤、2型糖尿病、癫痫灶切除、海马梗塞和原发性年龄相关神经变性疾病。海马损伤通常会导致暂时性的退化性遗忘，无法形成新的陈述性记忆。更好地理解海马体能够选择性地将重要记忆门控到长期存储的机制，将为开发修复装置以挽救海马体损伤个体的记忆功能提供信息。

 DESCRIPTION (provided by applicant): Damage to the hippocampal formation results in loss of recent memory and an inability to form and maintain new long-term memories. Consequently, there is agreement that the hippocampal formation plays a crucial role in memory consolidation, the process by which `labile' memory traces are transferred from hippocampal networks to permanent cortical storage over weeks or months. Understanding the mechanisms by which motivationally- salient memory traces are selected for consolidation is a major objective of systems-level neuroscience research. Dopamine (DA) is required for the maintenance of long-term potentiation in hippocampal networks. Disruption of ventral tegmental area (VTA) DA signaling to hippocampus leads to deficits in long-term memory formation. The VTA is also the primary source of DAergic projections to brain areas that serve important motivational roles, such as the nucleus accumbens and medial prefrontal cortex. For these reasons, it has been widely postulated that VTA DA signaling may serve as a `salience tag' for important hippocampus-dependent memories, designating them from long-term storage. Recent work from our lab has revealed distinct forms of VTA-hippocampal activity coordination during active spatial exploration compared to hippocampal `replay' of previous experience that occurs during quiet-wakefulness. This suggests that the role of VTA DA signaling in spatial learning may be switched rapidly depending on behavioral and/or neural state. However, a causal role for VTA-hippocampal activity coordination in spatial memory has not yet been established. In the work proposed here, VTA DA neurons will be optogenetically suppressed contingent on either active exploratory behavior or the detection of memory trace reactivation during quiet wakefulness. This closed-loop approach will allow selective, state-dependent disruption of VTA-hippocampal coordination. Consequent effects on spatial learning can then be directly attributed to the presence or absence of DA signaling during active exploration or mentation of previous experience. The intense scientific interest in understanding the mechanistic basis of memory consolidation is a result of its far-reaching clinical implications. Damage to the hippocampal formation can occur for a number of reasons including traumatic brain injury, type 2 diabetes, resection of epileptic foci, hippocampal infarct, and primary age- related neurodegenerative diseases. Hippocampal damage often results in temporally-graded retrograded amnesia and an inability to form new declarative memories. Better understanding the mechanisms by which the hippocampus is able to selectively gate important memories to long-term storage will inform the development of prosthetic devices to rescue memory function in individuals with hippocampal damage.