Sleepy Fruit Flies Provide Clues
to Learning and Memory
(Philadelphia, PA) - Researchers at the University
of Pennsylvania School of Medicine have discovered that a brain
region previously known for its role in learning and memory also serves
as the location of sleep regulation in fruit flies. Through further examination
of this brain structure, researchers hope to shed light on sleep regulation
and its role in memory.
Despite its importance in everyday human function, very little is known
about the regulation of sleep. In search of the underlying brain region
responsible for sleep regulation, senior author Amita Sehgal,
PhD, Professor of Neuroscience and a Howard Hughes Medical Institute
(HHMI) Investigator, and colleagues turned their attention to the fruit
“Fruit flies and humans share similar resting patterns,” explains
Sehgal. “Like humans, the sleeping states of fruit flies are characterized
by periods of immobility over a twenty-four hour period, during which
the fruit flies demonstrate reduced responsiveness to sensory stimuli.”
By tinkering with the gene expression of multiple regions of the fruit
fly brain, the research team was able to zero in on the adult mushroom
body as the sleep center of the brain. They reported their findings in
last week’s issue of Nature.
To locate the brain region involved in sleep regulation, Sehgal manipulated
the activity of an enzyme known as protein kinase A (PKA). Previous work
in Sehgal’s lab revealed that the higher the level of PKA activity,
the lower the period of immobility, or sleep, in the fruit fly. By building
upon this work, Sehgal and others set out to increase PKA activity in
various regions of the brain and examine the subsequent sleeping patterns
in the fruit flies. “Sleeping fruit flies” were defined as
those that remained immobile for at least five minutes.
“From the beginning, we took the unbiased approach,” explains
Sehgal. “We targeted PKA activity to different areas of the fly
brain to find out where PKA acts to regulate sleep.”
Sehgal was able to selectively turn on PKA activity in a variety of brain
locations, which promoted PKA expression in designated regions. Of the
different regions targeted, only two regions, both present in the adult
mushroom bodies, led to changes in sleeping patterns of fruit flies. The
fly mushroom body has been likened to the human hippocampus. The changes
in sleep caused by the increased PKA activity in the adult mushroom bodies
highlighted this region as the sleep-regulating region of the fruit fly
When PKA activity was expressed in one of the two distinct regions of
the mushroom bodies, increased sleep occurred while expression in the
other region decreased sleep in the flies. Thus, the adult mushroom bodies
possess both sleep-promoting and sleep-inhibiting areas.
“Although people typically think of mushroom bodies as possessing
similar functions to the human hippocampus, the site where long-term memories
are made, our lab tends to think of the mushroom bodies functioning more
like the thalamus, the relay station through which most sensory input
to the brain is targeted,” explains Sehgal. “Previous research
links the thalamus to a role in human sleep.” (There is no human
structure that is anatomically similar to the adult mushroom bodies of
Identifying the role of adult mushroom bodies in sleep may offer insight
into how and why sleep is needed to assist in learning and memory consolidation.
In mammals, sleep deprivation suppresses the performance of learned tasks,
and sleep permits memory consolidation. Distinct anatomical regions of
adult mushroom bodies have been shown to be important for at least some
forms of memory in fruit flies.
In a paper also published last week in Current Biology, Sehgal and colleagues
showed that serotonin affects sleep in fruit flies by acting at the site
of the adult mushroom bodies.
Sehgal’s lab reduced the function of three types of serotonin receptors
in the brains of fruit flies (5HT1A, 5HT1B, and 5HT2). The reduced 5HT1A
receptor activity in the fruit flies led to fragmented and reduced overall
sleep. In essence, the fruit flies tossed and turned in their sleep. But,
the flies with reduced 5HT1B and 5HT2 receptor activity displayed no change
in their sleeping pattern. Penn researchers were able to treat the fruit
flies to a good night’s sleep by administering serotonin to the
adult mushroom bodies.
The finding that serotonin plays a role in increasing sleep in fruit flies
offers hope for the future of therapeutics for sleep disorders. “Serotonin
may also promote sleep in humans,” suggests Sehgal. “This
may explain why serotonin-increasing antidepressants increase sleep.”
Future work by Sehgal’s lab will attempt to look for a connection
among sleep, serotonin, and learning, and memory, while looking deeper
into the cellular and molecular activity that enables mushroom bodies
to regulate sleep.
Coauthors of the Nature study are William J. Joiner and Amanda Crocker,
both from Penn, and Benjamin H. White, from the National Institutes of
Health. Coauthors of the Current Biology study are Quan Yuan and William
J. Joiner, both from Penn. These studies were funded by the Howard Hughes
Medical Institute, the National Sleep Foundation and by the National Institutes
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