(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 fly.
“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 brain.
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
“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 fruit flies.)
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
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 of Health.
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