Memory
processes, such as acquisition, consolidation and retrieval are temporally
regulated events. An intrinsic circadian (circa: about; dies:
day) timing system influencing the dynamics in memory processing has been
detected in animal models, ranging from invertebrates to mammalian species.
Several recent investigations, addressing the molecular mechanism behind the
circadian modulation of mnemonic processes shed light onto pathways known to be
essential in memory processing, such as the cAMP-CREB-MAPK-pathway, which by
itself is regulated by the circadian system. Notable, an important role for
rhythmic clock gene expressions in the hippocampus and in hippocampus-dependent
memory processes has been recently detected. However, the link between the
circadian gating of memory processes and its importance for daily life remain
highly elusive.In
the here presented work [1], Kondratova and co-workers approached the possible
effects of ageing on cognitive performances, with the experimental design
taking the known parallel decline in functional integrity of the circadian
system and cognitive performance into account. For this purpose, the authors
used 3-4 months old mice that are deficient for central clock genes, and thus,
no longer exhibit circadian rhythms. Importantly, among the mice used, was the Bmal1-deficient
mouse strain,
known for its accelerated ageing phenotype. Kondratova and co-workers observed
that behaviors, such as habituation to a novel environment were altered in mice
with deficiencies/mutations of core clock genes. Habituation to a novel
environment can be considered a form of non-associative learning, and is
dependent on (a) hippocampus-dependent working memory, a form of short-term
memory with regards to intra-session habituation and (b) long-term memory for
inter-session habituation. Bmal1- and Clock-knockout mice showed
deficiencies in both types of habituation in contrast to Cry1/2-deficient
mice that demonstrated facilitated habituation. The authors also proved by
using an open field test that elevated anxiety, which often correlates with
high locomotor activity and rearing, and deficits in contextual habituation
does not attribute to deficits in behavioral learning in the here used
clock-gene-knockout mice: Cry1,2-knockout mice showed
facilitated habituation in parallel to elevated levels of anxiety, while Bmal1-knockout
mice showed deficits in contextual habituation at significantly lower anxiety
levels.The
presented results confirm that a disruption of circadian clockwork impairs or
facilitates in parallel the intra- and inter-session contextual habituation of
mice. This observation acknowledges an essential regulatory role of core clock
gene proteins in the herein analyzed behaviors, and thus in memory processes.If
this is the case, then the interesting hypothesis, that an age-associated
dampening in the amplitude of rhythmic core clock protein expressions, or
alternative "ageing associated imbalance between circadian clock proteins", can
be linked to age-associated declines in mental performances.Many
questions remain: - Will
an in depth comparative analyses of hippocampus-based behavior between wildtype
and clock gene-deficient mice support the hypothesis? -
Is the age-associated decline in clock gene expression hippocampus-specific, or
a general phenomenon, and -
Does the decline in clock gene expression amplitude or in phase-stability in
the peripheral oscillator hippocampus, and/or in the brain circadian master
clock residing in the hypothalamic suprachiasmatic nucleus (SCN) matter, with
respect to the observed deterioration in mental performance? -
Are the observed deficits in habituation in clock gene-deficient mice based on
a hippocampal-intrinsic perturbation in time management, or -
Is the disrupted temporal gating of hippocampal function related to the
lesioned SCN clock in these knockout animals? -
Is the observed impairment of long-term memory formation related to
deficiencies of memory retrieval into working memory on the second day of
habituation testing, rather than to impairments in memory consolidation? A
clear answer to these urgent questions requires additional experiments, and
demands the generation and investigation of a forebrain-specific conditional
clock gene-knockout animal model. Then, the potential role of an ageing
clockwork in the brain on mnemonic processes can be refined and attributed to a
spatial component.So
while the time is ripe to acknowledge the effect of ageing on the time-of-day
dependency of cognitive performances, much work remains to support the here
hypothesized link between ageing associated decline in circadian behavior and
memory formation.