Thalamus key to holding thoughts in the mind

Long assumed to be a mere “relay”, an often-overlooked egg-like structure in the middle of the brain also turns out to play a pivotal role in tuning-up thinking circuity. A trio of studies in mice funded by the US National Institutes of Health are revealing that the thalamus sustains the ability to distinguish categories and hold thoughts in mind.

By manipulating activity of thalamus neurons, scientists were able to control an animal’s ability to remember how to find a reward. In the future, the thalamus might even become a target for interventions to reduce cognitive deficits in psychiatric disorders such as schizophrenia, researchers say.

“If the brain works like an orchestra, our results suggest the thalamus may be its conductor,” explained Michael Halassa, M.D., Ph.D., of New York University (NYU) Langone Medical Center, a BRAINS Award grantee of the NIH’s National Institute of Mental Health (NIMH), and also a grantee of the National Institute of Neurological Disorders and Stroke (NINDS). “It helps ensembles play in-sync by boosting their functional connectivity.”

Three independent teams of investigators led by Halassa, Joshua Gordon, M.D., Ph.D., formerly of Columbia University, New York City, now NIMH director, in collaboration with Christoph Kellendonk, Ph.D. of Columbia, and Karel Svoboda, PhD, at Howard Hughes Medical Institute Janelia Research Campus, Ashburn, Virginia, in collaboration with Charles Gerfen, Ph.D., of the NIMH Intramural Research Program, report on the newfound role for the thalamus online May 3, 2017 in the journals Nature and Nature Neuroscience.

The prevailing notion of the thalamus as a relay was based on its connections with parts of the brain that process inputs from the senses. But the thalamus has many connections with other parts of the brain that have yet to be explored, say the researchers.

All three groups investigated a circuit that connects the mid/upper (mediodorsal) thalamus with the prefrontal cortex (PFC), the brain’s thinking and decision making center. Brain imaging studies have detected decreased connectivity in this circuit in patients with schizophrenia, who often experience working memory problems.

Halassa and colleagues found that neurons in the thalamus and PFC appear to talk back and forth with each other. They monitored neural activity in mice performing a task that required them to hold in mind information about categories, so that they could act on cues indicating which of two doors hid a milk reward.

Optogenetically suppressing neuronal activity in the thalamus blocked the mice’s ability to choose the correct door, while optogenetically stimulating thalamus neural activity improved the animals’ performance on the working memory task. This confirmed a previously known role for the structure, extending it to the specialized tasks Halassa and colleagues used and demonstrating for the first time a specific role in the maintenance of information in working memory.

What kind of information was the thalamus helping to maintain? The researchers found sets of neurons in the PFC that held in memory the specific category of information required in order to choose the correct door. They determined that the thalamus did not (at least in this case) relay such specific category information, but instead broadly provided amplification that was crucial in sustaining memory of the category in the PFC. It accomplished this by boosting the synchronous activity, or functional connectivity, of these sets of PFC neurons.

“Our study may have uncovered the key circuit elements underlying how the brain represents categories,” suggested Halassa.

Gordon and colleagues saw similar results when they tested how the same circuit controlled a mouse’s ability to find milk in a maze. The animals had to remember whether they had turned left or right to get their reward prior to a brief delay – and do the opposite. Also using optogenetics, the study teased apart differing roles for subgroups of PFC neurons and interactions with the brain’s memory hub, the hippocampus.

Thalamus inputs to the PFC sustained the maintenance of working memory by stabilizing activity there during the delay. “Top-down” signals from the PFC back to the thalamus supported memory retrieval and taking action. Consistent with previous findings, inputs from the hippocampus, were required to encode in PFC neurons the location of the reward – analogous to the correct door in the Halassa experiment.

“Strikingly, we found two separate populations of neurons in the PFC. One encoded for spatial location and required hippocampal input; the other was active during memory maintenance and required thalamic input,” noted Gordon. “Our findings should have translational relevance, particularly to schizophrenia. Further study of how this circuit might go awry and cause working memory deficits holds promise for improved diagnosis and more targeted therapeutic approaches.”

In their study, the Janelia team and Gerfen similarly showed that the thalamus plays a crucial role in sustaining short-term memory, by cooperating with the cortex through bi-directional interactions. Mice needed to remember where to move after a delay of seconds, to gather a reward. In this case, the thalamus was found to be in conversation with a part of the motor cortex during planning of those movements. Neuronal electrical monitoring revealed activity in both structures, indicating that they together sustain information held inthe cortex that predicted in which direction the animal would subsequently move. Optogenetic probing revealed that the conversation was bidirectional, with cortex activity dependent on thalamus and vice versa.

“Our results show that cortex circuits alone can’t sustain the neural activity required to prepare for movement,” explained Gerfen. “It also requires reciprocal participation across multiple brain areas, including the thalamus as a critical hub in the circuit.” n

Chikungunya vaccine trial begins

A clinical trial of an experimental vaccine to prevent infection with chikungunya virus is now enrolling healthy adult volunteers at three sites in the United States. The Phase 1/2 trial, which is sponsored by the US National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, is being conducted at several NIAID-funded Vaccine and Treatment Evaluation Units. The candidate vaccine, MV-CHIKV, was developed by Themis Bioscience of Vienna, Austria.

Although chikungunya is rarely fatal, the mosquito-transmitted virus causes an intense inflammatory reaction resulting in severe joint pain, fever, rash and muscle pain. While most symptoms usually resolve in days, the joint inflammation can linger.

“Chikungunya virus can cause debilitating joint pain that can last for months or even longer,” said NIAID Director Anthony S. Fauci, M.D. “A vaccine to prevent infection with this virus would be of considerable benefit to people living in the more than 60 countries where chikungunya transmission has occurred, as well as travelers to those countries.”

Chikungunya virus has been endemic in East Africa since at least the 1950s, when it was first discovered. There it circulates among monkeys and, occasionally, humans. The virus likely arrived in the Caribbean in late 2013, and as of March 2017, may have infected more than two million people in the Americas, according to the Pan American Health Organization (PAHO).

A 2014 Phase 1 trial of the MV-CHIKV vaccine conducted in Austria by Themis Bioscience showed that the experimental vaccine was safe and induced an immune response. The candidate vaccine is a measles vaccine virus modified to produce chikungunya virus proteins. Once inside a human cell, the vaccine induces the production of both measles and chikungunya proteins. The immune system then develops antibodies against those proteins, which may protect the vaccinated person from future infection by chikungunya virus.

Led by principal investigator Patricia Winokur, M.D., of the University of Iowa Carver College of Medicine, the new vaccine study will enrol 180 healthy adults ages 18 to 45 at three sites: the University of Iowa in Iowa City; Baylor College of Medicine in Houston; and Emory University in Atlanta. Participants will receive two injections of either low-dose or highdose experimental vaccine or placebo. Neither the participants nor the investigators will know whether a volunteer is receiving placebo or investigational vaccine. The volunteers will be assigned at random into different groups that receive the two injections at different intervals (29, 85, or 169 days after the initial injection) in order to help the researchers determine which schedule is most effective.

Clinic staff will follow up with study participants by phone and during clinic visits over the course of 8 to 13 months to monitor for any adverse reactions or safety issues. The participants will provide blood samples to be analysed for evidence of antibody production, which would indicate that the vaccine is prompting an immune response.

Themis Bioscience is currently conducting a Phase 2 trial in Europe with the same vaccine candidate. Other chikungunya vaccine candidates are also under investigation in different trials, including one that uses virus-like particles (VLPs) to induce an immune response in recipients. NIAID sponsored the Phase 1 trial of the VLP vaccine candidate; a Phase 2 trial began in 2015.

Glutamine suppresses herpes in mice

Glutamine supplements can suppress reactivation of herpes simplex virus (HSV) in mice and guinea pigs, according to findings recently published in the Journal of Clinical Investigation. The research was conducted by scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and at the US Food and Drug Administration.

There is no cure for infection with HSV-1 and HSV2, viruses that can cause recurrent outbreaks of cold sores and genital sores in humans. Although antiviral medications can help shorten outbreaks, the virus persists in the body and can reactivate, which underscores the need for new treatment approaches. Prior research demonstrated the importance of HSVspecific T cells for controlling recurrent HSV outbreaks, and that activated T cells require increased metabolism of glutamine (an amino acid produced by the body and found in food). Therefore, the authors speculated that glutamine supplementation might increase T-cell function and improve infection control.

To test this hypothesis, scientists infected mice with HSV-1 and guinea pigs with HSV-2 and randomly assigned the animals to different treatment groups. Two weeks after infection, some animals received an oral glutamine supplement and others did not. Results showed that mice that received glutamine were less likely to have HSV-1 reactivation than those that did not, and similarly, guinea pigs that received glutamine were less likely to have recurrent outbreaks of HSV-2 than those that did not receive the supplement.

Evaluation of host cellular gene expression in mice treated with glutamine showed that several genes inducible by interferon gamma (IFN-y) had an increased response. IFN-y is produced by virus-specific T cells and can inhibit viral reactivation. Mice treated with glutamine also had high numbers of virus-specific T cells in infected nerve tissues. Together, the results suggest glutamine may reduce HSV reactivation by improving the T-cell response to infection. Clinical trials are needed to determine whether this novel treatment approach would effectively treat HSV in humans, according to the authors.

  • doi:10.1172/JCI88990 (2017).

Researchers connect blood brain vessel lesions to gut bacteria

A study in mice and humans suggests that bacteria in the gut can influence the structure of the brain’s blood vessels, and may be responsible for producing malformations that can lead to stroke or epilepsy. The research, published in Nature, adds to an emerging picture that connects intestinal microbes and disorders of the nervous system. The study was funded by the US National Institute of Neurological Disorders and Stroke (NINDS), a part of the National Institutes of Health.

Cerebral cavernous malformations (CCMs) are clusters of dilated, thinwalled blood vessels that can lead to seizures or stroke when blood leaks into the surrounding brain tissue. A team of scientists at the University of Pennsylvania investigated the mechanisms that cause CCM lesions to form in genetically engineered mice and discovered an unexpected link to bacteria in the gut. When bacteria were eliminated the number of lesions was greatly diminished.

“This study is exciting because it shows that changes within the body can affect the progression of a disorder caused by a genetic mutation,” said Jim I. Koenig, Ph.D., program director at NINDS.

The researchers were studying a wellestablished mouse model that forms a significant number of CCMs following the injection of a drug to induce gene deletion. However, when the animals were relocated to a new facility, the frequency of lesion formation decreased to almost zero. “It was a complete mystery. Suddenly, our normally reliable mouse model was no longer forming the lesions that we expected,” said Mark L. Kahn, M.D., professor of medicine at the University of Pennsylvania, and senior author of the study. “What’s interesting is that this variability in lesion formation is also seen in humans, where patients with the same genetic mutation often have dramatically different disease courses.”

While investigating the cause of this sudden variability, Alan Tang, a graduate student in Dr Kahn’s lab, noticed that the few mice that continued to form lesions had developed bacterial abscesses in their abdomens – infections that most likely arose due to the abdominal drug injections. The abscesses contained Gram-negative bacteria, and when similar bacterial infections were deliberately induced in the CCM model animals, about half of them developed significant CCMs.

“The mice that formed CCMs also had abscesses in their spleens, which meant that the bacteria had entered the bloodstream from the initial abscess site,” said Tang. “This suggested a connection between the spread of a specific type of bacteria through the bloodstream and the formation of these blood vascular lesions in the brain.”

The question remained as to how bacteria in the blood could influence blood vessel behaviour in the brain. Gram-negative bacteria produce molecules called lipopolysaccharides (LPS) that are potent activators of innate immune signalling. When the mice received injections of LPS alone, they formed numerous large CCMs, similar to those produced by bacterial infection. Conversely, when the LPS receptor, TLR4, was genetically removed from these mice they no longer formed CCM lesions. The researchers also found that, in humans, genetic mutations causing an increase in TLR4 expression were associated with a greater risk of forming CCMs.

“We knew that lesion formation could be driven by Gram-negative bacteria in the body through LPS signalling,” said Kahn. “Our next question was whether we could prevent lesions by changing the bacteria in the body.”

The researchers explored changes to the body’s bacteria (microbiome) in two ways. First, newborn CCM mice were raised in either normal housing or under germ-free conditions. Second, these mice were given a course of antibiotics to “reset” their microbiome. In both the germfree conditions and following the course of antibiotics, the number of lesions was significantly reduced, indicating that both the quantity and quality of the gut microbiome could affect CCM formation. Finally, a drug that specifically blocks TLR4 also produced a significant decrease in lesion formation. This drug has been tested in clinical trials for the treatment of sepsis, and these findings suggest a therapeutic potential for the drug in the treatment of CCMs, although considerable research remains to be done.

“These results are especially exciting because they show that we can take findings in the mouse and possibly apply them at the human patient population,” said Koenig. “The drug used to block TLR4 has already been tested in patients for other conditions, and it may show therapeutic potential in the treatment of CCMs, although considerable research still remains to be done.”

Kahn and his colleagues plan to continue to study the relationship between the microbiome and CCM formation, particularly as it relates to human disease.

Sleep loss can lead to weight gain

Sleep loss increases the risk of obesity through a combination of effects on energy metabolism. This research, presented at the European Congress of Endocrinology in Lisbon in May, highlights how disrupted sleep patterns, a common feature of modern living, can predispose to weight gain, by affecting people’s appetite and responses to food and exercise.

In the 24/7 culture of the modern world, an increasing number of people report routine reduced quality of sleep and several studies have correlated sleep deprivation with weight gain. The underlying cause of increased obesity risk from sleep disruption is unclear but may relate to changes in appetite, metabolism, motivation, physical activity or a combination of factors.

Dr Christian Benedict from Uppsala University, Sweden and his group have conducted a number of human studies to investigate how sleep loss may affect energy metabolism. These human studies have measured and imaged behavioural, physiological and biochemical responses to food following acute sleep deprivation. The behavioural data reveal that metabolically healthy, sleep-deprived human subjects prefer larger food portions, seek more calories, exhibit signs of increased food-related impulsivity, experience more pleasure from food, and expend less energy.

The group’s physiological studies indicate that sleep loss shifts the hormonal balance from hormones that promote fullness (satiety), such as GLP-1, to those that promote hunger, such as ghrelin. Sleep restriction also increased levels of endocannabinoids, which is known to have appetite-promoting effects. Further work from Dr Benedict’s team shows that acute sleep loss alters the balance of gut bacteria, which has been widely implicated as key for maintaining a healthy metabolism. The same study also found reduced sensitivity to insulin after sleep loss.

Dr Christian Benedict remarked: “Since perturbed sleep is such a common feature of modern life, these studies show it is no surprise that metabolic disorders, such as obesity are also on the rise.”

Although Dr Benedict’s work has shed light on how short periods of sleep loss can affect energy metabolism, longerterm studies are needed to validate these findings. The group are now investigating longer-term effects and also whether extending sleep in habitual short sleepers can restore these alterations in appetite and energy metabolism.

Dr Christian Benedict said: “My studies suggest that sleep loss favours weight gain in humans. It may also be concluded that improving sleep could be a promising lifestyle intervention to reduce the risk of future weight gain.”

  • doi:10.1530/endoabs.49.S28.1

UAEU research collaboration unlocks potential new medicine breakthrough

The process of making medicine from microalgae – and potentially developing new treatments for some of the world’s most serious diseases – could be boosted through a new discovery by an international research partnership that includes UAEU scientists.

A scientific research group affiliated to the university’s Chemical and Petroleum Engineering Department and the School of Biological Sciences at the University of Essex in the UK has devised a mechanism to extract proteins and pigments from microalgae, which can be used in the manufacture of medicine.

Microalgae proteins and pigments have been effectively extracted using an enzymatic technique. Aligning with an intensive global focus on extracting medicinal material from natural sources, the group’s research is now turning to testing the effectiveness of the proteins and substances extracted through their method in treating cancer and bacterial diseases, which paves the way for the manufacture of this innovative strand of medicine.

Professor Sulaiman Al Zuhair, of UAEU’s Chemical and Petroleum Engineering Department, explained that research funded by medicine companies around the world is currently looking to invent and produce new, non-chemical treatment options that reduce the risk of potentially harmful side-effects of the chemically synthesized conventional medicine. For the project he is involved in, he says, microalgae – a single-cell organism – were considered to present a potential opportunity for medical discovery.

“Specific types of microalgae are used in the manufacture of medicine, which is our main subject in this scientific research,” he said.

“We evaluated the effectiveness of enzymatic treatment resulting from implementing the extracted proteins and pigments from microalgae, and compared innovative and organic natural extraction technique with traditional treatments, such as ultrasound waves and high-pressured water.”

According to Professor Al Zuhair, enzymatic treatment has seen “many positive and successful results” from using the proteins extracted from the microalgae, which was not exposed to high temperatures. The ongoing research project, he says, is the latest step in a long relationship between UAEU scientists and studies of microalgae.

“These studies started in the Chemical and Petroleum Engineering Department in UAEU’s College of Engineering in 2010, for the purpose of producing biodiesel,” he said. “The research group succeeded in increasing the percentage of oil components from 12% to 70%.”

During deliberations and discussions in front of the research group from the School of Biological Sciences at the University of Essex, the different research parties agreed to consider and focus on other components present in the algae, in particular the proteins and colorful substances, for the purpose of using them in the manufacture of medicine.”



Date of upload: 19th Jul 2017

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