Biology Reference
In-Depth Information
polymorphisms in the gene encoding Opn4 are linked to
SAD
[151]
. Furthermore, gene-association studies have
also found strong correlation in polymorphisms within the
clock genes Bmal1, Npas2 and Per2 with susceptibility to
SAD
[152]
. Similar roles of the circadian system have been
identified in other diseases such as schizophrenia
[153,154]
, addiction
[144,146,155,156]
and anxiety/
hyperactivity-based disorders
[119,157,158]
. Taken
together these studies emphasize the strong relationship
between circadian system-driven homeostasis and our
neuropsychological state.
How does the circadian state influence such a diverse
range of neuropsychiatric disorders? Although recent
studies provide some insight, research is required to
provide in-depth mechanistic details for the cross-talk
between the biological clock and CNS processes. As dis-
cussed above, lithium, used clinically to treat BPD and
other mood disorders, is also known to be a potent inhibitor
of glycogen synthase kinase 3
b
(GSK3
b
)
[6,7]
. Interest-
ingly, GSK3
b
can influence the nuclear localization and
stability of circadian clock proteins REV-ERB
a
[159]
and
PER2
[160,161]
. In the nucleus, REV-ERB
a
functions as
a potent repressor of Bmal1 transcription
[162]
. However,
lithium has many more targets than just GSK3
b
, and it
remains to be seen whether its effect on depression is
mediated through the clock.
The dopamine system provides another potential
mechanism. Dopamine-mediated neurotransmission in the
midbrain, specifically in the ventral tegmental area (VTA),
is a crucial component of the brain's reward circuit.
Deregulation of dopamine-based neurocircuitry is often
associated with susceptibility to drugs of abuse such as
cocaine and methamphetamines and neuropsychiatric
disorders such as depression, attention deficit hyperactivity
disorder (ADHD) and schizophrenia
[141]
. As discussed
above, Clk
D
19
mice were found to exhibit BPD-like
behavior
[144]
. The same study also found that the activity
of tyrosine hydroxylase, the principal enzyme involved in
dopamine synthesis, is elevated in the VTA of these mice.
Restoration of the wild-type clock gene in the VTA rescued
the mice from some of the mood-related abnormalities. A
more recent study identified monoamine oxidase A
(MAOA), a key enzyme involved in the breakdown of
dopamine under circadian control
[163]
. This study shows
that transcription of MAOA both in vitro and in vivo is
under the control of clock genes Npas2, Bmal1, and Per2.
Additionally, the Per2-mutant mice (Per2
Brdm
) display
reduced MAOA levels with increased dopamine levels, and
interestingly were found to be more resilient than wild-type
mice in behavioral tests that induced a depression-like
phenotype
[163]
. Finally, disruption in the circadian
secretion of neurotransmitters such as neuropeptide Y
(NPY) or vasoactive intestinal peptide (VIP) could also
lead to anxiety-like behavior and aggression
[164,165]
.
In hindsight, time-of-day effects on our emotional and
mental faculties seem obvious, but the molecular relevance
of these effects is only beginning to be appreciated. The
causal roles of 'nature vs. nurture' in an individual's
cognitive/behavioral output have been a long-standing
debate. We know that genetic make-up can predispose one
to neurological and behavioral imbalances; however,
circadian research has provided insight into how these
genetically driven imbalances can at times be compensated
or exacerbated by environmental perturbations. For
example, the influence of social pressures such as 'social
jet-lag', regimented/restricted sleep or activity, or light/
noise exposure at night (especially for city dwellers) could
have neurological
consequences during development
[166
e
171]
.
CLOCKS IN ENERGY AND METABOLIC
HOMEOSTASIS
What are Peripheral Clocks?
The need to metabolize and generate energy for sustenance,
growth and reproduction is an inescapable fact of all forms
of life. It is therefore not surprising that this primeval
requirement is intricately connected with our biological
clock. Soon after identifying the first clock genes
[172]
,
ground-breaking studies from the Kay and Schibler groups
changed our perception that clocks were restricted to the
brain. Kay's group showed that body parts from Drosophila
were able to oscillate in culture
[173]
, and Schibler's group
next demonstrated robust oscillations in immortalized Rat1
fibroblasts
[174]
. We now know that robust gene-expres-
sion rhythms can be detected in tissue explants from almost
all peripheral organs
[175,176]
.
(Exceptions
include
thymus and testis
organs populated largely by undiffer-
e
entiated cells
[177
179]
). Subsequently, using genome-
wide gene-expression profiling of peripheral tissues such
as liver
e
183]
, skeletal muscle
[184,185]
, heart
[186,187]
and adrenal glands
[188]
, our laboratory and
others have shown that ~10% of the expressed transcripts in
each tissue exhibit circadian rhythms in expression.
Intriguingly, by increasing the time resolution of tissue
collection we have also identified rhythmic genes with
ultradian periods in the second or third harmonics (12 h and
8 h) of the circadian rhythms
[181]
. Taken together, we can
definitively state that the clock seems to be ubiquitously
present
[180
e
within the brain (referred to as the SCN and
extra-SCN clocks) and in most peripheral organs (referred
to as peripheral clocks). We can follow this statement by
three obvious questions: Are peripheral clocks similar to
the central clock?, How does one clock 'talk' with another?
and Why do we need so many clocks? Let us try to address
these questions in the order listed.
e
