Suprachiasmatic Nucleus Output Pathway for Learning and Memory

描述（由申请人提供）：学习信息的获取和回忆受到昼夜节律系统的调节，时差或轮班工作对昼夜节律定时的破坏会损害记忆。昼夜节律计时起源于视交叉上核（SCN），并且海马体因其在某些类型的记忆中的作用而被很好地理解（例如，空间的、上下文的）。 SCN不直接支配海马，但支配内侧隔（MS），这是海马的主要皮质下输入。20多年前，有人提出这条通路是SCN调节学习和记忆的机制（Watts，1991），但这一想法从未得到过验证。考虑到昼夜节律领域的主要问题之一是识别SCN的功能输出通路，缺乏对该主题的研究是显著的。 在西伯利亚仓鼠（Photopus sungorus）中，通过将它们暴露于在一个昼夜节律周期内给出的相位推进和相位延迟光信号，可以很容易地消除昼夜节律时间。这种心律失常导致物体识别和空间导航方面的主要记忆缺陷。这些缺陷不是由于动机，知觉或注意力因素，也不是由于睡眠相关的问题。我们建议，海马SCN释放GABA（其主要的神经递质）在一个noncircadian的方式，从而提供了持续的抑制MS。有一个强大的文献表明，GABAA激动剂，蝇蕈醇，降低海马突触兴奋性和损害记忆。我们的研究表明，全身注射GABAA受体拮抗剂，戊四唑（PTZ）完全恢复物体识别和空间记忆的仓鼠。因此，我们建议测试的假设，慢性SCN GABA能抑制的MS在仓鼠造成记忆缺陷的物体识别，空间记忆，和上下文的恐惧条件反射。 这个项目将连接昼夜节律领域 以及学习和记忆，并为认知的SCN输出途径提供功能证据。这个应用程序的主要优点是，我们的操作应该恢复记忆，而不是诱导缺陷。神经解剖学研究表明，SCN支配大鼠，小鼠和金黄地鼠的MS，因此，我们坚信在西伯利亚仓鼠中建立的SCN和MS之间的功能关系将推广到其他物种。仓鼠是人类昼夜节律功能障碍的一个很好的模型，因为光治疗使动物的神经和遗传完整。因此，这项建议的一个主要好处是，结果将导致一个急需的动物模型，我们可以在其中研究昼夜节律对临床医生感兴趣的人类病理学的贡献。 公共卫生相关性：人类昼夜节律系统功能障碍与睡眠障碍、癌症和老年人记忆丧失等多种疾病有关，但目前还没有一种人类昼夜节律功能障碍的动物模型能够使动物在神经和遗传上保持完整。因此，该提议的主要益处是，它将产生急需的动物模型，用于开发人类病理学的新疗法。

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. PUBLIC HEALTH RELEVANCE: Dysfunction of the human circadian system has been implicated in a number of diseases from sleep disorders to cancer and to memory loss among the elderly, but there has not been an animal model of circadian dysfunction in humans that leaves the animal neurologically and genetically intact. Thus, a major benefit of this proposal is that it will result in a much needed animal model for developing new treatments of human pathologies.