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Monday, August 20th, 2018
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| 12:00a |
Antidepressant restores youthful flexibility to aging inhibitory neurons A new study provides fresh evidence that the decline in the capacity of brain cells to change (called “plasticity”), rather than a decline in total cell number, may underlie some of the sensory and cognitive declines associated with normal brain aging. Scientists at MIT’s Picower Institute for Learning and memory show that inhibitory interneurons in the visual cortex of mice remain just as abundant during aging, but their arbors become simplified and they become much less structurally dynamic and flexible.
In their experiments published online in the Journal of Neuroscience they also show that they could restore a significant degree of lost plasticity to the cells by treating mice with the commonly used antidepressant medication fluoxetine, also known as Prozac.
“Despite common belief, loss of neurons due to cell death is quite limited during normal aging and unlikely to account for age-related functional impairments,” write the scientists, including lead author Ronen Eavri, a postdoc at the Picower Institute, and corresponding author Elly Nedivi, a professor of biology and brain and cognitive sciences. “Rather it seems that structural alterations in neuronal morphology and synaptic connections are features most consistently correlated with brain age, and may be considered as the potential physical basis for the age-related decline.”
Nedivi and co-author Mark Bear, the Picower Professor of Neuroscience, are affiliated with MIT’s Aging Brain Initiative, a multidisciplinary effort to understand how aging affects the brain and sometimes makes the brain vulnerable to disease and decline.
In the study the researchers focused on the aging of inhibitory interneurons which is less well-understood than that of excitatory neurons, but potentially more crucial to plasticity. Plasticity, in turn, is key to enabling learning and memory and in maintaining sensory acuity. In this study, while they focused on the visual cortex, the plasticity they measured is believed to be important elsewhere in the brain as well.
The team counted and chronically tracked the structure of inhibitory interneurons in dozens of mice aged to 3, 6, 9, 12 and 18 months. (Mice are mature by 3 months and live for about 2 years, and 18-month-old mice are already considered quite old.) In previous work, Nedivi’s lab has shown that inhibitory interneurons retain the ability to dynamically remodel into adulthood. But in the new paper, the team shows that new growth and plasticity reaches a limit and progressively declines starting at about 6 months.
But the study also shows that as mice age there is no significant change in the number or variety of inhibitory cells in the brain.
Retraction and inflexibility with age
Instead the changes the team observed were in the growth and performance of the interneurons. For example, under the two-photon microscope the team tracked the growth of dendrites, which are the tree-like structures on which a neuron receives input from other neurons. At 3 months of age mice showed a balance of growth and retraction, consistent with dynamic remodeling. But between 3 and 18 months they saw that dendrites progressively simplified, exhibiting fewer branches, suggesting that new growth was rare while retraction was common.
In addition, they saw a precipitous drop in an index of dynamism. At 3 months virtually all interneurons were above a crucial index value of 0.35, but by 6 months only half were, by 9 months barely any were, and by 18 months none were.
Bear’s lab tested a specific form of plasticity that underlies visual recognition memory in the visual cortex, where neurons respond more potently to stimuli they were exposed to previously. Their measurements showed that in 3-month-old mice “stimulus-selective response potentiation” (SRP) was indeed robust, but its decline went hand in hand with the decline in structural plasticity, so that it was was significantly lessened by 6 months and barely evident by 9 months.
Fountain of fluoxetine
While the decline of dynamic remodeling and plasticity appeared to be natural consequences of aging, they were not immutable, the researchers showed. In prior work Nedivi’s lab had shown that fluoxetine promotes interneuron branch remodeling in young mice, so they decided to see whether it could do so for older mice and restore plasticity as well.
To test this, they put the drug in the drinking water of mice at various ages for various amounts of time. Three-month-old mice treated for three months showed little change in dendrite growth compared to untreated controls, but 25 percent of cells in 6-month-old mice treated for three months showed significant new growth (at the age of 9 months). But among 3-month-old mice treated for six months, 67 percent of cells showed new growth by the age of 9 months, showing that treatment starting early and lasting for six months had the strongest effect.
The researchers also saw similar effects on SRP. Here, too, the effects ran parallel to the structural plasticity decline. Treating mice for just three months did not restore SRP, but treating mice for six months did so significantly.
“Here we show that fluoxetine can also ameliorate the age-related decline in structural and functional plasticity of visual cortex neurons,” the researchers write. The study, they noted, adds to prior research in humans showing a potential cognitive benefit for the drug.
“Our finding that fluoxetine treatment in aging mice can attenuate the concurrent age-related declines in interneuron structural and visual cortex functional plasticity suggests it could provide an important therapeutic approach towards mitigation of sensory and cognitive deficits associated with aging, provided it is initiated before severe network deterioration,” they continued.
In addition to Eavri, Nedivi and Bear, the paper’s other authors are Jason Shepherd, Christina Welsh, and Genevieve Flanders.
The National Institutes of Health, the American Federation for Aging Research, the Ellison Medical Fondation, and the Machiah Foundation supported the research. | | 12:00a |
A "GPS for inside your body" Investigating inside the human body often requires cutting open a patient or swallowing long tubes with built-in cameras. But what if physicians could get a better glimpse in a less expensive, invasive, and time-consuming manner?
A team from MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) led by Professor Dina Katabi is working on doing exactly that with an “in-body GPS" system dubbed ReMix. The new method can pinpoint the location of ingestible implants inside the body using low-power wireless signals. These implants could be used as tiny tracking devices on shifting tumors to help monitor their slight movements.
In animal tests, the team demonstrated that they can track the implants with centimeter-level accuracy. The team says that, one day, similar implants could be used to deliver drugs to specific regions in the body.
ReMix was developed in collaboration with researchers from Massachusetts General Hospital (MGH). The team describes the system in a paper that's being presented at this week's Association for Computing Machinery's Special Interest Group on Data Communications (SIGCOMM) conference in Budapest, Hungary.
Tracking inside the body
To test ReMix, Katabi’s group first implanted a small marker in animal tissues. To track its movement, the researchers used a wireless device that reflects radio signals off the patient. This was based on a wireless technology that the researchers previously demonstrated to detect heart rate, breathing, and movement. A special algorithm then uses that signal to pinpoint the exact location of the marker.
Interestingly, the marker inside the body does not need to transmit any wireless signal. It simply reflects the signal transmitted by the wireless device outside the body. Therefore, it doesn't need a battery or any other external source of energy.
A key challenge in using wireless signals in this way is the many competing reflections that bounce off a person's body. In fact, the signals that reflect off a person’s skin are actually 100 million times more powerful than the signals of the metal marker itself.
To overcome this, the team designed an approach that essentially separates the interfering skin signals from the ones they're trying to measure. They did this using a small semiconductor device, called a “diode,” that mixes signals together so the team can then filter out the skin-related signals. For example, if the skin reflects at frequencies of F1 and F2, the diode creates new combinations of those frequencies, such as F1-F2 and F1+F2. When all of the signals reflect back to the system, the system only picks up the combined frequencies, filtering out the original frequencies that came from the patient’s skin.
One potential application for ReMix is in proton therapy, a type of cancer treatment that involves bombarding tumors with beams of magnet-controlled protons. The approach allows doctors to prescribe higher doses of radiation, but requires a very high degree of precision, which means that it’s usually limited to only certain cancers.
Its success hinges on something that's actually quite unreliable: a tumor staying exactly where it is during the radiation process. If a tumor moves, then healthy areas could be exposed to the radiation. But with a small marker like ReMix’s, doctors could better determine the location of a tumor in real-time and either pause the treatment or steer the beam into the right position. (To be clear, ReMix is not yet accurate enough to be used in clinical settings. Katabi says a margin of error closer to a couple of millimeters would be necessary for actual implementation.)
"The ability to continuously sense inside the human body has largely been a distant dream," says Romit Roy Choudhury, a professor of electrical engineering and computer science at the University of Illinois, who was not involved in the research. "One of the roadblocks has been wireless communication to a device and its continuous localization. ReMix makes a leap in this direction by showing that the wireless component of implantable devices may no longer be the bottleneck."
Looking ahead
There are still many ongoing challenges for improving ReMix. The team next hopes to combine the wireless data with medical data, such as that from magnetic resonance imaging (MRI) scans, to further improve the system’s accuracy. In addition, the team will continue to reassess the algorithm and the various tradeoffs needed to account for the complexity of different bodies.
"We want a model that's technically feasible, while still complex enough to accurately represent the human body," says MIT PhD student Deepak Vasisht, lead author on the new paper. "If we want to use this technology on actual cancer patients one day, it will have to come from better modeling a person's physical structure."
The researchers say that such systems could help enable more widespread adoption of proton therapy centers. Today, there are only about 100 centers globally.
"One reason that [proton therapy] is so expensive is because of the cost of installing the hardware," Vasisht says. "If these systems can encourage more applications of the technology, there will be more demand, which will mean more therapy centers, and lower prices for patients."
Katabi and Vasisht co-wrote the paper with MIT PhD student Guo Zhang, University of Waterloo professor Omid Abari, MGH physicist Hsaio-Ming Lu, and MGH technical director Jacob Flanz. | | 12:00a |
Biological engineers discover new antibiotic candidates The human body produces many antimicrobial peptides that help the immune system fend off infection. Scientists hoping to harness these peptides as potential antibiotics have now discovered that other peptides in the human body can also have potent antimicrobial effects, expanding the pool of new antibiotic candidates.
In the new study, researchers from MIT and the University of Naples Federico II found that fragments of the protein pepsinogen, an enzyme used to digest food in the stomach, can kill bacteria such as Salmonella and E. coli.
The researchers believe that by modifying these peptides to enhance their antimicrobial activity, they may be able to develop synthetic peptides that could be used as antibiotics against drug-resistant bacteria.
“These peptides really constitute a great template for engineering. The idea now is to use synthetic biology to modify them further and make them more potent,” says Cesar de la Fuente-Nunez, an MIT postdoc and Areces Foundation Fellow, and one of the senior authors of the paper.
Other MIT authors of the paper, which appears in the Aug. 20 issue of the journal ACS Synthetic Biology, are Timothy Lu, an associate professor of electrical engineering and computer science and of biological engineering, and Marcelo Der Torossian Torres, a former visiting student.
Discovering new functions
Antimicrobial peptides, which are found in nearly all living organisms, can kill many microbes, but they are typically not powerful enough to act as antibiotic drugs on their own. Many scientists, including de la Fuente-Nunez and Lu, have been exploring ways to create more potent versions of these peptides, in hopes of finding new weapons to combat the growing problem posed by antibiotic-resistant bacteria.
In this study, the researchers wanted to explore whether other proteins found in the human body, outside of the previously known antimicrobial peptides, might also be able to kill bacteria. To that end, they developed a search algorithm that analyzes databases of human protein sequences in search of similarities to known antimicrobial peptides.
“It’s a data-mining approach to very easily find peptides that were previously unexplored,” de la Fuente-Nunez says. “We have patterns that we know are associated with classical antimicrobial peptides, and the search engine goes through the database and finds patterns that look similar to what we know makes up a peptide that kills bacteria.”
In a screen of nearly 2,000 human proteins, the algorithm identified about 800 with possible antimicrobial activity. In the ACS Synthetic Biology paper, the research team focused on the peptide pepsinogen, whose role is to break down proteins in food. After pepsinogen is secreted by cells that line the stomach, hydrochloric acid in the stomach mixes with pepsinogen, converting it into pepsin A, which digests proteins, and into several other small fragments.
Those fragments, which previously had no known functions, showed up as candidates in the antimicrobial screen.
Once the researchers identified those candidates, they tested them against bacteria grown in lab dishes and found that they could kill a variety of microbes, including foodborne pathogens, such as Salmonella and E. coli, as well as others, including Pseudomonas aeruginosa, which often infects the lungs of cystic fibrosis patients. This effect was seen at both acidic pH, similar to that of the stomach, and neutral pH.
“The human stomach is attacked by many pathogenic bacteria, so it makes sense that we would have a host defense mechanism to defend ourselves from such attacks,” de la Fuente-Nunez says.
More potent drugs
The researchers also tested the three pepsinogen fragments against a Pseudomonas aeruginosa skin infection in mice, and found that the peptides significantly reduced the infections. The exact mechanism by which the peptides kill bacteria is unknown, but the researchers’ hypothesis is that their positive charges allow the peptides to bind to the negatively charged bacterial membranes and poke holes in them, a mechanism similar to that of other antimicrobial peptides.
The researchers now hope to modify these peptides to make them more effective, so that they could be potentially used as antibiotics. They are also seeking new peptides from organisms other than humans, and they plan to further investigate some of the other human peptides identified by the algorithm.
“We have an atlas of all these molecules, and the next step is to demonstrate whether each of them actually has antimicrobial properties and whether each of them could be developed as a new antimicrobial,” de la Fuente-Nunez says. |
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