Medical Bulletin 09/ March/ 2024

Researchers from MIT have discovered a brain circuit that drives vocalization and ensures that you talk only when you breathe out, and stop talking when you breathe in.

The study, published in the Journal Science, highlights a newly identified circuit governing two essential vocalization actions: larynx narrowing and lung exhalation. Located in the larynx, the vocal cords are two muscular bands that can open and close. When they are mostly closed, or adducted, air exhaled from the lungs generates sound as it passes through the cords.

Additionally, researchers also discovered that this vocalization circuit is commanded by a brainstem area regulating breathing rhythm, thereby prioritizing breathing over speech.

“When you need to breathe in, you have to stop vocalization. We found that the neurons that control vocalization receive direct inhibitory input from the breathing rhythm generator,” said Fan Wang, an MIT professor of brain and cognitive sciences, a member of MIT’s McGovern Institute for Brain Research, and the senior author of the study.

For the study, the MIT researchers investigated how the brain controls vocalization in mice, who communicate through ultrasonic vocalizations (USVs). By mapping synaptic connections between neurons, they traced back from laryngeal motor neurons controlling vocal cord adduction to identify the neurons innervating them.

The findings revealed that specific RAm neurons, active during ultrasonic vocalizations (USVs), are essential for vocalization. Targeting these neurons, called RAmVOC, and manipulating their activity revealed that blocking them prevents vocalization because the vocal cords remain open and abdominal muscles don't contract as usual during exhalation. Conversely, activating RAmVOC neurons leads to vocalization: vocal cords close, mice exhale, and USVs are produced. However, prolonged stimulation causes interruptions by inhalations, indicating the process is regulated by the brain's breathing control center.

“Breathing is a survival need. Even though these neurons are sufficient to elicit vocalization, they are under the control of breathing, which can override our optogenetic stimulation,” said Wang.

Reference: JAEHONG, SEONMI CHOI, JUN TAKATOH, SHENGLI ZHAO, ANDREW HARRAHILL, BAO-XIA HAN, AND FAN WANG; Journal: Science; DOI: 10.1126/science.adi8081

Vitamin A could have a key role in both stem cell biology and wound healing

A new study published in the Journal Science demonstrated that once stem cells have transitioned into lineage plasticity, they are unable to operate efficiently until they commit to a specific fate. During a screening process to identify crucial regulators of this phenomenon, retinoic acid, the active form of Vitamin A, emerged unexpectedly as a significant factor.

Lineage plasticity, observed in various tissues in response to injury and in cancer, is best studied in minor skin injuries due to the skin's constant exposure to damage. When scratches or abrasions damage the epidermis, hair follicle stem cells are the first to respond, with other skin stem cells following suit to regenerate the skin. Some stem cells, originally dedicated to hair growth, transition into epidermal stem cells to aid in repair. This transition involves temporary expression of transcription factors from both hair and epidermal stem cells.

“Our goal was to understand this state well enough to learn how to dial it up or down,” said Elaine Fuchs professor at Rockefeller University. “We now have a better understanding of skin and hair disorders, as well as a path toward preventing lineage plasticity from contributing to tumor growth.”

The researchers explored lineage plasticity, highlighting its dual role: crucial for directing stem cells to areas needing repair, yet potentially leading to prolonged repair states and certain cancers if uncontrolled. To understand the mechanism, they screened small molecules in cultured mouse hair follicle stem cells, mimicking wound conditions were surprised to find that retinoic acid, the active form of vitamin A, was essential for these stem cells to exit lineage plasticity and differentiate into hair or epidermal cells in vitro.

“Through our studies, first in vitro and then in vivo, we discovered a previously unknown function for vitamin A, a molecule that has long been known to have potent but often puzzling effects on skin and many other organs,” said Fuchs.

The findings revealed that genetic, dietary, and topical interventions boosted or removed retinoic acid from mice and confirmed its role in balancing how stem cells respond to skin injuries and hair regrowth. Retinoids did not operate on their own: their interplay with signalling molecules such as BMP and WNT influenced whether the stem cells should maintain quiescence or actively engage in regrowing hair.

“By defining the minimal requirements needed to form mature hair cell types from stem cells outside the body, this work has the potential to transform the way we approach the study of hair biology,” said Matthew Tierney, lead author of the paper.

Reference: MATTHEW T. TIERNEY, LISA POLAK, YIHAO YANG, MERVE DENIZ ABDUSSELAMOGLU, INWHA BAEK, KATHERINE S. STEWART, AND ELAINE FUCHS; Journal: Science; DOI: 10.1126/science.adi7342

‘DNA Diet’ may help lower health risks related to high blood sugar

A study conducted by Imperial College London and DnaNudge found that personalized dietary advice based on genetic information, along with in-person coaching from a healthcare professional, was more effective at lowering blood glucose levels than standard dietary coaching.

The results are Published in the Journal Nature Scientific Reports.

Pre-diabetes occurs when blood glucose levels are consistently elevated but not yet at the level of type 2 diabetes (T2D). While pre-diabetes is reversible, if left untreated, up to 10% of individuals with pre-diabetes progress to T2D annually. T2D is a leading cause of sight loss, kidney failure, heart attacks, stroke, and lower limb amputation, affecting 90% of the 4.9 million people living with diabetes. However, lifestyle changes have been shown to significantly reduce this risk. Moreover, genetic traits can provide insights into an individual's susceptibility to diet-related chronic conditions, highlighting the importance of personalized dietary modifications to mitigate these risks.

To understand the impact of DNA-based diets on pre-diabetes, researchers enlisted 148 individuals with elevated blood sugar levels. Baseline measurements of fasting plasma glucose (FPG) and glycated haemoglobin (HbA1c) were taken, along with dietary information. Participants were then divided into three groups: a control group receiving NICE-guided coaching, an intervention group receiving coaching and a DNA-based diet, and an exploratory group using DnaNudge's app and wearable device for self-guided DNA-personalized food recommendations. FPG and HbA1c levels were reassessed at 6, 12, and 26 weeks.

No statistically significant difference between the groups at six weeks was found, but a significant reduction in both FPG and HbA1c in participants using the DNA-based diet, both with and without the DnaNudge app, compared to the control group at 26 weeks was observed.

At 26 weeks, compared with the control group, the intervention group saw an average reduction in FPG of 0.019 mmol/L and a reduction in HbA1c by 0.038 mmol/mol, while the exploratory group saw a 0.021 mmol/L reduction in FPG with no reduction in HbA1c.

“Though clinical research into personalised nutrition and type 2 diabetes is still developing, our study adds to evidence that supports the value of such personalised approaches. If validated, our intervention could provide a cost-effective, widely distributable, and easily scalable prevention tool for improving glucose regulation in high-risk individuals.” said Joint first author Dr Maria Karvela, from Imperial College London’s Department of Electrical and Electronic Engineering and DnaNudge.

Reference: Maria Karvela, Caroline T. Golden, Nikeysha Bell, Stephanie Martin-Li, Judith Bedzo-Nutakor, Natalie Bosnic, Pierre DeBeaudrap, Sara de Mateo-Lopez, Ahmed Alajrami, Yun Qin, Maria Eze, Tsz-Kin Hon, Javier Simón-Sánchez, Rashmita Sahoo, Jonathan Pearson-Stuttard, Patrick Soon-Shiong, Christofer Toumazou & Nick Oliver; Journal: Nature Scientific Reports