Tag Archives: #whitematter

How HIV Infection Shrinks The Brain’s White Matter? (Neuroscience)

Researchers from Penn and CHOP detail the mechanism by which HIV infection blocks the maturation process of brain cells that produce myelin, a fatty substance that insulates neurons.

It’s long been known that people living with HIV experience a loss of white matter in their brains. As opposed to gray matter, which is composed of the cell bodies of neurons, white matter is made up of a fatty substance called myelin that coats neurons, offering protection and helping them transmit signals quickly and efficiently. A reduction in white matter is associated with motor and cognitive impairment.

Earlier work by a team from the University of Pennsylvania and Children’s Hospital of Philadelphia (CHOP) found that antiretroviral therapy (ART)—the lifesaving suite of drugs that many people with HIV use daily—can reduce white matter, but it wasn’t clear how the virus itself contributed to this loss. 

In a new study using both human and rodent cells, the team has hammered out a detailed mechanism, revealing how HIV prevents the myelin-making brain cells called oligodendrocytes from maturing, thus putting a wrench in white matter production. When the researchers applied a compound blocking this process, the cells were once again able to mature. 

The work is published in the journal Glia.

“Even when people with HIV have their disease well-controlled by antiretrovirals, they still have the virus present in their bodies, so this study came out of our interest in understanding how HIV infection itself affects white matter,” says Kelly Jordan-Sciutto, a professor in Penn’s School of Dental Medicine and co-senior author on the study. “By understanding those mechanisms, we can take the next step to protect people with HIV infection from these impacts.”

“When people think about the brain, they think of neurons, but they often don’t think about white matter, as important as it is,” says Judith Grinspan, a research scientist at CHOP and the study’s other co-senior author. “But it’s clear that myelination is playing key roles in various stages of life: in infancy, in adolescence, and likely during learning in adulthood too. The more we find out about this biology, the more we can do to prevent white matter loss and the harms that can cause.”

Jordan-Sciutto and Grinspan have been collaborating for several years to elucidate how ART and HIV affect the brain, and specifically oligodendrocytes, a focus of Grinspan’s research. Their previous work on antiretrovirals had shown that commonly used drugs disrupted the function of oligodendrocytes, reducing myelin formation.

In the current study, they aimed to isolate the effect of HIV on this process. Led by Lindsay Roth, who recently earned her doctoral degree within the Biomedical Graduate Studies group at Penn and completed a postdoctoral fellowship working with Jordan-Sciutto and Grinspan, the investigation began by looking at human macrophages, one of the major cell types that HIV infects.

Scientists had hypothesized that HIV’s impact on the brain arose indirectly through the activity of these immune cells since the virus doesn’t infect neurons or oligodendrocytes. To learn more about how this might affect white matter specifically, the researchers took the fluid in which macrophages infected with HIV were growing and applied it to rat oligodendrocyte precursor cells, which mature into oligodendrocytes. While this treatment didn’t kill the precursor cells, it did block them from maturing into oligodendrocytes. Myelin production was subsequently also reduced.

“Immune cells that are infected with the virus secrete harmful substances, which normally target invading organisms, but can can also kill nearby cells, such as neurons, or stop them from differentiating,” Grinspan says. “So the next step was to figure out what was being secreted to cause this effect on the oligodendrocytes.” 

The researchers had a clue to go on: Glutamate, a neurotransmitter, is known to have neurotoxic effects when it reaches high levels. “If you have too much glutamate, you’re in big trouble,” says Grinspan. Sure enough, when the researchers applied a compound that blunts glutamate levels to HIV-infected macrophages before the transfer of the growth medium to oligodendrocyte precursors, the cells were able to mature into oligodendrocytes. The result suggests that glutamate secreted by the infected macrophages was the culprit behind the precursor cells getting “stuck” in their immature form.

There was another mechanism, however, that the researchers suspected might be involved: the integrated stress response. This response integrates signals from four different signaling pathways, resulting in changes in gene expression that serve to protect the cell from stress or to prompt the cell to die, if the stress is overwhelming. Earlier findings from Jordan-Sciutto’s lab had found the integrated stress response was activated in other types of brain cells in patients who had cognitive impairment associated with HIV infection, so the team looked for its involvement in oligodendrocytes as well. 

Indeed, they found evidence that the integrated stress response was activated in cultures of oligodendrocyte precursor cells. 

Taking this information with what they had found out about glutamate, “Lindsay was able to tie these two things together,” Jordan-Sciutto says. She demonstrated that HIV-infected macrophages secreted glutamate, which activated the integrated stress response by turning on a pathway governed by an enzyme called PERK. “If you blocked glutamate, you prevented the activation of the integrated stress response,” Jordan-Sciutto says.

To take these findings further, and potentially test out new drug targets to address HIV-related cognitive impairments, the team hopes to use a well-characterized rat model of HIV infection.  

“HIV is a human disease, so it’s a hard one to model,” says Grinspan. “We want to find out if this model recapitulates human disease more accurately than others we’ve used in the past.”

By tracking white matter in this animal model and comparing it to imaging studies done on patients with HIV, they hope to get at a better understanding of what factors shape white matter loss. They’re particularly interested in looking at a cohort of adolescents being treated at CHOP, as teens are a group in whom HIV infection rates are climbing.

Ultimately, the researchers want to discern the effects of the virus from the drugs used to treat it in order to better evaluate the risks of each. 

“When we put people on ART, especially kids or adolescents, it’s important to understand the implications of doing that,” says Jordan-Sciutto. “Antiretrovirals may prevent the establishment of a viral reservoir in the central nervous system, which would be wonderful, but we also know that the drugs can cause harm, particularly to white matter.

“And then of course we can’t forget the 37 million HIV-infected individuals who live outside the United States and may not have access to antiretrovrials like the patients here,” she says. “We want to know how we can help them too.”

Kelly Jordan-Sciutto is vice chair and professor in the University of Pennsylvania School of Dental Medicine’s Department of Basic & Translational Sciences and is director of Biomedical Graduate Studies.

Judith Grinspan is research scientist at the Children’s Hospital of Philadelphia and research professor of neurology at the the Perelman School of Medicine at the University of Pennsylvania.

Lindsay Roth, who recently earned her doctoral degree from the Biomedical Graduate Group at the University of Pennsylvania, was first author on the paper. 

Roth, Grinspan, and Jordan-Sciutto’s coauthor was Çagla Akay-Espinoza, from Penn’s School of Dental Medicine.

The study was supported by the National Institutes of Health (grants MH098742, MH118121, and MH109382) and the Cellular Neuroscience Core of the Institutional Intellectual and Developmental Disabilities Research Core of the Children’s Hospital of Philadelphia (grants HD26979 and GM008076).

Featured image: A confocal microscope image shows an oligodendrocyte in cell culture, labeled to show the cell nucleus in blue and myelin proteins in red, green, and yellow. Researchers from Penn and CHOP have shown that HIV infection prevents oligodendrocytes from maturing, leading to a reduction in white matter in the brain. (Image: Raj Putatunda)


Provided by Penn Today

How HIV Infection Shrinks the Brain’s White Matter? (Medicine)

Researchers from Penn and CHOP detail the mechanism by which HIV infection blocks the maturation process of brain cells that produce myelin, a fatty substance that insulates neurons.

It’s long been known that people living with HIV experience a loss of white matter in their brains. As opposed to gray matter, which is composed of the cell bodies of neurons, white matter is made up of a fatty substance called myelin that coats neurons, offering protection and helping them transmit signals quickly and efficiently. A reduction in white matter is associated with motor and cognitive impairment.

Earlier work by a team from the University of Pennsylvania and Children’s Hospital of Philadelphia (CHOP) found that antiretroviral therapy (ART)—the lifesaving suite of drugs that many people with HIV use daily—can reduce white matter, but it wasn’t clear how the virus itself contributed to this loss. 

In a new study using both human and rodent cells, the team has hammered out a detailed mechanism, revealing how HIV prevents the myelin-making brain cells called oligodendrocytes from maturing, thus putting a wrench in white matter production. When the researchers applied a compound blocking this process, the cells were once again able to mature. 

The work is published in the journal Glia.

“Even when people with HIV have their disease well-controlled by antiretrovirals, they still have the virus present in their bodies, so this study came out of our interest in understanding how HIV infection itself affects white matter,” says Kelly Jordan-Sciutto, a professor in Penn’s School of Dental Medicine and co-senior author on the study. “By understanding those mechanisms, we can take the next step to protect people with HIV infection from these impacts.”

“When people think about the brain, they think of neurons, but they often don’t think about white matter, as important as it is,” says Judith Grinspan, a research scientist at CHOP and the study’s other co-senior author. “But it’s clear that myelination is playing key roles in various stages of life: in infancy, in adolescence, and likely during learning in adulthood too. The more we find out about this biology, the more we can do to prevent white matter loss and the harms that can cause.”

Jordan-Sciutto and Grinspan have been collaborating for several years to elucidate how ART and HIV affect the brain, and specifically oligodendrocytes, a focus of Grinspan’s research. Their previous work on antiretrovirals had shown that commonly used drugs disrupted the function of oligodendrocytes, reducing myelin formation.

In the current study, they aimed to isolate the effect of HIV on this process. Led by Lindsay Roth, who recently earned her doctoral degree within the Biomedical Graduate Studies group at Penn and completed a postdoctoral fellowship working with Jordan-Sciutto and Grinspan, the investigation began by looking at human macrophages, one of the major cell types that HIV infects.

Scientists had hypothesized that HIV’s impact on the brain arose indirectly through the activity of these immune cells since the virus doesn’t infect neurons or oligodendrocytes. To learn more about how this might affect white matter specifically, the researchers took the fluid in which macrophages infected with HIV were growing and applied it to rat oligodendrocyte precursor cells, which mature into oligodendrocytes. While this treatment didn’t kill the precursor cells, it did block them from maturing into oligodendrocytes. Myelin production was subsequently also reduced.

“Immune cells that are infected with the virus secrete harmful substances, which normally target invading organisms, but can can also kill nearby cells, such as neurons, or stop them from differentiating,” Grinspan says. “So the next step was to figure out what was being secreted to cause this effect on the oligodendrocytes.” 

The researchers had a clue to go on: Glutamate, a neurotransmitter, is known to have neurotoxic effects when it reaches high levels. “If you have too much glutamate, you’re in big trouble,” says Grinspan. Sure enough, when the researchers applied a compound that blunts glutamate levels to HIV-infected macrophages before the transfer of the growth medium to oligodendrocyte precursors, the cells were able to mature into oligodendrocytes. The result suggests that glutamate secreted by the infected macrophages was the culprit behind the precursor cells getting “stuck” in their immature form.

There was another mechanism, however, that the researchers suspected might be involved: the integrated stress response. This response integrates signals from four different signaling pathways, resulting in changes in gene expression that serve to protect the cell from stress or to prompt the cell to die, if the stress is overwhelming. Earlier findings from Jordan-Sciutto’s lab had found the integrated stress response was activated in other types of brain cells in patients who had cognitive impairment associated with HIV infection, so the team looked for its involvement in oligodendrocytes as well. 

Indeed, they found evidence that the integrated stress response was activated in cultures of oligodendrocyte precursor cells. 

Taking this information with what they had found out about glutamate, “Lindsay was able to tie these two things together,” Jordan-Sciutto says. She demonstrated that HIV-infected macrophages secreted glutamate, which activated the integrated stress response by turning on a pathway governed by an enzyme called PERK. “If you blocked glutamate, you prevented the activation of the integrated stress response,” Jordan-Sciutto says.

To take these findings further, and potentially test out new drug targets to address HIV-related cognitive impairments, the team hopes to use a well-characterized rat model of HIV infection.  

“HIV is a human disease, so it’s a hard one to model,” says Grinspan. “We want to find out if this model recapitulates human disease more accurately than others we’ve used in the past.”

By tracking white matter in this animal model and comparing it to imaging studies done on patients with HIV, they hope to get at a better understanding of what factors shape white matter loss. They’re particularly interested in looking at a cohort of adolescents being treated at CHOP, as teens are a group in whom HIV infection rates are climbing.

Ultimately, the researchers want to discern the effects of the virus from the drugs used to treat it in order to better evaluate the risks of each. 

“When we put people on ART, especially kids or adolescents, it’s important to understand the implications of doing that,” says Jordan-Sciutto. “Antiretrovirals may prevent the establishment of a viral reservoir in the central nervous system, which would be wonderful, but we also know that the drugs can cause harm, particularly to white matter.

“And then of course we can’t forget the 37 million HIV-infected individuals who live outside the United States and may not have access to antiretrovrials like the patients here,” she says. “We want to know how we can help them too.”

Kelly Jordan-Sciutto is vice chair and professor in the University of Pennsylvania School of Dental Medicine’s Department of Basic & Translational Sciences and is director of Biomedical Graduate Studies.

Judith Grinspan is research scientist at the Children’s Hospital of Philadelphia and research professor of neurology at the the Perelman School of Medicine at the University of Pennsylvania.

Lindsay Roth, who recently earned her doctoral degree from the Biomedical Graduate Group at the University of Pennsylvania, was first author on the paper. 

Roth, Grinspan, and Jordan-Sciutto’s coauthor was Çagla Akay-Espinoza, from Penn’s School of Dental Medicine.

The study was supported by the National Institutes of Health (grants MH098742, MH118121, and MH109382) and the Cellular Neuroscience Core of the Institutional Intellectual and Developmental Disabilities Research Core of the Children’s Hospital of Philadelphia (grants HD26979 and GM008076).

Featured image: A confocal microscope image shows an oligodendrocyte in cell culture, labeled to show the cell nucleus in blue and myelin proteins in red, green, and yellow. Researchers from Penn and CHOP have shown that HIV infection prevents oligodendrocytes from maturing, leading to a reduction in white matter in the brain. (Image: Raj Putatunda)


Reference: Lindsay Roth, Cagla Akay-Espinoza, Judith B. Grinspan, Kelly L. Jordan-Sciutto, “HIV-induced neuroinflammation inhibits oligodendrocyte maturation via glutamate-dependent activation of the PERK arm of the integrated stress response”, Glia, 31 May 2021. https://doi.org/10.1002/glia.24033


Provided by Penn Today

Big Brains And White Matter: New Clues About Autism Subtypes (Psychiatry)

UC Davis MIND Institute researchers tracked brain changes in children over many years using MRI scans.

Two groundbreaking studies at the UC Davis MIND Institute provide clues about possible types of autism linked to brain structure, including size and white matter growth.

The research is based on brain scans taken over many years as part of the Autism Phenome Project (APP) and Girls with Autism, Imaging of Neurodevelopment (GAIN) studies. It shows the value of longitudinal studies that follow the same children from diagnosis into adolescence.

“There is no other single site data set like ours anywhere,” said Christine Wu Nordahl, associate professor in the Department of Psychiatry and Behavioral Sciences, MIND Institute faculty member and co-senior author on both papers. “In one of the studies we have over 1,000 MRI scans from 400 kids, which is unheard of. It’s been 15 years of work to get here.”

The researchers tracked brain growth and structure in hundreds of children from age 3 to age 12 © UC Davis Health

Big brains: An autism subtype?

In the first study, published in Biological Psychiatry, the researchers used magnetic resonance imaging (MRI) to track brain size (volume) in 294 children with autism and 135 children without autism between the ages of 3 and 12. In children with autism, they found evidence of larger brain size relative to height – or disproportionate megalencephaly – a subtype that has been linked to higher rates of intellectual disability and poorer overall prognosis.

Previous cross-sectional research had found that children with autism have larger brains at early ages, but no evidence of larger brains in later childhood. The widely accepted theory is that these brains “normalized” or shrank as the children grew up.

The MIND Institute study found that wasn’t the case. The children who had bigger brains at age 3 still had bigger brains at age 12. Why? Unlike most research, which studies different individuals at different time points, this research studied the same children longitudinally, or over time.

Also, unlike most other studies, this one includes children with significant intellectual disabilities. These were the children who tended to have the “big brain” form of autism.

David Amaral, co-senior author on both studies, suggested that the difference between this and previous research was that children with intellectual disability were left out of previous cross-sectional studies focused on older children.

“Bigger brain size in autism has been linked to lower IQ, and children with intellectual disabilities are harder to scan as they get older,” said Amaral, a distinguished professor of psychiatry and behavioral sciences and MIND Institute faculty member. “It’s a matter of sampling bias and the previous “dogma” appears to be an artefact of who got scanned when,” he explained.

Children under age 5 can be scanned while they’re asleep, but Nordahl and her team have created unique, innovative protocols that allow researchers to more easily scan older children with intellectual disabilities while they’re awake.

“It’s so critical that we include those aspects of the autism spectrum that most impact quality of life, such as intellectual disability, anxiety and verbal functioning.” said Joshua Lee, postdoctoral scholar at the MIND Institute and the lead author on the study. “It’s important to capture everyone who has autism, not just the ones who are easiest to get images from.” 

White matter: Connecting the clinical dots

The second study, also published in Biological Psychiatry, linked changes in the brain’s white matter growth with autism traits in some children.

The researchers used a type of MRI scan called diffusion-weighted imaging, which allowed them to look at white matter regions, or tracts, in the brain. White matter provides the structural connections in the brain, allowing different regions to communicate with each other.

The study included 125 children with autism and 69 typically developing children who served as controls, between the ages of 2.5 and 7.

The researchers found that the development of the white matter tracts in the brain was linked to changes in autism symptom severity. They observed slower development in children whose symptom severity increased over time, and faster development in those with decreased severity over time.

“From a biological standpoint, this emphasizes the role of white matter development in autism and autism symptoms,” said Derek Sayre Andrews, postdoctoral scholar at the MIND Institute and lead author on the paper. “We hope that in the future, measurements like this can identify children who would benefit from more intensive intervention – and serve as a marker to determine the effectiveness of an intervention for a particular child,” he said. 

Changes in autism severity over time

The white matter research builds on a previous MIND Institute study, which found that while many children experience fairly stable levels of autism symptoms throughout childhood, a significant portion can be expected to increase or decrease in their symptom severity over time.

“This new analysis provides an important clue about the brain mechanism that may be involved in some of these changes,” said Amaral.

Studying sex differences

The studies are unusual not only because they include children with severe intellectual disability, but also because they include a larger number of girls, who tend to be under-represented in autism research.

“For the first time, we are able to have a large enough sample of girls, where we are able to evaluate their brain trajectories separate from boys to see how they’re different,” said Nordahl. “For example, we don’t see the big brain subtype as frequently in girls, but we do see subtle differences in how autistic girls’ brains are growing.”

Nordahl, who has also studied the role amygdala size may play in psychiatric challenges for young girls, noted that the MIND Institute’s longitudinal data set is likely to play a key role in many future studies about sex differences in autism.

“Collectively, I believe these studies are so important because they get us closer to a point where we can use our understanding of the underlying biology of autism to directly improve the quality of life for individuals in the autistic community,” Andrews said. “And that really is the ultimate goal of our research.”

Co-authors on “Longitudinal Evaluation of Cerebral Growth Across Childhood in Boys and Girls with Autism Spectrum Disorder” include Sally Ozonoff, Marjorie Solomon, Sally J. Rogers and Derek Sayre Andrews.

Funding for this study was provided by the National Institute of Mental Health (R01MH104438, R01MH103284, R01MH103371); the UC Davis MIND Institute Intellectual and Developmental Disabilities Research Center (U54HD079125); and Autism Center of Excellence (P50HD093079).

doi: https://doi.org/10.1016/ j.biopsych.2020.10.014

Co-authors on “A Longitudinal Study of White Matter Development in Relation to Changes in Autism Severity Across Early Childhood” include Joshua K. Lee, Danielle Jenine Harvey, Einat Waizbard-Bartov, Marjorie Solomon and Sally J. Rogers

Funding for this study was provided by the National Institute of Mental Health (R01MH104438 R01MH103284, R01MH103371). This project was also supported by the MIND Institute Intellectual and Developmental Disabilities Research Center (U54HD079125) and the MIND Institute Autism Research Training Program (T32MH073124).

doi: https://doi.org/10.1016/j.biopsych.2020.10.013.

Provided by UC Davis Health

What Lies Between Grey And White In The Brain? (Neuroscience)

Traditionally, neuroscience regards the brain as being made up of two basic tissue types. Billions of neurons make up the grey matter, forming a thin layer on the brain’s surface. These neuronal cells are interlinked in a mindboggling network by hundreds of millions of white matter connections, running in bundles, deeper in the brain. Until very recently, not much was known about the interface between the white and grey matter – the so-called superficial white matter – because methods were lacking to study it in living human brains. Yet, previous investigations had suggested the region to be implicated in devastating conditions such as Alzheimer’s disease and autism. Now a multidisciplinary team led by Nikolaus Weiskopf from the Max Planck Institute for Human Cognitive and Brain Sciences has succeeded in making the superficial white matter visible in the living human brain.

The team created very high resolution maps of the white-grey matter border across the entire living brain. Using biophysical modeling informed by quantitative ion beam microscopy on postmortem brain tissue, they demonstrate that MR contrast in SWM is driven by iron and can be linked to the microscopic iron distribution. Higher SWM iron concentrations were observed in U-fiber–rich frontal, temporal, and parietal areas, potentially reflecting high fiber density or late myelination in these areas. © MPI CBS

“We demonstrated that the superficial white matter contains a lot of iron. It is known that iron is necessary for the process of myelination,” explains Evgeniya Kirilina, first author of the study published in Science Advances. Myelin is what makes the white matter white. It’s the fatty coating of nerve cell axons that speeds up transmission of information through the brain. The myelination process can occur throughout the lifespan but is predominant during development. In fact, the largest concentration of iron the researchers found was in the superficial white matter in regions of the frontal cortex, which happens to be the slowest developing structure in the human brain. Incredibly, the human frontal cortex is not fully myelinated until the forth decade of life.

The key to the new method is MRI (Magnetic Resonance Imaging) but at very high field strength. While typical clinical MRI scanners work at 1.5 or 3 Tesla, in terms of the strength of the magnetic field, the Max Planck Institute for Human Cognitive and Brain Sciences houses a powerful 7 Tesla scanner. This, in combination with advanced biophysical model, allowed the team to create very high resolution maps of the white-grey matter border across the entire living brain. The accuracy of their submillimetre maps was assessed against classic and advanced histological methods involving physical dissection and analysis of post mortem brains.

The new method promises many further insights into the organisation of the interface between white and grey matter. Evgeniya Kirilina adds, “We hope the method can be used to increase our understanding of brain development as well as pathological conditions involving the superficial white matter.”

References: Evgeniya Kirilina, Saskia Helbling, Markus Morawski, “Superficial white matter imaging: Contrast mechanisms and whole-brain in vivo mapping”, Science Advances 07 Oct 2020: Vol. 6, no. 41, eaaz9281 DOI: 10.1126/sciadv.aaz9281