Mikkelsen J D, Larsen P J, Mick G, Vrang N, Ebling F J, Maywood E S, Hastings M H, Møller M
Institute of Medical Anatomy B, University of Copenhagen, Denmark.
Neurochem Int. 1995 Sep;27(3):263-72. doi: 10.1016/0197-0186(95)00039-b.
The mammalian circadian clock, located in the hypothalamic suprachiasmatic nucleus (SCN) is important in the regulation of many circadian rhythms, including regulation of pineal gland metabolism and melatonin secretion. Transsection of the optic nerves, disrupting the retinohypothalamic pathway, lesion of the SCN, or lesion of the hypothalamic paraventricular nucleus (PVN) abolish the regulation of pineal serotonin N-acetyltransferase activity by light. Therefore, the pathways linking the retina and the pineal gland must be channelled from the retina through the SCN and the PVN. Many lines of evidence indicate that the major neurotransmitter in the retinal afferents is glutamate. The first aim was therefore to study the retinal target neurons by localising glutamate receptors in the rodent SCN. Using in situ hybridisation, we detected NMDA-R1 and NMDA-R2C mRNA subunits in the SCN. Using immunocytochemistry, immunoreactivity for the AMPA type receptors GluR1, GluR2,3 and GluR4 was also detected in the SCN. Presentation of a short light pulse during the subjective night [i.e. circadian time (CT) 14 or 19], when light induced phase-shifting of activity-rest cycles can be accomplished, also induces expression of the immediate early-genes c-fos and junB in the rodent SCN. The second aim was to use this cellular correlate of behavioural function to determine the location of potential retinal target neurons in the SCN, and to investigate the hypothesis that glutamatergic neurotransmission mediates the effects of light on the circadian system. Thus, the ability of the NMDA receptor antagonist MK-801 to block light-induced c-fos expression in the SCN was studied. In the rat, this antagonist blocked c-fos mRNA expression in a subpopulation of cells in the ventral SCN at doses of 6, but not 2 mg/kg. In contrast, in the hamster both doses blocked light-induced c-fos expression in the ventral SCN. These data provide support for the hypothesis that glutamate mediates effects of light in the SCN, although it appers that the complexes of NMDA receptor subunits, which are involved in light-induced expression of c-fos after light, are relatively insensitive to MK-801. The diversity, heterogeneous distribution, and complexity of glutamate receptor subunits in the SCN suggest that processing of light pulses in the SCN is mediated by several cell types in the SCN. Via an integration process in the clock, the transmission of photic information takes place to other brain structures.
哺乳动物的生物钟位于下丘脑视交叉上核（SCN），对许多昼夜节律的调节很重要，包括对松果体代谢和褪黑素分泌的调节。切断视神经、破坏视网膜下丘脑通路、损毁SCN或损毁下丘脑室旁核（PVN）会消除光照对松果体血清素N - 乙酰转移酶活性的调节。因此，连接视网膜和松果体的通路必定是从视网膜经SCN和PVN传导的。许多证据表明，视网膜传入神经中的主要神经递质是谷氨酸。因此，第一个目标是通过定位啮齿动物SCN中的谷氨酸受体来研究视网膜靶神经元。我们使用原位杂交技术在SCN中检测到NMDA - R1和NMDA - R2C mRNA亚基。使用免疫细胞化学方法，在SCN中也检测到了AMPA型受体GluR1、GluR2,3和GluR4的免疫反应性。在主观夜间[即昼夜时间（CT）14或19]呈现短光脉冲时，此时光照可使活动 - 休息周期发生相移，也会诱导啮齿动物SCN中即刻早期基因c - fos和junB的表达。第二个目标是利用这种行为功能的细胞关联物来确定SCN中潜在视网膜靶神经元的位置，并研究谷氨酸能神经传递介导光照对昼夜节律系统影响的假说。因此，研究了NMDA受体拮抗剂MK - 801阻断光照诱导的SCN中c - fos表达的能力。在大鼠中，该拮抗剂在剂量为6mg/kg时可阻断腹侧SCN中一部分细胞的c - fos mRNA表达，但2mg/kg剂量时则不能。相比之下，在仓鼠中，这两个剂量均可阻断光照诱导的腹侧SCN中c - fos的表达。这些数据支持了谷氨酸介导SCN中光照效应的假说，尽管参与光照后c - fos诱导表达的NMDA受体亚基复合物似乎对MK - 801相对不敏感。SCN中谷氨酸受体亚基的多样性、异质性分布和复杂性表明，SCN中光脉冲的处理是由SCN中的几种细胞类型介导的。通过生物钟中的整合过程，光信息传递到其他脑结构。
