A “light switch” in the brain illuminates neural networks

Researchers from NTNU’s Kavli Institute of Systems Neuroscience are able to see which cells communicate with each other in the brain by flipping a neural light switch. The results of their efforts are presented in an article in the 5 April issue of Science magazine.

There are cells in your brain that recognize very specific places, and have that and nothing else as their job. These cells, called place cells, are found in an area behind your temple called the hippocampus. While these cells must be sent information from nearby cells to do their job, so far no one has been able to determine exactly what kind of cells work with place cells to craft the code they create for each location. Neurons come in many different types with specialized functions. Some respond to edges and borders, others to specific locations, others act like a compass and react to which way you turn your head.

Now, researchers at the Kavli Institute for Systems Neuroscience have developed a range of advanced techniques that enable them to identify which neurons communicate with each other at different times in the rat brain, and in doing so, create the animal’s sense of direction.

"A rat’s brain is the size of a grape. Inside there are about fifty million neurons that are connected together at a staggering 450 billion places (roughly)," explains Professor Edvard Moser, director of the Kavli Institute. "Inside this grape-sized brain are areas on each side that are smaller than a grape seed, where we know that memory and the sense of location reside. This is also where we find the neurons that respond to specific places, the place cells. But from which cells do these place cells get information?"

From spaghetti to light switches
The problem is, of course, that researchers cannot simply cut open the rat brain to see which cells have had contact. That would be the equivalent of taking a giant pile of cooked spaghetti, chopping it into little pieces, and then trying to figure out how the various spaghetti strands were tangled together before the pile was cut up.
A job like this requires the use of a completely different set of neural tools, which is where the “light switches” come into play.

Neurons share many similarities with electric cables when they send signals to each other. They send an electric current in one direction – from the “body” of the neuron and down a long arm, called the axon, which goes to another nerve cell next in line. Place cells thus get their small electric signals from a whole series of such arms.

So how do light switches play into all of this?

Viruses do the work
“What we did first was to give these nerve arms a harmless viral infection,” Moser says. “We designed a unique virus that does not cause disease, but that acts as a pathway for delivering genes to specific cells. The virus creeps into the neurons, crawls up against the electric current, and uses the nerve cell’s own factory to make the genetic recipe that we gave to the virus to carry.”

The genetic recipe enabled the cell to make the equivalent of a light switch. Our eyes actually contain the same kind of biological light switch, which allows us to see. The virus infection converts neurons that have previously existed only in darkness, deep inside the brain, to now be sensitive to light.

Then the researchers inserted optical fibres in the rat’s brain to transmit light to the place cells that had light switches in them. They also implanted thin microelectrodes down between the cells so they could detect the signals sent through the axons every time the light from the optical fibre was turned on.

"Now we had everything set up, with light switches installed in cells around the place cells, a lamp, and a way to record the activity," Moser said.

10,000 times
The researchers then turned the lights on and off more than ten thousand times in their rat lab partners, while they monitored and recorded the activity of hundreds of individual cells in the rats’ grape-sized brains. The researchers did this research while the rats ran around in a metre-square box, gathering treats. As the rats explored their box and found the treats, the researchers were able to use the light-sensitive cells to reveal how the rat’s brain created the map of where the rat had been.

When the researchers put together all the information afterwards they concluded that there is a whole range of different specialized cells that together provide place cells their information. The brain’s GPS – its sense of place – is created by signals from head direction cells, border cells, cells that have no known function in creating location points and grid cells. Place cells receive both information about the rat’s surroundings and landmarks, but also continuously update their own movement, which is actually independent on sensory input.

"The biggest mystery is the role that the cells that are not part of the sense of direction play. They send signals to place cells, but what do they actually do?" wonders Moser.

"We also wonder how the cells in the hippocampus are able to sort out the various signals they receive. Do they ‘listen’ to all of the cells equally effectively all the time, or are there some cells that get more time than others to ‘talk’ to place cells?"

Forget about plaque when diagnosing Alzheimer’s Disease

An Australian study has shown that plaque, long considered to be the hallmark of Alzheimer’s disease, is one of the last events to occur in the Alzheimer’s brain. This finding will impact the current debate about how best to diagnose and treat Alzheimer’s disease.

PhD student Amanda Wright and Dr Bryce Vissel from Sydney’s Garvan Institute of Medical Research studied a mouse model of Alzheimer’s disease in order to identify early versus late disease mechanisms and markers.

The data, published online today in the journal PLOS ONE, suggest that plaques occur long after memory loss, so may not be a useful early pathological marker for Alzheimer’s disease.

The Investigators found that significant nerve cell loss and a range of brain pathologies, including inflammation, began at the same time as subtle memory problems appeared, early in the disease process. Plaques occurred much later, well after significant memory loss.

“Ever since Alois Alzheimer first described this disease in 1906, plaque has been regarded as the definitive Alzheimer’s diagnosis,” said project leader Dr Vissel.

“Just last year, the first ever method of plaque detection through positron emission tomography (PET) was introduced into the clinic to assist in the diagnosis of Alzheimer’s disease – precisely because plaque is regarded as the conclusive marker for Alzheimer’s disease. Our study suggests that this method may not be accurate in earlier disease stages.”

Dr Vissel said that many billions of dollars have been spent around the world in trying to develop markers and drugs to block the development of plaque. Several drug trials based on this idea have failed recently.

“Our study supports the increasingly common view that treatment should start much earlier in the disease process. It also suggests that brain inflammation and cell loss may be an earlier indicator of disease pathology than plaque and an alternative target for treatment.”

“In addition, what’s coming out in various studies is that mild cognitive impairment may be another early predictor of Alzheimer’s. This seems to fit perfectly with our findings, which show mild memory loss and behavioural changes at an early stage before plaque appears.”

“I can see that the development of some clever learning and language tests to test for early signs of cognitive impairment will be an important indicator of dementia, when combined with a range of yet to be developed tests.”

(Image: Getty Images)

Developing Our Sense of Smell

When our noses pick up a scent, whether the aroma of a sweet rose or the sweat of a stranger at the gym, two types of sensory neurons are at work in sensing that odor or pheromone. These sensory neurons are particularly interesting because they are the only neurons in our bodies that regenerate throughout adult life—as some of our olfactory neurons die, they are soon replaced by newborns. Just where those neurons come from in the first place has long perplexed developmental biologists.

Previous hypotheses about the origin of these olfactory nerve cells have given credit to embryonic cells that develop into skin or the central nervous system, where ear and eye sensory neurons, respectively, are thought to originate. But biologists at the California Institute of Technology (Caltech) have now found that neural-crest stem cells—multipotent, migratory cells unique to vertebrates that give rise to many structures in the body such as facial bones and smooth muscle—also play a key role in building olfactory sensory neurons in the nose.

"Olfactory neurons have long been thought to be solely derived from a thickened portion of the ectoderm; our results directly refute that concept," says Marianne Bronner, the Albert Billings Ruddock Professor of Biology at Caltech and corresponding author of a paper published in the journal eLIFE on March 19 that outlines the findings.

The two main types of sensory neurons in the olfactory system are ciliated neurons, which detect volatile scents, and microvillous neurons, which usually sense pheromones. Both of these types are found in the tissue lining the inside of the nasal cavity and transmit sensory information to the central nervous system for processing.

In the new study, the researchers showed that during embryonic development, neural-crest stem cells differentiate into the microvillous neurons, which had long been assumed to arise from the same source as the odor-sensing ciliated neurons. Moreover, they demonstrated that different factors are necessary for the development of these two types of neurons. By eliminating a gene called Sox10, they were able to show that formation of microvillous neurons is blocked whereas ciliated neurons are unaffected.

They made this discovery by studying the development of the olfactory system in zebrafish—a useful model organism for developmental biology studies due to the optical clarity of the free-swimming embryo. Understanding the origins of olfactory neurons and the process of neuron formation is important for developing therapeutic applications for conditions like anosmia, or the inability to smell, says Bronner.

"A key question in developmental biology—the extent of neural-crest stem cell contribution to the olfactory system—has been addressed in our paper by multiple lines of experimentation," says Ankur Saxena, a postdoctoral scholar in Bronner’s laboratory and lead author of the study. "Olfactory neurons are unique in their renewal capacity across species, so by learning how they form, we may gain insights into how neurons in general can be induced to differentiate or regenerate. That knowledge, in turn, may provide new avenues for pursuing treatment of neurological disorders or injury in humans."

Next, the researchers will examine what other genes, in addition to Sox10, play a role in the process by which neural-crest stem cells differentiate into microvillous neurons. They also plan to look at whether or not neural-crest cells give rise to new microvillous neurons during olfactory regeneration that happens after the embryonic stage of development.

Researchers image most of vertebrae brain at single cell level

Misha Ahrens and Philipp Keller, researchers with the Howard Hughes Medical Institute have succeeded in making a near real-time video of most of a zebrafish’s brain showing individual neuron cells firing. To create the video, as the team reports in their paper published in the journal Nature Methods, the two developed a type of modified light-sheet microscopy and used it in on genetically modified fish.

To create the video, the researchers turned to zebrafish in their larval state—their brains are transparent and small. To cause firing neurons to be visible they genetically altered the fish’s brains, giving them a protein that glows when responding to changes in calcium ion levels, which happen when nerve cells fire. Next, they used a microscope that was able to broadcast a sheet of light through the fish’s brain allowing for the detection of the firing neurons. The system recorded images every 1.3 seconds. The final step was stitching the images together to create a video. The result is nothing short of breathtaking—looking like something out of a science fiction movie’s special effects department.

The video marks the first visual capture of most of a living vertebrae brain at the neuron level, as it works in near real-time and offers striking evidence of the complexity of the brain—even one as small as 100,000 neurons. The researchers say their video shows approximately 80 percent of the zebrafish’s brain as it operates—though what all those firing neurons represent in particular, is still unknown.

The researchers are careful to point out that what they’ve accomplished does not portend the creation of a video of a human brain in action—our brains are much larger, have billions more neurons and perhaps more importantly, are not transparent and are covered by a thick skull. Instead they suggest that studying a simpler brain in action might help to explain how biological neural networks actually work, perhaps leading to theories that can be generalized over larger animals.

But before that can happen, the procedure the team has developed needs to be improved—neurons can fire at hundreds of times per second, which means a lot of firing in the video has been missed. Capturing at a faster rate would mean generating nearly unmanageable amounts of data—at the current rate, just one hour of capture creates a terabyte of data. Thus a new way to store and process the data must be developed.

Mutations in VCP gene implicated in a number of neurodegenerative diseases

New research, published in Neuron, gives insight into how single mutations in the VCP gene cause a range of neurological conditions including a form of dementia called Inclusion Body Myopathy, Paget’s Disease of the Bone and Frontotemporal Dementia (IBMPFD), and the motor neuron disease Amyotrophic Lateral Sclerosis (ALS).

Single mutations in one gene rarely cause such different diseases. This study shows that these mutations disrupt energy production in cells shedding new light on the role of VCP in these multiple disorders.

In healthy cells VCP helps remove damaged mitochondria, the energy-producing engines of cells. The mutant protein can’t do this and as a result, the dysfunctional mitochondria build up.

The new study led by Dr Fernando Bartolome, Dr Helene Plun-Favreau and Dr Andrey Abramov of the UCL Institute of Neurology, found that mitochondria are damaged in cells from patients with mutant VCP. Mitochondria generate a cell’s energy, and the study found these damaged mitochondria are less efficient, burning more nutrients but producing less energy. This reduction in available energy makes cells more vulnerable, which could explain why mutations in the VCP gene lead to neurological disorders.

Lead author Dr Fernando Bartolome said, “We have found that VCP mutations are associated with mitochondrial dysfunction. VCP had previously been shown to be important in the removal of damaged mitochondria and proteins, accumulation of which is potentially very toxic to cells. A single mutation in the VCP gene could cause multiple neurological diseases because a different type of protein is accumulating in each disorder”.

In the study, the researchers used live imaging techniques to examine the functioning of mitochondria in patient cells carrying three independent VCP mutations, and in nerve cells in which the amount of VCP has been reduced.

“The next step will be to find small molecules able to correct the mitochondrial dysfunction in the VCP deficient cells”, added Dr Bartolome .

Dr Brian Dickie, the Motor Neuron Disease Association’s Director of Research Development says: “Neurons - and motor neurons in particular - are incredibly energy hungry cells. These new findings from the team at UCL show that there is a significant interruption of energy supply in this hereditary form of MND, which has strong implications for understanding the degenerative process underpinning all forms of the disease.”

Monday’s medical myth: alcohol kills brain cells

Do you ever wake up with a raging hangover and picture the row of brain cells that you suspect have have started to decay? Or wonder whether that final glass of wine was too much for those tiny cells, and pushed you over the line?

Well, it’s true that alcohol can indeed harm the brain in many ways. But directly killing off brain cells isn’t one of them.

The brain is made up of nerve cells (neurons) and glial cells. These cells communicate with each other, sending signals from one part of the brain to the other, telling your body what to do. Brain cells enable us to learn, imagine, experience sensation, feel emotion and control our body’s movement.

Alcohol’s effects can be seen on our brain even after a few drinks, causing us to feel tipsy. But these symptoms are temporary and reversible. The available evidence suggests alcohol doesn’t kill brain cells directly.

There is some evidence that moderate drinking is linked to improved mental function. A 2005 Australian study of 7,500 people in three age cohorts (early 20s, early 40s and early 60s) found moderate drinkers (up to 14 drinks for men and seven drinks for women per week) had better cognitive functioning than non-drinkers, occasional drinkers and heavy drinkers.

But there is also evidence that even moderate drinking may impair brain plasticity and cell production. Researchers in the United States gave rats alcohol over a two-week period, to raise their alcohol blood concentration to about 0.08. While this level did not impair the rats’ motor skills or short-term learning, it impacted the brain’s ability to produce and retain new cells, reducing new brain cell production by almost 40%. Therefore, we need to protect our brains as best we can.

Excessive alcohol undoubtedly damages brain cells and brain function. Heavy consumption over long periods can damage the connections between brain cells, even if the cells are not killed. It can also affect the way your body functions. Long-term drinking can cause brain atrophy or shrinkage, as seen in brain diseases such as stroke and Alzheimer’s disease.

There is debate about whether permanent brain damage is caused directly or indirectly.

We know, for example, that severe alcoholic liver disease has an indirect effect on the brain. When the liver is damaged, it’s no longer effective at processing toxins to make them harmless. As a result, poisonous toxins reach the brain, and may cause hepatic encephalopathy (decline in brain function). This can result in changes to cognition and personality, sleep disruption and even coma and death.

Alcoholism is also associated with nutritional and absorptive deficiencies. A lack of Vitamin B1 (thiamine) causes brain disorders called Wernicke’s ncephalopathy (which manifests in confusion, unsteadiness, paralysis of eye movements) and Korsakoff’s syndrome (where patients lose their short-term memory and coordination).

So, how much alcohol is okay?

To reduce the lifetime risk of harm from alcohol-related disease or injury, the National Health and Medical Research Council recommends healthy adults drink no more than two standard drinks on any day. Drinking less frequently (such as weekly rather than daily) and drinking less on each occasion will reduce your lifetime risk.

To avoid alcohol-related injuries, adults shouldn’t drink more than four standard drinks on a single occasion. This applies to both sexes because while women become intoxicated with less alcohol, men tend to take more risks and experience more harmful effects.

For pregnant women and young people under the age of 18, the guidelines say not drinking is the safest option.

So while alcohol may not kill brain cells, if this myth encourages us to rethink that third beer or glass of wine, I won’t mind if it hangs around.