Gerstner Frontiers Mol Neurosci 2012


Published on

  • Be the first to comment

  • Be the first to like this

No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide

Gerstner Frontiers Mol Neurosci 2012

  1. 1. PERSPECTIVE ARTICLE published: 28 February 2012MOLECULAR NEUROSCIENCE doi: 10.3389/fnmol.2012.00023On the evolution of memory: a time for clocksJason R. Gerstner*Center for Sleep and Circadian Neurobiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USAEdited by: Evolutionarily, what was the earliest engram? Biology has evolved to encode representa-Kristin Eckel-Mahan, University of tions of past events, and in neuroscience, we are attempting to link experience-dependentCalifornia at Irvine, USA changes in molecular signaling with cellular processes that ultimately lead to behavioralReviewed by:Urs Albrecht, University of Fribourg, output. The theory of evolution has guided biological research for decades, and since phy-Switzerland logenetically conserved mechanisms drive circadian rhythms, these processes may serveTrongha Phan, Massachusetts as common predecessors underlying more complex behavioral phenotypes. For example,Institute of Technology, USA the cAMP/MAPK/CREB cascade is interwoven with the clock to trigger circadian output,*Correspondence: and is also known to affect memory formation. Time-of-day dependent changes have beenJason R. Gerstner, Center for Sleepand Circadian Neurobiology, Perelman observed in long-term potentiation (LTP) within the suprachiasmatic nucleus and hippocam-School of Medicine at the University pus, along with light-induced circadian phase resetting and fear conditioning behaviors.of Pennsylvania, 125 South 31st Together this suggests during evolution, similar processes underlying metaplasticity inStreet, Philadelphia, PA 19104, USA. more simple circuits may have been redeployed in higher-order brain regions. Therefore,e-mail: this notion predicts a model that LTP and metaplasticity may exist in neural circuits of other species, through phylogenetically conserved pathways, leading to several testable hypotheses. Keywords: transcription, translation, metabolism, sleep, excitabilityEVOLUTIONARY EMERGENCE OF “MEMORY”: metaplasticity (Bienenstock et al., 1982; Abraham and Bear, 1996;A PERSPECTIVE Jedlicka, 2002), a term adopted from neuroscience describing theEarly forms of life likely encoded molecular processes which plasticity of synaptic plasticity. For this discussion, “metaplastic-integrated basic information necessary for survival: simple envi- ity” refers to any biological system to change its ability to be plastic.ronmental stimuli and nutrition, such as light or temperature and Further modifications to periodicity can be influenced by Earth’sessential chemicals (nutrients) for biological energy utilization orbit eccentricity, axial tilt, and precession. These changes areand early metabolic chemical reactions. The cyclical nature of the believed to contribute too much larger periodic environmentalearth’s rotation on its axis, and orbit around the sun, would have oscillations called Milankovitch cycles, leading to a global cli-provided daily (circadian) and seasonal (circannual) oscillatory matic “pacemaker of the ice ages” (Hays et al., 1976). Individualcues from which biology would have evolved molecular mecha- components can vary in period length, and oscillate over largenisms that optimized energy expenditure from energy acquisition spans of time, from tens to over hundreds of thousands of years.and storage (bioenergetics). Therefore these cyclical events could These variations would induce changes in seasonal alterations inbe considered one basis from which primordial molecular memory daily periodicity broadly over evolutionary time, reinforcing aevolved. metaplastic quality in the biological system (Figure 1). However, The repetitive nature of cycling environmental stimulus factors, within early life, the repetitive nature of specific features on shortersuch as light and temperature, and their overlap with the availabil- time-courses would have allowed more “predictable” alterations inity of essential nutrients would have led to early life exhibiting biochemical reactions, leading to a rudimentary process of mem-a “timed” and coordinated molecular signature, and in turn this ory. Thus, an outcome of natural selection on these entrainedcould have led to an organization of molecular and cellular pro- clocks would have been the ability to “free-run” in the absence ofcesses contributing to a behavioral response which coincided with external cues (Pittendrigh, 1993), exhibiting the earliest form ofregular, cyclical, and predictable stimuli (Figure 1). These stimu- “memory” in biology.lating events, while repetitive, would have retained some variance Optimization set-points in environmental conditions wouldover time, such as annual periodic changes in day length. Modu- have provided extremes for life to exist and thrive, similar to limitslation of stimuli would therefore have led this “timing” machinery on a spectrum. For life to survive optimally, an adaptive qualitysubject to an adaptive quality, making the system plastic, and able with this changing spectrum is absolutely essential, and ratio-to adjust to the changing environment, setting optimization lim- nale for why circadian clocks are thought to have evolved outits for energy use and storage. Additional variations in the relative of periodic changes in the environment (Paranjpe and Sharma,amount of periodicity, due to changes in periods of other regularly 2005; McIntosh et al., 2010). This manuscript is not meant to set aoccurring environmental cycles, such as circalunar and circati- base for this argument, but instead propose that the metaplastic-dal rhythms (Tessmar-Raible et al., 2011), contributed further ity that is observed in neuronal networks and complex behaviorplasticity within this rhythmic biological mechanism, producing in higher-order organisms today could have evolved out of morean additive ability to be plastic, referred to here broadly as simple adaptive molecular machinery, such as from clock-formingFrontiers in Molecular Neuroscience February 2012 | Volume 5 | Article 23 | 1 “fnmol-05-00023” — 2012/2/28 — 9:36 — page 1 — #1
  2. 2. Gerstner Ancient memory and metaplasticity FIGURE 1 | Evolutionary progress of the clock and metaplasticity. Upper : regularly occurring cue (for example, a daily light–dark cycle), the mechanism In early life, recurring environmental stimuli would set up a biological timing would continue to persist. This would be evolutionarily advantageous, and mechanism that involves an autoregulatory feedback loop, which would be permit the organism to place itself in its appropriate niche through memory. integrated with metabolic processes. These in turn would lead to behavioral This mechanism would necessarily require an adaptive component, since output processes that optimize chances for survival, through gating the there would be alterations in the environment that would “reset” optimization organism to appropriate environmental niches. Lower : This process would limits, rendering the system to have a “metaplastic” quality. The become much more refined over evolutionary time, such that environmental metaplasticity of the system instills a scaled learning component balanced oscillators which occur on regular frequencies would render the timing against resistance (memory) mechanisms, creating an integrated processor mechanism some resistance to change, such that in the absence of the that improves fitness during natural selection.cellular processes and circuits from long ago. Therefore, this adap- (McIntosh et al., 2010). PAS molecules in this loop are criti-tive quality needs to be a part of a general programming scheme cal for the oscillatory nature of the circadian clock, and havewithin the organism, but could be viewed as fundamental to persis- also been shown to be involved in various temporal-sensitivetent behavioral qualities that better suited species survival during processes, such as cell cycle regulation, metabolism, and learn-natural selection. ing and memory. While there is some overlap in circadian The notion that biochemical and molecular mechanisms which gene homology and function across certain phyla (Panda et al.,drive circadian rhythms known to exist in life today represent 2002), strict phylogenetic conservation of specific clock genesan ancient memory-coding strategy that evolved from earlier is not as completely conserved, but instead resembles a similarlife seems quite plausible. Basic cellular processes, such as tran- operational pathway, consisting of an autoregulatory activa-scription and translation, are necessary for a functional clock tion and repression loop structure (Friesen and Block, 1984;broadly throughout life. It is well known that circadian core Brenner et al., 1990; Bass and Takahashi, 2011). The phylogeneti-clock molecules, such as CLOCK and BMAL are transcription cally conserved mechanism then is an activation and repressionfactors themselves, and operate on a transcriptional, translational feedback system (Figure 1), which can persist in an oscilla-autoregulatory feedback loop (Figure 2). These proteins are a part tory nature in the absence of environmental cues to maintainof the Per-Arnt-Sim (PAS) domain family that regulate antici- cycling, but retains adaptive qualities to react to changes in thepatory and adaptive responses to changes in the environment environment.Frontiers in Molecular Neuroscience February 2012 | Volume 5 | Article 23 | 2 “fnmol-05-00023” — 2012/2/28 — 9:36 — page 2 — #2
  3. 3. Gerstner Ancient memory and metaplasticity FIGURE 2 | Molecular components of the core clock. Light stimulates varying degrees based on the time-of-day. This shifting balance in the capacity glutamatergic synaptic activation via the retinohypothalamic tract on NMDA of the system to regulate changes in behavioral output differentially is central receptors within the mammalian SCN, to generate signaling cascades to the notion of circadian metaplasticity in physiology and behavior. Refer which are mediated by various plasticity-related proteins. The cascade to text for further information regarding the signaling pathways and can reset the transcriptional/translational autoregulatory feedback loop to abbreviations. Recently, it has been shown that persistent cycling processes cellular memory properties reused in higher-order organisms withof peroxiredoxin enzymatic activity occurs independently of tran- central nervous systems.scription in both humans and green algae (O’Neill and Reddy, Periodic cycles of environmental stimuli would have con-2011; O’Neill et al., 2011). The KaiC protein of cyanobacteria tributed to selection pressures for these least common time-can also be phosphorylated in a cyclical manner, and persist in keeping mechanisms, and allowed for an adaptive advantage,the absence of a zeitgeber (“time-giver”) independently of tran- since survival could be enhanced with properly timed antici-scriptional and translational mechanisms (Nakajima et al., 2005; patory behavior that better matched nutrient availability andTomita et al., 2005). However, it should be noted that in intact reproductive fitness. Therefore, these clocks likely emerged duringcyanobacteria, KaiC cyclic phosphorylation is coupled with tran- evolution out of natural selection; a primitive process predat-scriptional rhythms (Kitayama et al., 2008). Therefore it is likely ing higher-order memory processes tied to later evolved neuronalthat basic timing systems, such as those coupling nucleotide systems. These ancient molecular and cellular “timing” mecha-signaling and energy utilization in a simple negative feedback nisms serve as a basis for supporting more complex learning andstructure, may have predated more complex cellular processes, memory-coding strategies that we are now trying to understandin order to optimize internal bioenergetic signaling with vary- today. By understanding the functional relationships betweening environmental conditions, thus generating rhythmic outputs these circadian time-keeping mechanisms in simple organisms,which remain adaptive and able to enhance fitness and sur- we may be able to better approach the questions to test invival (Figure 1). Evolutionarily more recent oscillators involving higher-order species with more complex nervous systems andtranscriptional–translational feedback loops may have emerged behaviors.after, but remain coupled to, more ancient metabolic oscilla-tors. This coupling would have contributed to enhancement of CIRCADIAN PLASTICITY: FROM MOLECULES TO CIRCUITSfuel-utilization cycling, and predicts yet to be identified signaling TO BEHAVIORcofactors which link circadian and metabolic processes together The biological clock resides within the suprachiasmatic nucleus(Bass and Takahashi, 2011). Taken together, this suggests that some (SCN) of the hypothalamus in mammals, and the underlyingleast common ancient time-keeping mechanism linking energetic molecular biology and neurophysiology can “free-run” in theand adaptive qualities would have evolved to increase fitness and absence of environmental cues, or be reset to environmental stim-survival, and derive the historical predecessor of molecular and uli, depending on the time-of-day or type of input, leading toFrontiers in Molecular Neuroscience February 2012 | Volume 5 | Article 23 | 3 “fnmol-05-00023” — 2012/2/28 — 9:36 — page 3 — #3
  4. 4. Gerstner Ancient memory and metaplasticitydifferential changes in behavioral output (Golombek and Rosen- et al., 2011), suggesting conservation in cAMP/MAPK/CREB-stein, 2010). The basic core clock consists of a transcriptional dependent mechanisms that underlie plasticity and behavior. Thefeedback network where CLOCK and BMAL heterodimerize to ability to phase-shift circadian rhythms is also dependent ontransactivate Period (Per) and Cryptochrome (Cry) gene expres- de novo protein synthesis (Jacklet, 1977; Comolli et al., 1994;sion through E-box elements in the promoter (Figure 2). Per Zhang et al., 1996), indicating that similar to those in long-and Cry heterodimerize in the cytoplasm upon phosphoryla- term memory, activity-dependent plasticity-related processes alsotion by proteins such as casein kinase I (CKI) that regulate mediate circadian behavioral responses (Amir et al., 2002). Pre-protein turnover to inhibit CLOCK:BMAL (Mohawk and Taka- viously it has been shown that the number of photons of lighthashi, 2011). While the majority of neurons in the SCN are correlated with the amount of the immediate-early gene c-fosGABAergic (Moore and Speh, 1993), photic stimulation of gluta- mRNA expression in the SCN, which in turn correlated with thematergic N-methyl-D-aspartate receptors (NMDA-R) - mediates amount of phase-shift behavioral response, at times when thecalcium (Ca2+ ) influx, leading to downstream signaling cascades. circadian clock is susceptible to phase-shifts (Kornhauser et al.,Voltage-dependent calcium channels (VDCC) are rhythmically 1990), and these effects are tightly coupled with CREB phospho-expressed (Nahm et al., 2005), and have been implicated in rylation (Ginty et al., 1993). These data suggest that activationlight- and glutamate-induced phase shifts (Kim et al., 2005), and of the SCN stimulates plasticity-related processes during a specifictie Ca2+ influx to downstream clock machinery (Ikeda et al., 2003; temporal window, but CREB-related mechanisms exist which ren-Ikeda, 2004). Inositol trisphosphate receptor (IP3 R) expression der the neurons permissive to changes in stimulation based on thealso cycles, with Type I peaking during the early dark phase, time-of-day.and Type III peaking near the late dark period (Hamada et al., Exactly how the transcriptional/translational molecular clock1999b), and can regulate the level of Ca2+ in the SCN (Hamada operates on neurophysiological changes is not well understoodet al., 1999a). NMDA-R mediated Ca2+ influx also triggers nitric- (Ko et al., 2009; Colwell, 2011), but is believed to involve inter-oxide synthase (NOS) to liberate nitric oxide (NO) causing a cellular coupling of these cellular processes with synchronizationphase delay when light is delivered in the early dark phase, or of neuronal networks (Mohawk and Takahashi, 2011). Circadiana phase advance when given later in the dark period (Ding et al., modulation of action potential firing rates (Green and Gillette,1994). NO-dependent activation of a neuronal ryanodine receptor 1982; Cutler et al., 2003; Atkinson et al., 2011) and amplitude (Belle(RyR) and protein kinase G (PKG) pathways have been impli- et al., 2009) are known to exist, and include changes in the activ-cated in phase shifts (Weber et al., 1995; Mathur et al., 1996; ity of ion channels, such as the fast-delayed rectifier (Itri et al.,Ding et al., 1998; Oster et al., 2003; but see Langmesser et al., 2005), BK-channel induced calcium-activated potassium current2009). NOS activation by CaMKII phosphorylation (P) is nec- (Kent and Meredith, 2008), and the A-type potassium currents (Itriessary for normal light-induced phase shifts in the SCN (Agostino et al., 2010). Changes in SCN neurophysiology has been shown toet al., 2004), and gates the activation of soluble guanylyl cyclase regulate gene expression, since blockage of firing using TTX has(GC) and thought to lead to cGMP–PKG signaling (Golombek been shown to reduce the amplitude of Period transcript levelsand Rosenstein, 2010). The time-of-day sensitivity of this mech- (Yamaguchi et al., 2003). Additionally, the neuropeptide vasoac-anism to respond to light-induced phase shifts also appears to be tive intestinal peptide (VIP) has been shown to regulate molecularregulated through phosphodiesterase (PDE) activity, via cGMP oscillations (Maywood et al., 2006) and firing rates (Aton et al.,degradation (Ferreyra and Golombek, 2001). These events are 2005) in the SCN. Intracellular production of cAMP via adeny-in anti-phase to what is observed for cAMP-regulated phase late cyclase is stimulated by VIP acting on the VPAC2 receptorshifts that occur during the light phase (Prosser and Gillette, (Harmar et al., 2002). Time-of-day changes in the levels of intra-1989; Prosser et al., 1989). Activation of the cAMP–protein kinase cellular cAMP are thought to contribute to persistent oscillationsA (PKA) pathway in the SCN is also known to promote the of the transcriptional clock (O’Neill et al., 2008). Since the activ-effects of light/glutamate on Period1 gene expression early in the ity of hyperpolarization-activated, cyclic nucleotide-gated (HCN)dark period, but not late in the dark period (Tischkau et al., channels is also necessary for circadian gene expression to be main-2000), suggesting variable pathways could converge on CREB tained in slice preparations of the SCN (O’Neill et al., 2008), itactivation to promote changes in SCN clock gene expression was thought that cAMP could regulate firing rates of SCN neu-(Figure 2). rons through activation of HCN channels (Atkinson et al., 2011). Stimulation of the SCN by light, exogenous glutamate, or However, cAMP was not a potent regulator of HCN channel func-NO was able to generate a phase-response curve that corre- tion in SCN slice preparations, suggesting that the way in whichlated with the amount of time-of-day dependent induction of cAMP signaling maintains the molecular clock and AP firing inCREB phosphorylation (Ding et al., 1994, 1997; von Gall et al., the SCN still needs to be determined (Atkinson et al., 2011). It is1998). Both CREB phosphorylation and downstream transcrip- interesting to note, however, that the peaks in time-of-day varia-tion follow a circadian rhythm in the SCN (Obrietan et al., tions in cAMP and CRE–Luc activity (O’Neill et al., 2008) occur at1999), an effect that is mediated by mitogen-activated protein the same time as peaks in both firing rate and resting membranekinase (MAPK; Obrietan et al., 1998), which has been shown potential (Green and Gillette, 1982; Groos and Hendriks, 1982;to influence BMAL activity (Sanada et al., 2002; Akashi et al., de Jeu et al., 1998; Pennartz et al., 2002; Kuhlman and McMahon,2008). Similar processes are in common with the time-of-day 2004; Kononenko et al., 2008) and long-term potentiation (LTP;expression and persistence of hippocampal-dependent memory Nishikawa et al., 1995) in the SCN (Figure 3), suggesting func-(Eckel-Mahan et al., 2008), which depends on an intact SCN (Phan tional links related to changes in expression of these moleculesFrontiers in Molecular Neuroscience February 2012 | Volume 5 | Article 23 | 4 “fnmol-05-00023” — 2012/2/28 — 9:36 — page 4 — #4
  5. 5. Gerstner Ancient memory and metaplasticity FIGURE 3 | Models for testing circadian metaplasticity. Left : The Changes in cycling environmental inputs signal to the organism’s timing mammalian SCN has an endogenous circadian rhythm of cAMP and mechanisms, and integrates the incoming signal with the endogenous cAMP responsive element (CRE)–luciferase (Luc)-mediated transcription oscillators, engaging adaptive and resistant molecular and cellular processes. (O’Neill et al., 2008), that are elevated temporally with time-of-day These biological processes confer a neurophysiological correlate in the neural increases in firing rate (Green and Gillette, 1982; Welsh et al., 1995; network in the metaplastic synaptic response, which in turn generates a Quintero et al., 2003; Meredith et al., 2006) and long-term potentiation “metaplastic” change in behavior, based on the time-of-day. A typical (LTP; Nishikawa et al., 1995). Drosophila clock cells, the large Lateral phase-response (PR) curve is shown for photic and non-photic stimulation Ventral neurons (lLNv) have a similar circadian profile of firing rate (Cao and (Golombek and Rosenstein, 2010). This scheme can be generalized to more Nitabach, 2008; Sheeba et al., 2008; Fogle et al., 2011). While Drosophila complex cognitive processes, such as hippocampal molecular signaling, exhibit robust circadian-driven CRE–Luc activity broadly (Belvin et al., 1999), synaptic plasticity and memory, which also display time-of-day dependent it is unclear whether cAMP or CRE–Luc activity correlates with this activity changes in cAMP/MAPK/CREB activity, LTP and fear conditioning (Gerstner in the lLNvs, or if these cells exhibit LTP based on the time-of-day. Right : , and Yin, 2010).and as of yet to be identified channels may underlie the observed the rat optic nerve induced SCN LTP that was inhibited by bothchanges in neurophysiology. NOS inhibitors or Ca2+ /calmodulin kinase (CaMKII) inhibitors High-frequency stimulation of the optic tract induces LTP in (Fukunaga et al., 2002). Further, SCN LTP induction correlatedthe rat SCN that varies in field excitatory postsynaptic potentials with increases in phosphorylation of CaMKII, MAPK, and CREBbased on the time-of-day (Nishikawa et al., 1995). This effect can (Fukunaga et al., 2002), corroborating previous evidence whichbe considered a bona-fide occurrence of metaplasticity (Abraham, showed increases in CaMKII activation in the SCN following acute2008) since the same stimulation regimen can generate differ- light exposure (Yokota et al., 2001). Importantly, SCN LTP wasences in fEPSP. Time-of-day metaplasticity is also observed in induced to a greater extent at times-of-day that were unable tohippocampal circuits (Barnes et al., 1977; Harris and Teyler, 1983; alter phase-shifts in behavior. This may be predictable, since theDana and Martinez Jr., 1984; Raghavan et al., 1999; Chaudhury clock is already “tuned” to have an elevated firing rate duringet al., 2005) and memory behavior (Chaudhury and Colwell, 2002; this range of time (Figure 3). Therefore, changes in excitabilityEckel-Mahan and Storm, 2009), perhaps suggesting similar molec- could account for increases in LTP during the daytime, and a lackular and cellular processes that are likely conserved (Gerstner and in the photic-stimulated phase-response. Further, Fukunaga et al.Yin, 2010). SCN LTP is observed maximally during the subjective (2002) reported that they observed HFS-induced LTP during thelight phase, at a time that correlates with higher cAMP levels and night period, while their earlier report showed minimal inductionfiring rate (Figure 3). Interestingly, high-frequency stimulation of (Nishikawa et al., 1995). An important difference between the twoFrontiers in Molecular Neuroscience February 2012 | Volume 5 | Article 23 | 5 “fnmol-05-00023” — 2012/2/28 — 9:36 — page 5 — #5
  6. 6. Gerstner Ancient memory and metaplasticitystudies was that, as the authors noted, SCN slices were derived for regulators of both circadian rhythms and memory formation.a 12:12 LD cycle (Fukunaga et al., 2002) compared to “free-run” The similarities between these systems offers an opportunity toDD conditions in the previous study (Nishikawa et al., 1995). One study more simple models from which to further characterize thepossible explanation for the differences in results could revolve role of these molecules in the temporal gating that differentiatesaround the capacity of light to reinforce the underlying clock- allocation from long-term storage (Won and Silva, 2008). Futuremechanisms, establishing a “priming” effect that could potentially work examining the role of these molecules, and how they relatechange the susceptibility of the neurons to changes in metaplas- to SCN period-length-dependent phase shifting, should provideticity. Future studies determining the parameters in variations fundamental information on basic nervous system function, andof light–dark periods with stimulation protocols to evoke SCN could prove to be a very useful model for examining how itsLTP and phase-response curves will be important before consider- networks integrate properties of excitability with metaplasticitying the underlying molecular mechanisms involved in generating (Jedlicka, 2002; Abraham, 2008) or other forms of plasticity, suchcircadian metaplasticity. as homeostatic plasticity (Nelson and Turrigiano, 2008). The SCN action potential firing rate is under circadian con- Circadian molecules not previously implicated in synaptictrol (Green and Gillette, 1982; Welsh et al., 1995; Quintero et al., plasticity or learning may be implicated in higher-order cog-2003; Meredith et al., 2006). The time-of-day changes in baseline nitive processes, and essential for memory allocation and/orfiring rate could affect the sensitivity of time-of-day changes in cel- storage. For example, how important are these clock gene path-lular responsivity, network properties, and subsequent behavioral ways for the metaplasticity underlying the time-of-day changes inphase-shifts in response to light-stimulation. These changes, while limbic- or cortical-dependent LTP or memory? Similarly, aremetaplastic, could result from non-synaptic plasticity-related molecules that are known to regulate metaplasticity and mem-mechanism, such as spike timing-dependent plasticity or changes ory, such as PKMzeta (Drier et al., 2002; Sacktor, 2011; Sajikumarin neuronal excitability (Debanne and Poo, 2010), and still involve and Korte, 2011), able to regulate circadian rhythm plasticity? ThecAMP/MAPK/CREB signaling (Benito and Barco, 2010). These hypothesis would predict that the mechanisms are likely shared,changes could provide a mechanism for a “permissive state” to and therefore testable, especially in simple models, where simi-allow synaptic modifications that would be necessary for long- lar functions are likely conserved. Drosophila is a unique animallasting changes, analogous to those that are believed to be necessary model which offers the possibility to quickly study these questions.for memory storage (Mozzachiodi and Byrne, 2010). Indeed, net- If LTP and metaplasticity exist in the SCN through similar mech-work organization appears to dictate the plasticity of phase shifting anisms as the hippocampus of mammals, then this also predictsin the SCN (Schaap et al., 2003; Johnston et al., 2005; Rohling that LTP and metaplasticity should be observed in the clock cells ofet al., 2006; Inagaki et al., 2007; vanderLeest et al., 2007; Naito Drosophila (Figure 3). Since Drosophila also have well character-et al., 2008), which can vary in capacity depending on the intrin- ized phase-responses in circadian behavior to light manipulationssic photoperiod length (vanderLeest et al., 2009). Together, these (Rosato and Kyriacou, 2006), and conservation of most of thedata suggest that the synchronization of the SCN network can molecules involved in both circadian rhythms and memory for-influence the ability of the circuits to adapt to changes in envi- mation (Gerstner and Yin, 2010), these questions are also testable,ronmental stimuli. In addition to the underlying differences in and have specific predictions based on what is known in othermolecular oscillators discussed earlier, differences in excitability systems of higher-order species. Further, recent discoveries of theof ion channels, versus LTP-related mechanisms, could provide modulatory role of glial cells in plasticity-related processes andsome explanation for the observed changes in SCN period-length- synaptic scaling (Panatier et al., 2006; Stellwagen and Malenka,dependent phase shifting (vanderLeest et al., 2009). What is clear 2006; Henneberger et al., 2010), cognitive and memory processesis that time-of-day dependent changes exist in the response to (Halassa et al., 2009; Halassa and Haydon, 2010; Florian et al.,photic input stimulation on network properties within the SCN, 2011; Suzuki et al., 2011), along with a role in circadian rhythmswhich translate to alteration in phase-response behavioral output (Prolo et al., 2005; Suh and Jackson, 2007; Jackson, 2011; Marpe-(Figure 3). These metaplastic changes that are exhibited in the gan et al., 2011; Ng et al., 2011), suggest that this cell type is inSCN may mirror those that are observed in higher-order net- a unique position to integrate time-of-day dependent metaplas-work properties responsible for the memory trace, suggesting ticity. While a considerable amount of progress has been madeconservation of underlying molecular and cellular mechanisms in elucidating components of the molecular clock, it is clear thatfor adaptive and long-term changes in neural firing and synaptic a lot of work still remains in the field of circadian rhythms, andplasticity. future study using it as a model from which to examine functional links between molecular, cellular, and circuit mechanisms, andCONCLUSION how they contribute to metaplasticity and behavior should offerBasic timing mechanisms likely evolved to encode more complex a wealth of information for more complex higher-order cognitiveplasticity-related processes, and a fundamental aspect is the ability gate persistence from adaptation. How relevant environmentalinformation is encoded in biology to form “memory” would have ACKNOWLEDGMENTSevolved using this principle, thereby establishing a metaplastic Thanks to Dr. Allan Pack and the Center for Sleep and Circadianquality. The molecular mechanisms which appear to gate circa- Neurobiology for support and to Kartik Ramamoorthi for usefuldian metaplasticity likely involve the Ca2+ signaling, cGMP/PKG, discussions. Jason R. Gerstner is currently supported by NIH T32and cAMP/MAPK/CREB cascades, and likely represent conserved HL07713.Frontiers in Molecular Neuroscience February 2012 | Volume 5 | Article 23 | 6 “fnmol-05-00023” — 2012/2/28 — 9:36 — page 6 — #6
  7. 7. Gerstner Ancient memory and metaplasticityREFERENCES development of neuron selectivity: clock: mediation of nocturnal cir- entrainment. Physiol. Rev. 90, 1063–Abraham, W. C. (2008). Metaplastic- orientation specificity and binocu- cadian shifts by glutamate and NO. 1102. ity: tuning synapses and networks for lar interaction in visual cortex. J. Science 266, 1713–1717. Green, D. J., and Gillette, R. (1982). Cir- plasticity. Nat. Rev. Neurosci. 9, 387. Neurosci. 2, 32–48. Ding, J. M., Faiman, L. E., Hurst, W. J., cadian rhythm of firing rate recordedAbraham, W. C., and Bear, M. F. Brenner, S., Dove, W., Herskowitz, I., Kuriashkina, L. R., and Gillette, M. U. from single cells in the rat suprachi- (1996). Metaplasticity: the plasticity and Thomas, R. (1990). Genes and (1997). Resetting the biological clock: asmatic brain slice. Brain Res. 245, of synaptic plasticity. Trends Neurosci. development: molecular and logical mediation of nocturnal CREB phos- 198–200. 19, 126–130. themes. Genetics 126, 479–486. phorylation via light, glutamate, and Groos, G., and Hendriks, J. (1982).Agostino, P. V., Ferreyra, G. A., Cao, G., and Nitabach, M. N. nitric oxide. J. Neurosci. 17, 667–675. Circadian rhythms in electrical dis- Murad, A. D., Watanabe, Y., and (2008). Circadian control of mem- Drier, E. A., Tello, M. K., Cowan, M., charge of rat suprachiasmatic neu- Golombek, D. A. (2004). Diurnal, brane excitability in Drosophila Wu, P., Blace, N., Sacktor, T. C., and rones recorded in vitro. Neurosci. circadian and photic regulation melanogaster lateral ventral clock Yin, J. C. (2002). Memory enhance- Lett. 34, 283–288. of calcium/calmodulin-dependent neurons. J. Neurosci. 28, 6493–6501. ment and formation by atypical PKM Halassa, M. M., Florian, C., Fellin, T., kinase II and neuronal nitric oxide Chaudhury, D., and Colwell, C. S. activity in Drosophila melanogaster. Munoz, J. R., Lee, S. Y., Abel, T., synthase in the hamster suprachi- (2002). Circadian modulation of Nat. Neurosci. 5, 316–324. Haydon, P. G., and Frank, M. G. asmatic nuclei. Neurochem. Int. 44, learning and memory in fear- Eckel-Mahan, K. L., Phan, T., Han, S., (2009). Astrocytic modulation of 617–625. conditioned mice. Behav. Brain Res. Wang, H., Chan, G. C., Scheiner, Z. S., sleep homeostasis and cognitive con-Akashi, M., Hayasaka, N., Yamazaki, 133, 95–108. and Storm, D. R. (2008). Circadian sequences of sleep loss. Neuron 61, S., and Node, K. (2008). Mitogen- Chaudhury, D., Wang, L. M., and oscillation of hippocampal MAPK 213–219. activated protein kinase is a func- Colwell, C. S. (2005). Circadian reg- activity and cAmp: implications for Halassa, M. M., and Haydon, P. G. tional component of the autonomous ulation of hippocampal long-term memory persistence. Nat. Neurosci. (2010). Integrated brain circuits: circadian system in the suprachias- potentiation. J. Biol. Rhythms 20, 11, 1074–1082. astrocytic networks modulate neu- matic nucleus. J. Neurosci. 28, 4619– 225–236. Eckel-Mahan, K. L., and Storm, D. R. ronal activity and behavior. Annu. 4623. Colwell, C. S. (2011). Linking neu- (2009). Circadian rhythms and mem- Rev. Physiol. 72, 335–355.Amir, S., Beaule, C., Arvanitogiannis, ral activity and molecular oscillations ory: not so simple as cogs and gears. Hamada, T., Liou, S. Y., Fukushima, A., and Stewart, J. (2002). Modes of in the SCN. Nat. Rev. Neurosci. 12, EMBO Rep. 10, 584–591. T., Maruyama, T., Watanabe, S., plasticity within the mammalian cir- 553–569. Ferreyra, G. A., and Golombek, D. A. Mikoshiba, K., and Ishida, N. cadian system. Prog. Brain Res. 138, Comolli, J., Taylor, W., and Hastings, (2001). Rhythmicity of the cGMP- (1999a). The role of inositol 191–203. J. W. (1994). An inhibitor of protein related signal transduction pathway trisphosphate-induced Ca2+ releaseAtkinson, S. E., Maywood, E. S., Che- phosphorylation stops the circadian in the mammalian circadian system. from IP3-receptor in the rat supra- sham, J. E., Wozny, C., Colwell, C. S., oscillator and blocks light-induced Am. J. Physiol. Regul. Integr. Comp. chiasmatic nucleus on circadian Hastings, M. H., and Williams, S. R. phase shifting in Gonyaulax polyedra. Physiol. 280, R1348–R1355. entrainment mechanism. Neurosci. (2011). Cyclic AMP signaling con- J. Biol. Rhythms 9, 13–26. Florian, C., Vecsey, C. G., Halassa, Lett. 263, 125–128. trol of action potential firing rate and Cutler, D. J., Haraura, M., Reed, H. E., M. M., Haydon, P. G., and Abel, T. Hamada, T., Niki, T., Ziging, P., molecular circadian pacemaking in Shen, S., Sheward, W. J., Morrison, (2011). Astrocyte-derived adenosine Sugiyama, T., Watanabe, S., Miko- the suprachiasmatic nucleus. J. Biol. C. F., Marston, H. M., Harmar, A. J., and A1 receptor activity contribute shiba, K., and Ishida, N. (1999b). Rhythms 26, 210–220. and Piggins, H. D. (2003). The mouse to sleep loss-induced deficits in hip- Differential expression patterns ofAton, S. J., Colwell, C. S., Harmar, VPAC2 receptor confers suprachias- pocampal synaptic plasticity and inositol trisphosphate receptor types A. J., Waschek, J., and Herzog, matic nuclei cellular rhythmicity and memory in mice. J. Neurosci. 31, 1 and 3 in the rat suprachiasmatic E. D. (2005). Vasoactive intesti- responsiveness to vasoactive intesti- 6956–6962. nucleus. Brain Res. 838, 131–135. nal polypeptide mediates circadian nal polypeptide in vitro. Eur. J. Fogle, K. J., Parson, K. G., Dahm, N. Harmar, A. J., Marston, H. M., Shen, rhythmicity and synchrony in mam- Neurosci. 17, 197–204. A., and Holmes, T. C. (2011). CRYP- S., Spratt, C., West, K. M., Sheward, malian clock neurons. Nat. Neurosci. Dana, R. C., and Martinez, J. L. Jr. TOCHROME is a blue-light sensor W. J., Morrison, C. F., Dorin, J. R., 8, 476–483. (1984). Effect of adrenalectomy on that regulates neuronal firing rate. Piggins, H. D., Reubi, J. C., Kelly,Barnes, C. A., McNaughton, B. L., the circadian rhythm of LTP. Brain Science 331, 1409–1413. J. S., Maywood, E. S., and Hastings, Goddard, G. V., Douglas, R. M., Res. 308, 392–395. Friesen, W. O., and Block, G. D. (1984). M. H. (2002). The VPAC(2) recep- and Adamec, R. (1977). Circadian Debanne, D., and Poo, M. M. What is a biological oscillator? Am. J. tor is essential for circadian function rhythm of synaptic excitability in rat (2010). Spike-timing dependent plas- Physiol. 246, R847–R853. in the mouse suprachiasmatic nuclei. and monkey central nervous system. ticity beyond synapse – pre- and Fukunaga, K., Horikawa, K., Shibata, Cell 109, 497–508. Science 197, 91–92. post-synaptic plasticity of intrinsic S., Takeuchi, Y., and Miyamoto, E. Harris, K. M., and Teyler, T. J. (1983).Bass, J., and Takahashi, J. S. (2011). neuronal excitability. Front. Synap- (2002). Ca2+ /calmodulin-dependent Age differences in a circadian influ- Circadian rhythms: redox redux. tic Neurosci. 2:21. doi: 10.3389/fnsyn. protein kinase II-dependent long- ence on hippocampal LTP. Brain Res. Nature 469, 476–478. 2010.00021 term potentiation in the rat suprachi- 261, 69–73.Belle, M. D., Diekman, C. O., Forger, de Jeu, M., Hermes, M., and Pen- asmatic nucleus and its inhibition Hays, J. D., Imbrie, J., and Shackle- D. B., and Piggins, H. D. (2009). nartz, C. (1998). Circadian mod- by melatonin. J. Neurosci. Res. 70, ton, N. J. (1976). Variations in the Daily electrical silencing in the mam- ulation of membrane properties in 799–807. earth’s orbit: pacemaker of the ice malian circadian clock. Science 326, slices of rat suprachiasmatic nucleus. Gerstner, J. R., and Yin, J. C. (2010). ages. Science 194, 1121–1132. 281–284. Neuroreport 9, 3725–3729. Circadian rhythms and memory for- Henneberger, C., Papouin, T., Oliet, S.Belvin, M. P., Zhou, H., and Yin, J. C. Ding, J. M., Buchanan, G. F., Tischkau, mation. Nat. Rev. Neurosci. 11, H., and Rusakov, D. A. (2010). Long- (1999). The Drosophila dCREB2 gene S. A., Chen, D., Kuriashkina, L., 577–588. term potentiation depends on release affects the circadian clock. Neuron 22, Faiman, L. E., Alster, J. M., McPher- Ginty, D. D., Kornhauser, J. M., Thomp- of D-serine from astrocytes. Nature 777–787. son, P. S., Campbell, K. P., and son, M. A., Bading, H., Mayo, K. E., 463, 232–236.Benito, E., and Barco, A. (2010). CREB’s Gillette, M. U. (1998). A neuronal Takahashi, J. S., and Greenberg, M. E. Ikeda, M. (2004). Calcium dynamics control of intrinsic and synaptic ryanodine receptor mediates light- (1993). Regulation of CREB phos- and circadian rhythms in suprachias- plasticity: implications for CREB- induced phase delays of the circadian phorylation in the suprachiasmatic matic nucleus neurons. Neuroscien- dependent memory models. Trends clock. Nature 394, 381–384. nucleus by light and a circadian clock. tist 10, 315–324. Neurosci. 33, 230–240. Ding, J. M., Chen, D., Weber, E. T., Science 260, 238–241. Ikeda, M., Sugiyama, T., Wallace,Bienenstock, E. L., Cooper, L. N., and Faiman, L. E., Rea, M. A., and Gillette, Golombek, D. A., and Rosenstein, R. C. S., Gompf, H. S., Yoshioka, T., Munro, P. W. (1982). Theory for the M. U. (1994). Resetting the biological E. (2010). Physiology of circadian Miyawaki, A., and Allen, C. N. (2003).Frontiers in Molecular Neuroscience February 2012 | Volume 5 | Article 23 | 7 “fnmol-05-00023” — 2012/2/28 — 9:36 — page 7 — #7
  8. 8. Gerstner Ancient memory and metaplasticity Circadian dynamics of cytosolic and Kornhauser, J. M., Nelson, D. E., Mayo, Nahm, S. S., Farnell, Y. Z., Griffith, W., Panatier, A., Theodosis, D. T., Mothet, nuclear Ca2+ in single suprachias- K. E., and Takahashi, J. S. (1990). and Earnest, D. J. (2005). Circadian J. P., Touquet, B., Pollegioni, L., matic nucleus neurons. Neuron 38, Photic and circadian regulation of regulation and function of voltage- Poulain, D. A., and Oliet, S. H. 253–263. c-fos gene expression in the hamster dependent calcium channels in the (2006). Glia-derived D-serine con-Inagaki, N., Honma, S., Ono, D., suprachiasmatic nucleus. Neuron 5, suprachiasmatic nucleus. J. Neurosci. trols NMDA receptor activity and Tanahashi, Y., and Honma, K. (2007). 127–134. 25, 9304–9308. synaptic memory. Cell 125, 775–784. Separate oscillating cell groups in Kuhlman, S. J., and McMahon, Naito, E., Watanabe, T., Tei, H., Panda, S., Hogenesch, J. B., and Kay, mouse suprachiasmatic nucleus cou- D. G. (2004). Rhythmic regulation Yoshimura, T., and Ebihara, S. (2008). S. A. (2002). Circadian rhythms ple photoperiodically to the onset and of membrane potential and potas- Reorganization of the suprachias- from flies to human. Nature 417, end of daily activity. Proc. Natl. Acad. sium current persists in SCN neu- matic nucleus coding for day length. 329–335. Sci. U.S.A. 104, 7664–7669. rons in the absence of environ- J. Biol. Rhythms 23, 140–149. Paranjpe, D. A., and Sharma, V. K.Itri, J. N., Michel, S., Vansteensel, M. J., mental input. Eur. J. Neurosci. 20, Nakajima, M., Imai, K., Ito, H., Nishi- (2005). Evolution of temporal order Meijer, J. H., and Colwell, C. S. 1113–1117. waki, T., Murayama, Y., Iwasaki, H., in living organisms. J. Circadian (2005). Fast delayed rectifier potas- Langmesser, S., Franken, P., Feil, S., Oyama, T., and Kondo, T. (2005). Rhythms 3, 7. sium current is required for circa- Emmenegger, Y., Albrecht, U., and Reconstitution of circadian oscilla- Pennartz, C. M., de Jeu, M. T., Bos, N. dian neural activity. Nat. Neurosci. 8, Feil, R. (2009). cGMP-dependent tion of cyanobacterial KaiC phos- P., Schaap, J., and Geurtsen, A. M. 650–656. protein kinase type I is implicated in phorylation in vitro. Science 308, (2002). Diurnal modulation of pace-Itri, J. N., Vosko, A. M., Schroeder, the regulation of the timing and qual- 414–415. maker potentials and calcium current A., Dragich, J. M., Michel, S., and ity of sleep and wakefulness. PLoS Nelson, S. B., and Turrigiano, G. G. in the mammalian circadian clock. Colwell, C. S. (2010). Circadian regu- ONE 4, e4238. doi: 10.1371/journal. (2008). Strength through diversity. Nature 416, 286–290. lation of a-type potassium currents pone.0004238 Neuron 60, 477–482. Phan, T. X., Chan, G. C., Sindreu, C. in the suprachiasmatic nucleus. J. Marpegan, L., Swanstrom, A. E., Chung, Ng, F. S., Tangredi, M. M., and Jack- B., Eckel-Mahan, K. L., and Storm, Neurophysiol. 103, 632–640. K., Simon, T., Haydon, P. G., Khan, son, F. R. (2011). Glial cells phys- D. R. (2011). The diurnal oscillationJacklet, J. W. (1977). Neuronal circadian S. K., Liu, A. C., Herzog, E. D., and iologically modulate clock neurons of MAP (mitogen-activated protein) rhythm: phase shifting by a pro- Beaule, C. (2011). Circadian regula- and circadian behavior in a calcium- kinase and adenylyl cyclase activities tein synthesis inhibitor. Science 198, tion of ATP release in astrocytes. J. dependent manner. Curr. Biol. 21, in the hippocampus depends on the 69–71. Neurosci. 31, 8342–8350. 625–634. suprachiasmatic nucleus. J. Neurosci.Jackson, F. R. (2011). Glial cell modu- Mathur, A., Golombek, D. A., and Nishikawa, Y., Shibata, S., and 31, 10640–10647. lation of circadian rhythms. Glia 59, Ralph, M. R. (1996). cGMP- Watanabe, S. (1995). Circadian Pittendrigh, C. S. (1993). Temporal 1341–1350. dependent protein kinase inhibitors changes in long-term potentiation of organization: reflections of a Dar-Jedlicka, P. (2002). Synaptic plastic- block light-induced phase advances rat suprachiasmatic field potentials winian clock-watcher. Annu. Rev. ity, metaplasticity and BCM theory. of circadian rhythms in vivo. Am. J. elicited by optic nerve stimulation in Physiol. 55, 16–54. Bratisl. Lek. Listy 103, 137–143. Physiol. 270, R1031–R1036. vitro. Brain Res. 695, 158–162. Prolo, L. M., Takahashi, J. S., and Her-Johnston, J. D., Ebling, F. J., and Haz- Maywood, E. S., Reddy, A. B., Wong, Obrietan, K., Impey, S., Smith, D., zog, E. D. (2005). Circadian rhythm lerigg, D. G. (2005). Photoperiod G. K., O’Neill, J. S., O’Brien, Athos, J., and Storm, D. R. generation and entrainment in astro- regulates multiple gene expression J. A., McMahon, D. G., Harmar, (1999). Circadian regulation of cytes. J. Neurosci. 25, 404–408. in the suprachiasmatic nuclei and A. J., Okamura, H., and Hast- cAMP response element-mediated Prosser, R. A., and Gillette, M. U. (1989). pars tuberalis of the Siberian hamster ings, M. H. (2006). Synchronization gene expression in the suprachias- The mammalian circadian clock in (Phodopus sungorus). Eur. J. Neurosci. and maintenance of timekeeping in matic nuclei. J. Biol. Chem. 274, the suprachiasmatic nuclei is reset 21, 2967–2974. suprachiasmatic circadian clock cells 17748–17756. in vitro by cAMP. J. Neurosci. 9,Kent, J., and Meredith, A. L. (2008). by neuropeptidergic signaling. Curr. Obrietan, K., Impey, S., and Storm, 1073–1081. BK channels regulate spontaneous Biol. 16, 599–605. D. R. (1998). Light and cir- Prosser, R. A., McArthur, A. J., and action potential rhythmicity in the McIntosh, B. E., Hogenesch, J. B., and cadian rhythmicity regulate MAP Gillette, M. U. (1989). cGMP induces suprachiasmatic nucleus. PLoS ONE Bradfield, C. A. (2010). Mammalian kinase activation in the suprachi- phase shifts of a mammalian circa- 3, e3884. doi: 10.1371/journal.pone. Per-Arnt-Sim proteins in environ- asmatic nuclei. Nat. Neurosci. 1, dian pacemaker at night, in antiphase 0003884 mental adaptation. Annu. Rev. Phys- 693–700. to cAMP effects. Proc. Natl. Acad. Sci.Kim, D. Y., Choi, H. J., Kim, J. S., Kim, iol. 72, 625–645. O’Neill, J. S., Maywood, E. S., Chesham, U.S.A. 86, 6812–6815. Y. S., Jeong, D. U., Shin, H. C., Kim, Meredith, A. L., Wiler, S. W., Miller, J. E., Takahashi, J. S., and Hastings, M. Quintero, J. E., Kuhlman, S. J., and M. J., Han, H. C., Hong, S. K., and B. H., Takahashi, J. S., Fodor, H. (2008). cAMP-dependent signal- McMahon, D. G. (2003). The bio- Kim, Y. I. (2005). Voltage-gated cal- A. A., Ruby, N. F., and Aldrich, ing as a core component of the mam- logical clock nucleus: a multiphasic cium channels play crucial roles in the R. W. (2006). BK calcium-activated malian circadian pacemaker. Science oscillator network regulated by light. glutamate-induced phase shifts of the potassium channels regulate circa- 320, 949–953. J. Neurosci. 23, 8070–8076. rat suprachiasmatic circadian clock. dian behavioral rhythms and pace- O’Neill, J. S., and Reddy, A. B. (2011). Raghavan, A. V., Horowitz, J. M., and Eur. J. Neurosci. 21, 1215–1222. maker output. Nat. Neurosci. 9, Circadian clocks in human red blood Fuller, C. A. (1999). Diurnal mod-Kitayama, Y., Nishiwaki, T., Terauchi, 1041–1049. cells. Nature 469, 498–503. ulation of long-term potentiation in K., and Kondo, T. (2008). Dual Mohawk, J. A., and Takahashi, J. S. O’Neill, J. S., van Ooijen, G., Dixon, the hamster hippocampal slice. Brain KaiC-based oscillations constitute (2011). Cell autonomy and syn- L. E., Troein, C., Corellou, F., Bouget, Res. 833, 311–314. the circadian system of cyanobacte- chrony of suprachiasmatic nucleus F. Y., Reddy, A. B., and Millar, A. J. Rohling, J., Wolters, L., and Meijer, J. ria. Genes Dev. 22, 1513–1521. circadian oscillators. Trends Neurosci. (2011). Circadian rhythms persist H. (2006). Simulation of day-lengthKo, G. Y., Shi, L., and Ko, M. L. (2009). 34, 349–358. without transcription in a eukaryote. encoding in the SCN: from single-cell Circadian regulation of ion channels Moore, R. Y., and Speh, J. C. (1993). Nature 469, 554–558. to tissue-level organization. J. Biol. and their functions. J. Neurochem. GABA is the principal neurotrans- Oster, H., Werner, C., Magnone, M. C., Rhythms 21, 301–313. 110, 1150–1169. mitter of the circadian system. Neu- Mayser, H., Feil, R., Seeliger, M. W., Rosato, E., and Kyriacou, C. P.Kononenko, N. I., Kuehl-Kovarik, M. rosci. Lett. 150, 112–116. Hofmann, F., and Albrecht, U. (2003). (2006). Analysis of locomotor activ- C., Partin, K. M., and Dudek, F. E. Mozzachiodi, R., and Byrne, J. H. cGMP-dependent protein kinase II ity rhythms in Drosophila. Nat. Pro- (2008). Circadian difference in firing (2010). More than synaptic plastic- modulates mPer1 and mPer2 gene toc. 1, 559–568. rate of isolated rat suprachiasmatic ity: role of nonsynaptic plasticity in induction and influences phase shifts Sacktor, T. C. (2011). How does nucleus neurons. Neurosci. Lett. 436, learning and memory. Trends Neu- of the circadian clock. Curr. Biol. 13, PKMzeta maintain long-term mem- 314–316. rosci. 33, 17–26. 725–733. ory? Nat. Rev. Neurosci. 12, 9–15.Frontiers in Molecular Neuroscience February 2012 | Volume 5 | Article 23 | 8 “fnmol-05-00023” — 2012/2/28 — 9:36 — page 8 — #8
  9. 9. Gerstner Ancient memory and metaplasticitySajikumar, S., and Korte, M. (2011). of locomotor activity. Neuron 55, the SCN neuronal network organi- Involvement of calcium-calmodulin Metaplasticity governs compartmen- 435–447. zation. PLoS ONE 4, e4976. doi: protein kinase but not mitogen- talization of synaptic tagging and Suzuki, A., Stern, S. A., Bozdagi, O., 10.1371/journal.pone.0004976 activated protein kinase in light- capture through brain-derived neu- Huntley, G. W., Walker, R. H., von Gall, C., Duffield, G. E., Hastings, induced phase delays and Per gene rotrophic factor (BDNF) and protein Magistretti, P. J., and Alberini, M. H., Kopp, M. D., Dehghani, F., expression in the suprachiasmatic kinase Mzeta (PKMzeta). Proc. Natl. C. M. (2011). Astrocyte-neuron lac- Korf, H. W., and Stehle, J. H. (1998). nucleus of the hamster. J. Neurochem. Acad. Sci. U.S.A. 108, 2551–2556. tate transport is required for long- CREB in the mouse SCN: a molecular 77, 618–627.Sanada, K., Okano, T., and Fukada, term memory formation. Cell 144, interface coding the phase-adjusting Zhang, Y., Takahashi, J. S., and Turek, F. Y. (2002). Mitogen-activated protein 810–823. stimuli light, glutamate, PACAP, and W. (1996). Critical period for cyclo- kinase phosphorylates and negatively Tessmar-Raible, K., Raible, F., and melatonin for clockwork access. J. heximide blockade of light-induced regulates basic helix-loop-helix-PAS Arboleda, E. (2011). Another place, Neurosci. 18, 10389–10397. phase advances of the circadian loco- transcription factor BMAL1. J. Biol. another timer: marine species and Weber, E. T., Gannon, R. L., and Rea, M. motor activity rhythm in golden Chem. 277, 267–271. the rhythms of life. Bioessays 33, A. (1995). cGMP-dependent protein hamsters. Brain Res. 740, 285–290.Schaap, J., Albus, H., vanderLeest, 165–172. kinase inhibitor blocks light-induced H. T., Eilers, P. H., Detari, L., and Tischkau, S. A., Gallman, E. A., phase advances of circadian rhythms Conflict of Interest Statement: The Meijer, J. H. (2003). Heterogeneity Buchanan, G. F., and Gillette, in vivo. Neurosci. Lett. 197, 227–230. author declares that the research was of rhythmic suprachiasmatic nucleus M. U. (2000). Differential cAMP gat- Welsh, D. K., Logothetis, D. E., Meis- conducted in the absence of any com- neurons: implications for circadian ing of glutamatergic signaling regu- ter, M., and Reppert, S. M. (1995). mercial or financial relationships that waveform and photoperiodic encod- lates long-term state changes in the Individual neurons dissociated from could be construed as a potential con- ing. Proc. Natl. Acad. Sci. U.S.A. 100, suprachiasmatic circadian clock. J. rat suprachiasmatic nucleus express flict of interest. 15994–15999. Neurosci. 20, 7830–7837. independently phased circadian fir- Received: 27 October 2011; paper pendingSheeba, V., Gu, H., Sharma, V. K., Tomita, J., Nakajima, M., Kondo, ing rhythms. Neuron 14, 697–706. published: 12 December 2011; accepted: O’Dowd, D. K., and Holmes, T., and Iwasaki, H. (2005). No Won, J., and Silva, A. J. (2008). 11 February 2012; published online: 28 T. C. (2008). Circadian- and light- transcription–translation feedback in Molecular and cellular mechanisms February 2012. dependent regulation of resting circadian rhythm of KaiC phospho- of memory allocation in neuronet- Citation: Gerstner JR (2012) On the membrane potential and sponta- rylation. Science 307, 251–254. works. Neurobiol. Learn. Mem. 89, evolution of memory: a time for clocks. neous action potential firing of vanderLeest, H. T., Houben, T., Michel, 285–292. Front. Mol. Neurosci. 5:23. doi: 10.3389/ Drosophila circadian pacemaker neu- S., Deboer, T., Albus, H., Vansteensel, Yamaguchi, S., Isejima, H., Matsuo, fnmol.2012.00023 rons. J. Neurophysiol. 99, 976–988. M. J., Block, G. D., and Meijer, J. H. T., Okura, R., Yagita, K., Kobayashi, Copyright © 2012 Gerstner. This isStellwagen, D., and Malenka, R. C. (2007). Seasonal encoding by the cir- M., and Okamura, H. (2003). Syn- an open-access article distributed under (2006). Synaptic scaling mediated cadian pacemaker of the SCN. Curr. chronization of cellular clocks in the the terms of the Creative Commons by glial TNF-alpha. Nature 440, Biol. 17, 468–473. suprachiasmatic nucleus. Science 302, Attribution Non Commercial License, 1054–1059. vanderLeest, H. T., Rohling, J. H., 1408–1412. which permits non-commercial use, dis-Suh, J., and Jackson, F. R. (2007). Michel, S., and Meijer, J. H. (2009). Yokota, S., Yamamoto, M., Moriya, tribution, and reproduction in other Drosophila ebony activity is required Phase shifting capacity of the cir- T., Akiyama, M., Fukunaga, K., forums, provided the original authors and in glia for the circadian regulation cadian pacemaker determined by Miyamoto, E., and Shibata, S. (2001). source are credited.Frontiers in Molecular Neuroscience February 2012 | Volume 5 | Article 23 | 9 “fnmol-05-00023” — 2012/2/28 — 9:36 — page 9 — #9