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: 9096666
• 负责人: Jonathan Newman
• 金额: $ 5.61万
• 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/9096666
• 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（由应用程序提供）：对海马形成的损害导致近期记忆的丧失以及无法形成和维护新的长期记忆。因此，有同意海马形成在记忆巩固中起着至关重要的作用，在数周或几个月内将“不稳定”记忆痕迹从海马网络传递到永久性皮质存储的过程。了解选择动机的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。腹侧换段区域（VTA）DA信号传导对海马的信号导致在长期记忆形成中定义。 VTA也是针对大脑区域的Daergic项目的主要来源。由于这些原因，已经广泛发布了VTA DA信号传导可能是重要海马依赖性记忆的“显着性标签”，从而从长期存储中设计它们。我们实验室的最新工作揭示了与海马“重播”相比，在静giment静态期间发生的海马“重播”相比，在主动空间探索过程中，VTA - 海马活动协调的不同形式。这表明VTA DA信号在空间学习中的作用可能会根据行为和/或神经元状态迅速切换。但是，尚未确定VTA - 海马活动协调的因果关系。在此处提出的工作中，VTA DA神经元将因主动探索行为或在安静清醒期间检测记忆痕量重新激活而受到光抑制。这种闭环方法将允许选择性，依赖于状态的VTA-HAPPOCAMPAL协调。因此，对空间学习的影响可以直接归因于在主动探索或以前的经验菜单中的存在或不存在DA信号传导。理解记忆巩固的机械基础的强烈科学兴趣是其深远的临床意义的结果。海马形成的损害可能出于多种原因，包括脑外伤，2型糖尿病，癫痫病灶切除，海马感染和与年龄相关的神经退行性疾病。海马损害通常会导致暂时分级的失忆症，并且无法形成新的声明性记忆。更好地理解海马能够选择性地对长期存储的重要记忆的机制将为挽救海马损害个体的记忆功能的发展提供信息。