SLU study explores the pandemic’s impact on breastfeeding practices in historically marginalized communities

COVID-19 provided the elements for an organic experiment, researchers say

Saint Louis University

ST. LOUIS — A Saint Louis University study explored the impact of COVID-19 stay-at-home orders on breastfeeding practices in the U.S.

The study, recently published in the Maternal and Child Health Journal, provides critical insights into how pandemic-induced changes affected breastfeeding habits. Thirty-four percent of mothers said stay-at-home orders facilitated easier breastfeeding at home, stronger mother-child bonding, and extended breastfeeding duration for many women. However, the pandemic also presented significant barriers, including limited access to lactation support and heightened maternal stress.

Earlier studies on mothers' breastfeeding habits yielded samples of a majority of White, non-Hispanic, well-educated, partnered, and employed respondents. This study surveyed the breastfeeding practices of a large and diverse sample of U.S. mothers across various regions, income levels, and racial/ethnic backgrounds.

María José Romo-Palafox, Ph.D., assistant professor of nutrition and dietetics at SLU, is the paper’s senior author. Romo-Palafox is a registered dietitian and researcher focusing on maternal-child health in historically marginalized communities.

“As a Mexican immigrant, I am dedicated to addressing the systemic barriers that disproportionately affect breastfeeding and maternal health. Observing the pandemic's impact on breastfeeding illuminated the urgent need for holistic, supportive work policies,” she said. “I am passionate about contributing to solutions that support breastfeeding and provide mental health and financial stability resources for mothers, creating healthier outcomes for both mothers and children across diverse backgrounds.”

Breastfeeding is one of the best investments in a child’s health, laying a solid nutritional foundation early in life. The World Health Organization recommends exclusively breastfeeding infants up to six months of age; however, in the U.S., only 26% of infants met this recommendation in 2020. 

Returning to work has emerged as one of the main barriers to exclusive and continued breastfeeding. Women attempting to continue breastfeeding by pumping at work often find it challenging to meet their goals due to incomplete support from their management and organization, such as the lack of a designated lactation space and limited time to pump.

The U.S. Senate passed the Providing Urgent Maternal Protections (PUMP) for Nursing Mothers Act in December 2022 and the Pregnant Workers Fairness Act.

While valuable, Romo-Palafox and her team argue that existing policies like the PUMP Act and Pregnant Workers Fairness Act may not adequately meet the needs of low-income, racially diverse mothers who often return to work early out of financial necessity. The COVID-19 stay-at-home orders provided a unique natural experiment where many women found that working from home allowed for more sustained breastfeeding and promoted stronger mother-infant bonding—this period highlighted that even with current policies, many mothers particularly those from historically marginalized backgrounds—require more comprehensive support beyond the lactation accommodation alone.

Romo-Palafox and her team propose policies that go beyond current mandates by ensuring flexibility in work location, especially for roles that typically require in-person attendance. Additionally, policies should include expanded financial stability and mental health resources alongside telehealth lactation services.

“For instance, offering telehealth options for lactation consultants through programs like WIC, which proved effective during the pandemic, is essential to maintain. Although many programs temporarily offered these flexible services, they have since reduced access, leaving gaps in support,” she said. “Reinstating and standardizing telehealth lactation services for breastfeeding mothers, particularly through WIC, would enhance breastfeeding success, reduce stress, and better address the unique challenges faced by low-income and diverse populations.”

Other authors include Valerie Graham, Department of Nutrition and Dietetics, Saint Louis University; Haley Pritz, Department of Nutrition and Dietetics, Saint Louis University; and Zoe Henkes, Saint Louis University School of Medicine.

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About Saint Louis University

Founded in 1818, Saint Louis University is one of the nation’s oldest and most prestigious Catholic institutions. Rooted in Jesuit values and its pioneering history as the first university west of the Mississippi River, SLU offers more than 15,200 students a rigorous, transformative education of the whole person. At the core of the University’s diverse community of scholars is SLU’s service-focused mission, which challenges and prepares students to make the world a better, more just place.

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Journal

Maternal and Child Health Journal

DOI

10.1007/s10995-024-03990-8 

Article Title

Breastfeeding During COVID-19 Stay-at-Home Orders: Implications for Future Maternal Work Policies and Health Equity

 

Plant roots change their growth pattern during ‘puberty’

Research by Prof. Bert De Rybel’s team (VIB-UGent), in collaboration with the VIB Screening Core and Ghent University, uncovers how roots go through a puberty phase, which could have important implications for developing climate-resilient agriculture

Vlaams Instituut voor Biotechnologie

Ghent, November 15, 2024 – Understanding how roots grow can help us develop plants that, for example, are more resistant to drought. Research by Prof. Bert De Rybel’s team (VIB-UGent), in collaboration with the VIB Screening Core and Ghent University, uncovers how roots go through a puberty phase, which could have important implications for developing climate-resilient agriculture. Their work appears in Science.  

Plant puberty 

Plants, like all living organisms, transition through various developmental stages, starting as a seed, becoming a shoot, and eventually a full-grown, fertile plant. They even go through a sort of ‘puberty’ during which a young shoot changes its growth patterns, which is vital for survival and adaptation to the environment. By altering the direction in which cells divide, plants can grow more in width than in height, or vice versa.  

But what happens below the ground? Do the roots go through puberty too?  

Between the first and third week of development, roots undergo a lot of changes. Researchers from the team of Prof. Bert De Rybel (VIB-UGent Center for Plant Systems Biology) and the VIB Screening Core, together with the Department of Chemistry of the University of Ghent, now provide molecular details on 'root puberty’. Their findings highlight the crucial role of SQUAMOSA PROMOTER BINDING-LIKE 13 (SPL13) in regulating oriented cell divisions, a process essential for proper root growth and morphology. 

"Our research provides molecular insights into the age-dependent changes occurring in the root during this crucial phase," says Prof. De Rybel. "We discovered that a change in gene expression of SPL transcription factors, particularly SPL13, is crucial for this transition by regulating the orientation of cell division." 

Complexities of growth  

The transition that results from SPL13 activity is characterized by distinct changes in the morphology and molecular profile of the roots, which are critical for the plant's overall development. 

Dr. Dominique Audenaert, head of the VIB Screening Core (part of VIB Technologies), explains, “We provided advanced microscopy-based screening technology that allowed to screen for molecules that alter cell division orientation in cell cultures. By assessing the mode-of-action of the identified compounds, we could demonstrate that altering SPL13 production in the cells makes the root systems grow steeper and deeper.”  

Changing expression levels of SPL13 even allowed the scientists to speed up or slow down root aging.  

“Our research,” explains Prof. De Rybel, “not only presents a previously unknown fundamental mechanism of plant development, but it also opens new avenues for improved crop yields and plant resilience in changing environmental conditions.”  

As the global population continues to grow, optimizing plant growth and development will be crucial for food security. The importance of SPL transcription factors in plant biology highlights their potential applications in agriculture through changing root growth patterns, which may make crops more resilient to drought, for example.  

By revealing the previously hidden complexity of root development, this study also identifies a gap in current plant research. Most studies use root samples that are one week old, but it is now clear that roots go through significant changes in morphology and gene expression, which means the way we look at root growth in lab conditions will have to be reconsidered.  

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Journal

Science

DOI

10.1126/science.ado4298 

Method of Research

Experimental study

Subject of Research

Cells

Article Title

SPL13 controls a root apical meristem phase change by triggering oriented cell divisions

Article Publication Date

15-Nov-2024

 

New insights reveal how house dust mites trigger allergic asthma by activating the immune system

University of Pittsburgh

 

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Mouse lymph node with hotspots of IL2 activity circled

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Credit: Kun He

New research from the University of Pittsburgh uncovers how inhaled house dust mites, a common trigger of allergic asthma, activate the immune system and drive this disease in mice.

The findings, published recently in Nature Immunology, offer important insights into how seemingly harmless substances such as dust mites, pet dander and pollen can overcome the immune system to trigger allergic reactions and could eventually pave the way for identifying new therapeutics to treat and manage allergic asthma.

“We often think of the immune system as an army that fights the bad guys,” said senior author Amanda C. Poholek, Ph.D., director of the Health Sciences Sequencing Core and assistant professor in the Department of Immunology at Pitt’s School of Medicine. “And while that’s true, most of the time your immune system is not encountering pathogens but dealing with dust and pollen that you breathe in, plants and animals that you eat, and things that you touch in the environment. A big question that motivates my research is: How does our immune system know to respond to pathogens and not to self and the environment?”

When the immune system does this job correctly, it’s known as immune tolerance. But when tolerance breaks down, typically harmless environmental allergens can activate T Helper 2 (Th2) cells, which are a type of immune cell that drives inflammation in allergic asthma and other allergic diseases.

Allergic asthma is the most common form of asthma, characterized by symptoms such as coughing, chest tightness, shortness of breath and wheezing. This debilitating condition is on the rise worldwide and places a substantial burden on the health care system, according to Poholek.

To learn more about how allergens activate Th2 cells and cause allergic asthma, Poholek and her team used a mouse model of the disease triggered by inhalation of house dust mites. This model is a more accurate representation of how humans encounter allergens compared to studies that used under-the-skin or systemic injections of allergen.

Using new tools that allowed them to track Th2 cells and see exactly when they get activated and where they went, the researchers found that in response to inhaled house dust mite, a specific molecular pathway involving a protein called BLIMP1 was needed to generate Th2 cells in the lymph node. These cells then move to the lung and drive disease. In contrast, when house dust mite is injected, that molecular pathway is not needed.

They also found that two signaling molecules, or cytokines, called IL2 and IL10 were required for expression of BLIMP1.

“IL10 is normally thought of as an anti-inflammatory cytokine, which dampens immune responses, so we were really surprised to find that it was actually promoting inflammation,” said Poholek. “This finding opens that door to therapeutic options targeting IL10, which hadn’t previously been considered, particularly for newly diagnosed patients.”

According to Poholek, most patients with allergic asthma receive steroids, which treat the symptoms but not the root of the disease. There is a huge need for new treatments that allow early intervention before allergic asthma causes long-term damage to the airways.

When the researchers mapped the location of Th2 activation in the lymph node, they were also surprised to find hotspots of IL2 activity.

“IL2 is a very prominent cytokine, so we expected that it would be dispersed throughout the lymph node,” said Poholek. “Instead, we discovered that IL2 was localized to certain regions. Now, we have a lot more work to figure out how these regions form and whether disrupting these regions could disrupt the formation of Th2 cells, halting allergic asthma.”

In collaboration with colleagues in the Pitt Division of Pulmonology, Allergy, Critical Care and Sleep Medicine, Poholek is also planning to look at lung tissue samples to investigate whether IL2 and IL10 could also be important drivers of Th2 cells in patients with allergic asthma and explore potential avenues for developing new therapeutic options.

Other authors are listed in the Nature Immunology paper.

This work was supported by the National Institutes of Health (DP2AI164325, AI153104 and AI156093), the American Lung Association Innovation Award, the Research Advisory Committee at UPMC Children’s Hospital of Pittsburgh and the Clinical and Translational Science Institute Pilot Award.

 

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Journal

Nature Immunology

DOI

10.1038/s41590-024-01986-8 

Article Title

Spatial microniches of IL-2 combine with IL-10 to drive lung migratory TH2 cells in response to inhaled allergen

 

Fewer than 1 in 5 know the 988 suicide lifeline

Annenberg Public Policy Center of the University of Pennsylvania

 

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US adults who know that 988 is the Suicide and Crisis Lifeline. From the Annenberg Public Policy Center's Annenberg Science and Public Health (ASAPH) knowledge surveys from January 2023-September 2024.

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Credit: Annenberg Public Policy Center

PHILADELPHIA – Annenberg Public Policy Center survey data show that public recall of the 988 Suicide & Crisis Lifeline number has grown slowly since the three-digit phone number was introduced in July 2022. Just 15% of U.S. adults are familiar with it, as of September 2024.

Survey respondents who accurately report awareness of the Suicide & Crisis Lifeline number increased significantly from August 2023 (11%) to September 2024 (15%). Those 15% of respondents reported both that they knew the number and, when asked in an open-ended format, said the number was 988. The number who inaccurately reported that the number was 911 (the nationwide emergency phone number) decreased to 1% in September 2024 from 4% in August 2023.

“The help that can be found at the 988 helpline can only save lives if those in need and their loved ones and friends know the number,” said Kathleen Hall Jamieson, director of the Annenberg Public Policy Center of the University of Pennsylvania. “When 988 is as readily recalled as 911, the nation will have cause to celebrate.”

Although the survey found a year-over-year increase, it did not detect an increase in accurate responses between October 2023 and September 2024, a period that included the launch of an eight-month 988 awareness ad campaign by the Substance Abuse and Mental Health Services Administration (SAMHSA) in June 2024. The SAMHSA media campaign targets especially vulnerable subsets of the population, which may be too small to impact the overall awareness estimates in our nationally representative, general population sample.

APPC’s Annenberg Science and Public Health knowledge survey

The survey data come from the 21st wave of a nationally representative panel of 1,744 U.S. adults conducted for the Annenberg Public Policy Center by SSRS, an independent market research company. Most have been empaneled since April 2021. To account for attrition, small replenishment samples have been added over time using a random probability sampling design. The most recent replenishment, in September 2024, added 360 respondents to the sample. This wave of the Annenberg Science and Public Health Knowledge (ASAPH) survey was fielded Sept. 13-22 and Sept. 26-30, 2024. The margin of sampling error (MOE) is ± 3.5 percentage points at the 95% confidence level. All figures are rounded to the nearest whole number and may not add to 100%. Combined subcategories may not add to totals in the topline and text due to rounding.

Download the topline and the methods report.

The policy center has been tracking the American public’s knowledge, beliefs, and behaviors regarding vaccination, Covid-19, flu, RSV, and other consequential health issues through this survey panel over the past two-and-a-half years. In addition to Jamieson and Gibson, APPC’s team on the survey includes research analyst Shawn Patterson Jr., Patrick E. Jamieson, director of the Annenberg Health and Risk Communication Institute, and Ken Winneg, managing director of survey research.

The Annenberg Public Policy Center was established in 1993 to educate the public and policy makers about communication’s role in advancing public understanding of political, science, and health issues at the local, state, and federal levels.

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Method of Research

Survey

Germany’s first-ever professorship in suicide studies and suicide prevention established at Goethe University Frankfurt

Ute Lewitzka appointed – Heightened focus on suicide prevention within the Faculty of Medicine

Goethe University Frankfurt

 

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Prof. Dr. Ute Lewitzka, Goethe University Frankfurt (Photo: Maria Schlotte)

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Credit: Photo: Maria Schlotte

FRANKFURT. More than 10,000 people took their own lives in Germany last year, a figure that is more than three times as great as the number of traffic accident fatalities. The number of attempted suicides is significantly higher, affecting people across all age groups. Suicide studies focus on the factors that lead to suicide and its prevention. This important field is now receiving special attention in Frankfurt, where the first-ever German professorship for suicide studies and suicide prevention has been set up at Goethe University’s Faculty of Medicine.

Dr. Ute Lewitzka, who has been researching and working in this field for more than 25 years and currently serves as chair of the German Society for Suicide Prevention [Deutsche Gesellschaft für Suizidprävention], has been appointed to the position. “I’m very pleased to see suicide studies, which unfortunately still remain a niche topic, gain this level of recognition,” says Lewitzka, who transitions to Frankfurt from Dresden University Hospital, adding that a professorship can help further destigmatize mental illnesses. Her goals include the systematic tracking and analysis of suicide attempts and suicides to further develop effective preventive measures and potentially also implement these at the political level.

The professorship is based at University Hospital Frankfurt's Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, headed by Prof. Andreas Reif, which has long specialized in treating mood disorders, such as depression. The goal is to establish a German Center for Suicide Prevention in collaboration with the German Foundation for Depression Relief and Suicide Prevention [Stiftung Deutsche Depressionshilfe und Suizidprävention] and the European Alliance against Depression. A well-developed regional network already exists, uniting various stakeholders who drive research and treatment of suicidality and engage in prevention work, including school-based programs. Alongside research, specialist education and training are set to play a central role.

The project has secured funding for the next five years, thanks to the support of Crespo Foundation, Henryk Sznap Stiftung, and Dr. Elmar und Ellis Reiss Stiftung, with the latter contributing the majority of funds. Dr. Elmar Reiss, who set up the foundation with his wife in 2018, explained that the professorship’s goals align closely with the foundation’s mission: “Our main goal in establishing the foundation was to help people with depression and alleviate their suffering. Depression is a condition that can increase suicide risk. Our foundation aims to help those affected find other paths and once again see light at the end of the tunnel.”

Developing effective prevention methods requires an extensive amount of data. As part of a pilot project in Saxony, Lewitzka demonstrated that the prompt recording and evaluation of suicide attempts by specially trained emergency dispatchers enables the creation of “heat maps” that visually represent the locations and frequencies of incidents. Combined with targeted monitoring of the methods used in suicide (and suicide attempts), this approach can prevent many suicides. Frequently chosen methods of self-harm can be regulated — for instance, by controlling access to specific buildings or sites. “Restricting methods is one of the most effective prevention measures,” Lewitzka explains.

About Prof. Dr. Ute Lewitzka
Born in 1972, Prof. Dr. med. Ute Lewitzka studied medicine in Berlin and Dresden and trained as a specialist in psychiatry and psychotherapy at Dresden’s Carl Gustav Carus University Hospital. Her doctoral thesis in 2004 and her habilitation in 2018 both focused on suicide studies. In 2017, she founded the Werner Felber Institute for Suicide Prevention and Interdisciplinary Research in Healthcare [Werner Felber Institut für Suizidprävention und interdisziplinäre Forschung im Gesundheitswesen], of which she remains the chair. Since 2018, she has also served as volunteer chair of the Deutsche Gesellschaft für Suizidprävention (DGS) and the Suicide Studies Committee of the German Association for Psychiatry, Psychotherapy and Psychosomatics [Deutsche Gesellschaft für Psychiatrie und Psychotherapie, Psychosomatik und Nervenheilkunde, DGPPN].

 

New nasal vaccine shows promise in curbing whooping cough spread

With whooping cough cases on the rise new nasal vaccine aims to stop transmission

Tulane University

As whooping cough cases rise in the U.S., a new nasal vaccine developed by Tulane University may hold the key to reducing the spread of the highly contagious respiratory disease.

Current pertussis vaccines are widely used and effective at preventing whooping cough, caused by the Bordetella pertussis bacteria.  However, the vaccines fail to clear bacteria from the upper respiratory tract, allowing even vaccinated individuals to spread the disease.

The new vaccine combines the traditional pertussis antigens with an innovative adjuvant called T-vant, which boosts the body’s immune response specifically in the respiratory tract. In a study published in npj Vaccines, mice immunized intranasally with the new T-vant vaccine showed no signs of the bacteria in the lungs and nasopharynx – the upper throat area behind the nose – three weeks after infection. The bacteria remained prevalent in upper respiratory tract of mice that received the traditional vaccine intramuscularly.

“By developing a vaccine that can not only protect individuals but also prevent transmission, we hope to improve on existing vaccines and limit the spread of whooping cough in communities,” said lead study author Lisa Morici, professor of microbiology and immunology at Tulane University School of Medicine.

The T-vant adjuvant is derived from bacterial outer membrane vesicles, tiny particles that naturally stimulate the immune system. The study found that the adjuvant encouraged a mucosal immune response, spurring the activation of immune cells in the respiratory tract critical for halting the bacteria’s ability to colonize.

The study also found no adverse effects on lung tissue following immunization, highlighting the vaccine’s safety.

The findings are significant and come at a time when whooping cough cases are surging. Recent data from the Centers for Disease Control and Prevention showed a five-fold increase in U.S. cases over last year. The disease affects roughly 24 million people a year worldwide and primarily impacts infants and those with weakened immune systems.

A vaccine that can successfully prevent infection and transmission of whooping cough in humans could lay the groundwork for eliminating the disease altogether, said James McLachlan, co-author of the study and associate professor of microbiology and immunology at Tulane School of Medicine.

“These findings underscore the need for enhanced vaccines that can do more than just protect the individual,” McLachlan said. “We need vaccines that can effectively stop the bacteria from spreading within communities, and this new approach offers an encouraging step in that direction.”

T-vant was developed through support from the NIH Adjuvant Development Program. More information on T-vant can be found at https://vac.niaid.nih.gov/view?id=61.

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Journal

npj Vaccines

DOI

10.1038/s41541-024-00990-1 

Subject of Research

Animals

Article Title

A novel outer membrane vesicle adjuvant improves vaccine protection against Bordetella pertussis

 

Anti-anxiety and hallucination-like effects of psychedelics mediated by distinct neural circuits

Mouse study suggests path to decouple benefits from hallucinogenic effects

University of California - Davis

 

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Working in a mouse model, UC Davis researchers are able to distnguish brain cells activated by a psychedelic drug. This image shows the prefrontal cortex of a mouse injected with scFLARE2 (purple) which drives the expression of a light-responsive channel in psychedelic-activated neurons (green or red). This allows researchers to visualize and artificially reactive these neurons at a later time point. 

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Credit: Christina Kim, UC Davis

New research suggests that it could be possible to separate treatment from hallucinations when developing new drugs based on psychedelics. The anti-anxiety andhallucination-inducing qualities of psychedelic drugs work through different neural circuits, according to research using a mouse model. The work is published Nov. 15 in Science. 

The research shows that decoupling the beneficial effects of psychedelics from their hallucinogenic effects isn’t just a matter of chemical compound design. It’s a matter of targeted neural circuitry.

“In the past, we did this using chemistry by making new compounds, but here we focused on identifying the circuits responsible for the effects, and it does seem that they are distinct,” said study co-author David E. Olson, director of the Institute for Psychedelics and Neurotherapeutics (IPN) and a professor of chemistry and of biochemistry and molecular medicine at the University of California, Davis. “This is an important mechanistic study that validates our earlier results.” 

Measuring anti-anxiety behaviors in mice

The researchers measured anxiety in mouse models with two tests: the elevated plus maze and the marble burying test. 

In the elevated plus maze, mice are placed in a cross-shaped maze raised a couple of feet off the ground. Two arms of the maze have high walls while the other two arms remain open and have no walls. Mice with high anxiety tend to stay in the closed arms with high walls, not willing to explore the open arms.

In the marble burying test, mice with high anxiety tend to continuously and compulsively bury marbles in their bedding. 

“It is well known that in mice, psychedelics induce reduced marble burying and promote exploration of the open arms of the plus maze,” said Christina Kim, the study’s corresponding author and an assistant professor of neurology, core member of the Center for Neuroscience and IPN affiliate. “But there is also an intoxicating or hallucinogenic-like effect, which can be measured through head twitches in mice.” 

In the study, the team dosed mouse models with the psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI). They found that six hours after the dose, the mice still exhibited reduced marble burying and increased open arm time in the elevated plus maze. However, the head twitches associated with hallucinations had disappeared. 

“We thought that if we could identify which neurons activated by DOI were responsible for reducing anxiety, then we might be able to reactivate them at a later time to mimic those anti-anxiety-like effects,” Kim said. 

To identify the specific neural circuits associated with anti-anxiety effects, the team used a molecular tagging tool called scFLARE2 to highlight the neurons activated by DOI in the medial prefrontal cortex — a brain region known to be involved in reducing anxious behavior in mice. 

The tagging allowed the team to isolate a psychedelic responsive network that extends beyond 5-HT2AR expressing neurons, the main receptor avenue through which psychedelics promote neuroplasticity. 

Using light to promote anti-anxiety effects

Equipped with a fluorescent map of the neurons activated by DOI, the team then used optogenetics, or light, to reactivate those neurons.

“When we performed the scFLARE2 tagging and reactivation of these specific prefrontal cortex cells, we could still drive a reduction in anxiety-like behaviors, measured as decreased marble burying and increased open arm exploration in the elevated plus maze,” Kim said. “We could do this just by targeting the DOI-activated cells and then reactivating them the next day.” 

The team also used single nucleus RNA sequencing to genetically profile the specific types of neurons in the DOI-activated network. Of the nine neuron group types identified, three exhibited high activation.

“While some of the cell types activated by DOI had strong 5-HT2AR expression, there were others that did not,” Kim said. “What is likely happening is that we are getting direct activation of cells that express 5-HT2AR, and then they go on to activate additional downstream cells that can trigger behavioral changes.” 

“It is important to realize that the cells that we are tagging and reactivating extend beyond just those that express the receptor for the drug,” she added.

The finding emphasizes how activating single touchpoints in the brain spirals out into the rest of the network. 

“While DOI is a potent psychedelic, it is not being explored as a potential therapeutic drug in the clinic. Thus the findings here are focused on dissecting the basic circuit mechanisms of this important class of drugs,” Kim said.

Elucidating exactly how psychedelics affect the brain is a major goal of the IPN. 

“Understanding which neural circuits psychedelics activate to elicit their effects is the kind of basic science needed to ultimately develop targeted therapeutics with better safety profiles,” Olson said. 

Co-authors Jessie Muir, a postdoctoral researcher at the Center for Neuroscience, and Sophia Lin, a junior specialist at the Center for Neuroscience, spearheaded the DOI study. Additional authors on the study include I.K. Aarrestad, H.R. Daniels, J. Ma and L. Tian.

Funding for the research was provided by the Burroughs Wellcome Fund Career Award at the Scientific Interface, the Brain & Behavior Research Foundation Young Investigator Award, the Searle Scholars Program, The Kavli Foundation, the UC Davis Behavioral Health Center for Excellence Pilot Award, the Canadian Institutes of Health Research postdoctoral training award, the National Institutes of Health, the Boone Family Foundation and the Camille Dreyfus Teacher-Scholar Award. 

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Journal

Science

DOI

10.1126/science.adl0666 

Method of Research

Experimental study

Subject of Research

Animals

Article Title

Isolation of psychedelic-responsive neurons underlying anxiolytic behavioral states

Article Publication Date

15-Nov-2024

COI Statement

David Olson is a cofounder of Delix Therapeutics, Inc., and serves as the chief innovation officer and head of the scientific advisory board. The remaining authors declare no other competing interests.

Study: How can low-dose ketamine, a ‘lifesaving’ drug for major depression, alleviate symptoms within hours? UB research reveals how

University at Buffalo

 

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How can low-dose ketamine, a ‘lifesaving’ drug for major depression, alleviate symptoms within hours? UB research reveals how

 

These images demonstrate the different binding sites in NMDA receptors that the UB team has discovered are responsible for ketamine’s distinct clinical effects, as an anesthetic at high doses and as an anti-depressant at very low doses. The image on the left shows ketamine bound in the central pore of the receptor, which results in anesthetic action; the one on the right shows ketamine bound in the lateral sites, which results in anti-depressive action. 

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Credit: Jamie Abbott/University at Buffalo

BUFFALO, N.Y. — University at Buffalo neuroscientists have identified the binding site of low-dose ketamine, providing critical insight into how the medication, often described as a wonder drug, alleviates symptoms of major depression in as little as a few hours with effects lasting for several days.

 

Published in September in Molecular Psychiatry, the UB discovery will also help scientists identify how depression originates in the brain, and will stimulate research into using ketamine and ketamine-like drugs for other brain disorders.

 

PHOTOS: https://www.buffalo.edu/news/releases/2024/11/How-ketamine-lifts-depression-so-quickly.html

 

A lifesaving drug

 

Ketamine has been used since the 1960s as an anesthetic, but in 2000, the first trial of far lower doses of ketamine proved its rapid efficacy in treating major depression and suicidal ideation.

 

“Due to its fast and long-lasting effects, low-dose ketamine proved to be literally a lifesaving medicine,” says Gabriela K. Popescu, PhD, senior author on the research and professor of biochemistry in the Jacobs School of Medicine and Biomedical Sciences at UB.

 

Traditional antidepressants take months to kick in, which increases the risk for some patients to act on suicidal thoughts during the initial period of treatment. Ketamine provides almost instant relief from depressive symptoms and remains effective for several days and up to a week after administration. Since this observation was published in the early 2000s, ketamine clinics, where the drug is administered intravenously to treat depression, have been established in cities nationwide.

 

But just how ketamine achieves such a dramatic antidepressive effect so quickly has been poorly understood at the molecular level. This information is critical to understanding not only how best to use ketamine, but also to developing similar drugs.

 

Selective effects on NMDA receptors

 

Ketamine binds to a class of neurotransmitter receptors called N-methyl-D-aspartate (NMDA) receptors. Popescu is an expert on how these receptors produce electrical signals that are essential for cognition, learning and memory, and how these signals, when dysregulated, result in psychiatric symptoms. 

“We demonstrate in this article how ketamine at very low concentrations can affect the activity of only select populations of NMDA receptors,” says Popescu.

NMDA receptors are present throughout the brain and are essential for maintaining consciousness. For this reason, she explains, drugs that act indiscriminately on all NMDA receptors have unacceptable psychiatric side effects. “We believe that the selectivity we uncovered in our research explains how low-dose ketamine can treat major depression and prevent suicides in people with depression,” Popescu says.  

The research was sparked by an observation in her lab by co-author Sheila Gupta, then a UB undergraduate. “Sheila noticed that when applied onto NMDA receptors that were chronically active, ketamine had a stronger inhibitory effect than expected based on the literature,” Popescu explains. “We were curious about this discrepancy.”

 

Back when ketamine’s antidepressant effects first became known, researchers tried to find out how it worked by applying it onto synaptic currents produced by NMDA receptors, but the drug produced little or no effect.

 

“This observation caused many experts to turn their attention to receptors located outside synapses, which might be mediating ketamine’s antidepressive effects,” Popescu says. “Sheila’s observation that ketamine is a stronger inhibitor of receptors that are active for longer durations inspired us to look for mechanisms other than the direct current block, which was assumed to be the only effect of ketamine on NMDA receptors.”

 

Few labs with this NMDA expertise

 

Popescu’s lab is among a handful in the world with the expertise to quantify the process by which NMDA receptors become active. This allowed Popescu and her colleagues to identify and measure what exactly changed during the NMDA activations when ketamine was present at very low doses versus when it was present at high (anesthetic) doses.

 

“Because we track activity from a single receptor molecule over an extended period of time, we can chart the entire behavioral repertoire of each receptor and can identify which part of the process is altered when the receptor binds a drug or when it harbors a mutation,” Popescu explains.

 

“The mechanism we uncovered suggests that at low doses, ketamine will only affect the current carried by receptors that had been active in the background for a while, but not by synaptic receptors, which experience only brief, intermittent activations,” she continues. “This results in an immediate increase in excitatory transmission, which in turn lifts depressive symptoms. Moreover, the increase in excitation initiates the formation of new or stronger synapses, which serve to maintain higher excitatory levels even after ketamine has cleared from the body, thus accounting for the long-term relief observed in patients.”  

 

The UB research helps explain why such low doses of ketamine are effective.

“Our results show that very low levels of ketamine, on the nanoscale, are sufficient to fill two lateral grooves of the NMDA receptors to selectively slow down extra-synaptic receptors, alleviating depression. Increasing the dose causes ketamine to spill over from the grooves into the pore and begin to block synaptic currents, initiating the anesthetic effect.” says Popescu.

 

Popescu’s co-authors in the Department of Physics in the College of Arts and Sciences simulated the three-dimensional structure of the NMDA receptor and predicted the exact residues to which ketamine binds in the lateral sites. “These interactions are strong and account for the high affinity of the receptor for low doses of ketamine,” she says.

 

“The simulations show that at high concentrations, which is how it is used as an anesthetic, ketamine indeed lodges itself in the central ion-conducting pore of the receptors, where it stops ionic current from flowing through the receptor,” says Popescu.

 

In contrast, at low concentrations, ketamine functions very differently, attaching to two symmetrical sites on the sides of the pore, such that instead of stopping the current, ketamine makes receptors slower to open, reducing the current only a little bit. “Finding the exact binding site on the receptor offers the perfect template for developing ketamine-like drugs that could be administered orally and may lack the addictive potential of ketamine,” says Popescu.

 

The natural next step is to screen existing drugs that can fit in the lateral grooves of NMDA receptors, first computationally and then experimentally.  

 

Lead authors are Jamie A. Abbott, PhD, in the Department of Biochemistry, and Han Wen in the Department of Physics. Other co-authors are Gupta, Wenjun Zheng Beiying Liu and Gary J. Iacobucci. The research was funded by the National Institutes of Health.

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Journal

Molecular Psychiatry

DOI

10.1038/s41380-024-02729-9 

Method of Research

Experimental study

Subject of Research

Human tissue samples

Article Title

Allosteric inhibition of NMDA receptors by low dose ketamine