Light-induced c-fos mRNA expression in the suprachiasmatic nucleus and the retina of C3H/HeN mice
Introduction
Synchronization of biological functions with the environmental light/dark cycle is accomplished by daily adjustment of the biological clock by light. Light perceived by the retinal photoreceptors reaches the biological clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus via the retino-hypothalamic pathway which originates in the retinal ganglion cells [27]. Photic stimuli phase shift circadian rhythms and induce the expression of a specific set of immediate early genes (e.g., c-fos and jun-B) and their protein products in amacrine and ganglion cells of the retina and in the SCN of the hypothalamus [2,6,13,15,29,30,[32], [33], [34]]. Proteins of the Fos and Jun family associate to form the AP1 transcription factor, which upon binding to specific DNA sequences regulates gene transcription. Additionally, the composition and binding activity of the AP1 complexes are modified by photic stimuli [24,40]. Immediate early gene induction (e.g., c-fos and jun-B), phosphorylation of the cAMP response element-binding protein (CREB) and formation of the AP1 transcription factor occur only during the subjective night, the period when photic stimuli phase shift circadian rhythms [20,23,24,44]. Immediate early genes appear to be involved in the molecular mechanism by which light induces phase shifts of the circadian pacemaker, since intra-ventricular administration of c-fos and jun-B antisense oligonucleotides to rats blocks light-induced phase shifts of circadian rhythms [43]. However, non-photic stimuli such as carbachol [8] or saline [26] phase shift circadian rhythms without the concomitant induction of immediate early gene expression in the SCN.
The C3H/HeN strain of mouse possesses an rd mutation (retinal degeneration), which leads to the accumulation of cGMP in the retinal photoreceptors due to a defective cGMP-phosphodiesterase [4,16]. This mutation results in a total loss of rods and a substantial loss of cones [41], but does not impair light-induced phase shifts of circadian rhythms [19,28]. C3H/HeN mice entrain to light/dark cycles, adjust circadian activity rhythms to abrupt advances or delays in the light/dark cycle, and phase shift circadian activity rhythms following a pulse of light similarly to other strains of mice [3,9,11,12,17,36]. This study investigated the light-induced c-fos mRNA expression in the retina and SCN of the C3H/HeN mouse which expresses the rd mutation. We demonstrated c-fos mRNA expression in retinal ganglion cells and retino-recipient SCN areas during the subjective night and early subjective day.
Section snippets
Animals
Male C3H/HeN mice (5–6 weeks old, Harlan, Indianapolis, IN), were housed in groups of four and maintained in temperature (22 ± 1°C) and humidity-controlled rooms. Food and water were provided ad libitum. Animals were maintained for 2 weeks on a 12-h light/dark cycle (300 lux at the level of the cage), then placed in constant dark in individual cages equipped with activity wheels.
Measurements of circadian phase
Wheel running activity was measured with a magnetic microswitch on line with a computer. Data were collected in 10 min
Light-induced c-fos mRNA expression in the C3H/HeN mouse SCN
Expression of c-fos mRNA in the retina and in the SCN of C3H/HeN mice held in constant dark was measured by in-situ hybridization autoradiography using an 35S-labeled c-fos riboprobe. Basal expression was very low both during subjective day (CT2–CT10) and subjective night (CT14–CT22) (optical density 15.3 ± 4.3, n = 11). Light (300 lux, 15 min) delivered during the subjective night (CT20) increased c-fos mRNA expression in the SCN with peak expression observed 30 min after the initiation of the
Discussion
C3H/HeN mice maintained in constant darkness responded to a pulse of light with the induction of c-fos mRNA in cells of the ganglion cell layer of the retina and in the retino-recipient areas of the SCN. The response in both the retina and the SCN was dependent on the circadian time, occurring during the subjective night and the early subjective day.
Several findings support the hypothesis that immediate early genes are involved in the molecular mechanism by which light induces phase shifts of
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