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THE STOPWATCH OF BRAIN; THE INTERVAL TIMER
The daily cycles of light and darkness drive the molecular machinery of the internal biologic clocks of the eukaryotes and some prokaryotes. These cycles are associated with the rhythmic production of melatonin by the pineal gland. The amount of melatonin in the peripheral blood increases after dusk and declines near dawn. During pregnancy, the internal clock of the fetus is driven by the mother's circadian clock by virtue of the melatonin that passes through the placenta. In the full term infants, it takes about 9 to 12 weeks for the circadian clock to fully develop its rhythmicity. In the premature infants, the development of this rhythmic release of melatonin is delayed. Kenaway et al report that shielding the eye of the premature infants nearly doubled the amount of the urinary metabolite of the melatonin (6- sulfatoxymealtonin). Based on this finding it has been suggested that artificial day-night cycles may allow normal development of rhythmic melatonin release in the premature infants. These infants are at a high risk for sudden infant death syndrome (SIDS). However, it has not yet been possible to link the delayed development of the biological clock to SIDS. The effect of melatonin is mediated by binding of melatonin to specific receptors. In humans and sheeps, two G-protein associated receptors, Mel1a and Mel1b, have been described. In humans, Mel1a is encoded by a gene on chromosome 4 and Mel1b by a gene on the chromosome 11. A third melatonin receptor Mel1c has been described in the frogs and birds but as yet no mammalian homolog has been described. Mel1a mediates the binding of melatonin in the brain while Mel1b is expressed in the retina. The work of two independent groups of scientists has unraveled the molecular basis of the rhythmic production of melatonin. Steven Coon and his colleagues in the Dec 8, 1995 issue of Science, and Jimo Borjigin and his collaborators in the Dec 21/28, 1995 issue of Nature reported in the sheep and rat the cloning of the enzyme responsible for production of melatonin (N-acetyl-5-methoxytryptamine) through the acetylation of serotonin (5 hydroxy tryptamine). The activity of this enzyme, serotonin N-acetyltransferase or arylalkalyamine N-acetyl transferase (AA-NAT) is exquisitely controlled in the pinealocytes. The acetylation of melatonin rapidly increases at dusk and significantly declines at dawn. The amount of the AA-NAT mRNA in the pineal gland of sheep and rat increases nearly two and 150 fold from day to night. The fact that the activity of the enzyme rapidly declines by the cessation of the transcription indicates that the enzymatic activity is regulated by the transcriptional control of the enzyme. Melatonin mediates the effect of seasonal change on the reproductive tract and behavior. For example, the shrinkage of the testes in the hamsters and the sheep during the non- breeding winter seasons may be related to the greater production of melatonin during these seasons. In humans with hypothalamic amenorrhea which is associated with decreased frequency of LH surges and men with transient or permanent gonadotropin releasing hormone (GnRH) deficiency which can lead to delayed puberty, the nocturnal melatonin secretion is elevated. Hastening puberty in male patients with GnRH deficiency by the administration of the testosterone led to the normalization of the nighttime melatonin secretion. Androgens and estrogens may directly regulate the production of the melatonin in the pineal gland through the androgen and estrogen receptors found in this structure. Growing evidence for the role of melatonin in the circadian clock has led to increasing interest in the use of this hormone. This hormone is being used in the treatment of sleep disorders, jet lags and for normalizing the circadian cycles in blind people and individuals who work night shifts. Lack of regulation by FDA has led to a remarkable increase in the sale of melatonin by the health food and drug stores. Despite the beneficial effects of melatonin, extreme care should be exercised in the long term use of this hormone since the side effects of such long term use is not known at the present time. In addition, although melatonin may be an anti-oxidant, the doses that have to be used are 100- 1000 times more than the physiologic concentrations of the hormone.
Circadian rhythms are found in eukaryotes and some prokaryotes. These ryhthms which are approximately 24 hours in duration are maintained by an internal clock. Both cycles of light and temperature seem to be the main switches that set this clock. In the Drosophila melanogaster two genes, period and timeless are the master molecules involved in the proper functioning of the circadian clock. The proteins encoded by these genes which are called PER and TIM physically interact. It is believed that the cycles of transcription of these genes is regulated by their association and nuclear localization. Now, a team led by Young et al in the March 28, 96 issue of Science report that TIM can be degraded by light. In the same issue, the team of Edery et al report that the association of the TIM with PER is disrupted by light. Light also perturbs the timing of the cycles of PER mRNA and protein expression and leads to a delay in the phosphorylation of the PER and its entry into the nuclei. These exciting findings unravel the nature of the intricate links that exists between the molecular pacemakers of the circadian clock and the environment. CIRCADIAN RHYTHMS IN MAMMALIAN RETINA Virtually all organisms have circadian (about 24 hour) rhythms. The endogenous oscillators that drive these rhythms reside, in non-mammalian species, in the pineal gland, the retina and probably hypothalamus. In mammals, however, presence of these oscillators has been shown only in the suprachiasmatic nucleus of the hypothalamus. However, Tosini and Menaker show in the April 19, 1996 issue of Science that circadian rhythms are also present in the retina of golden hamsters (Mesocricetus auratus). When the neural retinas from these animals were maintained at 27C in culture, circadian rhythms of melatonin synthesis could be shown for at least 5 days. In light:dark cycles, the synthesis of melatonin by the neural retinas took place during the dark phase of the cycle. Light inhibited such melatonin synthesis. These rhythms of melatonin synthesis could be entrained by light cycles but were free running in the darkness. The circadian mutation, tau, shortens the free-running period of the circadian rhythms by 4 hours. The retinas of the hamsters, homozygous for this mutation, shortened the free-running period of melatonin synthesis. These findings show that, in addition to suprachiasmatic nucleus of the hypothalamus, the mammalian retina contains an oscillator that is responsible for circadian rhythms of melatonin synthesis. REFERENCE: Tosini G, Menaker M: Circadian rhythms in cultured mammlian retina: Science 272, 419-421, 1996 |
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Two types of biological clocks help the brain to keep track of time. The circadian clock responds and gets reset by the cycles of days and nights and regulates cycles of sleep and hormone production. The interval timer on the other hand keeps track of time in terms of minutes and seconds during the performance of the daily tasks. John Gibbon, the chief of biopsychology at the New York State Psychiatric Institute in New York and his team at the annual meeting of the American Association for the Advancement of Science in Feb 96 reported that the the striato-cortical loops are the location of the biological timer clock. The frontal cortex, caudate-putamen and thalamus actively engage in humans in the interval timing tasks. According to the developing hypothesis, the neurotransmitter actively participating in the neuronal pathway of this timer clock may be dopamine. Pulses of dopamine is received by the caudate-putamen a part of the basal ganglia. Ultimeatly, the perception of these pulses from the basal ganglia takes place in the brain cortex. In fact, induction of lesions in the frontal cortex in animals is associated with failure to appropriately respond to interval timing tasks. Similarly, patients with in Parkinson's disease which is associated with loss of dopamine-producing neurons in the substantia nigra also fail to keep track of time. 
