Figure 1: Elevated plus maze,
a
test for anxiety in rodents.
(Source: Bd008)
|
Schizophrenia
affects 1 in 100 people globally and in the United States. The onset of
symptoms is during late adolescence to mid-adulthood (16-30 yrs of age). There
are several ideas regarding how brain function changes before, during, and
after symptoms begin. The most common hypothesis is that there is an imbalance
of the neurotransmitter dopamine in different brain areas. Becoming more
popular is the idea that NMDA receptors are not functioning as well as they
could be. There have also been some correlative studies showing potential links
between maternal stress and schizophrenia in offspring. Dr. Maria Victoria
Tejada-Simon’s lab at the University of Houston, is studying the NMDA theory in
conjunction with maternal stress.
Alexander
Oderhowho, an undergraduate student in Dr. Tejada-Simon’s lab, has been doing
preliminary control studies on the maternal stress side of this project. For
his experiments, he induced stress in pregnant mice just days after mating and
continued the stress throughout the pregnancy. The stressors included
confinement to a tube, a test that pairs a tone with a foot shock, tail
suspension, and forced swim. He
had a control group of mothers, which were not stressed. After the pups were
born, Alexander used behavioral testing to assess anxiety behavior and
fear-related cognition in the mothers and their offspring. They hypothesized
that highly stressful events during pregnancy would result in increased anxiety-like
behavior in the mothers and the pups and may impair cognition in the pups.
The
tests they used for anxiety included the light dark exploration and the
elevated plus maze. Both tests rely on the behaviors mice exhibit as prey
animals. Mice prefer small dark spaces and tend to avoid open and bright spaces
where they could become the next meal for a predator. In the lab, anxiety can
be tested using a light dark exploration box with two sides: small/ dark and
large/ open. The elevated plus maze has four arms: two with walls and two
without (Figure 1). They also assessed locomotor activity and anxiety behavior
in the open field test (a box similar to the light dark box, not a real field of
pretty green grass). Similar to the other tests, anxious mice tend to spend
less time in the center area of an open field and more time sitting near or
walking around the edges. This edge circling behavior is called thigmotaxis.
For cognition, Alexander used a fear-conditioning test that uses a tone paired
with a foot shock to assess fear-related learning. Mice freeze when frightened
in an attempt to “hide” from predators. The fear-conditioning test assesses
freezing behavior, the
percentage of time they freeze after a sound is given, as they learn that a
mild shock will follow the tone. Alexander’s
results were largely similar to what he predicted in his hypothesis.
Mother
mice showed increased anxiety following the stressful pregnancy in comparison
with unstressed mothers. The previously stressed mothers spent less time in the
light side of light dark exploration box and did not venture out into the open
arms of the elevated plus maze at all. They even spent less time in the center
of the elevated plus maze between the closed and open arms. In the open field
test, the stressed mothers had decreased activity overall and decreased
thigmotaxis. Normally, decreased thigmotaxis suggests a lower anxiety level. However,
because the stressed mothers moved less overall this may account for the
reduction in thigmotaxis, despite the increased anxiety response in the other
tests.
In
the fear-conditioning test, the stressed mothers did not perform well during the test when being trained on the
paradigm. Alexander thinks this might have been because they were already
familiar with the box used for fear-conditioning test after having experienced
it as a stressor during their pregnancy. The offspring, however, had all
clearly increased anxiety behaviors but the fear
responses were different from mothers.
Pups
from stressed mothers, at approximately 40 d of age, also spent a decreased
amount of time in the light side of the light dark box and an increase in the
amount of time spent in the closed arms of the elevated plus maze. There was no
change in the time they spent in the center of the plus maze and they did
venture out into the open areas, in contrast to the stressed mothers. There was
no change in the basal level of locomotion in the open field when compared with
pups from non-stressed mothers. However, thigmotaxis in the pups from stressed
mothers was increased, suggesting higher anxiety.
In
the fear-conditioning test, pups from stressed mothers had better pairing (more
freezing behavior) than pups from non-stressed mothers. This makes sense
because the pups tended to be more anxious in the other tests and were likely
hyper-aware of scary stimuli.
As
hypothesized, mothers stressed during pregnancy showed increased anxiety after
birth and pups born from stressed mothers also had higher anxiety. The
implication of these results is that there may be epigenetic changes being
passed from mother to pup during pregnancy. Epigenetic means the genes themselves
are not changing but the way the DNA is wound up together means some genes can
be expressed or inhibited that normally are not based on stimuli. Epigenetic
changes are not always passed from generation to generation but, in this case, it may be so. In the future,
Dr. Tejada-Simon’s lab will combine NMDA receptor hypofunction with stress in mother mice and examine anxiety and
cognitive behavior in the mothers and offspring. She would also like to study
the biochemical changes occurring in the brain during these periods and
morphology of cells in the hippocampus, a brain area important for learning and
memory.
Alexander Oderhowho and his advisor Dr. Maria Victoria Tejada-Simon, University of Houston. |
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