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A team of Columbia University researchers has reported new evidence that cognitive abnormalities seen in neuropsychiatric disorders such as schizophrenia may be traceable to altered activity in the thalamus during adolescence, a time window of heightened vulnerability for schizophrenia.
The research, published on May 19 in the journal Nature Neuroscience, holds promise for a more targeted therapeutic for schizophrenia and other brain disorders where cognitive dysfunction is related to altered prefrontal cortex function.
“Cognitive deficits are central to schizophrenia, but the underlying mechanisms still remain unclear,” said Christoph Kellendonk, PhD, associate professor in psychiatry and molecular pharmacology and therapeutics and senior author of the paper. “This study puts emphasis on the thalamus and its importance during adolescence in regulating prefrontal cortex circuit maturation. We hope that our findings will inspire future studies to disentangle the influences of thalamic nuclei on the prefrontal cortex and cognitive control, paving the way for new treatment options.”
Brain Abnormalities Seen Early
Schizophrenia, a disabling brain disorder characterized by delusional thinking and hallucinations, is typically diagnosed in young adults — with the average age of onset for men in the late teens to the early 20s for women in the late 20s to early 30s. The abnormal developmental trajectory of the brain appears to be established during development, long before clinical symptoms of the disease appear in early adult life.
The prefrontal cortex — an area of the brain responsible for executive functions, such as planning, working memory, and impulse control — has long been implicated in the pathophysiology of schizophrenia. The thalamus is a structure in the middle of the brain that regulates prefrontal cortex function in the adult. However, its role during adolescent development is elusive.
To test how cortical development may go awry in the disease, Laura Benoit, first author and a MD, PhD graduate student at Columbia, manipulated the activity of thalamic neurons in the brains of mice during adolescence and examined how it affects prefrontal cortex function later in life.
Rescuing Cognitive Impairment
The scientists discovered that thalamic inhibition during adolescence led to adult deficits in attentional set shifting — a form of cognitive flexibility that is impaired in individuals with schizophrenia. Strikingly, excitation of the thalamus during adulthood reversed the cognitive deficit in mice with developmentally altered cortical function.
“This shows that even in a developmentally altered brain, boosting thalamic function can still rescue cognitive impairments,” said Sarah Canetta, PhD, Assistant Professor in Psychiatry who co-led the study with Dr. Kellendonk and Alexander Harris, MD, PhD, Assistant Professor in Psychiatry. “Our findings in the mouse suggest a neurodevelopmental framework in which the thalamus plays an important role in shaping the maturation of the prefrontal cortex. It has translational relevance, particularly for schizophrenia, and proposes a treatment strategy for enhancing cognition in humans.”
The study, “Adolescent thalamic inhibition leads to long-lasting impairments in schizophrenia,” was conducted in collaboration with the Center for Theoretical Neuroscience at Columbia’s Zuckerman Mind Brain Behavior Institute. Stefano Fusi, PhD, professor of neuroscience and principal investigator, and Lorenzo Posani, a postdoctoral research scientist, contributed to the research.

Two recent discoveries co-led by scientists at Cedars-Sinai may help lead to new ways to treat patients with Allan-Herndon-Dudley syndrome (AHDS), a brain development disorder that causes severe intellectual disability and problems with movement.
In the first study, published in the peer-reviewed journal Thyroid, scientists at Cedars-Sinai and at the University of Chicago identified a gene therapy that can potentially help prevent or reduce the devastating neurological symptoms in patients diagnosed with AHDS.
“There currently are no successful therapies for treating the neurological symptoms that occur as a result of this condition,” said co-corresponding author Clive Svendsen, PhD, professor of Biomedical Sciences and Medicine and executive director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute. “However, we’re finding gene therapies to be a promising new way to treat developmental neurological disorders, like AHDS.”
The disorder, typically diagnosed in childhood and only in males, is caused by a mutation in a thyroid hormone “transporter” known as MCT8, that is tasked with carrying thyroid hormones across the blood-brain barrier and into brain cells. This process is critical for human brain development and function. A breakdown in the process can lead to serious intellectual disability and problems with speech and movement. Most affected children do not walk or talk.
To counteract this issue, investigators tested the potential of a viral gene therapy, AAV9-MCT8, to determine whether it could correct brain defects in mice that carry the mutation and possess symptoms of the disease. The AAV9 vector acts as a carrier that helps deliver genetic material, like MCT8, into cells.
“We thought we might be able to get the transporter back with an AAV9 vector by genetically modifying it so it will produce the protein MCT8,” said Svendsen, who is also the Kerry and Simone Vickar Family Foundation Distinguished Chair in Regenerative Medicine.

If you are a new parent who, in a more or less sleep-deprived state, googles this question, then the answer could reassure you.
Many top google hits will refer you to an old study which concludes that infant crying normally peaks at around the age of six weeks, after which it decreases markedly and stabilises at a low level after three months.
Typically referred to as the ‘cry curve’, parents might expect their infants to cry radically less after the initial peak. However, a new study from Denmark, challenges this “cry curve” pattern, by pooling data from parents in 17 different countries.
“We’ve created two mathematical models that reasonably represent the available data. Neither of them show that the duration of crying falls so markedly after five weeks, which is what is otherwise seen in the graphs that are presented to parents. The available data shows that crying is still a significant part of many infants’ repertoire after six months,” says Christine Parsons, who is an associate professor at the Department of Clinical Medicine at Aarhus University.
Widely used cry curve
The researchers behind the study have compiled data from 57 research articles from all over the world, in which parents have registered how much their infants cry every day.

Most research looking at the impact of climate change on human life has focused on how extreme weather events affect economic and societal health outcomes on a broad scale. Yet climate change may also have a strong influence on fundamental daily human activities — including a host of behavioral, psychological, and physiological outcomes that are essential to wellbeing. In a study published May 20th in the journal One Earth, investigators report that increasing ambient temperatures negatively impact human sleep around the globe.
The team says their findings suggest that by the year 2099, suboptimal temperatures may erode 50 to 58 hours of sleep per person per year. In addition, they found that the temperature effect on sleep loss is substantially larger for residents from lower income countries as well as in older adults and females.
“Our results indicate that sleep — an essential restorative process integral for human health and productivity — may be degraded by warmer temperatures,” says first author Kelton Minor of the University of Copenhagen. “In order to make informed climate policy decisions moving forward, we need to better account for the full spectrum of plausible future climate impacts extending from today’s societal greenhouse gas emissions choices.”
It’s long been known that hot days increase deaths and hospitalizations and worsen human performance, yet the biological and behavioral mechanisms underlying these impacts have not been well understood. Recent self-reported data from the United States have suggested that subjective sleep quality decreases during periods of hot weather, but how temperature fluctuations may impact changes in objective sleep outcomes in people living across a variety of global climates has remained unclear.
“In this study, we provide the first planetary-scale evidence that warmer-than-average temperatures erode human sleep,” Minor says. “We show that this erosion occurs primarily by delaying when people fall asleep and by advancing when they wake up during hot weather.”
To conduct this research, the investigators used anonymized global sleep data collected from accelerometer-based sleep-tracking wristbands. The data included 7 million nightly sleep records from more than 47,000 adults across 68 countries spanning all continents except for Antarctica. Measures from the type of wristbands used in this study had previously been shown to align with independent measures of wakefulness and sleep.

Scientists at St. Jude Children’s Research Hospital have solved an immunology puzzle. A CD8+ T cell can have two functionally distinct daughter cells after it divides, despite the cells being genetically identical. The researchers have explained how, revealing one method the immune system uses to provide immediate and long-term protection. The research appears today in Molecular Cell.
The researchers showed how a specific protein complex guides translation of an important immune transcription factor in one region of the parent T cell. When the cell divides, because the transcription factor is only in one region, it is then inherited asymmetrically into two daughter cells. The transcription factor drives expression of a set of genes in one daughter cell, pushing it to become an effector cell, while the other becomes a memory cell.
“Our results hint that events that happen very early in a T cell’s life can influence the function of the cell much later,” said corresponding author Doug Green, Ph.D., St. Jude Department of Immunology chair. “We have uncovered one way in which the immune system ensures that when T cells are activated, the response will be diverse, with some cells, the effectors, launching a rapid assault on the invader and others hanging back in reserve for later, as memory cells.”
Two very different daughters with the same DNA
The immune system has many different cell types with varied functions. One major cell type is CD8+ T cells. These cells are responsible for directly killing infected and tumor cells. They are activated by a special cell that presents a bit of virus or tumor cell, called an antigen, on their surface. The point of contact between T cells and the antigen-presenting cells is called the immune synapse. After activation, the T cells divide into genetically identical daughter cells.
Many of the daughter cells become effector cells that also kill infected or cancer cells. However, some of the daughter cells become memory cells to help protect against future infections or the same cancer. Before this study, it was unclear how both effector and memory cells could come from the same parent T cell.

Scientists at St. Jude Children’s Research Hospital are studying voltage-gated ion channels (VGICs). Their work revealed a previously unknown mechanism of inactivation for one such channel that plays an important role in how neurons and muscles respond to electric signals sent by the nervous system. A paper on the work appeared today in Molecular Cell.
VGICs are transmembrane proteins that form a pore that opens and closes to allow the passage of ions into or out of a cell. Cells such as neurons and muscle cells respond to electric signals by opening (activating) and closing their VGICs. Proper activation and closing of VGICs allows these cells to properly coordinate their functions.
The researchers used cryogenic electron microscopy (cryo-EM), biochemistry and electrophysiology approaches to study a VGIC called Kv4. Mutations in Kv4 are linked to neurological and cardiac conditions. Understanding how Kv4 functions may help researchers identify therapeutic strategies to treating such disorders.
“Neuronal communication is based on how electro-signals are transmitted, which is mediated by the action of proteins in the neuronal membrane. Many researchers are interested in studying this process, but it has been difficult to capture,” said corresponding author Chia-Hsueh Lee, Ph.D., St. Jude Department of Structural Biology. “We were able to capture multiple states of this specific ion channel to get a better picture of how this protein works in molecular detail. We were excited to find that Kv4 functions in a way that is distinct from other types of VGICs.”
The researchers were able to complement and validate the structural findings with electrophysiology work from collaborators at University of California San Francisco.
Finding out why the car won’t go: understanding Kv4 inactivation
VGICs occupy different states to function. The channels can transition from resting/closed to activated/open states. Think of a car: when turned off, it is like the VGIC in the resting/closed state. When you’ve turned it on and are driving, that is like the VGIC in the activated/open state. However, Kv4 can also enter an inactivated state, where the pore is closed and unresponsive. Imagine a car where the engine is on and you’re stepping on the gas, but the car won’t go, because the handbrake is applied.
The researchers wanted to understand how Kv4 transitions between these different states. Using cryo-EM, they initially captured the channel in three different conformations (shapes), corresponding to the activated/open, inactivated and intermediate states. Those structures revealed the mechanisms behind Kv4 inactivation, which featured an unexpected symmetry breakdown from four- to two-fold symmetry.
Like other VGICs, Kv4 is composed of four identical copies of a protein (imagine a four-leaf clover), and in the activated/open and intermediate states, all four copies adopt the same conformation. In contrast, in the inactivated state, the two pairs facing each other have different conformations. To capture Kv4 in its resting/closed state, the researchers needed to “lock” the channel into that position, using protein engineering and certain reagents.
This the first time that researchers have identified the mechanism for closed-state inactivation, and the approaches used here could be applied to other ion channels.
“I think our study is quite exciting for the field because we were able to get multiple structures that are related to functional states for one ion channel,” said first author Hongtu Zhao, Ph.D., St. Jude Structural Biology. “Being able to determine several structures of the same protein and in a single study enabled us to draw a lot of information from comparing them. This really reflects the power of cryo-EM.”
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James Bibb, Ph.D., and colleagues have described a novel preclinical drug that could have the potential to combat depression, brain injury and diseases that impair cognition. The drug, which notably is brain-permeable, acts to inhibit the kinase enzyme Cdk5.
Cdk5 is a crucial regulator of signaling in brain neurons. Over three decades of study, it has been implicated in neuropsychiatric and neurodegenerative conditions, including Alzheimer’s disease and Parkinson’s disease. Knocking out the enzyme in mice makes them resilient to stress, enhances their cognition, protects neurons from stroke and head trauma, and lessens neurodegeneration.
While inhibitors of Cdk5 could offer potential therapeutic benefits and new ways to study basic brain function, previous first- and second-generation anti-Cdk5 compounds largely get blocked at the blood-brain barrier that restricts movement of solutes from the blood to the central nervous system’s extracellular fluid. To date, no Cdk5 inhibitor has been approved to treat any neuropsychiatric or degenerative diseases.
Bibb and colleagues now report details of their anti-Cdk5, brain-permeable compound, 25-106. They also show that systemic administration of 25-106 alters neurobehavior in mice, reducing anxiety-like behavior.
“As perhaps the first robust systemic inhibitor, 25-106 represents an exciting and expandable and translatable pharmacological tool to study the function of Cdk5 activity in wild-type animals,” said Bibb, a professor in the University of Alabama at Birmingham Department of Surgery. “Achieving systemic applicability may be considered a step forward toward the testing of Cdk5 inhibitors to treat neuropsychiatric and neurodegenerative diseases. This provides a promising landscape for future studies to assess the effects of brain-permeable Cdk5 inhibitors to combat stress, anxiety, depression, addiction, cancer and neurodegeneration.”
The study, “Systemic administration of a brain permeable Cdk5 inhibitor alters neurobehavior,” is published in the journal Frontiers in Pharmacology.
In the paper, researchers describe synthesis of the aminopyrazole-based inhibitor, and they used molecular modeling to show that 25-106 appears to occupy the same hydrophobic binding pocket as the well-established Cdk5 inhibitor roscovitine.

There have been dozens of cases reported in recent weeks among populations not typically vulnerable to the disease.The rare monkeypox virus, usually confined mostly to Central and West Africa, has spread in unusual ways this year, and among populations that have not been vulnerable in the past.But while the transmissions have created some alarm among officials and infectious disease experts, and while a Covid-weary world is on high alert for new outbreaks, there are several reasons monkeypox is not being treated with the same level of concern as the coronavirus.Here’s what to know about monkeypox and the risks it poses.What is monkeypox?Monkeypox is a virus endemic in parts of Central and West Africa. It is a more benign version of smallpox.It was discovered in 1958, after outbreaks occurred in monkeys kept for research, according to the Centers for Disease Control and Prevention.What are the symptoms?Monkeypox creates a rash that starts with flat red marks that become raised and filled with pus. Infected people will also have a fever and body aches.Symptoms typically appear in six to 13 days but can take as long as three weeks after exposure. They can last for two to four weeks, with severe cases occurring more commonly among children, according to the World Health Organization.The C.D.C. says there is “no proven, safe treatment” for monkeypox.How infectious is it?Typically it does not lead to major outbreaks — in most years there are just a handful of cases outside Africa, if any. The most severe outbreak in the United States came in 2003, when dozens of cases were linked to exposure to infected prairie dogs and other pets. It was the first time there had been a monkeypox outbreak outside of Africa, according to the World Health Organization.Within Africa, 11 countries have reported cases since 1970, when the first human case was identified in a 9-year-old boy in the Democratic Republic of Congo. Nigeria has experienced a large outbreak, with more than 500 suspected cases and 200 confirmed cases since 2017, the W.H.O. said.The virus can spread via body fluids, skin contact and respiratory droplets. The majority of cases this year have been in young men, many of whom self-identified as men who have sex with men.“Most cases presented with lesions on the genitalia or peri-genital area, indicating that transmission likely occurs during close physical contact during sexual activities,” the European Center for Disease Prevention and Control said on Friday.How many cases have there been this year, and where have they been?There have been 38 cases worldwide this year as of Thursday, including 37 with no history of travel to endemic countries, according to the European Centre for Disease Prevention and Control. Britain reported an additional 11 cases on Friday.In the United States, the first case of 2022 was diagnosed in Massachusetts on Wednesday. The man had recently traveled to Canada, which has had two cases this year. New York City health authorities announced on Thursday that they were investigating a possible case.Europe has been hit much harder. As of Thursday, Portugal had reported 17 cases, Spain has had seven, Belgium has had two, and France, Italy and Sweden have each had one.Britain had reported nine cases as of Thursday, but Sajid Javid, Britain’s health secretary, said on Friday that the number had risen to 20. The W.H.O. said on Thursday that the country’s infections appeared to be locally acquired, but “the extent of local transmission is unclear at this stage and there is the possibility of identification of further cases.”None of the infected people have died, according to the European Centre for Disease Prevention and Control.How is the current outbreak different?This is the first time that chains of transmission were reported in Europe without links to West or Central Africa, according to the European Center for Disease Prevention and Control. The agency also said this year’s cases included the first that have been reported among men who have sex with men.Should I be worried?The likelihood of the virus being spread during sexual contact is high, but the risk of transmission from other forms of close contact is low, the European Center for Disease Prevention and Control said.The symptoms are typically mild, and most people recover within weeks, but the virus has had a fatality rate of about 3.3 percent in Nigeria, with children, young adults and immunocompromised people most susceptible.

Thanks to over a century of modern neuroscience, we have made significant strides in our understanding of the brain. Nonetheless, we have only just begun to scratch the surface of how this amazingly complex organ works.
Digging deeper into this perplexing puzzle, researchers from Kyushu University’s Faculty of Pharmaceutical Sciences have now analyzed in unprecedented detail the development and genetic profile of a set of cells that construct the brain’s immune system.
Their new insights, published in the journal Nature, could pave the way for better understanding the origins and mechanisms behind leading brain-related pathologies such as Alzheimer’s disease and multiple sclerosis.
“Many people are familiar with how neurons connect together to send signals across the brain, but there are also blood vessels that supply the brain with oxygen, and glial cells that act as the brain’s support network and immune system,” explains Takahiro Masuda, who led the study. “In fact, even the most generous estimates suggest only about half of the cells in our brains are neurons, so studying the other cells is just as vital for uncovering how the brain works.”
With this in mind, the research team has been focusing on a series of cells called ‘central nervous system associated macrophages’ a type of immune cells that protect the brain from infection. These macrophages are thought to be involved in almost all known neurodegenerative diseases due to their critical role as the immune cells of the brain.
Over the years, research has shown that many different kinds of these cells exist. For this study, the team was particularly interested in the macrophages surrounding blood vessels and those located in the meninges — the layers that surround the brain — known as ‘perivascular macrophages’ and ‘meningeal macrophages,’ respectively.

The Helsinki Health Study at the University of Helsinki investigated the development of insomnia symptoms in midlife and their effects on memory, learning ability and concentration after retirement. The follow-up period was 15-17 years.
According to the study, long-term insomnia symptoms and later poorer cognitive functioning have a clear connection.
“The findings indicate that severe insomnia symptoms were associated with worse cognitive function among those who were on statutory pension,” says Doctoral Researcher Antti Etholén, describing the results of the study.
The study also found that the memory problems, and problems in learning ability and concentration increased as the insomnia symptoms were prolonged.
Sleeping well already in middle age
Prior research has shown that there are a number of mechanisms that can explain how sleep can affect cognitive functioning. What makes the recently published study exceptional is the long follow-up period for insomnia symptoms.
Among other things, the study demonstrated that if insomnia symptoms eased over the years, cognitive functioning was also found to be better at retirement age compared to the problems persisting.
According to the researchers, long-lasting insomnia symptoms should be considered as risk factors for poor cognitive functioning.
“Based on our findings, early intervention tackling insomnia symptoms, or measures aimed at improving the quality of sleep would be justified,” says Professor Tea Lallukka.
There are many ways to improve the quality of sleep, including the regularity of the sleep rhythm, the appropriate temperature and brightness of the sleeping environment, and the optimal timing of physical exercise, coffee consumption and eating.
However, Lallukka believes that intervention studies are still needed to ascertain the effects of measures in support of good sleep.
“In subsequent studies, it would be interesting to shed further light on, for example, whether the treatment of insomnia can also slow down the development of memory disorders,” Lallukka says. She points outs that only self-reported memory symptoms could be taken into consideration in the present study.
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