Smart Rat 'Hobbie-J' Produced By Over-expressing A Gene That Helps Brain Cells Communicate

Over-expressing a gene that lets brain cells communicate just a fraction of a second longer makes a smarter rat, report researchers from the Medical College of Georgia and East China Normal University.Dubbed Hobbie-J after a smart rat that stars in a Chinese cartoon book, the transgenic rat was able to remember novel objects, such as a toy she played with, three times longer than the average Long Evans female rat, which is considered the smartest rat strain. Hobbie-J was much better at more complex tasks as well, such as remembering which path she last traveled to find a chocolate treat.

The report comes about a decade after the scientists first reported in the journal Nature that they had developed "Doogie," a smart mouse that over-expresses the NR2B gene in the hippocampus, a learning and memory center affected in diseases such as Alzheimer's. Memory improvements they found in the new genetically modified Long Evans rat were very similar to Doogie's. Subsequent testing has shown that Doogie maintained superior memory as he aged.

"This adds to the notion that NR2B is a universal switch for memory formation," says Dr. Joe Z. Tsien, co-director of the MCG Brain & Behavior Discovery Institute and co-corresponding author on the paper published Oct. 19 in PLoS One. Dr. Xiaohua Cao at East China Normal University also is a co-corresponding author.

The finding also further validates NR2B as a drug target for improving memory in healthy individuals as well as those struggling with Alzheimer's or mild dementia, the scientists says.

NR2B is a subunit of NMBA receptors, which are like small pores on brain cells that let in electrically-charged ions that increase the activity and communication of neurons. Dr. Tsien refers to NR2B as the "juvenile" form of the receptor because its levels decline after puberty and the adult counterpart, NR2A, becomes more prevalent.

While the juvenile form keeps communication between brain cells open maybe just a hundred milliseconds longer, that's enough to significantly enhance learning and memory and why young people tend to do both better, says Dr. Tsien, the Georgia Research Alliance Eminent Scholar in Cognitive and Systems Neurobiology. This trap door configuration that determines not just how much but how fast information flows is unique to NMBA receptors.

Scientists found that Hobbie-J consistently outperformed the normal Long Evans rat even in more complex situations that require association, such as working their way through a water maze after most of the designated directional cues and the landing point were removed. "It's like taking Michael Jordan and making him a super Michael Jordan," Deheng Wang, MCG graduate student and the paper's first author, says of the large black and white rats already recognized for their superior intellect.

But even a super rat has its limits. For example with one test, the rats had to learn to alternate between right and left paths to get a chocolate reward. Both did well when they only had to wait a minute to repeat the task, after three minutes only Hobbie-J could remember and after five minutes, they both forgot. "We can never turn it into a mathematician. They are rats, after all," Dr. Tsien says, noting that when it comes to truly complex thinking and memory, the size of the brain really does matter.

That's one of the reasons scientists pursue this type of research: to see if increased production of NR2B in more complex creatures, such as dogs and perhaps eventually humans, gets the same results. He also is beginning studies to explore whether magnesium – a mineral found in nuts, legumes and green vegetables such as spinach – can more naturally replicate the results researchers have obtained through genetic manipulation. Magnesium ion blocks entry to the NMDA receptor so more magnesium forces the brain cell to increase expression levels of the more efficient NR2B to compensate. This is similar to how statin drugs help reduce cholesterol levels in the blood by inhibiting its synthesis in the liver.

Scientists created Hobbie-J and Doogie by making them over-express CaMKII, an abundant protein that works as a promoter and signaling molecule for the NMDA receptor, something that likely could not be replicated in humans. In October 2008, they reported in Neuron that they could also safely and selectively erase old and new memories alike in mice by over-expressing CaMKII while the memory was being recalled

"We want to make sure this is a real phenomenon," Dr. Tsien says of the apparent connection between higher levels of NR2B and better memory. "You should never assume that discovery you made in a cell line or a mouse can be translated to other species or systems unless you do the experiments." He adds that the failure of new drugs and other disappointments result from the lack of sufficient scientific evidence.

The transgenic rat has other practical value as well. There is substantial scientific and behavior data already available on rats and because rats are larger, it's easier to do memory tests and record signals from their brain. For example they are strong enough to press levers to get a food reward and their size and comfort level with water means they won't just float aimlessly in a water maze as "fluffy" mice tend to do.

Smoking Bans Reduce Risk Of Heart Attacks Associated With Secondhand Smoke

Smoking bans are effective at reducing the risk of heart attacks and heart disease associated with exposure to secondhand smoke, says a new report from the Institute of Medicine. The report also confirms there is sufficient evidence that breathing secondhand smoke boosts nonsmokers' risk for heart problems, adding that indirect evidence indicating that even relatively brief exposures could lead to a heart attack is compelling."It's clear that smoking bans work," said Lynn Goldman, professor of environmental health sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, and chair of the committee of experts that wrote the report. "Bans reduce the risks of heart attack in nonsmokers as well as smokers. Further research could explain in greater detail how great the effect is for each of these groups and how secondhand smoke produces its toxic effects. However, there is no question that smoking bans have a positive health effect."

About 43 percent of nonsmoking children and 37 percent of nonsmoking adults are exposed to secondhand smoke in the United States, according to public health data. Despite significant reductions in the percentages of Americans breathing environmental tobacco smoke over the past several years, roughly 126 million nonsmokers were still being exposed in 2000.

A 2006 report from the U.S. Surgeon General's office, The Health Consequences of Involuntary Exposure to Tobacco Smoke, concluded that exposure to secondhand smoke causes heart disease and indicated that smoke-free policies are the most economical and effective way to reduce exposure. However, the effectiveness of smoking bans in reducing heart problems has continued to be a source of debate.

The IOM committee conducted a comprehensive review of published and unpublished data and testimony on the relationship between secondhand smoke and short-term and long-term heart problems. Eleven key studies that evaluated the effects of smoking bans on heart attack rates informed the committee's conclusions about the positive effects of smoke-free policies. The studies calculated that reductions in the incidence of heart attacks range from 6 percent to 47 percent. Given the variations in how the studies were conducted and what they measured, the committee could not determine more precisely how great the effect is. Only two of the studies distinguished between reductions in heart attacks suffered by smokers versus nonsmokers. However, the repeated finding of decreased heart attack rates overall after bans were implemented conclusively demonstrates that smoke-free policies help protect people from the cardiovascular effects of tobacco smoke, the committee said.

The report also provides a detailed discussion of the evidence from animal research and epidemiological studies showing a cause-and-effect relationship between secondhand smoke exposure and heart problems. The committee was not able to determine the exact magnitude of the increased risk presented by breathing environmental tobacco smoke, but noted that studies consistently indicate it increases the risks by 25 percent to 30 percent. Although there is no direct evidence that a relatively brief exposure to secondhand smoke could precipitate a heart attack, the committee found the indirect evidence compelling. Data on particulate matter in smoke from other pollution sources suggest that a relatively brief exposure to such substances can initiate a heart attack, and particulate matter is a major component of secondhand smoke.

The report was sponsored by the U.S. Centers for Disease Control and Prevention. Established in 1970 under the charter of the National Academy of Sciences, the Institute of Medicine provides independent, objective, evidence-based advice to policymakers, health professionals, the private sector, and the public. The National Academy of Sciences, National Academy of Engineering, Institute of Medicine, and National Research Council make up the National Academies.

Those With Severe H1N1 At Risk For Pulmonary Emboli, Researchers Find

University of Michigan researchers have found that patients with severe cases of the H1N1 virus are at risk for developing severe complications, including pulmonary emboli, according to a study published today in the American Journal of Roentgenology.A pulmonary embolism occurs when one or more arteries in the lungs become blocked. The condition can be life-threatening. However, if treated aggressively, blood thinners can reduce the risk of death.

“The high incidence of pulmonary embolism is important. Radiologists have to be aware to look closely for the risks of pulmonary embolism in severely sick patients,” said Prachi P. Agarwal, M.D., assistant professor of radiology at the U-M Medical School and lead author of the study.

“With the upcoming annual influenza season in the United States, knowledge of the radiologic features of H1N1 is important, as well as the virus’s potential complications. The majority of patients with H1N1 that undergo chest X-rays have normal radiographs. CT scans proved valuable in identifying those patients at risk of developing more serious complications as a possible result of the H1N1 virus,” says Agarwal.

Working with Agarwal on the research were Ella Kazerooni, M.D., director of U-M’s division of cardiothoracic radiology and professor of radiology and Sandro K. Cinti, clinical assistant professor in U-M’s Department of Internal Medicine. The research included 66 patients diagnosed with the H1N1 flu. Of those, 14 were patients that were severely ill and required Intensive Care Unit admission.

All 66 patients underwent chest X-rays for the detection of H1N1 abnormalities. Pulmonary emboli were seen in CT scans on five of the 14 ICU patients.

Another important finding is that initial chest radiographs were normal in more than half of the patients with H1N1, says Kazerooni.

“These findings indicate that imaging studies would have to be repeated in severely ill patients to monitor disease progression,” said Kazerooni. “It’s important to heighten awareness not only among the radiologists, but also among the referring clinicians.”

There was no outside funding for the research.

The study will be published in the December issue of the AJR.