Researchers target, switch off serotonin-producing neurons in mice; New insights may be relevant to sudden infant death syndrome

ScienceDaily (July 28, 2011) — Researchers have developed a toolkit that enables them to turn off targeted cell populations while leaving others unaffected.

Led by Susan Dymecki, a professor of genetics at Harvard Medical School, the group focused on serotonin-producing neurons, observing how mice behave in a normal environment when suddenly their serotonin neurons are turned down. While their findings affirm earlier studies, the researchers used a technique that is non-invasive and does not require anesthesia, surgeries, or knocking out a gene -- each of which can cause problems when interpreting results.

"By selectively and abruptly switching off the serotonin-producing cells, we can get a definite idea of what bodily functions the serotonin cells specifically control," said Dymecki. "These findings and the new tools in neuroscience that it brings to the table will help us understand the role of serotonergic neurons in many human disorders."

One such disorder particularly relevant to these findings is Sudden Infant Death Syndrome, or SIDS.

These findings will appear in the July 29 edition of the journal Science.

The mammalian brain contains multiple chemical messengers, called neurotransmitters, which transfer information between nerve cells in order to regulate basic behaviors and functions like walking, eating, and sleeping. Serotonin is a major brain neurotransmitter produced solely by cells in the lower brain, or brainstem. Cells that make serotonin can convey information to large numbers of neurons distributed throughout the brain and can affect behavior as complex as mood.

In order to better understand how these serotonin-producing cells in the brain relate to basic physiology, Russell Ray and Rachael Brust, a postdoctoral researcher and a graduate student in Dymecki's lab, along with Jun Chul Kim, a prior postdoctoral fellow in Dymecki's lab who is now at the University of Toronto, and Andrea Corcoran, a postdoctoral researcher in the lab of Eugene Nattie at Dartmouth Medical School along with George Richerson, a professor of neurology at the University of Iowa, developed and characterized a method for selectively silencing neurons that produce serotonin.

The group began with a molecule genetically engineered by Bryan Roth and his colleagues at the University of North Carolina School of Medicine. Using a method that Dymecki's group had developed and optimized over the years called "intersectional genetics," they incorporated this molecule, a receptor, into the serotonin-producing brain cells in mice. As a result, the mice naturally generated this "unnatural" receptor on the surface of their serotoninergic neurons.

Receptors are key players in cellular communications, the initial recipients of chemical signals sent by other cells. Here, the researchers injected the mice with clozapine-N-oxide, a chemical compound designed to bind to and trigger the engineered receptor. Within minutes, the chemical and the foreign receptor acted together as a kind of dimmer switch, dampening the action of serotonin networks in the brains of these mice.

"This gave us the ability to selectively shut down serotonergic neuron function in the mouse brain," said Ray. "The mice remained awake, thus we could study their behavior in a normal environment."

When serotonergic neuron activity was diminished, the mice lost their capacity to maintain body temperature, and their temperatures plummeted to that of their surrounding environment.

Also, the ability of the mice to physiologically respond to elevations in carbon dioxide levels -- typically in the form of heavy, rapid breathing to rid the body of excessive carbon dioxide buildup before it might reach dangerous levels -- was roughly half that of normal mice when serotonergic neuron activity was low.

"What is particularly powerful to note is that we were able to study the mice both before and after we switched off the serotonergic neurons," said Ray. "We were able to demonstrate that prior to activating this foreign receptor switch -- that is prior to silencing the serotonin neurons -- the mice responded normally to temperature and carbon dioxide challenges."

The researchers believe this work may help us better understand the mechanisms underlying SIDS in humans.

Recent findings from the lab of Hannah Kinney at Children's Hospital Boston suggest that SIDS babies may have a deficiency of serotonin in circuits in the brainstem. Such deficiencies may lead directly to abnormal responses to elevated levels of carbon dioxide, such as when a baby rebreathes exhaled stale gases with high carbon dioxide levels while lying facedown.

"These infants may be vulnerable to sudden death due to impaired serotonin function in brainstem circuits important for protective responses to life threatening challenges, such as increased levels of carbon dioxide," said Dymecki. "What's more, a SIDS-vulnerable infant may be less equipped to maintain a normal body temperature."

Dymecki, along with her lab members and her colleagues at Dartmouth and University of Iowa, are now investigating how serotonergic neurons influence vital functions in young mice that are in the comparable age range to human infants at peak risk for SIDS. They also plan to use this genetic platform to selectively turn off subsets of serotonergic neurons, to better understand their specific functioning in health, and in other serotonin-linked disorders.

This research was funded by the National Institutes of Health.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Harvard Medical School. The original article was written by David Cameron.

Journal Reference:

R. S. Ray, A. E. Corcoran, R. D. Brust, J. C. Kim, G. B. Richerson, E. Nattie, S. M. Dymecki. Impaired Respiratory and Body Temperature Control Upon Acute Serotonergic Neuron Inhibition. Science, 2011; 333 (6042): 637 DOI: 10.1126/science.1205295

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

View the original article here

How bats stay on target despite the clutter

ScienceDaily (July 30, 2011) — In a paper published this week in Science, researchers at Brown University and from the Republic of Georgia have learned how bats can home in on a target, while nearly instantaneously taking account of and dismissing other objects in their midst. The trick lies in their neurons: Bats can separate the cavalcade of echoes returning from their sonar pulses by distinguishing changes in amplitude -- the intensity of the sound -- between different parts of each echo within 1.5 decibels, to decide whether the object is a target or just background clutter.

The minute change in amplitude is enough to cause a delay in the bats' neural response to an echo, letting the bat know what is clutter and what is the target. It is as if the bat is using two screens -- a main screen that keeps it locked in on its target by virtue of its neural response to the echo and another, secondary screen that keeps note of surrounding objects but doesn't fixate on them.

"Everything the bat sees using sonar is based on the timing of the neural responses and nothing else," said James Simmons, professor of neuroscience at Brown and an author on the paper.

The research is important because it could help refine the maneuverability of sonar-led vehicles and improve their ability to remain fixed on a target even in dense, distracting surroundings.

In a paper in the Proceedings of the National Academy of Sciences last year, Simmons and Mary Bates, who studied under Simmons and earned her doctorate last May, showed how bats avoid colliding with objects while flying in tight quarters. The key, they determined, is that bats tweak their sounds (chirps) and thus the echoes they receive to differentiate one broadcast/echo set from another. Building on that research, Bates and Simmons sought to determine how bats take note of objects in their sonar surroundings without being deterred by them -- how bats prioritize the waves of echoes they are receiving from their broadcasts.

"The problem the bat is facing is that it's flying around in this really complicated environment. It's getting all these echoes back [from the sonar broadcasts it emits], and the echoes are all arriving at almost the same time," said Bates, lead author on the Science paper. "And they have no trouble at all dealing with that. We're trying to figure out perceptually how these bats distinguish an echo from a nearby target from all the background echoes that are arriving within a similar time window."

In a series of experiments, the researchers studied those times when the bats would encounter a "blind spot," when the echoes were so close together that the bat could not distinguish its target from the surrounding clutter. The range in which the bats can detect when one echo interferes with another is a mere 50 milliseconds, the researchers report.

Harmonics plays a major role. Bat chirps -- sounds -- generally have two harmonics. When a bat chirps, it waits for the corresponding echo. It makes a mental fingerprint of the emitted sound and its echo; if the broadcast/echo fingerprints match up precisely, then the bat "will process it and produce an image," Simmons said. In many cases, that image is an object it is targeting. But when the second harmonic is weaker in the echo fingerprint, the neurons' response is delayed by as few as 3 microseconds. That delay, while undetectable to humans, is enough to tell the bat that the object is present, but it is not its primary interest.

"What the bat does is it takes clutter and defocuses it, like a camera would, so the target remains highly defined and in focus," Simmons said.

Tengiz Zorikov from the Institute of Cybernetics in the Republic of Georgia contributed to the research. The U.S. Office of Naval Research, National Institutes of Health, and the National Science Foundation funded the work.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Brown University.

Journal Reference:

M. E. Bates, J. A. Simmons, T. V. Zorikov. Bats Use Echo Harmonic Structure to Distinguish Their Targets from Background Clutter. Science, 2011; 333 (6042): 627 DOI: 10.1126/science.1202065

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

View the original article here