Skip to main content

The suprachiasmatic nucleus: age-related decline in biological rhythms


Aging is associated with changes in sleep duration and quality, as well as increased rates of pathologic/disordered sleep. While several factors contribute to these changes, emerging research suggests that age-related changes in the mammalian central circadian clock within the suprachiasmatic nucleus (SCN) may be a key factor. Prior work from our group suggests that circadian output from the SCN declines because of aging. Furthermore, we have previously observed age-related infertility in female mice, caused by a mismatch between environmental light–dark cycles and the intrinsic, internal biological clocks. In this review, we address regulatory mechanisms underlying circadian rhythms in mammals and summarize recent literature describing the effects of aging on the circadian system.


Sufficient duration of high-quality sleep is important to maintain an individual’s physical and mental health. However, it has often been reported that age-related declines in alertness during active and deep sleep phases, as well as fragmented sleep, are observed in elderly adults. Disturbances in circadian rhythms are suspected as the primary cause of age-related changes to the biological clock. Circadian output from the suprachiasmatic nucleus (SCN) of the hypothalamus, the central biological clock, decreases with age [1]. In previous experiments using rodents, loss and reduced rhythmic expression of neuropeptides in the SCN [2], as well as decreased glucose metabolism [3], have been reported. Surprisingly, age-related declines in behavioral rhythmicity can be partially reversed by implanting fetal SCN tissue into the third ventricle of aged animals [47], indicating that the SCN plays an important role in age-related behavioral changes. Reproductive functions are also influenced by the aging and circadian process [8]. For instance, daily timing signals were shown to be essential for normal estrous cyclicity, even before researchers discovered the SCN [9]. SCN-lesioned animals do not demonstrate an estrous cycle, and transplantation of fetal SCN tissue cannot restore reproductive functions [10]. We have recently reported that in order to ameliorate early-onset estrous cycle irregularity, and resultant infertility in mice, it is important to synchronize the environmental day/night (light and dark) cycles with each individual’s endogenous circadian rhythms [11]. However, disharmony in this cycle and circadian rhythms does not lead to reproductive dysfunction in young adults. Thus, the present review outlines regulatory circadian rhythm mechanisms in mammals. We also discuss aging mechanisms that influence SCN neural circuits and resultant decreases in physiological functions.

Circadian rhythm characteristics

In constant dark (DD) conditions, whereby mice lose their time cues, wheel-running activity starts approximately 15 min earlier each day [12, 13] (Fig. 1a). Activity onset regularly starts earlier thereafter, and the periodicity is extremely accurate. The 24-h behavioral rhythm can be regarded as an exogenous (reactive) rhythm, created by the light period in a day/night cycle. However, the approximately 24-h rhythm that continues at a steady state is an endogenous rhythm. This rhythm indicates the presence of an approximate 24-h cycle mechanism derived from inside the body, a phenomenon that is referred to as “free-running.” The free-running period is not exactly 24 h, but the period has the ability to be synchronized into a 24-h cycle. This is referred to as “entrainment.” Light responses of the circadian rhythm are time-dependent. Phase response curves for light pulses have been proposed as a model for enabling entrainment of the 24-h period due to the light environment. When a light pulse is applied to a free-running mouse in a constant dark environment early in the active phase (referred to as “subjective night”), activity onset the following day is greatly delayed. Moreover, when a light pulse is applied during late subjective night, or the beginning of a rest phase, the activity onset for the following rhythm is shifted toward an advanced direction. Even if a similar light pulse is applied during the rest phase (e.g., subjective daytime for mice), the phase for subsequent rhythms does not change [14, 15] (Fig. 1b). This phase-dependent shift in circadian rhythms has revealed differences in factors such as responsiveness to light intensity and degrees of shift among species; however, this is also fundamentally conserved in humans [16, 17] (Fig. 1c).

Fig. 1

Circadian rhythm characteristics. a A representative double-plotted actogram of wheel-running activity in a C57BL/6J mouse showing entrainment to the LD cycle, free-running under DD, and phase responses to 6-h light pulses. b Phase response curves detailing wheel-running activity rhythms for 6-h light pulses in male mice. The activity onset time was defined as CT; circadian time, 12. The free-running period is set to 24 circadian-hours. c Phase response curves of human sleep rhythms for 3 h of bright light. Open circles by Honma and Honma [16] and closed circles by Minors et al. [17]

Aging effects on activity rhythms

Aging is commonly associated with changes to the quantity and quality of sleep, as well as rates of acquired sleep disorders (including sleep episode fragmentation), in humans and other mammals [1820]. In rodents, aging induces changes to locomotor activity rhythms, including decreased amplitudes, increased fragmentation, shortened or lengthened free-running periods, slower re-entrainment following LD cycle shifts, and altered light sensitivity [2124] (Fig. 2). For aged mice, a distinct “variation” between active and rest is lacking during both the night (active phase) and day (rest phase), respectively. Furthermore, early morning awakening in humans can be regarded as reflecting a change in the entrainment phase angle due to age-related changes to the endogenous period and photic response. Based on the similarities described above, examinations of neural mechanisms using rodents as an aging model are currently underway.

Fig. 2

Reduced behavioral circadian rhythms in middle-aged mice. Representative double-plotted actograms of wheel-running activity in C57BL/6J mice. These plots show the effects of aging on circadian rhythms influencing locomotor activity for both young (a) and middle-aged (b) mice. The mice were maintained in an LD cycle for 2 weeks and then transferred into DD. Light conditions are indicated at the top of the figure; open bars are light phases, and closed bars are dark

The SCN regulates behavioral circadian rhythms

The SCN is located just above the medial portion of the optic chiasm on the left and right side of the third ventricle (Fig. 3a). The SCN’s size in mice is approximately that of a poppy seed; however, because of its characteristic structure of nearly 8000, tightly packaged neurons, identification is relatively easy. When the SCN is experimentally lesioned, behavioral circadian rhythms and photic entrainment are completely lost [25] (Fig. 3c). However, behavioral circadian rhythms recover when an SCN obtained from fetuses or newborns is transplanted into a lesioned animal [2628]. Results of an experiment using mutant hamsters with a naturally occurring “tau”; circadian period, mutation (which creates genetically shortened circadian free-running periods; [29]) indicates the SCN’s importance as the circadian pacemaker. When a wild-type SCN that possessed an approximate 24-h cycle was transplanted into hamsters with tau-mutant SCN lesions, behavioral rhythm cycles returned to 24-h cycles. Conversely, when a tau-mutant SCN is transplanted into hosts with wild-type SCN lesions (causing a lack of periodicity), short-period behavioral circadian rhythms are recovered [30]. Results of SCN transplants with different genetic free-running periods provide conclusive evidence that the SCN is the circadian pacemaker regulating behavioral circadian rhythms. Moreover, an experiment assessing a transplanted SCN within a semipermeable polymeric capsule before transplantation (which prevents neural outgrowth but allows diffusion of humoral signals) indicates that behavioral circadian rhythms are not controlled by neural projections and synapses. Rather, circadian rhythms function through the regulation of secreted substances from the transplanted SCN [31]. Moreover, it has become apparent that both behavioral activation and inhibiting factors related to the SCN functions in a coordinated manner [32].

Fig. 3

The SCN regulates behavioral circadian rhythms. a The SCN in a coronal section (50-μm thickness) of the hypothalamus stained by neutral red. The scale bar indicates 200 μm. A pair of nuclei with densely packed neurons is apparent in the middle base of the brain. b A male mouse on a running wheel. c A representative actogram of wheel-running activity in an SCN-lesioned mouse under an LD cycle. The nocturnal (night-active) rhythm has disappeared except for an ultradian rhythm, with a period of 2–4 h. Light condition is indicated at the top of the figure; the open bar is a light phase, and the closed bar is dark

Multiple circadian oscillators in the SCN

Since the identification of the mammalian clock genes—period1 and clock—in 1997 [33, 34], mechanisms underlying circadian rhythms generated by the molecular clock have been considered to consist transcriptional-translational feedback loops. These loops involve clock genes that exist within single cells. Two years before our initial understanding of this molecular mechanism, Welsh et al. [35] dissected the SCN from a rat that was treated with enzymes, dispersed, and cultured. The spontaneous firing rates of individual SCN neurons revealed circadian patterns, and these patterns revealed that each cell had its own period (Fig. 4a, c). These results indicated that the smallest circadian unit is inherent within a single cell. Although it is possible to reveal a circadian rhythm in a single cell, without the underlying SCN mechanism available for synchronizing individual rhythms, the SCN is unable to produce a stable, holistic rhythm. Even if 8000 SCN neurons oscillating within their own rhythm gathered (without coupling) in the SCN region, misalignment would eventually occur in regards to neuronal firing. This would lead to constant firing throughout the day. In fact, SCN neurons dispersed in a culture oscillate the circadian rhythm with their individual cycles. However, individual cells in an SCN slice culture exhibit the same coordinated circadian periods between neurons [3639] (Fig. 4b, d).

Fig. 4

Multiple circadian oscillators in the SCN. a, b Phase-contrast photomicrograph of SCN neurons in a dispersed cell culture (a) and slice culture (b) on a multi-electrode dish. The black squares indicate the 64 electrodes with a size of 50 μm square, with 150 μm separation (a), and 20 μm square, with 100 μm separation (b). c, d Circadian firing rhythms of four representative SCN neurons from a dispersed cell culture (c) and a slice culture (d). Numbers on the right margin of the first lane indicate the firing rate (mean spikes/s in 15 min)

Importance of neural output from the SCN

How does a timing signal from the SCN regulate physiological functions, including behavioral circadian rhythms? In an experiment where tetrodotoxin, a voltage-gated Na+ channel blocker, was perfused near the SCN, it was shown that behavioral circadian rhythms in a rat disappeared [40]. This result indicates that neural firing (action potentials) is important for the SCN rhythm output. In another study, we inserted two stainless wires (100 μm in diameter) into the SCN and constructed an experimental system (in vivo multi-unit neural activity recording: MUA) to record neuronal activity in freely moving mice with a running wheel [41]. Neuronal groups in the SCN actively fired during the daytime (light period), the rest period, but firing frequency gradually decreased from several dozen minutes before the light was turned off and remained at a low level during the night. Conversely, SCN neuronal firing frequency gradually increased from approximately 1 h before the light was turned on, and a high firing level was maintained during the daytime. Additionally, we observed that even when the action rhythm was obtained during free-running under DD conditions, the neuronal firing rhythm that was active during the subjective day (and decreased during the subjective night) was maintained. In nocturnal rodents, with reference to the day-active neural activity in the SCN, behavioral inhibiting factors have been looked for. To date, three SCN-secreted factors have been proposed and all of them show an expression peak during the day, the time of behavioral resting phase and in parallel to the neural rhythm [4244]. The main nerve projection path from the SCN goes through the subparaventricular zone (SPZ), dorsally adjacent to the SCN, and reaches the dorsomedial hypothalamic nucleus (DMH) [45]. This is where time information is sent to the central nervous system, which is responsible for various biological functions related to the DMH [46]. A cell-specific lesion study indicated that the dorsal part of the SPZ is relaying circadian signals from the SCN for body temperature rhythms, on the other hand the ventral part is responsible for rhythms of sleep and locomotor activity [47]. In other words, the SCN-SPZ output system reflects the major SCN pathway for circadian rhythms of sleep, locomotor activity, body temperature, and furthermore reproductive functions.

Age-related declines in SCN output

We measured in vivo MUA in aged mice [1]. SCN neuronal firing rhythms in aged mice are generally maintained at a high level during the day and at a low level at night. However, the neural firing frequency variance during measurement time bouts (1 min) is large, and day–night variations are diminished. These results demonstrated that circadian rhythm amplitudes significantly decreased in aged relative to young mice (Fig. 5). This decrease in amplitude is similar in the SPZ; these results suggest that the behavioral decrease in circadian rhythms in aged mice could be due to decreased functioning in the output system from the SCN [1]. Furthermore, single cell imaging for PER2::LUCIFERASE reporter mice using an ultra-sensitive CCD camera system revealed that each SCN cell’s rhythm was approximately normal, but each rhythm was dissociated [48]. These results demonstrate that SCN cells can normally produce circadian rhythms, but due to decreased functioning in the neural network inside the SCN, the SCN output system is weakened. Given that significant decreases in activity rhythms associated with aging were not observed for degenerated dopamine neurons in the substantia nigra [49], it appears that the circadian aging mechanism is not due to the molecular clocks in the individual SCN cells. Rather, this mechanism is due to a decrease in the SCN output rhythm associated with diminished neural networks in the SCN.

Fig. 5

Reduced MUA rhythms in the SCN of middle-aged mice in vivo. Representative serial-plotted actograms of neural and locomotor activity showing diurnal and circadian rhythms of MUA in the SCN of young (a) and middle-aged (b) mice. Light conditions are indicated at the top of the figure; open bars are light phases, and closed bars are dark. The bottom trace represents simultaneously recorded locomotor activity. The number of spikes for MUA or locomotor activity was counted every minute

Circadian fluctuations during the estrous cycle

Humans have a menstrual cycle of approximately 28 days, however, rodents (such as rats, mice, and hamsters) have estrous cycles that range from 4 to 5 days and are divided into four phases: proestrus, estrus, metestrus, and diestrus. Estrogen levels in the circulating blood increase rapidly from the beginning of the proestrus light period, a subsequent mass secretion of gonadotropin (LH; luteinizing hormone, surge) induces ovulation, and progesterone concentration also rises [50]. However, behavioral rhythms increase at night, from the proestrus to estrus phases, and progress toward the active period. This phenomenon is referred to as “scalloping”. Accelerations in activity and phase advances are only observed during a transition from the proestrus to the estrus and are not seen during other stages [51]. Scalloping was observed in wheel-running activity rhythms from normal, young, female, experimental mice. Molecular machinery of the circadian rhythm, which has been observed in almost every organ of the body, can autonomously exhibit a circadian rhythm in each organ [52, 53]. Molecular clocks are also present in organs that comprise the hypothalamus-pituitary-gonadal axis (HPG-axis) responsible for estrous cycle regulation [54, 55]. We compared the expression rhythm of clock genes (Per1, Per2, and Bmal1) in the SCN and peripheral tissues using in situ hybridization and quantitative real-time PCR. Results revealed that the SCN is largely unaffected by the estrous cycle, but estrous cycle effects were observed in peripheral tissues (liver, uterus, and ovaries). Although the types of genes and tissues were not constant, when we focused on the expression of Per2 mRNA in the uterus and ovaries, the rhythm amplitude during the proestrus stage was large, and the phase had advanced in comparison with that in the other stages [56]. Furthermore, we confirmed through in vivo and in vitro experiments that these changes in clock gene expression rhythms during the estrous cycle are due to the effects of estrogen and progesterone [57, 58]. In other words, quantitative changes in ovarian steroid hormones associated with the estrous cycle are effective in influencing timing. Thus, it appears that desynchronization between the SCN and other tissues affects the female reproductive system.

Interactions between circadian rhythms and the estrous cycle

We recently reported a relationship between circadian rhythms and reproductive functioning in female animals. During the early aging stage of clock gene knockout mice (Cry KO mice), in which the shortening (22.5 h, for Cry1 KO) or lengthening (24.5 h, for Cry2 KO) of genotype-specific circadian periods are known, estrous cycle irregularities and resultant infertility were observed [10]. When the light–dark environmental cycles were adjusted to intrinsic periods of the biological clock, the estrous cycle irregularities were ameliorated, and successful pregnancy rates dramatically increased. Moreover, when wild-type mice with no genetic defects were placed in light–dark environmental conditions that caused “weekly jet lag” during “middle age”, in which normal pregnancies and birth are possible (8–12 months of age), the regular estrous cycle diminished and became irregular (Fig. 6). These results indicate that age-related changes in early onset estrous cycle irregularities and resultant infertility are strongly dependent on biological clock functioning. Desynchronization between the environment and the biological clock (i.e., “circadian timing shift”) has a major impact on female reproductive functions.

Fig. 6

Interactions between circadian rhythms and the estrous cycle. A scheme for age-related decline in biological rhythms. Stable circadian rhythms are essential for regular estrous cycles (a). Age-related declines in circadian output of the SCN and environmental perturbations of LD cycles may be potential risk factors for irregular estrous cycles and resultant infertilities (b)


The SCN autonomously produces circadian timing in mammals and adjusts the biological clock on the basis of this timing information from environmental cycles. The SCN then acts like a control tower by outputting timing signals to the peripheral clocks responsible for various physiological functions. In other words, the SCN’s clock mechanism is important for predicting changes in the environment and taking appropriate actions at proper times. Currently, the effects of aging on the SCN are unavoidable. However, our data shows the importance of circadian output from the SCN, and an appropriate light environment, for ameliorating age-related changes to certain physiological functions [59, 60]. Although aging in mice may well differ from aging in humans, our analysis reveals a hidden vulnerability in the SCN, suggesting that the aging circadian system is more sensitive to environmental challenges than previously suspected. We speculate that this vulnerability plays a role in age-related circadian dysfunction, including reproductive system issues. If our speculations are correct, these findings re-enforce the importance of living in a temporally structured environment.



Suprachiasmatic nucleus


Subparaventricular zone




Constant dark


Circadian time


Multi-unit neural activity


  1. 1.

    Nakamura TJ, Nakamura W, Yamazaki S, Kudo T, Cutler T, Colwell CS, Block GD (2011) Age-related decline in circadian output. J Neurosci 31:10201–10205

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Kawakami F, Okamura H, Tamada Y, Maebayashi Y, Fukui K, Ibata Y (1997) Loss of day–night differences in VIP mRNA levels in the suprachiasmatic nucleus of aged rats. Neurosci Lett 222:99–102

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Wise PM, Cohen IR, Weiland NG, London ED (1988) Aging alters the circadian rhythm of glucose utilization in the suprachiasmatic nucleus. Proc Natl Acad Sci USA 85:5305–5309

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Cai A, Scarbrough K, Hinkle DA, Wise PM (1997) Fetal grafts containing suprachiasmatic nuclei restore the diurnal rhythm of CRH and POMC mRNA in aging rats. Am J Physiol 273:R1764–R1770

    CAS  PubMed  Google Scholar 

  5. 5.

    Li H, Satinoff E (1998) Fetal tissue containing the suprachiasmatic nucleus restores multiple circadian rhythms in old rats. Am J Physiol 275:R1735–R1744

    CAS  PubMed  Google Scholar 

  6. 6.

    Van Reeth O, Zhang Y, Zee PC, Turek FW (1994) Grafting fetal suprachiasmatic nuclei in the hypothalamus of old hamsters restores responsiveness of the circadian clock to a phase shifting stimulus. Brain Res 643:338–342

    Article  PubMed  Google Scholar 

  7. 7.

    Viswanathan N, Davis FC (1995) Suprachiasmatic nucleus grafts restore circadian function in aged hamsters. Brain Res 686:10–16

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Munetomo A, Hojo Y, Higo S, Kato A, Yoshida K, Shirasawa T, Shimizu T, Barron A, Kimoto T, Kawato S (2015) Aging-induced changes in sex-steroidogenic enzymes and sex-steroid receptors in the cortex, hypothalamus and cerebellum. J Physiol Sci 65:253–263

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Everett JW, Sawyer CH (1950) A 24-hour periodicity in the “LH-release apparatus” of female rats, disclosed by barbiturate sedation. Endocrinology 47:198–218

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Takasu NN, Nakamura TJ, Tokuda IT, Todo T, Block GD, Nakamura W (2015) Recovery from age-related infertility under environmental light-dark adjusted to the intrinsic circadian period. Cell Rep 12:1407–1413

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Meyer-Bernstein EL, Jetton AE, Matsumoto SI, Markuns JF, Lehman MN, Bittman EL (1999) Effects of suprachiasmatic transplants on circadian rhythms of neuroendocrine function in golden hamsters. Endocrinology 140:207–218

    CAS  PubMed  Google Scholar 

  12. 12.

    Pittendrigh C, Daan S (1976) A functional analysis of circadian pacemakers in nocturnal rodents. J Comp Physiol 106:223–252

    Article  Google Scholar 

  13. 13.

    Refinetti R (2015) Comparison of light, food, and temperature as environmental synchronizers of the circadian rhythm of activity in mice. J Physiol Sci 65:359–366

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Daan S, Pittendrigh C (1976) A Functional analysis of circadian pacemakers in nocturnal rodents. J Comp Physiol 106:253–266

    Article  Google Scholar 

  15. 15.

    Honma K, Honma S, Hiroshige T (1985) Response curve, free-running period, and activity time in circadian locomotor rhythm of rats. Jpn J Physiol 35:643–658

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Honma K, Honma S (1988) A human phase response curve for bright light pulses. Jpn J Psychiatr Neurol 42:167–168

    Google Scholar 

  17. 17.

    Minors DS, Waterhouse JM, Wirz-Justice A (1991) A human phase-response curve to light. Neurosci Lett 133:36–40

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Bliwise DL (1993) Sleep apnea and cognitive function: where do we stand now? Sleep 16:S72–S73

    CAS  PubMed  Google Scholar 

  19. 19.

    Turek FW, Penev P, Zhang Y, van Reeth O, Zee P (1995) Effects of age on the circadian system. Neurosci Biobehav Rev 19:53–58

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Van Someren EJ (2000) Circadian and sleep disturbances in the elderly. Exp Gerontol 35:1229–1237

    Article  PubMed  Google Scholar 

  21. 21.

    Pittendrigh CS, Daan S (1974) Circadian oscillations in rodents: a systematic increase of their frequency with age. Science 186:548–550

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Scarbrough K, Losee-Olson S, Wallen EP, Turek FW (1997) Aging and photoperiod affect entrainment and quantitative aspects of locomotor behavior in Syrian hamsters. Am J Physiol 272:R1219–R1225

    CAS  PubMed  Google Scholar 

  23. 23.

    Valentinuzzi VS, Scarbrough K, Takahashi JS, Turek FW (1997) Effects of aging on the circadian rhythm of wheel-running activity in C57BL/6 mice. Am J Physiol 273:R1957–R1964

    CAS  PubMed  Google Scholar 

  24. 24.

    Zhang Y, Kornhauser JM, Zee PC, Mayo KE, Takahashi JS, Turek FW (1996) Effects of aging on light-induced phase-shifting of circadian behavioral rhythms, fos expression and CREB phosphorylation in the hamster suprachiasmatic nucleus. Neuroscience 70:951–961

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Stephan FK, Zucker I (1972) Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions. Proc Natl Acad Sci USA 69:1583–1586

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Drucker-Colín R, Aguilar-Roblero R, García-Hernández F, Fernández-Cancino F, Rattoni FB (1984) Fetal suprachiasmatic nucleus transplants: diurnal rhythm recovery of lesioned rats. Brain Res 311:353–357

    Article  PubMed  Google Scholar 

  27. 27.

    Sawaki Y, Nihonmatsu I, Kawamura H (1984) Transplantation of the neonatal suprachiasmatic nuclei into rats with complete bilateral suprachiasmatic lesions. Neurosci Res 1:67–72

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Sujino M, Masumoto KH, Yamaguchi S, van der Horst GT, Okamura H, Inouye ST (2003) Suprachiasmatic nucleus grafts restore circadian behavioral rhythms of genetically arrhythmic mice. Curr Biol 13:664–668

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Ralph MR, Menaker M (1988) A mutation of the circadian system in golden hamsters. Science 241:1225–1227

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Ralph MR, Foster RG, Davis FC, Menaker M (1990) Transplanted suprachiasmatic nucleus determines circadian period. Science 247:975–978

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Silver R, LeSauter J, Tresco PA, Lehman MN (1996) A diffusible coupling signal from the transplanted suprachiasmatic nucleus controlling circadian locomotor rhythms. Nature 382:810–813

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Vogelbaum MA, Menaker M (1992) Temporal chimeras produced by hypothalamic transplants. J Neurosci 12:3619–3627

    CAS  PubMed  Google Scholar 

  33. 33.

    King DP, Zhao Y, Sangoram AM, Wilsbacher LD, Tanaka M, Antoch MP, Steeves TD, Vitaterna MH, Kornhauser JM, Lowrey PL et al (1997) Positional cloning of the mouse circadian clock gene. Cell 89:641–653

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Tei H, Okamura H, Shigeyoshi Y, Fukuhara C, Ozawa R, Hirose M, Sakaki Y (1997) Circadian oscillation of a mammalian homologue of the Drosophila period gene. Nature 389:512–516

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Welsh DK, Logothetis DE, Meister M, Reppert SM (1995) Individual neurons dissociated from rat suprachiasmatic nucleus express independently phased circadian firing rhythms. Neuron 14:697–706

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Honma S, Nakamura W, Shirakawa T, Honma K (2004) Diversity in the circadian periods of single neurons of the rat suprachiasmatic nucleus depends on nuclear structure and intrinsic period. Neurosci Lett 358:173–176

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Honma S, Shirakawa T, Nakamura W, Honma K (2000) Synaptic communication of cellular oscillations in the rat suprachiasmatic neurons. Neurosci Lett 294:113–116

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Nakamura W, Honma S, Shirakawa T, Honma K (2001) Regional pacemakers composed of multiple oscillator neurons in the rat suprachiasmatic nucleus. Eur J Neurosci 14:666–674

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Nakamura W, Honma S, Shirakawa T, Honma K (2002) Clock mutation lengthens the circadian period without damping rhythms in individual SCN neurons. Nat Neurosci 5:399–400

    CAS  PubMed  Google Scholar 

  40. 40.

    Schwartz WJ, Gross RA, Morton MT (1987) The suprachiasmatic nuclei contain a tetrodotoxin-resistant circadian pacemaker. Proc Natl Acad Sci USA 84:1694–1698

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Nakamura W, Yamazaki S, Nakamura TJ, Shirakawa T, Block GD, Takumi T (2008) In vivo monitoring of circadian timing in freely moving mice. Curr Biol 18:381–385

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Cheng MY, Bullock CM, Li C, Lee AG, Bermak JC, Belluzzi J, Weaver DR, Leslie FM, Zhou QY (2002) Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus. Nature 417:405–410

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Kramer A, Yang FC, Snodgrass P, Li X, Scammell TE, Davis FC, Weitz CJ (2001) Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling. Science 294:2511–2515

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Kraves S, Weitz CJ (2006) A role for cardiotrophin-like cytokine in the circadian control of mammalian locomotor activity. Nat Neurosci 9:212–219

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Vujovic N, Gooley JJ, Jhou TC, Saper CB (2015) Projections from the subparaventricular zone define four channels of output from the circadian timing system. J Comp Neurol 523:2714–2737

    Article  PubMed  Google Scholar 

  46. 46.

    Saper CB, Scammell TE, Lu J (2005) Hypothalamic regulation of sleep and circadian rhythms. Nature 437:1257–1263

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Lu J, Zhang YH, Chou TC, Gaus SE, Elmquist JK, Shiromani P, Saper CB (2001) Contrasting effects of ibotenate lesions of the paraventricular nucleus and subparaventricular zone on sleep-wake cycle and temperature regulation. J Neurosci 21:4864–4874

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Nakamura TJ, Nakamura W, Tokuda IT, Ishikawa T, Kudo T, Colwell CS, Block GD (2015) Age-related changes in the circadian system unmasked by constant conditions. eNeuro. doi:10.1523/ENEURO.0064-15.2015

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Tanaka M, Yamaguchi E, Takahashi M, Hashimura K, Shibata T, Nakamura W, Nakamura TJ (2012) Effects of age-related dopaminergic neuron loss in the substantia nigra on the circadian rhythms of locomotor activity in mice. Neurosci Res 74:210–215

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Butcher RL, Collins WE, Fugo NW (1974) Plasma concentration of LH, FSH, prolactin, progesterone and estradiol-17beta throughout the 4-day estrous cycle of the rat. Endocrinology 94:1704–1708

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Wollnik F, Turek FW (1988) Estrous correlated modulations of circadian and ultradian wheel-running activity rhythms in LEW/Ztm rats. Physiol Behav 43:389–396

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Yamazaki S, Numano R, Abe M, Hida A, Takahashi R, Ueda M, Block GD, Sakaki Y, Menaker M, Tei H (2000) Resetting central and peripheral circadian oscillators in transgenic rats. Science 288:682–685

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Yoo SH, Yamazaki S, Lowrey PL, Shimomura K, Ko CH, Buhr ED, Siepka SM, Hong HK, Oh WJ, Yoo OJ et al (2004) PERIOD2:LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues USA. Proc Natl Acad Sci USA 101:5339–5346

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Chappell PE, White RS, Mellon PL (2003) Circadian gene expression regulates pulsatile gonadotropin-releasing hormone (GnRH) secretory patterns in the hypothalamic GnRH-secreting GT1-7 cell line. J Neurosci 23:11202–11213

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Sellix MT, Menaker M (2010) Circadian clocks in the ovary. Trends Endocrinol Metab 21:628–636

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Nakamura TJ, Sellix MT, Kudo T, Nakao N, Yoshimura T, Ebihara S, Colwell CS, Block GD (2010) Influence of the estrous cycle on clock gene expression in reproductive tissues: effects of fluctuating ovarian steroid hormone levels. Steroids 75:203–212

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Nakamura TJ, Moriya T, Inoue S, Shimazoe T, Watanabe S, Ebihara S, Shinohara K (2005) Estrogen differentially regulates expression of Per1 and Per2 genes between central and peripheral clocks and between reproductive and nonreproductive tissues in female rats. J Neurosci Res 82:622–630

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Nakamura TJ, Sellix MT, Menaker M, Block GD (2008) Estrogen directly modulates circadian rhythms of PER2 expression in the uterus. Am J Physiol Endocrinol Metab 295:E1025–E1031

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Mishima K, Okawa M, Shimizu T, Hishikawa Y (2001) Diminished melatonin secretion in the elderly caused by insufficient environmental illumination. J Clin Endocrinol Metab 86:129–134

    CAS  PubMed  Google Scholar 

  60. 60.

    Takasu N, Nigi H, Tokura H (2002) Effects of diurnal bright/dim light intensity on circadian core temperature and activity rhythms in the Japanese macaque. Jpn J Physiol 52:573–578

    Article  PubMed  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Wataru Nakamura.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.


This work was supported by JSPS KAKENHI Grant Numbers 26462809, 26860160, 26861780. N.N.T. is a research fellow of the Japan Society for the Promotion of Science.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Nakamura, T.J., Takasu, N.N. & Nakamura, W. The suprachiasmatic nucleus: age-related decline in biological rhythms. J Physiol Sci 66, 367–374 (2016).

Download citation


  • Circadian rhythm
  • Suprachiasmatic nucleus
  • Aging
  • Estrous cycle
  • Infertility