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circadian-dependent suppression was alleviated by phar-
macological facilitation of the MAPK pathway in Aplysia
[132]
, raising the interesting possibility of circadian-phase
specific de-repression of cognitive abilities.
In summary, a picture emerges wherein the hippo-
campus uses its own clock to enable cognitive homeostasis.
Just as light entrains the SCN, a tantalizing suggestion is
that cognitive processes could function as zeitgebers (time
cues) for the hippocampal clock
[134]
. If true, this would
indicate a reciprocal relationship between cognitive
performance and the circadian phase of the hippocampal
clock. Expounding on this hypothesis, it would be easy to
reason that cognitive tasks need to be performed in sync
with the master clock. Indeed, various studies have found
direct and significant correlation between an individual's
chronotype (preference for activity in either morning or
evening) and cognitive performance
[135,136]
. Further,
however impractical, this would argue against the rigid
design of timetables in schools and other educational
institutions
[137]
. Another implication involves professions
that have high demands for cognitive performance often
atop a compromised circadian homeostat, such as air traffic
controllers, pilots, shift workers or doctors. With improving
knowledge of signaling pathways it might become feasible
pharmaceutically to relieve the impact of the clock in at
least some aspects of cognitive performance.
peripheral tissues may take shorter or longer. In the CNS,
a loss in communication between the SCN and other brain
nuclei can aggravate or even result in neuropsychiatric
disorders. A comprehensive review of all neuropsychiatric
disorders influenced by the circadian system is beyond the
scope of
this discussion and is covered elsewhere
[141
143]
. Instead, we will briefly discuss a few well-
known links between the circadian system and some
neurological disorders followed by our current under-
standings/hypotheses regarding the mode of this action.
There is a strong link between disruption of circadian
homeostasis and bipolar disorder. Bipolar disorder (BPD) is
associated with rapid switching between a spectrum of
symptoms that range from depression to mood elevation
(mania and hypomania) and from low-grade mood cycling
to full psychosis. Disruption of the 24-hour sleep
e
wake
cycle is one of the strongest etiological triggers for
a relapse into mania, and therapies for BPD often involve
regimens of stable and adequate sleep
[141]
. Transgenic
mice carrying the dominant negative Clock (Clk
D
19
) allele
recapitulate hallmarks of BPD, namely a decreased need
for sleep, increased motor activity, lower anxiety, and an
increased susceptibility to drugs of abuse such as cocaine
[144]
. Similar results are obtained by RNAi-dependent
knockdown of the Clock gene (Clk) in the ventral tegmental
area (VTA), a brain region involved in the 'reward
circuitry' (discussed below;
[145]
). Furthermore, treatment
of Clk
D
19
mice with lithium, a mood-stabilizing drug used
in human patients, restores normal behavior
[146]
. SNP
analysis and gene-association studies have confirmed
association of Clock with BPD and have extended the
association of other clock genes, including Bmal1 and
Per3
[147]
.
Normal seasonal variation is enough to disrupt the
homeostasis of certain patients with seasonal affective
disorder (SAD). For example, in many parts of the world,
day length and light exposure change with the seasons.
SAD manifests circa-annually, with individuals having
normal mental health throughout most of the year but
experiencing depressive symptoms seasonally (usually in
the winter;
[148,149]
). In fact, SAD is considered to be
a type of major depressive disorder (MDD) according to
international classification schemes of psychiatric disorders
(the Diagnostic and Statistical Manual of Mental Disorders
(DSM-IV) of the American Psychiatric Association and the
International Classification of Disorders (ICD-10) of the
World Health Organization). Restoring light, i.e., light
therapy, is currently the most effective treatment for SAD
[150]
. Blue-light-photosensitive retinal ganglion cells
(pRGCs) use the photopigment melanopsin (Opn4) and
project from the retina into the SCN and VLPO. pRGCs can
trigger a cascade of neuronal activities that are critical for
the entrainment of the molecular clock to the local light
cycle and in regulating sleep
e
Neuropsychiatric Disorders
The clinical manifestations of many central nervous system
(CNS) disorders are deregulated circadian rhythms (core
body temperature, cortisol/melatonin levels) and/or sleep
cycles. Although it is difficult to directly resolve causality,
these studies indicate that disruption of circadian oscillators
can affect CNS disease severity.
In the mammalian brain, in addition to the hippo-
campus, various extra-SCN or slave oscillators have been
discovered in the last decade (see
Figure 21.1
;
[138]
).
Synchronizing factors such as hormones, neuronal
connections, paracrine signals, metabolites and body
temperature can cause changes in phase/expression levels
in a tissue-specific (and often sub-structural) level without
affecting the SCN (see below for more discussion on this
topic). For example, glucocorticoids such as corticosterone
can modulate expression of clock proteins such as Per1 in
the hippocampus but not in the SCN
[139,140]
. Thus,
rhythmic signals orchestrated by the SCN synchronize
peripheral clocks, including those within the brain. Various
aspects of modern life, including abnormal light exposure
via artificial lightning, sleep deprivation induced by shift
work, jet-lag due to travel across time zones, side effects of
medications, and abnormal social environments, ultimately
lead to desynchrony of these internal clocks
[141,142]
. This
is because the SCN resets over a period of days, whereas
wake cycles. Interestingly,
e
