University of Oregon

NEW YORK, Oct. 9, 2024 /PRNewswire/ -- Just as a musician can train to more sharply distinguish subtle differences in pitch, mammals can improve their ability to interpret hearing, vision, and other senses with practice. This process, which is called perceptual learning, may be enhanced by activating a major nerve that connects the brain to nearly every organ in the body, a new study in mice shows. Led by researchers at NYU Langone Health, the investigation centers on the vagus nerve, which carries signals between the brain and the heart, digestive system, and other organs. Experts have long explored targeting this nerve with mild electrical pulses to treat a wide variety of conditions ranging from epilepsy and depression to posttraumatic stress disorder and hearing disorders. Results of such efforts have been mixed, however, and the underlying mechanisms that might lead to improved hearing had until now remained unclear. To more closely examine whether vagus nerve stimulation can boost perceptual learning, the study team trained 38 mice to tell apart musical tones. At first, performance improved for all animals, which made fewer and fewer mistakes over time. However, while those without the treatment maxed out after about a week of training, rodents that received nerve stimulation continued to get better at the task, making roughly 10% fewer errors on average for most tests than they did prior to simulation. In addition, mice in this group made half as many mistakes as their counterparts on the most challenging assessments, in which they needed to distinguish very similar tones. "Our findings suggest that activating the vagus nerve during training can push past the limits of what animals, and perhaps even humans, can learn to perceive," said study lead author Kathleen Martin, BS, a graduate student at the Neuroscience Institute at NYU Grossman School of Medicine. In a second part of the investigation, the researchers assessed how and where vagus nerve stimulation affects the brain. The results revealed that the technique boosts activity in the cholinergic basal forebrain, a region involved in attention and memory. When the team instead suppressed this area during nerve activation, rodents did not gain additional learning benefits. In addition, the team showed that vagus nerve stimulation increased neuroplasticity, a process in which brain cells become more able to adapt to new experiences and form memories, in the auditory cortex, the brain's main center of hearing. This can lead to long-term cellular changes that allow new skills to endure well after training occurred, says Martin. She notes that targeting the vagus nerve to boost hearing has previously been controversial among experts, with past studies in animals failing to show significant improvements. The new study, which published online Sept. 16 in the journal Nature Neuroscience, suggests that the method can indeed work, although results took longer to show up than researchers initially expected, the authors say. This delay, Martin adds, might in part arise because the electrical pulses used in the technique can distract test animals, which may need time to adjust to the sensation. The authors note that using vagus nerve stimulation to enhance hearing has potential applications far beyond maximizing musical ability. Perceptual learning is a key component of both understanding a new language and adjusting to cochlear implants, neuroprosthetic tools used to restore hearing loss. Notably, patients often take months to adjust to these devices and many continue to struggle with conversations even after years of use. "These results highlight the potential of vagus nerve stimulation to speed up hearing improvements from cochlear implants," said study senior author Robert Froemke, PhD. "By boosting perceptual learning, this method might make it easier for implant recipients to communicate with others, hear cars approaching, and engage more effectively with the world around them." Froemke, the Skirball Professor of Genetics in the Department of Neuroscience and Physiology at NYU Grossman School of Medicine, says that the electrical stimulator devices currently used to activate the vagus nerve are only a few centimeters across and can be implanted in an out-patient surgical procedure. Some devices, such as those used to ease migraines, are even less invasive and are simply held against the skin of the neck. Based on their findings, the researchers next plan to test vagus nerve stimulation in rodents with cochlear implants to see if it improves their function, says Froemke, also a professor in the Department of Otolaryngology – Head and Neck Surgery at NYU Grossman School of Medicine. Also a member of NYU Langone's Neuroscience Institute, Froemke cautions that since the vagus nerve is much larger and more complex in humans than in mice, the effects of stimulating it may differ and therefore warrant further testing in human patients. Funding for the study was provided by National Institutes of Health grant DC012557. Further study funding was provided by the United States Department of Defense and the National Science Foundation. In addition to Martin and Froemke, other NYU Langone researchers involved in the study are Eleni Papadoyannis, MA; Jennifer Schiavo, PhD; Saba Shokat Fadaei, MS; Habon Issa, BS; Soomin Song, PhD; and Sofia Orrey Valencia, BS. Other study co-investigators include Nesibe Temiz, PhD, at the Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland; Matthew McGinley, PhD, at Baylor College of Medicine in Houston, Tex.; and David McCormick, PhD, at the University of Oregon in Eugene. Media Inquiries: Shira Polan Phone: 212-404-4279 [email protected] SOURCE NYU Grossman School of Medicine and NYU Langone Health WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Harnessing nanoparticles to deliver drugs precisely to a surgically repaired tendon is a promising new approach that reduced scar tissue formation and improved mechanical function. Harnessing nanoparticles to deliver drugs precisely to a surgically repaired tendon is a promising new approach that reduced scar tissue formation and improved mechanical function in a study appearing in Science Advances. Researchers' success in pinpointing a drug therapy inside the body, at the cellular level, proved to be a highly efficient delivery method that could be used to treat other injuries. Whether it's a season-ending Achilles rupture by pro footballer Aaron Rodgers or an everyday workplace accident, tendon injuries are common and can be life-changing. They require 300,000 surgeries per year and often result in lost work time and permanent impaired physical function. Typically, traumatic tendon injuries are surgically repaired with sutures, but optimal healing is often impaired by the tendon's propensity to heal with scar tissue that restricts tendon movement and function. Researchers at the University of Rochester and University of Oregon combined their expertise in tendon cell biology and drug delivery systems to find a better way to deliver therapies that can reduce scar tissue and facilitate improved healing. "There are very few effective drug regimens to assist the tendon healing process, despite the high number of these injuries and the poor outcomes that often result," said Alayna Loiselle, PhD, associate professor at the University of Rochester's Center for Musculoskeletal Research. "Systemic drug treatments delivered orally or via injection show poor tendon homing; in some cases, less than 1 percent of a systemically delivered medication reaches the healing tendon. Local administration of drugs directly to the tendon has disadvantages as well, including potential tissue damage from the injection and poor control over drug concentrations at the point of injury." "We want to pivot from using suturing alone to incorporating therapeutics," said Emmanuela Adjei-Sowah, a Biomedical Engineering PhD student at the University of Rochester, who has spent the past several years working with co-authors Loiselle, Danielle S.W. Benoit, PhD, and others to develop the nanoparticle delivery system to improve healing in tendon injuries. "Advances in multiomics and drug delivery using nanoparticles open up new possibilities in treatment." The challenge for researchers was to identify which substances could assist tendon healing. Molecular 'map' of healing process charts a new therapeutic path "The fundamental cellular and molecular mechanisms that drive scar-mediated tendon healing are really only just beginning to be well-defined," Loiselle said. "Our prior work used spatial transcriptomic profiling to define a molecular map of the healing tendon. In subsequent analysis of this data, we found that the area right at the injury site had high levels of Acp5 gene expression, which was both surprising and exciting." The Acp5 gene produces a protein called Tartrate Resistant Acid Phosphatase (TRAP); both are known to occur as injured bones recover and rebuild. High TRAP activity within the healing tendon allowed researchers to employ a peptide that binds with TRAP to deliver medication directly to the healing tendon site. "While Benoit's lab has previously used TRAP-binding peptide nanoparticles (TBP-NP) for targeted drug delivery to bone, high TRAP activity in the healing tendon opened up an entirely new research direction," Loiselle said. Prior to initiating studies with therapeutic agents, the team completed a series of dose and timing studies, using a mouse model of complete transection and surgical repair of the flexor tendon, to define the window in which their drug delivery system could most effectively target the healing tendon. "Defining an optimal treatment window is critical to successfully developing an innovative and effective drug delivery system that improves tendon healing by encouraging a more regenerative, rather than fibrotic, healing cascade," said Benoit, the Lorry Lokey Department Chair and Professor in the Department of Bioengineering at the University of Oregon. "In addition, by defining the optimal therapeutic window for this drug delivery system, we can mitigate the unwanted side effects that typically accompany the high doses or multiple doses required to achieve sufficient drug accumulation in the tissue." As a therapeutic, the team chose Niclosamide, which inhibits S100a4, a protein that Loiselle's lab already identified as contributing to scar formation. Previous work from Loiselle's lab demonstrated that genetic knockdown of S100a4 improved mechanical and functional outcomes in this mouse tendon healing model. S100a4 has been implicated in scar formation in many tissues, including the liver, heart, lung, and oral submucosa; Loiselle's discovery that it complicates tendon healing gave them a therapeutic target for this study, where they used their TRAP-binding peptide nanoparticle drug delivery system to precisely affect the injured tendon. As a comparison, they delivered Niclosamide systemically; it did slightly reduce the amount of S100a4 in the healing tendon but it had no beneficial impact on the healing process. In contrast, delivery of the same dose of Niclosamide using the nanoparticle system resulted in robust inhibition of S100a4 mRNA and protein levels in the healing tendon. This targeted drug delivery method also significantly benefited the tendon healing process. TBP-NP delivery of Niclosamide improved both functional range of motion recovery and increased the mechanical integrity of the healing tendon across both short- and longer-term timepoints. Importantly, these sustained effects occurred with just a single treatment. Researchers will continue their work to define how broadly the system can be used for other tendon injuries and disease, as well as other types of tissue injury that result in scar formation. "The beauty of this system is that it can be loaded with different kinds of drugs to target different molecular processes or pathways," said Adjei-Sowah.

Could measuring protein clumps in our cells be a new way to find out our risk of getting age-related diseases? Researchers propose the concept of a 'protein aggregation clock' to measure aging and health. Could measuring protein clumps in our cells be a new way to find out our risk of getting age-related diseases? Professor Dorothee Dormann and Professor Edward Lemke of Johannes Gutenberg University Mainz (JGU), who are also adjunct directors at the Institute of Molecular Biology (IMB) in Mainz, propose the concept of a "protein aggregation clock" to measure ageing and health in a new perspective article published in Nature Cell Biology. As we age, the DNA and proteins that make up our bodies gradually undergo changes that cause our bodies to no longer work as well as before. This in turn makes us more prone to getting age-related diseases, such as cardiovascular disease, cancer, and Alzheimer's disease. One important change is that the proteins in our cells can sometimes become misfolded and clump together to form aggregates, so-called amyloids. Misfolding and aggregation can happen to any protein, but a specific group of proteins known as intrinsically disordered proteins (IDPs) are especially prone to forming amyloids. IDPs make up around 30 percent of the proteins in our cells and they are characterized by having no fixed structure. Instead, they are flexible and dynamic, flopping around like strands of cooked spaghetti. While the molecular mechanisms are widely debated and an important aspect of basic research, scientists know that aggregates formed from IDPs tend to accumulate in many long-lived cells -- such as neurons or muscle cells -- as we age. Moreover, they can cause many age-related diseases, particularly neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Thus, having many aggregates in a cell could be an indicator of how unhealthy the cell is or if a person is likely to develop an age-related disease soon. In their recently published article, Dormann and Lemke propose that IDP aggregation could be used as a biological "clock" to measure a person's health and age. If developed further into a sensitive diagnostic test, a protein aggregation clock could be extremely useful. Firstly, doctors could use it to help diagnose age-related diseases at very early stages or identify people who are not yet sick but have a higher risk of developing disease as they age. This would allow them to be given preventative treatments before they develop severe disease. Secondly, scientists could use it to assess the effects of new experimental treatments to reduce protein aggregation in order to prevent or delay age-related diseases. "In practice, we are still far away from a routine diagnostic test, and it is important that we improve our understanding of the fundamental mechanisms leading to IDP aggregation," said Dormann. "However, we want to stimulate thinking and research in the direction of studying protein aggregates to measure biological ageing processes," Lemke added. "We are optimistic that in the future we will be able to overcome the current challenges of reading a protein aggregation clock through more research on IDP dynamics and making further technological developments." Although there are other "clocks" to measure ageing and health, most of them are based on nucleic acids like DNA. Dormann and Lemke think that a biological clock based on proteins would be a useful complement to these existing clocks, as proteins are among the most abundant molecules in cells and are crucial for all cellular functions. With the help of such a protein aggregation clock, they hope that scientists and doctors will be able to move one step closer towards helping people age healthily and preventing age-related diseases. With their research, Dorothee Dormann and Edward Lemke contribute to the Center for Healthy Ageing (CHA), a virtual research center launched in 2021. The CHA brings together scientists in basic and clinical research from across Mainz who focus on ageing and age-related diseases. Their findings are to be used to promote healthy ageing and to find treatments that help prevent or cure age-related diseases.