Neuroendocrine Mechanisms of Circadian Rhythms in Diurnal Species
Summary and Keywords
Circadian rhythms are endogenous daily rhythms evident in behavior and physiology. In mammals, these rhythms are controlled by a hierarchical network of oscillators showing a coherent circadian coordination or coupling. The hypothalamic suprachiasmatic nucleus (SCN) sits on top of the hierarchy and coordinates the phase of oscillators in other brain regions and in peripheral organs, including endocrine glands. The phase of the SCN oscillator, in reference to the daily light-dark cycle, is identical across mammalian species regardless of whether they are most active during the day or night, that is, diurnal or nocturnal. However, the extra-SCN or peripheral oscillators are out of phase and are often reversed by 180° across diurnal and nocturnal mammals. In the endocrine system, with the notable exception of the pattern of pineal melatonin secretion, which features elevated levels at night regardless of the activity profile of the species, most endocrine rhythms show a 180° reversal when diurnal and nocturnal species are compared. There is also evidence of differences between nocturnal and diurnal species with respect to their rhythms in sensitivity or responsiveness to hormonal stimulation. One of the major unanswered questions in the field of comparative endocrinology relates to the mechanism responsible for the differential coupling in diurnal and nocturnal mammals of extra-SCN oscillators and overt circadian rhythms with the SCN oscillator and the light dark cycle. Viable hypotheses include species-specific switches from excitation to inhibition at key nodes between the SCN and its targets, the presence of extra-SCN signals that converge on SCN targets and reverse the outcome of SCN signals, and changes in oscillatory parameters between the oscillator of the SCN and those outside the SCN resulting in an anti-phase coupling among key oscillators.
There is nothing about our planet, or the lives of the mammals that inhabit it, that can be predicted with as much precision as the rate at which the earth spins on its axis. At every point on its surface, that spinning can produce 24-hour rhythms in ambient light and temperature, which presents animals with the challenge of surviving and reproducing in an environment that changes in striking ways from day to night and back. Evolutionary processes long ago endowed virtually all animals with an internal circadian timekeeping system that helps them anticipate and cope with those changes.
Circadian mechanisms interact with other systems to produce rhythms whose patterns and degree of plasticity vary considerably across species. There are four general patterns, nocturnal (most active at night), diurnal (most active during day), cathemeral (equally active day and night), and crepuscular (active at dawn and dusk), all of which can change significantly within an individual, to varying degrees and in different ways, from one species to another. For example, activity rhythms of many microtine rodents, such as voles, lemmings, and muskrats, can change across the year such that they are more diurnal in the winter than summer (Hoogenboom, Daan, Dallinga, & Schoenmakers, 1984). In the montane voles (Microtus montanus), that seasonal change is driven by changes in secretion of gonadal hormones (Rowsemitt, 1986). Mice, which are typically more active at night than during the day can become effectively diurnal when facing an energetic challenge, such as being forced to work for food or confronted with a decline in the ambient temperature; that energy challenge also leads to an increase in the absolute level of activity (van der Veen, Riede, Heideman, Hau, van der Vinne, & Hut, 2017; van der Vinne et al., 2014). In contrast, when diurnal red squirrels are confronted by colder temperatures, they become less active, but the phase of that activity does not change—they remain strictly diurnal (Williams et al., 2014). The factors that shaped the evolution of these species’ differences in plasticity have not been systematically explored but likely include phylogenetic history and vulnerability related to specialization of sensory systems, body size, and metabolic rates—for instance, mice, much smaller than squirrels, cannot survive as long without food. However, the evolutionary processes responsible for the more basic and fundamental temporal niche—nocturnal versus diurnal—that many species occupy have been analyzed in systematic ways.
There is considerable evidence that the first mammals evolved from their diurnal reptilian ancestors approximately 200 million years ago by passing through a “nocturnal bottleneck” and emerging with adaptations they needed to maintain a new night-active lifestyle (Crompton, Taylor, & Jagger, 1978; Walls, 1942; Wu, Yonezawa, & Kishino, 2017). The circadian timekeeping system of early mammals was almost certainly transformed at this point, such that it could now drive activity up at night and down during the day. Interestingly, recent evidence suggests that some non-mammalian synapsids were also likely to have been nocturnal approximately 100 million years ago (Angielczyk & Schmitz, 2014; Schmitz & Motani, 2011).
However, temporal niche evolution did not stop there. First, cathemeral patterns likely emerged 75 million years ago among the shrews and moles (Soricidae) and then, approximately 64 million years ago, after the dinosaurs became extinct, diurnality came back among the elephant shrews (Macroscelididae) (based on the long fuse phylogeny; Maor, Dayan, Ferguson-Gow, & Jones, 2017). Since then, it has resurfaced along numerous independent evolutionary pathways, most of which have involved a cathemeral bridge (Maor et al., 2017; Santini, Rojas, & Donatin, 2015; Wu et al., 2017). It has been estimated that today approximately 20% of mammals are diurnal (Bennie, Duffy, Inger, & Gaston, 2014).
Regardless of which evolutionary pathway led to diurnality, one of the remarkable things about its emergence is that each time it happened there had to be changes in a coordinated and far ranging suite of behavioral and physiological processes. This is clear when one considers neuroendocrine systems. The circadian influences on hormone secretion interact with a multitude of other factors to produce daily patterns that vary considerably with respect to the phase and waveform of the rhythms; the same is true if one considers rhythms in responsiveness to those hormones. Most of the patterns that emerge in circadian modulation of neuroendocrine system and vice versa are very different in day- and night-active animals.
Circadian System in Diurnal Species
The circadian system, which serves as an internal clock, produces endogenous rhythms in behavior and physiology, with a period ~24 hours, that persist in constant conditions, even without any external timing cues. Circadian oscillation has a molecular basis that has been described as interlocked transcriptional/translational feedback loops of clock genes and their protein products in various model organisms (Dunlap, 1999; King & Takahashi, 2000; Young, 1998). Although the model of a mammalian circadian clock was built initially from work in laboratory mice (King & Takahashi, 2000; Okamura, 2004; Reppert & Weaver, 2001), subsequent finding of strong associations between circadian phenotype and mutations in clock genes in humans (Toh et al., 2001; Xu et al., 2005), as well as the characterization of clock gene expression in sheep (Dardente, Fustin, & Hazlerigg, 2009) and in diurnal rodents (Dardente, Klosen, Caldelas, Pevet, & Masson-Pevet, 2002; Lambert, Machida, Smale, Nunez, & Weaver, 2005) have revealed that the transcriptional/translational mechanisms in circadian clocks are well conserved between diurnal and nocturnal mammals. This molecular machinery exists in each individual cell of almost all tissues and organs, and even in cultured cells lines (Ko & Takahashi, 2006; Mohawk, Green, & Takahashi, 2012; Schibler & Sassone-Corsi, 2002). These cellular oscillators in each tissue and organ are organized in a hierarchy to form a multi-oscillator network producing coherent circadian oscillations that are synchronized with the environmental day/night cycle and with each other (Davidson, Yamazaki, & Menaker, 2003). Thus, in both diurnal and nocturnal mammals, the hierarchical organization of the circadian oscillators ensures that each bodily event occurs at the right time of the day and under the optimal physiological condition.
In mammals, a central part of the circadian system includes three basic elements: (a) a principal brain clock located within the hypothalamic suprachiasmatic nucleus (SCN), (b) pathways that bring photic information to it from the retina and entrain its rhythms to the 24-h day, and (c) mechanisms through which the SCN emits circadian signals that influence a far-ranging suite of behavioral and physiological processes. The cellular oscillation in the SCN, extra-SCN brain regions, or peripheral tissues share the same molecular machinery discussed above to produce self-sustained circadian oscillation; however, the coherent rhythms in almost all of the other tissues depend upon the SCN (Davidson et al., 2003). Although most of what we know about how this system operates in mammals comes from a very limited set of species, primarily nocturnal ones, it is generally accepted that the SCN keeps these other oscillators synchronized with each other and with the environmental light/dark cycle, through behavioral, autonomic, and neuroendocrine mechanisms (Kalsbeek et al., 2006; Mohawk et al., 2012; Okamura, 2007).
Within the SCN, the molecular mechanisms underlying circadian rhythmicity and photic entrainment are very similar between diurnal and nocturnal species. The circadian expression patterns of the clock genes, or clock-controlled genes, as well as their protein products, have been observed in the SCN of diurnal species, including rodents, sheep, and non-human primates (Caldelas, Poirel, Sicard, Pevet, & Challet, 2003; Chakir, Dumont, Pevet, Ouarour, Challet, & Vuillez, 2015; Ikeno, Williams, Buck, Barnes, & Yan, 2017; Lambert et al., 2005; Lincoln, Messager, Andersson, & Hazlerigg, 2002; Mahoney, Ramanathan, Hagenauer, Thompson, Smale, & Lee, 2009; Mrosovsky, Edelstein, Hastings, & Maywood, 2001; Ramanathan, Nunez, Martinez, Schwartz, & Smale, 2006; Valenzuela et al., 2008). In contrast to the rest-activity cycle, the circadian expression of these genes in the SCN is in phase between diurnal and nocturnal mammals. The same has been found with electrical activity in the SCN, which peaks during daytime in both diurnal (Sato & Kawamura, 1984) and nocturnal rodents (Inouye & Kawamura, 1979, 1982; Meijer, Watanabe, Detari, & Schaap, 1996; Yamazaki, Kerbeshian, Hocker, Block, & Menaker, 1998). The photic regulation of the SCN in diurnal and nocturnal rodents also shares great similarity, in spatiotemporal pattern of light-induced expressions of clock genes per1 and per2 (Caldelas et al., 2003; Novak, Ehlen, Paul, Fukuhara, & Albers, 2006; Ramanathan, Campbell, Tomczak, Nunez, Smale, & Yan, 2009; Yan, 2009). These findings provide strong evidence that the pattern of coupling between the SCN oscillator and the LD cycle is the same in diurnal and nocturnal species. Furthermore, coupling between the core molecular clock and its output molecules—AVP, VIP and PK2—is the same in the SCN of diurnal Nile grass rats and nocturnal Norway rats (Smale, Nunez, & Schwartz, 2008). These data suggest that the control of diurnality or nocturnality lies downstream of the SCN. However, it remains possible that there are differences in coupling between the oscillator and efferent systems within the SCN that have not yet been explored, such that different signals are sent out from it in diurnal and nocturnal species.
An exception with respect to the similarities of the SCN of diurnal and nocturnal species is evident when photically responsive SCN cells are considered; specifically, the majority is suppressed by light in diurnal rodents but activated by light in nocturnal ones (Meijer et al., 1986, 1989; Jiao, Lee, & Rusak, 1999). This difference could be due to the fact that the sensitivity threshold of photic responsive neurons in the SCN of diurnal rodents is much higher, i.e., they are less sensitive to low light intensity, compared to nocturnal ones as revealed in the same studies (Meijer et al., 1986; Meijer et al., 1989; Jiao et al., 1999). Alternatively, it could reflect the different behavioral state induced by light, arousal in diurnal species and sleep in nocturnal ones, as vigilance state of the animal can affect the neuronal activity of the SCN (Deboer, Vansteensel, Detari, & Meijer, 2003). Another possibility is that, although the fundamental pattern that exists in the coupling between the SCN oscillator and the light dark cycle are the same, there may be more subtle differences in the mechanisms through which light entrains the oscillator within it.
In brain regions outside the SCN, circadian/daily rhythms have been observed in diurnal mammals. While in most regions the phase of the rhythms are inverted with respect to those of nocturnal species, there are also regions that are similarly phased and some regions that are intermediate, with phase differences of a few hours between diurnal and nocturnal rodents (Ramanathan, Nunez, & Smale, 2008a; Ramanathan, Smale, & Nunez, 2008b; Ramanathan, Stowie, Smale, & Nunez, 2010a). The rhythms in extra-SCN brain regions are regulated by outputs of the SCN, but can also be influenced by activity or feeding patterns (Ramanathan, Stowie, Smale, & Nunez, 2010b; Otalora, Hagenauer, Rol, Madrid, & Lee, 2013). Circadian patterns of clock-gene expression have also been observed in human brains, in cortical and limbic regions, with phases consistent with those of other diurnal mammals (Li et al., 2013).
Brain regions outside the SCN also show circadian rhythms in electrical activity. In nocturnal rodents, most extra-SCN regions show rhythms of electrical activity that are in antiphase to that of the SCN (Yamazaki et al., 1998; Tousson & Meissl, 2004). Much less is known about diurnal rodents. The electrical activity rhythms in extra-SCN hypothalamic regions were found in-phase with the SCN rhythms in the diurnal chipmunk (Sato & Kawamura, 1984) while the rhythmic expression of cFOS, a marker for neuronal activity, in the ventral subparaventricular zone was in a near-antiphase relationship with that in the SCN of Nile grass rats (Schwartz et al., 2004).
Peripheral clocks play important roles in regulation of circadian rhythms in the physiological function of peripheral tissues and organs (Stratmann & Schibler, 2006). In diurnal mammals, robust circadian patterns of clock-gene expression have been reported in the liver of diurnal Nile grass rats and sheep (Andersson et al., 2005; Lambert & Weaver, 2006), in the ovary of sheep (Murphy et al., 2015) and in the adrenal gland of a nonhuman primate (Lemos et al., 2006; Valenzuela et al., 2008). These rhythms of clock-gene expression are usually reversed in diurnal and nocturnal species.
Circadian Modulation of Neuroendocrine System and Neuroendocrine Feedback
The circadian system influences the daily patterning of a multitude of behavioral and physiological processes, including those regulating secretion of, and responses to, hormones (Kriegsfeld & Silver, 2006; Hastings et al., 2007). The SCN utilizes two type of output signals, namely humoral and axonal, to regulate circadian rhythms throughout the body. SCN lesion and transplant studies have demonstrated that while humoral signals from the SCN are sufficient for driving behavioral rhythms (Silver et al., 1990, 1996), rhythms in neuroendocrine systems require precise axonal connection (Nunez & Stephan, 1977; Swann & Turek, 1985; Meyer-Bernstein et al., 1999; de la Iglesia et al., 2003). Circadian modulation of a few major neuroendocrine systems and how those endocrine signals feed back to the circadian clocks will be discussed in the following text, with a focus on diurnal mammals while highlighting the differences between diurnal and nocturnal species (Figure 1).
Melatonin secretion is regulated by a multi-synaptic pathway extending from the SCN to the pineal gland (Pevet & Challet, 2011). Rhythms in the release of melatonin are unique in that their most fundamental features do not differ in nocturnal and diurnal mammals: melatonin is elevated at night but almost absent during the day in both chronotypes. The circadian influence is evident when animals are kept in constant darkness, but not when they are kept in constant light (Ganguly et al., 2002). This is because the SCN can drive melatonin secretion up during the subjective night but not the subjective day, and because light can counteract that influence at night by directly suppressing its release from the pineal gland (Schwartz et al., 2009).
Although the fundamental characteristics of the daily pattern of melatonin secretion are the same across species, there are some differences in the mechanisms regulating its production, which is governed by the rate limiting enzyme arylalkylamine N-acetyltransferase (AANAT). In some species, (e.g., nocturnal Norway rats and diurnal Sudanese grass rats), the melatonin rhythm is driven by changing patterns of AANAT gene transcriptional activation, whereas in others, (e.g., degus, primates and ungulates), posttranscriptional mechanisms are responsible for it (reviewed in (Lee et al., 2009; Maronde et al., 2011)). Interestingly, the latter species are all diurnal.
Effects of Melatonin on Circadian Time-Keeping Systems
Rhythms in melatonin secretion are driven by the circadian system but the hormone can also modify the circadian mechanisms that drive those rhythms (reviewed in (Redman, 1997)). Here, again, diurnal and nocturnal species are quite similar. Melatonin acts on receptors that are distributed in brain regions that vary across species and are found in the SCN of many, but not all, mammals (Bittman, 1993). There is no apparent relationship between melatonin binding in the SCN and the temporal niche of an animal; e.g., it is present in the SCN of humans and squirrels (diurnal) as well as hamsters (nocturnal) but not in that of sheep (diurnal) or shrews or skunks (nocturnal) (Bittman, 1993).
Effects that melatonin has on rhythms have been studied extensively in nocturnal mammals and humans but far less in other diurnal species (Redman, 1997). The modulation of the circadian systems of nocturnal rodents by melatonin has been established by studies in which free running rhythms have been entrained by administration of “pulses” of melatonin to animals at 24 hour intervals; as with light, the effect is dependent on the phase at which the melatonin is given. In addition, in nocturnal rodents maintained in an LD (light-dark) cycle, administration of melatonin one hour before lights-out causes a regular phase advance such that activity begins just prior to lights out. In some species of diurnal rodents (Sudanese grass rats and Indian palm squirrels), melatonin can also shift the phase of activity rhythms, and it does this in the same ways as in nocturnal ones—by producing significant effects during the transition points between active and inactive phases of the daily rhythm (whether animals are kept in a light-dark cycle or in constant conditions) (Challet, 2007; Rajaratnam & Redman, 1997; Slotten, Krekling, & Pevet, 2005). However, in at least one diurnal rodent, the Octadon degus, melatonin has no apparent effect on the phase of behavioral rhythms (Vivanco, Ortiz, Rol, & Madrid, 2007).
There is a substantial body of work characterizing effects of melatonin on basic circadian processes in humans. Many approaches have been taken, but perhaps the most compelling data have come from studies of people who are completely blind and unable to entrain under ordinary conditions (reviewed in Skene & Arendt, 2007)). These individuals, who exhibit free running rhythms with a period that is typically greater than 24 hours, are said to have “non-24 hour sleep/wake disorder”; light information is presumably unable to reach their SCN. However, systematic administration of melatonin at 24-hour intervals can entrain rhythms in such cases, and a rhythm in responsiveness to “pulses” of melatonin is evident. The phase response curve to these pulses is approximately 12 hours out of phase with that for light, and entrainment appears to occur via phase advances to melatonin administered during the subjective day. The circadian system of pineal-intact humans thus appears to be similar to that of other diurnal and nocturnal species with respect to its responsiveness to the administration of melatonin.
Direct Effects of Melatonin on Sleep and Arousal
An additional way in which a hormone can influence a daily rhythm is through its direct action on the parameter in question. Here, diurnal species appear to be very different from nocturnal ones. There has been considerable interest in the possibility that melatonin might promote sleep because it is secreted during the time of day at which sleep propensity is greatest (Morris et al., 2012). This issue has been explored most in humans but some work on it has also been done with diurnal non-human primates.
Acute effects of melatonin administration on activity have been seen in three species of Macaques, all diurnal (Zhdanova et al., 2002). Here, the hormone was provided orally (in a puree of fruit) two hours before lights-off, and sleep was inferred from the lack of activity picked up on actigraphic monitors. This treatment advanced sleep onset approximately 45-–65 minutes and had no effect on sleep offset; the treatment was said to have led to “no apparent changes in sleep efficiency,” but there was no real measure of that. Although the authors interpret the effect as an acute one, the possibility that it reflects an advance in a circadian clock (either a light or food entrainable one) could not be ruled out. The issue has also been examined in one macaque species by directly monitoring sleep in animals administered varying doses of melatonin or melatonin agonists just before lights off (Yukuhiro, Kimura, Nishikawa, Ohkawa, Yoshikubo, & Miyamoto, 2004). No effects of melatonin were observed, but Ramelteon, a selective MT1/MT2 melatonin receptor agonist, significantly decreased sleep latency and increased the duration of sleep each day. Although the question of whether endogenous melatonin promotes sleep directly remains an open one, these data suggest that activation of melatonin receptors does have a soporific effect on nonhuman primates.
Far more studies have addressed this issue in humans, and they provide solid evidence of such effects (Lavie, 1997; Wyatt, Dijk, Ritz-de Cecco, Ronda, & Czeisler, 2006; Zhdanova & Wurtman, 1997). Several basic protocols have been used. The first has been to administer melatonin to people at different times across a 24-hour day. These studies have revealed that, when it is given during the day, melatonin can increase sleep propensity and total sleep time (Lavie, 1997; Morris, Aeschbach, & Scheer, 2012). Furthermore, melatonin antagonists can reduce nighttime sleep, and this effect can be blocked by melatonin (Morris et al., 2012). A second approach has been to administer melatonin to people subjected to a forced desynchrony protocol, in which subjects maintain a 20-hour sleep/wakefulness routine over 24 cycles. Under this paradigm, the sleep episodes that desynchronize from the endogenous circadian rhythm could occur in either the subjective day or night, which enables investigators to determine whether the circadian time-keeping system influences acute responses to melatonin. Here too, soporific effects of the hormone are apparent when it is provided during the active period but not during the subjective night (Wyatt et al., 2006). Taken together, the evidence that melatonin can facilitate sleep directly, in a manner that changes across the circadian cycle, is quite strong in humans.
Hypothalamic-Pituitary-Adrenal (HPA) Axis
The SCN regulates circadian rhythms of the HPA axis through two distinct neural pathways. One is via projections to neurons containing the corticotrophin-releasing hormone (CRH) in the paraventricular nucleus (PVN), while the other is a multi-synaptic pathway that is part of the autonomic nervous system (Kalsbeek, van der Spek, Lei, Endert, Buijs, & Fliers,, 2012). Lesions of the SCN abolish the circadian rhythm in adrenocortical stimulating hormone (ACTH) and glucocorticoids (Cascio, Shinsako, & Dallman, 1987; Ibuka & Kawamura, 1975; Moore & Eichler, 1972; Szafarczyk, Ixart, Alonso, Malaval, Nouguier-Soule, & Assenmacher, 1983). However, the rhythms in the HPA axis are not just passively driven by the SCN, since molecular clocks exist in the pituitary (Becquet et al., 2014; Yoo et al., 2004) and the adrenal gland (Bittman, Doherty, Huang, & Paroskie, 2003; Oster, Damerow, Hut, & Eichele, 2006) in nocturnal rodents. Moreover, rhythmic clock gene expression in the adrenal gland has also been reported in non-human primates (Lemos, Downs, & Urbanski, 2006; Valenzuela et al., 2008).
In contrast to nocturnal species, in which glucocorticoids peak in early evening before lights-off, in diurnal mammals including humans and non-human primates, adrenal glucocorticoids peak in early morning before lights-on (Weitzman, Fukushima, Nogeire, Roffwarg, Gallagher, & Hellman, 1971; Cross & Rogers, 2004; Torres-Farfan et al., 2008). AVP is a major output signal released from the SCN regulating the daily rhythms in adrenal glucocorticoids (Kalsbeek, Buijs, van Heerikhuize, Arts, & van der Woude, 1992; Kalsbeek, van Heerikhuize, Wortel, & Buijs, 1996). As discussed earlier, the circadian expression of AVP, a clock-controlled gene, is in phase between diurnal and nocturnal mammals, which has made the nature of the underlying mechanisms, responsible for the opposite phase in adrenal glucocorticoid rhythms between the two chronotypes, an intriguing question. Recent work in the diurnal Sudanese grass rat (A. ansorgei) has shown that AVP, which normally comes from the SCN, infused into the PVN promotes the release of adrenal glucocorticoids, while the opposite is the case in nocturnal rats (Kalsbeek et al., 2008). A species difference in the local circuit of the PVN involving either glutamatergic or GABAergic neurons is one possible mechanism for a switch from a diurnal to a nocturnal pattern in the daily rhythm of glucocorticoid secretion (Kalsbeek et al., 2008).
Glucocorticoids, through their widely distributed receptors, are capable of resetting the phase of extra-SCN brain clocks and synchronizing peripheral clocks (Balsalobre et al., 2000; Le Minh, Damiola, Tronche, Schutz, & Schibler, 2001). Thus, the rhythmic secretion of glucocorticoids is an important output signal that conveys timing information to brain and peripheral extra-SCN oscillators (Leliavski, Dumbell, Ott, & Oster, 2015). The chronotype-specific rhythm in glucocorticoids secretion likely contributes to the reversed rhythms in peripheral organs and their physiological functions in diurnal and nocturnal mammals.
Hypothalamic-Pituitary-Gonadal (HPG) Axis
GnRH and LH
Female reproductive function is coordinated by the HPG axis, which is under circadian regulation (Miller & Takahashi, 2013). In women, shift work, a major disruptor of circadian rhythms, has been associated with menstrual disruption, increased infertility, and early miscarriage (Stocker, Macklon, Cheong, & Bewley, 2014). Female mice carrying a mutation that disturbs clock function often show subfertility or infertility (Miller & Takahashi, 2013). The mechanisms underlying circadian regulation of female reproductive function have been extensively studied in nocturnal rodents, revealing a critical role of both the SCN and extra-SCN clocks along the HPG axis (Sen & Sellix, 2016; Yan & Silver, 2016). In nocturnal species, the SCN projects directly and indirectly to the neuroendocrine cells containing gonadotropic releasing hormone (GnRH) in the hypothalamus, which controls the timing of the ovulatory surge in luteinizing hormone (LH) (Horvath, Cela, & van der Beek, 1998; Kriegsfeld, Silver, Gore, & Crews, 2002; Van der Beek, Horvath, Wiegant, Van den Hurk, & Buijs, 1997). In diurnal Nile grass rats, in which the SCN also contacts GnRH cells directly, the pre-ovulatory peak of neural activity in these cells and the LH surge are in antiphase to those of nocturnal lab rats; they occur in the early subjective day corresponding to the timing of ovulation and display of sexual behavior in this diurnal species (Mahoney et al., 2004; Mahoney & Smale, 2005; McElhinny et al., 1997).
Testosterone and Estradiol
Although the functional significance of cellular clocks along the HPG axis requires further investigation, recent work using conditioned deletion of clock genes in mice revealed that the ovarian clock contributes to the timing of ovulation through controlling the phasic sensitivity of the ovary to gonadotrophins (Sen & Sellix, 2016). In diurnal mammals, the presence of a molecular clock in the ovary has been reported in sheep, and it is likely involved in regulating rhythms in steroidogenesis (Murphy, Blake, Brown, Martin, Forde, Sweeney, & Evans, 2015). In contrast to the accumulating evidence of ovarian clocks, there is no clear evidence of a testicular clock. In diurnal Nile grass rats, clock-gene expression in the testis has been found to be arrhythmic, consistent with findings in nocturnal mice and rats (Lambert et al., 2005). For the reproductive success in male rodents, a steady, rather than cyclic, supply of sperm may provide conditions that allow them to take advantage of any opportunity to reproduce.
In both males and females, gonadal hormones play an important role in modulating the circadian system, thus resulting in sex differences and fine-tuning of time-keeping functions (Yan & Silver, 2016). Both androgen and estrogen receptors (ARs and ERs, respectively) are expressed in the SCN. The expression of ARs depends upon circulating androgen levels, thus it is predominant in the SCN of males. Expression of nuclear ERα is stronger in the SCN of women, but there is no significant sexual dimorphism in nuclear ERß or progesterone receptor abundance in humans (Kruijver & Swaab, 2002).
In rodents, the most clear sex difference in daily rhythms involves systematic changes in the time of the daily onset of activity that are closely associated with the phase of the estrous cycle (Krizo & Mintz, 2015). These patterns suggest that ovarian hormones play a role in modulating the phase of circadian rhythms. In female degus, the daily onset of locomotor activity advances approximately two hours on the day of estrus, followed by a delay on the day of metestrus (Labyak & Lee, 1995); and the sex differences in the period of circadian rhythms develop through puberty (Hummer, Jechura, Mahoney, & Lee, 2007; Lee, Hummer, Jechura, & Mahoney, 2004). In female diurnal Nile grass rats, who are induced cyclers (McElhinny, Sisk, Holekamp, & Smale, 1999), the typical scalloping in their daily activity is not evident in singly housed animals and only emerges when co-housed with a male (Castillo-Ruiz, Indic, & Schwartz, 2018). However, the drastic changes in the levels of ovarian hormones during pregnancy and lactation have no significant effects on the phase of the daily rhythms of Nile grass rats (Schrader, Walaszczyk, & Smale, 2009).
In humans, the best documented sex differences in circadian rhythms lie in the sleep phase or chronotype—morningness or eveningness (Roenneberg et al., 2004, 2007). During adulthood, women tend to have earlier sleep phase compared to men, which is consistent with the shorter circadian period observed in women (Cain et al., 2010; Duffy et al., 2011).
Leptin, Ghrelin, and Insulin
Leptin is a peptide produced by the white adipose tissue that serves as a satiety signal via its inhibitory actions on hypothalamic neuropeptide Y (NPY) circuits (Kalra, Bagnasco, Otukonyong, Dube, & Kalra, 2003). In laboratory rats, a rhythm in circulating levels of leptin displays elevated levels during the early night with the lowest levels found during the day (Kalsbeek et al., 2001). In sharp contrast, diurnal Sudanese grass rats (A. ansorgei) show peak levels of plasma leptin during the day with low levels at night (Cuesta, Clesse, Pevet, & Challet, 2009). It is not clear if the rhythm is secondary to the postprandial increase in leptin or independent of the stimulatory effects of feeding on leptin release (Bodosi, Gardi, Hajdu, Szentirmai, Obal, & Krueger, 2004). The data are less clear for other diurnal non-human species, like sheep (Marie, Findlay, Thomas, & Adam, 2001), in which frequency of meals may obscure a low amplitude rhythm. Perhaps surprisingly, when leptin rhythms are detected in humans, the pattern shows increased levels during the night (Shea, Hilton, Orlova, Ayers, & Mantzoros, 2005) and may be secondary to the display of sleep (Simon, Gronfier, Schlienger, & Brandenberger, 1998). The anorectic effects of leptin may contribute to sustaining human sleep through nocturnal fasting. In summary, species differences in the rhythmic release of leptin by white adipose tissue may depend more upon differences in patterns of sleep and feeding than upon temporal niche.
Ghrelin is a prominent gut peptide, which is produced by the oxyntic gland of the stomach and has effects opposite to those of leptin on NPY neurons, food intake, and body weight (Kalra et al., 2003). Ghrelin production increases during fasting and in anticipation of regularly scheduled meals in humans (Cummings, Purnell, Frayo, Schmidova, Wisse, & Weigle, 2001) and laboratory rodents (LeSauter, Hoque, Weintraub, Pfaff, & Silver, 2009). In addition to pre-prandial peaks, ghrelin shows a daily rhythm in nocturnal rodents with low values during the rest phase (LeSauter et al., 2009); there are no data available from diurnal rodents. In humans, baseline ghrelin levels show a daily rhythm with a pattern that matches that of circulating leptin, with high levels at night, decreasing to a nadir just before the first scheduled meal of the day (Cummings et al., 2001). Thus, a comparison of nocturnal rodents and humans fails to match the expectation of a reversal in the phase of the ghrelin rhythm across the two chronotypes. In humans, ghrelin during sleep may serve to partially counteract the anorectic effects of leptin during the nocturnal fast.
Plasma pancreatic insulin shows a low amplitude daily rhythm in nocturnal rodents (Challet, 2015) and humans (Cummings et al., 2001; Shea et al., 2005) with acute postprandial peaks. In rodents, the insulin rhythm is not always detected (Cuesta et al., 2009); and for humans, its detection often requires imposing a constant routine (CR) protocol, which involves maintaining constant wakefulness and minimal mobility, with rigorous control of caloric intake (Morris et al., 2012). Using a CR protocol with humans, Shea et al., 2005 reported a peak at the habitual awakening time of the subjects. Insulin levels rise at the beginning of the night in nocturnal rodents (Challet, 2015), the reverse of the case for humans. In addition to insulin, circadian regulation of the liver also contributes to daily rhythms in glucose levels. In diurnal A. ansorgei (Cuesta et al., 2009), blood glucose peaks at the beginning of the day as reported for humans (Shea et al., 2005).
Summary and Conclusion
Since the time that nocturnal mammals first evolved from their reptilian ancestors, diurnality has resurfaced numerous times over the course of mammalian evolution. Neuroendocrine mechanisms regulating hormone secretions and responses to those hormones changed in fundamental ways as diurnality emerged. For all mammals, the principal circadian oscillator is in the SCN, and its molecular oscillatory core is remarkably similar across species that are otherwise very different with respect to the phase of circadian rhythms in reference to the day-night cycle. In addition to the principal SCN oscillator, there are extra-SCN oscillators in the brain and peripheral organs, the phase of which influences the temporal phenotype of the species. Multiple factors, such as ambient light, temperature, and food availability interact with the circadian system to determine the expression (e.g., phase, wave form, amplitude) of circadian rhythms in behavior and physiology including hormone secretion.
In contrast to what is seen with other neuroendocrine systems, the neural control of the pineal and the nocturnal secretion of its hormone, melatonin, is fundamentally the same in diurnal and nocturnal mammals. However, the effects of melatonin on circadian organization, particularly the display of sleep, vary considerably across species. Endocrine rhythms that involve the HPA and HPG axes as a rule show a phase reversal when diurnal and nocturnal species are compared. This is also the case in both of these systems when oscillators within the endocrine organ, such as the gonad (ovary) and the adrenal gland, are considered, which could account for the patterns of hormone secretion seen in the diurnal species. In part, the pattern of secretion of metabolic hormones that affect feeding and energy balance is influenced by the temporal phenotype of the species, but in this case factors such as sleep and meal patterns often play dominant roles over the influence of circadian rhythms entrained to the day-night cycle.
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