The activity of the nervous system is fundamentally periodic and some hormones are also periodically secreted. The regulation of the endocrine secretion is influenced directly by the nervous system and every hormone can influence the activity of the nervous system. Several models using neuroendocrinological manipulations have been used in the investigation of the mechanisms of biological rhythmicity. The hypothyroidism model have been used with the objective to understand the functional mechanisms of the biological rhythmicity and the interactions between the endocrine system and the control system of the circadian rhythmicity.
 Alterations or manipulations of the thyroid function are known to influence behavioral and physiological circadian rhythms in laboratory animals and humans (Beasley and Nelson, 1982; Morin et al., 1986; Whybrow, 1991). We have shown that rats with hypothyroidism displayed shorter circadian periods on free-running conditions (Figure 1). This result was similar to that of McEachron et al. (1993), although  Beasley and Nelson (1982) and Morin et al., (1986) have shown that the hypothyroidism condition cause the circadian period lengthening on free-running in male and female hamster. We have shown also some alterations on circadian rhythm on synchronization conditions (Araujo, 1998). The rats with hypothyroidism have shown a compressed activity time (Figure 2) and furthermore, they showed testicular involution (Figure 3). Our results together with the data from the literature suggest that thyroid hormones could modulate the endogenous circadian pacemakers. Here, we are presenting one model that explain how the thyroid functions could modulate the circadian rhythms.

Possible mechanisms.

The underlying mechanisms are currently unknown, but it is already known that thyroid hormones seem to be involved in the regulation of the expression of the gene nitric oxide synthase (Ueta et al., 1995), the enzyme responsible for the formation of nitric oxide, and that the thyroid hormones nuclear receptors influence the induction of the c-fos promoter (Zhang et al., 1991). Both nitric oxide and c-Fos have been implicated in the transduction signal pathways that synchronize the endogenous circadian pacemakers of the hypothalamic suprachiasmatic nucleus to the external environment (Ding et al., 1994; Wollnik et al., 1995).
Evidence from the literature on circadian rhythmicity have shown that the activity of 5'D II in the central nervous system of rats synchronized to a light-dark cycle (12:12), have a larger activity of the 5'D II at the dark phase(Campos-Barros et al., 1997). A narrow temporary connection between the condition of the light-dark cycle and the activity of 5'D II indicates that the alternation of light and dark could be the signal that act as a synchronizer for the rhythmicity of the 5'D II activity. It is known that the 5'D II activity plays a critical role in the maintenance of the action of the thyroid hormones in the central nervous system. It has been suggested that this circadian variation of the activity of 5'D II in differents areas of the central nervous system (as the frontal cortex, limbic system, hypothalamus, hippocampus, midbrain, cerebellum) - (Campos-Barros et al., 1997), act as internal synchronizer promoting fine adjustment and modulating the activity of the circadian oscillator.
 The ideia to be discussed here, is a possible functional relationship exists between the circadian variation of the thyroid function in the central nervous system, through the  5'D II activity and the thyroid hormones, and the alterations in the circadian rhythmicity induced by the manipulation of the thyroid function. Rats in constant darkness, thyroidectomy also shortened the circadian period. This effect could be reverted after replacement with thyroid hormones (Schull et al., 1988; McEachron et al., 1993). In humans, maniac-depressive illness and depression has been associated with alterations of the thyroid function (Whybrow, 1991) Disturbances of the circadian rhythm of temperature , cortisone and sleep-wake cycle (Feinberg et al., 1982; Wehr & Wirtz-Justice, 1982). On the other hand, drugs with antidepressant action  modify the phase and lengthen the of the circadian rhythm period (Brown and Seggie, 1988; Campos-Barros et al., 1996). Furthermore, it has been demonstrated that different antidepressant therapies, such as with tricycle agent(Campos-Barros et al., 1994), the serotonergic reuptake inhibitor (Baumgartner et al., 1994), carbamazepine and lithium (Baumgartner et al., 1994), as well sleep deprivation (Campos-Barros et al., 1993). The changes of the 5'D II activity specific areas, dependent of the circadian hour and are also dose dependent of the T3 concentration (Campos-Barros et al., 1993, 1994, 1995; Campos-Barros & Baumgartner, 1994).
 Campos-Barros et al. (1997) proposes the hypothesis that the metabolism of the thyroid hormones in the central nervous system is rhythmically controlled by the 5'D II activity rhythm and that this rhythmic pattern of the thyroid hormones metabolism modulates the control of behavior and the control of the circadian rhythmicity. In agreement with this hypothesis the regulation of the thyroid hormones metabolism in the central nervous system would play an important role in the pathophysiology of several neuropsychiatry diseases and on the disturbances of several biological rhythms. One possible indicative for this hypothesis is related to the fact that antidepressant drugs alter the central metabolism of the thyroid hormones, and the replacement with thyroid hormones improves the therapeutic effects of the antidepressant (Baumgartner et al., 1994). All those results put together strengthen the idea that the thyroid hormones metabolism in the central nervous system can be altered in the depressive disease. This relationship could happen mainly in cases of seasonal affective disease where the depressions manifestation synchronized with seasons, are with main occurring in the winter. Our results shown that the alterations found in the hypometabolic state animals were similar to that induced by alteration of the photoperiod with short days, a photoperiod situation similar to that occur in winter. In birds it has been demonstrated that the use of thyroid hormones simulates the effects of increase of the light phase, the summer photoperiod, and thyroidectomy simulates the effects of a decrease of the light phase, as the winter photoperiod, in the reproduction system (Dawson, 1989a,b).
 Another important discovery is the relationship between the modifications of the thyroid function (Moorodian & Wong, 1994) and the circadian rhythmicity of the body temperature, the sleep wake cycle and with other metabolic and behavioral rhythms during aging in humans and animals (Wise et al., 1988; Mirmiran et al., 1989; Witting et al., 1990; Zhang et al., 1996).

Hypothesis:

 Our date contribute to the discussion in the current literature about the relationship between circadian rhythmicity and thyroid function. As the thyroid function is responsible for the homeodynamic control of the metabolism, we suggest that the thyroid function can be one of the elements of the temporal network, acting as an internal synchronier, for the actual condition of basal metabolism. It also could have the function of send temporal cues to maintain the internal temporal relationships with suprachiasmatic nucleus and to promote fine adjustment circadian an seasonal synchronization.
 
Mechanism by which the thyroid function do modulation of the circadian network.

Briefly we are thinking in 4 mechanisms by which thyroid function could influence or modulate circadian rhythmicity and suggesting how the thyroid function could act as one of the elements of the internal circadian rhythm network:

1 - alterations of synchronization mechanisms induced by light, acting by modification in the speed of nervous conduction on optical roads, as the RHT, or altering retinal function  and/ or the transduction of the photic signal that arrives to the neurons of SCN; through alteration of the mechanisms of activation of the c-fos and oxide nitric induced by thyroid hormones and/or for TRH;
2 - alterations in the mechanism of generation of internal circadian signals from the circadian oscillator; pulses of TRH promote phase modifications of the circadian rhytmicity or, indirectly by modifications of basal temperature, altering termossensible neurons;
3 - alterations in the output mechanisms, by modifications of pineal function and the melatonin production as well on the hypothalamus- pituitary-thyroid axis;
4 - alterations in the feedback loop by modifications of T3 and TRH levels, or the activity of the adrenergic system, by modulation and/or fine adjustments in the activity of the circadian oscillator.

 
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