Chronobiology Unit, Centre for Behaviour and Neurosciences, University of Groningen, Nijenborg 7, 9747 AG Groningen, The Netherlands.
Behav Brain Res. 2011 Aug 10;221(2):466-80. doi: 10.1016/j.bbr.2010.11.039. Epub 2010 Nov 27.
This review provides an overview of the interaction between the mammalian cholinergic system and circadian system, and its possible role in time memory. Several studies made clear that circadian (daily) fluctuations in acetylcholine (ACh) release, cholinergic enzyme activity and cholinergic receptor expression varies remarkably between species and even strains. Apparently, cholinergic features can be flexibly adjusted to the needs of a species or strain. Nevertheless, it can be generalized that circadian rhythmicity in the cholinergic system is characterized by high ACh release during the active phase of an individual. During the active phase, the activity of the ACh synthesizing enzyme Choline Acetyltransferase (ChAT) is enhanced, and the activity of the ACh degrading enzyme Acetylcholinesterase (AChE) is reduced. The number of free, unbound and thus available muscarinic acetylcholine receptors (mAChRs) is highest when ACh release is lowest. The cholinergic innervation of the suprachiasmatic nucleus (SCN), the hypothalamic circadian master clock, arises from the cholinergic forebrain and brain stem nuclei. The density of cholinergic fibers and terminals is modest as compared to other hypothalamic nuclei. This is the case for rat, hamster and mouse, three chronobiological model rodent species studied by us. A new finding is that the rat SCN contains some local cholinergic neurons. Hamster SCN contains less cholinergic neurons, whereas the mouse SCN is devoid of such cells. ACh has an excitatory effect on SCN cells (at least in vivo), and functions in close interaction with other neurotransmitters. Originally it was thought that ACh transferred retinal light information to the SCN. This turned out to be wrong. Thereafter, the phase shifting effects of ACh prompted researches to view ACh as an agent for nocturnal clock resetting. It is still not clear, however, what the function consequence is of SCN cholinergic neurotransmission. Here, we postulate the hypothesis that cholinergic neurotransmission in the SCN provides the brain with a mechanism to support the formation of time memory via 'time stamping'. We define time memory as the memory of a specific time of the day, for which an animal made an association with a certain event and/or location (for example in case of time-place association). We use the term 'time stamping' to refer to the process underlying the encoding of a specific time of day (the time stamp). Only relatively brief but arousing events seem to be time stamped at SCN level. This time stamping requires the engagement of mAChRs. New data suggests that the SCN uses the neuropeptide vasopressin (AVP) as an output system to transfer the specific time of day information to other brain regions such as hippocampus and neocortex where time memory is supposed to be acquired, consolidated and stored. Since time stamping is a cholinergically mediated function of the circadian system, the early disruption of the cholinergic and circadian systems as seen in Alzheimer's disease (AD) may contribute to the cognitive disruption of temporal organization of memory and behavior in these patients.
这篇综述概述了哺乳动物胆碱能系统与生物钟系统的相互作用，以及其在时间记忆中的可能作用。多项研究表明，乙酰胆碱（ACh）释放、胆碱能酶活性和胆碱能受体表达的昼夜（每日）波动在物种间甚至在品系间差异显著。显然，胆碱能特征可以灵活地适应物种或品系的需求。然而，可以概括的是，生物钟系统中的昼夜节律性特征表现为个体活跃期 ACh 释放增加。在活跃期，ACh 合成酶胆碱乙酰转移酶（ChAT）的活性增强，ACh 降解酶乙酰胆碱酯酶（AChE）的活性降低。当 ACh 释放最低时，游离、未结合且因此可用的毒蕈碱乙酰胆碱受体（mAChRs）数量最多。视交叉上核（SCN）的胆碱能神经支配来自于胆碱能前脑和脑干核。与其他下丘脑核相比，胆碱能纤维和末梢的密度适中。这是我们研究的三种生物钟模型啮齿动物（大鼠、仓鼠和小鼠）的情况。一个新发现是大鼠 SCN 含有一些局部胆碱能神经元。仓鼠 SCN 中的胆碱能神经元较少，而小鼠 SCN 则没有这种细胞。ACh 对 SCN 细胞具有兴奋作用（至少在体内），并与其他神经递质密切相互作用。最初人们认为 ACh 将视网膜的光信息传递给 SCN。事实证明这是错误的。此后，ACh 的相位移动作用促使研究人员将 ACh 视为夜间时钟重置的一种手段。然而，SCN 胆碱能神经传递的功能后果仍不清楚。在这里，我们提出假设，即 SCN 中的胆碱能神经传递为大脑提供了一种机制，通过“时间标记”来支持时间记忆的形成。我们将时间记忆定义为动物对一天中特定时间的记忆，动物与特定事件和/或地点建立了关联（例如，在时间-地点关联的情况下）。我们使用“时间标记”来表示编码特定时间（时间标记）的过程。只有相对短暂但令人兴奋的事件似乎在 SCN 水平上被时间标记。这种时间标记需要毒蕈碱受体的参与。新数据表明，SCN 利用神经肽加压素（AVP）作为输出系统，将特定时间的信息传递到海马体和新皮层等其他大脑区域，这些区域被认为是获得、巩固和存储时间记忆的地方。由于时间标记是生物钟系统中受胆碱能调节的功能，因此在阿尔茨海默病（AD）中早期破坏胆碱能和生物钟系统可能导致这些患者记忆和行为的时间组织认知障碍。
