Can a dangerous microbe offer a new way to silence pain?

Deadly anthrax toxin blocks multiple types of pain in mice, study shows

Now the findings of a new study suggest the dreaded microbe also has unexpected beneficial potential – one of its toxins can silence multiple types of pain in animals.

• The research reveals that this specific anthrax toxin works to alter signaling in pain-sensing neurons and, when delivered in a targeted manner into neurons of the central and peripheral nervous system, can offer relief to animals in distress.

• The work, led by investigators at Harvard Medical School in collaboration with industry scientists and researchers from other institutions, is published Dec. 20 in Nature Neuroscience.

• Furthermore, the team combined parts of the anthrax toxin with different types of molecular cargo and delivered it into pain-sensing neurons. The technique can be used to design novel precision-targeted pain treatments that act on pain receptors but without the widespread systemic effects of current pain-relief drugs, such as opioids.

• "This molecular platform of using a bacterial toxin to deliver substances into neurons and modulate their function represents a new way to target pain-mediating neurons," said study senior investigator Isaac Chiu, associate professor of immunology in the Blavatnik Institute at Harvard Medical School.

The need to expand the current therapeutic arsenal for pain management remains acute, the researchers said. Opioids remain the most effective pain medication, but they have dangerous side effects – most notably their ability to rewire the brain's reward system, which makes them highly addictive, and their propensity to suppress breathing, which can be fatal.

Researchers in the Chiu lab have long been interested in the interplay between microbes and the nervous and immune systems. Past work led by Chiu has demonstrated that other disease-causing bacteria can also interact with neurons and alter their signaling to amplify pain. Yet only a handful of studies so far have looked at whether certain microbes could minimize or block pain. This is what Chiu and Yang set out to do.

For the current study, they started out by trying to determine how pain-sensing neurons may be different from other neurons in the human body. To do so, they first turned to gene-expression data. One of the things that caught their attention: Pain fibers had receptors for anthrax toxins, whereas other types of neurons did not. In other words, the pain fibers were structurally primed to interact with the anthrax bacterium. They wondered why.

• The newly published research sheds light on that very question.

The findings demonstrate that pain silencing occurs when sensory neurons of dorsal root ganglia, nerves that relay pain signals to the spinal cord, connect with two specific proteins made by the anthrax bacterium itself. Experiments revealed that this occurs when one of the bacterial proteins, protective antigen (PA), binds to the nerve cell receptors it forms a pore that serves as a gateway for two others bacterial proteins, edema factor (EF) and lethal factor (LF), to be ferried into the nerve cell. The research further demonstrated PA and EF together, collectively known as edema toxin, alter the signaling inside nerve cells – in effect silencing pain.

• Using the quirks of microbial evolution for new therapies

In a series of experiments, the researchers found that the anthrax toxin altered signaling in human nerve cells in dishes, and it also did so in living animals…

The new findings raise another interesting question: Evolutionarily speaking, why would a microbe silence pain?

• Chiu thinks that one explanation a highly speculative one, he added may be that microbes have developed ways to interact with their host in order to facilitate their own spread and survival. In the case of anthrax, that adaptive mechanism may be through altered signaling that blocks the host's ability to sense pain and therefore the microbe's presence. This hypothesis could help explain why the black skin lesions that the anthrax bacterium sometimes forms are notably painless, Chiu added.

• The new findings also point to novel avenues for drug development beyond the traditional small-molecule therapies that are currently being designed across labs.

• "Bringing a bacterial therapeutic to treat pain raises the question 'Can we mine the natural world and the microbial world for analgesics?'" Chiu said. "Doing so can increase the range and diversity of the types of substances we look to in search for solutions."

https://www.sciencedaily.com/releases/2021/12/211220120629.htm

Key neural mechanism believed to support advanced cognitive abilities discovered

It is well established that humans can only hold a limited amount of information in mind at a time, and that they enlist different cognitive strategies, like organizing information into lists or groups, to overcome these constraints. The research team found that when the brain uses these strategies to organize information, neural codes in the prefrontal cortex become less dependent on the highly selective responses of single neurons.Instead, they become distributed among a larger pool of neurons, which may make the information more reliable or robust. The findings were published online in Neuron on December 20.

"Our study gives the field an important new perspective on how the brain allocates its resources to improve cognitive performance," says senior author Erin Rich, MD, PhD, Associate Professor of Neuroscience at the Icahn School of Medicine at Mount Sinai. "Findings from our study will help scientists to better understand, and in the future to potentially treat, disorders of memory and cognition."

The study was led by Feng-Kuei Chiang, PhD, a postdoctoral fellow in Dr. Rich's lab who has previously studied functions of the prefrontal cortex in sequencing tasks.

Traditionally, studies of neural coding which transforms electrical impulses from the neurons into memories, knowledge, decisions, and actions have focused on selective responses of single neurons. The Mount Sinai team demonstrated the shortcomings of such an approach by designing a task to probe changes in the prefrontal cortex that result in improved cognitive performance. The task allowed the subjects to use a mnemonic (or memory aid) strategy to order information into a sequence.

"We found that subjects spontaneously generated different selection patterns, including routine sequences, to decrease the working memory demands of the task," said Dr. Chiang.

Researchers were surprised to find that interpretable responses of single neurons were a poor predictor of memory performance when subjects used the sequencing strategy to organize information held in the mind. Using the strategy reduced error rates in the task, but the activity of single neurons appeared to convey less information. They were able to reconcile these findings by showing that the information was not lost, but more widely distributed among a larger population of neurons. The task-relevant information could be recovered as well or better than when the codes were dominated by a smaller number of highly tuned neurons, and the distributed codes appeared to be more reliable, since they improved behavioral performance.

"This is a brand-new discovery in the nature of prefrontal codes, and it could point to a key neural mechanism that supports advanced cognitive abilities like planning, strategizing, and problem-solving that depend on real-time organization of information," explains Dr. Rich. "By shifting the focus from selective responses of single neurons, we've shown that the collective activity of neural populations needs to be considered when developing new strategies to improve cognitive performance or treat cognitive disorders."

https://www.sciencedaily.com/releases/2021/12/211221162718.htm

==People with IBD have more microplastics in their feces

Microplastics== tiny pieces of plastic less than 5 mm in length are everywhere, from bottled water to food to air. According to recent estimates, people consume tens of thousands of these particles each year, with unknown health consequences. Now, researchers reporting in ACS' Environmental Science & Technology found that people with inflammatory bowel disease (IBD) have more microplastics in their feces than healthy controls, suggesting that the fragments could be related to the disease process.

The prevalence of IBD, which includes Crohn's disease and ulcerative colitis, is rising globally. Characterized by chronic inflammation of the digestive tract, IBD can be triggered or made worse by diet and environmental factors. Microplastics can cause intestinal inflammation, gut microbiome disturbances and other problems in animal models, so Faming Zhang, Yan Zhang and colleagues wondered if they could also contribute to IBD. As a first step toward finding out, the researchers wanted to compare the levels of microplastics in feces from healthy subjects and people with different severities of IBD.

The team obtained fecal samples from 50 healthy people and 52 people with IBD from different geographic regions of China. Analysis of the samples showed that feces from IBD patients contained about 1.5 times more microplastic particles per gram than those from healthy subjects. The microplastics had similar shapes (mostly sheets and fibers) in the two groups, but the IBD feces had more small (less than 50 ?m) particles. The two most common types of plastic in both groups were polyethylene terephthalate (PET; used in bottles and food containers) and polyamide (PA; found in food packaging and textiles). People with more severe IBD symptoms tended to have higher levels of fecal microplastics. Through a questionnaire, the researchers found that people in both groups who drank bottled water, ate takeaway food and were often exposed to dust had more microplastics in their feces. These results suggest that people with IBD may be exposed to more microplastics in their gastrointestinal tract. However, it's still unclear whether this exposure could cause or contribute to IBD, or whether people with IBD accumulate more fecal microplastics as a result of their disease, the researcher say.

https://www.sciencedaily.com/releases/2021/12/211222084024.htm