The research team, led by Dr Sara Mederos and Professor Sonja Hofer, mapped out how the brain learns to suppress responses to perceived threats that prove harmless over time.

“Humans are born with instinctive fear reactions, such as responses to loud noises or fast-approaching objects,” explains Dr Mederos, Research Fellow in the Hofer Lab at SWC. “However, we can override these instinctive responses through experience — like children learning to enjoy fireworks rather than fear their loud bangs. We wanted to understand the brain mechanisms that underlie such forms of learning.”

Using an innovative experimental approach, the team studied mice presented with an overhead expanding shadow that mimicked an approaching aerial predator. Initially, the mice sought shelter when encountering this visual threat. However, with repeated exposure and no actual danger, the mice learned to remain calm instead of escaping, providing researchers with a model to study the suppression of fear responses.

Based on previous work in the Hofer Lab, the team knew that an area of the brain called the ventrolateral geniculate nucleus (vLGN) could suppress fear reactions when active and was able to track knowledge of previous experience of threat. The vLGN also receives strong input from visual areas in the cerebral cortex, and so the researchers explored whether this neural pathway had a role in learning not to fear a visual threat.

The study revealed two key components in this learning process: (1) specific regions of the visual cortex proved essential for the learning process, and (2) a brain structure called the ventrolateral geniculate nucleus (vLGN) stores these learning-induced memories.

“We found that animals failed to learn to suppress their fear responses when specific cortical visual areas where inactivated. However, once the animals had already learned to stop escaping, the cerebral cortex was no longer necessary,” explained Dr Mederos.

“Our results challenge traditional views about learning and memory,” notes Professor Hofer, senior author of the study. “While the cerebral cortex has long been considered the brain’s primary centre for learning, memory and behavioural flexibility, we found the subcortical vLGN and not the visual cortex actually stores these crucial memories. This neural pathway can provide a link between cognitive neocortical processes and ‘hard-wired’ brainstem-mediated behaviours, enabling animals to adapt instinctive behaviours.”

The researchers also uncovered the cellular and molecular mechanisms behind this process. Learning occurs through increased neural activity in specific vLGN neurons, triggered by the release of endocannabinoids — brain-internal messenger molecules known to regulate mood and memory. This release decreases inhibitory input to vLGN neurons, resulting in heightened activity in this brain area when the visual threat stimulus is encountered, which suppresses fear responses.

The implications of this discovery extend beyond the laboratory. “Our findings could also help advance our understanding of what is going wrong in the brain when fear response regulation is impaired in conditions such as phobias, anxiety and PTSD. While instinctive fear reactions to predators may be less relevant for modern humans, the brain pathway we discovered exists in humans too,” explains Professor Hofer. “This could open new avenues for treating fear disorders by targeting vLGN circuits or localised endocannabinoid systems.”

The research team is now planning to collaborate with clinical researchers to study these brain circuits in humans, with the hope of someday developing new, targeted treatments for maladaptive fear responses and anxiety disorders.

This research was funded by the Sainsbury Wellcome Centre core grant from the Gatsby Charity Foundation and Wellcome (090843/F/09/Z); a Wellcome Investigator Award (219561/Z/19/Z); an EMBO postdoctoral fellowship (EMBO ALTF 327-2021) and a Wellcome Early Career Award (225708/Z/22/Z).

Northwestern University researchers have discovered how mantis shrimp remain impervious to their own punches. Their fists, or dactyl clubs, are covered in layered patterns, which selectively filter out sound. By blocking specific vibrations, the patterns act like a shield against self-generated shockwaves.

The study will be published on Friday (Feb. 7) in the journal Science.

The findings someday could be applied to developing synthetic, sound-filtering materials for protective gear as well as inspire new approaches to reducing blast-related injuries in military and sports.

“The mantis shrimp is known for its incredibly powerful strike, which can break mollusk shells and even crack aquarium glass,” said Northwestern’s Horacio D. Espinosa, the study’s co-corresponding author. “However, to repeatedly execute these high-impact strikes, the mantis shrimp’s dactyl club must have a robust protection mechanism to prevent self-damage. Most prior work has focused on the club’s toughness and crack resistance, treating the structure as a toughened impact shield. We found it uses phononic mechanisms — structures that selectively filter stress waves. This enables the shrimp to preserve its striking ability over multiple impacts and prevent soft tissue damage.”

An expert on bio-inspired materials, Espinosa is the James N. and Nancy J. Farley Professor in Manufacturing and Entrepreneurship and a professor of mechanical engineering at Northwestern’s McCormick School of Engineering, where he directs the Institute for Cellular Engineering Technologies. Espinosa led the study in partnership with M. Abi Ghanem of the Institute of Light and Matter, a joint research unit between Claude-Bernard-Lyon-I University and the Center for National Scientific Research in France.

A devastating blow

Living in shallow, tropical waters, mantis shrimp are armed with one hammer-like dactyl club on each side of its body. These clubs store energy in elastic, spring-like structures, which are held in place by latch-like tendons. When the latch is released, the stored energy, too, is released — propelling the club forward with explosive force.

With a single blow, mantis shrimp can slaughter prey or defend their territory from interloping competitors. As the punch rips through surrounding water, it creates a low-pressure zone behind it, causing a bubble to form.

“When the mantis shrimp strikes, the impact generates pressure waves onto its target,” Espinosa said. “It also creates bubbles, which rapidly collapse to produce shockwaves in the megahertz range. The collapse of these bubbles releases intense bursts of energy, which travel through the shrimp’s club. This secondary shockwave effect, along with the initial impact force, makes the mantis shrimp’s strike even more devastating.”

Protective patterns

Surprisingly, this force does not damage the shrimp’s delicate nerves and tissues, which are encased within its armor.

To investigate this phenomenon, Espinosa and colleagues used two advanced techniques to examine the mantis shrimp’s armor in fine detail. First, they applied transient grating spectroscopy, a laser-based method that analyzes how stress waves propagate through materials. Second, they employed picosecond laser ultrasonics, which provide further insights into the armor’s microstructure.

Their experiments revealed two distinct regions — each engineered for a specific function — within the mantis shrimp’s club. The impact region, responsible for delivering crushing blows, consists of mineralized fibers arranged in a herringbone pattern, giving it resistance to failure. Beneath this layer, the periodic region features twisted,corkscrew-like fiber bundles. These bundles form a Bouligand structure, a layered arrangement, in which each layer is progressively rotated relative to its neighbors.

While the herringbone pattern reinforces the club against fractures, the corkscrew arrangement governs how stress waves travel through the structure. This intricate design acts as a phononic shield, selectively filtering high-frequency stress waves to prevent damaging vibrations from propagating back into the shrimp’s arm and body.

“The periodic region plays a crucial role in selectively filtering out high-frequency shear waves, which are particularly damaging to biological tissues” Espinosa said. “This effectively shields the shrimp from damaging stress waves caused by the direct impact and bubble collapse.”

In this study, the researchers analyzed 2D simulations of wave behavior. Espinosa said 3D simulations are needed to fully understand the club’s complex structure.

“Future research should focus on more complex 3D simulations to fully capture how the club’s structure interacts with shockwaves,” Espinosa said. “Additionally, designing aquatic experiments with state-of-the-art instrumentation would allow us to investigate how phononic properties function in submerged conditions.”

The study, “Does the mantis shrimp pack a phononic shield?” was supported by the Air Force Office of Scientific Research, the Office of Naval Research and the National Science Foundation.

The prevalence of mental health disorders has been rising over the years. According to the latest nationwide study, 1 in 7 people in Singapore has experienced a mental health disorder, which includes depressive and anxiety disorders[1]. In 2019, mental health disorders were one of the top four leading causes of disease burden in Singapore[2].

The research team thus set out to investigate the role microbes play in anxious behaviour. In pre-clinical studies, the scientists observed that in a germ-free environment, those which were not exposed to live microbes, showed significantly more anxiety-related behaviour than those with typical resident live microbes.

Further investigation revealed that the increased anxiety was associated with heightened activity in a brain region involved in processing emotions such as fear and anxiety, the basolateral amygdala (BLA). This was further identified to be related to specialised proteins within brain cells known as the calcium dependent SK2 channels, associated with anxiety behaviour. In conditions when the body and brain are exposed to live microbe metabolites, the SK2 channels act like a clutch, thus preventing neurons from becoming overly excited and firing too frequently.

Associate Professor Shawn Je from Duke-NUS’ Neuroscience and Behavioural Disorders Programme and one of the lead authors, explained:

“Our findings reveal the specific and intricate neural process that link microbes to mental health. Those without any live microbes showed higher levels of anxious behavior than those with live bacteria. Essentially, the lack of these microbes disrupted the way their brains functioned, particularly in areas that control fear and anxiety, leading to anxious behavior.”

To better understand the role of microbes in this process, the researchers introduced live microbes into germ-free mice[3]. This reduced the elevated neuronal activity in the basolateral amygdala and thus SK2 channel activity. As a result, the mice showed significantly less anxiety-related behavior — their emotional responses became like those exposed to microbes.

The researchers also tried treatment with indoles, microbial metabolites produced by certain microbes. When the germ-free mice were given indoles, they showed reduced activity in the basolateral amygdala and displayed less anxiety-related behaviour. This demonstrated that our indigenous microbes produce metabolites, which suggest a direct link between our microbiota and maintaining mental balance.

Professor Sven Pettersson from the Department of Research, National Neuroscience Institute of Singapore, who is also a lead author of the study, said:

“Establishing hunger signals and controlling hunger is an evolutionarily conserved defence mechanism. The physiological switch at birth, can therefore, be viewed as a first major wave of anxiety exposure for the newborn, which simply says, “If you don’t eat, you will die.” Additionally, birth is associated with exposure to breast milk, known to contain microbes that can produce molecules known as indoles. Indoles are known to be secreted in plants when they are exposed to stress or malnutrition (draught) and in this paper we report a similar mechanism in which indoles can regulate anxiety levels in mammals. That is, different levels of circulating microbial plasma indoles in the blood may reflect different sensitivity and vulnerability to stressful situations and therefore variable risk of experiencing anxiety-related situations.”

The implications of these observations are multiple: for example, it opens for the therapeutic potential of targeting the gut-brain axis to treat anxiety-related disorders by restoring the microbe composition through dietary supplementation with indoles or by introducing indole-producing gut microbes as probiotics. “In other words, it opens for tailor-made therapies in line with 21st-century precision medicine. Studies such as this illustrate the close hereditary relationship that exists between our indigenous microbes and the higher complexity of life,” concludes Pettersson.

Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, said:

“Our findings underscore the deep evolutionary links between microbes, nutrition and brain function. This has huge potential for people suffering from stress-related conditions, such as sleep disorders or those unable to tolerate standard psychiatric medications. It’s a reminder that mental health is not just in the brain-it’s in the gut too.”

The team now hopes to explore clinical trials to determine whether indole-based probiotics or supplements can be effectively used in humans as a natural anxiety treatment. If successful, this could mark the beginning of a new era in mental health care — one where gut microbes help keep our minds at ease.

[1] Institute of Mental Health, Singapore Mental Health study

[2] Ministry of Health 28 October 2020 Global Burden of Disease 2019 Study Findings https://www.moh.gov.sg/news-highlights/details/global-burden- of-disease-2019-study-findings

[3] The study was conducted according to the National Advisory Committee for Laboratory Animal Research (NACLAR) guidelines.

Biological age — a measure of how well one’s body is functioning — differs from chronological age — the amount of time since someone was born. While chronological age can be correlated to disease risk, researchers and medical doctors can use biological age, which can be slowed or accelerated by environmental or behavioral factors, to more precisely understand a person’s risk for certain diseases, including cancers and dementia.

The correct type of tissue is needed to estimate biological age accurately, according to the study led by Abner Apsley, doctoral candidate in the Penn State Molecular, Cellular, and Integrative Biosciences Graduate Program, and his adviser, Idan Shalev, associate professor of biobehavioral health at Penn State. Their results were published in Aging Cell.

In recent years, researchers created several epigenetic clocks — tools that compare a person’s biological age to their chronological age. As these clocks have become widely available, multiple companies have begun to offer services that estimate people’s biological age by comparing customer tissue samples to established epigenetic clocks.

Researchers construct epigenetic clocks by collecting tissue samples from a large number of people and examining differences in epigenetic markers — which indicate points of DNA methylation — across the lifespan. Using machine learning to identify which epigenetic markers predict chronological age, the researchers can then determine if a person’s epigenome, or the set of markers, matches their chronological age.

In theory, knowing a person’s biological age could indicate what behaviors that person needs to modify in order to extend their life. In clinical settings, however, scientifically validated uses of epigenetic clocks are not common yet, the researchers said.

“Aging is the main driver for a host of common diseases including dementia, heart disease and cancer,” Shalev said. “Measurement of biological age is not a diagnosis of a health problem, but it can be used to identify a person’s risk for age-related conditions.”

Some commercial companies offer to measure biological age by requiring customers to spit into a test tube and mail the sample to the company. The company analyzes epigenetic information in the saliva and uses established epigenetic clocks to predict the customer’s biological age. Epigenetic clocks, however, are most commonly created using blood, not saliva, which is why the researchers in this study said they wanted to compare the performance of different tissue-sample types.

The researchers evaluated five types of tissue samples and compared them with seven epigenetic clocks. The study included 284 distinct tissue samples from 83 individuals between the ages of nine and 70 years old. In six of the seven clocks tested, the team found that oral tissue resulted in substantially less accurate estimates of biological age than blood-based samples.

“We tested three types of blood samples and two types of oral tissues — saliva and cheek swabs,” said Apsley, the lead author of the study. “For almost every epigenetic clock, the oral tissue led to significantly higher estimates of the subject’s biological age. In some cases, the estimates were 30 years higher; that is extremely inaccurate. It is very clear that the tissue used to measure someone’s biological age must match the tissue used when the clock was created. Otherwise, estimates of biological age will not be valid.”

Results from this study demonstrated that blood-tissue types led to similar biological age estimates across the different epigenetic clocks. Oral tissue performed very differently than blood tissue and was generally not as accurate, estimating older biological ages across the clocks. The one exception to this trend was the only epigenetic clock in the study created using both blood and cheek swabs. For that clock, the age estimates across different tissues were much more accurate than they were on the other clocks.

“Most of the popular clocks were created using blood samples,” Apsley said. “So, these results represent an important lesson for this burgeoning field. If companies or physicians want to use saliva or cheek swabs to measure biological age, then researchers need to develop epigenetic clocks using those tissues. Currently, blood is needed to accurately estimate biological age in most circumstances.”

While tests of biological age are not commonly measured in medical settings yet, the researchers said that biological age could be used someday to identify patients who may need medication to delay the onset of an age-related disease due to their advanced biological age. Alternatively, patients with delayed biological age might be better candidates for surgery than other people of the same chronological age. There are other uses for biological age estimates, as well.

“Researchers are still discovering how to apply biological age,” said Shalev, a Social Science Research Institute co-funded faculty member. “Our research focuses on medical applications, but epigenetic clocks have also been used with blood samples from crime scenes to help forensic scientists identify the approximate age of criminal suspects. Who knows where this field will lead us next?”

Other researchers who contributed to this study include Qiaofeng Ye, Christopher Chiaro, John Kozlosky and Hannah Schreier of the Penn State Department of Biobehavioral Health; Avshalom Caspi, Laura Etzel-House and Karen Sugden of Duke University; Waylon Hastings of Texas A&M University; Christine Heim of the Berlin Institute of Health at Charite; and Jennie Noll and Chad Shenk of the University of Rochester.

The National Institute on Aging, National Institute of Environmental Health Sciences, National Institute of Child Health and Human Development, National Center for Advancing Translational Sciences and the Penn State College of Medicine funded this research.

The findings published today in the journal Science Advances suggests that the decline of global sulphur emissions as the result of clean air policies, coupled with the warming and fertilization effects of carbon dioxide emissions lifts a lid on wetland methane production resulting in increased emissions.

The resulting additional future release of 20-34 million tonnes of methane each year from natural wetlands would mean targets to reduce human-caused emissions need to be more stringent than currently set out in the Global Methane Pledge.

Methane, which is one of the most potent greenhouse gases in trapping heat in the atmosphere, is produced in wetlands around the world. Sulphur (in the form of sulphate) has a very specific effect in natural wetlands that reduces methane emissions, while CO₂ increases methane production by increasing growth in plants that make the food for methane-producing microbes.

Professor Vincent Gauci from the University of Birmingham and a senior author of the study said:

“Well-meaning policies aimed at reducing atmospheric sulphur appear to be having the unintended consequence of lifting this sulphur ‘lid’ on wetland methane production. This coupled with increased CO₂ means we have a double whammy effect that pushes emissions much higher.

“How has this happened? Put simply, sulphur provides the conditions for one set of bacteria to outmuscle another set of microbes that produce methane when they compete over the limited food available in wetlands. Under the conditions of acid rain sulphur pollution during the past century, this was enough to reduce wetland methane emissions by up to 8%.

“Now that clean air policies have been introduced, the unfortunate consequence of reducing sulphur deposition, which does have important and welcome effects for the world’s ecosystems, is that we will need to work much harder than we thought to stay within the safe climate limits set out in the Paris agreement.”

More than 150 nations signed up to the Global Methane Pledge at COP26 in Glasgow, which seeks to reduce human-caused emissions of methane by 30% on a 2020 baseline, by 2030.

The study is the latest to implicate reductions in atmospheric sulphur in driving warming at a faster rate than anticipated. In 2020 shipping pollution controls were introduced to reduce emissions of sulphur dioxide and fine particles that are harmful to human health. This reduction in atmospheric sulphur over the oceans has been implicated in larger warming that expected in what has come to be known as ‘termination shock’.

Lead author of the paper Lu Shen of Peking University said:

“Our study points to the complexity of the climate system. Representation of these complex biogeochemical interactions has not previously been well integrated into estimates of future methane emissions. We show that it is essential to consider these feedbacks to get a true understanding of the likely future of this important greenhouse gas.”