Processes of the Old Period in A Bio Electronic Model of Life_Crimson Publishrs
Gerstner Frontiers Mol Neurosci 2012
1. PERSPECTIVE ARTICLE
published: 28 February 2012
MOLECULAR NEUROSCIENCE doi: 10.3389/fnmol.2012.00023
On the evolution of memory: a time for clocks
Jason R. Gerstner*
Center for Sleep and Circadian Neurobiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Edited 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-dependent
California at Irvine, USA
changes in molecular signaling with cellular processes that ultimately lead to behavioral
Reviewed 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 serve
Trongha 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 been
Jason R. Gerstner, Center for Sleep
and 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 in
Street, Philadelphia, PA 19104, USA.
more simple circuits may have been redeployed in higher-order brain regions. Therefore,
e-mail: gerstner@upenn.edu
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, excitability
EVOLUTIONARY EMERGENCE OF “MEMORY”: metaplasticity (Bienenstock et al., 1982; Abraham and Bear, 1996;
A PERSPECTIVE Jedlicka, 2002), a term adopted from neuroscience describing the
Early 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’s
essential chemicals (nutrients) for biological energy utilization orbit eccentricity, axial tilt, and precession. These changes are
and early metabolic chemical reactions. The cyclical nature of the believed to contribute too much larger periodic environmental
earth’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). Individual
cues from which biology would have evolved molecular mecha- components can vary in period length, and oscillate over large
nisms 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 in
be considered one basis from which primordial molecular memory daily periodicity broadly over evolutionary time, reinforcing a
evolved. 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 shorter
such as light and temperature, and their overlap with the availabil- time-courses would have allowed more “predictable” alterations in
ity 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 entrained
could have led to an organization of molecular and cellular pro- clocks would have been the ability to “free-run” in the absence of
cesses contributing to a behavioral response which coincided with external cues (Pittendrigh, 1993), exhibiting the earliest form of
regular, 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 would
over time, such as annual periodic changes in day length. Modu- have provided extremes for life to exist and thrive, similar to limits
lation of stimuli would therefore have led this “timing” machinery on a spectrum. For life to survive optimally, an adaptive quality
subject 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 out
its 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 a
occurring 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 behavior
plasticity within this rhythmic biological mechanism, producing in higher-order organisms today could have evolved out of more
an additive ability to be plastic, referred to here broadly as simple adaptive molecular machinery, such as from clock-forming
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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 have
within the organism, but could be viewed as fundamental to persis- also been shown to be involved in various temporal-sensitive
tent 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 genes
an ancient memory-coding strategy that evolved from earlier is not as completely conserved, but instead resembles a similar
life 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 repression
factors 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 maintain
of the Per-Arnt-Sim (PAS) domain family that regulate antici- cycling, but retains adaptive qualities to react to changes in the
patory and adaptive responses to changes in the environment environment.
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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 with
of 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 and
Tomita et al., 2005). However, it should be noted that in intact reproductive fitness. Therefore, these clocks likely emerged during
cyanobacteria, 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 neuronal
that 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 and
structure, may have predated more complex cellular processes, memory-coding strategies that we are now trying to understand
in order to optimize internal bioenergetic signaling with vary- today. By understanding the functional relationships between
ing 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 in
vival (Figure 1). Evolutionarily more recent oscillators involving higher-order species with more complex nervous systems and
transcriptional–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 CIRCUITS
fuel-utilization cycling, and predicts yet to be identified signaling TO BEHAVIOR
cofactors 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 underlying
least common ancient time-keeping mechanism linking energetic molecular biology and neurophysiology can “free-run” in the
and 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 to
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4. Gerstner Ancient memory and metaplasticity
differential 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. The
feedback network where CLOCK and BMAL heterodimerize to ability to phase-shift circadian rhythms is also dependent on
transactivate 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 also
tion 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 light
hashi, 2011). While the majority of neurons in the SCN are correlated with the amount of the immediate-early gene c-fos
GABAergic (Moore and Speh, 1993), photic stimulation of gluta- mRNA expression in the SCN, which in turn correlated with the
matergic N-methyl-D-aspartate receptors (NMDA-R) - mediates amount of phase-shift behavioral response, at times when the
calcium (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 activation
light- and glutamate-induced phase shifts (Kim et al., 2005), and of the SCN stimulates plasticity-related processes during a specific
tie 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 the
also 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 clock
1999b), and can regulate the level of Ca2+ in the SCN (Hamada operates on neurophysiological changes is not well understood
et 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 synchronization
phase delay when light is delivered in the early dark phase, or of neuronal networks (Mohawk and Takahashi, 2011). Circadian
a 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 current
2009). NOS activation by CaMKII phosphorylation (P) is nec- (Kent and Meredith, 2008), and the A-type potassium currents (Itri
essary for normal light-induced phase shifts in the SCN (Agostino et al., 2010). Changes in SCN neurophysiology has been shown to
et 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 levels
and 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 molecular
regulated 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 receptor
shifts 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 oscillations
A (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), it
activation 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 which
lated with the amount of time-of-day dependent induction of cAMP signaling maintains the molecular clock and AP firing in
CREB phosphorylation (Ding et al., 1994, 1997; von Gall et al., the SCN still needs to be determined (Atkinson et al., 2011). It is
1998). 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 at
1999), an effect that is mediated by mitogen-activated protein the same time as peaks in both firing rate and resting membrane
kinase (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 molecules
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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 both
changes 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 correlated
the rat SCN that varies in field excitatory postsynaptic potentials with increases in phosphorylation of CaMKII, MAPK, and CREB
based on the time-of-day (Nishikawa et al., 1995). This effect can (Fukunaga et al., 2002), corroborating previous evidence which
be considered a bona-fide occurrence of metaplasticity (Abraham, showed increases in CaMKII activation in the SCN following acute
2008) since the same stimulation regimen can generate differ- light exposure (Yokota et al., 2001). Importantly, SCN LTP was
ences in fEPSP. Time-of-day metaplasticity is also observed in induced to a greater extent at times-of-day that were unable to
hippocampal circuits (Barnes et al., 1977; Harris and Teyler, 1983; alter phase-shifts in behavior. This may be predictable, since the
Dana and Martinez Jr., 1984; Raghavan et al., 1999; Chaudhury clock is already “tuned” to have an elevated firing rate during
et al., 2005) and memory behavior (Chaudhury and Colwell, 2002; this range of time (Figure 3). Therefore, changes in excitability
Eckel-Mahan and Storm, 2009), perhaps suggesting similar molec- could account for increases in LTP during the daytime, and a lack
ular 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 the
light phase, at a time that correlates with higher cAMP levels and night period, while their earlier report showed minimal induction
firing rate (Figure 3). Interestingly, high-frequency stimulation of (Nishikawa et al., 1995). An important difference between the two
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6. Gerstner Ancient memory and metaplasticity
studies 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 to
DD conditions in the previous study (Nishikawa et al., 1995). One study more simple models from which to further characterize the
possible explanation for the differences in results could revolve role of these molecules in the temporal gating that differentiates
around the capacity of light to reinforce the underlying clock- allocation from long-term storage (Won and Silva, 2008). Future
mechanisms, establishing a “priming” effect that could potentially work examining the role of these molecules, and how they relate
change the susceptibility of the neurons to changes in metaplas- to SCN period-length-dependent phase shifting, should provide
ticity. Future studies determining the parameters in variations fundamental information on basic nervous system function, and
of light–dark periods with stimulation protocols to evoke SCN could prove to be a very useful model for examining how its
LTP and phase-response curves will be important before consider- networks integrate properties of excitability with metaplasticity
ing the underlying molecular mechanisms involved in generating (Jedlicka, 2002; Abraham, 2008) or other forms of plasticity, such
circadian metaplasticity. as homeostatic plasticity (Nelson and Turrigiano, 2008).
The SCN action potential firing rate is under circadian con- Circadian molecules not previously implicated in synaptic
trol (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/or
firing 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 in
phase-shifts in response to light-stimulation. These changes, while limbic- or cortical-dependent LTP or memory? Similarly, are
metaplastic, 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; Sajikumar
in neuronal excitability (Debanne and Poo, 2010), and still involve and Korte, 2011), able to regulate circadian rhythm plasticity? The
cAMP/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 animal
lasting 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 predicts
in the SCN (Schaap et al., 2003; Johnston et al., 2005; Rohling that LTP and metaplasticity should be observed in the clock cells of
et 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 manipulations
sic photoperiod length (vanderLeest et al., 2009). Together, these (Rosato and Kyriacou, 2006), and conservation of most of the
data 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 other
molecular oscillators discussed earlier, differences in excitability systems of higher-order species. Further, recent discoveries of the
of ion channels, versus LTP-related mechanisms, could provide modulatory role of glial cells in plasticity-related processes and
some 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 processes
is 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 rhythms
which 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 in
SCN 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 made
conservation of underlying molecular and cellular mechanisms in elucidating components of the molecular clock, it is clear that
for adaptive and long-term changes in neural firing and synaptic a lot of work still remains in the field of circadian rhythms, and
plasticity. future study using it as a model from which to examine functional
links between molecular, cellular, and circuit mechanisms, and
CONCLUSION how they contribute to metaplasticity and behavior should offer
Basic timing mechanisms likely evolved to encode more complex a wealth of information for more complex higher-order cognitive
plasticity-related processes, and a fundamental aspect is the ability processes.
to gate persistence from adaptation. How relevant environmental
information is encoded in biology to form “memory” would have ACKNOWLEDGMENTS
evolved using this principle, thereby establishing a metaplastic Thanks to Dr. Allan Pack and the Center for Sleep and Circadian
quality. The molecular mechanisms which appear to gate circa- Neurobiology for support and to Kartik Ramamoorthi for useful
dian metaplasticity likely involve the Ca2+ signaling, cGMP/PKG, discussions. Jason R. Gerstner is currently supported by NIH T32
and cAMP/MAPK/CREB cascades, and likely represent conserved HL07713.
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