Study Connects Sleep Deficits Among Young Fruitflies to Disruption in Mating Later in Life

Mom always said you need your sleep, and it turns out, she was right. According to a new study published in Science this week from researchers at the Perelman School of Medicine at the University of Pennsylvania, lack of sleep in young fruit flies profoundly diminishes their ability to do one thing they do really, really well – make more flies.

The study, led by Amita Sehgal PhD, professor of Neuroscience and a Howard Hughes Medical Institute (HHMI) Investigator, links sleep disruption in newborn fruit flies with a critical adult behavior: courtship and mating.

The team, addressed sleep in the very youngest of flies. “These flies sleep considerably more than adults and that behavior repeats across the animal kingdom,” Sehgal says. “Infant humans, rats, and flies, they all sleep a lot.”

Co-author Matthew Kayser, MD, PhD, in the Department of Psychiatry and Center for Sleep and Circadian Neurobiology, whose research centers on the link between sleep disruption and human neuropsychiatric diseases, used the fly – which is far more genetically pliant than mammals — to ask two basic questions: Why do young animals sleep so much? And, what is the implication of altering those patterns?

The team used genetically manipulated flies to show that young flies normally produce relatively little dopamine – a wake-promoting neurotransmitter — in certain neural circuits that feed into the sleep-promoting brain region called the dorsal fan-shaped body (dFSB). Premature activation of those circuits profoundly inhibits the dFSB, reducing sleep.

That answers the first question, Sehgal explains: Young flies make less dopamine, which keeps the dFSB active and sleep levels high. These animals sleep more than adults and are harder to rouse from sleep.

Some clues to the second question – what is the consequence of sleep loss – came from Kayser’s finding that increased dopamine in young flies not only causes sleep loss, but also affects their ability to court when they’re older. “The flies spend less time courting, and those that do usually don’t make it all the way to the end,” Sehgal says.

To address whether sleep loss in young flies affects development of courtship circuits, the team investigated a group of neurons implicated in courtship. One particular subset of those neurons, localized in a specific brain region called VA1v, was smaller in sleep-deprived animals than normal flies, suggesting a possible mechanism for how sleep deprivation can lead to altered courting behavior.

That sleep-deprived flies have altered behavior is not itself a novel finding, Sehgal notes. Earlier studies from her lab and others used mechanical disruption to alter sleep patterns, but in the current study, Sehgal’s team was able to drill down to the specific neural network that is affected. “We identified the circuit that is less active in young flies. If you activate that circuit, you disrupt courtship by impairing the development of a different, courtship-relevant circuit.”

The question now is how these findings relate to human behavior – Kayser’s original question. Though no direct lines can be drawn, the study “does provide the first mechanistic link between sleep in early life and adult behavior,” says Sehgal.

Study finds modified stem cells offer potential pathway to treat Alzheimer’s disease

UC Irvine neurobiologists have found that genetically modified neural stem cells show positive results when transplanted into the brains of mice with the symptoms and pathology of Alzheimer’s disease. The pre-clinical trial is published in the journal Stem Cells Research and Therapy, and the approach has been shown to work in two different mouse models.

Alzheimer’s disease, one of the most common forms of dementia, is associated with accumulation of the protein amyloid-beta in the brain in the form of plaques. While the search continues for a viable treatment, scientists are now looking into non-pharmaceutical ways to slow onset of this disease.

One option being considered is increasing the production of the enzyme neprilysin, which breaks down amyloid-beta, and shows lower activity in the brains of people with Alzheimer’s disease. Researchers from UC Irvine investigated the potential of decreasing amyloid-beta by delivering neprilysin to mice brains.

“Studies suggest that neprilysin decreases with age and may therefore influence the risk of Alzheimer’s disease,” said Mathew Blurton-Jones, an assistant professor of neurobiology & behavior. “If amyloid accumulation is the driving cause of Alzheimer’s disease, then therapies that either decrease amyloid-beta production or increase its degradation could be beneficial, especially if they are started early enough.”

The brain is protected by a system called the blood-brain-barrier that restricts access of cells, proteins, and drugs to the brain. While the blood-brain-barrier is important for brain health, it also makes it challenging to deliver therapeutic proteins or drugs to the brain. To overcome this, the researchers hypothesized that stem cells could act as an effective delivery vehicle. To test this hypothesis the brains of two different mouse models (3xTg-AD and Thy1-APP) were injected with genetically modified neural stem cells that over-expressed neprilysin.

These genetically modified stem cells were found to produce 25-times more neprilysin than control neural stem cells, but were otherwise equivalent to the control cells. The genetically modified and control stem cells were then transplanted into the hippocampus or subiculum of the mice brains – two areas of the brain that are greatly affected by Alzheimer’s disease. The mice transplanted with genetically modified stem cells were found to have a significant reduction in amyloid-beta plaques within their brains compared to the controls. The effect remained even one month after stem cell transplantation. This new approach could provide a significant advantage over unmodified neural stem cells because neprilysin-expressing cells could not only promote the growth of brain connections but could also target and reduce amyloid-beta pathology.

Before this can be investigated in humans, more work needs to be done to see if this affects the accumulation of soluble forms of amyloid-beta. Further investigation is also needed to determine whether this new approach improves cognition more than the transplantation of un-modified neural stem cells.

“Every mouse model of Alzheimer’s disease is different and develops varying amounts, distribution, and types of amyloid-beta pathology,” Blurton-Jones said. “By studying the same question in two independent transgenic models, we can increase our confidence that these results are meaningful and applicable to Alzheimer’s disease. But there is clearly a great deal more research needed to determine whether this kind of approach could eventually be translated to the clinic.”

(Image caption:The image depicts mice having a normal nerve (left) as compared to an incomplete nerve, a condition resulting in permanent downward gaze in both mice and humans. Image courtesy of Jeremy Duncan)

Researchers track down cause of eye mobility disorder

Imagine you cannot move your eyes up, and you cannot lift your upper eyelid. You walk through life with your head tilted upward so that your eyes look straight when they are rolled down in the eye socket. Obviously, such a condition should be corrected to allow people a normal position of their head. In order to correct this condition, one would need to understand why this happens.

In a paper published in the April 16 print issue of the journal Neuron, University of Iowa researchers Bernd Fritzsch and Jeremy Duncan and their colleagues at Harvard Medical School, along with investigator and corresponding author Elizabeth Engle, describe how their studies on mutated mice mimic human mutations.

It all started when Engle, a researcher at the Howard Hughes Medical Institute (HHMI), and Fritzsch, professor and departmental executive officer in the UI College of Liberal Arts and Sciences Department of Biology, began their interaction on the stimulation of eye muscles by their nerves, or “innervation,” around 20 years ago.

Approximately 10 years ago, Engle had identified the mutated genes in several patients with the eye movement disorder and subsequently developed a mouse with the same mutation she had identified in humans. However, while the effect on eye muscle innervation was comparable, there still was no clue as to why this should happen.

Fritzsch and his former biology doctoral student, Jeremy Duncan, worked with the Harvard researchers on a developmental study to find the point at which normal development of eye muscle innervations departs from the mutants. To their surprise, it happened very early in development. In fact, they found—only in mutant mice—a unique swelling in one of the nerves to the eye muscle.

More detailed analysis showed that these swellings came about because fibers extending to the eyes from the brain tried to leave the nerve as if they were already in the orbit, or eye socket. Since it happened so early, the researchers reasoned that something must be transported more effectively by this mutation to the motor neurons trying to reach the orbit and the eye muscles; something must be causing these motor neurons to assume they have already reached their target, the orbit of the eye.

To verify this enhanced function, the researchers developed another mouse that lacked the specific protein and found no defects in muscle innervation. Moreover, when they bred mice that carried malformed proteins with those that had none of these proteins, the mice developed a normal innervation.

This data provided clear evidence of what was going wrong and why, but it did not provide a clue as to the possible product that was more effectively transported in the mutant mice and, by logical extension, in humans. Further analysis revealed that breeding their mutant mice with another mutant having eye muscle innervation defects could enhance the effect of either mutation.

With this finding, they had identified the mutated protein, its enhanced function, and at least some of the likely cargo transported by this protein to allow normal innervation of eye muscles. This data provides the necessary level of understanding to design rational approaches to block the defect from developing.

Knowing what goes wrong and at what time during development can allow the problem to be corrected before it develops through proper manipulations. Engle, Fritzsch, and their collaborators currently are designing new approaches to rescue normal innervation in mice. In the future, their work may help families carrying such genetic mutations to have children with normal eye movement.

(Image caption: Newly discovered neuron type (yellow) helps zebrafish to coordinate its eye and swimming movements. The image shows the blue-stained brain of a fish larva with the suggested position of the eyes. Credit: © Max Planck Institute of Neurobiology/Kubo)

How vision makes sure that little fish do not get carried away

Our eyes not only enable us to recognise objects; they also provide us with a continuous stream of information about our own movements. Whether we run, turn around, fall or sit still in a car – the world glides by us and leaves a characteristic motion trace on our retinas. Seemingly without effort, our brain calculates self-motion from this “optic flow”. This way, we can maintain a stable position and a steady gaze during our own movements. Together with biologists from the University of Freiburg, scientists from the Max Planck Institute of Neurobiology in Martinsried near Munich have now discovered an array of new types of neurons, which help the brain of zebrafish to perceive, and compensate for, self-motion.

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Eavesdropping on brain cell chatter

Everything we do — all of our movements, thoughts and feelings – are the result of neurons talking with one another, and recent studies have suggested that some of the conversations might not be all that private. Brain cells known as astrocytes may be listening in on, or even participating in, some of those discussions. But a new mouse study suggests that astrocytes might only be tuning in part of the time — specifically, when the neurons get really excited about something. This research, published in Neuron, was supported by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.

For a long time, researchers thought that the star-shaped astrocytes (the name comes from the Greek word for star) were simply support cells for the neurons.

It turns out that these cells have a number of important jobs, including providing nutrients and signaling molecules to neurons, regulating blood flow, and removing brain chemicals called neurotransmitters from the synapse. The synapse is the point of information transfer between two neurons. At this connection point, neurotransmitters are released from one neuron to affect the electrical properties of the other. Long arms of astrocytes are located next to synapses, where they can keep tabs on the conversations going on between neurons.

In recent years, it has been shown that astrocytes may also play a role in neuronal communication. When neurons release neurotransmitters, levels of calcium change within astrocytes. Calcium is critical for many processes, including release of molecules from the cell, and activation of a host of proteins within the cell. The role of this astrocytic calcium signaling for brain function remains a mystery.

In this study, Baljit S. Khakh, Ph.D., of the University of California, Los Angeles and his colleagues wanted to know when astrocytes responded to neuron activity with changes in their internal calcium levels. Using calcium indicator dyes, the researchers were able to image, for the first time, changes in calcium levels in the entire astrocyte. Previously, it was only possible to look at certain areas of the cell at one time, which provided an incomplete picture of what was happening.

Dr. Khakh said one of the most important outcomes of this work was in the methods that were used. “What our use of these calcium indicators shows is that we can image calcium throughout the entire astrocyte. This provides a new set of tools for the research community to use and to extend these findings,” he said.

“There has been intense interest in understanding how astrocytes facilitate communication between neurons, but it is only recently that studies with this level of precision have been possible,” said Edmund Talley, Ph.D., program director at NINDS. “Dr. Khakh’s study is an example of an exciting basic, or fundamental, research project that could have an important contribution to the shifting field of astrocyte biology,” he added.

For these experiments, researchers focused on the mossy fiber pathway, which connects two areas of the hippocampus, the structure involved in learning and memory. “This pathway has a unique architecture and although it has been very well studied, the role of astrocytes in this circuit has not been previously explored. This study provides one of the first really detailed understandings of astrocytes within this particular circuit,” said Dr. Khakh.

Dr. Khakh’s team activated neurons (getting them to release neurotransmitter by a variety of techniques) and then looked for a response in the neighboring astrocyte. As calcium levels rose, the astrocyte would light up quickly. They discovered that two neurotransmitters, glutamate and GABA, triggered the astrocytes to release calcium from their internal stores. Importantly, the researchers discovered that calcium levels increased through the entire astrocyte only if there was a large burst of neurotransmitter being released.

“We found that astrocytes in the mossy fiber pathway do not listen to the constant, millisecond by millisecond synaptic chatter that neurons engage in. Instead, they listen when neurons get excessively excited during bursts of activation,” said Dr. Khakh.

These findings suggest that astrocytes in the mossy fiber system may act as a switch that reacts to large amounts of neuronal activity by raising their levels of calcium. These calcium increases occur over multiple seconds, a relatively long time period compared to that seen in neurons. The spatial extent of the astrocyte calcium increases was also relatively large in comparison to the size of the synapse.

“Astrocytes may be sitting there quietly and when there is excessive activation in the neuronal circuit, they immediately respond with an increase in calcium which we could detect. And the next big question becomes, what they do with that calcium?” said Dr. Khakh.

Dr. Khakh’s results in the mossy fiber system differ from those others have described in other brain regions. This raises the intriguing possibility that astrocytes are not all the same and may serve various roles throughout the brain.

“It would be really interesting and important to find that astrocytes function differently in different areas of the brain, in a circuit-specific manner. This study gives a hint that this might be true,” said Dr. Talley.

Study provides new insight into how toddlers learn verbs

Parents can help toddlers’ language skills by showing them a variety of examples of different actions, according to new research from the University of Liverpool.

Previous research has shown that verbs pose particular difficulties to toddlers as they refer to actions rather than objects, and actions are often different each time a child sees them.

To find out more about this area of child language, University psychologists asked a group of toddlers to watch one of two short videos.

They then examined whether watching a cartoon star repeat the same action, compared to a character performing three different actions, affected the children’s understanding of verbs.

Developmental psychologist, Dr Katherine Twomey, said: “Knowledge of how children start to learn language is important to our understanding of how they progress throughout preschool and school years.

“This is the first study to indicate that showing toddlers similar but, importantly, not identical actions actually helped them understand what a verb refers to, instead of confusing them as you might expect.”

Dr Jessica Horst from the University of Sussex who collaborated on the research added: “It is a crucial first step in understanding how what children see affects how they learn verbs and action categories, and provides the groundwork for future studies to examine in more detail exactly what kinds of variability affect how children learn words.”