Neuroscience biweekly vol. 88, 21st June — 5th July
TL;DR
- Measuring human brain activity down to the cellular level: until now, this has been possible only to a limited extent. With a new approach, it will now be much easier. The method relies on microelectrodes along with the support of brain tumor patients, who participate in studies while undergoing ‘awake’ brain surgery. This enabled the team to identify how our brain processes numbers.
- Molecular imaging with 18F-flubatine PET/MRI has shown that neuroreceptors in the brains of individuals with obesity respond differently to food cues than those in normal-weight individuals, making the neuroreceptors a prime target for obesity treatments and therapy. This research contributes to the understanding of the fundamental mechanisms underlying obesity and offers valuable insights into potential medical interventions.
- Scientists identify the first genetic marker for MS severity, opening the door to preventing long-term disability.
- Major depressive disorder (MDD) is not only among the most common mental illnesses, affecting over 8% of Americans, but it is also extremely variable from one person to another. Researchers have recently begun making strides toward understanding the neurophysiology underlying different subtypes of depression, which could speed the development of better treatments, but much remains to be discovered. Now, a new study identifies multiple subtypes of MDD using brain imaging.
- Researchers have identified a group of nerve cells in the mouse brain that are involved in creating negative emotional states and chronic stress. The neurons, which have been mapped with a combination of advanced techniques, also have receptors for estrogen, which could explain why women as a group are more sensitive to stress than men.
- New research has revealed everyone’s brain has a ‘pain fingerprint’ that varies from person to person. The University of Essex-led study, in collaboration with the neuroscience of pain group at the Ludwig Maximilians University of Munich, found fast-oscillating brain waves linked to brief pain and touch can differ widely in scans.
- An international team of researchers, studying macaque brains, has mapped out neurotransmitter receptors, revealing a potential role in distinguishing internal thoughts and emotions from those generated by external influences.
- Researchers have solved a long-standing mystery about how a protein helps rid the body of damaged mitochondria, in findings that could help lead to potential new treatments for Parkinson’s disease.
- A study analyzed data from people aged 40 to 69 and found a causal link between habitual napping and larger total brain volume — a marker of good brain health linked to a lower risk of dementia and other diseases.
- A new study of a brain region called the rostro-medial prefrontal could potentially advance diagnosis and therapies for Borderline Personality Disorder (BPD).
- And more!
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The latest news and research
Human acute microelectrode array recordings with broad cortical access, single-unit resolution, and parallel behavioral monitoring
by Viktor M. Eisenkolb, Lisa M. Held, Alexander Utzschmid, Xiao-Xiong Lin, Sandro M. Krieg, Bernhard Meyer, Jens Gempt, Simon N. Jacob in Cell Reports
Measuring human brain activity down to the cellular level: until now, this has been possible only to a limited extent. With a new approach developed by researchers at the Technical University of Munich (TUM), it will now be much easier. The method relies on microelectrodes along with the support of brain tumor patients, who participate in studies while undergoing “awake” brain surgery. This enabled the team to identify how our brain processes numbers.
We use numbers every day. It happens in a very concrete way when we count objects. And it happens abstractly, for example when we see the symbol “8” or do complex calculations.
In a study published in the journal Cell Reports, a team of researchers and clinicians working with Simon Jacob, Professor of Translational Neurotechnology at the Department of Neurosurgery at TUM’s university hospital Klinikum rechts der Isar, was able to show how the brain processes numbers. The researchers found that individual neurons in the brains of participants were specialized in handling specific numbers. Each one of these neurons was particularly active when its “preferred” number of elements in a dot pattern was presented to the patient. To a somewhat lesser degree, this was also the case when the subjects processed number symbols.
“We already knew that animals processed numbers of objects in this way,” says Prof. Jacob. “But until now, it was not possible to demonstrate conclusively how it works in humans. This has brought us a step closer to unravelling the mechanisms of cognitive functions and developing solutions when things go wrong with these brain functions, for example.”
To get to this result, Prof. Jacob and his team first had to solve a fundamental problem.
“The brain functions by means of electrical impulses,” says Simon Jacob. “So it is by detecting these signals directly that we can learn the most about cognition and perception.”
There are, however, few opportunities for direct measurements of human brain activity. Neurons cannot be individually recorded through the skull. Some medical teams surgically implant electrodes in epilepsy patients. However, these procedures do not reach the brain region believed to be responsible for processing numbers.
Simon Jacob and an interdisciplinary team, therefore, developed an approach that adapts established technologies and opens up entirely new possibilities in neuroscience. At the heart of the procedure are microelectrode arrays that have undergone extensive testing in animal studies.
To ensure that the electrodes would produce reliable data in awake surgeries on the human brain, the researchers had to reconfigure them in close collaboration with the manufacturer. The trick was to increase the distance between the needle-like sensors used to record the electrical activities of a cell.
“In theory, tightly packed electrodes will produce more data,” says Simon Jacob. “But in practice the large number of contacts stuns the implanted brain region, so that no usable data are recorded.”
The development of the procedure was possible only because patients with brain tumors agreed to support the research team. While undergoing brain surgery, they permitted sensors to be implanted and performed test tasks for the researchers. According to Simon Jacob, the experimental procedures did not negatively affect the work of the surgical team.
“Our procedure has two key advantages,” says Simon Jacob. First, such tumor surgeries provide access to a much larger area of the brain. “And second, with the electrodes we used, which have been standardized and tested in years of animal trials, many more medical centers will be able to measure neuronal activity in the future” says Jacob. While epilepsy operations are performed only at a small number of centers and on relatively few patients, he explains, many more university hospitals perform awake operations on patients with brain tumors. “With a significantly larger number of studies with standardized methods and sensors, we can learn a lot more in the coming years about how the human brain functions,” says Simon Jacob.
Molecular imaging identifies brain changes in response to food cues; offers insight into obesity interventions
by the Society of Nuclear Medicine and Molecular Imaging
Molecular imaging with 18F-flubatine PET/MRI has shown that neuroreceptors in the brains of individuals with obesity respond differently to food cues than those in normal-weight individuals, making the neuroreceptors a prime target for obesity treatments and therapy. This research, presented at the Society of Nuclear Medicine and Molecular Imaging 2023 Annual Meeting, contributes to the understanding of the fundamental mechanisms underlying obesity and offers valuable insights into potential medical interventions.
Worldwide, more than one billion people are obese. The global obesity epidemic poses a major challenge for healthcare systems worldwide, and the search for interventions to achieve sustainable weight loss is a high priority. By investigating biological and behavioral mechanisms in individuals with obesity, scientists are seeking to identify potential pathways for treatments and interventions.
“The brain’s cholinergic system is a unique area of interest when it comes to studying obesity,” said Swen Hesse, MD, clinical scientist and professor in the Department of Nuclear Medicine at the University of Leipzig in Leipzig, Germany. “Cholinergic changes in the brain’s reward and attentional networks seem to play an important role in how people decide what foods are most desirable, or salient. In our study, we aimed to measure changes in α4β2* nicotinic acetylcholine receptors found in the cholinergic system in response to high-caloric food cues.”
In the study, 15 individuals with obesity and 16 normal-weight controls underwent PET/MRI with 18F-flubatine twice on separate days, once while in a resting state and once while viewing food pictures. The total distribution volume of 18F-flubatine was estimated, and a visual analog scale was used to assess states of hunger/satiety, appetite, disinhibition, craving and taste. Eating behavior was also measured using the Three-Factor Eating Questionnaire (TFEQ).
In the resting state, no significant difference in total distribution volume of 18F-flubatine was noted between the participants with obesity and normal-weight controls. While viewing photos of food, however, the total distribution volume of 18F-flubatine was higher in the obese compared with normal-weight controls in the thalamus of the brain, particularly in those with a higher TFEQ score.
For normal-weight controls, there was a stronger connectivity to the dorsal attention network of the brain when viewing food cues, whereas for participants with obesity, a stronger connectivity was found with the salience network. Finally, analyses of the total volume distribution and different behavioral measures showed a significant correlation between total volume distribution in the hypothalamus and the measure for satiety in normal-weight controls. In participants with obesity, there was a significant correlation with measures of disinhibition and the nucleus accumbens.
“We anticipate that the results of our study will pave the way for novel drug treatments and behavioral interventions to effectively combat obesity worldwide,” noted, Osama Sabri, MD, PhD, professor, director, and chairman of the Department of Nuclear Medicine at the University of Leipzig. “In addition, the imaging technology utilized in this study holds promise for identifying biomarkers that can aid in patient stratification and facilitate personalized medicine approaches in the near future.”
Locus for severity implicates CNS resilience in progression of multiple sclerosis
by Adil Harroud, Pernilla Stridh, Jacob L. McCauley, Janna Saarela, Aletta M. R. van den Bosch, Hendrik J. Engelenburg, Ashley H. Beecham, et al. in Nature
Scientists identify the first genetic marker for MS severity, opening the door to preventing long-term disability.
A study of more than 22,000 people with multiple sclerosis has discovered the first genetic variant associated with faster disease progression that can rob patients of their mobility and independence over time. Multiple sclerosis (MS) is the result of the immune system mistakenly attacking the brain and the spinal cord, resulting in symptom flares known as relapses as well as longer-term degeneration known as progression. Despite the development of effective treatments for relapses, none can reliably prevent the accumulation of disability. The breakthrough findings, published in Nature, point to a genetic variant that increases the disease’s severity and provide the first real progress in understanding and eventually fighting this aspect of MS.
“Inheriting this genetic variant from both parents accelerates the time to needing a walking aid by almost four years,” said Sergio Baranzini, PhD, professor of neurology at the University of California, San Francisco (UCSF) and co-senior author of the study. The work was the result of a large international collaboration of more than 70 institutions from around the world, led by researchers from UCSF and the University of Cambridge. “Understanding how the variant exerts its effects on MS severity will hopefully pave the way to a new generation of treatments that are able to prevent disease progression,” said Stephen Sawcer, a professor at Cambridge and the other co-senior author of the study.
To address the mystery of MS severity, two large MS research consortia joined forces: The International Multiple Sclerosis Genetics Consortium (IMSGC) and The MultipleMS Consortium. This enabled MS researchers from around the world to pool the resources needed to begin to identify the genetic factors influencing MS outcomes. Previous studies have shown that MS susceptibility, or risk, stems in large part from dysfunction in the immune system, and some of this dysfunction can be treated, slowing down the disease.
But “these risk factors don’t explain why, 10 years after diagnosis, some MS patients are in wheelchairs, while others continue to run marathons,” explained Baranzini.
The two consortia combined data from more than 12,000 people with MS to complete a genome-wide association study (GWAS), which uses statistics to carefully link genetic variants to particular traits. In this case, the traits of interest were related to MS severity, including the years it took for each individual to advance from diagnosis to a certain level of disability. After sifting through more than 7 million genetic variants, the scientists found one that was associated with faster disease progression. The variant sits between two genes with no prior connection to MS, called DYSF and ZNF638. The first is involved in repairing damaged cells, and the second helps to control viral infections. The variant’s proximity to these genes suggests that they may be involved in the disease’s progression.
“These genes are normally active within the brain and spinal cord, rather than the immune system,” said Adil Harroud, MD, lead author of the study and former postdoctoral researcher in Baranzini’s lab. “Our findings suggest that resilience and repair in the nervous system determine the course of MS progression and that we should focus on these parts of human biology for better therapies.”
The findings give the field its first leads to address the nervous system component of MS.”Although it seems obvious that your brain’s resilience to injury would determine the severity of a disease like MS, this new study has pointed us towards the key processes that underlie this resilience,” Sawcer said.
To confirm their findings, the scientists investigated the genetics of nearly 10,000 additional MS patients. Those with two copies of the variant became disabled faster.
But how do we know how relevant this DNA variant actually is? That’s where the Dutch Brain Bank steps in. A team of researchers from the Netherlands Institute for Neuroscience (Aletta van den Bosch, Jeen Engelenburg, Dennis Wever, Jorg Hamann, Inge Huitinga and Joost Smolders), within the International MS Genetics Consortium (IMSGC), looked at the genetic architecture underlying the course of MS, using donor brains.
Joost Smolders (aside from his employment at the Netherlands Institute for Neuroscience, also working as a neurologist at Erasmus MC Rotterdam and member of the IMSGC):
‘In terms of treatment, there’s already a lot that we can do for people with MS, but we can’t yet predict the speed at which their health deteriorates. For this we need more insight into underlying mechanisms, with the discovery of the SNP being an important first step. An SNP is a variation in the DNA of a single DNA building block. At the Netherlands Institute for Neuroscience, we can perform the second step, which involves looking into the brain tissue to see the effect of this SNP. At the Brain Bank, we have brains from deceased donors with MS who already have an entire disease history behind them, all available for research. We asked ourselves whether carriers of the genetic abnormality had more severe MS-related changes in their brains.’
‘Our results show that homozygous carriers of the risk allele (rs10191320), or double carriers of the gene, have almost twice as many MS abnormalities in their gray and white matter than MS donors without this genetic variation. This is very important because it allows us to validate that this SNP may really be relevant to people with MS. This also illustrates the strength of the Brain Bank: you can look at the pathology very closely. The effect of such an SNP is magnified far more in the pathology than in the effect it has on someone’s experience with MS. Something that would typically require tens of thousands of people with MS for living measurements can be confirmed with a hundred or so of these particular MS brain donors.’
Further work will be necessary to determine exactly how this genetic variant affects DYSF, ZNF638, and the nervous system more generally. The researchers are also collecting an even larger set of DNA samples from people with MS, expecting to find other variants that contribute to long-term disability.
“This gives us a new opportunity to develop new drugs that may help preserve the health of all who suffer from MS,” said Harroud. Could we say instead, “treatments to prevent long-term disability”?
Mapping Neurophysiological Subtypes of Major Depressive Disorder Using Normative Models of the Functional Connectome
by Xiaoyi Sun, Jinrong Sun, Xiaowen Lu, Qiangli Dong, Liang Zhang, Wenxu Wang, Jin Liu, Qing Ma, Xiaoqin Wang, Dongtao Wei, Yuan Chen, Bangshan Liu, Chu-Chung Huang, Yanting Zheng, Yankun Wu, Taolin Chen, Yuqi Cheng, Xiufeng Xu, Qiyong Gong, Tianmei Si, Shijun Qiu, Ching-Po Lin, Jingliang Cheng, Yanqing Tang, Fei Wang, Jiang Qiu, Peng Xie, Lingjiang Li, Yong He, Mingrui Xia in Biological Psychiatry
Major depressive disorder (MDD) is not only among the most common mental illnesses, affecting over 8% of Americans, but it is also extremely variable from one person to another. Researchers have recently begun making strides toward understanding the neurophysiology underlying different subtypes of depression, which could speed development of better treatments, but much remains to be discovered. Now, a new study in Biological Psychiatry, published by Elsevier, identifies multiple subtypes of MDD using brain imaging.
John Krystal, MD, Editor of Biological Psychiatry, said of the work:
“We have long known that disorders like major depressive disorder are highly heterogeneous. This study in a large sample of depressed patients provides leads that can be pursued in subtyping depression on the basis of functional magnetic resonance imaging (fMRI) tests that measure the degree of coordination across brain regions, also known as ‘functional connectivity.’”
The researchers used resting-state fMRI collected at multiple clinical sites from a large cohort of more than 1,000 MDD patients and over 1,000 healthy controls (HC). The study used the so-called normative model, which uses data from a large reference population to quantify individual deviations, much like the growth charts used by pediatricians. The researchers examined the functional connectivity among brain regions and mapped individual functional deviations in the MDD patients compared to this normative prediction across the lifespan.
Senior author Mingrui Xia, PhD, from Beijing Normal University, said:
“This approach led to the identification of two reproducible neurophysiological subtypes exhibiting distinct deviation patterns, depressive item scores, and longitudinal treatment predictability.”
One subtype of patients showed severe positive deviations — indicating increased brain connectivity — in the default mode network, limbic, and subcortical areas, and negative deviations in the sensorimotor and attention areas. The second subtype of patients featured a milder and opposite pattern of deviation, highlighting the heterogeneity of depression at the neurophysiological level. The authors speculate that the altered activity could be related to the tendency to ruminate in people with MDD.
The work is particularly exciting in that it moves the field toward finding biomarkers, or biological markers, of depression, which currently relies on patient-reported clinical symptoms for diagnosis, treatment, and prognostics. Biomarkers could offer a way to improve all these aspects of treatment for MDD.
Dr. Xia went on to say:
“These findings shed light on the diverse neurobiological mechanisms from a connectomics perspective underlying the complex clinical heterogeneity observed in individuals with depression. The implications of this research are far-reaching, providing valuable insights into the development of imaging-based candidate biomarkers. These biomarkers have the potential to guide future precise diagnostic and treatment strategies tailored to each patient’s specific neurophysiological subtype.”
Dr. Xia noted:
“By embracing the concept of neurophysiological subtypes, we can potentially revolutionize the field of mental health by enabling clinicians to personalize treatments based on an individual’s unique connectome characteristics. This approach opens up new avenues for precision medicine and holds the promise of improving therapeutic interventions for depression.”
Esr1+ hypothalamic-habenula neurons shape aversive states
by Daniela Calvigioni, Janos Fuzik, Pierre Le Merre, Marina Slashcheva, Felix Jung, Cantin Ortiz, Antonio Lentini, Veronika Csillag, Marta Graziano, Ifigeneia Nikolakopoulou, Moritz Weglage, Iakovos Lazaridis, Hoseok Kim, Irene Lenzi, Hyunsoo Park, Björn Reinius, Marie Carlén, Konstantinos Meletis in Nature Neuroscience
Researchers at Karolinska Institutet in Sweden have identified a group of nerve cells in the mouse brain that are involved in creating negative emotional states and chronic stress. The neurons, which have been mapped with a combination of advanced techniques, also have receptors for oestrogen, which could explain why women as a group are more sensitive to stress than men. The study is published in Nature Neuroscience.
Just which networks in the brain give rise to negative emotions (aversion) and chronic stress have long been unknown to science.
By using a combination of advanced techniques, such as Patch-seq, large-scale electrophysiology (Neuropixels) and optogenetics (see factbox), KI researchers Konstantinos Meletis and Marie Carlén and their team have been able to map out a specific neuronal pathway in the mouse brain leading from the hypothalamus to the habenula that controls aversion.
The researchers used optogenetics to activate the pathway when the mice entered a particular room, and found that the mice soon started to avoid the room even though there was nothing in it.
“We discovered this connection between the hypothalamus and the habenula in a previous study but didn’t know what types of neurons the pathway was made up of,” says Konstantinos Meletis, professor at the Department of Neuroscience, Karolinska Institutet. “It’s incredibly exciting to now understand what type of neuron in the pathway controls aversion. If we can understand how negative signals in the brain are created, we can also find mechanisms behind affective diseases like depression, which will open the way for novel drug treatments.”
The study was led by three postdocs at the same department, Daniela Calvigioni, Janos Fuzik and Pierre Le Merre, and as Professor Meletis explains, is an example of how scientists can use advanced techniques to identify neuronal pathways and neurons that control emotions and behaviour.
Another interesting discovery is that the neurons linked to aversion have a receptor for oestrogen, making them sensitive to oestrogen levels. When male and female mice were subjected to the same type of unpredictable mild aversive events, the female mouse developed a much more lasting stress response than the male.
“It has long been known that anxiety and depression are more common in women than in men, but there hasn’t been any biological mechanism to explain it,” says Marie Carlén, professor at the Department of Neuroscience. “We’ve now found a mechanism that can at least explain these sex differences in mice.”
The study was mainly financed by the Knut and Alice Wallenberg Foundation, the Swedish Research Council, the Swedish Brain Foundation and the David and Astrid Hagelén Foundation. The researchers report no potential conflicts of interest.
Interindividual variability and individual stability of pain- and touch-related neuronal gamma oscillations
by Elia Valentini, Alina Shindy, Viktor Witkovsky, Anne Stankewitz, Enrico Schulz in Journal of Neurophysiology
New research has revealed everyone’s brain has a ‘pain fingerprint’ that varies from person to person.
The University of Essex-led study, in collaboration with the neuroscience of pain group at the Ludwig Maximilians University of Munich, found fast-oscillating brain waves linked to brief pain and touch can differ widely in scans.
These waves, called gamma oscillations, were previously thought to represent pain perception in the brain — with past research focussing on group data and overlooking individual differences, even discarding them as ‘noise’ in scans.
The Department of Psychology’s Dr Elia Valentini found major differences in timing, frequency and location of the gamma oscillations and incredibly some people showed no waves at all.
Dr Valentini said: “Not only, for the first time, can we pinpoint the extreme variability in the gamma response across individuals, but we also show that the individual response pattern is stable across time. This pattern of group variability and individual stability may apply to other brain responses, and characterising it may allow us to identify individual pain fingerprints in the activity of the brain.”
The study, published in the Journal of Neurophysiology, was able to map patterns in participants from another lab, suggesting a replicable phenomenon.
In total, data from 70 people were examined. The experiments were split into two studies with a laser used to generate pain.
Overall, it was discovered that the subject’s gamma waves were “remarkably stable” and created similar individual patterns when stimulated. Interestingly, some recorded feeling pain and having no gamma response, whilst others had a large response. At this stage, it is not known why there is such variation — but it is hoped this will be a springboard for future research.
Dr Valentini added: “I think we need to go back to square one because past findings on the relationship between pain and gamma oscillations do not represent all the participants. Unfortunately, this minority can drive the research results and lead to misleading conclusions about the functional significance of these responses. We don’t mean for gamma oscillations not to have a role in pain perception, but we certainly won’t find its true role if we keep quantifying it as we did thus far.”
Dr Valentini hopes this study will also change the way gamma oscillations are measured in other sensory domains.
Gradients of neurotransmitter receptor expression in the macaque cortex
by Sean Froudist-Walsh, Ting Xu, Meiqi Niu, Lucija Rapan, Ling Zhao, Daniel S. Margulies, Karl Zilles, Xiao-Jing Wang, Nicola Palomero-Gallagher in Nature Neuroscience
Receptor patterns define key organisational principles in the brain, scientists have discovered.
An international team of researchers, studying macaque brains, has mapped out neurotransmitter receptors, revealing a potential role in distinguishing internal thoughts and emotions from those generated by external influences.
The comprehensive dataset has been made publicly available, serving as a bridge linking different scales of neuroscience — from the microscopic to the whole brain.
Lead author Sean Froudist-Walsh, from the University of Bristol’s Department of Computer Science explained:
“Imagine the brain as a city. In recent years, brain research has been focused on been studying its roads, but in this research, we’ve made the most detailed map yet of the traffic lights — the neurotransmitter receptors — that control information flow. We’ve discovered patterns in how these ‘traffic lights’ are arranged that help us understand their function in perception, memory, and emotion. It’s like finding the key to a city’s traffic flow, and it opens up exciting possibilities for understanding how the normal brain works. Potentially in the future, other researchers may use these maps to target particular brain networks and functions with new medicines. Our study aimed to create the most detailed map yet of these ‘traffic lights’.”
The team used a technique called in-vitro receptor autoradiography to map the density of receptors from six different neurotransmitter systems in over 100 brain regions.
To find the patterns in this vast data, they applied statistical techniques and used modern neuroimaging techniques, combined with expert anatomical knowledge. This allowed them to uncover the relationships between receptor patterns, brain connectivity, and anatomy.
By understanding the receptor organisation across the brain, it is hoped new studies can better link brain activity, behaviour, and the action of drugs.
Moreover, because receptors are the targets of medicines, the research could, in the future, guide the development of new treatments targeting specific brain functions.
Dr Froudist-Walsh added:
“Next, we aim to use this dataset to develop computational models of the brain. These brain-inspired neural network models will help us understand normal perception and memory, as well as differences in people with conditions like schizophrenia or under the influence of substances like ‘magic mushrooms’. We also plan to better integrate findings across species — linking detailed circuit-level neuroscience often conducted in rodents, to large-scale brain activity seen in humans.”
Creating openly-accessible maps of receptor expression across the cortex that integrate neuroimaging data could speed up translation across species.
“It is being made freely available to the neuroscientific community via the Human Brain Project’s EBRAINS infrastructure, so that they can be used by other computational neuroscientists aiming to create other biologically informed models,” added Nicola Palomero-Gallagher, HBP researcher at the Forschungszentrum Jülich and senior author of the paper.
Unconventional initiation of PINK1/Parkin mitophagy by Optineurin
by Thanh Ngoc Nguyen, Justyna Sawa-Makarska, Grace Khuu, Wai Kit Lam, Elias Adriaenssens, Dorotea Fracchiolla, Stephen Shoebridge, Daniel Bernklau, Benjamin Scott Padman, Marvin Skulsuppaisarn, Runa S.J. Lindblom, Sascha Martens, Michael Lazarou in Molecular Cell
While mitochondria play a crucial role in producing the energy our cells need to carry out their various functions, when damaged, they can have profound effects on cellular function and contribute to the development of various diseases.
Broken-down mitochondria are usually removed and recycled through a garbage disposal process known as ‘mitophagy’.
PINK1 and Parkin are two proteins vital to this process, responsible for ‘tagging’ malfunctioning mitochondria for destruction. In Parkinson’s disease, mutations in these proteins can result in the accumulation of damaged mitochondria in the brain, which can lead to motor symptoms such as tremors, stiffness and difficulty with movement.
The new research, published in Molecular Cell, solves a mystery about how the protein Optineurin recognises unhealthy mitochondria ‘tagged’ by PINK1 and Parkin, enabling their delivery to our body’s garbage disposal system.
Associate Professor Michael Lazarou, a Laboratory Head in WEHI’s Ubiquitin Signalling Division, said the discovery filled a vital knowledge gap that would transform our understanding of this cellular pathway.
“Until this study, Optineurin’s precise role in initiating our body’s garbage disposal process was unknown,” Assoc Prof Lazarou, who also holds a co-appointment with Monash University, said.
“While there are many proteins that link damaged cellular materials to the garbage disposal machinery, we found that Optineurin does this in a highly unconventional way that is unlike anything else we’ve seen from similar proteins. This finding is significant because the human brain relies on Optineurin to degrade its mitochondria through the garbage disposal system driven by PINK1 and Parkin. “Knowing how Optineurin does this provides us with a framework on how we might be able to target PINK1 and Parkin mitophagy in disease and prevent the build-up of damaged mitochondria in neurons as we age. Achieving this would be instrumental to people with Parkinson’s disease — a condition that continues to impact more than 10 million people worldwide, including 80,000 Australians.”
PINK1 acts as a ‘watch-house’ inside the mitochondria, responsible for monitoring their health. When it detects problems, it activates Parkin, which tags damaged mitochondria for removal.
They work together to instruct our body to generate cellular ‘garbage bags’ around broken-down mitochondria and enlist the help of Optineurin to initiate this process.
The new study revealed that Optineurin removes damaged mitochondria by binding to an enzyme known as TBK1. From there, they found that TBK1 goes on to activate a specific cellular machine that is key to generating these garbage bags around unhealthy mitochondria.
First author Dr Thanh Nguyen said:
“Other proteins don’t need TBK1 to help them trigger this degradation process, making Optineurin a real outlier when it comes to how our bodies remove mitochondria. This has allowed us to look at the features of this pathway involving TBK1 as a potential drug target, which is a significant step forward in our search for new Parkinson’s disease treatments. The ultimate goal would be to find a way to boost levels of PINK1/Parkin mitophagy in the body — especially the brain — so that damaged mitochondria can be removed more effectively. We also hope to design a molecule that could mimic what Optineurin does, so damaged mitochondria could be removed even without PINK1 or Parkin. Given Optineurin is critical in activating the garbage disposal system in our brains, this could then prevent the accumulation of damaged mitochondria in this region, which is a significant precursor to Parkinson’s disease.”
Dr Nguyen said while clinical application of the research is years away, the discovery had laid the essential foundation needed to understand how Optineurin works and realise the pathway’s potential as a future therapeutic target.
“Our next step is to work with WEHI’s Parkinson’s Disease Centre to validate our findings in neuronal model systems to understand why Optineurin behaves this way, which will provide further insight into how we can target Optineurin and TBK1 to enhance treatment options for people with PINK1/Parkin mutations in the future.”
Is there an association between daytime napping, cognitive function, and brain volume? A Mendelian randomization study in the UK Biobank
by Valentina Paz, Hassan S. Dashti, Victoria Garfield in Sleep Health
Daytime napping may help to preserve brain health by slowing the rate at which our brains shrink as we age, suggests a new study led by researchers at UCL and the University of the Republic in Uruguay.
The study, published in the journal Sleep Health, analyzed data from people aged 40 to 69 and found a causal link between habitual napping and larger total brain volume — a marker of good brain health linked to a lower risk of dementia and other diseases.
Senior author Dr Victoria Garfield (MRC Unit for Lifelong Health & Ageing at UCL) said: “Our findings suggest that, for some people, short daytime naps may be a part of the puzzle that could help preserve the health of the brain as we get older.”
Previous research has shown that napping has cognitive benefits, with people who have had a short nap performing better in cognitive tests in the hours afterward than counterparts who did not nap.
The new study aimed to establish if there was a causal relationship between daytime napping and brain health.
Using a technique called Mendelian randomisation, they looked at 97 snippets of DNA thought to determine people’s likelihood of habitual napping. They compared measures of brain health and cognition of people who are more genetically “programmed” to nap with counterparts who did not have these genetic variants, using data from 378,932 people from the UK Biobank study, and found that, overall, people predetermined to nap had a larger total brain volume.
The research team estimated that the average difference in brain volume between people programmed to be habitual nappers and those who were not was equivalent to 2.6 to 6.5 years of aging.
But the researchers did not find a difference in how well those programmed to be habitual nappers performed on three other measures of brain health and cognitive function — hippocampal volume, reaction time and visual processing.
Lead author and PhD candidate Valentina Paz (University of the Republic (Uruguay) and MRC Unit for Lifelong Health & Ageing at UCL) said:
“This is the first study to attempt to untangle the causal relationship between habitual daytime napping and cognitive and structural brain outcomes. By looking at genes set at birth, Mendelian randomisation avoids confounding factors occurring throughout life that may influence associations between napping and health outcomes. Our study points to a causal link between habitual napping and larger total brain volume.”
Dr Garfield added: “I hope studies such as this one showing the health benefits of short naps can help to reduce any stigma that still exists around daytime napping.”
The genetic variants influencing our likelihood to nap were identified in an earlier study looking at data from 452,633 UK Biobank participants. The study, led by Dr Hassan Dashti (Harvard University and Massachusetts General Hospital), also an author on the new study, identified the variants on the basis of self-reported napping, and this was supported by objective measurements of physical activity recorded by a wrist-worn accelerometer.
In the new study, researchers analyzed health and cognition outcomes for people with these genetic variants as well as several different subsets of these variants, adjusted to avoid potential bias, for instance avoiding variants linked to excessive daytime sleepiness.
Genetic data and magnetic resonance imaging (MRI) scans of the brain were available for 35,080 individuals drawn from the larger UK Biobank sample.
In terms of study limitations, the authors noted that all of the participants were of white European ancestry, so the findings might not be immediately generalizable to other ethnicities.
While the researchers did not have information on nap duration, earlier studies suggest that naps of 30 minutes or less provide the best short-term cognitive benefits, and napping earlier in the day is less likely to disrupt night-time sleep.
Previous research looking at the UK and the Netherlands found that nearly a third of adults aged 65 or over had a regular nap.
Rejection Distress Suppresses Medial Prefrontal Cortex in Borderline Personality Disorder
by Eric A. Fertuck, Barbara Stanley, Olena Kleshchova, J. John Mann, Joy Hirsch, Kevin Ochsner, Paul Pilkonis, Jeff Erbe, Jack Grinband in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
A new study of a brain region called the rostro-medial prefrontal could potentially advance diagnosis and therapies for Borderline Personality Disorder (BPD). Entitled “Rejection Distress Suppresses Medial Prefrontal Cortex in Borderline Personality Disorder,” the research appears in the journal Biological Psychiatry: Cognitive Neuroscience and Neuroimaging.
Researchers from The City College of New York, Columbia University, and New York State Psychiatric Institute led by CCNY psychologist Eric A. Fertuck discovered that the rostro-medial prefrontal specifically becomes more active when people are rejected by others at greater rates. However, individuals with BPD — characterized by interpersonal sensitivity to rejection and emotional instability — do not display rostro-medial prefrontal cortex activity when rejected.
The brain reacts with rostro-medial prefrontal activity to rejection as if there is something “wrong” in the environment. This brain activity may activate an attempt to try to restore and maintain close social ties to survive and thrive. This region of the brain also is activated when humans try to understand other peoples’ behavior in light of their mental and emotional state.
“Inactivity in the rostro-medial prefrontal cortex during rejection may explain why those with BPD are more sensitive and more distressed by rejection. Understanding why individuals with this debilitating and high risk disorder experience emotional distress to rejection goes awry will help us develop more targeted therapies for BPD,” said Fertuck, associate professor in CCNY’s Colin Powell School for Civic and Global Leadership, and the Graduate School, CUNY.
On the significance of the study, Fertuck noted that while previous findings in this area have been mixed, “what we’ve done is improve the specificity and resolution of our rejection assessment, which improves on prior studies.”
Research continues with several investigations underway examining the role of social rejection in different mental health problems including post-traumatic stress disorder, depression, and social anxiety.
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