Serotonin, one of the chemical "messengers", or neurotransmitters,
in the brain, is used by neurons to communicate with each other. It
plays an important role in the regulation of sleep, movement and other
behaviors which are essential for animal survival. But for motivation in
particular, it was unclear whether serotonin was involved.
Since low serotonin levels in the brain are associated with
depression, drugs called "selective serotonin reuptake inhibitors" (or
SSRI, such as Prozac), which increase serotonin levels in the brain by
preventing uptake of excess serotonin, are used to treat depressive
‘Serotonin is involved in a biological mechanism which affects the animals' motivation, suggests a new study.’
However, it is unclear how the excess serotonin acts biologically
to alleviate those symptoms. A new study in mice shows that increasing serotonin affects motivation - but only in
certain circumstances. Furthermore, the study revealed that the short
and long term effects of increased serotonin levels are opposed - a
completely unforeseen property of this neurotransmitter's functional
A surprising behavioral effect, discovered in mice by
neuroscientists at the Champalimaud Center for the Unknown (CCU), in
Lisbon, Portugal, strongly suggests that serotonin is involved in a
biological mechanism which affects the animals' motivation. The study
has now been published in the online open access journal eLife
Serotonin-producing neurons are located in an area of the brainstem
(the most "primitive" part of the brain in evolutionary terms) called
the raphe nuclei. Because these neurons project their axons to multiple
brain regions, serotonin acts widely across the brain. After being
released by the neurons in the raphe nuclei, those same neurons reabsorb
the excess of serotonin.
Peaks of serotonin
Until recently, it was very difficult to study the biological
mechanism underlying serotonin's action because there were no fast and
specific ways to stimulate the release of this neurotransmitter in the
brain while simultaneously looking at a mouse's behavior. But nowadays,
thanks to a technique called optogenetics, which uses light to
manipulate neurons (by stimulating or silencing them), it is possible to
observe the impact of serotonin on the behavior of these animals.
Using optogenetics, the team stimulated the release of serotonin
from neurons in the raphe nuclei. They first induced "peaks" of
serotonin by stimulating these neurons with pulses of light, lasting
three seconds every ten seconds, over three five-minute time periods.
The mice, placed in a box, were left free to explore their
environment. In these conditions, their most frequent spontaneous
behaviors are walking around, rearing, grooming, digging holes or
keeping relatively still, but nevertheless alert.
The only difference the scientists saw was that stimulation caused
the mice to reduce their locomotive speed by about 50%. In general, this
stimulation of serotonin-producing neurons did not affect other
The effect of these serotonin "peaks" on locomotion was almost
instantaneous (speed reduction manifested one second after stimulation)
and transient, with things going back to normal after five seconds. But
during this short period of time, "the animals acted as if they weren't
motivated", says Zach Mainen, who led the study.
However, locomotive speed was affected only when the animals were
not immersed in a particularly engaging task at the time of stimulation.
"These stimulations reduced the animals' motor activity only when they
were freely exploring a new environment, with no directed 'goals'", says
co-author Patrícia Correia, who carried out the experiments, and,
together with colleague and co-author Eran Lottem, analised the results.
"But the same stimulation does not have any effect if the animal is
already engaged in a specific task such as running to get a reward", she
adds. "Our study reveals that serotonin has a direct effect on the
mouse's locomotion and exploration, and potentially on motivation."
The scientists further showed that the slowing-down effect is not
due to an increase of their anxiety levels - a factor that could
seriously hinder movement. "What we see is some other motivational
component, which is neither anxiety nor reward expectation", explains
A second effect
The next step was to determine what would happen if they stimulated
the serotonin-producing neurons repeatedly for a longer period of time.
To do this, in a second series of experiments, the team stimulated
the mice daily over 24 consecutive days. Surprisingly, even though each
stimulation still transiently reduced locomotive speed, overall
locomotive speed progressively increased. At the end of more than three
weeks of this regimen, it was 30% to 40% higher than it had been
compared to the starting point. "This long term effect took us
completely by surprise", says Zach Mainen. "Long term stimulation
triggered a second effect. The mice became globally more active",
explains Patrícia Correia.
This second effect "is a weird but important feature of the
serotonin system", says Zach Mainen. "We don't know what it means in
terms of depression, but the motivation to move may be related to a
state of apathy."
The existence of this second effect, which is associated with the
long term increase of serotonin levels in the brain, may nonetheless
also explain why SSRIs take about three weeks to have an effect on
depressive symptoms. "SSRIs work, in part, on the serotonin system - and
maybe we've stumbled on something related to why they take so long to
produce an effect", concludes Zach Mainen.