The Institute of Physiology of the Czech Academy of Sciences (CAS) has been involved in the field of chronobiology, i.e., in research on temporal regulation of physiological processes, since 1970. The review describes the first 35 years of the research mostly on the effect of light and daylength, i.e., photoperiod, on entrainment or resetting of the pineal rhythm in melatonin production and of intrinsic rhythms in the central biological clock. This clock controls pineal and other circadian rhythms and is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. During the early chronobiological research, many original findings have been reported, e.g. on mechanisms of resetting of the pineal rhythm in melatonin production by short light pulses or by long exposures of animals to light at night, on modulation of the nocturnal melatonin production by the photoperiod or on the presence of high affinity melatonin binding sites in the SCN. The first evidence was given that the photoperiod modulates functional properties of the SCN and hence the SCN not only controls the daily programme of the organism but it may serve also as a calendar measuring the time of a year. During all the years, the chronobiological community has started to talk about "the Czech school of chronobiology". At present, the today´s Laboratory of Biological Rhythms of the Institute of Physiology CAS continues in the chronobiological research and the studies have been extended to the entire circadian timekeeping system in mammals with focus on its ontogenesis, entrainment mechanisms and circadian regulation of physiological functions. Key words: Pineal, Melatonin, AA-NAT rhythm, Light entrainment, Photoperiod, SCN clock.

Laboratory of Biological Rhythms Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic

Zobrazit více v PubMed

Fiske VM, Bryant GK, Putnam J. Effect of light on the weight of the pineal in the rat. Endocrinology. 1960;66:489–491. doi: 10.1210/endo-66-3-489. DOI

Quay WB. Cellular and Physiological Mechanisms. Charles C Thomas; Springfield, Illinois: 1974. Pineal Chemistry; pp. 1–430.

Lerner AB, Case JD, Takahashi Y, Lee TH, Mori W. Isolation of melatonin, the pineal gland factor that lightens melanocytes. J Am Chem Soc. 1958;80:2587–2591. doi: 10.1021/ja01543a060. DOI

Lerner AB, Case JD, Heinzelman RV. Structure of melatonin. J Am Chem Soc. 1959;81:6084–6088. doi: 10.1021/ja01531a060. DOI

Arendt J. Melatonin and the Mammalian Pineal Gland. Chapman C Hall; London: 1995. pp. 1–321.

Axelrod J. The pineal gland: a neurochemical transducer. Science. 1974;184:1341–1348. doi: 10.1126/science.184.4144.1341. PubMed DOI

Klein DC. Serotonin N-acetylltransferase. A personal historical perspective. In: OLCESE J, editor. Melatonin after Four Decades. Kluwer Academic, Plenum Publishers; New York: 2000. pp. 5–16. DOI

Quay WB. Circadian rhythm in the rat pineal serotonin and its modification by estrous cycle and photoperiod. Gen Comp Endocrinol. 1963;31:473–479. doi: 10.1016/0016-6480(63)90079-0. PubMed DOI

Klein DC, Weller JL. Indole metabolism in the pineal gland. A circadian rhythm in N-acetyltransferase activity. Science. 1970;169:1093–1095. doi: 10.1126/science.169.3950.1093. PubMed DOI

Illnerová H, Vaněček J. Dynamics of discrete entrainment of the circadian rhythm in the rat pineal N-acetyltransferase activity during transient cycles. J Biol Rhythms. 1987;2:85–108. doi: 10.1177/074873048700200202. PubMed DOI

Illnerová H. Effect of light on the serotonin content of the pineal gland. Life Sci. 1971;10(Part I):956–960. doi: 10.1016/0024-3205(71)90360-2. PubMed DOI

Pittendrigh CS. Circadian rhythms and the circadian organization in living systems. In: Cold Spring Harbor Symposia on Quantitative Biology. 1960;25:159–184. doi: 10.1101/SQB.1960.025.01.015. PubMed DOI

Aschoff J. Exogenous and endogenous components in circadian rhythms. Cold Spring Harbor Symposia on Quantitative Biolology. 1960;25:11–28. doi: 10.1101/SQB.1960.025.01.004. PubMed DOI

Klein DC, Weller JL. Rapid light induced decrease in pineal serotonin N-acetyltransferase. Science. 1972;177:532–533. doi: 10.1126/science.177.4048.532. PubMed DOI

Deguchi T, Axelrod J. Control of circadian change in serotonin N-acetyltransferase in the pineal organ by the beta-adrenergic receptor. Proc Natl Acad Sci USA. 1972;69:2547–2550. doi: 10.1073/pnas.69.9.2547. PubMed DOI PMC

Arendt J, Paunier L, Sizonenko PD. Melatonin radioimmunoassay. J Clin Endocr Metab. 1975;40:347–350. doi: 10.1210/jcem-40-2-347. PubMed DOI

Illnerová H, Backström M, Sääf J, Wetterberg L, Vangbo B. Melatonin in the rat pineal and serum: rapid parallel decline after light exposure at night. Neurosci Lett. 1978;9:189–193. doi: 10.1016/0304-3940(78)90070-8. PubMed DOI

Illnerová H. Circadian Rhythms in the Mammalian Pineal Gland. Rozpravy Československé akademie věd. 1986;96(1):1–105.

Illnerová H, Vaněček J, Hoffmann K. Regulation of the pineal melatonin concentration in the rat (RATTUS NORVEGICUS) and in the Djungarian hamster (PHODOPUS SUNGORUS) Comp Biochem Physiol. 1983;74 A:155–159. doi: 10.1016/0300-9629(83)90727-2. PubMed DOI

Illnerová H, Vaněček J, Křeček J, Wetterberg L, Sääf J. Effect of one minute exposure to light at night on rat pineal serotonin N-acetyltransferase and melatonin. J Neurochem. 1979;32:673–675. doi: 10.1111/j.1471-4159.1979.tb00407.x. PubMed DOI

Illnerová H, Vaněček J. Response of the rat pineal serotonin N-acetyltransferase to one min light pulse at different night times. Brain Res. 1979;167:431–434. doi: 10.1016/0006-8993(79)90841-2. PubMed DOI

Illnerová H, Vaněček J. Two oscillator structure of the pacemaker controlling the circadian rhythm of N-acetyltransferase in the rat pineal gland. J Comp Physiol. 1982;145:539–548. doi: 10.1007/BF00612819. DOI

Illnerová H. Entrainment of Mammalian Circadian Rhythms in Melatonin Production by Light. Pineal Research Reviews. 1988;6:173–217.

Illnerová H, Vaněček J. Complex contol of the circadian rhythm in N-acetyltransferase activity in the rat pineal gland. In: ASCHOFF J, DAAN S, GROSS G, editors. Vertebrate Circadian Systems. Springer Verlag; Berlin, Heidelberg: 1982. pp. 285–291. DOI

Illnerová H, Vaněček J. Complex control of the circadian rhythm in pineal melatonin production. In: BMESS, RÚZSÁS Cs, TIMA L, PÉVET P., editors. The Pineal. Current State of Pineal Research. Akadémiai Kiadó, Budapest and Elsevier; Amsterdam: 1985. pp. 137–153.

Illnerová H, Vaněček J. Entrainment of the rat pineal rhythm in melatonin production by light. Reprod Nutr Develop. 1988;28:515–526. doi: 10.1051/rnd:19880315. PubMed DOI

Illnerová H, Vaněček J, Hoffmann K. Different mechanisms of phase delays and phase advances of the circadian rhythm in the rat pineal N-acetyltransferase activity. J Biol Rhythms. 1989;4:187–200. doi: 10.1177/074873048900400207. PubMed DOI

Illnerová H, Vaněček J, Hoffmann K. Adjustment of the rat pineal N-acetyltransferase rhythm to eight hour shifts of the light-dark cycle: advance of the cycle disturbs the rhythm more than delay. Brain Res. 1987;417:167–171. doi: 10.1016/0006-8993(87)90194-6. PubMed DOI

Humlová M, Illnerová H. Rate of re-entrainment of circadian rhythms to advances of light-dark cycles may depend on ways of shifting the cycles. Brain Res. 1990;531:304–306. doi: 10.1016/0006-8993(90)90790-I. PubMed DOI

Pittendrigh CS, Daan S. A functional analysis of circadian pacemakers in nocturnal rodents. V. Pacemaker structure: A clock for all seasons. J Comp Physiol. 1976;103:333–355. doi: 10.1007/BF01417860. DOI

Illnerová H, Vaněček J. Entrainment of the circadian rhythm in the rat pineal N-acetyltransferase activity by prolonged periods of light. J Comp Physiol A. 1987;165:495–510. doi: 10.1007/BF00603974. PubMed DOI

Illnerová H, Vaněček J. Pineal rhythm in N-acetyltransferase activity in rats under different artificial photoperiods and in natural daylight in the course of a year. Neuroendocrinology. 1980;31:321–326. doi: 10.1159/000123095. PubMed DOI

Rollag MD, Panke ES, Reiter RJ. Pineal melatonin content in male hamsters throughout the seasonal reproductive cycle. Proc Soc Exp Biol and Med. 1980;165:330–334. doi: 10.3181/00379727-165-40981. PubMed DOI

Arendt J, Symons AM, Laud C. Pineal function in the sheep: evidence for possible mechanism mediating seasonal reproductive activity. Experientia. 1981;37:584–586. doi: 10.1007/BF01990063. PubMed DOI

Hoffmann K, Illnerová H, Vaněček J. Effect of photoperiod and of one minute light at night-time on the pineal rhythm in N-acetyltransferase activity in the Djungarian hamster Phodopus sungorus. Biol Reprod. 1981;24:551–556. doi: 10.1095/biolreprod24.3.551. PubMed DOI

Petterborg L, Richardson BA, Reiter RJ. Effect of long and short photoperiod on pineal melatonin content in the white-footed mouse, Peromyscus leucopus. Life Sci. 1981;29:1623–1627. doi: 10.1016/0024-3205(81)90063-1. PubMed DOI

Illnerová H, Vaněček J. The evening rise in the rat pineal N-acetyltransferase activity under various photoperiods. Neurosci Lett. 1983;36:279–284. doi: 10.1016/0304-3940(83)90013-7. PubMed DOI

Illnerová H. The suprachiasmatic nucleus and rhythmic pineal melatonin production. In: Klein DC, Moore RY, Reppert SM, editors. Suprachiasmatic Nucleus. The Mind’s Clock. Oxford University Press; New York, Oxford: 1991. pp. 197–216.

Illnerová H, Hoffmann K, Vaněček J. Adjustment of the rat pineal N-acetyltransferase rhythm to a change from long to short photoperiod depends on the direction of the extension of the dark period. Brain Res. 1985;362:403–408. doi: 10.1016/0006-8993(86)90473-7. PubMed DOI

Beck-Fries D, Van Rosen D, Kjelmann BF, Ljungren JG, Wetterberg L. Melatonin in relation to body measures, sex, age, season and the use of drugs in patients with major affective disorders and healthy subjects. Psychoneuroendocrinology. 1985;10:173–183. PubMed

Makkison J, Arendt J. Melatonin secretion in humans on two different arctic bases (68° and 75°S) J Interdisc Cycle Res. 1991;22:149–150.

Illnerová H, Zvolský P, Vaněček J. The circadian rhythm in plasma melatonin concentration of the urbanized man: the effect of summer and winter time. Brain Res. 1985;328:186–189. doi: 10.1016/0006-8993(85)91342-3. PubMed DOI

Vondrašova D, Hájek I, Illnerová H. Exposure to long summer days affects the human melatonin and cortisol rhythms. Brain Res. 1997;759:166–170. doi: 10.1016/S0006-8993(97)00358-2. PubMed DOI

Illnerová H, Hoffmann K, Vaněček J. Adjustment of pineal melatonin and N-acetyltransferase rhythms to change from long to short photoperiod in the Djungarian hamster Phodopus sungorus. Neuroendocrinology. 1984;38:226–231. doi: 10.1159/000123895. PubMed DOI

Hoffmann K, Illnerová H. Photoperiodic effects in the Djungarian hamster. Rate of testicular regression and extension of pineal melatonin pattern depends on the way of change from long to short photoperiod. Neuroendocrinology. 1986;43:317–321. doi: 10.1159/000124562. PubMed DOI

Carter DS, Goldman BD. Antigonadal effects of timed melatonin infusion in pinealectomized male Djungarian hamsters Phodopus sungorus: duration is the critical parameter. Endocrinology. 1983;113:1261–1267. doi: 10.1210/endo-113-4-1261. PubMed DOI

Carter DS, Goldman BD. Progonadal role of the pineal in the Djungarian hamster (Phodopus sungorus): mediation by melatonin. Endocrinology. 1983;113:1268–1273. doi: 10.1210/endo-113-4-1268. PubMed DOI

Hoffmann K, Illnerová H, Vaněček J. Change in duration of the nighttime melatonin peak may be a signal driving photoperiodic responses in the Djungarian hamsters (Phodopus sungorus) Neurosci Lett. 1986;67:68–72. doi: 10.1016/0304-3940(86)90210-7. PubMed DOI

Illnerová H, Vaněček J. Entrainment of the circadian rhythm in rat pineal N-acetyltransferase under extremely long and short photoperiods. J Pineal Res. 1985;2:67–78. doi: 10.1111/j.1600-079X.1985.tb00628.x. PubMed DOI

Klein DC, Moore RJ. Pineal N-acetyltransferase and hydroxyindole-O-methyltransferase : control by the retinal hypothalamic tract and the suprachiasmatic nucleus. Brain Res. 1979;174:245–262. doi: 10.1016/0006-8993(79)90848-5. PubMed DOI

Moore RY, Eichler VB. Loss of a circadian adrenal corticosteron rhythm following suprachiasmatic lesions in the rat. Brain Res. 1972;42:201–206. doi: 10.1016/0006-8993(72)90054-6. PubMed DOI

Stephan FK, Zucker J. Circadian rhythms in drinking, behavior and locomotor activity of rats are eliminated by hypothalamic lesions. Proc Natl Acad Sci USA. 1972;69:1583–1586. doi: 10.1073/pnas.69.6.1583. PubMed DOI PMC

Sumová A, Trávníčková Z, Mikkelsen JD, Illnerová H. Spontaneous rhythm in c-Fos immunoreactivity in the dorsomedial part of the rat suprachiasmatic nucleus. Brain Res. 1998;801:254–258. doi: 10.1016/S0006-8993(98)00619-2. PubMed DOI

Moore RY, Speh JC, Leak RK. Suprachiasmatic nucleus organization. Cell Tissue Res. 2002;309:89–98. doi: 10.1007/s00441-002-0575-2. PubMed DOI

Schwartz WJ, Aronin N, Takeuchi J, Bennet MR, Peters RJ. Towards a molecular biology of the suprachiasmatic nucleus: photic and temporal regulation of c-fos gene expression. Semin Neurosci. 1995;7:53–60. doi: 10.1016/1044-5765(95)90017-9. DOI

Sumová A, Trávníčková Z, Peters R, Schwartz WJ, Illnerová H. The rat suprachiasmatic nucleus is a clock for all seasons. Proc Natl Acad Sci USA. 1995;92:7754–7758. doi: 10.1073/pnas.92.17.7754. PubMed DOI PMC

Kornhauser JM, Mayo KM, Takahashi JS. Immediate-early genes expression in a mammalian circadian pacemaker, the suprachiasmatic nucleus. In: Young MW, editor. Molecular Genetics of Biological Rhythms. Dekker; New York: 1993. pp. 271–307.

Sumová A, Illnerová H. Photic resetting of intrinsic rhythmicity of the rat suprachiasmatic nucleus under various photoperiods. Am J Physiol. 1998;274(Regulatory Integrative Comp Physiol 43):R 857–R 863. doi: 10.1152/ajpregu.1998.274.3.R857. PubMed DOI

Trávníčková Z, Sumová A, Peters R, Schwartz WJ, Illnerová H. Photoperiod-dependent correlation between light-induced SCN c-fos expression and resetting of circadian phase. Am J Physiol. 1996;271(Regulatory Integrative Comp Physiol 40):R 825–R 831. doi: 10.1152/ajpregu.1996.271.4.R825. PubMed DOI

Jelínková D, Illnerová H, Sumová A. Gate for photic resetting of intrinsic rhythmicity of the rat suprachiasmatic nucleus under a long photoperiod. Neurosci Lett. 2000;280:143–146. doi: 10.1016/S0304-3940(00)00773-4. PubMed DOI

Sumová A, Illnerová H. Endogenous melatonin signal does not mediate the effect of photoperiod on the rat suprachiasmatic nucleus. Brain Res. 1996;725:281–283. doi: 10.1016/0006-8993(96)00408-8. PubMed DOI

Schwartz WJ, de la Iglesia HO, Zlomanczuk P, Illnerová H. Encoding Le Quatro Stagioni within the Mammalian Brain: Photoperiodic Orchestration through the Suprachiasmatic Nucleus. J Biol Rhythms. 2001;16:302–311. doi: 10.1177/074873001129002024. PubMed DOI

Illnerova H, Sumová A. Photic entrainment of the mammalian rhythm in melatonin production. J Biol Rhythms. 1997;12:547–555. doi: 10.1177/074873049701200609. PubMed DOI

Illnerová H, Sumová A, Trávníčková Z, Jáč M, Jelínková D. Hormones, subjective night and season of the year. Physiol Res. 2000;49(Suppl 1):S1–S10. PubMed

Jagota A, de la Iglesia HO, Schwartz WJ. Morning and evening circadian oscillations in the suprachiasmatic nucleus in vitro. Nature Neurosci. 2000;3:372–376. doi: 10.1038/73943. PubMed DOI

Stoleru D, Peng Y, Agosto J, Rosbasch M. Coupled oscillators control morning and evening locomotor behaviour in Drosophila. Nature. 2004;431:862–866. doi: 10.1038/nature02926. PubMed DOI

Lamba P, Bilodeau Wentworth D, Emery P, Zhang Y. Morning and evening oscillators cooperate to reset circadian behaviour in response to light input. Cell Reports. 2014;7:601–606. doi: 10.1016/j.celrep.2014.03.044. PubMed DOI PMC

Inagaki N, Honma S, Ono D, Tanahashi Y, Honma K. Proc Natl Acad Sci USA. 2007;104:7664–7669. doi: 10.1073/pnas.0607713104. PubMed DOI PMC

Hashimoto S, Endo T, Honma S, Yamanaka Y, Honma K. Differential responses to artificial photoperiods of the raising and falling phases of human melatonin rhythm are consistent with a dual oscillator hypothesis. Am J Physiol Regul Integr Comp Physiol. 2023;325:R619–R628. doi: 10.1152/ajpregu.00095.2023. PubMed DOI

Hashimoto S, Endo T, Honma S, Yamanaka Y, Honma K. Two oscillator components detected by forced splitting of the sleep-wake cycle in humans. Am J Physiol Regul Integr Comp Physiol. 2024;326:R19–R28. doi: 10.1152/ajpregu.00094.2023. PubMed DOI

Jáč M, Sumová A, Illnerová H. c Fos rhythm in subdivisions of the rat suprachiasmatic nucleus under artificial and natural photoperiods. Am J Physiol Regul Integr Comp Physiol. 2000;279:R2270–R2276. doi: 10.1152/ajpregu.2000.279.6.R2270. PubMed DOI

Jáč M, Kiss A, Sumová A, Illnerová H, Ježová D. Daily profiles of arginin vasopressin mRNA in the suprachiasmatic, supraoptic and paraventricular nuclei of the rat hypothalamus under various photoperiods. Brain Res. 2000;887:472–476. doi: 10.1016/S0006-8993(00)03050-X. PubMed DOI

Sumová A, Trávníčková Z, Illnerová H. Spontaneous c-Fos rhythm in the rat suprachiasmatic nucleus: location and effect of photoperiod. Am J Physiol Regul Integr Comp Physiol. 2000;279:R2262–R2269. doi: 10.1152/ajpregu.2000.279.6.R2262. PubMed DOI

King DP, Takahashi JS. Molecular genetics of circadian rhythms in mammals. Annu Rev Neurosci. 2000;23:713–742. doi: 10.1146/annurev.neuro.23.1.713. PubMed DOI

Reppert SM, Weaver DR. Molecular analysis of mammalian circadian rhythms. Annu Rev Physiol. 2001;63:647–676. doi: 10.1146/annurev.physiol.63.1.647. PubMed DOI

Sumová A, Sládek M, Jáč M, Illnerová H. The circadian rhythm of Per 1 gene product in the rat suprachiasmatic nucleus and its modulation by seasonal changes in daylength. Brain Res. 2002;947:260–270. doi: 10.1016/S0006-8993(02)02933-5. PubMed DOI

Sumová A, Jáč M, Sládek M, Šauman I, Illnerová H. Clock gene daily profiles and their phase relationship in the rat suprachiasmatic nucleus are affected by photoperiod. J Biol Rhythms. 2003;18:134–144. doi: 10.1177/0748730403251801. PubMed DOI

Sumová A, Bendová Z, Sládek M, Kovačíková Z, Illnerová H. Seasonal molecular timekeeping within the rat circadian clock. Physiol Res. 2004;53(Suppl 1):S167–S176. doi: 10.33549/physiolres.930000.53.S167. PubMed DOI

Hazlerigg DG, Ebling FJ, Johnston JD. Photoperiod differentially regulates gene expression rhythms in the rostral and caudal SCN. Curr Biol. 2005;15:R449–R450. doi: 10.1016/j.cub.2005.06.010. PubMed DOI

Sosniyenko S, Hut RA, Daan S, Sumová A. Influence of photoperiod duration and light-dark transition on entrainment of Per 1 and Per 2 gene and protein expression in subdivisions of the mouse suprachiasmatic nucleus. Eur J Neurosci. 2009;30:1802–1814. doi: 10.1111/j.1460-9568.2009.06945.x. PubMed DOI

Sosniyenko S, Parkanová D, Illnerová H, Sládek M, Sumová A. Different mechanisms of adjustment to a change of the photoperiod in the suprachiasmatic and liver circadian clocks. Am J Physiol Regul Integr Comp Physiol. 2010;298:R959–R971. doi: 10.1152/ajpregu.00561.2009. PubMed DOI

Vaněček J, Pavlík A, Illnerová H. Hypothalamic melatonin receptor sites revealed by autoradiography. Brain Res. 1987;435:359–362. doi: 10.1016/0006-8993(87)91625-8. PubMed DOI

Redman J, Armstrontg S, Ng KT. Free running activity rhythms in the rat: entrainment by melatonin. Science. 1983;219:1089–1091. doi: 10.1126/science.6823571. PubMed DOI

Arendt J, Bojkowski C, Folkard S, Franey C, Marks V, Minors D, Waterhouse J, Wever RA, Wildgruber C, Wright J. Some effects of melatonin and the control of its secretion in humans. In: Evered D, Clark S, editors. Ciba Foundation Symposium 117, Photoperiodism, Melatonin and the Pineal. Pitman; London: 1985. pp. 266–283. PubMed DOI

Lewy AJ, Saeeduddin A, Latham-Jackson JM, et al. Melatonin shifts human circadian rhythms according to a phase response curve. Chronobiology International. 1992;9:380–392. doi: 10.3109/07420529209064550. PubMed DOI

Humlová M, Illnerová H. Melatonin entrains the circadian rhythm in the rat pineal N-acetyltransferase activity. Neuroendocrinology. 1990;52:196–199. doi: 10.1159/000125573. PubMed DOI

Humlová M, Illnerová H. Entrainment of the rat pineal N-acetyltransferase activity by melatonin is photoperiod dependent. J Pineal Res. 1992;13:151–157. doi: 10.1111/j.1600-079X.1992.tb00070.x. PubMed DOI

Mc Arthur AJ, Gillette MU, Prosser RA. Melatonin directlyt resets the rat suprachiasmatic clock in vitro. Brain Res. 1991;565:158–161. doi: 10.1016/0006-8993(91)91748-P. PubMed DOI

Sumová A, Illnerová H. Melatonin instantaneously resets intrinsic circadian rhythmicity in the rat suprachiasmatic nucleus. Neurosci Lett. 1996;218:181–184. doi: 10.1016/S0304-3940(96)13159-1. PubMed DOI

Illnerová H, Trentini GP, Maslova L. Melatonin accelerates reentrainment of the circadian rhythm of its own production after an 8-h advance of the light dark cycle. J Comp Physiol A. 1989;166:97–102. doi: 10.1007/BF00190214. PubMed DOI

Balsalobre A, Damiola F, Schibler U. A serum shock induces circadian gene expression ín mammalian tissue culture cells. Cell. 1998;93:929–937. doi: 10.1016/S0092-8674(00)81199-X. PubMed DOI

Kalsbeek A, Palm IF, La Fleur SE, Scheer SA, Perreau-Lenz S, Reiter M, Kreier F, Cailotto C, Buijs RM. SCN outputs and the hypothalamic balance of life. J Biol Rhythms. 2006;21:458–469. doi: 10.1177/0748730406293854. PubMed DOI