Study Refutes Accepted Model of Memory Formation

A study by Johns Hopkins researchers has shown that a widely accepted model of long-term memory formation — that it hinges on a single enzyme in the brain — is flawed. The new study, published in the Jan. 2 issue of Nature, found that mice lacking the enzyme that purportedly builds memory were in fact still able to form long-term memories as well as normal mice could.

“The prevailing theory is that when you learn something, you strengthen connections between your brain cells called synapses,” explains Richard Huganir, Ph.D., a professor and director of the Johns Hopkins University School of Medicine’s Solomon H. Snyder Department of Neuroscience. “The question is, how exactly does this strengthening happen?”

A research group at SUNY Downstate, led by Todd Sacktor, Ph.D., has suggested that key to the process is an enzyme they discovered, known as PKM-zeta. In 2006, Sacktor’s group made waves when it created a molecule that seemed to block the action of PKM-zeta — and only PKM-zeta. When the molecule, dubbed ZIP, was given to mice, it erased existing long-term memories. The molecule caught the attention of reporters and bloggers, who mused on the social and ethical implications of memory erasure.

But for researchers, ZIP was exciting primarily as a means for studying PKM-zeta. “Since 2006, many papers have been published on PKM-zeta and ZIP, but no one knew what PKM-zeta was acting on,” says Lenora Volk, Ph.D., a member of Huganir’s team. “We thought that learning the enzyme’s target could tell us a lot about how memories are stored and maintained.”

For the current study, Volk and fellow team member Julia Bachman made mice that lacked working PKM-zeta, so-called genetic “knockouts.” The goal was to compare the synapses of the modified mice with those of normal mice, and find clues about how the enzyme works.

But, says Volk, “what we got was not at all what we expected. We thought the strengthening capacity of the synapses would be impaired, but it wasn’t.” The brains of the mice without PKM-zeta were indistinguishable from those of other mice, she says. Additionally, the synapses of the PKM-zeta-less mice responded to the memory-erasing ZIP molecule just as the synapses of normal mice do.

The team then considered whether, in the absence of PKM-zeta, the mouse brains had honed a substitute synapse-building pathway, much in the way that a blind person learns to glean more information from her other senses. So the researchers made mice whose PKM-zeta genes functioned normally until they were given a drug that would suddenly shut the gene down. This allowed them to study PKM-zeta-less adult mice that had had no opportunity to develop a way around the loss of the gene. Still, the synapses of the so-called conditional knockout mice responded to stimuli just as synapses in normal mice did.

What this means, the researchers say, is that PKM-zeta is not the key long-term memory molecule previous studies had suggested, although it may have some role in memory. “We don’t know what this ZIP peptide is really acting on,” says Volk. “Finding out what its target is will be quite important, because then we can begin to understand at the molecular level how synapses strengthen and how memories form in response to stimuli.”

Imaging Study Examines Effect of Fructose on Brain Regions That Regulate Appetite

In a study examining possible factors regarding the associations between fructose consumption and weight gain, brain magnetic resonance imaging of study participants indicated that ingestion of glucose but not fructose reduced cerebral blood flow and activity in brain regions that regulate appetite, and ingestion of glucose but not fructose produced increased ratings of satiety and fullness, according to a preliminary study published in the January 2 issue of JAMA.

“Increases in fructose consumption have paralleled the increasing prevalence of obesity, and high-fructose diets are thought to promote weight gain and insulin resistance. Fructose ingestion produces smaller increases in circulating satiety hormones compared with glucose ingestion, and central administration of fructose provokes feeding in rodents, whereas centrally administered glucose promotes satiety,” according to background information in the article. “Thus, fructose possibly increases food-seeking behavior and increases food intake.” How brain regions associated with fructose- and glucose-mediated changes in animal feeding behaviors translates to humans is not completely understood.

Kathleen A. Page, M.D., of Yale University School of Medicine, New Haven, Conn., and colleagues conducted a study to examine neurophysiological factors that might underlie associations between fructose consumption and weight gain. The study included 20 healthy adult volunteers who underwent two magnetic resonance imaging sessions in conjunction with fructose or glucose drink ingestion. The primary outcome measure for the study was the relative changes in hypothalamic (a region of the brain) regional cerebral blood flow (CBF) after glucose or fructose ingestion.

The researchers found that there was a significantly greater reduction in hypothalamic CBF after glucose vs. fructose ingestion. “Glucose but not fructose ingestion reduced the activation of the hypothalamus, insula, and striatum—brain regions that regulate appetite, motivation, and reward processing; glucose ingestion also increased functional connections between the hypothalamic-striatal network and increased satiety.”

“The disparate responses to fructose were associated with reduced systemic levels of the satiety-signaling hormone insulin and were not likely attributable to an inability of fructose to cross the blood-brain barrier into the hypothalamus or to a lack of hypothalamic expression of genes necessary for fructose metabolism.”

(Image: iStockphoto)

Second impact syndrome: A devastating injury to the young brain

Physicians at Indiana University School of Medicine and the Northwest Radiology Network (Indianapolis, Indiana) report the case of a 17-year-old high school football player with second impact syndrome (SIS). A rare and devastating traumatic brain injury, SIS occurs when a person, most often a teenager, sustains a second head injury before recovery from an earlier head injury is complete. To the best of the authors’ knowledge, this is the first reported case in which imaging studies were performed after both injuries, adding new knowledge of the event. Findings in this case are reported and discussed in “Second impact syndrome in football: new imaging and insights into a rare and devastating condition. Case report,” by Elizabeth Weinstein, M.D., and colleagues, published today online, ahead of print, in the Journal of Neurosurgery: Pediatrics.

Definitive proof for receptor’s role in synapse development

Jackson Laboratory researchers led by Associate Professor Zhong-wei Zhang, Ph.D., have provided direct evidence that a specific neurotransmitter receptor is vital to the process of pruning synapses in the brains of newborn mammals.

Faulty pruning at this early developmental stage is implicated in autism-spectrum disorders and schizophrenia. The definitive evidence for N-methyl-D-aspartate receptor (NMDAR) in pruning has eluded researchers until now, but in research published in the Proceedings of the National Academy of Sciences, Zhang’s lab had serendipitous help in the form of a mouse model containing brain cells lacking NMDAR side-by-side with cells containing the receptor.

Soon after birth, mammals’ brains undergo significant development and change. Initially, large numbers of synapses form between neurons. Then, in response to stimuli, the synaptic connections are refined—some synapses are strengthened and others eliminated, or pruned.

In most synapses, glutamate serves as the neurotransmitter, and NMDAR, a major type of post-synaptic glutamate receptor, was previously known to play an important role in neural circuit development. Previous research has implicated the importance of NMDARs in pruning, but it remained unclear whether they played a direct or indirect role.

Zhang and colleagues focused on the thalamus, a brain region where synapse pruning and strengthening can be monitored and quantified with relative ease. They got unexpected help when they realized the mouse model they were using had thalamus cells lacking NMDARs right next to cells with normal NMDAR levels.

The researchers showed that the refinement process was disrupted in the absence of NMDARs. At the same time, neighboring neurons with the receptors proceeded through normal synaptic strengthening and pruning, clearly establishing the necessity of NMDARs in postsynaptic neurons for synaptic refinement.

"Whenever I give a talk or meet colleagues," Zhang says, "the first question that comes up is whether the NMDA receptor is important. It’s good that this is now settled definitively."

There has been extensive research into synaptic strengthening, and most of these studies indicate that the presence of NMDARs may support the recruitment of larger numbers of another kind of glutamate receptor to strengthen the synaptic connections. How NMDARs regulate the pruning process remains largely unknown, however.

Houston, We Have Another Problem: Study Shows that Space Travel is Harmful to the Brain

As if space travel was not already filled with enough dangers, a new study out today in the journal PLOS ONE shows that cosmic radiation – which would bombard astronauts on deep space missions to places like Mars – could accelerate the onset of Alzheimer’s disease. 

“Galactic cosmic radiation poses a significant threat to future astronauts,” said M. Kerry O’Banion, M.D., Ph.D., a professor in the University of Rochester Medical Center (URMC) Department of Neurobiology and Anatomy and the senior author of the study. “The possibility that radiation exposure in space may give rise to health problems such as cancer has long been recognized. However, this study shows for the first time that exposure to radiation levels equivalent to a mission to Mars could produce cognitive problems and speed up changes in the brain that are associated with Alzheimer’s disease.”

While space is full of radiation, the earth’s magnetic field generally protects the planet and people in low earth orbit from these particles. However, once astronauts leave orbit, they are exposed to constant shower of various radioactive particles. With appropriate warning, astronauts can be shielded from dangerous radiation associated with solar flares. But there are also other forms of cosmic radiation that, for all intents and purposes, cannot be effectively blocked.

Because this radiation exists in low levels, the longer an astronaut is in deep space, the greater the exposure. This is a concern for NASA as the agency is planning manned missions to a distant asteroid in 2021 and to Mars in 2035. The round trip to the red planet, in particular, could take as long as three years. 

For over 25 years, NASA has been funding research to determine the potential health risks of space travel in an effort to both develop countermeasures and determine whether or not the risks warranted sending men and women on extended missions in deep space.  

Since that time, several studies have demonstrated the potential cancer, cardiovascular, and musculoskeletal impact of galactic cosmic radiation. The study out today for the first time examines the potential impact of space radiation on neurodegeneration, in particular, the biological processes in the brain that contribute to the development of Alzheimer’s disease. O’Banion – whose research focuses on how radiation affects the central nervous system – and his team have been working with NASA for over eight years.

The researchers studied the impact of a particular form of radiation called high-mass, high-charged (HZE) particles. These particles – which are propelled through space at very high speeds by the force of exploding stars – come in many different forms. For this study the researcher chose iron particles. Unlikely hydrogen protons, which are produced by solar flares, the mass of HZE particles like iron, combined with their speed, enable them to penetrate solid objects such as the wall and protective shielding of a spacecraft. 

“Because iron particles pack a bigger wallop it is extremely difficult from an engineering perspective to effectively shield against them,” said O’Banion. “One would have to essentially wrap a spacecraft in a six-foot block of lead or concrete.”

Doctor Dolphin

Dolphin-assisted therapy for children with mental disabilities has made a splash in the West, and China is now riding the experimental tide. Shi Yingying and Erik Nilsson examine the impact these marine mammals have on the children they come into contact with.

Zheng Jun says 15 sessions with a pair of bottle-nosed dolphins at Hangzhou Polar Ocean Park have helped his 5-year-old autistic son become “aware” and “alert” enough to become his kindergarten’s class monitor. The father believes the dolphin-assisted therapy has been more effective than any other treatment. “Now, you can’t tell he’s different from his classmates,” he says. Zheng became a believer after he visited an Australian dolphin-swim program years ago. He says his son is elated when he splashes with the creatures in the park in Zhejiang province’s capital.

More than 80 parents of children with severe mental disabilities have booked all of next year’s spots in the program (sessions only run in the summer because the water temperatures are too cold for the kids in other seasons).

So, newcomers must wait until 2014, says Liu Quansheng, manager of the park’s owner, Zhejiang Aquarium Investment Group. Despite the demand, dolphin-assisted therapy has not been scientifically proven. Still, many experts and parents of special-needs children swear by it.

(Image: dolphin-therapy.org)

'Lady of the Cells' Dead at 103

Italy has lost a truly fascinating centenarian. Nobel Prize winner Rita Levi-Montalcini died at her home yesterday at age 103, leading Rome’s mayor to declare the scientist’s death a loss “for all of humanity.” It may not be much of an exaggeration: The so-called “Lady of the Cells” faced many obstacles, reports the AP: a father who believed women should not study (she ultimately obtained a degree in medicine and surgery), a Fascist regime (Levi-Montalcini lost her neurobiology job in 1938 when Jews were banned from major professions), and the Nazis, whose 1943 invasion of Italy forced her family to flee to Florence and live underground.

But the petite woman’s determination was formidable: In the face of the Fascist regime she studied chicken embryos in a makeshift lab in her bedroom. She chose not to marry or have a family—without hesitation or regret, she once said—fearing doing so would weaken her independence. She claimed to sleep no more than three hours a night, and worked well into her final years. That effort produced contributions that were just as formidable.

Levi-Montalcini shared the Nobel medicine prize in 1986 with American biochemist Stanley Cohen for their groundbreaking cellular research. Her research increased the understanding of many conditions, including tumors, developmental malformations, and senile dementia.

(Image: AP Photo/Riccardo De Luca)