Serotonin is a major signaling chemical in the brain, and it has long been thought to be involved in aggressive behavior in a wide variety of animals as well as in humans. Another brain chemical signal, neuropeptide Y (known as neuropeptide F in invertebrates), is also known to affect an array of behaviors in many species, including territoriality in mice. A new study by Drs. Herman Dierick and Ralph Greenspan of The Neurosciences Institute in San Diego shows that these two chemicals also regulate aggression in the fruit fly, Drosophila melanogaster.

In a series of studies that used drug treatments and genetic engineering we have produced flies that make increased or decreased amounts of serotonin, or whose nerve cells that use serotonin or neuropeptide F are silent or inactive. Our investigations showed that the more serotonin a fly makes, the more aggressive it will be towards other flies. Conversely, presence of neuropeptide F has an opposite modulatory effect on the flies’ behavior, reducing aggression. Serotonin and neuropeptide F are part of separate circuits in the brain, circuits which also differ to some extent between males and females. Male flies are much more aggressive.

Both of these chemical modulators affect aggression in mammals, and finding these effects in flies suggests that the molecular and neural roots for this complex social behavior are of ancient evolutionary origin.

Drs. Dierick and Greenspan are Fellows at The Neurosciences Institute, an independent, nonprofit, privately supported, scientific research organization dedicated to studying the workings of the brain at the most fundamental level. Under the leadership of Nobel Laureate, Gerald M. Edelman, M.D., Ph.D., the Institute is dedicated to a research environment that encourages creativity and innovation in a collaborative atmosphere with true freedom of scientific inquiry, in the expectation that such an environment provides the best chance for making vital advances for the benefit of mankind.

Herman A. Dierick and Ralph J. Greenspan
“Serotonin and neuropeptide F have opposite modulatory effects on fly aggression.”
Manuscript reference number: doi 10.1038/ng2029

The Neurosciences Institute.

Researchers of the heart and headaches at Thomas Jefferson University Hospital are combining efforts to determine if a common heart defect may be the cause of some forms of migraine headaches.

Investigators from the Jefferson Heart Institute and the Jefferson Headache Center are enrolling participants in a blinded study to determine if closing a Patent Foramen Ovale (PFO), a small hole or flap that can allow blood to flow between the right and left sides of the heart, can stop migraines. In newborns, the PFO closes at or shortly after birth, but in 20 percent of adults the gap remains open to some degree.

More than 28 million Americans suffer from migraine headaches. Debilitating migraine headaches cause major disruption in individual’s lives and cost billions of dollars in lost work, school and medical treatment each year. More than one quarter of the people who struggle with migraines have the heart defect.

Most people who have a PFO are never screened for it because doctors rarely suspect it of causing health problems but new evidence suggests that individuals with PFO are more susceptible to migraine. This susceptibility is believed to be due to the passage of material from the right side of the heart to the left side of the heart via the PFO. Blood and material that travels through the PFO is not filtered or oxygenated and in this form may travel to the brain, which can trigger the changes in the blood vessels that underlies migraine.

“Strokes, for example are sometimes triggered when blood clots passing through the PFO travel to the brain,” said one of the study’s primary investigators, David Fischman, M.D., Co-Director of the Cardiac Catherization Laboratory at Thomas Jefferson University Hospital, and Associate Professor of Medicine, Jefferson Medical College of Thomas Jefferson University.

“Up until now cardiologists have told us that patients with migraine get better when they have their PFO closed for other reasons,” said Stephen Silberstein, M.D., director of the Jefferson Headache Center, the study’s other primary investigator.

“We need to be able to prove that closure of a PFO by itself will actually diminish migraines,” said Dr. Silberstein, Professor of Neurology, Jefferson.

In this study, participants will be randomly assigned to one of two groups. One group will undergo a minimally-invasive procedure to close their PFO. An interventional cardiologist will insert a catheter into the heart and release a device which will form a seal around the PFO to prevent the incorrect blood flow. Typically, the procedure lasts one to two hours under local anesthesia.

The other group will not have their PFO closed but will undergo a procedure that only mimics the closure and will continue medical therapy for their migraines. But none of the participants will know to which group they have been assigned to. However, all participants will receive the same post-operative care and will leave the hospital within 24 hours.

To participate in the study, patients must:

Have experienced six to 14 days of migraines per month

Be between 18 and 55 years of age

Be unable to control migraines with medications currently available

For more information about the migraine study, please call 1-800-JEFF-NOW or 215-955-2037, or visit www.jeffersonhospital.org.

Yale School of Medicine and University of Crete School of Medicine researchers report in Cell April 20 the first evidence of a molecular mechanism that dynamically alters the strength of higher brain network connections.

This discovery may help the development of drug therapies for the cognitive deficits of normal aging, and for cognitive changes in schizophrenia, bipolar disorder, or attention deficit hyperactivity disorder (ADHD).

“Our data reveal how the brain’s arousal systems influence the cognitive networks that subserve working memory-which plays a key role in abstract thinking, planning, and organizing, as well as suppressing attention to distracting stimuli,” said http://info.med.yale.edu/neurobio/arnsten/arnsten.html Amy Arnsten, lead author and neurobiology professor at Yale.

The brain’s prefrontal cortex (PFC) normally is responsible for so-called executive functions. The ability of the PFC to maintain such memory-based functions declines with normal aging, is weakened in people with ADHD, and is severely disrupted in disorders such as schizophrenia and bipolar disorder.

The current study found that brain cells in PFC contain ion channels called hyperpolarization-activated cyclic nucleotide-gated channels (HCN) that reside on dendritic spines, the tiny protrusions on neurons that are specialized for receiving information. These channels can open when they are exposed to cAMP (cyclic adenosine monophosphate). When open, the information can no longer flow into the cell, and thus the network is effectively disconnected. Arnsten said inhibiting cAMP closes the channels and allows the network to reconnect.

The study also found alpha-2A adrenergic receptors near the channels that inhibit the production of cAMP and allow the information to pass through into the cell, connecting the network. These receptors are stimulated by a natural brain chemical norepinephrine or by medications like guanfacine.

“Guanfacine can strengthen the connectivity of these networks by keeping these channels closed, thus improving working memory and reducing distractibility,” she said. “This is the first time we have observed the mechanism of action of a psychotropic medication in such depth, at the level of ion channels.”

Arnsten said the excessive opening of HCN channels might underlie many lapses in higher cognitive function. Stress, for example, appears to flood PFC neurons with cAMP, which opens HCN channels, temporarily disconnects networks, and impairs higher cognitive abilities.

There is also evidence that this pathway may not be properly regulated with advancing age, resulting in destruction of cAMP. The dysregulation of the pathway may contribute to increased forgetfulness and susceptibility to distraction as we grow older.

The research is also relevant to common disorders such as ADHD, which is associated with weaker regulation of attention and behavior. ADHD is highly heritable, and some patients with ADHD may have genetic changes in molecules that weaken the production of norepinephrine. Treatments for ADHD all enhance stimulation of the norepinephrine receptors.

These new data also have important implications for the researchers’ studies of more severe mental illnesses like schizophrenia and bipolar disorder, which can involve mutations of a molecule called DISC1 (Disrupted in Schizophrenia) that normally regulates cAMP. Loss of function of DISC1 in patients with schizophrenia or bipolar disorder would increase vulnerability to cortical network disconnection and profound PFC deficits. This may be especially problematic during exposure to even mild stress, which may explain the frequent worsening of symptoms following exposure to stress. “We find it remarkable to relate a genetic mutation in patients to the regulation by an ion channel of PFC neuronal networks,” said Arnsten.

Co-authors include Min Wang, Brian Ramos, Yousheng Shu, Arthur Simen, Alvaro Duqye, Avis Brennan, Susheel Vijayraghavan, Anne Dudley, Eric Nou, David McCormick, James Mazer and Constantinos Paspalas, who also has an appointment at the University of Crete School of Medicine in Heraklion, Greece.

Source: Yale.

Scientists know little about how the brain assigns cells to participate in encoding and storing memories. Now a UCLA/University of Toronto team has discovered that a protein called CREB controls the odds of a neuron playing a role in memory formation. The April 20 edition of Science reports the findings, which suggest a new approach for preserving memory in people suffering from Alzheimer’s or other brain injury.

"Making a memory is not a conscious act," explained Alcino Silva, principal investigator and a professor of neurobiology and psychiatry at the David Geffen School of Medicine at UCLA. "Learning triggers a cascade of chemicals in the brain that influence which memories are kept and which are lost.

"Earlier studies have linked the CREB protein to keeping memories stable," added Silva, a member of the UCLA Brain Research Institute. "We suspected it also played a key role in channeling memories to brain cells that are ready to store them."

Silva and his colleagues used a mouse model to evaluate their hypothesis. They implanted CREB into a virus, which they introduced into some of the cells in the animal’s amygdala, a brain region critical to emotional memory.

Next they tested the mouse’s ability to recall a specific cage it had visited before. The cage was outfitted with patterned walls and a unique smell.

To visualize which brain cells stored the mouse’s memories about the cage, the scientists tracked a genetic marker that reveals recent neuron activity. When the team examined the animals’ amygdalas after the experiment, they found substantial amounts of CREB and the marker in neurons.

"We discovered that the amount of CREB influences whether or not the brain stores a memory," said Silva. "If a cell is low in CREB, it is less likely to keep a memory. If the cell is high in CREB, it is more likely to store the memory."

Human implications of the new research could prove profound.

"By artificially manipulating CREB levels among groups of cells, we can determine where the brain stores its memories," he explained. "This approach could potentially be used to preserve memory in people suffering from Alzheimer’s or other brain injury. We may be able to guide memories into healthy cells and away from sick cells in dying regions of the brain."

Our memories define who we are, so learning how the brain stores memory is fundamental to understanding what it is to be human, Silva observed.

"A memory is not a static snapshot," he said. "Memories serve a purpose. They are about acquiring information that helps us deal with similar situations in the future. What we recall helps us learn from our past experiences and better shape our lives."

Silva’s coauthors included Steven Kushner and Robert Brown of UCLA; Sheena Josselyn, Jin-Hee Han, Adelaide Yiu and Christy Cole of the University of Toronto; Rachel Neve of Harvard University; and John Guzowski of UC Irvine.

Source: UCLA