Organization of circadian functions: interaction with the body

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Abstract

The hypothalamus integrates information from the brain and the body; this activity is essential for survival of the individual (adaptation to the environment) and the species (reproduction). As a result, countless functions are regulated by neuroendocrine and autonomic hypothalamic processes in concert with the appropriate behaviour that is mediated by neuronal influences on other brain areas. In the current chapter attention will be focussed on fundamental hypothalamic systems that control metabolism, circulation and the immune system. Herein a system is defined as a physiological and anatomical functional unit, responsible for the organisation of one of these functions. Interestingly probably because these systems are essential for survival, their function is highly dependent on each other's performance and often shares same hypothalamic structures. The functioning of these systems is strongly influenced by (environmental) factors such as the time of the day, stress and sensory autonomic feedback and by circulating hormones. In order to get insight in the mechanisms of hypothalamic integration we have focussed on the influence of the biological clock; the suprachiasmatic nucleus (SCN) on processes that are organized by and in the hypothalamus. The SCN imposes its rhythm onto the body via three different routes of communication: 1.Via the secretion of hormones; 2. via the parasympathetic and 3.via the sympathetic autonomous nervous system. The SCN uses separate connections via either the sympathetic or via the parasympathetic system not only to prepare the body for the coming change in activity cycle but also to prepare the body and its organs for the hormones that are associated with such change. Up till now relatively little attention has been given to the question how peripheral information might be transmitted back to the SCN. Apart from light and melatonin little is known about other systems from the periphery that may provide information to the SCN. In this chapter attention will be paid to e.g. the role of the circumventricular organs in passing info to the SCN. Herein especially the role of the arcuate nucleus (ARC) will be highlighted. The ARC is crucial in the maintenance of energy homeostasis as an integrator of long- and short-term hunger and satiety signals. Receptors for metabolic hormones like insulin, leptin and ghrelin allow the ARC to sense information from the periphery and signal it to the central nervous system. Neuroanatomical tracing studies using injections of a retrograde and anterograde tracer into the ARC and SCN showed a reciprocal connection between the ARC and the SCN which is used to transmit feeding related signals to the SCN. The implications of multiple inputs and outputs of the SCN to the body will be discussed in relation with metabolic functions.

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

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