Differential control of peripheral circadian rhythms by suprachiasmatic-dependent neural signals

Abstract

Although dependent on the integrity of a central pacemaker in the suprachiasmatic nucleus of the hypothalamus (SCN), endogenous daily (circadian) rhythms are expressed in a wide variety of peripheral organs. The pathways by which the pacemaker controls the periphery are unclear. Here, we used parabiosis between intact and SCN-lesioned mice to show that nonneural (behavioral or bloodborne) signals are adequate to maintain circadian rhythms of clock gene expression in liver and kidney, but not in heart, spleen, or skeletal muscle. These results indicate that the SCN regulates expression of circadian oscillations in different peripheral organs by diverse pathways.A wide variety of physiological events and behaviors exhibit pronounced endogenous daily (circadian) rhythms. Experimental destruction of the suprachiasmatic nucleus of the hypothalamus (SCN) results in arrhythmicity that is reversed by neurotransplantation of this structure. Persistence of rhythmicity depends on the operation of transcriptional-translational feedback loops among the products of critical genes, including Per1, Per2, and Bmal1 within the SCN. Circadian oscillations of Per1, Per2, and Bmal1 also occur in a variety of peripheral organs. Evidence has accumulated for both neural and humoral control of peripheral rhythms. For example, serum shock initiates oscillations of mPer1 expression in cultured hepatocytes and HeLa cells (1), and implants of fibroblasts that receive no innervation adopt the circadian phase of the host (2). Endocrine signals, including glucocorticoids, angiotensin II, and retinoic acid can shift the phase of peripheral clock gene expression (3-5). In addition, metabolites such as glucose may directly entrain peripheral oscillators or act indirectly to induce endocrine signals that regulate circadian rhythms of gene expression (6). On the other hand, the autonomic innervation of peripheral organs provides a potential pathway for entrainment (7-9). For example, SCN lesions that compromise catecholamine rhythms eliminate oscillations of clock gene expression in mouse liver (10).Neural and endocrine pathways for peripheral entrainment are not mutually exclusive. Furthermore, different organs may vary in their dependence on one or another entraining signal. Such variation is not without precedent. Whereas behavioral rhythms appear to depend on humoral outputs of the SCN (11), endocrine rhythms may rely on axonal projections (12).The technique of parabiosis offers unique advantages for investigation of the importance of blood-borne cues in the control of a variety of physiologic systems. This approach has been exploited in the study of cockroach circadian rhythms (13). Despite its useful application to study of metabolic signals in mice (14, 15), the effect on peripheral circadian rhythms of establishing vascular exchange without neural communication has not previously been investigated in vertebrates. We now report that parabiotic linkage of SCN-lesioned mice to intact partners reinstates circadian rhythmicity in some, but not o...

The regulation of neuroendocrine function: Timing is everything

“…These connections provide a mechanism for the SCN to coordinate peripheral cellular oscillators to optimize responses to slower endocrine signals. Several lines of evidence support the notion that neural communication from the SCN to the periphery is responsible for the timing of clock gene expression in targets organs and glands (Guo et al, 2005;Shibata, 2004;Terazono et al, 2003).…”

A diversity of paracrine signals sustains molecular circadian cycling in suprachiasmatic nucleus circuits

“…For example, SCN grafts can restore genotypically specific in vivo rest activity and (some) physiological cycles in SCN-ablated adult hosts (13)(14)(15). Moreover, SCN grafts encapsulated in semipermeable membrane to prevent neuronal outgrowth restore behavioral, but not other, circadian rhythms (16), whereas in vitro, SCN cells (17) and slices (18) can restore gene oscillations in fibroblasts and rhythmic electrical activity in the PVN (19).…”

Regulation of Circadian Gene Expression in Liver by Systemic Signals and Hepatocyte Oscillators

“…As outlined below, the SCN master pacemaker, which itself is synchronized by the photoperiod, appears to set the phase in peripheral oscillators by employing a multitude of different timing cues (zeitgebers). Elegant parabiosis studies by Bittman and coworkers suggest that at least for liver and kidney cells, some of these zeitgebers are probably blood-borne signals, such as hormones and metabolites (Guo et al 2005). Thus, in a parabiosed pair composed of an intact and an SCN-lesioned hamster, circadian liver and kidney gene expression is synchronized in both parabiosed partners.…”