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: 9228393
• 负责人: Jonathan Newman
• 金额: $ 5.92万
• 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/9228393
• 关键词: Affect; Agreement; Amnesia; Anatomy; Anterior; Area; Back; Behavior; Behavioral; Biological Preservation; Brain; Brain Injuries; Cells; Clinical; Control Animal; Desire for food; 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; Motivation; 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; dopaminergic neuron; experience; experimental study; in vivo; interest; long term memory; memory acquisition; memory consolidation; memory process; memory trace reactivation; neural patterning; optogenetics; place fields; public health relevance; relating to nervous system; 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）：海马结构的损伤导致近期记忆丧失，并且无法形成和维持新的长期记忆。经检查，海马结构在记忆巩固过程中起着至关重要的作用。通过这种方式，“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中，了解选择动机显着的记忆痕迹进行巩固的机制是系统级的一个主要目标。神经科学研究表明，多巴胺 (DA) 是维持海马网络的长期增强所必需的。腹侧被盖区 (VTA) 的 DA 信号传导中断会导致长期记忆形成缺陷。 DAergic 投射到具有重要动机作用的大脑区域，例如伏隔核和内侧前额叶皮层，因此人们普遍认为 VTA DA 是重要的。信号传导可以作为重要的海马依赖性记忆的“显着标签”，通过长期存储来设计它们，揭示了与海马“重放”相比，在主动空间探索过程中VTA-海马活动协调的不同形式。先前在安静-清醒期间发生的经验表明，VTA DA 信号在空间学习中的作用可能会根据行为和/或神经状态而快速切换，但 VTA-海马活动的因果作用。空间记忆的协调尚未建立。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状态。 VTA-海马协调的随之而来的影响可以直接归因于在主动探索或对先前经验的认知过程中存在或缺乏 DA 信号。记忆巩固的基础是其深远的临床影响的结果。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的神经退行性疾病。海马体损伤通常会导致暂时性的逆行性遗忘，并且无法形成新的陈述性记忆。长期存储的重要记忆将为假肢装置的开发提供信息，以挽救海马损伤个体的记忆功能。