Suprachiasmatic Nucleus Output Pathway for Learning and Memory

学习和记忆的视交叉上核输出通路

• 批准号: 8860241
• 负责人: H Craig Heller
• 金额: $ 40.04万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-24 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8860241
• 关键词: Ablation; Agonist; Allylglycine; Animal Model; Animals; Arrhythmia; Behavior; Chronic; Circadian Rhythms; Cognition; Disease; Elderly; Equilibrium; Exhibits; Functional disorder; Gene Expression; Hamsters; High Pressure Liquid Chromatography; Hippocampus (Brain); Human; Human Pathology; Injection of therapeutic agent; Jet Lag Syndrome; Lead; Learning; Letters; Light; Link; Literature; Malignant Neoplasms; Medial; Memory; Memory Loss; Memory impairment; Mesocricetus auratus; Microdialysis; Modeling; Mus; Muscimol; Neurotransmitters; Output; Pathway interactions; Pentylenetetrazole; Phase; Phodopus sungorus; Phototherapy; Rattus; Research; Role; Siberian Hamster; Signal Transduction; Site; Sleep; Sleep Disorders; Structure; Synapses; System; Task Performances; Testing; Time; Work; conditioned fear; gamma-Aminobutyric Acid; improved; in vivo; inhibitor/antagonist; interest; long term memory; novel; object recognition; receptor; shift work; spatial memory; suprachiasmatic nucleus; way finding

DESCRIPTION (provided by applicant): The acquisition and recall of learned information is modulated by the circadian system, and disruption of circadian timing by jet-lag or shift-work impairs memory. Circadian timing originates in the suprachiasmatic nucleus (SCN), and the hippocampus is well understood for its role in certain types of memory (e.g., spatial, contextual). The SCN does not innervate the hippocampus directly, but innervates the medial septum (MS), which is the primary subcortical input to the hippocampus. Over 20 years ago, this pathway was proposed as the mechanism by which the SCN could modulate learning and memory (Watts, 1991), but this idea has never been tested. The lack of research on this topic is remarkable considering that one of the major problems in the field of circadian rhythms has been to identify functional output pathways of the SCN. Circadian timing is easily eliminated in Siberian hamsters (Phodopus sungorus) by exposing them to a phase-advancing and a phase-delaying light signal given within one circadian cycle. This arrhythmia results in major memory deficits in object recognition and spatial navigation. These deficits were not due to motivational, perceptual, or attentional factors, nor were they due to sleep-related issues. We propose that the arrhythmic SCN releases GABA (its principal neurotransmitter) in a noncircadian manner, and thereby provides continuous inhibition of the MS. There is a robust literature showing that the GABAA agonist, muscimol, reduces synaptic excitability in the hippocampus and impairs memory. Our studies show that systemic injections of the GABAA receptor antagonist, pentylenetetrazole (PTZ) completely restore object recognition and spatial memory in arrhythmic hamsters. Therefore, we propose to test the hypothesis that chronic SCN GABAergic inhibition of the MS in arrhythmic hamsters causes memory deficits in object recognition, spatial memory, and contextual fear conditioning. This project will bridge the fields of circadian rhythms and learning and memory, and provide functional evidence for an SCN output pathway for cognition. The main strength of this application is that our manipulations should restore memory rather than induce deficits. Neuroanatomical studies have shown that the SCN innervates the MS of rats, mice, and golden hamsters, thus, we firmly believe that the functional relationship between the SCN and MS established in Siberian hamsters will generalize to other species. The arrhythmic hamster is an excellent model of circadian dysfunction in humans because the light treatment leaves animals neurologically and genetically intact. Thus, a major benefit of this proposal is that the results will lead to a much needed animal model in which we can study circadian contributions to human pathologies that are of interest to clinicians.

描述（由申请人提供）：学习信息的采集和回忆是由昼夜节律系统调节的，并且通过喷射滞后或轮班工作破坏了记忆的昼夜节律时机的破坏。昼夜节律定时起源于上核（SCN），海马在某些类型的记忆中的作用（例如，空间，上下文）以其在某些类型的记忆中的作用而被广泛理解。 SCN不会直接支配海马，而是支配了内侧隔膜（MS），这是海马的主要皮质下输入。 20年前，该途径被提出为SCN可以调节学习和记忆的机制（Watts，1991），但从未对此进行测试。考虑到昼夜节律领域的主要问题之一是识别SCN的功能输出途径，因此缺乏对该主题的研究。 在西伯利亚仓鼠（Phodopus sungorus）中，很容易消除昼夜节律时机，将它们暴露于一个昼夜节律范围内给出的相位延伸的光信号。这种心律不齐会导致对象识别和空间导航的主要记忆缺陷。这些缺陷不是由于动机，感知或注意因素所致，也不是由于与睡眠有关的问题所致。我们建议心律不齐的SCN以非circadian的方式释放GABA（其主要神经递质），从而提供了对MS的持续抑制。有强大的文献表明，Gabaa激动剂Muscimol降低了海马中的突触兴奋性并损害记忆。我们的研究表明，GABAA受体拮抗剂，甲状酸甲甲苯唑（PTZ）的全身注射完全恢复了心律失常仓鼠中的物体识别和空间记忆。因此，我们建议检验以下假设：心律不齐仓鼠中对MS的慢性SCN GABA能抑制会导致对象识别，空间记忆和上下文恐惧条件的记忆缺陷。 该项目将弥合昼夜节律的领域 以及学习和记忆，并为认知的SCN输出途径提供功能证据。该应用的主要优势在于，我们的操纵应恢复记忆而不是引起赤字。神经解剖学研究表明，SCN支配了大鼠，小鼠和金仓鼠的MS，因此，我们坚信，在西伯利亚仓鼠中建立的SCN与MS之间的功能关系将推广到其他物种。心律不齐的仓鼠是人类昼夜节律功能障碍的出色模型，因为光治疗使动物神经和遗传完整。因此，该提案的主要好处是结果将导致急需的动物模型，在该模型中，我们可以研究昼夜节律对临床医生感兴趣的人类病理的贡献。