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Thursday, July 28, 2011

Researchers show how memory is lost -- and found

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.
Provided by Yale University
"Researchers show how memory is lost -- and found." July 27th, 2011.

Psychopharmacology (Berl). 2005 Oct;182(2):205-13. Epub 2005 Oct 19.

Lack of effects of guanfacine on executive and memory functions in healthy male volunteers.
Müller U, Clark L, Lam ML, Moore RM, Murphy CL, Richmond NK, Sandhu RS, Wilkins IA, Menon DK, Sahakian BJ, Robbins TW.

Department of Experimental Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK.

RATIONALE: Guanfacine is an alpha2-adrenergic receptor agonist that has been shown to have beneficial effects on working memory and attentional functions in monkeys and in patients with attention deficit hyperactivity disorder. OBJECTIVES: The aim of this study was to further investigate the cognitive-enhancing properties of guanfacine using an established battery of tasks measuring executive and memory functions. METHODS: Sixty healthy male volunteers were randomised into three groups. Cognitive testing was performed from +2 to +4 h after double-blind administration of a single oral dose of 1 or 2 mg of guanfacine or placebo. RESULTS: Systolic blood pressure was significantly reduced by both doses of guanfacine at the end of the testing session. There were no statistically significant effects on any of the cognitive measures. Two trend effects were observed with poorer performance on digit span backward and slower 'Go' reaction times after guanfacine.
CONCLUSION: This study found no improvement of prefrontal memory or executive functions after guanfacine. Negative effects on blood pressure and trend effects on digit span backward and go reaction time indicate a mild sedative effect of guanfacine at these doses, possibly via mechanisms of autoreceptor down-regulation.

PMID: 16078088 [PubMed - indexed for MEDLINE]

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Robert Karl Stonjek

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