Tag: neurology

Categories : Antibiotics Obstetrics & Gynaecology PaediatricsTags :

In Utero or Neonatal Antibiotic Exposure Could Lead to Brain Disorders

On By ModernMedia
Image by Ahmad Ardity from Pixabay
Image by Ahmad Ardity from Pixabay

According to a new study, antibiotic exposure early in life could alter human brain development in areas responsible for cognitive and emotional functions.

The study suggests that penicillin alters the body’s microbiome as well as gene expression, which allows cells to respond to its changing environment, in key areas of the developing brain. The findings, published in the journal iScience, suggest reducing widespread antibiotic use or using alternatives when possible to prevent neurodevelopment problems.
Penicillin and related medicines, such as ampicillin and amoxicillin, are the most widely used antibiotics in children worldwide. In the United States, the average child receives nearly three courses of antibiotics before age 2, and similar or greater exposure rates occur elsewhere.

“Our previous work has shown that exposing young animals to antibiotics changes their metabolism and immunity. The third important development in early life involves the brain. This study is preliminary but shows a correlation between altering the microbiome and  changes in the brain that should be further explored,” said lead author Martin Blaser, director of the Center for Advanced Biotechnology and Medicine at Rutgers.

In the study, mice were exposed to low-dose penicillin in utero or immediately after birth. Researchers found that, compared to the unexposed controls, mice given penicillin had large changes in their intestinal microbiota, with altered gene expression in the frontal cortex and amygdala. These two key brain areas are responsible for the development of memory as well as fear and stress responses.

Increasing evidence links conditions in the intestine to the brain in the ‘gut-brain axis‘. If this pathway is disturbed, it can lead to permanent altering of the brain’s structure and function and possibly lead to neuropsychiatric or neurodegenerative disorders in later childhood or adulthood.

“Early life is a critical period for neurodevelopment,” Blaser said. “In recent decades, there has been a rise in the incidence of childhood neurodevelopmental disorders, including autism spectrum disorder, attention deficit/hyperactivity disorder and learning disabilities. Although increased awareness and diagnosis are likely contributing factors, disruptions in cerebral gene expression early in development also could be responsible.”

Whether it is antibiotics directly affecting brain development or if molecules from the microbiome travelling to the brain, disturbing gene activity and causing cognitive deficits needs to be determined by future studies.

Source: Rutgers University-New Brunswick

Categories : Obstetrics & Gynaecology Substance UseTags :

Prenatal CBD and THC Stunts Prozac Responsiveness in Offspring

On By ModernMedia
Photo by Thought Catalog on Unsplash

Scientists have found that significant amounts of THC and CBD, the two main components of cannabis enter the embryonic brain of mice in utero and impair the mice’s ability as adults to respond to fluoxetine (Prozac).

The study suggests that when the developing brain is exposed to THC or CBD, normal interactions between endocannabinoid and serotonin signaling may be diminished as exposed individuals become adults.

“Hemp-derived CBD is a legal substance in the US, and we are in a time of increasing state-level legalisation of cannabis. Therefore, use of cannabis components have increased across most levels of society, including among pregnant women. The study marks the beginning of an effort to understand the effects of THC and CBD on the endogenous cannabinoid system (ECS) in the developing brain and body,” explained Hui-Chen Lu, director of the Linda and Jack Gill Center and professor in the Department of Psychological and Brain Sciences in the IU Bloomington College of Arts and Sciences.

Researchers studied four groups of pregnant mice. Some received daily moderate doses of either THC, CBD, or a combination of equal parts THC and CBD; a control group had placebo injections throughout pregnancy. Using mass spectrometry, IU psychological and brain sciences professor Heather Bradshaw tested embryos and found that CBD and THC both could cross the placenta and reach the embryonic brain.

“The surprising part is that maternal exposure to CBD alone — a drug that is often considered as safe and harmless and is a popular ‘natural’ therapy for morning sickness — resulted in a lasting impact on adult mice offspring,” Lu said. “Both prenatal THC and CBD exposure impaired the adult’s ability to respond to fluoxetine. The results suggest taking a cautious approach to using CBD during pregnancy.”

There is however some evidence for CBD’s effectiveness in treating chronic pain and anxiety, though currently the only FDA-approved indication for CBD is the treatment of severe seizure disorders.

“We still know very little about the effects of CBD on the developing brain,” Prof Lu said.

The new paper is one of the first studies to see the potential negative impact of CBD on the developing brain and later behaviours. However observational studies in the 1980s saw increased anxiety and depression in offspring of mothers who used the lower-strength cannabis available at the time. Since women may take cannabis products for nausea and vomiting, this has relevance for public health awareness.

Study co-author Ken Mackie, Gill Chair of Neuroscience at IU Bloomington, said researchers know that prenatal cannabis exposure may increase the risk for anxiety and depression, so it is important to evaluate the response to a class of drug used to treat anxiety and depression.

Though normal mouse behaviours were seen in many tests, one test — to determine their response to stress — had a strongly atypical result. In all groups, the mice responded normally to a stressful situation. As expected, fluoxetine increased stress resilience in mice whose mothers had received the placebo. However, the drug was ineffective in mice whose mothers had received THC, CBD or their combination.

Fluoxetine works by increasing the amount of serotonin available at brain synapses, an effect known to require the endocannabinoid system. This internal system of receptors, enzymes and molecules both mediates the effects of cannabis and plays a role in regulating various bodily systems, such as appetite, mood, stress and chronic pain.

To test if maternal exposure to THC and/or CBD impaired endocannabinoid signaling in the adult offspring, the researchers tested whether boosting the ECS with a drug would restore fluoxetine’s effectiveness. They found that the ECS boosting restored normal fluoxetine responses in mice that had received THC or CBD while their brains were developing.

Source: Indiana University

Journal reference: de Sousa Maciel, I., et al. (2021) Perinatal CBD or THC Exposure Results in Lasting Resistance to Fluoxetine in the Forced Swim Test: Reversal by Fatty Acid Amide Hydrolase Inhibition. Cannabis and Cannabinoid Research. doi.org/10.1089/can.2021.0015.

Categories : Gender NeurologyTags :

Dopamine Involved in Both Autistic Behaviour and Motivation

On By ModernMedia

Dopamine can help explain both autistic behaviours and men’s need for motivation or ‘passion’ in order to succeed compared to women’s ‘grit’, according to a new study.

Men – more often than women – need passion to succeed at things. At the same time, boys are diagnosed as being on the autism spectrum four times as often as girls. Both statistics may be related to dopamine, one of our body’s neurotransmitters.

“This is interesting. Research shows a more active dopamine system in most men” than in women, says Hermundur Sigmundsson, a professor at the Norwegian University of Science and Technology’s (NTNU) Department of Psychology.

He is behind a new study addressing gender differences in key motivating factors to excel in something. The study uses men’s and women’s differing activity in the dopamine system as an explanatory model. The study enrolled 917 participants aged 14 to 77, consisting of 502 women and 415 men.

“We looked at gender differences around passion, self-discipline and positive attitude,” said Prof Sigmundsson. The study refers to these qualities as passion, grit and mindset. The researchers also applied theories to possible links with dopamine levels. Dopamine, a neurotransmitter that is released in the brain, is linked to learning, attention and our ability to focus. It can contribute to a feeling of satisfaction.

Men generally secrete more dopamine, but it plays a far more complex role than simply being a ‘happy hormone’. Dopamine is linked to learning, attention and our ability to focus.Previous studies on Icelandic students have shown that men are more dependent on passion in order to succeed at something. This study confirms the earlier findings. In six out of eight test questions, men score higher on passion than women.

However, the association with dopamine levels has not been established previously.

“The fact that we’ve developed a test to measure passion for goal achievement means that we can now relate dopamine levels to passion and goal achievement,” explained Prof Sigmundsson.

Women, on the other hand, may have greater self-discipline – or grit – and be more conscientious, according to other studies. Their level of passion may not be as pronounced in general, but they are also able to use this to excel.

The results for the women, however, are somewhat more ambiguous than men’s need to have a passion for something, and this study found no such gender difference. Nor did the researchers find any difference between the sexes in terms of growth mindset.

Previous studies have associated the dopamine system with many different conditions, such as ADHD, psychoses, manias and Parkinson’s disease. However, it may also be related to a certain form of autistic behaviour.

Some individuals with autism may develop a deep interest in certain topics, something which others may find strange or even off putting. People on the autism spectrum can focus intensely on these topics or pursuits, at least for a while, and dopamine may play a role in this.

“Other research in neuroscience has shown hyperactivity in the dopamine system in individuals with autism, and boys make up four out of five children on the autism spectrum. This, and dopamine’s relationship to passion, might be a mechanism that helps to explain this behaviour,” concluded Prof Sigmundsson.

Source: Norwegian University of Science and Technology


Journal reference: Sigmundsson, H., et al. (2021) Passion, grit and mindset: Exploring gender differences. New Ideas in Psychology. doi.org/10.1016/j.newideapsych.2021.100878.

Categories : NeurologyTags :

Study Uncovers a Key Brain Building Block

On By ModernMedia
Astrocytes (red) from a rat brain. Credit: Jeffrey C. Smith Lab, National Institute of Neurological Disorders and Stroke, NIH

A new study from Duke and UNC scientists has discovered a crucial protein involved in the communication and coordination between astrocytes as they build synapses — essentially a brain building block. 

Astrocytes, specialised, star-shaped glial cells that outnumber the neurons they support over fivefold and which make up about half the mass of a human brain, are increasingly being viewed as having a critical role in shaping the development of the brain.  Astrocytes tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS, including guiding development of the brain. 

The researchers found that a molecule, called hepaCAM, is a key component of this process. Without it, astrocytes aren’t as sticky as they should be, and tend to stick to themselves rather than forming connections with their neighbouring astrocytes.

This finding, in studies on mice with the gene for hepaCAM deleted from their astrocytes, helps in the understanding of several brain disorders, including cognitive decline, epilepsy and autism spectrum disorders.

One rare brain disorder, called megalencephalic leukoencephalopathy (MLC) is also known to be caused by a mutation in the hepaCAM gene, and this work might provide answers about what exactly has gone wrong. MLC is a developmental disorder that grows progressively worse, causing macrocephaly (a large head), swelling of the brain’s white matter, intellectual disability and epilepsy.

By deleting hepaCAM from astrocytes to see what it does, “we sort of made the cells into introverts,” explained senior author Cagla Eroglu, an associate professor of cell biology at the Duke University School of Medicine. “They’re normally wanting to reach out, but without hepaCAM, they started to hug themselves instead.”

“If the astrocyte makes junctions to its neighbours, then you start to have a network,” Prof Eroglu said. “To make a functional brain, you need a functional astrocytic network.”

The researchers zeroed in on hepaCAM by searching for highly active genes in astrocytes, and which have been implicated in brain dysfunction. They partnered with another group working on hepaCAM at the University of Barcelona, but that group has been  looking at the molecule for its role in regulating chloride signaling channels in astrocytes.

The Duke group found that deleting hepaCAM from astrocytes led to a synaptic network that was too easily excited and not as well dampened. “The effect on the inhibitory synapses was the strongest,” said first author Katie Baldwin, who recently became an assistant professor of cell biology and physiology at the University of North Carolina at Chapel Hill. “You’re putting the inhibition down and the excitation up, so that really could point to a mechanism for epilepsy.”

Prof Baldwin plans to test whether hepaCAM-deficient mice have behavioural differences or changes in learning and memory, or whether they exhibit the stress and social anxiety that are markers of autism spectrum disorders. She said they might also reintroduce the disease-mutation versions of the protein to mice that were born without it to see what effects it has.

“We know hepaCAM is interacting with itself between two astrocytes, but we don’t know what it’s interacting with at the synapse,” Prof Baldwin said. “We don’t know if it could be interacting with hepaCAM which is also found in the neurons, or if it could be some other protein that we don’t know about yet.

Source: Duke University School of Nursing

Journal information: Katherine T. Baldwin et al, HepaCAM controls astrocyte self-organization and coupling, Neuron (2021). DOI: 10.1016/j.neuron.2021.05.025

Categories : Cardiovascular Disease NeurologyTags :

Statins not Associated With Cognitive Decline

On By ModernMedia
Photo by Matteo Vistocco on Unsplash

A new study has found that statin use in adults 65 years old or older is not associated with incident dementia, mild cognitive impairment (MCI) or decline in individual cognition domains.

Major health concerns in the elderly, cognitive decline and dementia affect about 10% of people over 60 years old. Statins are used to reduce low-density lipoprotein cholesterol, and are a fundamental treatment for prevention of primary and secondary cardiovascular disease (CVD) events. 
In 2012 the Food and Drug Administration issued a warning about cases of apparent short-term cognitive impairment with statin use, while acknowledging that the cardiovascular benefits outweigh their risks. Systematic reviews have since shown insufficient evidence on the impact of statins, and research has shown mixed results, with some showing a neurocognitive benefit of statins and others reporting a null effect.

“With statins being increasingly prescribed to older adults, their potential long-term effects on cognitive decline and dementia risk have attracted growing interest,” said lead author Zhen Zhou, PhD, Menzies Institute for Medical Research at the University of Tasmania. “The present study adds to previous research by suggesting that statin use at baseline was not associated with subsequent dementia incidence and long-term cognitive decline in older adults.”

Researchers of this study analysed data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial. ASPREE was a large prospective, randomized placebo-controlled trial of daily low-dose aspirin with adults 65 or older. One of the key selection criteria of ASPREE was that participants had to have a score of 78 for the Modified Mini-Mental State Examination test, a screening test for cognitive abilities, at enrollment.

The study had 18 846 participants, grouped by their baseline statin use (31.3% of participants) versus non-statin use. The study aimed to measure outcomes including incident dementia and its subclassifications (probable Alzheimer’s disease [AD], mixed presentations); MCI and its subclassifications (MCI consistent with AD, MCI-other); changes in domain-specific cognition including global cognition, memory, language and executive function, and psychomotor speed; and in the composite of these domains.

After a median of 4.7 years of follow-up, researchers found 566 incident cases of dementia (including probable AD and mixed presentations). Compared with no statin use, statin use was not associated with risk of all-cause dementia, probable AD or mixed presentations of dementia. There were 380 incident cases of MCI found (including MCI consistent with AD and MCI-other). Compared to no statin use, statin use was not associated with risk of MCI, MCI consistent with AD or other MCI. No statistically significant difference in the change of composite cognition and any individual cognitive domains between statin users versus non-statin users was seen. However, researchers did find interaction effects between baseline cognitive ability and statin therapy for all dementia outcomes.

The researchers acknowledged several limitations, including observational study bias and lack of data on the length of prior use of statins; and the dose of statins was not recorded in the ASPREE trial, so their effects could not be fully explored. Researchers conclude the study must be interpreted with caution and will require confirmation by randomized clinical trials designed to explore the neurocognitive effects of statins in older populations.

In an accompanying editorial comment, Christie M. Ballantyne, MD, professor at Baylor College of Medicine in Houston, noted study limitations that the authors address, but agreed the findings suggest statins do not contribute to cognitive decline.

“Overall, the analysis was well done, and its main strengths are a large cohort with a battery of standardised tests that allowed the investigators to track both cognition and incidence of dementia and its subtypes over time,” Ballantyne said. “Lingering questions such as the one raised by this analysis regarding potential adverse effects of statins in individuals with mildly impaired cognition can only be answered in randomised controlled trials in the appropriate age group and population and with appropriate testing and adequate follow-up. In the meantime, practising clinicians can have confidence and share with their patients that short-term lipid lowering therapy in older individuals, including with statins, is unlikely to have a major impact on cognition.”

Source: American College of Cardiology

Categories : NeurologyTags :

What Causes Us to Sneeze?

On By ModernMedia
Photo by Andrea Piacquadio from Pexels

A new study has identified, in mice, specific cells and proteins that control the sneeze reflex. 

Better understanding of what causes us to sneeze, and especially how neurons behave in response to allergens and viruses, may lead to treatments which can slow the spread of infectious respiratory diseases.

A tickle in the nose can help trigger a sneeze, which expels irritants and disease-causing pathogens. But the cellular pathways that control the sneeze reflex go far beyond the sinuses and have been poorly understood. Now, a team led by researchers at Washington University School of Medicine in St. Louis has identified, in mice, specific cells and proteins that control the sneeze reflex.

“Better understanding what causes us to sneeze — specifically how neurons behave in response to allergens and viruses — may point to treatments capable of slowing the spread of infectious respiratory diseases via sneezes,” said Qin Liu, PhD, an associate professor of anesthesiology and the study’s senior investigator.

“We study the neural mechanism behind sneezing because so many people, including members of my own family, sneeze because of problems such as seasonal allergies and viral infections,” explained Prof Liu, a researcher in the university’s Center for the Study of Itch and Sensory Disorders. “Our goal is to understand how neurons behave in response to allergies and viral infections, including how they contribute to itchy eyes, sneezing and other symptoms. Our recent studies have uncovered links between nerve cells and other systems that could help in the development of treatments for sneezing and for fighting infectious respiratory diseases.”

Sneezing is the most common and forceful way of spreading infectious droplets from respiratory infections. Over two decades ago, researchers discovered a sneeze-evoking region in the central nervous system, but since then there has been little progress in understanding the mechanism of the sneeze reflex at the cellular and molecular level.

For the new study, Prof Liu and her team used a mouse model to figure out which nerve cells send signals that make mice sneeze. The researchers exposed the mice to aerosolised droplets containing either histamine or capsaicin, a pungent compound made from chili peppers, both of which caused the mice to sneeze.

By examining nerve cells that already were known to react to capsaicin, Liu’s team was able to identify a class of small neurons linked to sneezing that was caused by that substance. The researchers then searched for neuropeptides that could transmit sneeze signals to those nerve cells, and hit upon a molecule called neuromedin B (NMB), which they found was required for sneezing.

By eliminating the NMD-sensitive neurons in the part of the nervous system that evoked sneezes in the mice, they blocked the sneeze reflex. Those neurons all make a protein called the neuromedin B receptor. In mice lacking that receptor, sneezing again was greatly reduced.

“Interestingly, none of these sneeze-evoking neurons were housed in any of the known regions of the brainstem linked to breathing and respiration,” Prof Liu said. “Although we found that sneeze-evoking cells are in a different region of the brain than the region that controls breathing, we also found that the cells in those two regions were directly connected via their axons, the wiring of nerve cells.”

By exposing part of the mouse brain to the NMB peptide, the researchers found they could directly stimulate the sneeze reflex, even though they had not been exposed to any capsaicin, histamine or other allergens.

Since many viruses and other pathogens are spread in part by aerosolised droplets, Prof Liu said it may be possible to limit the spread of those pathogens by targeting NMB or its receptor to limit sneezing in those known to be infected.

“A sneeze can create 20 000 virus-containing droplets that can stay in the air for up to 10 minutes,” Liu Prof explained. “By contrast, a cough produces closer to 3000 droplets, or about the same number produced by talking for a few minutes. To prevent future viral outbreaks and help treat pathological sneezing caused by allergens, it will be important to understand the pathways that cause sneezing in order to block them. By identifying neurons that mediate the sneeze reflex, as well as neuropeptides that activate these neurons, we have discovered targets that could lead to treatments for pathological sneezing or strategies for limiting the spread of infections.”

Source: Washington University School of Medicine

Journal information: Li, F., et al. (2021) Sneezing reflex is mediated by a peptidergic pathway from nose to brainstem. Cell. doi.org/10.1016/j.cell.2021.05.017.

Categories : Injury & Trauma NeurologyTags :

White Matter Changes Uncovered in Repeated Brain Injury

On By ModernMedia
Photo by MART PRODUCTION from Pexels

A new study has uncovered insights into white matter changes that occur during chronic traumatic encephalopathy (CTE), a progressive brain disease associated with repetitive head impacts. This discovery may help in identifying new targets for therapies.

CTE been diagnosed after death in the brains of American football players and other contact sport athletes as well as members of the armed services. The disease has been identified as causing impulsivity, explosivity, depression, memory impairment and executive dysfunction.

Though much prior research focused on repetitive head trauma leading to the development of abnormal tau, this study focused on white matter changes, particularly the oligodendrocytes which myelinate nerve sheaths. The results have been published online [PDF] in the journal Acta Neuropathologica.

“Research to date has focused on the deposition of abnormal tau in the gray matter in CTE. This study shows that the white matter undergoes important alterations as well.  There is loss of oligodendrocytes and alteration of oligodendrocyte subtypes in CTE that might provide new targets for prevention and therapies,” explained corresponding author Ann McKee, MD, chief of neuropathology at VA Boston Healthcare, director of the BU CTE Center.

Dr McKee and her team isolated cellular nuclei from the postmortem dorsolateral frontal white matter in eight cases of CTE and eight matched controls. They conducted single-nucleus RNA-seq (snRNA-seq) with these nuclei, revealing transcriptomic, cell-type-specific differences between the CTE and control cases. In doing so, they discovered that the white matter in CTE had fewer oligodendrocytes and the oligodendroglial subtypes were altered compared to control tissue.

Since previous studies have largely focused on the CTE-specific tau lesion located in the cortex in the brain, these findings are particularly informative as they explain a number of features of the disease. “In comparison, the cellular death process occurring in white matter oligodendrocytes in CTE appears to be separate from the accumulation of hyperphosphorylated tau,” she said. “We know that the behavioural and mood changes that occur in CTE are not explained by tau deposition. This study suggests that white matter alterations are also important features of the disease, and future studies will determine whether these white matter changes play a role in the production of behavioral or mood symptoms in CTE, such as explosivity, violence, impulsivity, and depression.”

Source: Boston University School of Medicine

Journal information: Chancellor, K. B., et al. (2021) Altered oligodendroglia and astroglia in chronic traumatic Encephalopathy. Acta Neuropathologica. doi.org/10.1007/s00401-021-02322-2.

Categories : NeurologyTags :

Autism Gene Impedes Neuron Development

On By ModernMedia
Image source: Pixabay

Researchers at the Institute of Science and Technology (IST) Austria have uncovered the role of a high-risk gene in autism spectrum disorder (ASD) and its important role during a critical phase of brain development.

Within the European Union alone, about three million people are affected by an autism spectrum disorder (ASD). Some are only mildly affected and can live independent lives. while others have severe disabilities. What the different forms have in common is difficulty with social interaction and communication, as well as repetitive-stereotypic behaviors. Mutations in a few hundred genes are associated with ASD. One of them is called Cullin 3, and it is a high-risk gene, and a mutation of it almost certainly leads to a disorder. 

To learn more about how the gene affects the brain, PhD students Jasmin Morandell and Lena Schwarz with Professor Gaia Novarino’s research group, turned to mice whose Cullin 3 gene has been partially switched off, comparing them to their healthy siblings. 

The three-chamber sociability test

In a series of behavioural and motoric tests, the team wanted to see if the modified mice mimicked some of the characteristics of patients with this form of autism and could therefore be used as model organisms. In one of these tests, the so-called three-chamber sociability test, a mouse could freely explore three adjacent chambers of a box connected by small doors. Two other mice were put in the outer boxes: One familiar to the studied mouse, the other mouse it had never met. “Healthy mice usually prefer the new over the already familiar mouse,” explained co-first author Jasmin Morandell. However, the mouse with the altered Cullin 3 gene, showed no recognition. The mice also had motor coordination deficits and other ASD-relevant cognitive impairments. This mouse model helped the researchers get to the heart of the problem. 

Dangerous protein buildup

While studying the mouse brain, the researchers noticed a very slight but consistent change in the position of some neurons. These neurons originate from a certain region in the brain, migrating toward the uppermost layers until they find their designated place in the cortex. The process is very sensitive, and even small changes in the speed at which they travel can alter the structure of the cortex. The scientists marked the migrating neurons to trace their movements. “We could observe migration deficits – the neurons are stranded in the lower cortex layers,” described the study’s other co-first author, Lena Schwarz. 

Malformations of the cortex
The reason for their poor movement lay in Cullin 3’s role in taggings old cells for degradation – a process that has to be tightly regulated to prevent proteins from accumulating. To find out which proteins are misregulated when Cullin 3 is defective, Morandell and Schwarz systematically analysed the protein composition of the mouse brain. “We were looking at proteins that accumulate in the mutant brain and found a protein called Plastin 3. Then Gaia [the professor they worked under] came across a poster describing the work of IST Austria’s Schur group in the hallway, and we got very excited,” said Jasmin Morandell. “They independently had been working on Plastin 3 as a regulator of cell motility and had complementary results to ours. That’s when we started working together,” Professor Gaia Novarino remembers.

The protein Plastin 3, which was previously unknown in the context of neuronal cell migration, turned out to have a key part in this process. “If the Cullin 3 gene is deactivated, the Plastin 3 protein accumulates, causing cells to migrate slower and over shorter distances. This is exactly what we saw happening in the cortex of the Cullin 3 mutant mice,” said Lena Schwarz.

Early developmental stage

All this occurs during a very early stage of brain development around halfway through pregnancy. “Determining these critical windows during brain development could be extremely important to fine-tune the treatment of patients with specific forms of ASD,” explained Prof Novarino, who is committed to improving diagnosis and treatment options for people with ASD. “Following up with the research on Plastin 3 could pave the way for some therapeutics. Inhibiting the accumulation of this protein could eventually alleviate some of the symptoms patients have,” Schwarz said.

 “We now know that defective Cullin 3 leads to increased levels of Plastin 3. This tight correlation shows that Plastin 3 protein levels may be an important factor for the control of cell-intrinsic movements,” said Jasmin Morandell. 

Source: IST Austria

Journal information: Jasmin Morandell, Lena A. Schwarz et al. 2021. Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. Nature Communications. DOI: 10.1038/s41467-021-23123-x

Categories : Mental Health NeurologyTags :

Scientists Find How Enriched Environments Boost Brains

On By ModernMedia
Image by Colin Behrens from Pixabay

A recent study in Frontiers in Molecular Neuroscience has shown how environmental enrichment ‘opens up’ chromosomes through the action of ‘master switches’.

Environmental enrichment, that is, making stimulating and interesting surroundings, is often used in zoos, laboratories, and farms to stimulate animals and increase their wellbeing.

Stimulating environments are better for mental health and cognition because they boost the growth and function of neurons and their connections, the glia cells that support and feed neurons, and blood vessels within the brain. But what are the deeper molecular mechanisms that first set in motion these large changes in neurophysiology? 

The study investigators utilised a large molecular toolbox to map how environmental enrichment leads to changes in the 3D organisation of chromosomes in neurons and glia cells of the mouse brain, which change the activation of some genes within the genome. 

They show that genes which in humans are important for cognitive mental health are particularly affected, possibly leading to new treatments.

Chromosome ‘opens up’ with enrichment

“Here we show for the first time, with large-scale data from many state-of-the-art methods, that young adolescent mice that grew up in an extra stimulating environment have highly specific ‘epigenetic’ changes—that is, molecular changes other than in DNA sequence—to the chromosomes within the cells of the brain cortex,” said corresponding author Dr Sergio Espeso-Gil from the Centre for Genomic Regulation in Barcelona, Spain.

He continued, “These increase the local ‘openness’ and ‘loopiness’ of the chromosomes, especially around DNA stretches called enhancers and insulators, which then fine-tune more ‘downstream’ genes. This happens not only in neurons but also in the supportive glia cells, too often ignored in studies about learning.”

The team raised mice for the first month after birth in social groups inside housing with Lego blocks, ladders, balls, and tunnels that were frequently changed and moved around. As a control, other mice were raised in smaller groups inside standard housing. The researchers then used a variety of tools to pick up molecular changes in neurons and glia cells within the brain cortex. These included alterations in the 3D structure of chromosomes, particularly the local “chromatin accessibility” (openness) and “chromatin interactions” (where distant genes are brought together through loops, to coordinate activity). Chromatins are the proteins which make up chromosomes, carrying DNA and the proteins to package them.

Epigenetic ‘master’ switches

They show that two ‘master’ switches operational after environmental enrichment increase chromatin interactions and another increases chromatin availability, important for the pyramidal neurons involved in cognition. A third works on a key chromosomal protein histone H3, activating nearby genes as a result.

These switches mainly occur around genomic regions that contain enhancers, regulatory DNA that (when bound to proteins called transcription factors) can activate neighboring genes. Also affected were genomic regions with insulators, regulatory DNA that can override the gene-activating effect of neighboring enhancers.

The team concluded that growing up in an enriched environment causes highly local and specific epigenetic changes in neurons and glia cells. These then mostly increase the activity of a few genes within the genome.

Mental health in humans

“Our results show that many of the genes involved are known to play a role in the growth and differentiation of neurons, the development of blood vessels, the formation and patterning of new synaptic connections on neurons, and molecular pathways implicated in memory and learning in mice,” said Dr Espeso-Gil.

“And when we look for parallel regions in the human genome, we find many regions that are statistically associated with differences in complex traits such as insomnia, schizophrenia, and Alzheimer’s in humans, which means that our study could inform future research on these disorders. This points to the potential of environmental enrichment in therapies for mental health. Our research could also help to guide future research on chromatin interactions and the poorly known importance of glial cells for cognitive mental health.”

Source: Medical Xpress

Journal information: Sergio Espeso-Gil et al, Environmental Enrichment Induces Epigenomic and Genome Organization Changes Relevant for Cognition, Frontiers in Molecular Neuroscience (2021). DOI: 10.3389/fnmol.2021.664912

Categories : NeurologyTags :

Study Explores the Circadian Rhythm Control Centre

On By ModernMedia
Woman sleeping with an alarm clock on bedside. Photo by cottonbro from Pexels

Researchers in Japan have offered new insights into how the brain’s circadian rhythm control centre regulates behaviour.

Circadian rhythms are a force in the background that shapes many human behaviours such feeling tired and falling asleep, as well as influencing our health. Michihiro Mieda and his team at Kanazawa University in Japan are researching just how the brain’s circadian rhythm control centre regulates behaviour.

The control centre, known as the superchiasmatic nucleus, or SCN, contains many types of neurons that transmit signals using the molecule GABA, but little is known about how each type contributes to our bodily rhythms. In this most recent study, the researchers focused on GABA neurons that produce arginine vasopressin, a hormone that regulates kidney function and blood pressure in the body, and which the team recently showed is also involved in the regulation of the interval of rhythms produced by the SCN.

To examine the function of these neurons separate to all others, the researchers first deleted a gene in mice which was needed for GABA signaling between neurons, but only in vasopressin-producing SCN neurons. “We removed a gene that codes for a protein that allows GABA to be packaged before it is sent to other neurons,” explained Mieda. “Without packaging, none of the vasopressin neurons could send out any GABA signals.”

Thus, these neurons could not use GABA to communicate with the rest of the SCN anymore. The mice showed longer periods of activity, beginning activity earlier and ending activity later than control mice, a simple enough result. It might seem that losing the packaging gene in the neurons disrupted the molecular clock signal but the result was not so simple. Closer examination deepened the mystery as the molecular clock seemed to progress unhindered.
Using calcium imaging, the researchers examined the clock rhythms within the vasopressin neurons. They found that while the rhythm of activity matched the timing of behaviour in control mice, this relationship was disturbed in the mice with missing GABA transmission in the vasopressin neurons. The rhythm of SCN output, ie SCN neuronal electrical activity, in the modified mice had the same irregular rhythm as their behaviour.

“Our study shows that GABA signaling from vasopressin neurons in the suprachiasmatic nucleus help fix behavioral timing within the constraints of the molecular clock,” concluded Mieda.

Source: News-Medical.Net

Journal reference: Maejima, T., et al. (2021) GABA from vasopressin neurons regulates the time at which suprachiasmatic nucleus molecular clocks enable circadian behavior. PNAS. doi.org/10.1073/pnas.2010168118.