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An exciting study by researchers in the laboratory of Dr. Huda Zoghbi, distinguished service professor at Baylor College of Medicine and director of the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital, has discovered that diminished memory recall in Rett syndrome mice can be restored by activating specific inhibitory cells in the hippocampus. The findings are published in the current edition of Neuron.
Rett syndrome is a neurodevelopmental disorder characterized by loss of acquired cognitive, motor, language and social skills after the first year of life as well as profound learning and memory impairments. In particular, contextual memories, those that encode an event and the circumstances in which the event was experienced, are diminished in mouse models of Rett syndrome. Previous research has suggested that diminished contextual memories result from disruptions in the finely tuned balance between excitatory and inhibitory synaptic inputs that constantly bombard hippocampal neurons.
Zoghbi’s team hypothesized that disruptions in this balance may alter the size and composition of ensembles of hippocampal neurons needed to encode a contextual memory. Using a miniature microscope, they directly monitored these ensembles as mice recalled a fearful experience. They found that Rett mice have larger and more correlated ensembles of neurons than wild-type mice, suggesting that hippocampal pyramidal neurons are not receiving enough inhibition in Rett mice. “An optimal balance between excitatory and inhibitory input is critical for the proper formation and retrieval of contextual memories,” said Lingjie He, postdoctoral associate in the Zoghbi lab and first author.
The next big question that the team addressed was, Which neuron is not providing the inhibition?
To hunt for this neuron, the team recorded neuronal activity from identified cell types in brain slices. They found a significant reduction in connectivity between pyramidal cells and a subset of somatostatin-expressing (SOM) inhibitory neurons, the OLM cells. They found that these cells, which are normally recruited by hippocampal pyramidal neurons in healthy mice during memory recall, were poorly engaged in Rett mice.
This led the team to wonder if activating these inhibitory neurons during memory recall would help Rett mice remember better. To address this, they selectively enhanced the activity of somatostatin cells in the hippocampus using a chemical-genetic approach that allows for the activation of a specific cell type. Incredibly, activating somatostatin expressing cells in Rett mice restored contextual memory recall.
“This is the first study to demonstrate that upregulating the activity of SOM neurons can improve memory recall and retrieval capacity in Rett mice,” said Zoghbi, Howard Hughes Medical Institute investigator. “It opens exciting areas of research to explore therapeutic possibilities that could improve contextual memory recall in individuals affected by Rett syndrome. These findings have a much broader implication and are also applicable to other neurological disorders in which the development and function of inhibitory circuits are altered.”
Other authors involved in the study are Matthew Caudill, Junzhan Jing, Wei Wang, Yaling Sun, Jianrong Tang and Xiaolong Jiang. The authors are affiliated with one or more of the following institutions: Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine and Howard Hughes Medical Institute. The study was funded by Howard Hughes Medical Institute, National Institutes of Health, Baylor College of Medicine, the Charif Souki Fund and the Yasmine Gibellini fund.
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Materials provided by Baylor College of Medicine. Original written by Graciela Gutierrez. Note: Content may be edited for style and length.

Some people are gifted with genes that pack the benefits of slumber into an efficient time window, keeping them peppy on only four or six hours of sleep a night, according to researchers at UC San Francisco. In addition, the scientists said, these “elite sleepers” show psychological resilience and resistance to neurodegenerative conditions that may point the way to fending off neurological disease.
“There’s a dogma in the field that everyone needs eight hours of sleep, but our work to date confirms that the amount of sleep people need differs based on genetics,” said neurologist Louis Ptacek, MD, one of the senior authors on the study, which appears in iScience on March 15, 2022 “Think of it as analogous to height; there’s no perfect amount of height, each person is different. We’ve shown that the case is similar for sleep.”
For over a decade, Ptacek and co-senior author, Ying-Hui Fu, PhD, both members of the UCSF Weill Institute for Neurosciences, have been studying people with Familial Natural Short Sleep (FNSS), the ability to function fully on — and have a preference for — four to six hours of sleep a night. They’ve shown that it runs in families and, thus far have identified five genes across the genome that play a role in enabling this efficient sleep. There are still many more FNSS genes to find, the researchers said.
This study tested Fu’s hypothesis that elite sleep can be a shield against neurodegenerative disease. Her ideas contrast somewhat with current thinking that, for many people, lack of sleep can accelerate neurodegeneration. The difference, Fu said, is that with FNSS, the brain accomplishes its sleep tasks in a shorter time. In other words, less time spent efficiently sleeping may not equate to a lack of sleep.
The team chose to look at mouse models of Alzheimer’s disease because that condition is so prevalent, said Fu. They bred mice that had both short-sleep gene and genes that predisposed them to Alzheimer’s and found that their brains developed much less of the hallmark aggregates associated with dementia. To confirm their findings, they repeated the experiment using mice with a different short-sleep gene and another dementia gene and saw similar results.
Fu and Ptacek believe that similar investigations of other brain conditions would show the efficient-sleep genes conferring comparable protections. improving peoples’ sleep could delay progression of disease across a whole spectrum of conditions, they said.

Treating cancer and other diseases with laser light is not currently considered routine in the clinical setting, but new approaches using nanoparticles show some promise in improving existing techniques.
One technique, known as photothermal therapy (PTT), converts laser light into heat that can target and kill tumor cells. Another technique, photodynamic therapy (PDT), uses laser light to generate reactive oxygen species (ROS), such as hydroxyl radicals, singlet oxygen, superoxide radicals, and hydrogen peroxide, which can wreak devastation on tumor cells.
In Applied Physics Reviews, by AIP Publishing, a multinational team of researchers reviews the current status of the field of nanoparticle-enhanced PDT and PTT and focuses on combining the two techniques to achieve the highest level of treatment efficiency.
By combining PTT or PDT with nanomaterials, investigators have been able to apply these types of phototherapies while also delivering drugs to sites in the body that are otherwise inaccessible. It is also possible to combine PTT and PDT into a single treatment, creating an even more powerful treatment method.
The surface of the nanoparticle can be modified to attach a photosensitive molecule to the surface. This allows the absorption of light at a particular wavelength. In the PTT method, this light is converted to heat. In PDT, the light creates ROS. For PDT to be successful, sufficient ambient oxygen must be present to produce enough ROS to kill tumor cells.
“In cancer therapies using this strategy, the penetration depth of laser light into the tissues is critical in determining the therapeutic efficiency,” said author Masoud Mozafari, from the Iran University of Medical Sciences.
Factors that control the penetration depth include the shape of the beam, wavelength of the light, intensity of the laser, and the radius of the beam.
A powerful approach is to combine PDT with traditional medical treatments, such as chemotherapy, to create photodynamic antibacterial chemotherapy.
The nanoparticles can be used to deliver chemotherapeutic agents or antibiotics to the tumor site. When light is applied, generating ROS molecules in the tumor and killing both tumor cells and bacteria, the antibiotics can be released to prevent infection in the treated area.
Other modifications to the nanoparticle surface could allow it to cross the blood-brain barrier so that brain tumors can be treated.
One set of studies reviewed in this work involved gold nanorods that had a glycoprotein from the rabies virus attached to their surface. Since this virus naturally infects the brain, the gold nanorods were able to penetrate the blood-brain barrier and target the brain tumor. Applying light from a laser then allowed the nanorods to generate localized heat, killing the tumor cells.
These techniques can also be used to treat other medical issues, such as atherosclerosis, scar removal, abscesses, nonhealing ulcers, or dental infections.
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Materials provided by American Institute of Physics. Note: Content may be edited for style and length.

During the first wave of the COVID-19 pandemic, many patients in intensive care units did not recover consciousness after their breathing tubes were removed and their sedation was stopped, leaving clinicians and families with difficult decisions about whether to continue life-sustaining therapy. Remarkably, the majority of these patients ultimately recovered consciousness, but often after days or even weeks. To help provide accurate prognostic information moving forward, a team at Massachusetts General Hospital (MGH), NewYork-Presbyterian/Columbia University Irving Medical Center, Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center launched a multicenter study to better understand the recovery timeline and the causes of delayed recovery of consciousness in patients with severe COVID-19.
The study, which is published in the Annals of Neurology, involved a retrospective analysis of 795 patients with severe COVID-19 who were treated with mechanical ventilators in the intensive care units of the investigators’ medical centers for at least six days. After respiratory support ended, clinicians performed daily assessments to see whether patients could respond purposefully to a verbal command, a standard measure of consciousness.
Of the 795 patients, 72% survived and ultimately recovered consciousness prior to hospital discharge. For those who survived, 25% recovered consciousness 10 or more days after ventilator support was stopped, and 10% took more than three weeks to recover.
“When we examined the potential causes of delayed recovery of consciousness, we found that low blood oxygen levels correlated with the time to recovery, even after accounting for other factors such as exposure to sedatives,” says co-senior author Brian L. Edlow, MD, associate director of the Center for Neurotechnology and Neurorecovery at MGH and associate professor of neurology at Harvard Medical School. “This relationship was dose-dependent — the more episodes of low blood oxygen that a patient experienced, the longer it took them to wake up.”
Most patients had normal brain scans, suggesting that the prolonged time to recover consciousness was not related to stroke, swelling, or bleeding in the brain. “These observations were consistent across all three medical centers and during the first and second surges of the COVID-19 pandemic,” says Jan Claassen, MD, a co-leader of the study and associate professor of neurology at Columbia University Vagelos College of Surgeons and Physicians.
Additional research is needed to understand the mechanisms behind the link between low blood oxygen levels and prolonged time to recover consciousness. “We’ve seen similar phenomena in rare patients with cardiac arrest who were treated with hypothermia,” says Nicholas D. Schiff, MD, a co-leader of the study and the Jerold B. Katz Professor of Neurology and Neuroscience in the Feil Family Brain and Mind Research Institute and co-director of the Consortium for the Advanced Study of Brain Injury (CASBI) at Weill Cornell Medicine and an attending neurologist at NewYork-Presbyterian/Weill Cornell Medical Center. “Hypothermia appears to protect cardiac arrest patients from neurological damage in ways we still don’t understand. We’re now moving forward with studies aimed at uncovering common underlying mechanisms of neuroprotection that might connect these two groups of patients.”
Regardless of the underlying mechanisms yet to be uncovered, the study’s results could have an immediate clinical impact. “These findings provide us with more accurate information to guide families who are deciding whether to continue life-sustaining therapy in unconscious COVID-19 patients,” says Edlow. “The fact that delayed recovery of consciousness was consistently seen at three different medical centers, across two surges of COVID-19, suggests that we should consider the possibility of delayed recovery when making life-of-death decisions for these patients in the intensive care unit.”
The results may also be applied to critically ill patients with other medical conditions. “We are trying to determine whether the lessons learned from patients with severe COVID-19 can inform our approach to oxygenation targets and sedation management in the intensive care unit for the broad spectrum of patients who require mechanical ventilation,” says co-author Emery N. Brown, MD, PhD, professor of anesthesia at Harvard Medical School, anesthesiologist at MGH, and professor of medical engineering and computational neuroscience at Massachusetts Institute of Technology.
Co-first author Megan E. Barra, PharmD, a clinical pharmacy specialist in neurocritical care at MGH, notes that additional research is also needed to determine the degree of functional recovery in patients with COVID-19 or other conditions who experience prolonged unconsciousness after ventilator support is stopped. “We did not look at long-term recovery of cognition or functional independence in our study, but this is an important consideration for patients and their families,” she says.
Additional study co-authors include Greer Waldrop, MD, ScM; Seyed A. Safavynia, MD, PhD; Sachin Agarwal, MD, MPH; David A. Berlin, MD; Amelia K Boehme, PhD, MSPH; Daniel Brodie, MD; Jacky M. Choi, MPH; Kevin Doyle, MA; Joseph J. Fins, MD; Wolfgang Ganglberger, MSc; Katherine Hoffman, MS; Aaron M. Mittel, MD; David Roh, MD; Shibani S. Mukerji, MD, PhD; Caroline Der Nigoghossian, PharmD,; Soojin Park, MD; Edward J. Schenck, MD; John Salazar-Schicchi, MD; Qi Shen, PhD; Evan Sholle, MS; Angela G. Velazquez, MD; Maria C. Walline, MD; M. Brandon Westover, MD, PhD; Jonathan Victor, MD, PhD.
The study was supported by the James S. McDonnell Foundation.

Disease of the small airways in the lungs is a potential long-lasting effect of COVID-19, according to a new study published in the journal Radiology. The study found that small airways disease occurred independently of initial infection severity. The long-term consequences are unknown.
“There is some disease happening in the small airways independent of the severity of COVID-19,” said study senior author Alejandro P. Comellas, M.D., professor of internal medicine and faculty in the Division of Pulmonary and Critical Care Medicine at the Carver College of Medicine, University of Iowa in Iowa City. “We need to investigate further to see whether it is transient or more permanent.”
Early reports indicate that more than 50% of adult survivors of SARS-CoV-2 infection experience post-acute sequelae of COVID-19 (PASC), more commonly known as “long COVID.” Respiratory symptoms, including cough and dyspnea, are reported by nearly 30% of patients with long COVID, including those who experienced mild infection.
The study grew out of observations from University of Iowa clinicians that many patients with initial SARS-CoV-2 infection who were either hospitalized or treated in the ambulatory setting later showed signs of chronic lung disease such as shortness of breath and other respiratory symptoms.
Dr. Comellas and colleagues put a protocol in place to perform both inspiratory and expiratory CT in these patients. Inspiratory CT, performed after patients inhale, is the standard imaging technique for viewing lung tissue, but post-exhalation expiratory scans are needed to assess air trapping, a condition in which people are not able to empty their lungs when they breathe out. Air trapping is found in many obstructive airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD).
For the study, the researchers compared CT findings in people who had COVID-19 and persistent symptoms with those of a healthy control group. They enrolled 100 adults with confirmed COVID-19 who had remained symptomatic more than 30 days following diagnosis, along with 106 healthy participants. The 100 COVID-19 survivors, median age 48 years, included 67 who were classified as ambulatory, or not requiring hospitalization, 17 who were hospitalized, and 16 who required care in the intensive care unit (ICU) during acute infection.

A Johns Hopkins Children’s Center-led study in animals suggests that high doses of a widely used antibiotic called rifampin may safely treat and reduce the duration of treatment for the deadliest form of tuberculosis that affects the brain, potentially improving survival rates for patients and decreasing the likelihood of lasting adverse effects of the disease. Additional studies in a small number of people also shed light on how rifampin moves through the body, including into the brain, and how rifampin levels could change during treatments, showing how the research could potentially translate to humans.
According to the World Health Organization, an estimated 10 million people worldwide developed disease by the bacterium that causes TB in 2020. It’s also one of the leading infectious disease killers. Previous studies have shown the deadliest form of TB, TB meningitis, affects more than 100,000 people each year, damaging brain tissue and even proving fatal, especially among young children and those with HIV and AIDS due to a weakened immune system. Treatment generally requires lengthy courses of antibiotics and monitoring to assure compliance with therapy.
In a study published March 15 in The Journal of Clinical Investigation, Johns Hopkins Medicine investigators showed that higher doses of rifampin can treat TB meningitis more effectively by killing bacteria faster while not increasing brain inflammation.
“Based on what is seen clinically and in previous research, most peope with TB meningitis will die and, even if treated, may suffer lasting brain damage, since it is difficult to recognize the disease in early, more treatable stages,” according to study first author, Camilo Ruiz-Bedoya, M.D., pediatric infectious diseases fellow at Johns Hopkins University School of Medicine.
Treatments for TB meningitis are long and can take up to 12 months. Shorter regimens can lead to better compliance, lower costs, and better outcomes for patients, adds senior author Sanjay Jain, M.D., professor of pediatrics, and of radiology and radiological sciences at the school of medicine and a pediatric infectious diseases specialist at Johns Hopkins Children’s Center.
The standard therapy for TB meningitis is a combination of antibiotics, including rifampin, a 50-year-old drug that has been a mainstay in the global fight against TB and other bacterial diseases. However, the currently recommended dose of rifampin (10-15 mg/kg/day) given orally does not lead to sufficient rifampin levels in the brain to target and kill the bacteria. This is because of the blood-brain barrier, which protects the brain and prevents the entry of infections, toxins, and drugs, including antibiotics. This limits the drug’s effectiveness and can also lead to the development of antibiotic-resistant strains. Previous clinical studies revealed conflicting results on whether higher doses of rifampin were a more effective treatment for TB meningitis.

The time of day that people with diabetes eat certain foods may be just as important to their well-being as portion size and calories, according to a new study published in the Endocrine Society’s Journal of Clinical Endocrinology and Metabolism.
Mealtimes should be in line with the biological clock — a natural, internal process that regulates the sleep-wake cycle and repeats every 24 hours. Health outcomes for people with diabetes may be improved if certain foods are eaten at different times of the day.
“We observed that eating potatoes in the morning, whole grains in the afternoon, greens and milk in the evening and less processed meat in the evening was associated with better long-term survival in people with diabetes,” said Qingrao Song, M.D., of Harbin Medical University in Harbin, China. “Nutritional guidelines and intervention strategies for diabetes should integrate the optimal consumption times for foods in the future.”
The researchers analyzed data from 4,642 people with diabetes from the National Health and Nutrition Examination Survey to determine their risk of dying from heart disease. They found people with diabetes who ate potatoes or starchy vegetables in the morning, whole grains in the afternoon, and dark vegetables such as greens and broccoli and milk in the evening were less likely to die from heart disease. Those who ate a lot of processed meat in the evening were more likely to die from heart disease.
Other authors of this study include: Wenbo Jiang, Jia Zhang, Yunyan Chen, Hongyan Jiang, Yujia Long, Ying Li, Tianshu Han, Hongru Sun and Wei Wei of Harbin Medical University.
The study received funding from the National Natural Science Foundation of China.
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There is a lack of understanding as to why some people suffer from long-lasting symptoms after COVID-19 infection. A new study from Karolinska Institutet in Sweden, the Helmholtz Center Munich (HMGU) and the Technical University of Munich (TUM), both in Germany, now demonstrates that a certain type of immune cell called macrophages show altered inflammatory and metabolic expression several months after mild COVID-19. The findings are published in the journal Mucosal Immunology.
“We can show that the macrophages from people with mild COVID-19 exhibit an altered inflammatory and metabolic expression for three to five months post-infection,” says Craig Wheelock, docent at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, and one of the study’s authors. “Even though the majority of these people did not have any persistent symptoms, their immune system was more sensitive than that of their healthy counterparts.”
Long-term symptoms are relatively common after severe COVID-19 infection but may also affect some individuals with previous mild disease. More research is needed to understand the long-term immune aberrations in patients who have recovered from the acute phase of the infection.
To examine this aspect, the researchers in the current study analysed blood samples from 68 people with previous mild COVID-19 infection and a control group of 36 people who had not had COVID-19.
The researchers isolated the macrophages in the laboratory and stimulated them with spike protein, steroids and lipopolysaccharides (LPS), a molecule that triggers the immune system. The cells were then RNA sequenced to measure active genes. The researchers also measured the presence of eicosanoid signaling molecules, which are a fundamental feature of inflammation.
“It is not surprising to find a large number of eicosanoid molecules in people with COVID-19 as the disease causes inflammation, but it was surprising that they were still being produced in high quantities several months after the infection,” Craig Wheelock says.

Osaka City University suggests a possible mechanism linking diabetes to Alzheimer’s disease in new discovery that amyloid-β in the blood comes from periphery organs like the pancreas and liver, not only the brain, and aids in blood glucose clearance by inhibiting insulin secretion.
A research group has revealed that amyloid-β (Aβ) detected in blood is secreted from peripheral tissues (pancreas, adipose tissue, skeletal muscle, liver, etc.) that are sensitive to glucose and insulin. Also, that Aβ secreted from peripheral tissues acts as a regulator on pancreatic β-cells to suppress insulin secretion. The results of this study indicate that blood Aβ levels fluctuate significantly with diet, and special care should be taken when using blood samples as a diagnostic marker for Alzheimer’s disease, such as taking blood samples during fasting.
Researchers have identified amyloid beta (Aβ) detected in blood to originate from peripheral tissues, and that the peptide acts on pancreaticβ-cells to suppress insulin secretion, thereby regulating blood glucose levels. The study, which urges us to be careful when using blood Aβ levels as a diagnostic marker for Alzheimer’s disease (AD), was published in The Proceedings of the National Academy of Sciences (PNAS), the official journal of the National Academy of Sciences.
“This work was finally published after about 11 years,” says Professor Takami Tomiyama of the Department of Translational Neuroscience, Osaka City University Graduate School of Medicine. “It is not only an academic discovery, but also has implications in how we diagnose AD.”
Based on what is known, this study sought to explore some unknowns. First, as AD is caused by the accumulation of Aβ in the brain, it is thought that Aβ levels in the blood reflect the pathology in the brain and are currently used as a diagnostic marker. However, Aβ is generated from the amyloid precursor protein (APP) through the function of two enzymes, β- and γ-secretases, and this mechanism is expressed in many of the body’s peripheral tissues, not only in the brain, causing the origin of blood Aβ to remain unknown. Second, epidemiological studies have shown type 2 diabetes to be a strong risk factor for the development of AD, yet the mechanism linking these two diseases has eluded researchers as well.
“In our previous studies on mice injected with glucose,” Professor Tomiyama explains, “we showed a transient increase in glucose and insulin to peak at 15 minutes, but blood Aβ levels to peak some 30-120 minutes later.” In addition, previous studies have shown the oral administration of glucose to increase blood Aβ levels in patients with AD. These findings led the professor and his research team to explore the hypothesis that blood Aβ is secreted from peripheral tissues (pancreas, adipose tissue, skeletal muscle, liver, etc.) and it may contribute to the metabolism of glucose and insulin.

A new target in the brain which underpins the eliciting of anxiety and fear behaviours such as ‘freezing’ has been identified by neuroscientists. The University of Bristol researchers say the discovery of a key pathway in the brain, published in the journal eLife, offers a potential new drug target for treating anxiety and psychological disorders, which affect an estimated 264-million people worldwide.
Existing anxiety-reducing drugs are not always effective for all patients and often have unwanted side effects. Understanding the brain networks and mechanisms which underlie fear and anxiety may offer a new approach to developing better treatments for anxiety disorders.
Neuroscientists from Bristol’s School of Physiology, Pharmacology and Neuroscience, sought to investigate how the brain’s cerebellum, which is connected to many brain regions associated with survival networks, influences activity in another area of the brain called the periaqueductal grey (PAG). This PAG area lies at the hub of central networks that co-ordinate survival mechanisms including fear-evoked coping responses such as ‘freezing’.
To investigate this, researchers fitted animal models with electrodes to record activity within the brain’s PAG region and applied a conditioning task, whereby an auditory tone is paired with a small foot shock, eliciting the formation of a ‘fear memory’ and freezing, a behavioural index of fear. The team showed that within the brain’s PAG area, a subset of brain cells increased their responsiveness to the conditioned tone, consistent with encoding a fear memory.
However, when cerebellar output was altered during conditioning, the subsequent timing of fear-related neuronal activity in the PAG became less precise and the duration of fear-related freezing behaviour was increased confirming that cerebellar-periaqueductal grey interactions contribute to fear conditioning processes. The team showed that the manipulation of a direct cerebellar-PAG pathway, also caused impairments in fear conditioned freezing and ultrasonic vocalisations.
The study’s lead authors, Dr Charlotte Lawrenson and Dr Elena Paci, explain: “Until now, little was understood about how the cerebellum modulates neuronal activity in other brain regions, especially those related to fear and anxiety. Importantly, our results show that the cerebellum is part of the brain’s survival network that regulates fear memory processes at multiple timescales and in multiple ways; raising the possibility that dysfunctional interactions in the brain’s cerebellar-survival network may underlie fear-related disorders and comorbidities.”
The study’s findings provide new insights into the way the PAG encodes fear memory and also provides evidence that the cerebellum is an additional key structure in the list of brain regions that contribute to the fear/anxiety network and offers a novel target for treating psychological conditions including post-traumatic stress disorder.
The Biotechnology and Biological Sciences Research Council (BBSRC) and Wellcome Trust-funded study is published in the journal eLife.
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