Organization of circadian functions: interaction with the body
Introduction
The suprachiasmatic nucleus (SCN) is essential for synchronizing our daily activity to the light dark cycle in such a way that the physiology of the body is optimally prepared and adapted to these changes in activity. Many SCN neurons have a circadian rhythm in electrical activity resulting in circadian changes of transmitter secretion in the target areas of the SCN (Gillette and Reppert, 1987; Bos and Mirmiran, 1990, Bos and Mirmiran, 1993; Mirmiran et al., 1995). There is some evidence that direct synaptic transfer of information is not necessary to transmit all circadian signals from the SCN but that diffusion of peptide transmitters may convey such signals (Silver et al., 1996; Kraves and Weitz, 2006). However some rhythms could not be restored with diffusion alone (Meyer-Bernstein et al., 1999). Furthermore, it is unclear whether diffusion of peptide transmitters plays an important role in normal physiology. On the other hand, the presence of the amino acid transmitters gamma aminobutyric acid (GABA) and/or glutamate in the majority of SCN neurons, their circadian rhythm in release, and their effect and physiology on target cells in the hypothalamus indicates the important role of synaptic transfer of the daily SCN rhythm in normal physiology (Hermes et al., 1996; Cui et al., 2002; Perreau-Lenz et al., 2003, Perreau-Lenz et al., 2004). At least one cannot envision yet how amino acid transmission can take place via diffusion. Consequently, knowledge about the sites in the brain where information from the SCN is relayed to other neurons is essential. Therefore, much attention was given to the question by which transmitters the SCN transmits its message and which structures in the brain are essential for the integration of this information.
By means of anterograde-tracing techniques, we and several other groups have mapped the projections of the SCN and identified the termination sites in the rodent and human brain (Watts and Swanson, 1987; Kalsbeek et al., 1993a, Kalsbeek et al., 1993b; Buijs et al., 1994; Dai et al., 1998; Lesauter and Silver, 1999a). All these studies indicate that the majority of SCN termination sites is within the medial hypothalamus where the key cell groups are involved in the organization of hormonal secretion and autonomic control. Consequently, this seems the foremost way in which the SCN transmits its daily message to the rest of the brain and body, affecting mono- and multisynaptically hormone-producing neurons and preautonomic neurons primarily located in the paraventricular nucleus (PVN) of the hypothalamus. However, estimated from the density of SCN projections, the cell groups that seem to fulfill an intermediary function within the hypothalamus receive a much more prominent SCN input. These cell groups (the medial preoptic area (MPO); the sub-PVN and the dorso medial hypothalamus (DMH)), located in the area directly in front, under and behind the PVN, are known to project extensively within the hypothalamus (Ter Horst and Luiten, 1986; Roland and Sawchenko, 1993) and thus appear perfect for an intermediary function. In fact, our studies on the role of the SCN in corticosterone secretion show that the DMH is an important target area for SCN VP fibers in this respect (Kalsbeek et al., 1996a, Kalsbeek et al., 1996b).
In the present review, attention will be given to observations that indicate that one of the major functions of the SCN is to prepare our body for the daily changes in activity periods. Hereto, we propose that the SCN affects the functionality of our organs by at least two mechanisms; it organizes the daily rhythm of several hormones and it influences via the autonomic nervous system the activity of many organs directly or affects their sensitivity for these hormones. Studies will be discussed that indicate that once this function of the SCN to prepare our body for the upcoming activity period is lost or dysfunctional, it will result in the development of disease. The mechanisms that may lead to such loss in function will be discussed. In addition, recent studies will be presented that have provided evidence that also the body “talks” back to the SCN. Hereby, we will not only consider the feedback via the autonomic nervous system but also by hormones.
Section snippets
Circadian rhythm of SCN neurons and their anatomical organization
Clearly, many studies have shown that neurons of the biological clock maintain an activity in cell firing with a rhythm of about 24 h, irrespective of whether they were studied in vivo, in vitro, in isolation, in slice, or in cultured conditions (Groos et al., 1983; Gillette and Reppert, 1987; Bos and Mirmiran, 1993; Mirmiran et al., 1995; Xie et al., 2003).
In order to examine whether all cells in the same area of the suprachiasmatic nucleus (SCN) had the same firing characteristics, we examined
Hypothalamic projections of the SCN
Projections of the SCN to hypothalamic structures were initially determined by injection of anterograde tracers into the SCN. Injection of Phaseolus vulgaris leucoagglutinin, a plant lectin, into the SCN by means of iontophoresis resulted in clearly labeled fiber processes emanating from the SCN and reaching hypothalamic target sites (Watts and Swanson, 1987; Kalsbeek et al., 1993a, Kalsbeek et al., 1993b; Buijs et al., 1994; Dai et al., 1998; Lesauter and Silver, 1999a). Most conspicuously,
SCN prepares the body for changes in activity
The influence of the SCN on hormonal secretion seems one of the important routes by which the SCN may affect the body. This conjecture is enforced by the fact that the secretion of several hormones is influenced or even completely regulated (melatonin) by the SCN (Perreau-Lenz et al., 2003). Concerning hormones, such as corticosterone, that are mainly influenced by the SCN, usually the basal secretion follows a circadian pattern. Thus, the rhythmic secretion of corticosterone (cortisol in
Autonomic control of our organs
Initially, it was assumed that the SCN would affect the body by hormones only and thus would support its effect on the daily sleep/wake cycle. However, early studies by Niijima and Nagai (Niijima et al., 1992) showed that autonomic nerve activity is changed after exposure to light, while this effect is gone after lesioning the SCN, indicating that the light effect on the autonomic nervous system is mediated by the SCN. Consequently, this was the first step to show that the SCN by influencing
An unbalanced autonomic output; leading to disease?
Until recently, a number of organs such as white adipose tissue were thought to be excluded from parasympathetic input. However, we recently obtained evidence for parasympathetic input to white adipose tissue, not only as visceral organ but also as subcutaneous tissue. We also showed that the parasympathetic input has the function to build up the fat depot, while the sympathetic input serves to burn fat (Kreier et al., 2002). This evidence fits quite well with the observations that exercise
Input to the biological clock
The previous studies revealed three important elements.
- 1.
A diminished function of the SCN is associated with hypertension and probably diabetes. This diminishment is demonstrated anatomically and/or functionally and might be the result of the change in lifestyle or might be inborn.
- 2.
Therapies need to be developed aimed at restoring this weakened function of the SCN.
- 3.
It needs to be understood how the functionality of the SCN can be affected by a change in lifestyle. Consequently, the way information
Transmission of metabolic information to the SCN
There are two major ways by which metabolic information may reach the SCN, one is by the autonomic nervous feedback from our organs, and the other is by hormonal feedback or by that of metabolites. Up till now, there is hardly anything known about these two types of feedback to the SCN. From the sites where visceral sympathetic information enters the brain (the dorsal horn) and visceral parasympathetic information enters the brain (the NTS), no projections are known to the SCN; so if any
Conclusions
We have reviewed evidence that the SCN is not only involved in the organization of the physiology of the body in association with the light dark cycle, but that the body also communicates back to the SCN. Hereto the SCN also receives information from the circulation. The observation that in diseases such as diabetes and hypertension, a flattened rhythm is observed in autonomic parameters together with a decrease in activity of the SCN suggests that the biological clock may play an important
References (106)
- et al.
Glutamate injection into the suprachiasmatic nucleus stimulates brown fat thermogenesis in the rat
Brain Res.
(1989) - et al.
Circadian rhythms in spontaneous neuronal discharges of the cultured suprachiasmatic nucleus
Brain Res.
(1990) - et al.
Effects of excitatory and inhibitory amino acids on neuronal discharges in the cultured suprachiasmatic nucleus
Brain Res. Bull.
(1993) - et al.
Novel environment induced inhibition of corticosterone secretion: physiological evidence for a suprachiasmatic nucleus mediated neuronal hypothalamo-adrenal cortex pathway
Brain Res.
(1997) - et al.
The hypothalamic arcuate nucleus: a key site for mediating leptin's effects on glucose homeostasis and locomotor activity
Cell Metab.
(2005) - et al.
The intergeniculate leaflet does not mediate the disruptive effects of constant light on circadian rhythms in the rat
Neuroscience
(1999) - et al.
CNS structures presumably involved in vagal control of ovarian function
J. Auton. Nerv. Syst.
(2000) - et al.
The hypothalamic suprachiasmatic nuclei: circadian patterns of vasopressin secretion and neuronal activity in vitro
Brain Res. Bull.
(1987) - et al.
Differential responses of identified rat paraventricularneurons to suprachiasmatic nucleus stimulation
Neuroscience
(1993) - et al.
Light activates the adrenal gland: timing of gene expression and glucocorticoid release
Cell Metab.
(2005)