Category: Neurology

Categories : Ageing NeurologyTags :

Extra Year of Education does Not Protect the Brain

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Photo by Andrea Piacquadio on Pexels

Thanks to a ‘natural experiment’ involving 30 000 people, researchers at Radboud university medical centre were able to very precisely determine the effect of an extra year of education to the brain in the long term. To their surprise, they found no effect on brain structure and no protective benefit of additional education against brain ageing. Their findings appear in eLife.

It is well-known that education has many positive effects. People who spend more time in school are generally healthier, smarter, and have better jobs and higher incomes than those with less education. However, whether prolonged education actually causes changes in brain structure over the long term and protects against brain ageing, was still unknown.

It is challenging to study this, because alongside education, many other factors influence brain structure, such as the conditions under which someone grows up, DNA traits, and environmental pollution. Nonetheless, researchers Rogier Kievit (PI of the Lifespan Cognitive Dynamics lab) and Nicholas Judd from Radboudumc and the Donders Institute found a unique opportunity to very precisely examine the effects of an extra year of education.

Ageing

In 1972, a change in the law in the UK raised the number of mandatory school years from 15 to 16, while all other circumstances remained constant. This created an interesting ‘natural experiment’, an event not under the control of researchers which divides people into an exposed and unexposed group. Data from approximately 30 000 people who attended school around that time, including MRI scans taken much later (46 years after), is available. This dataset is the world’s largest collection of brain imaging data.

The researchers examined the MRI scans for the structure of various brain regions, but they found no differences between those who attended school longer and those who did not. ‘This surprised us’, says Judd. ‘We know that education is beneficial, and we had expected education to provide protection against brain aging. Aging shows up in all of our MRI measures, for instance we see a decline in total volume, surface area, cortical thickness, and worse water diffusion in the brain. However, the extra year of education appears to have no effect here.’

Brain structure

It’s possible that the brain looked different immediately after the extra year of education, but that wasn’t measured. “Maybe education temporarily increases brain size, but it returns to normal later. After all, it has to fit in your head,” explains Kievit. “It could be like sports: if you train hard for a year at sixteen, you’ll see a positive effect on your muscles, but fifty years later, that effect is gone.” It’s also possible that extra education only produces microscopic changes in the brain, which are not visible with MRI.

Both in this study and in other, smaller studies, links have been found between more education and brain benefits. For example, people who receive more education have stronger cognitive abilities, better health, and a higher likelihood of employment. However, this is not visible in brain structure via MRI. Kievit notes: “Our study shows that one should be cautious about assigning causation when only a correlation is observed. Although we also see correlations between education and the brain, we see no evidence of this in brain structure.”

Source: Radboud University Medical Centre

Categories : Cardiovascular Disease NeurologyTags :

Heart Attacks Trigger a Greater Need for Sleep to Promote Healing

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A heart attack can trigger a desire to get more sleep, allowing the heart to heal and reduce inflammation as a result of the heart’s special signals to the brain, according to a new Mount Sinai study. This is the first study showing how the heart and brain communicate via the immune system to promote sleep and recovery after a major cardiovascular event.

The novel findings, published in Nature, highlight the importance of increased sleep after a heart attack, and suggest that sufficient sleep should be a focus of post-heart-attack clinical management and care, including in intensive care, where sleep is frequently disrupted, along with cardiac rehabilitation.

“This study is the first to demonstrate that the heart regulates sleep during cardiovascular injury by using the immune system to signal to the brain. Our data show that after a myocardial infarction (heart attack) the brain undergoes profound changes that augment sleep, and that in the weeks following a myocardial infarction, sleep abundance and drive is increased,” says senior author Cameron McAlpine, PhD, Assistant Professor of Medicine (Cardiology), and Neuroscience, at the Icahn School of Medicine at Mount Sinai. “We found that neuro-inflammation and the recruitment of immune cells called monocytes to the brain after a myocardial infarction is a beneficial and adaptive response that increases sleep to enable heart healing and the reduction of damaging cardiac inflammation.”

The researchers from the Cardiovascular Research Institute at Icahn Mount Sinai first used mouse models to discover this phenomenon. They induced heart attacks in half of the mice and performed high-resolution imaging and cell analysis, and used implantable wireless electroencephalogram devices to record electrical signals from their brains and analyse sleep patterns. After the heart attack, they found a three-fold increase in slow-wave sleep, a deep stage of sleep characterized by slow brain waves and reduced muscle activity. This increase in sleep occurred quickly after the heart attack and lasted one week.

When the researchers studied the brains of the mice with heart attacks, they found that immune cells called monocytes were recruited from the blood to the brain and used a protein called tumour necrosis factor (TNF) to activate neurons in an area of the brain called the thalamus, which caused the increase in sleep. This happened within hours after the cardiac event, and none of this occurred in the mice that did not have heart attacks.

The researchers then used sophisticated approaches to manipulate neuron TNF signaling in the thalamus and uncovered that the sleeping brain uses the nervous system to send signals back to the heart to reduce heart stress, promote healing, and decrease heart inflammation after a heart attack. To further identify the function of increased sleep after a heart attack, the researchers also interrupted the sleep of some of the mice. The mice with sleep disruption after a heart attack had an increase in heart sympathetic stress responses and inflammation, leading to slower recovery and healing when compared to mice with undisrupted sleep.

The research team also performed several human studies. The first studied the brains of patients 1–2 days after a heart attack and found an increase in monocytes compared to people without a heart attack or other CVD, mirroring the mice findings. The next analysed the sleep of more than 80 heart attack patients during the four weeks post-event and followed them for two years. The patients were divided into good sleepers and poor sleepers based on the quality of their sleep during the four weeks post-heart attack. The poor sleepers had a worse prognosis; their risk of having another cardiovascular event was twice as high as good sleepers. Additionally, the good sleepers had a significant improvement in heart function while poor sleepers had no or little improvement. 

In another human study, the researchers analysed the impact of five weeks of restricted sleep in 20 healthy adults. Sleep was monitored using electronic devices and the participants kept a sleep diary. During the five-week study period, half the participants slept for the recommended seven to eight hours a night uninterrupted, while the other half restricted their sleep by 1.5 hours each night – either delaying bedtime or waking up early. After the study period, researchers analysed blood monocytes and found similar sympathetic stress signaling and inflammatory responses in the sleep-restricted group as those that were identified in mice.

Source: The Mount Sinai Hospital / Mount Sinai School of Medicine

Categories : Neurodegenerative Diseases NeurologyTags :

Major Discovery for the Understanding of Parkinson’s Disease: New Neurotransmitter

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Neurotransmitters at a synapse. Credit: Scientific Animations CC4.0

The treatment of certain neurodegenerative diseases and the pages of neuroscience textbooks may soon be in need of a major update. A research team has discovered that a molecule in the brain – ophthalmic acid – unexpectedly acts like a neurotransmitter similar to dopamine in regulating motor function, offering a new therapeutic target for Parkinson’s and other movement diseases.

As reported in the journal Brain, researchers observed that ophthalmic acid binds to and activates calcium-sensing receptors in the brain, reversing the movement impairments of Parkinson’s mouse models for more than 20 hours.

Parkinson’s disease (PD) symptoms, which include tremors, shaking and lack of movement, are caused by decreasing levels of dopamine in the brain as those neurons die. L-dopa, the front-line drug for treatment, acts by replacing the lost dopamine and has a duration of two to three hours. While initially successful, the effect of L-dopa fades over time, and its long-term use leads to dyskinesia – involuntary, erratic muscle movements in the patient’s face, arms, legs and torso.

“Our findings present a groundbreaking discovery that possibly opens a new door in neuroscience by challenging the more-than-60-year-old view that dopamine is the exclusive neurotransmitter in motor function control,” said co-corresponding author Amal Alachkar, School of Pharmacy & Pharmaceutical Sciences professor. “Remarkably, ophthalmic acid not only enabled movement, but also far surpassed L-dopa in sustaining positive effects. The identification of the ophthalmic acid-calcium-sensing receptor pathway, a previously unrecognised system, opens up promising new avenues for movement disorder research and therapeutic interventions, especially for Parkinson’s disease patients.”

Alachkar began her investigation into the complexities of motor function beyond the confines of dopamine more than two decades ago, when she observed robust motor activity in Parkinson’s mouse models without dopamine. In this study, the team conducted comprehensive metabolic examinations of hundreds of brain molecules to identify which are associated with motor activity in the absence of dopamine. After thorough behavioural, biochemical and pharmacological analyses, ophthalmic acid was confirmed as an alternative neurotransmitter.

“One of the critical hurdles in Parkinson’s treatment is the inability of neurotransmitters to cross the blood-brain barrier, which is why L-DOPA is administered to patients to be converted to dopamine in the brain,” Alachkar said. “We are now developing products that either release ophthalmic acid in the brain or enhance the brain’s ability to synthesise it as we continue to explore the full neurological function of this molecule.”

Source: University of California – Irvine

Categories : Environmental Effects NeurologyTags :

PFAS Influence the Development and Function of the Brain

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Photo by Ryan Zazueta on Unsplash

Some per- and polyfluoroalkyl substances (PFAS) are poorly degradable and are also known as “forever chemicals”. They adversely affect health and can lead to liver damage, obesity, hormonal disorders, and cancer. A research team from the Helmholtz Centre for Environmental Research (UFZ) has investigated the effects of PFAS on the brain.

Using a combination of modern molecular biology methods and the zebrafish model, the researchers revealed the mechanism of action and identified the genes involved, which are also present in humans. The test procedure developed at the UFZ could be used for the risk assessment of other neurotoxic chemicals. The study was recently published in Environmental Health Perspectives. 

Because of their special properties – heat resistance, water and grease repellence, and high durability – PFAS are used in many everyday products (eg, cosmetics, outdoor clothing, and coated cookware). But it is precisely these properties that make them so problematic. “Because some PFAS are chemically stable, they accumulate in the environment and enter our bodies via air, drinking water, and food”, says UFZ toxicologist Prof Dr Tamara Tal. Even with careful consumption, it is nearly impossible to avoid this group of substances, which has been produced since the 1950s and now includes thousands of different compounds. “There is a great need for research, especially when it comes to developing fast, reliable, and cost-effective test systems for assessing the risks of PFAS exposure”, says Tal. So far, the environmental and health consequences have been difficult to assess.

In their current study, the researchers investigated how PFAS exposure affects brain development. To do this, they used the zebrafish model, which is frequently used in toxicology research. One advantage of this model is that around 70% of the genes found in zebrafish (Danio rerio) are also found in humans. The findings from the zebrafish model can therefore likely be transferred to humans. In their experiments, the researchers exposed zebrafish to two substances from the PFAS group (PFOS and PFHxS), which have a similar structure. The researchers then used molecular biological and bioinformatic methods to investigate which genes in the brains of the fish larvae exposed to PFAS were disrupted compared to the control fish, which were not exposed. “In the zebrafish exposed to PFAS, the peroxisome proliferator-activated receptor (ppar) gene group, which is also present in a slightly modified form in humans, was particularly active”, says Sebastian Gutsfeld, PhD student at the UFZ and first author of the study. “Toxicity studies have shown this to be the case as a result of exposure to PFAS – albeit in the liver. We have now also been able to demonstrate this for the brain”.

But what consequences does an altered activity of the ppar genes triggered by PFAS exposure have for brain development and behaviour of zebrafish larvae? The researchers investigated this in further studies using the zebrafish model. Using CRISPR/Cas9 ‘gene scissors’ the researchers were able to “selectively cut individual or several ppar genes and prevent them from functioning normally”, explains Gutsfeld. “We wanted to find out which ppar genes are directly linked to a change in larval behaviour triggered by PFAS exposure”. Proof of the underlying mechanism was directly provided. In contrast to genetically unaltered zebrafish, the knockdown fish in which the gene scissors were used should not show any behavioural changes after exposure to PFAS.

The two behavioural endpoints

In one series of experiments, the researchers continuously exposed zebrafish to PFOS or PFHxS during their early developmental phase between day one and day four and in another series of experiments only on day five. On the fifth day, the researchers then observed swimming behaviour. They used two different behavioural endpoints for this purpose. In one endpoint, swimming activity was measured during a prolonged dark phase. PFAS-exposed fish swam more than fish not exposed to PFAS, whether continuously exposed to PFAS during brain development or shortly before the behaviour test. Interestingly, hyperactivity was only present when the chemical was around. When the researchers removed PFOS or PFHxS, hyperactivity subsided. In the second endpoint, the startle response after a dark stimulus was measured. “In zebrafish exposed to PFOS for four days, we observed hyperactive swimming behaviour in response to the stimulus”, says Gutsfeld. In contrast, zebrafish only exposed to PFOS or PFHxS on the fifth day did not have a hyperactive startle response.

Based on these responses, the researchers conclude that PFOS exposure is associated with abnormal consequences – particularly during sensitive developmental phases of the brain. Using knockdown zebrafish, the researchers identified two genes from the ppar group that mediate the behaviour triggered by PFOS. 

“Because these genes are also present in humans, it is possible that PFAS also have corresponding effects in humans”, concludes Tal. The scientists working with Tal want to investigate the neuroactive effects of other PFAS in future research projects and expand the method so that it can ultimately be used to assess the risk of chemicals in the environment, including PFAS.

Source: Helmholtz Centre for Environmental Research – UFZ

Categories : NeurologyTags :

Cannabis Use in Adolescence has Visible Effects on Brain Structure

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Photo by Anna Shvets

Cannabis use may lead to thinning of the cerebral cortex in adolescents according to a recent study.  The study demonstrates that THC – or tetrahydrocannabinol, an active substance in cannabis – causes shrinkage of the dendritic arborisation, neurons’ “network of antennae” whose role is critical for communication between neurons. This results in the atrophy of certain regions of the cerebral cortex – bad news at an age when the brain is maturing.  

The study, led by Graciela Pineyro and Tomas Paus, involved researchers at CHU Sainte-Justine and professors at the Université de Montréal Faculty of Medicine, was published in The Journal of Neuroscience.

“If we take the analogy of the brain as a computer, the neurons would be the central processor, receiving all information via the synapses through the dendritic network,” explains Tomas Paus, who is also a professor of psychiatry and neuroscience at Université de Montréal. “So a decrease in the data input to the central processor by dendrites makes it harder for the brain to learn new things, interact with people, cope with new situations, etc. In other words, it makes the brain more vulnerable to everything that can happen in a young person’s life.”

A multi-level approach to better understand the effect on humans

This project is notable for the complementary, multi-level nature of the methods used. “By analysing magnetic resonance imaging (MRI) scans of the brains of a cohort of teenagers, we had already shown that young people who used cannabis before the age of 16 had a thinner cerebral cortex,” explains Tomas Paus. “However, this research method doesn’t allow us to draw any conclusions about causality, or to really understand THC’s effect on the brain cells.”  

Given the limitations of MRI, the introduction of the mouse model by Graciela Pineyro’s team was key. “The model made it possible to demonstrate that THC modifies the expression of certain genes affecting the structure and function of synapses and dendrites,” explains Graciela Pineyro, who is also a professor in the Department of Pharmacology and Physiology at Université de Montréal. “The result is atrophy of the dendritic arborescence that could contribute to the thinning observed in certain regions of the cortex.”  

Interestingly, these genes were also found in humans, particularly in the thinner cortical regions of the cohort adolescents who experimented with cannabis. By combining their distinct research methods, the two teams were thus able to determine with a high degree of certainty that the genes targeted by THC in the mouse model were also associated to the cortical thinning observed in adolescents. 

With cannabis use on the rise among North American youth, and commercial cannabis products containing increasing concentrations of THC, it’s imperative that we improve our understanding of how this substance affects brain maturation and cognition. This successful collaborative study, involving cutting-edge techniques in cellular and molecular biology, imaging and bioinformatics analysis, is a step in the right direction for the development of effective public health measures.

Source: University of Montreal

Categories : Neurology UncategorizedTags :

Can Space Radiation Affect Astronauts’ Long-term Cognition?

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Photo: Pixabay CC0

During missions into outer space, galactic cosmic radiation (GCR) will penetrate current spacecraft shielding and thus pose a significant risk to human health. Previous studies have shown that GCR can cause short-term cognitive deficits in male rodents. Now a study published in the Journal of Neurochemistry reveals that GCR exposure can also cause long-lasting learning deficits in female rodents.

The impact of GCR on cognition was lessened when mice were fed an antioxidant and anti-inflammatory compound called CDDO-EA.

Beyond its immediate implications for space exploration, the findings contribute to a broader understanding of radiation’s long-term impact on cognitive health.

“Our study lays the groundwork for future causal delineation of how the brain responds to complex GCR exposure and how these brain adaptations result in altered behaviours,” said co-corresponding author Sanghee Yun, PhD, of the Children’s Hospital of Philadelphia Research Institute and the University of Pennsylvania Perelman School of Medicine.

Source: Wiley

Categories : NeurologyTags :

Insights into How the Brain Regenerates Lost Myelin

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Myelin sheath damage. Credit: Scientific Animations CC4.0

The neurons of the brain are protected by an insulating layer called myelin. In certain diseases like multiple sclerosis, the protective myelin layer around neurons is damaged and lost, leading to death of neurons and disability. New research published in The FEBS Journal reveals the importance of a protein called C1QL1 for promoting the replacement of the specialised cells that produce myelin. The findings could have important implications for the ongoing effort to develop new and improved therapies for the treatment of demyelinating diseases.

In experiments conducted in mice, deleting the gene that codes for C1QL1 caused a delay in the rate at which oligodendrocytes (the cells that make myelin) mature, leading to reduced myelination of neurons.

After mice were fed a drug that destroys myelin, recovery of oligodendrocytes and myelination were delayed in mice lacking the C1QL1 protein. Causing mice to express more C1QL1, however, led to increased numbers of oligodendrocytes and more myelination upon drug withdrawal, suggesting that C1QL1 helps to restore the damaged myelin layer.  Thus, investigational therapies that boost C1QL1 may hold promise against demyelinating diseases.

“Our basic research on C1QL1 is nascent, but there is potential that it is relevant for a novel treatment for multiple sclerosis,” said corresponding author David C. Martinelli, PhD, of the University of Connecticut Health Center. “New drug treatment options for patients with multiple sclerosis could have a large impact on their quality of life.”

Source: Wiley

Categories : Lab Tests and Imaging NeurologyTags :

Scientists Definitively Reveal the Brain’s Elusive Glymphatic System

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Erin Yamamoto, MD, and Juan Piantino, MD, are among the co-authors of a new study from Oregon Health & Science University that used imaging of neurosurgery patients to definitively reveal the existence of waste-clearance pathways in the human brain known as the glymphatic system. (OHSU/Christine Torres Hicks)

Scientists have long theorised about a network of pathways in the brain that are believed to clear metabolic proteins that would otherwise build up and potentially lead to Alzheimer’s and other forms of dementia. But they had never definitively revealed this network in people – until now.

A new study involving five patients undergoing brain surgery at Oregon Health & Science University provides imaging of this network of perivascular spaces (fluid-filled structures along arteries and veins) within the brain for the first time.

“Nobody has shown it before now,” said senior author Juan Piantino, MD, associate professor of pediatrics (neurology) in the OHSU School of Medicine and a faculty member of the Neuroscience Section of the Papé Family Pediatric Research Institute at OHSU. “I was always skeptical about it myself, and there are still a lot of skeptics out there who still don’t believe it. That’s what makes this finding so remarkable.”

The findings appear in the Proceedings of the National Academy of Sciences.

The study combined the injection of an inert contrasting agent with a special type of magnetic resonance imaging to discern cerebrospinal fluid flowing along distinct pathways in the brain 12, 24 and 48 hours following surgery. In definitively revealing the presence of an efficient waste-clearance system within the human brain, the new study supports the promotion of lifestyle measures and medications already being developed to maintain and enhance it.

“This shows that cerebrospinal fluid doesn’t just get into the brain randomly, as if you put a sponge in a bucket of water,” Piantino said. “It goes through these channels.”

More than a decade ago, scientists at the University of Rochester first proposed the existence of a network of waste-clearance pathways in the brain akin to the body’s lymphatic system, part of the immune system. Those researchers confirmed it with real-time imaging of the brains of living mice. Due to its dependence on glial cells in the brain, they coined the term “glymphatic system” to describe it.

However, scientists had yet to confirm the existence of the glymphatic system through imaging in people.

Pathways revealed in patients

The new study examined five OHSU patients who underwent neurosurgery to remove tumours in their brains between 2020 and 2023. In each case, the patients consented to having a gadolinium-based inert contrasting agent injected through a lumbar drain used as part of the normal surgical procedure for tumour removal. The tracer would be carried with cerebrospinal fluid into the brain.

Afterward, each patient underwent magnetic resonance imaging, or an MRI, at different time points to trace the spread of cerebrospinal fluid.

Rather than diffusing uniformly through brain tissue, the images revealed fluid moving along pathways — through perivascular spaces in clearly defined channels. Researchers documented the finding with a specific kind of MRI known as fluid attenuated inversion recovery, or FLAIR. This type of imaging is sometimes used following the removal of tumors in the brain. As it turns out, it also revealed the gadolinium tracer in the brain, whereas the standard MRI sequences did not.

“That was the key,” Piantino said.

“You can actually see dark perivascular spaces in the brain turn bright,” said co-lead author Erin Yamamoto, MD, a resident in neurological surgery in the OHSU School of Medicine. “It was quite similar to the imaging the Rochester group showed in mice.”

Clearing waste from the brain

Scientists believe this network of pathways effectively flushes the brain of metabolic wastes generated by its energy-intensive work. Wastes include proteins such as amyloid and tau, which have been shown to form clumps and tangles in brain images of patients with Alzheimer’s disease.

Emerging research suggests medications that may be useful, but much of the focus around the glymphatic system has revolved around lifestyle-based measures to improve the quality of sleep, such as maintaining a regular sleep schedule, establishing a relaxing routine, and avoiding screens in the bedroom before bed. Especially at night during deep sleep, researchers believe a well-functioning glymphatic system efficiently carries waste proteins toward veins exiting the brain.

“People thought these perivascular spaces were important, but it had never been proved,” Piantino said. “Now it has.”

The authors credited the late Justin Cetas, MD, PhD, who initiated the study as an OHSU neurosurgeon before leaving the university to become chair of neurological surgery at his alma mater, the University of Arizona Health Sciences Center in Tucson. He died in a motorcycle accident in 2022.

Source: Oregon Health & Science University

Categories : NeurologyTags :

Risk Factor for Autism Linked to Y Chromosome

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Chromosomes. Credit: NIH

Increased risk for autism appears to be linked to the Y chromosome, a Geisinger study found, offering a new explanation for the greater prevalence of autism in males. The results were published in Nature Communications.

Autism spectrum disorder (ASD) is nearly four times more prevalent among males than females, but the reason for this disparity is not well understood. One common hypothesis involves the difference in sex chromosomes between males (XY) and females (XX).

“A leading theory in the field is that protective factors of the X chromosome lower autism risk in females,” said Matthew Oetjens, PhD, assistant professor at Geisinger’s Autism & Developmental Medicine Institute.

The Geisinger research team, led by Dr Oetjens and Alexander Berry, PhD, staff scientist, sought to determine the effects of the X and Y chromosomes on autism risk by examining ASD diagnoses in people with an abnormal number of X or Y chromosomes, a genetic condition known as sex chromosome aneuploidy.

The team analysed genetic and ASD diagnosis data on 177 416 patients enrolled in the Simons Foundation Powering Autism Research (SPARK) study and Geisinger’s MyCode Community Health Initiative.

They found that individuals with an additional X chromosome had no change in ASD risk, but that those with an additional Y chromosome were twice as likely to have an ASD diagnosis.

This suggests a risk factor associated with the Y chromosome instead of a protective factor associated with the X chromosome.

“While these may seem like two sides of the same coin, our results encourage us to look for autism risk factors on the Y chromosome instead of limiting our search to protective factors on the X chromosome,” Dr. Berry said.

“However, further research is needed to identify the specific risk factor associated with the Y chromosome.”

This analysis also confirms prior work by showing that the loss of an X or Y chromosome, known as Turner syndrome, is associated with a large increase in ASD risk. Further research is needed to determine whether the ASD risk factors associated with sex chromosome aneuploidy explains the sex difference in ASD prevalence.

Source: Geisinger Health System via Science Daily

Categories : NeurologyTags :

Research Reveals a New Target to Treat Anxiety

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A healthy neuron. Credit: NIH

Scientists at Université de Montréal and its affiliated Montreal Clinical Research Institute (IRCM) have uncovered unique roles for a protein complex in the structural organisation and function of brain cell connectivity, as well as in specific cognitive behaviours.

The work by a team led by Hideto Takahashi, director of the IRCM’s synapse development and plasticity research unit, in collaboration with Steven Connor’s team at York University and Masanori Tachikawa’s team at Japan’s Tokushima University is published in The EMBO Journal.

Although defects in synapse organisation are linked to many neuropsychiatric conditions, the mechanisms responsible for this organisation are poorly understood. The new study’s findings could provide valuable therapeutic insights, the researchers believe.

Two goals are important to bear in mind with this research, said Takahashi, an associate research medical professor in molecular biology and neuroscience at UdeM.

“One is to uncover novel molecular mechanisms for brain cell communication,” he said. “The other is to develop a new unique animal model of anxiety disorders displaying panic disorder- and agoraphobia-like behaviours, which helps us develop new therapeutic strategies.”

Understanding the mechanisms

Synapses are essential for neuronal signal transmission and brain functions. Defects in excitatory synapses, which activate signal transmission to target neurons, and those in synaptic molecules predispose to many mental illnesses.

Takahashi’s team has previously discovered a new protein complex within the synaptic junction, called TrkC-PTPσ, which is only found in excitatory synapses. The genes coding for TrkC (NTRK3) and PTPσ (PTPRS) are associated with anxiety disorders and autism, respectively. However, the mechanisms by which this complex regulates synapse development and contributes to cognitive functions are unknown.

The work carried out in the new study by first author Husam Khaled, a doctoral student in Takahashi’s laboratory, showed that the TrkC-PTPσ complex regulates the structural and functional maturation of excitatory synapses by regulating the phosphorylation, a biochemical protein modification, of many synaptic proteins, while disruption of this complex causes specific behavioural defects in mice.

Building blocks of the brain

Neurons are the building blocks of the brain and the nervous system that are responsible for sending and receiving signals that control the brain and body functions. Neighbouring neurons communicate through synapses, which act like bridges that allow the passage of signals between them.

This process is essential for proper brain functions such as learning, memory and cognition. Defects in synapses or their components can disrupt communication between neurons, and lead to various brain disorders.

By generating mice with specific genetic mutations that disrupt the TrkC-PTPσ complex, Takahashi’s team uncovered the unique functions of this complex. They demonstrated that this complex regulates the phosphorylation of many proteins involved in synapse structure and organisation.

High-resolution imaging of the mutant mice brains revealed abnormal synapse organisation, and further study of their signaling properties showed an increase in inactive synapses with defects in signal transmission. Observing the behaviour of the mutant mice, the scientists saw that they exhibited elevated levels of anxiety, especially enhanced avoidance in unfamiliar conditions, and impaired social behaviours.

Source: University of Montreal