Background
Practically
all life on earth is regulated by internal clocks. The clock that
programs your sleep/wake cycle shares many fundamental properties with
clocks in fruit flies and even in molds and cyanobacteria! The
study of these clocks represents one of the hottest areas in
biopsychology, neuroscience, molecular biology, and physiology.
For example, we know that there is a critical brain structure that serves as a master clock. If you destroy these 10,000 cells, all 24 h rhythms in behavior and physiology disappear. More remarkably, you can transplant cells from another organism into the same area, and some rhythms will reappear. Moreover, if you take these cells and grow them in a dish, a single cell will continue to show a 24 h fluctuation in its activity. Individual cells, thus, have all of the machinery to produce clock-like function.
We also
know a great deal about how molecular feedback loops produce these 24 h
oscillations in individual cells. A large handfull of genes and
their associated proteins go through a 24 h cycle. Briefly,
certain genes (e.g., period)
are transcribed in the nucleus (i.e., turned ON). The gene is
translated in the cytoplasm to make Period protein. This protein
gets modified by enzymes, forms a complex with other proteins, etc. and
then returns to the nucleus where it shuts off transcription of the period gene so more protein is not
made. Eventually, the proteins degrade and the negative feedback
is lifted and period gene is transcribed again. This whole cycle
happens to take about 24 h. If certain parts of this loop are
altered, the cycle length changes. For example, a mutation of one
of the enzymes which modifies proteins causes the whole process to
speed up. This mutation causes the animal to have a 20 h
rhythm. Comparable mutations have been found in humans where
approximately half of the people in the extended family feel
compelled to go to sleep around 7 or 8 p.m.
We also
know why these clocks exist. Since life evolved, the environment
has varied dramatically on a near 24 h basis (the earth's rotation has
slowed considerably over geological time). At the same time, the
environment varies dramatically from season to season, particularly as
you move north or south from the equator. Animals use their daily
clocks to figure out the season of the year, not based on factors like
temperature, but on the light environment, which corresponds perfectly
to the seasons. The hormone melatonin, which is secreted at
night, is directly controlled by the clock but serves as a mediator
between it and all other systems. Melatonin signals produced in
winter coordinate a whole suite of changes in mammals. For
example, it can turn off reproduction, turn on hibernation, cause
changes body weight, decrease sexual behavior etc. In
humans, winter depression (seasonal affective disorder) may be
related to this same system.
Finally,
in addition to telling us about the nature of life or earth and the
organization of the brain, the study of clocks is incredibly important
for our society. Medically, winter depression may be a
manifestation of clock dysfunction. But treatment outcomes for
cancer can be much improved by giving drugs at particular times of
day. People who work the graveyard shift have a hard time staying
awake at work and sleeping during the day. Their health suffers
also. People in the airline industry reportedly suffer ill health
as well. One line of our work described below is intended to find
ways to allow people to better adjust to schedules demanded by modern
living but not experienced in our evolutionary past.
Specific projects underway, anticipated or completed in my lab.
Understanding how the clock is put together.
An idea that has been around for a long time is that
the main circadian pacemaker is made up of smaller clock units.
This has been an important idea, but it has been difficult to study
effectively for various reasons. We have discovered a way
to break the clock into smaller units that has incredible appeal to us,
both because of what it says about circadian theory (not discussed
here), but also because we think there might be a direct application
for human benefit. Here's what we found.
Normally, hamsters, like humans, alternate between an active period and
a rest period every 24 h. If you put animals on a 24 h light:dark
cycle (e.g., 12 h of light followed by 12 h of dark), they will
synchronize, or entrain, with
their active period at night and their inactive period during the
day. Prior to our studies, if you put them on a 24 h
light:dark:light:dark cycle (e.g., 6 h of light, 6 h of dark etc) they
would be active in just one of the dark periods and be largely inactive
for the other 18 h. In other words, regardless of the lighting
conditions, mammals simply alternate between a rest and an active
period every 24 h. Our work showed, very surprisingly, that under
the right set of light:dark:light:dark conditions, that we could get
hamsters to break their active period into 2 components. They
would split their active period between the two dark periods and be
inactive in each of the two light phases. We call this rhythm
"splitting." Our work shows that the 2 activity components are
controlled by two clocks that have been temporally separated from one
another. We are interested in knowing about the neural basis of
these two clocks, how they interact with one another, and what the
positive and negative consequences might be of dissociating them.
How do they interact?
I indicated above that individual cells are
competent circadian oscillators. These must interact with each
other to keep coherent time. Working at a behavioral level, we
study the interaction, or coupling,
of clocks that make up the circadian pacemaker. One of our most
important ideas is that we can gain much greater access to the clock --
and thus manipulate it more readily -- by understanding this
coupling. We have shown that presenting hamsters with very
very very dim light at night renders their circadian clocks very very
very much more flexible, and we argue that this is due to an effect of
dim light on coupling between oscillators. The effects of dim
light are very large. For example, using lighting cycles where
the nights are completely dark, we can get hamsters to adjust to a 24 h
day, a 24.5 h day or even a 25 h day. But hamsters can't track
cycles much longer that that. However, if we give them the
tiniest amount of light at night, they can successfully entrain to 26,
27, 28, 29 or even a 30 h day. The same is true of cycles shorter
than 24 h. Our findings are very surprising because the light
that we are using was thought to be too dim to have much of an effect
on the circadian clock. We have several experiments in progress
to characterize how dim light is having its effect.
Could rhythm splitting help shift-workers?
People who work the graveyard shift are generally
not able to reverse their circadian clocks to reflect their work
schedule. There are a number of reasons for this. Sunlight
is very effective at setting the clock and it keeps all of us aligned
pretty much the same. So when someone leaves the factory or
hospital at 7 a.m. after a night shift, the sunlight tends to
synchronize their clock in the normal fashion. If people avoid
natural light completely, they can shift their clock. However,
when they have days off of work, they are tempted to go back to a
diurnal schedule and sunlight can re-entrain them to the normal
phase. We are hoping that splitting their rhythms might solve
these problems. Briefly, we anticipate that people might be able
to program alert intervals twice daily -- from midnight to 8 a.m. and
from noon to 8 p.m. for example. In between, their clocks would
program them to sleep. Using hamsters as a model, we have asked
whether deviating from this regular pattern (i.e., giving hamsters days
off) causes the system to revert to the normal condition or if it is
stable. Future work will simulate other aspects of shift-work to
build a case that this may or may not be useful for humans.
Timing and alcohol.
Having gotten in the habit of having a glass of wine
or a drink after work, I noticed that I grew to crave a drink right
around the time that I normally had it. But if I didn't satisfy
my craving, I noticed that the desire was gone a few hours later.
This suggested to me that cravings might be time-specific.
Indeed, the literature on nicotine addiction demonstrates just this
pattern. Moreover, there are a number of interesting connections
between circadian function and drug and alcohol addiction that
suggested to us that this area warranted further study. Graduate
student Jenny Trujillo, working is mice, is leading this line of
research in collaboration with Dr. Amanda Roberts of the Scripps
Research Institute and myself.
Clocks and aging.
One of the problems of old age is a disruption of
circadian function. Older people can have trouble staying awake
during the day and sleeping at night. And in older mice, repeated
jet-lag can actually accelerate death. There is also an
intriguing possibility that the circadian clock may contribute to the
rate of aging: in the mouse lemur, for instance, longevity was affected
by the yearly pattern of lighting conditions. Hamsters are great
animals to explore these kinds of issues. The light environment
will determine whether they go through puberty at 4 weeks of age or 6
months! We don't yet know, however, whether the light environment
affects the end of the life cycle. Experiments are in progress or
planned to see whether we can slow or reverse the deficits in clock
function associated with old age. Graduate
student Evan Raiewski is gearing up for such studies now. Already, grad student Jenn Evans has shown that adding
dim light at night (see above) allows hamsters to respond to jet-lag
shifts more rapidly -- and more similarly to young animals.
The Department of Psychology at UCSD offers a Ph.D.
in psychology. Students in other departments, e.g., Neuroscience,
Biology etc. may also work in the labs of our department. A
masters degree is available to UCSD undergraduates as part of a
combined
B.S./M.A. program. For more information, follow this link to the Department of
Psychology Graduate Program.
Undergraduate
research
My lab
owes a great debt to the efforts of numerous undergraduates who have
helped with running experiments and analyzing data. Additionally,
several undergraduates who have made a
longer-term
commitment to the lab (e.g., through the Honor's
program, as a master's student or informally) have conducted their own
projects under my supervision, leading to publications with them as
first authors. If you are interested in
working
in the lab for Psych199 credit, it is best to contact me well in
advance. If you make a longer-term commitment to the lab
(e.g., through the Honor's program, as a master's student or
informally), you can run a project of your own under my
supervision. Ideally, these projects will lead to a publication
with you as an author.