New research explains the interaction between brain state and the neural triggers responsible for learning, potentially opening up new ways of boosting cognitive function. (Credit: iStockphoto/Issam Khriji)

University of Bristol (BRISTOL, UK)  —  Medical researchers have found a missing link that explains the interaction between brain state and the neural triggers responsible for learning, potentially opening up new ways of boosting cognitive function in the face of diseases such as Alzheimer’s as well as enhancing memory in healthy people.

Much is known about the neural processes that occur during learning but until now it has not been clear why it occurs during certain brain states but not others. Now researchers from the University of Bristol have been able to study, in isolation, the specific neurotransmitter which enhances learning and memory.

Acetylcholine is released in the brain during learning and is critical for the acquisition of new memories. Its role is to facilitate the activity of NMDA receptors, proteins that control the strength of connections between nerve cells in the brain.

Currently, the only effective treatment for the symptoms of cognitive impairment seen in diseases such as Alzheimer’s is through the use of drugs that boost the amount of acetylcholine release and thereby enhance cognitive function.

Describing their findings in the journal Neuron, researchers from Bristol’s School of Physiology and Pharmacology have shown that acetylcholine facilitates NMDA receptors by inhibiting the activity of other proteins called SK channels whose normal role is to restrict the activity of NMDA receptors.

This discovery of a role for SK channels provides new insight into the mechanisms underlying learning and memory. SK channels normally act as a barrier to NMDA receptor function, inhibiting changes in the strength of connections between nerve cells and therefore restricting the brain’s ability to encode memories. Findings from this latest research show that the SK channel barrier can be removed by the release of acetylcholine in the brain in order to enhance our ability to learn and remember information.

Lead researcher Dr Jack Mellor, from the University of Bristol’s Medical School, said: “These findings are not going to revolutionise the treatment of Alzheimer’s disease or other forms of cognitive impairment overnight. However, national and international funding bodies have recently made research into aging and dementia a top priority so we expect many more advances in our understanding of the mechanisms underlying learning and memory in both health and disease.”

The team studied the effects of drugs that target acetylcholine receptors and SK channels on the strength of connections between nerve cells in animal brain tissue. They found that changes in connection strength were facilitated by the presence of drugs that activate acetylcholine receptors or block SK channels revealing the link between the two proteins.

Dr Mellor added: “From a therapeutic point of view, this study suggests that certain drugs that act on specific acetylcholine receptors may be highly attractive as potential treatments for cognitive disorders. Currently, the only effective treatments for patients with Alzheimer’s disease are drugs that boost the effectiveness of naturally released acetylcholine. We have shown that mimicking the effect of acetylcholine at specific receptors facilitates changes in the strength of connections between nerve cells. This could potentially be beneficial for patients suffering from Alzheimer’s disease or schizophrenia.”

The research team involved the University of Bristol’s MRC Centre for Synaptic Plasticity and the Division of Neuroscience in the School of Physiology & Pharmacology, part of the Bristol Neuroscience network. This work was supported by the Wellcome Trust, MRC, BBSRC and GSK.

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


Journal Reference:

1.                        Buchanan KA, Petrovic MM, Chamberlain SEL, Marrion NV & Mellor JR. Facilitation of Long-Term Potentiation by Muscarinic M1 Receptors is mediated by inhibition of SK channels. Neuron, DOI: 10.1016/j.neuron.2010.11.018

Daniel J. Rader, M.D. (Credit: Image courtesy of University of Pennsylvania School of Medicine)

University of Pennsylvania Medical School, January 13, 2011, (PHILADELPHIA) — The discovery that high levels of high-density lipoprotein (HDL) cholesterol (the “good cholesterol”) is associated with reduced risk of cardiovascular disease has fostered intensive research to modify HDL levels for therapeutic gain. However, recent findings have called into question the notion that pharmacologic increases in HDL cholesterol levels are necessarily beneficial to patients. Now, a new study from researchers at the University of Pennsylvania School of Medicine shows that a different metric, a measure of HDL function called cholesterol efflux capacity, is more closely associated with protection against heart disease than HDL cholesterol levels themselves.

Findings from the study could lead to new therapeutic interventions in the fight against heart disease. The new research will be published in the January 13 issue of the New England Journal of Medicine.

Atherosclerosis, a component of heart disease, occurs with a build-up along the artery wall of fatty materials such as cholesterol. Cholesterol efflux capacity, an integrated measure of HDL function, is a direct measure of the efficiency by which a person’s HDL removes cholesterol from cholesterol-loaded macrophages (a type of white blood cell), the sort that accumulate in arterial plaque.

“Recent scientific findings have directed increasing interest toward the concept that measures of the function of HDL, rather than simply its level in the blood, might be more important to assessing cardiovascular risk and evaluating new HDL-targeted therapies,” said Daniel J. Rader, MD, director, Preventive Cardiology at Penn. “Our study is the first to relate a measure of HDL function–its ability to remove cholesterol from macrophages–to measures of cardiovascular disease in a large number of people.”

In the present study, Rader and colleagues at Penn measured cholesterol efflux capacity in 203 healthy volunteers who underwent assessment of carotid artery intima-media thickness, a measure of arthrosclerosis, 442 patients with confirmed coronary artery disease, and 351 patients without such confirmed disease.

An inverse relationship was noted between cholesterol efflux capacity and carotid intima-media thickness both before and after adjustment for the HDL cholesterol level. After an age- and gender- adjusted analysis, increasing efflux capacity conferred decreased likelihood of having coronary artery disease. This relationship remained robust after the addition of traditional cardiovascular risk factors, including HDL cholesterol levels, as covariates. Additionally, men and current smokers had decreased efflux capacity.

The researchers noted that although cholesterol efflux from macrophages represents only a small fraction of overall flow through the cholesterol pathway, it is probably the component that is most relevant to protection against heart disease.

Rader said, “The findings from this study support the concept that measurement of HDL function provides information beyond that of HDL level, and suggests the potential for wider use of this measure of HDL function in the assessment of new HDL therapies. Future studies may prove fruitful in elucidating additional HDL components that determine cholesterol efflux capacity.”

This work was funded in part by grants from the National Heart, Lung, and Blood Institute, the National Center for Research Resources, and a Distinguished Clinical Scientist Award from the Doris Duke Charitable Foundation.

Journal Reference:

1.       Amit V. Khera, Marina Cuchel, Margarita de la Llera-Moya, Amrith Rodrigues, Megan F. Burke, Kashif Jafri, Benjamin C. French, Julie A. Phillips, Megan L. Mucksavage, Robert L. Wilensky, Emile R. Mohler, George H. Rothblat, Daniel J. Rader. Cholesterol Efflux Capacity, High-Density Lipoprotein Function, and Atherosclerosis. New England Journal of Medicine, 2011; 364 (2): 127 DOI: 10.1056/NEJMoa1001689

A new study led by CU-Boulder Associate Professor Kenneth Wright, above, indicates a
common sleep medication puts adults more at risk for nighttime falls and potential injuries.
(Credit: Photo by Patrick Campbell/University of Colorado)

University of Colorado, January 13, 2011, (BOULDER)— Adults who take one of the world’s most commonly prescribed sleep medications are significantly more at risk for nighttime falls and potential injury, according to a new study by the University of Colorado at Boulder.

The study, which involved 25 healthy adults, showed 58 percent of the older adults and 27 percent of the young adults who took a hypnotic, sleep-inducing drug called zolpidem showed a significant loss of balance when awakened two hours after sleep. The findings are important because falls are the leading cause of injury in older adults, and 30 percent of adults 65 and older who fall require hospitalization each year, said CU-Boulder Associate Professor Kenneth Wright, lead study author.

To measure balance, the research team used a technique known as a “tandem walk” in which subjects place one foot in front of the other with a normal step length on a 16-foot-long, six-inch-wide beam on the floor. In 10 previous practice trials with no medication, none of the 25 participants stepped off the beam, indicating no loss of balance. All participants were provided with stabilizing assistance to prevent falls during the trials, he said.

“The balance impairments of older adults taking zolpidem were clinically significant and the cognitive impairments were more than twice as large compared to the same older adults taking placebos,” said Wright, a faculty member in the integrative physiology department. “This suggests to us that sleep medication produces significant safety risks.”

The new CU-Boulder study is the first to measure both the walking stability and cognition of subjects taking hypnotic sleep medicines or placebos. In addition to the balance problems caused by zolpidem, the study also showed that waking up after two hours of sleep after taking zolpidem enhances sleep inertia, or grogginess, a state that temporarily impairs working memory. The study participants were given computerized performance tests that involved adding randomly generated numbers.

A paper on the subject was published Jan. 13 in the Journal of the American Geriatric Society. Co-authors included CU-Boulder’s Daniel Frey, Justus Ortega, Courtney Wiseman and Claire Farley. The study was funded primarily by the National Institutes of Health.

The effects of sleep inertia even without sleep medication has previously been shown to cause cognitive impairment, said Wright. But when the CU-Boulder study subjects took zolpidem rather than a placebo, the cognitive impairments essentially doubled.

One unexpected study finding was that young people taking placebos appear to be more cognitively impacted by sleep inertia than older adults taking placebos, he said.

A 2006 study led by Wright showed that study subjects who took no sleep medicine and were awakened after eight hours of sleep were more cognitively impaired, for a short period of time, than a totally sleep deprived person.

Several billion doses of zolpidem have been prescribed worldwide, said Wright, who also directs CU-Boulder’s Sleep and Chronobiology Laboratory. Zolpidem is a generic drug that is marketed under a number of different brand names, including Ambien, Zolpimist, Edluar, Hypogen, Somidem and Ivedal.

The CU-Boulder team also measured balance and cognition in older adults who took no sleep medication and were kept awake for two hours past their normal bedtime. They found that 25 percent of these older adults failed the tandem walking balance test, which is consistent with what is seen in people who have insomnia. “Just having insomnia itself increases your risk of falls, even without sleep medication,” he said.

The finding that zolpidem affected older adults more than younger adults in balance tests may be explained in part by the fact that both groups were given five milligram doses on study nights. While the normal dose for older adults is five milligrams, the standard dosage for younger adults being treated for insomnia is 10 milligrams. “This is an area that needs more study,” he said.

The study results showing that both hypnotic sleep medications and sleep inertia cause significant impairment have important public health implications, said Wright. In older adults, falls have caused millions of nonfatal injuries annually and more than 300,000 fatalities worldwide. “Falls can be very debilitating, especially when older people break their hips and require hospitalization, causing their quality of life to go down,” said Wright.

In addition, the cognitive impairments caused by both zolpidem and sleep inertia may impact decision-making, including responding to situations like fire alarms and medical emergencies as well as caring for sick children or driving to a clinic or hospital, said Wright.

“One of the goals of this study was to understand the risk of this sleep medication and of sleep inertia on human safety and cognition and to educate adults and health care workers about potential problems,” said Wright. “We are not suggesting that sleep medications should not be used, because they have their place in terms of the treatment of insomnia.”

One possible solution to reducing falls of older people due to zolpidem, other sleep medications or sleep inertia would be to install bedside commodes for those who frequently wake up in the night to void themselves, said Wright. Additional research is needed on this important public health and safety topic, he said.