Revealing the causal role of hippocampal dopamine signaling in spatial learning

 描述(申请人提供)：海马体结构受损导致近期记忆丧失，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发挥着关键作用，记忆巩固是指在几周或几个月的时间里，“不稳定”的记忆痕迹从海马网络转移到永久皮质存储的过程。系统水平的神经科学研究的一个主要目标是理解选择动机显著的记忆痕迹进行巩固的机制。多巴胺(DA)是维持海马网长时程增强所必需的。腹侧被盖区(VTA)DA信号传递到海马区的中断会导致长期记忆形成的缺陷。VTA也是向伏隔核和内侧前额叶皮质等发挥重要激励作用的脑区进行DAR能投射的主要来源。由于这些原因，人们普遍认为，VTA DA信号可能作为重要的海马体依赖记忆的“显著标签”，指定它们来自长期存储。我们实验室最近的工作揭示了主动空间探索期间VTA-海马区活动协调的不同形式，而不是在安静清醒时发生的海马区对先前经验的“重演”。这表明，VTA DA信号在空间学习中的作用可能会根据行为和/或神经状态而迅速切换。然而，VTA-海马区活动协调在空间记忆中的因果作用尚未确定。在这里提出的工作中，VTA DA神经元将受到光遗传抑制，这取决于主动的探索行为或在安静唤醒期间检测到记忆痕迹的重新激活。这种闭环方法将允许选择性的、依赖于状态的VTA-海马区协调中断。随后对空间学习的影响可以直接归因于在主动探索或积累先前经验的过程中DA信号的存在或不存在。人们对理解记忆巩固的机制基础产生了浓厚的科学兴趣，这是其深远的临床意义的结果。导致海马体结构受损的原因有很多，包括创伤性脑损伤、2型糖尿病、癫痫灶切除、海马区梗塞以及与年龄相关的原发神经退行性疾病。海马区的损伤通常会导致时间渐进性的退行性失忆和不能形成新的陈述性记忆。更好地了解海马体能够选择性地将重要记忆长期存储的机制，将有助于开发假体设备来挽救海马体受损个体的记忆功能。

 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.