The report by an international team of researchers led by Alexander Shackman, an associate professor of psychology at UMD, and Juyoen Hur, an assistant professor of psychology at Yonsei University in Seoul, South Korea, provides new evidence that fear and anxiety reflect overlapping brain circuits. The findings run counter to popular scientific accounts, highlighting the need for a major theoretical reckoning. The study was published last week in the Journal of Neuroscience.

"The conceptual distinction between 'fear' and 'anxiety' dates back to the time of Freud, if not the Greek philosophers of antiquity," said Shackman, a core faculty member of UMD's Neuroscience and Cognitive Science Program, and 2018 recipient of a seed grant award from UMD's Brain and Behavior Initiative, "In recent years, brain imagers and clinicians have extended this distinction, arguing that fear and anxiety are orchestrated by distinct neural networks.

However, Shackman says their new study adds to a rapidly growing body of new evidence suggesting that this old mode is wrong. "If anything, fear, and anxiety seem to be constructed in the brain using a massively overlapping set of neural building blocks," he said.

The prevailing scientific theory holds that fear and anxiety are distinct, with different triggers and strictly segregated brain circuits. Fear -- a fleeting reaction to certain danger -- is thought to be controlled by the amygdala, a small almond-shaped region buried beneath the wrinkled convolutions of the cerebral cortex. By contrast, anxiety -- a persistent state of heightened apprehension and arousal elicited when threat is uncertain -- is thought to be orchestrated by the neighboring bed nucleus of the stria terminalis (BNST). But new evidence from Shackman and his colleagues suggest that both of these brain regions are equally sensitive to certain and uncertain kinds of threats.

Leveraging cutting-edge neuroimaging techniques available at the Maryland Neuroimaging Center, their research team used fMRI to quantify neural activity while participants anticipated receiving a painful shock paired with an unpleasant image and sound -- a new task that the researchers dubbed the "Maryland Threat Countdown."

The timing of this "threat" was signaled either by a conventional countdown timer -- i.e. "3, 2, 1..." -- or by a random string of numbers -- e.g. "16, 21, 8." In both conditions, threat anticipation recruited a remarkably similar network of brain regions, including the amygdala and the BNST. Across a range of head-to-head comparisons, the two showed statistically indistinguishable responses.

The team examined the neural circuits engaged while waiting for certain and uncertain threats (i.e. "fear" and "anxiety"). Results demonstrated that both kinds of threat anticipation recruited a common network of core brain regions, including the amygdala and BNST.

These observations raise important questions about the Research Domain Criteria (RDoC) framework that currently guides the U.S. National Institute of Mental Health's quest to discover the brain circuitry underlying anxiety disorders, depression, and other common mental illnesses. "As it is currently written, RDoC embodies the idea that certain and uncertain threats are processed by circuits centered on the amygdala and BNST, respectively. It's very black-and-white thinking," Shackman noted, emphasizing that RDoC's "strict-segregation" model is based on data collected at the turn of the century.

"It's time to update the RDoC so that it reflects the actual state of the science. It's not just our study; in fact, a whole slew of mechanistic studies in rodents and monkeys, and new meta-analyses of the published human imaging literature are all coalescing around the same fundamental scientific lesson: certain and uncertain threat are processed by a shared network of brain regions, a common core," he said.

As the crown jewel of NIMH's strategic plan for psychiatric research in the U.S., the RDoC framework influences a wide range of biomedical stakeholders, from researchers and drug companies to private philanthropic foundations and foreign funding agencies. Shackman noted that the RDoC has an outsized impact on how fear and anxiety research is designed, interpreted, peer-reviewed, and funded here in the U.S. and abroad.

"Anxiety disorders impose a substantial and growing burden on global public health and the economy," Shackman said, "While we have made tremendous scientific progress, existing treatments are far from curative for many patients. Our hope is that research like this study can help set the stage for better models of emotion and, ultimately, hasten the development of more effective intervention strategies for the many millions of children and adults around the world who struggle with debilitating anxiety and depression."

This work was supported by the National Institute of Mental Health and University of Maryland, College Park.

Story Source:

Materials provided by University of Maryland. Note: Content may be edited for style and length.

https://www.sciencedaily.com/releases/2020/10/201019164939.htm 

Journal Reference:

1. Juyoen Hur, Jason F. Smith, Kathryn A. DeYoung, Allegra S. Anderson, Jinyi Kuang, Hyung Cho Kim, Rachael M. Tillman, Manuel Kuhn, Andrew S. Fox, Alexander J. Shackman. Anxiety and the Neurobiology of Temporally Uncertain Threat Anticipation. The Journal of Neuroscience, 2020; 40 (41): 7949 DOI: 10.1523/JNEUROSCI.0704-20.2020

Now, researchers from the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) have unraveled potential mechanisms behind the healing power of EVs and demonstrated their capacity to not only revive cells after a heart attack but keep cells functioning while deprived of oxygen during a heart attack. The researchers demonstrated this functionality in human tissue using a heart-on-a-chip with embedded sensors that continuously tracked the contractions of the tissue.

The team also demonstrated that these intercellular travelers could be derived from endothelial cells, which line the surface of blood vessels and are more abundant and easier to maintain than stem cells.

The research is published in Science Translational Medicine.

"Our organ-on-chip technology has progressed to the point where we can now fight drug targets instead of fighting the chip design," said Kit Parker, the Tarr Family Professor of Bioengineering and Applied Physics at SEAS and senior author of the study. "With this study, we have mimicked a human disease on a chip with human cells and developed a novel therapeutic approach to treat it."

Heart attacks, or myocardial infarctions, occur when blood flow to the heart is blocked. Of course, the best way to treat a heart attack is to restore blood flow but that process actually may cause more damage to the cells in the heart. So-called ischemia-reperfusion injury (IRI) or reoxygenation injury, happens when blood supply returns to tissue after a period of lack of oxygen.

"The cellular response to IRI involves multiple mechanisms, such as calcium and proton overload, oxidative stress, mitochondrial dysfunction and more," said Moran Yadid, a postdoctoral fellow at SEAS and The Wyss Institute for Biologically Inspired Engineering and first author of the paper. "This complex set of processes poses a challenge for the development of effective therapies that can address each of these problems."

That's where the endothelial-derived EVs (EEVs) come in. Because these vesicles are derived from vascular tissue, which is uniquely tuned to sense hypoxic stress, the researchers hypothesized that the cargo they carry could provide direct protection to cardiac muscle.

The researchers mapped the entire set of EEV proteins that are or can be, expressed by the vesicles.

"Surprisingly, even though these vesicles are only a hundred and fifty nanometers in diameter, they contain almost 2,000 different proteins," said Yadid. "A lot of these proteins relate to metabolic processes like respiration, mitochondrial function, signaling, and homeostasis. In other words, a lot of processes that relate to the cardiac response to stress. So, rather than one molecule that is therapeutic, we think that the exosomes contain a cocktail of molecules and proteins that can, all together, help the cell maintain homeostasis, deal with the stress, modify metabolic action and reduce the amount of injury."

The team tested the effect of EEVs on human heart tissue using the heart-on-a-chip model developed by the Disease Biophysics Group at SEAS. Organ-on-chip platforms mimic the structure and function of native tissue and allow researchers to observe, in real-time, the effects of injuries and treatments in human tissue. Here, the researchers simulated a myocardial infarction and reoxygenation on chips that were infused with EEVs and those that were not.

The researchers found that in tissues treated with EEVs, the cardiomyocytes could better adapt to stress conditions and sustain a higher workload. The researchers induced injury by three hours of oxygen restrictions followed by 90 minutes of reoxygenation and then measured the fraction of dead cells and the contractile force of the tissue. The heart tissue treated with EEVs had half as many dead cells and had a contractile force four times higher than the untreated tissue after injury.

The team also found that injured cardiomyocytes that had been treated with EEVs exhibited a set of proteins that was more similar to the uninjured ones compared with untreated cells. Surprisingly, the team also observed that cells treated with EEVs continued to contract even without oxygen.

"Our findings indicate that EEVs could protect cardiac tissue from reoxygenation injury in part by supplementing the injured cells with proteins and signaling molecules that support different metabolic processes, paving the way for new therapeutic approaches," said André G. Kléber, a Visiting Professor of Pathology at Harvard Medical School and co-author of the study.

"Exosomal cell therapies might be beneficial when the traditional model of one molecule, one target just won't cure the disease," said Parker. "With the vesicles we administered, we believe we are taking a shotgun approach to hitting a network of drug targets. With our organ on chip platform, we will be poised to use synthetic exosomes in a therapeutic manner that may be more efficient and amenable to more reliable manufacturing."

The research was co-authored by Johan U. Lind, a former postdoctoral fellow at SEAS and current Assistant Professor at the University of Copenhagen, Denmark; Herdeline Ann M. Ardoña, a former postdoctoral fellow at SEAS and current Assistant Professor at the University of California Irvine; Sean P. Sheehy, Lauren E. Dickinson, Feyisayo Eweje, Maartje M.C. Bastings, Benjamin Pope, Blakely B. O'Connor, Juerg R. Straubhaar and Bogdan Budnik.

It was supported by Harvard Materials Research Science and Engineering Center and the National Science Foundation under grant DMR-1420570, and the National Center for Advancing Translational Sciences of the NIH under award numbers UH3TR000522 and 1-UG3-HL-141798-01.

Story Source:

Materials provided by Harvard John A. Paulson School of Engineering and Applied Sciences. Original written by Leah Burrows. Note: Content may be edited for style and length.

https://www.sciencedaily.com/releases/2020/10/201014171322.htm 

Journal Reference:

1. Moran Yadid, Johan U. Lind, Herdeline Ann M. Ardoña, Sean P. Sheehy, Lauren E. Dickinson, Feyisayo Eweje, Maartje M.C. Bastings, Benjamin Pope, Blakely B. O’Connor, Juerg R. Straubhaar, Bogdan Budnik, Andre G. Kleber, Kevin Kit Parker. Endothelial extracellular vesicles contain protective proteins and rescue ischemia-reperfusion injury in a human heart-on-chip. Science Translational Medicine, 2020; 12 (565): eaax8005 DOI: 10.1126/scitranslmed.aax8005