Iterative Metaplasticity Across Timescales: How Circadian,Ultradian,and Infradian Rhythms Modulate Memory Mechanisms

Abstract

Work in recent years has provided strong evidence for the modulation of memory function and neuroplasticity mechanisms across circadian (daily), ultradian (shorter-than-daily), and infradian (longer-than-daily) timescales. Despite rapid progress, however, the field has yet to adopt a general framework to describe the overarching role of biological rhythms in memory. To this end, Iyer and colleagues introduced the term iterative metaplasticity, which they define as the “gating of receptivity to subsequent signals that repeats on a cyclic timebase.” The central concept is that the cyclic regulation of molecules involved in neuroplasticity may produce cycles in neuroplastic capacity—that is, the ability of neural cells to undergo activity-dependent change. Although Iyer and colleagues focus on the circadian timescale, we think their framework may be useful for understanding how biological rhythms influence memory more broadly. In this review, we provide examples and terminology to explain how the idea of iterative metaplasticity can be readily applied across circadian, ultradian, and infradian timescales. We suggest that iterative metaplasticity may not only support the temporal niching of neuroplasticity processes but also serve an essential role in the maintenance of memory function.

Keywords

iterative metaplasticity circadian rhythms ultradian rhythms infradian rhythms neuroplasticity neuroplastic capacity

Iterative Metaplasticity

Biological rhythms pervasively modulate memory function. Discourse in this domain tends to revolve around the circadian (daily) regulation of behavior and neuroplasticity (Krishnan and Lyons, 2015; Rawashdeh et al., 2018; Hartsock and Spencer, 2020). However, a growing body of work suggests that memory function is cyclically modulated also on ultradian (shorter-than-daily) and infradian (longer-than-daily) timescales. Studies across these 3 timescales are now beginning to converge, creating a need for language that can capture the complex phenomena they reveal.

Research in the memory field suggests that basal neural features may dictate neuroplastic capacity—that is, the ability of neural cells to undergo activity-dependent change. For instance, the basal excitability of the postsynaptic neuronal membrane determines the degree to which stimulation will induce postsynaptic neuroplasticity (Dong et al., 2006; Han, 2006; Zhou et al., 2009). Neuroplastic capacity can change over time, and this process is called metaplasticity (Abraham and Bear, 1996). In the context of circadian rhythms, circadian fluctuations in basal neural features may underlie circadian rhythms in neuroplastic capacity. We and others have described the circadian modulation of neuroplastic capacity as circadian metaplasticity (Gerstner and Yin, 2010; Gerstner, 2012; Hartsock and Spencer, 2020).

When we recently reviewed mechanisms of circadian metaplasticity (Hartsock and Spencer, 2020), we were unaware of another publication describing a related principle, iterative metaplasticity (Iyer et al., 2014). The authors define iterative metaplasticity as the “gating of receptivity to subsequent signals that repeats on a cyclic timebase.” In other words, iterative metaplasticity is the same as circadian metaplasticity but is not limited to the circadian timescale. Iyer and colleagues, however, provide examples drawn exclusively from the circadian literature. Here, we propose that iterative metaplasticity might be used as an umbrella term to encompass circadian, ultradian, and infradian forms. The literature we review spans a wide range of the phylogenetic scale, including studies from flies, crabs, birds, rodents, and humans. This body of work suggests that iterative metaplasticity across timescales may coordinate the adaptive timing of neuroplasticity processes and play a key role in the maintenance of optimal memory function.

Iterative Metaplasticity On A Daily Timescale: Circadian Metaplasticity

Circadian metaplasticity is a form of iterative metaplasticity that repeats on a daily timescale (Figure 1, middle panel). Circadian rhythms are generated and maintained endogenously by molecular clocks located in cells throughout the body (Reppert and Weaver, 2002). As first described in Drosophila (Bargiello et al., 1984; Zehring et al., 1984; Vosshall et al., 1994; Allada et al., 1998; Darlington, 1998; Price et al., 1998; Young and Kay, 2001) and subsequently found in many different vertebrate species, molecular clocks arise from daily transcriptional-translational feedback loops involving the 24-h oscillatory expression patterns of clock genes. The mammalian core clock genes include brain and muscle ARNT-like protein-1 (Bmal1), circadian locomotor output cycles kaput (Clock), period (Per1/2/3), and cryptochrome (Cry1/2) (Reppert and Weaver, 2002). Another clock gene, neuronal PAS domain protein 2 (Npas2), can replace Clock in certain circumstances (Reick, 2001; DeBruyne et al., 2006). Notably, many non-mammalian organisms exhibit a comparable molecular clock mechanism but with variations in the genetically encoded molecular players (Young and Kay, 2001). The existence of molecular clocks even in evolutionarily more ancient organisms, such as cyanobacteria (Swan et al., 2018), points to the phylogenetic conservation of molecular clocks and their importance for basic biological functions (Bhadra et al., 2017).

Figure 1.

Sources of iterative metaplasticity across timescales. Iterations in neuroplastic capacity may occur on ultradian (hourglass), circadian (solar cycle), and infradian (calendar) timescales. On each timescale, iterations generated by endogenous cyclic signals must be distinguished from iterations generated by environmental cyclic signals. Abbreviation: SCN = suprachiasmatic nucleus.

Although mammalian molecular clocks are expressed in cells throughout the body, they are organized into a hierarchy. At the top of this hierarchy sits the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN receives direct input from intrinsically photosensitive retinal ganglion cells, which support the time-of-day-dependent induction of Per1 and Per2 gene expression in SCN cells in response to ambient light exposure (Reppert and Weaver, 2001; Hattar, 2002; Güler et al., 2008). Thus, molecular clocks in the SCN are able to align their oscillations to the solar cycle (Colwell, 2011). Complex interactions among SCN neurons and astrocytes generate tissue-level synchrony of circadian rhythms in SCN firing rates (Green and Gillette, 1982; Herzog et al., 1998; Albus et al., 2002; Kudo et al., 2015), which convey solar timing information to nearby brain regions (Abrahamson and Moore, 2001). In turn, these downstream sites control a variety of signals—including hormones, body temperature, and neuronal firing—that relay solar timing information to molecular clocks local to other tissues (Koronowski and Sassone-Corsi, 2021). By synchronizing to these SCN-orchestrated signals, molecular clocks in tissues outside the SCN can coordinate their rhythms to the rhythm of the SCN master pacemaker.

The original reviews suggesting that circadian rhythms in neuroplasticity represent a form of metaplasticity focus on similarities between the SCN and hippocampus (Gerstner and Yin, 2010; Gerstner, 2012; Iyer et al., 2014). For example, daily solar resetting of molecular clocks in the SCN depends on key intracellular signals, particularly the cAMP-MAPK-CREB cascade (Ginty et al., 1993; Obrietan et al., 1998; Tischkau et al., 2003), that also mediate neuroplasticity in the hippocampus (Frey et al., 1993; Impey et al., 1998; Thomas and Huganir, 2004). In addition, the capacity of neurons to undergo long-term potentiation, an electrophysiological phenomenon important for many forms of activity-dependent neuroplasticity, is modulated in a time-of-day-dependent fashion in both the SCN (Nishikawa et al., 1995) and hippocampus (Harris and Teyler, 1983; Dana and Martinez, 1984; Raghavan et al., 1999). Thus, the circadian modulation of basal neural features underlies circadian solar entrainment in the SCN and the circadian modulation of activity-dependent neuroplasticity in the hippocampus.

In the hippocampus and other regions outside the SCN, circadian oscillations in neuroplastic capacity can arise from 3 main sources: molecular clocks, SCN-orchestrated intercellular signals, and circadian-regulated processes that influence neuroplasticity. Molecular clocks act largely through the control of gene transcription. The BMAL1:CLOCK/NPAS2 heterodimer acts as a transcription factor at E-box response elements that are associated with the promoter regions of not only some other core clock genes (Per and Cry) but also many non-clock genes (R. Zhang et al., 2014; Mure et al., 2018). Work in Drosophila suggests that the molecular clock belies rhythmic expression of many neuroplasticity-related transcripts (Figure 2, middle panel) (Claridge-Chang et al., 2001; Cirelli et al., 2004), including NCA localization factor 1 (Nlf-1), which controls the membrane localization of leak channels and basal membrane excitability in neurons (Flourakis et al., 2015). In the rodent ventral tegmental area, the dopamine synthetic enzyme tyrosine hydroxylase, whose promoter contains an E-box, exhibits greater expression during the active phase than the inactive phase even in constant darkness, pointing to a mechanism for the circadian regulation of dopaminergic neuromodulation (Chung et al., 2014; Logan et al., 2019). Similarly, the dopamine degradative enzyme monoamine oxidase A has an E-box in its promoter that binds BMAL1:NPAS2 and modulates nucleus accumbens dopamine concentrations in a time-of-day-dependent manner (Hampp et al., 2008). Many studies have shown that interactions between the molecular clock machinery and histone-modifying enzymes may also contribute to circadian rhythms in gene expression and memory-related behavior (Nakahata et al., 2008; Michan et al., 2010; Chung et al., 2014; Perreau-Lenz et al., 2017; Kwapis et al., 2018). Through transcriptional control, molecular clocks in the brain can generate rhythms in the availability of transcripts important for activity-dependent plasticity.

Figure 2.

Examples of iterative metaplasticity across timescales. On the ultradian timescale, work in mouse hippocampal neurons suggests glucocorticoid-dependent oscillations in AMPA receptor membrane localization that create oscillations in the capacity for long-term potentiation (Sarabdjitsingh et al., 2014). On the circadian timescale, studies of Drosophila demonstrate clock-regulated rhythms in the transcription of plasticity-related genes (Claridge-Chang et al., 2001; Cirelli et al., 2004). On the infradian timescale, canary research illustrates seasonal differences in the formation of perineuronal nets, which stabilize synapses (Cornez, Collignon, et al., 2020). Across timescale and organism, iterations in such basal neural features generate iterations in the capacity for activity-dependent plasticity and memory. Abbreviations: BMAL1 = brain and muscle ARNT-like protein-1; CLOCK = circadian locomotor output cycles kaput; PER = period; CRY = cryptochrome; CYC = cycle; TIM = timeless

Molecular clocks can also influence neuroplastic capacity through non-transcriptional means. For instance, the molecular clock protein PER1 acts as a nuclear chaperone for ribosomal s6 kinase (RSK) in the mouse hippocampus, modulating long-term potentiation and hippocampus-dependent memory (Rawashdeh et al., 2014; Rawashdeh et al., 2016). In addition, CRY proteins can bind directly to G_s proteins, and this binding appears to be a mechanism by which the presence of CRY proteins in the mouse nucleus accumbens regulates susceptibility to stress-induced impairments in escape learning (Porcu et al., 2020). Moreover, the quantity of many transcripts oscillates in synapses but not the cell cytoplasm, suggesting that the molecular clock influences transcript trafficking from the nucleus to the synapse (Noya et al., 2019). These findings are just a few among now abundant examples of how the direct regulation of neuroplasticity mechanisms by molecular clocks contributes to circadian metaplasticity (Krishnan and Lyons, 2015; Rawashdeh et al., 2018; Hartsock and Spencer, 2020).

SCN-orchestrated intercellular signals serve primarily to coordinate extra-SCN molecular clocks, but these signals can also generate circadian metaplasticity through direct actions on neuroplasticity processes. For instance, the secretion of glucocorticoid hormones (e.g. cortisol in humans, corticosterone in rodents) exhibits a circadian rhythm that is SCN-dependent (Moore and Eichler, 1972). Although glucocorticoids are believed to play an important role in circadian entrainment of extra-SCN molecular clocks in mammals (Oster et al., 2017; Spencer et al., 2018), they can also exert direct effects on mechanisms of neuroplasticity. Accordingly, the circadian peak in corticosterone secretion has been shown to enhance learning-induced spine formation in the murine motor cortex (Liston et al., 2013). In that study, corticosterone injection immediately after training was sufficient to increase spine formation at both the circadian peak and trough of endogenous glucocorticoid release, suggesting that the effect was mediated directly by glucocorticoids rather than through glucocorticoid entrainment of cortical molecular clocks. In addition, constant high corticosterone was disruptive to new spine formation, pointing to a need for circadian peaks and troughs in corticosterone secretion for optimal spine turnover. Furthermore, corticosterone injection enhanced new spine formation only when learning occurred, indicating that glucocorticoids did not directly alter spines but rather the capacity for learning to do so. Taken together, these findings suggest that circadian rhythms in glucocorticoid release can generate circadian rhythms in neuroplastic capacity.

Sleep is a clear example of how circadian-regulated processes can influence neuroplastic capacity. The timing of sleep is organized in part by the circadian system (Borbély et al., 2016), but sleep and the circadian system have discriminable effects on the regulation of neuroplasticity. For instance, circadian rhythms in messenger RNA (mRNA) abundance have been identified for 67% of synaptic mRNAs (Noya et al., 2019). Of those mRNAs, 93% exhibit circadian oscillation only in synaptic elements. Although 75% of the proteins associated with cycling transcripts are also rhythmic, sleep deprivation can eliminate oscillations in protein abundance. These data suggest that sleep may regulate the translation of synaptic mRNAs into proteins (Noya et al., 2019). Hence, circadian rhythms in sleep timing can contribute to circadian rhythms in neuroplastic capacity through sleep-dependent mechanisms.

Collectively, such findings illustrate multiple and likely interacting mechanisms by which the endogenous circadian system can produce circadian metaplasticity. In some cases, however, daily rhythms in neuroplastic capacity may emerge also in response to daily environmental signals independent of the circadian system. Such daily rhythms are described as diurnal rhythms to distinguish them from endogenously generated circadian rhythms. Retinal ganglion cells, including those carrying solar entrainment information to the SCN, also project to many other brain areas (Hattar et al., 2006; LeGates et al., 2014). In turn, significantly shortened light cycles impair hippocampal long-term potentiation and hippocampus-dependent memory without disrupting SCN clock gene expression (LeGates et al., 2012; Fernandez et al., 2018). The most straightforward explanation is that periodic light exposure can generate time-of-day differences in neuroplasticity processes not only through its effects on the circadian system but also through non-circadian modulatory influences (LeGates et al., 2014). Continued studies of metaplasticity on the daily timescale must identify whether iterations are generated through endogenous versus environmental cyclic signals.

Iterative Metaplasticity On A Shorter-Than-Daily Timescale: Ultradian Metaplasticity

Ultradian metaplasticity is a form of iterative metaplasticity repeating on a timescale shorter than 1 day (Figure 1, upper panel). In many mammals, basal glucocorticoid secretion exhibits not only a circadian rhythm but also a superimposed ultradian oscillation with a period of approximately 60 min (Lightman and Conway-Campbell, 2010; Spencer and Deak, 2017). The ultradian oscillation results primarily from glucocorticoid-mediated negative feedback on adrenocorticotrophic hormone release in the anterior pituitary gland (J. J. Walker et al., 2010). Pulsatile glucocorticoid administration is sufficient to generate pulsatile gene expression in the rat hippocampus (Conway-Campbell et al., 2010). In mouse hippocampal neurons, consecutive pulses of glucocorticoid have been shown to generate a decrease and rebound in the capacity for long-term potentiation, an effect that appears to depend on the trafficking of glutamatergic AMPA receptors in and out of the postsynaptic membrane (Sarabdjitsingh et al., 2014). This latter finding suggests that consecutive hourly pulses of glucocorticoid may toggle neurons back and forth between states of increased and decreased neuroplastic capacity (Figure 2, upper panel). Ultradian pulses in glucocorticoid secretion have been hypothesized to keep the glucocorticoid system dynamically engaged throughout the day (Lightman and Conway-Campbell, 2010). If true, downstream effects on neuroplasticity may represent either an incidental consequence or, conceivably, a mechanism serving the parallel function of maintaining neuroplastic capacity.

Ultradian rhythms in the activity of ventral tegmental area dopamine neurons may represent another mechanism of ultradian metaplasticity. Dopamine projections from the ventral tegmental area to the limbic forebrain play a key role in the neuroplasticity processes underlying motivated behavior (Baik, 2013; Morales and Margolis, 2017). For instance, dopamine receptor activation can modulate the activity of multiple intracellular cascades involved in neuroplasticity, including extracellular signal–regulated kinase (ERK) (Choi et al., 1999; Chen et al., 2004), protein kinase A (PKA) (Bateup et al., 2008), and calcium/calmodulin-dependent protein kinase II (CaMKII) (Anderson et al., 2008). In the mouse striatum, which receives strong innervation from the ventral tegmental area, extracellular dopamine concentrations fluctuate with a period of approximately 4 h (Blum et al., 2014). These ultradian dopamine rhythms correspond with ultradian rhythms in locomotion, which are disrupted by manipulations of dopamine (Blum et al., 2014). Ultradian rhythms in dopamine release have not yet been connected to ultradian rhythms in neuroplasticity, but the ability of dopamine to modulate numerous neuroplasticity processes suggests that dopamine is likely to mediate ultradian rhythms in neuroplastic capacity, especially for motivated behavior.

Circatidal (approximately one tidal cycle) rhythms, which exhibit a period of approximately 12.4 h, may represent another set of mechanisms for ultradian metaplasticity. Circatidal rhythms have been observed in multiple aquatic species, including crabs (Reid and Naylor, 1990), hooded shrimp (Akiyama, 2004), mussels (Zaldibar et al., 2004), leeches (L. Zhang et al., 2013), and mangrove crickets (Takekata et al., 2012; Satoh and Terai, 2019). To our knowledge, no studies to date have directly examined circatidal contributions to ultradian metaplasticity. One investigation, however, has demonstrated that transcripts relevant for cellular metabolism and endoplasmic reticulum function exhibit circatidal expression rhythms in the mangrove cricket head (Satoh and Terai, 2019), indicating the potential for circatidal influences on molecular processes supporting neuroplasticity. Circatidal rhythms in the expression of genes relevant for neuroplasticity have also been shown in the central nervous system of the horseshoe crab (Simpson et al., 2017). In addition, parallel and in some cases overlapping mechanisms appear to mediate circadian and circatidal rhythms (L. Zhang et al., 2013; O’Neill et al., 2015; Tran et al., 2020), suggesting that certain molecular processes underlying circadian metaplasticity may support circatidal rhythms in aquatic organisms. For these reasons, we expect that the characterization of circatidal contributions to ultradian metaplasticity will prove fruitful in future investigations.

Metaplasticity on the ultradian timescale may be generated also by periodic environmental signals. For instance, metabolic signals induced after food intake may regulate neuroplasticity processes (Mandal et al., 2018). Ghrelin, for example, is a gastrointestinal peptide regulated by food intake. Ghrelin can cross the blood-brain barrier and enhance inhibitory avoidance memory retention in a dose-dependent manner (Carlini et al., 2004; Rhea et al., 2018). Similarly, glucagon-like peptide-1 (GLP-1) is released after feeding, crosses the blood-brain barrier, and improves passive avoidance learning (During et al., 2003; Marathe et al., 2013). Thus, ultradian rhythms in food availability (e.g., breakfast-lunch-dinner schedules on a college campus) may be sufficient to generate rhythms in neuroplastic capacity. When periodic environmental signals give rise to oscillations in neuroplastic capacity, the oscillations themselves may or may not serve an important purpose in overall organism function. Such oscillations could simply reflect the ability of an organism to modulate neuroplastic capacity as environmental events demand. In any event, as for circadian metaplasticity, future studies on ultradian metaplasticity will need to discriminate whether oscillations are generated by endogenous versus environmental signals.

Iterative Metaplasticity On A Longer-Than-Daily Timescale: Infradian Metaplasticity

Infradian metaplasticity is a form of iterative metaplasticity repeating on a longer-than-daily timescale (Figure 1, lower panel). Circalunar (approximately one lunar cycle) rhythms, including moon-phase-dependent fluctuations in sleep quality (Casiraghi et al., 2021) and the human ovulatory cycle (Helfrich-Förster et al., 2021), may contribute to infradian metaplasticity. We have already discussed an example of how sleep may directly influence neuroplastic capacity (Noya et al., 2019). It follows that circalunar rhythms in sleep quality could potentially generate circalunar rhythms in neuroplastic capacity, but we have no knowledge of studies that have explicitly demonstrated this link.

In contrast, effects of the ovulatory cycle on neuroplasticity have been well documented. In rodents, which exhibit a 4-to-5-day ovulatory cycle similar in many respects to the human ovulatory cycle (Becker et al., 2005), ovarian steroid hormones directly influence processes such as neuromodulatory neurotransmission (Barth et al., 2015), cytoskeletal remodeling (Parducz et al., 2006; Hansberg-Pastor et al., 2015), and transcriptional regulation (Marino et al., 2006). Moreover, this hormonal modulation of neuroplasticity results in a fluctuation in hippocampal CA1 dendritic spine density throughout the ovulatory cycle (Woolley et al., 1990). In humans, performance in implicit memory tasks exhibits a fluctuation across the ovulatory cycle in a task- and estrogen-dependent manner (Maki et al., 2002). Similarly, declarative and motor memory consolidation have been shown to correlate with levels of estrogen and progesterone, respectively (Genzel et al., 2012). These data suggest a steroid-dependent fluctuation in basal neural physiology that sets the stage for circalunar rhythms in activity-dependent plasticity.

Circannual (approximately 1 year) rhythms are also likely to support infradian cycles in neuroplastic capacity. Circannual variations in songbird song learning have received a great deal of attention. For instance, brain nuclei important for song learning grow in volume during breeding season in a variety of species (Tramontin and Brenowitz, 2000; Van Meir et al., 2006; Surbhi et al., 2016), owing in part to neurogenesis (Nottebohm, 1989). In addition, the maintenance of new neural cells is enhanced at the beginning of the breeding season (Larson et al., 2019). In adult male canaries, seasonal elevations in song production have also been shown to correlate with increases in the formation of perineuronal nets, which stabilize synapses (Figure 2, lower panel) (Cornez, Collignon, et al., 2020). Some of these changes depend on testosterone (Nottebohm, 1980), the release of which fluctuates in a seasonal fashion in songbirds (Marler et al., 1988; Schlinger and Brenowitz, 2002). In captive female starlings, the volume of song control nuclei and the rate of song learning are elevated after testosterone implantation and return to baseline after implant removal (Orije et al., 2020). Testosterone also augments perineuronal net formation and song production in male canaries (Cornez, Shevchouk, et al., 2020). Together, these studies point to numerous mechanisms underlying circannual modulation of neuroplastic capacity in avian species.

In mammals, provocative evidence suggests effects of photoperiod on neurotransmission. In the mouse SCN, where gamma-aminobutyric acid (GABA) can exert both inhibitory and excitatory effects (Choi et al., 1999; De Jeu and Pennartz, 2002; Irwin and Allen, 2009), the ratio of inhibitory to excitatory GABAergic synapses increases with short photoperiods and decreases with long photoperiods (Farajnia et al., 2014). In rats, in hypothalamic regions outside the SCN, some neurons can even switch between dopamine and somatostatin expression based on the length of the photoperiod (Dulcis et al., 2013). One report in hamsters has shown that differences in day length produce differences in SCN spine density (Mendoza-Viveros et al., 2017). Similarly, a report in mice has shown that long days enhance novel and spatial object recognition (Dellapolla et al., 2017). Another study illustrates that short photoperiods disrupt hippocampal spine density and spatial memory in mice (Pyter et al., 2005). These findings suggest several mechanisms of metaplasticity on the infradian timescale in mammals.

Endogenous pathways supporting circannual timing are not yet well understood. In mammals, individual SCN neurons tend to increase their spontaneous firing activity for only a few hours each day (Schaap et al., 2003; Brown et al., 2006). In nocturnal and diurnal species alike, SCN neurons tend to be active during the daytime, but individual SCN neurons exhibit different phases in their peak firing (VanderLeest et al., 2007). During short photoperiods, as in winter, the phases of peak firing tend to be closely aligned; the opposite is true during long photoperiods. Consequently, short days give way to a short window of spontaneous SCN activity at the tissue level, and long days give way to a long window (VanderLeest et al., 2007; Coomans et al., 2015). The SCN is therefore well positioned to coordinate circannual timing information for the rest of the body. Pineal melatonin may represent one important signaling molecule used by the SCN for this purpose. The release of melatonin is controlled by a well-characterized polysynaptic relay from the SCN to the pineal gland (Larsen et al., 1998; Møller and Baeres, 2002; Coomans et al., 2015). In optimal conditions, melatonin is secreted for the duration of the daily dark period (Turek and Gillette, 2004). A melatonin sensor in the pituitary gland modulates the neuroendocrine output of the hypothalamus in a manner dependent on the length of the photoperiod (Wood and Loudon, 2014; Wood et al., 2020). How circannual photoentrainment information is then communicated throughout the rest of the brain remains an area of active inquiry.

Future studies will need to assess whether cycles in neuroplastic capacity on the infradian timescale emerge from endogenous versus environmental signals. In many geographical locations, for example, the passage of seasons brings about changes in ambient temperature, photoperiod, and weather patterns. These environmental fluctuations may function as both circannual entrainment signals and direct causes of metaplasticity, as is observed with environmental cues on the circadian timescale. Although mechanisms of infradian metaplasticity have yet to be fully elucidated, these findings indicate the potential for circalunar and circannual rhythms in neuroplastic capacity, highlighting an important avenue for continued investigation.

The Functions Of Iterative Metaplasticity

The circadian system is widely regarded as a mechanism for predictive homeostasis, the physiological ability to anticipate and adapt to periodic environmental challenges (Moore-Ede, 1986). We and others view circadian metaplasticity to serve this function by organizing learning processes into adaptive temporal domains (Gerstner, 2012; Krishnan and Lyons, 2015; Rawashdeh et al., 2018; Hartsock and Spencer, 2020). For instance, enhanced fear learning and recall during the daily sleep period may promote safety behaviors when a prey animal would otherwise be quite vulnerable to danger (Chaudhury and Colwell, 2002; Eckel-Mahan et al., 2008). Non-circadian forms of iterative metaplasticity that are also endogenously generated may be viewed to niche memory function on non-daily timescales. That songbirds are best at song learning during mating season is a fitting illustration (Van Meir et al., 2006; Surbhi et al., 2016; Cornez, Collignon, et al., 2020). Whereas endogenously generated forms of iterative metaplasticity support predictive homeostasis, environmentally generated forms of iterative metaplasticity may instead support reactionary homeostasis, the better known type of homeostasis (Moore-Ede, 1986). Thus, endogenously generated iterations in neuroplastic capacity may help an organism to predict environmental change, whereas iterations generated only in response to environmental signals may enable the organism to adjust its behavior in real time as conditions demand.

But conceiving of iterative metaplasticity strictly as a mechanism for homeostasis may miss something more profound about its functional importance. Liston and colleagues (2013) have shown that the daily peak in glucocorticoid concentrations is necessary for spine formation, while the daily trough in glucocorticoid concentrations is necessary for spine stabilization. Similarly, another report demonstrates that, whereas hippocampal adenylyl cyclase activity is necessary for optimal recall of contextual fear in mice, increasing hippocampal adenylyl cyclase activity during its daily trough impairs recall (Eckel-Mahan et al., 2008). A third study has shown that constitutively high expression of the normally oscillatory transcript microRNA-132 in the mouse forebrain can disrupt expression of the hippocampal plasticity proteins MeCP2 and SIRT1 as well as hippocampus-dependent memory (Aten et al., 2018). These data suggest that neuroplastic capacity that is oscillatory may better serve memory function than neuroplastic capacity that is always high. It is also noteworthy that iterative metaplasticity is observed virtually every time it is measured, which is especially clear in the growing body of work on circadian metaplasticity (Krishnan and Lyons, 2015; Rawashdeh et al., 2018; Hartsock and Spencer, 2020). Together, these findings lead us to consider the possibility that iterative metaplasticity may be necessary for maintaining neuroplastic capacity more generally.

We have discussed previously that sleep might be seen as one mechanism by which the circadian system regulates neuroplasticity (Hartsock and Spencer, 2020). From this perspective, sleep can help us to think about why iterations may be essential. Sleep maintains neuroplastic capacity ultimately by counteracting processes that occur during wakefulness. For instance, wakefulness tends to promote long-term potentiation, and sleep tends to promote long-term depression (Tononi and Cirelli, 2014). Wakefulness tends to promote neurotoxic metabolite accumulation, and sleep tends to promote neurotoxic metabolite clearance (Xie et al., 2013). Wakefulness tends to promote synaptic transmission, and sleep tends to promote metabolic recovery (Noya et al., 2019). This pattern is even seen in Drosophila, with dopamine neurons promoting active forgetting of olfactory memories during wakefulness but being suppressed during sleep (Berry et al., 2015). Sleep-driven iterations in neuroplastic capacity support optimal memory function in a variety of memory tasks (M. P. Walker and Stickgold, 2004; Rasch and Born, 2013; Tononi and Cirelli, 2014). Other forms of iterative metaplasticity may work the same way, maintaining memory function by toggling neural cells between states of cellular expenditure (increased neuroplastic capacity) and subsequent restoration (decreased neuroplastic capacity).

Further exploration of this hypothesis will require convergent evidence from many research areas. We will need to clarify exactly how basal neural parameters, such as membrane potential, kinase activity, and DNA methylation status, help to set the stage for activity-dependent neuroplasticity (Josselyn and Tonegawa, 2020). We can then begin to understand the functional impact of oscillations in these parameters. To this end, we will be challenged to develop techniques that can precisely alter oscillatory function with minimal off-target disturbance, as Aten and colleagues (2018) have achieved with a quadruple transgenic mouse in which the oscillatory expression profile of microRNA-132 is replaced by a constitutive expression profile. In addition, we will need to understand how oscillations in neuroplasticity may differ among species, with a particular focus on how environmental factors such as sunlight or tides may produce particular oscillatory signatures. Through these pursuits, we may gain a deeper appreciation of how iterative metaplasticity across timescales can modulate the capacity of an organism to learn and remember at any given moment in time.

Footnotes

Acknowledgements

This work was supported by a National Science Foundation predoctoral fellowship to M.J.H. (grant number DGE144083), a National Institutes of Health predoctoral fellowship to H.K.S. (grant number T32HL149646), and a National Institutes of Health research program grant to R.L.S. (grant number MH115947). Figure 2 was created with .

Conflict Of Interest Statement

The author(s) have no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

ORCID iD

Matthew J. Hartsock

References

Abraham

Bear

(1996) Metaplasticity: the plasticity of synaptic plasticity. Trends Neurosci 19:126-130.

Abrahamson

Moore

(2001) Suprachiasmatic nucleus in the mouse: retinal innervation, intrinsic organization and efferent projections. Brain Res 916:172-191.

Akiyama

(2004) Entrainment of the circatidal swimming activity rhythm in the cumacean Dimorphostylis asiatica (Crustacea) to 12.5-hour hydrostatic pressure cycles. Zoolog Sci 21:29-38.

Albus

Bonnefont

Chaves

Yasui

Doczy

van der Horst

GTJ

Meijer

(2002) Cryptochrome-deficient mice lack circadian electrical activity in the suprachiasmatic nuclei. Curr Biol 12:1130-1133.

Allada

White

Hall

Rosbash

(1998) A mutant Drosophila homolog of mammalian clock disrupts circadian rhythms and transcription of period and timeless. Cell 93:791-804.

Anderson

Famous

Sadri-Vakili

Kumaresan

Schmidt

Bass

Terwilliger

Cha

J-HJ

Pierce

(2008) CaMKII: a biochemical bridge linking accumbens dopamine and glutamate systems in cocaine seeking. Nat Neurosci 11:344-353.

Aten

Hansen

Snider

Wheaton

Kalidindi

Garcia

Alzate-Correa

Hoyt

Obrietan

(2018) miR-132 couples the circadian clock to daily rhythms of neuronal plasticity and cognition. Learn Mem 25:214-229.

Baik

J-H

(2013) Dopamine signaling in reward-related behaviors. Front Neural Circuits 7:152.

Bargiello

Jackson

Young

(1984) Restoration of circadian behavioural rhythms by gene transfer in Drosophila. Nature 312:752-754.

10.

Barth

Villringer

Sacher

(2015) Sex hormones affect neurotransmitters and shape the adult female brain during hormonal transition periods. Front Neurosci 9:37.

11.

Bateup

Svenningsson

Kuroiwa

Gong

Nishi

Heintz

Greengard

(2008) Cell type-specific regulation of DARPP-32 phosphorylation by psychostimulant and antipsychotic drugs. Nat Neurosci 11:932-939.

12.

Becker

Arnold

Berkley

Blaustein

Eckel

Hampson

Herman

Marts

Sadee

Steiner

, et al. (2005) Strategies and methods for research on sex differences in brain and behavior. Endocrinology 146:1650-1673.

13.

Berry

Cervantes-Sandoval

Chakraborty

Davis

(2015) Sleep facilitates memory by blocking dopamine neuron-mediated forgetting. Cell 161:1656-1667.

14.

Bhadra

Thakkar

Das

Pal Bhadra

(2017) Evolution of circadian rhythms: from bacteria to human. Sleep Med 35:49-61.

15.

Blum

Zhu

Moquin

Kokoeva

Gratton

Giros

Storch

K-F

(2014) A highly tunable dopaminergic oscillator generates ultradian rhythms of behavioral arousal. eLife 3:e05105.

16.

Borbély

Daan

Wirz-Justice

Deboer

(2016) The two-process model of sleep regulation: a reappraisal. J Sleep Res 25:131-143.

17.

Brown

Banks

Piggins

(2006) A novel suction electrode recording technique for monitoring circadian rhythms in single and multiunit discharge from brain slices. J Neurosci Methods 156:173-181.

18.

Carlini

Varas

Cragnolini

Schio

Scimonelli

de Barioglio

(2004) Differential role of the hippocampus, amygdala, and dorsal raphe nucleus in regulating feeding, memory, and anxiety-like behavioral responses to ghrelin. Biochem Biophys Res Commun 313:635-641.

19.

Casiraghi

Spiousas

Dunster

McGlothlen

Fernández-Duque

Valeggia

de la Iglesia

(2021) Moonstruck sleep: synchronization of human sleep with the moon cycle under field conditions. Sci Adv 7:eabe0465.

20.

Chaudhury

Colwell

(2002) Circadian modulation of learning and memory in fear-conditioned mice. Behav Brain Res 133:95-108.

21.

Chen

Rusnak

Luedtke

Sidhu

(2004) D1 dopamine receptor mediates dopamine-induced cytotoxicity via the ERK signal cascade. J Biol Chem 279:39317-39330.

22.

Choi

E-Y

Jeong

Park

Baik

J-H

(1999) G protein-mediated mitogen-activated protein kinase activation by two dopamine D2 receptors. Biochem Biophys Res Commun 256:33-40.

23.

Chung

Lee

Yun

Choe

Park

S-B

Son

Kim

K-S

Dluzen

Lee

Hwang

, et al. (2014) Impact of circadian nuclear receptor REV-ERBα on midbrain dopamine production and mood regulation. Cell 157:858-868.

24.

Cirelli

Gutierrez

Tononi

(2004) Extensive and divergent effects of sleep and wakefulness on brain gene expression. Neuron 41:35-43.

25.

Claridge-Chang

Wijnen

Naef

Boothroyd

Rajewsky

Young

(2001) Circadian regulation of gene expression systems in the Drosophila head. Neuron 32:657-671.

26.

Colwell

(2011) Linking neural activity and molecular oscillations in the SCN. Nat Rev Neurosci 12:553-569.

27.

Conway-Campbell

Sarabdjitsingh

McKenna

Pooley

Kershaw

Meijer

De Kloet

Lightman

(2010) Glucocorticoid ultradian rhythmicity directs cyclical gene pulsing of the clock gene Period 1 in rat hippocampus: clock gene pulsing by glucocorticoids in hippocampus. J Neuroendocrinol 22:1093-1100.

28.

Coomans

Ramkisoensing

Meijer

(2015) The suprachiasmatic nuclei as a seasonal clock. Front Neuroendocrinol 37:29-42.

29.

Cornez

Collignon

Müller

Ball

Cornil

Balthazart

(2020) Seasonal changes of perineuronal nets and song learning in adult canaries ( Serinus canaria). Behav Brain Res 380:112437.

30.

Cornez

Shevchouk

Ghorbanpoor

Ball

Cornil

Balthazart

(2020) Testosterone stimulates perineuronal nets development around parvalbumin cells in the adult canary brain in parallel with song crystallization. Horm Behav 119:104643.

31.

Dana

Martinez

(1984) Effect of adrenalectomy on the circadian rhythm of LTP. Brain Res 308:392-395.

32.

Darlington

(1998) Closing the circadian loop: CLOCK-induced transcription of its own inhibitors per and tim. Science 280:1599-1603.

33.

DeBruyne

Noton

Lambert

Maywood

Weaver

Reppert

(2006) A clock shock: mouse CLOCK is not required for circadian oscillator function. Neuron 50:465-477.

34.

De Jeu

Pennartz

(2002) Circadian modulation of GABA function in the rat suprachiasmatic nucleus: excitatory effects during the night phase. J Neurophysiol 87:834-844.

35.

Dellapolla

Kloehn

Pancholi

Callif

Wertz

Rohr

Hurley

Baker

Hattar

Gilmartin

, et al. (2017) Long days enhance recognition memory and increase insulin-like growth factor 2 in the hippocampus. Sci Rep 7:3925.

36.

Dong

Green

Saal

Marie

Neve

Nestler

Malenka

(2006) CREB modulates excitability of nucleus accumbens neurons. Nat Neurosci 9:475-477.

37.

Dulcis

Jamshidi

Leutgeb

Spitzer

(2013) Neurotransmitter switching in the adult brain regulates behavior. Science 340:449-453.

38.

During

Cao

Zuzga

Francis

Fitzsimons

Jiao

Bland

Klugmann

Banks

Drucker

, et al. (2003) Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med 9:1173-1179.

39.

Eckel-Mahan

Phan

Han

Wang

Chan

GC-K

Scheiner

Storm

(2008) Circadian oscillation of hippocampal MAPK activity and cAMP: implications for memory persistence. Nat Neurosci 11:1074-1082.

40.

Farajnia

van Westering

TLE

Meijer

Michel

(2014) Seasonal induction of GABAergic excitation in the central mammalian clock. Proc Natl Acad Sci 111:9627-9632.

41.

Fernandez

Fogerson

Lazzerini Ospri

Thomsen

Layne

Severin

Zhan

Singer

Kirkwood

Zhao

, et al. (2018) Light affects mood and learning through distinct retina-brain pathways. Cell 175:71-84.

42.

Flourakis

Kula-Eversole

Hutchison

Han

Aranda

Moose

White

Dinner

Lear

Ren

, et al. (2015) A conserved bicycle model for circadian clock control of membrane excitability. Cell 162:836-848.

43.

Frey

Huang

Kandel

(1993) Effects of cAMP simulate a late stage of LTP in hippocampal CA1 neurons. Science 260:1661-1664.

44.

Genzel

Kiefer

Renner

Wehrle

Kluge

Grözinger

Steiger

Dresler

(2012) Sex and modulatory menstrual cycle effects on sleep related memory consolidation. Psychoneuroendocrinology 37:987-998.

45.

Gerstner

(2012) On the evolution of memory: a time for clocks. Front Mol Neurosci 5:23.

46.

Gerstner

Yin

JCP

(2010) Circadian rhythms and memory formation. Nat Rev Neurosci 11:577-588.

47.

Ginty

Kornhauser

Thompson

Bading

Mayo

Takahashi

Greenberg

(1993) Regulation of CREB phosphorylation in the suprachiasmatic nucleus by light and a circadian clock. Science 260:238-241.

48.

Green

Gillette

(1982) Circadian rhythm of firing rate recorded from single cells in the rat suprachiasmatic brain slice. Brain Res 245:198-200.

49.

Güler

Ecker

Lall

Haq

Altimus

Liao

H-W

Barnard

Cahill

Badea

Zhao

, et al. (2008) Melanopsin cells are the principal conduits for rod-cone input to non-image-forming vision. Nature 453:102-105.

50.

Hampp

Ripperger

Houben

Schmutz

Blex

Perreau-Lenz

Brunk

Spanagel

Ahnert-Hilger

Meijer

, et al. (2008) Regulation of monoamine oxidase A by circadian-clock components implies clock influence on mood. Curr Biol 18:678-683.

51.

Han

M-H

(2006) Role of cAMP response element-binding protein in the rat locus ceruleus: regulation of neuronal activity and opiate withdrawal behaviors. J Neurosci 26:4624-4629.

52.

Hansberg-Pastor

González-Arenas

Piña-Medina

Camacho-Arroyo

(2015) Sex hormones regulate cytoskeletal proteins involved in brain plasticity. Front Psychiatry 6:165.

53.

Harris

Teyler

(1983) Age differences in a circadian influence on hippocampal LTP. Brain Res 261:69-73.

54.

Hartsock

Spencer

(2020) Memory and the circadian system: identifying candidate mechanisms by which local clocks in the brain may regulate synaptic plasticity. Neurosci Biobehav Rev 118:134-162.

55.

Hattar

(2002) Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science 295:1065-1070.

56.

Hattar

Kumar

Park

Tong

Tung

Yau

K-W

Berson

(2006) Central projections of melanopsin-expressing retinal ganglion cells in the mouse. J Comp Neurol 497:326-349.

57.

Helfrich-Förster

Monecke

Spiousas

Hovestadt

Mitesser

Wehr

(2021) Women temporarily synchronize their menstrual cycles with the luminance and gravimetric cycles of the moon. Sci Adv 7:eabe1358.

58.

Herzog

Takahashi

Block

(1998) Clock controls circadian period in isolated suprachiasmatic nucleus neurons. Nat Neurosci 1:708-713.

59.

Impey

Obrietan

Wong

Poser

Yano

Wayman

Deloulme

Chan

Storm

(1998) Cross talk between ERK and PKA is required for Ca2+ stimulation of CREB-dependent transcription and ERK nuclear translocation. Neuron 21:869-883.

60.

Irwin

Allen

(2009) GABAergic signaling induces divergent neuronal Ca2+ responses in the suprachiasmatic nucleus network. Eur J Neurosci 30:1462-1475.

61.

Iyer

Wang

Gillette

(2014) Circadian gating of neuronal functionality: a basis for iterative metaplasticity. Front Syst Neurosci 8:164.

62.

Josselyn

Tonegawa

(2020) Memory engrams: recalling the past and imagining the future. Science 367:eaaw4325.

63.

Koronowski

Sassone-Corsi

(2021) Communicating clocks shape circadian homeostasis. Science 371:eabd0951.

64.

Krishnan

Lyons

(2015) Synchrony and desynchrony in circadian clocks: impacts on learning and memory. Learn Mem 22:426-437.

65.

Kudo

Block

Colwell

(2015) The circadian clock gene Period1 connects the molecular clock to neural activity in the suprachiasmatic nucleus. ASN Neuro 7:1-14.

66.

Kwapis

Alaghband

Kramár

López

Vogel Ciernia

White

Shu

Rhee

Michael

Montellier

, et al. (2018) Epigenetic regulation of the circadian gene Per1 contributes to age-related changes in hippocampal memory. Nat Commun 9:3323.

67.

Larsen

Enquist

Card

(1998) Characterization of the multisynaptic neuronal control of the rat pineal gland using viral transneuronal tracing. Eur J Neurosci 10:128-145.

68.

Larson

Thatra

Hou

Brenowitz

(2019) Seasonal changes in neuronal turnover in a forebrain nucleus in adult songbirds. J Comp Neurol 527:767-779.

69.

LeGates

Altimus

Wang

Lee

H-K

Yang

Zhao

Kirkwood

Weber

Hattar

(2012) Aberrant light directly impairs mood and learning through melanopsin-expressing neurons. Nature 491:594-598.

70.

LeGates

Fernandez

Hattar

(2014) Light as a central modulator of circadian rhythms, sleep and affect. Nat Rev Neurosci 15:443-454.

71.

Lightman

Conway-Campbell

(2010) The crucial role of pulsatile activity of the HPA axis for continuous dynamic equilibration. Nat Rev Neurosci 11:710-718.

72.

Liston

Cichon

Jeanneteau

Jia

Chao

Gan

W-B

(2013) Circadian glucocorticoid oscillations promote learning-dependent synapse formation and maintenance. Nat Neurosci 16:698-705.

73.

Logan

Parekh

Kaplan

Becker-Krail

Williams

Yamaguchi

Yoshino

Shelton

Zhu

Zhang

, et al. (2019) NAD+ cellular redox and SIRT1 regulate the diurnal rhythms of tyrosine hydroxylase and conditioned cocaine reward. Mol Psychiatry 24:1668-1684.

74.

Maki

Rich

Shayna Rosenbaum

(2002) Implicit memory varies across the menstrual cycle: estrogen effects in young women. Neuropsychologia 40:518-529.

75.

Mandal

Prabhavalkar

Bhatt

(2018) Gastrointestinal hormones in regulation of memory. Peptides 102:16-25.

76.

Marathe

Rayner

Jones

Horowitz

(2013) Glucagon-like peptides 1 and 2 in health and disease: a review. Peptides 44:75-86.

77.

Marino

Galluzzo

Ascenzi

(2006) Estrogen signaling multiple pathways to impact gene transcription. Curr Genomics 7:497-508.

78.

Marler

Peters

Ball

Dufty

Wingfield

(1988) The role of sex steroids in the acquisition and production of birdsong. Nature 336:770-772.

79.

Mendoza-Viveros

Chiang

C-K

Ong

JLK

Hegazi

Cheng

Bouchard-Cannon

Fana

Lowden

Zhang

Bothorel

, et al. (2017) miR-132/212 modulates seasonal adaptation and dendritic morphology of the central circadian clock. Cell Rep 19:505-520.

80.

Michan

Chou

MM-H

Parrella

Long

Allard

Lewis

Miller

, et al. (2010) SIRT1 is essential for normal cognitive function and synaptic plasticity. J Neurosci 30:9695-9707.

81.

Møller

Baeres

(2002) The anatomy and innervation of the mammalian pineal gland. Cell Tissue Res 309:139-150.

82.

Moore

Eichler

(1972) Loss of a circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat. Brain Res 42:201-206.

83.

Moore-Ede

(1986) Physiology of the circadian timing system: predictive versus reactive homeostasis. Am J Physiol-Regul Integr Comp Physiol 250:737-752.

84.

Morales

Margolis

(2017) Ventral tegmental area: cellular heterogeneity, connectivity and behaviour. Nat Rev Neurosci 18:73-85.

85.

Mure

Benegiamo

Chang

Rios

Jillani

Ngotho

Kariuki

Dkhissi-Benyahya

Cooper

, et al. (2018) Diurnal transcriptome atlas of a primate across major neural and peripheral tissues. Science 359:eaao0318.

86.

Nakahata

Kaluzova

Grimaldi

Sahar

Hirayama

Chen

Guarente

Sassone-Corsi

(2008) The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 134:329-340.

87.

Nishikawa

Shibata

Watanabe

(1995) Circadian changes in long-term potentiation of rat suprachiasmatic field potentials elicited by optic nerve stimulation in vitro. Brain Res 695:158-162.

88.

Nottebohm

(1980) Testosterone triggers growth of brain vocal control nuclei in adult female canaries. Brain Res 189:429-436.

89.

Nottebohm

(1989) From bird song to neurogenesis. Sci Am 260:74-79.

90.

Noya

Colameo

Brüning

Spinnler

Mircsof

Opitz

Mann

Tyagarajan

Robles

Brown

(2019) The forebrain synaptic transcriptome is organized by clocks but its proteome is driven by sleep. Science 366:eaav2642.

91.

Obrietan

Impey

Storm

(1998) Light and circadian rhythmicity regulate MAP kinase activation in the suprachiasmatic nuclei. Nat Neurosci 1:693-700.

92.

O’Neill

Lee

Zhang

Feeney

Webster

Blades

Kyriacou

Hastings

Wilcockson

(2015) Metabolic molecular markers of the tidal clock in the marine crustacean Eurydice pulchra. Curr Biol 25:326-327.

93.

Orije

Cardon

De Groof

Hamaide

Jonckers

Van Massenhoven

Darras

Balthazart

Verhoye

Van der Linden

(2020) In vivo online monitoring of testosterone-induced neuroplasticity in a female songbird. Horm Behav 118:104639.

94.

Oster

Challet

Ott

Arvat

de Kloet

Dijk

D-J

Lightman

Vgontzas

Van Cauter

(2017) The functional and clinical significance of the 24-hour rhythm of circulating glucocorticoids. Endocr Rev 38:3-45.

95.

Parducz

Hajszan

MacLusky

Hoyk

Csakvari

Kurunczi

Prange-Kiel

Leranth

(2006) Synaptic remodeling induced by gonadal hormones: neuronal plasticity as a mediator of neuroendocrine and behavioral responses to steroids. Neuroscience 138:977-985.

96.

Perreau-Lenz

Hoelters

L-S

Leixner

Sanchis-Segura

Hansson

Bilbao

Spanagel

(2017) mPer1 promotes morphine-induced locomotor sensitization and conditioned place preference via histone deacetylase activity. Psychopharmacology (Berl) 234:1713-1724.

97.

Porcu

Vaughan

Nilsson

Arimoto

Lamia

Welsh

(2020) Vulnerability to helpless behavior is regulated by the circadian clock component CRYPTOCHROME in the mouse nucleus accumbens. Proc Natl Acad Sci 117:13771-13782.

98.

Price

Blau

Rothenfluh

Abodeely

Kloss

Young

(1998) double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation. Cell 94:83-95.

99.

Pyter

Reader

Nelson

(2005) Short photoperiods impair spatial learning and alter hippocampal dendritic morphology in adult male white-footed mice ( Peromyscus leucopus). J Neurosci 25:4521-4526.

100.

Raghavan

Horowitz

Fuller

(1999) Diurnal modulation of long-term potentiation in the hamster hippocampal slice. Brain Res 833:311-314.

101.

Rasch

Born

(2013) About sleep’s role in memory. Physiol Rev 93:681-766.

102.

Rawashdeh

Jilg

Jedlicka

Slawska

Thomas

Saade

Schwarzacher

Stehle

(2014) PERIOD1 coordinates hippocampal rhythms and memory processing with daytime: circadian rhythms in mouse hippocampus. Hippocampus 24:712-723.

103.

Rawashdeh

Jilg

Maronde

Fahrenkrug

Stehle

(2016) Period1 gates the circadian modulation of memory-relevant signaling in mouse hippocampus by regulating the nuclear shuttling of the CREB kinase pP90RSK. J Neurochem 138:731-745.

104.

Rawashdeh

Parsons

Maronde

(2018) Clocking in time to gate memory processes: the circadian clock is part of the ins and outs of memory. Neural Plast 2018:6238989.

105.

Reick

(2001) NPAS2: an analog of Clock operative in the mammalian forebrain. Science 293:506-509.

106.

Reid

Naylor

(1990) Entrainment of bimodal circatidal rhythms in the shore crab Carcinus maenas. J Biol Rhythms 5:333-347.

107.

Reppert

Weaver

(2001) Molecular analysis of mammalian circadian rhythms. Annu Rev Physiol 63:647-676.

108.

Reppert

Weaver

(2002) Coordination of circadian timing in mammals. Nature 418:935-941.

109.

Rhea

Salameh

Gray

Niu

Banks

Tong

(2018) Ghrelin transport across the blood-brain barrier can occur independently of the growth hormone secretagogue receptor. Mol Metab 18:88-96.

110.

Sarabdjitsingh

Jezequel

Pasricha

Mikasova

Kerkhofs

Karst

Groc

Joëls

(2014) Ultradian corticosterone pulses balance glutamatergic transmission and synaptic plasticity. PNAS 111:14265-14270.

111.

Satoh

Terai

(2019) Circatidal gene expression in the mangrove cricket Apteronemobius asahinai. Sci Rep 9:3719.

112.

Schaap

Albus

vanderLeest

Eilers

PHC

Detari

Meijer

(2003) Heterogeneity of rhythmic suprachiasmatic nucleus neurons: implications for circadian waveform and photoperiodic encoding. Proc Natl Acad Sci 100:15994-15999.

113.

Schlinger

Brenowitz

(2002) Neural and hormonal control of birdsong. In: Pfaff

Arnold

Etgen

Fahrbach

Rubin

, editors. Hormones, brain and behavior. New York (NY): Academic Press. p. 799-839.

114.

Simpson

Ramsdell

Watson

III Chabot

(2017) The draft genome and transcriptome of the Atlantic horseshoe crab, Limulus polyphemus. Int J Genomics 2017:7636513.

115.

Spencer

Deak

(2017) A users guide to HPA axis research. Physiol Behav 178:43-65.

116.

Spencer

Chun

Hartsock

Woodruff

(2018) Glucocorticoid hormones are both a major circadian signal and major stress signal: how this shared signal contributes to a dynamic relationship between the circadian and stress systems. Front Neuroendocrinol 49:52-71.

117.

Surbhi

Rastogi A

Malik

Rani

Kumar

(2016) Seasonal neuronal plasticity in song-control and auditory forebrain areas in subtropical nonmigratory and Palearctic-Indian migratory male songbirds: seasonal plasticity in brain structures. J Comp Neurol 524:2914-2929.

118.

Swan

Golden

LiWang

Partch

(2018) Structure, function, and mechanism of the core circadian clock in cyanobacteria. J Biol Chem 293:5026-5034.

119.

Takekata

Matsuura

Goto

Satoh

Numata

(2012) RNAi of the circadian clock gene period disrupts the circadian rhythm but not the circatidal rhythm in the mangrove cricket. Biol Lett 8:488-491.

120.

Thomas

Huganir

(2004) MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci 5:173-183.

121.

Tischkau

Mitchell

Tyan

S-H

Buchanan

Gillette

(2003) Ca2+/cAMP response element-binding protein (CREB)-dependent activation of Per1 is required for light-induced signaling in the suprachiasmatic nucleus circadian clock. J Biol Chem 278:718-723.

122.

Tononi

Cirelli

(2014) Sleep and the price of plasticity: from synaptic and cellular homeostasis to memory consolidation and integration. Neuron 81:12-34.

123.

Tramontin

Brenowitz

(2000) Seasonal plasticity in the adult brain. Trends Neurosci 23:251-258.

124.

Tran

Perrigault

Ciret

Payton

(2020) Bivalve mollusc circadian clock genes can run at tidal frequency. Proc R Soc B Biol Sci 287:1-9.

125.

Turek

Gillette

(2004) Melatonin, sleep, and circadian rhythms: rationale for development of specific melatonin agonists. Sleep Med 5:523-532.

126.

VanderLeest

Houben

Michel

Deboer

Albus

Vansteensel

Block

Meijer

(2007) Seasonal encoding by the circadian pacemaker of the SCN. Curr Biol 17:468-473.

127.

Van Meir

Pavlova

Verhoye

Pinxten

Balthazart

Eens

Van der Linden

(2006) In vivo MR imaging of the seasonal volumetric and functional plasticity of song control nuclei in relation to song output in a female songbird. NeuroImage 31:981-992.

128.

Vosshall

Price

Sehgal

Saez

Young

(1994) Block in nuclear localization of period protein by a second clock mutation, timeless. Science 263:1606-1609.

129.

Walker

Terry

Lightman

(2010) Origin of ultradian pulsatility in the hypothalamic–pituitary–adrenal axis. Proc R Soc B Biol Sci 277:1627-1633.

130.

Walker

Stickgold

(2004) Sleep-dependent learning and memory consolidation. Neuron 44:121-133.

131.

Wood

Loudon

(2014) Clocks for all seasons: unwinding the roles and mechanisms of circadian and interval timers in the hypothalamus and pituitary. J Endocrinol 222:39-59.

132.

Wood

Hindle

Mizoro

Cheng

Saer

BRC

Miedzinska

Christian

Begley

McNeilly

, et al. (2020) Circadian clock mechanism driving mammalian photoperiodism. Nat Commun 11:4291.

133.

Woolley

Gould

Frankfurt

McEwen

(1990) Naturally occurring fluctuation in dendritic spine density on adult hippocampal pyramidal neurons. J Neurosci 10:4035-4039.

134.

Xie

Kang

Chen

Liao

Thiyagarajan

O’Donnell

Christensen

Nicholson

Iliff

, et al. (2013) Sleep drives metabolite clearance from the adult brain. Science 342:373-377.

135.

Young

Kay

(2001) Time zones: a comparative genetics of circadian clocks. Nat Rev Genet 2:702-715.

136.

Zaldibar

Cancio

Marigómez

(2004) Circatidal variation in epithelial cell proliferation in the mussel digestive gland and stomach. Cell Tissue Res 318:395-402.

137.

Zehring

Wheeler

Reddy

Konopka

Kyriacou

Rosbash

Hall

(1984) P-element transformation with period locus DNA restores rhythmicity to mutant, arrhythmic Drosophila melanogaster. Cell 39:369-376.

138.

Zhang

Hastings

Green

Tauber

Sladek

Webster

Kyriacou

Wilcockson

(2013) Dissociation of circadian and circatidal timekeeping in the marine crustacean Eurydice pulchra. Curr Biol 23:1863-1873.

139.

Zhang

Lahens

Ballance

Hughes

Hogenesch

(2014) A circadian gene expression atlas in mammals: implications for biology and medicine. Proc Natl Acad Sci 111:16219-16224.

140.

Zhou

Won

Karlsson

Zhou

Rogerson

Balaji

Neve

Poirazi

Silva

(2009) CREB regulates excitability and the allocation of memory to subsets of neurons in the amygdala. Nat Neurosci 12:1438-1443.