Drugs and stimulating environments reverse memory loss in brain-damaged mice

Scientists have restored lost memories in brain-damaged mice by giving them an experimental group of drugs, or by placing them in a stimulating environment. Their remaining neurons re-wired themselves and retrieved memories that had been misplaced, not lost, providing hope for treating human conditions like dementia and Alzheimer’s disease.

Dementia results in massive neuron loss, but that doesn’t mean memories are destroyed.You swallow the pill. As it works its way through your digestive system, it slowly releases its chemical payload, which travels through your bloodstream to your brain. A biochemical chain reaction begins. Old disused nerve cells spring into action and form new connections with each other. And amazingly, lost memories start to flood back.

The idea of a pill for memory loss sounds like pure science fiction. But scientists from the Massachussetts Institute for Technology have taken a first important step to making it a reality, at least for mice.

Andre Fischer and colleagues managed to restore lost memories of brain-damaged mice by using a group of drugs called HDAC inhibitors, or by simply putting them in interesting surroundings.

They used a special breed of mouse, engineered to duplicate the symptoms of brain diseases that afflict humans, such as Alzheimer’s. The mice go about their lives normally, but if they are given the drug doxycycline, their brains begin to atrophy.

The drug switches on a gene called p25 implicated in various neurodegenerative diseases, which triggers a massive loss of nerve cells. The affected become unable to learn simple tasks and lose long-term memories of tasks they had been trained in some weeks earlier.

A richer environment

Lost memories can be recovered by encouraging surviving neurons to re-wire themselves.Fischer moved some of the brain-damaged mice from their usual Spartan cages, to more interesting accommodation. Their new cages were small adventure playgrounds, replete with climbing frames, tunnels and running wheels, together with plentiful food and water.

In their new stimulating environments, the mice returned to their normal selves. Their ability to learn improved considerably, and amazingly, seemingly lost memories were resurrected.

They didn’t grow any new neurons, and their brains remained the same size. But Fischer found that they did have many more synapses – the connections between nerve cells – than brain-damaged peers. Even though they had lost a substantial number of neurons, their enriched environments triggered the surviving cells to re-wire themselves.

These experiments suggest that lost memories are in fact not lost at all, but misplaced. The dead neurons take important connections with them and the survivors, though incommunicado, still retain latent traces of memory.

When they are jolted into action and form new networks, these trace memories are reinstated. And that provides genuine hope for people affected by dementia, Alzheimer’s and other conditions.

Memory-restoring drugs

Brain damage from Alzheimer’s disease could potentially be reversed by HDAC inhibitors.It would be a touch silly to suggest putting such people in the equivalent of a large playpen. But Fischer also found a group of drugs called HDAC inhibitors that have the same effect – the molecular equivalent of a stimulating environment.

HDACs or histone deacetylases control whether genes are switched on or off by altering other proteins called histones. DNA winds around histones like spools, which serves to package this long and unwieldy molecule into a compact and more manageable form.

HDACs change the histones so that they wrap more tightly around DNA and render its genetic code unreadable. Any genes contained in these stretches of DNA are silenced. Drugs like sodium butyrate (SB) neutralise HDACs, freeing DNA from the repressive grip of histones.

Any silenced genes can now be freely switched on and among these, are genes that allow the brain’s neurons to sprout new synapses. The details still need to be ironed out, but the results are clear – just like mice housed in fun cages, those treated with SB regained lost memories.

The next steps

Naysayers might point out that these results are all very good for mice, but are a long way off benefiting people. But while our brains outclass those of mice, we appear to store memories in very similar ways. New experienced are initially encoded among the neurons of the hippocampus, only to be transferred into deeper and long-term stores about three or four weeks later.

Four years ago, a man who had been barely conscious for almost 20 years began to move and speak again. His nerves, badly damaged by a car crash, had started to re-wire themselves and form new connections, in the same way that Fischer’s rats did. The possibilities are there; it’s just the method that needs refinement.

At the moment, the biggest problem with Fischer’s approach is that it’s akin to shooting at a fly with a shotgun. HDAC inhibitors have far-reaching effects on a multitude of different genes. It’s fortunate that these include genes that lead to brain re-wiring, but such a scattershot approach is prone to collateral damage.

Documenting the full actions of HDAC inhibitors is vital. It will allow scientists to understand what side effects such treatments would have in people, while designing more sophisticated drugs with a narrower range of targets.

Reference: Fischer, Sananbenesi, Wang, Dobbin & Tsai. 2007. Recovery of learning and memory is associated with chromatin remodelling. Nature doi:10.1038/nature05772

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Sneaking medicines past the brain’s defences

The brain is surrounded by a protective barrier designed to keep infections out. But it can also block out medicines intended to treat brain diseases. Now, scientists have developed a way of sneaking helpful proteins across the barrier by giving them fake molecular ID.

Using genetic engineering, a group of scientists have developed a way of sneaking a virus past the brain’s defences. Don’t panic – this isn’t some nightmare scenario. It could be the first step to curing a huge number of brain diseases.

The brain needs to be protected from incoming infections.The brain seems incredibly well protected amid its shell of bone and cushioning fluid. But even the strongest of forts needs supply lines, and brain is no exception.

A dense network of blood vessels carries vital oxygen to its cells. These vessels are a potential vulnerable spot, providing access for bacteria and other disease-causing organisms to migrate in from other body parts.

But even these weak spots are heavily guarded. The blood vessels in the brain are lined with a tightly packed layer of cells that restrict the flow of molecules from blood to brain. These cells form a protective shield called the blood-brain barrier, or BBB.

It is a superb defence but it can do its job too well. Not only does it block out dangerous microbes, but it can also exclude large proteins and drugs designed to treat brain diseases. Usually, these large molecules need to be distributed throughout the entire brain to be effective. With the BBB in the way, they don’t stand a chance.

Now, Brian Spencer and Inder Verma from the Salk Institute of Biological Studies have come up with a way to disguise helpful molecules to sneak them past the brain’s defences.

The blood brain barrier controls the import of molecules into the brain with the tight security of airport immigration.Their method exploits special gates in the barrier that control the import of essential nutrients and molecules like cholesterol into the brain. These molecules are escorted by a large protein called apoliprotein B (apoB), and are presented to sentinel proteins that guard the gates.

One of these guardians, called LDLR, is designed to recognise a specific segment of apoB. Once it has confirmed the visitor’s identity, it escorts apoB and the molecules it accompanies through the barrier. The whole system works with the tight control of a maximum security prison.

Spencer and Verma managed to fool the system. They took the part of apoB that is recognised by LDLR and stuck it to various proteins, giving them the molecular equivalent of a fake pass.

First, they tested their method in mice. They injected the animals with a harmless virus designed to travel to its liver and spleen. There, the virus sets about building the disguised protein, which is secreted en masse into the bloodstream.

The beauty of this method is that it works after a single injection that transforms the liver and spleen into factories for the protein of choice.

Spencer and Yerma’s method works for glucocerebrosidaseTheir first candidate was GFP, a jellyfish protein that glows in the dark with a greenish hue, allowing it to be easily tracked. Sure enough, the injected mice soon gave off a greenish glow from their brains and the rest of their central nervous systems.

Better still, their method showed real practical potential by sneaking an enzyme called glucocerebrosidase (right) into the brain. Glucocerebrosidase is vital for the storage of fats. People who lack it suffer form a condition called Gaucher’s disease, where fatty desposits collect on various organs and cause brain damage, among other symptoms.

The disease is relatively easy to fix using regular injections, but the resulting brain damage is not for the injected enzyme is usually repelled by the blood-brain barrier. But Spencer and Verma’s method may change all that.

The duo fully admit that their work is merely a first step, but it is an important one nonetheless. The technique must first be refined and tested in people before it can be widely used. Developing drugs and proteins for treating brain disorders is pointless if those new medicines just congregate uselessly outside the blood-brain barrier. Spencer and Verma may have given them a way in.


Reference: Spencer & Verma. 2007. Targeted delivery of proteins across the blood-brain barrier. PNAS 104: 7594-7599.

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A woman in a vegetative state shows awareness of her surroudings

Patients in a vegetative state are supposed to be completely unaware of their surroudings. Whether this is true is important for negotiating round the complicated legal and ethical tangles that surround the care of such patients. Now, scientists have used brain imaging technology to show that at least one patient is indeed aware of her surroundings and can respond to instructions.

 

A woman is playing a game of tennis. As she swats the ball around, she is being watched by a stranger. We might automatically read something sinister into this scene but there is a catch. This game isn’t real – it’s taking place entirely in the woman’s mind. The woman herself lies in a hospital bed, where she has stayed for the past year in what doctors call a ‘vegetative state’. The stranger is no voyeur – he is a neuroscientist, watching the woman’s brain on a monitor, and what he is seeing could shake the medical world.

Protesters at the Terri Schiavo caseFew medical conditions pose more difficult ethical dilemmas than the vegetative state. Cases like Terri Schiavo’s, where relatives have to make the unenviable decision to cut off support, can attract international notoriety, even drawing stances from the Vatican and the White House (right: protesters at the Schiavo case, killbyte@flickr).

The problem with the vegetative state is that we know precious little about it. It is defined as a state of wakefulness with no awareness, differing from a coma in that patients go through sleep-wake cycles like the rest of us. They may even open their eyes or smile, but it won’t be in response to a friendly face or a good jokes. Their responses are neither purposeful nor consistent, and this is a key element for diagnosing the condition.

After a month, the patient is said to be in a persistent vegetative state, and if the condition does not improve within 3-12 months, the state is said to be permanent. The key questions are these: are these people really incapable of responding to the world around them, and will they ever truly ‘wake up’? The debate has been fuelled by people like Terry Wallis, who spent 19 years in a vegetative state before waking up and rejoining his family. If cases like Terry exist, how can we be sure that other patients will never recover?

Communicating through thought

To get some answers, Adrian Owen at the MRC Cognition and Brain Sciences Unit, Cambridge, has been using brain scanning techniques to visualise the thoughts of people in vegetative states. Most recently, his team has been working with a 23-year old woman who was left with severe brain injuried following a car accident in July 2005. Since then, a team of different medical specialists concluded that she fulfilled all the diagnostic criteria for being in a vegetative state.

An fMRI scan of a patient's brainOwen begs to differ. He used a brain-scanning technique called functional magnetic resonance imaging – fMRI – to look at how the woman’s brain responded to simple stimuli. At first, he played simple sentences to her, as well as garbled nonsense that sounded very similar. The spoken words alone caused neurons to fire in the woman’s superior and middle temporal gyri, regions of the brain involved in processing speech and language. And if the sentences contained ambiguous words, even more speech-related regions were brought into play.

While these findings provided tantalising hints of purposeful brain activity, they were far from conclusive. For their next test, Owen’s team asked the woman to imagine playing a game of tennis, and as predicted, the neurons in her motor area lit up. When they asked her to imagine more precise activities, such as walking through the rooms of her house, her brain became a hive of activity. The motor cortex was again brought into play, but this time, the team also saw activity in the parahippocampal gyrus (responsible for retrieving geographical memories) and the posterior parietal cortex (responsible for mapping object locations). And amazingly, her responses in all the tests all the tests were completely indistinguishable from those of healthy volunteers.

The implications

“These are startling results,” says Owen. “The patient retained the ability to understand spoken commands and to respond to them through her brain activity, rather than through speech or movement Her decision to work with us by imagining particular tasks when asked represents a clear act of intent which confirmed beyond any doubt that she was consciously aware of herself and her surroundings.” This was no vegetative state.

These results clearly raise some massive ethical questions over the fates of other patients currently in vegetative states. But it would be vastly imprudent to make generalities based a single case, and it is unlikely that all such people are secretly aware of their surroundings. Nor is awareness the only possible explanation for the woman’s responses, and some scientists remain unconvinced. Nonetheless, the study provides compelling evidence that at least some vegetative state patients do indeed show awareness, and with fMRI, we can find them.

Whether responsive brain activity means that the woman in Owen’s study will eventually join the ranks of Terry Wallis is uncertain. But identifying such patients may prompt increased care and attention from loved ones and hospital staff, perhaps with positive results. In the mean time, more research, improving imaging techniques and a growing understanding of the brain could allow these patients to communicate with their loved ones through their thoughts.

 

Owen, Coleman, Boly, Davis, Laureys & Pickard. 2006. Science. Epub ahead of print.