More on Carry the One

I apologize for the hiatus in blog posts, but The Gray Area is back with another shameless plug for Carry the One Radio! This month, we talk to Lisa Stowers, who is an Assistant Professor at the Scripps Research Institute in San Diego. Her lab uses mice to study how chemical signals known as pheromones activate particular groups of neurons, and how this activity produces instinctive behaviors of fear, attraction, and aggression. By studying this system, Dr. Stowers hopes to shed new light on how the brain processes senses and generates behavior. Check it out at the link below!

http://www.carrytheoneradio.com/2012/08/01/lisa-stowers/

Carry the One Radio

I recently joined a UCSF Neuroscience initiative called Carry the One Radio, a series of 10 minute long interviews with scientists from various backgrounds and institutions. Started two years ago by fellow graduate student Sama Ahmed, Carry the One aims to get high school and college students interested in science through relaying a scientist's story about he or she got interested in science, and "the one" project that creates the fire in their belly. I'm co-hosting the show with Sama, and we're now posting episodes on the web every month. This month, Sama talks to Cori Bargmann, a professor at the Rockefeller University and investigator at the Howard Hughes Medical Institute. Dr.Bargmann studies the neuronal circuitry underyling animal behavior using the humble worm, C.elegans, as a model system. She has also been featured on the Charlie Rose Brain Series and The New York Times. 

The website is still under construction, but please check out the latest episode here!:

http://www.carrytheoneradio.com/2012/07/01/cornelia-bargmann/

Please also check out the Facebook page at: http://www.facebook.com/carrytheone

Bacteria that influences happiness

In a recent study from the Alimentary Pharmabiotic Center, scientists showed that the bacteria that live in our gut during development can affect adult brain function and emotional states. Specifically, these little microbes are able to affect levels of the chemical serotonin in our brains. Serotonin, a neurotransmitter, plays an important role in the regulation of mood and emotion. Research has found that serotonin levels are altered during stress, anxiety and depression and many antidepressant drugs are designed to target this neurotransmitter. 

In this study, the scientists were able to demonstrate that mice that were raised in a germ-free environment and therefore had very little gut flora or microbiota during early life. This early absence of gut bacteria significantly elevated concentrations of serotonin in the adult brain, specifically in the hippocampus, a neuronal structure that has important roles in episodic and emotional memory. Most importantly, these germ-free mice with increased levels of serotonin during development displayed less anxious behavior when tested as adults, as compared to mice that were raised in normal conditions and had normal gut flora. Interestingly, this effect seemed to be sex-specific; male mice with reduced gut flora and subsequent elevated levels of hippocampal serotonin showed a much more marked effect than female mice. 

Intriguingly, the neurochemical effect seems to be irreversible. When the scientists recolonized the young germ-free mice in a normal environment that would allow the restoration of intestinal microbiota, they found that hippocampal serotonin levels continued to be elevated in these mice. Paradoxically, the restoration of the gut flora was able to reverse the behavioral effect, such that the germ-free mice no longer showed reduced anxiety compared to the control animals. 

This study follows  earlier work from several groups, showing that a microbiome-gut-brain axis exists and that it is essential for maintaining normal health which can affect brain and behaviour. The research was carried out by Dr Gerard Clarke, Professor Fergus Shanahan, Professor Ted Dinan and Professor John F Cryan and colleagues at the Alimentary Pharmabiotic Centre in UCC.

“As a neuroscientist these findings are fascinating as they highlight the important role that gut bacteria play in the bidirectional communication between the gut and the brain, and opens up the intriguing opportunity of developing unique microbial-based strategies for treatment for brain disorders”, said Professor John F Cryan, senior author on the publication and Head of the Department of Anatomy & Neuroscience at UCC.

The results from this study have many implications, as it shows that manipulating the natural microbiota that exist in our body, whether it be through infection, antibiotics or diet, can profoundly affect other bodily functions, including brain function and behavior. “We’re really excited by these findings” said lead author Dr Gerard Clarke. “Although we always believed that the microbiota was essential for our general health, our results also highlight how important our tiny friends are for our mental wellbeing.”

Vaccine trial for Alzheimer's Disease

Alzheimer’s disease (AD) is a complex neurological disease that is the most common form of dementia, or loss of brain function. Individuals suffering from Alzheimer's display impairments in learning and memory, as well as changes in personality and mood. According to the World Health Organisation, dementia is currently the fastest growing global health epidemic. AD is most often diagnosed in people that are older than 65, although there are a few rare cases of early-onset of the disease. The prevailing hypothesis about the cause of AD involves the protein amyloid precursor protein (APP), which is found in the outer membrane of nerve cells and that, instead of being broken down, forms a harmful substance called beta-amyloid. This noxious version of the protein can accumulate as plaques and kill brain cells. Needless to say, the disease is devastating to many all over the world, and a huge cost for society. 

Researchers around the world have been investigating genetic and environmental factors that may put individuals at risk, as well as how beta-amyloid can cause neurodegeneration. Moreover, other theories besides the APP theory exist to explain the cause of AD. While there is currently no cure for the disease, scientists have been trying different approaches to treat the disease; one of them has been vaccines. The first vaccination study conducted almost a decade ago, showed some efficiency in clearing up beta-amyloid plaques, but did not help with dementia at all. Furthermore, the vaccine caused too many adverse side effects, including an autoimmune reaction, and was soon abandoned. 

A recent study from researchers at the Karolinska Institutet in Stockholm points to the first successful attempt at a vaccine treatment for AD. The new treatment is an active vaccine and the idea is to use a type of vaccine designed to trigger the body's immune defence against beta-amyloid. In this set of clinical trials, the vaccine was modified such that it only affects the harmful form of APP, that is beta-amyloid. The investigators observed that 80 per cent of the participating patients developed protective antibodies against beta-amyloid, without suffering any side effects that were observed in previous trials of this study. The researchers believe that the treatnent, called CAD106 vaccine, could be an effective and tolerable way to treat patients with mild to moderade AD. More large-scale clinical trials have to be conducted to further determine the efficacy of CAD106, but the discovery is very encouraging for AD patients and their families.

What's the buzz: Microglia

There is growing evidence demonstrating that immune cells and signaling molecules serve as carriers in an intricate network of bidirectional communication between the immune system and the brain. This occurs via peripheral immune pathways as well as through interactions between neurons and the resident immune cells in the brain known as microglia. It turns out that microglia are involved in a lot more than just protecting the brain from infections; it has been shown that microglia are capable of influencing the growth and activity of neighbouring neurons. This affects the plastic nature of neuronal networks, and thus microglia are able to affect cognitive and social behaviors. 

In a recent study from Jonathan Kipnis' lab at University of Virginia, School of Medicine, researchers showed that restoring microglial function in a mouse model of Rett Syndrome, a severe autism-spectrum disorder that affects 1 in 10,000-20,000 girls worldwide. The disease is caused by a mutation in the gene MECP2, which is carried on the X chromosome. Since males carry only one copy of the X chromosome, males with the mutation die very soon after being born, whereas girls with one copy of the mutation develop the disease. 

Signs of the disease typically set in between 6 and 18 months of age. Affected females often have trouble developing speech, walking and putting on weight. Many patients also develop breathing problems and apnoeas. They also display repeated behaviors such as hand washing and wringing. 

MECP2 is an important epigenetic regulator, meaning it is able to regulate the expression of genes by recruiting enzymes that modify the structure of chromatin network. How exactly a mutation in the gene is sufficient to cause Rett Syndrome is still a mystery, but researchers have been able to detect its expression widely in the brain. In fact, rescuing MECP2 expression in neurons in Rett Syndrome mice reverses some of the disease phenotypes. More recently however, researchers lie Kipnis began to look for MECP2 function in other cell types in the brain, like microglia. It is now known that microglia indeed do express MECP2, so Kipnis and colleagues began to ask whether restoring MECP2 function in microglia in a Rett Syndrome mouse would improve the symptoms. 

The researchers accomplished this by essentially replacing the immune system of the mutant mouse lacking MECP2. They first had to kill of the existing immune system using radiation, and then used a bone marrow transplant from a healthy wildtype mouse to the mutant mouse; thus the new microglia in the Rett Syndrome mouse now have MECP2 in them. In an unexpected result, the restoration of MECP2 function in microglia resulted in drastic improvements in the mutant mice; they began to breathe and walk better, and even gain weight more easily compared to the non-transplanted mutant mice. 

These findings, while exciting, are very preliminary in terms of bone marrow transplants being used in human Rett Syndrome patients.  At this point, Kipnis speculates that their results could be explained by the fact that microglia in mutant Rett Syndrome animals are unable to clear up and protect the neurons from cellular waste build up and potential pathogens, and thus neuronal function is impaired. More research is required to identify the mechanism of microglia function in Rett Syndrome. However, the study does provide a novel role for microglia in the brain, and a new target for treatment of Rett Syndrome.

Remember to remember

As someone who is studying neuroscience, I come across the topic of memory very often. Finding out how memories are formed and stored is after all a major impetus that drives research in neuroscience. This Ted Talk by Josh Foer, a science journalist who writes for a number of publications including National Geographic and The New York Times, gives an interesting perspective on how we make memories. In 2005, Josh went to cover the U.S Memory Championship, a competition of mental sports in which participants have to memorize as much information as possible within a given amount of time. There he met many extraordinary people with extraordinary memories, or so he thought, until he began training with some of the participants and realized the strategies they used basically came down to creating a visual and spatial framework to place memories. Called a 'memory palace', this context within your mind's eye allows you to extract memories more easily. But Josh points out that, this strategy is in fact not novel; before the advent of technological tools, strategies like the 'memory palace' was an effective way to memorize speeches and even academic material for tests. We've just forgotten how to use it because we have other places to store the memory palace besides our brain: our computers, our smartphones, and for the really old school people, photo albums. In other words, we've forgotten how to make memories, and therefore how to remember. What really drives the point home is that, after a year of training with the top European memorizer, Josh entered in the national Memory Championship in New York- and won. Because he remembered to remember. 

Check the talk out at:

http://www.ted.com/talks/joshua_foer_feats_of_memory_anyone_can_do.html

Hmmm.....

 

After a two week hiatus, The Gray Area is back with a post describing a study that investigated how the feeling of suspicion is created in our brains. One of my first posts was about researchers have been trying to study how person's brain activity is altered when he/she is telling a lie vs. telling a truth, that is, the neural basis of deception. This current study attempts to describe how brain activity may change when we think someone might be telling a lie, that is, the neural basis for the feeling of suspicion. 

Using the same technique of fMRI, these scientists at Virginia Tech Carilion Research have identified two regions that may be involved in creating the feeling of suspicion- the amygdala and parahippocampal gyrus. The amygdala is involved in processing fear and emotional memories, while the parahippocampal gyrus plays a central role in declarative memory. The task was this: There were 76 pairs of participants, each with a buyer and a seller. Each pair competed in 60 rounds of a bargaining game, while having their brains scanned by the fMRI machine. At the start of each round, the buyer was told the value of a hypothetical widget, and then they were asked to suggest a price to the seller. The seller was then asked to set a selling price; if the seller's price fellow below the stipulated widget, the trade would go through, with the seller receiving the selling price and the buyer receiving any difference between the selling price and the stipulated value. However, if the seller's value exceeded the stipulated price, the trade would not go through, and neither the buyer or seller would receive cash. 

The researchers found that the buyers fell into three categories: 42% were incrementalists, meaning they were actually quite honest about the stipulated value; 37% were conservatives, meaning they tended to withhold information; 21% were strategists, who intentionally deceived the sellers by pretending to be incrementalists (making higher value suggestions when the stipulated value was low, and vice versa). The sellers did have the monetary incentive to correctly predict the stipulated value, but they had no feedback about the buyer's accuracy. The investigators found that the more uncertain the seller was about the buyer's suggested price, the more active his or her amygdala and parahippocampal gyrus became. The activation of the amygdala was not very surprising to the authors, as suspicion is an emotional state. But Read Montague, the lead investigator 

and director of the Human Neuroimaging Laboratory and the Computational Psychiatry Unit at the Virginia Tech Carilion Research Institute, says the activation of the parahippocampal gyrus could be "an inborn lie detector" or a reminder of an untrustworthy person. 

While this study is not a great replication of real life situations in which we may encounter suspicious behaviors or people, it may be important in understanding the neurological basis of increased suspicion and distrust in neuropsychiatric disorders such as anxiety disorders and paranoia.