Scientists devise new theory for why we need sleep

Most people know it from experience: After so many hours of being awake, your brain feels unable to absorb any more – and several hours of sleep will refresh it.

New research from the University of Wisconsin School of Medicine and Public Health in the US clarifies this phenomenon, supporting the idea that sleep plays a critical role in the brain’s ability to change in response to its environment. This ability, called plasticity, is at the heart of learning.

Reporting in the 20 January 2008, online version of Nature Neuroscience, the UW-Madison scientists showed by several measures that synapses were very strong when rodents had been awake and weak when they had been asleep.

The new findings reinforce the hypothesis about the role of sleep in which it is believed that people sleep so that their synapses can downsize and prepare for a new day and the next round of learning and synaptic strengthening.

The human brain expends up to 80% of its energy on synaptic activity, constantly adding and strengthening connections in response to all kinds of stimulation, explains study author Chiara Cirelli, associate professor of psychiatry.

Given that each of the millions of neurons in the human brain contains thousands of synapses, this energy expenditure “is huge and can’t be sustained”. “We need an off-line period, when we are not exposed to the environment, to take synapses down,” Cirelli says.

“We believe that’s why humans and all living organisms sleep. Without sleep, the brain reaches a saturation point that taxes its energy budget, its store of supplies and its ability to learn further.”

To test the theory, researchers conducted both molecular and electro-physiological studies in rats to evaluate synaptic potentiation, or strengthening, and depression, or weakening, following sleeping and waking times. The Wisconsin group was surprised to find that rats had an almost 50% receptor increase after a period of wakefulness compared to rats that had been asleep.

To strengthen their case, Cirelli and colleagues also performed studies in live rats to evaluate electrical signals reflecting synaptic changes at different times. This involved stimulating one side of each rat’s brain with an electrode following waking and sleeping and then measuring the “evoked response”, which is similar to an EEG, on another side.

“Taken together, these molecular and electro-physiological measures fit nicely with the idea that our brain circuits get progressively stronger during wakefulness and that sleep helps to recalibrate them to a sustainable baseline,” says Cirelli.

The theory Cirelli and collaborator Dr Giulio Tononi, professor of psychiatry, have developed, called the synaptic homeostasis hypothesis, runs against the grain of what many scientists currently think about how sleep affects learning. The most popular notion these days, says Cirelli, is that during sleep synapses are hard at work replaying the information acquired during the previous waking hours, consolidating that information by becoming even stronger.

“That’s different from what we think,” she says. “We believe that learning occurs only when we are awake, and sleep’s main function is to keep our brains and all its synapses lean and efficient.”

Researchers near breakthrough for spinal injury repair

An Action Medical Research (charity) funded project, based at the Cambridge University Centre for Brain Repair, in the UK, is on the brink of a major potential breakthrough in the repair of spinal cord injuries.

Spinal cord injuries are a major cause of disability, which can take the form of anything from loss of sensation to full paralysis. Until now, despite the attempts of many scientists to find a cure, the problem facing neurologists has been that the body simply cannot repair damage to the brain or spinal cord.

Although it is possible for nerves to regenerate, they are blocked by the scar tissue that forms at the site of the spinal injury. However, Professor James Fawcett’s Cambridge-based team believes it is close to a clinical treatment that could allow nerve fibres to regenerate within the spinal cord and also encourage remaining nerve fibres to work more effectively.

This revolutionary discovery may ultimately mean treatments to improve the lives of people paralysed through spinal damage. The Action Medical Research team has found that a bacterial enzyme called chondroitinase is capable of digesting molecules within scar tissue to allow some nerve fibres to regrow. Excitingly it also promotes something called nerve plasticity.

This means that any remaining undamaged nerve fibres have an increased likelihood of making new connections that could bypass the area of damage. Recent work by Professor Fawcett’s team has found that using chondroitinase in conjunction with rehabilitation allows greater opportunity for nerve recovery than by using either technique alone. This is an important finding, because it shows that the treatment can open up a window of opportunity during which rehabilitation can be much more effective.

The finding will probably also be important for rehabilitation after stroke and brain injury. This ground-breaking discovery will need to be tested before it can be given to patients, to establish the optimum time for it to be administered. Professor Fawcett said, “It is rare to find that a spinal cord is completely severed, generally there are still some nerve fibres that are undamaged.

“Chondroitinase offers us hope in two ways; firstly it allows some nerve fibres to regenerate and secondly it enables other nerves to take on the role of those fibres that cannot be repaired. Clinical trials have not yet been started, but the treatment is under pre-clinical development by Acorda Therapeutics, a biotechnology company in New York.

What makes leukaemia cells resist treatment?

Researchers at the University of East Anglia have discovered for the first time a pathway that makes cancerous leukaemia cells resistant to treatment. The scientists found that death-resistant Acute Myeloid Leukaemia cells are given their resistance by a genetic antioxidant pathway called hemeoxygenase-1 or HO-1.

This resistance pathway leads to relapse of the disease and non-responsiveness to treatments. When this pathway is inhibited, the cells lose their resistance and become responsive to death-inducing agents.

Published online in the journal Blood on 18 January 2008, the discovery is the first stage in the development of new drugs that could significantly improve survival rates for leukaemia sufferers. “This is a major step forward in the treatment of leukaemia and other cancers,” said Professor David MacEwan who led the research team.

“The next step will be a programme to develop a new set of targeted therapies to treat not only Acute Myeloid Leukaemia, but other leukaemias and other cancers.” More people die of Acute Myeloid Leukaemia (AML) than any other form of leukaemia. AML attacks the white blood cells and is a common form in both children and adults with leukaemia.

It is currently treated by a range of chemotherapy drugs. Many patients go on to have bone marrow transplants due to commonly developing drugresistance to their initial chemotherapy.

The antioxidant response element (ARE) genes which include HO-1, protect cells from damage and their killing off by cytotoxic agents such as chemotherapy drugs. The team found that drug-resistant leukaemia cells have overactive ARE genes that cause them to be completely resistant to cytotoxic drugs, and that blocking this pathway reverts the cells into responding normally to cytotoxic agents.

New cellular mechanism for insulin resistance

Researchers at the Swedish medical university Karolinska Institutet have in collaboration with researchers from Finland, China, Japan and the US discovered new cellular mechanisms that lead to insulin resistance in people with diabetes.

The results are published in the scientific journal Cell. Professor Juleen R. Zierath at Karolinska Institutet in Stockholm, who lead the research team, has identified previously unknown molecular mechanisms by which elevated blood sugar leads to impaired insulin sensitivity in people with diabetes. The research team identified a ‘fat-burning’ gene, the products of which are required to maintain the cells insulin sensitivity.

They also discovered that this gene is reduced in muscle tissue from people with high blood sugar and type 2 diabetes. In the absence of the enzyme that is made by this gene, muscles have reduced insulin sensitivity, impaired fat burning ability, which leads to an increased risk of developing obesity.

“The expression of this gene is reduced when blood sugar rises, but activity can be restored if blood sugar is controlled by pharmacological treatment or exercise,” says Prof Zierath. “Our results underscore the importance of tight regulation of blood sugar for people with diabetes.”

Drinkable tap water fine for wounds

Using drinkable tap water to clean wounds does not increase infection rates, according to the findings of a Cochrane Review. There is, however, no evidence that it reduces infection rates or increases healing rate over leaving the wound alone.

Cleaning wounds caused by injuries is part of standard medical care, but there is a vigorous debate about how best to do it. Research shows that using chemicalcontaining antiseptic may slow wound healing. Many people recommend saline (salt solution) instead, but others worry that this will wash away growth promoters and infection- fighting white blood cells.

Sterile saline is also not always available and can be expensive. As an alternative to saline, some suggest using drinkable tap water, or clean water that has been boiled. Cochrane Researchers considered data from eleven trials that compared rates of infection and healing in wounds when treated with various cleansing regimes. In adults, wounds cleansed with tap water had significantly fewer infections than those cleansed with saline. There was no difference between wounds cleansed with tap water and those that received no cleaning.

In situations where a broken bone had punctured the skin, there was no significant difference between cleansing with saline, distilled water or boiled water. “The decision to use tap water to cleanse wounds should take into account the quality of water, nature of wounds and the patient’s general condition,” says lead author Ritin Fernandez who works in the Centre for Applied Nursing Research in Liverpool BC, Australia.

Smoking effects gene expression

Smoking plays a role in lung cancer development, and now scientists have shown that smoking also affects the way genes are expressed, leading to alterations in cell division and regulation of immune response.

Notably, some of the changes in gene expression persisted in people who had quit smoking many years earlier. These findings by researchers at the US National Cancer Institute (NCI), part of the US National Institutes of Health, appeared in the 20 February 2008 issue of PLoS ONE.

“Smoking, we are well aware, is the leading cause of lung cancer worldwide,” said NCI director John E. Niederhuber, MD. “Yet, a mechanistic understanding of the effects of smoking on the cells of the lung remains incomplete. This study demonstrates an important piece of this complicated puzzle.

Greater understanding of the genetic alterations that occur with smoking should provide greater insight into the development of cellular targets for treating, and possibly preventing, lung cancer.”

“We were able to look at actual lung tissue, tumour and non-tumour, taking into account the differences by gender, verifying the smoking status by measuring levels of cotinine, a metabolite of nicotine, in participants' plasma, and confirming results in independent samples,” said Maria Teresa Landi, MD, PhD, in NCI's Division of Cancer Epidemiology and Genetics, the first author of the study report. Using microarray techniques, which allow researchers to look at the activity of thousands of genes simultaneously, they identified 135 genes that were differently expressed in tumours of smokers vs. people who had never smoked.

Among these genes, 81 showed decreased expression and 54 showed increased expression in tumour tissue. “Our results indicate that smoking causes changes in genes that control mitotic spindle formation (the cell apparatus responsible for the proper division of chromosomes),” said Jin Jen, PhD, in NCI’s Center for Cancer Research, a senior author of the study report.

“Irregular division of chromosomes and chromosome instability are two common abnormalities that occur in cancer cells when the chromosomes do not separate equally between the daughter cells. Therefore, changes in the mitotic process are very relevant in the development of cancer.”

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