Suprachiasmatic Nucleus Output Pathway for Learning and Memory

描述(申请人提供)：习得信息的获取和回忆受昼夜节律系统的调节，而时差或倒班工作扰乱了昼夜节律会损害记忆。昼夜节律起源于视交叉上核(SCN)，而海马体因其在某些类型的记忆(如空间记忆、语境记忆)中的作用而广为人知。 SCN并不直接支配海马区，而是支配内侧隔(MS)，内侧隔(MS)是海马区的主要皮质下输入。20多年前，这一途径被认为是SCN调节学习和记忆的机制(Watts，1991)，但这个想法从未被检验过。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，在这个问题上缺乏研究是值得注意的。通过将西伯利亚仓鼠暴露在一个昼夜节律周期内给出的相位超前和相位延迟的光信号中，很容易消除昼夜节律。这种心律失常导致在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、知觉或注意力因素造成的，也不是由于与睡眠有关的问题造成的。我们认为，心律失常的SCN以非昼夜节律的方式释放GABA(其主要神经递质)，从而对MS提供持续的抑制。有强有力的文献表明，GABAA激动剂Muscimol降低了海马区突触的兴奋性，并损害了记忆。我们的研究表明，全身注射GABAA受体拮抗剂戊四唑(PTZ)完全恢复了心律失常仓鼠的目标识别和空间记忆。因此，我们建议检验这一假说，即在心律失常仓鼠中，慢性抑制MS的SCN-GABA能导致物体识别、空间记忆和背景恐惧条件反射的记忆缺陷。这个项目将在昼夜节律领域架起一座桥梁 以及学习和记忆，并为认知的SCN输出途径提供了功能证据。这个应用程序的主要优点是，我们的操作应该恢复记忆，而不是导致缺陷。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。心律失常仓鼠是人类昼夜节律紊乱的优秀模型，因为光治疗使动物在神经学和遗传上保持完好。因此，这一建议的一个主要好处是，结果将导致一个亟需的动物模型，在其中我们可以研究临床医生感兴趣的昼夜节律对人类病理的贡献。 与公共卫生相关：从睡眠障碍到癌症，再到老年人的记忆力丧失，人类昼夜节律系统的失调与许多疾病有关，但还没有一个动物模型可以使人类的昼夜节律失调在神经学和基因上保持完好。因此，这一建议的一个主要好处是，它将产生一个亟需的动物模型，用于开发人类病理的新疗法。

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.