How memory is lost: Loss of memory due to aging may be reversible

ScienceDaily (July 28, 2011) — Yale University researchers can't tell you where you left your car keys -- but they can tell you why you can't find them.

A new study published July 27 in the journal Nature shows the neural networks in the brains of the middle-aged and elderly have weaker connections and fire less robustly than in youthful ones. Intriguingly, the research suggests that this condition is reversible.

"Age-related cognitive deficits can have a serious impact on our lives in the Information Age as people often need higher cognitive functions to meet even basic needs, such as paying bills or accessing medical care," said Amy Arnsten, Professor of Neurobiology and Psychology and a member of the Kavli Institute for Neuroscience. "These abilities are critical for maintaining demanding careers and being able to live independently as we grow older."

As people age, they tend to forget things more often, are more easily distracted and disrupted by interference, and have greater difficulty with executive functions. While these age-related deficits have been known for many years, the cellular basis for these common cognitive difficulties has not been understood. The new study examined for the first time age-related changes in the activity of neurons in the prefrontal cortex (PFC), the area of the brain that is responsible for higher cognitive and executive functions.

Networks of neurons in the prefrontal cortex generate persistent firing to keep information "in mind" even in the absence of cues from the environment. This process is called "working memory," and it allows us to recall information, such as where the car keys were left, even when that information must be constantly updated. This ability is the basis for abstract thought and reasoning, and is often called the "Mental Sketch Pad." It is also essential for executive functions, such as multi-tasking, organizing, and inhibiting inappropriate thoughts and actions.

Arnsten and her team studied the firing of prefrontal cortical neurons in young, middle-aged and aged animals as they performed a working memory task. Neurons in the prefrontal cortex of the young animals were able to maintain firing at a high rate during working memory, while neurons in older animals showed slower firing rates. However, when the researchers adjusted the neurochemical environment around the neurons to be more similar to that of a younger subject, the neuronal firing rates were restored to more youthful levels.

Arnsten said that the aging prefrontal cortex appears to accumulate excessive levels of a signaling molecule called cAMP, which can open ion channels and weaken prefrontal neuronal firing. Agents that either inhibited cAMP or blocked cAMP-sensitive ion channels were able to restore more youthful firing patterns in the aged neurons. One of the compounds that enhanced neuronal firing was guanfacine, a medication that is already approved for treating hypertension in adults, and prefrontal deficits in children, suggesting that it may be helpful in the elderly as well.

Arnsten's finding is already moving to the clinical setting. Yale is enrolling subjects in a clinical trial testing guanfacine's ability to improve working memory and executive functions in elderly subjects who do not have Alzheimer's Disease or other dementias.

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Yale University.

Journal Reference:

Min Wang, Nao J. Gamo, Yang Yang, Lu E. Jin, Xiao-Jing Wang, Mark Laubach, James A. Mazer, Daeyeol Lee, Amy F. T. Arnsten. Neuronal basis of age-related working memory decline. Nature, 2011; DOI: 10.1038/nature10243

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Epigenetic 'memory' key to nature versus nurture

ScienceDaily (July 25, 2011) — Researchers at the John Innes Centre have made a discovery, reported this evening (24 July) in Nature, that explains how an organism can create a biological memory of some variable condition, such as quality of nutrition or temperature. The discovery explains the mechanism of this memory -- a sort of biological switch -- and how it can also be inherited by offspring.

The work was led by Professor Martin Howard and Professor Caroline Dean at the John Innes Centre.

Professor Dean said "There are quite a few examples that we now know of where the activity of genes can be affected in the long term by environmental factors. And in some cases the environment of an individual can actually affect the biology or physiology of their offspring but there is no change to the genome sequence."

For example, some studies have shown that in families where there was a severe food shortage in the grandparents' generation, the children and grandchildren have a greater risk of cardiovascular disease and diabetes, which could be explained by epigenetic memory. But until now there hasn't been a clear mechanism to explain how individuals could develop a "memory" of a variable factor, such as nutrition.

The team used the example of how plants "remember" the length of the cold winter period in order to exquisitely time flowering so that pollination, development, seed dispersal and germination can all happen at the appropriate time.

Professor Howard said "We already knew quite a lot about the genes involved in flowering and it was clear that something goes on in winter that affects the timing of flowering, according to the length of the cold period."

Using a combination of mathematical modelling and experimental analysis the team has uncovered the system by which a key gene called FLC is either completely off or completely on in any one cell and also later in its progeny. They found that the longer the cold period, the higher the proportion of cells that have FLC stably flipped to the off position. This delays flowering and is down to a phenomenon known as epigenetic memory.

Epigenetic memory comes in various guises, but one important form involves histones -- the proteins around which DNA is wrapped. Particular chemical modifications can be attached to histones and these modifications can then affect the expression of nearby genes, turning them on or off. These modifications can be inherited by daughter cells, when the cells divide, and if they occur in the cells that form gametes (e.g. sperm in mammals or pollen in plants) then they can also pass on to offspring.

Together with Dr Andrew Angel (also at the John Innes Centre), Professor Howard produced a mathematical model of the FLC system. The model predicted that inside each individual cell, the FLC gene should be either completely activated or completely silenced, with the fraction of cells switching to the silenced state increasing with longer periods of cold.

To provide experimental evidence to back up the model, Dr Jie Song in Prof. Dean's group used a technique where any cell that had the FLC gene switched on, showed up blue under a microscope. From her observations, it was clear that cells were either completely switched or not switched at all, in agreement with the theory.

Dr Song also showed that the histone proteins near the FLC gene were modified during the cold period, in such a way that would account for the switching off of the gene.

Funding for the project came from BBSRC, the European Research Council, and The Royal Society.

Professor Douglas Kell, Chief Executive, BBSRC said "This work not only gives us insight into a phenomenon that is crucial for future food security -- the timing of flowering according to climate variation -- but it uncovers an important mechanism that is at play right across biology. This is a great example of where the research that BBSRC funds can provide not only a focus on real life problems, but also a grounding in the fundamental tenets of biology that will underpin the future of the field. It also demonstrates the value of multidisciplinary working at the interface between biology, physics and mathematics."

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Biotechnology and Biological Sciences Research Council, via EurekAlert!, a service of AAAS.

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Fear boosts activation of immature brain cells: Adult neural stem cells play role in creating emotional context of memory

ScienceDaily (June 15, 2011) — Fear burns memories into our brain, and new research by University of California, Berkeley, neuroscientists explains how.

Scientists have long known that fear and other highly emotional experiences lead to incredibly strong memories. In a study appearing online in advance of publication in the journal Molecular Psychiatry, UC Berkeley's Daniela Kaufer and colleagues report a new way for emotions to affect memory: The brain's emotional center, the amygdala, induces the hippocampus, a relay hub for memory, to generate new neurons.

In a fearful situation, these newborn neurons get activated by the amygdala and may provide a "blank slate" to strongly imprint the new fearful memory, she said. In evolutionary terms, it means new neurons are likely helping you to remember the lion that nearly killed you.

"We remember emotional events much more strongly than daily experiences, and for a long time we have known that connections between the amygdala and hippocampus help to encode this emotional information," said Kaufer, an assistant professor of integrative biology and a member of UC Berkeley's Wills Neuroscience Institute. "Our research shows that amygdala input actually pushes the hippocampus to make new neurons from a unique population of neural stem cells. This provides completely new cells that get activated in response to emotional input."

The finding has implications for post traumatic stress disorder (PTSD) and other problems caused by faulty regulation of emotional memory.

"Many affective disorders involve disordered emotional memories like PTSD, depression and anxiety. We think that newborn neurons may play a role in creating these emotional memories," she said.

The finding comes a year after brain researcher Fred Gage at the Salk Institute for Biological Studies in La Jolla, Calif., showed that the formation of new memories is associated with increased activation of two-week-old newborn nerve cells in the hippocampus that are derived from adult neural stem cells. Adult stem cells appear to differentiate continually into new nerve cells -- nearly 100 each day -- yet half of those newborn neurons are slated for death within four weeks after their birth. If they are highly activated, however -- such as in learning new complex information -- many more of them will survive and presumably help in establishing new memories in the brain.

Kaufer, who conducts research on the effects of stress on the brain, knew that many types of positive and negative experiences, such as exercise and stress, affect the rate of neurogenesis in the hippocampus. Along with graduate students Elizabeth Kirby, the lead author of the study, and Aaron Friedman, she was intrigued by the idea that emotions might affect neurogenesis in the hippocampus, since the brain's clearinghouse for emotions, the amygdala, is connected to the hippocampus via multiple neural circuits. To test this, Kirby focused on the basolateral amygdala, the region of the almond-shaped structure that handles negative emotions, including stress, anxiety and fear.

Using rats, Kirby surgically destroyed the basolateral amygdala and discovered that the production of new nerve cells in the hippocampus decreased. To make sure that the cell damage created when the amygdala was surgically destroyed was not affecting the experiment, the researchers borrowed a gene therapy technique from Robert Sapolsky's lab at Stanford University to genetically introduce potassium channels into the amygdala, which shut down the activity of the nerve cells without causing injury. This also decreased neurogenesis in the hippocampus.

They next tested Gage's theory that new neurons are especially sensitive to input two weeks after they form. Kirby and Kaufer labeled hippocampal cells created over a three-day period in a group of rats, and then conditioned a fear response in these rats two weeks later. They then confronted the rats with the same fearful situation or a neutral yet novel context the next day. When they examined the brains, they found that the newborn neurons had been specifically activated by the fearful situation. However, when they destroyed the basolateral amygdala, new neurons were no longer activated in response to the fearful memory.

"The research suggests that newborn neurons play a role not only in the formation of memory, but also in helping to create the emotional context of memory," Kirby said. It also suggests that the basolateral amygdala drives the ability of new neurons to be part of an emotional memory.

The team now plans to see whether other negative stimuli, such as stress and anxiety, similarly cooperate with amygdala activity to alter neurogenesis in the hippocampus.

The coauthors of the paper with Kaufer, Kirby and Friedman are UC Berkeley graduate student David Covarrubias and undergraduates Carl Ying and Wayne G. Sun; Ki Ann Goosens, an assistant professor of brain and cognitive sciences in the McGovern Institute for Brain Research at the Massachusetts Institute of Technology; and Stanford's Sapolsky.

Kaufer's work is funded by a 2010 BRAINS (Biobehavioral Research Awards for Innovative New Scientists) award from the National Institute of Mental Health of the National Institutes of Health and a young investigator award from The Brain and Behavior Research Foundation, formerly the National Alliance for Research on Schizophrenia and Depression (NARSAD). Kirby is supported by a California Institute for Regenerative Medicine pre-doctoral fellowship and a National Defense Science and Engineering Graduate Research fellowship from the U. S. Department of Defense.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by University of California - Berkeley. The original article was written by Robert Sanders, Media Relations.

Journal Reference:

E D Kirby, A R Friedman, D Covarrubias, C Ying, W G Sun, K A Goosens, R M Sapolsky, D Kaufer. Basolateral amygdala regulation of adult hippocampal neurogenesis and fear-related activation of newborn neurons. Molecular Psychiatry, 2011; DOI: 10.1038/mp.2011.71

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