Biology Reference
In-Depth Information
knockout of Dec2 did not result in a decrease in sleep, but
transgenic mice carrying the specific point mutation
exhibited decreased sleep time without affecting circadian
period, suggesting a dominant effect
[83]
.
One caveat of the genetic studies mentioned above is
the possibility of a tissue-specific non-circadian role of
core clock genes, i.e., a given gene might regulate the
core clock in SCN but homeostatic sleep drive in another
brain region such as VLPO. Under such conditions global
deletion of a clock gene will presumably produce circa-
dian and sleep
But how are memories made? The hippocampus,
located deep within the mediotemporal lobe, is considered
a basecamp for cognitive processes (see
Figure 21.1
).
Having paid attention to an event (learning), memory of
that event can be acquired, retained, and eventually recal-
led. Consolidation is a process by which short-term
memory (STM), which lasts on a scale of seconds to
minutes, is stabilized (by association with cortical circuitry)
to long-term memory (LTM) that can last for hours,
months, and even years
[85,86]
. Although the molecular
distinction of these two processes has been difficult to
dissect, the sensitivity of these two processes seems to
differ across phylogeny. STM in invertebrates has been
shown to be sensitive to circadian perturbations
[87,88]
.
Interestingly, in vertebrates STM remains unaffected, but
the consolidation and recall of memory was found to be
profoundly affected by circadian perturbation
[89]
.
Over the last few decades, studies have explored the
role of circadian rhythms in cognition using behavioral,
neurophysiological, and genetic perturbation. However,
given our discussion on the influence of sleep or behavior
state, we can now appreciate the complexity of under-
standing the circadian component in cognition. To over-
come the influence of the master oscillator, early studies
included electrolytic lesioning of the SCN followed by
behavioral analysis of hippocampal-specific tasks such as
inhibitory avoidance conditioning
[90]
. These studies
found clear time-of-day memory retention deficits (
[90]
;
but also see;
[91,92]
). Others have approached this question
differently, using behavioral perturbations similar to those
discussed above in the section on sleep. In a recent publi-
cation by the Colwell group
[93]
, circadian perturbations
were achieved by acute phase-shifts in the light
wake phenotypic defects. Hence to
elucidate clearly whether Process-C directly impinges on
homeostatic sleep, sleep analysis may need to be con-
ducted in animals with SCN-specific gene ablation of the
core clock genes
[84]
.
In summary, the sleep homeostat and the circadian
clock are highly interconnected at the molecular and
behavioral levels. The clock, which is thought to help
maintain adaptive homeostasis, and sleep, which is a crit-
ical homeostatic need, work together.
e
HOMEOSTASIS: YOU NOTICE IT WHEN
IT'S BROKEN
In vertebrates, much of what we know about the role of the
clock in physiology and behavior is driven by observational
studies in normal animals or human subjects, or in mouse
models of core clock genes. Conceptually, it is easy to
understand how the clock and sleep are related: after all,
each of us experiences this relationship almost every day.
Less well understood, however, is the way that the clock
influences other less obvious systems such as cognition and
metabolism. Finally, how it does so, largely through
a cascade of signaling between the hypothalamus, other
nuclei in the CNS, and the periphery, remains largely
a mystery.
dark cycle
that mimicked 'jet-lag'. These mice displayed no change in
overall sleep-time but showed clear deficits in memory
recall in a fear-conditioning paradigm (see also
[94]
). This
work neatly adds to previous observations that the peak-
time in memory acquisition and recall exhibits a circadian
profile in mice (
[95]
; but also see
[96,97]
). Next, studies
exploring adult hippocampal neurogenesis have provided
an unexpected glimpse at the influence of the circadian
homeostat in learning and memory
[98]
. Adult hippo-
campal neurogenesis has been shown to increase after two
circadian-driven events, namely a hippocampal-dependent
learning task
[98,99]
and exercise, i.e., wheel running
activity
[100,101]
. Indeed Per2
Brdm
(non-functional Per2)
mice were shown to have increased neuronal stem cell
proliferation, suggesting the involvement of core clock
proteins in the cell cycle
[102
e
Cognition (Learning and Memory)
You are likely familiar with the phrase 'I'm too tired to
think'. Disruption of the circadian clock disrupts not only
the sleep
wake cycle but many other dependent processes,
notably cognition. Mammals are able to learn the charac-
teristics of their environment, remember them, anticipate
their recurrence, and adapt their behavior accordingly. Put
differently,
e
animals
schedule
their
feeding patterns,
sleep
wake cycles, and associated homeostatic processes
based on experience. However, as an added layer of
complexity, the circadian homeostat impinges on our
ability to perform cognitive tasks and we show time-of-day
difference in tasks such as learning, registering and
recalling memories. Maybe we are too tired to think
because we are not supposed to think at certain times of day
(or night).
e
104]
, and more specifically
adult neurogenesis
[105]
. This view has been strengthened
by studies wherein experimental jet-lag (a 6-hour phase
advance every 3 days for 25 days) in adult hamsters led to
pronounced deficits in hippocampal neurogenesis and
concurrent deficit in hippocampal learning and memory
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