Biology Reference
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[106]
. Furthermore, these deficits persisted even after the
animals were returned to normal LD cycles, suggesting
a long-term effect of circadian disruption on cognitive
functions.
Our discussion thus far suggests a causal role of the
SCN master clock in learning and memory processes in the
hippocampus. However, over the last decade studies have
enabled us to appreciate the hippocampus as a circadian
pacemaker in its own right. First, circadian rhythms
observed at the molecular and neurophysiological levels
persisted in hippocampal tissue culture, i.e., in the absence
of SCN connections
[107]
. Importantly, time-of-harvest
did not seem to influence the hippocampus clock, giving
further credence for the presence of an endogenous oscil-
lator within the hippocampus. Second, circadian rhythms
observed in at least some forms of learned behavior do not
seem to require an intact SCN
[91, 92]
. So what drives the
clock in the hippocampus? The same set of core clock
genes as seen in the SCN seems to be responsible for
driving rhythms in the hippocampus. Bmal1 [108,109],
Clock [108], Cry(1&2)
[109]
and Per(1&2)
[105,107]
are
all known to oscillate robustly in the hippocampus, albeit
often peaking out of phase with the SCN and even at
different phases within the sub-regions of the hippo-
campus. For example, Per2 expression in the CA1
But why do we need a functional clock in the hippo-
campus? In 1949 Donald Hebb posited that repeated
feedback loops of actively firing neurons are required for
memory consolidation (also referred to as the Hebbian or
the dual-trace theory)
[114,115]
. We also know that
repeated and persistent kinase activation, protein synthesis,
and gene expression are needed for new memory formation.
Such reverberating loops of activity/inactivity are best
achieved by the oscillating components of the hippocampal
clock
[106]
. In summary, the hippocampal clock can be
postulated to perform three main functions: (a) it provides
a time-stamp for certain forms of memory; (b) it sub-serves
pleiotropic function using the same network of core clock
genes; and (c) it provides a framework for 'reverberating
circuits' enabling memory consolidation. In support of this
hypothesis, mice with global deletion of clock genes such
as Npas2
-/-
[117]
, Cry(1,2)
-/-
[118]
, Per2
-/-
[107]
, Bmal1
-/-
[119]
and VIP
-/-
[120]
exhibit cognitive defects. However,
global deletion of clock genes is confounded by the
potential role of clock genes in sleep and other behavioral
states of these animals (as discussed above). Hence,
although a strong precedent exists for the role of clock
genes in cognition, there is a clear need for a re-evaluation
of cognitive abilities in mice with tissue-specific ablation of
clock genes. Various genetic methods are now available for
tissue-specific ablation or silencing of genes (see reviews
[121
3
regions is anti-phase to the SCN, with peaks in the former
at ZT2 and in the latter at ZT14
[107]
. Also, Bmal1
expression peaks around ZT10 in the CA3 region of the
hippocampus but at ZT2 in the CA1 region
[108]
.One
speculation is that by peaking at different phases, circadian
genes guide the diverse biological and physiological
functions within these sub-regions. Within the hippo-
campus molecular rhythms of clock genes most likely
drive the rhythms observed in its synaptic plasticity,
a neurophysiological correlate of learning and memory.
Long-term potentiation (LTP) is a synaptic plasticity event
that is often regarded as an onset marker for learning and
memory. Following repeated stimulation, a neuronal
circuit can be said to have undergone LTP if it is rendered
more sensitive to subsequent stimulations. Studies span-
ning three decades have consistently reported a time-of-
day effect on the incidence and magnitude of LTP in
electrophysiological recordings from mouse hippocampal
slices
[110
e
124]
).
The cross-talk between circadian timing, synaptic
plasticity mechanisms and memory formation has been
evolutionarily conserved between invertebrates (insects
(Drosophila), gastropods (Aplysia)) and vertebrates
(zebrafish, mouse, and human)
[125]
. The extracellular
signal-regulated kinase (ERK) isoforms participate in the
MAPK/cAMP cascade and have long been known to be
indispensable for memory consolidation
[126
e
128]
as well
as light-dependent phase resetting of the SCN
[129
e
131]
.
In recent landmark studies, circadian rhythms of ERK and
other signaling components of the MAPK/cAMP cascade
were shown to influence the time-of-day differences in
cognition
[96,132]
. Eckel-Mahan et al.
[96]
provided the
first molecular and mechanistic details of this cross-talk in
a mammalian system. They demonstrated that within the
CA1 and CA3 sub-regions of the hippocampus, (a) ERK
phosphorylation occurred in a circadian fashion, and (b)
these rhythms were indispensable for the consolidation of
hippocampal-dependent contextual fear-conditioned
memory. Furthermore, the authors showed that the circa-
dian peak in Erk phosphorylation coincided with the
animal's peak capacity in forming new long-term hippo-
campal-dependent memory. A follow-up study from the
same group confirmed that SCN-lesioned mice lose
hippocampal rhythms in the signaling components of
the cAMP-MAPK-CREB pathway along with deficits
in fear-conditioned memory
[133]
.
e
112]
. Thus the circadian homeostat enables
metaplasticity
[113]
wherein one level of plasticity, time-
of-day, layers atop another, synaptic plasticity. Behavior-
ally, hippocampal-dependent tasks such as spatial/novel
object recognition and classic fear conditioning are
thought to elicit LTP-like responses and concurrently
exhibit time-of-day differences in such tests. Taken
together, the hippocampus utilizes the same set of core-
clock genes as found in the SCN to drive circadian rhythms
found in hippocampal-related molecular, physiological
and behavioral assays.
e
Interestingly,
this
