Revealing the causal role of hippocampal dopamine signaling in spatial learning

揭示海马多巴胺信号在空间学习中的因果作用

• 批准号: 8903494
• 负责人: Jonathan Newman
• 金额: $ 5.24万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8903494
• 关键词: Affect; Agreement; Amnesia; Anterior; Area; Back; Behavior; Behavioral; Biological Preservation; Brain; Brain Injuries; Cells; Clinical; Control Animal; Detection; Development; Dopamine; Electrophysiology (science); Epilepsy; Event; Excision; Experimental Designs; Exploratory Behavior; Future; Hippocampal Formation; Hippocampus (Brain); Individual; Infarction; Laboratories; Lateral; Learning; Link; Location; Long-Term Potentiation; Maintenance; Medial; Memory; Methods; Neurodegenerative Disorders; Neurosciences Research; Non-Insulin-Dependent Diabetes Mellitus; Nucleus Accumbens; Patients; Performance; Phase; Physiological; Play; Positioning Attribute; Prefrontal Cortex; Process; Prosthesis; Radial; Rattus; Research; Retrograde amnesia; Rewards; Role; Sampling; Short-Term Memory; Signal Transduction; Source; Stimulus; System; Temporal Lobe; Testing; Theta Rhythm; Training; Traumatic Brain Injury; Ventral Tegmental Area; Wakefulness; Work; age related; arm; base; dopaminergic neuron; experience; in vivo; interest; long term memory; memory acquisition; memory consolidation; memory trace reactivation; neural patterning; optogenetics; place fields; public health relevance; relating to nervous system; research study; spatial memory; success; tool

 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.

 描述（由申请人提供）：海马结构受损会导致近期记忆丧失，并且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至关重要的作用，在记忆巩固过程中，“不稳定”的记忆痕迹在数周或数月内从海马网络转移到永久的皮质存储。了解选择动机显着记忆痕迹进行巩固的机制是系统级神经科学研究的主要目标。多巴胺 (DA) 是维持海马网络长期增强所必需的。腹侧被盖区 (VTA) DA 信号传导至海马体的破坏会导致长期记忆形成缺陷。 VTA 也是 DAergic 投射到具有重要激励作用的大脑区域（例如伏隔核和内侧前额叶皮层）的主要来源。由于这些原因，人们普遍认为 VTA DA 信号传导可能充当重要的海马依赖性记忆的“显着标签”，将它们指定为长期存储。我们实验室最近的工作揭示了主动空间探索期间腹侧被盖区-海马活动协调的不同形式，与安静清醒期间发生的先前经历的海马“重放”相比。这表明 VTA DA 信号在空间学习中的作用可能会根据行为和/或神经状态快速切换。然而，VTA-海马活动协调在空间记忆中的因果作用尚未确定。在此提出的工作中，VTA DA 神经元将根据主动探索行为或安静清醒期间检测到记忆痕迹重新激活而受到光遗传学抑制。这种闭环方法将允许选择性地、依赖于状态地破坏 VTA-海马协调。对空间学习的后续影响可以直接归因于主动探索或先前经验的心理化过程中 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强烈的科学兴趣，这是因为其具有深远的临床意义。海马结构的损伤可能由多种原因引起，包括创伤性脑损伤、2型糖尿病、癫痫病灶切除、海马梗塞和原发性年龄相关神经退行性疾病。海马损伤通常会导致暂时性的逆行性遗忘症，并且无法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储存的机制，将为开发修复海马体损伤个体的记忆功能的假体装置提供信息。