Brain region essential for social memory identified

Scientists have long understood that the hippocampus—a pair of seahorse-shaped structures in the brain’s temporal lobes—plays a critical role in our ability to remember the who, what, where, and when of our daily lives. Recent studies have shown that different subregions of the hippocampus have different functions. For instance, the dentate gyrus is critical for distinguishing between similar environments, while CA3 enables us to recall a memory from partial cues (e.g., Proust’s famous madeleine). The CA1 region is critical for all forms of memory.


“However, the role of CA2, a relatively small region of the hippocampus sandwiched between CA3 and CA1, has remained largely unknown,” said senior author Steven A. Siegelbaum, PhD, professor of neuroscience and pharmacology, chair of the Department of Neuroscience, a member of the Mortimer B. Zuckerman Mind Brain Behavior Institute and Kavli Institute for Brain Science, and a Howard Hughes Medical Institute Investigator. A few studies have suggested that CA2 might be involved in social memory, as this region has a high level of expression of a receptor for vasopressin, a hormone linked to sexual motivation, bonding, and other social behaviors.

To learn more about this part of the hippocampus, the researchers created a transgenic mouse in which CA2 neurons could be selectively inhibited in adult animals. Once the neurons were inhibited, the mice were given a series of behavioral tests. “The mice looked quite normal until we looked at social memory,” said first author Frederick L. Hitti, an MD-PhD student in Dr. Siegelbaum’s laboratory, who developed the transgenic mouse. “Normally, mice are naturally curious about a mouse they’ve never met; they spend more time investigating an unfamiliar mouse than a familiar one. In our experiment, however, mice with an inactivated CA2 region showed no preference for a novel mouse versus a previously encountered mouse, indicating a lack of social memory.”

In two separate novel-object recognition tests, the CA2-deficient mice showed a normal preference for an object they had not previously encountered, showing that the mice did not have a global lack of interest in novelty. In another experiment, the researchers tested whether the animals’ inability to form social memories might have to do with deficits in olfaction (sense of smell), which is crucial for normal social interaction. However, the mice showed no loss in ability to discriminate social or non-social odors.

In humans, the importance of the hippocampus for social memory was famously illustrated by the case of Henry Molaison, who had much of his hippocampus removed by surgeons in 1953 in an attempt to cure severe epilepsy. Molaison (often referred to as HM in the scientific literature) was subsequently unable to form new memories of people. Scientists have observed that lesions limited to the hippocampus also impair social memory in both rodents and humans.

“Because several neuropsychiatric disorders are associated with altered social behaviors, our findings raise the possibility that CA2 dysfunction may contribute to these behavioral changes,” said Dr. Siegelbaum. This possibility is supported by findings of a decreased number of CA2 inhibitory neurons in individuals with schizophrenia and bipolar disorder and altered vasopressin signaling in autism. Thus, CA2 may provide a new target for therapeutic approaches to the treatment of social disorders.

Story Source:

The above story is based on materials provided by Columbia University Medical CenterNote: Materials may be edited for content and length. [via Science Daily]

Is PTSD influenced by immune cells in the spleen?

A new study in mice finds that an excessive response provoked in the immune system by chronic stress results in anxiety symptoms resembling post-traumatic stress disorder.

The scientists behind the study, had previously found that – in mice with chronic stress – immune system cells traveled to the brain, resulting in anxiety symptoms. The scientists also found that monocytes – a subset of these immune system cells – could be targeted with drugs to treat mood disorders.


In the new study, the researchers would allow a group of male mice living together to establish a hierarchy but would then introduce an aggressive male mouse to the group for 2-hour sessions over 6 days.

The aggressive mouse would dominate the hierarchy, resulting in “social defeat” to the resident mice. This social defeat manifested itself by triggering the sympathetic nervous system and the “fight-or-flight” response.

Over 6 days of exposure to the aggressive mouse, this reaction led to inflamed immune cells in the spleen and anxious behavior in the mice.

At follow-ups of 14 hours and 8 days after achieving the state of chronic stress, the researchers observed high levels – compared with the mice in a control group – of pro-inflammatory proteins in the bloodstream and monocytes accumulating in the brains of the mice.

The stressed mice would not return to normal behavioral and physiological levels until 24 days later.

Brief exposure to a stressor resulted in PTSD symptoms

Taking both the stress-sensitized mice and the control group mice, plus a third group of mice new to the experiment, the scientists then exposed all mice to an aggressive mouse for 2 hours.

“That one exposure to an acute stressor produced a similar pattern to what we’d expect to see if they had experienced the chronic stress of repeated social defeat,” says study lead author Prof. Jonathan Godbout.

There was no change in the biology or behavior of the unstressed mice, but the mice who had been stress-sensitized returned immediately to their chronically stressed state, exhibiting more anxious behaviors and higher levels of pro-inflammatory proteins. The researchers assumed that these symptoms had been brought on by monocytes traveling to the brain.

“That retriggering is a component of post-traumatic stress,” says Prof. Godbout. “The previously stressed mice are living a normal rodent life, and then this acute stress brings everything back. Animals that have never been exposed to stress before were unaffected by that one event – it didn’t change behavioral or physiological properties.”

Removing the mice’s spleens removed their anxiety

The researchers then removed the spleens of the stressed mice. It was the spleen where the immune cells in the mice had been “primed” into a constant state of alert by their chronic stress.

After spleen removal, the stress-sensitized mice no longer re-established anxiety when exposed again to the aggressive mouse. The scientists also noticed that immune cells were no longer traveling to the brain in the stress-sensitized mice.

“Our colleagues who study behavior talk about sensitization,” senior author Prof. John Sheridan says. “Clearly, the repeatedly stressed mice were sensitized. What we’re adding is that sensitization is associated with a specific cell type that resides in the spleen after the initial sensitization.”

“The key is those cells. They originate in the bone marrow but in terms of sensitization, the spleen is a significant organ.”

For the next stage of their research, Prof. Godbout and team will compare the immune cells that travel to the brain with those that remain in the spleen during stress response.

Other scientists are looking for PTSD biomarkers in patients by testing blood samples, and Sheridan considers that “this work will validate some of their approaches.”

Recently, Medical News Today reported on another trial in mice examining whether a memory-rewriting drug could help treat PTSD.

[via: Medical News Today]

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Acupuncture ‘could treat inflammation and save lives’

In Western medicine, the jury is still out on whether acupuncture delivers health benefits. But now, a new study adds further evidence of its worthiness, as scientists have shown a direct connection between acupuncture and physical mechanisms that heal sepsis, a common condition in hospital intensive care units that springs from infection and inflammation.

The researchers, from Rutgers New Jersey Medical School, published their results in the journal Nature Medicine.

They note that sepsis causes around 250,000 deaths in the US each year, making it a major cause of death.

“But in many cases patients don’t die because of the infection,” says lead author Luis Ulloa, an immunologist at Rutgers. “They die because of the inflammatory disorder they develop after the infection. So we hoped to study how to control the inflammatory disorder.”

Although acupuncture has been practiced for thousands of years in Eastern countries, it is relatively new to Western medicine. The technique works by stimulating specific points on the body with tiny needles that penetrate the skin.

Researchers from this latest study say they already knew that stimulating the vagus nerve – a major nerve in the body – activates mechanisms in the body that reduce inflammation.


As such, they tested whether electroacupuncture – a form of acupuncture that involves sending a small electric current through the nerves – reduces inflammation and organ injury in mice with sepsis. This type of electrification has been approved by the FDA for treating pain in humans.

Half of septic mice who received electroacupuncture survived

By increasing the electrical current, Ulloa explains that it heightens the effect of needle placement. As predicted, when they performed the electroacupuncture on septic mice, the researchers found that cytokines – molecules that help reduce inflammation – were stimulated.

The team notes that whereas none of the mice that did not receive acupuncture survived, half of the mice that did receive the treatment survived for at least a week.

Though they were pleased with their results, upon further investigation into why the acupuncture worked so well, Ulloa and his colleagues found that when they removed adrenal glands, which produce hormones in the body, the electroacupuncture stopped being effective.

This finding initially dashed their hopes for using this technique in humans because most human sepsis cases carry with them reduced adrenal function. Though electroacupuncture might help a small number of patients with functioning adrenal glands, it would not work in many others.

Not deterred, the scientists looked into the anatomical changes that took place when the technique was carried out with fully functional adrenal glands.

They found these changes included raised levels of dopamine, which is a neurotransmitter that influences the immune system. However, simply adding dopamine by itself did not help reduce the inflammation.

It was not until they used a drug called fenoldopam – which mimics the effects of dopamine – that they were able to succeed in reducing deaths caused by sepsis by 40%.

Potential treatment for other inflammatory diseases

The team notes that, even without acupuncture, fenoldopam was able to achieve the reduction in deaths.

They say their findings are significant because they provide evidence of acupuncture’s benefits beyond what has been shown before, and they also show uses for treating other inflammatory diseases besides sepsis, such as rheumatoid arthritis, osteoarthritis and Crohn’s disease.

Additionally, they say they have provided a potential avenue for developing drugs for humans that could reduce sepsis deaths. Because there is currently no FDA-approved drug to treat sepsis, Ulloa says this finding is advantageous.

But Ulloa adds:

“I don’t even know whether in the future the best solution for sepsis will be electroacupuncture or some medicine that will mimic electroacupuncture.”

However, he says their findings have opened up new roads for both acupuncture and a drug for treating sepsis.


Tylenol During Pregnancy Linked to Higher Risk of ADHD

Pregnancy is already a fraught time for expectant moms, as more research shows how quickly the foods that women eat, the air they breathe, and the compounds to which they are exposed can traverse the placenta and affect their growing child. Now there’s another thing to add to the growing list of agents — including tobacco from cigarettes,mercury from fish, and alcohol — that may affect their babies’ development.


An international group of researchers led by Dr. Jorn Olsen at the University of Aarhus in Denmark found a strong correlation between acetaminophen (found in common pain killers such as Tylenol) use among pregnant women and the rate of attention deficit-hyperactivity disorder (ADHD) diagnoses and prescriptions for ADHD medications in their children. Overall, moms who used the pain reliever to treat things like headaches or to reduce fevers saw a 37% increased risk in their kids receiving an ADHD diagnosis and a 29% increased risk in the chances that their kids needed ADHD medications compared with moms who didn’t use the over-the-counter medication at all.

Even after the team accounted for factors that could explain the connection, such as why the mom needed to take the drug in the first place, the link remained strong, suggesting that there is something specific about the drug, and how it affects fetal development, that might explain the higher risk of behavioral issues.

The findings are especially troubling since more than half of the 64,322 women in the study reported using acetaminophen in the three months prior to the survey. The participants included mothers and singleton children born in Denmark between 1996 and 2002 and registered in the Danish National Birth Cohort, so it included a diverse group of mothers from different social and environmental backgrounds. The study also evaluated hyperactivity on three different levels — from symptom reports by mothers or caregivers, hospital diagnoses, and prescriptions to treat ADHD. Higher acetaminophen use among mothers was linked to higher rates of all three outcomes in their children.

“[The results] are worrisome because more than 50% of the women took acetaminophen; it’s an over-the-counter drug and they can freely buy, and use it at their discretion,” says Dr. Beate Ritz, one of the co-authors and chair of the department of epidemiology at the Fielding School of Public Health, University of California Los Angeles. “It’s considered relatively safe, and maybe it’s not.”

Previous studies have raised concerns about acetaminophen; both animal and human work showed that the drug can interfere with hormone systems, so prenatal exposure may adversely affect development of the brain. Some studies showed the drug hampers the ability of the testes to descend during development as well. “Pregnancy is a very special period,” says Ritz. “Acetaminophen may not harm adults in any other way, but fetal development is special.”

The latest investigations from the neuroscientists studying developmental and behavioral disorders like autism and ADHD suggest that problems in the connection between different brain regions may contribute to the symptoms of these conditions, and hormone disruptions in utero, triggered by acetaminophen, may unbalance the brain enough to make certain children more vulnerable to autism or hyperactivity later in life.

The results are likely to launch waves of questions about how safe the drug is for pregnant women to take. Kate Langley, a lecturer in the school of psychology at Cardiff University who wrote an accompanying editorial for the study, cautions that the findings only suggest an association, and do not establish that acetaminophen causes ADHD. “This is an interesting research paper, but it is way too early for it to inform our clinical practice at the moment,” she says.

Some women have a medical need to take acetaminophen, and they should continue to talk to their doctors about this latest risk. But for those who turn to the over the counter remedy for less medically urgent needs, such as relieving a headache or the pain of sore muscles, they should have a different kind of discussion with their doctors about the possible risks that the drug poses for their unborn child.

Ritz says more studies are needed using different sets of data to confirm and replicate what she and her colleagues found. But she appreciates how difficult it might be for expectant moms, or women who plan on having children soon, to wait for those studies to be completed. “As a scientist, I never want to be alarmist and use one study [to make clinical decisions],” she says. “But as a woman, when I see something like that, I would be worried, and wouldn’t take Tylenol during pregnancy any more.”

She says that women who need to take a pain reliever or need to control their fever should consider other alternatives, such as getting more rest or even gritting through the episode if they are especially worried about what their developing child might be exposed to. If more studies verify the potential harms on developing brains, it might also fall to regulatory agencies like the Food and Drug Administration to rethink the label of acetaminophen and warn users to avoid the medication during pregnancy.

Read more: Tylenol Tied to ADHD: Exposure In Utero Can Raise Risk of Hyperactivity |

A paper diagnostic for cancer: Low-cost urine test amplifies signals from growing tumors to detect disease

Cancer rates in developing nations have climbed sharply in recent years, and now account for 70 percent of cancer mortality worldwide. Early detection has been proven to improve outcomes, but screening approaches such as mammograms and colonoscopy, used in the developed world, are too costly to be implemented in settings with little medical infrastructure.


To address this gap, MIT engineers have developed a simple, cheap, paper test that could improve diagnosis rates and help people get treated earlier. The diagnostic, which works much like a pregnancy test, could reveal within minutes, based on a urine sample, whether a person has cancer. This approach has helped detect infectious diseases, and the new technology allows noncommunicable diseases to be detected using the same strategy.

The technology, developed by MIT professor and Howard Hughes Medical Institute investigator Sangeeta Bhatia, relies on nanoparticles that interact with tumor proteins called proteases, each of which can trigger release of hundreds of biomarkers that are then easily detectable in a patient’s urine.

“When we invented this new class of synthetic biomarker, we used a highly specialized instrument to do the analysis,” says Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science. “For the developing world, we thought it would be exciting to adapt it instead to a paper test that could be performed on unprocessed samples in a rural setting, without the need for any specialized equipment. The simple readout could even be transmitted to a remote caregiver by a picture on a mobile phone.”

Bhatia, who is also a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science, is the senior author of a paper describing the particles in the Proceedings of the National Academy of Sciences the week of Feb. 24. The paper’s lead authors are graduate student Andrew Warren, postdoc Gabriel Kwong, and former postdoc David Wood.

Amplifying cancer signals

In 2012, Bhatia and colleagues introduced the concept of a synthetic biomarker technology to amplify signals from tumor proteins that would be hard to detect on their own. These proteins, known as matrix metalloproteinases (MMPs), help cancer cells escape their original locations by cutting through proteins of the extracellular matrix, which normally holds cells in place.

The MIT nanoparticles are coated with peptides (short protein fragments) targeted by different MMPs. These particles congregate at tumor sites, where MMPs cleave hundreds of peptides, which accumulate in the kidneys and are excreted in the urine.

In the original version of the technology, these peptides were detected using an instrument called a mass spectrometer, which analyzes the molecular makeup of a sample. However, these instruments are not readily available in the developing world, so the researchers adapted the particles so they could be analyzed on paper, using an approach known as a lateral flow assay — the same technology used in pregnancy tests.

To create the test strips, the researchers first coated nitrocellulose paper with antibodies that can capture the peptides. Once the peptides are captured, they flow along the strip and are exposed to several invisible test lines made of other antibodies specific to different tags attached to the peptides. If one of these lines becomes visible, it means the target peptide is present in the sample. The technology can also easily be modified to detect multiple types of peptides released by different types or stages of disease.

“This is a clever and inspired technology to develop new exogenous compounds that can detect clinical conditions with aberrantly high protease concentrations,” says Samuel Sia, an associate professor of biological engineering at Columbia University who was not involved in the research. “Extending this technology to detection by strip tests is a big leap forward in bringing its use to outpatient clinics and decentralized health settings.”

In tests in mice, the researchers were able to accurately identify colon tumors, as well as blood clots. Bhatia says these tests represent the first step toward a diagnostic device that could someday be useful in human patients.

“This is a new idea — to create an excreted biomarker instead of relying on what the body gives you,” she says. “To prove this approach is really going to be a useful diagnostic, the next step is to test it in patient populations.”

Developing diagnostics

To help make that happen, the research team recently won a grant from MIT’s Deshpande Center for Technological Innovation to develop a business plan for a startup that could work on commercializing the technology and performing clinical trials.

Bhatia says the technology would likely first be applied to high-risk populations, such as people who have had cancer previously, or had a family member with the disease. Eventually, she would like to see it used for early detection throughout developing nations.

Such technology might also prove useful in the United States, and other countries where more advanced diagnostics are available, as a simple and inexpensive alternative to imaging. “I think it would be great to bring it back to this setting, where point-of-care, image-free cancer detection, whether it’s in your home or in a pharmacy clinic, could really be transformative,” Bhatia says.

With the current version of the technology, patients would first receive an injection of the nanoparticles, then urinate onto the paper test strip. To make the process more convenient, the researchers are now working on a nanoparticle formulation that could be implanted under the skin for longer-term monitoring.

The team is also working to identify signatures of MMPs that could be exploited as biomarkers for other types of cancer, as well as for tumors that have metastasized.

The research was funded by a National Science Foundation Graduate Research Fellowship, a Mazumdar-Shaw International Oncology Fellowship, the Ruth L. Kirschstein National Research Service Award from the National Institutes of Health, the Burroughs Wellcome Fund, the National Cancer Institute, and the Howard Hughes Medical Institute.

Story Source:

The above story is based on materials provided by Massachusetts Institute of Technology. The original article was written by Anne Trafton. [via Science Daily]

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Psychologist shows why talking to kids really matters

Fifty years of research has revealed the sad truth that the children of lower-income, less-educated parents typically enter school with poorer language skills than their more privileged counterparts. By some measures, 5-year-old children of lower socioeconomic status (SES) score two years behind on standardized language development tests by the time they enter school.

In recent years, Anne Fernald, a psychology professor at Stanford University, has conducted experiments revealing that the language gap between rich and poor children emerges during infancy. Her work has shown that significant differences in both vocabulary and real-time language processing efficiency were already evident at age 18 months in English-learning infants from higher- and lower-SES families. By age 24 months, there was a six-month gap between SES groups in processing skills critical to language development.


Fernald’s work has also identified one likely cause for this gap. Using special technology to make all-day recordings of low-SES Spanish-learning children in their home

environments, Fernald and her colleagues found striking variability in how much parents talked to their children. Infants who heard more child-directed speech d


greater efficiency in language processing and learned new words more quickly. The results indicate that exposure to child-directed speech — as opposed to overheard speech — sharpens infants’ language processing skills, with cascading benefits for vocabulary learning.

Fernald and colleagues are now running a parent-education intervention study with low-income Spanish-speaking mothers in East San Jose, California, funded by the W. K. Kellogg Foundation. This new program, called ¡Habla conmigo! (Talk with Me!), teaches Latina mothers how they can support their infants’ early brain development and helps them learn new strategies for engaging verbally with their children. Although they only have data from 32 families so far, the preliminary results are promising. Mothers in the ¡Habla conmigo! program are communicating more and using higher quality language with their 18-month-olds compared to mothers in a control group.

“What’s most exciting,” said Fernald, “is that by 24 months the children of more engaged moms are developing bigger vocabularies and processing spoken language more efficiently. Our goal is to help parents understand that by starting in infancy, they can play a role in changing their children’s life trajectories.”

[Source: Science Daily]

Human lungs successfully grown in a lab for the first time

Scientists at the University of Texas Medical Branch in Galveston have succeeded in growing human lungs in the laboratory, using components from the lungs of deceased children.

Stem cell specialists have been working on growing lung tissue for some years, but the lung is a complex organ, which presents more problems than regenerating other organ tissue, such as human skin.

The University of Texas Medical Branch (UTMB) first announced their solution for growing lungs in 2010.

“In terms of different cell types, the lung is probably the most complex of all organs – the cells near the entrance are very different from those deep in the lung,” UTMB researcher Dr. Joaquin Cortiella said at that time.

“People ask us why we’re doing the lung, because it’s so hard. But the potential is so great, and the technology is here. It’s going to take time, but I think we’re going to create a system that works.”

“If we can make a good lung for people, we can also make a good model for injury,” researcher Dr. Joan Nichols suggested, adding that:

“We can create a fibrotic lung, or an emphysematous lung, and evaluate what’s happening with those, what the cells are doing, how well stem cell or other therapy works. We can see what happens in pneumonia, or what happens when you’ve got a hemorrhagic fever, or tuberculosis, or hantavirus – all the agents that target the lung and cause damage in the lung.”

The 2010 research involved destroying the cells of rat lungs by repeatedly freezing and thawing and then “reseeding” the lungs with embryonic stem cells from mice.

Following that work up with similar but more large-scale experiments on pig lungs, the researchers now applied the same regenerative engineering principles to human lungs.

Human lungs grown in a ‘fish tank’ using cells from deceased children

Taking lungs from two children who had died from trauma (most likely a car accident), the researchers stripped one of the lungs down to a bare “skeleton” of just collagen and elastin – the main proteins in connective tissue.

Using this stripped-down lung as a “scaffold,” they then harvested cells from the other lung, which were applied to the scaffolding.

This lung structure was then placed in a chamber filled with a nutritious liquid, which Nichols describes as “resembling Kool-Aid.”

After 4 weeks of immersion, the team extracted a complete human lung from the liquid – “just pinker, softer and less dense.” The team then successfully replicated the process using a second set of lungs.

It is UTMB’s Dr. Michael Riddle who is credited with accelerating the procedure for growing the lungs, and he did so by improvising new equipment out of the most everyday of home furniture.

“He’s the one who went home and actually built using – I’m not kidding – a fish tank that he went and bought from a pet store,” Dr. Nichols says.

Can lab-grown lungs be used in transplants?

Lung transplants are often the only treatment for incurable lung disorders such as cystic fibrosis and chronic obstructive pulmonary disease (COPD). But successful lung transplants are rare, as finding matching donors is very difficult – many patients die while on a waiting list for transplants.

UTMB’s work represents a landmark in regenerative engineering, but the reality of lab-engineered lungs being used in transplants could be at least 12 years away, Nichols says. The next phase of the research will be to test lab-grown lungs in pigs.

Although the science fiction-type nature of the research sounds incredible, UTMB were reluctant to announce their results. Indeed, the team grew the lungs a year ago, but the story has only just been picked up by the media.


“It’s taken us a year to prove to ourselves that we actually did a good job with it. You don’t run out immediately and tell the world you have something wonderful until you’ve proved it to ourselves that we really did something amazing,” Dr. Nichols says.

[Source: Medical News Today]