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Depression’s Two Faces Revealed by Switching Off Symptoms

In a lab at Stanford University, a mouse is showing signs of depression. For around 10 weeks, it has experienced a series of irritations, from bouts without food or water, to erratic sleep patterns. Now, its motivation is low—when picked up by the tail, it makes few attempts to escape, and it doesn’t try to explore new spaces. It’s also less willing to sip from a sugary liquid– a sign that it gets less pleasure from normally pleasurable activities. It is never easy to assess the mental health of an animal, but this mouse is clearly showing some of the classic symptoms of depression.

But not for long.

Earlier, Kay Tye and Julie Mirzabekov altered the mouse so that a flash of light can activate a small part of its brain—the ventral tegmental area (VTA), near the bottom of the brain and close to the midline. A burst of light, and the mouse’s behaviour changes almost instantly. It struggles when held aloft, it explores open areas, and it regains its sweet tooth. A burst of light, and its symptoms disappear.

But on the other side of the country, at the Mount Sinai School of Medicine, Dipesh Chaudhury and Jessica Walsh are doing the same thing to completely different effect. Their mice have been altered in a similar way, so that light can also switch on their VTA neurons. But these rodents have endured a shorter but more intense form of stress—10 days of being placed in cages with dominant, aggressive rivals. Because of the resulting attacks, some of them have developed depressive symptoms. Others are more resilient. But when Chaudhury and Walsh flashed the VTAs of these mice, resilient individuals transformed into susceptible ones.

Both studies used the same methods to trigger neurons in the same part of the brain… and got completely different effects. In Tye and Mirzabekov’s experiment, depressed mice resumed their normal behaviour. In Chaudhury and Walsh’s study, the resilient mice showed more depressed symptoms.

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Facing sexual rejection, male flies turn to booze

“A male fruitfly will try to court a female by nuzzling her genitals, tapping her abdomen and singing with his wings. If all that fails, he drowns his sorrows in booze.”

That’s how my latest piece for Nature News starts. It’s obviously a cute result, but there’s some serious and intriguing science underlying it. These twin rewarding activities – sex and drinking – are linked by a chemical called neuropeptide F (NPF), which acts as a sort of currency of reward in the brain.

The study suggests that NPF is part of a system that acts like a ‘reward-thermostat’. If flies aren’t getting rewarding feelings from sex, their levels of NPF fall, and this compels them to get their kicks elsewhere, such as in a boozy meal.

Mammals also have a counterpart of NPF, known as NPY, which may play a similar role. It’s depleted in the brains of people who attempt suicide or suffer from PTSD, and some clinical trials are testing it as a way of dealing with addictions or mood disorders.

Go read the Nature News piece for more.

 

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Man with schizophrenia has out-of-body experience in lab, gains knowledge, controls his psychosis

RM had his first out-of-body experience at the age of 16. Now, at the age of 55, he has had more than he can count. They usually happen just before he falls asleep; for ten minutes, he feels like he is floating above his body, looking down on himself. If the same thing happens when he’s awake, it’s a far less tranquil story. The sense of displacement is stronger – his real body feels like a marionette, while he feels like a puppeteer. His feelings of elevation soon change into religious delusions, in which he imagines himself talking to angels and demons. Psychotic episodes follow. After four or five days, RM is hospitalised.

This has happened between 15 to 20 times, ever since RM was first diagnosed with schizophrenia at the age of 23. He hears voices, and he suffers from hallucinations and delusions. Despite these problems, he managed to hold down a job as a reporter until 2002 and more recently, he has been working in restaurants and volunteering as an archivist. Then, about a year ago, he took part in a study that seems to have changed his life.

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New neurons buffer the brains of mice against stress and depressive symptoms

For large swathes of the brain, the neurons we’re born with are the ones we’re stuck with. But a few small areas, such as the hippocampus, create new neurons throughout our lives, through a process known as neurogenesis. This production line may be important for learning and memory. But it has particularly piqued the interest of scientists because of the seductive but controversial idea that it could protect against depression, anxiety and other mood disorders.

Now, by studying mice, Jason Snyder from the National Institute of Mental Health has found some of the strongest evidence yet for a connection between neurogenesis and depression (or, at least, mouse behaviours that resemble depression). He found that the new neurons help to buffer the brains of mice against stress. Without them, the rodents become more susceptible to stress hormones and they behave in unusual ways that are reminiscent of depressive symptoms in humans.

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Tetris could prevent post-traumatic stress disorder flashbacks (but quiz games make them worse)

TetrisThis is an updated version of one of my favourite stories from last year, edited to include a sequel study that develops and expands on the first one.

You’ve just been in a horrific car crash. You’re unharmed but the vividness of the experience – the sight of a looming car, the crunching of metal, the overwhelming panic – has left you a bit traumatised. You want something to help take the edge off and fortunately a doctor is on hand to prescribe you with… Tetris.

Yes, that Tetris. According to Emily Holmes from the University of Oxford, the classic video game of falling coloured blocks could prevent people who have suffered through a traumatic experience from developing full-blown post-traumatic stress disorder (PTSD). As ideas go, it’s practically the definition of quirky, but there is scientific method behind the madness.

Every traumatic experience flips a mental hourglass that runs out in about six hours. After that time, memories of the original event become firmly etched in the brain, greatly increasing the odds that the person will experience the vivid, distressing flashbacks that are the hallmark of PTSD. But the brain, powerful though it is, only has so much processing power available for laying down such memories. If something can be done soon enough to interfere with this process, the symptoms of PTSD could potentially be prevented.

Tetris, it seems, makes an ideal choice for that. To position its rotating blocks, players need good “visuospatial skills” – they need to see, focus on, and act upon the positions of different objects, all at high speed. These are the same sort of mental abilities that provide the foundations for flashback images.

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Delay not deviance: brains of children with ADHD mature later than other

This article is reposted from the old WordPress incarnation of Not Exactly Rocket Science.

Attention-deficit hyperactivity disorder is the most common developmental disorder in children, affecting anywhere between 3-5% of the world’s school-going population. As the name suggests, kids with ADHD are hyperactive and easily distracted; they are also forgetful and find it difficult to control their own impulses.

While some evidence has suggested that ADHD brains develop in fundamentally different ways to typical ones, other results have argued that they are just the result of a delay in the normal timetable for development.

Now, Philip Shaw, Judith Rapaport and others from the National Institute of Mental Health have found new evidence to support the second theory. When some parts of the brain stick to their normal timetable for development, while others lag behind, ADHD is the result.

The idea isn’t new; earlier studies have found that children with ADHD have similar brain activity to slightly younger children without the condition. Rapaport’s own group had previously found that the brain’s four lobes developed in very much the same way, regardless of whether children had ADHD or not.

But looking at the size of entire lobes is a blunt measure that, at best, provides a rough overview. To get an sharper picture, they used magnetic resonance imaging to measure the brains of 447 children of different ages, often at more than one point in time.

At over 40,000 parts of the brain, they noted the thickness of the child’s cerebral cortex, the brain’s outer layer, where its most complex functions like memory, language and consciousness are thought to lie. Half of the children had ADHD and using these measurements, Shaw could work out how their cortex differed from typical children as they grew up.

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Flu and Parkinson’s – how H5N1 bird flu causes neural degeneration in mice

Blogging on Peer-Reviewed ResearchPeople infected with the bird flu virus – influenza A subtype H5N1 – go through the usual symptoms of fever, aching muscles and cough. The virus is so virulent that 60% of infected humans have died. But according to a study in mice, the infection could also take a more inconspicuous toll on the brain, causing the sorts of damage that could increase the risk of diseases like Parkinson’s and Alzheimer’s many years after the virus has been cleared.

The link between influenza and Parkinson’s disease is hardly old but certainly controversial. Previous studies have found no traces of flu genetic material in Parkinson’s patients, but one of the strongest pieces of evidence for a link comes from analysing an outbreak of von Economo disease  following the 1918 flu pandemic.

To date, 433 people have been infected with H5N1, and a few cases have shown problems with their nervous system, running the gamut from inflammation of the brain to coma. For the survivors, it’s too early to say if their brief time with the virus could lead to neurological problems later on in life. Instead, Haeman Jang from St Jude’s Children’s Research Hospital turned to mice for answers.

He clearly showed that the H5N1 virus can infect mouse neurons within a few days, where it causes certain proteins to gather in the sorts of clumps that are so strongly associated with neurodegenerative disease. It kills off important cells, triggers symptoms reminiscent of Parkinson’s like tremors, and even stimulates an over-the-top immune response that lasted for months after the original infection was cleared.

Jang thinks that this long-lasting immune response may be how the virus leads to a higher risk of chronic diseases long after it has left its host. It’s a hit-and-run strategy, where the initial infection paves the way for something else to come along later on in life and make a “second hit”. According to this model, the flu virus doesn’t directly cause Parkinson’s or related diseases, but it primes the neurons for other things that do. This could also explain why scientists have been unable to detect influenza RNA in Parkinson’s patients.

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Deformed skull of prehistoric child suggests that early humans cared for disabled children

Blogging on Peer-Reviewed ResearchFor all appearances, this looks like the skull of any human child. But there are two very special things about it. The first is that its owner was clearly deformed; its asymmetrical skull is a sign of a medical condition called craniosynostosis that’s associated with mental retardation. The second is that the skull is about half a million years old. It belonged to a child who lived in the Middle Pleistocene period.

The skull was uncovered in Atapuerca, Spain by Ana Gracia, who has named it Cranium 14. It’s a small specimen but it contains enough evidence to suggest that the deformity was present from birth and that the child was about 5-8 years old. The remains of 28 other humans have been recovered from the same site and none of them had any signs of deformity.

These facts strongly suggest that prehistoric humans cared for children with physical and mental deformities that would almost have certainly prevented them from caring for themselves. Without such assistance, it’s unlikely that the child would have survived that long.

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Autistic children are less sensitive to the movements of living things

Blogging on Peer-Reviewed ResearchFor any animal, it pays to be able to spot other animals in order to find mates and companions and to avoid predators. Fortunately, many animals move in a distinct way, combining great flexibility with the constraints of a rigid skeleton – that sets them apart from inanimate objects like speeding trains or flying balls. The ability to detect this “biological motion” is incredibly important. Chicks have it. Cats have it. Even two-day-old babies have it. But autistic children do not.

Ami Klim from Yale has found that two-year-old children with autism lack normal preferences for natural movements. This difference could explain many of the problems that they face in interacting with other people because the ability to perceive biological motion – from gestures to facial expressions – is very important for our social lives.

Indeed, the parts of the brain involved in spotting them overlap with those that are involved in understanding the expressions on people’s faces or noticing where they are looking. Even the sounds of human motion can activate parts of the brain that usually only fire in response to sights.

You can appreciate the importance of this “biological motion” by looking at “point-light” animations, where a few points of light placed at key joints can simulate a moving animal. Just fifteen dots can simulate a human walker. They can even depict someone male or female, happy or sad, nervous or relaxed. Movement is the key – any single frame looks like a random collection of dots but once they move in time, the brain amazingly extracts an image from them.

But Klim found that autistic children don’t have any inclination toward point-light animations depicting natural movement. Instead, they were attracted to those where sounds and movements were synchronised – a feature that normal children tend to ignore. Again, this may explain why autistic children tend to avoid looking at people’s eyes, preferring instead to focus on their mouths.

Alim created a series of point-light animations used the type of motion-capture technology used by special effects technicians and video game designers. He filmed adults playing children’s games like “peek-a-boo” and “pat-a-cake” and converted their bodies into mere spots of light. He then showed two animations side-by-side to 76 children, of whom 21 had autism, 16 were developing slowly but were not autistic, and 39 were developing normally.

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Fishing expedition reveals unexpected link between Alzheimer’s and prion diseases

Blogging on Peer-Reviewed ResearchAlzheimer’s disease is the most common form of dementia in the world, affecting more than 26 million people. Creutzfeld-Jacob disease (CJD), another affliction is far less common, but both conditions share many of the same qualities. They are fatal within a few years of diagnosis, they are incurable and they involved the crippling degeneration of the brain’s neurons. Now, a group of Yale researchers have discovered that the two diseases are also linked by a pair of critical proteins.

Look into the brain of someone with Alzheimer’s disease and you will see large, insoluble “plaques” sitting between nerve cells. They consist of a protein fragment (or “peptide”) called amyloid-beta, accumulating in its thousands. These plaques are a hallmark of the disease, but even before they have formed, amyloid-beta peptides have already begun to cluster in small soluble groups. Even at this stage, they can impair memory, degrading the connections between separate neurons.

Juha Lauren wanted to work out how exactly clusters of amyloid-beta wreak havoc in neurons before they form plaques. In particular, he was after the identity of its molecular accomplices. Many proteins work their will in a cell by attaching to other proteins called receptors. To see if amyloid-beta does the same, Lauren’s team went fishing for receptors.

They created a synthetic version of the amyloid-beta peptide and connected it to a molecule called biotin – these were their hooks. Lauren lowered them into a massive pool of different proteins found in the brains of mice; if one of those was a receptor for amyloid-beta, it should take the bait and stick to it. As a rod, he used beads covered in a molecule called avidin, which sticks very strongly to biotin. The beads attracted biotin, which was stuck to amyloid-beta, which was in turn bound to its receptor. 

From hundreds of thousands of proteins, their fishing trips pulled out just one that stuck to amyloid-beta, and it’s a familiar one – the prion protein. Incorrectly folded versions of this protein (PrPSC) are the culprits behind diseases like CJD, mad cow disease and scrapie. And now it seems that the normal, correctly folded version (PrPC) plays a role in Alzheimer’s disease too, by acting as the receptor for amyloid-beta. It’s the accomplice through which amyloid-beta clusters work their damaging effects on neurons.

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Child abuse permanently modifies stress genes in brains of suicide victims

Blogging on Peer-Reviewed ResearchThe trauma of child abuse can last a lifetime, leading to a higher risk of anxiety, depression and suicide further down the line. This link seems obvious, but a group of Canadian scientists have found that it has a genetic basis.

By studying the brains of suicide victims, Patrick McGowan from the Douglas Mental Health University Institute, found that child abuse modifies a gene called NR3C1 that affects a person’s ability to deal with stress. The changes it wrought were “epigenetic”, meaning that the gene’s DNA sequence wasn’t altered but it’s structure was modified to make it less active. These types of changes are very long-lasting, which strongly suggests that the trauma of child abuse could be permanently inscribed onto a person’s genes.

Child abuse, from neglect to physical abuse, affects the workings of an important group of organs called the “hypothalamic-pituitary-adrenal axis” or HPA. This trinity consists of the hypothalamus, a funnel-shaped part of the brain; the pituitary gland, which sits beneath it; and the adrenal glands, which sit above the kidneys.  All three organs secrete hormones. Through these chemicals, the HPA axis controls our reactions to stressful situations, triggering a number of physiological changes that prime our bodies for action.

The NR3C1 gene is part of this system. It produces a protein called the glucocorticoid receptor, which sticks to cortisol, the so-called “stress hormone”. Cortisol is produced by the adrenal glands in response to stress, and when it latches on to its receptor,  it triggers a chain reaction that deactivates the HPA axis. In this way, our body automatically limits its own response to stressful situations.

Without enough glucocorticoid receptors, this self-control goes awry, which means that the HPA is active in normal situations, as well as stressful ones. No surprise then, that some scientists have found a link between low levels of this receptor and schizophrenia, mood disorders and suicide. So, childhood trauma alters the way the body reacts to stress, which affects a person’s risk of suicide or mental disorders later in life. Now, McGowan’s group have revealed part of the genetic (well, epigenetic) basis behind this link.

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Beta-blocker drug erases the emotion of fearful memories

Blogging on Peer-Reviewed ResearchThe wiping of unwanted memories is a common staple of science-fiction and if you believe this weekend’s headlines, you might think that the prospect has just become a reality. The Press Association said that a “drug helps erase fearful memories“, while the ever-hyperbolic Daily Mail talked about a “pill to erase bad memories“. The comparisons to The Eternal Sunshine of the Spotless Mind were inevitable, but the actual study, while fascinating and important, isn’t quite the mind-wiper these headlines might have you believe.

The drug in question is propranolol, commonly used to treat high blood pressure and prevent migraines in children. But Merel Kindt and colleagues from the University of Amsterdam have found that it can do much more. By giving it to people before they recalled a scary memory about a spider, they could erase the fearful response it triggered.

The critical thing about the study is that the entire memory hadn’t been erased in a typical sci-fi way. Kindt had trained the volunteers to be fearful of spidery images by pairing them with electric shocks. Even after they’d been given propranolol, they still expected to receive a shock when they saw a picture of a spider – they just weren’t afraid of the prospect. The drug hadn’t so much erased their memories, as dulled their emotional sting. It’s more like removing all the formatting from a Word document than deleting the entire file. Congatulations to Forbes and Science News who actually got it right.

Kindt’s work hinges on the fact that memories of past fears aren’t as fixed as previously thought. When they are brought back to mind, proteins at the synapses – the junctions between two nerve cells – are broken down and have to be created from scratch. This process is called “reconsolidation” and scientists believe that it helps to incorporate new information into existing memories. The upshot is that when we recall old memories, they have to be rebuilt on some level, which creates an opportunity for changing them.

A few years ago, two American scientists managed to use propranolol to banish fearful responses in rats. They injected the animals in their amygdalae, a part of their brains involved in processing emotional memories. The drug didn’t stop a fearful memory from forming in the first place, but it did impair the memory when the rats tried to retrieve it. Now, Kindt has shown that the chemical has the same effect in humans.

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Ask an IVF baby: does smoking while pregnant lead to antisocial behaviour?

Blogging on Peer-Reviewed ResearchOur health isn’t just affected by the things we do after we’re born – the conditions we face inside our mother’s womb can have a lasting impact on our wellbeing, much later in life. This message comes from a growing number of studies that compare a mother’s behaviour during pregnancy to the subsequent health of her child.

But all of these studies have a problem. Mothers also pass on half of their genes to their children, and it’s very difficult to say which aspects of the child’s health are affected by conditions in the womb, and which are influenced by mum’s genetic legacy.

Take the case of smoking. Doing it while pregnant is bad news for the foetus, and studies have suggested that children whose mothers smoke during pregnancy are more likely to be born prematurely, be born lighter, have poorer lung function, and be more likely to die suddenly before their first birthday. More controversially, they may even show higher levels of behavioural problems including autistic disorders and antisocial tendencies.

Biologically, these results make sense, but many of these risks can be inherited too. For example, genetic factors can strongly influence both a person’s susceptibility to nicotine addiction and their propensity for violent behaviour. A mother’s genes could also affect the birth weight of her child.

To untangle these influences, the ideal experiment would involve randomly implanting foetuses either in the wombs of their own mothers, or those of unrelated women.  That’s possible in animals but deliberately doing so in humans would be both unethical and impractical. Nonetheless, Frances Rice from Cardiff University realised that this experiment was actually well underway.

Since the advent of in vitro fertilisation (IVF) technology in the late 1970s, many mothers have nourished babies in their womb, who weren’t genetically related to them. Here was an ideal chance to study the effects of conditions in the womb, without any confusion caused by shared genes.

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Tetris to prevent Post-Traumatic Stress Disorder flashbacks

Blogging on Peer-Reviewed ResearchYou’ve just been in a horrific car crash. You’re unharmed but the vividness of the experience – the sight of a looming car, the crunching of metal, the overwhelming panic – has left you a bit traumatised. You want something to help take the edge off and fortunately a doctor is on hand to prescribe you with… Tetris.

Tetris.jpgYes, that Tetris. According to Emily Holmes from the University of Oxford, the classic video game of falling coloured blocks could prevent people who have suffered through a traumatic experience from developing full-blown post-traumatic stress disorder (PTSD). As ideas go, it’s practically the definition of quirky, but there is scientific method behind the madness.

Every traumatic experience flips a mental hourglass that runs out in about six hours. After that time, memories of the original event become firmly etched in the brain, greatly increasing the odds that the person will experience the vivid, distressing flashbacks that are the hallmark of PTSD. But the brain, powerful though it is, only has so much processing power available for laying down such memories. If something can be done soon enough to interfere with this process, the symptoms of PTSD could potentially be prevented.

Tetris, it seems, makes an ideal choice for that. To position its rotating blocks, players need good “visuospatial skills” – they need to see, focus on, and act upon the positions of different objects, all at high speed. These are the same sort of mental abilities that provide the foundations for flashback images.

Holmes’s idea is that playing Tetris after a shocking event would take up the same mental resources that would normally be used to consolidate future flashbacks. In doing so, the notoriously addictive game could act as a “cognitive vaccine” against PTSD and provide an ironic example of a video game actually being good for you…

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Same gene underlies two language disorders

Blogging on Peer-Reviewed ResearchSpecific language impairment (SLI) is a language disorder that affects growing children, who find it inexplicably difficult to pick up the spoken language skills that their peers acquire so effortlessly. Autism is another (perhaps more familiar) developmental disorder and many autistic children also have problems in picking up normal speech and communication. These two conditions have a common theme of language difficulties running through them, but a new study reveals a deeper connection – both are linked to a gene called CNTNAP2.

FOXP2.jpgThe story of CNTNAP2 actually begins with another gene, whose name will be familiar to anyone with a passing interest in the genetics of language – FOXP2. Earlier this year, I wrote a long feature on the history of FOXP2 for New Scientist, but here’s a potted version.

FOXP2 was catapulted into the limelight earlier this decade when it became the first gene to be linked to an inherited language disorder. Initially heralded as “a language gene”, the hype surrounding FOXP2 was soon pierced by a number of studies which showed that the gene is an ancient one – it is present in a variety of different animals and has changed very little over the course of evolutionary time. In other species, it is hardly involved in language and in some, it isn’t even involved in communication.

The latest evidence suggests that FOXP2 affects the learning and production of complex sequences of movements. Such sequences are, of course, crucial for speech so it’s understandable that faults in FOXP2 leads to linguistic difficulties. So much for the hype, but the FOXP2 story isn’t over yet.

One of the most interesting things about it is that it’s a ‘transcription factor’, an executive gene that controls the activity of several subordinates. It was the quest to identify the genes that FOXP2 lords over that led to CNTNAP2. And lo and behold, it too plays a role in language.

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