The light‐dark cycle controls peripheral rhythmicity in mice with a genetically ablated suprachiasmatic nucleus clock

Abstract

The mammalian circadian timing system consists of a master pacemaker in the suprachiasmatic nucleus (SCN), which is thought to synchronize peripheral clocks in various organs with each other and with external time. Our knowledge about the role of the SCN clock is based mainly on SCN lesion and transplantation studies. We have now directly deleted the SCN clock using the Cre/LoxP system and investigated how this affects synchronization of peripheral rhythms. Impaired locomotor activity and arrhythmic clock gene expression in the SCN confirm that the SCN clockwork was efficiently abolished in our mouse model. Nonetheless, under light-dark (LD) conditions, peripheral clocks remained rhythmic and synchronized to the LD cycle, and phase relationships between peripheral clocks were sustained. Adaptation to a shifted LD cycle was accelerated in SCN clock-deficient mice. Moreover, under zeitgeber-free conditions, rhythmicity of the peripheral clock gene expression was initially dampened, and after several days peripheral clocks were desynchronized. These findings suggest that the SCN clock is dispensable for the synchronization of peripheral clocks to the LD cycle. A model describing an SCN clock-independent pathway that synchronizes peripheral clocks with the LD cycle is discussed.-Husse, J., Leliavski, A., Tsang, A. H., Oster, H., Eichele, G. The light-dark cycle controls peripheral rhythmicity in mice with a genetically ablated suprachiasmatic nucleus clock. FASEB J. 28, 4950 -4960 (2014). www.fasebj.org Key Words: circadian ⅐ synaptotagmin10Circadian clocks coordinate a broad range of physiological processes such as the sleep-wake cycle, endocrine functions, locomotion, and various aspects of metabolism. The mammalian circadian timing system is hierarchically organized with a master pacemaker residing in the suprachiasmatic nucleus (SCN) and subordinate peripheral clocks present in most tissues (1). How different tissue clocks interact to orchestrate circadian rhythms and how this network of clocks is synchronized to external time remains one of the most intensely investigated areas of chronobiology.Circadian clockwork in the SCN and in the periphery is based on interlocked transcriptional-translational feedback loops driven by a common set of circadian clock genes (2). The circadian clockwork drives the rhythmic expression of tissue-specific clock output genes, some of which encode signaling molecules, which, in the case of the SCN, include neuropeptides (e.g., prokineticin 2 or arginine vasopressin; refs. 3, 4). SCN neurons are tightly coupled via gap junctions and neuropeptidergic signaling, resulting in coherent rhythms of electrical activity (5, 6). Both electrical activity and neuropeptide rhythms serve to transmit time information from the SCN to subordinate clocks in the brain and in the periphery (7,8).The function of the circadian timing system is to adapt an organism's physiology to changes in the environment caused by the rotation of the Earth. Thus, synchronization of the circadian system to the...

Genetic Disruption of Circadian Rhythms in the Suprachiasmatic Nucleus Causes Helplessness, Behavioral Despair, and Anxiety-like Behavior in Mice

“…In this study, we show that mice with disrupted SCN rhythms have abnormally high corticosterone levels toward the end of their subjective night, manifesting as a second peak of corticosterone release in addition to the expected increase at the beginning of the subjective night. Another study investigated corticosterone levels in a different SCN clock–deficient mouse model achieved by neuron-specific knockout of Bmal1 using Cre recombinase expressed under a Syt10 promoter (3). In that study, performed in a light/dark cycle, corticosterone rhythms were not different in SCN clock–deficient mice and control mice, suggesting that the light/dark cycle may compensate for the loss of SCN rhythms by directly modulating corticosterone release (3–5).…”

“…Another study investigated corticosterone levels in a different SCN clock–deficient mouse model achieved by neuron-specific knockout of Bmal1 using Cre recombinase expressed under a Syt10 promoter (3). In that study, performed in a light/dark cycle, corticosterone rhythms were not different in SCN clock–deficient mice and control mice, suggesting that the light/dark cycle may compensate for the loss of SCN rhythms by directly modulating corticosterone release (3–5). Because our experiment was carried out in constant darkness, without potential “masking” influences of light, we were able to detect more directly the impact of SCN rhythms on rhythmic release of corticosterone from the adrenals.…”

Intrinsically Photosensitive Retinal Ganglion Cells (ipRGCs) Are Necessary for Light Entrainment of Peripheral Clocks

“…This notion is strongly supported by findings that selective ablation of the SCN leads to a complete loss of circadian rhythmicity, whereas transplantation of an intact SCN into arrhythmic mutant animals restores circadian rhythmicity [35, 36]. However, the recent development and description of forebrain- or SCN-specific knockout mice for the essential clock gene Bmal1 [37–39] raises important questions. In these mice, peripheral oscillators are able to sustain circadian rhythmicity that are phase-locked with external LD cycles, even in the absence of a functional central SCN oscillator [37–39].…”

Circadian rhythms and clocks in adipose tissues: current insights

“…26,84,85 While under light-dark (LD) conditions peripheral clock gene and behavioral rhythms are preserved in SCN Bmal1-KO mice, they become in constant darkness behaviorally arrhythmic while peripheral clocks and hormone rhythms only gradually desynchronize and, thus, continue to cycle for some days. 85 Microarray studies in WAT of these mice reveal that many adipose transcripts associated with lipid and carbohydrate metabolism lose their rhythm suggesting a dependence on SCN clock-driven rhythmic behavior independent of adipocyte clock function. 26 Interestingly, expression of some immune genes gains rhythmicity in the absence of a functional SCN clock.…”