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What emotional memories are made of

Mouse experiments reveal ‘flight or fight’ hormone’s role

Contact: Nick Zagorski
nzagors1@jhmi.edu
443-287-2251
Johns Hopkins Medical Institutions

Both extensive psychological research and personal experiences confirm that events that happen during heightened states of emotion such as fear, anger and joy are far more memorable than less dramatic occurrences. In a report this week in Cell, Johns Hopkins researchers and their collaborators at Cold Spring Harbor and New York University have identified the likely biological basis for this: a hormone released during emotional arousal “primes” nerve cells to remember events by increasing their chemical sensitivity at sites where nerves rewire to form new memory circuits.

Describing the brain as a big circuit board in which each new experience creates a new circuit, Hopkins neuroscience professor Richard Huganir, Ph.D. says that he and his team found that during emotional peaks, the hormone norepinephrine dramatically sensitizes synapses – the site where nerve cells make an electro-chemical connection – to enhance the sculpting of a memory into the big board.

Image showing phosphorylated GluR1 receptors congregating around sites of neuronal synapses.

Norepinephrine, more widely known as a “fight or flight” hormone, energizes the process by adding phosphate molecules to a nerve cell receptor called GluR1. The phosphates help guide the receptors to insert themselves adjacent to a synapse. “Now when the brain needs to form a memory, the nerves have plenty of available receptors to quickly adjust the strength of the connection and lock that memory into place,” Huganir says.

Huganir and his team suspected that GluR1might be a target of norepinephrine since disruptions in this receptor cause spatial memory defects in mice. They tested the idea by either injecting healthy mice with adrenaline or exposing them to fox urine, both of which increase norepinephrine levels in brain. Analyzing brain slices of the mice, the researchers saw increased phosphates on the GluR1 receptors and an increased ability of these receptors to be recruited to synapses.

When the researchers put mice in a cage, gave a mild shock, took them out of that cage and put them back in it the next day, mice who had received adrenaline or fox urine tended to “freeze” in fear – an indicator they associated the cage as the site of a shock – more frequently, suggestive of enhanced memory.

However, in a similar experiment with mice genetically engineered to have a defective GluR1 receptor that phosphates cannot attach to, adrenaline injections had no effect on mouse memory, further evidence of the “priming” effect of the receptor in response to norepinephrine.

The researchers plan on continuing their work by going in the opposite direction and engineering another mouse strain that has a permanently phosphorylated or “primed” receptor. “We’re curious to see how these mice will behave,” Huganir says. “We suspect that they’ll be pretty smart, but at the same time constantly anxious.”

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The research was funded by the National Institutes of Health, Damon Runyon Postdoctoral Fellowship, NARSAD, and the Ale Davis and Maxine Harrison Foundation

Authors on the paper are Hailan Hu, Eleonore Real, and Roberto Malinow of Cold Spring Harbor Laboratory; Joe LeDoux of New York University; and Kogo Takamiya, Myoung-Goo Kang, and Huganir of Johns Hopkins

On the Web:
http://neuroscience.jhu.edu/RichardHuganir.php
http://www.cell.com

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October 5, 2007 Posted by | General Psychiatry, Global Health Vision, Global News, Johns Hopkins University, journal Cell, Medical Journals, New York University, Norepinephrine, Research, RSS Feed, Science, W. Garfield Weston Fellows, Washington DC City Feed | 1 Comment

U-M study finds lymphoma drug effective over long term

Contact: Nicole Fawcett
nfawcett@umich.edu
734-764-2220
University of Michigan Health System

86 percent of patients treated with Bexxar survived after 8 years of follow-up

ANN ARBOR, Mich. — Eight years after being treated with a new drug for non-Hodgkin’s lymphoma, 86 percent of patients were still alive and half had not had a relapse of their disease, according to researchers from the University of Michigan Comprehensive Cancer Center.

The patients had follicular lymphoma, a type of cancer that is not considered to be curable using traditional treatments. Even if patients initially respond to treatment, the disease almost always comes back and becomes more difficult to treat.

The study followed 76 patients with follicular non-Hodgkin’s lymphoma, a cancer of the lymph system, who received the radioimmunotherapy drug Bexxar as their first treatment for the disease. Ninety-five percent of the patients saw their tumors shrink from the treatment and three-quarters of patients went into complete remission. Patients were followed for a median of eight years, and nearly two-thirds have remained in complete remission eight years after treatment.

“For years we have known radioimmunotherapy such as Bexxar is one of the most effective treatments for patients with relapsed follicular lymphoma. These data show Bexxar is particularly effective when used as a frontline treatment,” says Mark Kaminski, M.D., professor of internal medicine at the U-M Medical School. Kaminski will present these results June 4 at the American Society of Clinical Oncology annual meeting in Chicago.

“These results compare quite favorably with those achieved with state-of-the-art chemotherapy regimens that take months to deliver. But Bexxar is given as a single treatment, completed within one week, which makes it an extremely convenient regimen for patients,” Kaminski says.

Non-Hodgkin’s lymphoma, the nation’s sixth leading cause of cancer death, is a cancer of the lymph system, which is part of the immune system. Follicular lymphoma is the second most common type of non-Hodgkin’s lymphoma. Lymphoma spreads easily through the lymph system and the bloodstream and consequently tends to be widespread when it is diagnosed. Traditional treatment often involves intensive chemotherapy, or a combination of chemotherapy and the monoclonal antibody rituximab. These treatments are usually given every three weeks over a span of up to six months and can cause many unpleasant side effects, including nausea, hair loss and infections.

Bexxar, whose chemical name is tositumomab and iodine I 131 tositumomab, combines an antibody that seeks out cancer cells, and a radioactive form of the element iodine. When injected, it travels like a guided missile through the bloodstream to bind to a protein found on the surface of the cancerous cells. The radiation zaps these malignant cells with minimal exposure to normal tissues.

With the Bexxar therapeutic regimen, a patient receives an injected test dose of radioactive Bexxar, followed one to two weeks later with a custom-tailored therapeutic dose. After that, the therapy is considered complete. The most common side effect is a temporary lowering of blood counts several weeks after the treatment. There is no hair loss and nausea is rare.

Kaminski and his colleague Richard Wahl (formerly at U-M and now at Johns Hopkins University) developed the Bexxar regimen, which received approval from the U.S. Food and Drug Administration in June 2003 to treat follicular non-Hodgkin’s lymphoma after other treatments have failed. The current results involve Bexxar as a first-line treatment for this disease.

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In addition to Kaminski and Wahl, U-M study authors were Judith Estes, R.N., a nurse practitioner; Missy Tuck, clinical research coordinator; and Charles Ross, M.D., associate professor of pathology.

Funding for the study was from the National Institutes of Health and GlaxoSmithKline. The University of Michigan holds patents for the Bexxar therapeutic regimen, which is marketed by GlaxoSmithKline under a licensing agreement. U-M receives royalties on sales of Bexxar, a portion of which goes to Kaminski and his co-inventors.

For information about non-Hodgkin’s lymphoma, visit http://www.mcancer.org or call the Cancer AnswerLine at 800-865-1125. For information about Bexxar from its manufacturer, call 877-4-BEXXAR or visit http://www.bexxar.com.

Reference: American Society of Clinical Oncology 43rd annual meeting, June 1-5, 2007, Chicago, Ill. Abstract No. 8033.

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June 4, 2007 Posted by | Calgary, Cancer, Global, Global Health Vision, Global News, Johns Hopkins University, News, News Australia, News Canada, News UK, News US, non-Hodgkin's lymphoma, Research, University of Michigan, Virginia, Washington DC, World News | Leave a comment