Circadian rhythm regulation

How is melatonin involved in regulation of circadian rhythms, and are there any other hormones that contribute to circadian rhythm regulation?

Melatonin communicates a chemical message of LD cycling peripherally, that is, to the remainder of the body. Melatonin levels are involved in synchronization of circadian rhythms through a circuitous neural communication to the SCN and periphery. As mentioned, the intrinsic circadian rhythm from neuronal activity in the SCN is slightly > 24 hours; therefore, the SCN clock must be reset daily by extrinsic time cues, most importantly the LD cycle. The SCN projects into PVH, mediating melatonin synthesis. Melatonin levels in the pineal gland are inhibited by light and increase at sundown, peaking at mid-darkness. This makes the neurohormone, melatonin, the chemical message communicating photoperiod “fine tuning” to the autonomous master clock in the SCN. This communication occurs through specific melatonin receptors. The MT1 and MT2 melatonin receptors are G-protein coupled with characteristic seven transmembrane domains. These two melatonin-receptor families are distributed throughout the brain (including the SCN itself) and in peripheral tissues, such as adipocytes, macrophages, platelets, gastrointestinal tract, liver, heart, kidneys, and adrenal glands. The melatonin receptors are only receptive at the LD transitions, and thus, exogenous administration of melatonin is most effective at these transitions. Therefore, pineal circadian melatonin production results from direct neuronal input from the SCN and can be regarded as hormonal output from the central circadian clock.

The glucocorticoid (GC) hormone profile joins melatonin as a major modulator of the circadian rhythm, which then confers time-giving properties from central to peripheral clocks. In contrast to other endocrine end-organ hormones (e.g., free thyroxine [fT ], insulin-like growth factor-1 [IGF-1]), which remain generally stable, the blood concentration of GCs oscillates through a 24-hour period and shorter periods (ultradian) for necessary episodic release. The former provides “gearing up” for the anticipated needs of the body, whereas the latter is episodically called out in rapid response to stressful stimuli. The major external synchronizer for the SCN master clock is ambient light, with melatonin regarded as hormonal output from the central (i.e., SCN) circadian clock. It is the central SCN clock that governs normal CRH secretion, which then governs pituitary ACTH release and the attendant GC secretion from the adrenal cortex. This normal release pathway, CRF→ACTH→GC, ultimately works through the glucocorticoid receptor (GR). However, the master SCN circadian clock does not express GR in significant amounts, and thus, it is not sensitive to the 24-hour CG changes or to episodic CG changes. It follows then that adrenalectomy has little influence on SCN circadian gene expression. Yet, given the ubiquitous somatic distribution of GR, circadian GC release becomes the synchronizer of the central clocks with somatic peripheral clocks. Molecular feedback loops generating central and now peripheral circadian rhythmicity work through the CLOCK and BMAL1 positive feedback loop, which includes the CRY and PER genes that can inhibit their own CLOCK/BMAL1 translocation, constituting a primary negative feedback loop (see question 12). The key hypothalamic nuclei, including the PVH (stress response, sympathetic tone modulation) and arcuate nucleus (hunger, appetite feeding modulation), have a generous distribution of GR, which allow for synchronization of non-SCN brain clocks with the 24-hour GC profile.


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