Researchers from Gladstone Institute uncovered the therapeutic benefits of genetically improving interneurons with a voltage-gated sodium channel Nav1.1 and transplanting them into the brain of a mouse model of Alzheimer’s disease. This study is led by Jorge Palop, Ph.D., an assistant investigator at the Gladstone Institutes. The study findings are published in journal Neuron.
Inhibitory interneurons are essential for managing brain rhythms. They regulate the oscillatory rhythms and network synchrony that are required for cognitive functions. Network dysrhythmias in Alzheimer’s disease and multiple neuropsychiatric disorders are associated with hypofunction of Nav1.1, a voltage-gated sodium channel subunit predominantly expressed in interneurons in Alzheimer’s disease (AD).
Researchers found a way to re-engineer inhibitory interneurons genetically boosted by adding protein Nav1.1 to improve their function. They showed that these enhanced interneurons, when transplanted into the abnormal brain of Alzheimer mice, can properly control the activity of excitatory cells and restore brain rhythms.
The researchers then discovered that the interneurons with enhanced function were able to overcome the toxic disease environment and restore brain function. The findings could eventually lead to the development of new treatment options for patients with Alzheimer’s disease.
In addition to examining if the cell therapy could be translated from mice to humans, researchers are working on pharmaceutical drugs to enhance the function of inhibitory interneurons.
Citation: Martinez-Losa, Magdalena, Tara E. Tracy, Keran Ma, Laure Verret, Alexandra Clemente-Perez, Abdullah S. Khan, Inma Cobos, Kaitlyn Ho, Li Gan, Lennart Mucke, Manuel Alvarez-Dolado, and Jorge J. Palop. “Nav1.1-Overexpressing Interneuron Transplants Restore Brain Rhythms and Cognition in a Mouse Model of Alzheimer’s Disease.” Neuron, 2018. doi:10.1016/j.neuron.2018.02.029.
Research funding: National Institutes of Health, Alzheimer’s Association; S.D. Bechtel, Jr. Foundation.
Adapted from press release by Gladstone Institutes.
Research by University of Houston scientists discovered a possible link between nuclear receptor protein LXRβ (Liver X receptor Beta) and autism spectrum disorder. They found that nuclear receptor LXRβ deletion causes poor development of dentate gyrus, a part of brain’s hippocampus. The dentate gyrus, or DG, is responsible for emotion and memory and is known to be involved in autism spectrum disorders (ASD).
This study is led by Margaret Warner and Jan-Åke Gustafsson. The results are published in journal Proceedings of the National Academy of Sciences.”Our findings suggest early changes in dentate gyrus neurogenesis ultimately provide an aberrant template upon which to build the circuitry that is involved in normal social function,” said Warner.
Researchers conducted an animal study using LXRβ-deficient mice. Behavior analysis of these mice showed autistic-like behaviors, including social interaction deficits and repetitive behavior.”Knocking out LXRβ led to autistic behavior and reduced cognitive flexibility,” said Warner. “In this paper, we share our findings that that deletion of the LXRβ (Liver X receptor Beta) causes hypoplasia or underdevelopment in the dentate gyrus and autistic-like behaviors, including abnormal social interaction and repetitive behavior.”
Citation: Cai, Yulong, Xiaotong Tang, Xi Chen, Xin Li, Ying Wang, Xiaohang Bao, Lian Wang, Dayu Sun, Jinghui Zhao, Yan Xing, Margaret Warner, Haiwei Xu, Jan-Åke Gustafsson, and Xiaotang Fan. “Liver X receptor β regulates the development of the dentate gyrus and autistic-like behavior in the mouse.” Proceedings of the National Academy of Sciences, 2018, 201800184. doi:10.1073/pnas.1800184115.
Adapted from press release by the University of Houston.
Researchers have come closer towards advancing technology to create computer simulations of the brain networks using exascale-class supercomputers. Their findings are published in journal Frontiers in Neuroinformatics.
|Credit: Forschungszentrum Jülich|
The human brain is a complex network composed of approximately 100 billion neurons. With current computing power, it is impossible to simulate 100 percent working brain. Currently, researchers use simulating software called NEST to simulate the brain. NEST, a free, open-source simulation code in widespread use by the neuroscientific community and a core simulator of the European Human Brain Project.
“Since 2014, our software can simulate about one percent of the neurons in the human brain with all their connections,” says Markus Diesmann, Director at the Jülich Institute of Neuroscience and Medicine (INM-6). To achieve this impressive feat, the software requires the entire main memory of petascale supercomputers.
With NEST, the behavior of each neuron in the network is represented by a handful of mathematical equations. Future exascale computers, such as the post-K computer planned in Kobe and JUWELS in Jülich, will exceed the performance of today’s high-end supercomputers by 10- to 100-fold. For the first time, researchers will have the computer power available to simulate neuronal networks on the scale of the human brain.
While current simulation technology enabled researchers to begin studying large neuronal networks, it also represented a dead end on the way to exascale technology. Supercomputers are composed of about 100,000 small computers, called nodes, each equipped with many processors doing the actual calculations.
“Before a neuronal network simulation can take place, neurons and their connections need to be created virtually, which means that they need to be instantiated in the memory of the nodes. During the simulation, a neuron does not know on which of the nodes it has target neurons. Therefore, its short electric pulses need to be sent to all nodes. Each node then checks which of all these electric pulses are relevant for the virtual neurons that exist on this node,” explains Susanne Kunkel of KTH Royal Institute of Technology in Stockholm.
The current algorithm for network creation is efficient because all nodes construct their particular part of the network at the same time. However, sending all electric pulses to all nodes is not suitable for simulations on exascale systems.
“Checking the relevance of each electric pulse efficiently requires one Bit of information per processor for every neuron in the whole network. For a network of 1 billion neurons, a large part of the memory in each node is consumed by just this single Bit of information per neuron,” adds Markus Diesmann.
This is the main problem when simulating even larger networks: the amount of computer memory required per processor for the extra Bits per neuron increases with the size of the neuronal network. At the scale of the human brain, this would require the memory available to each processor to be 100 times larger than in today’s supercomputers. This, however, is unlikely to be the case in the next generation of supercomputers. The number of processors per compute node will increase, but the memory per processor and the number of compute nodes will rather stay the same.
The breakthrough published in Frontiers in Neuroinformatics is a new way of constructing the neuronal network in the supercomputer. Due to the algorithms, the memory required on each node no longer increases with network size. At the beginning of the simulation, the new technology allows the nodes to exchange information about who needs to send neuronal activity data to whom. Once this knowledge is available, the exchange of neuronal activity data between nodes can be organized such that a node only receives the information it requires. An additional Bit for each neuron in the network is no longer necessary.
While testing their new ideas, the scientists made an additional key insight, reports Susanne Kunkel: “When analyzing the new algorithms we realized that our novel technology would not only enable simulations on exascale systems, but it would also make simulations faster on presently available supercomputers.”
In fact, as the memory consumption is now under control, the speed of simulations becomes the main focus of further technological developments. For example, a large simulation of 0.52 billion neurons connected by 5.8 trillion synapses running on the supercomputer JUQUEEN in Jülich previously required 28.5 minutes to compute one second of biological time. With the improved data structures simulation, the time is reduced to 5.2 minutes.
“With the new technology we can exploit the increased parallelism of modern microprocessors a lot better than previously, which will become even more important in exascale computers,” remarks Jakob Jordan, lead author of the study, from Forschungszentrum Jülich.
“The combination of exascale hardware and appropriate software brings investigations of fundamental aspects of brain function, like plasticity and learning unfolding over minutes of biological time within our reach,” adds Markus Diesmann.
With one of the next releases of the simulation software NEST, the researchers will make their achievement freely available to the community as open source.
“We have been using NEST for simulating the complex dynamics of the basal ganglia circuits in health and Parkinson’s disease on the K computer. We are excited to hear the news about the new generation of NEST, which will allow us to run whole-brain-scale simulations on the post-K computer to clarify the neural mechanisms of motor control and mental functions,” says Kenji Doya of Okinawa Institute of Science and Technology (OIST).
“The study is a wonderful example of the international collaboration in the endeavor to construct exascale computers. It is important that we have applications ready that can use these precious machines from the first day they are available,” concludes Mitsuhisa Sato of the RIKEN Advanced Institute for Computer Science in Kobe.
Citation: Jordan, Jakob, Tammo Ippen, Moritz Helias, Itaru Kitayama, Mitsuhisa Sato, Jun Igarashi, Markus Diesmann, and Susanne Kunkel. “Extremely Scalable Spiking Neuronal Network Simulation Code: From Laptops to Exascale Computers.” Frontiers in Neuroinformatics 12 (2018). doi:10.3389/fninf.2018.00002.
Research funding: Helmholtz Portfolio Supercomputing and Modeling for the Human Brain (SMHB), Helmholtz young investigator group, EU 7th Framework Programme (Human Brain Project), EU Horizon 2020 research and innovation programme (Human Brain Project).
Adapted from press release by Frontiers.
Group of researchers from Germany and USA studied effects of influenza virus on brain cells. The study published in the Journal of Neuroscience finds that female mice infected with two different strains of the flu shows changes in structure and function of the hippocampus. These changes persist for one month after infection.
Influenza could present with neurological symptoms in some cases. So far research has not studied the long-term effect of the virus in the brain.
Researchers investigated three different influenza strains (H1N1, H3N2, H7N7). Two of these strains, H3N2 and H7N7, caused memory impairments that were associated with structural changes such as dendritic spine loss to neurons in the hippocampus. These changes persist up to 30 days following infection and fully recovered in 120 days.
Researchers feel that in the acute phase of influenza infection, this neuroinflammation in hippocampus alters the neuronal morphology and can cause cognitive deficits. The results also provide evidence that neuroinflammation induced by influenza virus infection can lead to longer-lasting alterations in neuronal connectivity with associated impairments in spatial memory formation.
Citation: Hosseini, Shirin, Esther Wilk, Kristin Michaelsen-Preusse, Ingo Gerhauser, Wolfgang Baumgärtner, Robert Geffers, Klaus Schughart, and Martin Korte. “Long-term neuroinflammation induced by influenza A virus infection and the impact on hippocampal neuron morphology and function.” The Journal of Neuroscience, 2018, 1740-17. doi:10.1523/jneurosci.1740-17.2018.
Research funding: Ministry of Science and Culture of Lower Saxony, Helmholtz-Association.
Adapted from press release by the Society for Neuroscience.
Research team from Daegu Gyeongbuk Institute Of Science And Technology (DGIST) has performed a high-throughput screening method to identify drug candidates that promote dopaminergic neuronal cell activation by inducing the expression of the parkin protein, the cell protection gene which can inhibit the death of dopaminergic neurons. The results of study are published in Scientific Reports.
Results of the study identified that cortisol induces the expression of the parkin protein and prevents dopaminergic neuronal death by eliminating the accumulation of cell death factors through ubiquitin proteasome system.
In addition, the team has demonstrated the mechanism by which cortisol induces the expression of the parkin protein and CREB (cAMP response element-binding protein) transcriptional regulator through the hormone receptor regulates the expression of the parkin protein through the cell and animal model experiments.
Citation: Ham, Sangwoo, Yun-Il Lee, Minkyung Jo, Hyojung Kim, Hojin Kang, Areum Jo, Gum Hwa Lee, Yun Jeong Mo, Sang Chul Park, Yun Song Lee, Joo-Ho Shin, and Yunjong Lee. “Hydrocortisone-induced parkin prevents dopaminergic cell death via CREB pathway in Parkinson’s disease model.” Scientific Reports 7, no. 1 (2017).
Adapted from press release by Daegu Gyeongbuk Institute Of Science And Technology.
A new test using peripheral vision reaction time could lead to earlier diagnosis and more effective treatment of mild traumatic brain injury, often referred to as a concussion, according to Peter J. Bergold, PhD, professor of physiology and pharmacology at SUNY Downstate Medical Center and corresponding author of a study published by the Journal of Neurotrauma.
While most patients with mild traumatic brain injury or concussion fully recover, a significant number do not, and earlier diagnosis could lead to better management of patients at risk for developing persistent symptoms, according to Dr. Bergold and his co-authors. Lingering symptoms may include loss of concentration and/or memory, confusion, anxiety, headaches, irritability, noise and light sensitivity, dizziness, and fatigue.
“Mild traumatic brain injury is currently diagnosed with subjective clinical assessments,” says Dr. Bergold. “The potential utility of the peripheral vision reaction test is clear because it is an objective, inexpensive, and rapid test that identifies mild traumatic brain injury patients who have a more severe underlying injury.”
Reference: Womack, Kyle B., Christopher Paliotta, Jeremy F. Strain, Johnson S. Ho, Yosef Skolnick, William W. Lytton, L. Christine Turtzo, Roderick Mccoll, Ramon Diaz-Arrastia, and Peter J. Bergold. “Measurement of Peripheral Vision Reaction Time Identifies White Matter Disruption in Patients with Mild Traumatic Brain Injury.” Journal of Neurotrauma, 2017. doi:10.1089/neu.2016.4670.
Research funding: United States Army Medical Research and Materiel Command, Center for Neuroscience and Regenerative Medicine.
Adapted from press release by SUNY Downstate Medical Center.
New clinical trial results provide evidence that high-dose immunosuppressive therapy followed by transplantation of a person’s own blood-forming stem cells can induce sustained remission of relapsing-remitting multiple sclerosis (MS).
Five years after receiving the treatment, called high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT), 69 percent of trial participants had survived without experiencing progression of disability, relapse of MS symptoms or new brain lesions. Notably, participants did not take any MS medications after receiving high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT). Other studies have indicated that currently available MS drugs have lower success rates.
The trial, called HALT-MS, was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and conducted by the NIAID-funded Immune Tolerance Network (ITN). The researchers published three-year results from the study in December 2014, and the final five-year results appear in Neurology, the medical journal of the American Academy of Neurology.
“These extended findings suggest that one-time treatment with high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT) may be substantially more effective than long-term treatment with the best available medications for people with a certain type of MS,” said NIAID Director Anthony S. Fauci, M.D. “These encouraging results support the development of a large, randomized trial to directly compare high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT) to the standard of care for this often-debilitating disease.”
In HALT-MS, researchers tested the safety, efficacy and durability of high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT) in 24 volunteers aged 26 to 52 years with relapsing-remitting multiple sclerosis (MS) who, despite taking clinically available medications, experienced active inflammation, evidenced by frequent severe relapses, and worsened neurological disability.
The experimental treatment aims to suppress active disease and prevent further disability by removing disease-causing cells and resetting the immune system. During the procedure, doctors collect a participant’s blood-forming stem cells, give the participant high-dose chemotherapy to deplete the immune system, and return the participant’s own stem cells to rebuild the immune system. The treatment carries some risks, and many participants experienced the expected side effects of high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT), such as infections. Three participants died during the study; none of the deaths were related to the study treatment.
Five years after high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT), most trial participants remained in remission, and their MS had stabilized. In addition, some participants showed improvements, such as recovery of mobility or other physical capabilities.
“Although further evaluation of the benefits and risks of high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT) is needed, these five-year results suggest the promise of this treatment for inducing long-term, sustained remissions of poor-prognosis relapsing-remitting MS,” said Richard Nash, M.D., of Colorado Blood Cancer Institute and Presbyterian-St. Luke’s Hospital. Dr. Nash served as principal investigator of the HALT-MS study.
“If these findings are confirmed in larger studies, high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT) may become a potential therapeutic option for patients with active relapsing-remitting multiple sclerosis (MS), particularly those who do not respond to existing therapies,” said Daniel Rotrosen, M.D., director of NIAID’s Division of Allergy, Immunology and Transplantation.
Citation: Nash, Richard A., George J. Hutton, Michael K. Racke, Uday Popat, Steven M. Devine, Linda M. Griffith, Paolo A. Muraro et al. “High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS): a 3-year interim report.” JAMA neurology 72, no. 2 (2015): 159-169.
Research funding: NIH/National Institute of Allergy and Infectious Diseases.
Adapted from press release by NIH/National Institute of Allergy and Infectious Diseases.
There are important, long-term gains from hastening the processes around surgical interventions against epilepsy, before the disease has had too much negative impact on brain functions and patients’ lives. These are some of the findings of a thesis for which more than 500 patients were studied and followed up.
“Around one third of those undergoing surgery today are children and the percentage is growing, which is encouraging. But the average time until operation for adults is still 20 years, and that’s a very long time. There’s a major lack of knowledge among the treating neurologists about which patients may benefit from epilepsy surgery,” says Anna Edelvik, researcher at Sahlgrenska Academy and Senior Physician on the Sahlgrenska University Hospital epilepsy team.
Around 60,000 people have epilepsy in Sweden, making it our most common chronic neurological disease. Around one out of three patients do not become seizure free from medication and it is primarily here that surgery comes in. If the epilepsy is focal, which implies that seizure onset is clearly delimited in the brain, surgery may be possible.
“We try to locate the origin of the seizures as precisely as possible, and determine the proximity to areas of vital functional importance. It’s important to be able to give good information to the patients about possible risks and benefits before making a decision to operate or not,” says Anna Edelvik.
Her research shows that 58 percent of those who underwent surgery were seizure-free after five to ten years compared with 17 percent in the group of those who were not operated. The longer the individuals had had epilepsy, the fewer were seizure-free on the long term.
The importance of acting faster is also apparent from the study concerning how many of those who underwent epilepsy surgery who were gainfully employed at long-term.
“The highest number of persons in full-time employment at long-term was found among those who worked full-time before surgery, but even if they dropped out of the labor market before surgery, about one third of the persons who were seizure-free had full-time employment after ten to 15 years. It’s important to identify the patients as early as possible before the epilepsy has had too large of an impact,” says Anna Edelvik.
In another study, when non-surgical patients rated their health-related quality of life, it was considerably lower than among comparable individuals without epilepsy. The group who underwent surgery scored higher and was more like the age- and gender-matched reference group, but still had lower ratings for social function and mental health.
“They want to have a job and a family like everyone else, but that doesn’t happen just by becoming seizure-free. Even if the whole lifestyle situation doesn’t change, many would in any case benefit from being examined or evaluated for epilepsy surgery earlier than today,” says Anna Edelvik.
Citation: Edelvik, Anna. “Long-term outcomes of epilepsy surgery-prospective studies regarding seizures, employment and quality of life.” (2016).University of Gothenburg, Sahlgrenska Academy Doctoral thesis.
Adapted from press release by University of Gothenburg.
Zika virus (ZIKV) interferes with the cellular machinery controlling cell division and alters the expression of hundreds of genes responsible for guiding the formation and development of brain cells, according to findings of research published in Scientific Reports.
|Zika virus structure. Credit: Wikipedia / David Goodwill|
The association between Zika virus (ZIKV) infection and microcephaly has been previously established. Nevertheless, the cellular changes caused by the virus and leading to microcephaly are largely unknown. “Elucidating the foundations of Zika virus infection is crucial in order to develop tools against it”, says Stevens Rehen, the principal investigator of the study and a researcher working at the D’ Or Institute for Research and Education (IDOR) and at the Institute of Biomedical Sciences at Federal University of Rio de Janeiro (UFRJ) in Brazil.
In a previous study published by the group in Science magazine, researchers observed that the pool of human neural stem cells infected by the Brazilian strain of Zika virus was rapidly and completely depleted if compared to non-infected cells. This finding led the group to further investigate how Zika virus disrupts the interactome map (or molecular fingerprinting) of infected cells – which is the entire set of cellular and molecular interactions in a given cell group. The analysis of the interactome of Zika-infected cells may reveal the cellular targets and pathways with which the virus interacts or which it modulates, offering valuable opportunities for drug design.
To this end, human neural cells were infected by a strain of Zika virus (ZIKV) obtained from a Brazilian patient. These cells were then made into neurospheres, which are organized 3D aggregates of neural cells resembling fetal brain tissue that recapitulate many of the normal early and crucial processes that the brain undergoes through development and thus are a great model for studying the human brain. Next, the group identified the molecular fingerprinting of infected and non-infected cells by checking the expression level and status of innumerous genes and proteins.
The analysis revealed that more than 500 proteins in infected neurospheres had their expression level or status (upregulated vs downregulated) altered, if compared to non-infected neurospheres. A number of these altered proteins are normally involved with tasks such as fixing DNA damage or assuring chromosomal stability. Also, proteins that are normally required for cell growth were silent in infected neurospheres, which may explain why Zika-infected cells die much sooner than their non-infected counterparts. Interestingly, genes driving cell specialization were also silent in infected neurospheres, precluding that specialized brain cells were generated. On the other hand, proteins associated with viral replication were over-abundant, most likely the result of a strategy adopted by the virus to promote its own replication in the host cell. A complete list of all human proteins that have been found altered in Zika-infected neurospheres is available in the study entitled “Zika virus disrupts molecular fingerprinting of human neurospheres”, published in Scientific Reports this week.
According to Patricia Garcez, Assistant Professor at the Federal University of Rio de Janeiro and the first author of the study: “these findings provide insights into the molecular mechanisms of Zika virus (ZIKV) infection over the course of brain development and may explain some of the consequences seen in the brain of newborns with microcephaly”.
Citation: Patricia P. Garcez, Juliana Minardi Nascimento, Janaina Mota de Vasconcelos, Rodrigo Madeiro da Costa, Rodrigo Delvecchio, Pablo Trindade, Erick Correia Loiola, Luiza M. Higa, Juliana S. Cassoli, Gabriela Vitória, Patricia C. Sequeira, Jaroslaw Sochacki, Renato S. Aguiar, Hellen Thais Fuzii, Ana M. Bispo de Filippis, João Lídio da Silva Gonçalves Vianez Júnior, Amilcar Tanuri, Daniel Martins-de-Souza & Stevens K. Rehen. “Zika virus disrupts molecular fingerprinting of human neurospheres.” Scientific Reports 7, Article number: 40780 (2017).
Research funding: Brazilian Development Bank, Funding Authority for Studies and Projects, National Council of Scientific and Technological Development, Foundation for Research Support – State of Rio de Janeiro, São Paulo Research Foundation.
Adapted from press release by D’ Or Institute for Research and Education (IDOR).