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Making Memories: How 1 Protein Does It

MicroRNAs key to memory and learning process.

Studying tiny bits of genetic material that control protein formation in the brain, Johns Hopkins scientists say they have new clues to how memories are made and how drugs might someday be used to stop disruptions in the process that lead to mental illness and brain wasting diseases.

In a report published in the March 2 issue of Cell, the researchers said certain microRNAs—genetic elements that control which proteins get made in cells— are the key to controlling the actions of so-called brain-derived neurotrophic factor (BDNF), long linked to brain cell survival, normal learning and memory boosting.

During the learning process, cells in the brain’s hippocampus release BDNF, a growth-factor protein that ramps up production of other proteins involved in establishing memories. Yet, by mechanisms that were never understood, BDNF is known to increase production of less than 4 percent of the different proteins in a brain cell.

That led Mollie Meffert, M.D., Ph.D., associate professor of biological chemistry and neuroscience at the Johns Hopkins University School of Medicine to track down how BDNF specifically determines which proteins to turn on, and to uncover the role of regulatory microRNAs.

MicroRNAs are small molecules that bind to and block messages that act as protein blueprints from being translated into proteins. Many microRNAs in a cell shut down protein production, and, conversely, the loss of certain microRNAs can cause higher production of specific proteins.

The researchers measured microRNA levels in brain cells treated with BDNF and compared them to microRNA levels in neurons not treated with BDNF. The researchers noticed that levels of certain microRNAs were lower in brain cells treated with BDNF, suggesting that BDNF controls the levels of these microRNAs and, through this control, also affects protein production. Homing in on those specific microRNAS that disappeared when cells were treated with BDNF, the team found all were of the same type, so-called Let-7 microRNAs, and that all shared a common genetic sequence.

“This short genetic sequence has been shown by other researchers to behave like a bar code that can selectively prevent production of Let-7 microRNAs,” says Meffert.

To test if the loss of Let-7 microRNAs lets BDNF increase production of specific proteins, Meffert’s team genetically engineered neurons so they could no longer decrease Let-7 microRNAs. They found that treating these neurons with BDNF no longer resulted in decreased microRNA levels or an increase in learning and memory proteins.

In measuring microRNA levels in cells treated with BDNF, the researchers also found more than 174 microRNAs that increased with BDNF treatment. This suggested to the research team that BNDF treatment also can increase other microRNAs and, thereby, decrease production of certain proteins. Says Meffert, some of these proteins may need to be decreased during learning and memory, whereas others may not contribute to the process at all.

To confirm that BDNF, via microRNA action, halts the production of certain proteins, the researchers monitored living brain cells to find out where messages go in response to BDNF. Messages that aren’t translated into proteins can accumulate inside small formations within cells. Using a microscope, the researchers watched a lab dish containing brain cells that had been marked with a fluorescent molecule that labels these formations as glowing spots. Treating cells with BDNF caused the number and size of the glowing spots to increase. The researchers determined that BDNF uses microRNA to send messages to these spots where they can be exiled away from the translating machinery that turns them into protein.

“Monitoring these fluorescent complexes gave us a window that we needed to understand how BDNF is able to target the production of only certain proteins that help neurons to grow and make learning possible,” Meffert says.

Adds Meffert, “Now that we know how BDNF boosts production of learning and memory proteins, we have an opportunity to explore whether therapeutics can be designed to enhance this mechanism for treatment of patients with mental disorders and neurodegenerative diseases like Alzheimer’s disease.”

Notes about this memory research article

Additional authors of the study included Yu-Wen Huang, Claudia Ruiz, Elizabeth Eyler and Kathie Lin all from Johns Hopkins University, School of Medicine.

This research was supported by funds from the Braude Foundation and the Brain Science Institute of Johns Hopkins.

Contacts: Vanessa McMains & Audrey Huang – Johns Hopkins Medical Institutions
Source: Johns Hopkins Medicine press release
Video Source: Neuroscience video made available by YouTube.com user JohnsHopkinsMedicine.
Image Source: Neuroscience image adapted from press release above.

Neuron (red) accumulates messages (green) when treated with BDNF. Image from Johns Hopkins Medicine press release. This image is distorted from the original.

Source: Nature Neuroscience
http://neurosciencenews.com/bdnf-micro-rna-protein-making-memories/

Posted by
Robert Karl Stonjek

Can you die of a broken heart? Bereavement can weaken the body's ability to fight infections

(Medical Xpress) -- Immunity experts at the University of Birmingham have found biological evidence to suggest that bereavement lowers physical immunity, putting older people at risk of life-threatening infections..

They found that the emotional stress of bereavement is associated with a drop in the efficiency of white blood cells known as neutrophils, which combat infections such a pneumonia, a major cause of death in older adults.

The research, which was funded by the Dunhill Medical Trust, helps to explain why, for example, it is not uncommon for both partners in a long and happy marriage to die within a relatively short period.

As we age our immune system becomes less efficient. We also experience the adrenopause. The adrenal glands produce the stress hormone cortisol, an immune suppressor which has long been prescribed as steroids to reduce inflammation. The adrenals also produce Dehydroepiandrosterone DHEAS, which counters the negative effects of cortisol and helps to increase immune function. 

‘We hypothesised that the emotional stress of bereavement would suppress immune function, specifically neutrophil bactericidal activity, in older adults,’ explains Dr Anna Phillips, of the School of Sports and Exercise Sciences (SportEx), who co-authored the research with Riyad Khanfer, also of SportEx, and Professor Janet Lord, Professor of Immune Cell Biology at Birmingham.

The researchers assessed neutrophil phagocytosis (engulfing by white blood cells) and stimulated superoxide (killing chemical) production against E.coli in 24 bereaved and 24 age and sex-matched non-bereaved controls all aged 65 years and over. Cortisol and DHEAS levels were determined in serum to assess potential mechanisms. Neutrophil superoxide production was significantly reduced among the bereaved when challenged with E.coli. The same group also had a significantly higher cortisol: DHEAS ratio compared to the controls. There was no difference in neutrophil phagocytosis between the two groups.

Alongside the clinical tests, the results of a psychological questionnaire showed that bereaved older people had significantly greater depression and anxiety symptoms that the non-bereaved.

‘The emotional stress of bereavement is associated with suppressed neutrophil superoxide production and with a raised cortisol:DHEAS ratio,’ the authors conclude. ‘The stress of bereavement exaggerates the age-related decline in hypothalamic-pituitary-adrenal axis (HPA axis) and combines with immune ageing to further suppress immune function, which may help to explain increased risk of infection in bereaved older adults.’

The latest results build on research previously published by Dr Phillips and her team which has shown that older adults who have suffered bereavement in the past 12 months had a poorer antibody response to the annual flu jab compared to non-bereaved adults. The team has also shown that a significant physical stress, hip fracture, can worsen neutrophil bactericidal ability in older adults, which has been associated with increased susceptibility to infection following surgery.

Dr Phillips comments: ‘We would like to catch elderly people at the crucial point when cortisol is going to be doing the most damage. We think if they were prescribed DHEA shortly after bereavement this would do the most good. It wouldn’t just help with their immunity but would boost their mood as well, as DHEA is known to increase feelings of well-being. Ideally, this could be combined with other treatments such as psycho-social therapies, to help older people through very difficult times and help to prevent them becoming ill.’

Professor Lord, who heads the University’s Centre for Healthy Ageing Research, added: ‘I think the most important aspect of our work is showing that bereavement does have a physiological impact on the body and that the bereaved need to be supported by friends, relatives and clinicians rather than being told to keep a stiff upper lip’

The research was published in the journal Brain Behaviour and Immunity.

Provided by University of Birmingham

"Can you die of a broken heart? Bereavement can weaken the body's ability to fight infections." March 28th, 2012.http://medicalxpress.com/news/2012-03-die-broken-heart-bereavement-weaken.html

Posted by
Robert Karl Stonjek