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Research provides insight into neurobiology of aggression and bullying

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Duke-NUS researchers have discovered that a growth factor protein, called brain-derived neurotrophic factor (BDNF), and its receptor, tropomyosin receptor kinase B (TrkB) affects social dominance in mice. The research has implications for understanding the neurobiology of aggression and bullying.

“Humans and rodents are social animals. Our every interaction follows rules according to a social hierarchy. Failure to navigate this hierarchy can be detrimental.” explained senior author A/Prof. Hyunsoo Shawn Je, from the Neuroscience and Behavioural Disorders Signature Research Programme at Duke-NUS Medical School. “Our paper may be the first to demonstrate that specific molecular signaling pathways in specialized nerve cells, in a particular location in the brain, are important for the balanced navigation of social hierarchies.”

Difficulties in navigating these hierarchies can lead to problems like aggression and bullying. “Given the heavy societal cost of bullying and aggression, understanding the biological causes is a step towards their effective prevention and treatment,” A/Prof. Je added.

Activity within the brain is mediated by circuits made up of excitatory neurons, which ramp up activity, and GABA-ergic interneurons, which inhibit and quiet the excitatory activity. Previous studies have shown that BDNF-TrkB signaling is important for the maturation of GABA-ergic interneurons and the development of nerve circuits in the brain. But researchers have not been able to pinpoint the behavioral consequences of disrupted BDNF-TrkB signaling.

A/Prof. Je’s team generated transgenic mice in which the TrkB receptor was removed specifically in the GABAergic interneurons in the area of the brain regulating emotional and social behavior, known as the corticolimbic system. The transgenic mice exhibited unusual aggressive behavior when housed together with normal mice. To understand the origin of this behavior, the team conducted behavioral tests. They found that the mice were not being aggressive to protect their territory. They were also not being aggressive because they were stronger; the transgenic mice were injured more than other mice during acts of aggression. Instead, their aggressive behavior was a result of increased fighting for status and dominance over other mice in the group.

The researchers found that due to the loss of BDNF-TrkB, GABA-ergic interneurons in these transgenic mice supplied weaker inhibition to surrounding excitatory cells, which became overactive. They proceeded to shut down excitatory neurons in a specific area of the transgenic mice brains, which re-established the “excitatory/inhibitory” balance and which “instantaneously reversed the abnormal social dominance”, says Duke-NUS post-doctoral research fellow Dr. Shawn Pang Hao Tan, who was the first author of the paper.

A significant amount of research has focused on the roles of family and peer networks on aggressive behavior. This study, together with other recently published findings, demonstrates that genetic and biological factors can play an unexpected role in social behaviors, said Je.

Reference: Tan, S., Xiao, Y., Yin, H., Chen, A., Soong, T. and Je, H. (2018). Postnatal TrkB ablation in corticolimbic interneurons induces social dominance in male mice. Proceedings of the National Academy of Sciences, p.201812083. DOI: 10.1073/pnas.1812083115

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Scientists grow functioning human neural networks in 3-D from stem cells

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A team of Tufts University-led researchers has developed three-dimensional (3-D) human tissue culture models for the central nervous system that mimic structural and functional features of the brain and demonstrate neural activity sustained over a period of many months. With the ability to populate a 3-D matrix of silk protein and collagen with cells from patients with Alzheimer’s disease, Parkinson’s disease, and other conditions, the tissue models allow for the exploration of cell interactions, disease progression and response to treatment. The development and characterization of the models are reported today in ACS Biomaterials Science & Engineering, a journal of the American Chemical Society.

The new 3-D brain tissue models overcome a key challenge of previous models -the availability of human source neurons. This is due to the fact that neurological tissues are rarely removed from healthy patients and are usually only available post-mortem from diseased patients. The 3-D tissue models are instead populated with human induced pluripotent stem cells (iPSCs) that can be derived from many sources, including patient skin. The iPSCs are generated by turning back the clock on cell development to their embryonic-like precursors. They can then be dialed forward again to any cell type, including neurons.

The 3-D brain tissue models were the result of a collaborative effort between engineering and the medical sciences and included researchers from Tufts University School of Engineering, Tufts University School of Medicine, the Sackler School of Graduate Biomedical Sciences at Tufts, and the Jackson Laboratory.

“We found the right conditions to get the iPSCs to differentiate into a number of different neural subtypes, as well as astrocytes that support the growing neural networks,” said David L. Kaplan, Ph.D., Stern Family Professor of Engineering, chair of the Department of Biomedical Engineering at Tufts’ School of Engineering and program faculty member at the Sackler School of Graduate Biomedical Sciences at Tufts. “The silk-collagen scaffolds provide the right environment to produce cells with the genetic signatures and electrical signaling found in native neuronal tissues.”

Compared to growing and culturing cells in two dimensions, the three-dimensional matrix yields a significantly more complete mix of cells found in neural tissue, with the appropriate morphology and expression of receptors and neurotransmitters, according to the paper.

Others have used iPSCs to create brain-like organoids, which are small dense spherical structures useful for understanding brain development and function, but can still make it difficult to tease out what individual cells are doing in real time. Also, cells in the center of the organoids may not receive enough oxygen or nutrients to function in a native state. The porous structure of the 3-D tissue cultures described in this study provides ample oxygenation, access for nutrients and measurement of cellular properties. A clear window in the center of each 3-D matrix enables researchers to visualize the growth, organization and behavior of individual cells.

“The growth of neural networks is sustained and very consistent in the 3-D tissue models, whether we use cells from healthy individuals or cells from patients with Alzheimer’s or Parkinson’s disease,” said William Cantley, Ph.D., 2018 graduate of the Cell, Molecular & Developmental Biology program at the Sackler School of Graduate Biomedical Sciences at Tufts and first author of the study, which was completed as part of his Ph.D. dissertation. “That gives us a reliable platform to study different disease conditions and the ability to observe what happens to the cells over the long term.”

The researchers are looking ahead to take greater advantage of the 3-D tissue models with advanced imaging techniques, and the addition of other cell types, such as microglia and endothelial cells, to create a more complete model of the brain environment and the complex interactions that are involved in signaling, learning and plasticity, and degeneration.

More information: William L. Cantley et al, Functional and Sustainable 3D Human Neural Network Models from Pluripotent Stem Cells, ACS Biomaterials Science & Engineering (2018). DOI: 10.1021/acsbiomaterials.8b00622

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RIKEN Researchers create a functional salivary gland organoid

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A research group led by scientists from Showa University and the RIKEN Center for Biosystems Dynamics Research in Japan have, for the first time, succeeded in growing three-dimensional salivary gland tissue that, when implanted into mice, produces saliva like normal glands.

When patients lose some organ function due to disease or injury, it would be ideal to regrow the lost organ. But this is difficult—organogenesis is a complex and tightly regulated process that involves special stem cells that are fated to become specific tissues. However, with the exception of some organs such as hair follicles, those precursor cells are only present during early development.

The alternative is to use embryonic stem cells or induced pluripotent stem (iPS) cells—which have the ability to transform into many types of cell to create what is called an organoid—a simplified three-dimensional tissue that resembles the structure of a real organ. Growing functional organoids in the laboratory would enable patients with failing organs to recover at least some of the functions that the original organs had.

For the present study, published in Nature Communications, the researchers, led by Professor Kenji Mishima of Showa University and Takashi Tsuji of RIKEN BDR, took on the challenge of recreating salivary gland tissue. Salivary glands are important for digesting starch and for facilitating swallowing, but can be damaged by an autoimmune condition known as Sjogren’s syndrome or by radiation therapy for cancer.

These glands develop from an early structure called the oral ectoderm, but the actual process is not fully understood. It is known that organ development takes place through a complex process of chemical signaling and changes in gene expression, so the scientists began to unravel what the important changes were. They identified two transcription factors—Sox9 and Foxc1-as being key to the differentiation of stem cells into salivary gland tissue, and also identified a pair of signaling chemicals—FGF7 and FGF10-which induced cells expressing those transcription factors to differentiate into salivary gland tissue.

They then took on the challenge of creating an organoid. First, they used a cocktail of chemicals that allowed the formation of the oral ectoderm. They used this cocktail to induce the embryonic stem cells to form the ectoderm, and then used viral vectors to get the cells to express both Sox9 and Foxc1. Adding the two chemicals to the mix induced the cells to form tissue that genetic analysis revealed was very similar to actual developing salivary glands in the embryo.

The final step was to see if the organoid would actually function in a real animal. They implanted the organoids into actual mice without saliva glands and tested them by feeding them citric acid. When the organoids were transplanted along with mesenchymal tissue—another embryonic tissue that is important as it forms the connecting tissue that allows the glands to attach to other tissues—the implanted tissues were found to be properly connected to the nerve tissue, and in response to the stimulation secreted a substance that was remarkably similar to real saliva.

According to Kenji Mishima of Showa University, whose lab conducted the mouse experiments, “It was incredibly exciting to see that the tissues we created actually functioned in a living animal. This is an important proof of concept that organoids are a valid alternative to actual organs.”

According to Takashi Tsuji of the RIKEN Center for Biosystems Dynamics Research, who has worked on a variety of tissues such as hair and skin, “We continue to work to develop functional tissues to replace the functions of various organs, and we hope that these experiments will soon find their way into the clinic and help patients suffering from a variety of disorders.”

More information: Junichi Tanaka et al, Generation of orthotopically functional salivary gland from embryonic stem cells, Nature Communications (2018). DOI: 10.1038/s41467-018-06469-7

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Study finds standard treatment for common STD doesn’t eliminate parasite in some women

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A new study led by an infectious disease epidemiologist at Tulane University School of Public Health and Tropical Medicine could change the way doctors treat a common sexually transmitted disease.

Professor Patricia Kissinger and a team of researchers found the recommended single dose of medication isn’t enough to eliminate trichomoniasis, the most common curable STD, which can cause serious birth complications and make people more susceptible to HIV. Results of the research are published in Lancet Infectious Diseases.

Globally, an estimated 143 million new cases of trichomoniasis among women occur each year and most do not have symptoms, yet the infection is causing unseen problems. The recommended treatment for more than three decades has been a single dose of the antibiotics metronidazole or tinidazole.

The researchers recruited more than 600 women for the randomized trial in New Orleans; Jackson, Mississippi; and Birmingham, Alabama. Half the women took a single dose of metronidazole and the other half received treatment over seven days.

Kissinger and her team found the women who received multiple doses of the treatment were half as likely to still have the infection after taking all the medication compared to women who only took a single dose.

“There about 3.7 million new cases of trichomoniasis each year in the United States,” Kissinger said. “That means a lot of women have not been getting inadequate treatment for many decades.”

Trichomoniasis can cause preterm delivery in pregnant women and babies born to infected mothers are more likely to have low birth weight. The parasite can also increase the risk of getting or spreading HIV.

Kissinger believes the CDC will change its treatment recommendations because of the results of this study.

“We need evidence-based interventions to improve health,” Kissinger says. “We can no longer do something because it’s what we’ve always done. I hope that this study will help to change the recommendations so that women can get the proper treatment for this common curable STD.”

More information: Lancet Infectious Diseases (2018). DOI: 10.1016/S1473-3099(18)30423-7

Provided by: Tulane University

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