News Article | April 7, 2016
A tiny juvenile fish. That’s what’s at the center of a big effort to image the brain of a vertebrate organism like never before. Spencer Smith, Ph.D., assistant professor in the Department of Cell Biology and Physiology and the UNC Neuroscience Center at the UNC School of Medicine, is part of an international team that hopes to create a new imaging system to study individual neurons in high resolution throughout the entire brain of a freely moving vertebrate. This sort of technological feat has never been accomplished. “We will image neural activity in high resolution, enough to see individual neurons, as if we’re reading the zebrafish’s mind while it’s completely unrestrained and performing natural movements and behaviors,” Smith said. “There will be no surgery, nothing tethered to the animals.” Smith, who is also a member of the Carolina Institute for Developmental Disabilities, added, “This is basic science, for sure, but if we’re successful, we hope our work will allow us and other scientists to gain insights that will have broader applicability to human health down the road.” To bring this unique project to life, the team received a $900,000 grant from the Human Frontier Science Program (HSFP), an organization that funds basic scientific research through the financial support of 15 countries, including the United States. We all know about MRIs, PET scans, and CT scans. These important diagnostic tools can provide images that tell us a lot about human biology, disease, and to an extent what’s happening in the human brain. But they can’t be used to study what specific kinds of neurons are doing, what roles these neurons play in various neurological conditions, or even which neurons are important for typical behaviors and where the cells are located. For that, scientists need technology that can focus in on individual neurons, and it would be best if scientists could focus on individual neurons throughout the brain while the animals are freely moving about. That kind of microscope doesn’t exist. Smith and his colleagues – German scientist Benjamin Judkewitz, Ph.D., of Charité Berlin & Humboldt University, and Spain’s Ruben Portugues, Ph.D., at the Max Planck Institute of Neurobiology – are taking on this challenge. They’re building a new kind of microscope with a wide enough field of view to image nearly the entire brain of a juvenile zebrafish while the fish is living its life. That is, the researchers hope to create real-time high-resolution visualizations of individual neurons firing throughout the brain of the transparent fish while it’s hunting for prey, swimming back and forth, darting here and there. “That’s the high bar,” Smith said. “The low bar would be to track neuronal activity throughout most of the brain while the fish is stationary or moving slowly. Both are difficult challenges, but tracking the fish during fast motion will be quite a trick and will require the expertise of the entire team. That’s why this grant is a good fit for the HFSP, which funds high-risk, high-reward international and interdisciplinary projects that are, frankly, difficult to get funded otherwise.” Smith’s lab at UNC is building the optics – the microscope they hope is capable of capturing images of individual neurons firing throughout the juvenile zebrafish’s brain while it navigates its world. One fish is four millimeters long. Therefore, it can live in a small dish, swim freely, and hunt for even tinier critters. Still, optics large enough for this sort of experiment have never been made before, which is why Smith’s lab is custom-designing the optics and having the parts custom-made. He is also creating a new kind of scanning engine to rapidly image the moving fish. The other scientists are working on the fast-tracking system so that the microscope can capture high resolution images of individual neurons across the brain even while the fish moves quickly through three dimensions. Smith’s European colleagues will also conduct the actual experiments on the zebrafish. The grant is for three years. By the end, the scientists hope to have a new piece of technology that they and other scientists can use to gain insights into how vertebrates process visual information while moving to achieve a goal, such as hunting prey. Down the line, it’s conceivable that Smith and his colleagues could extend this kind of technology to other organisms and answer various questions about brain functions of other model animals, including other complex vertebrate organisms. This work builds upon Smith’s other projects – the creation of imaging systems that can image multiple brain areas of a mouse. The limitation of this innovation is that the mouse must be stationary. Therefore, there are a limited number of experiments related to visual processing that Smith and others can perform. “Scientists have developed computer models of neural activity related to visual processing and motor activity,” Smith said. “But if we can’t measure neural activity during an animal’s natural behavior, then we can’t completely validate those models.” He added, “This won’t happen soon, but we’re already thinking about optically monitoring individual neural activity throughout the brains of freely moving rodents without any instrumentation on their heads or tethers,” Smith said. “From a physics standpoint, there’s no reason why we couldn’t do that. If we can, then we could learn a lot about brain function related to behaviors and even neurological conditions. This zebrafish research is a big, complicated first step in that direction.”
News Article | January 7, 2016
Rapidly dividing cells rely on an enzyme called Dicer to help them repair the DNA damage that occurs as they make mistakes in copying their genetic material over and over for new cells. UNC Lineberger Comprehensive Cancer Center researchers have built on the discovery of Dicer’s role in fixing DNA damage to uncover a new potential strategy to kill rapidly dividing, cancerous cells in the brain. In the journal Cell Reports, researchers report that when they removed Dicer from preclinical models of medulloblastoma, a common type of brain cancer in children, they found high levels of DNA damage in the cancer cells, leading to the cells’ death. The tumor cells were smaller, and also more sensitive to chemotherapy. “This is the first time that the specific function of Dicer for DNA damage has been looked at in the context of the developing brain or even in brain tumors, despite that the fact that the protein has been extensively studied,” said Mohanish Deshmukh, Ph.D., a UNC Lineberger member and professor in the UNC School of Medicine Department of Cell Biology and Physiology and also the Neuroscience Center. “We have found that targeting Dicer could be an effective therapy to either prevent cancer development or to actually sensitize tumors to chemotherapy.” Scientists have understood for more than a decade that Dicer plays an important role in the cell for processing microRNAs, which regulate the expression of genes in cells. But Deshmukh said it was in 2012 that scientists discovered a direct role of Dicer in repairing DNA damage. And that function, he said, is of importance for cancer research. That’s because rapidly dividing cells -- such as cancer cells -- incur DNA damage as they divide. And chemotherapy and radiation treatments often work by damaging the cells’ DNA, leading to cell death. Removing a key enzyme that repairs DNA in cancerous cells could help prevent DNA repair. “We found that cancerous cells upregulate Dicer,” said Vijay Swahari, MBBS, MS, a postdoctoral fellow at the UNC Neuroscience Center and the first author of this study. “We think tumors upregulate Dicer because its function is to repair DNA.” In their study, Deshmukh and his team studied the effect of deleting Dicer in several types of rapidly dividing cells, including of preclinical brain cancer models. They deleted Dicer in the normal, rapidly dividing developing brain cells in the cerebellum of animal models, finding spontaneous DNA damage in the brain cells, leading to severe degeneration of the cerebellum. They also tested whether Dicer had a similar effect on rapidly dividing cells outside of the brain. Upon deleting Dicer from embryonic stem cells, the authors found a similar effect. To test whether they could exploit the role of Dicer to kill cancerous cells, Swahari and his collaborators also deleted Dicer in medulloblastoma models, and found that these cells also had high DNA damage levels and degeneration. The tumor load was lower, and the cells were more sensitive to chemotherapy. “We found that when you delete Dicer, these tumors are more sensitive to DNA damage,” Swahari said. “We also took the next step by injecting chemotherapy into models where Dicer was deleted, finding that not only are the tumors smaller, but the tumors are also more sensitive to chemotherapy.” Based on their findings, the researchers believe that Dicer could be investigated as a potential drug target for medulloblastoma and other types of brain cancer. “We are excited about these results because of the implication that Dicer inhibitors could be developed as a potential therapy for treating rapidly-dividing tumors like medulloblastoma,” Deshmukh said. The study was supported by grants from the National Institutes of Health.
News Article | October 28, 2016
MIAMI, FL--(Marketwired - October 28, 2016) - Dr. Sergio Gonzalez-Arias, chief of neurological surgery at Baptist Hospital and chair of the Department of Neuroscience at FIU's Herbert Wertheim College of Medicine, will join the College of Medicine's executive team as executive associate dean for clinical affairs. Gonzalez-Arias, who will begin his new position with the Herbert Wertheim College of Medicine in January 2017, will oversee all clinical functions at the College of Medicine, including the students' clinical experience; all strategic partnerships with hospitals and other clinical sites where students perform their clinical rotations; and development of Graduate Medical Education. "We have been fortunate to work with Dr. Gonzalez-Arias as a key member of our faculty since 2010. Now he brings to his new position a wealth of clinical experience that will add to the development of clinical programs to the College of Medicine," said Dr. John A. Rock, founding dean of the Herbert Wertheim College of Medicine and FIU senior vice president for health affairs. Wayne Brackin, executive vice president and chief operating officer for Baptist Health South Florida, said Gonzalez-Arias has made important contributions to the field of neuroscience. "Dr. Gonzalez-Arias is a well-respected neurosurgeon who has advanced his profession and expanded the comprehensive neuroscience offerings at Baptist Health," Brackin said. "As the founding medical director of Baptist Health Neuroscience Center he has developed and implemented surgical and technological advancements that have had a profound impact on our patients." Gonzalez-Arias is the founding and current medical director of Baptist Health Neuroscience Center. He has served as chief of Baptist Hospital's Department of Surgery and is a past president of the medical staff. He is a fellow of the American Association of Neurological Surgeons and the American College of Surgeons. He served as chair of the international committee of the Joint Council of State Neurosurgical Societies and is a past president of the Florida Neurological Society. "I am excited about this new opportunity at the FIU College of Medicine, which will allow me to continue building on its impressive growth, which I am honored to have been part of for several years," Gonzalez-Arias said. "In keeping with the best practice of a multidisciplinary approach to medicine, I look forward to collaborating with the university's hospital and community partners to research, innovate and continue making a significant positive impact on medical education and healthcare in our community." Dr. Gonzalez-Arias is a graduate of the University of Zaragoza (Spain) and completed his residencies at Rush-Presbyterian St. Luke's Medical Center and the University of Miami/Jackson Memorial Hospital. About Baptist Health South Florida: Baptist Health South Florida is the largest healthcare organization in the region, with seven hospitals (Baptist Hospital, Baptist Children's Hospital, Doctors Hospital, Homestead Hospital, Mariners Hospital, South Miami Hospital and West Kendall Baptist Hospital), nearly 50 outpatient and urgent care facilities, Baptist Health Medical Group, Baptist Health Quality Network and internationally renowned centers of excellence. The not-for-profit, faith-based Baptist Health has approximately 16,000 employees and 2,300 affiliated physicians. Baptist Health South Florida has been recognized as one of the 100 Best Companies to Work For in America and as one of the World's Most Ethical Companies. For more information, visit BaptistHealth.net and connect with us on Facebook at facebook.com/BaptistHealthSF and on Twitter and Instagram @BaptistHealthSF. About The FIU Herbert Wertheim College of Medicine: The Herbert Wertheim College of Medicine was approved in 2006 by the Florida Board of Governors and the Florida Legislature, and in February 2013 the medical degree program received full accreditation from the Liaison Committee for Medical Education. The College graduated its inaugural class on April 29, 2013. Among the innovative elements of the HWCOM is a program called Green Family Foundation NeighborhoodHELP™ that sends teams of medical students along with their counterparts in social work, nursing, and law into the community. The College of Medicine's mission is to lead the next generation of medical education and improve the quality of health care available to the South Florida community. For more information visit http://medicine.fiu.edu/ About FIU: Florida International University is classified by Carnegie as a "R1: Doctoral Universities - Highest Research Activity" and recognized as a Carnegie Community Engaged university. It is a public research university with colleges and schools that offers bachelor's, master's and doctoral programs in fields such as business engineering, computer science, international relations, architecture, law and medicine. As one of South Florida's anchor institutions, FIU contributes almost $9 billion each year to the local economy and is ranked second in Florida in Forbes Magazine's "America's Best Employers" list. FIU graduates are consistently among the highest paid college graduates in Florida and are among the leaders of public and private organizations throughout South Florida. FIU is Worlds Ahead in finding solutions to the most challenging problems of our time. FIU emphasizes research as a major component of its mission with multiple state-of-the-art research facilities including the Wall of Wind Research and Testing Facility, FIU's Medina Aquarius Program and the Advanced Materials Engineering Research Institute. FIU has awarded more than 220,000 degrees and enrolls more than 54,000 students in two campuses and centers including FIU Downtown on Brickell, FIU@I-75, the Miami Beach Urban Studios, and Tianjin, China. FIU also supports artistic and cultural engagement through its three museums: Patricia & Phillip Frost Art Museum, the Wolfsonian-FIU, and the Jewish Museum of Florida-FIU. FIU is a member of Conference USA and more than 400 student-athletes participating in 18 sports. For more information about FIU, visit http://www.fiu.edu/.
News Article | February 22, 2017
Published today in Nature, the discovery has major implications for the study of motivation, decision making, as well as addiction and other disorders CHAPEL HILL, NC - The prefrontal cortex, a large and recently evolved structure that wraps the front of the brain, has powerful "executive" control over behavior, particularly in humans. The details of how it exerts that control have been elusive, but UNC School of Medicine scientists, publishing today in Nature, have now uncovered some of those details, using sophisticated techniques for recording and controlling the activity of neurons in live mice. The UNC scientists, led by Garret Stuber, PhD, associate professor in UNC's departments of psychiatry and cell biology & physiology, examined two distinct populations of prefrontal neurons, each of which project to a different brain region outside the cortex. The researchers found that as mice learn to associate a particular sound with a rewarding sugary drink, one set of prefrontal neurons becomes more active and promotes what researchers call reward-seeking behavior - a sign of greater motivation. By contrast, other prefrontal neurons are silenced in response to the tone, and those neurons act like a brake on reward-seeking. "We've known that there are a lot of differences in how prefrontal neurons respond to stimuli, but nobody has really been able to map these differences onto the intrinsic wiring of the brain," said Stuber, senior author of the study and member of the UNC Neuroscience Center. Stuber and colleagues obtained their findings with the use of three sophisticated and relatively new neuroscience tools: deep-brain two-photon imaging, optogenetics, and genetic techniques for labeling neurons by their projection targets in the brain. The successful combination of these tools heralds their future common use in defining the pathways and functions of many other brain networks to help uncover the roots of both normal and abnormal behavior. The study, conducted by first authors and UNC postdoctoral fellows James Otis, PhD, and Vijay Namboodiri, PhD, focused on the dorsomedial (upper-middle) prefrontal cortex, or dmPFC. "This region is critical for reward processing, decision making, and cognitive flexibility among other things, but how distinct populations of neurons within dmPFC orchestrate such phenomena were unclear," Stuber said. Stuber and colleagues examined how the activity of dmPFC neurons changes during a Pavlovian reward-conditioning process. In this process, mice learn to associate an auditory tone with a taste of sugary liquid until the tone itself is enough to make the animals start licking around their mouths in anticipation. "This simple experiment models a learning phenomenon that occurs in lots of different brain regions," Stuber said. "It is critical for motivation and decision making, and of course it can go awry in drug and food addiction, depression, and other neuropsychiatric disorders." As the mice in the experiment learned to associate the tone with the sweet drink, the researchers found that a subset of the mouse dmPFC neurons became increasingly excited when the tone sounded, whereas another subset went increasingly silent. The researchers were able to observe this phenomenon by using a deep-brain version of two-photon imaging, a technique in which a microscope visualizes hundreds of brain cells simultaneously in mice that are awake and able to perform some ordinary behaviors. The dmPFC is known to output many of its chemical signals to two other brain regions, the nucleus accumbens (NAc) and the paraventricular nucleus of the thalamus (PVT), both of which are considered important for reward-directed behavior. Stuber's team found that the NAc-projecting neurons in the dmPFC were the ones that became increasingly excited by the tone, and the PVT-projecting neurons were the ones that became increasingly suppressed. The two sets of neurons turned out to be physically separate within the dmPFC only by a few hundred micrometers. The team then used optogenetic techniques to artificially drive the activities of these neurons. Optogenetics allows researchers to use beams of light to activate specific populations of neurons. Driving the NAc-projecting neurons caused the mice to anticipate their sweet reward more intensely, with more licks after the tone. By contrast, driving the PVT-projecting neurons muted that anticipatory, reward-seeking behavior. The findings represent a basic demonstration of how the dmPFC has evolved anatomically distinct neuronal populations that have functionally distinct control over behavior, Stuber said. And the discovery points to the existence of similar combinations of control mechanisms elsewhere in the brain. He and his colleagues are now following up with studies of dmPFC neurons that project to other brain regions. Other co-authors were UNC undergraduate students Ana M. Matan and Emily P. Mohorn, visiting graduate student from the university of Utrecht Elisa Voets, UNC MD/PhD student Elliot Robinson, Stuber lab manager Oksana Kosyk, and UNC postdoctoral researchers Jenna A. McHenry, PhD, Shanna L. Resendez, PhD, and Mark A. Rossi, PhD, all of the Stuber lab. Funding was provided by the National Institutes of Health, the Brain and Behavior Research Foundation, the Children's Tumor Foundation, and the Foundation of Hope.
News Article | November 3, 2016
The goal of finding a treatment for concussions may be one step closer due to a new study being launched by University of Miami researchers. As part of a $16 million research grant from Scythian Biosciences, researchers at the university's The Miami Project to Cure Paralysis and Miller School of Medicine will begin studying whether a simple pill could someday be a solution to the growing concussion epidemic. A multi-disciplinary team of researchers from neurology, neurological surgery and otolaryngology will embark on this five-year study to address the effects of combining CBD (a cannabinoid derivative of hemp), and an NMDA antagonist for the treatment of traumatic brain injury (TBI) and concussion. Researchers believe the combination could reduce post-injury brain cell inflammation, headache, pain and other symptoms associated with concussion. Traumatic brain injury is a major cause of death and disability in the United States, contributing to about 30 percent of all injury deaths and impacting approximately 2 million children and teenagers annually, according to the Centers for Disease Control and Prevention. There have been some 345,000 diagnosed cases among U.S. Armed Forces members since 2000, and professional and amateur football and hockey players, as well as other athletes, continue to be plagued at alarming rates. Most of these individuals face short-term effects such as headaches and dizziness, while others are at increased risk for longer-term chronic medical problems, including disorders of attention, memory, anxiety, depression and dementia. While the prevalence of TBI, which includes concussion, is on the rise, research and treatment options are still very much in the early stages. The partnership between the University of Miami and the Canada-based Scythian Biosciences aims to propel this research and potential treatment forward by using two classes of drugs in a combination that scientists believe will reduce brain inflammation and the immune response. Researchers hypothesize that this unique CBD and NMDA antagonist compound will impact the CB2 and NMDA cell receptors, reversing the effects of concussion through a reduction of immune response decreasing brain inflammation. "The acute and chronic effects of mild TBI and concussion are well documented, but poorly understood," said W. Dalton Dietrich, Ph.D., scientific director of The Miami Project and professor of neurological surgery at the Miller School. "We face a number of major obstacles, such as clinically relevant models that address the complex pathophysiology of circuit dysfunction and recovery mechanisms associated with TBI. The testing of novel compounds, including this approach using the cannabinoid/NMDA antagonist combination, are needed to treat cognitive and emotional consequences of single and repetitive brain injuries." This project will require close collaboration between the pre-clinical and clinical investigators, and will be completed in three phases. In years one and two of the study, researchers will begin pre-clinical studies evaluating several rodent models of TBI. In parallel, nine proposed outcome fields, which include cognitive, behavioral, psychosocial, sleep, pain, sensorimotor, cardiovascular, inflammatory biomarkers, as well as neuroimaging studies, will be reviewed and evaluated. During this time the research team will address any shortcomings in methodology. Once data comes back conclusive, they will enter year two and phase two of the study. Phase two will involve a small human pilot study, likely administering the compounds in pill form to a control group and two groups of TBI patients, acute and chronic. Researchers will use the nine outcome measures listed above to evaluate the drug's efficacy. Once completed, data will be analyzed and any safety concerns will be addressed. If deemed safe and effective, the third phase of the research will begin a fully-powered clinical trial over the next three years. With FDA oversight, data will reveal whether the compound is an effective therapeutic treatment for those suffering from different severities of TBI and concussion. "The implications for the study are extraordinary," said Michael Hoffer, M.D., professor of otolaryngology at the Miller School of Medicine. "To have such a large team of multidisciplinary neuroscience experts attaching themselves to research that could change the outcome of TBI and concussion care is the opportunity researchers have been looking for to curb the growing trend of concussion." The study will be led by Gillian Hotz, Ph.D., research professor of neurological surgery, director of the KIDZ Neuroscience Center at The Miami Project to Cure Paralysis and director of the concussion program at University of Miami Health System Sports Medicine. "Throughout the course of my career, my team and I have developed a national model. Our concussion protocol includes education and training for medical students, residents, fellows and certified athletic trainers in an effort to provide a solution to the growing concern of managing concussions in youth, high school, collegiate and professional sports athletes," said Hotz. "One thing has eluded us - a clinically proven medication to treat concussion. Whether or not this study leads to a pill that could treat concussion, this type of research will pave the way for UM and other researchers to better manage concussion. It's a privilege to help lead this journey." "Dr. Hotz is the ideal principal investigator for this important study because she has been at the forefront of TBI and concussion research, and has already developed a national model countywide concussion program along with a comprehensive assessment and treatment program," said Barth Green, M.D., chairman of The Miami Project and professor of neurological surgery. Scythian Biosciences said choosing to partner with the University of Miami Miller School of Medicine and fund the $16 million research was an easy decision because of UM's reputation as the nation's leading neuroscience center with expertise in TBI and concussion research. "Our collaboration with UM will allow us to access their extensive knowledge base in the fields of neuroscience, traumatic brain injury and concussion, and will allow for our pre-clinical and clinical studies to be carried out at their world-class facilities," said Jonathan Gilbert, CEO of Scythian Biosciences. "Our mission is to develop and implement the first accepted drug regimen for the treatment of concussions." The UM and Scythian research study is kicking off with pre-clinical work directed by Dietrich, Hoffer and Helen Bramlett, Ph.D., professor of neurological surgery. Translational and clinical research will be directed by Bonnie Levin, Ph.D., director of neuropsychology and professor of neurology, and a team of neuro-outcome experts. "This is our chance to explore a therapeutic pill for the treatment of concussion," said Hotz. "The scientific community and public know the risks associated with TBI, and because of the funding graciously provided by Scythian, we will soon know more about how the brain can respond to compounds that include cannabinoids designed to treat concussion. We can only hope that our hypotheses and trials lead us to the ending we all desire - a simple pill to treat concussion."
News Article | March 31, 2016
Scientists at the UNC School of Medicine have found a class of commonly used fungicides that produce gene expression changes similar to those in people with autism and neurodegenerative conditions, including Alzheimer’s disease and Huntington’s disease. The study, published in the journal Nature Communications, describes a new way to home in on chemicals that have the potential to affect brain functions. Mark Zylka, Ph.D., senior author of the study and associate professor of cell biology and physiology at UNC, and his team exposed mouse neurons to approximately 300 different chemicals. Then the researchers sequenced RNA from these neurons to find out which genes were misregulated when compared to untreated neurons. This work created hundreds of data sets of gene expression; genes give rise to products, including proteins or RNA. Zylka’s team then used computer programs to deduce which chemicals caused gene expression changes that were similar to each other. “Based on RNA sequencing, we describe six groups of chemicals,” Zylka said. “We found that chemicals within each group altered expression in a common manner. One of these groups of chemicals altered the levels of many of the same genes that are altered in the brains of people with autism or Alzheimer’s disease.” Chemicals in this group included the pesticides rotenone, pyridaben, and fenpyroximate, and a new class of fungicides that includes pyraclostrobin, trifloxystrobin, fenamidone, and famoxadone. Azoxystrobin, fluoxastrobin, and kresoxim-methyl are also in this fungicide class. “We cannot say that these chemicals cause these conditions in people,” Zylka cautioned. “Many additional studies will be needed to determine if any of these chemicals represent real risks to the human brain.” Zylka, a member of the UNC Neuroscience Center, and his group found that these chemicals reduced the expression of genes involved in synaptic transmission – the connections important for communication between neurons. If these genes are not expressed properly, then our brains cannot function normally. Also, these chemicals caused an elevated expression of genes associated with inflammation in the nervous system. This so-called neuroinflammation is commonly seen in autism and neurodegenerative conditions. The researchers also found that these chemicals stimulated the production of free radicals – particles that can damage the basic building blocks of cells and that have been implicated in a number of brain diseases. The chemicals also disrupted neuron microtubules. “Disrupting microtubules affects the function of synapses in mature neurons and can impair the movement of cells as the brain develops,” Zylka said. “We know that deficits in neuron migration can lead to neurodevelopmental abnormalities. We have not yet evaluated whether these chemicals impair brain development in animal models or people.” Jeannie T. Lee, M.D., Ph.D., professor of genetics at Harvard Medical School and Massachusetts General Hospital, who was not involved in this research, said, “This is a very important study that should serve as a wake-up call to regulatory agencies and the general medical community. The work is timely and has wide-ranging implications not only for diseases like autism, Parkinson's, and cancer, but also for the health of future generations. I suspect that a number of these chemicals will turn out to have effects on transgenerational inheritance.” Zylka’s group also analyzed information from the U.S. Geological Survey, which monitors countywide pesticide usage, as well as the Food and Drug Administration and the U.S. Department of Agriculture, which test foodstuffs yearly for pesticide residues. Of the chemicals Zylka’s team studied, only the usage of pyridaben has decreased since 2000. Rotenone use has remained the same since 2000. However, the use of all the fungicides in this group has increased dramatically over the past decade. Indeed, a study from the Environmental Protection Agency found that pyraclostrobin is found on foods at levels that could potentially affect human biology, and another study linked pyraclostrobin usage to honeybee colony collapse disorder. The pesticide rotenone was previously implicated in Parkinson’s disease through replicated animal experiments and through human epidemiological studies. A separate 2015 UNC study found that Parkinson’s disease is much more common in older adults with autism than in older adults without autism. Previous work has also shown that a single dose of the fungicide trifloxystrobin reduced motor activity for several hours in female rats and for days in male rats. Disrupted motor function is a common symptom of Parkinson’s disease and other neurological disorders. The related fungicide picoxystrobin impaired motor activity in rats at the lowest dose tested. Zylka added, “The real tough question is: if you eat fruits, vegetables or cereals that contain these chemicals, do they get into your blood stream and at what concentration? That information doesn’t exist.” Also, given their presence on a variety of foodstuffs, might long term exposure to these chemicals – even at low doses – have a cumulative effect on the brain? Zylka noted that conventionally grown leafy green vegetables such as lettuce, spinach, and kale have the highest levels of these fungicides. But due to each chemical’s effectiveness at reducing fungal blights and rust, crop yields have increased and farmers are expanding their use of these chemicals to include many additional types of food crops. Zylka’s team hopes their research will encourage other scientists and regulatory agencies to take a closer look at these fungicides and follow up with epidemiological studies. “Virtually nothing is known about how these chemicals impact the developing or adult brain,” Zylka said. “Yet these chemicals are being used at increasing levels on many of the foods we eat.”
News Article | February 27, 2017
Prolonged epileptic seizures may cause serious problems that will continue for the rest of a patient's life. As a result of a seizure, neural connections of the brain may be rewired in an incorrect way. This may result in seizures that are difficult to control with medication. Mechanisms underlying this phenomenon are not entirely known, which makes current therapies ineffective in some patients. A study conducted with a rat epilepsy model at the Neuroscience Center of the University of Helsinki showed that a change in the function of gamma-aminobutyric acid (GABA), a main neurotransmitter in the brain, is an underlying cause in the creation of harmful neural connections. After a prolonged convulsive seizure, instead of the usual inhibitory effect of the transmitter, GABA accelerates brain activity. This, in turn, creates new, harmful neural connections, says Research Director Claudio Rivera. The accelerating effect of GABA was blocked for three days with a drug called bumetanide given soon after a seizure. Two months after the seizure, the number of harmful connections detected in the brain was significantly lower. "Most importantly, the number of convulsive seizures diminished markedly," says Claudio Rivera. In this study, new indications may be found for bumetanide in the treatment of epilepsy. Bumetanide is a diuretic already in clinical use. Extensive clinical studies have already been conducted with bumetanide regarding its ability to reduce the amount of convulsions or prevent them entirely in the acute phase of seizures. This, however, is the first time that bumetanide has been found to have a long-term effect on the neural network structure of the brain. Further study of the newly found mechanism may eventually help limit the exacerbation of epilepsy and prevent the onset of permanent epilepsy after an individual serious seizure. It may also be possible that a similar mechanism is responsible for the onset of epilepsy after a traumatic brain injury. "The next step is to study bumetanide both by itself and in combination with other clinically used drugs. We want to find out the ways in which it may offer additional benefits in the treatment of epilepsy in combination with and even in place of currently used antiepileptic drugs," says Claudio Rivera.
Sinnett S.E.,University of North Carolina at Chapel Hill |
Brenman J.E.,Neuroscience Center
Pharmacology and Therapeutics | Year: 2014
AMP-activated protein kinase (AMPK) is a promising therapeutic target for cancer, type II diabetes, and other illnesses characterized by abnormal energy utilization. During the last decade, numerous labs have published a range of methods for identifying novel AMPK modulators. The current understanding of AMPK structure and regulation, however, has propelled a paradigm shift in which many researchers now consider ADP to be an additional regulatory nucleotide of AMPK. How can the AMPK community apply this new understanding of AMPK signaling to translational research? Recent insights into AMPK structure, regulation, and holoenzyme-sensitive signaling may provide the hindsight needed to clearly evaluate the strengths and weaknesses of past AMPK drug discovery efforts. Improving future strategies for AMPK drug discovery will require pairing the current understanding of AMPK signaling with improved experimental designs. © 2014 Elsevier Inc.
Lukiw W.J.,Neuroscience Center
Alzheimer's Research and Therapy | Year: 2012
Abundant neurochemical, neuropathological, and genetic evidence suggests that a critical number of proinflammatory and innate immune system-associated factors are involved in the underlying pathological pathways that drive the sporadic Alzheimer's disease (AD) process. Most recently, a series of epigenetic factors - including a select family of inducible, proinflammatory, NF-κB-regulated small noncoding RNAs called miRNAs - have been shown to be significantly elevated in abundance in AD brain. These upregulated miRNAs appear to be instrumental in reshaping the human brain transcriptome. This reorganization of mRNA speciation and complexity in turn drives proinflammatory and pathogenic gene expression programs. The ensuing, progressively altered immune and inflammatory signaling patterns in AD brain support immunopathogenetic events and proinflammatory features of the AD phenotype. This report will briefly review what is known concerning NF-κB-inducible miRNAs that are significantly upregulated in AD-targeted anatomical regions of degenerating human brain cells and tissues. Quenching of NF-κB-sensitive inflammatory miRNA signaling using NF-κB-inhibitors such as the polyphenolic resveratrol analog trans-3,5,4′-trihydroxystilbene (CAY10512) may have some therapeutic value in reducing inflammatory neurodegeneration. Antagonism of NF-κB-inducing, and hence proinflammatory, epigenetic and environmental factors, such as the neurotrophic herpes simplex virus-1 and exposure to the potent neurotoxin aluminum, are briefly discussed. Early reports further indicate that miRNA neutralization employing anti-miRNA (antagomir) strategies may hold future promise in the clinical management of this insidious neurological disorder and expanding healthcare concern. © 2012 BioMed Central Ltd.
News Article | December 22, 2016
Doral Chamber of Commerce Welcomes Design Neuroscience Center as a Gold Member